BTK inhibitors

Abstract

# imgabs0. The invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which has BTK inhibitory activity and is thus suitable for use in therapy and methods of treatment in the human or animal body. The invention also relates to processes for the manufacture of said compounds, pharmaceutical compositions containing them and their use in the manufacture of medicaments for therapeutic effects in warm-blooded animals such as humans.

Description

[0001] This application is a divisional application of a Chinese patent application with an application number of 202080091669.X, a filing date of December 29, 2020, and an invention title of "BTK Inhibitor". The original application is a national stage application with an international application number of PCT / CN2020 / 140517, and this international application claims the priority of PCT patent applications with a filing date of January 2, 2020, an application number of PCT / CN2020 / 070034, and a filing date of December 8, 2020, an application number of PCT / CN2020 / 134601. All of the above applications are incorporated into this application by reference. Field of the Invention

[0002] This application relates to oxane-substituted imidazopyrazines and imidazotriazines inhibitors of Bruton's tyrosine kinase (BTK) (including mutant BTK), which are suitable for treating diseases or disorders related to BTK kinase. These compounds have potential utility in treating immune disorders, cancer, cardiovascular diseases, viral infections, inflammation, metabolic / endocrine dysfunctions, and neurological disorders.

[0003] Specifically, this application relates to compounds that inhibit BTK and their compositions, methods for treating diseases or disorders related to BTK, and methods for synthesizing these compounds. Background Art

[0004] 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 initiate many cellular processes, including cell proliferation, survival, differentiation, motility, angiogenesis, cytokine production, and antigen presentation.

[0005] BTK-deficient mouse models have shown that BTK plays a role in allergic disorders and / or autoimmune diseases 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.

[0006] The role of BTK in apoptosis also attests to the utility of inhibiting BTK activity for treating cancers such as B-cell lymphoma, leukemia, and other hematological malignancies. Additionally, BTK has a role in osteoclast function, and thus inhibiting BTK activity has potential utility in treating bone disorders such as osteoporosis.

[0007] Approved compounds that inhibit BTK include ibrutinib (for B-cell malignancies such as mantle cell lymphoma, chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia macroglobulinemia)); acalabrutinib (mantle cell lymphoma and CLL); and zanubrutinib (mantle cell lymphoma). Additionally, there are several BTK inhibitors in clinical trials, including evobrutinib (for multiple sclerosis); ABBV-105 (for systemic lupus erythematosus (SLE)); ONO-4059 / GS-4059 (for non-Hodgkin lymphoma and CLL); spebrutinib (for relapsed or refractory B-cell non-Hodgkin lymphoma, CLL, and Waldenström macroglobulinemia); and HM71224 (for autoimmune diseases).

[0008] Despite significant therapeutic progress in using BTK inhibitors to treat B-cell malignancies, cases of primary and secondary resistance with poor prognosis and limited treatment options have emerged.

[0009] 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 degrades. The advantage of these irreversible inhibitors is that they are potent and usually only effective with short-term exposure. However, their clinical benefits are limited by off-target toxicity, resulting in a high discontinuation rate, and resistance is acquired due to the BTK C481 mutation that disrupts the covalent binding to BTK, thereby reducing the binding affinity of the compound and weakening its ability to inhibit BTK enzyme activity (Leukaemia, April 2015; 29(4):895-900). Due to the development of the C481S mutation, most (>50%) CLL patients undergoing covalent BTK inhibitor therapy develop resistance to the treatment (New England Journal of Medicine, 370;24, 2014; JAMA Oncology, 2015; 1(1):80-87; Journal of Clinical Oncology, 35:1437-1443, 2017).

[0010] 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 approximately 1% of all lymphomas and 2% to 5% of all primary brain tumors. The vast majority (approximately 95%) of PCNSL is diffuse large B-cell lymphoma (DLBCL). Mutations in the CD79B and MYD88 genes are commonly (approximately 30-80%) associated with PCNSL (Neuropathol Appl Neurobiol, April 2016; 42(3):279-90). Although BTK inhibitors have not been approved for the treatment of DLBCL to date, data suggest that DLBCL with CD79B and MYD88 mutations is more sensitive to BTK inhibition (Nat Med, August 2015; 21(8):922-6).

[0011] Secondary CNS lymphoma (SCNSL) refers to the spread of lymphoma originating elsewhere to the central nervous system (as opposed to primary CNS lymphoma). It is usually non-Hodgkin lymphoma and can be an isolated recurrence or part of a systemic disease at presentation. Different from primary CNS lymphoma, it more commonly involves the leptomeninge.

[0012] PRN2246 (SAR442168), a blood-brain barrier (BBB)-penetrable covalent BTK inhibitor, was well tolerated in a Phase I trial in multiple sclerosis (MS). Additionally, some trials (Grommes C et al., Cancer Discov. September 2017; 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. August 2019; 117:121-130) have shown that high-dose ibrutinib (840 mg) is effective in CNS lymphoma (PCNSL and secondary central nervous system lymphoma (SCNSL)), but to date, no BTK inhibitor targeting the BTK-C481 mutation or active in PCNSL has been approved. These unmet medical needs remain.

[0013] WO 2009 / 143051 discloses certain substituted imidazopyrazines and imidazotriazines, including certain hexane-substituted imidazopyrazines and imidazotriazines, as activated p21 cdc42Hs-related kinase (ACK1) inhibitors. However, the compounds of WO2009 / 143051 exhibit high human hepatocyte clearance, meaning that even at the maximum absorbable dose, the compounds may not achieve sufficient sustained drug coverage (rendering the compounds ineffective); and / or require extremely high doses to inhibit the target, resulting in high maximum drug concentrations (which may cause secondary pharmacological (i.e., adverse) effects and toxicity issues).

[0014] WO2017111787A1 discloses tetrahydropyranyl amino-pyrrolopyrimidinones that modulate BTK activity; WO2018039310A1 discloses amino-pyrrolopyrimidinone compounds and methods of use thereof; WO2017103611A1 discloses compounds used as BTK inhibitors; and WO2011152351 discloses purinone derivatives with BTK-selective inhibitory activity. However, none of these compounds have the combination of desired properties of the compounds of the present invention.

[0015] Certain novel oxane-substituted imidazopyrazines and imidazotriazines are disclosed herein, which are potent and selective inhibitors of BTK with a C481 mutation (e.g., C481S, C481Y, C481R or C481F mutation), wild-type BTK, and both. These compounds are non-covalent reversible inhibitors, exhibit low human hepatocyte clearance and have blood-brain barrier (BBB) penetration properties. Summary of the Invention

[0016] The present disclosure provides compounds of formula (I):

[0017]

[0018] and their pharmaceutically acceptable salts, and their use as BTK inhibitors, particularly in therapy. Detailed Description of the Invention

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

[0020] The present disclosure provides a compound of formula (I):

[0021]

[0022] Wherein:

[0023] R 1 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, N-C 1-6 alkylamino, N,N-(C 1-6 alkyl) 2 amino, carbocyclic group, and heterocyclic group; wherein R 1 may optionally be substituted by one or more R 5 ;

[0024] R 2 is selected from halogen, C 1-3 alkyl, C 1-3 alkoxy, carbocyclic group, and heterocyclic group; or two R 2 on the same atom or adjacent atoms may together with the atom to which they are attached form a 3- to 7-membered ring;

[0025] k is 0 - 4;

[0026] R 3 is selected from halogen, C 1-3 alkyl, and C 1-3 alkoxy;

[0027] n is 0 - 4;

[0028] R 4 is selected from halogen, C1-3 Alkyl and C 1-3 alkoxy groups;

[0029] m is 0 - 5;

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

[0031] R 5 is selected from halogen, hydroxyl, C 1-6 alkoxy, amino, N-C 1-6 alkylamino, N,N-(C 1-6 alkyl) 2 amino, carbocyclic group and heterocyclic group; wherein R 5 may independently and optionally be substituted by one or more R 7 substituents;

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

[0033] R 7 is selected from halogen, hydroxyl, amino, C 1-3 alkyl and C 1-3 alkoxy;

[0034] or a pharmaceutically acceptable salt thereof.

[0035] In one embodiment, R 1 is selected from hydrogen and C 1-6 alkyl; wherein R 1 may optionally be substituted by one R 5 substituent; wherein R 5 is selected from hydroxyl, C 1-6 alkoxy, N,N-(C 1-6 alkyl) 2 amino and heterocyclic group.

[0036] In one embodiment, R 1 is selected from hydrogen and C 1-3 alkyl; wherein R 1 may optionally be substituted by one R 5 substituent; wherein R 5 is selected from hydroxyl, C 1-3 alkoxy, N,N-(C 1-2 alkyl) 2 amino and azetidinyl.

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

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

[0039] In one embodiment, R 2 is selected from a halogen group or a C 1-3 alkoxy group.

[0040] In one embodiment, R 2 is selected from fluorine or methoxy.

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

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

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

[0044] In one embodiment, k is 0.

[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 is a halogen group.

[0050] In one embodiment, R 3 is fluorine.

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

[0052] In one embodiment, n is 0.

[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 is a halogen group.

[0058] In one embodiment, R 4 is 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 the “trans” configuration (meaning that the two substituents on the oxane ring point to opposite faces of the oxane ring); and in the “cis” configuration (meaning that the two substituents on the oxane ring point to the same face of the oxane ring). Structures (IA) and (IB) below show the cis isomers of the compound of formula (I), and structures (IC) and (ID) below show the trans isomers of the compound of formula (I).

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

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

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

[0076]

[0077]

[0078] In one aspect of the present invention, the compound of formula (I) is the compound of formula (IB):

[0079]

[0080] In one aspect of the present invention, the compound of formula (I) is a compound of formula (IC):

[0081]

[0082] In one aspect of the present invention, the compound of formula (I) is a compound of formula (ID):

[0083]

[0084] In one aspect of the present invention, the compound of formula (I) is selected from:

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

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

[0087] (5-(8-Amino-1-(2,3-difluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0088] (5-(8-Amino-1-(4-(2,3-difluorophenoxy)phenyl)imidazo[1,5-a]pyrazin-3-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-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0091] (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;

[0092] (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;

[0093] 3-(6-((Dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine;

[0094] 7-(6-((Dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-4-amine;

[0095] 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;

[0096] 5-(2-Fluoro-4-phenoxyphenyl)-7-(6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine;

[0097] 5-(2-Fluoro-4-phenoxyphenyl)-7-(tetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine; and

[0098] 5-(2-Fluoro-4-phenoxyphenyl)-7-(6-methyltetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine.

