HK40120533A - Btk inhibitors - Google Patents

Description

BTK inhibitors

This application is a divisional application of Chinese Patent Application No. 202080091669.X, filed on December 29, 2020, entitled "BTK Inhibitor". The original application was a national phase application, International Application No. PCT/CN2020/140517, which claimed priority to PCT patent applications filed on January 2, 2020 (PCT/CN2020/070034) and December 8, 2020 (PCT/CN2020/134601). All of the above applications are incorporated herein by reference.

Invention Field

This application relates to oxane-substituted imidazopyrazine and imidazotriazine inhibitors of Bruton's tyrosine kinase (BTK) (including mutant BTK), which are indicated for the treatment of diseases or conditions associated with BTK kinase. These compounds have potential utility in the treatment of immune disorders, cancer, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine dysfunctions, and neurological disorders.

Specifically, this application relates to compounds and compositions thereof that inhibit BTK, methods for treating BTK-related diseases or conditions, and methods for synthesizing these compounds.

Background Technology

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

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

The role of BTK in apoptosis has also demonstrated the efficacy of inhibiting BTK activity in treating cancers such as B-cell lymphoma, leukemia, and other hematologic malignancies. Furthermore, BTK plays a role in osteoclast function; therefore, inhibiting BTK activity has potential efficacy in treating bone diseases such as osteoporosis.

Approved BTK inhibitors include ibrutinib (for B-cell malignancies such as mantle cell lymphoma, chronic lymphocytic leukemia (CLL), and Waldenström macroglobulinemia); acalabrutinib (for mantle cell lymphoma and CLL); and zanubrutinib (for mantle cell lymphoma). Several other BTK inhibitors are 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).

Despite significant advancements in the use of BTK inhibitors to treat B-cell malignancies, cases of primary and secondary resistance with poor prognosis and limited treatment options have emerged.

Covalent (irreversible) BTK inhibitors (such as ibrutinib and acalatinib) bind to the C481 site of BTK, thereby inactivating its kinase. This binding is permanent until the BTK protein is degraded. The advantage of these irreversible inhibitors is that they are potent and usually effective only with short exposures. However, their clinical benefits are limited by off-target toxicity, resulting in high discontinuation rates and resistance due to BTK C481 mutations that disrupt 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 C481S mutations, most (>50%) CLL patients undergoing covalent BTK inhibitor therapy develop resistance to treatment (New England Journal of Medicine 370; 24, 2014; JAMA Oncol. 2015; 1(1):80-87; J Clin Oncol. 35:1437-1443, 2017).

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, accounting 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 generally (approximately 30–80%) consistent with PCNSL (Neuropathol. Appl. Neurobiol. 2016 Apr; 42(3):279–90). Although BTK inhibitors have not yet been approved for the treatment of DLBCL, data suggest that DLBCL with CD79B and MYD88 mutations is more sensitive to BTK inhibition (Nature Medicine 2015 Aug; 21(8):922–6).

Secondary CNS lymphoma (SCNSL) refers to the central nervous system spread of lymphoma originating elsewhere (as opposed to primary CNS lymphoma). It is usually non-Hodgkin's lymphoma and can be an isolated recurrence or, at its onset, part of a systemic disease. Unlike primary CNS lymphoma, it more often involves the leptomeninges.

PRN2246 (SAR442168) (a blood-brain barrier (BBB)-penetrating covalent BTK inhibitor) was well tolerated in a phase I trial for multiple sclerosis (MS). In addition, several trials (Grommes C et al., Cancer Discovery, Sep 2017; 7(9):1018-1029; Grommes C et al., Blood, 2019; 133(5):436-445; Lionakis et al., Cancer Cell, 2017; 31,833-843; and Soussain C et al., European Journal of Cancer, Aug 2019; 117:121-130) have shown that high doses of ibrutinib (840 mg) are effective in CNS lymphomas (PCNSL and secondary nervous system lymphoma (SCNSL)), but to date, no BTK inhibitors targeting BTK-C481 mutations or active in PCNSL have been approved. These do not meet the medical needs.

WO 2009/143051 discloses certain substituted imidazopyrazines and imidazotriazines, including some hexane-substituted imidazopyrazines and imidazotriazines, as inhibitors of activated p21cdc42Hs-associated kinase (ACK1). However, the compounds of WO 2009/143051 exhibit high clearance from human hepatocytes, implying that even at the maximally absorbable dose, the compounds may not achieve sufficient sustained drug coverage (making the compounds ineffective); and/or extremely high doses may be required to inhibit the target, resulting in high maximal drug concentrations (potentially leading to minor pharmacological (i.e., adverse) effects and toxicity issues).

WO2017111787A1 discloses a tetrahydropyranoamino-pyrrolopyrimidinone that modulates BTK activity; WO2018039310A1 discloses an amino-pyrrolopyrimidinone compound and its method of use; WO2017103611A1 discloses a compound used as a BTK inhibitor; and WO2011152351 discloses a purine ketone derivative with selective BTK inhibitory activity. However, none of these compounds possesses the combination of properties required by the compounds of this invention.

This article discloses novel oxane-substituted imidazopyrazines and imidazotriazines as potent and selective inhibitors of BTK with C481 mutations (e.g., C481S, C481Y, C481R, or C481F mutations), wild-type BTK, and both. These compounds are non-covalent reversible inhibitors, exhibiting low clearance from human hepatocytes and blood-brain barrier (BBB) penetration properties.

Summary of the Invention

This article discloses the compound of formula (I):

And its pharmaceutically acceptable salts, and its use as a BTK inhibitor, particularly in therapeutic applications.

Detailed Implementation

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

This article discloses a compound of formula (I):

in:

^R1 is selected from hydrogen, _C1-6 alkyl, _C1-6 alkoxy, _NC1-6 alkylamino, N,N-( _C1-6 alkyl) _2amino , carbocyclic and heterocyclic groups; wherein ^R1 may optionally be substituted by one or more ^R5 ;

^R2 is selected from halogen, _C1-3 alkyl, _C1-3 alkoxy, carbocyclic and heterocyclic groups; or two ^R2s on the same or adjacent atoms can form a 3-7 membered ring together with the atom they are attached to.

k is 0-4;

^R3 is selected from halogen, _C1-3 alkyl, and _C1-3 alkoxy groups;

n is 0-4;

^R4 is selected from halogen, _C1-3 alkyl, and _C1-3 alkoxy groups;

m is 0-5;

A is either =N- or =C(R ⁶ )-;

^R5 is selected from halogen, hydroxyl, _C1-6 alkoxy, amino, _NC1-6 alkylamino, N,N-( _C1-6 alkyl) _2amino , carbocyclic and heterocyclic groups; wherein ^R5 may be independently and optionally substituted by one or more ^R7s ;

^R6 is selected from hydrogen and halogen groups;

^R7 is selected from halogen, hydroxyl, amino, _C1-3 alkyl, and _C1-3 alkoxy groups;

Or its pharmaceutically acceptable salt.

In one embodiment, ^R1 is selected from hydrogen and _C1-6 alkyl; wherein ^R1 may optionally be substituted by an ^R5 ; wherein ^R5 is selected from hydroxyl, _C1-6 alkoxy, N,N-( _C1-6 alkyl) _2amino and heterocyclic groups.

In one embodiment, ^R1 is selected from hydrogen and _C1-3 alkyl; wherein ^R1 may optionally be substituted by an ^R5 ; wherein ^R5 is selected from hydroxyl, _C1-3 alkoxy, N,N-( _C1-2 alkyl) _2amino and aziridine.

In one embodiment, ^R1 is selected from hydrogen, methyl, hydroxymethyl, methoxymethyl, N,N-dimethylaminomethyl and aziridine-1-ylmethyl.

In one embodiment, ^R1 is a hydroxymethyl group.

In one embodiment, ^R2 is selected from a halogen or a _C1-3 alkoxy group.

In one embodiment, ^R2 is selected from fluorine or methoxy.

In one embodiment, two ^{R2 atoms} on the same or adjacent atoms may form a 3-7 membered ring together with the atom to which they are attached.

In one embodiment, or two ^{R2 atoms} on the same atom, together with the atoms they are attached to, can form a 3-7 membered ring.

In one embodiment, two ^R2s on adjacent atoms may form a 3-7 membered ring together with the atoms they are attached to.

In one embodiment, k is 0.

In one embodiment, k is 1.

In one embodiment, k is 2.

In one embodiment, k is 3.

In one embodiment, k is 4.

In one embodiment, ^R3 is a halogen group.

In one embodiment, ^R3 is fluorine.

In one embodiment, n is 0-2.

In one embodiment, n is 0.

In one embodiment, n is 1.

In one embodiment, n is 2.

In one embodiment, n is 3.

In one embodiment, n is 4.

In one embodiment, ^R4 is a halogen group.

In one embodiment, ^R4 is fluorine.

In one embodiment, m is 0-2.

In one embodiment, m is 0.

In one embodiment, m is 1.

In one embodiment, m is 2.

In one embodiment, m is 3.

In one embodiment, m is 4.

In one embodiment, m is 5.

In one embodiment, A is either =N- or =C(H)-.

In one embodiment, A is = N-.

In one embodiment, A is =C(R ⁶ )-.

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

Compound (I) (when R1 ≠ hydrogen) contains two chiral centers (marked with "*"):

These chiral centers can exist in a “trans” configuration (meaning the two substituents on the oxane ring point to opposite sides of the oxane ring) and in a “cis” configuration (meaning the two substituents on the oxane ring point to the same side of the oxane ring). Structures (IA) and (IB) below show the cis isomers of compound (I), and structures (IC) and (ID) below show the trans isomers of compound (I).

In one aspect of the invention, the compound of formula (I) is a trans compound of formula (I).

