Pyridone and pyrimidone inhibitors of hematopoietic procell kinase 1

Abstract

The present invention relates to compounds of formula (I). The compounds are useful for modulating the activity of the HPK-1 protein and thereby treating cancer, viral infections and immune-mediated conditions. # imgabs0 #

Description

[0001] The present invention relates to compounds and methods useful for inhibiting hematopoietic progenitor kinase 1 (HPK-1, MAP4K1). Thus, inhibitors are useful for treating diseases such as cancer and viral infections. The invention also extends to compounds, pharmaceutical compositions, methods for preparing the compounds, and methods for inhibiting HPK-1 protein.

[0002] HPK-1 is a member of the Ste20 family of serine / threonine kinases and is primarily expressed in hematopoietic cells. HPK-1 acts as a MAP4K kinase by phosphorylating MAP3K proteins including MEKK1, MLK3, and TAK1, thereby participating in the regulation of various downstream signaling pathways via activation of the JNK / SAPK signaling pathway (Hu et al., Genes Develop., 1996, 10, 2251-2264). This leads to functional regulation of various cellular processes such as cell proliferation, differentiation, and stress response, helping to maintain cell hematopoiesis. Other members of the MAP4K family include MAP4K2 / GCK, MAP4K3 / GLK, MAP4K4 / HGK, MAP4K5 / KHS, and MAP4K6 / MINK. Although most kinases positively regulate cellular function, HPK-1 is a negative regulator of T cell receptor signaling, making it a potential immunomodulatory target for the treatment of cancer and viral infections.

[0003] Immuno-oncology is playing an increasingly important role as a cancer treatment modality that mobilizes immune cells to recognize and ultimately eliminate cancer cells. Recently, monoclonal antibodies targeting T cell inhibitory checkpoints such as CTLA-4, PD-1, and PD-L1 have shown remarkable success in driving durable anti-tumor responses in patients (Lee et al., Molecules, 2019, 24, 1190-1205).

[0004] In an effective immune response to tumors, the release of tumor antigens binds to antigen receptors on immune cells (including dendritic cells and antigen-presenting cells), ultimately activating and activating T cells. These antigen-specific T cells are transported to the tumor site, infiltrate the tumor, and kill the target cancer cells that make up the tumor (Chen and Mellman, Immunity, 2013, 39, 1-10). However, this delicate process balance may be interrupted by mechanisms designed to evade immune system detection and bypass normal immune surveillance. The response rate to checkpoint inhibitor treatment varies depending on the type of cancer targeted and appears to be sensitive to inhibitory factors in the tumor microenvironment that lead to reduced T cell effector function and resistance to treatment (Sharma et al., Cell, 2017, 168, 707-723). Antibody therapy is also limited to targeting only extracellular inhibitory checkpoints / negative regulators, requiring the use of different modalities to access intracellular targets, such as the use of cell-permeable small molecules.

[0005] Therefore, there is a need for alternative approaches for modulating immune responses, and in particular T cell immune responses, to broaden the clinical applicability of immuno-oncology treatments, for example by using small molecules.

[0006] Several small molecule kinase inhibitors have been proposed that target specific pathways involved in negatively regulating T cell responses to tumors (Adams et al., Nat. Revs. Drug Disc., 2015, 14, 603-622; Weinmann, ChemMedChem, 2016, 11, 450-466; Sasikumar et al., BioDrugs, 2018, 32, 481-497).

[0007] Due to its restricted expression in hematopoietic cells such as T cells, B cells, macrophages, dendritic cells, neutrophils, and mast cells, HPK-1 has been studied as a possible immuno-oncology target (Kiefer et al., EMBO J., 1996, 15, 7013-7025). It has been shown to negatively regulate T cell and dendritic cell function. Studies on HPK-1 knockout (KO) mice have confirmed its role in regulating T cell activation. HPK-1 KO or kinase activity-deficient mice show enhanced antigen presentation ability, enhanced ERK1 / 2 activation, and are able to enhance anti-tumor responses (Sawasdikisol et al., Immunol. Res., 2012, 54, 262-265; Liu et al., PLoS One, 2019, 14, e0212670; Hernandez et al., Cell Rep., 2018, 25, 80-94; Shui et al., Nat. Immunol., 2007, 8, 84-91). Recently, a potent small molecule inhibitor of HPK-1 has been shown to stimulate cytokine secretion from activated human T cells and completely reverse immunosuppression driven by prostaglandin E2 and adenosine pathways (Wang et al., Public Library of Science Comprehensive, 2020, 15, e0243145). Another potent small molecule has also been shown to inhibit tumor growth in MC38 mouse syngeneic tumor models and CT26 mouse tumor explant models when combined with anti-PD1 antibodies (You et al., Journal of Cancer Immunotherapy (J. Immunother. Cancer), 2021, 9, e001402). These data clearly show that the loss of HPK-1 functional activity by both gene deletion and pharmacological inhibition will promote T cell activation and anti-tumor efficacy in preclinical models.

[0008] T cell activation involves several enzymes, including kinases, to propagate activation signals. HPK-1 kinase activity is induced by: activation of T cell and B cell receptors (Liou et al., Immunity, 2000, 12, 399-408; Han et al., Immunity, 2003, 19, 621-632; Sauer et al., J. Biol. Chem., 2001, 276, 45207-45216); activation of transforming growth factor receptor (TGF-PR) (Wang et al., J. Biol. Chem., 1997, 272, 22771-22775); activation of PGE2 receptors EP2 and EP4 HPK-1 is involved in the activation of mitochondria (Ikegami et al., J. Immunol., 2001, 166, 4689-4696); activation of LPS receptors (Alzabin et al., J. Immunol., 2009, 182, 6187-6194); and caspase-mediated proteolytic cleavage of HPK-1 (Chen et al., Oncogene, 1999, 18, 7370-7377; Arnold et al., J. Biol. Chem., 2001, 276, 14675-14684). The activation, signaling, and immunobiology of HPK-1 were recently reviewed by Savardicasso et al. (eLife, 2020, 9, e55122). HPK-1 is fully activated by ZAP-70 phosphorylation of Tyr379 and autophosphorylation of Thr165 and Ser171 (Sauer et al., Mol. Cell Biol., 2005, 25, 2364-2383). Once catalytically active, HPK-1 acts as a negative regulator of various immune cells, including T cells, by phosphorylating SLP-76 at Ser376, disrupting the downstream T cell activation signalosome complex and ultimately leading to proteasome-mediated degradation of SLP-76 (DiBartolo et al., J. Expt. Med., 2007, 204, 681-691; Lasserre et al., J. Cell Biol., 2011, 195, 839-853; Wang et al., J. Biol., 2012, 287, 34091-34100). Negative regulation of B cells operates in a very similar manner (Sauer et al., J. Biol., 2001, 276, 45207-45216; Wang et al., J. Biol., 2012, 287, 11037-11048).

[0009] Recently, the structure of the HPK-1 kinase domain has been solved in apo form and in co-structure with small molecule ligands (Wu et al., Structure, 2019, 27, 125-133; Johnson et al., Journal of Biological Chemistry, 2019, 294, 9029-9036). The HPK-1 protein consists of multiple domains: an N-terminal kinase domain, a C-terminal citron homology domain, and an essentially disordered central domain containing four proline-rich (PR) motifs. The PR motifs mediate interactions with SH3 domain-containing proteins (such as Grb2 and Gads), and the central domain contains a caspase cleavage site. The reported structure consists of a domain-swapped dimer, in which the activation fragment presents a well-preserved dimer interface.

[0010] Several small-molecule inhibitors of HPK-1 have been reported, but their primary pharmacological mechanism is off-target effects rather than HPK-1 inhibition. These inhibitors include staurosporine, bosutinib, sunitinib, lestaurtinib, crizotinib, foretinib, dovitinib, and KW-2449. All of these compounds are potent inhibitors of receptor tyrosine kinases, with HPK-1 inhibition being a weaker off-target activity. Subsequently, several more potent HPK-1 inhibitors have been described in the literature (You et al., J Cancer Immunotherapy, 2021, 9, e001402; Yu et al., ACS Med Chem Letts., 2021, 12, 459-466; Degnan et al., ACS Med Chem Letts., 2021, 12, 443-450; Vara et al., ACS Med Chem Letts., 2021, 12, 653-661), with varying degrees of HPK-1 enzyme potency, cell-based potency, and kinase selectivity.

[0011] Therefore, there remains a need in the art for improved therapies for treating diseases such as cancer that may be difficult to treat with traditional therapeutic approaches. Immunological strategies show promise for treating cancer, and there is a need for the development of improved compositions and methods in this area. Specifically, there is a need for potent and selective small molecule inhibitors of HPK-1 and methods for treating diseases that could benefit from such inhibition.

[0012] Pyridone inhibitors of kinases are known in the literature. For example, Georges et al. (WO2009024332) have described pyridone amide inhibitors of focal adhesion kinase (FAK), Bryan et al. (ACS Medicinal Chemistry Communications, 2016, 7, 100-104) have described pyridone inhibitors of the T790M double mutant of epidermal growth factor receptor kinase, and Pierre et al. (Beilstein J. Org. Chem., 2021, 17, 156-165) have detailed synthetic methods for preparing pyridone amides. None of these reports indicate any HPK-1 activity data. The first two reports describe specific substituents designed to optimize the activity of FAK and EGFR, respectively, in particular 4-aminophenyl substituents, which are not preferred substituents for HPK-1 activity. The inventors of this case have found that certain substituted pyridone carboxamides are potent and selective HPK-1 inhibitors.

[0013] According to the first aspect of the present invention, there is provided a compound of formula (I):

[0014]

[0015] in:

[0016] X is CH or N;

[0017] Z is phenyl or 5 or 6 membered heteroaryl, wherein the phenyl or heteroaryl is substituted by one or more substituents selected from the group consisting of halogen, optionally substituted C 1- C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, CN, OR 8 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 8 、COOR 8 、CONR 8 R 9 NR 8 COR 9 NR 8 SO2R 9 NR 8 R 9 , an optionally substituted 3- to 10-membered heterocyclyl, an optionally substituted 5- to 10-membered heteroaryl, an optionally substituted C 6-10 Aryl or optionally substituted C 3-9cycloalkyl; and / or wherein adjacent substituents of the phenyl or heteroaryl groups may be combined together with the atoms to which they are attached to form an optionally substituted 3 to 6 membered heterocyclic ring or an optionally substituted 5 or 6 membered heteroaryl group;

[0018] R 1 to R 7 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, CN, OR 10 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 10 、COOR 8 、CONR 10 R 11 NR 10 COR 11 NR 10 SO2R 11 NR 10 R 11 , optionally substituted C3-C6 cycloalkyl, optionally substituted 3 to 8 membered heterocyclyl, optionally substituted 5 to 10 membered heteroaryl or optionally substituted phenyl; and / or R 3 and R 4 and / or R 5 and R 6 Together with the C atom to which it is attached, it forms a C=O group, an optionally substituted C3-C6 cycloalkyl group or an optionally substituted 3- to 8-membered heterocyclyl group; and / or R 3 and R 5 Together with the C atom to which it is attached, it forms an optionally substituted C3-C6 cycloalkyl or an optionally substituted 3- to 8-membered heterocyclyl;

[0019] R 8 and R 9 are independently hydrogen, optionally substituted C1-C 12 Alkyl, optionally substituted C2-C 12 Alkenyl, optionally substituted C2-C 12 Alkynyl, optionally substituted C 6-12 aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl; and

[0020] R 10 and R 11 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-12 aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl;

[0021] or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof.

[0022] In a second aspect of the present invention, a pharmaceutical composition is provided, comprising the compound according to the first aspect or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof, and a pharmaceutically acceptable vehicle.

[0023] In a third aspect, the present invention also provides a method for preparing a composition according to the second aspect, the method comprising contacting a therapeutically effective amount of a compound of the first aspect or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof and a pharmaceutically acceptable vehicle.

[0024] The present inventors have discovered that the compounds of the present invention can be used in therapy or as pharmaceutical agents.

[0025] Thus, in a fourth aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or a composition of the second aspect, for use in therapy.

[0026] The inventors of the present invention have discovered that the compound of formula (I) effectively regulates the activity of HPK-1.

[0027] Therefore, in the fifth aspect, a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or the composition of the second aspect is provided for use in modulating the activity of HPK-1 protein.

[0028] In a sixth aspect, there is provided use of a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof in the manufacture of a medicament for modulating the activity of an HPK-1 protein.

[0029] In a seventh aspect, a method for regulating the activity of HPK-1 protein is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or the composition of the second aspect.

[0030] Preferably, the compounds of formula (I) are used to inhibit or antagonize HPK-1 protein.

[0031] It should be understood that when referring to ligands and HPK-1, "inhibitors" encompass molecules, combinations of molecules, or complexes that inhibit, antagonize, counteract, downregulate, and / or desensitize HPK-1. "Inhibitors" encompass any agent that inhibits the constitutive activity of HPK-1. Constitutive activity is activity that is manifested in the absence of a ligand / HPK-1 interaction. "Inhibitors" also encompass any agent that inhibits or prevents stimulated (or regulated) activity of HPK-1.

