Inhibitors of BTK and its mutants

Abstract

The present disclosure includes compounds of formula (I)(1), wherein Q 0 , Q 1 , Q 2 , Q 3 , Q 4 , Z, W, i, j, m, n, warhead, R 0 , R 1 , R 3 , R 4 , R 5 , R 6 and R 7 As defined herein. Also disclosed are methods of using these compounds to treat neoplastic diseases, autoimmune diseases and inflammatory conditions. #imgabs0#

Description

[0001] References to related applications

[0002] This application claims the benefit of the filing dates of U.S. Provisional Patent Applications 62 / 810,169, filed February 25, 2019; 62 / 837,535, filed April 23, 2019; and 62 / 911,212, filed October 5, 2019, each of which is incorporated herein by reference in its entirety. Background Art

[0003] Bruton's tyrosine kinase (Btk) is a non-receptor protein kinase of the Tec family, 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 new approach to treating many different human diseases, such as B cell malignancies, autoimmune diseases, and inflammatory disorders [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].

[0004] Covalent Bruton's tyrosine kinase (BTK) inhibitors, including ibrutinib and acalabrutinib, have transformed the treatment of several BTK-dependent B-cell malignancies, including chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia, mantle cell lymphoma, and marginal zone lymphoma. Despite the impressive clinical responses of ibrutinib in B-cell malignancies, cases of primary and secondary resistance have occurred, with a poor prognosis and limited treatment options. Most CLL patients who develop resistance to irreversible BTK inhibitors such as ibrutinib develop BTK-C481S mutations. It has been reported that 80% of patients with relapsed CLL will have a C481S mutation [Maddocks KJ, et al. JAMA Oncol. 2015; 1: 80–87]. Another research group at Ohio State University reported in the Journal of Clinical Oncology [Vol 35, No. 13, 2017, p. 1437] that at year four, about 20% of patients taking ibrutinib had clinical progression. Of these patients who relapsed, 85% acquired the C481S mutation. Moreover, these mutations were detected, on average, nine months before relapse.

[0005] Although BTK inhibitors such as ibrutinib and ACP-196 have made significant contributions to the art, there is a strong need in the art to continue to search for highly potent and selective BTK inhibitors that can not only irreversibly inhibit WT BTK, but also reversibly inhibit C481S mutant BTK. SUMMARY OF THE INVENTION

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

[0008] In one aspect, the present invention relates to a compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug of the compound of formula (I) or its N-oxide:

[0009]

[0010] in

[0011] Q 0 is a 5-9 membered aryl group or a 5-9 membered heterocyclic ring;

[0012] Q 1 is a 5-9 membered aryl group or a 5-9 membered heterocyclic ring;

[0013] Q 2 is a 5-8 membered heterocycloalkyl or a 5-8 membered heteroaryl;

[0014] Q 3 is a 5-6 membered heteroaryl or a 6 membered aryl;

[0015] Q 4 is a 5-6 membered heteroaryl or a 6 membered aryl;

[0016] W is -C(O)- or -S(O 2 )-;

[0017] Z is NH or O;

[0018] The warhead is

[0019] R 0 , R 1 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 Each is 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(CH 2 ) p R a 、C(O)R a 、S(O)R a 、SO 2 R 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 、SO 2 N(R b )R c or N(R b )SO 2 R c wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl are optionally substituted by one or more R d replace;

[0020] R 3 is H, halogen, alkyl, haloalkyl or hydroxyalkyl;

[0021] R 4 is H, halogen or lower alkyl;

[0022] R 0 and R 1 The groups, together with the atoms to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl group, which may be optionally substituted by one or more R d replace;

[0023] Two R's 1 The groups, together with the atoms to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl group, which may be optionally substituted by one or more R d replace;

[0024] Two R's 5 The groups, together with the atoms to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl group, which may be optionally substituted by one or more R d replace;

[0025] Two R's 6 The groups, together with the atoms to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl group, which may be optionally substituted by one or more R d replace;

[0026] Two R's 7 The groups, together with the atoms to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl group, which may be optionally substituted by one or more R d replace;

[0027] R a , R b , R c and R d are independently H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxyl, =O, -P(O)R b R c , -alkyl-P(O)Rb 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)NH 2 , 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 is optionally substituted by one or more R e replace;

[0028] R e is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =O, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo-alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl;

[0029] Two R's d The groups, together with the atoms to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl group, which may be optionally substituted by one or more R e replace; and

[0030] i, j, m, n, p and q are each independently 0, 1, 2, 3 or 4.

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

[0032]

[0033] In a more preferred embodiment, the compound is represented by formula (III):

[0034]

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

[0036]

[0037] in

[0038] k is 0, 1 or 2.

[0039] Compounds of the present invention may contain one or more asymmetric carbon atoms. Therefore, compounds may exist as diastereomers, enantiomers or mixtures thereof. Each asymmetric carbon atom may be in R or S configuration, and these two configurations are within the scope of the present invention.

[0040] Modified compounds of any of these compounds are also contemplated, including modifications having improved (e.g., enhanced, greater) drug solubility, stability, bioavailability, and / or therapeutic index compared to the unmodified compound. Exemplary modifications include, but are not limited to, applicable prodrug derivatives and deuterium-enriched compounds.

[0041] It will be appreciated that the compounds of the invention may exist in the form of salts or solvates and may optionally be administered in this form. The present invention encompasses any pharmaceutically acceptable salts and solvates of any of the above compounds and modifications thereof.

[0042] Also within the scope of the present invention are 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, said pharmaceutical compositions containing one or more of the above-mentioned compounds, modifications and / or salts thereof.

[0043] The present invention also relates to a method for treating neoplastic diseases, particularly B-cell malignancies, including but not limited to B-cell lymphoma, lymphoma (including Hodgkin's lymphoma and non-Hodgkin's lymphoma), hairy cell 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 lymphocytic leukemia, by administering to a subject in need thereof an effective amount of one or more of the compounds, modifications and / or salts thereof and compositions described above.

[0044] Autoimmune and / or inflammatory diseases that can be affected using the compounds and compositions according to the present invention include, but are not limited to, psoriasis, allergies, Crohn's disease, irritable bowel syndrome, Sjogren's disease, tissue graft rejection and hyperacute rejection of transplanted organs, asthma, systemic lupus erythematosus (and related glomerulonephritis), dermatomyositis, multiple sclerosis, scleroderma, vasculitis (ANCA-associated and other vasculitic diseases), autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome (and related 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.

[0045] The details of one or more embodiments of the present invention are set forth in the following description. Other features, objects and advantages of the present invention will become apparent from the specification and claims. It should be understood that all embodiments / features (compounds, pharmaceutical compositions, preparation / use methods, etc.) of the present invention described herein, including any specific features described in the examples and original claims, can be combined with each other unless not applicable or explicitly excluded. DETAILED DESCRIPTION OF THE INVENTION

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

[0048] Part 1: CH3-OH

[0049] N-(5-((6-(3-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0050] N-(5-((6-(3-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-2-(hydroxymethyl)phenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0051] (S)-N-(5-((6-(3-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

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

[0053] N-(5-((6-(3-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-ynamide,

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

[0055] (S)-N-(5-((6-(3-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)piperazin-1-yl)phenyl)but-2-ynamide,

[0056] N-(3-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0057] (E)-N-(3-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0058] (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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)pyrrolidin-1-yl)phenyl)acrylamide,

[0059] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)piperidin-4-yl)phenyl)acrylamide,

[0060] N-(3-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0061] N-(3-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0062] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-ynamide,

[0063] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)piperazin-1-yl)phenyl)but-2-ynamide,

[0064] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)piperazin-1-yl)phenyl)but-2-ynamide,

[0065] (Z)-2-cyano-N-(3-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)piperazin-1-yl)pent-2-enamide,

[0066] (Z)-2-cyano-N-(3-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0067] (Z)-2-cyano-N-(3-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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(oxetan-3-yl)amino)pent-2-enamide,

[0068] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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)propan-2-yl)phenyl)acrylamide,

[0069] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-morpholinopropan-2-yl)phenyl)acrylamide,

[0070] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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(oxetan-3-yl)amino)propan-2-yl)phenyl)acrylamide,

[0071] N-(2-(2-(4,4-difluoropiperidin-1-yl)propan-2-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0072] N-(2-(2-(3,3-difluoropyrrolidin-1-yl)propan-2-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0073] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)piperazin-1-yl)propan-2-yl)phenyl)acrylamide,

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

[0075] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-3-methyl-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0076] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)acrylamide,

[0077] (S)-N-(3-cyano-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0078] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-3-(isopropylsulfonyl)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0079] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)piperazin-1-yl)-3-((trifluoromethyl)sulfonyl)phenyl)acrylamide,

[0080] (S)-N-(5-((6-(2-(8,8-dimethyl-1-oxo-1,4,5,7,8,9-hexahydrocyclopenta[4,5]pyrrolo[1,2-a][1,4]diazepine-2(3H)-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0081] (S)-N-(5-((6-(2-(8,8-dimethyl-1-oxo-1,4,5,7,8,9-hexahydrocyclopenta[4,5]pyrrolo[1,2-a][1,4]diazepine-2(3H)-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-3-fluoro-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0082] (S)-N-(5-((6-(2-(8,8-dimethyl-1-oxo-1,4,5,7,8,9-hexahydrocyclopenta[4,5]pyrrolo[1,2-a][1,4]diazepine-2(3H)-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-3-methyl-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0083] (S)-N-(5-((6-(2-(8,8-dimethyl-1-oxo-1,4,5,7,8,9-hexahydrocyclopenta[4,5]pyrrolo[1,2-a][1,4]diazepine-2(3H)-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)acrylamide,

[0084] (S)-N-(3-cyano-5-((6-(2-(8,8-dimethyl-1-oxo-1,4,5,7,8,9-hexahydrocyclopenta[4,5]pyrrolo[1,2-a][1,4]diazepine-2(3H)-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0085] (S)-N-(5-((6-(2-(8,8-dimethyl-1-oxo-1,4,5,7,8,9-hexahydrocyclopenta[4,5]pyrrolo[1,2-a][1,4]diazepine-2(3H)-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-3-(isopropylsulfonyl)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0086] (S)-N-(5-((6-(2-(8,8-dimethyl-1-oxo-1,4,5,7,8,9-hexahydrocyclopenta[4,5]pyrrolo[1,2-a][1,4]diazepine-2(3H)-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)-3-((trifluoromethyl)sulfonyl)phenyl)acrylamide,

[0087] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)acrylamide,

[0088] (S)-N-(5-((6-(2-(8,8-dimethyl-1-oxo-1,4,5,7,8,9-hexahydrocyclopenta[4,5]pyrrolo[1,2-a][1,4]diazepine-2(3H)-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)acrylamide,

[0089] (S)-N-(5-((6-(2-(7,7-bis(methyl-d3)-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-(methyl-d3)-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0090] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)oxy)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0091] (S)-N-(6-((2'-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3'-(hydroxymethyl)-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridyl]-5-yl)amino)-3-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)acrylamide,

[0092] (S)-N-(5-((6-(5-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-4-(hydroxymethyl)pyridin-3-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0093] (S)-N-(5-((6-(4-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-2-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0094] (S)-N-(5-((6-(3-(hydroxymethyl)-2-(4-oxo-1,4,7,8,9,10-hexahydrobenzo[f]isoquinolin-3(2H)-yl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0095] (S)-N-(5-((6-(2-(8,8-dimethyl-4-oxo-1,2,4,7,8,9-hexahydro-3H-cyclopenta[f]isoquinolin-3-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0096] (S)-N-(5-((6-(2-(7,7-dimethyl-1,1-dioxido-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-e][1,2,5]thiadiazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0097] (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)piperazin-1-yl)thiophen-3-yl)acrylamide,

[0098] 2-(4-(6-((5-acryloyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-(hydroxymethyl)pyridin-2-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one,

[0099] 2-(4-(6-((1-(1-acryloyl-4-methyl-1,4-diazepan-6-yl)-1H-indol-5-yl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-(hydroxymethyl)pyridin-2-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one,

[0100] N-(5-((6-(2-(8,8-dimethyl-4-oxo-1,2,4,7,8,9-hexahydro-3H-cyclopenta[c][2,7]naphthyridin-3-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-((2S)-4-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-methylpiperazin-1-yl)phenyl)acrylamide,

[0101] N-(5-((6-(2-(8,8-dimethyl-4-oxo-1,2,4,7,8,9-hexahydro-3H-cyclopenta[c][1,7]naphthyridin-3-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-((2S)-4-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-methylpiperazin-1-yl)phenyl)acrylamide,

[0102] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]imidazo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-((2S)-4-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-methylpiperazin-1-yl)phenyl)acrylamide,

[0103] (S)-N-(5-((6-(3-(hydroxymethyl)-2-(1-oxo-3,4,5,6,7,8-hexahydrobenzofurano[2,3-c]pyridin-2(1H)-yl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0104] (S)-N-(5-((6-(3-(hydroxymethyl)-2-(1-oxo-1,3,4,5,6,7,8,9-octahydro-2H-pyrido[3,4-b]indol-2-yl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0105] N-(5-((6-(2-(7,7-dimethyl-1,1-dioxido-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-e][1,2,5]thiadiazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-((2S)-4-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-methylpiperazin-1-yl)phenyl)acrylamide,

[0106] N-(2-((2S)-4-((2S,6R)-2,6-dimethylmorpholino)-2-methylpiperidin-1-yl)-5-((6-(3-(hydroxymethyl)-2-((S)-1-oxo-7-(trifluoromethyl)-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)phenyl)acrylamide,

[0107] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)acrylamide,

[0108] (S)-N-(5-((6-(2-(8,8-dimethyl-1-oxo-1,4,5,7,8,9-hexahydrocyclopenta[4,5]pyrrolo[1,2-a][1,4]diazepine-2(3H)-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0109] N-(5-((6-(2-(8,8-dimethyl-1-oxo-1,4,5,7,8,9-hexahydrocyclopenta[4,5]pyrrolo[1,2-a][1,4]diazepine-2(3H)-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-((2S)-4-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-methylpiperazin-1-yl)phenyl)acrylamide,

[0110] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-3-fluoro-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0111] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-3-methyl-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0112] (S)-N-(5-((6-(3-(hydroxymethyl)-2-(5-oxo-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0113] (S)-N-(5-((6-(3-(hydroxymethyl)-2-(1-oxo-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0114] (S)-N-(5-((6-(3-(hydroxymethyl)-2-(8-oxo-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0115] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-morpholinopiperidin-1-yl)phenyl)acrylamide,

[0116] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide,

[0117] N-(2-(4,4-difluoro-[1,4'-bipiperidinyl]-1'-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0118] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0119] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-morpholinopiperidin-1-yl)phenyl)acrylamide,

[0120] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-((2S,6R)-2,6-dimethylmorpholino)-2-methylpiperidin-1-yl)phenyl)acrylamide,

[0121] N-(2-((2'S)-4,4-difluoro-2'-methyl-[1,4'-bipiperidinyl]-1'-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0122] N-(2-((2S)-4-(3,3-difluoropyrrolidin-1-yl)-2-methylpiperidin-1-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0123] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0124] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0125] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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(oxetan-3-yl)amino)piperidin-1-yl)phenyl)acrylamide,

[0126] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0127] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0128] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0129] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0130] (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-cyclopenta[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,

[0131] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0132] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-((S)-4-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-methylpiperazin-1-yl)phenyl)acrylamide,

[0133] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-((S)-4-((2S,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-methylpiperazin-1-yl)phenyl)acrylamide,

[0134] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-methylpiperazin-1-yl)phenyl)acrylamide,

[0135] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-((S)-4-((2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-methylpiperazin-1-yl)phenyl)acrylamide,

[0136] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-((S)-2-methyl-4-((2S,4S)-2-methyltetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide,

[0137] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-((S)-2-methyl-4-((2S,4R)-2-methyltetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide,

[0138] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-((S)-2-methyl-4-((R)-tetrahydrofuran-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0139] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-((S)-2-methyl-4-((R)-oxepan-4-yl)piperazin-1-yl)phenyl)acrylamide,

[0140] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-methylpiperazin-1-yl)phenyl)acrylamide,

[0141] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-dimethylpiperazin-1-yl)phenyl)acrylamide,

[0142] (S)-N-(2-(4-cyclopropyl-2-methylpiperazin-1-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0143] (S)-N-(2-(4-cyclopentyl-2-methylpiperazin-1-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0144] (S)-N-(2-(4-(cyclopropylmethyl)-2-methylpiperazin-1-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0145] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(pyridin-2-ylmethyl)piperazin-1-yl)phenyl)acrylamide,

[0146] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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)methyl)piperazin-1-yl)phenyl)acrylamide,

[0147] N-(2-((S)-4-(((S)-1,4-dioxane-2-yl)methyl)-2-methylpiperazin-1-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0148] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(1,4-dithiaspiro[4.5]dec-8-yl)piperazin-1-yl)phenyl)acrylamide,

[0149] N-(2-((2S)-4-(2-oxabicyclo[2.2.2]oct-5-yl)-2-methylpiperazin-1-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0150] N-(2-((2S)-4-((1S,4R)-2-oxabicyclo[2.2.1]hept-5-yl)-2-methylpiperazin-1-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0151] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-((3S)-3-methyltetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide,

[0152] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(7-methyl-4-(tetrahydro-2H-pyran-4-yl)-1,4-diazepan-1-yl)phenyl)acrylamide,

[0153] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-((3R)-3-methyltetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide,

[0154] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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)-1,4-diazepan-1-yl)phenyl)acrylamide,

[0155] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-oxo-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide,

[0156] (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(1,4-dimethyl-6-oxopiperazin-2-yl)phenyl)acrylamide,

[0157] (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)acrylamide,

[0158] (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-methyl-3-oxo-1-(tetrahydro-2H-pyran-4-yl)piperazin-2-yl)phenyl)acrylamide,

[0159] (R)-N-(2-(1,4-diisopropyl-5-oxopiperazin-2-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0160] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-((2R)-1,4-dimethyl-3-oxo-5-(tetrahydro-2H-pyran-4-yl)piperazin-2-yl)phenyl)acrylamide,

[0161] (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-methyl-6-oxo-4-(tetrahydro-2H-pyran-4-yl)piperazin-2-yl)phenyl)acrylamide,

[0162] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-methyl-1-(oxetan-3-yl)-3-oxo-1,4-diazepan-5-yl)phenyl)acrylamide,

[0163] (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-methyl-4-(oxetan-3-yl)-7-oxo-1,4-diazepan-2-yl)phenyl)acrylamide,

[0164] N-(5-((6-(2-(8-fluoro-1-oxo-6-(1,1,1-trifluoro-2-methylpropan-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-methyl-1-(oxetan-3-yl)-3-oxopiperazin-2-yl)phenyl)acrylamide,

[0165] N-(5-((6-(2-(6-(tert-butyl)-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-methyl-1-(oxetan-3-yl)-3-oxopiperazin-2-yl)phenyl)acrylamide,

[0166] (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-isopropyl-5,5-dimethyl-4-(oxetan-3-yl)-6-oxopiperazin-2-yl)phenyl)acrylamide,

[0167] (R)-N-(2-(1-cyclopropyl-5,5-dimethyl-4-(oxetan-3-yl)-6-oxopiperazin-2-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0168] (S)-N-(5-((6-(2-(6,6-dimethyl-1-oxo-1,3,4,5,6,7-hexahydro-2H-cyclopenta[4,5]thieno[2,3-c]pyridin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0169] (S)-N-(5-((6-(3-(hydroxymethyl)-2-(1-oxo-3,4,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-c]pyridin-2(1H)-yl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0170] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,5,6,7-hexahydro-2H-cyclopenta[4,5]thieno[2,3-c]pyridin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0171] (S)-N-(5-((6-(2-(2-(tert-butyl)-7-oxo-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0172] (S)-N-(5-((6-(2-(6-(tert-butyl)-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0173] (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-methyl-1-(oxetan-3-yl)-3-oxopiperazin-2-yl)phenyl)acrylamide,

[0174] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-methyl-1-(oxetan-3-yl)-3-oxopiperazin-2-yl)phenyl)acrylamide,

[0175] (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-methyl-1-(oxetan-3-yl)-5-oxopiperazin-2-yl)phenyl)acrylamide,

[0176] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-methyl-1-(oxetan-3-yl)-5-oxopiperazin-2-yl)phenyl)acrylamide,

[0177] (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-methyl-4-(oxetan-3-yl)-6-oxopiperazin-2-yl)phenyl)acrylamide,

[0178] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-methyl-4-(oxetan-3-yl)-6-oxopiperazin-2-yl)phenyl)acrylamide,

[0179] (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-isopropyl-4-(oxetan-3-yl)-6-oxopiperazin-2-yl)phenyl)acrylamide,

[0180] (R)-N-(2-(1-cyclopropyl-4-(oxetan-3-yl)-6-oxopiperazin-2-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0181] N-(5-((6-(2-(2-(tert-butyl)-7-oxo-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-methyl-1-(oxetan-3-yl)-3-oxopiperazin-2-yl)phenyl)acrylamide,

[0182] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,5,6,7-hexahydro-2H-cyclopenta[4,5]thieno[2,3-c]pyridin-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-methyl-1-(oxetan-3-yl)-3-oxopiperazin-2-yl)phenyl)acrylamide,

[0183] (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)piperazin-1-yl)phenyl)acrylamide,

[0184] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)piperazin-1-yl)phenyl)acrylamide,

[0185] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(2,2-dimethyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide,

[0186] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(7-(tetrahydro-2H-pyran-4-yl)-4,7-diazaspiro[2.5]oct-4-yl)phenyl)acrylamide,

[0187] (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)-2-(trifluoromethyl)piperazin-1-yl)phenyl)acrylamide,

[0188] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)-2-(trifluoromethyl)piperazin-1-yl)phenyl)acrylamide,

[0189] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(2,2-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0190] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(7-(oxetan-3-yl)-4,7-diazaspiro[2.5]oct-4-yl)phenyl)acrylamide,

[0191] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(6-methyl-2-(oxetan-3-yl)-2,7-diazaspiro[3.5]non-7-yl)phenyl)acrylamide,

[0192] (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)-6-(trifluoromethyl)-2,7-diazaspiro[3.5]non-7-yl)phenyl)acrylamide,

[0193] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)-6-(trifluoromethyl)-2,7-diazaspiro[3.5]non-7-yl)phenyl)acrylamide,

[0194] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(1,1-dioxido-5-(tetrahydro-2H-pyran-4-yl)-1,2,5-thiadiazin-2-yl)phenyl)acrylamide,

[0195] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(5-(oxetan-3-yl)-1,1-dioxido-1,2,5-thiadiazin-2-yl)phenyl)acrylamide,

[0196] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)-2-oxopiperazin-1-yl)phenyl)acrylamide,

[0197] Part 2: CH3

[0198] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0199] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-morpholinopropan-2-yl)phenyl)acrylamide,

[0200] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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)propan-2-yl)phenyl)acrylamide,

[0201] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-1-carbonyl)phenyl)acrylamide,

[0202] (S)-N-(5-((6-(2-(8,8-dimethyl-1-oxo-1,4,5,7,8,9-hexahydrocyclopenta[4,5]pyrrolo[1,2-a][1,4]diazepine-2(3H)-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0203] (S)-N-(5-((6-(2-(7,7-difluoro-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0204] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0205] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0206] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)acrylamide,

[0207] (S)-N-(3-cyano-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0208] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0209] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)piperazin-1-yl)-3-((trifluoromethyl)sulfonyl)phenyl)acrylamide,

[0210] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)acrylamide,

[0211] (S)-N-(5-((6-(2-(8,8-dimethyl-1-oxo-1,4,5,7,8,9-hexahydrocyclopenta[4,5]pyrrolo[1,2-a][1,4]diazepine-2(3H)-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)acrylamide,

[0212] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0213] N-(2-(4,4-difluoro-[1,4'-bipiperidinyl]-1'-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0214] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0215] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-morpholinopiperidin-1-yl)phenyl)acrylamide,

[0216] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0217] N-(2-((2'S)-4,4-difluoro-2'-methyl-[1,4'-bipiperidinyl]-1'-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0218] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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.

[0219] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0220] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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,

[0221] (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-cyclopenta[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,

[0222] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-((S)-2-methyl-4-((S)-tetrahydrofuran-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0223] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-((S)-2-methyl-4-((R)-tetrahydrofuran-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0224] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-((S)-2-methyl-4-((S)-oxepan-4-yl)piperazin-1-yl)phenyl)acrylamide,

[0225] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-((S)-2-methyl-4-((R)-oxepan-4-yl)piperazin-1-yl)phenyl)acrylamide,

[0226] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,5,6,7-hexahydro-2H-cyclopenta[4,5]thieno[2,3-c]pyridin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0227] (S)-N-(5-((6-(2-(6,6-dimethyl-1-oxo-1,3,4,5,6,7-hexahydro-2H-cyclopenta[4,5]thieno[2,3-c]pyridin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0228] (S)-N-(5-((6-(2-(2-(tert-butyl)-7-oxo-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0229] (S)-N-(2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)-5-((4-methyl-6-(3-methyl-2-(1-oxo-3,4,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-c]pyridin-2(1H)-yl)pyridin-4-yl)-3-oxo-3,4-dihydropyrazin-2-yl)amino)phenyl)acrylamide,

[0230] (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(1,4-dimethyl-6-oxopiperazin-2-yl)phenyl)acrylamide,

[0231] (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)acrylamide,

[0232] (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-methyl-3-oxo-1-(tetrahydro-2H-pyran-4-yl)piperazin-2-yl)phenyl)acrylamide,

[0233] (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-methyl-1-(oxetan-3-yl)-3-oxopiperazin-2-yl)phenyl)acrylamide,

[0234] N-(5-((6-(2-(2-(tert-butyl)-7-oxo-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-methyl-1-(oxetan-3-yl)-3-oxopiperazin-2-yl)phenyl)acrylamide,

[0235] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,5,6,7-hexahydro-2H-cyclopenta[4,5]thieno[2,3-c]pyridin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-methyl-1-(oxetan-3-yl)-3-oxopiperazin-2-yl)phenyl)acrylamide,

[0236] N-(2-(4-methyl-1-(oxetan-3-yl)-3-oxopiperazin-2-yl)-5-((4-methyl-6-(3-methyl-2-(1-oxo-3,4,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-c]pyridin-2(1H)-yl)pyridin-4-yl)-3-oxo-3,4-dihydropyrazin-2-yl)amino)phenyl)acrylamide,

[0237] N-(5-((6-(2-(6,6-dimethyl-1-oxo-1,3,4,5,6,7-hexahydro-2H-cyclopenta[4,5]thieno[2,3-c]pyridin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-methyl-1-(oxetan-3-yl)-3-oxopiperazin-2-yl)phenyl)acrylamide,

[0238] N-(5-((6-(2-(6-(tert-butyl)-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-methyl-1-(oxetan-3-yl)-3-oxopiperazin-2-yl)phenyl)acrylamide,

[0239] (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)piperazin-1-yl)phenyl)acrylamide,

[0240] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)piperazin-1-yl)phenyl)acrylamide,

[0241] (S)-N-(2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-5-((4-methyl-6-(3-methyl-2-(1-oxo-3,4,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-c]pyridin-2(1H)-yl)pyridin-4-yl)-3-oxo-3,4-dihydropyrazin-2-yl)amino)phenyl)acrylamide,

[0242] (R)-N-(5-((4-methyl-6-(3-methyl-2-(1-oxo-3,4,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-c]pyridin-2(1H)-yl)pyridin-4-yl)-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)piperazin-1-yl)phenyl)acrylamide,

[0243] (S)-N-(5-((4-methyl-6-(3-methyl-2-(1-oxo-3,4,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-c]pyridin-2(1H)-yl)pyridin-4-yl)-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)piperazin-1-yl)phenyl)acrylamide,

[0244] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)oxy)-2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide,

[0245] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)oxy)-2-(4-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)piperazin-1-yl)phenyl)acrylamide,

[0246] (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)oxy)-2-(4-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)piperazin-1-yl)phenyl)acrylamide

[0247] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(1-isopropyl-6-oxo-4-(tetrahydro-2H-pyran-4-yl)piperazin-2-yl)phenyl)acrylamide,

[0248] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(1-methyl-4-(tetrahydro-2H-pyran-4-yl)-6-(trifluoromethyl)piperazin-2-yl)phenyl)acrylamide,

[0249] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)piperazin-1-yl)phenyl)-N-methylacrylamide,

[0250] (S)-N-(5-((6-(2-(7,7-dimethyl-1,1-dioxido-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-e][1,2,5]thiadiazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0251] N-(2-((S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl)-5-((4-methyl-6-(3-methyl-2-(1-oxo-7-(trifluoromethyl)-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)pyridin-4-yl)-3-oxo-3,4-dihydropyrazin-2-yl)amino)phenyl)acrylamide,

[0252] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)-2-oxopiperazin-1-yl)phenyl)acrylamide,

[0253] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(5-(oxetan-3-yl)-1,1-dioxido-1,2,5-thiadiazin-2-yl)phenyl)acrylamide,

[0254] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-oxo-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide,

[0255] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(1,1-dioxido-5-(tetrahydro-2H-pyran-4-yl)-1,2,5-thiadiazin-2-yl)phenyl)acrylamide,

[0256] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(7-(tetrahydro-2H-pyran-4-yl)-4,7-diazaspiro[2.5]oct-4-yl)phenyl)acrylamide,

[0257] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2,2-dimethyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)acrylamide,

[0258] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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)pyridin-3-yl)acrylamide,

[0259] (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)-2-(trifluoromethyl)piperazin-1-yl)phenyl)acrylamide,

[0260] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(oxetan-3-yl)-2-(trifluoromethyl)piperazin-1-yl)phenyl)acrylamide,

[0261] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-methylpyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(7-(oxetan-3-yl)-4,7-diazaspiro[2.5]oct-4-yl)phenyl)acrylamide,

[0262] Part 3: CF3

[0263] N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(trifluoromethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-((2S)-2-methyl-4-morpholinopiperidin-1-yl)phenyl)acrylamide,

[0264] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(trifluoromethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0265] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(trifluoromethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-3-fluoro-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0266] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(trifluoromethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-3-methyl-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0267] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(trifluoromethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)acrylamide,

[0268] (S)-N-(3-cyano-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(trifluoromethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0269] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(trifluoromethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-3-(isopropylsulfonyl)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0270] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(trifluoromethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)-3-((trifluoromethyl)sulfonyl)phenyl)acrylamide,

[0271] (S)-N-(5-((6-(2-(8,8-dimethyl-1-oxo-1,4,5,7,8,9-hexahydrocyclopenta[4,5]pyrrolo[1,2-a][1,4]diazepine-2(3H)-yl)-3-(trifluoromethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide,

[0272] (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-(trifluoromethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)acrylamide,

[0273] (S)-N-(5-((6-(2-(8,8-dimethyl-1-oxo-1,4,5,7,8,9-hexahydrocyclopenta[4,5]pyrrolo[1,2-a][1,4]diazepine-2(3H)-yl)-3-(trifluoromethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)acrylamide,

[0274] 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. The synthesis of compounds may use racemates, diastereomers or enantiomers as starting materials or intermediates. Diastereomeric compounds may be separated by chromatography or crystallization. Similarly, enantiomeric mixtures may be separated using the same technology or other techniques known in the art. Each asymmetric carbon atom may be in R or S configuration, and these two configurations are within the scope of the present invention.