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

In one aspect of the invention, the compound of formula (I) is the compound of formula (IA):

       

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

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

In one aspect of the invention, the compound of formula (I) is the compound of formula (ID):

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

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

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

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

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

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

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

(5-(4-amino-5-(2,3-difluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

(5-(4-amino-5-(4-(2,3-difluorophenoxy)phenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

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

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

7-(6-(azacyclobutane-1-ylmethyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazolium[5,1-f][1,2,4]triazine-4-amine;

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

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

5-(2-fluoro-4-phenoxyphenyl)-7-(6-methyltetrahydro-2H-pyran-3-yl)imidazol[5,1-f][1,2,4]triazine-4-amine.

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

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

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

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

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

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

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

(5-(4-amino-5-(2,3-difluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

(5-(4-amino-5-(4-(2,3-difluorophenoxy)phenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

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

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

7-(6-(azacyclobutane-1-ylmethyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazolium[5,1-f][1,2,4]triazine-4-amine;

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

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

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

Or its pharmaceutically acceptable salt.

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

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

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

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

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

((2R,5R)-5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

((2R,5R)-5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

((2R,5R)-5-(4-amino-5-(2,3-difluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

((2R,5R)-5-(4-amino-5-(4-(2,3-difluorophenoxy)phenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

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

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

7-((3R,6R)-6-(azacyclobutane-1-ylmethyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazolium[5,1-f][1,2,4]triazine-4-amine;

5-(2-fluoro-4-phenoxyphenyl)-7-((3R,6R)-6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)imidazol[5,1-f][1,2,4]triazine-4-amine;

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

5-(2-fluoro-4-phenoxyphenyl)-7-((3R,6R)-6-methyltetrahydro-2H-pyran-3-yl)imidazol[5,1-f][1,2,4]triazine-4-amine;

Or its pharmaceutically acceptable salt.

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

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

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

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

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

((2S,5S)-5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

((2S,5S)-5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

((2S,5S)-5-(4-amino-5-(2,3-difluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

((2S,5S)-5-(4-amino-5-(4-(2,3-difluorophenoxy)phenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

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

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

7-((3S,6S)-6-(azacyclobutane-1-ylmethyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazolium[5,1-f][1,2,4]triazine-4-amine;

5-(2-fluoro-4-phenoxyphenyl)-7-((3S,6S)-6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)imidazol[5,1-f][1,2,4]triazine-4-amine;

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

5-(2-fluoro-4-phenoxyphenyl)-7-((3S,6S)-6-methyltetrahydro-2H-pyran-3-yl)imidazol[5,1-f][1,2,4]triazine-4-amine;

Or its pharmaceutically acceptable salt.

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

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

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

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

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

((2S,5R)-5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

((2S,5R)-5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

((2S,5R)-5-(4-amino-5-(2,3-difluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

((2S,5R)-5-(4-amino-5-(4-(2,3-difluorophenoxy)phenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

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

7-((3S,6R)-6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazolium[5,1-f][1,2,4]triazine-4-amine;

7-((3S,6R)-6-(azacyclobutane-1-ylmethyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazolium[5,1-f][1,2,4]triazine-4-amine;

5-(2-fluoro-4-phenoxyphenyl)-7-((3S,6R)-6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)imidazolium[5,1-f][1,2,4]triazine-4-amine; and

5-(2-fluoro-4-phenoxyphenyl)-7-((3S,6R)-6-methyltetrahydro-2H-pyran-3-yl)imidazol[5,1-f][1,2,4]triazine-4-amine;

Or its pharmaceutically acceptable salt.

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

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

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

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

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

((2R,5S)-5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

((2R,5S)-5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

((2R,5S)-5-(4-amino-5-(2,3-difluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

((2R,5S)-5-(4-amino-5-(4-(2,3-difluorophenoxy)phenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol;

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

7-((3R,6S)-6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazolium[5,1-f][1,2,4]triazine-4-amine;

7-((3R,6S)-6-(azacyclobutane-1-ylmethyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazolium[5,1-f][1,2,4]triazine-4-amine;

5-(2-fluoro-4-phenoxyphenyl)-7-((3R,6S)-6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)imidazolium[5,1-f][1,2,4]triazine-4-amine; and

5-(2-fluoro-4-phenoxyphenyl)-7-((3R,6S)-6-methyltetrahydro-2H-pyran-3-yl)imidazol[5,1-f][1,2,4]triazine-4-amine;

Or its pharmaceutically acceptable salt.

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

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

In one aspect of the invention, synthetic intermediates for preparing compounds of formula (I) as disclosed herein are provided.

In one aspect of the invention, synthetic intermediates for preparing compounds of formula (I) as disclosed herein or pharmaceutically acceptable salts thereof are provided.

Linking substituents are described in several places in this disclosure. Where the structure explicitly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl", then it should be understood that "alkyl" refers to a linked alkylene group.

As used herein, when referring to a chemical group, the term "substituted" means that the chemical group has one or more hydrogen atoms that have been removed and replaced by substituents. As used herein, the term "substituent" has the common meaning known in the art and refers to a chemical moiety covalently attached to or fused with the parent group where appropriate. As used herein, the terms "optionally substituted" or "optionally replaced by…" mean that the chemical group may not have substituents (i.e., unsubstituted) or may have one or more substituents (i.e., substituted). It should be understood that substitution at a given atom is limited by valence number.

As used herein, the term "C_{_ij}" represents a range of carbon atoms, where i and j are integers, and the range includes the endpoints (i.e., i and j) and every integer point in between, where j is greater than i. For example, C _{_1-6} represents a range of one to six carbon atoms, including one, two, three, four, five, 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.

As used herein, whether as part of another term or independently, the term "alkyl" refers to a saturated hydrocarbon chain. The hydrocarbon chain mentioned above can be straight or branched. The term "C_{_ij}alkyl" refers to an alkyl group having i to j carbon atoms. Examples of C _₁-6 alkyl groups include (but are not limited to) methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologues such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylbutyl, etc. Examples of "C _₁-3 alkyl" are methyl, ethyl, propyl, and isopropyl.

As used herein, the terms “halogen” and “halogen” refer to atoms selected from fluorine, chlorine, bromine, and iodine.

As used herein, whether as part of another term or independently, the term "alkoxy" refers to a group of the formula -O-alkyl. The term "C _{_ij}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.

Examples of “N-(C _1-6 alkyl)amino” are methylamino and ethylamino. Examples of “N,N-(C _1-6 alkyl) _2amino ” are N,N-dimethylamino, N,N-diethylamino and N-ethyl-N-methylamino.

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

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 cyclic -CH _2- group may be replaced by a cyclic -C(O)- group. In some embodiments, the cyclic 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) azaheterocyclic butyl, piperidyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazine, morpholinyl, etc.

In one embodiment, two ^{R2 atoms} on the same atom, together with the atoms they are attached to, form a 3-7 membered ring. The resulting "spirocyclic" ring has two rings (one of which is an oxane of formula (I)) connected by a single common atom. The non-oxane ring can be a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring. Examples of two ^R2 atoms on the same atom forming a 3-7 membered ring (described by an oxane of formula (I)) include:

(It depicts the connection with the rest of the molecule).

In one embodiment, two ^{R2 atoms} on adjacent atoms, together with the atoms they are attached to, form a 3-7 membered ring. The resulting "fused ring" has two rings sharing two adjacent atoms (one of which is an oxane of formula (I)). The non-oxane ring can be a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring. Or examples of two ^{R2 atoms} on adjacent atoms forming a 3-7 membered ring (described by an oxane of formula (I)) include:

(It depicts the connection with the rest of the molecule).

Unless otherwise stated, the term "compound" in this disclosure is intended to cover all stereoisomers, geometric isomers and tautomers of the described structures.

The term "stereoisomer" refers to any of the various stereoisomer configurations (e.g., enantiomers, diastereomers, and racemates) of an asymmetric compound (e.g., those having one or more asymmetricly substituted carbon atoms or "asymmetric centers"). Compounds of this disclosure containing asymmetric centers can be separated in optically active (enantiomer or diastereomer) or optically inactive (racemate) form. The term "enantiomer" includes stereoisomer pairs that are not mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemate mixture". The term "diastereomer" refers to a stereoisomer having at least two asymmetric atoms that are not mirror images of each other. Certain compounds containing one or more asymmetric centers can produce enantiomers, diastereomers, or other stereoisomers, which can be defined as (R)- or (S)- at each asymmetric center according to the absolute configuration, based on the Cahn-Ingold-Prelog R-S system. Resolved compounds with unknown absolute configurations can be specified using the term "or" at the asymmetric center. Methods for preparing optically active forms from racemic mixtures are known in the art, such as by HPLC resolution or stereoselective synthesis.

The terms “geometric isomers” or “cis and trans isomers” refer to compounds that have the same formula but whose functional groups are rotated to different orientations in three-dimensional space.

The term "tautomer" includes proton transfer tautomers of compounds in isoprotonated states having the same formula and total charge. Examples of proton transfer tautomers include (but are not limited to) keto-enol pairs, amide-imine pairs, lactam-lactamimide pairs, enamine-imide pairs, and cyclic forms in which the proton may occupy two or more positions in the 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 may be in equilibrium or spatially locked into one form by appropriate substitution. Unless otherwise stated, the compounds disclosed herein identified as a particular tautomer form by name or structure are intended to include other tautomer forms.

The term "compound" in this disclosure is also intended to cover all isotopes of atoms in the compound. An isotope of an atom comprises atoms having the same number of atoms but different mass numbers. For example, unless otherwise stated, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in ^the term "compound" in this disclosure ^means that it also contains isotopes such as (but not limited to): ^¹H , ^²H , ^³H , ^¹¹C , ^¹²C , ^¹³C , ^¹⁴C , ^¹⁴N , ^¹⁵N , ^¹⁶O , ^¹⁷O , ^¹⁸O , ^³¹P , ^³²P , ^³²S , ^³³S , ^³⁴S , ³⁶S, ^¹⁷F , ¹⁹F, ^³⁵Cl , ^³⁷Cl , ^⁷⁹Br , ^⁸¹Br , ^¹²⁷I , and ^¹³¹I . In some embodiments, hydrogen comprises 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 terms "deuterium-substituted" or "deuterium-substituted" refer to other isomorphs (e.g., protium) in which hydrogen in a chemical group is replaced by deuterium. In some embodiments, carbon comprises ^12C and ^13C .

