Inhibitors of btk and mutants thereof

Abstract

The present disclosure includes compounds of Formula (I), wherein Q1, Q2, Q3, W, X, Y, Z1, m, n, warhead, R1, R2, R3, R4, and R5 are defined herein. Also disclosed are methods of treating neoplastic diseases, autoimmune diseases, and inflammatory conditions with these compounds

Description

[0001] This application is a divisional application of Chinese invention patent application No. 201980013997.5, filed on February 15, 2019, entitled "Inhibitors of BTK and Mutants Thereof".

[0002] Cross-reference to related applications

[0003] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 631,945, filed February 19, 2018, pursuant to 35U.SC119(e), the entire contents of which are incorporated herein by reference. Background of the Invention

[0004] Bruton's tyrosine kinase (Btk) is a non-receptor protein kinase of the Tec family. It is expressed in most hematopoietic cells such as B cells, mast cells and macrophages, but not in T cells, natural killer cells and plasma cells [Smith, CI et al. Journal of Immunology (1994), 152(2), 557-65]. Btk is a key part of the BCR and FcR signaling pathways, and targeted inhibition of Btk is a novel approach to treat many different human diseases, such as B-cell malignancies, autoimmune diseases, and inflammatory conditions [Uckun, Fatih M. et al, Anti-Cancer Agents in Medicinal Chemistry (2007), Shinohara et al, Cell 132 (2008) pp794-806; Pan, Zhengying, Drug News & Perspectives (2008), 21(7); 7(6), 624-632; Gilfillan et al, Immunological Reviews 288 (2009) pp 149-169; Davis et al, Nature, 463 (2010) pp 88-94].

[0005] Covalent Bruton's tyrosine kinase (BTK) inhibitors, including ibrutinib and acalabrutinib, have revolutionized the treatment of some BTK-dependent B-cell malignancies, including chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia, mantle cell lymphoma, and marginal zone lymphoma. Despite the impressive clinical response to ibrutinib in B-cell malignancies, cases of primary and secondary resistance have emerged, with poor prognosis and limited treatment options. Most CLL patients who develop resistance to irreversible BTK inhibitors such as ibrutinib have the BTK-C481S mutation. It has been reported that 80% of patients with relapsed CLL will have the C481S mutation [Maddocks KJ, et al. JAMA Oncol. 2015; 1:80–87]. Another research team at Ohio State University reported in the Journal of Clinical Oncology [Vol 35, No. 13, 2017, p. 1437] that approximately 20% of patients using ibrutinib experienced clinical progression in the fourth year. Among these relapsed patients, 85% acquired the C481S mutation. Furthermore, these mutations were detected on average within nine months prior to relapse.

[0006] Despite the significant contributions of BTK inhibitors such as ibrutinib and ACP-196 to the field, there is a strong need to continue the search for highly potent and selective BTK inhibitors that can irreversibly inhibit not only WTBTK but also C481S mutant BTK. Invention Overview

[0007] This invention relates to a class of potent and selective Btk inhibitors rationally designed to irreversibly inhibit not only WT BTK but also C481S mutant BTK. Therefore, the compounds of this invention can be used to treat patients resistant / refractory to first-generation BTK inhibitors such as ibrutinib and ACP-196 (acalabrutinib), particularly those with BTK C481S mutations. The compounds of this invention can also be used to treat patients with diseases such as autoimmune diseases or inflammatory conditions.

[0008] In one aspect, the present invention relates to compounds of formula (I) or their N-oxides, or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, stereoisomers, isotopic forms, or prodrugs of compounds of formula (I) or their N-oxides:

[0009]

[0010] in

[0011] Q1 is a 5-6 aryl or heteroaryl group;

[0012] Q2 is a 5-7 membered heterocyclic alkyl or heteroaryl group;

[0013] Q3 is a 5-membered heteroaryl group;

[0014] W, X, Y, and Z1 are each independent of C(R) a ) or N;

[0015] R1 and R5 are independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halogen, nitro, oxo, cyano, OR a SR a alkyl-R a NH(CH2) p R a C(O)R a S(O)R a SO2R a C(O)OR a OC(O)R a NR b R c C(O)N(R) b )R c 、N(R b )C(O)R c -P(O)R b R c ,-alkyl-P(O)R b R c -S(O)(=N(R) b ))R c -N=S(O)R b R c =NR b SO2N(R) b )R c or N(R) b SO2R c The cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl groups are optionally represented by one or more R groups. d replace;

[0016] R2 is H or an alkyl group;

[0017] R3 is H, halo, alkyl, haloalkyl or hydroxyalkyl;

[0018] R4 is H, a halogenated or a lower alkyl group;

[0019] The two atoms of the R1 group, together with the atoms to which they are attached, can optionally form a group with one or more R groups. d Substituted cycloalkyl or heterocycloalkyl;

[0020] The two atoms of the R5 group, together with their attached atoms, can optionally form a group with one or more R groups. d Substituted cycloalkyl or heterocycloalkyl;

[0021] R a R b R c and R d Independently, it can be H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogenated, cyano, amine, nitro, hydroxyl, =O, -P(O)R b R c ,-alkyl-P(O)R b R c -S(O)(=N(R) b ))R c -N=S(O)R b R c =NR b C(O)NHOH, C(O)OH, C(O)NH2, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo-alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl are optionally represented by one or more R e replace;

[0022] R e It is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxyl, =O, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo-alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl;

[0023] m, n, p, and q are each independently 0, 1, 2, 3, or 4; and

[0024] The warhead is

[0025] In a preferred embodiment, the compound is represented by formula (II):

[0026]

[0027] in

[0028] k is 0, 1, or 2;

[0029] s is 0, 1, 2, or 3; and

[0030] Q4 is a 5-7 membered cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; and the remaining variables are as defined in formula (I).

[0031] In a more preferred embodiment, the compound is represented by formula (III):

[0032]

[0033] in

[0034] r is 0, 1, 2 or 3; and the remaining variables are as defined in equation (I) or equation (II).

[0035] In a more preferred embodiment, the compound is represented by formula (IV):

[0036] in

[0037]

[0038] k is 1 or 2; and

[0039] r is 1 or 2; and the remaining variables are defined as in equation (I) or equation (II).

[0040] The compounds of the present invention may contain one or more asymmetric carbon atoms. Therefore, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. Each asymmetric carbon atom may be of R or S configuration, and both configurations are within the scope of the present invention.

[0041] Modified compounds of any of these types are also considered, including modifications that result in improved (e.g., enhanced, larger) drug solubility, stability, bioavailability, and / or therapeutic index compared to unmodified compounds. Exemplary modifications include (but are not limited to) suitable prodrug derivatives and deuterium-rich compounds.

[0042] It should be understood that the compounds of the present invention may exist in the form of salts or solvates and may be optionally administered in this form. The present invention covers any pharmaceutically acceptable salts and solvates of any of the above-described compounds and their modifications.

[0043] Pharmaceutical compositions for treating neoplastic diseases, autoimmune diseases, and inflammatory conditions, their therapeutic uses, and the use of compounds in the preparation of medicaments for treating diseases / conditions are also within the scope of this invention, said pharmaceutical compositions containing one or more of the above-mentioned compounds, their modifications, and / or salts.

[0044] The present invention also relates to a method of treating neoplastic diseases by administering an effective amount of one or more of the above-mentioned compounds, their modifications and / or salts and compositions to a subject in need, particularly B-cell malignancies, including but not limited to B-cell lymphoma, lymphoma (including Hodgkin lymphoma and non-Hodgkin lymphoma), pilocellular lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL), multiple myeloma, chronic and acute myeloid leukemia and chronic and acute lymphoblastic leukemia.

[0045] Autoimmune and / or inflammatory diseases that can be affected by the compounds and compositions according to the present invention include, but are not limited to: psoriasis, allergic reactions, Crohn's disease, irritable bowel syndrome, Sjogren's disease, tissue graft rejection and hyperacute rejection of transplanted organs, asthma, systemic lupus erythematosus (and associated glomerulonephritis), dermatomyositis, multiple sclerosis, scleroderma, vasculitis (ANCA-related and other vasculitis), autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome (and associated glomerulonephritis and pulmonary hemorrhage), atherosclerosis, rheumatoid arthritis, chronic idiopathic thrombocytopenic purpura (ITP), Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, and myasthenia gravis.

[0046] Details of one or more embodiments of the invention are set forth in the following description. Other features, objects, and advantages of the invention will become apparent from the description and claims. It should be understood that all embodiments / features of the invention described herein (compounds, pharmaceutical compositions, methods of preparation / use, etc.), including any specific features set forth in the examples and original claims, may be combined with each other unless inapplicable or expressly excluded. Invention Details

[0047] The exemplary compounds described herein include, but are not limited to, the following:

[0048] N-(3-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)phenyl)acrylamide,

[0049] (E)-N-(3-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)phenyl)-4-(dimethylamino)but-2-enamide,

[0050] (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidine-1-yl)phenyl)acrylamide,

[0051] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-methylpiperazin-1-yl)phenyl)acrylamide,

[0052] N-(5-((6-(3-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-2-(hydroxymethyl)phenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-methylpiperazin-1-yl)phenyl)acrylamide,

[0053] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-(oxetane-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0054] N-(5-((6-(3-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-2-(hydroxymethyl)phenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-(oxetane-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0055] (S)-N-(5-((6-(3-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-2-(hydroxymethyl)phenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetane-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0056] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetane-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0057] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide,

[0058] (S)-N-(2-(4-(4,4-difluorocyclohexyl)-2-methylpiperazin-1-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)phenyl)acrylamide,

[0059] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-((2S)-4-(2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-methylpiperazin-1-yl)phenyl)acrylamide,

[0060] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-morpholinopiperidin-1-yl)phenyl)acrylamide,

[0061] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(methyl(oxetane-3-yl)amino)piperidin-1-yl)phenyl)acrylamide,

[0062] N-(2-((2'S)-4,4-difluoro-2'-methyl-[1,4'-bispiperidin]-1'-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)phenyl)acrylamide,

[0063] N-(2-((2S)-4-(3,3-difluoropyrrolidone-1-yl)-2-methylpiperidin-1-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)phenyl)acrylamide,

[0064] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-((2S)-2-methyl-4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide,

[0065] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-((2S)-4-(dimethylamino)-2-methylpiperidin-1-yl)phenyl)acrylamide,

[0066] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(1-(oxetane-3-yl)piperidin-4-yl)phenyl)acrylamide,

[0067] N-(5-((6-(3-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-2-(hydroxymethyl)phenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(1-(oxetane-3-yl)piperidin-4-yl)phenyl)acrylamide,

[0068] N-(3-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-5-(4-methylpiperazin-1-yl)phenyl)acrylamide,

[0069] N-(3-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-5-((4-methylpiperazin-1-yl)methyl)phenyl)acrylamide,

[0070] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-methylpiperazin-1-yl)phenyl)but-2-yneamide,

[0071] N-(5-((6-(3-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-2-(hydroxymethyl)phenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-methylpiperazin-1-yl)phenyl)but-2-yneamide,

[0072] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-(oxetane-3-yl)piperazin-1-yl)phenyl)but-2-yneamide,

[0073] N-(5-((6-(3-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-2-(hydroxymethyl)phenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-(oxetane-3-yl)piperazin-1-yl)phenyl)but-2-yneamide,

[0074] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetane-3-yl)piperazin-1-yl)phenyl)but-2-yneamide,

[0075] (S)-N-(5-((6-(3-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-2-(hydroxymethyl)phenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetane-3-yl)piperazin-1-yl)phenyl)but-2-yneamide,

[0076] (Z)-2-cyano-N-(3-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)phenyl)-4-methyl-4-(4-(oxetane-3-yl)piperazin-1-yl)pent-2-enamide,

[0077] (Z)-2-cyano-N-(3-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)phenyl)-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enamide,

[0078] (Z)-2-cyano-N-(3-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)phenyl)-4-methyl-4-(methyl(oxetane-3-yl)amino)pentyl -2-Acrylamide, N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-(4-methylpiperazin-1-yl)propyl-2-yl)phenyl)acrylamide,

[0079] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-morpholinopropyl-2-yl)phenyl)acrylamide,

[0080] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-(methyl(oxetane-3-yl)amino)propyl-2-yl)phenyl)acrylamide,

[0081] N-(2-(2-(4,4-difluoropiperidin-1-yl)propyl-2-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)phenyl)acrylamide,

[0082] N-(2-(2-(3,3-difluoropyrrolidone-1-yl)propyl-2-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)phenyl)acrylamide,

[0083] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-(4-(oxetane-3-yl)piperazin-1-yl)propyl-2-yl)phenyl)acrylamide,

[0084] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-1-morpholinopropyl-2-yl)phenyl)acrylamide,

[0085] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-1-(4-methylpiperazin-1-yl)propyl-2-yl)phenyl)acrylamide,

[0086] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(piperidin-3-yl)phenyl)acrylamide,

[0087] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-methylpiperazine e-1-carbonyl)phenyl)acrylamide,

[0088] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetane-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0089] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide,

[0090] (S)-N-(2-(4-(4,4-difluorocyclohexyl)-2-methylpiperazin-1-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)phenyl)acrylamide,

[0091] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-((2S)-2-methyl-4-morpholinopiperidin-1-yl)phenyl)acrylamide,

[0092] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-morpholinopiperidin-1-yl)phenyl)acrylamide,

[0093] N-(2-(4,4-difluoro-[1,4'-bispiperidin]-1'-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)phenyl)acrylamide,

[0094] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide,

[0095] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-3-fluoro-2-(2-methyl-4-(oxetane-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0096] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-3-methyl-2-(2-methyl-4-(oxetane-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0097] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetane-3-yl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)acrylamide,

[0098] (S)-N-(3-cyano-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetane-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0099] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-3-(isopropylsulfonyl)-2-(2-methyl-4-(oxetane-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0100] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetane-3-yl)piperazin-1-yl)-3-((trifluoromethyl)sulfonyl)phenyl)acrylamide,

[0101] N-(2-((2'S)-4,4-difluoro-2'-methyl-[1,4'-bispiperidin]-1'-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)phenyl)acrylamide,

[0102] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-((2S)-2-methyl-4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide.

[0103] The compounds of this invention may contain one or more asymmetric carbon atoms. Therefore, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. The synthesis of the compounds may employ racemic, diastereomer, or enantiomer as starting materials or intermediates. Diastereomeric compounds may be separated by chromatography or crystallization. Similarly, enantiomeric mixtures may be separated using the same techniques or other techniques known in the art. Each asymmetric carbon atom may be of an R or S configuration, and both configurations are within the scope of this invention.

[0104] This also covers any modified compounds of this kind, including modifications that result in improved (e.g., enhanced, larger) pharmaceutical solubility, stability, bioavailability, and / or therapeutic index compared to unmodified compounds. Examples of modifications include, but are not limited to, prodrug derivatives and deuterium-enriched compounds. For example:

[0105] • Prodrug derivatives: When administered to a subject, the prodrug is converted in vivo into the active compound of the present invention [Nature Reviews of Drug Discovery, 2008, Volume 7, p255]. It should be noted that in several instances, the prodrug itself also falls within the scope of the compounds according to the present invention. Prodrugs of the compounds of the present invention can be prepared by standard organic reactions, for example, by reaction with carbamates (e.g., 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, etc.) or acylating agents. Other examples of methods and strategies for preparing prodrugs are described in Bioorganic and Medicinal Chemistry Letters, 1994, Vol. 4, p. 1985.

[0106] • Compounds enriched in deuterium: deuterium (D or 2 H is a stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen is naturally occurring as an isotope. X H (hydrogen or protium), D ( 2 H or deuterium), and T (H or deuterium), and T ( 3 It exists as a mixture of H (or tritium). The natural abundance of deuterium is 0.015%. Those skilled in the art will recognize that in all compounds containing H atoms, the H atoms are actually represented as a mixture of H and D, with about 0.015% being D. Therefore, compounds having a deuterium content that is enriched to more than 0.015% of their natural abundance should be considered non-natural and thus novel relative to their non-enriched counterparts.

[0107] It should be understood that the compounds of the present invention can exist and be optionally applied in the form of salts and solvates. For example, it is within the scope of the present invention to convert the compounds of the present invention into pharmaceutically acceptable forms derived from a variety of organic and inorganic acids, as well as organic and inorganic bases, according to processes known in the art and to use the compounds in such forms.

[0108] When the compounds of the present invention have a free base form, they can be prepared into pharmaceutically acceptable acid addition salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, such as hydrohalides, hydrobromide, hydroiodide; other mineral acids, such as sulfates, nitrates, phosphates, etc.; and alkyl and monoaryl sulfonates, such as ethanesulfonate, toluenesulfonate, and benzenesulfonate; as well as other organic acids and their corresponding salts, such as acetate, tartrate, maleate, succinate, citric acid, benzoate, salicylate, and ascorbate. Other acid addition salts of the present invention include, but are not limited to: adipate, alginate, arginine, aspartate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphor sulfonate, octanoate, hydrochloride, chlorobenzoate, cyclopentylpropionate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, fumarate, galacturonate (from mucoacid), galacturonate, gluconate, gluconate, glutamate, glycerol phosphate, hesuccinate, hesulate, heptanate, hexanoate, hippurate, 2-hydroxyethanesulfonate, iodide, hydroxyethyl sulfonate, isobutyrate, lactate, lacturonate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogen phosphate, 2-naphthalenesulfonate, nicotinate, oxalate, oleate, dihydroxynaphthalate, pectate, persulfate, phenylacetate, 3-phenylpropionate, phosphonates, and phthalates. It should be understood that the physical properties of the free base form, such as its solubility in polar solvents, are typically somewhat different from those of its respective salt form, but for the purposes of this invention, the salt is equivalent to its respective free base form.

[0109] When the compounds of the present invention are in a free acid form, pharmaceutically acceptable base addition salts can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Examples of such bases are alkali metal hydroxides, including potassium hydroxide, sodium hydroxide, and lithium hydroxide; alkaline earth metal hydroxides, such as barium hydroxide and calcium hydroxide; alkali metal alkoxides, such as potassium ethoxide and sodium propoxide; and various organic bases, such as ammonium hydroxide, piperidine, diethanolamine, and N-methylglutamine. Aluminum salts of the compounds of the present invention are also included. Other base addition salts of the present invention include, but are not limited to, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, and zinc salts. Organic base addition salts include, but are not limited to, primary amine salts, secondary amine salts, tertiary amine salts, salts of substituted amines including naturally occurring substituted amines, salts of cyclic amines, and salts of basic ion exchange resins, such as arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, etc. N-Ethylmorpholine, N-Ethylpiperidine, reduced glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine, and tris(hydroxymethyl)methylamine (tromethamine). It should be understood that the physical properties of the free acid form, such as its solubility in polar solvents, are typically somewhat different from those of its respective salt form, but for the purposes of this invention, the salt is equivalent to its respective free acid form.

[0110] On the one hand, pharmaceutically acceptable salts are hydrochloride, hydrobromide, methanesulfonate, toluenesulfonate, acetate, fumarate, sulfate, hydrogen sulfate, succinate, citrate, phosphate, maleate, nitrate, tartrate, benzoate, bicarbonate, carbonate, sodium hydroxide, calcium hydroxide, potassium hydroxide, tromethamine, or mixtures thereof.

[0111] The compounds of the present invention containing tertiary nitrogen groups can be quaternized using, for example, the following reagents: (C 1-4 Alkyl halides, such as chlorides, bromides, and iodides of methyl, ethyl, isopropyl, and tert-butyl alkyl halides; di(C) sulfate 1-4 Alkyl esters, such as dimethyl sulfate, diethyl sulfate, and dipentyl sulfate; alkyl halides, such as chlorides, bromides, and iodides of decyl, dodecyl, lauryl, myristyl, and stearyl groups; and aryl (C 1-4Alkyl halides, such as benzyl chloride and phenylethyl bromide. These salts allow for the preparation of both water-soluble and oil-soluble compounds of the present invention.

[0112] Ammonium oxides of anticancer agents containing tertiary nitrogen atoms, also known as ammonia-N-oxides and N-oxides, have been developed as prodrugs [Mol Cancer Therapy. 2004 Mar; 3(3):233-44]. Compounds of the present invention containing tertiary nitrogen atoms can be oxidized by reagents such as hydrogen peroxide (H2O2), carboxylic acids, or peracids such as m-chloroperoxybenzoic acid (mCPBA) to form ammonium oxides.

[0113] This invention covers pharmaceutical compositions comprising the compounds and pharmaceutical excipients of this invention, as well as other conventional pharmaceutically inactive agents. Any inert excipient generally used as a carrier or diluent may be used in the compositions of this invention, such as sugars, polyols, soluble polymers, salts, and lipids. Suitable sugars and polyols include, but are not limited to, lactose, sucrose, mannitol, and sorbitol. Exemplary suitable soluble polymers include polyoxyethylene, poloxamer, polyvinylpyrrolidone, and dextran. Suitable salts include, but are not limited to, sodium chloride, magnesium chloride, and calcium chloride. Suitable lipids include, but are not limited to, fatty acids, glycerol fatty acid esters, glycolipids, and phospholipids.

[0114] In addition, the pharmaceutical composition may further include binders (e.g., gum arabic, corn starch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrants (e.g., corn starch, potato starch, alginate, silica, croscarmellose sodium, croscarmellose, guar gum, carboxyacetic acid starch sodium, Primogel), buffers of various pH and ionic strengths (e.g., tris-HCl, acetate, phosphate), additives to prevent absorption to the surface such as albumin or gelatin, and detergents (e.g., Tween 20, Tween 80, Pluronic). F68, bile salts), protease inhibitors, surfactants (e.g., sodium lauryl sulfate), penetration enhancers, solubilizers (e.g., glycerol, polyvinylglycerol, cyclodextrin), flow aids (e.g., colloidal silica), antioxidants (e.g., ascorbic acid, sodium metabisulfite, butyrated hydroxyanisole), stabilizers (e.g., hydroxypropyl cellulose, hydroxypropyl methyl cellulose), viscosity enhancers (e.g., carbomer, colloidal silica, ethyl cellulose, guar gum), sweeteners (e.g., sucrose, aspartame, citric acid), flavorings (e.g., peppermint oil, methyl salicylate, or orange flavoring). Agents, preservatives (e.g., thimerosal, benzyl alcohol, parabens), lubricants (e.g., stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow aids (e.g., colloidal silica), plasticizers (e.g., diethyl terephthalate, triethyl citrate), emulsifiers (e.g., carbomer, hydroxypropyl cellulose, sodium lauryl sulfate, methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose), polymer coatings (e.g., poloxamer or poloxamine), coating and film forming agents (e.g., ethyl cellulose, acrylates, polymethyl methacrylate) and / or adjuvants.

[0115] In one embodiment, the pharmaceutical composition is prepared having a carrier, such as a controlled-release formulation, that protects the compound from rapid elimination from the body, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene-vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations are apparent to those skilled in the art. Materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (including liposomes targeted to infected cells with monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example as described in US Patent No. 4,522,811.

[0116] Furthermore, this invention covers pharmaceutical compositions comprising compounds of the invention in any solid or liquid physical form. For example, the compound may be in crystalline or amorphous form and have any particle size. The particles may be micronized or may be clumps of microparticles, powder, oil, oily suspension, or any other solid or liquid physical form.

[0117] When the compound according to the invention exhibits insufficient solubility, a method for solubilizing the compound can be used. Such methods are known to those skilled in the art and include, but are not limited to, pH adjustment and salt formation; the use of co-solvents such as ethanol, propylene glycol, polyethylene glycol (PEG) 300, PEG 400, DMA (10-30%), DMSO (10-20%), and NMP (10-20%); the use of surfactants such as polysorbate 80, polysorbate 20 (1-10%), cremophor EL, cremophor RH40, cremophor RH60 (5-10%), Pluronic F68 / Poloxamer 188 (20-50%), Solutol HS15 (20-50%), vitamin ETPGS, and d-α-tocopherol PEG 1000 succinate (20-50%); the use of complexing agents such as HPβCD and SBEβCD (10-40%); and the use of advanced pathways such as micelles, polymer addition, nanoparticle suspensions, and liposome formation.

[0118] Numerous administration methods can be combined with the compounds of the present invention. The compounds of the present invention can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, orally, intranasally, via liposomes, via inhalation, vaginally, intraocularly, via local delivery (e.g., through a catheter or stent), subcutaneously, intra-abdominally, intra-articularly, or intrathecally, or in combination. The compounds according to the present invention can also be administered in sustained-release formulations or co-administered. The compounds can be in gaseous, liquid, semi-liquid, or solid form, formulated in a manner suitable for the intended route of administration. For oral administration, suitable solid oral formulations include tablets, capsules, pills, granules, microcapsules, effervescent tablets, powders, etc. Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils, etc. For parenteral administration, reconstitution of lyophilized powders is typically used.

[0119] As used herein, “acyl” refers to a carbonyl substituent represented by the formula -C(O)-R, wherein R is H, alkyl, carbocyclic, heterocyclic, carbocyclic-substituted alkyl, or heterocyclic-substituted alkyl, wherein the alkyl, alkoxy, carbocyclic, and heterocyclic are as defined herein. Acyl groups include alkylacyl groups (e.g., acetyl), aromatic acyl groups (e.g., benzoyl), and heteroaromatic acyl groups.

[0120] "Aliphatic" refers to a part characterized by a straight or branched arrangement of carbon atoms, which can be saturated or have one or more unsaturated double or triple bonds.

[0121] The term "alkyl" refers to straight-chain or branched hydrocarbons containing 1 to 20 carbon atoms (e.g., C1-C1). 10 Examples of alkyl groups include, but are not limited to, methyl, methylene, ethyl, ethylene, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. Preferably, the alkyl group has 1 to 10 carbon atoms. More preferably, the alkyl group has 1 to 4 carbon atoms.

[0122] The term "alkenyl" refers to a group containing 2 to 20 carbon atoms (e.g., C2-C). 10 Alkenes are straight-chain or branched hydrocarbons with one or more double bonds. Examples of alkenes include, but are not limited to, vinyl, propenyl, and allyl. Preferably, the alkenyl group has 2 to 10 carbon atoms. More preferably, the alkenyl group has 2 to 4 carbon atoms.

[0123] The term "alkynyl" refers to a group containing 2 to 20 carbon atoms (e.g., C2-C). 10 The alkynyl group is a straight-chain or branched hydrocarbon with one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, and 1-methyl-2-butynyl. Preferably, the alkynyl group has 2 to 10 carbon atoms. More preferably, the alkynyl group has 2 to 4 carbon atoms.

[0124] The term "alkylamino" refers to -N(R)-alkyl, where R can be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl.

[0125] "Alkoxy" refers to an oxygen moiety having further alkyl substituents.

[0126] "Alkoxycarbonyl" refers to an alkoxy group attached to a carbonyl group.