[0275] Modified compounds of any of these compounds are also contemplated, including modifications having improved (e.g., enhanced, greater) pharmaceutical solubility, stability, bioavailability, and / or therapeutic index compared to the unmodified compound. Examples of modifications include, but are not limited to, prodrug derivatives and deuterium-enriched compounds. For example:

[0276] Prodrug derivatives: When administered to a subject, the prodrug will be converted into the active compound of the present invention in vivo [Nature Reviews of Drug Discovery, 2008, Volume 7, p255]. Note that in many examples, the prodrug itself also falls within the scope of the compound according to the present invention. The prodrug of the compound of the present invention can be prepared by standard organic reactions, for example, by reacting with a carbamoylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate, p-nitrophenyl carbonate, etc.) or an acylating agent. Other examples of methods and strategies for preparing prodrugs are described in Bioorganic and Medicinal Chemistry Letters, 1994, Vol.4, p.1985.

[0277] Deuterium-enriched compounds: Deuterium (D or 2 H) is a stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen occurs naturally as an isotope X H (hydrogen or protium), D ( 2 H or deuterium), and T( 3 H or tritium). The natural abundance of deuterium is 0.015%. Those skilled in the art recognize that in all compounds having 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 has been enriched to greater than 0.015% of its natural abundance should be considered unnatural and therefore novel relative to their non-enriched counterparts.

[0278] It should be appreciated that the compounds of the present invention may exist in the form of salts and solvates and may be optionally administered in this form. 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 and organic and inorganic bases and use the compounds in this form according to processes well known in the art.

[0279] When the compound of the present invention has a free base form, the compound can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid or organic acid, for example, hydrohalide salts such as hydrochloride, hydrobromide, hydroiodide; other mineral acids such as sulfates, nitrates, phosphates, etc.; and alkyl and monoaryl sulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate; and other organic acids and their corresponding salts, such as acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate and ascorbate. Other acid addition salts of the present invention include, but are not limited to, adipate, alginate, argininate, aspartate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, octanoate, hydrochloride, chlorobenzoate, cyclopentylpropionate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, fumarate, galactonate (from mucic acid), galacturonate, glucoheptonate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogen phosphate, 2-naphthalenesulfonate, nicotinate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphonate, and phthalate. It should be appreciated that the free base forms typically differ somewhat from their respective salt forms in physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base forms for the purposes of the present invention.

[0280] When the compound of the present invention has a free acid form, a pharmaceutically acceptable base addition salt can be prepared by reacting the compound in the free acid form with a pharmaceutically acceptable inorganic base 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, manganic salts, manganous 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, N-ethylmorpholine, N-ethylpiperidine, reduced glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris(hydroxymethyl)methylamine (tromethamine). It should be understood that the physical properties of the free acid forms, such as solubility in polar solvents, typically differ to some extent from their respective salt forms, but the salts are equivalent to their respective free acid forms for purposes of the present invention.

[0281] In one aspect, the pharmaceutically acceptable salt is a hydrochloride, hydrobromide, methanesulfonate, toluenesulfonate, acetate, fumarate, sulfate, bisulfate, succinate, citrate, phosphate, maleate, nitrate, tartrate, benzoate, bicarbonate, carbonate, sodium hydroxide salt, calcium hydroxide salt, potassium hydroxide salt, tromethamine salt, or a mixture thereof.

[0282] The compounds of the present invention containing tertiary nitrogen-containing groups can be quaternized using, for example, the following reagents: (C 1-4 ) alkyl halides, such as methyl, ethyl, isopropyl and tert-butyl chlorides, bromides and iodides; di(C 1-4 ) alkyl esters, such as dimethyl sulfate, diethyl sulfate and diamyl sulfate; alkyl halides, such as decyl, dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aryl (C 1-4) alkyl halides, such as benzyl chloride and phenethyl bromide. Such salts allow the preparation of both water-soluble and oil-soluble compounds of the present invention.

[0283] Ammonia oxides of anticancer agents having 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]. The compounds of the present invention containing tertiary nitrogen atoms can be catalyzed by reagents such as hydrogen peroxide (H 2 O 2 ), Caro acid or a peracid such as meta-chloroperbenzoic acid (mCPBA) to form an ammonia oxide.

[0284] The present invention encompasses pharmaceutical compositions comprising the compounds of the present invention and pharmaceutical excipients, as well as other conventional pharmaceutical compositions without pharmaceutically active agents. Any inert excipient generally used as a carrier or diluent can be used in the composition of the present invention, such as sugars, polyols, soluble polymers, salts and lipids. Adoptable sugars and polyols include, but are not limited to, lactose, sucrose, mannitol and sorbitol. Exemplary employable soluble polymers are polyoxyethylene, poloxamer, polyvinyl pyrrolidone and dextran. Available salts include, but are not limited to, sodium chloride, magnesium chloride and calcium chloride. Adoptable lipids include, but are not limited to, fatty acids, glycerol fatty acid esters, glycolipids and phospholipids.

[0285] In addition, the pharmaceutical composition may further comprise a binder (e.g., gum arabic, corn starch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), a disintegrant (e.g., corn starch, potato starch, alginic acid, silicon dioxide, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, guar gum, sodium starch glycolate, Primogel), a buffer of various pH and ionic strength (e.g., tris-HCL, acetate, phosphate), an additive to prevent absorption to the surface such as albumin or gelatin, a detergent (e.g., Tween 20, Tween 80, Pluronic F68, bile salts), protease inhibitors, surfactants (e.g., sodium lauryl sulfate), penetration enhancers, solubilizers (e.g., glycerol, polyethylene glycol, cyclodextrins), glidants (e.g., colloidal silicon dioxide), antioxidants (e.g., ascorbic acid, sodium metabisulfite, hydroxyanisole butyrate), stabilizers (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose), viscosity enhancers (e.g., carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum), sweeteners (e.g., sucrose, aspartame, citric acid), flavoring agents (e.g., peppermint oil, methyl salicylate, or orange flavor) ), preservatives (e.g., thimerosal, benzyl alcohol, parabens), lubricants (e.g., stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow aids (e.g., colloidal silicon dioxide), 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, polymethacrylates) and / or adjuvants.

[0286] In one embodiment, the pharmaceutical composition is prepared with a carrier that protects the compound from being quickly removed from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene-vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. The method for preparing such formulations is obvious to those skilled in the art. The material can also be purchased from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to 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.

[0287] In addition, the present invention encompasses pharmaceutical compositions comprising the compounds of the present invention in any solid or liquid physical form. For example, the compound can be in crystalline or amorphous form and have any particle size. The particles can be micronized or can be agglomerated particles, powders, oils, oily suspensions, or any other solid or liquid physical form.

[0288] When the compounds according to the invention exhibit insufficient solubility, methods of solubilizing the compounds may be used. Such methods are known to those skilled in the art and include, but are not limited to, pH adjustment and salt formation; use of cosolvents such as ethanol, propylene glycol, polyethylene glycol (PEG) 300, PEG 400, DMA (10-30%), DMSO (10-20%), NMP (10-20%); 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 E TPGS, and d-α-tocopherol PEG 1000 succinate (20-50%); use of complexation such as HPβCD and SBEβCD (10-40%); and use of advanced approaches such as micelles, addition of polymers, nanoparticle suspensions, and liposome formation.

[0289] A wide variety of administration methods can be used in conjunction with the compounds of the present invention. The compounds of the present invention can be administered orally, parenterally, intraperitoneally, intravenously, intra-arterially, transdermally, sublingually, intramuscularly, rectally, orally, intranasally, liposomes, via inhalation, vaginally, intraocularly, via local delivery (e.g., by catheter or stent), subcutaneously, intra-fatally, intra-articularly, or intrathecally or in combination. The compounds according to the present invention can also be administered or co-administered in a sustained-release dosage form. The compound can be in gas, liquid, semi-liquid or solid form, formulated in a mode suitable for the route of administration to be used. For oral administration, suitable solid oral formulations include tablets, capsules, pills, granules, micropills, capsules and effervescents, powders, etc. Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils, etc. For parenteral administration, typically freeze-dried powders are used for reconstruction.

[0290] As used herein, "acyl" refers to a carbonyl-containing substituent represented by the formula -C(O)-R, wherein R is H, alkyl, carbocycle, heterocycle, carbocycle-substituted alkyl, or heterocycle-substituted alkyl, wherein the alkyl, alkoxy, carbocycle, and heterocycle are as defined herein. Acyl includes alkanoyl (e.g., acetyl), aroyl (e.g., benzoyl), and heteroaroyl.

[0291] "Aliphatic" refers to a moiety characterized by a straight or branched chain arrangement of carbon atoms and may be saturated or partially unsaturated having one or more double or triple bonds.

[0292] The term "alkyl" refers to a straight or branched chain hydrocarbon containing 1 to 20 carbon atoms (e.g., C 1 -C 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.

[0293] The term "alkenyl" refers to a group containing 2 to 20 carbon atoms (e.g., C 2 -C 10 ) and one or more double bonds. Examples of alkenyl groups 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.

[0294] The term "alkynyl" refers to a group containing 2 to 20 carbon atoms (e.g., C 2 -C 10 ) and one or more triple bonds. Examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl and 2-butynyl and 1-methyl-2-butynyl. Preferably, the alkynyl has 2 to 10 carbon atoms. More preferably, the alkynyl has 2 to 4 carbon atoms.

[0295] The term "alkylamino" refers to -N(R)-alkyl, where R can be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl.

[0296] "Alkoxy" refers to an oxygen moiety having a further alkyl substituent.

[0297] "Alkoxycarbonyl" refers to an alkoxy group attached to a carbonyl group.

[0298] "Oxoalkyl" refers to an alkyl group further substituted with a carbonyl group. The carbonyl group may be an aldehyde, ketone, ester, amide, acid or acid chloride.

[0299] The term "cycloalkyl" refers to a cycloalkyl group having 3 to 30 carbon atoms (e.g., C 3 -C 12 , C 3 -C 8 , C 3 -C 6 ) is a saturated hydrocarbon ring system. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term "cycloalkenyl" refers to a cycloalkyl group having 3 to 30 carbon atoms (e.g., C 3-C 12 ) and one or more double bonds. Examples include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0300] The term "heterocycloalkyl" refers to a non-aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (e.g., O, N, S, P, or Se). Examples of heterocycloalkyl include, but are not limited to, piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, and tetrahydrofuranyl.

[0301] The term "heterocycloalkenyl" 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.

[0302] The term "aryl" refers to a monocyclic, 10-carbon-atom, or 14-carbon-atom tricyclic aromatic ring system. Examples of aryl include, but are not limited to, phenyl, naphthyl, and anthracenyl. The term "heteroaryl" refers to a 5- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 14-membered tricyclic aromatic ring system having one or more heteroatoms (e.g., O, N, S, P, or Se). Examples of heteroaryl include pyridyl, furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolyl, indolyl, and thiazolyl.

[0303] The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, alkylamino, aryl and heteroaryl mentioned above include both substituted and unsubstituted parts. Possible substituents on alkylamino, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl and heteroaryl include, but are not limited to, C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 3 -C 20 Cycloalkyl, C 3 -C 20 Cycloalkenyl, C 1 -C 20 Heterocycloalkyl, C 1 -C 20 Heterocycloalkenyl, C 1 -C 10 Alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C 1 -C 10 Alkylamino, arylamino, hydroxy, halogen, oxo (O=), thio (S=), thio, silicon, C1 -C 10 Alkylthio, arylthio, C 1 -C 10 alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amidino, thiol, amido, thiourea, thiocyanate, sulfonamide, guanidine, urea, cyano, nitro, acyl, thioacyl, acyloxy, urea, carbamoyl, carboxyl and carboxylate. On the other hand, possible substituents on the alkyl, alkenyl or alkynyl groups include, except C 1 -C 10 All the substituents mentioned above except the alkyl group. The cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, heterocycloalkenyl group, aryl group and heteroaryl group may also be condensed with each other.

[0304] "Amino" refers to a nitrogen moiety further having two substituents, wherein each substituent has a hydrogen or carbon atom alpha-bonded to the nitrogen. Unless expressly indicated, the compounds of the present invention containing amino moieties may include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butyloxycarbonyl, benzyloxycarbonyl, and the like.

[0305] "Aromatic" refers to a moiety 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 have ring atoms that are only carbon atoms or can include carbon atoms and non-carbon atoms (see heteroaryl).

[0306] "Carbamyl" refers to the group -OC(O)NR a R b , where R a and R b Each independently represents two further substituents in which a hydrogen or carbon atom is located alpha to the nitrogen. Note that the carbamoyl moiety may include protected derivatives thereof. Examples of suitable protecting groups for the carbamoyl moiety include acetyl, tert-butyloxycarbonyl, benzyloxycarbonyl, and the like. Note that both unprotected derivatives and protected derivatives fall within the scope of the present invention.

[0307] "Carbonyl" refers to the group -C(O)-. Note that the carbonyl group can be further substituted with a variety of substituents to form different carbonyl groups, including acids, acyl halides, amides, esters, and ketones.

[0308] "Carboxyl" refers to the group -C(O)O-. Note that compounds of the present invention containing carboxyl moieties may include protected derivatives thereof, i.e., wherein the oxygen atom is replaced by a protecting group. Suitable protecting groups for carboxyl moieties include benzyl, tert-butyl, and the like.

[0309] "Cyano" refers to the radical -CN.

[0310] "Formyl" refers to the group -CH=O.

[0311] "Iminomethyl" refers to the group -HC=NH.

[0312] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0313] As an isolated group or part of a larger group, "halogen-substituted alkyl" refers to an "alkyl" substituted with one or more "halogen" atoms, such terms as defined in this application. Halogen-substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl, etc.

[0314] "Hydroxy" refers to the group -OH.

[0315] "Imine derivative" refers to a derivative comprising a -C(=NR)- moiety, wherein R comprises a hydrogen or carbon atom alpha to the nitrogen.

[0316] "Isomer" means any compound that has the same molecular formula but differs in the nature or sequence of bonding of its atoms or in the arrangement of its atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of one another are called "diastereoisomers," and stereoisomers that are non-superimposable mirror images are called "enantiomers" or sometimes "optical isomers." A carbon atom to which four different substituents are bonded is called a "chiral center." A compound with one chiral center exists in two enantiomeric forms of opposite chirality. A mixture of the two enantiomeric forms is called a "racemic mixture."

[0317] "Nitro" refers to the group -NO 2 .

[0318] "Protected derivatives" refer to derivatives of compounds in which reactive sites are blocked by protecting groups. Protected derivatives may be used to prepare drugs or may themselves have inhibitory activity. A comprehensive list of suitable protecting groups can be found in TW Greene, Protecting Groups in Organic Synthesis, 3rd Edition, Wiley & Sons, 1999.

[0319] The term "substituted" refers to an atom or group of atoms that has replaced a hydrogen as a substituent attached to another group. For aryl and heteroaryl, the term "substituted" refers to any level of substitution where such substitution is allowed, i.e., mono-, di-, tri-, tetra- or penta-substitution. The substituents are independently selected and may be located at any chemically accessible position. The term "unsubstituted" refers to a given portion that may consist only of hydrogen substituents (unsubstituted) through available valence states.

[0320] If a functional group is described as "optionally substituted", the functional group may be (1) unsubstituted or (2) substituted. If a carbon of a functional group is described as optionally substituted with one or more of a list of substituents, one or more hydrogen atoms on the carbon (if present, in any degree) may be replaced individually and / or collectively with independently selected optional substituents.

[0321] "Sulfide" means -SR, where R is H, alkyl, carbocyclic, heterocyclic, carbocycloalkyl, or heterocycloalkyl. Specific sulfide groups are mercapto; alkyl sulfides, for example, methyl sulfide (-S-Me); aryl sulfide, for example, phenyl sulfide; aralkyl sulfide, for example, benzyl sulfide.

[0322] "Sulfinyl" means the group -S(O)-. Note that the sulfinyl group can be further substituted with a variety of substituents to form different sulfinyl groups, including sulfinic acid, sulfinamide, sulfinate, and sulfoxide.

[0323] "Sulfonyl" means the group -S(O)(O)-. Note that the sulfonyl group can be further substituted with a variety of substituents to form different sulfonyl groups, including sulfonic acids, sulfonamides, sulfonate esters, and sulfones.

[0324] "Thiocarbonyl" means the group -C(S)-. Note that the thiocarbonyl can be further substituted with a variety of substituents to form different thiocarbonyl groups, including thioacids, thioamides, thioesters, and thioketones.

[0325] "Animal" includes humans, non-human mammals (e.g., non-human primates, rodents, mice, rats, hamsters, dogs, cats, rabbits, cows, horses, sheep, goats, pigs, deer, etc.) and non-mammals (e.g., birds, etc.).

[0326] As used herein, "bioavailability" is the fraction or percentage of a dose of a drug or pharmaceutical composition that reaches the systemic circulation completely. 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, bioavailability decreases). Methods for improving bioavailability include prodrug approaches, salt synthesis, particle size reduction, complexation, changing physical form, solid dispersions, spray drying, and hot melt extrusion.

[0327] "Disease" specifically includes any ill-health condition of an animal or part thereof, and includes ill-health conditions that may result from or accompany medical or veterinary treatment applied to the animal, ie, "side effects" of such treatment.

[0328] "Pharmaceutically acceptable" means generally safe, nontoxic, and neither biologically nor otherwise undesirable for use in preparing pharmaceutical compositions and includes those that are acceptable for veterinary as well as human medical use.

[0329] "Pharmaceutically acceptable salts" refer to pharmaceutically acceptable organic or inorganic salts of the compounds of the invention as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic or organic acids. Pharmaceutically acceptable salts also include base addition salts, which may 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, bitartrates, ascorbates, succinates, maleates, gentisates, fumarates, gluconates, glucuronates, sucrose salts, formates, benzoates, glutamates, methanesulfonates "mesylate", ethanesulfonates, benzenesulfonates, p-toluenesulfonates, pamoates (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthoate)), 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 counter ions. The counterion can be any organic or inorganic moiety that stabilizes the charge of the parent compound. In addition, a pharmaceutically acceptable salt can have more than one charged atom in its structure. For examples where multiple charged atoms are part of a pharmaceutically acceptable salt, the salt can have multiple counterions. Thus, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counterions.

[0330] "Pharmaceutically acceptable carrier" refers to a non-toxic solvent, dispersant, excipient, adjuvant or other material mixed with the compound 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 glycols (e.g., PEG400), surfactants (e.g., Cremophor) or cyclopolysaccharides (e.g., hydroxypropyl-β-cyclodextrin or sulfobutyl ether β-cyclodextrin), polymers, liposomes, micelles, nanospheres, and the like.

[0331] As defined by the International Union of Pure and Applied Chemistry, a "pharmacophore" is a collection of steric and electronic features necessary to ensure optimal supramolecular interaction with a specific biological target and 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 series of widely used nitrogen mustard drugs such as Melphalan, Cyclophosphamide, Bendamustine, etc.

[0332] "Prodrug" means a compound that is metabolically converted in vivo to an active drug according to the invention. For example, an inhibitor containing a hydroxy group may be administered in the form of an ester that is converted in vivo by hydrolysis to the hydroxy compound.

[0333] "Stability" generally refers to the length of time a drug retains its properties without losing its potency. Sometimes this refers to shelf life. Factors affecting drug stability also include, among other things, the chemical structure of the drug, 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 can alter hydration kinetics; different crystals that can have different properties), excipients (e.g., anything other than the active substance in the dosage form), packaging conditions, storage conditions, etc.

[0334] The "therapeutically effective amount" of the composition described herein refers to the amount of the composition that provides a therapeutic effect on the treated subject at a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutic effect can be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject shows signs or feelings of the effect). The effective amount of the above composition 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 composition of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for a particular patient will depend on a variety of factors, including the condition being treated and the severity of the condition; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, 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 or concomitantly with the specific compound used; and similar factors known in the medical field.

[0335] As used herein, the term "treatment" refers to the administration of a compound to a subject having a neoplastic or immune disorder, or having symptoms or predispositions thereof, for the purpose of curing, healing, alleviating, relieving, altering, remedying, alleviating, improving or affecting the disorder, the symptoms of the disorder or the predispositions for the disorder. The term "effective amount" refers to the amount of active agent required to impart the desired therapeutic effect in the subject. As known to those skilled in the art, the effective amount may vary depending on the route of administration, the use of excipients, and the possibility of sharing with other agents.

[0336] "Subject" refers to humans and non-human animals. Examples of non-human animals include all vertebrates, such as mammals, such as non-human primates (especially higher primates), dogs, rodents (such as 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 an experimental animal or an animal suitable as a disease model.

[0337] "Combination therapy" includes administering to a subject a test compound of the present invention and another biologically active ingredient (such as, but not limited to, a second and different anti-neoplastic agent) and non-drug therapy (such as, but not limited to, surgery or radiation therapy) in further combination with the compound. For example, the compounds of the present invention can be used in combination with other pharmaceutically active compounds or non-drug therapies, preferably compounds that can enhance the effects of the compounds of the present invention. The compounds of the present invention can be administered simultaneously with other therapies (as a single preparation or separate preparations) or sequentially. Typically, combination therapy envisions the administration of two or more drugs / therapies in a single treatment cycle or a single course of treatment.

[0338] In one embodiment, the compounds of the present invention are administered in combination with one or more traditional chemotherapeutic agents. Traditional chemotherapeutic agents include a variety of treatment methods in the field of oncology. In order to shrink tumors, destroy the remaining cancer cells remaining after surgery, induce remission, maintain remission and / or alleviate the symptoms associated with cancer or its treatment, these agents are administered at various stages of the disease. Examples of such agents include, but are not limited to, alkylating agents, such as nitrogen mustards (e.g., bendamustine, cyclophosphamide, melphalan, benzyl chlorbutyrate, ifosfamide), nitrosoureas (e.g., carmustine, lomustine and streptozocin), ethyleneimines (e.g., thiotepa, hexamethylmelanocin), alkyl sulfonates (e.g., busulfan), hydrazines 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 teniposide), taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vincristine, vinblastine, and vinorelbine); antitumor antibiotics, such as chromomycins (e.g., actinomycin D and plicamycin), anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, mitoxantrone, and idarubicin), and Miscellaneous antibiotics such as mitomycin and bleomycin; antimetabolites such as folate antagonists (e.g. methotrexate), pyrimidine antagonists (e.g. 5-fluorouracil, floxuridine, 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 (e.g. amsacrine, etoposide, etoposide phosphate, teniposide), and miscellaneous anti-neoplastic agents, such as ribonucleotide reductase inhibitors (hydroxyurea), adrenocortical steroid inhibitors (mitotane), anti-microtubule agents (estramustine), and retinoids (bexarotene, isotretinoin, tretinoin (ATRA).

[0339] In one aspect of the invention, the compounds can be administered in combination with one or more targeted anticancer agents that modulate protein kinases associated with a variety of 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, Aurora A, Aurora B, 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-cell Cyclin T1, CHK1, CHK2, CK1a1, CK1d, CK1epsilon, CK1g1, CK1g2, CK1g3, CK2a, CK2a2, c-KIT, CLK1, CLK2, CLK3, CLK4, c-MER, c-MET, COT1 / MAP3K8, CSK, c-SRC, CTK / MATK, DAPK1, DAPK2, DCAMKL1, DCAMKL2, DDR 1. DDR2, DLK / MAP3K12, DMPK, DMPK2 / CDC42BPG, DNA-PK, DRAK1 / STK17A, DYRK1 / DYRK1A, DYRK1B, DYRK2 , DYRK3, 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, 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 UNIT32b / YANK2, UNIT32c / YANK3, UNIT33, UNIT38 / NDR1, UNIT38L / NDR2, UNIT39 / 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).

[0340] In another aspect of the present invention, the compounds of the present 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 ADP (adenosine diphosphate)-ribose polymerase (PARP), hypoxia-inducible factor (HIF), proteasomes, Wnt / Hedgehog / Notch signaling proteins, TNF-α, matrix metalloproteinases, farnesyl transferases, apoptotic pathways (e.g., Bcl-xL, Bcl-2, Bcl-w), histone deacetylase (HDAC), histone acetyltransferase (HAT) and methyltransferases (e.g., histone lysine methyltransferase, histone arginine methyltransferase, DNA methyltransferase, etc.).

[0341] 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, chemoprotectants (e.g., amfostine, mesna, dexrazoxane), 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.).