[0032] The compounds of the present invention and pharmaceutically related compositions thereof are useful in treating a variety of diseases, disorders and conditions associated with the modulation of signaling pathways involving HPK-1.

[0033] By administering a compound of the present invention that inhibits HPK-1 protein, an enhanced immune response can be manifested in an individual in need thereof. This enhanced immune response may include a population of T cells that exhibit enhanced activation, enhanced activation, enhanced migration, enhanced proliferation, enhanced survival, and enhanced cytolytic activity relative to before the administration of the compound or pharmaceutical composition. T cell activation is characterized by an increase in the secretion of cytokines (such as IFNγ and IL-2) or an increase in the number of CD8 T cells relative to before the administration of the compound or pharmaceutical composition. In certain aspects of this embodiment, the T cells are antigen-specific CD8 T cells. In certain aspects of this embodiment, the maturation and activation of the antigen-presenting cells of the individual are enhanced relative to before the administration of the compound or pharmaceutical composition. In certain aspects of this embodiment, the antigen-presenting cells are dendritic cells.

[0034] The compounds of the present invention directly bind to the HPK-1 protein and inhibit its kinase activity. In certain embodiments, the compounds of the present invention reduce, inhibit, antagonize or otherwise attenuate HPK-1-mediated phosphorylation of SLP76 and / or Gads.

[0035] The compounds of the present invention may or may not be specific inhibitors of HPK-1. Specific HPK-1 inhibitors reduce the biological activity of HPK-1 by an amount statistically greater than the inhibitor's inhibitory effect on any other protein or biological target, such as another serine / threonine kinase or another type of kinase. In certain embodiments, the compounds of the present invention specifically inhibit the serine / threonine kinase activity of HPK-1. In some of these embodiments, the HPK-1 inhibitor has an IC of 100 for HPK-1. 50 The IC of HPK-1 inhibitors targeting another type of kinase 50 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001% or less of.

[0036] Any method known in the art for measuring the kinase activity of HPK-1 can be used to determine whether HPK-1 has been inhibited, including in vitro enzymatic kinase assays, immunoblotting using antibodies specific for phosphorylated targets of HPK-1 (such as SLP76), FRET-based detection of specific phosphorylated targets of HPK-1 (such as SLP76), or measurement of downstream biological effects of HPK-1 kinase activity (e.g., T cell or B cell activation).

[0037] The compounds of the present invention are useful for treating diseases, disorders, and conditions associated with modulation of signaling pathways involving HPK-1. These diseases, disorders, and conditions are pathological conditions in which HPK-1 activity is essential for the development or maintenance of the pathological condition. In certain embodiments, the pathological condition is cancer.

[0038] The compounds of the present invention are useful for treating diseases caused by T cell dysfunction, characterized by reduced or absent responsiveness to antigenic stimulation. In certain embodiments, T cell dysfunction is associated with increased HPK-1 kinase activity. T cell dysfunction can lead to ineffective control of pathogens or tumors. Examples of diseases caused by T cell dysfunction include unresolved acute infections, chronic infections, and cancer.

[0039] By inhibiting HPK-1 protein, cancer, viral infection and immune-mediated diseases can be treated, improved or prevented.

[0040] Therefore, in the eighth aspect, a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or the composition of the second aspect is provided for treating, ameliorating or preventing a disease selected from cancer, viral infection and immune-mediated disorders.

[0041] Preferably, the treatment, improvement or prevention comprises inhibiting HPK-1 protein.

[0042] In a ninth aspect, there is provided use of a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof in the manufacture of a medicament for treating, ameliorating or preventing a disease selected from cancer, viral infection and immune-mediated disorders.

[0043] In the tenth aspect, a method for treating, ameliorating or preventing a disease selected from cancer, viral infection and immune-mediated disorders is provided, the method comprising administering to an individual in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or a composition of the second aspect.

[0044] It will be understood that the term "prevent" may mean "reduce the likelihood of."

[0045] In an eleventh aspect, a compound of formula (I) for use in regulating the activity of HPK-1 protein is provided:

[0046]

[0047] X is CH or N;

[0048] Z is phenyl or 5 or 6 membered heteroaryl, wherein the phenyl or heteroaryl is substituted by one or more substituents selected from the group consisting of halogen, optionally substituted C 1- C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, CN, OR 8 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 8 、COOR 8 、CONR 8 R 9 NR 8 COR 9 NR 8 SO2R 9 NR 8 R 9 , an optionally substituted 3- to 10-membered heterocyclyl, an optionally substituted 5- to 10-membered heteroaryl, an optionally substituted C 6-10 Aryl or optionally substituted C 3-9 cycloalkyl; and / or wherein adjacent substituents of the phenyl or heteroaryl groups may be combined together with the atoms to which they are attached to form an optionally substituted 3 to 6 membered heterocyclic ring or an optionally substituted 5 or 6 membered heteroaryl group;

[0049] R 1 to R 7 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, CN, OR 10 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 10 、COOR 8 、CONR 10 R 11 NR 10 COR 11 NR 10 SO2R 11 NR 10R 11 , optionally substituted C3-C6 cycloalkyl, optionally substituted 3 to 8 membered heterocyclyl, optionally substituted 5 to 10 membered heteroaryl or optionally substituted phenyl; and / or R 3 and R 4 and / or R 5 and R 6 Together with the C atom to which it is attached, it forms a C=O group, an optionally substituted C3-C6 cycloalkyl group or an optionally substituted 3- to 8-membered heterocyclyl group; and / or R 3 and R 5 Together with the C atom to which it is attached, it forms an optionally substituted C3-C6 cycloalkyl or an optionally substituted 3- to 8-membered heterocyclyl;

[0050] R 8 and R 9 are independently hydrogen, optionally substituted C1-C 12 Alkyl, optionally substituted C2-C 12 Alkenyl, optionally substituted C2-C 12 Alkynyl, optionally substituted C 6-12 aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl; and

[0051] R 10 and R 11 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C 6-12 aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl;

[0052] or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof.

[0053] In some embodiments, the compounds of the present invention can be used to treat viral infections in individuals in need thereof. In some embodiments, the compounds of the present invention can be used as adjuvants to enhance the efficacy of vaccination.

[0054] The viral illness may be hepatitis B, hepatitis C, or HIV.

[0055] In a preferred embodiment, the disease is cancer. The cancer may be selected from the group consisting of colorectal cancer, aerodigestive squamous cell carcinoma, lung cancer, brain cancer, liver cancer, gastric cancer, sarcoma, leukemia, lymphoma, multiple myeloma, ovarian cancer, uterine cancer, breast cancer, melanoma, prostate cancer, bladder cancer, glioma, pancreatic cancer, or renal cancer.

[0056] In some embodiments, cancers that can be treated using the compounds of Formula (I) include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer), blood cancer (e.g., lymphoma, leukemia (such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML)), non-Hodgkin's lymphoma, Hodgkin's lymphoma, or multiple myeloma), and combinations of such cancers.

[0057] In some embodiments, HPK-1 inhibitors can be used to treat tumors that produce PGE2 (tumors that overexpress COX-2) and / or tumors that produce adenosine (tumors that overexpress CD73 and CD39). Overexpression of COX-2 has been detected in several tumors, such as colorectal cancer, breast cancer, pancreatic cancer, and lung cancer. CD73 is upregulated in various cancers, including colon cancer, lung cancer, pancreatic cancer, and ovarian cancer.

[0058] In an alternative preferred embodiment, the disease is a viral infection. The viral infection may be hepatitis B, hepatitis C virus (HCV) infection or human immunodeficiency virus (HIV) infection.

[0059] Unless the context indicates otherwise, the following definitions apply in connection with the compounds of the present invention.

[0060] Throughout the embodiments and claims of this specification, the word "comprise" and other forms of the word, such as "comprising" and "comprises" are meant to include but not limited to, and are not intended to exclude, for example, other additives, components, integers or steps.

[0061] As used in the embodiments and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a composition" includes a mixture of two or more such compositions.

[0062] “Optional” or “optionally” means that the subsequently described event, operation or circumstance may or may not occur, and means that the embodiments include instances where the event, operation or circumstance occurs and instances where it does not.

[0063] Unless otherwise specified, the term "alkyl" as used herein refers to a saturated straight or branched hydrocarbon. In certain embodiments, an alkyl group is a primary hydrocarbon, a secondary hydrocarbon, or a tertiary hydrocarbon. In certain embodiments, an alkyl group includes one to six carbon atoms, i.e., a C1-C6 alkyl group. A C1-C6 alkyl group includes, for example, a methyl group, an ethyl group, a n-propyl group (1-propyl group), and an isopropyl group (2-propyl group, 1-methylethyl group), a butyl group, a pentyl group, a hexyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, a neopentyl group, and an isohexyl group. In alternative embodiments, an alkyl group includes one to three carbon atoms, i.e., a C1-C3 alkyl group. An alkyl group may be unsubstituted or substituted with one or more of the following: halogen, oxo, CN, OR 16 SR 16 、SOR 16 、SO2R 16 、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 NR 16 R 17 , optionally substituted C 6-12 Aryl, optionally substituted C 3-6 cycloalkyl, an optionally substituted 3 to 6 membered heterocycle or an optionally substituted 5 to 10 membered heteroaryl. Thus, it is understood that the optionally substituted C1-C6 alkyl may be an optionally substituted C1-C6 haloalkyl, i.e., a C1-C6 alkyl substituted with at least one halogen and optionally further substituted with one or more of the following: oxo, CN, OR 16 SR 16 、SOR 16 、SO2R 16 、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 NR 16 R 17 , optionally substituted C 6-12 Aryl, optionally substituted C 3-6 cycloalkyl, an optionally substituted 3- to 6-membered heterocycle, or an optionally substituted 5- to 10-membered heteroaryl. The optionally substituted C1-C6 alkyl may be a polyfluoroalkyl, preferably a C1-C3 polyfluoroalkyl, and most preferably CF3.

[0064] R 16 and R 17 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-12 aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, or optionally substituted 5- to 10-membered heteroaryl.

[0065] The term "halo" or "halogen" includes fluorine (-F), chlorine (-Cl), bromine (-Br) and iodine (-I).

[0066] The term "polyfluoroalkyl" may refer to a C1-C3 alkyl group in which two or more hydrogen atoms are replaced by fluorine atoms. The term may include perfluoroalkyl groups, i.e., C1-C3 alkyl groups in which all hydrogen atoms are replaced by fluorine atoms. Thus, the term C1-C3 polyfluoroalkyl includes, but is not limited to, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, and 2,2,2-trifluoro-1-(trifluoromethyl)ethyl.

[0067] "Alkenyl" refers to an ethylenically unsaturated hydrocarbon group that can be unbranched or branched. In certain embodiments, the alkenyl group has 2 to 6 carbon atoms, i.e., it is a C2-C6 alkenyl group. C2-C6 alkenyl groups include, for example, vinyl, allyl, propenyl, butenyl, pentenyl, and hexenyl. In alternative embodiments, the alkenyl group has 2 to 3 carbon atoms, i.e., it is a C2-C3 alkenyl group. The alkenyl group may be unsubstituted or substituted with one or more of the following: optionally substituted C2-C6 alkynyl, halogen, oxo, CN, OR 16 SR 16 、SOR 16 、SO2R 16 、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 NR 16 R 17 , optionally substituted C 6-12 Aryl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3- to 6-membered heterocyclic ring, or optionally substituted 5- to 10-membered heteroaryl. 16 and R 17 May be as defined above.

[0068] "Alkynyl" refers to an acetylenically unsaturated hydrocarbon group that can be unbranched or branched. In certain embodiments, the alkynyl group has 2 to 6 carbon atoms, i.e., it is a C2-C6 alkynyl group. C2-C6 alkynyl groups include, for example, propargyl, propynyl, butynyl, pentynyl, and hexynyl. In alternative embodiments, the alkynyl group has 2 to 3 carbon atoms, i.e., it is a C2-C3 alkynyl group. The alkynyl group may be unsubstituted or substituted with one or more of the following: optionally substituted C2-C6 alkenyl, halogen, oxo, CN, OR16 SR 16 、SOR 16 、SO2R 16 、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 NR 16 R 17 , optionally substituted C 6-12 Aryl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3- to 6-membered heterocyclic ring, or optionally substituted 5- to 10-membered heteroaryl. 16 and R 17 May be as defined above.

[0069] "Cycloalkyl" refers to a non-aromatic, saturated or partially saturated monocyclic, bicyclic or polycyclic hydrocarbon 3 to 6 membered ring system. Representative examples of C3-C6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl may be unsubstituted or substituted with one or more of the following: optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, oxo, CN, OR 16 SR 16 、SOR 16 、SO2R 16 、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 NR 16 R 17 , optionally substituted C 6-12 Aryl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3- to 6-membered heterocyclic ring, or optionally substituted 5- to 10-membered heteroaryl. 16 and R 17 May be as defined above.