[0127] "Oxoalkyl" refers to an alkyl group that has been further substituted with a carbonyl group. This carbonyl group can be an aldehyde, ketone, ester, amide, acid, or acyl chloride.

[0128] The term "cycloalkyl" refers to a group having 3 to 30 carbon atoms (e.g., C3-C4). 12, Saturated hydrocarbon ring systems (C3-C8, C3-C6). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term "cycloalkenyl" refers to a ring system having 3 to 30 carbon atoms (e.g., C3-C6). 12 (and one or more double-bonded non-aromatic ring systems. Examples include cyclopentenyl, cyclohexenyl, and cycloheptenyl.)

[0129] The term "heterocyclic alkyl" refers to a non-aromatic 5- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 14-membered tricyclic ring system having one or more heteroatoms (e.g., O, N, S, P, or Se). Examples of heterocyclic alkyl groups include, but are not limited to, piperazine, pyrrolidinyl, dioxane, morpholinyl, and tetrahydrofuranyl.

[0130] The term "heterocyclic alkenyl" refers to a non-aromatic 5- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 14-membered tricyclic ring system having one or more heteroatoms (e.g., O, N, S, P, or Se) and one or more double bonds.

[0131] The term "aryl" refers to an aromatic ring system with 6 carbon atoms (monocyclic), 10 carbon atoms (bicyclic), or 14 carbon atoms (tricyclic). Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracene. The term "heteroaryl" refers to an aromatic ring system with 5 to 8 members (monocyclic), 8 to 12 members (bicyclic), or 11 to 14 members (tricyclic), having one or more heteroatoms (e.g., O, N, S, P, or Se). Examples of heteroaryl groups include pyridyl, furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thiophene, quinolinyl, indolyl, and thiazolyl.

[0132] The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, alkylamino, aryl, and heteroaryl groups mentioned above include both substituted and unsubstituted portions. Possible substituents located on alkylamino, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl groups include, but are not limited to, C1-C... 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 20 cycloalkyl, C3-C 20 Cycloalkenyl, C1-C 20 Heterocyclic alkyl, C1-C 20 Heterocyclic alkenyl, C1-C 10 Alkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C1-C 10 Alkylamino, arylamino, hydroxyl, halogen, oxo (O=), thio (S=), thio, silyl, C1-C 10 Alkylthio, Arylthio, C1-C 10 Alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amido, mercapto, acylamino, thiourea, thiocyanate, sulfonamide, guanidine, urea, cyano, nitro, acyl, thioacyl, acyloxy, urea, carbamoyl, carboxyl, and carboxylic acid esters. On the other hand, possible substituents on the alkyl, alkenyl, or alkynyl groups include those other than C1-C1. 10All substituents mentioned above, other than alkyl groups. Cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl groups may also fused together.

[0133] "Amino" refers to a nitrogen moiety further having two substituents, wherein each substituent has a hydrogen or carbon atom α-bonded to nitrogen. Unless explicitly stated otherwise, compounds containing an amino moiety according to the present invention may include their protected derivatives. Suitable protecting groups for the amino moiety include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, etc.

[0134] "Aromatic" refers to a group in which the constituent atoms form an unsaturated ring system, in which all atoms are sp2 hybridized and the total number of π electrons is equal to 4n+2. Aromatic rings can consist of only carbon atoms or may include both carbon and non-carbon atoms (see heteroaryl).

[0135] "Carbamoyl" refers to the group -OC(O)NR a R b , where R a and R b Each of the two substituents is independent of the other two, wherein a hydrogen or carbon atom is located at the α-position of nitrogen. Note that the carbamoyl moiety may include its protected derivatives. Examples of protecting groups suitable for the carbamoyl moiety include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, etc. Note that both unprotected and protected derivatives fall within the scope of this invention.

[0136] "Carbonyl" refers to the group -C(O)-. Note that the carbonyl group can be further substituted with various substituents to form different carbonyl groups, including acids, acyl halides, amides, esters, and ketones.

[0137] "Carboxyl group" refers to the group -C(O)O-. Note that compounds containing a carboxyl moiety in this invention may include their protected derivatives, i.e., wherein the oxygen atom is substituted by a protecting group. Protecting groups suitable for the carboxyl moiety include benzyl, tert-butyl, etc.

[0138] “Cyano” refers to the group -CN.

[0139] "Formyl group" refers to the group -CH=O.

[0140] "Imine methyl" refers to the group –HC=NH.

[0141] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0142] As a separate group or part of a larger group, "halogen-substituted alkyl" refers to an alkyl group substituted with one or more halogen atoms, as defined in this application. Halogen-substituted alkyl groups include haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl, etc.

[0143] "Hydroxy group" refers to the -OH group.

[0144] "Imine derivatives" refer to derivatives containing a -C (=NR)- moiety, where R contains a hydrogen or carbon atom at the α-position of the nitrogen.

[0145] An "isomer" is any compound with the same molecular formula but different atomic bonding characteristics or sequences, or different spatial arrangements of its atoms. Isomers with different spatial arrangements of atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," while stereoisomers that are non-overlapping mirror images are called "enantiomers" or sometimes "optical isomers." A carbon atom with four different substituents is called a "chiral center." A compound with one chiral center has two enantiomers with opposite chirality. A mixture of two enantiomers is called a "racemic mixture."

[0146] "Nitro" refers to the group -NO2.

[0147] "Protected derivatives" refer to derivatives of compounds in which the reactive sites are blocked by protecting groups. Protected derivatives can be used to prepare pharmaceuticals or may themselves have inhibitory activity. A comprehensive list of applicable protecting groups can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3rd Edition, Wiley & Sons, 1999.

[0148] The term "substituted" means that an atom or group of atoms has replaced hydrogen as a substituent attached to another group. For aryl and heteroaryl groups, the term "substituted" means any level of substitution where such substitution is permitted, i.e., monosubstituted, disubstituted, trisubstituted, tetrasubstituted, or pentasubstituted. The substituent is chosen independently, and the substitution can be located at any chemically accessible position. The term "unsubstituted" means that a given moiety can consist only of hydrogen substituents by means of available valence states (unsubstituted).

[0149] If the functional group is described as “optionally substituted”, then the functional group may be (1) unsubstituted or (2) substituted. If the carbon of the functional group is described as optionally substituted with one or more of a series of substituents, then one or more hydrogen atoms on the carbon (to any extent possible, as long as they are present) may be replaced independently and / or together with independently selected optional substituents.

[0150] The term "sulfide" is derived from -SR, where R is H, alkyl, carbocyclic, heterocyclic, carbocycloalkyl, or heterocyclic alkyl. Specific sulfide groups include mercapto; alkyl sulfides, such as methyl sulfides (-S-Me); aryl sulfides, such as phenyl sulfides; and aralkyl sulfides, such as benzyl sulfides.

[0151] "Sulfinyl group" means the group -S(O)-. Note that the sulfinyl group can be further substituted with various substituents to form different sulfinyl groups, including sulfinic acids, sulfinamides, sulfinic esters, and sulfoxides.

[0152] "Sulfoyl group" means the group -S(O)(O)-. Note that the sulfonyl group can be further substituted with various substituents to form different sulfonyl groups, including sulfonic acids, sulfonamides, sulfonates, and sulfones.

[0153] "Thiocarbonyl" means the group -C(S)-. Note that thiocarbonyl can be further substituted with various substituents to form different thiocarbonyl groups, including thioacids, thioamides, thioesters, and thioketones.

[0154] "Animal" includes humans, non-human mammals (such as non-human primates, rodents, mice, rats, hamsters, dogs, cats, rabbits, cattle, horses, sheep, goats, pigs, deer, etc.) and non-mammals (such as birds, etc.).

[0155] As used herein, “bioavailability” refers to the fraction or percentage of an administered dose of a drug or pharmaceutical composition that completely reaches the systemic circulation. Typically, when a drug is administered intravenously, its bioavailability is 100%. However, when a drug is administered via other routes (e.g., oral), its bioavailability decreases (e.g., due to incomplete absorption and first-pass metabolism). Methods to improve bioavailability include prodrug pathways, salt synthesis, particle size reduction, complexation, alteration of physical form, solid dispersions, spray drying, and hot melt extrusion.

[0156] "Disease" specifically includes any unhealthy condition of an animal or its parts, including unhealthy conditions that may be caused by or accompany medical or veterinary treatments applied to the animal, i.e., "side effects" of such treatments.

[0157] "Pharmaceutical acceptable" means that the substances used to prepare pharmaceutical compositions are generally safe, non-toxic, and neither biologically nor otherwise undesirable, and include those acceptable for veterinary and human medical use.

[0158] "Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of the compounds of the present invention as defined above, and the salt possesses the desired pharmacological activity. Such salts include acid addition salts that form with inorganic or organic acids. Pharmaceutically acceptable salts also include base addition salts, which can be formed in the presence of acidic protons capable of reacting with inorganic or organic bases. Exemplary salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, tartrate, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucurons, sucrose salts, formates, benzoates, glutamates, mesylates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, bis(hydroxynaphthyl)ates (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthylcarbamate)), alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. Pharmaceutically acceptable salts may involve the inclusion of another molecule such as an acetate ion, a succinate ion, or other counterions. The counter ion can be any organic or inorganic part that stabilizes the charge of the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. For examples where multiple charged atoms are part of a pharmaceutically acceptable salt, the salt may have multiple counter ions. Therefore, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counter ions.

[0159] "Pharmaceutically acceptable carrier" refers to a non-toxic solvent, dispersant, excipient, adjuvant, or other material that is mixed with the compounds of the present invention to form a pharmaceutical composition, i.e., a dosage form that can be administered to a patient. Examples of pharmaceutically acceptable carriers include suitable polyethylene glycol (e.g., PEG400), surfactants (e.g., Cremophor) or cyclic polysaccharides (e.g., hydroxypropyl-β-cyclodextrin or sulfobutyl ether β-cyclodextrin), polymers, liposomes, micelles, nanospheres, etc.

[0160] As defined by the International Union of Pure and Applied Chemistry (IUCN), a pharmacophore is a set of spatial and electronic features necessary to ensure optimal supramolecular interaction with a specific biological target and to trigger (or block) its biological response. For example, camptothecin is the pharmacophore of the well-known drugs topotecan and irinotecan. Nitrogen mustard is the pharmacophore of a range of widely used nitrogen mustard drugs such as melphalan, cyclophosphamide, and bendamustine.

[0161] "Prodrug" means a compound that can be metabolized in vivo into the active pharmaceutical ingredient according to the invention. For example, an inhibitor containing a hydroxyl group can be administered in the form of an ester, which can be hydrolyzed in vivo to form a hydroxyl compound.

[0162] "Stability" generally refers to the length of time a drug retains its properties without losing its potential. Sometimes this refers to shelf life. Factors affecting drug stability also include, in particular, the drug's chemical structure, impurities in the formulation, pH, water content, and environmental factors such as temperature, oxidation, light, and relative humidity. Stability can be improved by providing appropriate chemical and / or crystal modifications (e.g., surface modifications that alter hydration kinetics; different crystals with different properties), excipients (e.g., any substance other than the active ingredient in the dosage form), encapsulation conditions, storage conditions, etc.

[0163] The “therapeutic effective dose” of the compositions described herein refers to the amount of the composition that provides a therapeutic effect to the treated subject with a reasonable benefit / risk ratio suitable for any medical intervention. This therapeutic effect can be objective (i.e., measurable by some test or biomarker) or subjective (i.e., the subject presents signs or feelings of effect). The effective dose of the above-described compositions can range from about 0.1 mg / kg to about 500 mg / kg, preferably from about 0.2 to about 50 mg / kg. The effective dose will also vary depending on the route of administration and the possibility of co-administration with other agents. However, it should be understood that the total daily dose of the compositions of the present invention will be determined by the attending physician within the scope of reliable medical judgment. The specific therapeutic effective dose level for a particular patient will depend on a variety of factors, including the condition being treated and its severity; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health condition, sex, and diet; the time of administration, route of administration, and the excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors known in the medical field.

[0164] As used herein, the term "treatment" means the administration of a compound to a subject having a neobiological or immune disorder, or having its symptoms or causes, with the aim of curing, resolving, alleviating, altering, remedying, reducing, improving, or influencing the disorder, its symptoms, or its causes. The term "effective amount" means the amount of active agent required to impart the desired therapeutic effect to the subject. As those skilled in the art will recognize, the effective amount can vary depending on the route of administration, the use of excipients, and the possibility of co-administration with other agents.

[0165] "Subject" refers to both humans and non-human animals. Examples of non-human animals include all vertebrates, such as mammals, non-human primates (especially higher primates), dogs, rodents (e.g., mice or rats), guinea pigs, cats, and non-mammals such as birds, amphibians, reptiles, etc. In a preferred embodiment, the subject is a human. In another specific embodiment, the subject is a laboratory animal or an animal suitable as a disease model.

[0166] "Combination therapy" includes administering the test compound of the present invention to a subject in combination with another bioactive ingredient (e.g., but not limited to, a second and different anti-biological agent) and a non-pharmacological therapy (e.g., but not limited to surgery or radiation therapy). For example, the compounds of the present invention may be used in combination with other pharmaceutically active compounds or non-pharmacological therapies, preferably compounds capable of enhancing the effects of the compounds of the present invention. The compounds of the present invention may be administered simultaneously (as a single formulation or a separate formulation) or sequentially with other therapies. Typically, combination therapy envisions the administration of two or more drugs / therapies in a single treatment cycle or a single course of treatment.

[0167] In one embodiment, the compounds of the present invention are administered in combination with one or more conventional chemotherapeutic agents. Conventional chemotherapeutic agents encompass a variety of treatments in the field of oncology. These agents are administered at various stages of the disease to shrink tumors, destroy residual cancer cells after surgery, induce remission, maintain remission, and / or alleviate symptoms associated with cancer or its treatment. Examples of such agents include, but are not limited to, alkylating agents such as nitrogen mustard (e.g., bendamustine, cyclophosphamide, melphalan, benzyl chlorobutyrate, ifosfamide), nitrosoureas (e.g., carmustine, lomustine, and streptozocin), ethyleneimines (e.g., thiotepa, hexamethyl melanin), alkyl sulfonates (e.g., busulfan), hydrazides and triazines (e.g., hexamethylmelamine, procarbazine, dacarbazine, and temozolomide), and platinum-based agents (e.g., carboplatin, ...). Cisplatin and oxaliplatin); plant alkaloids, such as podophyllotoxins (e.g., etoposide and tenisopide), taxanes (e.g., paclitaxel and docetaxel), vinblastine alkaloids (e.g., vincristine, vinblastine, and vinorelbine); antitumor antibiotics, such as chromomycin (e.g., actinomycin D and procainamide), anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, mitoxantrone, and idarubicin), and Miscellaneous antibiotics such as mitomycin and bleomycin; antimetabolites such as folic acid antagonists (e.g., methotrexate), pyrimidine antagonists (e.g., 5-fluorouracil, fluorouracil (Foxuridine), cytarabine, capecitabine, and gemcitabine), purine antagonists (e.g., 6-mercaptopurine and 6-thioguanine), and adenosine deaminase inhibitors (e.g., cladribine, fludarabine, nelarabine, and pentostatin). Topoisomerase inhibitors, such as topoisomerase I inhibitors (topotecan, irinotecan), topoisomerase II inhibitors (such as acridine, etoposide, etoposide phosphate, teniposide), and miscellaneous anti-neoplastic drugs, such as ribonucleotide reductase inhibitors (hydroxyurea), corticosteroid inhibitors (mitotane), antimicrotubule agents (estradiol), and retinoids (bexarotin, isotretinoin, retinoic acid (ATRA)).

[0168] In one aspect of the invention, the compound can be administered in combination with one or more targeted anticancer agents that regulate protein kinases associated with various disease states. Examples of such kinases may include, but are not limited to, ABL1, ABL2 / ARG, ACK1, AKT1, AKT2, AKT3, ALK, ALK1 / ACVRL1, ALK2 / ACVR1, ALK4 / ACVR1B, ALK5 / TGFBR1, ALK6 / BMPR1B, AMPK(A1 / B1 / G1), AMPK(A1 / B1 / G2), AMPK(A1 / B1 / G3), AMPK(A1 / B2 / G1), AMPK(A2 / B1 / G1), AMPK(A2 / B2 / G1), AMPK(A2 / B2 / G2), ARAF, ARK5 / NUAK1, ASK1 / MAP3K5, ATM, AuroraA, Aurora B, and Aurora C, AXL, BLK, BMPR2, BMX / ETK, BRAF, BRK, BRSK1, BRSK2, BTK, CAMK1a, CAMK1b, CAMK1d, CAMK1g, CAMKIIa, CAMKIIb, CAMKIId, CAMKIIg, CAMK4, CAMKK1, CAMKK2, CDC7-DBF4, CDK1-cyclin A, CDK1-cyclin B, CDK1-cyclin E, CDK2-cyclin A, CDK2-cyclin A1, CDK2-cyclin E, CDK3-cyclin E, CDK4-cyclin D1, CDK4-cyclin D3, CDK5-p25, CDK5-p35, CDK6-cyclin D1, CDK6-cyclin D3, CDK7-cyclin H, CDK9-cyclin K, CDK9-cyclin Protein T1, CHK1, CHK2, CK1a1, CK1d, CK1epsilon, CK1g1, CK1g2, CK1g3, CK2a, CK2a2, c-KIT, CLK1, CLK2, CLK 3. CLK4, c-MER, c-MET, COT1 / MAP3K8, CSK, c-SRC, CTK / MATK, DAPK1, DAPK2, DCAMKL1, DCAMKL2, DDR1, DD R2, DLK / MAP3K12, DMPK, DMPK2 / CDC42BPG, DNA-PK, DRAK1 / STK17A, DYRK1 / DYRK1A, DYRK1B, DYRK2, DYRK 3. DYRK4, EEF2K, EGFR, EIF2AK1, EIF2AK2, EIF2AK3, EIF2AK4 / GCN2, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5,EPHA6、EPHA7、EPHA8、EPHB1、EPHB2、EPHB3、EPHB4、ERBB2 / HER2、ERBB4 / HER4、ERK1 / MAPK3、ERK2 / MAPK1、ERK5 / MAPK7、FAK / PTK2、FER、FES / FPS、FGFR1、FGFR2、FGFR3、FGFR4、FGR、FLT1 / VEGFR1、FLT3、FLT4 / VEGFR3、FMS、FRK / PTK5、FYN、GCK / MAP4K2、GRK1、GRK2、GRK3、GRK4、GRK5、GRK6、GRK7、GSK3a、GSK3b、Haspin、HCK、HGK / MAP4K4、HIPK1、HIPK2、HIPK3、HIPK4、HPK1 / MAP4K1、IGF1R、IKKa / CHUK、IKKb / IKBKB、IKKe / IKBKE、IR、IRAK1、IRAK4、IRR / INSRR、ITK、JAK1、JAK2、JAK3、JNK1、JNK2、JNK3、KDR / VEGFR2、KHS / MAP4K5、LATS1、LATS2、LCK、LCK2 / ICK、LKB1、LIMK1、LOK / STK10、LRRK2、LYN、LYNB、MAPKAPK2、MAPKAPK3、MAPKAPK5 / PRAK、MARK1、MARK2 / PAR-1Ba、MARK3、MARK4、MEK1、MEK2、MEKK1、MEKK2、MEKK3、MELK、MINK / MINK1、MKK4、MKK6、MLCK / MYLK、MLCK2 / MYLK2、MLK1 / MAP3K9、MLK2 / MAP3K10、MLK3 / MAP3K11、MNK1、MNK2、MRCKa / 、CDC42BPA、MRCKb / 、CDC42BPB、MSK1 / RPS6KA5、MSK2 / RPS6KA4、MSSK1 / STK23、MST1 / STK4、MST2 / STK3、MST3 / STK24、MST4、mTOR / FRAP1、MUSK、MYLK3、MYO3b、NEK1、NEK2、NEK3、NEK4、NEK6、NEK7、NEK9、NEK11、NIK / MAP3K14、NLK、OSR1 / OXSR1、P38a / MAPK14、P38b / MAPK11、P38d / MAPK13、P38g / MAPK12、P70S6K / RPS6KB1、p70S6Kb / 、RPS6KB2、PAK1、PAK2、PAK3、PAK4、PAK5、PAK6、PASK、PBK / TOPK、PDGFRa、PDGFRb、PDK1 / PDPK1、PDK1 / PDHK1、PDK2 / PDHK2、PDK3 / P DHK3, PDK4 / PDHK4, PHKg1, PHKg2, PI3Ka (p110a / p85a), PI3Kb (p110b / p8). 5a) PI3Kd (p110d / p85a), PI3Kg (p120g), PIM1, PIM2, PIM3, PKA, PKAcb, P KAcg, PKCa, PKCb1, PKCb2, PKCd, PKCepsilon, PKCeta, PKCg, PKCiota, PKCm u / PRKD1, PKCnu / PRKD3, PKCtheta, PKCzeta, PKD2 / PRKD2, PKG1a, PKG1b, and PK G2 / PRKG2, PKN1 / PRK1, PKN2 / PRK2, PKN3 / PRK3, PLK1, PLK2, PLK3, PLK4 / SAK PRKX, PYK2, RAF1, RET, RIPK2, RIPK3, RIPK5, ROCK1, ROCK2, RON / MST1R, RO S / ROS1, RSK1, RSK2, RSK3, RSK4, SGK1, SGK2, SGK3 / SGKL, SIK1, SIK2, SLK / S TK2, SNARK / NUAK2, SRMS, SSTK / TSSK6, STK16, STK22D / TSSK1, STK25 / YSK1 STK32b / YANK2, STK32c / YANK3, STK33, STK38 / NDR1, STK38L / NDR2, STK39 / S TLK3, SRPK1, SRPK2, SYK, TAK1, TAOK1, TAOK2 / TAO1, TAOK3 / JIK, TBK1, TEC. TESK1, TGFBR2, TIE2 / TEK, TLK1, TLK2, TNIK, TNK1, TRKA, TRKB, TRKC, TRPM7 / CHAK1、TSSK2、TSSK3 / STK22C、TTBK1、TTBK2、TTK、TXK、TYK1 / LTK、TYK2、TY RO3 / SKY、ULK1、ULK2、ULK3、VRK1、VRK2、WEE1、WNK1、WNK2、WNK3、YES / YES1 ZAK / MLTK, ZAP70, ZIPK / DAPK3, KINASE, ABL1(E255K), ABL1(F317). I) ABL1(G250E), ABL1(H396P), ABL1(M351T), ABL1(Q252H), ABL1(T315I).ABL1(Y253F), ALK(C1156Y), ALK(L1196M), ALK(F1174L), ALK(R1275Q), BRAF(V599E), BTK(E41K), CHK2(I157T), c-Kit(A829P), c-KIT(D816H), c-KIT(D816V), c-Kit(D820E), c-Kit(N822K), C-Kit(T670I), c-Kit(V559D), c-Kit(V559D / V654A), c-Kit(V559D / T670I), C-Kit(V560G), c-KIT(V654A), C-MET(D1228H), C-MET(D1228N), C-MET(F1200I), c-MET(M1250T), C-MET(Y1230A), C-MET(Y1230C), C-MET(Y1230D), C-MET(Y1230H), c-Src(T341M), EGFR(G719C), EGFR(G719S), EGFR(L858R), EGFR(L861Q), EGFR(T790M), EGFR, (L858R,T790M), EGFR(d746-750 / T790M), EGFR(d746-750), EGFR(d747-749 / A750P), EGFR(d747-752 / P753S), EGFR(d752-759), FGFR1(V561M), FGFR2(N549H), FGFR3(G697C), FGFR3(K650E), FGFR3(K650M), FGFR4(N535K), FGFR4(V550E), FGFR4(V550L), FLT3(D835Y), FLT3(ITD), JAK2(V617F), LRRK2(G2019S), LRRK2(I2020T), LRRK2(R1441C), p38a(T106M), PDGFRa(D842V), PDGFRa(T674I), PDGFRa(V561D), RET(E762Q), RET(G691S), RET(M918T), RET(R749T), RET(R813Q), RET(V804L), RET(V804M), RET(Y791F), TIF2(R849W), TIF2(Y897S) and TIF2(Y1108F).

[0169] In another aspect of the invention, the compounds of the invention can be co-administered with one or more targeted anticancer agents that regulate non-kinase biological targets, pathways, or processes. Such target pathways or processes include, but are not limited to, heat shock proteins (e.g., HSP90), poly(adenosine diphosphate)-ribose polymerase (PARP), hypoxia-inducible factor (HIF), proteasomes, Wnt / Hedgehog / Notch signaling proteins, TNF-α, matrix metalloproteinases, farnesyltransferases, apoptosis pathways (e.g., Bcl-xL, Bcl-2, Bcl-w), histone deacetylases (HDAC), histone acetyltransferases (HAT), and methyltransferases (e.g., histone lysine methyltransferase, histone arginine methyltransferase, DNA methyltransferase, etc.).

[0170] In another aspect of the invention, the compounds of the invention are administered in combination with one or more other anticancer agents, including but not limited to gene therapy, RNAi cancer therapy, chemopreservatives (e.g., amfostine, mesna, dexazosin), drug-antibody conjugates (e.g., brentuximab vedotin, ibritumomab tioxetan), cancer immunotherapy (e.g., interleukin-2), cancer vaccines (e.g., sipuleucel-T), or monoclonal antibodies (e.g., bevacizumab, alemtuzumab, rituximab, trastuzumab, etc.).

[0171] In another aspect of the invention, the subject compound is administered in combination with radiotherapy or surgery. Radiation is typically delivered internally (by implanting radioactive material near the cancer site) or externally from a machine that uses photons (X-rays or gamma rays) or particle radiation. Where the combination therapy further includes radiotherapy, radiotherapy can be administered at any suitable time, provided that the beneficial effects resulting from the combined action of the therapeutic agent and the radiotherapy are achieved. For example, where appropriate, the beneficial effects may persist for days or even weeks after the radiotherapy is temporarily removed from the administration of the therapeutic agent.

[0172] In some embodiments, the compounds of the present invention are administered in combination with one or more of radiotherapy, surgical, or anticancer agents, including but not limited to DNA disruptors, antimetabolites, topoisomerase inhibitors, antimicrotubule agents, kinase inhibitors, epigenetic agents, HSP90 inhibitors, PARP inhibitors, BCL-2 inhibitors, drug-antibody conjugates, and antibodies targeting VEGF, HER2, EGFR, CD50, CD20, CD30, CD33, etc.