[0342] In another aspect of the present invention, the subject compound is administered in combination with radiotherapy or surgery. Radiation is usually delivered internally (implanting radioactive material near the cancer site) or from the outside of a machine using photons (X-rays or gamma rays) or particle radiation. In the case where the combined therapy further includes radiotherapy, radiotherapy can be performed at any suitable time, as long as the beneficial effect produced by the combined effect of the therapeutic agent and radiotherapy is obtained. For example, in appropriate cases, when radiotherapy is temporarily removed from the administration of the therapeutic agent, it may be until a few days or even weeks, and a beneficial effect can still be obtained.

[0343] In certain embodiments, the compounds of the invention are administered in combination with one or more of radiation therapy, surgery, or anticancer agents, including but not limited to DNA damaging agents, 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, and the like.

[0344] In certain embodiments, the compounds of the invention are administered in combination with one or more of abarelix, abiraterone acetate, aldesleukin, alemtuzumab, hexamethylmelamine, anastrozole, asparaginase, bendamustine, bevacizumab, bexarotene, bicalutamide, bleomycin, bortezombi, brentuximab vedotin, busulfan, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, clomiphene, crizotinib, cyclophosphamide, dasatinib, daunorubicin liposomal, decitabine, degarelix, denileukin diftitox, denileukin 2, denosumab, docetaxel, doxorubicin, doxorubicin liposomal, epirubicin, eribulin mesylate, mesylate), erlotinib, estramustine, etoposide phosphate, everolimus, exemestane, fludarabine, fluorouracil, fotemustine, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, ipilimumab, ixabepilone, lapatinib dibesylate ditosylate), lenalidomide, letrozole, leucovorin, leuprolide, 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, streptozocin, sunitinib maleate, tamoxifen, temsirolimus, teniposide, thalidomide, toremifene, tositumomab, trastuzumab, tretinoin, uramustine, vandetanib, vemurafenib, vinorelbine, zoledronic acid, radiation therapy, or surgery.

[0345] In certain embodiments, the compounds of the invention are administered in combination with one or more anti-inflammatory agents. Anti-inflammatory agents include, but are not limited to, NSAIDs, nonspecific 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, a combination 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.

[0346] In some embodiments, the anti-inflammatory agent is a salicylate. Salicylate includes but is 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.

[0347] In other embodiments, the anti-inflammatory agent is a gold compound, such as gold sodium thiomalate or auranofin.

[0348] The invention also includes embodiments wherein 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.

[0349] Other embodiments of the invention relate to combinations wherein 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.

[0350] In certain embodiments, compounds of the invention are administered in combination with one or more immunosuppressive agents.

[0351] In some embodiments, the immunosuppressant is a glucocorticoid, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, leflunomide, cyclosporine, tacrolimus, and mycophenolate mofetil, actinomycin D, anthracyclines, mitomycin C, bleomycin, mithramycin, or fingolimod.

[0352] The present invention further provides methods for preventing or treating a neoplastic disease, an autoimmune disease, or an inflammatory condition. In one embodiment, the present invention relates to a method for treating a neoplastic disease, an autoimmune disease, or an inflammatory condition in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention. In one embodiment, the present invention further provides the use of a compound of the present invention in the preparation of a medicament for stopping or reducing a neoplastic disease, an autoimmune disease, or an inflammatory condition.

[0353] In one embodiment, the neoplastic disease is a B-cell malignancy, which includes but is not limited to B-cell lymphoma, lymphoma (including Hodgkin's lymphoma and non-Hodgkin's lymphoma), hairy cell 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 lymphocytic leukemia.

[0354] Autoimmune and or inflammatory diseases that can be affected using the compounds and compositions according to the present invention include, but are not limited to, allergies, 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 related glomerulonephritis and pulmonary hemorrhage), Graves' disease Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, interstitial cystitis, irritable bowel syndrome, lupus erythematosus, morphea, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyotonia, 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 vasculitides and other vasculitic diseases), vitiligo, and Wegener's granulomatosis.

[0355] It should be understood that the present invention is not limited to the particular embodiments shown and described herein, and that various changes and modifications may be made without departing from the spirit and scope of the present invention as defined by the appended claims.

[0356] Compounds according to the present invention can be synthesized according to a variety of reaction schemes. Necessary starting materials can be obtained by standard organic chemical processes. The compounds and processes of the present invention can be better understood by contacting the following representative synthesis schemes and examples, which are only used as examples and do not limit the scope of the present invention. Various changes and modifications to the disclosed embodiments are obvious to those skilled in the art, and changes and modifications can be made, including but not limited to changes and modifications related to chemical structures, substituents, derivatives, and / or methods of the present invention, without departing from the spirit of the present invention and the scope of the appended claims.

[0357] In Scheme A, reactant 5 can be prepared by reacting 3,5-dibromo-1-methylpyrazin-2(1H)-one with an appropriate aniline. The nitro group in reactant 5 can be other groups, such as a protected amine group or a -NHC(O)- warhead.

[0358] Typical starting materials (CAS 1346674-23-4) is commercially available. However, the reported routes to this intermediate (e.g. in WO 2013067274) require at least 7 synthetic steps. The synthesis is not only long, but also includes several toxic or hazardous and environmentally responsible reagents and solvents. We describe in Scheme 1 herein a new, more efficient and cost-effective route (three synthetic steps) that focuses on the use of sustainable chemistry:

[0359]

[0360] In Scheme I, the starting material 3-methylcyclopent-2-en-1-one is converted to 3,3-dimethylcyclopent-1-one in high yield via standard organic reactions, which can be further converted to intermediate 3. Finally, intermediate 3 can react with piperazin-2-one to produce the target molecule of CAS 1346674-23-4.

[0361] Intermediates wherein k, r and s are each independently 0, 1, 2 or 3, can be prepared by a method similar to Scheme I by using different starting materials and reagents.

[0362] Intermediates wherein k, r and s are each independently 0, 1, 2 or 3, and can be prepared by methods similar to those disclosed in WO / 2013 / 067260, WO / 2013 / 067274, WO / 2013 / 067277, and WO / 2015 / 000949.

[0363] Intermediates The preparation can be carried out by analogous methods to Scheme I, by using different starting materials and reagents, or by standard organic reactions.

[0364] Intermediates It can be prepared by methods analogous to Scheme 1 by using different starting materials and reagents, or by standard organic reactions.

[0365] Intermediates Where W is C(O) or S(O2) can be prepared by methods similar to Scheme 1 by using different starting materials and reagents, or by standard organic reactions.

[0366] Intermediates It can be prepared by Scheme 1 described below.

[0367]

[0368] In Scheme 1, the starting material 2,4-dibromopyridine is converted to intermediate 1-2 in high yield by standard organic reactions, which can be further reacted with 7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one (CAS 1346674-23-4) to give intermediate 1-3. Finally, 1-3 can be converted to the target boronate intermediate 1-4 by standard organic reactions.

[0369] Intermediates The preparation can be carried out by methods analogous to Scheme 1 using different starting materials and reagents, or by standard organic reactions.

[0370] Intermediates The preparation can be carried out by methods analogous to Scheme 1 using appropriate starting materials and reagents, or by standard organic reactions.

[0371] Intermediates It can be prepared by Scheme 2 described below.

[0372]

[0373] In Scheme 2, the starting material 2,4-dibromopyridine is converted to 2,4-dibromonicotinaldehyde in high yield via standard organic reactions, which can be further reduced to the alcohol intermediate 2-3. Afterwards, the OH group of intermediate 2-3 can be protected by THP to form intermediate 2-4, which can react with 7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one (CAS 1346674-23-4) to give intermediate 2-5. Next, intermediate 2-5 can be converted to intermediate 2-6, which can undergo a ring closure reaction to give intermediate 2-7.

[0374] Intermediates The preparation can be carried out by methods analogous to Scheme 1 using different starting materials and reagents, or by standard organic reactions.

[0375] Intermediates The preparation can be carried out by methods analogous to Scheme 2 using appropriate starting materials and reagents, or by standard organic reactions.

[0376] Synthetic compounds (R 3 -CH 2 An improved method for OH) is described in Scheme A. 1 and m in General Scheme A are the same as those described in the Summary of the Invention section above.

[0377]

[0378] In Scheme A, the appropriate starting material 3-nitroaniline A-1 can react with 3,5-dibromo-1-methylpyrazin-2(1H)-one to produce the nitro intermediate A-2, which can be reduced to the amine intermediate A-3. A-3 can react with an appropriate acryloyl chloride to give A-4, which reacts with 2-7 to produce the target compound.

[0379] Synthetic compounds (R 3 -CH 3 ) is described in Scheme B. R in Scheme B 1 and m are the same as described in the Summary of the Invention section above.

[0380]

[0381] In scheme B, the appropriate starting material 3-nitroaniline B-1 can react with 3,5-dibromo-1-methylpyrazin-2(1H)-one to produce nitro intermediate B-2, which can be reduced to amine intermediate B-3. B-3 can react with an appropriate acryloyl chloride to give B-4, which can react with 1-4 to produce the target compound.

[0382] Compounds of formula (IV) It can be prepared by methods similar to Schemes A and B by using different starting materials, intermediates and reagents.

[0383] Compound of formula (III) It can be prepared by methods similar to Schemes A and B by using different starting materials, intermediates and reagents.

[0384] Compound of formula (II) It can be prepared by methods similar to Schemes A and B by using different starting materials, intermediates and reagents.

[0385] Compound of formula (I) It can be prepared by methods similar to Schemes A and B by using different starting materials, intermediates and reagents.

[0386] The compounds and processes of the present invention may be better understood in connection with the following examples, which are intended to be used only as illustrations 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 changes and modifications may be made, including but not limited to changes and modifications associated with chemical structures, substituents, derivatives, and / or methods of the present invention, without departing from the spirit of the present invention and the scope of the appended claims.

[0387] If NMR data are presented,1 The H spectrum was obtained on XL400 (400 MHz) and was derived from Me 4 Si is reported in ppm downfield with the number of protons, multiplicity and coupling constant in Hertz indicated in parentheses. Where HPLC data are presented, the analysis was performed using an Agilent 1100 system. Where LC / MS data are presented, the analysis was performed using an Applied Biosystems API-100 mass spectrometer and a Shimadzu SCL-10A LC column.

[0388] Example 1: Preparation of 7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one.

[0389] A solution of CuI (47.6 g, 249.93 mmol, 1.20 equivalents) in ether (500 mL) was placed in a 1000-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere. MeLi (286 mL / 2M, 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-ene-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. Then, when TLC showed that SM disappeared (PE: EA = 1: 1), 500 mL of NH 4 The reaction was quenched with Cl (aq.). The resulting solution was extracted with 3×200 ml of ether, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain 21 g (90%) of 3,3-dimethylcyclopentan-1-one as a colorless oil.

[0390] A solution of N,N-dimethylformamide (41.6 g, 569.16 mmol, 3.00 equiv) in dichloromethane (200 mL) was placed in a 500 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen. POCl was added to the solution at 0 °C. 3(57.3g, 373.70mmol, 2.00 equivalents), the reaction mixture was then stirred at room temperature for 1.5 hours. 3,3-dimethylcyclopentan-1-one (21.0g, 187.22mmol, 1.00 equivalents) was added to the solution at the same temperature. The resulting solution was stirred overnight at 55 ° C in an oil bath. Then when TLC showed that the reaction was complete (PE: EA = 1: 1), the reaction was quenched by adding 200mL of aqueous NaAcO. 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) of 2-chloro-4,4-dimethylcyclopentan-1-ene-1-carbaldehyde (carbaldehyde) was obtained as a brown oil.

[0391] 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 with a nitrogen inert atmosphere. 2-chloro-4,4-dimethylcyclopent-1-ene-1-carboxaldehyde (29.7 g, 187.23 mmol, 1.00 equivalent) was then added dropwise to the solution at 100 ° C. The resulting solution was stirred in an oil bath at 100 ° C for 30 minutes. Then, when TLC showed that the reaction was complete (EA), the reaction was quenched by adding 200 mL of water. The solid was collected by filtration. 20 g (52%) of 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one was obtained as an off-white solid. LC-MS: (ES, m / z): 205 [M+H] + . 1 H-NMR:(300MHz,d 6 -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).

[0392] Example 2: Preparation of N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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

[0393] 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 kept at reflux for 24 h, then the mixture was allowed to cool to room temperature, the reaction was concentrated in vacuo and filtered to give 4-(4-methylpiperazin-1-yl)-3-nitroaniline (131 g, 86%) as a red solid. 1H-NMR (300 MHz, CDCl 3 )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).

[0394] A mixture of 4-(4-methylpiperazin-1-yl)-3-nitroaniline (14.53 g, 0.0615 mol), 3,5-dibromo-1-methylpyrazin-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 added after bubbling nitrogen through the resulting suspension for 30 minutes, and 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 2h, after which the mixture was cooled to room temperature and diluted with 90:10 dichloromethane / methanol (500ml) and water (300ml), the layers were separated, the aqueous layer was extracted with 90:10 dichloromethane / methanol (500ml), the combined organic layers were washed with brine and dried over sodium sulfate. The desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (90:10 dichloromethane / methanol) to give D (12g, 46%) 1H-NMR (300MHZ, 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).

[0395] Commercially available starting materials: 4-chloro-2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)nicotinaldehyde (CAS#1434050-55-1, 1.5 g, 4.37 mmol, 1.0 equiv), Pin 2 B 2(2.8 g, 11 mmol, 2.5 equiv), Pd(dppf)Cl 2 A mixture of 1,4-dioxane (150 mL) and 1,4-dioxane (356 mg, 0.44 mmol, 0.1 eq.) was stirred at 4 ℃ for 2 h. 2 Reflux for 4 h under atmosphere. The mixture was cooled to room temperature and filtered. The filtrate was concentrated to give (2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-formylpyridin-4-yl)boronic acid (3.0 g) as a brown oil, which was used in the next step without further purification. ESI-MS (M+H) + :354.2.

[0396] (2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-3-formylpyridin-4-yl)boronic acid (crude from the previous step, 4.37 mmol, 1.0 equiv), 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 equiv), Pd(dppf)Cl 2 (360 mg, 0.44 mmol, 0.1 eq) and K 2 CO 3 (1.5 g, 13 mmol, 3.0 equiv) in dioxane (50 mL) and H 2 O (5 mL) at 90 °C and N 2 Stir for 4 hours under 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-cyclopenta[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.

[0397] A mixture of 2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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 equiv) and Pd / C (120 mg, 20% wt) in MeOH (20 mL) was stirred at 1 atm of H 2 The mixture was hydrogenated at room temperature for 16 hours under a pressure atmosphere. The catalyst was filtered off through a Celite pad, 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-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)nicotinaldehyde as a brown solid (600 mg). ESI-MS (M+H) + :622.1.

[0398] To 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-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)nicotinaldehyde (crude from the previous step, 0.92 mmol, 1.0 equiv) in MeOH (10 mL) at 0 °C was added NaBH 4 (70 mg, 1.8 mmol, 2.0 equiv) in MeOH (10 mL). The solution was stirred at room temperature for 16 hours. The residue was concentrated and purified by preparative HPLC (A:H 2 O, 0.05% NH 3 .H 2 O, 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-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one as a brown solid (150 mg, two steps Y: 56%). ESI-MS (M+H) + :624.1.

[0399] 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-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one (150 mg, 0.24 mmol, 1.0 eq), acrylic acid (26 mg, 0.36 mmol, 1.5 eq) and HATU (123 mg, 0.36 mmol, 1.5 eq) in DMF (5 mL) was added TEA (73 mg, 0.72 mmol, 3.0 eq). The mixture was stirred at room temperature for 4 hours. The reaction mixture was purified by preparative HPLC (A:H 2 O, 0.05% NH 3 .H 2 O; B: MeCN) to give N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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. 1 H NMR (400 MHz, DMSO-d 6 )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=2.0 Hz,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).

[0400] Example 3: Preparation of (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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

[0401] 4-Fluoro-3-nitroaniline (50 g, 320.28 mmol, 1.00 equiv), CH 3 CN (500 mL), NMM (64.7 g, 639.64 mmol, 2.00 equiv), Cbz-Cl (87.4 g, 512.34 mmol, 1.60 equiv) were placed in a 1000-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen. The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:1). 45 g (48%) of N-(4-fluoro-3-nitrophenyl)benzylcarbamate was obtained as a yellow solid. LC-MS: (ES, m / z): [M+H] + =291, 1 H-NMR:(300MHz,CDCl 3 , 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).

[0402] A solution of N-(4-fluoro-3-nitrophenyl)benzyl carbamate (10 g, 34.45 mmol, 1.00 equivalent) in DMSO (100 mL), (3S)-tert-butyl 3-methylpiperazine-1-carboxylate (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 with a nitrogen inert atmosphere. The resulting solution was stirred overnight at 110 ° C in an oil bath. 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 and eluted with ethyl acetate / petroleum ether (1: 1). 10 g (62%) of (3S)-4-(4-[[(benzyloxy)carbonyl]amino]-2-nitrophenyl)-tert-butyl 3-methylpiperazine-1-carboxylate was obtained as a brown oil. LC-MS: (ES, m / z): [M+H] + =471. 1 H-NMR:(300MHz,CDCl 3,ppm): δ7.86(s,1H),7.60(m,1H),7.44-7.31(m,7H),5.21(s,2H),3.90(t,J=11.4 Hz, 2H), 3.21-3.02 (m, 3H), 2.79-2.72 (m, 2H), 1.49 (s, 9H), 0.80 (d, J = 6.3Hz, 3H).

[0403] A solution of (3S)-4-(4-[[(benzyloxy)carbonyl]amino]-2-nitrophenyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (12.5 g, 26.57 mmol, 1.00 equiv) in dioxane (100 mL) and hydrogen chloride in dioxane (25 mL) were placed in a 250-mL round-bottom flask purged and maintained with 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-methylpiperazine-1-yl]-3-nitrophenyl]benzyl carbamate was obtained as a brown oil. LC-MS: (ES, m / z): 371 [M+H] + .

[0404] A solution of benzyl N-[4-[(2S)-2-methylpiperazin-1-yl]-3-nitrophenyl]carbamate in ethanol (100 ml), oxetane-3-one (oxetan-3-one) (2.2 g, 30.53 mmol, 1.20 equivalents), NaBH 3 CN (1.67 g, 26.58 mmol, 1.00 equiv) was placed in a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen. 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 and eluted with ethyl acetate / petroleum ether (1:1). 5 g (35%) of N-[4-[(2S)-2-methyl-4-(oxetane-3-yl)piperazine-1-yl]-3-nitrophenyl]carbamic acid benzyl ester was obtained as a brown oil. LC-MS: (ES, m / z): 427 [M+H] +1 H-NMR (300MHz, CD 3 OD,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).

[0405] A solution of N-[4-[(2S)-2-methyl-4-(oxetanes-3-yl)piperazine-1-yl]-3-nitrophenyl]benzyl carbamate (5.0 g, 11.72 mmol, 1.00 equiv) in ethanol (50 ml) and AcOH (7.0 g, 116.57 mmol, 10.00 equiv) were placed in a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen. Powdered Zn (4.6 g, 6.00 equiv) was subsequently 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-(oxetanes-3-yl)piperazine-1-yl]phenyl]benzyl carbamate was obtained as a brown oil. LC-MS: (ES, m / z): 397 [M+H] + . 1 H-NMR (300MHz, CD 3 OD,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).

[0406] A solution of benzyl N-[3-amino-4-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]phenyl]carbamate in tetrahydrofuran (10 mL), NMM (510 mg, 5.04 mmol, 2.00 equiv), (Boc 2 O (820 mg, 3.76 mmol, 1.50 equiv) was placed in a 25-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere. The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1: 1). 0.9 g (72%) of N-(3-[[(tert-butoxy)carbonyl]amino]-4-[(2S)-2-methyl-4-(oxetanes-3-yl)piperazine-1-yl]phenyl)benzyl carbamate was obtained as a brown oil. LC-MS: (ES, m / z): 497 [M+H] + .

[0407] A solution of benzyl N-(3-[[(tert-butoxy)carbonyl]amino]-4-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]phenyl)carbamate in methanol (10 mL) and palladium on carbon (0.1 g, 0.10 equivalent) were placed in a flask containing H2 The mixture was concentrated under vacuum to give 0.6 g (91%) of tert-butyl N-[5-amino-2-[(2S)-2-methyl-4-(oxetane-3-yl)piperazine-1-yl]phenyl]carbamate as a brown oil. LC-MS: (ES, m / z): 363 [M+H] +1 H-NMR-PH-:(300MHz,CD 3 OD,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).

[0408] A solution of tert-butyl N-[5-amino-2-[(2S)-2-methyl-4-(oxetanes-3-yl)piperazine-1-yl]phenyl]carbamate in IPA (10 mL), 3,5-dibromo-1-methyl-1,2-dihydropyrazine-2-one (980 mg, 3.66 mmol, 1.00 equiv), DIEA (640 mg, 4.95 mmol, 1.50 equiv) were placed in a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen. The resulting solution was stirred overnight at 80 ° C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1: 1). 1.2 g (66%) of tert-butyl N-[5-[(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino]-2-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]phenyl]carbamate was obtained as a brown oil. LC-MS: (ES, m / z): 551 [M+H] +1 H-NMR:(300MHz,CDCl 3 ,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).

[0409] A solution of N-[5-[(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazine-2-yl)amino]-2-[(2S)-2-methyl-4-(oxetanes-3-yl)piperazine-1-yl]phenyl]carbamic acid tert-butyl ester (600mg, 1.09mmol, 1.00 equivalent) in dichloromethane (6ml) and trifluoroacetic acid (1.2mL) were placed in a 50-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere. The resulting solution was stirred at room temperature for 1h. The resulting mixture was concentrated under vacuum. 500mg (crude) of 3-([3-amino-4-[(2S)-2-methyl-4-(oxetanes-3-yl)piperazine-1-yl]phenyl]amino)-5-bromo-1-methyl-1,2-dihydropyrazine-2-one was obtained as a brown oil. LC-MS: (ES, m / z): 451 [M+H] + .

[0410] 3-([3-amino-4-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]phenyl]amino)-5-bromo-1-methyl-1,2-dihydropyrazin-2-one (500 mg, 1.11 mmol, 1.00 equiv) was dissolved in dioxane (15 mL) / H2O 2 O (1 mL), (2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-[(oxan-2-yloxy)methyl]pyridin-4-yl)boronic acid (431 mg, 0.98 mmol, 1.10 equiv), Pd(dppf)Cl 2 (50 mg, 0.07 mmol, 0.10 equiv) and potassium carbonate (307 mg, 2.22 mmol, 2.00 equiv) were placed in a 25-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere. The resulting solution was stirred in an oil bath at 100 °C for 1 hour. The resulting mixture was concentrated under vacuum and washed with H 2 O and extracted with EA. 500 mg (59%) of 10-[4-[6-([3-amino-4-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-[(oxanyl2-yloxy)methyl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one (crude) was obtained as a brown oil. LC-MS: (ES, m / z): 764 [M+H] + .

[0411] A solution of 10-[4-[6-([3-amino-4-[(2S)-2-methyl-4-(oxetanes-3-yl)piperazine-1-yl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]-3-[(oxan-2-yloxy)methyl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one (500mg, 0.65mmol, 1.00 equivalent) in dichloromethane (5mL) and trifluoroacetic acid (1mL) were placed in a 50-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere. The resulting solution was stirred in an oil bath at 40°C for 15 minutes. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC. 80 mg (18%) of 10-[4-[6-([3-amino-4-[(2S)-2-methyl-4-(oxetan-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]]dodeca-2(6),7-dien-9-one were obtained as a brown solid. LC-MS: (ES, m / z): 680 [M+H] + .

[0412] 10-[4-[6-([3-amino-4-[(2S)-2-methyl-4-(oxetan-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]]dodeca-2(6),7-dien-9-one (80 mg, 0.12 mmol, 1.00 equiv) was added in CH 3A solution in CN (1 mL), prop-2-enoic acid (10 mg, 0.14 mmol, 1.20 equiv), HATU (49.2 mg, 0.13 mmol, 1.10 equiv), NMM (17.7 mg, 0.17 mmol, 1.50 equiv) was placed in a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen. The resulting solution was stirred at room temperature for 1 h. The crude product was purified by preparative HPLC. 27 mg (31%) of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-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 were obtained as an off-white solid. LC-MS: (ES, m / z): 734 [M+H] + . 1 H-NMR:(300MHz,d 6 -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,1 H),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,1H),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).

[0413] Example 4: Preparation of (S)-N-(5-((6-(3-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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

[0414] A solution of 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one (3.0 g, 14.69 mmol, 1.00 equiv) in dioxane (30 mL), 2,6-dibromobenzaldehyde (4.65 g, 17.62 mmol, 1.20 equiv), Cs 2 CO 3 (9.6 g, 29.46 mmol, 2.00 equiv), Pd 2 (dba) 3 (300 mg, 0.33 mmol, 0.10 equiv.), Xantphos (300 mg, 0.52 mmol, 0.10 equiv.) were placed in a 50-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere. The resulting solution was stirred at 100 ° C for 1 hour in an oil bath. The reaction mixture was cooled to room temperature. The solid was filtered out. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column and eluted with 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]]12-2(6),7-diene-10-yl]benzaldehyde was obtained as an off-white solid. (ES, m / z): 387 [M+H] + . 1 H-NMR:(300MHz,CD 3 OD,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).

[0415] A solution of 2-bromo-6-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]benzaldehyde (1.0 g, 2.58 mmol, 1.00 equiv) in dioxane (10 mL) and Pin 2 B 2 (1.64 g, 2.50 equiv), Pd(dppf)Cl 2(100 mg, 0.14 mmol, 0.10 equiv), KOAc (760 mg, 7.74 mmol, 3.00 equiv) were placed in a 50-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere. The resulting solution was stirred at 100 ° C for 30 minutes in an oil bath. The reaction mixture was cooled to room temperature. The solid was filtered out. 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]]twelve-2(6),7-diene-10-yl]-2-formylphenyl)boronic acid was obtained as a brown solid. LC-MS: (ES, m / z): 353 [M+H] + .

[0416] (3-[4,4-Dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-2-formylphenyl)boronic acid (346 mg, 0.98 mmol, 1.00 equiv), 3-([3-amino-4-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]phenyl]amino)-5-bromo-1-methyl-1,2-dihydropyrazin-2-one (441 mg, 0.98 mmol, 1.00 equiv) were dissolved in dioxane (10 mL) / H2O. 2 O (1 mL), Pd(dppf)Cl 2 (30 mg, 0.04 mmol, 0.10 equiv), potassium carbonate (271 mg, 1.96 mmol, 2.00 equiv) were placed in a 50-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere. The resulting solution was stirred at 100° C. for 1 hour in an oil bath. 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-(oxetanes-3-yl)piperazine-1-yl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]-6-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-10-yl]benzaldehyde was obtained as a brown oil. LC-MS: (ES, m / z): 677 [M+H] + .

[0417] A solution of 2-[6-([3-amino-4-[(2S)-2-methyl-4-(oxetan-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]]dodeca-2(6),7-dien-10-yl]benzaldehyde (500 mg, 0.74 mmol, 1.00 equiv) in ethanol (10 mL) and NaBH 4 (16.8 mg, 0.44 mmol, 0.60 equiv) was placed in a 25-mL round-bottom flask purged and maintained with a nitrogen inert 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 preparative HPLC. 240 mg (48%) of 10-[3-[6-([3-amino-4-[(2S)-2-methyl-4-(oxetanes-3-yl)piperazine-1-yl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]-2-(hydroxymethyl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one was obtained as a light brown solid. LC-MS: (ES, m / z): 679[M+H] + .

[0418] 10-[3-[6-([3-amino-4-[(2S)-2-methyl-4-(oxetan-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]]dodeca-2(6),7-dien-9-one (240 mg, 0.35 mmol, 1.00 equiv) was added in CH 3A solution in CN (10 mL), prop-2-enoic acid (30.5 mg, 0.42 mmol, 1.20 equiv), HATU (147.7 mg, 0.39 mmol, 1.10 equiv), NMM (71.4 mg, 0.71 mmol, 2.00 equiv) was placed in a 10-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen. 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]]dodeca-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 were obtained as an off-white solid. LC-MS: (ES, m / z): 733 [M+H] + . 1 H-NMR:(300MHz,d 6 -DMSO,ppm): δ9.17(m,2H),8.91(s,1H),7.82-7.63(m,2H),7.49-7.42(m,2H),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).