[0070] "Heteroaryl" refers to a monocyclic or bicyclic aromatic 5- to 10-membered ring system in which at least one ring atom is a heteroatom. The term includes bicyclic groups in which one ring is aromatic and the other is not. For groups in which one ring is aromatic and the other is not aromatic, the group is considered a heteroaryl if either or both rings contain at least one ring atom that is a heteroatom. In some embodiments, a heteroaryl group is a monocyclic 5- or 6-membered ring system in which at least one ring atom is a heteroatom. The or each heteroatom may be independently selected from the group consisting of oxygen, sulfur, and nitrogen. A heteroaryl group may contain 1, 2, 3, or 4 heteroatoms. Examples of 5- to 10-membered heteroaryls include furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1-methyl-1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline. Bicyclic 5- to 10-membered heteroaryls include heteroaryls comprising a phenyl, pyridine, pyrimidine, pyrazine, or pyridazine ring fused to a 5- or 6-membered monocyclic heteroaryl ring. Heteroaryl may be unsubstituted or substituted by one or more of the following: optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, oxo, CN, OR 16 SR 16 、SOR 16 、SO2R 16 、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 NR 16 R 17 , optionally substituted C 6-12 Aryl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3- to 6-membered heterocyclic ring, or optionally substituted 5- to 10-membered heteroaryl. 16 and R 17 May be as defined above.

[0071] Unless otherwise specified, "heterocycle" or "heterocyclyl" refers to a 3- to 10-membered monocyclic, bicyclic, or bridged molecule in which at least one ring atom is a heteroatom. In some embodiments, a heterocycle is a 3- to 6-membered monocyclic molecule in which at least one ring atom is a heteroatom. The heteroatom or each heteroatom may be independently selected from the group consisting of oxygen, sulfur, and nitrogen. The heterocycle may contain 1, 2, 3, or 4 heteroatoms. The heterocycle may be saturated or partially saturated. Exemplary 3- to 8-membered heterocyclic groups include, but are not limited to, aziridine, oxirane, ethylene oxide, thioethane, pyrroline, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine, 1,2,3,6-tetrahydropyridin-1-yl, tetrahydropyran, pyran, morpholine, piperazine, thiolane, thiamine, piperazine, azepane, diazepane, and oxazine. The heterocyclyl group may be unsubstituted or substituted by one or more of the following: optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, oxo, CN, OR 16 SR 16 、SOR 16 、SO2R 16 、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 NR 16 R 17 , optionally substituted C 6-12 Aryl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3- to 6-membered heterocyclic ring, or optionally substituted 5- to 10-membered heteroaryl. 16 and R 17 May be as defined above.

[0072] "Aryl" refers to an aromatic 6- to 12-membered hydrocarbon group. The term includes bicyclic groups in which one ring is aromatic and the other is not. It is understood that in an aryl group, all ring atoms are carbon. 12 Examples of aryl groups include, but are not limited to, phenyl, α-naphthyl, β-naphthyl, biphenyl, tetrahydronaphthyl, and dihydroindanyl. Optionally substituted aryl groups may be optionally substituted phenyl groups. Optionally substituted aryl groups may be unsubstituted or substituted with one or more of the following: optionally substituted C1-C6 alkyl groups, optionally substituted C2-C6 alkenyl groups, optionally substituted C2-C6 alkynyl groups, optionally substituted C1-C6 alkoxy groups, halogen, CN, OR 16 SR 16 、SOR 16 、SO2R 16、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 NR 16 R 17 , optionally substituted C 6-12 Aryl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3- to 6-membered heterocyclic ring, or optionally substituted 5- to 10-membered heteroaryl. 16 and R 17 May be as defined above.

[0073] As used herein, the term "bicycle" or "bicyclic" refers to a molecule with two rings. Similarly, as used herein, "tricycle" refers to a molecule with three rings. Similarly, as used herein, "polycycle" refers to a molecule with three or more rings. In each case, the ring can be an optionally substituted phenyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, or a combination thereof. In one embodiment, the ring spans a bond fused between two atoms. The portion formed by the ring shares a bond between each ring and can be referred to as "fused". In another embodiment, the portion is formed by the fusion of a series of atoms across the ring to form a bridgehead. Similarly, a "bridge" is a non-branched chain with one or more atoms connecting two bridgeheads in a bicyclic or polycyclic compound. In another embodiment, the molecule is a "spiro" or "spirocyclic" portion. Spirocyclic group can be C3-C6 cycloalkyl or monocycle or bicyclic 3 yuan to 8 yuan heterocycle that is bonded to the single carbon atom of carbocyclic ring or heterocyclic ring moiety through the single carbon atom of spirocyclic moiety.In one embodiment, spirocyclic group is cycloalkyl and is bonded to another cycloalkyl.In another embodiment, spirocyclic group is cycloalkyl and is bonded to heterocyclic radical.In another embodiment, spirocyclic group is heterocyclic radical and is bonded to another heterocyclic radical.In another embodiment, spirocyclic group is heterocyclic radical and is bonded to cycloalkyl.

[0074] In some embodiments, R 8 and R 9 are independently hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C 6-12 aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl.

[0075] R 1It can be hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, CN, OR 10 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 10 、COOR 8 、CONR 10 R 11 NR 10 COR 11 NR 10 SO2R 11 or NR 10 R 11 More preferably, R 1 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, halogen, CN or OR 10 Even more preferably, R 1 is hydrogen, C1-C3 alkyl, CN or OR 10 . R 8 and R 9 R is independently hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl or optionally substituted C2-C3 alkynyl. 8 and R 9 are independently hydrogen, C1-C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl. Even more preferably, R 8 and R 9 is H or methyl, and most preferably is methyl. 10 and R 11 R is independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl or optionally substituted C2-C6 alkynyl. 10 and R 11 R is independently hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl or optionally substituted C2-C3 alkynyl. More preferably, R 10 and R 11 are independently hydrogen, C1-C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl. Even more preferably, R 10 and R 11 is H or methyl, and most preferably is methyl. 1 It can be hydrogen, methyl, CN or OCH3.

[0076] R 2It can be hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, CN, OR 10 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 10 、COOR 8 、CONR 10 R 11 NR 10 COR 11 NR 10 SO2R 11 or NR 10 R 11 More preferably, R 2 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, halogen, CN or OR 10 Even more preferably, R 2 is hydrogen, C1-C3 alkyl, CN or OR 10 . R 8 to R 11 As mentioned above about R 1 Most preferably, R 2 It's hydrogen.

[0077] R 3 and R 4 may independently be hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, CN, OR 10 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 10 、COOR 8 、CONR 10 R 11 NR 10 COR 11 NR 10 SO2R 11 NR 10 R 11 , optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted phenyl, or R 3 and R 4It can form a C=O group, an optionally substituted C3-C6 cycloalkyl group or an optionally substituted 3 to 8-membered heterocyclic group together with the C atom to which it is attached. 3 and R 4 are independently hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, halogen, CN, OR 10 , optionally substituted C3-C6 cycloalkyl or optionally substituted 3- to 8-membered heterocyclic group, or R 3 and R 4 and the C atom to which it is attached may form an optionally substituted C3-C6 cycloalkyl or an optionally substituted 3 to 8 membered heterocyclic group. Even more preferably, R 3 and R 4 are independently hydrogen, C1-C3 alkyl or halogen, or R 3 and R 4 Together with the C atom to which it is attached, it may form a C3-C6 cycloalkyl group. 8 to R 11 As mentioned above about R 1 Most preferably, R 3 and R 4 are independently hydrogen, methyl, ethyl, isopropyl or fluoro, or R 3 and R 4 Together with the C atom to which it is attached, it forms a cyclopropyl group.

[0078] R 5 and R 6 may independently be hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, CN, OR 10 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 10 、COOR 8 、CONR 10 R 11 NR 10 COR 11 NR 10 SO2R 11 NR 10 R 11 , optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted phenyl, or R 5 and R 6It can form a C=O group, an optionally substituted C3-C6 cycloalkyl group or an optionally substituted 3 to 8-membered heterocyclic group together with the C atom to which it is attached. 5 and R 6 are independently hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, halogen, CN, OR 10 , optionally substituted C3-C6 cycloalkyl or optionally substituted 3- to 8-membered heterocyclic group, or R 5 and R 6 can form a C=O group together with the C atom to which it is bound. Even more preferably, R 5 and R 6 are independently hydrogen, C1-C3 alkyl or halogen, or R 5 and R 6 Together with the C atom to which it is bound, it can form a C=O group. 8 to R 11 As mentioned above about R 1 Most preferably, R 5 and R 6 is hydrogen, or R 5 and R 6 Together with the C atom to which it is bound, it forms a C=O group.

[0079] R 7 It can be hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, CN, OR 10 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 10 、COOR 8 、CONR 10 R 11 NR 10 COR 11 NR 10 SO2R 11 or NR 10 R 11 More preferably, R 7 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, halogen, CN or OR 10 Even more preferably, R 7 is hydrogen, C1-C3 alkyl, CN or OR 10 . R 8 to R 11As mentioned above about R 1 Most preferably, R 7 is hydrogen or methyl.

[0080] Therefore, Y can be

[0081] Z may be a substituted phenyl group, a substituted pyrazole group or a substituted pyridyl group.

[0082] In a preferred configuration, the adjacent substituents of phenyl or 5 or 6 yuan heteroaryl Z are connected together with the C atom of the phenyl or heteroaryl to which they are combined to form 5 or 6 yuan heterocycles or heteroaromatic groups. It should be understood that in these embodiments, group Z is an optionally substituted fused group. In addition, the adjacent substituents of heterocycle or heteroaryl can be combined with the atom to which they are connected to form another optionally substituted 3 to 6 yuan heterocycle or another optionally substituted 5 or 6 yuan heteroaryl. Therefore, the optionally substituted fused group can be an optionally substituted bicyclic fused group or an optionally substituted tricyclic fused group. The optionally substituted bicyclic or tricyclic fused group can be an optionally substituted 8 to 14 yuan heterocycle or heteroaromatic group. In certain embodiments, Z is an optionally substituted bicyclic fused group and is an optionally substituted 9 or 10 yuan heterocycle or heteroaromatic group. In alternative embodiments, Z is an optionally substituted tricyclic fused group and is an optionally substituted 12 to 14 yuan heterocycle or heteroaromatic group. Preferred fused groups Z are optionally substituted benzo[d][1,3]dioxole, optionally substituted indoline, optionally substituted 1H-indazole, optionally substituted 1H-benzo[d]imidazole, optionally substituted benzo[d]thiazole, optionally substituted tetrahydroquinoline, optionally substituted tetrahydroisoquinoline, optionally substituted 3,4-dihydro-2H-benzo[b][1,4]oxazine, optionally substituted 2,3-dihydrobenzo[b][1,4]dioxine, optionally substituted isoquinoline, optionally substituted quinoxaline or optionally substituted 1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine. The fused group may be unsubstituted or substituted with one or more of the following: optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, oxo, CN, OR 16 SR 16 、SOR 16 、SO2R 16 、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 NR 16 R17 , optionally substituted C 6-12 Aryl, optionally substituted C 3-6 More preferably, the fused group is unsubstituted or substituted by one or more of the following: optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, halogen, oxo, CN, OR 16 SR 16 、SOR 16 、SO2R 16 、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 or NR 16 R 17 Most preferably, the fused group is unsubstituted or substituted with one or more of the following: optionally substituted C1-C3 alkyl, oxo, OR 16 or NR 16 COR 17 In embodiments where the fused group is substituted with an optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, the alkyl, alkenyl, or alkynyl group may be unsubstituted or substituted with one or more of: halogen, oxo, CN, OR 16 SR 16 、SOR 16 、SO2R 16 、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 and NR 16 R 17 More preferably, the alkyl, alkenyl or alkynyl group is unsubstituted or replaced by OR 16 Replace. R 16 and R 17 May be as defined above. Preferably, R 16 and R 17 may independently be H, optionally substituted C 1-3 Alkyl or optionally substituted C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl group is unsubstituted or substituted by halogen or OH. Most preferably, R 16 and R 17In a most preferred embodiment, the fused group is unsubstituted or substituted with one or more of the following: methyl, ethyl, OH, OCH3, oxo or

[0083] Preferably the group Z has the formula:

[0084]

[0085] where X 5 、X 6 、X 7 and X 8 Each independently selected from N and CR 21 , provided that X 5 、X 6 、X 7 and X 8 Only one of them is N; R 21 is independently H or halogen at each occurrence, preferably F; and A is selected from optionally substituted C1-C6 alkyl, COR 8 、COOR 8 、CONR 8 R 9 NR 8 COR 9 NR 8 R 9 , optionally substituted 3- to 10-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl. 8 and R 9 R is independently hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3 to 8 membered heterocyclyl, or optionally substituted 5 to 10 membered heteroaryl. More preferably, R 8 and R 9 is independently hydrogen, optionally substituted C1-C3 alkyl or optionally substituted 5 or 6 membered heterocyclyl. Alkyl may be unsubstituted or substituted by halogen, OR 16 or NR 16 R 17 One or more of R 16 and R 17 Can be as defined above. In some embodiments, R 16 and R17 Can independently be H or C1-C3 alkyl.