[0173] In some embodiments, the compounds of the present invention are administered in combination with one or more of the following: abaricicliz, abiraterone acetate, interleukin, alenzusmab, hexamethylmelamine, anastrozole, asparaginase, bendamustine, bevacizumab, bexarotine, bicalutamide, bleomycin, bortezombi, brentuximab vedotin, busulfan, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarapine, clomiphene, crizotinib, cyclophosphamide, dasatinib, daunorubicin liposomes, decitabine, degarelix, denileukin diftitox, denosumab, docetaxel, doxorubicin, doxorubicin liposomes, epirubicin, eribulin mesylate. mesylate), erlotinib, estradiol, etoposide phosphate, everolimus, exemestane, fludarabine, fluorouracil, formustin, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histamine relin acetate, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon ALFA 2A, ipilimumab, ixabepilone, lapatinib dibenzenesulfonate ditosylate), lenalidomide, letrozole, calcium leucovorin, leuprolide acetate, levamisole, lomustine, nitrogen mustard, melphalan, methotrexate, mitomycin C, mitoxantrone, nelarabine, nilotinib, oxaliplatin, paclitaxel, paclitaxel protein-bound particles, pamidronate, panitumumab, pegaspargase, PEG interference Alfa-2b, Pemetrexed disodium, Pentostatin, Raloxifene, Rituximab, Sorafenib, Strezoxine, Sunitinib Maleate, Tamoxifen, Sirolimus, Teniposide, Thalidomide, Toremifene, Tosimomab, Trastuzumab, Retinoic acid, Uramustin, Vandetanib, Vemurafenib, Vinorelbine, Zoledronic acid, Radiation therapy or surgery.

[0174] In some embodiments, the compounds of the present invention are administered in combination with one or more anti-inflammatory agents. Anti-inflammatory agents include, but are not limited to, NSAIDs, non-specific and COX-2 specific cyclooxygenase inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptor antagonists, immunosuppressants, and methotrexate. Examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, sodium nabumetone, sulfasalazine, tolmetin sodium, and hydroxychloroquine. Examples of NSAIDs also include COX-2 specific inhibitors such as celecoxib, valdecoxib, lumiracoxib, and / or etoricoxib.

[0175] In some implementations, the anti-inflammatory agent is a salicylate (ester). Salicylates (esters) include, but are not limited to, acetylsalicylic acid or aspirin, sodium salicylate and choline and magnesium salicylate. The anti-inflammatory agent can also be a corticosteroid. For example, a corticosteroid can be cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, or prednisone.

[0176] In another implementation, the anti-inflammatory agent is a gold compound, such as sodium gold thiomalate or auranophenol.

[0177] The invention also includes embodiments in which the anti-inflammatory agent is a metabolic inhibitor, such as a dihydrofolate reductase inhibitor, such as methotrexate, or a dihydroorotate dehydrogenase inhibitor, such as leflunomide.

[0178] Other embodiments of the invention involve combinations in which at least one anti-inflammatory compound is an anti-C5 monoclonal antibody (such as eculizumab or pexelizumab), a TNF antagonist such as entanercept or infliximab, which is an anti-TNF alpha monoclonal antibody.

[0179] In some embodiments, the compounds of the present invention are administered in combination with one or more immunosuppressants.

[0180] In some implementations, the immunosuppressants are glucocorticoids, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, leflunomide, cyclosporine, tacrolimus, mycophenolate mofetil, actinomycin D, anthracyclines, mitomycin C, bleomycin, mithramycin, or fingolimod.

[0181] The present invention further provides methods for preventing or treating neobial diseases, autoimmune diseases, or inflammatory conditions. In one embodiment, the present invention relates to a method of treating a neobial disease, autoimmune disease, or inflammatory condition in a subject requiring treatment, the method comprising administering a therapeutically effective amount of the compound of the present invention to the subject. In one embodiment, the present invention further provides the use of the compound of the present invention in the preparation of a medicament for stopping or reducing a neobial disease, autoimmune disease, or inflammatory condition.

[0182] In one implementation, the neoplastic disease is a B-cell malignancy, including but not limited to B-cell lymphoma, lymphoma (including Hodgkin's lymphoma and non-Hodgkin's lymphoma), pilocellular lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), multiple myeloma, chronic and acute myeloid leukemia, and chronic and acute lymphoblastic leukemia.

[0183] Autoimmune and / or inflammatory diseases that can be affected by the compounds and compositions according to the invention include, but are not limited to, allergic reactions, Alzheimer's disease, acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune hemolytic and thrombocytopenic states, autoimmune hepatitis, autoimmune inner ear disease, bullous pemphigoid, celiac disease, Chagas disease, chronic obstructive pulmonary disease, chronic idiopathic thrombocytopenic purpura (ITP), Churg-Strauss syndrome, Crohn's disease, dermatomyositis, type 1 diabetes, endometriosis, Goodpasture's syndrome (and associated glomerulonephritis and pulmonary hemorrhage), and Graves' disease. Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, interstitial cystitis, irritable bowel syndrome, lupus erythematosus, scleroderma, multiple sclerosis, myasthenia gravis, narcolepsy, neuromuscular syndrome, Parkinson's disease, pemphigus vulgaris, pernicious anemia, polymyositis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, schizophrenia, septic shock, scleroderma, Sjögren's syndrome, systemic lupus erythematosus (and related glomerulonephritis), temporal arteritis, organ graft rejection and hyperacute rejection of transplanted organs, vasculitis (ANCA-associated vasculitis and other vasculitis), vitiligo, and Wegener's granulomatosis.

[0184] It should be understood that the present invention is not limited to the specific embodiments shown and described herein, and various changes and modifications can be made without departing from the spirit and scope of the invention as defined by the claims.

[0185] The compounds according to the invention can be synthesized according to various reaction schemes. The necessary starting materials can be obtained through standard organic chemistry processes. A better understanding of the compounds and processes of the invention can be achieved by referring to the representative synthetic schemes and examples below, which are for illustrative purposes only and not for limiting the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and such changes and modifications can be made, including but not limited to changes and modifications related to chemical structure, substituents, derivatives, and / or the methods of the invention, without departing from the spirit of the invention and the scope of the appended claims.

[0186] In Scheme A, reactant 5 can be prepared by reacting 3,5-dibromo-1-methylpyrazine-2(1H)-one with a suitable aniline. The nitro group in reactant 5 can be other groups, such as a protected amine group or a -NHC(O)-head.

[0187] Typical starting materials (CAS1346674-23-4) is commercially available. However, the reported routes to this intermediate (e.g., in WO 2013067274) require at least seven synthetic steps. The synthesis is not only lengthy but also involves several toxic or hazardous reagents and solvents with environmental responsibility. In Scheme 1 of this paper, we describe a new, more efficient, and cost-effective route (three synthetic steps) focused on sustainable chemical use:

[0188]

[0189] In Scheme 1, the starting material 3-methylcyclopent-2-en-1-one is converted to 3,3-dimethylcyclopent-1-one in high yield via a standard organic reaction, which can be further converted to intermediate 3. Finally, intermediate 3 can react with piperazine-2-one to produce the target molecule CAS1346674-23-4.

[0190] intermediate It can be prepared by using different starting materials and reagents, similar to Scheme 1.

[0191] intermediate It can be prepared by a method similar to Scheme 1, by using different starting materials and reagents, or by standard organic reactions.

[0192] intermediate It can be prepared by a method similar to Scheme 1, by using different starting materials and reagents, or by standard organic reactions.

[0193] Scheme A describes the synthesis of compound (IV) in which R3 is -CH2OH. The typical approach. In general scheme A, R1, R4, X, warhead, and m are the same as those described in the overview section above.

[0194]

[0195] In scheme A, a suitable starting material 1 can react with 2 to form intermediate 3, which can be converted to 4 in high yield by a standard organic reaction. Simultaneously, intermediate 5 can be obtained by reacting a commercially available 3,5-dibromo-1-methylpyrazine-2(1H)-one (CAS 87486-34-8) with a suitable 4-substituted 3-nitroaniline. The coupling reaction of 4 and 5 then yields a nitro intermediate 6, which can be reduced to an amine intermediate 7. Finally, 7 can be reduced to an alcohol intermediate 8, which can be reacted with a suitable acryloyl chloride to produce formula (IV).

[0196] Compound (III) It can be prepared by using different starting materials and reagents, similar to scheme A.

[0197] Compound of formula (II) It can be prepared by using different starting materials and reagents, similar to scheme A.

[0198] Compound of formula (I) It can be prepared by using different starting materials and reagents, similar to scheme A.

[0199] The compounds and processes of the present invention can be better understood by referring to the following examples, which are intended to be illustrative only and not to limit the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and such changes and modifications can be made, including but not limited to changes and modifications related to chemical structure, substituents, derivatives, and / or the methods of the present invention, without departing from the spirit of the invention and the scope of the appended claims.

[0200] If NMR data is presented, then 1 ¹H spectra were obtained on an XL400 (400 MHz) and reported in ppm low magnetic field from Me4Si, with proton number, multiplicity, and coupling constant in Hertz indicated in parentheses. If HPLC data are presented, analysis was performed using an Agilent 1100 system. If LC / MS data are presented, analysis was performed using an Applied Biosystems API-100 mass spectrometer and a Shimadzu SCL-10 ALC column.

[0201] Example 1: Preparation of 7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one.

[0202] A solution of CuI (47.6 g, 249.93 mmol, 1.20 equivalents) in diethyl ether (500 mL) was placed in a 1000 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. MeLi (286 mL / 2 M, 2.20 equivalents) was added to the solution at 0 °C, and the mixture was stirred at the same temperature for 2 hours. 3-Methylcyclopent-2-en-1-one (20 g, 208.06 mmol, 1.00 equivalents) was added to the solution at the same temperature. The resulting solution was stirred in a water / ice bath at 0 °C for 2 hours. The reaction was then quenched by adding 500 mL of NH₄Cl (aq.) when TLC showed the disappearance of SM (PE:EA = 1:1). The resulting solution was extracted with 3 × 200 mL diethyl ether, the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. 21 g (90%) of 3,3-dimethylcyclopentan-1-one was obtained as a colorless oil.

[0203] A solution of N,N-dimethylformamide (41.6 g, 569.16 mmol, 3.00 equivalents) in dichloromethane (200 mL) was placed in a 500 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. POCl3 (57.3 g, 373.70 mmol, 2.00 equivalents) was added to the solution at 0 °C, and the reaction mixture was stirred at room temperature for 1.5 h. 3,3-dimethylcyclopentan-1-one (21.0 g, 187.22 mmol, 1.00 equivalents) was added to the solution at the same temperature. The resulting solution was stirred overnight in an oil bath at 55 °C. The reaction was then quenched by adding 200 mL of aqueous NaAcO when TLC showed the reaction was complete (PE:EA = 1:1). The resulting solution was extracted with 3 × 200 dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. 30g (crude product) of 2-chloro-4,4-dimethylcyclopent-1-ene-1-carbaldehyde was obtained as a brown oil.

[0204] A solution of piperazine-2-one (18.7 g, 186.78 mmol, 1.00 equivalent) and DIEA (24.2 g, 187.25 mmol, 1.00 equivalent) in NMP (45 mL) was placed in a 250 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. Then, 2-chloro-4,4-dimethylcyclopent-1-ene-1-carboxaldehyde (29.7 g, 187.23 mmol, 1.00 equivalent) was added dropwise to the solution at 100 °C. The resulting solution was stirred in an oil bath at 100 °C for 30 min. The reaction was then quenched by adding 200 mL of water when TLC showed that the reaction was complete (EA). The solid was collected by filtration. 20 g (52%) of 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one was obtained as a grayish-white solid. LC-MS: (ES, m / z): 205 [M+H] + . 1 H-NMR: (300MHz, d6-DMSO, ppm): δ7.38 (s, 1H), 6.36 (s, 1H), 3.92 (t, J = 5.9Hz, 2H), 3.45 (m, 2H), 2.50 (s, 2H), 2.38 (s, 2H), 1.19 (s, 6H).

[0205] Example 2: Preparation of N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-methylpiperazin-1-yl)phenyl)acrylamide

[0206] A mixture of 4-fluoro-3-nitroaniline (100 g, 0.64 mol) and N-methylpiperazine (256 g, 2.56 mol) was dissolved in ethanol. The mixture was refluxed for 24 h, then allowed to cool to room temperature. The reaction was concentrated under vacuum and filtered to give 4-(4-methylpiperazin-1-yl)-3-nitroaniline (131 g, 86%) as a red solid. ¹H-NMR (300 MHz, CDCl₃): 7.11 (d, 1H), 7.02 (d, 1H), 6.807–6.845 (m, 1H), 3.76 (s, 2H), 2.98 (m, 4H), 2.557 (m, 4H), 2.35 (s, 3H).

[0207] A mixture of 4-(4-methylpiperazin-1-yl)-3-nitroaniline (14.53 g, 0.0615 mol), 3,5-dibromo-1-methylpyrazine-2(1H)-one (16.5 g, 0.0615 mol), cesium carbonate (40.1 g, 0.123 mol), DMF (14 ml) and 1,4-dioxane (200 ml) was bubbled with nitrogen gas through the resulting suspension for 30 minutes. Then, Xantphons (3.5 g, 0.00615 mol) and tris(dibenzylideneacetone)dipalladium (0) (6.3 g, 0.00615 mol) were added. The reaction mixture was then heated at 100 °C for 2 h. Afterward, the mixture was cooled to room temperature and diluted with 90:10 dichloromethane / methanol (500 ml) and water (300 ml). The layers were separated, and the aqueous layer was extracted with 90:10 dichloromethane / methanol (500 ml). The combined organic layers were washed with brine and dried over sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by rapid column chromatography (90:10 dichloromethane / methanol) to give D (12 g, 46%) ¹H-NMR (300 MHz, CDCl₃), 8.31 (d, 2H), 7.85 (m, 1H), 7.23 (d, 1H), 6.82 (s, 1H), 3.55 (s, 3H), 3.08 (m, 4H), 2.59 (m, 4H), 2.38 (s, 3H).

[0208] A mixture of commercially available starting materials, 4-chloro-2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)nicotinaldehyde (CAS#1434050-55-1, 1.5 g, 4.37 mmol, 1.0 equivalent), Pin2B2 (2.8 g, 11 mmol, 2.5 equivalent), Pd(dppf)Cl2 (356 mg, 0.44 mmol, 0.1 equivalent), and KOAc (1.3 g, 13 mmol, 3.0 equivalent), in 1,4-dioxane (150 mL) was refluxed under N2 atmosphere for 4 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated to yield (3.0 g) of (2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-formylpyridin-4-yl)boronic acid as a brown oil, which could be used in the next step without further purification. ESI-MS (M+H) + :354.2.

[0209] (2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-carboxypyridin-4-yl)boronic acid (from the crude product of the previous step, 4.37 mmol, 1.0 eq), 5-bromo-1-methyl-3-((4-(4-methylpiperazin-1-yl)-3-nitrophenyl)amino)pyrazin-2(1H)-one (Example 1, 900 mg, 2.2 mmol, 0.5 eq), Pd(dppf)Cl2 (360 mg, 0.44 mmol, 0.1 eq) and K2CO3 (1.5 g, 13 mol, 3.0 eq) were stirred in dioxane (50 mL) and H2O (5 mL) for 4 hours at 90 °C under a N2 atmosphere. The mixture was cooled to room temperature and concentrated, and the residue was purified by column chromatography on silica gel (DCM:MeOH = 30:1) to give 2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-4-(4-methyl-6-((4-(4-methylpiperazin-1-yl)-3-nitrophenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)nicotinaldehyde as a brown solid (600 mg, two-step Y: 40%). ESI-MS (M+H) + :652.1.

[0210] A mixture of 2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-4-(4-methyl-6-((4-(4-methylpiperazin-1-yl)-3-nitrophenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)nicotinaldehyde (600 mg, 0.92 mmol, 1.0 equivalent) and Pd / C (120 mg, 20% wt) in MeOH (20 mL) was hydrogenated at room temperature for 16 hours under an atmosphere of 1 H2 pressure. The catalyst was filtered through a diatomaceous earth (Celite) mat, and the filtrate was concentrated to give 4-(6-((3-amino-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)nicotinaldehyde as a brown solid (600 mg). ESI-MS (M+H) + :622.1.

[0211] A solution of 4-(6-((3-amino-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)nicotinaldehyde (from the crude product of the previous step, 0.92 mmol, 1.0 equivalent) in MeOH (10 mL) was added at 0 °C to a solution of NaBH4 (70 mg, 1.8 mmol, 2.0 equivalent) in MeOH (10 mL). The solution was stirred at room temperature for 16 hours. Concentration was performed, and the residue was purified by Pre-HPLC (A: H₂O, 0.05% NH₃·H₂O, B: MeCN) to give 2-(4-(6-((3-amino-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-(hydroxymethyl)pyridin-2-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one as a brown solid (150 mg, two-step Y: 56%). ESI-MS (M+H) + :624.1.

[0212] TEA (73 mg, 0.72 mmol, 3.0 equivalent) was added to a mixture of 2-(4-(6-((3-amino-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-(hydroxymethyl)pyridin-2-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one (150 mg, 0.24 mmol, 1.0 equivalent), acrylic acid (26 mg, 0.36 mmol, 1.5 equivalent), and HATU (123 mg, 0.36 mmol, 1.5 equivalent) in DMF (5 mL). The mixture was stirred at room temperature for 4 hours. The reaction mixture was purified by Pre-HPLC (A: H₂O, 0.05% NH₃·H₂O; B: MeCN) to give N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-methylpiperazin-1-yl)phenyl)acrylamide as a brown solid (38 mg, Y: 23%). ESI-MS (M+H) + 678.1. 1H NMR (400MHz, DMSO-d6) δ: 9.24 (s, 1H), 9.06 (s, 1H), 8.88 (s, 1H), 8.46 (d, J = 5.2Hz, 1H), 7.88 (d, J = 4.8Hz, 1H), 7.75 (s, 1H), 7.63 (dd,J=2.0Hz,4.4Hz,1H), 7.12(d,J=8.4Hz,1H), 6.66-6.56(m,1H), 6.57(s,1H), 6.33-6.28(m,1H), 5.79-5.76(m,1H), 5.04(br s,1H), 4.60-4.46(m,2H), 4.26-4.18(m,3H), 3.86-3.83(m,1H), 3.55(s,3H), 2.79-2.75(m,4H), 2.67-2.57(m,6H), 2.43(s,2H), 2.24(s,3H), 1.22(s,6H). Example 3: Preparation of (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetane-3-yl)piperazin-1-yl)phenyl)acrylamide

[0213] 4-Fluoro-3-nitroaniline (50 g, 320.28 mmol, 1.00 equivalent), CH3CN (500 mL), NMM (64.7 g, 639.64 mmol, 2.00 equivalent), and Cbz-Cl (87.4 g, 512.34 mmol, 1.60 equivalent) were placed in a 1000 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was fed onto a silica gel column containing ethyl acetate / petroleum ether (1:1). 45 g (48%) of N-(4-fluoro-3-nitrophenyl)carbamate was given as a yellow solid. LC-MS: (ES, m / z): [M+H] + =291, 1 H-NMR: (300MHz, CDCl3, ppm): δ8.15(m,1H), 7.65(m,1H), 7.42-7.32(m,5H), 7.22(m,1H), 6.80(s,2H), 5.22(s,2H).

[0214] A solution of N-(4-fluoro-3-nitrophenyl)carbamate benzyl ester (10 g, 34.45 mmol, 1.00 equivalent) in DMSO (100 mL), (3S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (7.58 g, 37.85 mmol), and DIEA (6.67 g, 51.61 mmol, 1.50 equivalent) were placed in a 250 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred overnight in an oil bath at 110 °C. The resulting solution was diluted with water. The resulting solution was extracted with ethyl acetate, the organic layers were combined, and concentrated under vacuum. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (1:1). 10 g (62%) of (3S)-4-(4-[[(benzyloxy)carbonyl]amino]-2-nitrophenyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester was obtained as a brown oil. LC-MS:(ES,m / z):[M+H] + =471. 1 H-NMR: (300MHz, CDCl3, ppm): δ7.86 (s, 1H), 7.60 (m, 1H), 7.44-7.31 (m, 7H), 5.21 (s, 2H), 3.9 0(t,J=11.4Hz,2H), 3.21-3.02(m,3H), 2.79-2.72(m,2H), 1.49(s,9H), 0.80(d,J=6.3Hz,3H).

[0215] A solution of (3S)-4-(4-[[(benzyloxy)carbonyl]amino]-2-nitrophenyl)-3-methylpiperazin-1-carboxylic acid tert-butyl ester (12.5 g, 26.57 mmol, 1.00 equivalent) in dioxane (100 mL) and dioxane hydrogen chloride (25 mL) were placed in a 250 mL round-bottom flask purged and maintained under a nitrogen inert atmosphere. The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under vacuum. 12.5 g (crude) of N-[4-[(2S)-2-methylpiperazin-1-yl]-3-nitrophenyl]carbamate was obtained as a brown oil. LC-MS: (ES, m / z): 371 [M+H] + .

[0216] A solution of N-[4-[(2S)-2-methylpiperazin-1-yl]-3-nitrophenyl]carbamate in ethanol (100 mL), oxetan-3-one (2.2 g, 30.53 mmol, 1.20 equivalent), and NaBH3CN (1.67 g, 26.58 mmol, 1.00 equivalent) were placed in a 250 mL round-bottom flask purged and maintained under a nitrogen inert atmosphere. The resulting solution was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (1:1). 5 g (35%) of N-[4-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]-3-nitrophenyl]carbamate was obtained as a brown oil. LC-MS:(ES,m / z):427[M+H] +1 H-NMR (300MHz, CD3OD, ppm): δ7.86(s,1H), 7.60(m,1H), 7.48-7.31(m,6H), 5.21(s,2H), 4.75-4.55(m,5H), 3.55(m,1H ), 3.26-3.10(m,2H), 2.97-2.72(m,3H), 2.30-2.11(m,3H), 1.80(t,J=4.7Hz,1H), 1.49(s,9H), 0.80(d,J=6.3Hz,3H).

[0217] A solution of N-[4-[(2S)-2-methyl-4-(oxetane-3-yl)piperazin-1-yl]-3-nitrophenyl]benzyl carbamate (5.0 g, 11.72 mmol, 1.00 equivalent) in ethanol (50 mL) and AcOH (7.0 g, 116.57 mmol, 10.00 equivalent) were placed in a 100 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. Powdered Zn (4.6 g, 6.00 equivalent) was then added. The resulting solution was stirred at room temperature for 1 h. The solid was filtered off. The resulting mixture was concentrated under vacuum and applied to a silica gel column. 1.0 g (22%) of N-[3-amino-4-[(2S)-2-methyl-4-(oxetane-3-yl)piperazin-1-yl]phenyl]benzyl carbamate was obtained as a brown oil. LC-MS:(ES,m / z):397[M+H] + . 1H-NMR (300MHz, CD3OD, ppm): δ7.46-7.31(m,5H), 7.02(m,2H), 6.75(d,J=8.4,1H), 5.20(s,2H), 4.85-4.64( m,4H), 3.67-3.55(m,3H), 3.17(m,1H), 2.92-2.78(m,4H), 2.25(m,1H), 1.95(m,1H), 0.80(d,J=6.0Hz,3H).

[0218] A solution of N-[3-amino-4-[(2S)-2-methyl-4-(oxetane-3-yl)piperazin-1-yl]phenyl]benzyl carbamate in tetrahydrofuran (10 mL), NMM (510 mg, 5.04 mmol, 2.00 equivalent), and (Boc)₂O (820 mg, 3.76 mmol, 1.50 equivalent) were placed in a 25 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (1:1). 0.9 g (72%) of N-(3-[[(tert-butoxy)carbonyl]amino]-4-[(2S)-2-methyl-4-(oxetane-3-yl)piperazin-1-yl]phenyl)benzyl carbamate was obtained as a brown oil. LC-MS:(ES,m / z):497[M+H] + .

[0219] A solution of N-(3-[[(tert-butoxy)carbonyl]amino]-4-[(2S)-2-methyl-4-(oxetane-3-yl)piperazin-1-yl]phenyl]benzyl carbamate in methanol (10 mL) and palladium on carbon (0.1 g, 0.10 equivalent) were placed in a 50 mL round-bottom flask purged and maintained under an inert atmosphere of H2. The resulting solution was stirred at room temperature for 1 h. The solid was filtered off. The resulting mixture was concentrated under vacuum. 0.6 g (91%) of N-[5-amino-2-[(2S)-2-methyl-4-(oxetane-3-yl)piperazin-1-yl]phenyl]phenyl]carbamate tert-butyl ester was given as a brown oil. LC-MS: (ES, m / z): 363 [M+H] +1 H-NMR-PH-: (300MHz, CD3OD, ppm): δ7.46-7.31(m,5H), 7.02(m,2H), 6.75(d,J=8.4,1H), 4.78- 4.64(m,4H), 3.60(m,1H), 3.10-2.70(m,5H), 2.22(m,1H), 1.95(m,1H), 0.77(d,J=6.0Hz,3H).

[0220] A solution of N-[5-amino-2-[(2S)-2-methyl-4-(oxecyclobutan-3-yl)piperazin-1-yl]phenyl]carbamate tert-butyl in IPA (10 mL), 3,5-dibromo-1-methyl-1,2-dihydropyrazin-2-one (980 mg, 3.66 mmol, 1.00 equivalent), and DIEA (640 mg, 4.95 mmol, 1.50 equivalent) were placed in a 50 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred overnight in an oil bath at 80 °C. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (1:1). 1.2 g (66%) of N-[5-[(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino]-2-[(2S)-2-methyl-4-(oxecyclobutan-3-yl)piperazin-1-yl]phenyl]carbamate tert-butyl ester was obtained as a brown oil. LC-MS: (ES, m / z): 551 [M+H] +1 H-NMR: (300MHz, CDCl3, ppm): δ8.31(s,1H), 8.20(s,1H), 7.99(s,1H), 7.20(d,J=8.7,1H), 6.95(d,J=8.7,1H), 6 .75(s,1H), 4.78-4.64(m,5H), 3.60(m,1H), 3.20-2.72(m,7H), 2.22(m,1H), 1.95(m,1H), 0.79(d,J=6.0Hz,3H).

[0221] A solution of N-[5-[(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino]-2-[(2S)-2-methyl-4-(oxetane-3-yl)piperazin-1-yl]phenyl]carbamate tert-butyl ester (600 mg, 1.09 mmol, 1.00 equivalent) in dichloromethane (6 mL) and trifluoroacetic acid (1.2 mL) were placed in a 50 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. 500 mg (crude) of 3-([3-amino-4-[(2S)-2-methyl-4-(oxetane-3-yl)piperazin-1-yl]phenyl]amino)-5-bromo-1-methyl-1,2-dihydropyrazin-2-one) as a brown oil was obtained. LC-MS:(ES,m / z):451[M+H] + .