[0419] Example 5: Preparation of N-(3-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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

[0420] Tert-butyl N-(3-aminophenyl)carbamate (5 g, 24.01 mmol, 1.00 equiv.), 3,5-dibromo-1-methyl-1,2-dihydropyrazine-2-one (5.8 g, 21.65 mmol, 1.50 equiv.), DIEA (4.9 g, 37.98 mmol, 2.00 equiv.), isopropanol (50 mL) were placed in a 250-mL round-bottom flask. The resulting solution was stirred at 80 ° C overnight. The resulting mixture was concentrated under vacuum. The crude product was purified by rapid PE: EA = 100 / 20 increasing to PE: EA = 100 / 50 within 30 minutes. 7.4 g (78%) of tert-butyl N-[3-[(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazine-2-yl) amino] phenyl] carbamate was obtained as a light yellow solid. LC-MS: (ES, m / z): [M+H] + =395. 1 H-NMR-:(300MHz,CDCl 3 , 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).

[0421] Tert-butyl N-[3-[(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino]phenyl]carbamate (400 mg, 0.51 mmol, 1.00 equiv) 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 obtained as a yellow solid. LC-MS: (ES, m / z): [M+H] + =295.

[0422] 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]dodeca-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)Cl 2(58 mg, 0.07 mmol, 0.10 equiv), potassium carbonate (281 mg, 2.04 mmol, 3.00 equiv), dioxane (12 mL), water (2 mL) were placed in a 50-mL round-bottom flask purged and maintained with a nitrogen inert 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 MeCN:H 2 O = 25 / 75 increased to MeCN:H in 13 minutes 2 O=50 / 50 purification. 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]]dodeca-2(6),7-dien-9-one was obtained as a brown solid. LC-MS (ES, m / z): [M+H] + =610.

[0423] 10-(4-[6-[(3-aminophenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]-3-[(oxan-2-yloxy)methyl]pyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one (230 mg, 0.38 mmol, 1.00 equiv), 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]]dodeca-2(6),7-dien-9-one was obtained as a colorless oil. LC-MS--714-4: (ES, m / z): [M+H] + =526.

[0424] 10-(4-[6-[(3-aminophenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]-3-(hydroxymethyl)pyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one (150 mg, 0.28 mmol, 1.00 equiv), prop-2-enoic acid (20.1 mg, 0.28 mmol, 1.00 equiv), NMM (58 mg, 0.38 mmol, 2.00 equiv), HATU (141 mg, 0.25 mmol, 1.30 equiv), 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 preparative HPLC. 32.4 mg (18%) of N-(3-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-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 were obtained as an off-white solid. LC-MS: (ES, m / z): [M+H] + =580. 1 H-NMR:(300MHz,CDCl 3 ,ppm): δ9.99(s,1H),9.24(s,1H),8.47(m,2H),7.84-7.73(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),3.88(m,1 H), 3.57 (s, 3H), 2.59 (d, J = 5.1Hz, 2H), 2.42 (d, J = 5.1Hz, 2H), 1.22 (s, 6H).

[0425] Example 7: Preparation of N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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

[0426] 4-Bromo-3-nitroaniline (5 g, 23.04 mmol, 1.00 equiv), tert-butyl 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (14 g, 45.28 mmol, 2.00 equiv), Pd(dppf)Cl 2 (2g, 2.33mmol, 0.10 equiv), potassium carbonate (19g, 137.47mmol, 6.00 equiv), dioxane (80mL), water (20mL) were placed in a 250-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere. The resulting solution was stirred at 90°C overnight. The solid was filtered off. The resulting mixture was concentrated under vacuum. The crude product was purified by rapid PE:EA=50 / 50 increasing to PE:EA=20 / 80 within 30 minutes. 5.7g (77%) of tert-butyl 4-(4-amino-2-nitrophenyl)-1,2,3,6-tetrahydropyridine-1-carboxylate was obtained as a light yellow oil. LC-MS--1: (ES, m / z): [M+H] + =320. 1 H-NMR-PH--1:(300MHz,d 6 -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).

[0427] 4-(4-amino-2-nitrophenyl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (7g, 21.92mmol, 1.00 equivalent), water (10mL), sodium carbonate (4.6g, 43.40mmol, 2.00 equivalent), dichloromethane (50mL) were placed in a 250-mL round-bottom flask. The resulting solution was stirred at 0°C for 30 minutes. Cbz-Cl (4.5g, 26.47mmol, 1.20 equivalent) was then added dropwise at 0°C and stirred for 5 minutes. The resulting solution was stirred at room temperature overnight. The resulting mixture was washed with 2x100mL of brine. The resulting mixture was concentrated under vacuum. 7g (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,d 6-DMSO,ppm): δ10.27(s,1H),8.13(s,1H),7.68(d,J=8.4Hz,1H),7.46-7.32(m,7 H), 5.62 (s, 1H), 5.19 (s, 2H), 3.92 (m, 2H), 3.53 (t, J = 10.8Hz, 2H), 2.24 (s, 2H).

[0428] 4-(4-[[(Benzyloxy)carbonyl]amino]-2-nitrophenyl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (5 g, 11.03 mmol, 1.00 equiv) and hydrogen chloride / dioxane (40 mL) 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-tetrahydropyridin-4-yl)phenyl]carbamic acid benzyl ester was obtained as a light yellow solid. LC-MS--3: (ES, m / z): [M+H] + =354.

[0429] Benzyl N-[3-nitro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]carbamate (4.5 g, 25.47 mmol, 1.00 equiv), oxetan-3-one (1.35 g, 37.47 mmol, 1.50 equiv), NaCNBH 3 (1.6 g, 50.79 mmol, 2.00 equiv.), methanol (30 mL) were placed in a 250-mL round-bottom flask. The resulting solution was stirred at 50 ° C for 4 hours. The resulting solution was extracted with ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 2x100 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]carbamic acid benzyl ester was obtained as a white solid. LC-MS--4: (ES, m / z): [M+H] + =410. 1 H-NMR-PH--4:(300MHz,d 6 -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).

[0430] N-[3-nitro-4-[1-(oxetanes-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl]carbamic acid benzyl ester (3.6 g, 8.79 mmol, 1.00 equiv), acetic acid (5.25 g, 87.42 mmol, 10.00 equiv), ethanol (25 mL), zinc (2.8 g, 42.81 mmol, 5.00 equiv) 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 2x200 mL H 2 O. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by rapid PE:EA=100 / 30 increasing to PE:EA=100 / 50 within 45 minutes. 2.5 g (75%) of N-[3-amino-4-[1-(oxetane-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl]carbamic acid benzyl ester was obtained as a yellow oil. LC-MS--5: (ES, m / z): [M+H] + =380. 1 H-NMR-PH--5:(300MHz,d 6 -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).

[0431] Benzyl N-[3-amino-4-[1-(oxetanes-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl]carbamate (2.5 g, 13.18 mmol, 1.00 equiv), TEA (2 g, 39.53 mmol, 3.00 equiv), di-tert-butyl dicarbonate (1.75 g, 16.04 mmol, 1.30 equiv), tetrahydrofuran (30 mL) were placed in a 250-mL round-bottom flask. The resulting solution was stirred at 65 ° C overnight. The resulting mixture was concentrated under vacuum. The crude product was purified by rapid PE:EA=100 / 30 increasing to PE:EA=100 / 50 within 25 minutes. 2 g (63%) of benzyl N-(3-[[(tert-butoxy)carbonyl]amino]-4-[1-(oxetan-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,d 6 -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).

[0432] Benzyl N-(3-[[(tert-butoxy)carbonyl]amino]-4-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl)carbamate (1.4 g, 2.92 mmol, 1.00 equivalent), palladium on carbon (140 mg, 0.10 equivalent) and ethyl acetate (40 mL) were placed in a flask with H 2 Inert atmosphere was purged and maintained in a 250-mL round-bottom flask. The resulting solution was stirred at room temperature overnight. 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 obtained as a light yellow solid. LC-MS--7: (ES, m / z): [M+H] + =348. 1 H-NMR-PH--7:(300MHz,d 6-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).

[0433] Tert-butyl N-[5-amino-2-[1-(oxetanes-3-yl)piperidin-4-yl]phenyl]carbamate (600 mg, 2.30 mmol, 1.00 equiv), 3,5-dibromo-1-methyl-1,2-dihydropyrazine-2-one (550 mg, 2.74 mmol, 1.20 equiv), DIEA (435 mg, 4.50 mmol, 2.50 equiv), isopropanol (25 mL) were placed in a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen. The resulting solution was stirred at 80 ° C overnight. The resulting mixture was concentrated under vacuum. The crude product was purified by flash PE: EA = 100 / 85. 600 mg (65%) of tert-butyl N-[5-[(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino]-2-[1-(oxetan-3-yl)piperidin-4-yl]phenyl]carbamate was obtained as a light yellow solid. LC-MS--8: (ES, m / z): [M+H] + =534. 1 H-NMR-PH--8:(300MHz,d 6 -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).

[0434] Tert-butyl N-[5-[(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazine-2-yl)amino]-2-[1-(oxetanes-3-yl)piperidin-4-yl]phenyl]carbamate (600 mg, 1.12 mmol, 1.00 equiv), 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 hours. 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-(oxetanes-3-yl)piperidin-4-yl]phenyl]amino)-5-bromo-1-methyl-1,2-dihydropyrazine-2-one was obtained as a light yellow solid. LC-MS--9: (ES, m / z): [M+H] + =434.

[0435] 3-([3-amino-4-[1-(oxetan-3-yl)piperidin-4-yl]phenyl]amino)-5-bromo-1-methyl-1,2-dihydropyrazin-2-one (300 mg, 0.7 mmol, 1.00 equiv), (2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-[(oxan-2-yloxy)methyl]pyridin-4-yl)boronic acid (350 mg, 0.8 mmol, 1.10 equiv), Pd(dppf)Cl 2 (60 mg, 0.03 mmol, 0.10 equiv), K 2 CO 3 (286 mg, 2.03 mmol, 3.00 equiv), dioxane (20 mL), and water (2 mL) were placed in a 50-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere. The resulting solution was stirred at 100 ° C for 30 minutes. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with methanol. The crude product was purified by rapid MeCN:H 2 O = 20 / 80 increased to MeCN:H in 12 minutes 2 O=55 / 45 purification. 210 mg (81%) of 10-[4-[6-([3-amino-4-[1-(oxetan-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]]dodeca-2(6),7-dien-9-one was obtained as a light yellow solid. LC-MS--10: (ES, m / z): [M+H] +=749.

[0436] 10-[4-[6-([3-amino-4-[1-(oxetanes-3-yl)piperidin-4-yl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]-3-[(oxan-2-yloxy)methyl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one (210 mg, 0.28 mmol, 1.00 equivalent), dichloromethane (10 mL), trifluoroacetic acid (1 mL) were placed in a 25-mL round-bottom flask. The resulting solution was stirred at room temperature for 1 hour. 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-(oxetan-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]]dodeca-2(6),7-dien-9-one was obtained as a light yellow solid. LC-MS--11: (ES, m / z): [M+H] + =665. 1 H-NMR-PH--11:(300MHz,CDCl 3 ,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).

[0437] 10-[4-[6-([3-amino-4-[1-(oxetanes-3-yl)piperidin-4-yl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]-3-(hydroxymethyl)pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one (135 mg, 0.23 mmol, 1.00 equiv), prop-2-enoic acid (17 mg, 0.23 mmol, 1.00 equiv), HATU (94 mg, 0.25 mmol, 1.10 equiv), NMM (54 mg, 0.53 mmol, 2.50 equiv), 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 preparative HPLC. 15.2 mg (11%) of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-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 were obtained as a white solid. LC-MS--0: (ES, m / z): [M+H] + =719. 1 H-NMR-PH--0:(300MHz,CDCl 3 ,ppm): δ9.54(s,1H),9.32(s,1H),8.45(d,J=4.8Hz,1H),8.32(m,1H),7.79-7.7 0(m,3H),7.25(d,J=8.7Hz,1H),6.61-6.44(m,2H),6.27(m,1H),5.75(d,J=10.8H z,1H),5.01(m,1H),4.67-4.42(m,6H),4.35-4.15(m,3H),3.87(m,1H),3.57(s,3 H),3.40(m,1H),2.85-2.57(m,5H),2.45(m,2H),1.84-1.55(m,6H),1.23(s,6H).

[0438] Example 8: Preparation of N-(5-((6-(3-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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

[0439] 3-([3-amino-4-[1-(oxetan-3-yl)piperidin-4-yl]phenyl]amino)-5-bromo-1-methyl-1,2-dihydropyrazin-2-one (300 mg, 0.69 mmol, 1.00 equiv), (3-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-diene-10-yl]-2-formylphenyl)boronic acid (260 mg, 0.74 mmol, 1.10 equiv), Pd(dppf)Cl 2 (35 mg, 0.05 mmol, 0.10 equiv), potassium carbonate (286 mg, 2.07 mmol, 3.00 equiv), dioxane (15 mL), water (2 mL) were placed in a 25-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere. The resulting solution was stirred for 40 minutes at 100 ° C for 2 h. 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 rapid MeCN:H 2 O = 30 / 70 increased to MeCN:H in 12 min 2 O=65 / 35 purification. 268 mg (59%) of 2-[6-([3-amino-4-[1-(oxetan-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]]dodeca-2(6),7-diene-10-yl]benzaldehyde was obtained as a light yellow solid. LC-MS--1: (ES, m / z): 662 [M+H] + .

[0440] 2-[6-(3-amino-4-[1-(oxetan-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]dodeca-2(6),7-dien-10-ylbenzaldehyde (240 mg, 0.36 mmol, 1.00 equiv), NaBH 4(7 mg, 0.18 mmol, 0.50 equiv.), 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 out and the filtrate was concentrated under vacuum. 132 mg (55%) of 10-[3-[6-([3-amino-4-[1-(oxetanes-3-yl)piperidin-4-yl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]-2-(hydroxymethyl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one was obtained as a light yellow oil. LC-MS--2: (ES, m / z): 664 [M+H] +1 H-NMR-PH--2:(300MHz,d 6 -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,1H),2.80(m,2H),2.55(s,2H),2.45(s,2H),1.95-1.4(m,7H),1.22(s,6H).

[0441] 10-[3-[6-([3-amino-4-[1-(oxetanes-3-yl)piperidin-4-yl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]-2-(hydroxymethyl)phenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one (100 mg, 0.15 mmol, 1.00 equiv), prop-2-enoic acid (12 mg, 0.17 mmol, 1.10 equiv), HATU (68 mg, 0.18 mmol, 1.20 equiv), NMM (30 mg, 0.30 mmol, 2.00 equiv), 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 preparative HPLC. 20.5 mg (20%) of N-(5-[[6-(3-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-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,CDCl 3 ,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).

[0442] Example 9: Preparation of N-(3-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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

[0443] A solution of 1-bromo-3,5-dinitrobenzene (5.5 g, 22.27 mmol, 1.00 equiv) in dioxane (50 mL), 1-methylpiperazine (2.64 g, 26.36 mmol, 1.20 equiv), Cs 2 CO 3 (14.5 g, 44.50 mmol, 2.00 equiv) was placed in a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen. Pd was then added 2 (dba) 3 (550 mg, 0.60 mmol, 0.10 equiv), BINAP (770 mg, 1.24 mmol, 0.15 equiv). The resulting solution was stirred in an oil bath at 100 ° C overnight. The reaction mixture was cooled to 25 ° C. The solid was filtered off. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column and eluted with 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] + .

[0444] A solution of 1-(3,5-dinitrophenyl)-4-methylpiperazine (1.3 g, 4.88 mmol, 1.00 equiv) in methanol (10 mL) and palladium on carbon (0.1 g, 0.10 equiv) were placed in a flask containing H 2 The inert atmosphere was purged and maintained in a 25-mL round-bottom flask. The resulting solution was stirred at room temperature for 2 hours. The solid was filtered off. The resulting mixture was concentrated under vacuum. 1.0 g (99%) of 5-(4-methylpiperazine-1-yl)benzene-1,3-diamine was obtained as a brown oil. LC-MS-2: (ES, m / z): 207 [M+H] + . 1 H-NMR-PH-1:(300MHz,d 6 -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).

[0445] A solution of 3,5-dibromo-1-methyl-1,2-dihydropyrazine-2-one (1.0 g, 3.73 mmol, 1.00 equiv) in IPA (10 mL), 5-(4-methylpiperazine-1-yl)benzene-1,3-diamine (1.0 g, 4.85 mmol, 1.00 equiv), DIEA (530 mg, 4.10 mmol, 1.10 equiv) were placed in a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen. The resulting solution was stirred at 40 ° C for 1 hour in an oil bath. The reaction mixture was cooled to 25 ° C. The solid was collected by filtration. 0.5 g (34%) of 3-[[3-amino-5-(4-methylpiperazine-1-yl)phenyl]amino]-5-bromo-1-methyl-1,2-dihydropyrazine-2-one was obtained as a brown solid. LC-MS-3: (ES, m / z): 392 [M+H] + .

[0446] 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 equiv) was dissolved in dioxane (10 mL) / H2O 2 O (1 mL), (2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-[(oxan-2-yloxy)methyl]pyridin-4-yl)boronic acid (300 mg, 0.68 mmol, 1.00 equiv), potassium carbonate (240 mg, 1.74 mmol, 2.00 equiv) were placed in a 25-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere. Pd(dppf)Cl was then added 2 (30 mg, 0.04 mmol, 0.10 equiv.). The resulting solution was stirred at 100 °C in an oil bath for 1 hour. The resulting mixture was concentrated under vacuum. The residue was applied to a column with CH 3 CN:H 2 O (1: 1) column. 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]]dodeca-2(6),7-dien-9-one was obtained as a brown solid. LC-MS-4: (ES, m / z): 708 [M+H] + .

[0447] A solution of 10-[4-(6-[[3-amino-5-(4-methylpiperazine-1-yl)phenyl]amino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl)-3-[(oxan-2-yloxy)methyl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one (190 mg, 0.27 mmol, 1.00 equiv) in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) were placed in a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen. The resulting solution was stirred in an oil bath at 40 ° C for 20 minutes. 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]]dodeca-2(6),7-dien-9-one was obtained as a brown oil. LC-MS-5: (ES, m / z): 624 [M+H] + .

[0448] Propyl-2-enoic acid (21 mg, 0.29 mmol, 1.10 equiv), HATU (122.5 mg, 0.32 mmol, 1.20 equiv), NMM (54 mg, 0.53 mmol, 2.00 equiv) were placed in a 25-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere. The resulting mixture was stirred for 10 minutes. 10-[4-(6-[[3-amino-5-(4-methylpiperazine-1-yl)phenyl]amino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl)-3-(hydroxymethyl)pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]12-2(6),7-diene-9-one (190 mg, 0.30 mmol, 1.00 equiv) was added to the mixture. The resulting solution was stirred at room temperature for 1 hour. The crude product was purified by flash preparative HPLC. 23 mg (11%) of N-(3-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-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-0: (ES, m / z): 678 [M+H] + . 1 H-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).

[0449] Example 10: Preparation of N-(3-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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

[0450] Synthesis of 1-[(3,5-dinitrophenyl)methyl]-4-methylpiperazine: 1-(Chloromethyl)-3,5-dinitrobenzene (3 g, 13.85 mmol, 1.00 equiv), 1-methylpiperazine (1.38 g, 13.78 mmol, 1.00 equiv), potassium carbonate (4.8 g, 34.73 mmol, 2.50 equiv), and tetrahydrofuran (30 mL) were placed in a 250-mL round-bottom flask. The resulting solution was stirred at 70 ° C overnight. The reaction mixture was cooled to room temperature. The solid was filtered out. 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 obtained as a yellow solid. LC-MS--718-1: (ES, m / z): 281 [M+H] +1 H-NMR-PH--718-1:(300MHz,d 6 -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).

[0451] Synthesis of 5-[(4-methylpiperazin-1-yl)methyl]benzene-1,3-diamine: 1-[(3,5-dinitrophenyl)methyl]-4-methylpiperazine (2.0 g, 7.14 mmol, 1.00 equivalent), palladium carbon (0.2 g, 0.10 equivalent), and methanol (40 mL) were placed in a flask with H 2 The inert atmosphere was purged and maintained in a 250-mL round-bottom flask. The resulting solution was stirred at room temperature for 3 hours. The solid was filtered out. The filtrate was concentrated under vacuum. 1.1 g (70%) of 5-[(4-methylpiperazine-1-yl)methyl]benzene-1,3-diamine was obtained as a colorless oil. LC-MS--718-2: (ES, m / z): 221 [M+H] + . 1 H-NMR-PH--718-2:(300MHz,d 6 -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).

[0452] 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 equiv), 5-[(4-methylpiperazin-1-yl)methyl]benzene-1,3-diamine (0.7 g, 1.00 equiv), DIEA (1.0 g, 7.74 mmol, 2.50 equiv), isopropanol (15 mL) were placed in a 50-mL round-bottom flask. The resulting solution was stirred at 80 ° C overnight. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative 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 light yellow solid. LC-MS--718-3: (ES, m / z): 407 [M+H] + . 1 H-NMR-PH--718-3:(300MHz,d 6 -DMSO,ppm): δ8.92(s,1H),7.28(s,1H),6.95-6.93(m,2H),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).

[0453] 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]]dodeca-2(6),7-diene-9-one: 3-([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]]dodeca-2(6),7-diene-9-one =((2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-[(oxan-2-yloxy)methyl]pyridin-4-yl)boronic acid (120 mg, 0.27 mmol, 1.10 equiv), Pd(dppf)Cl 2 (20 mg, 0.03 mmol, 0.10 equiv), potassium carbonate (68 mg, 0.49 mmol, 2.00 equiv), dioxane (10 mL), water (1 mL) were placed in a 50-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere. The resulting solution was stirred at 80 ° C for 30 minutes. The reaction mixture was cooled to room temperature. The solid was filtered out. The filtrate was concentrated under vacuum. The crude product was purified by preparative 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]]dodeca-2(6),7-dien-9-one was obtained as a brown solid. LC-MS--718-4: (ES, m / z): 722 [M+H] + .

[0454] 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]]dodeca-2(6),7-dien-9-one: dichloromethane (2 mL), trifluoroacetic acid (0.2 mL), 10-4-[6 -(3-amino-5-[(4-methylpiperazine-1-yl)methyl]phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]-3-[(oxacyclohexane-2-yloxy)methyl]pyridin-2-yl-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^2,6]twelve-2(6),7-diene-9-one (30 mg, 0.03 mmol, 1.00 equiv) 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]]dodeca-2(6),7-dien-9-one was obtained as a yellow oil. LC-MS--718-5: (ES, m / z): 638 [M+H] + .

[0455] Synthesis of N-(3-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-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: Prop-2-enoic acid (20 mg, 0.28 mmol, 1.00 equiv), 10-4-[6-(3 -amino-5-[(4-methylpiperazine-1-yl)methyl]phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]-3-(hydroxymethyl)pyridin-2-yl-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^2,6]twelve-2(6),7-diene-9-one (2.7 mg, 1.20 equivalents), HATU (14 mg, 1.20 equivalents), NMM (8 mg, 2.50 equivalents), 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 preparative HPLC. 5 mg (3%) of N-(3-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-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,d 6 -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).

[0456] Example 11: Preparation of (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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

[0457] Synthesis of 2,4-dibromo-3-methylpyridine: (i-Pr) 2 A solution of NH (3.19 g, 1.50 equiv.) in tetrahydrofuran (50 mL) was placed in a 250-mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen. Then nC was added at -30 °C. 4 H 9 Li (10ml, 1.5 equivalents) and the mixture was stirred at the same temperature for 30 minutes. Subsequently, 2,4-dibromopyridine (5g, 21.11mmol, 1.00 equivalent) was added at -70°C and the mixture was stirred at the same temperature for 30 minutes. Iodomethane (4.5g, 1.50 equivalents) was added to the above solution at -70°C. The resulting solution was stirred at -70°C for 30 minutes. Then 100mL of aqueous NH 4 The reaction was quenched with Cl. The resulting solution was extracted with 3x50 mL of ethyl acetate, and the organic layers were combined and dried over Na2SO4. The solid was filtered out. The filtrate was concentrated under vacuum. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:1). 3.0 g (57%) of 2,4-dibromo-3-methylpyridine was obtained as a white solid. LC-MS--727-1: (ES, m / z): 252 [M+H] +1 H-NMR-PH--727-1:(300MHz,CDCl 3 , ppm): δ7.99(d,J=5.1Hz,1H),7.45(d,J=5.1Hz,1H),2.58(s,3H).

[0458] Synthesis of 10-(4-bromo-3-methylpyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one: A solution of 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one (1.0 g, 4.90 mmol, 1.00 equiv) in dioxane (10 mL) was placed in a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen. Then 2,4-dibromo-3-methylpyridine (1.59 g, 6.34 mmol, 1.30 equiv), Pd2 (dba) 3 (100 mg, 0.11 mmol, 0.10 equiv), Xantphos (100 mg, 0.17 mmol, 0.10 equiv), Cs 2 CO 3 (3.19 g, 9.79 mmol, 2.00 equiv) was added to the mixture. The resulting solution was stirred at 100 ° C in an oil bath for 1.5 hours. The reaction mixture was cooled to room temperature. The solid was filtered out. The filtrate was concentrated under vacuum. The residue was applied to a silica gel column and eluted with 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]]12-2(6),7-diene-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,CDCl 3 ,ppm): δ8.10(d,J=5.4Hz,1H),7.41(d,J=5.1Hz,1H),6.79(s,1H),4.44-4.41(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).

[0459] Synthesis of (2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-methylpyridin-4-yl)boronic acid: A solution of 10-(4-bromo-3-methylpyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one (500 mg, 1.34 mmol, 1.00 equiv) in dioxane (5 mL) was placed in a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, and Pin was then added to the solution. 2 B 2 (850 mg, 2.50 equiv), KOAc (400 mg, 4.08 mmol, 3.00 equiv), Pd(dppf)Cl 2 (50 mg, 0.07 mmol, 0.10 equiv). The resulting solution was stirred at 100 °C in an oil bath for 1 hour. The reaction mixture was cooled to room temperature. The solid was filtered off. The filtrate was concentrated under vacuum. 3 CN:H 2O (1: 1) and the residue was purified by flash preparative HPLC. 150 mg (33%) of (2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-diene-10-yl]-3-methylpyridin-4-yl)boronic acid was obtained as a brown solid. LC-MS--727-3: (ES, m / z): 340 [M+H] + .

[0460] Synthesis of 10-[4-[6-([3-amino-4-[(2S)-2-methyl-4-(oxetan-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]]twelve-2(6),7-diene-9-one: A solution of 3-([3-amino-4-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]phenyl]amino)-5-bromo-1-methyl-1,2-dihydropyrazin-2-one (100 mg, 0.22 mmol, 1.10 equiv) in dioxane (1 mL) was placed in a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, and then 3-([3-amino-4-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]phenyl]amino)-5-bromo-1-methyl-1,2-dihydropyrazin-2-one (100 mg, 0.22 mmol, 1.10 equiv), Pd(dppf)Cl 2 (10 mg, 0.01 mmol, 1.00 equiv), potassium carbonate (73 mg, 0.53 mmol, 2.00 equiv). The resulting solution was stirred at 100 ° C in an oil bath for 1 hour. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by flash preparative HPLC. 120 mg (51%) of 10-[4-[6-([3-amino-4-[(2S)-2-methyl-4-(oxetanes-3-yl)piperazine-1-yl]phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]-3-methylpyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one was obtained as a brown solid. LC-MS--727-4: (ES,m / z): 664[M+H] + .