It should also be understood that the “compounds” of this disclosure may exist in both solvated and non-solventized forms (e.g., hydrated or solid forms), and this disclosure is intended to cover all such solvated and non-solventized forms.

It should be further understood that the "compounds" of this disclosure may exist in pharmaceutically acceptable salt forms.

As used herein, the term "pharmaceutically acceptable" means, to the extent of reasonable medical judgment, compounds, materials, compositions, and/or dosage forms suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to 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 approved by regulatory agencies (such as the U.S. Food and Drug Administration, the China National Medical Products Administration (NMPA), 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.

As used herein, "pharmaceutically acceptable salt" refers to a derivative of the compounds disclosed herein, wherein the parent compound is modified by converting an existing acidic moiety (e.g., a carboxyl group, etc.) or a basic moiety (e.g., an amine, alkali metal, etc.) into its salt form. In many cases, the compounds of this disclosure are capable of forming acid and/or basic salts by virtue of the presence of amino and/or carboxyl groups or similar groups. Furthermore, pharmaceutically acceptable salts are acid and/or basic salts that retain the bioavailability and properties of the parent compound and are generally not biologically or otherwise undesirable. Suitable pharmaceutically acceptable salts of the compounds disclosed herein include, for example, acid addition salts 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, benzoic acid, citric acid, lactic acid, phenylacetic acid, benzoic acid, mandelic acid, methanesulfonic acid, naphthalene disulfonic acid, ethanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, salicylic acid, sulfosalicylic acid, etc.).

Suitable pharmaceutically acceptable salts of the compounds disclosed herein also include, for example, base addition salts, which may be derived from, for example, inorganic bases (e.g., sodium, potassium, ammonium, and hydroxide, carbonate, and bicarbonate salts of metals (such as calcium, magnesium, iron, silver, zinc, copper, etc.) in columns I through XII of the periodic table) or organic bases (e.g., primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, etc.). Certain organic amines include (but are not limited to) isopropylamine, benzathine, bile salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and thiamethoxam. Those skilled in the art will understand that, in addition to those shown in the examples, it is also possible to add an acid or base to form the acid/base addition salt. Other suitable salts can be found in, for example, Remington's Pharmaceutical Sciences, 20th edition, Mack Publishing Company, Easton, PA, (1985); and Stahl and Wermuth's Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, Weinheim, Germany, 2002).

We have discovered that the compounds defined in this invention, or pharmaceutically acceptable salts thereof, are potent BTK inhibitors and can be used to produce BTK inhibition in warm-blooded animals requiring such treatment. Therefore, the compounds of this invention are intended for the treatment of diseases or medical conditions mediated solely or in part by BTK.

Therefore, the compounds of the present invention are intended to be suitable for treating immune disorders, cancer, cardiovascular diseases, viral infections, metabolic/endocrine disorders and neurological disorders, allergic diseases, 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.

Due to their BTK inhibitor properties, the compounds of the present invention are expected to possess a broad range of anticancer properties, as BTK-mediated growth has been observed in human cancers (including, but not limited to, B-cell malignancies). Specifically, these compounds of the present invention are expected to be suitable for the treatment of lymphomas and leukemias. More specifically, these compounds 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's lymphoma, primary central nervous system lymphoma, secondary central nervous system lymphoma, or diffuse large B-cell lymphoma. Specifically, the compounds of the present invention are suitable for the treatment of diffuse large B-cell lymphoma, primary central nervous system lymphoma, or secondary central nervous system lymphoma that has metastasized to the brain. Specifically, the compounds of the present invention are suitable for the treatment of chronic lymphocytic leukemia. Specifically, the compounds of the present invention are suitable for second-line treatment of chronic lymphocytic leukemia. Specifically, the compounds of the present invention are suitable for first-line treatment of chronic lymphocytic leukemia. Specifically, the compounds of the present invention are suitable for treating diffuse large B-cell lymphoma. Specifically, the compounds of the present invention are suitable for treating primary central nervous system lymphoma.

In some embodiments, the compounds of this disclosure or pharmaceutically acceptable salts thereof have anticancer activity in early-stage, actively 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.

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

In one embodiment of the invention that refers to BTK inhibition, this refers to wild-type BTK.

In one embodiment of the invention that refers to BTK inhibition, this refers to BTK with the C481 mutation.

In one embodiment of the invention that refers to BTK inhibition, this refers to BTK with the C481S mutation.

In one embodiment of the invention that refers to BTK inhibition, this refers to BTK with the C481Y mutation.

In one embodiment of the invention that refers to BTK inhibition, this refers to BTK with the C481R mutation.

In one embodiment of the invention that refers to BTK inhibition, this refers to BTK with the C481F mutation.

Drug composition, dosage and administration

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

Generally, pharmaceutically acceptable carriers are conventional pharmaceutical carriers in the field and can be prepared in a manner well known in the pharmaceutical field. In some embodiments, the compounds of this disclosure or their pharmaceutically acceptable salts can be mixed with a pharmaceutically acceptable carrier to prepare a pharmaceutical composition.

The form of a pharmaceutical composition depends on a variety of criteria, including (but not limited to) route of administration, disease severity, or dosage to be administered. Pharmaceutical compositions can be formulated for oral, nasal, rectal, transdermal, intravenous, or intramuscular administration. Depending on the desired route of administration, pharmaceutical compositions can be formulated as tablets, capsules, pills, powders, granules, capsules, lozenges, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), sprays, ointments, pastes, creams, lotions, gels, patches, inhalers, or suppositories.

In some embodiments, the pharmaceutical composition comprises from about 1 mg to about 500 mg of the disclosed compound or a pharmaceutically acceptable salt thereof, specifically from 1 mg to about 200 mg. The pharmaceutical composition may also be administered once, twice, three times, 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. Therefore, the optimal dose can be determined by the physician treating any particular patient.

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

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

In another aspect of the invention, a pharmaceutical composition is provided 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 inhibition in warm-blooded animals such as humans.

In another aspect of the invention, a pharmaceutical composition is provided comprising a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier, for producing an anticancer effect in warm-blooded animals such as humans.

In another aspect of the invention, a pharmaceutical composition is provided 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's lymphoma, primary central nervous system lymphoma, secondary central nervous system lymphoma, or diffuse large B-cell lymphoma in warm-blooded animals such as humans.

In another aspect of the invention, a pharmaceutical composition is provided 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.

combination

In some embodiments, the pharmaceutical composition comprises one or more compounds disclosed herein or pharmaceutically acceptable salts thereof as a first active ingredient, and further comprises a second active ingredient. The second active ingredient may be any antitumor agent known in the art, such as PI3K inhibitors, anti-CD20 antibodies, anti-PD-1/L1 antibodies, and other approved pharmaceuticals or combinations thereof for non-Hodgkin's lymphoma. Representative examples of antitumor agents with a second active ingredient include (but are not limited to) idelalisib, duvelisib, obinutuzumab, ofatumumab, rituximab, alemtuzumab, bleomycin, brentuximab, vedotin, carmustine, cyclophosphamide, chlorambucil, dacarbazine, and dexamethasone. Xamethasone, doxorubicin, lomustine, mechlorethamine, procarbazine, prednisone, bendamustine, venetoclax, prednisone, CVP (a combination of C-chemotherapeutic drugs cyclophosphamide, V-chemotherapeutic drugs vincristine and P-steroid prednisolone), midostaurin, and vinblastine.

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

Therefore, in another aspect of this disclosure, a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof is provided, as well as an antitumor agent selected from the antitumor agents listed above herein.

Therefore, in another aspect of this disclosure, a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and an antitumor agent selected from the antitumor agents listed above herein are provided for producing an anticancer effect.

Therefore, in another aspect of this disclosure, a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and an antitumor agent selected from the antitumor agents listed above, are provided for the treatment of small lymphocytic lymphoma (SLL), follicular lymphoma, Richter's transformation, mantle cell lymphoma, chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia, non-Hodgkin's lymphoma, primary central nervous system lymphoma, secondary central nervous system lymphoma, or diffuse large B-cell lymphoma.

Therefore, in another aspect of this disclosure, a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and an antitumor agent selected from the antitumor agents listed above herein, are provided 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.

According to this aspect of the disclosure, a combination suitable for treating cancer is provided, comprising a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and any one of the antitumor agents listed above.

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

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

According to another aspect of this disclosure, a pharmaceutical composition is provided comprising a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, an antitumor agent selected from the antitumor agents listed above herein, and a pharmaceutically acceptable diluent or carrier for the treatment of small lymphocytic lymphoma (SLL), follicular lymphoma, Richter's transformation, mantle cell lymphoma, chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia, non-Hodgkin's lymphoma, primary central nervous system lymphoma, secondary central nervous system lymphoma, or diffuse large B-cell lymphoma.

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

According to another aspect of this disclosure, a kit is provided comprising a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and an antitumor agent selected from the antitumor agents listed above herein.

According to another aspect of this disclosure, a kit is provided, comprising:

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

b) Antitumor agents selected from the antitumor agents listed above in this article; which are in the form of a second unit; and

c) A container device for containing the first and second dosage forms.

Pharmacological tools

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

Treatment

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

According to another feature of this aspect of the invention, a method for producing BTK inhibition in a warm-blooded animal such as a human is provided, comprising administering to said animal an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

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

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

According to an additional feature of this aspect of the invention, a method is provided for 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.

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

This disclosure also provides a method for screening patients suitable for treatment with compounds of formula (I) as defined herein or pharmaceutically acceptable salts thereof. The method includes sequencing a tumor sample from the patient and detecting BTK accumulation or the presence of BTK mutations.

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

Uses of compounds

In some embodiments, this disclosure provides for the use of the compounds of this disclosure, their pharmaceutically acceptable salts, or pharmaceutical compositions for the manufacture of medicaments for the treatment of BTK-mediated or dependent diseases or conditions.