[0099] In one aspect of the present invention, the compound of formula (I) is selected from:

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

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

[0102] (5-(8-Amino-1-(2,3-difluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0103] (5-(8-Amino-1-(4-(2,3-difluorophenoxy)phenyl)imidazo[1,5-a]pyrazin-3-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-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0106] (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;

[0107] (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;

[0108] 3-(6-((Dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine;

[0109] 7-(6-((Dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-4-amine;

[0110] 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;

[0111] 5-(2-Fluoro-4-phenoxyphenyl)-7-(6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine;

[0112] 5-(2-Fluoro-4-phenoxyphenyl)-7-(tetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine; and

[0113] 5-(2-Fluoro-4-phenoxyphenyl)-7-(6-methyltetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine;

[0114] or a pharmaceutically acceptable salt thereof.

[0115] In one aspect of the present invention, the compound of formula (I) is selected from:

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

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

[0118] ((2R,5R)-5-(8-Amino-1-(2,3-difluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0119] ((2R,5R)-5-(8-Amino-1-(4-(2,3-difluorophenoxy)phenyl)imidazo[1,5-a]pyrazin-3-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-fluoro-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-(2,3-difluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0123] ((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;

[0124] 3-((3R,6R)-6-((Dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine;

[0125] 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;

[0126] 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;

[0127] 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;

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

[0129] 5-(2-Fluoro-4-phenoxyphenyl)-7-((3R,6R)-6-methyltetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine;

[0130] or a pharmaceutically acceptable salt thereof.

[0131] In one aspect of the present invention, the compound of formula (I) is selected from:

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

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

[0134] (((2S,5S)-5-(8-Amino-1-(2,3-difluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0135] (((2S,5S)-5-(8-Amino-1-(4-(2,3-difluorophenoxy)phenyl)imidazo[1,5-a]pyrazin-3-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-fluoro-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-(2,3-difluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0139] ((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;

[0140] 3-((3S,6S)-6-((Dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine;

[0141] 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;

[0142] 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;

[0143] 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;

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

[0145] 5-(2-Fluoro-4-phenoxyphenyl)-7-((3S,6S)-6-methyltetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine;

[0146] or a pharmaceutically acceptable salt thereof.

[0147] In one aspect of the present invention, the compound of formula (I) is selected from:

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

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

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

[0151] ((2S,5R)-5-(8-Amino-1-(4-(2,3-difluorophenoxy)phenyl)imidazo[1,5-a]pyrazin-3-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-fluoro-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-(2,3-difluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0155] ((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;

[0156] 3-((3S,6R)-6-((Dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine;

[0157] 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;

[0158] 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;

[0159] 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

[0160] 5-(2-Fluoro-4-phenoxyphenyl)-7-((3S,6R)-6-methyltetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine;

[0161] or a pharmaceutically acceptable salt thereof.

[0162] In one aspect of the present invention, the compound of formula (I) is selected from:

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

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

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

[0166] ((2R,5S)-5-(8-Amino-1-(4-(2,3-difluorophenoxy)phenyl)imidazo[1,5-a]pyrazin-3-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-fluoro-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-(2,3-difluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

[0170] ((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;

[0171] 3-((3R,6S)-6-((Dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-8-amine;

[0172] 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;

[0173] 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;

[0174] 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

[0175] 5-(2-Fluoro-4-phenoxyphenyl)-7-((3R,6S)-6-methyltetrahydro-2H-pyran-3-yl)imidazo[5,1-f][1,2,4]triazin-4-amine;

[0176] or a pharmaceutically acceptable salt thereof.

[0177] In one aspect of the invention, there is provided any compound of formula (I) disclosed herein.

[0178] In one aspect of the invention, there is provided any compound of formula (I) disclosed herein or a pharmaceutically acceptable salt thereof.

[0179] In one aspect of the invention, there is provided a synthetic intermediate for preparing a compound of formula (I) as disclosed herein.

[0180] In one aspect of the invention, there is provided a synthetic intermediate for preparing a compound of formula (I) as disclosed herein or a pharmaceutically acceptable salt thereof.

[0181] Throughout this disclosure, linking substituents are described. Wherever the structure clearly requires a linking group, the Markush variables recited for that group should be understood as linking groups. For example, if the structure requires a linking group and the Markush group definition of the variable recites "alkyl", then it should be understood that the "alkyl" represents a linking alkylene.

[0182] 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 its ordinary meaning known in the art and refers to a chemical moiety covalently attached to or, where appropriate, fused to the parent group. As used herein, the term "optionally substituted" or "optionally substituted with..." means that the chemical group may or may not have a substituent (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.

[0183] As used herein, the term "C i-j " represents a range of carbon atom numbers, where i and j are integers, and the range of carbon atom numbers includes the endpoints (i.e., i and j) and every integer point therebetween, and where j is greater than i. By way of 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 " represents 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3, or particularly 1 to 2 carbon atoms.

[0184] As used herein, whether as part of another term or used independently, the term "alkyl" refers to a saturated hydrocarbon chain. The hydrocarbon chain mentioned above can be straight-chain or branched-chain. The term "C i-j alkyl" refers to an alkyl group having i to j carbon atoms. Examples of C 1-6 alkyl include (but are not limited to) methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylbutyl, etc. Examples of "C 1-3 alkyl" are methyl, ethyl, propyl, and isopropyl.

[0185] As used herein, the terms "halo" and "halogen" refer to atoms selected from fluorine, chlorine, bromine, and iodine.

[0186] As used herein, whether as part of another term or used independently, the term "alkoxy" refers to a group of the formula -O-alkyl. The term "C i-j alkoxy" means that the alkyl portion of the alkoxy group has i to j carbon atoms. Examples of alkoxy groups include (but are not limited to) methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, etc. Examples of "C 1-6 alkoxy" are methoxy, ethoxy, and propoxy. Examples of "C 1-3 alkoxy" are methoxy, ethoxy, and propoxy.

[0187] “N-(C 1-6 alkyl)amino” examples are methylamino and ethylamino. “N,N-(C 1-6 alkyl) 2 amino” examples are N,N-dimethylamino, N,N-diethylamino, and N-ethyl-N-methylamino.

[0188] As used herein, whether used as part of another term or independently, the term “carbocyclic group” 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 carbocyclic group may contain 3 to 7 ring-forming carbon atoms or 3 to 6 ring-forming carbon atoms. In some embodiments, the ring-CH 2 - group may be replaced by a ring-C(O)- group. Examples of carbocyclic groups include (but are not limited to) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0189] As used herein, the term “heterocyclic group” refers to a monocyclic, saturated carbocyclic group in which one or more (e.g., 1, 2, or 3) ring atoms are replaced by heteroatoms, which include (but are not limited to) oxygen, sulfur, nitrogen, phosphorus, etc. In some embodiments, the ring-CH 2 - group may be replaced by a ring-C(O)- group. In some embodiments, the ring sulfur atom may optionally be oxidized to form an S-oxide. In some embodiments, the heterocyclic group is carbon-linked. In some embodiments, the heterocyclic group is nitrogen-linked. Exemplary heterocyclic groups include (but are not limited to) azetidinyl, piperidyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, etc.

[0190] In one embodiment, two R 2 on the same atom together with the atom to which they are attached form a 3- to 7-membered ring. The product “spirocycle” has two rings connected by a single common atom (one of which is the oxane of formula (I)). The non-oxane ring can be a 3- to 7-membered carbocyclic ring or a 3- to 7-membered heterocyclic ring. Examples of two R 2 on the same atom together with the atom to which they are attached forming a 3- to 7-membered ring (depicted with the oxane of formula (I)) include:

[0191]

[0192] (where depicts the connection to the rest of the molecule).

[0193] In one embodiment, two R 2Together with the atom to which it is attached, form a 3-7 membered ring. The product "fused ring" has two rings sharing two adjacent atoms (one of which is the oxane of formula (I)). The non-oxane ring can be a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring. Or two Rs on adjacent atoms 2 Examples of together forming a 3-7 membered ring (depicted with the oxane of formula (I)) include:

[0194]

[0195] (where depicts the connection to the rest of the molecule).

[0196] Unless otherwise specified, the "compounds" of the present disclosure are intended to cover all stereoisomers, geometric isomers, and tautomers of the depicted structures.

[0197] The term "stereoisomer" refers to any of the various stereoisomeric configurations (e.g., enantiomers, diastereomers, and racemates) of an asymmetric compound (e.g., those compounds having one or more asymmetrically substituted carbon atoms or "asymmetric centers"). The compounds of the present disclosure containing an asymmetric center can be separated in optically active (enantiomeric or diastereomeric) or optically inactive (racemic) forms. The term "enantiomer" includes a pair 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" includes stereoisomers having at least two asymmetric atoms but not being mirror images of each other. Certain compounds containing one or more asymmetric centers can give rise to enantiomers, diastereomers, or other stereoisomeric forms, which can be defined as (R)- or (S)- at each asymmetric center according to the Cahn-Ingold-Prelog R-S system based on the absolute configuration. A resolved compound of unknown absolute configuration can be designated using the term "or" at the asymmetric center. Methods for how to prepare optically active forms from racemic mixtures are known in the art, such as by HPLC resolution or stereoselective synthesis.

[0198] The term "geometric isomers" or "cis and trans isomers" refers to compounds having the same formula but with their functional groups rotated to different orientations in three-dimensional space.

[0199] The term "tautomer" includes prototropic tautomers in isomeric protonated states of compounds having the same formula and total charge. Examples of prototropic tautomers include, but are not limited to, keto-enol pairs, amide-imino acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which a proton 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 sterically locked into one form by appropriate substitution. Unless otherwise indicated, compounds of the present disclosure identified by name or structure as a particular tautomeric form are intended to include other tautomeric forms.

[0200] "Compound" of the present disclosure is also intended to cover all isotopes of atoms in the compound. Isotopes of an atom include atoms having the same atomic number but different mass numbers. By way of example, unless otherwise indicated, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in a "compound" of the present disclosure is meant to also include its isotopes, such as, but not limited to: 1 H, 2 H, 3 H, 11 C, 12 C, 13 C, 14 C, 14 N, 15 N, 16 O, 17 O, 18 O, 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br, 127 I and 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 by deuterium" or "deuterium-substituted" means the replacement of hydrogen (e.g., protium) in a chemical group with deuterium. In some embodiments, carbon includes 12 C and 13 C.

[0201] It should also be understood that the "compounds" of the present disclosure can exist in solvated forms as well as non-solvated forms (e.g., hydrated forms, solid forms), and the present disclosure is intended to cover all such solvated and non-solvated forms.

[0202] It should be further understood that the "compounds" of the present disclosure can exist in pharmaceutically acceptable salt forms.

[0203] As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of reasonable medical judgment, are suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic reaction, or other problems or complications, and are commensurate with a reasonable benefit / risk ratio. In some embodiments, pharmaceutically acceptable compounds, materials, compositions, and / or dosage forms refer to those compounds, materials, compositions, and / or dosage forms that are approved by regulatory agencies (such as the U.S. Food and Drug Administration, the National Medical Products Administration of China, or the European Medicines Agency) or listed in recognized pharmacopoeias (such as the U.S. Pharmacopoeia, the China Pharmacopoeia, or the European Pharmacopoeia) for use in animals and particularly in humans.