[0461] Synthesis of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-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-(oxetan-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]]dodeca-2(6),7-dien-9-one (200 mg, 0.30 mmol, 1.00 equiv) in CH 3 The solution in CN (1 mL) was placed in a 25-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere, and prop-2-enoic acid (21.7 mg, 0.30 mmol, 1.00 equiv), HATU (115 mg, 0.30 mmol, 1.00 equiv), NMM (61 mg, 0.60 mmol, 2.00 equiv) were then added to the solution. The resulting solution was stirred at room temperature for 4 hours. The resulting mixture was concentrated under vacuum. The crude product was purified by rapid preparative HPLC. 21.1 mg (10%) of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-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 light yellow solid. LC-MS--727-0: (ES, m / z): 718 [M+H] + . 1 H-NMR-PH--727-1:(300MHz,d 6 -DMSO 3,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=11.4Hz,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,3H),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).

[0462] Example 12: Preparation of N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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 Synthesis of tert-butyl 2-methyl-4-(morpholin-4-yl)piperidine-1-carboxylate: tert-butyl 2-methyl-4-oxopiperidin-1-carboxylate (18 g, 84.40 mmol, 1.00 equiv), morpholine (8 g, 91.83 mmol, 1.10 equiv), NaCNBH 3 (10 g, 2.00 equiv.), ethanol (200 mL) were placed in a 500-mL round-bottom flask. The resulting solution was stirred at 50 °C overnight. The resulting mixture was concentrated under vacuum. The crude product was purified by flash preparative HPLC. 9.4 g (39%) of tert-butyl 2-methyl-4-(morpholin-4-yl)piperidin-1-carboxylate was obtained as a colorless oil. LC-MS--729-1: (ES, m / z): 285 [M+H] + . 1 H-NMR-PH--729-1:(300MHz,CDCl 3 ,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),2.4 2-2.37(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).

[0463] Synthesis of 4-(2-methylpiperidin-4-yl)morpholine: tert-butyl 2-methyl-4-(morpholin-4-yl)piperidine-1-carboxylate (5 g, 17.58 mmol, 1.00 equiv) and hydrogen chloride / dioxane (50 mL) were placed in a 250-mL round-bottom flask. The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with MeCN and basified with potassium carbonate. The mixture was filtered and the filtrate was concentrated. 3 g (93%) of 4-(2-methylpiperidin-4-yl)morpholine was obtained as a white solid. LC-MS--729-2: (ES, m / z): 185 [M+H] + .

[0464] Synthesis of N-[4-[2-methyl-4-(morpholine-4-yl)piperidin-1-yl]-3-nitrophenyl] benzyl carbamate, 4-(2-methylpiperidin-4-yl)morpholine (3g, 16.28mmol, 1.00 equivalent), N-(4-fluoro-3-nitrophenyl) benzyl carbamate (5.6g, 19.29mmol, 1.20 equivalent), potassium carbonate (6.75g, 48.91mmol, 3.00 equivalent), MeCN (60mL) were placed in a 250-mL round-bottom flask. The resulting solution was stirred at 90 ° C overnight. The solid was collected by filtration. The resulting mixture was concentrated under vacuum and applied to a silica gel column and eluted with ethyl acetate / petroleum ether (75:25). The crude product was purified by fast preparative HPLC, wherein MeCN: 0.1% TFA / H 2 O=20 / 80 increased to MeCN:0.1% TFA / H in 12 min 2 O = 45 / 55. 1.5 g (21%) of benzyl N-[4-[2-methyl-4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl]carbamate was obtained as a yellow solid. LC-MS--729-3: (ES, m / z): 455 [M+H] + . 1 H-NMR-PH--729-3:(300MHz,d 6 -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).

[0465] Synthesis of benzyl N-[3-amino-4-[2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl]carbamate: benzyl N-[4-[2-methyl-4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl]carbamate (1.2 g, 2.64 mmol, 1.00 equiv), Zn (1.0 g, 15.38 mmol, 6.00 equiv), NH 4 Cl (1.7 g, 31.78 mmol, 12.00 equiv.), MeOH (15 mL) were placed in a 100-mL round-bottom flask. The resulting solution was stirred at room temperature for 1 hour. The solid was collected by filtration. The filtrate was concentrated under vacuum. The residue was applied to a silica gel column and eluted with dichloromethane / methanol (15:1). 0.84 g (75%) of N-[3-amino-4-[2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl]carbamic acid benzyl ester was obtained as a brown solid. LC-MS--729-4: (ES, m / z): 425 [M+H] + .

[0466] Synthesis of benzyl N-(3-[[(tert-butyloxy)carbonyl]amino]-4-[2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl)carbamate: benzyl N-[3-amino-4-[2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl]carbamate (0.5 g, 3.53 mmol, 1.00 equiv), Boc 2 O (0.38 g, 5.28 mmol, 1.50 equiv.), DIEA (0.38 g, 8.84 mmol, 2.50 equiv.), tetrahydrofuran (15 mL) were placed in a 250-mL round-bottom flask. The resulting solution was stirred at 75 ° C overnight. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column and eluted with 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)benzyl carbamate was obtained as a light yellow solid. LC-MS--729-5: (ES, m / z): 252 [M+H] + . 1 H-NMR-PH--729-5:(300MHz,d 6-DMSO,ppm): δ9.69(s,1H),8.19(s,1H),8.05(s,1H),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).

[0467] Synthesis of tert-butyl N-[5-amino-2-[2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl]carbamate: Benzyl N-(3-[[(tert-butyloxy)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 molten-water bath containing H 2 In a 250-mL round-bottom flask purged and maintained with an inert atmosphere. The resulting solution was stirred at 25°C for 3 hours. The mixture was concentrated under vacuum. 381 mg (crude) of tert-butyl N-[5-amino-2-[2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl]carbamate was obtained as a colorless oil. LC-MS--729-6: (ES, m / z): 391 [M+H] + .

[0468] Synthesis of tert-butyl N-[5-[(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazine-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 (300 mg, 1.54 mmol, 1 equivalent), 3,5-dibromo-1-methyl-1,2-dihydropyrazine-2-one (250 mg, 1.87 mmol, 1.21 equivalents), DIEA (250 mg, 3.87 mmol, 2.52 equivalents), i-PrOH (10 mL) were placed in a 100-mL round-bottom flask. The resulting solution was stirred at 80 ° C overnight. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate. 265 mg (59.73%) of tert-butyl 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 was obtained as a yellow solid. LC-MS--729-7: (ES, m / z): 577 [M+H] + . 1 H-NMR-PH--729-7:(300MHz,d 6 -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),3.65-3.5 5(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).

[0469] 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: tert-butyl 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 (200 mg, 0.31 mmol, 1 eq.), 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 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 light yellow solid. LC-MS--729-8: (ES, m / z): 477 [M+H] + .

[0470] 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]]dodeca-2(6),7-diene-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 equiv), (2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-[(oxan-2-yloxy)methyl]pyridin-4-yl)boronic acid (147 mg, 0.33 mmol, 1.00 equiv), Pd(dppf)Cl 2 (30 mg, 0.03 mmol, 0.10 equiv), K 2 CO 3 (116 mg, 0.84 mmol, 2.50 equiv), dioxane (5 mL, unlimited mmol, unlimited equiv), H 2O (0.5mL) was placed in a 25-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere. The resulting solution was stirred at 90°C for 40 minutes. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. And purified by fast preparative HPLC. 210mg (79.12%) of 10-(4-[6-[(3-aminophenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]-3-[(oxacyclohexane-2-yloxy)methyl]pyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one was obtained as a solid. LC-MS--729-9: (ES, m / z): 792[M+H] + .

[0471] 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]]dodeca-2(6),7-diene-9-one: 10-(4-[6-[(3-aminophenyl)amino]-4-methyl-5-oxo- 4,5-dihydropyrazine-2-yl]-3-[(oxacyclohexane-2-yloxy)methyl]pyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one (200 mg, 0.38 mmol, 1.00 equiv), 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 basified with aqueous sodium bicarbonate solution. The solid was filtered out 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]]dodeca-2(6),7-dien-9-one was obtained as a colorless oil. LC-MS--729-10: (ES, m / z): 708 [M+H] + .

[0472] Synthesis of N-(3-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-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)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]12-2(6),7-diene-9-one (100 mg, 0.19 mmol, 1.00 equivalent), prop-2-enoic 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), 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 preparative HPLC. 19.7 mg (18%) of N-(3-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-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 an off-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).

[0473] Example 13: Preparation of (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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)pyrrolidin-1-yl)phenyl)acrylamide

[0474] Synthesis of benzyl N-[4-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-3-nitrophenyl]carbamate as a yellow solid: (3R)-N,N-dimethylpyrrolidin-3-amine dihydrochloride (5 g, 26.72 mmol, 1 eq.), benzyl N-(4-fluoro-3-nitrophenyl)carbamate (9.3 g, 32.07 mmol, 1.20 eq.), TEA (10.8 g, 106.89 mmol, 4.00 eq.), and DMF (80 mL) were placed in a 250-mL round-bottom flask. The resulting solution was stirred at 100 °C overnight. 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 2x200 ml of ethyl acetate. The organic mixture was washed with 2x200 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 benzyl N-[4-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-3-nitrophenyl]carbamate was obtained as a yellow solid. LC-MS--729-C-1: (ES, m / z): 385 [M+H] + . 1 H-NMR-PH--729-C-1:(300MHz,d 6 -DMSO,ppm): δ9.78(s,1H),7.96(s,1H),7.52-7.37(m,6H),7.06(d,J=9.3Hz,1H),5.15(s,2 H),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).

[0475] Synthesis of benzyl N-[3-amino-4-[3-(dimethylamino)pyrrolidin-1-yl]phenyl]carbamate: benzyl N-[4-[3-(dimethylamino)pyrrolidin-1-yl]-3-nitrophenyl]carbamate (5 g, 13.01 mmol, 1 equivalent), zinc (5.1 g, 78.04 mmol, 6.00 equivalent), NH 4 Cl (8.3 g, 156.07 mmol, 12.00 equiv.) 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]carbamic acid benzyl ester was obtained as a gray solid. LC-MS--729-C-2: (ES, m / z): 365 [M+H] + .

[0476] Synthesis of benzyl N-(3-[[(tert-butoxy)carbonyl]amino]-4-[3-(dimethylamino)pyrrolidin-1-yl]phenyl)carbamate: benzyl N-[3-amino-4-[3-(dimethylamino)pyrrolidin-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), THF (50 mL) were placed in a 250-mL round-bottom flask. The resulting solution was stirred at 75 ° C overnight. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (50:50). 2.6 g (68%) of benzyl N-(3-[[(tert-butoxy)carbonyl]amino]-4-[3-(dimethylamino)pyrrolidin-1-yl]phenyl)carbamate was obtained 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).

[0477] Synthesis of tert-butyl N-[5-amino-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl]carbamate: Benzyl N-(3-[[(tert-butyloxy)carbonyl]amino]-4-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl)carbamate (2 g, 0.44 mmol, 1 equivalent), Pd / C (200 mg), and MeOH (50 mL) were placed in a molten-water mixture containing H 2 Inert atmosphere was purged and maintained in a 250-mL round-bottom flask. The resulting solution was stirred at room temperature for 2 hours. The solid was filtered out. The filtrate was concentrated under vacuum. The resulting mixture was concentrated. 1.15 g of tert-butyl N-[5-amino-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl]carbamate was obtained as a brown oil. LC-MS--729-C-4: (ES, m / z): 321 [M+H] + .

[0478] Synthesis of tert-butyl 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 N-[5-amino-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl]carbamate (1 g, 1 eq), 3,5-dibromo-1-methyl-1,2-dihydropyrazin-2-one (1 g, 1.20 eq), DIEA (1 g, 2.49 eq), i-PrOH (10 mL) were placed in a 250-mL round-bottom flask. The resulting solution was stirred at 80 ° C overnight. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. The residue was applied to a silica gel column and eluted with EA / PE (50:50). 1 g (60.62%) of tert-butyl N-[5-[(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino]-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl]carbamate was obtained as a yellow solid. LC-MS--729-C-5: (ES, m / z): 507 [M+H] + .

[0479] Synthesis of 3-([3-amino-4-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl]amino)-5-bromo-1-methyl-1,2-dihydropyrazin-2-one: tert-Butyl N-[5-[(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino]-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl]carbamate (1 g, 0.39 mmol, 1 eq.), 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 concentrated. 750 mg (93.43%) of 3-([3-amino-4-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl]amino)-5-bromo-1-methyl-1,2-dihydropyrazin-2-one was obtained as a light yellow solid. LC-MS--729-C-6: (ES, m / z): 407 [M+H] + .

[0480] 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 eq), prop-2-enoic acid (127.2 mg, 2.36 mmol, 1.2 eq), HATU (672 mg, 2.36 mmol, 1.2 eq), NMM (596 mg, 7.86 mmol, 4.0 eq), 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 preparative HPLC. 307 mg (45.25%) 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 was obtained as a light yellow solid. LC-MS--729-C-1: (ES, m / z): 461 [M+H] + .

[0481] Synthesis of N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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)pyrrolidin-1-yl)phenyl)acrylamide: N-[5-[(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazine -2-yl)amino]-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl]prop-2-enamide (50 mg, 0.11 mmol, 1 equiv), (2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-(hydroxymethyl)pyridin-4-yl)boronic acid (50.0 mg, 0.14 mmol, 1.3 equiv), Pd(dppf)Cl 2 (9.3 mg, 0.01 mmol, 0.1 eq), K 2 CO 3 (37.4 mg, 0.27 mmol, 2.5 equiv), dioxane (5 mL), H 2O (0.5mL) was placed in a 25-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere. The resulting solution was stirred at 90°C for 1 hour. The reaction mixture was cooled to room temperature. The solid was filtered out. The filtrate was concentrated. The crude product was purified by preparative HPLC. 14mg (18.67%) 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]pyrazine-2-yl)-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxo-3,4-dihydropyrazine-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)acrylamide was obtained as a white solid. LC-MS--729-C-0: (ES, m / z): 692[M+H] + . 1 H-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).

[0482] Example 14: Preparation of N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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

[0483] Synthesis of tert-butyl 3-(4-amino-2-nitrophenyl)-5,6-dihydro-2H-pyridine-1-carboxylate: tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (8.55 g, 27.647 mmol, 1.20 equivalents), 4-bromo-3-nitroaniline (5.00 g, 23.039 mmol, 1.00 equivalents), Pd(dppf)Cl 2 CH 2 Cl 2 (1.88 g, 2.304 mmol, 0.10 equiv), K 2 CO 3 (6.37 g, 46.091 mmol, 2.00 equiv), dioxane (80.00 mL), H 2 O (20.00 mL) was placed in a 500-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere. The resulting solution was stirred at 100°C for 2 hours. The solid was filtered off. The combined organic layer was concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (60:40). 7 g (95.14%) of tert-butyl 3-(4-amino-2-nitrophenyl)-5,6-dihydro-2H-pyridine-1-carboxylate was obtained as a white solid. LC-MS--751-1: (ES, m / z): 320 [M+H] + .

[0484] Synthesis of tert-butyl 3-(4-[[(benzyloxy)carbonyl]amino]-2-nitrophenyl)-5,6-dihydro-2H-pyridine-1-carboxylate: tert-butyl 3-(4-amino-2-nitrophenyl)-5,6-dihydro-2H-pyridine-1-carboxylate (7.00 g, 21.919 mmol, 1.00 equiv), Na 2 CO 3 (4.65 g, 43.838 mmol, 2.00 equiv) and DCM (50.00 mL) were placed in a 250-mL three-necked round-bottom flask. Then, H 2 O (10.00mL). To the mixture was added benzyl chloroformate (4.49 g, 26.303 mmol, 1.20 equiv). The resulting solution was stirred at room temperature overnight. The reaction was then quenched by adding water. The mixture was dried over anhydrous sodium sulfate and concentrated. 9 g of tert-butyl 3-(4-[[(benzyloxy)carbonyl]amino]-2-nitrophenyl)-5,6-dihydro-2H-pyridine-1-carboxylate was obtained as a light yellow oil. LC-MS--751-2: (ES, m / z): 454 [M+H] + .

[0485] Synthesis of tert-butyl 3-(2-amino-4-[[(benzyloxy)carbonyl]amino]phenyl)-5,6-dihydro-2H-pyridine-1-carboxylate: tert-butyl 3-(4-[[(benzyloxy)carbonyl]amino]-2-nitrophenyl)-5,6-dihydro-2H-pyridine-1-carboxylate (5.00 g, 11.025 mmol, 1.00 equiv), Fe (3.08 g, 55.127 mmol, 5.00 equiv), CH 3 COOH (20.00 mL), H 2 O (2.00 mL) was 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. NaHCO 3 The pH value of the solution was adjusted to 7. 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 and eluted with ethyl acetate / petroleum ether (60:40). 4 g (85.66%) of tert-butyl 3-(2-amino-4-[[(benzyloxy)carbonyl]amino]phenyl)-5,6-dihydro-2H-pyridine-1-carboxylate was obtained as a yellow solid. LC-MS--751-3: (ES, m / z): 424 [M+H] + . 1 H NMR--751-3:(300MHz,DMSO-d 6 ,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),5.7 8-5.70(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).

[0486] Synthesis of tert-butyl 3-(4-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]phenyl)-5,6-dihydro-2H-pyridine-1-carboxylate: tert-butyl 3-(2-amino-4-[[(benzyloxy)carbonyl]amino]phenyl)-5,6-dihydro-2H-pyridine-1-carboxylate (4.00 g, 9.445 mmol, 1.00 equiv), di-tert-butyl dicarbonate (4.12 g, 18.890 mmol, 2.00 equiv), K 2 CO 3 (2.61 g, 18.885 mmol, 2.00 equiv), dioxane (80.00 mL), H 2O (40.00mL) was placed in a 250-mL round-bottom flask. The resulting solution was stirred at room temperature overnight. 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 and eluted with ethyl acetate / petroleum ether (40:60). 5g (101.10%) of tert-butyl 3-(4-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]phenyl)-5,6-dihydro-2H-pyridine-1-carboxylate was obtained as a white solid. LC-MS--751-4: (ES, m / z): 524[M+H] + . 1 H NMR--751-4:(300MHz,DMSO-d 6 ,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),7.0 7(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).

[0487] Synthesis of tert-butyl 3-[4-amino-2-[(tert-butoxycarbonyl)amino]phenyl]piperidine-1-carboxylate: tert-butyl 3-(4-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]phenyl)-5,6-dihydro-2H-pyridine-carboxylate (5.00 g, 9.549 mmol, 1.00 equiv), Pd / C (500.00 mg), MeOH (100 mL), EA (50.00 mL) were placed in a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen. The resulting solution was stirred at room temperature overnight. 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-carboxylate was obtained as a colorless oil. LC-MS--751-5: (ES,m / z): 392[M+H] + .

[0488] Synthesis of tert-butyl 3-[4-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-[(tert-butoxycarbonyl)amino]phenyl]piperidine-1-carboxylate: tert-butyl 3-[4-amino-2-[(tert-butoxycarbonyl)amino]phenyl]piperidine-1-carboxylate (3.40 g, 8.684 mmol, 1.00 equiv), 3,5-dibromo-1-methylpyrazin-2-one (2.56 g, 9.553 mmol, 1.1 equiv), i-PrOH (50.00 mL), DIEA (2.24 g, 17.369 mmol, 2.0 equiv) were placed in a 250-mL round-bottom flask. The resulting solution was stirred at 90 ° C overnight. The resulting mixture was concentrated. The residue was applied to a silica gel column and eluted with 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-carboxylate were obtained as a light yellow solid.

[0489] LC-MS--751-6: (ES,m / z): 578[M+H] + .

[0490] Synthesis of 3-[[3-amino-4-(piperidin-3-yl)phenyl]amino]-5-bromo-1-methylpyrazin-2-one: tert-butyl 3-[4-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-[(tert-butoxycarbonyl)amino]phenyl]piperidine-1-carboxylate (4.00 g) was placed in a 250-mL round-bottom flask. HCl(g) / MeOH (80.00 mL) was added to the above. The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated. 2.9 g of 3-[[3-amino-4-(piperidin-3-yl)phenyl]amino]-5-bromo-1-methylpyrazin-2-one was obtained as a white solid. LC-MS--751-7: (ES, m / z): 378[M+H] + .

[0491] Synthesis of tert-butyl 3-[2-amino-4-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]phenyl]piperidine-1-carboxylate: 3-[[3-amino-4-(piperidin-3-yl)phenyl]amino]-5-bromo-1-methylpyrazin-2-one (2.90 g, 7.666 mmol, 1.00 equiv), Boc 2O (1.84 g, 8.431 mmol, 1.10 equiv), TEA (1.55 g, 15.333 mmol, 2.00 equiv), DCM (50 ml) were placed in a 250-mL round-bottom flask. The resulting solution was stirred at room temperature overnight. 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-carboxylate was obtained as a white solid. LC-MS--751-8: (ES, m / z): 478 [M+H] + . 1 H NMR--751-8:(300MHz,DMSO-d 6 ,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,2H),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).

[0492] Synthesis of tert-butyl 3-[4-[(6-bromo-4-methyl-3-oxopyrazine-2-yl)amino]-2-(prop-2-enamide)phenyl]piperidine-1-carboxylate: tert-butyl 3-[2-amino-4-[(6-bromo-4-methyl-3-oxopyrazine-2-yl)amino]phenyl]piperidine-1-carboxylate (500.00 mg, 1.045 mmol, 1.00 equiv), acryloyl chloride (141.90 mg, 1.568 mmol, 1.5 equiv), NMM (211.43 mg, 2.090 mmol, 2.00 equiv), 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 and eluted with ethyl acetate / petroleum ether (70:30). 300 mg (53.91%) of tert-butyl 3-[4-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-(prop-2-enamido)phenyl]piperidine-1-carboxylate was obtained as a yellow solid. LC-MS--751-9: (ES, m / z): 532 [M+H] + . 1 HNMR--751-9:(300MHz,DMSO-d 6, 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).

[0493] Synthesis of tert-butyl 3-(4-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-methylpyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-(prop-2-enamido)phenyl)piperidine-1-carboxylate: 3-[4-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]- tert-Butyl 2-(prop-2-enylamido)phenyl]piperidine-1-carboxylate (300.00 mg, 0.563 mmol, 1.00 equiv), 2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-methylpyridin-4-ylboronic acid (248.46 mg, 0.732 mmol, 1.30 equiv), Pd(dppf)Cl 2 CH 2 Cl 2 (46.01 mg, 0.056 mmol, 0.10 equiv), K 2 CO 3 (155.51 mg, 1.127 mmol, 2.00 equiv), DME (10.00 mL), H 2 O (2.00mL) was placed in a 40-mL microwave tube maintained with 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 and eluted with ethyl acetate / petroleum ether (40:60). 240mg (57.03%) of 3-(4-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-10-yl]-3-methylpyridin-4-yl)-4-methyl-3-oxopyrazine-2-yl]amino]-2-(prop-2-enamide)phenyl)piperidine-1-carboxylic acid tert-butyl ester was obtained as a yellow solid. LC-MS--751-10: (ES, m / z): 747[M+H]+ .

[0494] Synthesis of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-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-diazatricyclo[6.4.0.0^[2,6]]dodeca-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 Azatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-10-yl]-3-methylpyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-(prop-2-enamide)phenyl)piperidine-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. Then, NaHCO 3 The reaction was quenched. 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 preparative HPLC. 80 mg (61.59%) of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-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-d 6, 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=16.6Hz,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).

[0495] Example 15: Preparation of N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-1-carbonyl)phenyl)acrylamide

[0496] Synthesis of methyl 2-amino-4-nitrobenzoate. 2-amino-4-nitrobenzoic acid (2.00 g), SOCl 2 (4.00mL), MeOH (20.00mL) 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 obtained as a yellow solid. LC-MS--752-1: (ES, m / z): 197 [M+H] + . 1 H NMR--752-1:(300MHz,CDCl 3 , ppm): δ8.02(d,J=8.8Hz,1H),7.53(d,J=2.2Hz,1H),7.42(dd,J=8.8,2.2Hz,1H),6.05(brs,2H),3.94(s,3H).

[0497] Synthesis of 2-[bis(tert-butoxycarbonyl)amino]-4-nitrobenzoic acid methyl ester: 2-amino-4-nitrobenzoic acid methyl ester (1.00 g, 5.098 mmol, 1.00 equivalent), Boc2 O (3.34 g, 15.293 mmol, 3.00 equiv), TEA (1.03 g, 10.196 mmol, 2.00 equiv), DMAP (0.06 g, 0.510 mmol, 0.10 equiv), 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 obtained as a yellow solid. LC-MS--752-2: (ES, m / z): 397 [M+H] + . 1 H NMR--752-2:(300MHz,CDCl 3 , 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).

[0498] 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), H 2 O (4.00 mL) and THF (20.00 mL) were placed in a 100-mL round-bottom flask. The resulting solution was stirred at room temperature overnight. The reaction was then quenched by adding 1N aqueous hydrochloric acid to the reaction solution and extracted with ethyl acetate. The organic layer was washed with anhydrous Na 2 SO 4 The residue was dried and concentrated to obtain 1 g (57.59%) of 2-[bis(tert-butoxycarbonyl)amino]-4-nitrobenzoic acid as a yellow solid.

[0499] LC-MS--752-3: (ES,m / z): 383[M+H] + .

[0500] Synthesis of tert-butyl N-(tert-butoxycarbonyl)-N-[2-(4-methylpiperazine-1-carbonyl)-5-nitrophenyl]carbamate-: 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), 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 and eluted with ethyl acetate / petroleum ether (100: 1). 500 mg (41.16%) of tert-butyl N-(tert-butoxycarbonyl)-N-[2-(4-methylpiperazine-1-carbonyl)-5-nitrophenyl]carbamate was obtained as a light yellow solid. LC-MS--752-4: (ES, m / z): 465 [M+H] + .

[0501] Synthesis of tert-butyl N-[5-amino-2-(4-methylpiperazine-1-carbonyl)phenyl]-N-(tert-butoxycarbonyl)carbamate: tert-butyl N-(tert-butoxycarbonyl)-N-[2-(4-methylpiperazine-1-carbonyl)-5-nitrophenyl]carbamate (500.00 mg), MeOH (20.00 ml), and Pd / C (500.00 mg) were placed in a molten-water mixture with H 2 Inert atmosphere was purged and maintained in a 100-mL round-bottom flask. The resulting solution was stirred at room temperature for 6 hours. The solid was collected by filtration. The combined organic layer was concentrated. 400 mg of tert-butyl N-[5-amino-2-(4-methylpiperazine-1-carbonyl)phenyl]-N-(tert-butoxycarbonyl)carbamate was obtained as a colorless oil. LC-MS--752-5: (ES, m / z): 435 [M+H] + .

[0502] Synthesis of tert-butyl N-[5-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-(4-methylpiperazine-1-carbonyl)phenyl]-N-(tert-butoxycarbonyl)carbamate: tert-butyl N-[5-amino-2-(4-methylpiperazine-1-carbonyl)phenyl]-N-(tert-butoxycarbonyl)carbamate (400.00 mg, 0.921 mmol, 1.00 equiv), 3,5-dibromo-1-methylpyrazin-2-one (369.92 mg, 1.381 mmol, 1.5 equiv), Pd 2 (dba) 3(168.59 mg, 0.184 mmol, 0.2 eq.), XantPhos (213.05 mg, 0.368 mmol, 0.4 eq.), Cs 2 CO 3 (599.85 mg, 1.841 mmol, 2.0 equiv.), toluene (25.00 mL) were placed in a 250-mL round-bottom flask purged and maintained with a nitrogen inert 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 and eluted with ethyl acetate / petroleum ether (70:30). 200 mg (34.96%) of N-[5-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-(4-methylpiperazine-1-carbonyl)phenyl]-N-(tert-butoxycarbonyl)carbamic acid tert-butyl ester was obtained as a light yellow solid. LC-MS--752-6: (ES, m / z): 621 [M+H] + .