[0222] 3-([3-amino-4-[(2S)-2-methyl-4-(oxecyclobutane-3-yl)piperazin-1-yl]phenyl]amino)-5-bromo-1-methyl-1,2-dihydropyrazin-2-one (500 mg, 1.11 mmol, 1.00 equivalent) was dissolved in a solution of dioxane (15 mL) / H2O (1 mL), and (2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2, 6]] Dodeca-2(6),7-dien-10-yl]-3-[(oxane-2-yloxy)methyl]pyridin-4-yl)boronic acid (431 mg, 0.98 mmol, 1.10 equivalent), Pd(dppf)Cl2 (50 mg, 0.07 mmol, 0.10 equivalent), and potassium carbonate (307 mg, 2.22 mmol, 2.00 equivalent) were placed in a 25-mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred in an oil bath at 100 °C for 1 hour. The resulting mixture was concentrated under vacuum, diluted with H2O, and extracted with EA. 500 mg (59%) of 10-[4-[6-([3-amino-4-[(2S)-2-methyl-4-(oxecyclobutan-3-yl)piperazin-1-yl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-[(oxane-2-yloxy)methyl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one (crude product) was obtained as a brown oil. LC-MS: (ES, m / z): 764 [M+H] + .

[0223] A solution of 10-[4-[6-([3-amino-4-[(2S)-2-methyl-4-(oxecyclobutan-3-yl)piperazin-1-yl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-[(oxane-2-yloxy)methyl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one (500 mg, 0.65 mmol, 1.00 equivalent) in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) were placed in a 50 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred in an oil bath at 40 °C for 15 min. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC. 80 mg (18%) of 10-[4-[6-([3-amino-4-[(2S)-2-methyl-4-(oxecyclobutan-3-yl)piperazin-1-yl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-(hydroxymethyl)pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one was obtained as a brown solid. LC-MS: (ES, m / z): 680 [M+H] + .

[0224] 10-[4-[6-([3-amino-4-[(2S)-2-methyl-4-(oxetane-3-yl)piperazin-1-yl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-(hydroxymethyl)pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one(8 A solution of 0 mg, 0.12 mmol, 1.00 equivalents of propionic acid (10 mg, 0.14 mmol, 1.20 equivalents), HATU (49.2 mg, 0.13 mmol, 1.10 equivalents), and NMM (17.7 mg, 0.17 mmol, 1.50 equivalents) in CH3CN (1 mL), along with 25 mL round-bottom flasks purged and maintained under an inert nitrogen atmosphere, was placed in the flasks. The resulting solution was stirred at room temperature for 1 h. The crude product was purified by Prep-HPLC. 27 mg (31%) of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl]amino]-2-[(2S)-2-methyl-4-(oxetane-3-yl)piperazin-1-yl]phenyl)prop-2-enamide was obtained as a grayish-white solid. LC-MS: (ES, m / z): 734 [M+H] +.1H-NMR: (300MHz, d6-DMSO, ppm): δ9.25 (s, 1H), 9.19 (s, 1H), 9.11 (s, 1H), 8.49 (d, J = 5.1Hz, 1H), 7.95 (d, J =5.1Hz,1H), 7.77(s,1H), 7.60(d,J=8.7,1H), 7.25(d,J=8.7,1H), 6.63-6.57(m,2H), 6.30(m,1H), 5.80(d, J=3.9Hz,1H), 5.02(m,1H), 4.65-4.41(m,6H), 4.35-4.15(m,3H), 3.85(m,1H), 3.60-3.43(m,4H), 3.10(m,1 H), 2.85-2.54(m,6H), 2.45(m,2H), 2.22(m,1H), 1.95(t,J=6.6Hz,1H), 1.25(s,6H), 0.76(d,J=6.0Hz,3H). Example 4: Preparation of (S)-N-(5-((6-(3-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-2-(hydroxymethyl)phenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetane-3-yl)piperazin-1-yl)phenyl)acrylamide

[0225] A solution of 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one (3.0 g, 14.69 mmol, 1.00 equivalent) in dioxane (30 mL), 2,6-dibromobenzaldehyde (4.65 g, 17.62 mmol, 1.20 equivalent), Cs₂CO₃ (9.6 g, 29.46 mmol, 2.00 equivalent), Pd₂(dba)₃ (300 mg, 0.33 mmol, 0.10 equivalent), and Xantphos (300 mg, 0.52 mmol, 0.10 equivalent) were placed in a 50 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred in an oil bath at 100 °C for 1 hour. The reaction mixture was cooled to RT. The solids were filtered off. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (1:1). 4.0 g (70%) of 2-bromo-6-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]benzaldehyde was obtained as a grayish-white solid. (ES, m / z): 387 [M+H] +.1H-NMR: (300MHz, CD3OD, ppm): δ10.36 (s, 1H), 7.43 (d, J = 7.8Hz, 1H), 7.25 (m, 2H), 6.60 (s ,1H), 3.99(t,J=6.0Hz,2H), 3.63(t,J=6.0Hz,3H), 2.55(s,2H), 2.45(s,2H), 1.24(s,6H).

[0226] A solution of 2-bromo-6-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]benzaldehyde (1.0 g, 2.58 mmol, 1.00 equivalent) in dioxane (10 mL), Pin2B2 (1.64 g, 2.50 equivalent), Pd(dppf)Cl2 (100 mg, 0.14 mmol, 0.10 equivalent), and KOAc (760 mg, 7.74 mmol, 3.00 equivalent) were placed in a 50 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred in an oil bath at 100 °C for 30 min. The reaction mixture was cooled to RT. The solid was filtered off. The resulting mixture was concentrated under vacuum. 400 mg (44%) of (3-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-2-formylphenyl)boronic acid was obtained as a brown solid. LC-MS (ES, m / z): 353 [M+H] + .

[0227] (3-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-2-carboxyphenyl)boronic acid (346 mg, 0.98 mmol, 1.00 equivalent), 3-([3-amino-4-[(2S)-2-methyl-4-(oxetane-3-yl)piperazin-1-yl]phenyl]amino)-5-bromo-1 A solution of methyl-1,2-dihydropyrazin-2-one (441 mg, 0.98 mmol, 1.00 equivalent) in dioxane (10 mL) / H₂O (1 mL), Pd(dppf)Cl₂ (30 mg, 0.04 mmol, 0.10 equivalent), and potassium carbonate (271 mg, 1.96 mmol, 2.00 equivalent) were placed in a 50 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred in an oil bath at 100 °C for 1 hour. The solid was filtered off. The resulting mixture was concentrated under vacuum. 500 mg (75%) of 2-[6-([3-amino-4-[(2S)-2-methyl-4-(oxecyclobutan-3-yl)piperazin-1-yl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-6-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]benzaldehyde was obtained as a brown oil. LC-MS: (ES, m / z): 677 [M+H] + .

[0228] A solution of 2-[6-([3-amino-4-[(2S)-2-methyl-4-(oxecyclobutan-3-yl)piperazin-1-yl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-6-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]benzaldehyde (500 mg, 0.74 mmol, 1.00 equivalent) in ethanol (10 mL) and NaBH4 (16.8 mg, 0.44 mmol, 0.60 equivalent) were placed in a 25 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC. 240 mg (48%) of 10-[3-[6-([3-amino-4-[(2S)-2-methyl-4-(oxecyclobutan-3-yl)piperazin-1-yl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-(hydroxymethyl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one was obtained as a light brown solid. LC-MS: (ES, m / z): 679 [M+H] + .

[0229] 10-[3-[6-([3-amino-4-[(2S)-2-methyl-4-(oxetane-3-yl)piperazin-1-yl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-(hydroxymethyl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one (240 mg) A solution of 0.35 mmol (1.00 equivalent) in CH3CN (10 mL), propionic acid (30.5 mg, 0.42 mmol, 1.20 equivalent), HATU (147.7 mg, 0.39 mmol, 1.10 equivalent), and NMM (71.4 mg, 0.71 mmol, 2.00 equivalent) was placed in a 10-mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at room temperature for 1 h. The crude product was purified by preparative HPLC. 60 mg (23%) of N-(5-[[6-(3-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-2-(hydroxymethyl)phenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl]amino]-2-[(2S)-2-methyl-4-(oxetane-3-yl)piperazin-1-yl]phenyl)prop-2-enamide was obtained as a grayish-white solid. LC-MS: (ES, m / z): 733 [M+H] + .1H-NMR: (300MHz, d6-DMSO, ppm): δ9.17(m,2H), 8.91(s,1H), 7.82-7.63(m,2H), 7.49-7.42(m,2 H), 7.40-7.23(m,2H), 6.67-6.49(m,2H), 6.25(m,1H), 5.80(d,J=10.5Hz,1H), 4.81(m,1H), 4.62- 4.40(m,6H), 4.25-4.02(m,3H), 3.93(m,1H), 3.60-3.40(m,4H), 3.10(m,1H), 2.80-2.60(m,4H), 2.55(s,2H), 2.45(s,2H), 2.22(m,1H), 1.95(t,J=6.8Hz,1H), 1.22(s,6H), 0.73(d,J=6.0Hz,3H).

[0230] Example 5: Preparation of N-(3-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)phenyl)acrylamide

[0231] N-(3-aminophenyl)carbamate tert-butyl ester (5 g, 24.01 mmol, 1.00 equivalent), 3,5-dibromo-1-methyl-1,2-dihydropyrazin-2-one (5.8 g, 21.65 mmol, 1.50 equivalent), DIEA (4.9 g, 37.98 mmol, 2.00 equivalent), and isopropanol (50 mL) were placed in a 250 mL round-bottom flask. The resulting solution was stirred overnight at 80 °C. The resulting mixture was concentrated under vacuum. The crude product was purified by rapidly increasing PE:EA = 100 / 20 to PE:EA = 100 / 50 over 30 minutes. 7.4 g (78%) of N-[3-[(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino]phenyl]carbamate tert-butyl ester was given as a pale yellow solid. LC-MS:(ES,m / z):[M+H] + =395. 1 H-NMR-: (300MHz, CDCl3, ppm): δ9.32 (s, 1H), 9.28 (s, 1H), 7.91 (s, 1H), 7.52 (d, J = 5.4Hz, 1H), 7.16-7.09 (m, 2H), 3.45 (s, 3H), 1.47 (s, 9H).

[0232] N-[3-[(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino]phenyl]carbamate tert-butyl ester (400 mg, 0.51 mmol, 1.00 equivalent) and hydrogen chloride / dioxane (10 mL) were added. The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under vacuum. 300 mg (90%) of 3-[(3-aminophenyl)amino]-5-bromo-1-methyl-1,2-dihydropyrazin-2-one was given as a yellow solid. LC-MS: (ES, m / z): [M+H] + =295.

[0233] 3-[(3-aminophenyl)amino]-5-bromo-1-methyl-1,2-dihydropyrazin-2-one (200 mg, 0.68 mmol, 1.00 equivalent), (2-4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^2,6]dodecyl-2(6),7-dien-10-yl-3-[(oxan-2-yloxy)methyl]pyridin-4-yl)boronic acid (298 mg, 0.68 mmol, 1.00 equivalent), Pd(dppf)Cl2 (58 mg, 0.07 mmol, 0.10 equivalent), potassium carbonate (281 mg, 2.04 mmol, 3.00 equivalent), dioxane (12 mL), and water (2 mL) were placed in a 50-mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at 100 °C for 30 minutes. After cooling, the resulting mixture was concentrated under vacuum. The resulting solution was diluted with methanol. The crude product was purified by rapid addition of MeCN:H2O = 25 / 75 to MeCN:H2O = 50 / 50 over 13 minutes. 280 mg (68%) of 10-(4-[6-[(3-aminophenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-[(oxan-2-yloxy)methyl]pyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one was given as a brown solid. LC-MS (ES, m / z): [M+H] + =610.

[0234] 10-(4-[6-[(3-aminophenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-[(oxan-2-yloxy)methyl]pyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one (230 mg, 0.38 mmol, 1.00 equivalent), trifluoroacetic acid (1 mL), and dichloromethane (20 mL) were placed in a 50-mL round-bottom flask. The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with ethyl acetate. The pH of the solution was adjusted to 8 with a saturated sodium bicarbonate solution. The solid was filtered off. The resulting mixture was concentrated under vacuum. 150 mg (76%) of 10-(4-[6-[(3-aminophenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-(hydroxymethyl)pyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one was obtained as a colorless oil. LC-MS--714-4:(ES,m / z):[M+H] + =526.

[0235] 10-(4-[6-[(3-aminophenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-(hydroxymethyl)pyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one (150 mg, 0.28 mmol, 1.00 equivalent), propionic acid (20.1 mg, 0.28 mmol, 1.00 equivalent), NMM (58 mg, 0.38 mmol, 2.00 equivalent), HATU (141 mg, 0.25 mmol, 1.30 equivalent), and MeCN (5 mL) were placed in a 25 mL round-bottom flask. The resulting solution was stirred at room temperature for 30 minutes. The crude product was purified by Prep-HPLC. 32.4 mg (18%) of N-(3-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl]amino]phenyl)prop-2-enamide was obtained as a grayish-white solid. LC-MS: (ES, m / z): [M+H] + =580. 1 H-NMR: (300MHz, CDCl3, ppm): δ9.99(s,1H), 9.24(s,1H), 8.47(m,2H), 7.84-7.7 3(m,2H), 7.60(d,J=7.5Hz,1H), 7.30-7.20(m,2H), 6.58(s,1H), 6.55-6.25(m,2H ), 5.76(d,J=9.9Hz,1H), 4.97(m,1H), 4.64-4.45(m,2H), 4.33-4.15(m,3H), 3.8 8(m,1H), 3.57(s,3H), 2.59(d,J=5.1Hz,2H), 2.42(d,J=5.1Hz,2H), 1.22(s,6H).

[0236] Example 7: Preparation of N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(1-(oxetane-3-yl)piperidin-4-yl)phenyl)acrylamide with 4-bromo-3-nitroaniline (5 g, 23.04 mmol, 1 2.00 equivalents of 4-(tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (14 g, 45.28 mmol, 2.00 equivalents), Pd(dppf)Cl2 (2 g, 2.33 mmol, 0.10 equivalents), potassium carbonate (19 g, 137.47 mmol, 6.00 equivalents), dioxane (80 mL), and water (20 mL) were placed in a 250 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred overnight at 90 °C. The solid was filtered off. The resulting mixture was concentrated under vacuum. The crude product was purified by rapidly increasing PE:EA = 50 / 50 to PE:EA = 20 / 80 over 30 minutes. 5.7 g (77%) of tert-butyl 4-(4-amino-2-nitrophenyl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid was obtained as a pale yellow oil. LC-MS-1:(ES,m / z):[M+H] + =320. 1 H-NMR-PH--1: (300MHz, d6-DMSO, ppm): δ7.05 (m, 2H), 6.80 (d, J = 8.1Hz, 1H), 5.74(s,2H), 5.49(s,1H), 3.88(m,2H), 3.46(t,J=10.8Hz,2H), 2.17(s,2H).

[0237] 4-(4-amino-2-nitrophenyl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (7 g, 21.92 mmol, 1.00 equivalent), water (10 mL), sodium carbonate (4.6 g, 43.40 mmol, 2.00 equivalent), and dichloromethane (50 mL) were placed in a 250-mL round-bottom flask. The resulting solution was stirred at 0 °C for 30 minutes. Subsequently, Cb2-Cl (4.5 g, 26.47 mmol, 1.20 equivalent) was added dropwise at 0 °C and stirred for 5 minutes. The resulting solution was stirred overnight at room temperature. The resulting mixture was washed with 2 x 100 mL of brine. The resulting mixture was concentrated under vacuum. 7 g (70%) of 4-(4-[[(benzyloxy)carbonyl]amino]-2-nitrophenyl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester was obtained as a yellow oil. LC-MS--2:(ES,m / z):[M+H] + =454. 1 H-NMR-PH--2: (300MHz, d6-DMSO, ppm): δ10.27 (s, 1H), 8.13 (s, 1H), 7.68 (d, J = 8.4Hz, 1H), 7. 46-7.32(m,7H),5.62(s,1H),5.19(s,2H),3.92(m,2H),3.53(t,J=10.8Hz,2H),2.24(s,2H).

[0238] 5 g (11.03 mmol, 1.00 equivalent) of 4-(4-[[(benzyloxy)carbonyl]amino]-2-nitrophenyl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester and 40 mL of hydrogen chloride / dioxane were placed in a 250 mL round-bottom flask. The resulting solution was stirred at room temperature for 1.5 hours. The resulting mixture was concentrated under vacuum. 4.5 g (crude) of N-[3-nitro-4-(1,2,3,6-tetrahydropyridine-4-yl)phenyl]carbamate was obtained as a pale yellow solid. LC-MS-3:(ES,m / z):[M+H] + =354.

[0239] 4.5 g (25.47 mmol, 1.00 equivalent) of N-[3-nitro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]carbamate, oxetane-3-one (1.35 g, 37.47 mmol, 1.50 equivalent), NaCNBH3 (1.6 g, 50.79 mmol, 2.00 equivalent), and methanol (30 mL) were placed in a 250 mL round-bottom flask. The resulting solution was stirred at 50 °C for 4 h. The solution was extracted with ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 2 x 100 mL of sodium chloride. The solid was dried under reduced pressure in an oven and concentrated under vacuum. 3.6 g (61%) of N-[3-nitro-4-[1-(oxetane-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl]carbamate was given as a white solid. LC-MS--4:(ES,m / z):[M+H] + =410. 1 H-NMR-PH--4: (300MHz, d6-DMSO, ppm): δ10.27 (s, 1H), 8.09 (s, 1H), 7.67 (d, J = 8.4Hz, 1H), 7.46-7.32 (m, 6H), 5.59 (s,1H), 5.19(s,2H), 4.56(t,J=9Hz,2H), 4.49(t,J=9Hz,2H), 3.60(m,1H), 2.92(s,2H), 2.48(m,2H), 2.26(s,2H).

[0240] N-[3-nitro-4-[1-(oxecyclobutan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl]carbamate (3.6 g, 8.79 mmol, 1.00 equivalent), acetic acid (5.25 g, 87.42 mmol, 10.00 equivalent), ethanol (25 mL), and zinc (2.8 g, 42.81 mmol, 5.00 equivalent) were placed in a 50-mL round-bottom flask. The resulting solution was stirred at room temperature for 30 minutes. The solid was filtered off. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with ethyl acetate. The pH was adjusted to 8 with sodium carbonate (1 mol / L). The resulting mixture was washed with 2 x 200 mL H₂O. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by rapidly increasing PE:EA = 100 / 30 to PE:EA = 100 / 50 over 45 minutes. 2.5 g (75%) of N-[3-amino-4-[1-(oxetane-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl]carbamate was obtained as a yellow oil. LC-MS--5:(ES,m / z):[M+H] + =380. 1H-NMR-PH--5: (300MHz, d6-DMSO, ppm): δ9.61 (s, 1H), 7.52-7.28 (m, 5H), 6.87 (s, 1H), 6.77 (d, J = 7.8Hz, 1H), 6.61 (d, J = 8.1Hz, 1H), 5.60(s,1H), 5.13(s,2H), 4.74(s,2H), 4.57(t,J=9Hz,2H), 4.50(t,J=9Hz,2H), 3.52(m,1H), 2.92(s,2H), 2.48(m,2H), 2.28(s,2H).

[0241] N-[3-amino-4-[1-(oxecyclobutan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl]carbamate (2.5 g, 13.18 mmol, 1.00 equivalent), TEA (2 g, 39.53 mmol, 3.00 equivalent), di-tert-butyl dicarbonate (1.75 g, 16.04 mmol, 1.30 equivalent), and tetrahydrofuran (30 mL) were placed in a 250 mL round-bottom flask. The resulting solution was stirred overnight at 65 °C. The resulting mixture was concentrated under vacuum. The crude product was purified by rapidly increasing PE:EA = 100 / 30 to PE:EA = 100 / 50 over 25 minutes. Two g (63%) of N-(3-[[(tert-butoxy)carbonyl]amino]-4-[1-(oxecyclobutan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl)carbamate was obtained as a yellow oil. LC-MS--6:(ES,m / z):[M+H] + =480. 1 H-NMR-PH--6: (300MHz, d6-DMSO, ppm): δ9.74(s,1H), 8.20(s,1H), 7.47-7.28(m,6H), 7.24(d,J=8.1Hz,1H), 7.05(d,J=8.4Hz,1H), 5.75(s ,1H), 5.14(s,2H), 4.57(s,2H), 4.57(t,J=9Hz,2H), 4.50(t,J=9Hz,2H), 3.54(m,1H), 2.92(s,2H), 2.48(m,2H), 2.28(s,2H), 1.22(s,9H).

[0242] 1.4 g (2.92 mmol, 1.00 equivalent) of benzyl N-(3-[[(tert-butoxy)carbonyl]amino]-4-[1-(oxetane-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl)carbamate, 1.4 g, 1.00 equivalent, palladium on carbon (140 mg, 0.10 equivalent), and ethyl acetate (40 mL) were placed in a 250 mL round-bottom flask purged and maintained under an inert H2 atmosphere. The resulting solution was stirred overnight at room temperature. The solid was filtered off. The resulting mixture was concentrated under vacuum. 610 mg (60%) of tert-butyl N-[5-amino-2-[1-(oxetane-3-yl)piperidin-4-yl]phenyl]carbamate was given as a pale yellow solid. LC-MS-7: (ES, m / z): [M+H] + =348. 1 H-NMR-PH--7: (300MHz, d6-DMSO, ppm): δ8.26 (s, 1H), 6.90 (d, J = 7.8Hz, 1H), 6.40 (m, 2H), 4.87 (s, 2H), 4.54 (t, J = 7 .2Hz,2H), 4.46(t,J=7.2Hz,2H), 3.37(m,1H), 2.78(d,J=10.8Hz,2H), 2.60(m,1H), 1.80-1.45(m,6H), 1.21(s,9H).

[0243] N-[5-amino-2-[1-(oxecyclobutan-3-yl)piperidin-4-yl]phenyl]carbamate tert-butyl ester (600 mg, 2.30 mmol, 1.00 equivalent), 3,5-dibromo-1-methyl-1,2-dihydropyrazin-2-one (550 mg, 2.74 mmol, 1.20 equivalent), DIEA (435 mg, 4.50 mmol, 2.50 equivalent), and isopropanol (25 mL) were placed in a 50 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred overnight at 80 °C. The resulting mixture was concentrated under vacuum. The crude product was purified by rapid PE:EA = 100 / 85. 600 mg (65%) of N-[5-[(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino]-2-[1-(oxecyclobutan-3-yl)piperidin-4-yl]phenyl]carbamate tert-butyl ester was obtained as a pale yellow solid. LC-MS--8:(ES,m / z):[M+H] + =534. 1H-NMR-PH--8: (300MHz, d6-DMSO, ppm): δ9.40(s,1H), 8.57(s,1H), 7.79(s,1H), 7.72(d,J=8.4Hz,1H), 7.32(s,1H), 7.23(d,J= 8.4Hz,1H), 4.54(t,J=6.3Hz,2H), 4.46(t,J=6.3Hz,2H), 3.45-3.37(m,5H), 2.83-2.70(m,3H), 1.83-1.52(m,6H), 1.38(s,9H).

[0244] N-[5-[(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino]-2-[1-(oxetane-3-yl)piperidin-4-yl]phenyl]carbamate tert-butyl ester (600 mg, 1.12 mmol, 1.00 equivalent), trifluoroacetic acid (2 mL), and dichloromethane (20 mL) were placed in a 250 mL round-bottom flask. The resulting solution was stirred at room temperature for 3 h. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with methanol and the pH was adjusted to 8 with potassium carbonate. The solid was filtered off. The resulting mixture was concentrated under vacuum. 410 mg (84%) of 3-([3-amino-4-[1-(oxetane-3-yl)piperidin-4-yl]phenyl]amino)-5-bromo-1-methyl-1,2-dihydropyrazin-2-one was given as a pale yellow solid. LC-MS--9:(ES,m / z):[M+H] + =434.

[0245] 3-([3-amino-4-[1-(oxetane-3-yl)piperidin-4-yl]phenyl]amino)-5-bromo-1-methyl-1,2-dihydropyrazin-2-one (300 mg, 0.7 mmol, 1.00 equivalent), (2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-[( Dioxane (350 mg, 0.8 mmol, 1.10 equivalents), Pd(dppf)Cl2 (60 mg, 0.03 mmol, 0.10 equivalents), K2CO3 (286 mg, 2.03 mmol, 3.00 equivalents), dioxane (20 mL), and water (2 mL) were placed in a 50 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at 100 °C for 30 min. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with methanol. The crude product was purified by rapidly increasing the MeCN:H2O ratio from 20 / 80 to 55 / 45 over 12 min. 210 mg (81%) of 10-[4-[6-([3-amino-4-[1-(oxecyclobutan-3-yl)piperidin-4-yl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-[(oxan-2-yloxy)methyl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one was obtained as a pale yellow solid. LC-MS-10:(ES,m / z):[M+H] + =749.

[0246] 10-[4-[6-([3-amino-4-[1-(oxecyclobutan-3-yl)piperidin-4-yl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-[(oxan-2-yloxy)methyl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one (210 mg, 0.28 mmol, 1.00 equivalent), dichloromethane (10 mL), and trifluoroacetic acid (1 mL) were placed in a 25-mL round-bottom flask. The resulting solution was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum and the pH was adjusted to 8 with sodium bicarbonate solution. The resulting mixture was extracted with EA and washed with brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. 135 mg (72%) of 10-[4-[6-([3-amino-4-[1-(oxecyclobutan-3-yl)piperidin-4-yl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-(hydroxymethyl)pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one was obtained as a pale yellow solid. LC-MS-11:(ES,m / z):[M+H] + =665. 1 H-NMR-PH--11: (300MHz, CDCl3, ppm): δ8.55 (d, J = 5.1Hz, 1H), 8.20 (s, 1H), 8.00 (s, 1H) ), 7.76(d,J=5.1Hz,1H), 7.29(s,1H), 7.23(d,J=5.7Hz,1H), 7.23(d,J=5.4Hz,1H), 6. 85(s,1H), 5.02(m,1H), 4.82-4.37(m,7H), 4.20(m,2H), 3.92(m,1H), 3.70-3.50(m,5H ), 2.98(m,2H), 2.62-2.47(m,5H), 2.07-1.82(m,6H), 1.73-1.45(m,5H), 1.28(s,6H).