[0204] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the compounds of the present disclosure, in which the parent compound is modified by converting an existing acidic moiety (e.g., carboxyl group, 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 similar groups thereof. 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, trimellitic acid, citric acid, lactic acid, phenylacetic acid, benzoic acid, mandelic acid, methanesulfonic acid, naphthalenedisulfonic acid, ethanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, salicylic acid, sulfosalicylic acid, etc.).

[0205] Pharmaceutically acceptable salts of suitable compounds of the present disclosure also include, for example, base addition salts, which can be derived from, for example, inorganic bases (such as sodium salts, potassium salts, ammonium salts, and hydroxides, carbonates, bicarbonates of metals in columns I to XII of the periodic table (such as calcium, magnesium, iron, silver, zinc, copper, etc.)) or organic bases (such as primary amines, secondary amines, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, etc.). Some organic amines include (but are not limited to) isopropylamine, benzathine, cholate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine. Those skilled in the art will appreciate that, in addition to those shown in the examples, it is also possible to add acids or bases for forming acid / base addition salts. Lists of other suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 20th Edition, Mack Publishing Company, Easton, Pa., (1985); and Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0206] We have found that the compounds or their pharmaceutically acceptable salts as defined in the present invention are effective BTK inhibitors and can be used to produce BTK inhibition in warm-blooded animals in need of such treatment. Accordingly, the compounds of the present invention are expected to be suitable for treating diseases or medical conditions that are mediated, either alone or in part, by BTK.

[0207] Accordingly, the compounds of the present invention are expected to be suitable for treating immune disorders, cancers, cardiovascular diseases, viral infections, metabolic / endocrine dysfunctions, 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.

[0208] 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, compounds of this type of the present invention are expected to be suitable for the treatment of lymphoma and leukemia. More specifically, compounds of this type of the present invention or pharmaceutically acceptable salts thereof are expected to be suitable for the treatment of small lymphocytic lymphoma (SLL), follicular lymphoma, Richter's transformation, mantle cell lymphoma, chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia, non-Hodgkin 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 the second-line treatment of chronic lymphocytic leukemia. Specifically, the compounds of the present invention are suitable for the first-line treatment of chronic lymphocytic leukemia. Specifically, the compounds of the present invention are suitable for the treatment of diffuse large B cell lymphoma. Specifically, the compounds of the present invention are suitable for the treatment of primary central nervous system lymphoma.

[0209] In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof have anti-cancer activity in early stage, aggressively progressing, metastatic, and / or drug-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.

[0210] In one embodiment of the present invention referring to BTK inhibition, this refers to wild-type BTK and BTK having a C481 mutation (e.g., C481S, C481Y, C481R, or C481F mutation).

[0211] In one embodiment of the present invention referring to BTK inhibition, this refers to wild-type BTK.

[0212] In one embodiment of the present invention referring to BTK inhibition, this refers to BTK having a C481 mutation.

[0213] In one embodiment of the present invention referring to BTK inhibition, this refers to BTK having a C481S mutation.

[0214] In one embodiment of the present invention that refers to BTK inhibition, this refers to BTK having a C481Y mutation.

[0215] In one embodiment of the present invention that refers to BTK inhibition, this refers to BTK having a C481R mutation.

[0216] In one embodiment of the present invention that refers to BTK inhibition, this refers to BTK having a C481F mutation.

[0217] Drug Compositions, Dosages, and Administration

[0218] The present disclosure provides drug compositions that include at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the drug composition includes more than one compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the drug composition includes one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0219] Generally, 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 their pharmaceutically acceptable salts can be mixed with a pharmaceutically acceptable carrier to prepare a drug composition.

[0220] The form of the drug composition depends on various criteria, including (but not limited to) the route of administration, the degree of the disease, or the dose to be administered. The drug composition can be formulated for oral, nasal, rectal, transdermal, intravenous, or intramuscular administration. Depending on the desired route of administration, the drug composition can 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.

[0221] In certain embodiments, the drug composition includes from about 1 mg to about 500 mg of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, specifically from 1 mg to about 200 mg. The drug composition can also be administered once a day, twice a day, three times a day, or even four times a day. However, the daily dose will have to vary depending on the host being treated, the specific route of administration, and the severity of the disease being treated. Thus, the optimal dose can be determined by a physician treating any particular patient.

[0222] A therapeutically effective amount of the compounds provided herein or their pharmaceutically acceptable salts will depend on various factors known in the art, such as body weight, age, medical history, current medications, the general health status of the individual and cross-reactivity, allergies, sensitivity, and the likelihood of adverse side effects, as well as the route of administration and the degree of disease progression. As indicated by these and other circumstances or requirements, one of ordinary skill in the art (e.g., a physician or veterinarian) may reduce or increase the dosage proportionally.

[0223] In another aspect of the 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.

[0224] In another aspect of the 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 producing BTK inhibitory effects in warm-blooded animals such as humans.

[0225] In another aspect of the 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 producing anti-cancer effects in warm-blooded animals such as humans.

[0226] In another aspect of the 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 the treatment of small lymphocytic lymphoma (SLL), follicular lymphoma, Richter's transformation, mantle cell lymphoma, chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia, non-Hodgkin lymphoma, primary central nervous system lymphoma, secondary central nervous system lymphoma, or diffuse large B-cell lymphoma in warm-blooded animals such as humans.

[0227] In another aspect of the 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 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.

[0228] Combination

[0229] In some embodiments, the pharmaceutical composition comprises one or more compounds of the present disclosure or pharmaceutically acceptable salts thereof as a first active ingredient, and further comprises a second active ingredient. The second active ingredient can be any anti-tumor agent known in the art, such as PI3K inhibitors, anti-CD20 antibodies, anti-PD-1 / L1 antibodies, and other approved drugs or drug combinations for non-Hodgkin lymphoma. Representative examples of the second active ingredient anti-tumor agents include (but are not limited to) idelalisib, duvelisib, obinutuzumab, ofatumumab, rituximab, alemtuzumab, bleomycin, brentuximab, vedotin, carmustine, cyclophosphamide, chlorambucil, dacarbazine, dexamethasone, doxorubicin, lomustine, mechlorethamine, procarbazine, prednisone, bendamustine, venetoclax, prednisone, CVP (combination therapy of the chemotherapy drug cyclophosphamide, the chemotherapy drug vincristine, and the steroid prednisolone), midostaurin, and vinblastine.

[0230] Herein, when the term "combination" is used, it should be understood that this refers to administration simultaneously, separately, or sequentially. 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 yet another aspect of the present disclosure, "combination" refers to sequential administration. When administered sequentially or separately, a delay in administering the second component should not result in the loss of the beneficial effects of the combination.

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

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

[0233] Accordingly, 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 enumerated above herein, for the treatment of small lymphocytic lymphoma (SLL), follicular lymphoma, Richter's transformation, mantle cell lymphoma, chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia, non-Hodgkin lymphoma, primary central nervous system lymphoma, secondary central nervous system lymphoma or diffuse large B-cell lymphoma.

[0234] Accordingly, 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 enumerated above herein, 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.

[0235] According to this aspect of the present disclosure, there is provided a combination suitable for treating cancer, which comprises a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and any one of the anti-tumor agents enumerated above.

[0236] According to another aspect of the present disclosure, there is provided a pharmaceutical composition 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 enumerated above herein, and a pharmaceutically acceptable diluent or carrier.

[0237] According to another aspect of the present disclosure, there is provided a pharmaceutical composition 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 enumerated above herein, and a pharmaceutically acceptable diluent or carrier, for producing an anti-cancer effect.

[0238] According to another aspect of the present disclosure, there is provided a pharmaceutical composition 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 enumerated 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), Waldenström macroglobulinemia, non-Hodgkin lymphoma, primary central nervous system lymphoma, secondary central nervous system lymphoma or diffuse large B-cell lymphoma.

[0239] According to another aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein, an anti-tumor agent selected from the anti-tumor agents listed above herein, and a pharmaceutically acceptable diluent or carrier for treating diffuse large B-cell lymphoma, primary central nervous system lymphoma or secondary central nervous system lymphoma that has metastasized to the brain.

[0240] According to another aspect of the present disclosure, there is provided a kit comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein, and an anti-tumor agent selected from the anti-tumor agents listed above herein.

[0241] According to another aspect of the present disclosure, there is provided a kit comprising:

[0242] a) a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein, in a first unit dosage form;

[0243] b) an anti-tumor agent selected from the anti-tumor agents listed above herein; in a second unit dosage form; and

[0244] c) a container device for containing the first and second dosage forms.

[0245] Pharmacological tool

[0246] In addition to its use in therapeutic medicine, the compound of formula (I) or a pharmaceutically acceptable salt thereof is also suitable as a pharmacological tool for developing and standardizing in vitro and in vivo test systems for evaluating the effect of BTK inhibition in experimental animals such as cats, dogs, rabbits, monkeys, rats and mice as part of the search for new therapeutic agents.

[0247] Therapeutic method

[0248] According to another aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein for use in a method of treatment of the human or animal body by therapy.

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

[0250] According to another feature of this aspect of the present 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) or a pharmaceutically acceptable salt thereof as defined herein.

[0251] According to an additional feature of this aspect of the invention, there is provided a method of treating small lymphocytic lymphoma (SLL), follicular lymphoma, Richter's transformation, mantle cell lymphoma, chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia, non-Hodgkin 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.

[0252] According to an additional feature of this aspect of the invention, there is provided a method of treating diffuse large B-cell lymphoma, primary central nervous system lymphoma, or secondary central nervous system lymphoma that has metastasized to the brain 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.

[0253] As used herein, the term "treatment / treat" means reversing, alleviating a disease or disorder or one or more symptoms thereof as described herein, delaying its onset, or inhibiting its progression. In some embodiments, treatment may be carried out after one or more symptoms have appeared. In other embodiments, treatment may be carried out in the absence of symptoms. For example, a susceptible individual may be treated before the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic or other susceptibility factors). Treatment may also continue after the symptoms have subsided, for example to prevent or delay their recurrence.

[0254] The present disclosure also provides a method of 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.

[0255] According to another feature of this aspect of the present disclosure, there is provided a method of treating cancer in a warm-blooded animal such as a human, which comprises (1) determining whether the warm-blooded animal has a cancer that is susceptible to BTK inhibition, and (2) if so, then administering to the animal an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0256] Use of the compound

[0257] 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.

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

[0259] Accordingly, in this 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 as a medicament.

[0260] Accordingly, in this 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 therapy.

[0261] In 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 a BTK inhibitory effect in warm-blooded animals such as humans.