[0503] Synthesis of 3-[[3-amino-4-(4-methylpiperazine-1-carbonyl)phenyl]amino]-5-bromo-1-methylpyrazin-2-one: N-[5-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-(4-methylpiperazine-1-carbonyl)phenyl]-N-(tert-butoxycarbonyl)carbamic acid tert-butyl ester (200.00 mg) and HCl (gas) in 1,4-dioxane (10.00 mL) 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-methylpiperazine-1-carbonyl)phenyl]amino]-5-bromo-1-methylpyrazin-2-one was obtained as a white solid. LC-MS--752-7: (ES, m / z): 421 [M+H] + .

[0504] Synthesis of N-[5-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-(4-methylpiperazine-1-carbonyl)phenyl]prop-2-enamide: 3-[[3-amino-4-(4-methylpiperazine-1-carbonyl)phenyl]amino]-5-bromo-1-methylpyrazin-2-one (120.00 mg, 0.285 mmol, 1.00 equiv), acryloyl chloride (28.36 mg, 0.313 mmol, 1.10 equiv), NMM (57.62 mg, 0.570 mmol, 2.00 equiv), 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 concentrated. The crude product was purified by flash preparative HPLC 0.1% NH 3 .H 2O:MeCN = 30% increased to 0.1% NH in 9 minutes 3 .H 2 O: MeCN = 58% for purification. 80 mg (59.09%) of N-[5-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-(4-methylpiperazine-1-carbonyl)phenyl]prop-2-enamide was obtained as a white solid. LC-MS--752-8: (ES, m / z): 475 [M+H] + .

[0505] Synthesis-752-0: N-[5-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-(4-methylpiperazine-1-carbonyl)phenyl]prop-2-enamide (80.00 mg, 0.168 mmol, 1.00 equiv), 2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-diene-10-yl]-3-methylpyridin-4-ylboronic acid (73.00 mg, 0.219 mmol, 1.30 equiv), Pd(dppf)Cl 2 CH 2 Cl 2 (13.74 mg, 0.017 mmol, 0.10 equiv), K 2 CO 3 (46.52 mg, 0.337 mmol, 2.00 equiv), DME (8.00 mL), H 2 O (2.00 mL) was placed in an 8-mL vial purged and maintained with a nitrogen inert atmosphere. The resulting solution was stirred at 90° C. for 1 hour. The crude product was purified by preparative HPLC. 20 mg (17.23%) of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-10-yl]-3-methylpyridin-4-yl)-4-methyl-3-oxopyrazine-2-yl]amino]-2-(4-methylpiperazine-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-d 6,ppm): δ9.76(s,1H),9.52(s,1H),8.48(s,1H),8.34(d,J=5.0Hz,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=1 7.1,1.8Hz,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).

[0506] Example 16: Preparation of N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-morpholinopropan-2-yl)phenyl)acrylamide

[0507] Synthesis of 5-bromo-1-methyl-3-([4-[2-methyl-1-(morpholin-4-yl)propan-2-yl]-3-nitrophenyl]amino)pyrazin-2-one: 4-[2-methyl-1-(morpholin-4-yl)propan-2-yl]-3-nitroaniline (400.00 mg, 1.432 mmol, 1.00 equiv), 3,5-dibromo-1-methylpyrazin-2-one (498.72 mg, 1.862 mmol, 1.30 equiv), Pd 2 (dba) 3 (131.13 mg, 0.143 mmol, 0.10 equiv), XantPhos (165.71 mg, 0.286 mmol, 0.20 equiv), Cs 2 CO 3(933.11 mg, 2.864 mmol, 2.00 equiv), dioxane (20.00 mL) were placed in a 100-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere. The resulting solution was stirred at 100 ° C for 4 hours. The solid was collected by filtration. The combined organic layer was 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)propan-2-yl]-3-nitrophenyl]amino)pyrazin-2-one was obtained as a brown solid. LC-MS--753-1: (ES, m / z): 466 [M+H] + . 1 H NMR--753-1:(300MHz,DMSO-d 6 , 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).

[0508] Synthesis of 3-([3-amino-4-[2-methyl-1-(morpholin-4-yl)propan-2-yl]phenyl]amino)-5-bromo-1-methylpyrazin-2-one: 5-bromo-1-methyl-3-([4-[2-methyl-1-(morpholin-4-yl)propan-2-yl]-3-nitrophenyl]amino)pyrazin-2-one (350.00 mg, 0.751 mmol, 1.00 equiv), CH 3 COOH (1352.13 mg, 22.516 mmol, 30.00 equiv), Zn (736.37 mg, 11.258 mmol, 15.00 equiv), 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 layer was 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)propan-2-yl]phenyl]amino)-5-bromo-1-methylpyrazin-2-one was obtained as a brown oil. LC-MS--753-2: (ES, m / z): 436 [M+H] + .

[0509] Synthesis of N-[5-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-[2-methyl-1-(morpholin-4-yl)propan-2-yl]phenyl]propan-2-enamide: 3-([3-amino-4-[2-methyl-1-(morpholin-4-yl)propan-2-yl]phenyl]amino)-5-bromo-1-methylpyrazin-2-one (300.00 mg, 0.688 mmol, 1.00 equiv), acryloyl chloride (74.67 mg, 0.825 mmol, 1.20 equiv), NMM (139.08 mg, 1.375 mmol, 2.00 equiv), 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 concentrated. The crude product was purified by flash preparative HPLC 0.1% NH 4 HCO 3 :MeCN = 30% increased to 0.1% NH in 9 minutes 4 HCO 3 :MeCN=70% for purification. 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 obtained as a white solid. LC-MS--753-3: (ES, m / z): 490 [M+H] + . 1 H NMR--753-3:(300MHz,DMSO-d 6 ,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).

[0510] Synthesis of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-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 equiv), 2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-methylpyridin-4-ylboronic acid (193.67 mg, 0.571 mmol, 1.40 equiv), Pd(dppf)Cl 2 CH 2 Cl 2 (33.30 mg, 0.041 mmol, 0.10 equiv), K 2 CO 3 (112.73 mg, 0.816 mmol, 2.00 equiv), DME (10.00 mL), H 2 O (2.00 mL) was placed in a 40-mL microwave tube maintained with a nitrogen inert atmosphere. The resulting solution was stirred at 95 ° C for 2 hours. The crude product was purified by preparative HPLC. 150 mg (52.18%) of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-10-yl]-3-methylpyridin-4-yl)-4-methyl-3-oxopyrazine-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),3.57-3.47(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).

[0511] Example 17: Preparation of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-dien-10-yl]-3-methylpyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-[(2S)-2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl)prop-2-enamide

[0512] Synthesis of (2S)-2-methyl-4-(morpholin-4-yl)piperidine-1-carboxylic acid tert-butyl ester: In a 250 mL round-bottom flask, (2S)-2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (4.50 g, 21.099 mmol, 1.00 equiv), THF (70 mL), AcOH (1 mL), morpholine (3.68 g, 42.240 mmol, 2.00 equiv) were placed and stirred for 10 minutes. NaBH(AcO) was then added in portions at room temperature. 3 (8.94 g, 42.199 mmol, 2.00 equiv). The resulting solution was stirred at 30 ° C in an oil bath for 14 hours. The reaction was then quenched by adding 3 mL of MeOH. The resulting mixture was concentrated. The residue was applied to a silica gel column and eluted with PE / EA (1:4). 4.5 g (74.99%) of (2S)-2-methyl-4-(morpholin-4-yl)piperidine-1-carboxylic acid tert-butyl ester was obtained as a white solid. LCMS-1 (ES, m / z): M+1:285

[0513] Synthesis of 4-[(2S)-2-methylpiperidin-4-yl]morpholine: In a 100 mL round-bottom flask, place (2S)-2-methyl-4-(morpholin-4-yl)piperidine-1-carboxylic acid tert-butyl ester (3.50 g) and HCl (40 mL, 2 M) in dioxane. The resulting solution was stirred at room temperature for 14 hours. The resulting mixture was concentrated. 2.3 g of 4-[(2S)-2-methylpiperidin-4-yl]morpholine was obtained as a white solid. LCMS-2 (ES, m / z): M+1: 185

[0514] Synthesis of 5-bromo-1-methyl-3-([4-[(2S)-2-methyl-4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl]amino)pyrazin-2-one: 5-bromo-3-[(4-fluoro-3-nitrophenyl)amino]-1-methylpyrazin-2-one (3.91 g, 11.396 mmol, 1.00 equiv), 4-[(2S)-2-methylpiperidin-4-yl]morpholine (2.10 g, 11.396 mmol, 1.00 equiv), NMP (50.00 ml), DIEA (4.42 g, 34.199 mmol, 3.00 equiv) were placed in a 250 mL round-bottom flask. The resulting solution was stirred at 110° C. in an oil bath for 72 hours. The resulting solution was washed with 250 mL of H 2 The resulting solution was extracted with 3x50 mL of dichloromethane. The resulting mixture was washed with 3x20 mL of H 2 O. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column and eluted with dichloromethane / methanol (10:1). 2.6 g (31.48%) of 5-bromo-1-methyl-3-([4-[(2S)-2-methyl-4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl]amino)pyrazin-2-one was obtained as a brown solid. LCMS-3 (ES, m / z): M+1:507

[0515] Synthesis of 4-methyl-6-([4-[(2S)-2-methyl-4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl]amino)-5-oxopyrazin-2-ylboronic acid: In a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 5-bromo-1-methyl-3-([4-[(2S)-2-methyl-4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl]amino)pyrazin-2-one (2.60 g, 5.124 mmol, 1.00 equiv) was placed, bis(pinacolato)diboron (2.60 g, 10.239 mmol, 2.00 equiv) and XPhos PdG3 (216.87 mg, 0.256 mmol, 0.05 equiv), KOAc (1.01 g, 10.291 mmol, 2.01 equiv), THF (30.00 mL, 0.416 mmol, 0.08 equiv). The resulting solution was stirred at 70 ° C in an oil bath for 14 hours. The solid was filtered off. The resulting mixture was concentrated. 5 g (crude) of 4-methyl-6-([4-[(2S)-2-methyl-4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl]amino)-5-oxopyrazin-2-ylboronic acid was obtained as a brown solid. LCMS-4 (ES, m / z): M+1: 473

[0516] Synthesis of 4,4-dimethyl-10-[3-methyl-4-[4-methyl-6-([4-[(2S)-2-methyl-4-(oxan-4-yl)piperidin-1-yl]-3-nitrophenyl]amino)-5-oxopyrazin-2-yl]pyridin-2-yl]-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one: Into an 8-mL vial purged and maintained with an inert atmosphere of nitrogen was placed 4-methyl-6-([4-[ (2S)-2-methyl-4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl]amino)-5-oxopyrazin-2-ylboronic acid (450.00 mg, crude product), 10-(4-iodo-3-methylpyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one (100.00 mg, 0.237 mmol, 1.00 equivalent), Pd(dppf)Cl 2 (19.38 mg, 0.024 mmol, 0.10 equiv), THF (2.00 mL, infinite mmol, infinite equiv), H 2 O (0.50 mL, 0.028 mmol, 0.12 equiv), K 3 PO 4(201.54 mg, 0.949 mmol, 4.00 equiv). The resulting solution was stirred in an oil bath at 50 ° C for 14 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column and eluted with dichloromethane / methanol (10: 1). 120 mg (70.13%) of 4,4-dimethyl-10-[3-methyl-4-[4-methyl-6-([4-[(2S)-2-methyl-4-(oxacyclohexane-4-yl)piperidin-1-yl]-3-nitrophenyl]amino)-5-oxopyrazine-2-yl]pyridin-2-yl]-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one was obtained as a yellow solid. LCMS-1 (ES, m / z): M+1: 722

[0517] Synthesis of 10-[4-[6-([3-amino-4-[(2S)-2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl]amino)-4-methyl-5-oxopyrazin-2-yl]-3-methylpyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-diene-9-one: Place 4,4-dimethyl-10-[ 3-methyl-4-[4-methyl-6-([4-[(2S)-2-methyl-4-(oxan-4-yl)piperidin-1-yl]-3-nitrophenyl]amino)-5-oxopyrazin-2-yl]pyridin-2-yl]-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-diene-9-one (100.00 mg), THF (10.00 mL), and Pd / C (10.00 mg). H 2 (gas). The resulting solution was stirred at room temperature for 6 hours. The solid was filtered off. The residue was purified by preparative TLC with dichloromethane / methanol (10:1). 30 mg of 10-[4-[6-([3-amino-4-[(2S)-2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl]amino)-4-methyl-5-oxopyrazine-2-yl]-3-methylpyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one was obtained as a light yellow solid. LCMS-2 (ES, m / z): M+1:692

[0518] Synthesis of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-methylpyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-[(2S)-2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl)prop-2-enamide: Place 10-[4-[6-([3-amino-4-[(2S )-2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl]amino)-4-methyl-5-oxopyrazine-2-yl]-3-methylpyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one (25.00 mg, 0.036 mmol, 1.00 equiv), DCM (0.50 mL), DIEA (9.34 mg, 0.072 mmol, 2.00 equiv). Acryloyl chloride (4.91 mg, 0.054 mmol, 1.50 equiv) was then added dropwise with stirring at 0°C. The resulting solution was stirred in a water / ice bath at 0°C for 30 minutes. The reaction was then quenched by adding 0.1 mL of MeOH. The crude product was purified by preparative HPLC under the following conditions (Waters 2767): column, X Bridge Prep C18 OBD19*150mm 5um; mobile phase, A: 0.1% NH 3 -H 2 O / water; B: ACN; gradient: 37-52% B in 7.9 min; flow rate: 20 ml / min; detector, 220 nm. 7 mg (25.97%) of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-methylpyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-[(2S)-2-methyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl)prop-2-enamide were obtained as a white solid. LCMS-0 (ES, m / z): M+1: 746. H-NMR-0: (300 MHz, DMSO-d 6)δ9.20(d,J=9.9Hz,2H),9.05–8.94(m,1H),8.35(d,J=5.1Hz,1H),7.66(dt,J=10.1,5.4Hz,2H),7.41(s,1H),7.22(d,J=8 .7Hz,1H),6.65(dd,J=16.8,10.2Hz,1H),6.55(s,1H),6.25(dd,J=16.8,3.9Hz,1H),5.78(d,J=10.5Hz,1H),4.40–4.05(m, 3H),3.85(d,J=12.0Hz,1H),3.59(d,J=7.8Hz,7H),2.92(s,1H),2.80-2.75(m,1H),2.61–2.59(s,1H),2.43(s,2H),2.35–2 .25(m,4H),1.89(dd,J=29.1,12.0Hz,2H),1.70–1.50(m,1H),1.46–1.33(m,1H),1.23(s,6H),0.75(dd,J=6.3,2.1Hz,3H).

[0519] Example 18: Preparation of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-dien-10-yl]-3-methylpyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-[4-(morpholin-4-yl)piperidin-1-yl]phenyl)prop-2-enamide hydrochloride

[0520] Synthesis of 5-bromo-3-[(4-fluoro-3-nitrophenyl)amino]-1-methylpyrazin-2-one In a 250 mL round-bottom flask, 4-fluoro-3-nitroaniline (10.00 g, 64.055 mmol, 1.00 equiv), 3,5-dibromo-1-methylpyrazin-2-one (17.16 g, 64.052 mmol, 1.00 equiv) and NMP (30 ml) were placed. The resulting solution was stirred at 140 ° C in an oil bath for 1 hour. The resulting solution was diluted with 300 mL EA. The solid was collected by filtration. 13 g (59.15%) of 5-bromo-3-[(4-fluoro-3-nitrophenyl)amino]-1-methylpyrazin-2-one was obtained as a brown solid. LCMS-1 (ES, m / z): M+1: 343 / 345

[0521] Synthesis of 5-bromo-1-methyl-3-([4-[4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl]amino)pyrazin-2-one In a 50-mL round-bottom flask, 5-bromo-3-[(4-fluoro-3-nitrophenyl)amino]-1-methylpyrazin-2-one (1.00 g, 2.915 mmol, 1.00 equiv), 4-(piperidin-4-yl)morpholine (0.50 g, 2.915 mmol, 1.00 equiv), NMP (10.00 mL), DIEA (1.13 g, 8.743 mmol, 3.00 equiv) were placed. The resulting solution was stirred in an oil bath at 110° C. for 14 hours. The resulting solution was washed with 30 mL of H 2 The resulting solution was extracted with 3x10 mL of dichloromethane. The resulting mixture was washed with 3x5 of H 2 O. The resulting mixture was washed with 1x10 mL of NaCl aqueous solution and dried with sodium sulfate. The resulting mixture was concentrated. The residue was applied to a silica gel column and purified with dichloromethane / methanol (10:1). 800 mg (55.64%) of 5-bromo-1-methyl-3-([4-[4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl]amino)pyrazin-2-one was obtained as a brown solid. LCMS-2 (ES, m / z): M+1:493 / 495

[0522] Synthesis of 4-methyl-6-([4-[4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl]amino)-5-oxopyrazin-2-ylboronic acid Into a 50-mL round-bottom flask maintained with an inert atmosphere of nitrogen, were placed 5-bromo-1-methyl-3-([4-[4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl]amino)pyrazin-2-one (400.00 mg, 0.811 mmol, 1.00 equiv), bis(pinacolato)diboron (411.77 mg, 1.622 mmol, 2.00 equiv), 3G Xphos Pd (33.11 mg, 0.041 mmol, 0.05 equiv), KOAc (159.14 mg, 1.622 mmol, 2.00 equiv), and THF (10.00 mL). The resulting solution was stirred at 65 °C in an oil bath for 14 h. The solid was filtered off. The resulting mixture was concentrated. The resulting solution was washed with 1 mL of Et 2 O. The solid was collected by filtration. 250 mg (67.28%) of 4-methyl-6-([4-[4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl]amino)-5-oxopyrazin-2-ylboronic acid was obtained as an orange solid. LCMS-7-3 (ES, m / z): M+1: 459

[0523] Synthesis of 4,4-dimethyl-10-[3-methyl-4-[4-methyl-6-([4-[4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl]amino)-5-oxopyrazin-2-yl]pyridin-2-yl]-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one Into an 8-mL vial purged and maintained with an inert atmosphere of nitrogen was placed 4-methyl-6-([4-[4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl]amino)-5-oxopyrazin-2-yl]pyridin-2-yl]-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one. )piperidin-1-yl]-3-nitrophenyl]amino)-5-oxopyrazin-2-ylboronic acid (100.00 mg, 0.218 mmol, 1.00 equiv), 10-(4-iodo-3-methylpyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-diene-9-one (91.93 mg, 0.218 mmol, 1.00 equiv), Pd(dppf)Cl 2 (17.82 mg, 0.022 mmol, 0.10 equiv), K 3 PO 4 (138.95 mg, 0.655 mmol, 3.00 equiv), THF (0.80 mL), H 2 O (0.20mL). The resulting solution was stirred at 50 ° C in an oil bath for 14 hours. The residue was applied to a silica gel column and purified with dichloromethane / methanol (10: 1). 110mg (71.22%) of 4,4-dimethyl-10-[3-methyl-4-[4-methyl-6-([4-[4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl]amino)-5-oxopyrazine-2-yl]pyridin-2-yl]-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one was obtained as a brown solid. LCMS-4 (ES, m / z): M + 1: 708

[0524] Synthesis of 10-[4-[6-([3-amino-4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl]amino)-4-methyl-5-oxopyrazin-2-yl]-3-methylpyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one In a 50-mL round-bottom flask, 4,4-dimethyl-10-[3-methyl-4-[4-methyl-6-( [4-[4-(Morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl]amino)-5-oxopyrazin-2-yl]pyridin-2-yl]-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-diene-9-one (100.00 mg, 0.141 mmol, 1.00 equiv), Pd / C (15.94 mg, 0.042 mmol, 0.30 equiv), and THF (5.00 mL) were introduced into the above mixture. 2 (g). The resulting solution was stirred at room temperature for 14 hours. The solid was filtered off. The resulting mixture was concentrated. 70 mg (73.10%) of 10-[4-[6-([3-amino-4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl]amino)-4-methyl-5-oxopyrazin-2-yl]-3-methylpyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one was obtained as a brown solid. LCMS-5 (ES, m / z): M+1: 678

[0525] Synthesis of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-methylpyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-[4-(morpholin-4-yl)piperidin-1-yl]phenyl)prop-2-enamide hydrochloride In an 8-mL vial, 10-[4-[6-([3-amino-4-[4 -(morpholine-4-yl)piperidin-1-yl]phenyl]amino)-4-methyl-5-oxopyrazine-2-yl]-3-methylpyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one (60 mg, 0.089 mmol, 1.00 equiv), DCM (1.00 mL), TEA (17.91 mg, 0.177 mmol, 2.00 equiv). Acryloyl chloride (12.02 mg, 0.133 mmol, 1.50 equiv) was added at 0 ° C in a water / ice bath. The resulting solution was stirred at 0 ° C for 1 hour in a water / ice bath. The reaction was then quenched by adding 0.1 mL of MeOH. The resulting mixture was concentrated. The crude product was purified by preparative HPLC under the following conditions (Waters 2767): column, X Bridge Prep C18 OBD 19*150 mm5um; mobile phase, A: 0.1% HCl / water; B: ACN; gradient: 30-80% B in 7.9 min; flow rate: 20 ml / min; detector, 220 nm. 9 mg (13.23%) of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-methylpyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-[4-(morpholin-4-yl)piperidin-1-yl]phenyl)prop-2-enamide hydrochloride was obtained as a yellow solid. LCMS-0(ES,m / z):M+HCl+1:768H-NMR-0: 1 H NMR (300 MHz, DMSO-d 6)δ10.15(s,1H),9.22(s,1H),9.10(s,1H),8.72(s,1H),8.35(d,J=5.1Hz,1H),7.73–7.56(m,2H),7.4 1(s,1H),7.13(d,J=8.7Hz,1H),6.69–6.48(m,2H),6.34–6.24(m,1H),5.77(d,J=10.8Hz,1H),4.31-4 .12(s,3H),4.03(d,J=12.0Hz,2H),3.90–3.70(m,3H),3.58(s,3H),3.50–3.48(m,2H),3.23–3.02(m, 4H),2.70–2.52(m,5H),2.43(s,2H),2.30(s,3H),2.20-2.15(m,2H),2.00–1.85(m,2H),1.23(s,6H).

[0526] Example 19: Preparation of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-dien-10-yl]-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-[4-(morpholin-4-yl)piperidin-1-yl]phenyl)prop-2-enamide

[0527] Synthesis of 4,4-dimethyl-10-[4-[4-methyl-6-([4-[4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl]amino)-5-oxopyrazin-2-yl]-3-[(oxanyl-2-yloxy)methyl]pyridin-2-yl]-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one Into an 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 4-methyl-6-([4-[4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl]amino)-5-oxopyrazin-2-yl]-3-[(oxanyl-2-yloxy)methyl]pyridin-2-yl]-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one. )piperidin-1-yl]-3-nitrophenyl]amino)-5-oxopyrazin-2-ylboronic acid (100.00 mg, 0.218 mmol, 1.00 equiv), 10-[4-iodo-3-[(oxan-2-yloxy)methyl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one (113.77 mg, 0.218 mmol, 1.00 equiv), THF (4.00 mL), H 2 O (1.00 mL, 0.056 mmol, 0.25 equiv), Pd(dppf)Cl 2 (17.82 mg, 0.022 mmol, 0.10 equiv), K3 PO 4 (138.95 mg, 0.655 mmol, 3.00 equiv). The resulting solution was stirred at 50 ° C in an oil bath for 3 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column and eluted with dichloromethane / methanol (10: 1). 90 mg (51.05%) of 4,4-dimethyl-10-[4-[4-methyl-6-([4-[4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl]amino)-5-oxopyrazine-2-yl]-3-[(oxacyclohexane-2-yloxy)methyl]pyridin-2-yl]-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one was obtained as a brown solid. LCMS-1 (ES, m / z): M+1:808

[0528] Synthesis of 10-[4-[6-([3-amino-4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl]amino)-4-methyl-5-oxopyrazin-2-yl]-3-[(oxanyl-2-yloxy)methyl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one: Place 4,4-dimethyl in a 50-mL round-bottom flask. -10-[4-[4-methyl-6-([4-[4-(morpholin-4-yl)piperidin-1-yl]-3-nitrophenyl]amino)-5-oxopyrazin-2-yl]-3-[(oxanyl-2-yloxy)methyl]pyridin-2-yl]-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one (80.00 mg, 0.099 mmol, 1.00 equiv), PtO 2 (11.24 mg, 0.049 mmol, 0.50 equiv), THF (10.00 mL). H 2 (gas). The resulting solution was stirred at room temperature for 2 hours. The solid was filtered off. The resulting mixture was concentrated. The residue was applied to a silica gel column and eluted with dichloromethane / methanol (10:1). 50 mg (64.91%) of 10-[4-[6-([3-amino-4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl]amino)-4-methyl-5-oxopyrazine-2-yl]-3-[(oxacyclohexane-2-yloxy)methyl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one was obtained as a brown solid. LCMS-2 (ES, m / z): M+1:778

[0529] Synthesis of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-[(oxanyl-2-yloxy)methyl]pyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-[4-(morpholin-4-yl)piperidin-1-yl]phenyl)prop-2-enamide: In an 8-mL vial, place 10-[4-[6-([3-amino-4-[4-( [((((((morpholin-4-yl)piperidin-1-yl]phenyl]amino)-4-methyl-5-oxopyrazine-2-yl]-3-[(oxanyl-2-yloxy)methyl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one (40.00 mg, 0.051 mmol, 1.00 equiv), DCM (1.00 mL), DIEA (13.2 mg, 0.103 mmol, 2.00 equiv). Acryloyl chloride (6.98 mg, 0.077 mmol, 1.50 equiv) was then added at 0 ° C. The resulting solution was stirred at 0 ° C for 30 minutes in a water / ice bath. The reaction was then quenched by adding 0.2 mL of MeOH. The resulting mixture was concentrated. The residue was purified by preparative TLC using dichloromethane / methanol (10:1). 35 mg (81.82%) of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-[(oxanyl-2-yloxy)methyl]pyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-[4-(morpholin-4-yl)piperidin-1-yl]phenyl)prop-2-enamide was obtained as a brown solid. LCMS-3 (ES, m / z): M+1: 832

[0530] Synthesis of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-[4-(morpholin-4-yl)piperidin-1-yl]phenyl)prop-2-enamide hydrochloride: Place N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-[4-(morpholin-4-yl)piperidin-1-yl]phenyl)prop-2-enamide hydrochloride in an 8-mL vial. =( ... The crude product was purified by preparative HPLC under the following conditions (Waters 2767): column, X Bridge Prep C18 OBD 19*150 mm5um; mobile phase, A: 0.1% HCl / water; B: ACN; gradient: 45-75% B in 7.9 min; flow rate: 20 ml / min; detector, 220 nm. 14.5 mg (51.27%) of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-[4-(morpholin-4-yl)piperidin-1-yl]phenyl)prop-2-enamide hydrochloride was obtained as a yellow solid. LCMS-0 (ES, m / z): M+HCl+1: 784. H-NMR-0: (300 MHz, methanol-d 4)δ8.84(s,1H),8.62(d,J=5.7Hz,1H),8.16(d,J=5.7Hz,1H),7.85(s,1H),7.54(d,J=9.6Hz,1H),7.39( d,J=9.0Hz,1H),6.78(s,1H),6.63(dd,J=16.8,10.2Hz,1H),6.50–6.40(m,1H),5.88(d,J=11.1Hz,1H) ,4.78(s,2H),4.45–4.02(m,6H),4.04–3.72(m,4H),3.69(s,3H),3.60(d,J=11.4Hz,2H),3.50–3.40(m ,2H),3.01-3.00(m,2H),2.64(s,2H),2.51(s,2H),2.42-2.30(m,2H),2.02–2.01(m,2H),1.29(s,6H).