[0086] Alternatively preferred groups Z have the formula:

[0087]

[0088] where X 5 、X 6 、X 7 and X 8 Is N or CR 21 , provided that X 5 、X 6 、X 7 and X 8 Only one of them is N;

[0089] R 21 is independently at each occurrence H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, CN, OR 8 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 8 、COOR 8 、CONR 8 R 9 NR 8 COR 9 NR 8 SO2R 9 NR 8 R 9 , an optionally substituted 3- to 6-membered heterocyclyl, an optionally substituted 5- or 6-membered heteroaryl, an optionally substituted C 6-10 Aryl or optionally substituted C 3-9 cycloalkyl; and

[0090] A is selected from the group consisting of optionally substituted C1-C6 alkyl, OR 8 、SO2R 8 、SO2NR 8 R 9 、COR 8 、COOR 8 、CONR 8 R 9 NR 8 COR 9 NR 8 SO2R 9 NR 8 R 9, optionally substituted 3- to 10-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl.

[0091] In some embodiments, X 5 、X 6 、X 7 and X 8 All CR 21 .

[0092] In an alternative embodiment, X 5 、X 7 and X 8 All CR 21 , and X 6 It's N.

[0093] In one embodiment, the phenyl or 5 or 6 membered heteroaryl Z is substituted by an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted 5 to 10 membered heteroaryl, an optionally substituted C 6-10 Aryl or optionally substituted C 3-9 Cycloalkyl. It should be understood that optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or optionally substituted cycloalkyl can be group A in the above formula. In some embodiments, phenyl or 5- or 6-membered heteroaryl Z is substituted by optionally substituted 3- to 10-membered heterocyclyl or optionally substituted 5- to 10-membered heteroaryl.

[0094] Preferred optionally substituted heteroaryl groups (which are substituents on the Z group, which may optionally be A in the above formula) are optionally substituted pyridyl, optionally substituted pyrazolyl, optionally substituted oxazolyl or optionally substituted 2H-1,2,3-triazolyl. Preferred heteroaryl groups (which are substituents on the Z group, which may optionally be A in the above formula) are pyridyl, pyrazolyl or oxazolyl.

[0095] Preferred optionally substituted heterocyclic groups (which are substituents on the Z group, which may optionally be A in the above formula) are optionally substituted pyrrolidinyl, optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted tetrahydropyranyl, optionally substituted morpholinyl, optionally substituted thiomorpholinyl, optionally substituted azepanyl, optionally substituted octahydropyrrolo[1,2-a]pyrazinyl, optionally substituted octahydropyrrolidin ... imidazo[1,5-a]pyrazinyl, optionally substituted octahydropyrazino[2,1-c][1,4]oxazinyl, optionally substituted octahydro-2H-pyrido[1,2-a]pyrazinyl, optionally substituted 1,5-diazabicyclo[2.2.1]heptanyl, optionally substituted 3,8-diazabicyclo[3.2.1]octanyl or optionally substituted 2,5-diazabicyclo[2.2.2]octanyl.

[0096] Preferably the heterocyclic group (which is a substituent on the Z group, which may optionally be A in the above formula) is a group of formula (i) or (j):

[0097]

[0098] in:

[0099] T is N and M is NR 13 , CR 14 R 15 , O, S or SO2; or T is CR 18 , and M is NR 13 , O, S or SO2;

[0100] Q is C(R 12 )2, and n is 0, 1 or 2;

[0101] R 12 is independently at each occurrence H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, oxo, CN, OR 16 SR 16 、SOR 16 、SO2R 16 、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 NR 16 R 17 , optionally substituted C 6-12 Aryl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3- to 6-membered heterocycle, or optionally substituted 5- to 10-membered heteroaryl; and / or two R bound to the same carbon 12 The group can define an oxo group, bound to two R atoms on adjacent carbon atoms. 12 The groups may be linked to form a fused group or bonded to two R 12 The groups can be linked to form a bicyclic bridging group;

[0102] R 13 is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, oxo, CN, OR 16 SR 16 、SOR 16 、SO2R 16 、COR 16 、COOR16 、CONR 16 R 17 NR 16 COR 17 NR 16 R 17 , optionally substituted C 6-12 Aryl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3- to 6-membered heterocycle, or optionally substituted 5- to 10-membered heteroaryl;

[0103] R 14 and R 15 Each is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, oxo, CN, OR 16 SR 16 、SOR 16 、SO2R 16 、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 NR 16 R 17 , optionally substituted C 6-12 Aryl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3- to 6-membered heterocycle, or optionally substituted 5- to 10-membered heteroaryl.

[0104] Preferably the heterocyclic group (which is a substituent on the Z group, which may optionally be A in the above formula) is a group of formula (i) or (j):

[0105]

[0106] in:

[0107] T is N and M is NR 13 , CR 14 R 15 , O, S or SO2; or T is CR 18 , and M is NR 13 , O, S or SO2;

[0108] Q is C(R 12 )2, and n is 1 or 2;

[0109] R 12 is independently at each occurrence H, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-6 Cycloalkyl, OR 19 ; or NR 19 R 20 ; and / or two R bound to adjacent carbon atoms 12 The groups may be linked to form a fused group or bonded to two R 12 The groups can be linked to form a bicyclic bridging group;

[0110] R 13 is H, optionally substituted C1-C6 alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, COR 19 or CONR 19 R 20 ;

[0111] R 14 and R 15 are each independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C3-C6 cycloalkyl, OR 19 and NR 19 R 20 , or R 14 and R 15 The C atoms to which they are all bound may be linked together to form an optionally substituted 3- to 6-membered heterocyclic group or an optionally substituted C 3-6 Cycloalkyl;

[0112] R 18 is hydrogen or optionally substituted C1-C6 alkyl; and

[0113] R 19 and R 20 are each independently H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 3- to 6-membered heterocyclyl.

[0114] The heterocyclyl or heteroaryl group (which is a substituent on the Z group) may be unsubstituted or substituted with one or more optional substituents selected from the group consisting of an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C1-C6 alkoxy, an optionally substituted C2-C6 alkylene group, an optionally substituted C2-C6 alkynyl group, an optionally substituted C1-C6 alkoxyl group ...alkynyl group, an optionally substituted C2-C6 alk 3-6 Cycloalkyl, halogen, oxo, CN, OR 16 SR 16 、SOR 16 、SO2R 16 、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 or NR 16 R 17 More preferably, the heterocyclyl or heteroaryl (which is a substituent on the Z group) may be unsubstituted or substituted with one or more substituents selected from the group consisting of optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C 3-6 Cycloalkyl, halogen, oxo, COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 or NR 16 R 17 . Alkyl groups can be OR 16 and NR 16 R 17 Replace. R 16 and R 17 Can be as defined above. In some embodiments, R 16 and R 17 and alkyl, wherein the alkyl radicals are selected from the group consisting of H, C1-C3 alkyl, or an optionally halogenated 5- or 6-membered heterocycle.

[0115] The heterocyclyl, heteroaryl, aryl or cycloalkyl group (which is a substituent on the Z group and can be group A in the above formula) can be unsubstituted or substituted by one or more optional substituents selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, oxo, CN, OR 16 SR 16 、SOR 16 、SO2R 16 、COR 16 、COOR16 、CONR 16 R 17 NR 16 COR 17 NR 16 R 17 , optionally substituted C 6-12 Aryl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3 to 6 membered heterocycle or optionally substituted 5 to 10 membered heteroaryl. It is understood that these substituents may be groups R 12 、R 13 、R 14 and / or R 15 Therefore, R 13 、R 14 and / or R 15 R may be H or a substituent as defined below. 12 is H or a substituent as defined below, and / or two R bonded to the same carbon 12 The group can define an oxo group, bound to two R atoms on adjacent carbon atoms. 12 The groups may be linked to form a fused group or bonded to two R 12 The groups may be linked to form bicyclic bridging groups. Most preferably, these substituents may be groups R 13 or R 14 More preferably, the heterocyclyl, heteroaryl, aryl or cycloalkyl group (which is a substituent on the Z group) may be unsubstituted or substituted with one or more substituents selected from the group consisting of optionally substituted C1-C6 alkyl, oxo, CN, OR 16 、SO2R 16 、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 NR 16 R 17 , optionally substituted C 3-6 Cycloalkyl, optionally substituted 3- to 6-membered heterocyclic ring or optionally substituted 5- or 6-membered heteroaryl. 16 and R 17 May be as defined above. Preferably, R 16 and R 17 R is independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3 to 8-membered heterocyclyl or optionally substituted 5 to 10-membered heteroaryl. More preferably, R 16 and R 17is independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 4- to 8-membered heterocyclyl, or optionally substituted 5- or 6-membered heteroaryl. When heterocyclyl, heteroaryl, aryl, or cycloalkyl (which is a substituent on the Z group) is substituted directly or indirectly with optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, the alkyl, alkenyl, or alkynyl group may be unsubstituted or substituted with one or more of halogen, oxo, CN, OR 16a SR 16a 、SOR 16a 、SO2R 16a 、COR 16a 、COOR 16a 、CONR 16a R 17a NR 16a COR 17a NR 16a R 17a , optionally substituted C 6-12 Aryl, optionally substituted C 3-6 More preferably, the alkyl, alkenyl or alkynyl group is unsubstituted or substituted by one or more of: fluoro, OR 16a 、SO2R 16a , optionally substituted C 3-6 Cycloalkyl, optionally substituted 4- to 6-membered heterocycle or optionally substituted 5- or 6-membered heteroaryl. 16a and R 17a Can be combined with the above R 16 and R 17 More preferably, R 16a and R 17a R is independently hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl or optionally substituted C2-C3 alkynyl. More preferably, R 16a and R 17a are independently hydrogen and optionally substituted C1-C3 alkyl. When heterocyclyl, heteroaryl, aryl or cycloalkyl (which is a substituent on the Z group) is substituted directly or indirectly with optionally substituted cycloalkyl, optionally substituted heterocycle or optionally substituted heteroaryl, the cycloalkyl, heterocycle or heteroaryl may be unsubstituted or substituted with one or more of optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, oxo, CN, OR 16b SR 16b 、SOR 16b 、SO2R 16b 、COR 16b 、COOR 16b、CONR 16b R 17b NR 16b COR 17b or NR 16b R 17b More preferably, the cycloalkyl, heterocycle or heteroaryl is unsubstituted or substituted by one or more of the following: optionally substituted C1-C3 alkyl, halogen, oxo, CN, OR 16b 、COOR 16b 、CONR 16b R 17b or NR 16b R 17b Most preferably, the cycloalkyl, heterocycle or heteroaryl is unsubstituted or substituted with one or more of the following: C1-C3 alkyl, optionally substituted fluorine, OH or OCH3, fluorine, oxo or CONR 16b R 17b . R 16b and R 17b Can be combined with the above R 16 and R 17 More preferably, R 16b and R 17b R is independently hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl or optionally substituted C2-C3 alkynyl. More preferably, R 16b and R 17b Is CH3. If heterocyclyl, heteroaryl, aryl or cycloalkyl has a substituent comprising a group, it can be understood to be indirectly substituted by said group. In the embodiment where aryl or cycloalkyl is a substituent on the Z group, aryl or cycloalkyl is preferably unsubstituted. In the embodiment where heterocyclyl or heteroaryl is a substituent on the Z group, heterocyclyl or heteroaryl is preferably substituted. Preferably, heterocyclyl or heteroaryl has 1, 2 or 3 substituents, and most preferably has 1 substituent. Most preferably, heterocyclyl or heteroaryl (which is a substituent on the Z group) may be unsubstituted or substituted by one or more substituents selected from the group consisting of: methyl, ethyl, Oxo, CN, OH, OCH3, COOH, CONH2, NH2, and

[0116] Therefore, R 13 、R 14 and R 15 Can be independently H, methyl, ethyl, Oxo, CN, OH, OCH3, COOH, CONH2, NH2, In M is CR 14 R 15 In the embodiment, R 15 Can be H, and R 14 May be as defined above.