[0262] In this 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 anti-cancer effect in warm-blooded animals such as humans.

[0263] In 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 the treatment of the following diseases: small lymphocytic lymphoma (SLL), follicular lymphoma, Richter's transformation, mantle cell lymphoma, chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia, non-Hodgkin lymphoma, primary central nervous system lymphoma, secondary central nervous system lymphoma or diffuse large B-cell lymphoma.

[0264] In 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 the treatment of the following diseases: diffuse large B-cell lymphoma, primary central nervous system lymphoma or secondary central nervous system lymphoma that has metastasized to the brain.

[0265] In 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 warm-blooded animals such as humans.

[0266] In this 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 an anti-cancer effect in warm-blooded animals such as humans.

[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 the treatment of small lymphocytic lymphoma (SLL), follicular lymphoma, Richter's transformation, mantle cell lymphoma, chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia, non-Hodgkin lymphoma, primary central nervous system lymphoma, secondary central nervous system lymphoma or diffuse large B-cell lymphoma.

[0268] 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 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.

[0269] In the above pharmaceutical compositions, methods, uses and pharmaceutical manufacturing features, alternative and preferred embodiments of the compounds of the present disclosure described herein are also applicable.

[0270] Examples

[0271] General experiments

[0272] Abbreviations

[0273]

[0274]

[0275] The synthesis of the compounds (including their pharmaceutically acceptable salts) provided herein is illustrated in the synthetic schemes in the examples. The compounds provided herein can be prepared using any known organic synthesis techniques and can be synthesized according to any of a variety of possible synthetic routes, and thus, these schemes are illustrative only and are not intended to limit other possible methods that can be used to prepare the compounds provided herein. Additionally, the steps in the methods are for better illustration and can be changed as appropriate. Embodiments of the compounds in the examples are synthesized for research and for possible submission to regulatory authorities.

[0276] The reactions for preparing the compounds of the present disclosure can be carried out in a suitable solvent, which can be easily selected by a person skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates or products at the temperature at which the reaction is carried out, for example, at a temperature ranging from the freezing temperature to the boiling temperature of the solvent. The specified reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, a suitable solvent for a particular reaction step can be selected by a skilled person.

[0277] The preparation of the compounds of the present disclosure may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by those skilled in the art. The chemical nature of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0278] The reaction can be monitored according to any suitable method known in the art. For example, it 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 performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS) or thin layer chromatography (TLC) to monitor product formation. Those skilled in the art can purify the 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, 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.

[0279] The structures of the compounds in the examples are characterized by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in ppm. Using ICON-NMR (controlled by the TopSpin program) on a Bruker AVANCE NMR (400 MHz) spectrometer, or using tetramethylsilane as an internal standard on a Varian 400MR NMR or Varian VNMR400 NMR (400 MHz) spectrometer (controlled by the VnmrJ program) in dimethyl sulfoxide-d -6 (DMSO-d 6 (DMSO-d 6 ) or CDCl 3 or CD 3 OD or D 2O or acetone-d 6 or CD 3 CN (recorded from Aldrich or Cambridge Isotope Lab., Inc.) 1 H-NMR spectra.

[0280] MS measurements were performed on a series of instruments using electrospray, chemical, and electron impact ionization methods with a Shimadzu 2010 mass spectrometer or an Agilent 6110 AMSD or 1969 ATOF mass spectrometer. The detailed methods used in the present invention include:

[0281] LC-MS method A: 10-80AB_7min_220&254_Shimadzu.lcm

[0282] Mobile phase: 1.5 mL / 4 L TFA / water (solvent A) and 0.75 mL / 4 L TFA / acetonitrile (solvent B), elution gradient of 10%-80% (solvent B) was used over 6 minutes and held at 80% for 0.5 minutes at a flow rate of 0.8 mL / min;

[0283] Column: Xtimate C18 2.1*30 mm, 3 μm;

[0284] Wavelength: UV 220 nm, 254 nm;

[0285] Column temperature: 50 °C;

[0286] MS ionization: ESI

[0287] LC-MS method B: 10-80AB_4min_220&254_Shimadzu.lcm

[0288] Mobile phase: 1.5 mL / 4 L TFA / water (solvent A) and 0.75 mL / 4 L TFA / acetonitrile (solvent B), elution gradient of 10%-80% (solvent B) was used over 3 minutes and held at 80% for 0.5 minutes at a flow rate of 0.8 mL / min;

[0289] Column: Xtimate C18 2.1*30 mm, 3 μm;

[0290] Wavelength: UV 220 nm, 254 nm;

[0291] Column temperature: 50 °C;

[0292] MS ionization: ESI

[0293] LC-MS Method C: 10-80CD_7min_220&254_Agilent.lcm

[0294] Mobile phase: 0.2 mL / 1 L NH 3 .H 2 O / water (solvent A) and acetonitrile (solvent B), eluted with a 10%-80% (solvent B) gradient over 6 minutes and held at 80% for 0.5 minutes at a flow rate of 0.8 mL / min;

[0295] Column: Xbrige Shield RP-18, 5 μm, 2.1*50 mm;

[0296] Wavelength: UV 220 nm and 254 nm;

[0297] Column temperature: 30 °C;

[0298] MS ionization: ESI

[0299] On a Shimadzu LC-20A system or Shimadzu LC-2010HT series, or Agilent 1200LC or Agilent 1100 series, using an Ultimate XB-C18 column (3.0*50 mm, 3 μm or 3.0*150 mm, 3 μm), or an Xbridge shield RP18 column (5 μm, 50 mm*2.1 mm), or an Xtimate C18 column (3 μm, 2.1*30 mm), or a MERCK RP18 2.5-2 mm, etc. for high performance liquid chromatography (HPLC) measurements. The detailed methods used in the present invention include:

[0300] HPLC Method A: 10-80AB_8min.met

[0301] Mobile phase: 2.75 mL / 4 L TFA / water (solvent A) and 2.5 mL / 4 L TFA / acetonitrile (solvent B), eluted with a 10%-80% (solvent B) gradient over 6 minutes and held at 80% for 2 minutes at a flow rate of 1.2 mL / min;

[0302] Column: Ultimate C18 3.0*50 mm, 3 μm

[0303] Wavelength: UV220 nm, 215 nm, 254 nm;

[0304] Column temperature: 40 °C;

[0305] HPLC Method B: 10-80CD_8min.met

[0306] Mobile phase: 2.0 mL / 4 L NH 3 H 2 O / water (solvent A) and acetonitrile (solvent B), eluted with a gradient of 10%-80% (solvent B) over 4 minutes and held at 80% for 2 minutes at a flow rate of 1.2 mL / min;

[0307] Column: Xbrige Shield RP-18, 2.1*50 mm, 5 μm;

[0308] Wavelength: UV 220 nm, 215 nm, 254 nm;

[0309] Column temperature: 40 °C;

[0310] Supercritical fluid chromatography (SFC) measurements were carried out on an Agilent 1260 series or Waters UPCC series, or Shimadzu LC-20AB series, using a ChiralPak AD-3 column (3 μm, 150×4.6 mm), or a Chiralcel OJ-3 column (3 μm, 150×4.6 mm), or a Chiralpak IG-3 column (3 μm, 50 mm*4.6 mm), etc. The detailed methods used in the present invention include:

[0311] SFC method A: Mobile phase: A: CO 2 , B: ethanol (0.05% DEA), gradient: 5% to 40% of B in 5.5 min and held at 40% for 3 min, then 5% of B for 1.5 min, flow rate: 2.5 mL / min;

[0312] Column: ChiralPak AD-3 150×4.6 mm I.D., 3 μm;

[0313] Column temperature: 40 °C;

[0314] Back pressure: 100 bar.

[0315] SFC method B: Mobile phase: A: CO 2 , B: methanol (0.05% DEA), gradient: 5% to 40% of B in 5 min and 40% to 5% of B in 0.5 min, held at 5% of B for 1.5 min, flow rate: 2.5 mL / min

[0316] Column: Chiralcel OJ-3 150×4.6 mm I.D., 3 μm;

[0317] Column temperature: 35 °C;

[0318] ABPR: 1500 psi.

[0319] SFC Method C: Mobile Phase: A: CO 2 , B: Methanol (0.05% DEA), Isocratic: 40% B, Flow Rate: 4 mL / min;

[0320] Column: Chiralpak IG-3 50 mm × 4.6 mm I.D., 3 μm;

[0321] Column Temperature: 35 °C;

[0322] ABPR: 1500 psi.

[0323] 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) are 0.15 mm to 0.2 mm. The silica gel plates used for separating and purifying products by TLC are 0.4 mm to 0.5 mm.

[0324] The purification column uses silica gel as the carrier (100 - 200, 200 - 300 or 300 - 400 mesh, manufactured by Yantai Huanghai co., or Anhui Liang Chen Gui Yuan co., etc.), or a flash column (silica-CS flash column 40 - 60 μm, or reversed-phase C18 column 20 - 35 μm, manufactured by Agela Technologies, etc.) or Teledyne ISCO combi-flash or the flash column silica-CS (40 - 60 μm) or C18 column (20 - 40 μm) of Agela Technologies in the Biotage flash system. The size of the column is adjusted according to the amount of the compound.

[0325] 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, Shanghai Bepharm Co., Ltd., Shanghai Scochem Co., Ltd. (or Nanjing PharmaBlock Co., Ltd., Bide, Amatek, StruChem Co., Ltd., Firster Pharmaceutical Co., Ltd., Titan (Adamas), etc.).

[0326] Unless otherwise specified, the reactions are carried out under an argon or nitrogen atmosphere. An 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 specified, the reaction temperature in the examples is ambient temperature, which is 10 °C to 30 °C.

[0327] The progress of the reaction is monitored by TLC or / and LC-MS. The eluent system used for the reaction includes dichloromethane-methanol system and petroleum ether-ethyl acetate system. The volume ratio of the solvents is adjusted according to the different polarities of the compounds.

[0328] The elution system for column chromatography for purifying compounds and the eluent system for TLC include dichloromethane-methanol system and petroleum ether-ethyl acetate system. The volume ratio of the solvents is adjusted according to the different polarities of the compounds. A small amount of basic or acidic agent (0.1% - 1%), such as formic acid, or acetic acid, or TFA or ammonia water, can be added for adjustment.

[0329] The compounds of the present invention

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337] Table 1: Synthetic methods of the compounds of the present invention

[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: Ethyl 5-(((3-chloropyrazin-2-yl)methyl)carbamoyl)tetrahydro-2H-pyran-2-carboxylate

[0345]

[0346] To a mixture of 6-(ethoxycarbonyl)tetrahydro-2H-pyran-3-carboxylic acid (see WO2019001420A1) (5.90 g, 29.17 mmol) and Compound 1A (5.25 g, 29.17 mmol) in dichloromethane (150 mL) was added HATU (16.64 g, 43.76 mmol) and DIEA (11.31 g, 87.51 mmol). The mixture was stirred at room temperature (18 - 22 °C) for 12 hours. The reaction mixture 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 obtain the crude product. The crude product was purified by silica gel column chromatography (2.5 - 3.5% methanol / dichloromethane) to obtain Compound 2A as a yellow oil (9.0 g, yield 94.0%).