[0531] Example 20: Preparation of N-(2-[4,4-difluoro-[1,4'-bipiperidinyl]-1'-yl]-5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-dien-10-yl]-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]phenyl)prop-2-enamide

[0532] Synthesis of 5-bromo-3-[(4-fluoro-3-nitrophenyl)amino]-1-methylpyrazin-2-one In a 250 mL round-bottom flask, 4-fluoro-3-nitroaniline (10.00 g, 64.055 mmol, 1.00 equiv), 3,5-dibromo-1-methylpyrazin-2-one (17.16 g, 64.052 mmol, 1.00 equiv) and NMP (30 ml) were placed. The resulting solution was stirred at 140 ° C in an oil bath for 1 hour. The resulting solution was diluted with 300 mL EA. The solid was collected by filtration. 13 g (59.15%) of 5-bromo-3-[(4-fluoro-3-nitrophenyl)amino]-1-methylpyrazin-2-one was obtained as a brown solid. LCMS-1 (ES, m / z): M+1: 343 / 345

[0533] Synthesis of [(3,3-dimethylcyclopent-1-en-1-yl)oxy]trimethylsilane Into a 10-L 4-necked round-bottom flask purged and maintained with a nitrogen inert atmosphere, CuCl (20.60 g, 208.083 mmol, 0.05 equiv), LiCl (17.64 g, 416.108 mmol, 0.10 equiv), THF (2.50 L) were placed. Subsequently, 2-cyclopentene-1-one, 3-methyl- (400.00 g, 4161.075 mmol, 1.00 equiv) were added at -5 to 5°C. TMSCl (474.67 g, 4369.129 mmol, 1.05 equiv) was added dropwise to the mixture under stirring at -5 to 5°C. MeMgCl (1670.00 mL, 14495.069 mmol, 3.48 equiv) was added dropwise to the mixture under stirring at -5 to 10 °C. The resulting solution was stirred in an ice / salt bath at -5 to 10 °C for 2 hours. The reaction was then quenched by adding 34 g of MeOH. The resulting solution was washed with 5 L of NH 4 Cl was diluted. The solid was filtered off. The resulting solution was extracted with 3x5 L petroleum ether, dried over anhydrous sodium sulfate and concentrated. 780 g (crude) of [(3,3-dimethylcyclopent-1-en-1-yl)oxy]trimethylsilane was obtained as a yellow oil. GC-MS-2: (ES, m / z): M: 184

[0534] Synthesis of 3,3-dimethylcyclopentanone A 20-L 4-necked round-bottom flask was charged with [(3,3-dimethylcyclopent-1-en-1-yl)oxy]trimethylsilane (780.00 g, 4230.990 mmol, 1.00 equiv), DCM (7.8 L), H 2 O (30.49 g, 1692.396 mmol, 0.4 eq.) Then POCl was added dropwise at 25 to 30 °C with stirring. 3 (214.09 g, 1396.251 mmol, 0.33 equiv.). The resulting solution was stirred at 25°C for 0.5 h. The solvent was used directly in the next step. GC-MS-3: (ES, m / z): M: 112

[0535] Synthesis of 3,3-dimethylcyclopentanone A 20-L 4-necked round-bottom flask was charged with 3,3-dimethylcyclopentan-1-one (7.80 L) in DCM. DMF (619 g, 2.0 eq.) was then added dropwise under stirring at 25°C. POCl was added dropwise to the mixture under stirring at 40°C. 3 (1362 g, 2.1 eq.). The resulting solution was stirred overnight at 40 °C in an oil bath. Then, 2000 g of K 3 PO 4The reaction was quenched. The resulting solution was extracted with 3x10 L of dichloromethane, dried over anhydrous sodium sulfate and concentrated. 530 g (4804.86%) of 2-chloro-4,4-dimethylcyclopent-1-ene-1-carbaldehyde was obtained as a brown solid. GC-MS-4: (ES, m / z): M: 158

[0536] Synthesis of 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]12-2(6),7-diene-9-one In a 5-L 4-necked round-bottom flask, 2-chloro-4,4-dimethylcyclopent-1-ene-1-carbaldehyde (474.00 g, 2988.085 mmol, 1.00 equiv), DMF (3 L), piperazine-2-one (299.17 g, 2988.084 mmol, 1.00 equiv), DIEA (463.43 g, 3585.703 mmol, 1.2 equiv) were placed. The resulting solution was stirred overnight at 115 °C in an oil bath. The reaction mixture was cooled to room temperature with a water / ice bath. The solid was collected by filtration. The resulting mixture was washed with 3x2 L of H 2 O and 3x2L of PE. The solid was dried in an oven under reduced pressure. 230 g (37.68%) of 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-diene-9-one was obtained as a gray solid. LCMS-5: (ES, m / z): M+1: 205

[0537] Synthesis of 2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-10-yl]-4-iodopyridine-3-carbaldehyde Into a 2-L 4-necked round-bottom flask purged and maintained with a nitrogen inert atmosphere, 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one (38.00 g, 1.00 equiv.) and THF (500.00 mL) were placed. Subsequently, LiHMDS (558.80 mL, 3.00 equiv.) was added dropwise at 0° C. with stirring. 2-Fluoro-4-iodopyridine-3-carbaldehyde (93.50 g, 2.00 equiv.) was added to the mixture in batches at ° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by adding 1L of water. The pH of the solution was adjusted to 7 with HCl (2mol / L). The solid was filtered out. The resulting solution was extracted with 3x1L ethyl acetate and concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (2:3). The collected fractions were combined and concentrated. 12g of 2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]12-2(6),7-diene-10-yl]-4-iodopyridine-3-carboxaldehyde was obtained as a light yellow solid. LCMS-6 (ES, m / z): M+1:436

[0538] Synthesis of 10-[3-(hydroxymethyl)-4-iodopyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-diene-9-one 2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-diene-10-yl]-4-iodopyridine-3-carbaldehyde (10.00 g, 22.975 mmol, 1.00 equivalent) and EtOH (100.00 mL) were placed in a 250 mL round-bottom flask. NaBH was then added in portions at 0 °C. 4 (2.61 g, 68.987 mmol, 3.00 equiv). The resulting solution was stirred at room temperature for 3 hours. The reaction was subsequently quenched by adding 100 mL of water. The resulting solution was extracted with 3x200 mL of ethyl acetate and concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1: 1). The collected fractions were combined and concentrated. 8.24 g (82.02%) of 10-[3-(hydroxymethyl)-4-iodopyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]12-2(6),7-diene-9-one was obtained as a white solid. LCMS-7: (ES, m / z): M+1:438

[0539] Synthesis of 10-[4-iodo-3-[(oxacyclohexane-2-yloxy)methyl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one In a 500-mL round-bottom flask was placed 10-[3-(hydroxymethyl)-4-iodopyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one (7.30 g, 16.694 mmol, 1.00 equiv), DCM (200.00 mL), DHP (2.11 g, 0.025 mmol, 1.5 equiv), and PPTS (0.42 g, 0.002 mmol, 0.1 equiv). The resulting solution was stirred overnight at 45 ° C in an oil bath. The resulting mixture was concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:1). The collected fractions were combined and concentrated. 8 g (91.91%) of 10-[4-iodo-3-[(oxacyclohexane-2-yloxy)methyl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one was obtained as a light yellow solid. LCMS-8: (ES, m / z): M+1:522

[0540] Synthesis of tert-butyl 4,4-difluoro-[1,4'-bipiperidinyl]-1'-carboxylate In a 25-mL round-bottom flask, tert-butyl 4-oxopiperidine-1-carboxylate (1.00 g, 5.019 mmol, 1.00 equiv), 4,4-difluoropiperidine (0.73 g, 6.027 mmol, 1.20 equiv), THF (5.00 mL), AcOH (0.50 mL, 0.008 mmol), NaBH(OAc) were placed. 3 (2.13 g, 10.050 mmol, 2.00 equiv). The resulting solution was stirred at 30 °C in a water / ice bath for 14 h. The reaction was then quenched by adding 1 mL of MeOH. The resulting mixture was concentrated. The residue was applied to a silica gel column and eluted with dichloromethane / methanol (10:1). 1.5 g (98.19%) of tert-butyl 4,4-difluoro-[1,4'-bipiperidinyl]-1'-carboxylate was obtained as a white solid. LCMS-9 (ES, m / z): M+1:305

[0541] Synthesis of 4,4-difluoro-1,4'-bipiperidine Into a 50-mL round-bottom flask was placed tert-butyl 4,4-difluoro-[1,4'-bipiperidine]-1'-carboxylate (1.50 g) and HCl (2M) in dioxane (15.00 mL). The resulting solution was stirred at room temperature for 14 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column and eluted with dichloromethane / methanol (10:1). 1 g (crude) of 4,4-difluoro-1,4'-bipiperidine was obtained as a white solid. LCMS-10 (ES, m / z): M+1:205

[0542] Synthesis of 5-bromo-3-[(4-[4,4-difluoro-[1,4'-bipiperidinyl]-1'-yl]-3-nitrophenyl)amino]-1-methylpyrazin-2-one In a 50-mL round-bottom flask, 5-bromo-3-[(4-fluoro-3-nitrophenyl)amino]-1-methylpyrazin-2-one (1.00 g, 2.915 mmol, 1.00 equiv), 4,4-difluoro-1,4'-bipiperidinyl (0.60 g, 2.937 mmol, 1.01 equiv), NMP (15.00 mL), DIEA (1.13 g, 8.743 mmol, 3.00 equiv) were placed. The resulting solution was stirred at 110 °C in an oil bath for 14 h. The resulting solution was heated with 50 mL of H 2 O. The resulting solution was extracted with 3x20 mL of dichloromethane. The residue was applied to a silica gel column and eluted with dichloromethane / methanol (10:1). 250 mg (16.27%) of 5-bromo-3-[(4-[4,4-difluoro-[1,4'-bipiperidinyl]-1'-yl]-3-nitrophenyl)amino]-1-methylpyrazin-2-one was obtained as a yellow solid. LCMS-11 (ES, m / z): M+1:527 / 529

[0543] Synthesis of 6-[(4-[4,4-difluoro-[1,4'-bipiperidinyl]-1'-yl]-3-nitrophenyl)amino]-4-methyl-5-oxopyrazin-2-ylboronic acid Into an 8-mL vial purged and maintained with an inert atmosphere of nitrogen was placed 5-bromo-3-[(4-[4,4-difluoro-[1,4'-bipiperidinyl]-1'-yl]-3-nitrophenyl)amino]-1-methylpyrazin-2-one (100 mg, 0.190 mmol, 1.00 equiv), bis(pinacolato)diboron (96.30 mg, 0.379 mmol, 2.00 equiv), THF (3.00 mL), KOAc (37.22 mg, 0.379 mmol, 2 equiv), and XPhos Pd G3 (16.05 mg, 0.019 mmol, 0.1 equiv). The resulting solution was stirred at 70° C. in an oil bath for 6 hours. The solid was filtered off. The resulting mixture was concentrated. 120 mg (crude) of 6-[(4-[4,4-difluoro-[1,4'-bipiperidinyl]-1'-yl]-3-nitrophenyl)amino]-4-methyl-5-oxopyrazin-2-ylboronic acid was obtained as a black solid. LCMS-12 (ES, m / z): M+1: 493

[0544] Synthesis of 10-(4-[6-[(4-[4,4-difluoro-[1,4'-bipiperidinyl]-1'-yl]-3-nitrophenyl)amino]-4-methyl-5-oxopyrazin-2-yl]-3-[(oxanyl-2-yloxy)methyl]pyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one Into an 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 6-[(4- [4,4-difluoro-[1,4'-bipiperidinyl]-1'-yl]-3-nitrophenyl)amino]-4-methyl-5-oxopyrazin-2-ylboronic acid (110.00 mg, crude product), 10-[4-iodo-3-[(oxanyl-2-yloxy)methyl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one (116.50 mg), THF (3.00 mL), H 2 O (0.30 mL), Pd(dppf)Cl 2 (9.12 mg, 0.011 mmol, 0.05 eq), K 3 PO 4(142.29 mg, 0.670 mmol, 3.00 equiv). The resulting solution was stirred in an oil bath at 50 ° C for 14 hours. The resulting mixture was concentrated. The residue was purified by preparative TLC with dichloromethane / methanol (10: 1). 100 mg (38.80%) of 10-(4-[6-[(4-[4,4-difluoro-[1,4'-bipiperidinyl]-1'-yl]-3-nitrophenyl)amino]-4-methyl-5-oxopyrazine-2-yl]-3-[(oxacyclohexane-2-yloxy)methyl]pyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one was obtained as a brown solid. LCMS-13: M+1: 842

[0545] Synthesis of 10-(4-[6-[(4-[4,4-difluoro-[1,4'-bipiperidinyl]-1'-yl]-3-nitrophenyl)amino]-4-methyl-5-oxopyrazin-2-yl]-3-[(oxanyl-2-yloxy)methyl]pyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one In a 30-mL sealed tube were placed 10-(4-[6-[(4-[4,4-difluoro-[1,4'-bipiperidinyl]-1'-yl]-3-nitrophenyl)amino]-4-methyl-5-oxopyrazin-2-yl]-3-[(oxanyl-2-yloxy)methyl]pyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one. 2 (12.14 mg, 0.053 mmol, 0.50 equiv). H was passed into the above mixture at ℃. 2 (gas). The resulting solution was stirred at room temperature for 1 hour. The solid was filtered off. The residue was purified by preparative TLC with dichloromethane / methanol (10:1). 35 mg (40.32%) of 10-(4-[6-[(3-amino-4-[4,4-difluoro-[1,4'-bipiperidinyl]-1'-yl]phenyl)amino]-4-methyl-5-oxopyrazine-2-yl]-3-[(oxacyclohexane-2-yloxy)methyl]pyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one was obtained as a brown solid. LCMS-14: (ES, m / z): M+1:812

[0546] Synthesis of N-(2-[4,4-difluoro-[1,4'-bipiperidinyl]-1'-yl]-5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-[(oxanyl-2-yloxy)methyl]pyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]phenyl)prop-2-enamide In an 8-mL vial, 10-(4-[6-[(3-amino-4-[4,4- [(1,4'-bipiperidinyl]-1'-yl]phenyl)amino]-4-methyl-5-oxopyrazine-2-yl]-3-[(oxanyl-2-yloxy)methyl]pyridin-2-yl)-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one (30.00 mg, 0.037 mmol, 1.00 equiv), DCM (1.00 mL), DIEA (9.55 mg, 0.074 mmol, 2.00 equiv). Acryloyl chloride (5.02 mg, 0.055 mmol, 1.50 equiv) was then added at 0°C. The resulting solution was stirred at 0°C for 30 minutes in a water / ice bath. The reaction was then quenched by adding 0.2 mL of MeOH. The resulting mixture was concentrated. The residue was purified by preparative TLC using dichloromethane / methanol (10:1). 25 mg (78.13%) of N-(2-[4,4-difluoro-[1,4'-bipiperidinyl]-1'-yl]-5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-[(oxanyl-2-yloxy)methyl]pyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]phenyl)prop-2-enamide was obtained as a brown solid. LCMS-15 (ES, m / z): M+1: 866

[0547] Synthesis of N-(2-[4,4-difluoro-[1,4'-bipiperidinyl]-1'-yl]-5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]phenyl)prop-2-enamide In an 8-mL vial, place N-(2-[4,4-difluoro-[ 1,4'-bipiperidinyl]-1'-yl]-5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-[(oxanyl-2-yloxy)methyl]pyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]phenyl)prop-2-enamide (20 mg), DCM (1 mL), TFA (0.1 mL). The resulting solution was stirred at 0° C. for 2 hours in a water / ice bath. The pH value of the solution was adjusted to 7 with TEA at 0° C. in a water / ice bath. The resulting mixture was concentrated. The crude product was purified by preparative HPLC under the following conditions (Waters 2767): column, X Bridge Prep C18 OBD 19*150mm 5um; mobile phase, A: 0.1% NH 3 -H 2 O / water; B: ACN; gradient: 35%-75% B in 7.9 min; flow rate: 20 ml / min; detector, 220 nm. 7 mg (38.77%) of N-(2-[4,4-difluoro-[1,4'-bipiperidinyl]-1'-yl]-5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]phenyl)prop-2-enamide was obtained as a light yellow solid. LCMS-0: (ES, m / z): M+1: 782 1 H NMR (300 MHz, methanol-d 4)δ8.78(s,1H),8.52(d,J=5.1Hz,1H),7.90(d,J=5.1Hz,1H),7.68(s,1H),7.55(dd,J=8.7,2.7Hz,1H),7 .22(d,J=8.7Hz,1H),6.74(s,1H),6.55(dd,J=16.8,10.2Hz,1H),6.38(dd,J=16.8,1.8Hz,1H),5.82(d,J =10.8Hz,1H),4.85–4.72(m,1H),4.60(d,J=12.3Hz,1H),4.42–4.20(m,3H),3.96(d,J=12.0Hz,1H),3.6 6(s,3H),3.11-3.01(m,2H),2.90-2.40(m,11H),2.15-1.93(m,6H),1.81(t,J=10.2Hz,2H),1.28(s,6H).

[0548] Example 21: Preparation of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-dien-10-yl]-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl)prop-2-enamide

[0549] Synthesis of 2,4-dibromopyridine-3-carboxaldehyde: 2,4-dibromopyridine (40.00 g, 168.852 mmol, 1.00 equiv.) and THF (400.00 mL) were placed in a 1000-mL 3-neck round-bottom flask. LDA (2M in hexane, 126.60 mL, 1.5 equiv.) was then added dropwise at -78 °C with stirring. The resulting solution was stirred at -78 °C for 1 hour. Then, DMF (16.04, 219.507, 1.3 equiv.) was added dropwise at -78 °C with stirring. The resulting solution was stirred at -78 °C for 0.5 hour. Then, 500 mL of NH 4 The reaction was quenched with Cl. The resulting solution was extracted with 3x500 mL of ethyl acetate and concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (0:1-1:1). 24.4 g (54.55%) of 2,4-dibromopyridine-3-carboxaldehyde was obtained as a white solid. LCMS-1: (ES, m / z): M+1: 264

[0550] Synthesis of (2,4-dibromopyridin-3-yl)methanol: 2,4-dibromopyridine-3-carboxaldehyde (2.00 g, 7.550 mmol, 1.00 equivalent) and EtOH (30.00 mL) were placed in a 100 mL round-bottom flask. NaBH was then added in portions at 0 °C. 4 (285.64 mg, 7.550 mmol, 1 eq.). The resulting solution was stirred at room temperature for 3 hours. The reaction was then quenched by adding 30 mL of water. The resulting solution was extracted with 3x30 mL of ethyl acetate and concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:1). The collected fractions were combined and concentrated. 1.4 g (69.47%) of (2,4-dibromopyridin-3-yl)methanol was obtained as a light yellow solid. LCMS-2: (ES, m / z): M+1:266

[0551] Synthesis of 2,4-dibromo-3-[(oxacyclohexane-2-yloxy)methyl]pyridine: Into a 100mL round-bottom flask was placed (2,4-dibromopyridin-3-yl)methanol (1.40g, 5.245mmol, 1.00 equivalent), DCM (30.00mL, 0.353mmol, 0.07 equivalent), PPTS (131.81mg, 0.525mmol, 0.10 equivalent), DHP (661.79mg, 7.868mmol, 1.50 equivalent). The resulting solution was stirred overnight at 45°C in an oil bath. The reaction was subsequently quenched by adding 30mL of water. The resulting solution was extracted with 3x30mL of dichloromethane and concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:1). The collected fractions were combined and concentrated. 1.5 mg (0.08%) of 2,4-dibromo-3-[(oxanyl-2-yloxy)methyl]pyridine was obtained as a colorless oil. LCMS-3: (ES, m / z): M+1: 350

[0552] Synthesis of 10-[4-bromo-3-[(oxacyclohexane-2-yloxy)methyl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one: In a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one (1.00 g, 4.895 mmol, 1.00 equiv), dioxane (40.00 mL, 0.454 mmol, 0.09 equiv), Cs 2 CO 3(3.19 g, 9.791 mmol, 2 equiv), 2,4-dibromo-3-[(oxanyl-2-yloxy)methyl]pyridine (1.72 g, 4.900 mmol, 1.00 equiv), Pd 2 (dba) 3 (448.28 mg, 0.490 mmol, 0.1 eq.), XantPhos (283.26 mg, 0.490 mmol, 0.1 eq.). The resulting solution was stirred at 100 ° C. for 1 hour in an oil bath. The reaction was then quenched by adding 40 mL of water. The resulting solution was extracted with 3x40 mL of ethyl acetate and concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1: 1). The collected fractions were combined and concentrated. 900 mg (38.75%) of 10-[4-bromo-3-[(oxacyclohexane-2-yloxy)methyl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one was obtained as a brown solid. LCMS-4 (ES, m / z): M+1:474

[0553] Synthesis of 2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-[(oxanyl-2-yloxy)methyl]pyridin-4-ylboronic acid: In a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 10-[4-bromo-3-[(oxanyl-2-yloxy)methyl]pyridin-2-yl]-4,4- Dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-diene-9-one (1.00 g, 2.108 mmol, 1.00 equiv), dioxane (10.00 mL), bis(pinacol)diboron (1.34 g, 5.277 mmol, 2.50 equiv), KOAc (620.00 mg, 6.317 mmol, 3.00 equiv), Pd(dppf)Cl 2 (172.00 mg, 0.211 mmol, 0.10 equiv). The resulting solution was stirred at 100 ° C for 2 hours in an oil bath. The reaction mixture was cooled to room temperature. The solid was filtered out. The resulting mixture was concentrated in vacuo. 920 mg (crude) of 2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-10-yl]-3-[(oxacyclohexane-2-yloxy)methyl]pyridin-4-ylboronic acid was obtained as a brown oil. LCMS-5 (ES, m / z): M+1:436

[0554] Synthesis of 10-[1-hydroxy-3H-[1,2]oxaborol[4,3-c]pyridin-4-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one: In a 100 mL round-bottom flask, 2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-[(oxanyl-2-yloxy)methyl]pyridin-4-ylboronic acid (920 mg, 1.00 equivalent, crude), dioxane (10 mL), and HCl (6N, 10 mL) were placed. The resulting solution was stirred at 25° C. for 1 hour. The resulting mixture was concentrated in vacuo. The crude product was purified by flash preparative HPLC under the following conditions: column, C18 reverse phase column; mobile phase, H 2 O (0.05% NH 3 -H 2 O) and CH 3 CN (from 5% CH 3 CN reaches 30%); flow rate: 60 mL / min; detector, 254 / 220 nm. 350 mg of 10-[1-hydroxy-3H-[1,2]oxaborol[4,3-c]pyridin-4-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-diene-9-one was obtained as a light yellow solid. LCMS-6 (ES, m / z): M+1: 338

[0555] Synthesis of 5-bromo-3-[(4-fluoro-3-nitrophenyl)amino]-1-methylpyrazin-2-one: Into a 250 mL round-bottom flask, 4-fluoro-3-nitroaniline (10.00 g, 64.055 mmol, 1.00 equiv), 3,5-dibromo-1-methylpyrazin-2-one (17.16 g, 64.052 mmol, 1.00 equiv), and NMP (30 ml) were placed. The resulting solution was stirred at 140 ° C in an oil bath for 1 hour. The resulting solution was diluted with 300 mL EA. The solid was collected by filtration. 13 g (59.15%) of 5-bromo-3-[(4-fluoro-3-nitrophenyl)amino]-1-methylpyrazin-2-one was obtained as a brown solid. LCMS-7 (ES, m / z): M+1: 343 / 345

[0556] Synthesis of 5-bromo-1-methyl-3-([4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-nitrophenyl]amino)pyrazin-2-one: In a 50-mL round-bottom flask, 5-bromo-3-[(4-fluoro-3-nitrophenyl)amino]-1-methylpyrazin-2-one (3.00 g, 8.744 mmol, 1.00 equiv), 1-methyl-4-(piperidin-4-yl)piperazine (1.60 g, 8.729 mmol, 1.00 equiv), NMP (30.00 mL), DIEA (3.39 g, 26.230 mmol, 3.00 equiv) were placed. The resulting solution was stirred in an oil bath at 110° C. for 14 hours. The resulting solution was washed with 150 mL of H 2 The resulting solution was extracted with 3x50 mL of dichloromethane. The resulting mixture was washed with 3x30 mL of H 2 O. The resulting mixture was concentrated. The residue was applied to a silica gel column and eluted with dichloromethane / methanol (10:1). 1.2 g (27.10%) of 5-bromo-1-methyl-3-([4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-nitrophenyl]amino)pyrazin-2-one was obtained as a red solid. LCMS-8 (ES, m / z): M+1: 506 / 508

[0557] Synthesis of 3-([3-amino-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]amino)-5-bromo-1-methylpyrazin-2-one: In a 50-mL round-bottom flask, 5-bromo-1-methyl-3-([4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-nitrophenyl]amino)pyrazin-2-one (1.20 g, 2.370 mmol, 1.00 equiv) was placed. EtOH (10.00 mmol) and H 2 O (10.00 mL), Fe (0.53 g, 9.491 mmol, 4.01 equiv), NH 4 Cl (0.76 g, 14.208 mmol, 6.00 equiv). The resulting solution was stirred at 80 ° C in an oil bath for 2 hours. The solid was filtered off. The resulting mixture was concentrated. The residue was applied to a silica gel column and eluted with dichloromethane / methanol (5: 1). 200 mg (17.72%) of 3-([3-amino-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]amino)-5-bromo-1-methylpyrazin-2-one was obtained as a brown solid. LCMS-9 (ES, m / z): M+1: 476 / 478

[0558] Synthesis of N-[5-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]prop-2-enamide: In an 8-mL vial, 3-([3-amino-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]amino)-5-bromo-1-methylpyrazin-2-one (160.00 mg, 0.336 mmol, 1.00 equiv), acrylic acid (36.30 mg, 0.504 mmol, 1.50 equiv), DMF (4.00 mL), DIEA (86.81 mg, 0.672 mmol, 2.00 equiv), and HATU (153.23 mg, 0.403 mmol, 1.20 equiv) were placed. The resulting solution was stirred at room temperature for 14 hours. The resulting solution was washed with 20 mL of H 2 The resulting solution was extracted with 3x15 mL of dichloromethane. The resulting mixture was washed with 2x10 mL of H 2 O. The residue was applied to a silica gel column and eluted with dichloromethane / methanol (10:1). 40 mg (22.45%) of N-[5-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]prop-2-enamide were obtained as a brown solid. LCMS-10 (ES, m / z): M+1: 530 / 532

[0559] Synthesis of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl)prop-2-enamide: Into an 8-mL vial purged and maintained with an inert atmosphere of nitrogen was placed N-[5-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]prop-2-enamide. 1-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]prop-2-enamide (35.00 mg, 0.066 mmol, 1.00 equiv), 10-[1-hydroxy-3H-[1,2]oxaborol[4,3-c]pyridin-4-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one (22.25 mg, 0.066 mmol, 1.00 equiv), dioxane (3.00 mL), H 2 O (0.30 mL), Pd(dppf)Cl 2 (2.69 mg, 0.003 mmol, 0.05 eq), K 2 CO3 (27.36 mg, 0.198 mmol, 3.00 equiv.). The resulting solution was stirred at 90 °C in an oil bath for 1 hour. The resulting mixture was concentrated. The residue was purified by preparative TLC with dichloromethane / methanol (10:1). The crude product was purified by preparative HPLC under the following conditions (Waters 2767): column, X Bridge Prep C18 OBD19*150mm 5um; mobile phase, A: 0.1% NH 3 -H 2 O / water; B: ACN; gradient: 40%-75% B in 7.9 min; flow rate: 20 ml / min; detector, 220 nm. 13 mg (25.89%) of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl)prop-2-enamide were obtained as a white solid. LCMS-0 (ES, m / z): M+1: 761H-NMR-0: 1 H NMR (300 MHz, methanol-d 4 )δ8.79(s,1H),8.52(d,J=5.1Hz,1H),7.90(d,J=5.1Hz,1H),7.68(s,1H),7.56(dd,J=8.7,2.7Hz,1H),7.22(d, J=8.7Hz,1H),6.74(s,1H),6.65-6.60(m,1H),6.42–6.31(m,1H),5.82(d,J=10.2Hz,1H),4.80–4.72(m,1H),4. 70–4.50(m,1H),4.40–4.21(m,3H),3.96(d,J=11.8Hz,1H),3.67(s,3H),3.15-3.01(m,2H),2.90–2.67(m,5H), 2.66–2.46(m,6H),2.46–2.39(m,1H),2.33(s,3H),2.05(d,J=12.0Hz,2H),1.76(t,J=10.8Hz,2H),1.28(s,6H).