[0117] In another embodiment, the phenyl or 5 or 6 membered heteroaryl Z is not directly substituted by an optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl or optionally substituted cycloalkyl. Thus, in this embodiment, the phenyl or 5 or 6 membered heteroaryl Z is substituted by one or more substituents selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, CN, OR 8 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 8 、COOR 8 、CONR 8 R 9 NR 8 COR 9 NR 8 SO2R 9 and NR 8 R 9 It will be appreciated that these substituents may be group A. More preferably, the phenyl group or the 5- or 6-membered heteroaryl group Z is substituted by one or more substituents selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, OR 8 、SO2R 8 、SO2NR 8 R 9 、COR 8 、COOR 8 、CONR 8 R 9 NR 8 SO2R 9 and NR 8 R 9Most preferably, the phenyl group or the 5- or 6-membered heteroaryl group Z is substituted by one or more substituents selected from the group consisting of optionally substituted C1-C3 alkyl, OR 8 、SO2R 8 、SO2NR 8 R 9 、COR 8 、CONR 8 R 9 NR 8 SO2R 9 and NR 8 R 9 . R 8 and R 9 may independently be hydrogen, optionally substituted C1-C 12 Alkyl, optionally substituted C 6-12 aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3 to 8 membered heterocyclyl and optionally substituted 5 to 10 membered heteroaryl. More preferably, R 8 and R 9 are independently hydrogen, optionally substituted C1-C 10 alkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3 to 8-membered heterocyclyl or optionally substituted 5 to 10-membered heteroaryl. Most preferably, R 8 and R 9 Can be H, optionally substituted C 1- C8 alkyl, cyclopropyl, optionally substituted 5 or 6 membered heterocycle or optionally substituted phenyl. Alkyl may be unsubstituted or substituted by one or more of the following: halogen, oxo, CN, OR 16 SR 16 、SOR 16 、SO2R 16 、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 NR 16 R 17 , optionally substituted C 6-12 Aryl, optionally substituted C 3-6 More preferably, the alkyl group is unsubstituted or substituted by one or more of the following: halogen, OR 16 NR 16 R 17 , optionally substituted phenyl, optionally substituted C 3-6Cycloalkyl, optionally substituted 3- to 6-membered heterocyclic ring or optionally substituted 5- or 6-membered heteroaryl. 16 and R 17 Preferably H or C 1-3 Most preferably, the alkyl group is unsubstituted or substituted by one or more of the following: F, OH, N(CH3)2, N(CH2CH3)2, an optionally substituted 5- or 6-membered heterocycle, an optionally substituted 5- or 6-membered heteroaryl, or an optionally substituted phenyl group. 8 or R 9 When it is an optionally substituted cycloalkyl, an optionally substituted heterocycle or an optionally substituted heteroaryl, or when the alkyl group is substituted by an optionally substituted cycloalkyl, an optionally substituted heterocycle or an optionally substituted heteroaryl, the optionally substituted cycloalkyl, the optionally substituted heterocycle or the optionally substituted heteroaryl may be unsubstituted or substituted by one or more of the following: an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C1-C6 alkoxy, halogen, oxo, CN, OR 16 SR 16 、SOR 16 、SO2R 16 、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 NR 16 R 17 , optionally substituted C 6-12 Aryl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3 to 6 membered heterocycle or optionally substituted 5 to 10 membered heteroaryl. Most preferably, the optionally substituted cycloalkyl, optionally substituted heterocycle or optionally substituted heteroaryl may be unsubstituted or substituted with one or more of the following: C 1-3 Alkyl, halogen, oxo, OR 16 and NR 16 R 17 Preferably, R 16 and R 17 Is H or C 1-3 Most preferably, the optionally substituted cycloalkyl, optionally substituted heterocycle or optionally substituted heteroaryl is unsubstituted or substituted with one or more of CH3, OCH3 and / or oxo. 8 or R 9is an optionally substituted aryl group, or when an alkyl group is substituted with an optionally substituted aryl group, the optionally substituted aryl group may be unsubstituted or substituted with one or more of the following: an optionally substituted C1-C6 alkyl group, an optionally substituted C2-C6 alkenyl group, an optionally substituted C2-C6 alkynyl group, an optionally substituted C1-C6 alkoxy group, halogen, CN, OR 16 SR 16 、SOR 16 、SO2R 16 、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 NR 16 R 17 , optionally substituted C 6-12 Aryl, optionally substituted C 3-6 cycloalkyl, an optionally substituted 3 to 6 membered heterocycle or an optionally substituted 5 to 10 membered heteroaryl. Most preferably, the optionally substituted aryl is unsubstituted or replaced by C 1-3 Alkyl, halogen, OR 16 and NR 16 R 17 Preferably, R 16 and R 17 Is H or C 1-3 Most preferably, the optionally substituted aryl is unsubstituted or substituted by one or more of CH3 and / or OCH3. The phenyl or 5- or 6-membered heteroaryl Z may be substituted by one or more substituents selected from the group consisting of CH3, CH2CF3, CF3, SO2NH2, CONH2, and

[0118] In a preferred embodiment, heterocyclyl or heteroaryl (which is a substituent on the Z group, which may optionally be A in the above formula) is an optionally substituted 5- or 6-membered heterocyclyl or an optionally substituted 5- or 6-membered heteroaryl. In a preferred embodiment, heterocyclyl or heteroaryl (which is a substituent on the Z group, which may optionally be A in the above formula) is an optionally substituted 6-membered heterocyclyl or an optionally substituted 6-membered heteroaryl.

[0119] The heterocyclic or heteroaryl group (which is a substituent on the Z group, which may optionally be A in the above formula) may be unsubstituted or substituted by one or more of the following: optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, oxo, CN, OR16 SR 16 、SOR 16 、SO2R 16 、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 NR 16 R 17 , optionally substituted C 6-12 Aryl, optionally substituted C 3-6 Non-adjacent substituent pairs of cycloalkyl, optionally substituted 3 to 6 membered heterocycle or optionally substituted 5 to 10 membered heteroaryl, or 3 to 8 membered heterocyclyl can be combined to form a bridged group. More preferably, the optionally substituted heterocyclyl or optionally substituted heteroaryl (which is a substituent on the Z group, which may optionally be A in the above formula) may be unsubstituted or substituted with one or more of the following: optionally substituted C1-C3 alkyl, halogen, oxo, COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 or NR 16 R 17 , or non-adjacent pairs of substituents of a 3- to 8-membered heterocyclic group may be combined to form a bridge group. Even more preferably, the heterocyclic group or heteroaryl (which is a substituent on the Z group, which may optionally be A in the above formula) may be unsubstituted or substituted with one or more of the following: optionally substituted C1-C3 alkyl, fluorine, COR 16 or CONR 16 R 17 , or non-adjacent substituent pairs of 3 to 8 membered heterocyclic groups can be combined to form a bridge group. The alkyl group can be unsubstituted or substituted with halogen, OR 16 or NR 16 R 17 One or more of R 16 and R 17 Can be as defined above. In some embodiments, R 16 and R 17 may be independently selected from the group consisting of: H, optionally substituted C1-C3 alkyl, optionally substituted C 3-6 cycloalkyl, an optionally substituted 3- to 6-membered heterocycle, or an optionally substituted 5- to 10-membered heteroaryl. 16 and R 17 Each is independently selected from the group consisting of H, methyl and an optionally halogenated 5- or 6-membered heterocycle. Preferably, the bridging group is an optionally substituted methylene or ethylene group.

[0120] n can be 1 or 2. In some embodiments, n is 1.

[0121] In some embodiments, T is N and M is NR 13 In some embodiments, T is CR 18 , and M is NR 13 .

[0122] R 13 It can be H, optionally substituted C1-C6 alkyl, C 3-6 Cycloalkyl, COR 19 or CONR 19 R 20 . R 19 and R 20 may be each independently H, optionally substituted C 1-3 alkyl or an optionally substituted 5- or 6-membered heterocyclic group. More preferably, R 19 and R 20 are each independently H, optionally substituted C 1-3 Alkyl or an optionally halogenated 5 or 6 membered heterocyclic group. The alkyl group may be unsubstituted or substituted by halogen, oxo, CN, OR 16 or NR 16 R 17 One or more of R 16 and R 17 May be as defined above. Preferably, R 16 and R 17 is H or CH3. 13 Can be CH3, CH2CH3, CH2CH2OH, CH2CH2OCH3,

[0123] In some embodiments, T is N and M is CR 14 R 15 .

[0124] R 14 and R 15 may be independently selected from hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C3-C6 cycloalkyl, OR 19 -and-NR 19 R 20 , or R 14 and R 15 The C atoms to which they are all bound may be linked together to form an optionally substituted 3- to 6-membered heterocyclic group. 14 and R 15 are each independently selected from hydrogen, halogen, optionally substituted C1-C3 alkyl and NR 19 R20 , or R 14 and R 15 They may be joined together to form an optionally substituted 3- to 6-membered heterocyclic group. 19 and R 20 may each independently be H or optionally substituted C 1-3 Preferably, R 19 and R 20 Each is H. R 14 and R 15 can be independently H, F, NH2, or R 14 and R 15 They can be linked together with the C atoms to which they are all bound to form a 5-membered heterocyclic group.

[0125] In some embodiments, T is N, and M is O or SO2.

[0126] Preferably, R 18 It's hydrogen.

[0127] Preferably, R 12 is independently H, halogen or optionally substituted C 1-3 Alkyl; and / or two R bound to the same carbon atom 12 Group Definitions Oxo; and / or two R bound to non-adjacent carbon atoms 12 More preferably, R 12 H or CH3 at each occurrence; and / or two R bound to the same carbon atom 12 Group Definitions Oxo; and / or two R bound to non-adjacent carbon atoms 12 The groups are connected to form a bicyclic bridging group.

[0128] Exemplary bridging groups have the formula:

[0129]

[0130] The group A or heterocyclyl or heteroaryl may be the only substituent of the phenyl or pyridyl group Z, or one or more other substituents may be present. When present, the one or more other substituents may be selected from halogen; Ak; -OH; -OAk; -NH2; -NHAk; NAk2; optionally substituted heteroaryl; and optionally substituted heterocyclyl, wherein Ak is independently C at each occurrence. 1-6 Alkyl or C 3-6 The one or more other substituents are preferably halogen, more preferably F.

[0131] Phenyl or 5- or 6-membered heteroaryl may not contain any other substituents. 21 It can be H.

[0132] Alternatively, the phenyl or 5- or 6-membered heteroaryl may be further optionally substituted by one or more substituents selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, CN, OR 8 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 8 、COOR 8 、CONR 8 R 9 NR 8 COR 9 NR 8 SO2R 9 NR 8 R 9 , an optionally substituted 3 to 6 membered heterocyclyl or an optionally substituted 5 or 6 membered heteroaryl. It should be understood that these substituents may be one or more R 21 Other R in the above formula 21 The group may be H. Thus, each R 21 Phenyl or 5 or 6 membered heteroaryl may be further optionally substituted by one or more substituents selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, CN, OR 8 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 8 、COOR 8 、CONR 8 R 9 NR 8 COR 9 NR 8 SO2R 9 and NR 8 R 9 . R 8 and R 9 R is independently hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl or optionally substituted C2-C3 alkynyl, and preferably, R 8 and R 9 are independently H or C 1-3When phenyl or 5- or 6-membered heteroaryl is further substituted with an optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, the alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more of the following: halogen, oxo, CN, OR 16 SR 16 、SOR 16 、SO2R 16 、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 and NR 16 R 17 More preferably, the alkyl, alkenyl or alkynyl groups are unsubstituted or replaced by fluorine, OR 16 and NR 16 R 17 Replace. R 16 and R 17 May be as defined above. Preferably, R 16 and R 17 R is independently hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl or optionally substituted C2-C3 alkynyl, and preferably, R 16 and R 17 are independently H or C 1-3 In some embodiments, the phenyl or 5- or 6-membered heteroaryl Z is substituted with an optionally substituted 5- to 10-membered heterocyclyl, an optionally substituted 5- to 10-membered heteroaryl, an optionally substituted phenyl, or an optionally substituted C 3-6 In some embodiments, the phenyl or 5- or 6-membered heteroaryl Z is substituted with an optionally substituted 5- to 10-membered heterocyclyl or an optionally substituted 5- to 10-membered heteroaryl. The phenyl or 5- or 6-membered heteroaryl may not contain any other substituents. Alternatively, the phenyl or 5- or 6-membered heteroaryl may be further optionally substituted with one or more substituents selected from the group consisting of halogen, optionally substituted C1-C3 alkyl, CN, OR 8 、COOR 8 、CONR 8 R 9 NR 8 R 9Phenyl or 5 or 6 membered heteroaryl may further optionally be substituted with halogen. In certain embodiments, phenyl or 5 or 6 membered heteroaryl Z is substituted with: an optionally substituted 5 to 7 membered heterocyclic radical, an optionally substituted 5 or 6 membered heteroaryl, phenyl or cyclohexyl. In certain embodiments, phenyl or 5 or 6 membered heteroaryl Z is substituted with: an optionally substituted 5 to 7 membered heterocyclic radical or an optionally substituted 5 or 6 membered heteroaryl. Phenyl or 5 or 6 membered heteroaryl may not contain any other substituents. Alternatively, phenyl or 5 or 6 membered heteroaryl may further optionally be substituted with halogen. Halogen may be fluorine. In some embodiments, the phenyl or 5- or 6-membered heteroaryl Z is substituted with optionally substituted heterocyclyl or optionally substituted heteroaryl and further substituted with one or more of F, Cl, Br, CH3, CF3, CH2OH, CH2CH2OH, CH2NH2, CH2N(CH3)2, CN, OCH3, OCH2CH3, COOH, CON(CH3)2, NH2, NHCH3, N(CH3)2, or Therefore, each R 21 may independently be H, F, Cl, Br, CH3, CF3, CH2OH, CH2CH2OH, CH2NH2, CH2N(CH3)2, CN, OCH3, OCH2CH3, COOH, CON(CH3)2, NH2, NHCH3, N(CH3)2 or

[0133] In some embodiments, the phenyl group or the 5- or 6-membered heteroaryl group Z is further substituted by halogen, preferably further substituted by fluorine.

[0134] Z can be

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143] It should be understood that the above compounds can exist in the form of enantiomers and diastereomeric pairs. These isomers also represent other embodiments of the present invention.