[0247] 10-[4-[6-([3-amino-4-[1-(oxecyclobutan-3-yl)piperidin-4-yl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-(hydroxymethyl)pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one (135 mg, 0.23 mmol, 1.00 equivalent), propionic acid (17 mg, 0.23 mmol, 1.00 equivalent), HATU (94 mg, 0.25 mmol, 1.10 equivalent), NMM (54 mg, 0.53 mmol, 2.50 equivalent), and MeCN (5 mL) were placed in a 25 mL round-bottom flask. The resulting solution was stirred at room temperature for 30 minutes. The crude product was purified by Prep-HPLC. 15.2 mg (11%) of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl]amino]-2-[1-(oxetane-3-yl)piperidin-4-yl]phenyl)prop-2-enamide was obtained as a white solid. LC-MS--O:(ES,m / z):[M+H] + =719. 1 H-NMR-PH--0: (300MHz, CDCl3, ppm): δ9.54 (s, 1H), 9.32 (s, 1H), 8.45 (d, J = 4.8Hz, 1H), 8 .32(m,1H), 7.79-7.70(m,3H), 7.25(d,J=8.7Hz,1H), 6.61-6.44(m,2H), 6.27(m,1H), 5. 75(d,J=10.8Hz,1H), 5.01(m,1H), 4.67-4.42(m,6H), 4.35-4.15(m,3H), 3.87(m,1H), 3. 57(s,3H), 3.40(m,1H), 2.85-2.57(m,5H), 2.45(m,2H), 1.84-1.55(m,6H), 1.23(s,6H). Example 8: Preparation of N-(5-((6-(3-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-2-(hydroxymethyl)phenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(1-(oxetane-3-yl)piperidin-4-yl)phenyl)acrylamide

[0248] 3-([3-amino-4-[1-(oxecyclobutan-3-yl)piperidin-4-yl]phenyl]amino)-5-bromo-1-methyl-1,2-dihydropyrazin-2-one (300 mg, 0.69 mmol, 1.00 equivalent), (3-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-2-formylphenyl)boronic acid (260 mg, 0.74 mmol, 1.10 equivalent), Pd(dppf)Cl2 (35 mg, 0.05 mmol, 0.10 equivalent), potassium carbonate (286 mg, 2.07 mmol, 3.00 equivalent), dioxane (15 mL), and water (2 mL) were placed in a 25-mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred for 40 minutes at 100°C for 2 hours. The resulting mixture was concentrated under vacuum. The resulting solution was extracted with methanol, and the organic layers were combined. The crude product was purified by rapidly increasing the concentration of MeCN:H2O from 30 / 70 to 65 / 35 over 12 minutes. 268 mg (59%) of 2-[6-([3-amino-4-[1-(oxecyclobutan-3-yl)piperidin-4-yl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-6-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]benzaldehyde was obtained as a pale yellow solid. LC-MS-1:(ES,m / z):662[M+H] + .

[0249] 2-[6-(3-amino-4-[1-(oxecyclobutan-3-yl)piperidin-4-yl]phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-6-4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^2,6]dodecyl-2(6),7-diene-10-ylbenzaldehyde (240 mg, 0.36 mmol, 1.00 equivalent), NaBH4 (7 mg, 0.18 mmol, 0.50 equivalent), and ethanol (8 mL) were placed in a 25-mL round-bottom flask. The resulting solution was stirred at room temperature for 30 minutes. The resulting solution was concentrated and diluted with methanol. The pH was adjusted to 8 with potassium carbonate. The solid was filtered off, and the filtrate was concentrated under vacuum. 132 mg (55%) of 10-[3-[6-([3-amino-4-[1-(oxecyclobutan-3-yl)piperidin-4-yl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-(hydroxymethyl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one was obtained as a pale yellow oil. LC-MS--2:(ES,m / z):664[M+H] +1 H-NMR-PH--2: (300MHz, d6-DMSO, ppm): δ8.71 (s, 1H), 7.53-7.25 (m, 5H), 7.04 (d, J = 8.4Hz, 1H), 6.90 (d, J = 8.4Hz, 1H), 6.53 (s, 1H), 4.81 (m, 3H), 4 .62-4.40(m,6H), 4.25-4.02(m,3H), 3.93(m,1H), 3.55(s,1H), 3.35(m,1 H), 2.80(m,2H), 2.55(s,2H), 2.45(s,2H), 1.95-1.4(m,7H), 1.22(s,6H).

[0250] 10-[3-[6-([3-amino-4-[1-(oxecyclobutan-3-yl)piperidin-4-yl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-(hydroxymethyl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one (100 mg, 0.15 mmol, 1.00 equivalent), propionic acid (12 mg, 0.17 mmol, 1.10 equivalent), HATU (68 mg, 0.18 mmol, 1.20 equivalent), NMM (30 mg, 0.30 mmol, 2.00 equivalent), and MeCN (4 mL) were placed in a 25 mL round-bottom flask. The resulting solution was stirred at room temperature for 30 minutes. The crude product was purified by Prep-HPLC. 20.5 mg (20%) of N-(5-[[6-(3-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-2-(hydroxymethyl)phenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl]amino]-2-[1-(oxetane-3-yl)piperidin-4-yl]phenyl)prop-2-enamide was obtained as a white solid. LC-MS: 0:(ES,m / z):718 [M+H] +1 H-NMR-PH--0: (300MHz, CDCl3, ppm): δ8.28(s,1H), 7.95(s,1H), 7.70-7.20(m,7H), 6.80(s,1H), 6.45-6.25(m,2H), 5.73(s,1H), 4.70(m,4H), 4.62-4.37(m,3H), 4.25-4.10(m,3H), 3.95(m,1H), 3.65(s,3H), 3.55( m,1H), 2.90(m,2H), 2.70-2.45(m,6H), 2.04-1.80(m,5H), 1.26(s,6H).

[0251] Example 9: Preparation of N-(3-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-5-(4-methylpiperazin-1-yl)phenyl)acrylamide

[0252] A solution of 1-bromo-3,5-dinitrobenzene (5.5 g, 22.27 mmol, 1.00 equivalent) in dioxane (50 mL), 1-methylpiperazine (2.64 g, 26.36 mmol, 1.20 equivalent), and Cs₂CO₃ (14.5 g, 44.50 mmol, 2.00 equivalent) were placed in a 250 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. Pd₂(dba)₃ (550 mg, 0.60 mmol, 0.10 equivalent) and BINAP (770 mg, 1.24 mmol, 0.15 equivalent) were then added. The resulting solution was stirred overnight at 100 °C in an oil bath. The reaction mixture was cooled to 25 °C. The solids were filtered off. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column containing ethyl acetate / hexane (1:1). 4.0 g (67%) of 1-(3,5-dinitrophenyl)-4-methylpiperazine was obtained as a yellow solid. LC-MS-1: (ES, m / z): 267 [M+H] + .

[0253] A solution of 1-(3,5-dinitrophenyl)-4-methylpiperazine (1.3 g, 4.88 mmol, 1.00 equivalent) in methanol (10 mL) and palladium on carbon (0.1 g, 0.10 equivalent) were placed in a 25 mL round-bottom flask purged and maintained under an inert atmosphere of H2. The resulting solution was stirred at room temperature for 2 h. The solid was filtered off. The resulting mixture was concentrated under vacuum. 1.0 g (99%) of 5-(4-methylpiperazin-1-yl)phenyl-1,3-diamine was given as a brown oil. LC-MS-2: (ES, m / z): 207 [M+H] + . 1 H-NMR-PH-1: (300MHz, d6-DMSO, ppm): δ5.44(s,2H), 5.38(s,1H), 4.49(s,4H), 2.95(t,J=6.5Hz,4H), 2.38(t,J=6.5Hz,4H), 2.19(s,3H).

[0254] A solution of 3,5-dibromo-1-methyl-1,2-dihydropyrazin-2-one (1.0 g, 3.73 mmol, 1.00 equivalent) in IPA (10 mL), 5-(4-methylpiperazin-1-yl)phenyl-1,3-diamine (1.0 g, 4.85 mmol, 1.00 equivalent), and DIEA (530 mg, 4.10 mmol, 1.10 equivalent) were placed in a 50-mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred in an oil bath at 40 °C for 1 h. The reaction mixture was cooled to 25 °C. The solid was collected by filtration. 0.5 g (34%) of 3-[[3-amino-5-(4-methylpiperazin-1-yl)phenyl]amino]-5-bromo-1-methyl-1,2-dihydropyrazin-2-one was given as a brown solid. LC-MS-3:(ES,m / z):392[M+H] + .

[0255] A solution of 3-[[3-amino-5-(4-methylpiperazin-1-yl)phenyl]amino]-5-bromo-1-methyl-1,2-dihydropyrazin-2-one (300 mg, 0.76 mmol, 1.00 equivalent) in dioxane (10 mL) / H2O (1 mL), (2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-[(oxan-2-yloxy)methyl]pyridin-4-yl)boronic acid (300 mg, 0.68 mmol, 1.00 equivalent), and potassium carbonate (240 mg, 1.74 mmol, 2.00 equivalent) were placed in a 25-mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. Pd(dppf)Cl2 (30 mg, 0.04 mmol, 0.10 equivalent) was then added. The resulting solution was stirred in an oil bath at 100 °C for 1 h. The resulting mixture was concentrated under vacuum. The residue was applied to a column with CH3CN:H2O (1:1). 190 mg (35%) of 10-[4-(6-[[3-amino-5-(4-methylpiperazin-1-yl)phenyl]amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-[(oxan-2-yloxy)methyl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one was given as a brown solid. LC-MS-4:(ES, m / z): 708 [M+H] + .

[0256] A solution of 10-[4-(6-[[3-amino-5-(4-methylpiperazin-1-yl)phenyl]amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-[(oxan-2-yloxy)methyl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one (190 mg, 0.27 mmol, 1.00 equivalent) in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) were placed in a 25 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred in an oil bath at 40 °C for 20 min. The resulting mixture was concentrated under vacuum. 190 mg (crude) of 10-[4-(6-[[3-amino-5-(4-methylpiperazin-1-yl)phenyl]amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-(hydroxymethyl)pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one was obtained as a brown oil. LC-MS-5:(ES,m / z):624[M+H] + .

[0257] Propylene-2-enoic acid (21 mg, 0.29 mmol, 1.10 equivalent), HATU (122.5 mg, 0.32 mmol, 1.20 equivalent), and NMM (54 mg, 0.53 mmol, 2.00 equivalent) were placed in a 25-mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting mixture was stirred for 10 minutes. 10-[4-(6-[[3-amino-5-(4-methylpiperazin-1-yl)phenyl]amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-(hydroxymethyl)pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one (190 mg, 0.30 mmol, 1.00 equivalent) was added to the mixture. The resulting solution was stirred at room temperature for 1 hour. The crude product was purified by rapid Prep-HPLC. 23 mg (11%) of N-(3-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl]amino]-5-(4-methylpiperazin-1-yl)phenyl)prop-2-enamide was obtained as a light brown solid. LC-MS-O:(ES,m / z):678[M+H] + . 1H-NMR-PH-1: (300MHz, d6-DMSO, ppm): δ9.88 (s, 1H), 9.02 (s, 1H), 8.49 (d, J = 5.1Hz ,1H), 7.80-7.74(m,3H), 7.50(s,1H), 6.97(s,1H), 6.57(s,1H), 6.52-6.25(m,2H) , 5.75(d,J=9.6H,1H), 5.02(m,1H), 4.67-4.49(m,2H), 4.32-4.15(m,3H), 3.90(m, 1H), 3.55(s,3H), 3.13(m,4H), 2.60(m,2H), 2.45(m,6H), 2.25(s,3H), 1.23(s,3H).

[0258] Example 10: Preparation of N-(3-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-5-((4-methylpiperazin-1-yl)methyl)phenyl)acrylamide

[0259] Synthesis of 1-[(3,5-dinitrophenyl)methyl]-4-methylpiperazine: 1-(chloromethyl)-3,5-dinitrobenzene (3 g, 13.85 mmol, 1.00 equivalent), 1-methylpiperazine (1.38 g, 13.78 mmol, 1.00 equivalent), potassium carbonate (4.8 g, 34.73 mmol, 2.50 equivalent), and tetrahydrofuran (30 mL) were placed in a 250-mL round-bottom flask. The resulting solution was stirred overnight at 70 °C. The reaction mixture was cooled to room temperature. The solid was filtered off. The filtrate was concentrated under vacuum. The crude product was purified by recrystallization from diethyl ether. 3 g (77%) of 1-[(3,5-dinitrophenyl)methyl]-4-methylpiperazine was given as a yellow solid. LC-MS--718-1:(ES,m / z):281[M+H] +1 H-NMR-PH--718-1: (300MHz, d6-DMSO, ppm): δ8.73(s,1H), 8.56(s,2H), 3.74(s,2H), 2.44(br s,4H), 2.34(br s,4H), 2.16(s,3H).

[0260] Synthesis of 5-[(4-methylpiperazin-1-yl)methyl]phenyl-1,3-diamine: 1-[(3,5-dinitrophenyl)methyl]-4-methylpiperazine (2.0 g, 7.14 mmol, 1.00 equivalent), palladium on carbon (0.2 g, 0.10 equivalent), and methanol (40 mL) were placed in a 250 mL round-bottom flask purged and maintained under an inert atmosphere of H2. The resulting solution was stirred at room temperature for 3 h. The solid was filtered off. The filtrate was concentrated under vacuum to give 1.1 g (70%) of 5-[(4-methylpiperazin-1-yl)methyl]phenyl-1,3-diamine as a colorless oil. LC-MS--718-2:(ES, m / z): 221 [M+H] + . 1 H-NMR-PH--718-2: (300MHz, d6-DMSO, ppm): δ5.76(s,2H), 5.70(s,1H), 4.61(s,4H), 3.12(s,2H), 2.30(br s,8H), 2.15(s,3H).

[0261] Synthesis of 3-([3-amino-5-[(4-methylpiperazin-1-yl)methyl]phenyl]amino)-5-bromo-1-methyl-1,2-dihydropyrazin-2-one: 3,5-dibromo-1-methyl-1,2-dihydropyrazin-2-one (1.0 g, 1.00 equivalent), 5-[(4-methylpiperazin-1-yl)methyl]phenyl-1,3-diamine (0.7 g, 1.00 equivalent), DIEA (1.0 g, 7.74 mmol, 2.50 equivalent), and isopropanol (15 mL) were placed in a 50-mL round-bottom flask. The resulting solution was stirred overnight at 80 °C. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC. 153 mg (14%) of 3-([3-amino-5-[(4-methylpiperazin-1-yl)methyl]phenyl]amino)-5-bromo-1-methyl-1,2-dihydropyrazin-2-one was obtained as a pale yellow solid. LC-MS--718-3:(ES,m / z):407[M+H] + . 1 H-NMR-PH--718-3: (300MHz, d6-DMSO, ppm): δ8.92(s,1H),7.28(s,1H), 6.95-6.93(m,2 H), 6.28(s,1H),5.01(s,2H), 3.44(s,3H), 3.27(s,2H), 2.39-2.36(m,8H), 2.15(s,3H).

[0262] Synthesis of 10-[4-[6-([3-amino-5-[(4-methylpiperazin-1-yl)methyl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-[(oxan-2-yloxy)methyl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one: 3-([3-amino-5-[(4-methylpiperazin-1-yl)methyl]phenyl]amino)-5-bromo-1-methyl-1,2-dihydropyrazin-2-one (100 mg, 0.25 mmol, 1.0 0 equivalent), (2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-[(oxan-2-yloxy)methyl]pyridin-4-yl)boronic acid (120 mg, 0.27 mmol, 1.10 equivalent), Pd(dppf)Cl2 (20 mg, 0.03 mmol, 0.10 equivalent), potassium carbonate (68 mg, 0.49 mmol, 2.00 equivalent), dioxane (10 mL), and water (1 mL) were placed in a 50-mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at 80 °C for 30 minutes. The reaction mixture was cooled to room temperature. The solid was filtered off. The filtrate was concentrated under vacuum. The crude product was purified by Prep-HPLC. 30 mg (17%) of 10-[4-[6-([3-amino-5-[(4-methylpiperazin-1-yl)methyl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-[(oxan-2-yloxy)methyl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one was obtained as a brown solid. LC-MS: 718-4 (ES, m / z): 722 [M+H] + .

[0263] Synthesis of 10-[4-[6-([3-amino-5-[(4-methylpiperazin-1-yl)methyl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-(hydroxymethyl)pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one: dichloromethane (2 mL), trifluoroacetic acid (0.2 mL), 10-4- [6-(3-amino-5-[(4-methylpiperazin-1-yl)methyl]phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-[(oxan-2-yloxy)methyl]pyridin-2-yl-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^2,6]dodecyl-2(6),7-dien-9-one (30 mg, 0.03 mmol, 1.00 equivalent) was placed in a 25-mL round-bottom flask. The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under vacuum. 20 mg (74%) of 10-[4-[6-([3-amino-5-[(4-methylpiperazin-1-yl)methyl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-(hydroxymethyl)pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one was obtained as a yellow oil. LC-MS--718-5:(ES,m / z):638[M+H] + .

[0264] Synthesis of N-(3-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl]amino]-5-[(4-methylpiperazin-1-yl)methyl]phenyl)prop-2-enamide: Propylene-2-enoic acid (20 mg, 0.28 mmol, 1.00 equivalent), 10-4-[6-(3 -amino-5-[(4-methylpiperazin-1-yl)methyl]phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-(hydroxymethyl)pyridin-2-yl-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^2,6]dodecyl-2(6),7-dien-9-one (2.7 mg, 1.20 equivalent), HATU (14 mg, 1.20 equivalent), NMM (8 mg, 2.50 equivalent), and MeCN (2 mL) were placed in a 25 mL round-bottom flask. The resulting solution was stirred at room temperature for 30 minutes. The crude product was purified by Prep-HPLC. Five mg (3%) of N-(3-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl]amino]-5-[(4-methylpiperazin-1-yl)methyl]phenyl)prop-2-enamide was obtained as a brown solid. LC-MS: 718-0 (ES, m / z): 692 [M+H] + . 1 H-NMR-PH--718-0: (300MHz, d6-DMSO, ppm): δ8.56-8.52(m,2H), 8.33(s,1H), 7.83-7.78 (m,3H), 7.30(s,2H), 6.82(s,1H), 6.44(d,J=15.3Hz,1H), 6.30(dd,J=17.1,9.9Hz,1H), 5.74(dd,J=9.9,1.5Hz,1H), 4.84-4.79(m,1H), 4.54-4.50(m,2H), 4.16-4.12(m,2H), 3. 93-3.90(m,1H), 3.65(s,3H), 3.49(s,2H), 2.56-2.51(m,13H), 2.32(s,3H), 1.27(s,6H).

[0265] Example 11: Preparation of (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetane-3-yl)piperazin-1-yl)phenyl)acrylamide

[0266] Synthesis of 2,4-dibromo-3-methylpyridine: A solution of (i-Pr)₂NH (3.19 g, 1.50 equivalent) in tetrahydrofuran (50 mL) was placed in a 250 mL three-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. Then, n-C₄H₉Li (10 mL, 1.5 equivalent) was added at -30 °C, and the mixture was stirred at the same temperature for 30 min. Subsequently, 2,4-dibromopyridine (5 g, 21.11 mmol, 1.00 equivalent) was added at -70 °C, and the mixture was stirred at the same temperature for 30 min. Iodomethane (4.5 g, 1.50 equivalent) was added to the above solution at -70 °C. The resulting solution was stirred at -70 °C for 30 min. The reaction was then quenched by adding 100 mL of aqueous NH₄Cl. The resulting solution was extracted with 3 x 50 mL ethyl acetate, and the organic layers were combined and dried over Na₂SO₄. The solid was filtered off. The filtrate was concentrated under vacuum. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (1:1). 3.0 g (57%) of 2,4-dibromo-3-methylpyridine was given as a white solid. LC-MS--727-1:(ES, m / z): 252 [M+H] +1 H-NMR-PH--727-1: (300MHz, CDCl3, ppm): δ7.99 (d, J = 5.1 Hz, 1H), 7.45 (d, J = 5.1 Hz, 1H), 2.58 (s, 3H).

[0267] Synthesis of 10-(4-bromo-3-methylpyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodec-2(6),7-dien-9-one: A solution of 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodec-2(6),7-dien-9-one (1.0 g, 4.90 mmol, 1.00 equivalent) in dioxane (10 mL) was placed in a 50 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. Then, 2,4-dibromo-3-methylpyridine (1.59 g, 6.34 mmol, 1.30 equivalent), Pd₂(dba)₃ (100 mg, 0.11 mmol, 0.10 equivalent), Xantphos (100 mg, 0.17 mmol, 0.10 equivalent), and Cs₂CO₃ (3.19 g, 9.79 mmol, 2.00 equivalent) were added to the mixture. The resulting solution was stirred in an oil bath at 100 °C for 1.5 h. The reaction mixture was cooled to room temperature. The solid was filtered off. The filtrate was concentrated under vacuum. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (1:1). 1.0 g (55%) of 10-(4-bromo-3-methylpyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one was obtained as a brown solid. LC-MS--727-2(ES, m / z): 374 [M+H] + . 1 H-NMR-PH--727-1: (300MHz, CDCl3, ppm): δ8.10 (d, J = 5.4Hz, 1H), 7.41 (d, J = 5.1Hz, 1H), 6.79 (s, 1H), 4.4 4-4.41(m,1H), 4.15-4.09(m,2H), 3.90-3.86(m,1H), 2.54(s,2H), 2.49(s,2H), 2.34(s,3H), 1.25(s,6H).

[0268] Synthesis of (2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-methylpyridin-4-yl)boronic acid: 10-(4-bromo-3-methylpyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one (50 A solution of 0 mg (1.34 mmol, 1.00 equivalent) in dioxane (5 mL) was placed in a 25 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. Then, Pin₂B₂ (850 mg, 2.50 equivalent), KOAc (400 mg, 4.08 mmol, 3.00 equivalent), and Pd(dppf)Cl₂ (50 mg, 0.07 mmol, 0.10 equivalent) were added to the solution. The resulting solution was stirred in an oil bath at 100 °C for 1 h. The reaction mixture was cooled to room temperature. The solid was filtered off. The filtrate was concentrated under vacuum. The residue was purified by rapid Prep-HPLC using CH₃CN:H₂O (1:1). 150 mg (33%) of (2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-methylpyridin-4-yl)boronic acid was obtained as a brown solid. LC-MS--727-3:(ES,m / z):340[M+H] + .

[0269] Synthesis of 10-[4-[6-([3-amino-4-[(2S)-2-methyl-4-(oxecyclobutane-3-yl)piperazin-1-yl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-methylpyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one: (2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-methylpyridin-4-yl)boronic acid (1 A solution of 20 mg (0.35 mmol, 1.00 equivalent) in dioxane (1 mL) was placed in a 25 mL round-bottom flask purged and maintained under a nitrogen inert atmosphere. Then, 3-([3-amino-4-[(2S)-2-methyl-4-(oxecyclobutan-3-yl)piperazin-1-yl]phenyl]amino)-5-bromo-1-methyl-1,2-dihydropyrazin-2-one (100 mg, 0.22 mmol, 1.10 equivalent), Pd(dppf)Cl2 (10 mg, 0.01 mmol, 1.00 equivalent), and potassium carbonate (73 mg, 0.53 mmol, 2.00 equivalent) were added to the solution. The resulting solution was stirred in an oil bath at 100 °C for 1 h. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by rapid Prep-HPLC. 120 mg (51%) of 10-[4-[6-([3-amino-4-[(2S)-2-methyl-4-(oxecyclobutan-3-yl)piperazin-1-yl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-methylpyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one was obtained as a brown solid. LC-MS--727-4:(ES,m / z):664[M+H] + .

[0270] Synthesis of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl]amino]-2-[(2S)-2-methyl-4-(oxetane-3-yl)piperazin-1-yl]phenyl)prop-2-enamide: 10-[4-[6-([3-amino-4-[(2S)-2-methyl-4-(oxetane-3-yl)piperazin-1-yl]phenyl]amino)-4-methyl-5-oxo-4,5-di]prop-2-yl ... A solution of [200 mg, 0.30 mmol, 1.00 equivalent] of hydropyrazin-2-yl]-3-methylpyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one in CH3CN (1 mL) was placed in a 25 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. Then, propionic acid (21.7 mg, 0.30 mmol, 1.00 equivalent), HATU (115 mg, 0.30 mmol, 1.00 equivalent), and NMM (61 mg, 0.60 mmol, 2.00 equivalent) were added to the solution. The resulting solution was stirred at room temperature for 4 h. The resulting mixture was concentrated under vacuum. The crude product was purified by rapid Prep-HPLC. 21.1 mg (10%) of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl]amino]-2-[(2S)-2-methyl-4-(oxetane-3-yl)piperazin-1-yl]phenyl)prop-2-enamide was obtained as a pale yellow solid. LC-MS: 727-0 (ES, m / z): 718 [M+H] + . 1H-NMR-PH--727-1: (300MHz, d6-DMSO3, ppm): δ8.88(d,J=5.7Hz,1H), 8.32(d,J=5.7Hz,1H), 7. 67-7.59(m,2H), 7.33-7.27(m,2H), 6.64-6.55(m,2H), 6.24(d,J=16.5Hz,1H), 5.76(d,J=11.4 Hz,1H), 4.72-4.65(m,4H), 4.19-4.09(m,4H), 3.90-3.83(m,2H), 3.54(s,3H), 3.30-3.12(m,3 H), 3.00-2.83(m,3H), 2.51(s,2H), 2.40(s,2H), 2.26(s,3H), 1.18(s,6H), 0.74-0.71(m,3H).

[0271] Example 12: Preparation of N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-morpholinopiperidin-1-yl)phenyl)acrylamide

[0272] Synthesis of tert-butyl 2-methyl-4-(morpholin-4-yl)piperidine-1-carboxylate: 18 g of tert-butyl 2-methyl-4-oxopiridine-1-carboxylate (8 g, 84.40 mmol, 1.00 equivalent), morpholine (8 g, 91.83 mmol, 1.10 equivalent), NaCNBH3 (10 g, 2.00 equivalent), and ethanol (200 mL) were placed in a 500 mL round-bottom flask. The resulting solution was stirred overnight at 50 °C. The resulting mixture was concentrated under vacuum. The crude product was purified by rapid Prep-HPLC. 9.4 g (39%) of tert-butyl 2-methyl-4-(morpholin-4-yl)piperidine-1-carboxylate was given as a colorless oil. LC-MS--729-1:(ES, m / z): 285 [M+H] + . 1 H-NMR-PH--729-1: (300MHz, CDCl3, ppm): δ4.01-3.94(m,1H), 3.75-3.72(m,4H), 3.17-3.07(m,1H), 2.56- 2.51(m,4H), 2.42-2.37(m,1H), 1.89-1.83(m,2H), 1.68-1.53(m,3H), 1.48(s,9H), 1.27(d,J=6.3Hz,3H).

[0273] Synthesis of 4-(2-methylpiperidin-4-yl)morpholine: 5 g (17.58 mmol, 1.00 equivalent) of tert-butyl 2-methyl-4-(morpholino-4-yl)piperidin-1-carboxylic acid and 50 mL of hydrogen chloride / dioxane were placed in a 250 mL round-bottom flask. The resulting solution was stirred at room temperature for 30 min. The mixture was concentrated under vacuum. The mixture was diluted with MeCN and alkalized with potassium carbonate. The mixture was filtered and the filtrate was concentrated. 3 g (93%) of 4-(2-methylpiperidin-4-yl)morpholine was given as a white solid. LC-MS--729-2:(ES,m / z):185[M+H] + .