Therefore, according to this aspect of the invention, a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof is provided for use as a medicine.

Therefore, according to this aspect of the invention, the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof is provided as a medicine.

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

According to another aspect of the invention, the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for producing BTK inhibition in warm-blooded animals such as humans.

According to this aspect of the invention, the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for producing an anticancer effect in warm-blooded animals such as humans.

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

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

According to another aspect of the invention, the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof is provided for producing BTK inhibition in warm-blooded animals such as humans.

According to this aspect of the invention, the use of compounds of formula (I) as defined herein or pharmaceutically acceptable salts thereof is provided for producing anticancer effects in warm-blooded animals such as humans.

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

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

The alternative and preferred embodiments of the compounds disclosed herein described herein also apply to the pharmaceutical compositions, methods, uses and pharmaceutical manufacturing characteristics described above.

Example

General Experiment

abbreviation

The synthetic procedures described herein illustrate the synthesis of the compounds (including their pharmaceutically acceptable salts). The compounds provided herein can be prepared using any known organic synthetic technique and can be synthesized according to any of a variety of possible synthetic routes; therefore, these procedures are merely illustrative and not intended to limit other possible methods that can be used to prepare the compounds provided herein. Furthermore, the steps in the methods are for better illustration and may be changed where appropriate. Examples of synthesizing the compounds in the examples are provided for research purposes and possibly for submission to regulatory authorities.

The reactions used to prepare the compounds disclosed herein can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents are substantially non-reactive to the starting materials (reactants), intermediates, or products at the temperature at which the reaction takes place, 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 that specific reaction step can be selected by those skilled in the art.

The preparation of the compounds disclosed herein 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 properties of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

The reaction can be monitored using any suitable method known in the art. For example, product formation can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., ^1H or ^13C ), infrared spectroscopy, spectrophotometry (e.g., UV-Vis), mass spectrometry, or by chromatographic methods such as high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin-layer chromatography (TLC). Those skilled in the art can purify compounds using 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.

The structures of the compounds in the examples were characterized by nuclear magnetic resonance (NMR) and/or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in units of ^10⁻⁶ (ppm). ¹H-NMR spectra were recorded on a Bruker AVANCE NMR (400 MHz) spectrometer using ICON-NMR (under TopSpin program control) or on a Varian 400MR NMR or Varian VNMR400 NMR (400 MHz) spectrometer (under VnmrJ program control) using ^{tetramethylsilane} as an internal standard in dimethyl sulfoxide- _d₆ (DMSO- _d₆₆ ), _CD₃ , _CD₃OD , _D₂O , acetone- _d₆ , or _CD₃CN (from Aldrich or Cambridge Isotope Lab., Inc.).

MS measurements were performed using a Shimadzu 2010 mass spectrometer, an Agilent 6110AMSD, or a 1969ATOF mass spectrometer, employing electrospray, chemical, and electron collision ionization methods via a series of instruments. The detailed methods used in this invention include:

LC-MS Method A: 10-80AB_7min_220&254_Shimadzu.lcm

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

Column: Ultimate C18 2.1*30mm, 3μm;

Wavelength: UV 220nm, 254nm;

Column temperature: 50℃;

MS ionization: ESI

LC-MS Method B: 10-80AB_4min_220&254_Shimadzu.lcm

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

Column: Ultimate C18 2.1*30mm, 3μm;

Wavelength: UV 220nm, 254nm;

Column temperature: 50℃;

MS ionization: ESI

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

Mobile phase: 0.2 mL/1 L NH3 _{· H2O} /water (solvent A) and acetonitrile (solvent B), eluted with a gradient of 10%-80% (solvent B) for 6 minutes and maintained at 80% for 0.5 minutes at a flow rate of 0.8 mL/min;

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

Wavelengths: UV 220nm and 254nm;

Column temperature: 30℃;

MS ionization: ESI

High-performance liquid chromatography (HPLC) measurements were performed on a Shimadzu LC-20A system, a Shimadzu LC-2010HT series system, an Agilent 1200LC system, or an Agilent 1100 series system using an Ultimate XB-C18 column (3.0*50mm, 3μm or 3.0*150mm, 3μm), an Xbridge shield RP18 column (5μm, 50mm*2.1mm), an Ultimate C18 column (3μm, 2.1*30mm), or a MERCK RP18 2.5-2mm column, etc. The detailed method used in this invention includes:

HPLC method A: 10-80AB_8min.met

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 for 6 minutes and maintained at 80% for 2 minutes at a flow rate of 1.2 mL/min;

Column: Ultimate C18 3.0*50mm, 3μm

Wavelengths: UV 220nm, 215nm, 254nm;

Column temperature: 40℃;

HPLC Method B: 10-80 CD_8 min.met

Mobile phase: 2.0 mL/4 L _NH3H2O /water (solvent A) and acetonitrile (solvent B), eluted with a gradient _of 10%-80% (solvent B) for 4 minutes and maintained at 80% for 2 minutes at a flow rate of 1.2 mL/min;

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

Wavelengths: UV 220nm, 215nm, 254nm;

Column temperature: 40℃;

Supercritical fluid chromatography (SFC) measurements were performed on Agilent 1260 series, Waters UPCC series, or Shimadzu LC-20AB series columns using ChiralPak AD-3 columns (3μm, 150×4.6mm), Chiralcel OJ-3 columns (3μm, 150×4.6mm), or Chiralpak IG-3 columns (3μm, 50mm*4.6mm). The detailed method used in this invention includes:

SFC Method A: Mobile phase: A: _CO2 , B: ethanol (0.05% DEA), gradient: 5% to 40% B over 5.5 min and maintain 40% for 3 min, followed by 5% B for 1.5 min, flow rate: 2.5 mL/min;

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

Column temperature: 40℃;

Back pressure: 100 bar.

SFC Method B: Mobile phase: A: _CO2 , B: methanol (0.05% DEA), gradient: 5% to 40% B over 5 min and 40% to 5% B over 0.5 min, maintaining 5% B for 1.5 min, flow rate: 2.5 mL/min

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

Column temperature: 35℃;

ABPR: 1500psi.

SFC Method C: Mobile phase: A: _CO2 , B: methanol (0.05% DEA), isocratic ratio: 40% B, flow rate: 4 mL/min;

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

Column temperature: 35℃;

ABPR: 1500psi.

Thin-layer chromatography (TLC) was performed using Yantai Huanghai HSGF254 silica gel or Anhui Liang Chen Gui Yuan plates. The silica gel plates used for TLC were 0.15 mm to 0.2 mm. The silica gel plates used for product separation and purification by TLC were 0.4 mm to 0.5 mm.

Purification chromatographic columns used silica gel as the support (100–200, 200–300, or 300–400 mesh, manufactured by Yantai Huanghai Co., Ltd. or Anhui Liang Chen Gui Yuan Co., Ltd., etc.), or fast columns (silica-CS fast columns 40–60 μm, or reversed-phase C18 columns 20–35 μm, manufactured by Agera Technologies, etc.), or Agera Technologies' fast columns (silica-CS, 40–60 μm) or C18 columns (20–40 μm) in Teledyne ISCO combi-flash or Biotage fast systems. The column size was adjusted according to the amount of compound.

The known starting materials disclosed herein can be synthesized using or according to methods known in the art, or are available from Alfa Aesar, TCI, Aldrich, Bepharm, and Scochem (or PharmaBlock, Bide, Amatek, StruChem, Firster Pharmaceutical, Titan, Adamas, etc.).

Unless otherwise stated, 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 stated, the reaction temperatures in the examples are ambient temperatures, which are 10°C to 30°C.

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

The elution systems for column chromatography and TLC used to purify compounds include dichloromethane-methanol systems and petroleum ether-ethyl acetate systems. The volume ratio of the solvent is adjusted according to the different polarities of the compound. Small amounts of basic or acidic reagents (0.1%–1%), such as formic acid, acetic acid, TFA, or ammonia, can be added for adjustment.

The compounds of the present invention

Table 1: Compound synthesis method of the present invention

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

Method A

Method B

Method A

Compound 2A: ethyl 5-(((3-chloropyrazin-2-yl)methyl)carbamoyl)tetrahydro-2H-pyran-2-carboxylate

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

LCMS: tR = 0.689 min in 5-95AB_1.5min_220&254_Shimadzu.lcm chromatogram (Agilent Pursult 5C1820*2.0mm), MS (ESI) m/z = 328.2 [M+H] ⁺

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

_POCl₃ (21.05 g, 137.30 mmol) was added to a mixture of compound 2A (9.0 g, 27.46 mmol) and DMF (600 μL) in MeCN (150 mL). The mixture was stirred at 70 °C for 1 hour. The reaction mixture was concentrated and washed with water (50 mL) and saturated _NaHCO₃ (50 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (52–62% ethyl acetate/petroleum ether) to give compound 3A (3.5 g, 41.2% yield) as a yellow oil.

LCMS: t _R = in 5-95AB_1.5min_220&254_Shimadzu.lcm chromatography (Agilent Pursult 5C18)

In 20*2.0mm), the value is 0.742 min, and the MS(ESI) m/z = 310.2 [M+H] ⁺

^1H NMR (400MHz, CDCl3 ₎ ): δ＝7.80(d,J＝0.4Hz,1H),7.70-7.64(m,1H),7.37(d,J＝4.8Hz,0.3H),7.35(d ,J＝4.8Hz,0.7H),4.44(t,J＝4.4Hz,0.7H),4.30-4.25(m,2H),4.23-4.14(m,1H ),4.00(dd,J＝3.2,12.0Hz,1H),3.79(t,J＝11.2Hz,0.4H),3.42-3.19(m,1H),2 .47-2.37(m,0.8H),2.29-2.06(m,3H),1.91-1.77(m,0.4H),1.35-1.31(m,3H).

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

At 0 °C, a mixture of _LiAlH₄⁻ (860 mg, 22.60 mmol) and THF (20 mL) containing compound 3A (3.5 g, 11.30 mmol) was added to THF (20 mL). The mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched with water (860 μL), 15% NaOH (860 μL), and water (2580 μL). The mixture was dried over anhydrous sodium sulfate and stirred at room temperature for 0.5 hours, filtered, and concentrated to give compound 4A (2.7 g, 89.4% yield) as a yellow solid.