[0144] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

[0145] Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound (e.g., an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid). The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereomers can be converted to the corresponding pure enantiomer by methods well known to those skilled in the art.

[0146] The chiral compounds of the present invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form using chromatography (typically HPLC) on an asymmetric resin using a mobile phase consisting of a hydrocarbon (typically heptane or hexane) containing 0 to 50% by volume (typically 2% to 20%) of isopropanol and 0 to 5% by volume of an alkylamine (typically 0.1% diethylamine). Concentration of the eluate yields an enriched mixture.

[0147] Mixtures of stereoisomers can be separated by conventional techniques known to those skilled in the art; see, for example, EL Eliel and SH Wilen, Stereochemistry of Organic Compounds (Wiley, New York, 1994).

[0148] It will be appreciated that the compounds described herein, or pharmaceutically acceptable salts, solvates, tautomeric forms, or polymorphic forms thereof, can be used as agents that can be used in monotherapy (i.e., using only the compound) for inhibiting HPK-1 protein and / or treating, ameliorating, or preventing disease.

[0149] Alternatively, the compound or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof can be used as an adjuvant to or in combination with known therapies for inhibiting HPK-1 protein and / or treating, ameliorating or preventing disease.

[0150] Therefore, in one aspect, the second therapeutic agent can be administered together with the compound of formula (I). The compound of formula (I) can be administered before, after and / or simultaneously with the second therapeutic agent. The second therapeutic agent may include an antiviral agent, an anti-inflammatory agent, conventional chemotherapy, an anticancer vaccine and / or a hormone therapy or an anti-proliferative compound. Alternatively or in addition, the second therapeutic agent may include a B7 costimulatory molecule, interleukin-2, interferon-γ, GM-CSF, a CTLA-4 antagonist (such as ipilimumab and tremilimumab), an IDO inhibitor or an IDO / TDO inhibitor (such as epacadostat, CRD1152 and GDC-0919), a PD-1 inhibitor (such as nivolumab, pembrolizumab, pidilizumab), or a combination thereof. lizumab), PD-L1 inhibitors (such as durvalumab, avelumab and atezolizumab), OX-40 agonists, LAG3 inhibitors, TIM-3 inhibitors, anti-TIGIT monoclonal antibodies, CD40 ligands, 4-1BB / CD137 agonists, GITR agonists, ICOS agonists, KIR inhibitors, CD47 inhibitors, CD73 inhibitors, CSF1R inhibitors, NKG2A inhibitors, CD27 agonists, Bacille Calmette-Guerin (BCG), liposomes, alum, Freund's complete or incomplete adjuvant, TLR agonists (such as Poly I: C, MPL, LPS, bacterial flagellin, imiquimod, resiquimod, loxoribine and CpG dinucleotides), CAR T cells and / or detoxified endotoxins. Antiproliferative compounds include, but are not limited to, aromatase inhibitors (formestane, anastrozole), antiestrogens (tamoxifen, raloxifene, fulvestrant), topoisomerase inhibitors (camptothecin, irinotecan, doxorubicin, mitoxantrone, etoposide, epirubicin), microtubule-active compounds (paclitaxel, docetaxel, vinblastine, vincristine, discodermolide, colchicine, epothilone),Alkylating agents (ifosfamide, cyclophosphamide), histone deacetylase inhibitors (SAHA), antineoplastic metabolites (5-fluorouracil, gemcitabine, 5-azacytidine, methotrexate, pemetrexed), cyclooxygenase inhibitors (celecoxib, rofecoxib, valdecoxib), MMP inhibitors, mTOR inhibitors (sirolimus), platinum compounds (cisplatin, oxaliplatin), kinase inhibitors (imatinib, sunitinib, nilotinib, dasatinib, Herceptin, Iressa, tarceva, pacritinib),

[0015] The following are some of the drugs that may be used in the treatment of leukemia and leukemia: inib, tofacitinib, ruxolitinib, ibrutinib, fostamatinib), antiangiogenic compounds (thalidomide), gonadal-releasing hormone agonists (abarelix, goserelin), antiandrogens (bicalutamide), bisphosphonates, antiproliferative antibodies (Herceptin, Erbitux, bevacizumab, rituximab), heparinase inhibitors, inhibitors of Ras oncogenic isoforms, telomerase inhibitors (telomestatin), proteasome inhibitors (bortezomib), HSP-90 inhibitors, temozolomide, kinesin spindle protein inhibitors, and MEK inhibitors. In addition, the second therapeutic agent may include adefovir, tenofovir disoproxil fumarate + emtricitabine (Truvada), tenofovir disoproxil fumarate (Viread), entecavir, lamivudine, tenofovir alafenamide, telbivudine, clevudine, emtricitabine, peginterferon α2b, multiferon, interferon α1b, interferon α2b, peginterferon α2a, interferon αn1, ribavirin,Interferon beta 1a, bioferon, interferon alpha 2b, 4-ethynyl-2-fluoro-deoxyadenosine, HIV / HBV / HCV vaccines, HBV / HCV DNA polymerase inhibitors, HIV reverse transcriptase inhibitors, HIV / HBV / HCV protease inhibitors, HIV integrase inhibitors, HIV maturation inhibitors, HIV capsid inhibitors, HIV Vif inhibitors, gp41 inhibitors, CXCR4 antagonists, gp120 inhibitors, C5a antagonists, cyclophilin inhibitors, surface antigen inhibitors, viral entry inhibitors, antisense oligonucleotides targeting viral mRNA, CCR2 antagonists, CCR5 antagonists, cytokines, RIG-I stimulators, NOD2 stimulators, PI3K inhibitors, and pharmacokinetic enhancers.

[0151] Methods for co-administration with another therapeutic agent are well known in the art (Hardman et al. (Eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed., 2001, McGraw-Hill New York, NY; Poole and Peterson (Eds.), Pharmacotherapeutics for Advanced Practice: A Practical Approach, 2001, Lippincott, Williams & Wilkins, Philadelphia, PA; Chabner and Longo (Eds.), Cancer Chemotherapy and Biotherapy, 2001, Lippincott, Williams & Wilkins, Philadelphia, PA).

[0152] In one aspect, the disease is cancer and a chemotherapeutic agent may be administered together with a compound of formula (I). The chemotherapeutic agent may be further selected from the group consisting of: a cancer vaccine, a targeted drug, a targeted antibody, an antibody fragment, an antimetabolite, an antitumor, an antifolate, a toxin, an alkylating agent, a DNA strand-breaking agent, a DNA minor groove binder, a pyrimidine analog, a ribonucleotide reductase inhibitor, a microtubule-interacting agent, an antihormonal agent, an immunomodulator, an antiadrenal agent, a cytokine, radiotherapy, cell therapy, cell depletion therapy (such as B cell depletion therapy) and hormone therapy. Alternatively or additionally, the chemotherapeutic agent may comprise abiraterone, altretamine, vinblastine, auristatin, bexarotene, bicalutamide, bleomycin, cachectin, cemadotin, chlorambucil, cyclophosphamide, docetaxel, doxetaxel, carboplatin, cisplatin, cytarabine, dactinomycin, daunorubicin, decitabine, doxorubicin, etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea, streptozocin, mitomycin, methotrexate, a taxane, tamoxifen, vinblastine, vincristine, and / or vindesine.

[0153] Complexes of compounds of formula (I) are understood to be multi-component complexes in which the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes may be substances other than salts or solvates. Complexes of this type include clathrates (drug-host inclusion complexes) and cocrystals. The latter are generally defined as crystalline complexes of neutral molecular components bound together by non-covalent interactions, but may also be complexes of neutral molecules with salts. Cocrystals may be prepared by melt crystallization, by recrystallization from a solvent, or by physically grinding the components together, see O. Almarsson and MJ Zaworotko, Chem Commun, 17, 1889-1896 (2004), incorporated herein by reference. For a general review of multi-component complexes, see Haleblian, J Pharm Sci, 64(8), 1269-1288 (August 1975), incorporated herein by reference.

[0154] The term "pharmaceutically acceptable salt" is understood to mean any salt of the compounds provided herein that retains biological properties and is non-toxic or not otherwise unsuitable for pharmaceutical use. Such salts may be derived from various organic and inorganic counterions well known in the art. Such salts include, but are not limited to: (1) acid addition salts formed with organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, adipic acid, aspartic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzene Formic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphor, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfide or (2) base addition salts which are formed when an acidic proton present in the parent compound undergoes: (a) replacement by a metal ion, e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion, or an alkali metal or alkaline earth metal hydroxide, such as sodium, potassium, calcium, magnesium, aluminum, lithium, zinc, and barium hydroxides; , or (b) coordinated with an organic base, such as an aliphatic, alicyclic or aromatic organic amine, such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, etc.

[0155] Pharmaceutically acceptable salts may include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, and, when the compound contains a basic functional group, salts of non-toxic organic or inorganic acids such as hydrohalides (e.g., hydrochlorides, hydrobromides, and hydroiodides), carbonates or bicarbonates, sulfates or bisulfates, borates, phosphates, hydrogenphosphates, dihydrogenphosphates, pyroglutamates, glucarates, stearates, sulfamates, nitrates, orotates, oxalates, palmitic acids, salt, pamoate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, tannate, tartrate, toluenesulfonate, sorbate, ascorbate, malate, maleate, fumarate, tartrate, camphorsulfonate, citrate, cyclohexylsulfamate, benzoate, isethionate, ethanesulfonate, formate , 3-(4-hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate, mesylate, methylsulfate, naphthalene dicarboxylate, 2-naphthalenesulfonate, nicotinate, ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (benzenesulfonate / besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-methanesulfonate Benzenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, benzoate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate, hydroxynaphthoate, etc.

[0156] Hemi-salts of acids and bases, such as hemisulphates, can also be formed. Those skilled in the art will appreciate that the aforementioned salts include salts in which the relative ions are optically active, such as D-lactate, or salts in which the relative ions are racemic, such as DL-tartrate.

[0157] For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002).

[0158] Pharmaceutically acceptable salts of compounds of formula (I) can be prepared by one or more of three methods:

[0159] (i) by reacting a compound of formula (I) with a desired acid or base;

[0160] (ii) removing an acid- or base-labile protecting group from a suitable precursor of a compound of formula (I) by using the desired acid or base; or

[0161] (iii) converting a salt of a compound of formula (I) into another salt by reacting it with a suitable acid or base or with the aid of a suitable ion exchange column.

[0162] All three reactions are typically carried out in solution. The resulting salt can be precipitated and collected by filtration, or can be recovered by evaporating the solvent. The degree of ionization of the resulting salt can vary from fully ionized to almost non-ionized.

[0163] The term "solvate" is understood to refer to a compound or salt thereof as provided herein, further comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent of crystallization may be isotopically substituted, such as D2O, d6-acetone, and d6-DMSO.

[0164] The currently recognized classification system for organic hydrates is the classification system that defines isolated site, channel or metal ion coordinated hydrates, see KR Morris (KR Morris), Polymorphism in Pharmaceutical Solids (HG Brittain, ed., Marcel Dekker, 1995), which is incorporated herein by reference. Isolated site hydrates are hydrates in which water molecules are separated from each other by the insertion of organic molecules and are not in direct contact. In channel hydrates, water molecules are in lattice channels next to other water molecules. In metal-ion coordinated hydrates, water molecules are bound to metal ions.

[0165] When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry that is independent of humidity. However, when the solvent or water is weakly bound (as in channel solvates and hygroscopic compounds), the water / solvent content will depend on humidity and drying conditions. In these cases, non-stoichiometry will serve as the norm.

[0166] The compounds of the present invention can exist in a continuum of solid states ranging from completely amorphous to completely crystalline, including polymorphs of the crystalline materials. The term "amorphous" refers to a state in which a material lacks long-range regularity at the molecular level and exhibits the physical properties of a solid or liquid, depending on the temperature. Such materials generally do not produce a unique X-ray diffraction pattern and, while exhibiting solid properties, are more formally described as liquids. Upon heating, a change in solid properties to liquid properties occurs, characterized by a change in state, typically secondary ("glass transition"). The term "crystalline" refers to a solid phase in which a material has a regularly ordered internal structure at the molecular level and produces a unique X-ray diffraction pattern with defined peaks. Such materials will also exhibit the properties of a liquid when fully heated, but the change from solid to liquid is characterized by a phase change, typically primary ("melting point").

[0167] The compounds of the present invention can also exist in a mesomorphic state (interphase or liquid crystal) when undergoing suitable conditions. The mesomorphic state is an intermediate state between a true crystalline state and a true liquid state (melt or solution). The mesomorphic phenomenon that occurs due to temperature changes is described as "thermotropic", while the mesomorphic phenomenon that occurs due to the addition of a second component (such as water or another solvent) is described as "lyotropic". Compounds with the potential to form a lyotropic interphase are described as "amphiphilic" and are composed of molecules with ionic polar head groups (such as -COO-Na+, -COO-K+ or -SO3-Na+) or non-ionic polar head groups (such as -N-N+(CH3)3). For more information, see Crystals and the Polarizing Microscope by NH Hartshorne and A. Stuart, 4th edition (Edward Arnold, 1970), which is incorporated herein by reference.