[0560] Example 22: Preparation of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-dien-10-yl]-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-[(2S)-2-methyl-4-(oxacyclohexane-4-yl)piperazin-1-yl]phenyl)prop-2-enamide

[0561] Synthesis of [(3,3-dimethylcyclopent-1-en-1-yl)oxy]trimethylsilane: CuCl (20.60 g, 208.083 mmol, 0.05 eq.), LiCl (17.64 g, 416.108 mmol, 0.10 eq.), THF (2.50 L) were placed in a 10-L 4-neck round-bottom flask purged and maintained with a nitrogen inert atmosphere. Subsequently, 2-cyclopentene-1-one and 3-methyl- (400.00 g, 4161.075 mmol, 1.00 eq.) were added at -5 to 5°C. TMSCl (474.67 g, 4369.129 mmol, 1.05 eq.) was added dropwise to the mixture under stirring at -5 to 5°C. MeMgCl (1670.00 mL, 14495.069 mmol, 3.48 equiv) was added dropwise to the mixture under stirring at -5 to 10 °C. The resulting solution was stirred in an ice / salt bath at -5 to 10 °C for 2 hours. The reaction was then quenched by adding 34 g of MeOH. The resulting solution was washed with 5 L of NH 4 Cl was diluted. The solid was filtered off. The resulting solution was extracted with 3x5 L petroleum ether, dried over anhydrous sodium sulfate and concentrated. 780 g (crude) of [(3,3-dimethylcyclopent-1-en-1-yl)oxy]trimethylsilane was obtained as a yellow oil. GC-MS: (ES, m / z): M: 184

[0562] Synthesis of 3,3-dimethylcyclopentanone: To a 20-L 4-necked round-bottom flask were added [(3,3-dimethylcyclopent-1-en-1-yl)oxy]trimethylsilane (780.00 g, 4230.990 mmol, 1.00 equiv), DCM (7.8 L), H 2 O (30.49 g, 1692.396 mmol, 0.4 eq.) Then POCl was added dropwise at 25 to 30 °C with stirring. 3 (214.09 g, 1396.251 mmol, 0.33 equiv.). The resulting solution was stirred at 25°C for 0.5 h. The solvent was used directly in the next step. GC-MS: (ES, m / z): M: 112

[0563] Synthesis of 3,3-dimethylcyclopentanone: 3,3-dimethylcyclopentane-1-one in DCM (7.80 L) was added to a 20-L 4-neck round-bottom flask. DMF (619 g, 2.0 eq.) was then added dropwise under stirring at 25°C. POCl was added dropwise to the mixture under stirring at 40°C. 3 (1362 g, 2.1 eq.). The resulting solution was stirred overnight at 40 °C in an oil bath. Then, 2000 g of K 3 PO 4 The reaction was quenched. The resulting solution was extracted with 3x10 L of dichloromethane, dried over anhydrous sodium sulfate and concentrated. 530 g (4804.86%) of 2-chloro-4,4-dimethylcyclopent-1-ene-1-carbaldehyde was obtained as a brown solid. GC-MS: (ES, m / z): M: 158

[0564] Synthesis of 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one: In a 5-L 4-necked round-bottom flask, 2-chloro-4,4-dimethylcyclopent-1-ene-1-carbaldehyde (474.00 g, 2988.085 mmol, 1.00 equiv), DMF (3 L), piperazin-2-one (299.17 g, 2988.084 mmol, 1.00 equiv), DIEA (463.43 g, 3585.703 mmol, 1.2 equiv) were placed. The resulting solution was stirred overnight at 115 °C in an oil bath. The reaction mixture was cooled to room temperature with a water / ice bath. The solid was collected by filtration. The resulting mixture was washed with 3x2 L of H 2 O and 3x2L of PE. The solid was dried in an oven under reduced pressure. 230 g (37.68%) of 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one was obtained as a gray solid. LC-MS: (ES, m / z): M+1: 205

[0565] Synthesis of 2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-10-yl]-4-iodopyridine-3-carbaldehyde: In a 2-L 4-necked round-bottom flask purged and maintained with a nitrogen inert atmosphere, 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one (38.00 g, 1.00 equiv.) and THF (500.00 mL) were placed. LiHMDS (558.80 mL, 3.00 equiv.) was then added dropwise at 0°C with stirring. 2-Fluoro-4-iodopyridine-3-carbaldehyde (93.50 g, 2.00 equiv.) was added to the mixture in portions at ℃. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by adding 1L of water. The pH of the solution was adjusted to 7 with HCl (2mol / L). The solid was filtered out. The resulting solution was extracted with 3x1L of ethyl acetate and concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (2:3). The collected fractions were combined and concentrated. 12g of 2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-10-yl]-4-iodopyridine-3-carboxaldehyde was obtained as a light yellow solid. LC-MS: (ES, m / z): M+1:436

[0566] Synthesis of tert-butyl (3S)-4-[4-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-nitrophenyl]-3-methylpiperazine-1-carboxylate: In a 50-mL round-bottom flask, 5-bromo-3-[(4-fluoro-3-nitrophenyl)amino]-1-methylpyrazin-2-one (2.00 g, 5.829 mmol, 1.00 equiv), NMP (20.00 mL), tert-butyl (3S)-3-methylpiperazine-1-carboxylate (1.17 g, 5.842 mmol, 1.00 equiv) and DIEA (2.26 g, 17.487 mmol, 3.00 equiv) were placed. The resulting solution was stirred in an oil bath at 110° C. for 48 hours. The resulting solution was washed with 100 mL of H 2 O dilution. The resulting solution was extracted with 3x50mL dichloromethane / methanol (10:1). The resulting mixture was washed with 3x20ml NaCl. The resulting mixture was concentrated. The residue was applied to a silica gel column and eluted with dichloromethane / methanol (10:1). 3g (59.00%) of (3S)-4-[4-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-nitrophenyl]-3-methylpiperazine-1-carboxylic acid tert-butyl ester was obtained as a brown solid. LC-MS: (ES, m / z): M+1:523

[0567] Synthesis of 5-bromo-1-methyl-3-([4-[(2S)-2-methylpiperazin-1-yl]-3-nitrophenyl]amino)pyrazin-2-one: In a 100 mL round-bottom flask, (3S)-tert-butyl 4-[4-[(6-bromo-4-methyl-3-oxopyrazin-2-yl)amino]-2-nitrophenyl]-3-methylpiperazine-1-carboxylate (3.00 g, 1 eq., 60%) and HCl (2M) in 1,4-dioxane (30.00 mL) were placed. The resulting solution was stirred at room temperature for 13 hours. The resulting mixture was concentrated. The resulting solution was washed with 30 mL of H 2 Dilute with NH 3 -H 2 O and adjust the pH value of the solution to 8. The resulting solution was extracted with 3x15 mL of dichloromethane and concentrated. The residue was applied to a silica gel column and eluted with dichloromethane / methanol (10:1). 700 mg (48.09%) of 5-bromo-1-methyl-3-([4-[(2S)-2-methylpiperazin-1-yl]-3-nitrophenyl]amino)pyrazin-2-one was obtained as a red solid. LC-MS: (ES, m / z): M+1:423

[0568] Synthesis of 5-bromo-1-methyl-3-([4-[(2S)-2-methyl-4-(oxan-4-yl)piperazin-1-yl]-3-nitrophenyl]amino)pyrazin-2-one: In a 50-mL round-bottom flask, 5-bromo-1-methyl-3-([4-[(2S)-2-methylpiperazin-1-yl]-3-nitrophenyl]amino)pyrazin-2-one (250 mg, 0.591 mmol, 1.00 equiv), 4H-pyran-4-one, tetrahydro-(70.96 mg, 0.709 mmol, 1.20 equiv), THF (5 ml), AcOH (5 drops), NaBH(AcO) were placed. 3 (250.36 mg, 1.181 mmol, 2.00 equiv). The resulting solution was stirred in an oil bath at 30 ° C for 14 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column and eluted with dichloromethane / methanol (10: 1). 220 mg (73.41%) of 5-bromo-1-methyl-3-([4-[(2S)-2-methyl-4-(oxacyclohexane-4-yl)piperazin-1-yl]-3-nitrophenyl]amino)pyrazin-2-one was obtained as a white solid. LC-MS: (ES, m / z): M+1: 507

[0569] Synthesis of 4-methyl-6-([4-[(2S)-2-methyl-4-(oxan-4-yl)piperazin-1-yl]-3-nitrophenyl]amino)-5-oxopyrazin-2-ylboronic acid: Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 5-bromo-1-methyl-3-([4-[(2S)-2-methyl-4-(oxan-4-yl)piperazin-1-yl]-3-nitrophenyl]amino)pyrazin-2-one (200.00 mg, 0.394 mmol, 1.00 equiv), bis(pinacol)diboron (200.19 mg, 0.788 mmol, 2.00 equiv), THF (5.00 mL, 0.069 mmol, 0.1 equiv), XPhos Pd G3 (16.68 mg, 0.020 mmol, 0.05 equiv), KOAc (77.37 mg, 0.788 mmol, 2.00 equiv). The resulting solution was stirred in an oil bath at 70 °C for 4 hours. The solid was filtered off. 150 mg (53.98%) of 4-methyl-6-([4-[(2S)-2-methyl-4-(oxan-4-yl)piperazin-1-yl]-3-nitrophenyl]amino)-5-oxopyrazin-2-ylboronic acid was obtained as a black solid. LC-MS: (ES, m / z): M+1: 473

[0570] Synthesis of 2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-4-[4-methyl-6-([4-[(2S)-2-methyl-4-(oxan-4-yl)piperazin-1-yl]-3-nitrophenyl]amino)-5-oxopyrazin-2-yl]pyridine-3-carbaldehyde: In a 40-mL vial purged and maintained with an inert atmosphere of nitrogen was placed 2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-4-[4-methyl-6-([4-[(2S)-2-methyl-4-(oxan-4-yl)piperazin-1-yl]-3-nitrophenyl]amino)-5-oxopyrazin-2-yl]pyridine-3-carbaldehyde. Azatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-diene-10-yl]-4-iodopyridine-3-carbaldehyde (200.00 mg, 0.459 mmol, 1.00 equiv), 4-methyl-6-([4-[(2S)-2-methyl-4-(oxan-4-yl)piperazin-1-yl]-3-nitrophenyl]amino)-5-oxopyrazin-2-ylboronic acid (651.07 mg, 1.378 mmol, 3.00 equiv), THF (8.00 mL), H 2 O (2.00 mL), K 3 PO 4 (292.60 mg, 1.378 mmol, 3.00 equiv), Pd(dppf)Cl 2(33.62mg, 0.046mmol, 0.10 equivalent). The resulting solution was stirred at 50 ° C for 2 hours in an oil bath. The solid was filtered off. The resulting solution was extracted with 3x10mL ethyl acetate and concentrated. The residue was applied to a silica gel column and eluted with dichloromethane / methanol (10: 1). The collected fractions were combined and concentrated. 130mg (38.45%) of 2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]12-2(6),7-diene-10-yl]-4-[4-methyl-6-([4-[(2S)-2-methyl-4-(oxacyclohexane-4-yl)piperazine-1-yl]-3-nitrophenyl]amino)-5-oxopyrazine-2-yl]pyridine-3-carboxaldehyde was obtained as a brown solid. LC-MS: (ES, m / z): M+1: 736

[0571] Synthesis of 10-[3-(hydroxymethyl)-4-[4-methyl-6-([4-[(2S)-2-methyl-4-(oxacyclohexane-4-yl)piperazin-1-yl]-3-nitrophenyl]amino)-5-oxopyrazin-2-yl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one: Place 2-[4,4-dimethyl-9- Oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-4-[4-methyl-6-([4-[(2S)-2-methyl-4-(oxan-4-yl)piperazin-1-yl]-3-nitrophenyl]amino)-5-oxopyrazin-2-yl]pyridine-3-carbaldehyde (100.00 mg, 0.136 mmol, 1.00 equiv), THF (2.00 mL), H 2 O(200.00uL), K 2 HPO 4 (59.18 mg, 0.340 mmol, 2.50 equiv). Then NaOH (1 M) (300.00 uL, 7.501 mmol, 55.19 equiv) was added dropwise with stirring at 0°C. NaBH was added to the mixture in portions at 0°C. 4(5.14mg, 0.136mmol, 1.00 equivalent). The resulting solution was stirred at room temperature for 20min. The reaction was subsequently quenched by adding 2mL of water. The resulting solution was extracted with 3x5mL ethyl acetate and concentrated. The residue was applied to a silica gel column and eluted with dichloromethane / methanol (10:1). The collected fractions were combined and concentrated. 50mg (49.86%) of 10-[3-(hydroxymethyl)-4-[4-methyl-6-([4-[(2S)-2-methyl-4-(oxacyclohexane-4-yl)piperazine-1-yl]-3-nitrophenyl]amino)-5-oxopyrazine-2-yl]pyridine-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]12-2(6),7-diene-9-one was obtained as a yellow solid. LC-MS: (ES, m / z): M+1: 738

[0572] Synthesis of 10-[4-[6-([3-amino-4-[(2S)-2-methyl-4-(oxan-4-yl)piperazin-1-yl]phenyl]amino)-4-methyl-5-oxopyrazin-2-yl]-3-(hydroxymethyl)pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-diene-9-one: A 30-mL pressure tank reactor was charged with 10-[3-(hydroxymethyl)-4-[4-methyl- 6-([4-[(2S)-2-methyl-4-(oxan-4-yl)piperazin-1-yl]-3-nitrophenyl]amino)-5-oxopyrazin-2-yl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one (50.00 mg, 0.068 mmol, 1.00 equiv), THF (5.00 mL, 0.069 mmol, 1.02 equiv), PtO 2 (4.62 mg, 0.020 mmol, 0.30 equiv). H 2 (g). The resulting solution was stirred at room temperature for 2 hours. The solid was filtered off. The resulting mixture was concentrated. 30 mg (crude) of 10-[4-[6-([3-amino-4-[(2S)-2-methyl-4-(oxacyclohexane-4-yl)piperazine-1-yl]phenyl]amino)-4-methyl-5-oxopyrazine-2-yl]-3-(hydroxymethyl)pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one was obtained as a yellow solid. LC-MS: (ES, m / z): M+1:708

[0573] Synthesis of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-[(2S)-2-methyl-4-(oxacyclohexane-4-yl)piperazin-1-yl]phenyl)prop-2-enamide hydrochloride: Place 10-[4-[6-([3-amino-4-[ (2S)-2-methyl-4-(oxacyclohexane-4-yl)piperazin-1-yl]phenyl]amino)-4-methyl-5-oxopyrazin-2-yl]-3-(hydroxymethyl)pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one (20.00 mg, 0.028 mmol, 1.00 equiv), DCM (4.00 mL), DIEA (7.30 mg, 0.057 mmol, 2 equiv). Acryloyl chloride (2.56 mg, 0.028 mmol, 1.00 equiv) was then added dropwise with stirring at 0°C. The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated. The crude product was purified by preparative HPLC under the following conditions: column, X-bridge RP18; mobile phase, 0.05% FA / water and CH 3 CN (from 45% CH 3 CN reaches 60%); detector, UV 254nm. The collected solution was concentrated in vacuo to remove CH 3 CN, the resulting solution was dried by lyophilization (addition of concentrated HCl (1 drop)). 3.3 mg (14.63%) of N-(5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]-2-[(2S)-2-methyl-4-(oxan-4-yl)piperazin-1-yl]phenyl)prop-2-enamide hydrochloride was obtained as a light yellow solid. LC-MS: (ES, m / z): M+1-HCl: 762. 1 H NMR ((300 MHz, DMSO-d 6,ppm)δ10.38(s,1H),9.32(s,1H),9.19(s,2H),8.49(d,J=5.1Hz,1H),7.95(d,J=5.1Hz,1H),7.78(s,1H),7.69(d,J=9.0H z,1H),7.21(d,J=8.7Hz,1H),6.75(dd,J=17.1,10.2Hz,1H),6.57(s,1H),6.46–6.28(m,1H),5.89–5.77(m,1H),4.54(d,J= 17.1Hz,2H),4.22(s,3H),4.02(d,J=11.4Hz,2H),3.85(s,1H),3.57(s,3H),3.36(t,J=11.4Hz,2H),3.16(d,J=12.9Hz,1H) ,2.97(t,J=15.0Hz,2H),2.59(d,J=4.5Hz,3H),2.44(s,2H),2.09(s,2H),1.77(s,2H),1.23(s,6H),0.80(d,J=6.0Hz,3H).

[0574] Example 23: Preparation of N-[2-[(2S)-4-(4,4-difluorocyclohexyl)-2-methylpiperazin-1-yl]-5-[[6-(2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-dien-10-yl]-3-(hydroxymethyl)pyridin-4-yl)-4-methyl-3-oxopyrazin-2-yl]amino]phenyl]prop-2-enamide

[0575] Synthesis of 2,4-dibromopyridine-3-carboxaldehyde, 2,4-dibromopyridine (40.00 g, 168.852 mmol, 1.00 equiv.), THF (400.00 mL) were placed in a 1000-mL 3-neck round-bottom flask. LDA (2M in hexane, 126.60 mL, 1.5 equiv.) was then added dropwise under stirring at -78 ° C. The resulting solution was stirred at -78 ° C for 1 hour. DMF (16.04, 219.507, 1.3 equiv.) was then added dropwise under stirring at -78 ° C. The resulting solution was stirred at -78 ° C for 0.5 hour. It was then stirred by adding 500 mL of NH 4 The reaction was quenched with Cl. The resulting solution was extracted with 3x500 mL of ethyl acetate and concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (0:1-1:1). 24.4 g (54.55%) of 2,4-dibromopyridine-3-carboxaldehyde was obtained as a white solid. LC-MS: (ES, m / z): M+1:264

[0576] To synthesize (2,4-dibromopyridin-3-yl)methanol, 2,4-dibromopyridine-3-carboxaldehyde (2.00 g, 7.550 mmol, 1.00 equivalent) and EtOH (30.00 mL) were placed in a 100 mL round-bottom flask. NaBH was then added in portions at 0 °C. 4 (285.64 mg, 7.550 mmol, 1 eq.). The resulting solution was stirred at room temperature for 3 hours. The reaction was then quenched by adding 30 mL of water. The resulting solution was extracted with 3x30 mL of ethyl acetate and concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:1). The collected fractions were combined and concentrated. 1.4 g (69.47%) of (2,4-dibromopyridin-3-yl)methanol was obtained as a light yellow solid. LC-MS: (ES, m / z): M+1:266

[0577] Synthesis of 2,4-dibromo-3-[(oxacyclohexane-2-yloxy)methyl]pyridine, into a 100mL round-bottom flask was placed (2,4-dibromopyridin-3-yl)methanol (1.40g, 5.245mmol, 1.00 equivalent), DCM (30.00mL, 0.353mmol, 0.07 equivalent), PPTS (131.81mg, 0.525mmol, 0.10 equivalent), DHP (661.79mg, 7.868mmol, 1.50 equivalent). The resulting solution was stirred overnight at 45°C in an oil bath. The reaction was subsequently quenched by adding 30mL of water. The resulting solution was extracted with 3x30mL of dichloromethane and concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:1). The collected fractions were combined and concentrated. 1.5 mg (0.08%) of 2,4-dibromo-3-[(oxanyl-2-yloxy)methyl]pyridine was obtained as a colorless oil. LC-MS: (ES, m / z): M+1: 350

[0578] Synthesis of 10-[4-bromo-3-[(oxacyclohexane-2-yloxy)methyl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-diene-9-one: In a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-diene-9-one (1.00 g, 4.895 mmol, 1.00 equiv), dioxane (40.00 mL, 0.454 mmol, 0.09 equiv), Cs 2 CO 3(3.19 g, 9.791 mmol, 2 equiv), 2,4-dibromo-3-[(oxanyl-2-yloxy)methyl]pyridine (1.72 g, 4.900 mmol, 1.00 equiv), Pd 2 (dba) 3 (448.28 mg, 0.490 mmol, 0.1 eq.), XantPhos (283.26 mg, 0.490 mmol, 0.1 eq.). The resulting solution was stirred at 100 ° C. for 1 hour in an oil bath. The reaction was then quenched by adding 40 mL of water. The resulting solution was extracted with 3x40 mL of ethyl acetate and concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1: 1). The collected fractions were combined and concentrated. 900 mg (38.75%) of 10-[4-bromo-3-[(oxacyclohexane-2-yloxy)methyl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-9-one was obtained as a brown solid. LC-MS: (ES, m / z): M+1:474

[0579] To synthesize 2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-[(oxanyl-2-yloxy)methyl]pyridin-4-ylboronic acid, a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 10-[4-bromo-3-[(oxanyl-2-yloxy)methyl]pyridin-2-yl]-4,4- Dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-diene-9-one (1.00 g, 2.108 mmol, 1.00 equiv), dioxane (10.00 mL), bis(pinacol)diboron (1.34 g, 5.277 mmol, 2.50 equiv), KOAc (620.00 mg, 6.317 mmol, 3.00 equiv), Pd(dppf)Cl 2 (172.00 mg, 0.211 mmol, 0.10 equiv). The resulting solution was stirred at 100 ° C in an oil bath for 2 hours. The reaction mixture was cooled to room temperature. The solid was filtered off. The resulting mixture was concentrated in vacuo. 920 mg (crude) of 2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]twelve-2(6),7-diene-10-yl]-3-[(oxacyclohexane-2-yloxy)methyl]pyridin-4-ylboronic acid was obtained as a brown oil. LC-MS: (ES, m / z): M+1:436

[0580] To synthesize 10-[1-hydroxy-3H-[1,2]oxaborol[4,3-c]pyridin-4-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-9-one, 2-[4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-dien-10-yl]-3-[(oxanyl-2-yloxy)methyl]pyridin-4-ylboronic acid (920 mg, 1.00 equivalent, crude), dioxane (10 mL), and HCl (6N, 10 mL) were placed in a 100 mL round-bottom flask. The resulting solution was stirred at 25°C for 1 hour. The resulting mixture was concentrated in vacuo. The crude product was purified by flash preparative HPLC under the following conditions: column, C18 reverse phase column; mobile phase, H 2 O (0.05% NH 3 .H 2 O) and CH 3 CN (from 5% CH 3 CN reaches 30%); flow rate: 60 mL / min; detector, 254 / 220 nm. 350 mg of 10-[1-hydroxy-3H-[1,2]oxaborol[4,3-c]pyridin-4-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.0^[2,6]]dodeca-2(6),7-diene-9-one was obtained as a light yellow solid. LC-MS: (ES, m / z): M+1: 338

[0581] To synthesize 5-bromo-3-([4-[(2S)-4-(4,4-difluorocyclohexyl)-2-methylpiperazin-1-yl]-3-nitrophenyl]amino)-1-methylpyrazin-2-one, a 40-mL round-bottom flask was charged with 5-bromo-1-methyl-3-([4-[(2S)-2-methylpiperazin-1-yl]-3-nitrophenyl]amino)pyrazin-2-one (253.20 mg, 0.598 mmol, 1.00 equiv), 4,4-difluorocyclohexan-1-one (160.47 mg, 1.196 mmol, 2.00 equiv), THF (10.00 mL), HOAc (0.20 mL), and NaBH(OAc). 3(316.96 mg, 1.495 mmol, 2.5 equiv.). The resulting solution was stirred at room temperature overnight. The reaction was subsequently quenched by adding 20 mL of water. The resulting solution was extracted with 3x20 mL of ethyl acetate and concentrated. The residue was applied to a silica gel column and eluted with dichloromethane / methanol (10: 1). The collected fractions were combined and concentrated. 154 mg (47.55%) of 5-bromo-3-([4-[(2S)-4-(4,4-difluorocyclohexyl)-2-methylpiperazine-1-yl]-3-nitrophenyl]amino)-1-methylpyrazine-2-one was obtained as a brown solid. LC-MS: (ES, m / z): M+1: 541 [0582...

Claims

1. A compound of formula (IV), or a pharmaceutically acceptable salt thereof: in Q 3 is a 5-membered heteroaryl group having one heteroatom independently selected from oxygen, nitrogen and sulfur; R 1 Each is independently H, D, alkyl, alkenyl, alkynyl, cycloalkyl, 5-8 membered heterocycloalkyl, halogen, nitro, cyano, OR a or SR a wherein the cycloalkyl or 5-8 membered heterocycloalkyl is optionally substituted by one or more R d replace; R 3 is H, halogen, alkyl, haloalkyl or hydroxyalkyl; R 4 is H, halogen or C 1-4 alkyl; R5 are each independently alkyl; R6 are each independently H; R7 are each independently H, D or alkyl; Two R's 5 The groups, together with the atoms to which they are attached, may optionally form a cycloalkyl group, which may be optionally substituted by one or more R d replace; R a are each independently H, D, alkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =O, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylamino, halo-alkylamino or cycloalkyl, wherein the alkyl or cycloalkyl is optionally replaced by one or more R e replace; R d are each independently H, D, alkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, =O, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylamino, haloalkylamino, cycloalkyl or heterocycloalkyl, the heterocycloalkyl having one or more heteroatoms selected from N, O or S, wherein the alkyl, cycloalkyl or heterocycloalkyl is optionally replaced by one or more R e replace; R e is H, D, alkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylamino, oxo, halo-alkylamino or cycloalkyl; i and m are each independently 0, 1, 2, 3 or 4; n is 2, 3 or 4; and k is 1 or 2.

2. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-methyl-1-(oxetan-3-yl)-3-oxopiperazin-2-yl)phenyl)acrylamide, (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-methyl-1-(oxetan-3-yl)-5-oxopiperazin-2-yl)phenyl)acrylamide, (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-methyl-1-(oxetan-3-yl)-5-oxopiperazin-2-yl)phenyl)acrylamide, (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-methyl-4-(oxetan-3-yl)-6-oxopiperazin-2-yl)phenyl)acrylamide, (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-methyl-4-(oxetan-3-yl)-6-oxopiperazin-2-yl)phenyl)acrylamide, (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-isopropyl-4-(oxetan-3-yl)-6-oxopiperazin-2-yl)phenyl)acrylamide, (R)-N-(2-(1-cyclopropyl-4-(oxetan-3-yl)-6-oxopiperazin-2-yl)-5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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, (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)piperazin-1-yl)phenyl)acrylamide, (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)piperazin-1-yl)phenyl)acrylamide, (S)-N-(2-(2-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-5-((4-methyl-6-(3-methyl-2-(1-oxo-3,4,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-c]pyridin-2(1H)-yl)pyridin-4-yl)-3-oxo-3,4-dihydropyrazin-2-yl)amino)phenyl)acrylamide, (R)-N-(5-((4-methyl-6-(3-methyl-2-(1-oxo-3,4,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-c]pyridin-2(1H)-yl)pyridin-4-yl)-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)piperazin-1-yl)phenyl)acrylamide, (S)-N-(5-((4-methyl-6-(3-methyl-2-(1-oxo-3,4,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-c]pyridin-2(1H)-yl)pyridin-4-yl)-3-oxo-3,4-dihydropyrazin-2-yl)amino)-2-(4-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)piperazin-1-yl)phenyl)acrylamide, (R)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)piperazin-1-yl)phenyl)acrylamide, (S)-N-(5-((6-(2-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[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-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)piperazin-1-yl)phenyl)acrylamide.

3. A pharmaceutical composition comprising a compound as defined in claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

4. Use of a compound as defined in claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating B-cell malignancies and autoimmune diseases.

5. The use according to claim 4, wherein the autoimmune disease is pemphigus vulgaris, rheumatoid arthritis, multiple sclerosis or systemic lupus erythematosus.

6. Use of the compound defined in claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma and diffuse large B-cell lymphoma.

7. The use according to claim 6, wherein the diffuse large B-cell lymphoma is multiple myeloma.

8. Use of the compound defined in claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating asthma.

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