[0274] N-[4-[2-methyl-4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl]benzyl carbamate was synthesized by placing 4-(2-methylpiperidin-4-yl)morpholine (3 g, 16.28 mmol, 1.00 equivalent), N-(4-fluoro-3-nitrophenyl)benzyl carbamate (5.6 g, 19.29 mmol, 1.20 equivalent), potassium carbonate (6.75 g, 48.91 mmol, 3.00 equivalent), and MeCN (60 mL) into a 250 mL round-bottom flask. The resulting solution was stirred overnight at 90 °C. The solid was collected by filtration. The resulting mixture was concentrated under vacuum and applied to a silica gel column containing ethyl acetate / petroleum ether (75:25). The crude product was purified by rapid Prep-HPLC, where the concentration of MeCN:0.1% TFA / H2O = 20 / 80 was increased to MeCN:0.1% TFA / H2O = 45 / 55 within 12 minutes. 1.5 g (21%) of N-[4-[2-methyl-4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl]carbamate was given as a yellow solid. LC-MS--729-3:(ES,m / z):455[M+H] + . 1 H-NMR-PH--729-3: (300MHz, d6-DMSO, ppm): δ10.21 (s, 1H), 9.90 (br s,1H), 7.87(s,1H), 7.64-7.52(m,2H), 7.50-7.30(m,5H), 5.18(s,2H), 4.10-3.96(m,2H), 3.80-3.60(m,2H), 3.55-3.30(m,3 H), 3.20-2.97(m,4H), 2.69(t,J=11.1Hz,1H), 2.25-2.10(m,2H), 1.75-1.55(m,1H), 1.40-1.30(m,1H), 0.74(d,J=6.0Hz,3H).

[0275] Synthesis of N-[3-amino-4-[2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl]benzyl carbamate: N-[4-[2-methyl-4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl]benzyl carbamate (1.2 g, 2.64 mmol, 1.00 equivalent), Zn (1.0 g, 15.38 mmol, 6.00 equivalent), NH4Cl (1.7 g, 31.78 mmol, 12.00 equivalent), and MeOH (15 mL) were placed in a 100 mL round-bottom flask. The resulting solution was stirred at room temperature for 1 h. The solid was collected by filtration. The filtrate was concentrated under vacuum. The residue was applied to a silica gel column containing dichloromethane / methanol (15:1). 0.84 g (75%) of N-[3-amino-4-[2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl]carbamate was obtained as a brown solid. LC-MS--729-4:(ES,m / z):425[M+H] + .

[0276] Synthesis of N-(3-[[(tert-butoxy)carbonyl]amino]-4-[2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl)benzyl carbamate: N-[3-amino-4-[2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl]benzyl carbamate (0.5 g, 3.53 mmol, 1.00 equivalent), Boc₂O (0.38 g, 5.28 mmol, 1.50 equivalent), DIEA (0.38 g, 8.84 mmol, 2.50 equivalent), and tetrahydrofuran (15 mL) were placed in a 250 mL round-bottom flask. The resulting solution was stirred overnight at 75 °C. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (75:25). 0.5 g (80%) of N-(3-[[(tert-butoxy)carbonyl]amino]-4-[2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl)carbamate was obtained as a pale yellow solid. LC-MS--729-5:(ES,m / z):252[M+H] + . 1H-NMR-PH--729-5: (300MHz, d6-DMSO, ppm): δ9.69(s,1H), 8.19(s,1H), 8.05(s,1 H), 7.46-7.30(m,5H), 7.18-7.15(m,1H), 7.10-7.06(m,1H), 5.14(s,2H), 3.59(br s,4H), 2.90-2.47(m,4H), 2.42-2.25(m,2H), 2.0-1.82(m,2H), 1.72-1.60(m,1H), 1.50-1.32(m,12H), 0.71(d,J=6.0Hz,3H).

[0277] Synthesis of N-[5-amino-2-[2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl]carbamate tert-butyl ester: Benzyl N-(3-[[(tert-butoxy)carbonyl]amino]-4-[2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl)carbamate (500 mg, 1.52 mmol, 1.00 equivalent), palladium on carbon (50 mg), and methanol (30 mL) were placed in a 250 mL round-bottom flask purged and maintained under an inert H2 atmosphere. The resulting solution was stirred at 25 °C for 3 h. The mixture was concentrated under vacuum. 381 mg (crude) of N-[5-amino-2-[2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl]carbamate tert-butyl ester was obtained as a colorless oil. LC-MS--729-6:(ES,m / z):391[M+H] + .

[0278] Synthesis of N-[5-[(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino]-2-[2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl]carbamate tert-butyl: N-[5-amino-2-[2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl]carbamate tert-butyl (300 mg, 1.54 mmol, 1 equivalent), 3,5-dibromo-1-methyl-1,2-dihydropyrazin-2-one (250 mg, 1.87 mmol, 1.21 equivalent), DIEA (250 mg, 3.87 mmol, 2.52 equivalent), and i-PrOH (10 mL) were placed in a 100 mL round-bottom flask. The resulting solution was stirred overnight at 80 °C. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. The residue was applied to a silica gel column containing ethyl acetate. 265 mg (59.73%) of N-[5-[(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino]-2-[2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl]carbamate tert-butyl ester was obtained as a yellow solid. LC-MS: 729-7 (ES, m / z): 577 [M+H] + . 1 H-NMR-PH--729-7: (300MHz, d6-DMSO, ppm): δ9.38 (s, 1H), 8.41 (s, 1H), 8.04 (s, 1H), 7.59-7.55 (m, 1H), 7.32 (s, 1H), 7.23 (d, J = 0.9Hz ,1H), 3.65-3.55(m,4H), 3.44(s,3H), 2.92-2.52(m,4H), 2.42-2.28(m,2H), 2.00-1.82(m,2H), 1.50-1.30(m,13H), 0.73-0.69(m,3H).

[0279] Synthesis of 3-([3-amino-4-[2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl]amino)-5-bromo-1-methyl-1,2-dihydropyrazin-2-one: N-[5-[(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino]-2-[2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl]carbamate tert-butyl ester (200 mg, 0.31 mmol, 1 equivalent) and HCl / dioxane (5 mL) were placed in a 25 mL round-bottom flask. The resulting solution was stirred at room temperature for 4 hours. The resulting mixture was then concentrated. 160 mg (96.45%) of 3-([3-amino-4-[2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl]amino)-5-bromo-1-methyl-1,2-dihydropyrazin-2-one was obtained as a pale yellow solid. LC-MS--729-8:(ES,m / z):477[M+H] + .

[0280] Synthesis of 10-(4-[6-[(3-aminophenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-[(oxan-2-yloxy)methyl]pyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one: 3-([3-amino-4-[2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl]amino)-5-bromo-1-methyl-1,2-dihydropyrazin-2-one (160 mg, 0.34 mmol, 1 equivalent), (2-[4,4-dimethyl- 9-O-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-[(oxan-2-yloxy)methyl]pyridin-4-yl)boronic acid (147 mg, 0.33 mmol, 1.00 equivalent), Pd(dppf)Cl2 (30 mg, 0.03 mmol, 0.10 equivalent), K2CO3 (116 mg, 0.84 mmol, 2.50 equivalent), dioxane (5 mL, unlimited mmol, unlimited equivalent), and H2O (0.5 mL) were placed in a 25-mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at 90 °C for 40 min. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated and purified by rapid Prep-HPLC. 210 mg (79.12%) of 10-(4-[6-[(3-aminophenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-[(oxan-2-yloxy)methyl]pyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one was obtained as a solid. LC-MS: 729-9 (ES, m / z): 792 [M+H] + .

[0281] Synthesis of 10-(4-[6-[(3-aminophenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-(hydroxymethyl)pyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one: 10-(4-[6-[(3-aminophenyl)amino]-4-methyl-5-oxo-2-yl]-3-(hydroxymethyl)pyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one) [200 mg, 0.38 mmol, 1.00 equivalent]-4,5-dihydropyrazin-2-yl]-3-[(oxan-2-yloxy)methyl]pyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one, trifluoroacetic acid (1 mL), and dichloromethane (20 mL) were placed in a 50-mL round-bottom flask. The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with ethyl acetate and alkalized with an aqueous sodium bicarbonate solution. The solid was filtered off, and the filtrate was concentrated under vacuum. 130 mg (76%) of 10-(4-[6-[(3-aminophenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-(hydroxymethyl)pyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one was obtained as a colorless oil. LC-MS--729-10:(ES,m / z):708[M+H] + .

[0282] Synthesis of N-(3-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl]amino]phenyl)prop-2-enamide: 10-(4-[6-[(3-aminophenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-(hydroxymethyl)pyridin-2-yl)prop ... -4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-9-one (100 mg, 0.19 mmol, 1.00 equivalent), propionic acid (13.7 mg, 0.19 mmol, 1.00 equivalent), NMM (38.5 mg, 0.38 mmol, 2.00 equivalent), HATU (94 mg, 0.25 mmol, 1.30 equivalent), and MeCN (5 mL) were placed in a 25 mL round-bottom flask. The resulting solution was stirred at room temperature for 30 minutes. The crude product was purified by Prep-HPLC. 19.7 mg (18%) of N-(3-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl]amino]phenyl)prop-2-enamide was obtained as a grayish-white solid. LC-MS: 729-0 (ES, m / z): 762 [M+H] + . 1H-NMR-PH--729-0: (300MHz, DMSO, ppm): δ9.23 (s, 2H), 9.14 (s, 1H), 8.49 (d, J = 5.1Hz, 1H), 7.96-7.95 (m, 1H), 7.77 (s, 1H), 7.61(d,J=8.1Hz,1H), 7.23(d,J=8.7Hz,1H), 6.68-6.62(m,1H), 6.57(s,1H), 6.30(d,J=17.1Hz,1H), 5.80(d,J=11.7Hz,1H) ,5.03-5.00(m,1H),4.65-4.40(m,2H),4.32-4.16(m,4H),3.85-3.83(m,1H),3.68-3.55(m,7H),3.01-2.72(m,2H),2.71-2 .52(m,4H), 2.48-2.25(m,4H), 1.98-1.78(m,2H), 1.72-1.52(m,1H), 1.46-1.30(m,1H), 1.23(s,6H), 0.76(d,J=5.7Hz,3H).

[0283] Example 13: Preparation of (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidine-1-yl)phenyl)acrylamide

[0284] Synthesis of N-[4-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]-3-nitrophenyl]carbamate as a yellow solid: (3R)-N,N-dimethylpyrrolidine-3-amine dihydrochloride (5 g, 26.72 mmol, 1 equivalent), N-(4-fluoro-3-nitrophenyl)carbamate (9.3 g, 32.07 mmol, 1.20 equivalent), TEA (10.8 g, 106.89 mmol, 4.00 equivalent), and DMF (80 mL) were placed in a 250 mL round-bottom flask. The resulting solution was stirred overnight at 100 °C. The reaction mixture was cooled to room temperature. The reaction was then quenched by adding 200 mL of water. The resulting solution was extracted with 2 x 200 mL of ethyl acetate. The organic mixture was washed with 2 x 200 mL of brine. The organic phase was dried over anhydrous sodium sulfate. The solid was filtered off. The filtrate was concentrated under vacuum. The crude product was purified by recrystallization from MeCN. 5.2 g (50.62%) of N-[4-[(3R)-3-(dimethylamino)pyrrolidone-1-yl]-3-nitrophenyl]carbamate was given as a yellow solid. LC-MS: 729 C-1 (ES, m / z): 385 [M+H] + . 1 H-NMR-PH--729-C-1: (300MHz, d6-DMSO, ppm): δ9.78 (s, 1H), 7.96 (s, 1H), 7.52-7.37 (m, 6H), 7.06 (d, J = 9.3H z,1H), 5.15(s,2H), 3.30-3.27(m,1H), 3.13-3.01(m,3H), 2.71-2.68(m,1H), 2.17(s,6H), 1.83-1.71(m,1H).

[0285] Synthesis of N-[3-amino-4-[3-(dimethylamino)pyrrolidin-1-yl]phenyl]benzyl carbamate: N-[4-[3-(dimethylamino)pyrrolidin-1-yl]-3-nitrophenyl]benzyl carbamate (5 g, 13.01 mmol, 1 equivalent), zinc (5.1 g, 78.04 mmol, 6.00 equivalent), NH4Cl (8.3 g, 156.07 mmol, 12.00 equivalent), and MeOH (100 mL) were placed in a 250 mL round-bottom flask. The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated. 3.9 g (84.60%) of N-[3-amino-4-[3-(dimethylamino)pyrrolidin-1-yl]phenyl]benzyl carbamate was given as a gray solid. LC-MS--729-C-2:(ES,m / z):365[M+H] + .

[0286] Synthesis of N-(3-[[(tert-butoxy)carbonyl]amino]-4-[3-(dimethylamino)pyrrolidine-1-yl]phenyl)carbamate: N-[3-amino-4-[3-(dimethylamino)pyrrolidine-1-yl]phenyl]carbamate (3 g, 16.93 mmol, 1 equivalent), di-tert-butyl dicarbonate (2.2 mg, 20 mmol), DIEA (2.73 g, 40 mmol), and THF (50 mL) were placed in a 250 mL round-bottom flask. The resulting solution was stirred overnight at 75 °C. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (50:50). 2.6 g (68%) of N-(3-[[(tert-butoxy)carbonyl]amino]-4-[3-(dimethylamino)pyrrolidine-1-yl]phenyl)carbamate was given as a yellow solid. LC-MS--729-C-3:(ES,m / z):465[M+H] + . 1 H-NMR-PH--729-C-3: (300MHz, DMSO, ppm): δ9.51(s,1H), 8.06(s,1H), 7.54(s,1H), 7.41-7.33(m,5H), 7.14-7.11(m,1H), 6.89(d,J=9.0Hz, 1H), 5.13(s,2H), 3.21-3.12(m,1H), 3.09-2.99(m,3H), 2.79-2.69(m ,1H), 2.17(s,6H), 2.09-2.00(m,1H),1.78-1.65(m,1H),1.44(s,9H).

[0287] Synthesis of N-[5-amino-2-[(3S)-3-(dimethylamino)pyrrolidine-1-yl]phenyl]carbamate tert-butyl ester: 2 g (0.44 mmol, 1 equivalent) of N-(3-[[(tert-butoxy)carbonyl]amino]-4-[(3S)-3-(dimethylamino)pyrrolidine-1-yl]phenyl)carbamate, Pd / C (200 mg), and MeOH (50 mL) were placed in a 250 mL round-bottom flask purged and maintained under an inert H2 atmosphere. The resulting solution was stirred at room temperature for 2 hours. The solid was filtered off. The filtrate was concentrated under vacuum. The resulting mixture was concentrated. 1.15 g of N-[5-amino-2-[(3S)-3-(dimethylamino)pyrrolidine-1-yl]phenyl]carbamate tert-butyl ester was obtained as a brown oil. LC-MS--729-C-4:(ES,m / z):321[M+H] + .

[0288] Synthesis of N-[5-[(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino]-2-[(3S)-3-(dimethylamino)pyrrolidone-1-yl]phenyl]carbamate tert-butyl ester: N-[5-amino-2-[(3S)-3-(dimethylamino)pyrrolidone-1-yl]phenyl]carbamate tert-butyl ester (1 g, 1 equivalent), 3,5-dibromo-1-methyl-1,2-dihydropyrazin-2-one (1 g, 1.20 equivalent), DIEA (1 g, 2.49 equivalent), and i-PrOH (10 mL) were placed in a 250 mL round-bottom flask. The resulting solution was stirred overnight at 80 °C. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. The residue was applied to a silica gel column with EA / PE (50:50). 1 g (60.62%) of N-[5-[(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino]-2-[(3S)-3-(dimethylamino)pyrrolidine-1-yl]phenyl]carbamate tert-butyl ester was obtained as a yellow solid. LC-MS--729-C-5:(ES,m / z):507[M+H] + .

[0289] Synthesis of 3-([3-amino-4-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl]amino)-5-bromo-1-methyl-1,2-dihydropyrazin-2-one: N-[5-[(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino]-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl]carbamate tert-butyl ester (1 g, 0.39 mmol, 1 equivalent) and HCl / dioxane (10 mL) were placed in a 25 mL round-bottom flask. The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was then concentrated. 750 mg (93.43%) of 3-([3-amino-4-[(3S)-3-(dimethylamino)pyrrolidone-1-yl]phenyl]amino)-5-bromo-1-methyl-1,2-dihydropyrazin-2-one) was obtained as a pale yellow solid. LC-MS: 729-C-6 (ES, m / z): 407 [M+H] + .

[0290] Synthesis of N-[5-[(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino]-2-[3-(dimethylamino)pyrrolidin-1-yl]phenyl]prop-2-enamide: 3-([3-amino-4-[3-(dimethylamino)pyrrolidin-1-yl]phenyl]amino)-5-bromo-1-methyl-1,2-dihydropyrazin-2-one (600 mg, 1.96 mmol, 1 equivalent), propionic acid (127.2 mg, 2.36 mmol, 1.2 equivalent), HATU (672 mg, 2.36 mmol, 1.2 equivalent), NMM (596 mg, 7.86 mmol, 4.0 equivalent), and MeCN (15 mL) were placed in a 50 mL round-bottom flask. The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC. 307 mg (45.25%) of N-[5-[(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino]-2-[3-(dimethylamino)pyrrolidone-1-yl]phenyl]prop-2-enamide was obtained as a pale yellow solid. LC-MS: 729 C-1 (ES, m / z): 461 [M+H] + .

[0291] Synthesis of N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidine-1-yl)phenyl)acrylamide: N-[5-[(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino]-2-[(3S)-3-(dimethylamino)pyrrolidine-1-yl]phenyl]prop-2-enamide (50 mg, 0.11 mmol) 1.1 equivalent), (2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-(hydroxymethyl)pyridin-4-yl)boronic acid (50.0 mg, 0.14 mmol, 1.3 equivalent), Pd(dppf)Cl2 (9.3 mg, 0.01 mmol, 0.1 equivalent), K2CO3 (37.4 mg, 0.27 mmol, 2.5 equivalent), dioxane (5 mL), and H2O (0.5 mL) were placed in a 25-mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at 90 °C for 1 hour. The reaction mixture was cooled to room temperature. The solid was filtered off. The filtrate was concentrated. The crude product was purified by Prep-HPLC. 14 mg (18.67%) of N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidine-1-yl)phenyl)acrylamide was obtained as a white solid. LC-MS: 729 C-O (ES, m / z): 692 [M+H] + . 1H-NMR-PH--729-C-0: (300MHz, DMSO, ppm): δ9.38(d,J=5.1Hz,1H), 9.17(s,1H), 8.44(d,J=5.1Hz,1H), 8 .34-8.32(m,1H), 7.76-7.63(m,3H), 6.86(d,J=8.7Hz,1H), 6.62-6.48(m,2H), 6.27(d,J=16.2Hz,1H), 5 .73(d,J=11.4Hz,1H), 5.05-4.95(m,1H), 4.70-4.38(m,2H), 4.29-4.20(m,3H), 3.89-3.84(m,1H), 3.55 (s,3H), 3.14-3.07(m,3H), 2.74-2.49(m,6H), 2.15(s,6H), 2.05(m,1H), 1.75-1.69(m,1H), 1.23(s,6H).

[0292] Example 14: Preparation of N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(piperidin-3-yl)phenyl)acrylamide

[0293] Synthesis of tert-butyl 3-(4-amino-2-nitrophenyl)-5,6-dihydro-2H-pyridine-1-carboxylic acid: 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (8.55 g, 27.647 mmol, 1.20 equivalents) and 4-bromo-3-nitroaniline (5.00 g, 23. 0.39 mmol (1.00 equivalent), Pd(dppf)Cl2CH2Cl2 (1.88 g, 2.304 mmol, 0.10 equivalent), K2CO3 (6.37 g, 46.091 mmol, 2.00 equivalent), dioxane (80.00 mL), and H2O (20.00 mL) were placed in a 500 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at 100 °C for 2 hours. The solid was filtered off. The combined organic layers were concentrated. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (60:40). 7 g (95.14%) of 3-(4-amino-2-nitrophenyl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester was given as a white solid. LC-MS--751-1:(ES, m / z): 320 [M+H] + .

[0294] Synthesis of tert-butyl 3-(4-[[(benzyloxy)carbonyl]amino]-2-nitrophenyl)-5,6-dihydro-2H-pyridine-1-carboxylic acid: 7.00 g (21.919 mmol, 1.00 equivalent) of tert-butyl 3-(4-amino-2-nitrophenyl)-5,6-dihydro-2H-pyridine-1-carboxylic acid, 4.65 g (43.838 mmol, 2.00 equivalent), and 50.00 mL of DCM were placed in a 250 mL three-necked round-bottom flask. 10.00 mL of H2O was then added with stirring at 0 °C. Benzyl chloroformate (4.49 g, 26.303 mmol, 1.20 equivalent) was added to the mixture at 0 °C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by adding water. The mixture was dried over anhydrous sodium sulfate and concentrated. Nine g of tert-butyl 3-(4-[[(benzyloxy)carbonyl]amino]-2-nitrophenyl)-5,6-dihydro-2H-pyridine-1-carboxylic acid was obtained as a pale yellow oil. LC-MS--751-2:(ES,m / z):454[M+H] + .

[0295] Synthesis of tert-butyl 3-(2-amino-4-[[(benzyloxy)carbonyl]amino]phenyl)-5,6-dihydro-2H-pyridine-1-carboxylic acid: tert-butyl 3-(4-[[(benzyloxy)carbonyl]amino]-2-nitrophenyl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (5.00 g, 11.025 mmol, 1.00 equivalent), Fe (3.08 g, 55.127 mmol, 5.00 equivalent), CH3COOH (20.00 mL), and H2O (2.00 mL) were placed in a 100-mL round-bottom flask. The resulting solution was stirred at 60 °C for 1 hour. The resulting mixture was concentrated. The resulting solution was extracted with ethyl acetate. The pH of the solution was adjusted to 7 with NaHCO3. The resulting mixture was washed with brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (60:40). 4 g (85.66%) of 3-(2-amino-4-[[(benzyloxy)carbonyl]amino]phenyl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester was given as a yellow solid. LC-MS--751-3:(ES,m / z):424[M+H] + . 1HNMR--751-3: (300MHz, DMSO-d6, ppm): δ9.49 (s, 1H), 7.49-7.32 (m, 5H), 6.88 (d, J = 2.0Hz, 1H), 6.76 (d, J = 8.2Hz, 1H), 6.61 (dd, J = 8.2, 2.1Hz,1H), 5.78-5.70(s,1H), 5.13(s,2H), 4.84(s,2H), 3.89(d,J=2.7Hz,2H), 3.48(t,J=5.6Hz,2H), 2.25-2.13(s,2H), 1.42(s,9H).

[0296] Synthesis of tert-butyl 3-(4-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]phenyl)-5,6-dihydro-2H-pyridine-1-carboxylic acid: tert-butyl 3-(2-amino-4-[[(benzyloxy)carbonyl]amino]phenyl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (4.00 g, 9.445 mmol, 1.00 equivalent), ditert-butyl dicarbonate (4.12 g, 18.890 mmol, 2.00 equivalent), K₂CO₃ (2.61 g, 18.885 mmol, 2.00 equivalent), dioxane (80.00 mL), and H₂O (40.00 mL) were placed in a 250-mL round-bottom flask. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by adding water. The resulting solution was extracted with ethyl acetate. The resulting mixture was washed with brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (40:60). 5 g (101.10%) of 3-(4-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]phenyl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester was given as a white solid. LC-MS--751-4:(ES,m / z):524[M+H] + . 1 H NMR--751-4: (300MHz, DMSO-d6, ppm): δ9.79 (s, 1H), 8.31 (s, 1H), 7.51 (d, J = 2.1Hz, 1H), 7.50-7.31 (m, 5H), 7.25 (dd, J = 8.4, 2.2Hz,1H), 7.07(d,J=8.4Hz,1H), 5.69(s,1H), 5.16(s,2H), 3.97(s,2H), 3.45(t,J=5.7Hz,2H), 2.18(s,2H), 1.42(s,18H).

[0297] Synthesis of tert-butyl 3-[4-amino-2-[(tert-butoxycarbonyl)amino]phenyl]piperidine-1-carboxylic acid: 3-(4-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]phenyl)-5,6-dihydro-2H-pyridine-carboxylic acid tert-butyl ester (5.00 g, 9.549 mmol, 1.00 equivalent), Pd / C (500.00 mg), MeOH (100 mL), and EA (50.00 mL) were placed in a 250 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred overnight at room temperature. The solid was collected by filtration. The combined organic layers were concentrated. 3.4 g (90.95%) of tert-butyl 3-[4-amino-2-[(tert-butoxycarbonyl)amino]phenyl]piperidine-1-carboxylic acid was given as a colorless oil. LC-MS--751-5:(ES,m / z):392[M+H] + .

[0298] Synthesis of tert-butyl 3-[4-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-[(tert-butoxycarbonyl)amino]phenyl]piperidine-1-carboxylic acid: 3-[4-amino-2-[(tert-butoxycarbonyl)amino]phenyl]piperidine-1-carboxylic acid tert-butyl ester (3.40 g, 8.684 mmol, 1.00 equivalent), 3,5-dibromo-1-methylpyrazin-2-one (2.56 g, 9.553 mmol, 1.1 equivalent), i-PrOH (50.00 mL), and DIEA (2.24 g, 17.369 mmol, 2.0 equivalent) were placed in a 250-mL round-bottom flask. The resulting solution was stirred overnight at 90 °C. The resulting mixture was concentrated. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (40:60). 4 g (79.62%) of tert-butyl 3-[4-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-[(tert-butoxycarbonyl)amino]phenyl]piperidine-1-carboxylic acid was obtained as a pale yellow solid.

[0299] LC-MS--751-6:(ES,m / z):578[M+H] + .

[0300] Synthesis of 3-[[3-amino-4-(piperidin-3-yl)phenyl]amino]-5-bromo-1-methylpyrazin-2-one: 4.00 g of 3-[4-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-[(tert-butoxycarbonyl)amino]phenyl]piperidin-1-carboxylic acid tert-butyl ester was placed in a 250-mL round-bottom flask. 80.00 mL of HCl (g) / MeOH was added. The resulting solution was stirred at room temperature for 2 hours. The mixture was concentrated. 2.9 g of 3-[[3-amino-4-(piperidin-3-yl)phenyl]amino]-5-bromo-1-methylpyrazin-2-one was given as a white solid. LC-MS--751-7:(ES,m / z):378[M+H] + .