[0168] Formula (I) compound can be combined in the form of composition, and the composition has a variety of different forms depending on the mode of using the composition. Therefore, for example, the composition can be in the form of powder, tablet, capsule, liquid, ointment, emulsifiable paste, gel, hydrogel, aerosol, spray, microgel solution, transdermal patch, liposome suspension or any other suitable form that can be applied to the human or animal in need of treatment. It should be understood that the medium of the medicament according to the present invention should be a medium that is fully tolerated by the individual receiving it.

[0169] The pharmaceutical compositions comprising the compounds described herein can be used in a variety of ways. Suitable modes of administration include oral, intratumoral, parenteral, topical, inhalation / intranasal, rectal / vaginal, and ocular / aural administration.

[0170] Formulations suitable for the aforementioned modes of administration can be formulated for immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

[0171] The compounds of the present invention can be administered orally. Oral administration may involve swallowing so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed, thereby allowing the compound to enter the bloodstream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules (containing granules, liquids, or powders), buccal tablets (including liquid-filled buccal tablets), chewable tablets, multi-particulate and nanoparticulate formulations, gels, solid solutions, liposomes, films, oval suppositories, sprays, liquid formulations, and buccal / mucoadhesive patches.

[0172] Liquid formulations include suspensions, solutions, syrups, and elixirs. Such formulations can be used as fillers in soft or hard capsules and typically contain a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifiers and / or suspending agents. Liquid formulations can also be prepared by reconstituting a solid, such as a solid from a sachet.

[0173] The compounds of the present invention may also be used in fast dissolving, fast disintegrating dosage forms, such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents, 11(6), 981-986, (2001).

[0174] For tablet dosage forms, depending on the dosage, the drug may comprise 1 to 80 weight % of the dosage form, more typically 5 to 60 weight % of the dosage form. In addition to the drug, tablets typically contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, cross-linked polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, low-carbon alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. Disintegrants will typically comprise 1 to 25 weight % of the dosage form, preferably 5 to 20 weight %.

[0175] Binders are generally used to give cohesive qualities to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinyl pyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous matter, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dihydrated calcium phosphate.

[0176] Tablets may also optionally contain surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surfactants may comprise 0.2% to 5% by weight of the tablet, while glidants may comprise 0.2% to 1% by weight of the tablet.

[0177] Tablets also typically contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. Lubricants typically comprise 0.25% to 10% by weight of the tablet, preferably 0.5% to 3% by weight. Other possible ingredients include antioxidants, colorants, flavorings, preservatives, and taste masking agents.

[0178] Exemplary tablets contain up to about 80% drug, about 10% to about 90% binder by weight, about 0% to about 85% diluent by weight, about 2% to about 10% disintegrant by weight, and about 0.25% to about 10% lubricant by weight. Tablet blends can be compressed directly or by roller compression to form tablets. Tablet blends or portions of a blend can alternatively be wet-, dry-, or melt-granulated, melt-coagulated, or extruded prior to tableting. The final formulation can comprise one or more layers and can be coated or uncoated; it can even be encapsulated. The formulation of tablets is discussed in H. Lieberman and L. Lachman, Pharmaceutical Dosage Forms: Tablets, Vol. 1 (Marcel Dekker, Inc., New York, 1980).

[0179] Modified release formulations suitable for achieving the purposes of the present invention are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies, such as high energy dispersions and osmotic and coated particles, can be found in Verma et al., Pharmaceutical Technology On-line, 25(2), 1-14, (2001). The use of chewable tablets to achieve controlled release is described in WO 00 / 35298.

[0180] The compounds of the present invention can also be administered directly into the bloodstream, into muscle, or into internal organs. Suitable routes for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous administration. Suitable devices for parenteral administration include needle (including microneedle) syringes, needle-free syringes, and infusion techniques.

[0181] Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates, and buffers (preferably buffered to a pH of 3 to 9), but in some applications, parenteral formulations may be more suitably formulated as sterile non-aqueous solutions or in dry form for use with a suitable vehicle such as sterile pyrogen-free water.

[0182] The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0183] The solubility of the compound of formula (I) for the preparation of parenteral solutions can be increased by using appropriate formulation techniques (such as in combination with solubility enhancers). The formulation for parenteral administration can be formulated as immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulse release, controlled release, targeted release, and program-controlled release. Therefore, the compound of the present invention can be formulated as solid, semisolid, or thixotropic liquid to be used as an implantable reservoir form, thereby providing a modified release of the active compound. The example of this type of formulation includes a stent coated with a drug and poly (dl-lactic acid-co-glycolic acid) (PGLA) microspheres.

[0184] The compounds of the present invention may also be applied topically to the skin or mucous membranes, i.e., transdermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, powder sheets, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical vehicles include alcohol, water, mineral oil, liquid paraffin, white paraffin, glycerol, polyethylene glycol, and propylene glycol. Penetration enhancers may be incorporated, see, for example, Finnin and Morgan, Journal of Pharmaceutical Science, 88(10), 955-958 (October 1999).

[0185] Other means of local administration include electroporation, iontophoresis, phonophoresis, sonotrode and microneedle or needle-free (e.g., Powderject TM 、Bioject TM etc.) by injection.

[0186] The compounds of the invention can also be administered intranasally or by inhalation, usually in the form of a dry powder (alone, in admixture, for example, in the form of a dry blend with lactose; or in the form of mixed component particles, for example, mixed with a phospholipid (such as phosphatidylcholine)) from a dry powder inhaler; or in the form of an aerosol spray from a pressurized container, pump, sprayer, nebulizer (preferably a nebulizer using electrohydrodynamics to produce a fine mist) or aerosolizer with or without a suitable propellant (such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane). For intranasal use, the powder may contain a bioadhesive, for example, chitosan or cyclodextrin.

[0187] The pressurized container, pump, spray, nebulizer or aerosol contains a solution or suspension of the compound of the invention containing, for example, ethanol, aqueous ethanol or an alternative agent suitable for dispersing, solubilizing or prolonging the release of the active substance, a propellant as a solvent and optionally a surfactant, such as sorbitan trioleate, oleic acid or oligolactic acid.

[0188] Prior to use in dry powder or suspension formulations, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This can be achieved by any suitable comminution method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

[0189] Capsules (e.g., made of gelatin or hydroxypropylmethylcellulose), blisters, and cartridges for use in inhalers or insufflators can be formulated containing a powder mix of a compound of the invention, a suitable powder base (such as lactose or starch), and a performance-modifying agent (such as L-leucine, mannitol, or magnesium stearate). Lactose can be anhydrous or in the form of a monohydrate, the latter being preferred. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0190] The solution formulation suitable for an atomizer that generates a fine mist using electrohydrodynamics can contain 1 μg to 20 mg of the compound of the present invention per actuation, and the actuation volume can vary in the range of 1 μL to 100 μL. Typical formulations can include a compound of formula (I), propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that can be used instead of propylene glycol include glycerol and polyethylene glycol.

[0191] Suitable flavorings (such as menthol and levomenthol) or sweeteners (such as saccharin or saccharin sodium) may be added to formulations of the invention intended for inhaled / intranasal administration.

[0192] In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve delivering a metered amount. The unit according to the present invention is typically configured to administer a metered dose or "puff" containing 1 μg to 100 mg of formula (I) compound. The total daily dose will typically be in the range of 1 μg to 200 mg, which can be administered in a single dose, or more typically administered in divided doses throughout the day.

[0193] The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, microbicide, vaginal ring or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

[0194] The compound of the present invention can also be directly applied to eyes or ears, usually in the form of micron-sized suspension or solution drops in the isotonic sterile saline solution with adjusted pH. Other formulations suitable for use through the eye and through the ear include ointment, biodegradable (such as absorbable gel sponge, collagen) and non-biodegradable (such as silicone) implants, powder, crystal and particle or vesicle system, such as nonionic surfactant vesicle (niosome) or liposome. Polymer such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymer (such as hydroxypropyl methylcellulose, hydroxyethyl cellulose or methylcellulose) or heteropolysaccharide polymer (such as gellan gum) can be combined with preservatives (such as benzalkonium chloride). Such formulations can also be delivered by iontophoresis.

[0195] The compounds of the present invention can also be administered directly to the site of interest by injection of a solution or suspension containing the active drug substance. The site of interest may be a tumor, and the compound can be administered by intratumoral injection. Typical injection solutions contain propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that can be used instead of propylene glycol include glycerol and polyethylene glycol.

[0196] The compounds of the invention may be combined with soluble macromolecular entities such as cyclodextrins and suitable derivatives thereof or polyethylene glycol-containing polymers to improve solubility, dissolution rate, taste masking, bioavailability and / or stability for use in any of the aforementioned modes of administration.

[0197] For example, it has been found that drug-cyclodextrin complexes are generally applicable to most dosage forms and routes of administration. Both entrained and unentrained complexes can be used. As an alternative to direct complexation with the drug, cyclodextrins can be used as auxiliary additives, i.e., as vehicles, diluents, or solubilizers. The most commonly used for these purposes are α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, examples of which can be found in International Patent Applications Nos. WO 91 / 11172, WO 94 / 02518, and WO 98 / 55148.

[0198] It will be understood that the amount of compound required is determined by its biological activity and bioavailability, which in turn depends on the mode of administration, the physiochemical properties of the compound, and whether it is used as a monotherapy or in combination therapy. The frequency of administration will also be affected by the half-life of the compound in the individual being treated. The most preferred dose to be administered can be determined by one skilled in the art and will vary with the specific compound used, the strength of the pharmaceutical composition, the mode of administration, and the progression of the disease. Other factors depending on the specific individual being treated will require adjustment of the dose, including the individual's age, weight, sex, diet, and time of administration. In this regard, the amount of compound in the compositions of the present invention is sufficient to measurably inhibit HPK-1 or a mutant thereof in a biological sample or in a patient.

[0199] In general, for administration to humans, the total daily dose of the compounds of the present invention is typically in the range of 100 μg to 10g, such as 1 mg to 1g, for example, 10 mg to 500 mg. For example, oral administration may require a total daily dose of 25 mg to 250 mg. The total daily dose may be administered in a single dose or divided dose form and, at the physician's discretion, may exceed the typical ranges given herein. These doses are based on an average human individual weighing about 60 kg to 70 kg. The physician will be able to easily determine the dose for individuals whose weight exceeds this range, such as infants and the elderly.

[0200] However, those skilled in the art will appreciate that agents that modulate the immune system may be administered at dosages and frequencies that differ from those used for more traditional therapies. Specifically, agents that stimulate the immune system, such as those that stimulate the immune system by modulating HPK-1, may be administered at smaller dosages and less frequently, such as twice weekly, weekly, or monthly. Even smaller dosages may be effective when applied topically to small areas of skin.

[0201] The compounds may be administered before, during or after the onset of the condition to be treated.

[0202] Specific formulations containing the compounds of the invention and precise treatment regimens (such as daily doses and frequency of administration of the compounds) can be developed using known procedures, such as those commonly employed in the pharmaceutical industry (e.g., in vivo experiments, clinical trials, etc.). The inventors believe that they are the first to describe pharmaceutical compositions for treating diseases based on the use of the compounds of the invention.

[0203] Therefore, in a tenth aspect of the present invention, there is provided a pharmaceutical composition comprising the compound according to the first aspect or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof, and a pharmaceutically acceptable vehicle.

[0204] In the eleventh aspect, the present invention also provides a method for preparing a composition according to the tenth aspect, the method comprising contacting a therapeutically effective amount of a compound of the first aspect or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof and a pharmaceutically acceptable vehicle.

[0205] A "subject" can be a vertebrate, a mammal, or a domestic animal. Thus, the compounds, compositions, and medicaments according to the present invention can be used to treat any mammal, such as domestic animals (e.g., horses), pets, or can be used in other veterinary applications. However, most preferably, the subject is a human.

[0206] A "therapeutically effective amount" of a compound is any amount, ie, the amount of drug required to treat the target disease or produce the desired effect (ie, modulation of HPK-1 protein) when administered to a subject.

[0207] For example, the therapeutically effective amount of the compound used may be from about 0.01 mg to about 800 mg, and preferably from about 0.01 mg to about 500 mg. The amount of the compound is preferably from about 0.1 mg to about 250 mg, and most preferably from about 0.1 mg to about 20 mg.

[0208] The "pharmaceutically acceptable vehicle" referred to herein is any known compound or combination of known compounds known to those skilled in the art that can be used to formulate a pharmaceutical composition.

[0209] In one embodiment, the pharmaceutically acceptable vehicle can be solid, and the composition can be in the form of a powder or tablet. Solid pharmaceutically acceptable vehicles can include one or more substances, which can also serve as flavorings, lubricants, solubilizers, suspending agents, dyes, fillers, sliding agents, compression aids, inert adhesives, sweeteners, preservatives, dyes, coating agents or tablet disintegrants. Vehicles can also be encapsulated materials. In powders, vehicles are finely powdered solids mixed with finely powdered active agents according to the present invention (i.e., compounds according to the first, second, third and sixth aspects). In tablets, active compounds can be mixed with vehicles having necessary compression properties in a suitable ratio and compacted into desired shapes and sizes. Powders and tablets preferably contain up to 99% active compounds. Suitable solid vehicles include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, polyvinyl pyrrolidone, low melting point waxes and ion exchange resins. In another embodiment, pharmaceutical vehicles can be gels, and the composition can be in the form of creams and the like.