LCMS: t _R = in 5-95AB_1.5min_220&254_Shimadzu.lcm chromatography (Agilent Pursult 5C18)

In 20*2.0mm), the value is 0.635 min, and the MS(ESI) m/z = 267.8 [M+H] ⁺

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

NBS (2.34 g, 13.14 mmol) was added to a mixture of compound 4A (2.7 g, 10.11 mmol) and MeCN (100 mL). 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 (2.5 g, 71.63% yield) as a yellow solid.

LCMS: t _R = in 5-95AB_1.5min_220&254_Shimadzu.lcm chromatography (Agilent Pursult 5C18)

In 20*2.0mm), the value is 0.717 min, and the MS(ESI) m/z = 347.8 [M+H] ⁺

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

_NH₃ · _H₂O (15 mL) was added to a mixture of compound 5A (2.5 g, 7.21 mmol) and IPA (15 mL). The mixture was stirred at 100 °C for 12 hours in a 100 mL sealed test tube. The reaction mixture was concentrated to give compound 6A (2.4 g, 98.0% purity), which was a yellow oil.

LCMS: t _R = 10-80AB_3min_220&254_Shimadzu.lcm chromatography (Xtimate C18 2.1*30mm)

The mean value was 0.436 min, and the MS(ESI) m/z = 327.1 [M+H] ⁺

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

Under nitrogen atmosphere, Pd(dppf)Cl₂.CH₂Cl₂ (32 mg, 0.04 mmol) and K₂CO₃ (375 mg, 2.62 mmol) were added to a mixture of compound 6A (500 mg, 1.31 mmol, 97.99% purity) and ( ₄₅₀ mg, _1.95 mmol) boric acid in _{1,4 - dioxane} (15 mL)/ _H₂O (5 mL). The mixture was stirred under nitrogen atmosphere at 100 °C for 12 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL x 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 (a mixture of cis/trans racemic compounds) as a yellow solid (150 mg, yield 26.4%).

LCMS: t _R = in 5-95AB_1.5min_220&254_Shimadzu.lcm chromatography (Agilent Pursult 5C18)

In 20*2.0mm), the value is 0.723 min, and the MS(ESI) m/z = 435.1 [M+H] ⁺

2-Fluoro-4-phenoxyphenyl)boronic acid:

Compound 1a (10 g, 52.35 mmol) was added to a mixture _{of CH₂Cl₂} (480 mL), PhB(OH) _₂ (12.8 g, 104.71 mmol), Cu(OAc) _₂ (9.5 g, 52.35 mmol), NEt₃ ( ₂₁ mL, 151.05 mmol), and Ms (5 g) at room temperature (25–30 °C). The mixture was stirred in air at room temperature (25–30 °C) for 16 hours. The mixture was filtered through a diatomaceous earth mat. The filtrate was concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography (petroleum ether) to obtain compound 2a (11.3 g, 80.8% yield) as a colorless oil.

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

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). 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 x 3), and washed with brine (100 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was ground with petroleum ether (100 mL), filtered, and the filter cake was concentrated to give 2-fluoro-4-phenoxyphenyl)boronic acid (4.3 g) as a yellow oil. The filtrate was concentrated and purified by silica gel column chromatography (0–20% ethyl acetate/petroleum ether) to give 2-fluoro-4-phenoxyphenyl)boronic acid (3 g) as a yellow oil.

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

Trans isomer 1, Compound 2: trans-(5-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazol[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol

Trans isomer 2, compound 3: trans-(5-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazol[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol

Mixture 7A (150 mg, 0.35 mmol) was purified by passing it through a chiral SFC (column: DAICEL CHIRALPAK AD-H) (250 mm * 30 mm, 10 μm) under the conditions of 0.1% NH3 _{· H2O} /EtOH, 40%, flow rate 80 mL/min. The fraction containing the desired compounds was concentrated, diluted with _H2O (10 mL) and _CH3CN (10 mL), and lyophilized to give compound 2 (34.8 mg, 23.2% yield) and compound 3 (29.4 mg, 19.6%) as white solids. Neither cis enantiomer was collected.

Spectrum of compound 2:

LCMS t _R = in 10-80AB_7min_220&254_Shimadzu.lcm chromatography (Xtimate C18 2.1*30mm)

It is 2.037min, MS (ESI) m/z=435.3[M+H] ⁺ .

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

SFC t _R = 6.119 min, optical purity: 96.3%. Method notes: Column: ChiralPak AD-3 150×4.6mm ID, 3μm, mobile phase: A: _CO2 , B: ethanol (0.05% DEA), gradient: 5% to 40% B over 5.5 min and hold at 40% for 3 min, followed by 5% B for 1.5 min, flow rate: 2.5 mL/min, column temperature: 40℃, back pressure: 100 bar.

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

^19F NMR (CD ₃ OD)δ＝-112.240

Spectrum of compound 3:

LCMS t _R = in 10-80AB_7min_220&254_Shimadzu.lcm chromatography (Xtimate C18 2.1*30mm)

The value is 2.030 min, and the MS(ESI) m/z = 435.3 [M+H] ⁺ .

HPLC t _R = 3.02 min in 10-80AB_8min.met (HPLC-BJ Ultimate 3.0*50mm 3μm).

SFC t _R = 7.334, optical purity: 92.7%. Method notes: Column: ChiralPak AD-3 150×4.6mm I.D., 3μm, mobile phase: A: _CO2 , B: ethanol (0.05% DEA), gradient: 5% to 40% B over 5.5 min and hold at 40% for 3 min, followed by 5% B for 1.5 min, flow rate: 2.5 mL/min, column temperature: 40℃, back pressure: 100 bar.

¹ H NMR (400MHz, CD ₃ OD)δ=7.65(d,J=5.2Hz,1H),7.52-7.37(m,3H),7.29-7.21(m,1H),7.2 0-7.11(m,2H),7.04(d,J＝4.8Hz,1H),6.99-6.84(m,2H),4.24-4.13(m, 1H),3.77(t,J＝11.2Hz,1H),3.62-3.51(m,3H),3.48-3.77(m,1H),2.31 -2.17(m,1H),2.15-2.01(m,1H),1.91-1.74(m,1H),1.69-1.51(m,1H).

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

Synthesize the following compounds according to method A:

Method B

Compound 2B: ethyl 5-(((3-amino-5-hydroxy-1,2,4-triazine-6-yl)methyl)carbamoyl)tetrahydro-2H-pyran-2-carboxylate

Compound 1B (13 g, 60.88 mmol) and triethylamine (25 mL, 182.6 mmol) were added to a mixture of 5-(2,5-dioxopyrrolidone-1-yl)-2-ethyltetrahydro-2H-pyran-2,5-dicarboxylate (20 g crude product, 60.88 mmol) and acetonitrile (30 mL). The mixture was stirred at 50 °C for 16 hours. The mixture was concentrated to give compound 2B (35 g crude product) as a brown solid.

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

The time was 0.582 min, and the MS(ESI) m/z = 325.9 [M+H] ⁺

5-(2,5-dioxopyrrolidone-1-yl)2-ethyltetrahydro-2H-pyran-2,5-dicarboxylate:

Add 1-hydroxypyrrolidine-2,5-dione (877 mg, 7.61 mmol) and EDCI (1.6 g, 8.30 mmol) to a solution of _6- (ethoxycarbonyl)tetrahydro-2H-pyran- ₃ -carboxylic acid (1.4 g, 6.92 mmol) in CH₂Cl₂ (30 mL). Stir the mixture at 22–26 °C for 1.5 h. Dilute the mixture with dichloromethane (30 mL) and wash with brine (50 mL × 3). Dry the organic layer with anhydrous sodium sulfate, filter, and concentrate to obtain 5-(2,5-dioxopyrrolidine-1-yl)2-ethyltetrahydro-2H-pyran-2,5-dicarboxylic acid ester as a colorless oil for direct use.

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

Phosphorus oxychloride (23 mL, 243.52 mmol) was added to a solution of compound 2B (35 g crude product, 60.88 mmol) in acetonitrile (300 mL). The mixture was then stirred at 70 °C for 16 hours. The mixture was concentrated, and the residue was diluted with dichloromethane (150 mL), poured into a cooled saturated sodium bicarbonate solution (300 mL) to pH 8, and extracted with dichloromethane/methanol (10:1, 200 mL x 4), followed by extraction with IPA/ _CHCl3 (150 mL x 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.

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

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

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

NBS (11.8 g, 66.96 mmol) was added to a solution of compound 3B (45 g crude product, 60.88 mmol) in N,N-dimethylformamide (200 mL). 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 x 4), and washed with brine (500 mL x 4). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 4B (19 g crude product) as a black oil.

LCMS: t _R = 5-95AB_1min_220&254_Agilent chromatography (Agilent Poroshell 120EC-C18)

The value in 2.7μm (3.0*30mm) is 0.602 min, and the MS (ESI) m/z = 388.0 [M+H+2] ⁺ (bromine isotope).

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

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

LCMS: t _R = in 5-95AB_1.5min_220&254_Shimadzu.lcm chromatography (Agilent Pursult 5C18)

In 20*2.0mm), the value is 0.753 min, and the MS(ESI) m/z = 370.9 [M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD): δ=7.74(s,0.3H),7.72(s,0.5H),4.37(t,J=4.8Hz,0.7H),4.29-4.16(m,3H),4.12(dd,J=11.6,2.0Hz,0.3H),3 .92(dd,J＝11.6,4.0Hz,0.7H),3.70(t,J＝11.2Hz,0.4H),3.57-3.45(m,1H),2.35-1.92(m,4H),,1.33-1.27(m,3H).