[0301] Synthesis of tert-butyl 3-[2-amino-4-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]phenyl]piperidine-1-carboxylic acid: 3-[[3-amino-4-(piperidine-3-yl)phenyl]amino]-5-bromo-1-methylpyrazin-2-one (2.90 g, 7.666 mmol, 1.00 equivalent), Boc₂O (1.84 g, 8.431 mmol, 1.10 equivalent), TEA (1.55 g, 15.333 mmol, 2.00 equivalent), and DCM (50 mL) were placed in a 250 mL round-bottom flask. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated. The crude product was purified by recrystallization from diethyl ether. 2.5 g (68.17%) of tert-butyl 3-[2-amino-4-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]phenyl]piperidine-1-carboxylic acid was given as a white solid. LC-MS--751-8:(ES,m / z):478[M+H] + . 1 HNMR--751-8: (300MHz, DMSO-d6, ppm): δ8.99 (s, 1H), 7.27 (s, 1H), 7.11-7.01 (m, 2H), 6.92 (d, J = 9.0Hz, 1H), 4.90 (s, 2 H), 3.98(s,2H), 3.43(s,3H), 2.84-2.54(m,3H), 1.90-1.82(m,1H), 1.73-1.64(m,1H), 1.60-1.46(m,2H), 1.42(s,9H).

[0302] Synthesis of tert-butyl 3-[4-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-(propenamido)phenyl]piperidine-1-carboxylic acid: tert-butyl 3-[2-amino-4-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]phenyl]piperidine-1-carboxylic acid (500.00 mg, 1.045 mmol, 1.00 equivalent), acryloyl chloride (141.90 mg, 1.568 mmol, 1.5 equivalent), NMM (211.43 mg, 2.090 mmol, 2.00 equivalent), and DCM (10 mL) were placed in a 25 mL round-bottom flask. The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (70:30). 300 mg (53.91%) of 3-[4-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-(prop-2-enamido)phenyl]piperidine-1-carboxylic acid tert-butyl ester was obtained as a yellow solid. LC-MS--751-9:(ES,m / z):532[M+H] + . 1 HNMR--751-9: (300MHz, DMSO-d6, ppm): δ9.67(s,1H), 9.47(s,1H), 7.86-7. 75(m,2H), 7.36-7.25(m,2H), 6.58-6.43(m,1H), 6.24(dd,J=17.0,2.1Hz,1H ), 5.75(d,J=7.6Hz,1H), 4.10-3.81(m,2H), 3.44(s,3H), 2.83-2.62(m,3H) , 1.87-1.76 (m, 1H), 1.70 (d, J = 13.4Hz, 1H), 1.65-1.50 (m, 1H), 1.37 (s, 9H).

[0303] Synthesis of tert-butyl 3-(4-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-methylpyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-(prop-2-enamido)phenyl)piperidin-1-carboxylic acid: 3-[4-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2 300.00 mg (0.563 mmol, 1.00 equivalent) of tert-butyl 2-(propenamido)phenyl[piperidin-1-carboxylic acid), 2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-methylpyridin-4-ylboronic acid (248.46 mg, 0.732 mmol, 1.30 equivalent), Pd(dppf)Cl2CH2Cl2 (46.01 mg, 0.056 mmol, 0.10 equivalent), K2CO3 (155.51 mg, 1.127 mmol, 2.00 equivalent), DME (10.00 mL), and H2O (2.00 mL) were placed in a 40 mL microwave tube maintained under a nitrogen inert atmosphere. The resulting solution was stirred at 90 °C for 1 hour. The resulting mixture was concentrated. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (40:60). 240 mg (57.03%) of 3-(4-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-methylpyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-(propenamido)phenyl)piperidin-1-carboxylic acid tert-butyl ester was obtained as a yellow solid. LC-MS--751-10:(ES,m / z):747[M+H] + .

[0304] Synthesis of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-methylpyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-(piperidin-3-yl)phenyl)prop-2-enamide-: 3-(4-[[6-(2-[4,4-dimethyl-9-oxo-1,10-di] Azatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-methylpyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-(propenamido)phenyl)piperidin-1-carboxylic acid tert-butyl ester (150.00 mg, 0.201 mmol, 1.00 equivalent), DCM (8.00 mL), and TFA (1.5 mL) were placed in a 25-mL round-bottom flask. The resulting solution was stirred at room temperature for 2.5 hours. The resulting mixture was concentrated. The reaction was then quenched by adding NaHCO3. The resulting solution was extracted with dichloromethane. The resulting mixture was washed with brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by Prep-HPLC. 80 mg (61.59%) of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-methylpyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-(piperidin-3-yl)phenyl)prop-2-enamide was obtained as a white solid. LC-MS: 751-0 (ES, m / z): 647 [M+H] + . 1 H NMR--751-0: (300MHz, DMSO-d6, ppm): δ9.61 (s, 1H), 9.29 (s, 1H), 8.32 (d, J = 5.0Hz, 1H), 8.16 (d, J = 7.2Hz, 1H), 7. 77(d,J=8.5Hz,1H), 7.49(d,J=4.8Hz,1H), 7.43(s,1H), 7.21(d,J=8.6Hz,1H), 6.60-6.47(m,2H), 6.23(d,J=16.6 Hz,1H), 5.70(d,J=10.2Hz,1H), 4.30-4.11(m,3H), 3.84(d,J=12.5Hz,1H), 3.57(s,3H), 2.99-2.73(m,3H), 2.58( d,J=5.5Hz,2H), 2.43(s,3H), 2.29(s,3H), 1.83-1.69(m,1H), 1.69-1.58(m,1H), 1.58-1.37(m,2H), 1.23(s,7H).

[0305] Example 15: Preparation of N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-methylpiperazin-1-carbonyl)phenyl)acrylamide

[0306] Synthesizing methyl 2-amino-4-nitrobenzoate. 2-Amino-4-nitrobenzoic acid (2.00 g), SOCl2 (4.00 mL), and MeOH (20.00 mL) were placed in a 100-mL round-bottom flask. The resulting solution was stirred at 55 °C for 3 hours. The reaction mixture was cooled. The crude product was purified by recrystallization from diethyl ether. The solid was collected by filtration. 1 g of methyl 2-amino-4-nitrobenzoate was given as a yellow solid. LC-MS--752-1:(ES,m / z):197[M+H] + . 1 H NMR--752-1: (300MHz, CDCl3, ppm): δ 8.02 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 2.2 Hz, 1H), 7.42 (dd, J = 8.8, 2.2 Hz, 1H), 6.05 (brs, 2H), 3.94 (s, 3H).

[0307] Synthesis of methyl 2-[bis(tert-butoxycarbonyl)amino]-4-nitrobenzoate: Methyl 2-amino-4-nitrobenzoate (1.00 g, 5.098 mmol, 1.00 equivalent), Boc₂O (3.34 g, 15.293 mmol, 3.00 equivalent), TEA (1.03 g, 10.196 mmol, 2.00 equivalent), DMAP (0.06 g, 0.510 mmol, 0.10 equivalent), and THF (20.00 mL) were placed in a 100-mL round-bottom flask. The resulting solution was stirred at room temperature for 4 hours. The reaction was then quenched by adding water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. 1.8 g (89.08%) of methyl 2-[bis(tert-butoxycarbonyl)amino]-4-nitrobenzoate was given as a yellow solid. LC-MS--752-2:(ES,m / z):397[M+H] + . 1 HNMR--752-2: (300MHz, CDCl3, ppm): δ8.26 (dd, J=8.6, 2.2Hz, 1H), 8.17 (d, J=8.6Hz, 1H), 8.10 (d, J=2.2Hz, 1H), 3.94 (s, 3H), 1.42 (s, 18H).

[0308] Synthesis of 2-[bis(tert-butoxycarbonyl)amino]-4-nitrobenzoic acid: Methyl 2-[bis(tert-butoxycarbonyl)amino]-4-nitrobenzoate (1.80 g, 1 equivalent), LiOH (300.00 mg), H₂O (4.00 mL), and THF (20.00 mL) were placed in a 100-mL round-bottom flask. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by adding 1N hydrochloric acid aqueous solution to the reaction solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄ and concentrated. 1 g (57.59%) of 2-[bis(tert-butoxycarbonyl)amino]-4-nitrobenzoic acid was obtained as a yellow solid.

[0309] LC-MS--752-3:(ES,m / z):383[M+H] + .

[0310] Synthesis of N-(tert-butoxycarbonyl)-N-[2-(4-methylpiperazine-1-carbonyl)-5-nitrophenyl]carbamate tert-butyl: 2-[bis(tert-butoxycarbonyl)amino]-4-nitrobenzoic acid (1.00 g, 2.615 mmol, 1.00 equivalent), piperazine, 1-methyl- (0.31 g, 3.138 mmol, 1.20 equivalent), HATU (1.49 g, 3.923 mmol, 1.50 equivalent), NMM (0.53 g, 5.231 mmol, 2.00 equivalent), and DCM (15.00 mL) were placed in a 50-mL round-bottom flask. The resulting solution was stirred at room temperature for 4 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (100:1). 500 mg (41.16%) of tert-butyl N-(tert-butoxycarbonyl)-N-[2-(4-methylpiperazin-1-carbonyl)-5-nitrophenyl]carbamate was obtained as a pale yellow solid. LC-MS--752-4:(ES,m / z):465[M+H] + .

[0311] Synthesis of N-[5-amino-2-(4-methylpiperazin-1-carbonyl)phenyl]-N-(tert-butoxycarbonyl)carbamate tert-butyl ester: N-(tert-butoxycarbonyl)-N-[2-(4-methylpiperazin-1-carbonyl)-5-nitrophenyl]carbamate tert-butyl ester (500.00 mg), MeOH (20.00 mL), and Pd / C (500.00 mg) were placed in a 100 mL round-bottom flask purged and maintained under an inert H2 atmosphere. The resulting solution was stirred at room temperature for 6 hours. The solid was collected by filtration. The combined organic layers were concentrated. 400 mg of N-[5-amino-2-(4-methylpiperazin-1-carbonyl)phenyl]-N-(tert-butoxycarbonyl)carbamate tert-butyl ester was obtained as a colorless oil. LC-MS--752-5:(ES,m / z):435[M+H] + .

[0312] Synthesis of N-[5-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-(4-methylpiperazin-1-carbonyl)phenyl]-N-(tert-butoxycarbonyl)carbamate tert-butyl ester: N-[5-amino-2-(4-methylpiperazin-1-carbonyl)phenyl]-N-(tert-butoxycarbonyl)carbamate tert-butyl ester (400.00 mg, 0.921 mmol, 1.00 equivalent), 3,5-dibromo-1-methylpyrazin-2-one (369 mg, 400.00 mg, 0.921 mmol, 1.00 equivalent) 0.92 mg, 1.381 mmol, 1.5 equivalents), Pd2(dba)3 (168.59 mg, 0.184 mmol, 0.2 equivalents), XantPhos (213.05 mg, 0.368 mmol, 0.4 equivalents), Cs2CO3 (599.85 mg, 1.841 mmol, 2.0 equivalents), and toluene (25.00 mL) were placed in a 250 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at 100 °C for 4 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (70:30). 200 mg (34.96%) of N-[5-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-(4-methylpiperazin-1-carbonyl)phenyl]-N-(tert-butoxycarbonyl)carbamate tert-butyl ester was obtained as a pale yellow solid. LC-MS--752-6:(ES,m / z):621[M+H] + .

[0313] Synthesis of 3-[[3-amino-4-(4-methylpiperazin-1-carbonyl)phenyl]amino]-5-bromo-1-methylpyrazin-2-one: 200.00 mg of N-[5-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-(4-methylpiperazin-1-carbonyl)phenyl]-N-(tert-butoxycarbonyl)carbamate tert-butyl ester and HCl (gas) in 10.00 mL of 1,4-dioxane were placed in a 50 mL round-bottom flask. The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated. 120 mg of 3-[[3-amino-4-(4-methylpiperazin-1-carbonyl)phenyl]amino]-5-bromo-1-methylpyrazin-2-one was given as a white solid. LC-MS--752-7:(ES,m / z):421[M+H] + .

[0314] Synthesis of N-[5-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-(4-methylpiperazin-1-carbonyl)phenyl]prop-2-enamide: 3-[[3-amino-4-(4-methylpiperazin-1-carbonyl)phenyl]amino]-5-bromo-1-methylpyrazin-2-one (120.00 mg, 0.285 mmol, 1.00 equivalent), acryloyl chloride (28.36 mg, 0.313 mmol, 1.10 equivalent), NMM (57.62 mg, 0.570 mmol, 2.00 equivalent), and DCM (10.00 mL) were placed in a 50 mL round-bottom flask. The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was then concentrated. The crude product was purified by rapid Prep-HPLC with 0.1% NH3·H2O:MeCN = 30% increased to 0.1% NH3·H2O:MeCN = 58% over 9 minutes. 80 mg (59.09%) of N-[5-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-(4-methylpiperazin-1-carbonyl)phenyl]prop-2-enamide was given as a white solid. LC-MS--752-8:(ES, m / z): 475 [M+H] + .

[0315] Synthesis-752-0: N-[5-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-(4-methylpiperazin-1-carbonyl)phenyl]prop-2-enamide (80.00 mg, 0.168 mmol, 1.00 equivalent), 2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-methylpyridin-4-ylboronic acid (73.00 mg, 0.219 mmol, 1.30 equivalent), Pd(dppf)Cl2 CH₂Cl₂ (13.74 mg, 0.017 mmol, 0.10 equivalent), K₂CO₃ (46.52 mg, 0.337 mmol, 2.00 equivalent), DME (8.00 mL), and H₂O (2.00 mL) were placed in an 8-mL vial purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at 90 °C for 1 hour. The crude product was purified by Prep-HPLC. 20 mg (17.23%) of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-methylpyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-(4-methylpiperazin-1-carbonyl)phenyl)prop-2-enamide was obtained as a white solid. LC-MS: 752-0 (ES, m / z): 690 [M+H] + . 1 HNMR--752-0: (300MHz, DMSO-d6, ppm): δ9.76 (s, 1H), 9.52 (s, 1H), 8.48 (s, 1H), 8.34 (d, J = 5.0 Hz,1H), 7.81(dd,J=8.8,1.8Hz,1H), 7.58-7.47(m,2H), 7.20(d,J=8.5Hz,1H), 6.59-6.44(m,2H ), 6.24(dd,J=17.1,1.8Hz,1H), 5.74(dd,J=12.2,2.4Hz,1H), 4.29-4.10(m,3H), 3.86(d,J=11 .9Hz,1H), 3.59(s,3H), 2.68-2.54(m,2H), 2.43(s,2H), 2.29(s,7H), 2.16(s,3H), 1.23(s,6H).

[0316] Example 16: Preparation of N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-1-morpholinopropyl-2-yl)phenyl)acrylamide

[0317] Synthesis of 5-bromo-1-methyl-3-([4-[2-methyl-1-(morpholin-4-yl)propyl-2-yl]-3-nitrophenyl]amino)pyrazin-2-one: 4-[2-methyl-1-(morpholin-4-yl)propyl-2-yl]-3-nitroaniline (400.00 mg, 1.432 mmol, 1.00 equivalent), 3,5-dibromo-1-methylpyrazin-2-one (498.72 mg, 1.862 mmol, ... 1.30 equivalents), Pd2(dba)3 (131.13 mg, 0.143 mmol, 0.10 equivalents), XantPhos (165.71 mg, 0.286 mmol, 0.20 equivalents), Cs2CO3 (933.11 mg, 2.864 mmol, 2.00 equivalents), and dioxane (20.00 mL) were placed in a 100 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at 100 °C for 4 hours. The solid was collected by filtration. The combined organic layers were concentrated. The crude product was purified by recrystallization from MeCN. 350 mg (52.41%) of 5-bromo-1-methyl-3-([4-[2-methyl-1-(morpholin-4-yl)propyl-2-yl]-3-nitrophenyl]amino)pyrazin-2-one was given as a brown solid. LC-MS--753-1:(ES,m / z):466[M+H] + . 1 H NMR--753-1: (300MHz, DMSO-d6, ppm): δ9.90 (s, 1H), 8.19 (d, J = 2.4Hz, 1H), 8.08 (dd, J = 8.9, 2.5Hz, 1H), 7. 62(d,J=9.0Hz,1H), 7.43(s,1H), 3.53-3.39(m,7H), 2.53-2.47(m,2H), 2.23(t,J=4.6Hz,4H), 1.29(s,6H).

[0318] Synthesis of 3-([3-amino-4-[2-methyl-1-(morpholin-4-yl)propyl-2-yl]phenyl]amino)-5-bromo-1-methylpyrazin-2-one: 5-bromo-1-methyl-3-([4-[2-methyl-1-(morpholin-4-yl)propyl-2-yl]-3-nitrophenyl]amino)pyrazin-2-one (350.00 mg, 0.751 mmol, 1.00 equivalent), CH3COOH (1352.13 mg, 22.516 mmol, 30.00 equivalent), Zn (736.37 mg, 11.258 mmol, 15.00 equivalent), and EtOH (30.00 mL) were placed in a 100-mL round-bottom flask. The resulting solution was stirred at room temperature for 2 hours. The solid was collected by filtration. The combined organic layers were concentrated. The resulting solution was extracted with ethyl acetate. The resulting mixture was washed with brine. The mixture was dried over anhydrous sodium sulfate and concentrated. 300 mg (91.60%) of 3-([3-amino-4-[2-methyl-1-(morpholin-4-yl)propyl-2-yl]phenyl]amino)-5-bromo-1-methylpyrazin-2-one was given as a brown oil. LC-MS--753-2:(ES,m / z):436[M+H] + .

[0319] Synthesis of N-[5-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-[2-methyl-1-(morpholin-4-yl)propyl-2-yl]phenyl]prop-2-enamide: 3-([3-amino-4-[2-methyl-1-(morpholin-4-yl)propyl-2-yl]phenyl]amino)-5-bromo-1-methylpyrazin-2-one (300.00 mg, 0.688 mmol, 1.00 equivalent), acryloyl chloride (74.67 mg, 0.825 mmol, 1.20 equivalent), NMM (139.08 mg, 1.375 mmol, 2.00 equivalent), and DCM (10.00 mL) were placed in a 100-mL round-bottom flask. The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was then concentrated. The crude product was purified by rapid Prep-HPLC with 0.1% NH4HCO3:MeCN = 30% increased to 0.1% NH4HCO3:MeCN = 70% over 9 minutes. 260 mg (77.11%) of N-[5-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-[2-methyl-1-(morpholin-4-yl)prop-2-yl]phenyl]prop-2-enamide was given as a white solid. LC-MS--753-3:(ES, m / z): 490 [M+H] + . 1H NMR--753-3: (300MHz, DMSO-d6, ppm): δ10.75 (s, 1H), 9.40 (s, 1H), 7.95 (s, 1H), 7.77 (d, J = 8.5Hz, 1H), 7.39-7.25 (m, 2H), 6 .61-6.44(m,1H), 6.27(dd,J=16.9,2.1Hz,1H), 5.81(d,J=11.0Hz,1H), 3.54(s,4H), 3.44(s,3H), 2.36(s,4H), 1.35(s,6H).

[0320] Synthesis of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-methylpyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-[2-methyl-1-(morpholin-4-yl)prop-2-yl]phenyl)prop-2-enamide: N-[5-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2 -[2-methyl-1-(morpholin-4-yl)prop-2-yl]phenyl]prop-2-enamide (200.00 mg, 0.408 mmol, 1.00 equivalent), 2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-methylpyridin-4-ylboronic acid (193.67 mg, 0.571 mmol, 1.40 equivalent), Pd(dppf)Cl2 CH2Cl2 (33.30 mg, 0.041 mmol, 0.10 equivalent), K2CO3 (112.73 mg, 0.816 mmol, 2.00 equivalent), DME (10.00 mL), and H2O (2.00 mL) were placed in a 40-mL microwave tube maintained under an inert nitrogen atmosphere. The resulting solution was stirred at 95 °C for 2 hours. The crude product was purified by Prep-HPLC. 150 mg (52.18%) of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodecyl-2(6),7-dien-10-yl]-3-methylpyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-[2-methyl-1-(morpholin-4-yl)prop-2-yl]phenyl)prop-2-enamide was obtained as a light brown solid. LC-MS: 753-0 (ES, m / z): 705 [M+H] + . 1H NMR--753-0: (300MHz, DMSO-d6, ppm): δ10.78(s,1H), 9.26(s,1H), 8.38 -8.29(m,2H), 7.69(d,J=8.6Hz,1H), 7.54(d,J=5.2Hz,1H), 7.43(s,1H), 7.28(d,J=8.8Hz,1H), 6.58 -6.45(m,2H), 6.27(d,J=16.8Hz,1H), 5.76(d,J=10.2Hz,1H), 4.31-4.10(m,3H), 3.84(d,J=12.4Hz,1H), 3.57(s,3H), 3.5 7-3.47(m,4H), 2.58(d,J=5.8Hz,2H), 2.43(s,2H), 2.34(d,J=4.7Hz,4H), 2.29(s,3H), 1.34(d,J=4.2Hz,6H), 1.23(s,6H).

[0321] Example A: The following compounds were prepared by methods that are substantially the same as, similar to or similar to those disclosed in the general scheme and the examples above.

[0322]

[0323]

[0324]

[0325] Biological Example 1: Binding Constant (K) d ) Measurement

[0326] via KINOMEscan TM Determination of K in compounds by assay d This assay is the industry's most comprehensive high-throughput system for screening compounds against large numbers of human kinases. (KINOMEscan) TMThe assay is based on a competitive binding assay, which quantitatively measures the ability of a compound to compete with an immobilized, site-directed ligand. The assay is performed by combining three components: a DNA-tagged kinase; an immobilized ligand; and the test compound. The ability of the test compound to compete with the immobilized ligand is measured by quantitative PCR via the DNA tag. A kinase-tagged T7 phage strain was prepared in *E. coli* host derived from BL21 strain. *E. coli* was grown to the logarithmic phase and infected with T7 phage, then incubated at 32°C with shaking until lysis. The lysate was centrifuged and filtered to remove cell debris. The remaining kinase was produced in HEK-293 cells and subsequently DNA-tagged for qPCR detection. Streptomycin-coated magnetic beads were treated with a biotinylated small molecule ligand for 30 minutes at room temperature to generate an affinity resin for the kinase assay. The ligand beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligands and reduce nonspecific binding. Binding reactions were assembled by combining the kinase, ligand-containing affinity beads, and test compound in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). All reactions were performed in 96-well polystyrene plates with a final volume of 0.135 mL. The plates were incubated at room temperature with shaking for 1 hour, and the affinity beads were washed with washing buffer (1x PBS, 0.05% Tween 20). The beads were then resuspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the elution buffer was measured by qPCR. Prepare 11-point, 3-fold serial dilutions of each test compound in 100% DMSO at a final test concentration of 100x, then dilute to 1x (final DMSO concentration = 1%) in the assay. Most K compounds are determined using a maximum compound concentration of 30,000 nM. d If the initial K is measured d If the concentration is <0.5 nM (the lowest concentration tested), the measurement should be repeated with a series of dilutions starting from the lowest highest concentration. K d The reported value is 40,000 nM, indicating that K d It was determined to be >30,000 nM. Combined with the constant (K) d The response is calculated using the Hill equation through a standard dose-response curve: Response = Background + (Signal – Background) / [1 + (K d Hill斜率 / dose Hill斜率The Hill slope was set to -1. The curve was fitted using a nonlinear least square fit and the Levenberg-Marquardt algorithm. This type of determination, performed with a range of doses of the test compound, allows for the determination of an approximate K. d The determination of the K value. Although the K of the compound of the present invention... d The activity varies with the expected structural changes, but these reagents typically exhibit activity at K0. d = in the range of 0.1–1000 nM.

[0327] Biological Example 2: In Vitro Dialysis Assay (Irreversible Assay)

[0328] The IC50 of the test compound was determined in the presence of 0.1 nM enzyme and 40 mM ATP. 0.003 mM of the compound (39x IC50 @ 40 mM ATP) was pre-incubated with 2 nM BTK in an ATP-free assay buffer for 2 h. The compound-enzyme complex was dialyzed for 24 h in the same buffer supplemented with 40 mM ATP. The cumulative dialysate factor was >160,000x. After dialysing, BTK activity was measured in the presence of 40 mM ATP and 1 mM substrate peptide and compared with BTK activity in undialyzed samples. Assay buffer: 100 mM HEPES, pH 7.5; 0.1% BSA, 0.01% Triton-X 100; 5 mM MgCl2; 1 mM MDT. In this study, ibrutinib (an FDA-approved irreversible BTK inhibitor) was used as a positive control, and saurosporine (a reversible BTK inhibitor) was used as a negative control. The table below shows the recovery after 24 hours of dialysis.

[0329] In this assay, the reversible BTK inhibitor GDC-0853 was used as a reference compound. GDC-0853, disclosed in WO 2013067274, is an orally bioavailable, selective, and reversible Bruton's tyrosine kinase (BTK) inhibitor with an IC50 range of 2-9 nM, used for basophil activation, B-cell receptor activation, and constitutive p-BTK activity in whole blood lysates.1,2 In rats, treatment for more than 7 days resulted in pancreatic toxicity, but this did not occur in mice or dogs even at higher doses. Formulations containing GDC-0853 were well-tolerated in a Phase I clinical trial and are in further clinical trials for rheumatoid arthritis, lupus erythematosus, and other autoimmune diseases.

[0330] Data from the WT BTK dialysis assay clearly show that ibrutinib, Examples 2, 3, 11, and 12 are irreversible inhibitors of WT BTK, while GDC-0853 is a reversible WT BTK inhibitor.

[0331] Ibrutinib ～1％ Irreversible / Covalent Suppression Example 2 ～1％ Irreversible / Covalent Suppression Example 3 ～1％ Irreversible / Covalent Suppression Example 11 ～1％ Irreversible / Covalent Suppression Example 12 ～1％ Irreversible / Covalent Suppression GDC-0853 ～100％ Reversible

[0332] For the C481S BTK enzyme, ibrutinib and our compounds (as in Example 2) bind reversibly to C481S BTK because cysteine ​​residues are no longer available for covalent binding.

[0333] Biological Example 3: Biochemical Enzymatic Assay (IC50) for WT and C481S BTK

[0334] A caliper-based kinase assay (Caliper Life Sciences, Hopkinton, MA) was used to measure the inhibition of WT and C481S Btk kinase activity by the compounds disclosed herein. Ibrutinib and ACP=196 were used as control compounds. Serial dilutions of the test compounds were incubated at room temperature for 3 hours with recombinant human WT BTK or C481S Btk (0.5 nM), ATP (16 μM), and the phosphoreceptor peptide substrate FAM-GEEPLYWSFPAKKK-NH2 (1 μM). The reaction was then terminated with EDTA to a final concentration of 20 mM, and the phosphorylated reaction products were quantified on a Caliper Desktop Profiler (Caliper LabChip 3000). The percentage of inhibition for each compound dilution was calculated, and the concentration at which 50% inhibition was produced was determined.