[0347] LCMS: tR = 0.689 min in a 5 - 95 AB_1.5 min_220&254_Shimadzu.lcm chromatogram (Agilent Pursult5C18 20 × 2.0 mm), MS(ESI) m / z = 328.2 [M + H] +

[0348] Compound 3A: Ethyl 5-(8-chloroimidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-carboxylate

[0349]

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

[0351] LCMS: t R = in a 5 - 95 AB_1.5 min_220&254_Shimadzu.lcm chromatogram (Agilent Pursult5C18

[0352] It is 0.742 min in (20 * 2.0 mm), MS (ESI) m / z = 310.2 [M + H] +

[0353] 1 H NMR (400 MHz, CDCl 3 ): δ = 7.80 (d, J = 0.4 Hz, 1H), 7.70 - 7.64 (m, 1H), 7.37 (d, J = 4.8 Hz, 0.3H), 7.35 (d, J = 4.8 Hz, 0.7H), 4.44 (t, J = 4.4 Hz, 0.7H), 4.30 - 4.25 (m, 2H), 4.23 - 4.14 (m, 1H), 4.00 (dd, J = 3.2, 12.0 Hz, 1H), 3.79 (t, J = 11.2 Hz, 0.4H), 3.42 - 3.19 (m, 1H), 2.47 - 2.37 (m, 0.8H), 2.29 - 2.06 (m, 3H), 1.91 - 1.77 (m, 0.4H), 1.35 - 1.31 (m, 3H).

[0354] Compound 4A: (5-(8-chloroimidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol

[0355]

[0356] At 0 °C, THF (20 mL) containing compound 3A (3.5 g, 11.30 mmol) was added to a mixture of LiAlH 4 (860 mg, 22.60 mmol) in THF (20 mL). The mixture was stirred at 0 °C for 1 hour. The reaction 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 hour, filtered and concentrated to give compound 4A (2.7 g, yield 89.4%) as a yellow solid.

[0357] LCMS: t R = It is 0.635 min in the 5 - 95 AB_1.5min_220&254_Shimadzu.lcm chromatogram (Agilent Pursult5C18

[0358] 20 * 2.0 mm), MS (ESI) m / z = 267.8 [M + H] +

[0359] Compound 5A: (5-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol

[0360]

[0361] 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 reaction mixture was concentrated to give a crude product, which was purified by silica gel column chromatography (2.2% methanol / dichloromethane) to give Compound 5A as a yellow solid (2.5 g, yield 71.63%).

[0362] LCMS: t R = 0.717 min in a 5 - 95 AB_1.5 min_220 & 254_Shimadzu.lcm chromatogram (Agilent Pursult5 C18

[0363] 20 * 2.0 mm), MS(ESI) m / z = 347.8 [M + H] +

[0364] Compound 6A: (5-(8-Amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol

[0365]

[0366] 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 in a 100 mL sealed tube at 100 °C for 12 hours. The reaction mixture was concentrated to give Compound 6A as a yellow oil (2.4 g, purity 98.0%).

[0367] LCMS: t R = 0.436 min in a 10 - 80 AB_3 min_220 & 254_Shimadzu.lcm chromatogram (Xtimate C18 2.1 * 30 mm)

[0368] and MS(ESI) m / z = 327.1 [M + H] +

[0369] Compound 7A: (5-(8-Amino-1-(2-fluoro-4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol

[0370]

[0371] 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) / H 2 O (5 mL) was added Pd(dppf)Cl 2 .CH 2 Cl 2 (32 mg, 0.04 mmol) and K 2 CO 3 (375 mg, 2.62 mmol). The mixture was stirred at 100 °C for 12 h under nitrogen. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (2.2% methanol / dichloromethane) to give Compound 7A as a yellow solid (a mixture of cis / trans racemates) (150 mg, yield 26.4%).

[0372] LCMS: t R = 0.723 min in a chromatogram (Agilent Pursult5C18

[0373] 20×2.0 mm) at 5 - 95 AB_1.5 min_220&254_Shimadzu.lcm, MS(ESI) m / z = 435.1 [M+H] +

[0374] (2-Fluoro-4-phenoxyphenyl)boronic acid:

[0375]

[0376] At room temperature (25 - 30 °C), Compound 1a (10 g, 52.35 mmol) was added to CH 2 Cl 2 (480 mL), PhB(OH) 2 (12.8 g, 104.71 mmol), Cu(OAc) 2 (9.5 g, 52.35 mmol), NEt 3 (21 mL, 151.05 mmol) and A mixture in Ms(5g). The mixture was stirred in air at room temperature (25 - 30 °C) for 16 hours. The mixture was filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography (petroleum ether) to afford compound 2a (11.3 g, yield 80.8%) as a colorless oil.

[0377] 1 H NMR (400 MHz, CDCl 3 ): δ = 7.47 (t, J = 8.4 Hz, 1H), 7.42 - 7.36 (m, 2H), 7.19 (t, J = 8.4 Hz, 1H), 7.05 (d, J = 8.0 Hz, 2H), 6.78 (dd, J = 10.0, 2.8 Hz, 1H), 6.71 (dd, J = 8.8, 2.0 Hz, 1H).

[0378] At -65 °C, n-BuLi (19 mL, 46.53 mmol, 2.5 N in n-hexane) was added to a solution of compound 2a (11.3 g, 42.30 mmol) in THF (150 mL) at -65 °C. The mixture was stirred at -65 °C for 0.5 h. Then B(Oi-Pr) 3 (9.5 g, 50.76 mmol) was added at -65 °C. The mixture was stirred at -65 °C for 2 h. The mixture was quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL * 3), and washed with brine (100 mL * 2). The combined organic layers were 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 afford (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.

[0379] 1 H NMR (400 MHz, DMSO-d6): δ = 8.10 (s, 2H), 7.58 (t, J = 8.0 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.22 (t, J = 7.6 Hz, 1H), 7.09 (d, J = 7.6 Hz, 2H), 6.78 - 6.68 (m, 2H).

[0380] 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

[0381] 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

[0382]

[0383] Mixture 7A (150 mg, 0.35 mmol) was purified by chiral SFC (column: DAICEL CHIRALPAK AD-H) (250 mm * 30 mm, 10 μm), conditions: 0.1% NH 3 .H 2 O / EtOH, 40%, flow rate 80 mL / min). The fractions containing the desired compound were concentrated, diluted with H 2 O (10 mL) and CH 3 CN (10 mL), and lyophilized to give Compound 2 (34.8 mg, yield 23.2%) as a white solid and Compound 3 (29.4 mg, 19.6%) as a white solid. The two cis enantiomers were not collected.

[0384] Spectrum of Compound 2:

[0385] LCMS t R = 2.037 min in 10 - 80 AB_7min_220&254_Shimadzu.lcm chromatography (Xtimate C18 2.1*30 mm)

[0386] MS (ESI) m / z = 435.3 [M + H] + .

[0387] HPLC t R = 3.03 min in 10 - 80 AB_8min.met (HPLC - BJ Ultimate 3.0*50 mm 3 μm).

[0388] SFC t R = 6.119 min, optical purity: 96.3%. Method note: column: ChiralPak AD - 3 150×4.6 mm I.D., 3 μm, mobile phase: A: CO 2 , B: ethanol (0.05% DEA), gradient: 5% to 40% of B in 5.5 min and hold 40% for 3 min, then 5% of B for 1.5 min, flow rate: 2.5 mL / min, column temperature: 40 °C, back pressure: 100 bar.

[0389] 1 HNMR (400 MHz, CD3 OD) δ = 7.63 (d, J = 5.2 Hz, 1H), 7.54 - 7.36 (m, 3H), 7.27 - 7.18 (m, 1H), 7.14 (dd, J = 8.8, 0.8 Hz, 2H), 7.02 (d, J = 4.8 Hz, 1H), 6.98 - 6.82 (m, 2H), 4.23 - 4.07 (m, 1H), 3.75 (t, J = 11.2 Hz, 1H), 3.62 - 3.51 (m, 3H), 3.46 - 3.36 (m, 1H), 2.25 - 2.15 (m, 1H), 2.13 - 1.96 (m, 1H), 1.79 (d, J = 13.6 Hz, 1H), 1.66 - 1.49 (m, 1H).

[0390] 19 FNMR(CD 3 OD) δ = -112.240

[0391] Spectrum of Compound 3:

[0392] LCMS t R = In the 10 - 80AB_7min_220&254_Shimadzu.lcm chromatogram (Xtimate C18 2.1*30mm)

[0393] is 2.030 min, MS(ESI) m / z = 435.3 [M + H] + .

[0394] HPLC t R = In the 10 - 80AB_8min.met (HPLC - BJ Ultimate 3.0*50mm 3μm) is 3.02 min.

[0395] SFC t R = 7.334, Optical purity: 92.7%. Method note: Column: ChiralPak AD - 3 150×4.6mm I.D., 3μm, Mobile phase: A: CO 2 , B: Ethanol (0.05% DEA), Gradient: 5% to 40% of B in 5.5 min and hold 40% for 3 min, then 5% of B for 1.5 min, Flow rate: 2.5 mL / min, Column temperature: 40 °C, Back pressure: 100 bar.

[0396] 1 H NMR(400MHz,CD 3OD) δ = 7.65 (d, J = 5.2 Hz, 1H), 7.52 - 7.37 (m, 3H), 7.29 - 7.21 (m, 1H), 7.20 - 7.11 (m, 2H), 7.04 (d, J = 4.8 Hz, 1H), 6.99 - 6.84 (m, 2H), 4.24 - 4.13 (m, 1H), 3.77 (t, J = 11.2 Hz, 1H), 3.62 - 3.51 (m, 3H), 3.48 - 3.77 (m, 1H), 2.31 - 2.17 (m, 1H), 2.15 - 2.01 (m, 1H), 1.91 - 1.74 (m, 1H), 1.69 - 1.51 (m, 1H).

[0397] 19 F NMR (400 MHz, CD 3 OD) δ = -112.258.

[0398] The following compounds were synthesized according to Method A:

[0399]

[0400]

[0401]

[0402] Method B

[0403] Compound 2B: Ethyl 5 - ((((3 - amino - 5 - hydroxy - 1,2,4 - triazin - 6 - yl)methyl)carbamoyl)tetrahydro - 2H - pyran - 2 - carboxylate

[0404]

[0405] To a mixture of 5 - (2,5 - dioxopyrrolidin - 1 - yl) - 2 - ethyltetrahydro - 2H - pyran - 2,5 - dicarboxylate (20 g of 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 h. The mixture was concentrated to give Compound 2B as a brown solid (35 g of crude product).