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

At a temperature below 10°C, _POCl₃ (12.5 mL, 134.7 mol) was added to a solution of 1,2,4-triazole (28 g, 404.1 mmol) in acetonitrile (200 mL), followed by the addition of trimethylamine (56 mL, 404.1 mmol). The mixture was stirred at 10°C for 20 min, compound 5B (5 g, 13.47 mmol) was added, and the reaction mixture was stirred at 90°C for 1.5 h. The mixture was cooled to 10°C, ammonia (30 mL, 28%) was added, and the temperature was maintained below 20°C while stirring at 10°C for 0.5 h. Another batch of the same scale was then prepared. The mixture was combined and diluted with water (200 mL) and extracted with ethyl acetate (500 mL * 3), washed with brine (500 mL * 3), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The mixture was purified by silica gel column chromatography (2-4% methanol/dichloromethane) to give compound 6B (9 g, 90% yield) as a yellow solid.

LCMS: t _R = 0.614 min in \5-95AB_1min_220&254_Agilent chromatogram (Agilent Poroshell 120EC-C182.7μm 3.0*30mm), MS(ESI) m/z = 372.0 [M+H+2] ⁺ (bromide isotope).

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

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

_LiAlH₄ (1.20 g, 32.95 mmol) was added to a solution of compound 6B (6.1 g, 16.48 mmol) cooled at 0–5 °C in 120 mL of tetrahydrofuran, while 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 Na₂SO₄} · _10H₂O was added to the mixture, and the mixture was stirred for 2 h and filtered. The filter cake was resuspended twice with dichloromethane/methanol (100 mL of a 10:1 mixture) and filtered. The combined filtrates were concentrated under vacuum, and the residue was purified by silica column chromatography (0–10% methanol/dichloromethane) to give compound 7B (3.9 g, 72% yield) as a white solid and 0.6 g of the debromination byproduct as a yellow solid.

LCMS:t _R = in \0-60AB_7min_220&254_Shimadzu.lcm chromatography (Xtimate C18 2.1*30mm,

The values in 3μm were 1.958 and 2.016 min, and the MS(ESI) m/z = 328.1 [M+H] ⁺ .

¹ H NMR (400MHz, methanol-d ₄ ): δ＝7.80(s,0.3H),7.78(s,0.6H),4.47(dt,J＝10.0,2.0Hz,0.6H),4.20-4.13(m,0.3H),3.84(dd,J＝11.6,3.2Hz,0.6H),3.64(t,J＝1 0.8Hz,0.4H),3.60-3.38(m,4H),2.45-2.36(m,0.6H),2.22-2.13(m,0.3H),2.09-1.96(m,1H),1.93-1.73(m,1H),1.62-1.45(m,1H).

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

Compound 7B (106 mg, 0.457 mmol), Pd(dppf) _Cl₂ · _CH₂Cl₂ (25 mg, 0.0304 mmol) _, and potassium carbonate (84 mg, 0.608 mmol) were placed in a reaction tube and purged three times with nitrogen. Then, 1,4-dioxane (3 mL) containing (2-fluoro-4-phenoxyphenyl)boronic acid (100 mg, 0.304 mmol) and water (1 mL) were added. The resulting mixture was stirred at 100 °C under nitrogen for 2 hours. The mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography (0–100% ethyl acetate/petroleum ether) to give compound 8B (80 mg impure, a mixture of trans/cis racemic mixtures) as a yellow oil.

LCMS: t _R = 10-80AB_7min_220&254_Shimadzu.lcm chromatography (Xtimate C18 2.1*30mm)

The mean values are 2.274 min & 2.340 min, and the MS(ESI) m/z = 436.2 [M+H] ⁺ .

SFC: t _R = 4.171 min, 4.286 min, 4.454 min, and 5.581 min. Method: Column: Chiralcel OJ-3

150×4.6mm ID, 3μm Mobile phase: A: _CO2 , B: methanol, gradient: 5% to 40% B over 5 min and 40% to 5% B over 0.5 min, holding 5% B for 1.5 min, flow rate: 2.5 mL/min, column temperature: 35℃, ABPR: 1500 psi.

cis isomer 1, compound 8: cis-(5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol

cis isomer 2, compound 9: cis-(5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol

Trans isomer 1, compound 10: trans-(5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol

Trans isomer 2, compound 11: trans-(5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol

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% _{NH3 H2O} )/ _CO2 ; flow rate: 60 mL/min) to give 6.8 mg of impure compound 11, which was further purified by preparative HPLC (column: Welch Xtimate C18 100 * 40 mm * 3 μm; conditions: 25-55% (A: water (0.225% FA), B: _CH3 CN), flow rate: 25 mL/min) to give compound 11 as a white solid (1.7 mg, yield of 1% in both steps). Following the SFC, the mixture of the other three peaks (40 mg) was further purified by a chiral SFC (column: DAICL CHIRALPAK IG (250 mm * 30 mm, 10 μm); conditions: 55% MeOH (0.1% _{NH3 H2O} )/ _CO2 ; flow rate: 80 mL/min) to give compound 8 (8.6 mg, 6.4% yield in two steps), compound 9 (6.7 mg, 5% yield in two steps), and compound 10 (5.4 mg, 4% yield in two steps) as white solids.

Spectrum of compound 8:

LCMS: t _R = 10-80AB_7min_220&254_Shimadzu.lcm chromatography (Xtimate C18 2.1*30mm)

The mean value is 2.356 min, and the MS(ESI) m/z = 436.2 [M+H] ⁺ .

HPLC: t _R = 3.00 min in 10-80 CD_8 min.met. chromatography (XBridge Shield RP 18 2.1*50 mm 5 μm).

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

SFC: t _R = 4.059 min, optical purity 99.94%.

Methods: Column: Chiralcel OJ-3 150×4.6mm ID, 3μm; Mobile phase: A: _CO2 , B: methanol (0.05% DEA); Gradient: 5% to 40% B over 5 min and 40% to 5% B over 0.5 min, followed by holding 5% B for 1.5 min; Flow rate: 2.5 mL/min; Column temperature: 35℃; ABPR: 1500 psi.

Spectrum of compound 9:

LCMS: t _R = 10-80AB_7min_220&254_Shimadzu.lcm chromatography (Xtimate C18 2.1*30mm)

The mean value was 2.340 min, and the MS(ESI) m/z = 436.3 [M+H]+.

HPLC: t _R = 2.99 min in 10-80 CD_8 min.met. chromatography (XBridge Shield RP 18 2.1*50 mm 5 μm).

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

SFC: t _R = 4.161 min, optical purity 100%.

Methods: Column: Chiralcel OJ-3 150×4.6mm ID, 3μm; Mobile phase: A: _CO2 , B: methanol (0.05% DEA); Gradient: 5% to 40% B over 5 min and 40% to 5% B over 0.5 min, followed by holding 5% B for 1.5 min; Flow rate: 2.5 mL/min; Column temperature: 35℃; ABPR: 1500 psi.

Spectrum of compound 10:

LCMS: t _R = 10-80AB_7min_220&254_Shimadzu.lcm chromatography (Xtimate C18 2.1*30mm)

The mean value is 2.410 min, and the MS(ESI) m/z = 436.3 [M+H] ⁺ .

HPLC: t _R = 2.98 min in 10-80 CD_8 min.met. chromatography (XBridge Shield RP 18 2.1*50 mm 5 μm).

¹ H NMR (400MHz, CD ₃ OD): δ=7.86(s,1H),7.50(t,J=8.4Hz,1H),7.47-7.41(m,2H),7.26-7.20( m,1H),7.17-7.12(m,2H),6.94(dd,J＝8.4,2.4Hz,1H),6.88(dd,J＝10.8,2 .4Hz,1H),4.24-4.18(m,1H),3.75(t,J＝11.2Hz,1H),3.68-3.48(m,4H),2 .27-2.19(m,1H),2.16-2.04(m,1H),1.84-1.76(m,1H),1.59-1.47(m,1H).

SFC: t _R = 4.405 min, optical purity 99.83%.

Methods: Column: Chiralcel OJ-3 150×4.6mm ID, 3μm; Mobile phase: A: _CO2 , B: methanol (0.05% DEA); Gradient: 5% to 40% B over 5 min and 40% to 5% B over 0.5 min, followed by holding 5% B for 1.5 min; Flow rate: 2.5 mL/min; Column temperature: 35℃; ABPR: 1500 psi.

Spectrum of compound 11:

LCMS: t _R = 10-80AB_7min_220&254_Shimadzu.lcm chromatography (Xtimate C18 2.1*30mm)

The mean value is 2.365 min, and the MS(ESI) m/z = 436.2 [M+H] ⁺ .

HPLC: t _R = 3.05 min in 10-80 CD_8 min.met. chromatography (XBridge Shield RP 18 2.1*50 mm 5 μm).

¹ H NMR (400MHz, CD ₃ OD): δ=7.86(s,1H),7.50(t,J=8.4Hz,1H),7.47-7.41(m,2H),7.26-7.21( m,1H),7.17-7.12(m,2H),6.94(dd,J＝8.4,2.4Hz,1H),6.88(dd,J＝10.8,2 .4Hz,1H),4.24-4.18(m,1H),3.75(t,J＝10.8Hz,1H),3.68-3.47(m,4H),2 .26-2.18(m,1H),2.16-2.04(m,1H),1.84-1.76(m,1H),1.59-1.47(m,1H).

SFC: t _R = 5.802 min, optical purity 100%.

Methods: Column: Chiralcel OJ-3 150×4.6mm ID, 3μm; Mobile phase: A: _CO2 , B: methanol (0.05% DEA); Gradient: 5% to 40% B over 5 min and 40% to 5% B over 0.5 min, followed by holding 5% B for 1.5 min; Flow rate: 2.5 mL/min; Column temperature: 35℃; ABPR: 1500 psi.

Synthesize the following compounds according to method B:

biological data

BTK WT and BTK C481S HTRF kinase analysis

Recombinant BTK wild-type (BTK WT) was purchased from Thermo Fisher Scientific. Recombinant BTK (C481S) was purchased from SignalChem. The inhibitory efficacy of the compounds against BTK and BTK (C481S) was evaluated using a homogeneous time-resolved fluorescence approach.