[0335] The table below shows the IC50 values ​​for WT BTK, C481S BTK, and the IC50 ratio of C481S to WT BTK for ibrutinib, ACP-196, and certain compounds of this disclosure. As expected, both ibrutinib and ACP-196 showed a significant loss of binding affinity to the C481S BTK enzyme: ibrutinib was 990 times weaker than WT BTK in C481S BTK, while ACP-196 was 483 times weaker than WT BTK in C481S BTK. Conversely, the inventors unexpectedly found that our compounds still potently inhibited C481S BTK compared to WT BTK. Example 2 showed greater potency than ibrutinib (x64) and greater potency than ACT-196 (x477) in the C481S BTK assay. These data suggest that our compounds (as in Example 2) bind reversibly to BTK via a mechanism different from conventional covalent BTK inhibitors (such as ibrutinib and ACP-196), and therefore may be an important option for patients who are resistant to ibrutinib and ACP-196 due to mutations at the C481 binding site.

[0336]

[0337] Biological Example 4: Calcium Flux Fluorescence-Based Assay

[0338] According to the manufacturer's instructions, a calcium flux fluorescence-based assay was performed using the FlexStation II 384 Molecular Devices. In short, Ramos cells (ATCC) actively grown in RPM1 medium supplemented with 10% FBS (Invitrogen) were washed, and approximately 5 x 10⁶ cells per well were used at a concentration of 100 μl. 5 Cells were redistributed to low-serum medium in 96-well plates. The compound to be measured was dissolved in DMSO and then diluted in low-serum medium to a final concentration ranging from 0 to 10 μM (with a dilution factor of 0.3). The diluted compound was then added to each well (final DMSO concentration 0.01%) and incubated at 37°C for 1 hour in a 5% CO2 incubator. Afterward, 100 μl of a calcium-sensitive dye (from the Calcium 3 assay kit, Molecular Devices) was added to each well and incubated for another 1 hour. The compound-treated cells were stimulated with goat anti-human IgM antibody (80 μg / ml; Jackson ImmunoResearch) and λ was used. Ex =485nm and λ Em=538nm readout for 200 seconds on a FlexStation II384. Relative fluorescence units (RFU) and IC were recorded and analyzed using the built-in SoftMax program (Molecular devices). 50 .

[0339] Biological Example 5: Inhibition of B Cell Activation - B Cell FLIPR Assay in Ramos Cells

[0340] The inhibitory effect of the compounds of this invention on B cell activation was demonstrated by determining the effect of the test compounds on the response of B cells stimulated with anti-IgM. The B cell FLIPR assay is a functional method based on cells that determines the role of potential inhibitors of intracellular calcium increase induced by anti-IgM antibody stimulation. Ramos cells (human Burkitt's lymphoma cell line, ATCC-No. CRL-1596) were cultured in growth medium (as described below). One day prior to the assay, Ramos cells were resuspended in fresh growth medium (same as above) and placed in tissue culture flasks at 0.5 x 10⁻⁶. 6 The concentration was set at / mL. On the day of the assay, cells were counted and set to 1x10⁻¹ in tissue culture flasks supplemented with growth medium containing 1 μM FLUO-3AM (TefLabs Cat-No. 0116, prepared in anhydrous DMSO and 10% pyruvate). 6 Cells were incubated at a concentration of [value missing] mL at 37°C (5% CO2) for 1 hour. To remove extracellular dye, cells were collected by centrifugation (5 min, 1000 rpm) at a concentration of 1 x 10⁻⁶. 6 Resuspend cells / mL in FLIPR buffer (as described below), then fill each well with 1 x 10⁻⁶ cells / mL. 5 Cells were randomly assigned to 96-well poly-D-lysine-coated black / clear plates (BD Cat-No. 356692). Test compounds were added at various concentrations (7 concentrations, details below) ranging from 100 μM to 0.03 μM, and the cells were allowed to incubate at room temperature for 30 minutes. Ramos cells were stimulated with 10 μg / mL anti-IgM (SouthernBiotech, Cat-No. 2020-01). 2+ Signal transduction was performed and measured on a FLIPR (Molecular Devices, which uses a CCD camera with an argon laser excited by 480 nM to capture images of a 96-well plate).

[0341] • Growth medium: RPMI 1640 medium containing L-glutamine (Invitrogen, Cat-No. 61870-010), 10% fetal bovine serum (FBS, Summit Biotechnology Cat-No. FP-100-05), and 1mM sodium pyruvate (Invitrogen Cat. No. 11360-070).

[0342] • FLIPR buffer: HBSS (Invitrogen, Cat-No. 141175-079), 2 mM CaCl2 (Sigma Cat-No. C-4901), HEPES (Invitrogen, Cat-No. 15630-080), 2.5 mM Probenecid (Sigma, Cat-No. P-8761), 0.1% BSA (Sigma, Cat-No. A-7906), 11 mM Glucose (Sigma, Cat-No. G-7528);

[0343] • Assay and Analysis: Increases in intracellular calcium were reported using the maximum-minimum statistic (resting baseline was subtracted from the peak induced by the addition of the stimulating antibody using MolecularDevices FLIPR control and statistic export software). IC50 was determined using nonlinear curve fitting. 50 (GraphPad Prism).

[0344] Biological Example 6: In vitro anti-proliferative assay

[0345] via PerkinElmer ATPlite TM A luminescence assay system was used to determine cell proliferation resistance. In short, various test cancer cell lines were cultured at approximately 1 x 10⁻⁶ cells per well. 4 Cells were spaced at different densities in Costr 96-well plates and incubated with different concentrations of the compound for approximately 72 hours in medium supplemented with 5% FBS. A lyophilized substrate solution vial was then reconstituted by adding 5 mL of substrate buffer and gently stirring until homogeneous. Approximately 50 μL of mammalian cell lysis buffer was added to each well of the microplate containing 100 μL of cell suspension, and the plate was incubated on a track-mounted shaker at approximately 700 rpm for approximately 5 minutes. This procedure was used to lyse cells and stabilize ATP. Next, 50 μL of substrate solution was added to the wells, and the microplate was incubated on a track-mounted shaker at approximately 700 rpm for 5 minutes. Finally, the cells were analyzed using PerkinElmer. A microplate scintillation counter measures luminescence. Such assays, performed with test compounds within a defined dose range, allow for the determination of the cellular antiproliferative IC50 of the compounds of this invention. 50 .

[0346] Biological Example 7: In vivo xenograft research

[0347] Typically, athymic nude mice (CD-1nu / nu) or SCID mice are obtained from the supplier at 6-8 weeks of age and acclimatized for at least 7 days. Cancer cells are then implanted into the nude mice. Depending on the specific tumor type, tumors are usually detectable about two weeks after implantation. Tumors typically develop when they reach a size of approximately 100-200 mm. 3 Animals with detectable tumor size and shape were randomly assigned to groups of eight mice each, including a vector control group and a treatment group. Dosage varied depending on the purpose and length of each study (typically about 3–4 weeks). Tumor size and body weight were typically measured three times per week. In addition to determining changes in tumor size, the last tumor measurement was used to generate the tumor size change rate (T / C value), a standard metric developed by the National Cancer Institute for evaluating xenograft tumors. In most cases, the %T / C value is calculated using the following formula: %T / C = 100 × ΔT / ΔC, if ΔT > 0. However, when tumor regression occurs (ΔT < 0), the following formula is used: %T / T0 = 100 × ΔT / T0. Values ​​< 42% are considered significant.

[0348] Biological Example 8: Mice with Collagen-Induced Arthritis (mCIA)

[0349] On day 0, mice were injected with a type II collagen (id) emulsion in complete Freund's adjuvant (CFA) at several sites on the base of the tail or back. Following collagen immunization, animals developed arthritis approximately 21 to 35 days later. On day 21, a simultaneous (enhanced) arthritis attack was initiated by systemic administration of collagen in incomplete Freund's adjuvant (IFA; id). After day 20, animals were examined daily for any mild arthritis attacks (scores of 1 or 2; see scoring instructions below) as a sign of enhancement. Following enhancement, mice were scored, and candidate therapeutic agents were administered for a prescribed period (typically 2–3 weeks) and at a frequency of daily (QD) or twice daily (BID). Inflammation in the paw and limb joints was quantified using a scoring system involving assessment of four paws according to the following criteria:

[0350] score:

[0351] 1 = Swelling and / or redness of the claw or toe.

[0352] 2 = Two or more joints are swollen.

[0353] 3 = Severe swelling of the claws, affecting more than two joints.

[0354] 4 = Severe arthritis of the entire claw and toe.

[0355] Assessments were conducted on day 0 for baseline measurements, and reassessments were initiated at the first sign of disease or when swelling occurred up to three times per week until the end of the experiment. The arthritis index for each mouse was obtained by summing the four scores for each paw, with a maximum score of 16 for each animal.

[0356] Biological Example 9: Collagen-Induced Arthritis (rCIA) in Rats

[0357] On day 0, rats were given intradermal (id) injections of an emulsion of bovine type II collagen in incomplete Freund's adjuvant (IFA) at several sites on the back. Around day 7, booster injections (id) of the collagen emulsion were given at the base of the tail or alternating sites on the back. Arthritis was generally observed 12–14 days after the initial collagen injection. From day 14 onwards, the development of arthritis in animals was assessed as described below (Assessment of Arthritis). The candidate therapeutic agent was administered prophylactically to animals starting at the second challenge and for a prescribed period (usually 2–3 weeks) and frequency of administration, either daily (QD) or twice daily (BID). Inflammation in the paw and limb joints was quantified using a scoring system involving assessment of the four paws according to the criteria described above. Assessment was performed on day 0 for baseline measurements and reassessed at the first sign or up to three times per week of swelling until the end of the experiment. The arthritis index for each mouse was obtained by summing the four scores for each paw, with a maximum score of 16 for each animal.

[0358] Biological Example 10: In vivo asthma model in rats

[0359] Male Brown-Norway rats were sensitized weekly for three weeks (days 0, 7, and 14) with 100 μg of ovalbumin (OA) in 0.2 ml alum via intraperitoneal injection. On day 21 (one week after the last sensitization), rats were subcutaneously administered the medium or compound formulation qd 0.5 hours before an OA aerosol challenge (1% OA for 45 minutes) and the sensitization was terminated 4 or 24 hours after the challenge. At sacrifice, serum and plasma were collected from all animals for serological and pharmacokinetic analysis, respectively. Tracheostomy tubes were inserted, and the lungs were lavaged three times with PBS. Total white blood cell count and differential white blood cell count were analyzed in the BAL fluid. Total white blood cell count in aliquots (20–100 μl) was determined by Coulter counter. For differential white blood cell counts, 50–200 μl of sample were centrifuged in Cytospin and slides were stained with Diff-Quik. The proportions of monocytes, eosinophils, neutrophils, and lymphocytes were counted under optical microscopy using standard morphological criteria and expressed as percentages. Representative Btk inhibitors showed a decrease in total white blood cell count in the BAL of OA-sensitized and challenged rats compared to control levels.

[0360] This invention provides:

[0361] 1. A compound of formula (I) or its N-oxide, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of a compound of formula (I) or its N-oxide:

[0362]

[0363] in

[0364] Q1 is a 5-6 aryl or heteroaryl group;

[0365] Q2 is a 5-7 membered heterocyclic alkyl or heteroaryl group;

[0366] Q3 is a 5-membered heteroaryl group;

[0367] W, X, Y, and Z1 are each independent of C(R) a ) or N;

[0368] R1 and R5 are independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halogen, nitro, oxo, cyano, OR a SR a alkyl-R a NH(CH2) p R a C(O)R a S(O)R a SO2Ra C(O)OR a OC(O)R a NR b R c C(O)N(R) b )R c 、N(R b )C(O)R c -P(O)R b R c ,-alkyl-P(O)R b R c -S(O)(=N(R) b ))R c -N=S(O)R b R c =NR b SO2N(R) b )R c or N(R) b SO2R c The cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl groups are optionally represented by one or more R groups. d replace;

[0369] R2 is H or an alkyl group;

[0370] R3 is H, halo, alkyl, haloalkyl or hydroxyalkyl;

[0371] R4 is H, a halogenated or a lower alkyl group;

[0372] The two atoms of the R1 group, together with the atoms to which they are attached, can optionally form a group with one or more R groups. d Substituted cycloalkyl or heterocycloalkyl;

[0373] The two atoms of the R5 group, together with their attached atoms, can optionally form a group with one or more R groups. d Substituted cycloalkyl or heterocycloalkyl;

[0374] R a R b R c and R d Independently, it can be H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogenated, cyano, amine, nitro, hydroxyl, =O, -P(O)R b R c ,-alkyl-P(O)R b R c -S(O)(=N(R) b ))R c -N=S(O)R b R c=NR b C(O)NHOH, C(O)OH, C(O)NH2, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo-alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl are optionally represented by one or more R e replace;

[0375] R e It is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxyl, =O, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo-alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl;

[0376] m, n, p, and q are each independently 0, 1, 2, 3, or 4; and

[0377] The warhead is

[0378] 2. The compound of claim 1 or its N-oxide, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof, wherein the compound is represented by formula (II):

[0379]

[0380] in

[0381] k is 0, 1, or 2;

[0382] s is 0, 1, 2, or 3; and

[0383] Q4 is a 5-7 membered cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group.

[0384] 3. The compound of claim 2 or its N-oxide, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug thereof, wherein the compound is represented by formula (III):

[0385]

[0386] in

[0387] r can be 0, 1, 2, or 3.

[0388] 4. The compound of claim 2 or its N-oxide, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug, wherein the compound is represented by formula (IV), wherein:

[0389]

[0390] in

[0391] k is 1 or 2; and

[0392] r is 1 or 2.

[0393] 5. The compound of claim 1 or its N-oxide, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug, wherein said compound is

[0394] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetane-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0395] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-morpholinopiperidin-1-yl)phenyl)acrylamide,

[0396] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetane-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0397] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide,

[0398] (S)-N-(2-(4-(4,4-difluorocyclohexyl)-2-methylpiperazin-1-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)phenyl)acrylamide,

[0399] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-((2S)-2-methyl-4-morpholinopiperidin-1-yl)phenyl)acrylamide,

[0400] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-morpholinopiperidin-1-yl)phenyl)acrylamide,

[0401] N-(2-(4,4-difluoro-[1,4'-bipiperidin]-1'-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)phenyl)acrylamide,

[0402] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide,

[0403] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-3-methyl-2-(2-methyl-4-(oxetane-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0404] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-3-fluoro-2-(2-methyl-4-(oxetane-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0405] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetane-3-yl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)acrylamide,

[0406] (S)-N-(3-cyano-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadien[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetane-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0407] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-3-(isopropylsulfonyl)-2-(2-methyl-4-(oxetane-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0408] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetane-3-yl)piperazin-1-yl)-3-((trifluoromethyl)sulfonyl)phenyl)acrylamide,

[0409] N-(2-((2'S)-4,4-difluoro-2'-methyl-[1,4'-bipiperidin]-1'-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)phenyl)acrylamide,

[0410] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-((2S)-2-methyl-4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide.

[0411] 6. A pharmaceutical composition comprising a compound of formula (I) as defined in item 1 or its N-oxide, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug of a compound of formula (I) or its N-oxide, and a pharmaceutically acceptable diluent or carrier.

[0412] 7. A method for treating neobiological diseases, autoimmune diseases, and inflammatory conditions, comprising administering to a subject in need an effective amount of a compound of formula (I) as defined in item 1 or its N-oxide, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form, or prodrug of a compound of formula (I) or its N-oxide.

[0413] 8. The method of item 7, wherein the autoimmune disease and inflammatory condition are pemphigus vulgaris, rheumatoid arthritis (RA), asthma, multiple sclerosis, systemic lupus erythematosus, or allergic reactions.

[0414] 9. The method of item 8, wherein the neoplastic disease is a B-cell malignancy or a solid tumor.

[0415] 10. The method of item 9, wherein the neoplasm is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), or multiple myeloma (MM).

[0416] 11. Used for preparation The method includes making and Contacting the target compound under certain conditions for a period of time, wherein the conditions and time are sufficient to produce the target compound.

Claims

1. A compound of formula (IV), or a pharmaceutically acceptable salt thereof: (IV) in R1 is independently H, D, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne, 3- to 6-membered cycloalkyl, 5- to 8-membered monocyclic heterocyclic alkyl, halogen, nitro, cyano, OR a SR a C1-C 10 Alkyl-R a The 3- to 6-membered cycloalkyl group and the 5- to 8-membered monocyclic heterocyclic alkyl group are optionally represented by one or more R d replace; R3 is H, halogen, C1-C4 alkyl, halo-C1-C4 alkyl, or hydroxy-C1-C4 alkyl; R a and R d Each is independent of H, D, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne, halogen, cyano, nitro, hydroxyl, =O, C1-C 10 Alkoxy, halogenated C1-C 10 Alkyl, hydroxyl C1-C 10 Alkyl, amino C1-C 10 Alkyl, 3- to 6-membered cycloalkyl, 5- to 8-membered monocyclic heterocyclic alkyl, wherein the C1-C 10 Alkyl, 3- to 6-membered cycloalkyl, 5- to 8-membered heterocycloalkyl, optionally with one or more R e replace; R e It is H, D, C1-C 10 Alkyl, halogen, cyano, hydroxyl, C1-C 10 Alkoxy, 3- to 6-membered cycloalkyl, 5- to 8-membered monocyclic heterocyclic alkyl; m is 0, 1, 2, 3 or 4; k is 1; s is 0, 1, 2, or 3; and r is 1.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, in R1 is a 5- to 8-membered monocyclic heterocyclic alkyl group, wherein the 5- to 8-membered monocyclic heterocyclic alkyl group is optionally represented by one or more R1 groups. d Substitution; wherein the 5- to 8-membered monocyclic heterocyclic alkyl group is a monocyclic ring system having one or more N heteroatoms; wherein the R d Each independently consists of H, D, and C1-C. 10 Alkyl, amino C1-C 10 Alkyl, 5- to 8-membered monocyclic heterocyclic alkyl, R d The C1-C mentioned in 10 Alkyl, 5- to 8-membered monocyclic heterocyclic alkyl, optionally with one or more R e replace; R e Is it H, D, or C1-C? 10 alkyl; R3 is a hydroxyl C1-C4 alkyl group; (R d ) s The R mentioned in d For C1-C 10 alkyl; s is 2; m is 1; k is 1; and r is 1.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, in R1 is a 5- to 8-membered monocyclic heterocyclic alkyl group, wherein the 5- to 8-membered monocyclic heterocyclic alkyl group is optionally represented by one or more R1 groups. d Substitution; wherein the 5- to 8-membered monocyclic heterocyclic alkyl group is a monocyclic ring system having one or more N heteroatoms; wherein the R d Each is independent of H, D, C1-C 10 Alkyl, amino C1-C 10 Alkyl groups, 5- to 8-membered monocyclic heterocyclic alkyl groups, wherein the 5- to 8-membered monocyclic heterocyclic alkyl group is a monocyclic ring system having one or more heteroatoms selected from O or N, R d The C1-C mentioned in the text 10 Alkyl, 5- to 8-membered monocyclic heterocyclic alkyl, optionally with one or more R e replace; R e It is H, D, C1-C 10 alkyl; R3 is a hydroxymethyl group; (R d ) s The R mentioned in d It is methyl; s is 2; m is 1; k is 1; and r is 1.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, in R1 is a 5- to 8-membered monocyclic heterocyclic alkyl group, wherein the 5- to 8-membered monocyclic heterocyclic alkyl group is represented by one or more R1 d Substitution; wherein the 5- to 8-membered monocyclic heterocyclic alkyl group has one or more N heteroatoms; wherein the R d Each is independently methyl or 5 to 8-membered monocyclic heterocyclic alkyl group, R d The 5- to 8-membered monocyclic heterocyclic alkyl group described herein has one or more heteroatoms selected from O or N; wherein the methyl group, the 5- to 8-membered monocyclic heterocyclic alkyl group is optionally represented by one or more R atoms. e replace; R e It is H; R3 is a hydroxymethyl group; (R d ) s The R mentioned in d It is methyl; s is 2; m is 1; k is 1; and r is 1.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, in R1 is a piperazine group, wherein the piperazine group is represented by one or more R... d Replace; wherein the R d Each is independently methyl or 5 to 8-membered monocyclic heterocyclic alkyl group, R d The 5- to 8-membered monocyclic heterocyclic alkyl group described herein has one O heteroatom; wherein the methyl group, 5- to 8-membered monocyclic heterocyclic alkyl group is optionally represented by one or more R atoms. e replace; R e It is H; R3 is a hydroxymethyl group; (R d ) s The R mentioned in d It is methyl; s is 2; m is 1; k is 1; and r is 1.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, in R1 is C1-C 10 Alkyl, 5- to 8-membered monocyclic heterocyclic alkyl, halogen, cyano, SR a C1-C 10 Alkyl-R a The 5- to 8-membered monocyclic heterocyclic alkyl group is made of one or more R d Replace; wherein the R d Each is independent of the other (C1-C). 10 Alkyl, 3- to 6-membered cycloalkyl, or 5- to 8-membered monocyclic heterocyclic alkyl, wherein the C1-C 10 Alkyl, 5- to 8-membered monocyclic heterocyclic alkyl, optionally with one or more R e replace; R e Is it H, D, halogen, or C1-C? 10 alkyl; R3 is a C1-C4 alkyl group; (R d ) s The R mentioned in d For C1-C 10 alkyl; s is 2; m is 1 or 2; k is 1; and r is 1.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, in R1 is a 5- to 8-membered monocyclic heterocyclic alkyl group, wherein the 5- to 8-membered monocyclic heterocyclic alkyl group is optionally represented by one or more R1 groups. d Substitution; wherein the 5- to 8-membered monocyclic heterocyclic alkyl group has one or more N heteroatoms; wherein the R d Each is independent of the other (C1-C). 10 Alkyl or 5- to 8-membered monocyclic heterocyclic alkyl, wherein the 5- to 8-membered monocyclic heterocyclic alkyl has one or more heteroatoms selected from O or N, wherein the C1-C 10 Alkyl, 5- to 8-membered monocyclic heterocyclic alkyl, optionally with one or more R e replace; R e It is H; R3 is a methyl group; (R d ) s The R mentioned in d It is methyl; s is 2; m is 1; k is 1; and r is 1.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, in R1 is a piperazine group, wherein the piperazine group is represented by one or more R... d Replace; wherein the R d Each is independently methyl; wherein the methyl group is optionally represented by one or more R e replace; R e It is H; R3 is a hydroxymethyl group; (R d ) s The R mentioned in d It is methyl; s is 2; m is 1; k is 1; and r is 1.

9. A compound of formula (IV), or a pharmaceutically acceptable salt thereof, (IV) in R1 is a piperazine group, wherein the piperazine group is represented by one or more R... d Replace; wherein the R d Each is independently methyl or a 5-membered monocyclic heterocyclic alkyl group, R d The 5-membered monocyclic heterocyclic alkyl group described herein has one O heteroatom; wherein the methyl group or the 5-membered monocyclic heterocyclic alkyl group is optionally represented by one or more R atoms. e replace; R e It is H; R3 is a hydroxymethyl group; (R d ) s The R mentioned in d It is methyl; s is 2; m is 1; k is 1; and r is 1.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, in R1 is a 5- to 8-membered monocyclic heterocyclic alkyl group, wherein the 5- to 8-membered monocyclic heterocyclic alkyl group is optionally represented by one or more R1 groups. d Substitution; wherein the 5- to 8-membered monocyclic heterocyclic alkyl group has one or more N heteroatoms; wherein the R d Each is independently methyl or a 5-membered monocyclic heterocyclic alkyl group, wherein the 5-membered monocyclic heterocyclic alkyl group has a heteroatom selected from O or N, R d The methyl and 5-membered heterocyclic alkyl groups mentioned herein are optionally represented by one or more R e replace; R e It is H or halogen; R3 is a hydroxymethyl group; (R d ) s The R mentioned in d It is methyl; s is 2; m is 1; k is 1; and r is 1.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, in R1 is a 5- to 8-membered monocyclic heterocyclic alkyl group, wherein the 5- to 8-membered monocyclic heterocyclic alkyl group is represented by one or more R1 d Replace; wherein the R d Each is independent of the other (C1-C). 10 Alkyl, wherein the C1-C 10 Alkyl groups are optionally represented by one or more R e replace; R e Is it H, D, halogen, or C1-C? 10 alkyl; R3 is a methyl group; (R d ) s The R mentioned in d It is methyl; s is 2; m is 1; k is 1; and r is 1.

12. A compound of formula (IV), or a pharmaceutically acceptable salt thereof, (IV) in R1 is a piperazine group, wherein the piperazine group is represented by one or more R... d Replace; wherein the R d Each is independent of the other (C1-C). 10 Alkyl or 5- to 8-membered monocyclic heterocyclic alkyl, R d The 5- to 8-membered monocyclic heterocyclic alkyl group described herein has one O heteroatom; wherein the C1-C 10 Alkyl, 5- to 8-membered heterocyclic alkyl, optionally with one or more R e replace; R e It is H; R3 is a methyl group; (R d ) s The R mentioned in d It is methyl; s is 2; m is 1; k is 1; and r is 1.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, in R1 is a piperazine group, wherein the piperazine group is represented by one or more R... d Replace; wherein the R d Each is independent of the other (C1-C). 10 Alkyl; wherein the C1-C 10 Alkyl groups are optionally represented by one or more R e replace; R e It is H; R3 is a methyl group; (R d ) s The R mentioned in d It is methyl; s is 2; m is 1; k is 1; and r is 1.

14. A pharmaceutical composition comprising a compound of formula (IV) as defined in any one of claims 1-13, or a pharmaceutically acceptable salt of a compound of formula (IV), and a pharmaceutically acceptable diluent or carrier.

15. Use of a compound of formula (IV) as defined in any one of claims 1-13, or a pharmaceutically acceptable salt of a compound of formula (IV), or the composition of claim 14, in the preparation of a medicament for treating neoplastic diseases and inflammatory conditions.

16. Use of a compound of formula (IV) as defined in any one of claims 1-13, or a pharmaceutically acceptable salt of a compound of formula (IV), or the composition of claim 14 in the preparation of a medicament for the treatment of autoimmune diseases.

17. The use of claim 15, wherein the inflammatory condition is pemphigus vulgaris, rheumatoid arthritis, asthma, multiple sclerosis, systemic lupus erythematosus, or allergic reaction.

18. The use of claim 15, wherein the neoplastic disease is a B-cell malignancy or a solid tumor.

19. The use of claim 15, wherein the neoplastic disease is chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, or multiple myeloma.

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