[0406] LCMS: t R = 0.582 min in a 5 - 95 AB_1.5 min_220 & 254_Shimadzu.lcm chromatogram (Merck RP18 25 - 3 mm)

[0407] was 0.582 min, MS (ESI) m / z = 325.9 [M + H] +

[0408] 5-(2,5-Dioxopyrrolidin-1-yl) 2-ethyltetrahydro-2H-pyran-2,5-dicarboxylate:

[0409]

[0410] To a solution of 6-(ethoxycarbonyl)tetrahydro-2H-pyran-3-carboxylic acid (1.4 g, 6.92 mmol) in CH 2 Cl 2 (30 mL) was added 1-hydroxypyrrolidine-2,5-dione (877 mg, 7.61 mmol) and EDCI (1.6 g, 8.30 mmol). The mixture was stirred at 22 - 26 °C for 1.5 h. The mixture was diluted with dichloromethane (30 mL) and washed with brine (50 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give 5-(2,5-dioxopyrrolidin-1-yl) 2-ethyltetrahydro-2H-pyran-2,5-dicarboxylate as a colorless oil for direct use.

[0411] Compound 3B: Ethyl 5-(2-amino-4-hydroxyimidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-carboxylate

[0412]

[0413] To a solution of Compound 2B (35 g crude product, 60.88 mmol) in acetonitrile (300 mL) was added phosphorus oxychloride (23 mL, 243.52 mmol). The mixture was then stirred at 70 °C for 16 h. The mixture was concentrated, the residue was diluted with dichloromethane (150 mL), poured into cooled saturated sodium bicarbonate solution (300 mL) until pH = 8, extracted with dichloromethane / methanol (10:1, 200 mL * 4), and then extracted with IPA / CHCl 3 (150 mL * 4). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give Compound 3B (45 g crude product) as a black oil.

[0414] LCMS: t R = in 5 - 95 AB_1.5min_220&254_Shimadzu.lcm chromatography (Merck RP18 25 - 3mm)

[0415] was 0.13 min, MS(ESI) m / z = 308.0 [M + H] +

[0416] Compound 4B: Ethyl 5-(2-amino-5-bromo-4-hydroxyimidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-carboxylate

[0417]

[0418] To a solution of Compound 3B (45 g of 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 h. 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 layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give Compound 4B as a black oil (19 g of crude product).

[0419] LCMS: t R = 0.602 min in a 5 - 95 AB_1min_220&254_Agilent chromatogram (Agilent Poroshell 120EC-C18

[0420] 2.7 μm 3.0 * 30 mm), MS(ESI) m / z = 388.0 [M + H + 2] + (bromide isotope).

[0421] Compound 5B: Ethyl 5-(5-bromo-4-hydroxyimidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-carboxylate

[0422]

[0423] At 0 - 5 °C, tert-butyl nitrite (12 mL, 98.39 mmol) was added to a solution of Compound 4B (19 g impure, 49.19 mmol) in tetrahydrofuran (300 mL), and the mixture was stirred at room temperature (16 - 21 °C) for 16 h. The mixture was combined with another batch (7.2 g of 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 as a yellow solid (14.3 g, 44% yield over 5 steps).

[0424] LCMS: t R = 1.5 min in a 5 - 95 AB_1.5min_220&254_Shimadzu.lcm chromatogram (Agilent Pursult5C18

[0425] It is 0.753 min in (20 * 2.0 mm), MS(ESI) m / z = 370.9 [M + H] +

[0426] 1 H NMR (400 MHz, CD 3 OD): δ = 7.74 (s, 0.3H), 7.72 (s, 0.5H), 4.37 (t, J = 4.8 Hz, 0.7H), 4.29 - 4.16 (m, 3H), 4.12 (dd, J = 11.6, 2.0 Hz, 0.3H), 3.92 (dd, J = 11.6, 4.0 Hz, 0.7H), 3.70 (t, J = 11.2 Hz, 0.4H), 3.57 - 3.45 (m, 1H), 2.35 - 1.92 (m, 4H),, 1.33 - 1.27 (m, 3H).

[0427] Compound 6B: Ethyl 5-(4-amino-5-bromoimidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-carboxylate

[0428]

[0429] At a temperature below 10 °C, POCl was added to a solution of 1,2,4-triazole (28 g, 404.1 mmol) in acetonitrile (200 mL) 3 (12.5 mL, 134.7 mol), and then trimethylamine (56 mL, 404.1 mmol) was added. The mixture was stirred at 10 °C for 20 min, compound 5B (5 g, 13.47 mmol) was added, and the reaction mixture was stirred at 90 °C for 1.5 h. The mixture was cooled to 10 °C, ammonia water (30 mL, 28%) was added, the temperature was maintained below 20 °C, and the mixture was stirred at 10 °C for 0.5 h. Another batch of the same scale was carried out. The mixtures were 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. The mixture was purified by silica gel column chromatography (2 - 4% methanol / dichloromethane) to obtain compound 6B (9 g, yield 90%) as a yellow solid.

[0430] LCMS: t R = It is 0.614 min in \5 - 95AB_1min_220&254_Agilent chromatography (Agilent Poroshell 120 EC-C18 2.7 μm 3.0 * 30 mm), MS(ESI) m / z = 372.0 [M + H + 2] + (Bromide isotope).

[0431] 1 H NMR (400 MHz, CD 3 OD): δ = 7.81 (s, 0.3H), 7.79 (s, 0.6H), 4.36 (t, J = 5.2 Hz, 0.6H), 4.29 - 4.19 (m, 3H), 4.12 (dd, J = 11.6, 2.0 Hz, 0.3H), 3.93 (dd, J = 11.6, 4.0 Hz, 0.7H), 3.71 (t, J = 11.2 Hz, 0.3H), 3.63 - 3.48 (m, 1H), 2.35 - 2.20 (m, 1H), 2.17 - 1.94 (m, 2.7H), 1.79 - 1.68 (m, 0.3H), 1.34 - 1.26 (m, 3H).

[0432] Compound 7B: (5-(4-Amino-5-bromoimidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol

[0433]

[0434] To a solution of compound 6B (6.1 g, 16.48 mmol) in tetrahydrofuran (120 mL) cooled to 0 - 5 °C was added LiAlH 4 (1.20 g, 32.95 mmol), maintaining the temperature below 10 °C. The mixture was stirred at 0 - 10 °C for 1.5 h. At 0 - 5 °C, 25 g of Na 2 SO 4 ·10H 2 O was added to the mixture and stirred for 2 h and then filtered. The filter cake was suspended twice with dichloromethane / methanol (10:1 mixture of 100 mL) and filtered. The combined filtrates were concentrated in vacuo, and the residue was purified by silica column chromatography (0 - 10% methanol / dichloromethane) to give compound 7B (3.9 g, yield 72%) as a white solid and 0.6 g of a debrominated by-product as a yellow solid.

[0435] LCMS: t R = 1.958 and 2.016 min in the \0-60AB_7min_220&254_Shimadzu.lcm chromatogram (Xtimate C18 2.1*30 mm,

[0436] 3 μm), MS (ESI) m / z = 328.1 [M + H] + .

[0437] 1 H NMR (400 MHz, methanol-d 4): δ = 7.80 (s, 0.3H), 7.78 (s, 0.6H), 4.47 (dt, J = 10.0, 2.0 Hz, 0.6H), 4.20 - 4.13 (m, 0.3H), 3.84 (dd, J = 11.6, 3.2 Hz, 0.6H), 3.64 (t, J = 10.8 Hz, 0.4H), 3.60 - 3.38 (m, 4H), 2.45 - 2.36 (m, 0.6H), 2.22 - 2.13 (m, 0.3H), 2.09 - 1.96 (m, 1H), 1.93 - 1.73 (m, 1H), 1.62 - 1.45 (m, 1H).

[0438] Compound 8B: (5-(4-Amino-5-(2-fluoro-4-phenoxyphenyl)imidazo[5,1-f][1,2,4]triazin-7-yl)tetrahydro-2H-pyran-2-yl)methanol

[0439]

[0440] Compound 7B (106 mg, 0.457 mmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (25 mg, 0.0304 mmol) and potassium carbonate (84 mg, 0.608 mmol) were placed in a reaction tube and purged with nitrogen three 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 under nitrogen at 100 °C 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 give Compound 8B (80 mg impure, a mixture of trans / cis racemates) as a yellow oil.

[0441] LCMS: t R = 2.274 min & 2.340 min in chromatogram (Xtimate C18 2.1*30 mm) of 10 - 80 AB_7min_220&254_Shimadzu.lcm

[0442] and MS(ESI) m / z = 436.2 [M + H] + .

[0443] SFC: t R = 4.171 min, 4.286 min, 4.454 min and 5.581 min. Method: Column: Chiralcel OJ-3

[0444] 150×4.6 mm I.D., 3 μm Mobile phase: A: CO 2 , B: methanol, gradient: 5% to 40% of B in 5 min and 40% to 5% of B in 0.5 min, hold 5% of B for 1.5 min, flow rate: 2.5 mL / min, column temperature: 35 °C, ABPR: 1500 psi.

[0445] 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

[0446] 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

[0447] 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

[0448] 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

[0449]

[0450] Compound 8B (80 mg) was further separated by preparative SFC (column: DAICEL CHIRALCEL OJ-H (250 mm * 30 mm, 5 μm); conditions: 30% MeOH (0.1% NH 3 H 2 O) / CO 2 ; flow rate: 60 mL / min) to obtain 6.8 mg of impure Compound 11, which was further purified by preparative HPLC (column: Welch Xtimate C18 100 * 40 mm * 3 μm, conditions: 25 - 55% (A: water (0.225% FA), B: CH 3 CN), flow rate: 25 mL / min) to obtain Compound 11 as a white solid (1.7 mg, yield of 1% for 2 steps). After SFC, a mixture of the other three peaks (40 mg) was separated by chiral SFC (column: DAICEL CHIRALPAK IG (250 mm * 30 mm, 10 μm); conditions: 55% MeOH (0.1% NH3 H 2 O) / CO 2 ; Flow rate: 80 mL / min) was further purified to obtain Compound 8 as a white solid (8.6 mg, yield of 6.4% over 2 steps), Compound 9 as a white solid (6.7 mg, yield of 5% over 2 steps), and Compound 10 as a white solid (5.4 mg, yield of 4% over 2 steps).