In brief, the recombinant kinase was pre-incubated for 30 minutes at room temperature, with or without the compound. The reaction was initiated by adding ATP and a substrate peptide, in which the substrate peptide is 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 at 665 nm/615 nm was 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 utilizing XL-fit.

TMD8 cell line p-BTK ELISA analysis

TMD-8 cells were seeded at a density of 30,000 cells/well in 96-well plates containing RPMI 1640 medium with 1.5% fetal bovine serum. The test compound was added to the cells, and the cells were incubated at 37°C and 5% _CO2 for 0.5 h. Pervanadate solution was then added to the cells to bring the final concentration to 100 μM, and the cells were incubated at 37°C and 5% _CO2 for another 1 h. After compound treatment, the cells were lysed, and the p-BTK signal was detected according to the procedure precisely following the Phospho-BTK (Tyr223) sandwich ELISA kit (#23843). The plates were read on a Multiscan spectrometer set to 450 nm. These data were processed in GraphPad Prism software.

Compound numbering <![CDATA[p-BTK IC₅₀(nM)]]> Maximum inhibition level (%) Irutinib 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

HEK293-BTK(WT) and HEK293-BTK(C481S)

Full-length cDNA containing the C481S mutation of BTK was generated by mutation induction using the QuikChange II XL site-directed mutagenesis kit. The mutated BTK cDNA was confirmed by sequencing. The BTK(WT) and BTK-C481S cDNAs were then cloned into the PLVX-Puro lentiviral vector. Lentiviral viruses were encapsulated in 293T cells using a lentiviral vector transfection and encapsulation mixture. The BTK(WT) and BTK-C481S lentiviruses were transfected into HEK293 cells. Transfected cells were selected using 2 μg/mL puromycin. Stable polyclonal cell lines were confirmed by Western blotting and used for further studies. 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 kept in a humid incubator at 37°C with 5% _CO2 .

HEK293-BTK(WT) and HEK293-BTK(C481S) cells were seeded at a density of 5000 cells/well in 96-well plates containing RPMI 1640 medium with 1.5% fetal bovine serum. The test compound was added to the cells, and the cells were incubated at 37°C and 5% _CO2 for 1.5 h. After compound treatment, the cells were lysed, and the p-BTK signal was detected according to the procedure precisely followed by the Phospho-BTK(Tyr223) sandwich ELISA kit (#23843). The plates were read on a Multiscan spectrometer set to 450 nm. Data were processed in GraphPad Prism software.

Compound numbering <![CDATA[HEK293 WT IC₅₀(nM)]]> <![CDATA[HEK293 C481S IC₅₀(nM)]]> Irutinib 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

TMD-8 Antiproliferative Analysis

TMD-8 cells were prepared in RPMI 1640 medium containing 10% fetal bovine serum and seeded at 1500 cells per well in 384-well plates. Cells were incubated overnight at 37°C and 5% _CO2 . After incubation, different concentrations of the compound were added to the analysis plates, and the cells were incubated for an additional 72 hours at 37°C and 5% _CO2 . After 72 hours of incubation, 15 μL of CellTiter AQueous single-solution reagent was added to each well, and the plate was incubated at room temperature for 30 min. Cell viability was determined using CellTiter-Glo (Promega, USA). CellTiter-Glo analysis was performed according to the manufacturer's instructions, and fluorescence was measured using a multi-tag reader (Envision, PerkinElmer, USA). Data were processed in XLfit software.

In vitro rat/human hepatocyte clearance rate analysis

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

Remove the vials of cryopreserved hepatocytes from storage, ensuring the vials remain at a low temperature. Thaw the vials in a 37°C water bath with gentle agitation. Keep the vials in the water bath until all ice crystals have dissolved and are no longer visible. Spray the vials with 70% ethanol and then transfer them to a biosafety cabinet. Pour the contents into a 50 mL conical tube containing thawed culture medium. Centrifuge the vials at 100 g for 10 minutes at room temperature. Aspirate the thawed culture medium and resuspend the hepatocytes in serum-free culture medium to obtain approximately 1.5 × ^10⁶ cells/mL.

Cell viability and density were counted using trypan blue exclusion, followed by dilution of cells with serum-free culture medium to achieve a working cell density of 1 × ^10⁶ viable cells/mL. A portion of hepatocytes at 1 × ^10⁶ viable cells/mL was boiled for 10 min and then added to the plate as a negative control to eliminate enzyme activity, ensuring minimal or no substrate transition should be observed. Inactivated hepatocytes were used to prepare negative samples to exclude misleading factors caused by the instability of the chemicals themselves.

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 a fixed-track shaker for approximately 10 minutes. Aliquots of 2.5 μL of the 100 μM test compound were added to the corresponding well of the uncoated 96-well plate to initiate the reaction. This analysis was performed in duplicate. The plate was incubated in an incubator on a fixed-track 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 the internal standard to terminate the reaction. The sample was centrifuged at 4000 g for 20 minutes, and 100 μL of the supernatant was used for LC-MS/MS analysis to measure the test compound.

In vitro hepatocyte clearance was estimated based on the elimination half-life (T1/2) from the initial concentration of the compound. The peak area ratio of each compound (test or control) to the index (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 the in vitro intrinsic clearance CL _int (μL/min/E⁶) were calculated according to the following equation:

k = -slope

T _{_1/2} = 0.693/k

CL _int = k/Chep

Chep (cells × ^μL⁻¹ ) represents the cell concentration in the culture system.

Procedure for Log D determination

Place 10 μL of working solution from each kit into the corresponding 96-well shelf position (Log D plate). Add 500 μL of saturated octanol to each vial of the above uncapped Log D plate, followed by 500 μL of saturated phosphate buffer. Seal with the molded PTFE/SIL 96-well plate cap.

The Log D plate was transferred to an Eppendorf Thermomixer Comfort plate oscillator and oscillated at 25°C and 2,000 rpm for 2 hours.

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

Transfer 5 μL of octanol sample to a new 96-well plate, followed by the addition of 495 μL of a mixture of _H₂O and acetonitrile containing the internal standard (1:1) as a 100-fold octanol sample. Vortex at 1,000 rpm for 5 minutes.

Transfer 50 μL of the 100-fold sample to a new 96-well plate, followed by the addition of 450 μL of a mixture of _H₂O and acetonitrile containing the internal standard (1:1) as the 1,000-fold octanol sample. Vortex at 1,000 rpm for 5 minutes.

The 1,000-fold octanol sample was serially diluted to 10,000, 100,000, and 1,000,000 times using a mixture of _H₂O and acetonitrile containing an internal standard (1:1).

Transfer 50 μL of the buffer sample to a new 96-well plate, then add 450 μL of a mixture of _H₂O and acetonitrile containing the internal standard (1:1) as a 10-fold buffer sample. Vortex at 1,000 rpm for 5 minutes.

The 10-fold buffer sample was serially diluted to 100, 1,000, and 10,000-fold using a 1:1 mixture of _H₂O and acetonitrile containing an internal standard. The samples were evaluated by LC/MS/MS analysis. All compounds were tested in duplicate.

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

DF stands for dilution factor.

Procedure for measuring protein binding in human plasma using balanced dialysis

Add 597 μL of blank plasma to each vial of a new plastic plate or individual plastic tube by adding 3 μL of working solution per box, and vortex at 1,000 rpm for 5 minutes. The final volume percentage of organic solvent is 0.5% and the final concentration of the test compound is 5 μM. Immediately afterwards, transfer 50 μL of the spiked plasma suspension to a 96-well plate as a T=0 control sample. Process the samples in the same manner as the samples after incubation. Place all remaining spiked plasma in an incubator for the duration of the study.

Place the insert with the open end facing up into the well of the base plate. Add 500 μL of phosphate buffer (pH 7.4), indicated by the white circle, to the buffer chamber. Add 300 μL of spiked plasma sample, indicated by the red circle, to the sample chamber. Cover the unit with the breathable cap and incubate at 37°C on a stationary shaker at 300 rpm with 5% _CO2 for 18 hours in a _CO2 incubator. At the end of the incubation, remove the cap and aspirate 50 μL of the dialyzed sample from the buffer chamber and plasma chamber, respectively, into separate 96-well plates for analysis.

Meanwhile, the remaining spiked plasma samples in the plastic plates or individual plastic tubes were incubated at 37°C with 5% _CO2 in a _CO2 incubator for 18 hours. At T=18 hours, 50 μL of the original spiked plasma suspension was transferred to a 96-well plate for analysis.

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

Use Microsoft Excel for all calculations.

The unbound percentage, bound percentage, and recovery percentage of the test compound are calculated as follows:

Unbound % = (Conc. _{Buffer compartment} / Conc. _{Plasma compartment} ) × 100%

Bound % = 100% - Free %

Recovery % = (500 × Conc. _{buffer chamber} + 300 × Conc. _{plasma chamber} ) / (300 × Conc. _{total sample} ) × 100

Remaining percentage = Conc. _18hr / Conc. _0hr × 100%

result

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

The short oral absorption (SOA) model is an in vivo screening model used to identify the brain penetration of compounds. To assess the likelihood of compounds crossing the blood-brain barrier in rats, the total brain to plasma ratio (Kp _{, brain} ) was measured by AUC _brain /AUC _plasma . The CSF to plasma ratio ( _{Kp, CSF} ) was determined by the average of the AUC _CSF /AUC _plasma or CSF to plasma ratios at the available time points after oral administration. In separate studies, the free fraction in the biomatrix was determined by in vitro plasma and brain binding assays. _{Kp, uu, brain} and Kp _{, uu, CSF} were calculated by the following equations: (1) _{Kp, uu, brain} = Kp _{, brain} × f _u , _brain /f _{u, plasma} ; (2) Kp _{, uu, CSF} = Kp _{, CSF} /f _{u, plasma} .