[0451] Spectrum of Compound 8:

[0452] LCMS: t R = 2.356 min in a 10 - 80 AB_7min_220&254_Shimadzu.lcm chromatogram (Xtimate C18 2.1*30 mm), MS(ESI) m / z = 436.2 [M+H]

[0453] in which was 2.356 min, MS(ESI) m / z = 436.2 [M+H] + 。

[0454] HPLC: t R = 3.00 min in a 10 - 80 CD_8min.met. chromatogram (XBridge Shield RP 18 2.1*50 mm 5 μm).

[0455] 1 H NMR(400 MHz, CD 3 OD): δ = 7.84 (s, 1H), 7.54 (t, J = 8.4 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.26 - 7.20 (m, 1H), 7.17 - 7.12 (m, 2H), 6.94 (dd, J = 8.0, 2.0 Hz, 1H), 6.88 (dd, J = 10.8, 2.4 Hz, 1H), 4.56 - 4.51 (m, 1H), 3.89 (dd, J = 11.6, 3.6 Hz, 1H), 3.65 - 3.48 (m, 4H), 2.51 - 2.42 (m, 1H), 2.12 - 2.02 (m, 1H), 1.99 - 1.85 (m, 1H), 1.64 - 1.55 (m, 1H).

[0456] SFC: t R = 4.059 min, optical purity 99.94%.

[0457] Method: Column: Chiralcel OJ - 3 150×4.6 mm I.D., 3 μm Mobile phase: A: CO 2, B: Methanol (0.05% DEA), Gradient: 5% to 40% of B in 5 min and 40% to 5% of B in 0.5 min, hold 5% of B for 1.5 min, Flow rate: 2.5 mL / min, Column temperature: 35 °C, ABPR: 1500 psi.

[0458] Spectrum of Compound 9:

[0459] LCMS: t R = 2.340 min in 10 - 80 AB_7 min_220 & 254_Shimadzu.lcm chromatogram (Xtimate C18 2.1*30 mm), MS (ESI) m / z = 436.3 [M+H]+.

[0460] in it is 2.340 min, MS (ESI) m / z = 436.3 [M+H]+.

[0461] HPLC: t R = 2.99 min in 10 - 80 CD_8 min.met. chromatogram (XBridge Shield RP 18 2.1*50 mm 5 μm).

[0462] 1 H NMR (400 MHz, CD 3 OD): δ = 7.84 (s, 1H), 7.53 (t, J = 8.4 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.25 - 7.19 (m, 1H), 7.17 - 7.12 (m, 2H), 6.94 (dd, J = 8.4, 2.0 Hz, 1H), 6.87 (dd, J = 11.2, 2.4 Hz, 1H), 4.56 - 4.50 (m, 1H), 3.88 (dd, J = 12.0, 3.6 Hz, 1H), 3.65 - 3.48 (m, 4H), 2.50 - 2.41 (m, 1H), 2.12 - 2.02 (m, 1H), 1.97 - 1.86 (m, 1H), 1.64 - 1.55 (m, 1H).

[0463] SFC: t R = 4.161 min, optical purity 100%.

[0464] Method: Column: Chiralcel OJ-3 150×4.6 mm I.D., 3 μm Mobile phase: A: CO 2 , B: Methanol (0.05% DEA), Gradient: 5% to 40% of B in 5 min and 40% to 5% of B in 0.5 min, hold 5% of B for 1.5 min, Flow rate: 2.5 mL / min, Column temperature: 35 °C, ABPR: 1500 psi.

[0465] Spectrum of Compound 10:

[0466] LCMS: t R = 2.410 min in 10 - 80 AB_7min_220&254_Shimadzu.lcm chromatography (Xtimate C18 2.1*30 mm)

[0467] and MS (ESI) m / z = 436.3 [M+H] + 。

[0468] HPLC: t R = 2.98 min in 10 - 80 CD_8min.met. chromatography (XBridge Shield RP 18 2.1*50 mm 5μm).

[0469] 1 1H NMR (400 MHz, CD 3 OD): δ = 7.86 (s, 1H), 7.50 (t, J = 8.4 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.26 - 7.20 (m, 1H), 7.17 - 7.12 (m, 2H), 6.94 (dd, J = 8.4, 2.4 Hz, 1H), 6.88 (dd, J = 10.8, 2.4 Hz, 1H), 4.24 - 4.18 (m, 1H), 3.75 (t, J = 11.2 Hz, 1H), 3.68 - 3.48 (m, 4H), 2.27 - 2.19 (m, 1H), 2.16 - 2.04 (m, 1H), 1.84 - 1.76 (m, 1H), 1.59 - 1.47 (m, 1H).

[0470] SFC: t R = 4.405 min, optical purity 99.83%.

[0471] Method: Column: Chiralcel OJ - 3 150×4.6 mm I.D., 3μm Mobile phase: A: CO 2 , B: methanol (0.05% DEA), Gradient: 5% to 40% of B in 5 min and 40% to 5% of B in 0.5 min, hold 5% of B for 1.5 min, Flow rate: 2.5 mL / min, Column temperature: 35°C, ABPR: 1500 psi.

[0472] Spectrum of Compound 11:

[0473] LCMS: t R = 2.410 min in 10 - 80 AB_7min_220&254_Shimadzu.lcm chromatography (Xtimate C18 2.1*30 mm)

[0474] It is 2.365 min, MS(ESI) m / z = 436.2 [M+H] + .

[0475] HPLC: t R = It is 3.05 min in a chromatogram (XBridge Shield RP 18 2.1 * 50 mm 5 μm) with 10 - 80% CD_8 min.met.

[0476] 1 H NMR (400 MHz, CD 3 OD): δ = 7.86 (s, 1H), 7.50 (t, J = 8.4 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.26 - 7.21 (m, 1H), 7.17 - 7.12 (m, 2H), 6.94 (dd, J = 8.4, 2.4 Hz, 1H), 6.88 (dd, J = 10.8, 2.4 Hz, 1H), 4.24 - 4.18 (m, 1H), 3.75 (t, J = 10.8 Hz, 1H), 3.68 - 3.47 (m, 4H), 2.26 - 2.18 (m, 1H), 2.16 - 2.04 (m, 1H), 1.84 - 1.76 (m, 1H), 1.59 - 1.47 (m, 1H).

[0477] SFC: t R = 5.802 min, optical purity 100%.

[0478] Method: Column: Chiralcel OJ - 3 150 × 4.6 mm I.D., 3 μm Mobile phase: A: CO 2 , B: methanol (0.05% DEA), Gradient: 5% to 40% of B in 5 min and 40% to 5% of B in 0.5 min, hold 5% of B for 1.5 min, Flow rate: 2.5 mL / min, Column temperature: 35 °C, ABPR: 1500 psi.

[0479] Synthesize the following compounds according to Method B:

[0480]

[0481]

[0482]

[0483]

[0484] Biological data

[0485] BTK WT and BTK C481S HTRF Kinase Assay

[0486] Recombinant BTK wild type (BTK WT) was purchased from Thermo Fisher. Recombinant BTK (C481S) was purchased from SignalChem. The inhibitory potency of compounds against BTK and BTK (C481S) was evaluated using the Homogenous Time Resolved Fluorescence approach.

[0487] Briefly, at room temperature, the recombinant kinases were pre-incubated for 30 minutes in the presence or absence of compounds. The reaction was initiated by adding ATP and a substrate peptide, which could be phosphorylated by the kinase. After 120 minutes of incubation, the reaction was stopped by adding a detection reagent mixture containing EDTA. Fluorescence was measured at 615 nm and 665 nm, respectively, with an excitation wavelength of 320 nm. The calculated signal ratio of 665 nm / 615 nm is proportional to the kinase activity. The concentration (IC50) of the compound that produced 50% inhibition of the corresponding kinase was calculated using a four-parameter logistic fit with XL-fit.

[0488]

[0489]

[0490] TMD8 Cell Line p-BTK Elisa Assay

[0491] TMD-8 cells were seeded in 96-well plates at a density of 30,000 cells / well in RPMI1640 medium containing 1.5% fetal bovine serum. The test compounds were added to the cells and the cells were incubated at 37 °C, 5% CO 2 for 0.5 hour. Then, a solution of sodium orthovanadate was added to the cells to a final concentration of 100 μM, and the cells were incubated at 37 °C, 5% CO 2 for an additional 1 hour. After compound treatment, the cells were lysed and the p-BTK signal was detected following exactly the procedure of the Phospho-Btk (Tyr223) Sandwich ELISA Kit (#23843). The plates were read on a Multiscan spectrophotometer set at a wavelength of 450 nm. The data were processed in GraphPad Prism software.

[0492] Compound Number <![CDATA[p-BTK IC 50 (nM)]]> Maximum Inhibitory 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

[0493] HEK293 - BTK (WT) and HEK293 - BTK (C481S)

[0494] Mutagenesis was performed using the QuikChange II XL Site-Directed Mutagenesis Kit to generate the full-length cDNA of BTK containing the C481S mutation. The mutated BTK cDNA was confirmed by sequencing. Subsequently, the cDNAs of BTK (WT) and BTK-C481S were cloned into the PLVX-Puro lentiviral vector. Lentiviruses were packaged in 293T cells by transfecting and encapsulating the mixture with the lentiviral vector. The BTK (WT) and BTK-C481S lentiviruses were transfected into HEK293 cells. Transfected cells were selected in 2 μg / mL puromycin. The stable polyclonal cell lines were confirmed by WB and used for further study. The 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 in a humidified incubator at 37 °C with 5% CO 2 2.

[0495] The HEK293-BTK (WT) and HEK293-BTK (C481S) cells were seeded at a density of 5000 cells / well in a 96-well plate with RPMI1640 medium containing 1.5% fetal bovine serum. Test compounds were added to the cells and the cells were incubated at 37 °C with 5% CO 2 2 for 1.5 h. After compound treatment, the cells were lysed and the p-BTK signal was detected following the procedure of the Phospho-Btk (Tyr223) Sandwich ELISA Kit (#23843) exactly. The plates were read on a Multiscan spectrophotometer set at a wavelength of 450 nm. The data were processed in GraphPad Prism software. The plates were read on a Multiscan spectrophotometer set at a wavelength of 450 nm. The data were processed in GraphPad Prism software.

[0496] Compound Number <![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

[0497] TMD-8 Antiproliferation Assay

[0498] TMD-8 cells were prepared in RPMI1640 medium containing 10% fetal bovine serum and seeded at 1500 cells per well in a 384-well plate. The cells were incubated at 37 °C with 5% CO 2 2 overnight. After incubation, compounds at different concentrations were added to the assay plates and the cells were incubated for an additional 72 h at 37 °C with 5% CO 2 2. After 72 h of incubation, 15 μL of CellTiter An 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). The CellTiter-Glo assay was performed according to the manufacturer's instructions, and fluorescence was measured in a multi-label reader (Envision, PerkinElmer, USA). Data were processed in XLfit software.

[0499]

[0500]

[0501] In vitro rat / human hepatocyte clearance assay

[0502] Male rat hepatocytes and mixed-gender human hepatocytes were obtained from a commercial supplier (e.g., BioreclamationIVT) and stored at -150 °C before use. A 10 mM stock solution of the test compound was prepared in DMSO. Thawed medium and supplemented culture medium (serum-free) were placed in a 37 °C water bath for at least 15 min 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.

[0503] Remove the vial of cryopreserved hepatocytes from storage, ensuring that the vial remains at a low temperature. Thaw the vial in a 37 °C water bath with gentle agitation. Keep the vial in the 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. Then pour the contents into a 50 mL conical tube of thawed medium. Centrifuge the vial at 100 g for 10 min at room temperature. Aspirate the thawed medium and resuspend the hepatocytes in serum-free culture medium to obtain approximately 1.5×10 6 cells / mL.

[0504] Cell viability and density were counted using the Trypan Blue exclusion method, and then the cells were diluted with serum-free culture medium to achieve a working cell density of 1×10 6 viable cells / mL. A portion of the hepatocytes at 1×10 6 viable cells / mL was boiled for 10 min and then added to the plate as a negative control to eliminate enzyme activity, such 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.

[0505] Aliquots of 247.5 μL of hepatocytes were dispensed into each well of a 96-well uncoated plate. The plate was placed in an incubator on an orbital shaker for approximately 10 minutes. Aliquots of 2.5 μL of a 100 μM test compound were added to the corresponding wells of the uncoated 96-well plate to initiate the reaction. This analysis was performed in duplicate. The plate was incubated in an incubator on an orbital shaker for the designed time points. At time points of 5, 15, 30, 45, 60, 80, and 100 minutes, 20 μL of the contents were transferred and mixed with 6 volumes (120 μL) of cold acetonitrile containing an internal standard to terminate the reaction. The samples were centrifuged at 4000 g for 20 minutes and aliquots of 100 μL of the supernatant were used for LC-MS / MS analysis to measure the test compound.

[0506] In vitro hepatocyte clearance was estimated based on the elimination half-life (T1 / 2) determined from the disappearance of the compound from its initial concentration. The peak area ratio of each compound (test or control) to the IS was calculated. A curve of Ln(control %) versus incubation time (min) was plotted and the slope of the linear fit line was calculated. The drug elimination rate constant k (min -1 ), T1 / 2 (min), and in vitro intrinsic clearance CL int (μL / min / E6) were calculated according to the following equations:

[0507] k = -slope

[0508] T 1 / 2 = 0.693 / k

[0509] CL int = k / Chep

[0510] where Chep (cells × μL -1 ) is the cell concentration in the incubation system.

[0511] Procedure for Log D determination

[0512] Aliquots of 10 μL of the working solution of each vial were placed sequentially in the corresponding 96-well shelf positions (Log D plate). 500 μL of saturated octanol was added to each vial of the above uncovered Log D plate, followed by 500 μL of saturated phosphate buffer. It was sealed with a molded PTFE / SIL 96-well plate lid.

[0513] The Log D plate was transferred to an Eppendorf Thermomixer Comfort plate shaker and shaken at 25 °C and 2,000 rpm for 2 hours.

[0514] Centrifuge the sample at 4,000 rpm for 30 minutes at 25 °C to separate the phases. A pipette and a syringe are used to aspirate approximately 100 μL from the octanol and buffer phases into a new 96-well plate, respectively.

[0515] Transfer 5 μL of the octanol sample to a new 96-well plate, and then add 495 μL of a mixture of H 2 O and acetonitrile containing an internal standard (1:1) as a 100-fold octanol sample. Vortex at 1,000 rpm for 5 minutes.

[0516] Transfer 50 μL of the 100-fold sample to a new 96-well plate, and then add 450 μL of a mixture of H 2 O and acetonitrile containing an internal standard (1:1) as a 1,000-fold octanol sample. Vortex at 1,000 rpm for 5 minutes.

[0517] Use a mixture of H 2 O and acetonitrile containing an internal standard (1:1) to serially dilute the 1,000-fold octanol sample to 10,000, 100,000, and 1,000,000-fold.

[0518] Transfer 50 μL of the buffer sample to a new 96-well plate, and then add 450 μL of a mixture of H 2 O and acetonitrile containing an internal standard (1:1) as a 10-fold buffer sample. Vortex at 1,000 rpm for 5 minutes.

[0519] Use a mixture of H 2 O and acetonitrile containing an internal standard (1:1) to serially dilute the 10-fold buffer sample to 100, 1,000, and 10,000-fold. Evaluate the samples by LC / MS / MS analysis. Test all compounds in duplicate.

[0520] Perform all calculations using Microsoft Excel. Evaluate the concentration of the test compounds in the octanol / buffer solution by LC / MS / MS. Calculate the Log D value of the test compounds as follows:

[0521]

[0522] DF means dilution factor.

[0523] Procedure for protein binding measurement in human plasma by using equilibrium dialysis

[0524] 597 μL of blank plasma was added to each vial of a new plastic plate or individual plastic tubes by adding 3 μL of the working solution of each kit, vortexed for 5 minutes at 1,000 rpm. The final volume % of the organic solvent was 0.5% and the final concentration of the test compound was 5 μM. Immediately, 50 μL of the spiked plasma suspension was transferred to a 96-well plate to serve as the T = 0 control sample. The samples were processed in the same manner as the samples after incubation. All the remaining spiked plasma was placed in an incubator for the duration of the study.

[0525] The insert was placed in the well of the bottom plate with the open end facing up. 500 μL of phosphate buffer (pH 7.4) was added to the buffer chamber, which is indicated by the white circle. 300 μL of the spiked plasma sample was added to the sample chamber, which is indicated by the red circle. The unit was covered with a breathable lid and incubated at 37 °C on an orbital shaker in a CO 2 incubator at 300 rpm with 5% CO 2 for 18 hours. At the end of incubation, the lid was removed and 50 μL of the post-dialysis samples were aspirated from the buffer chamber and the plasma chamber into separate 96-well plates for analysis.

[0526] Meanwhile, the remaining spiked plasma samples in the plastic plate or individual plastic tubes were incubated at 37 °C in a CO 2 incubator with 5% CO 2 for 18 hours. At T = 18 hours, 50 μL of the original spiked plasma suspension was transferred to a 96-well plate for analysis.

[0527] 50 μL of human plasma was added to the buffer samples, and an equal volume of PBS was added to the collected plasma samples. The plate was vortexed at 1,000 rpm for 2 minutes and 400 μL of acetonitrile containing the appropriate internal standard (IS) was added to precipitate the proteins and release the compounds. It was vortexed at 1,000 rpm for 10 minutes. Centrifuged at 4,000 rpm for 30 minutes. 250 μL of the supernatant was transferred to a new 96-well plate and centrifuged again (4,000 rpm, 30 minutes). Then 100 μL of the 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 for analysis by LC-MS / MS. All compounds were tested in duplicate at 5 μM in human plasma.

[0528] All calculations were performed using Microsoft Excel.

[0529] The unbound percentage, bound percentage, and recovery percentage of the test compound were calculated as follows:

[0530] Unbound % = (Conc. 缓冲液室 / Conc. 血浆室 )×100%

[0531] Bound % = 100% - Free %

[0532] Recovery % = (500 × Conc. 缓冲液室 +300×Conc. 血浆室 ) / (300×Conc. 总样本 )×100

[0533]

[0534] Remaining % = Conc. 18hr / Conc. 0hr ×100%

[0535] result

[0536]

[0537]

[0538] Short-term oral absorption (SOA) analysis in rats.

[0539] 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 .

[0540] Compound Number <![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): Wherein: R 1 selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, N-C 1-6 alkylamino, N,N-(C 1-6 alkyl) 2 amino, carbocyclic group and heterocyclic group; wherein R 1 may optionally be substituted by one or more R 5 substituents; R 2 selected from halo, C 1-3 alkyl, C 1-3 alkoxy, carbocyclic group and heterocyclic group; or two Rs on the same atom or adjacent atoms 2 may together with the atom to which they are attached form a 3- to 7-membered ring; k is 0 - 4; R 3 selected from halogen groups, C 1-3 alkyl groups and C 1-3 alkoxy groups; n is 0 - 4; R 4 selected from halo groups, C 1-3 alkyl groups and C 1-3 alkoxy groups; m is 0 - 5; A is =N- or =C(R 6 )-; R 5 Selected from halo, hydroxy, C 1-6 alkoxy, amino, N-C 1-6 alkylamino, N,N-(C 1-6 alkyl) 2 amino, carbocyclic group and heterocyclic group; wherein R 5 may independently and optionally be substituted by one or more R 7 substituents; R 6 selected from hydrogen and halogen groups; R 7 selected from a halogen group, a hydroxyl group, an amino group, a C 1-3 alkyl group and a C 1-3 alkoxy group; 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 selected from hydrogen, methyl, hydroxymethyl, methoxymethyl, N,N-dimethylaminomethyl and azetidin-1-ylmethyl.

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

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 3 is fluorine.

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

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 4 is fluorine.

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

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

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

10. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, 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.

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

12. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier, for producing a BTK inhibitory effect in warm-blooded animals.

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

14. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, or a pharmaceutical composition according to any one of claims 11 - 13, in the manufacture of a medicament for the treatment of a disease or disorder in warm - blooded animals, said disease or disorder being selected from: immune disorders, cancer, cardiovascular diseases, viral infections, metabolic / endocrine dysfunctions and neurological disorders, allergic disorders, autoimmune diseases or inflammatory diseases.

15. The use according to claim 14, wherein the cancer is selected from: small lymphocytic lymphoma (SLL), follicular lymphoma, Richter's transformation, mantle cell lymphoma, chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia, non-Hodgkin lymphoma, primary central nervous system lymphoma, secondary central nervous system lymphoma or diffuse large B-cell lymphoma. macroglobulinemia), non-Hodgkin lymphoma, primary central nervous system lymphoma, secondary central nervous system lymphoma or diffuse large B-cell lymphoma.

16. Use according to claim 14, wherein the disease or disorder is selected from: urticaria / Sjögren's syndrome, rheumatoid arthritis, osteoporosis, vasculitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, asthma, multiple sclerosis and systemic lupus erythematosus.

17. Use according to claim 14, wherein the warm - blooded animal is a human.

18. Use according to claim 16, wherein the disease or disorder is multiple sclerosis.

19. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, or a pharmaceutical composition according to any one of claims 11 - 13, in the manufacture of a medicament for inhibiting BTK.

20. Use according to claim 19, wherein the BTK is wild - type BTK or BTK having a C481 mutation.

21. Use according to claim 20, wherein the BTK having a C481 mutation is selected from the group consisting of: BTK having a C481S mutation, BTK having a C481Y mutation, BTK having a C481R mutation and BTK having a C481F mutation.

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