Compound numbering <![CDATA[rat f_u,br(%)/f_u,pl(%)]]> <![CDATA[K_p,brain]]> <![CDATA[K_p,uubrain]]> <![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 (21)

1. A compound of formula (I): in: ^R1 is selected from hydrogen, _C1-6 alkyl, _C1-6 alkoxy, _NC1-6 alkylamino, N,N-( _C1-6 alkyl) _2amino , carbocyclic and heterocyclic groups; wherein ^R1 may optionally be substituted by one or more ^R5s ; ^R2 is selected from halogen, _C1-3 alkyl, _C1-3 alkoxy, carbocyclic and heterocyclic groups; or two ^R2s on the same or adjacent atoms can form a 3-7 membered ring together with the atom they are attached to. k is 0-4; ^R3 is selected from halogen, _C1-3 alkyl, and _C1-3 alkoxy groups; n is 0-4; ^R4 is selected from halogen, _C1-3 alkyl, and _C1-3 alkoxy groups; m is 0-5; A is either =N- or =C(R ⁶ )-; ^R5 is selected from halogen, hydroxyl, _C1-6 alkoxy, amino, _NC1-6 alkylamino, N,N-( _C1-6 alkyl) _2amino , carbocyclic and heterocyclic groups; wherein ^R5 may be independently and optionally substituted by one or more ^R7s ; ^R6 is selected from hydrogen and halogen groups; ^R7 is selected from halogen, hydroxyl, amino, _C1-3 alkyl, and _C1-3 alkoxy groups; Or its pharmaceutically acceptable salt. 2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ^R1 is selected from hydrogen, methyl, hydroxymethyl, methoxymethyl, N,N-dimethylaminomethyl and aziridine-1-ylmethyl. 3. The compound of formula (I) according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein k is 0. 4. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein ^R3 is fluorine. 5. The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein n is 0-2. 6. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein ^R4 is fluorine. 7. The compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein m is 0-2. 8. The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein A is =N- or =C(H)-. 9. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, selected from: (5-(8-amino-1-(4-phenoxyphenyl)imidazol[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; (5-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazol[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; (5-(8-amino-1-(2,3-difluoro-4-phenoxyphenyl)imidazol[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; (5-(8-amino-1-(4-(2,3-difluorophenoxy)phenyl)imidazol[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; (5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol; (5-(4-amino-5-(2,3-difluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol; (5-(4-amino-5-(4-(2,3-difluorophenoxy)phenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol; 3-(6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-1-(2-fluoro-4-phenoxyphenyl)imidazol[1,5-a]pyrazine-8-amine; 7-(6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazolium[5,1-f][1,2,4]triazine-4-amine; 7-(6-(azacyclobutane-1-ylmethyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazolium[5,1-f][1,2,4]triazine-4-amine; 5-(2-fluoro-4-phenoxyphenyl)-7-(6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)imidazol[5,1-f][1,2,4]triazine-4-amine; 5-(2-fluoro-4-phenoxyphenyl)-7-(tetrahydro-2H-pyran-3-yl)imidazol[5,1-f][1,2,4]triazine-4-amine; and 5-(2-fluoro-4-phenoxyphenyl)-7-(6-methyltetrahydro-2H-pyran-3-yl)imidazol[5,1-f][1,2,4]triazine-4-amine. 10. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, selected from: ((2R,5R)-5-(8-amino-1-(4-phenoxyphenyl)imidazol[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5R)-5-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazol[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5R)-5-(8-amino-1-(2,3-difluoro-4-phenoxyphenyl)imidazol[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5R)-5-(8-amino-1-(4-(2,3-difluorophenoxy)phenyl)imidazol[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5R)-5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5R)-5-(4-amino-5-(2,3-difluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5R)-5-(4-amino-5-(4-(2,3-difluorophenoxy)phenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol; 3-((3R,6R)-6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-1-(2-fluoro-4-phenoxyphenyl)imidazol[1,5-a]pyrazine-8-amine; 7-((3R,6R)-6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazolium[5,1-f][1,2,4]triazine-4-amine; 7-((3R,6R)-6-(azacyclobutane-1-ylmethyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazolium[5,1-f][1,2,4]triazine-4-amine; 5-(2-fluoro-4-phenoxyphenyl)-7-((3R,6R)-6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)imidazol[5,1-f][1,2,4]triazine-4-amine; (R)-5-(2-fluoro-4-phenoxyphenyl)-7-(tetrahydro-2H-pyran-3-yl)imidazol[5,1-f][1,2,4]triazine-4-amine; 5-(2-fluoro-4-phenoxyphenyl)-7-((3R,6R)-6-methyltetrahydro-2H-pyran-3-yl)imidazol[5,1-f][1,2,4]triazine-4-amine; ((2S,5S)-5-(8-amino-1-(4-phenoxyphenyl)imidazol[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2S,5S)-5-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazol[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2S,5S)-5-(8-amino-1-(2,3-difluoro-4-phenoxyphenyl)imidazol[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2S,5S)-5-(8-amino-1-(4-(2,3-difluorophenoxy)phenyl)imidazol[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2S,5S)-5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2S,5S)-5-(4-amino-5-(2,3-difluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2S,5S)-5-(4-amino-5-(4-(2,3-difluorophenoxy)phenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol; 3-((3S,6S)-6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-1-(2-fluoro-4-phenoxyphenyl)imidazol[1,5-a]pyrazine-8-amine; 7-((3S,6S)-6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazolium[5,1-f][1,2,4]triazine-4-amine; 7-((3S,6S)-6-(azacyclobutane-1-ylmethyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazolium[5,1-f][1,2,4]triazine-4-amine; 5-(2-fluoro-4-phenoxyphenyl)-7-((3S,6S)-6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)imidazol[5,1-f][1,2,4]triazine-4-amine; (S)-5-(2-fluoro-4-phenoxyphenyl)-7-(tetrahydro-2H-pyran-3-yl)imidazol[5,1-f][1,2,4]triazine-4-amine; 5-(2-fluoro-4-phenoxyphenyl)-7-((3S,6S)-6-methyltetrahydro-2H-pyran-3-yl)imidazol[5,1-f][1,2,4]triazine-4-amine; ((2S,5R)-5-(8-amino-1-(4-phenoxyphenyl)imidazol[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2S,5R)-5-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazol[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2S,5R)-5-(8-amino-1-(2,3-difluoro-4-phenoxyphenyl)imidazol[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2S,5R)-5-(8-amino-1-(4-(2,3-difluorophenoxy)phenyl)imidazol[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2S,5R)-5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2S,5R)-5-(4-amino-5-(2,3-difluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2S,5R)-5-(4-amino-5-(4-(2,3-difluorophenoxy)phenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol; 3-((3S,6R)-6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-1-(2-fluoro-4-phenoxyphenyl)imidazol[1,5-a]pyrazine-8-amine; 7-((3S,6R)-6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazolium[5,1-f][1,2,4]triazine-4-amine; 7-((3S,6R)-6-(azacyclobutane-1-ylmethyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazolium[5,1-f][1,2,4]triazine-4-amine; 5-(2-fluoro-4-phenoxyphenyl)-7-((3S,6R)-6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)imidazol[5,1-f][1,2,4]triazine-4-amine; 5-(2-fluoro-4-phenoxyphenyl)-7-((3S,6R)-6-methyltetrahydro-2H-pyran-3-yl)imidazol[5,1-f][1,2,4]triazine-4-amine; ((2R,5S)-5-(8-amino-1-(4-phenoxyphenyl)imidazol[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5S)-5-(8-amino-1-(2-fluoro-4-phenoxyphenyl)imidazol[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5S)-5-(8-amino-1-(2,3-difluoro-4-phenoxyphenyl)imidazol[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5S)-5-(8-amino-1-(4-(2,3-difluorophenoxy)phenyl)imidazol[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5S)-5-(4-amino-5-(2-fluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5S)-5-(4-amino-5-(2,3-difluoro-4-phenoxyphenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol; ((2R,5S)-5-(4-amino-5-(4-(2,3-difluorophenoxy)phenyl)imidazol[5,1-f][1,2,4]triazine-7-yl)tetrahydro-2H-pyran-2-yl)methanol; 3-((3R,6S)-6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-1-(2-fluoro-4-phenoxyphenyl)imidazol[1,5-a]pyrazine-8-amine; 7-((3R,6S)-6-((dimethylamino)methyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazolium[5,1-f][1,2,4]triazine-4-amine; 7-((3R,6S)-6-(azacyclobutane-1-ylmethyl)tetrahydro-2H-pyran-3-yl)-5-(2-fluoro-4-phenoxyphenyl)imidazolium[5,1-f][1,2,4]triazine-4-amine; 5-(2-fluoro-4-phenoxyphenyl)-7-((3R,6S)-6-(methoxymethyl)tetrahydro-2H-pyran-3-yl)imidazolium[5,1-f][1,2,4]triazine-4-amine; and 5-(2-fluoro-4-phenoxyphenyl)-7-((3R,6S)-6-methyltetrahydro-2H-pyran-3-yl)imidazol[5,1-f][1,2,4]triazine-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 BTK inhibition in warm-blooded animals. 13. The pharmaceutical composition according to claim 12, wherein the warm-blooded animal is a human. 14. Use of the compound of formula (I) according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 11 to 13, in the preparation of a medicament for treating a disease or condition in warm-blooded animals, said disease or condition being selected from: immune disorders, cancer, cardiovascular diseases, viral infections, metabolic/endocrine disorders and neurological disorders, allergic diseases, 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. 16. The use according to claim 14, wherein the disease or condition 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. The use according to claim 14, wherein the warm-blooded animal is a human. 18. The use according to claim 16, wherein the disease or condition is multiple sclerosis. 19. Use of the compound of formula (I) according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 11 to 13, in the preparation of a medicament for inhibiting BTK. 20. The use according to claim 19, wherein the BTK is wild-type BTK or BTK having the C481 mutation. 21. The use according to claim 20, wherein the BTK having the C481 mutation is selected from the group consisting of: BTK having the C481S mutation, BTK having the C481Y mutation, BTK having the C481R mutation, and BTK having the C481F mutation.