[0210] However, pharmaceutical vehicles can be liquids, and pharmaceutical compositions are in solution form. Liquid vehicles are used to prepare solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. Compounds according to the present invention can be dissolved or suspended in pharmaceutically acceptable liquid vehicles, such as water, organic solvents, mixtures thereof or pharmaceutically acceptable oils or fats. Liquid vehicles can contain other suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavorings, suspending agents, thickeners, pigments, viscosity modifiers, stabilizers or osmotic regulators. Suitable examples of liquid vehicles for oral and parenteral administration include water (partially containing additives such as above, such as cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohol (including monohydric alcohols and polyols, such as glycols) and their derivatives, and oils (such as fractionated coconut oil and peanut oil). For parenteral administration, vehicle can also be oily esters, such as ethyl oleate and isopropyl myristate. Sterile liquid vehicles can be used for compositions of sterile liquid form for parenteral administration. The liquid vehicle for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.

[0211] Liquid pharmaceutical compositions as sterile solutions or suspensions can be utilized by, for example, intramuscular, intrathecal, epidural, intraperitoneal, intravenous, and especially subcutaneous injection. The compound can be prepared as a sterile solid composition, which can be dissolved or suspended in sterile water, physiological saline, or other suitable sterile injectable media at the time of administration.

[0212] The compounds and compositions of the present invention can be administered in the form of sterile solutions or suspensions containing other solutes or suspending agents (e.g., physiological saline or glucose sufficient to make the solution isotonic), bile salts, gum arabic, gelatin, sorbitan monooleate, polysorbate 80 (oleate ester of sorbitol and anhydride copolymerized with ethylene oxide), etc. The compounds used according to the present invention can also be orally administered in the form of liquid compositions or solid compositions. Compositions suitable for oral administration include solid forms such as pills, capsules, granules, tablets, and powders; and liquid forms such as solutions, pastes, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.

[0213] Also included within the scope of the present invention are soft drugs or antedrugs, which are compounds of formula (I) containing metabolically or hydrolytically labile moieties that are converted in vivo to inactive derivatives. Methods for converting active drug substances into inactive derivatives include, but are not limited to, ester hydrolysis, S-oxidation, N-oxidation, dealkylation, and metabolic oxidation as described, for example, in Pearce et al., Drug Metab. Dispos., 2006, 34, 1035-1040; and B. Testa, Prodrug and Soft Drug Design, Comprehensive Medicinal Chemistry II, Vol. 5, Elsevier, Oxford, 2007, pp. 1009-1041; and Bodor, N., Chem. Tech. 1984, 14, 28-38.

[0214] It will be known to those skilled in the art that active pharmaceutical ingredients can be converted into prodrugs, which are metabolically unstable derivatives that are converted into active pharmaceutical substances in vivo. Prodrugs are also included within the scope of the present invention, and prodrugs are compounds of formula (I) containing metabolically or hydrolytically unstable moieties that are converted into active pharmaceutical substances of formula (I) in vivo. Methods for converting prodrugs into active pharmaceutical substances include, but are not limited to, ester hydrolysis, phosphate hydrolysis, S-oxidation, N-oxidation, dealkylation, and metabolic oxidation, as described in Beaumont et al., Curr. Drug Metab., 2003, 4, 461-485; and Huttenen et al., Pharmacol. Revs., 2011, 63, 750-771. Therefore, the aforementioned prodrug moiety may encompass functional groups including carbonates, carbamates, esters, amides, ureas, and lactams. Such prodrug derivatives may offer improved solubility, stability, or permeability compared to the parent drug substance, or may better allow administration of the drug substance by alternative routes of administration, such as as an intravenous solution.

[0215] The compounds contained herein can also be used as active ingredients in proteolysis-targeting chimeras (PROTACs). Inspired by the normal use of the ubiquitin-proteasome system (UPS) by cells to maintain intracellular homeostasis, PROTACs use endogenous ubiquitination mechanisms to recognize and degrade specific proteins that have been tagged with ligands that have affinity for the protein. PROTAC molecules are bifunctional and consist of three main components: a protein targeting moiety (PTM), a linker (L), and a portion that targets and recruits an E3 ubiquitin ligase complex (ULM) to degrade the target protein. It should be understood that the compounds of the present invention can be used as PTM components.

[0216] Thus, according to another aspect, there is provided a PROTAC of formula (II):

[0217] PTM-L-ULM

[0218] (II),

[0219] wherein PTM is a protein targeting moiety and is a compound of formula (I);

[0220] L is a linker; and

[0221] ULM is an E3 ubiquitination ligase complex;

[0222] or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof.

[0223] Suitable linkers and E3 ubiquitination ligase complexes are known in the art.

[0224] The compound of formula (I) may be linked to the linker via the group Z. Thus, the group Z may be as defined above except that a hydrogen atom is removed therefrom to render the group divalent.

[0225] Therefore, the PROTAC of formula (II) is preferably a PROTAC of formula (IIa):

[0226]

[0227] The scope of the present invention includes all pharmaceutically acceptable isotopically labeled compounds of the present invention wherein one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.

[0228] Examples of suitable isotopes for inclusion in the compounds of the present invention include isotopes of hydrogen such as 2 H and 3 H; isotopes of carbon, such as 11 C.13 C and 14 C; isotopes of chlorine, such as 36 Cl; isotopes of fluorine, such as 18 F; isotopes of iodine, such as 123 I and 125 I; isotopes of nitrogen, such as 13 N and 15 N; isotopes of oxygen, such as 15 O. 17 O and 18 O; isotopes of phosphorus, such as 32 P; and isotopes of sulfur, such as 35 S.

[0229] Certain isotopically-labeled compounds of the invention (e.g., compounds incorporating a radioactive isotope) are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 (i.e. 14 C) is particularly suitable for this purpose due to its ease of incorporation and readily available detection methods. 2 Isotopic substitutions such as H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. 11 C. 18 F. 15 O and 13 The N) substitution can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy.

[0230] Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and preparative schemes, using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.

[0231] According to another aspect, there is provided a compound of formula (I):

[0232]

[0233] in:

[0234] Y is selected from formula (a)-(h):

[0235]

[0236] X is N or CH;

[0237] X 1 Is N or CR1 ;

[0238] X 2 Is N or CR 2 ;

[0239] X 3 Is N or CR 3 ;

[0240] X 4 Is N or CR 4 ;

[0241] L is O, S, NR 6 or CR 6 R 7 ;

[0242] Z is phenyl or 5- or 6-membered heteroaryl, wherein the phenyl or heteroaryl is substituted by one or more substituents selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, CN, OR 8 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 8 、COOR 8 、CONR 8 R 9 NR 8 COR 9 NR 8 SO2R 9 NR 8 R 9 , optionally substituted 3 to 10 membered heterocyclyl, and optionally substituted 5 to 10 membered heteroaryl, and / or wherein adjacent substituents of the phenyl or heteroaryl can be combined together with the atoms to which they are attached to form an optionally substituted 3 to 6 membered heterocycle or an optionally substituted 5 or 6 membered heteroaryl;

[0243] R 1 to R 7 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, CN, OR 10 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 10 、COOR 8 、CONR 10R 11 NR 10 COR 11 NR 10 SO2R 11 NR 10 R 11 , optionally substituted C3-C6 cycloalkyl, optionally substituted 3 to 8 membered heterocyclyl, optionally substituted 5 to 10 membered heteroaryl or optionally substituted phenyl; and / or one or more pairs of adjacent R 1 to R 7 The group is combined with the atoms to which it is attached to form an optionally substituted 3 to 6 membered heterocyclic ring, an optionally substituted 5 or 6 membered heteroaryl, an optionally substituted 3 to 6 membered cycloalkyl or an optionally substituted phenyl, and / or a pair of R on the same C atom. 1 to R 5 Group and / or R 6 and R 7 Together with the C atom to which it is bound, it forms a C=O group;

[0244] R 8 and R 9 are independently hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C 6-12 aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl;

[0245] R 10 and R 11 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl or optionally substituted C2-C6 alkynyl, optionally substituted C 6-12 aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl; and

[0246] b is 0, 1, 2, 3, or 4;

[0247] or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof;

[0248] Provided that: the compound is not:

[0249]

[0250]

[0251]

[0252] Preferred fused groups Y include the following groups. For simplicity, each of these groups is illustrated without substituents, however, it should be understood that each ring of these fused groups may be independently unsubstituted or substituted with one or more independently selected R 1 to R 7 Substituents other than H groups (if applicable):

[0253]

[0254]

[0255] The bicyclic group Y is preferably a group of the formula: which may be unsubstituted or substituted with one or more substituents R 1 Substituted, preferably substituted by OH:

[0256]

[0257] Preferred substituents for the groups of formula (a)-(h) are selected from: C 1-6 Alkyl; C 3-6 Cycloalkyl; -C 1-6 Alkylene-OH; -OAk; OH, -C(=O)Ak; -NH2; -NHAk; NAK2; -CONH2; CONHAk; CON(Ak)2; C 1-6 Perfluoroalkyl, C 1-6 perfluoroalkoxy; CN; -NHC(=O)Ak; -NHC(=O)Ar; -NHSO2Ak; halogen, preferably F or Cl; optionally substituted phenyl; optionally substituted pyridyl; and heterocyclic groups having N and C ring atoms, such as pyrrolidinyl, piperidinyl or piperazinyl, which are unsubstituted or substituted by one or more substituents (e.g., one or more C 1-6 alkyl), wherein Ak is independently C 1-6 Alkyl or C 3-6 cycloalkyl; and Ar is aryl or heteroaryl which is unsubstituted or substituted with one or more substituents.

[0258] Ar is preferably selected from phenyl and 5 or 6 membered heteroaryl having ring atoms selected from C atoms, N atoms and optionally O or S atoms. Ar may be unsubstituted or substituted by one or more substituents, for example selected from C 1-6 Alkyl, C 1-6 One or more groups of alkoxy, F, Cl, NO2 and CN.

[0259] As explained above, Y is selected from formulae (a)-(h).

[0260] R 1 to R 7may independently be hydrogen, optionally substituted C1-C6 alkyl, halogen, CN, OR 10 、COR 10 、COOR 8 、CONR 10 R 11 NR 10 COR 11 NR 10 SO2R 11 NR 10 R 11 , optionally substituted C3-C6 cycloalkyl, optionally substituted 3 to 8 membered heterocyclyl, optionally substituted 5 to 10 membered heteroaryl or optionally substituted phenyl; and / or one or more pairs of adjacent R 1 to R 7 The groups can be combined with the atoms to which they are attached to form an optionally substituted 3 to 6 membered heterocyclic ring, an optionally substituted 5 or 6 membered heteroaryl, an optionally substituted 3 to 6 membered cycloalkyl or an optionally substituted phenyl, and / or a pair of R on the same C atom. 1 to R 5 Group and / or R 6 and R 7 It can form a C=O group together with the C atom to which it is bound. 1 to R 7 are independently hydrogen, optionally substituted C1-C3 alkyl, halogen, CN, OR 10 、COR 10 、CONR 10 R 11 NR 10 COR 11 NR 10 SO2R 11 NR 10 R 11 , optionally substituted C3-C6 cycloalkyl, optionally substituted 3 to 8 membered heterocyclyl, optionally substituted 5 to 10 membered heteroaryl or optionally substituted phenyl; and / or one or more pairs of adjacent R 1 to R 7 The groups can be combined with the atoms to which they are attached to form an optionally substituted 3 to 6 membered heterocyclic ring, an optionally substituted 5 or 6 membered heteroaryl, an optionally substituted 3 to 6 membered cycloalkyl or an optionally substituted phenyl, and / or a pair of R on the same C atom. 1 to R 5 Group and / or R 6 and R 7 Together with the C atom to which it is bound, it can form a C=O group. 8 and R 9may independently be hydrogen, optionally substituted C1-C3 alkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 5- or 6-membered heterocyclyl, and optionally substituted 5- or 6-membered heteroaryl. The or each alkyl group may be unsubstituted or substituted with one or more of halogen, OH, or OCH3. The or each cycloalkyl, heterocyclyl, or heteroaryl group may be unsubstituted or substituted with one or more of the following groups: halogen, C 1-3 Alkyl, OH and oxo, more preferably the or each cycloalkyl, heterocyclyl or heteroaryl may be unsubstituted or substituted by Cl, CH3 or oxo.

[0261] R 1 to R 7 can independently be hydrogen, methyl, CF3, CH2OH, F, Cl, CN, OH, OCH3, OCF3, COCH3, CONH2, NHCOCH3, NHSO2CH3、NH2、 or phenyl, and / or one or more pairs of adjacent R 1 to R 7 The group, together with the atoms to which it is attached, forms an optionally substituted 3- to 6-membered heterocyclic ring, an optionally substituted 5- or 6-membered heteroaryl group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted phenyl group, and / or a pair of R on the same C atom. 1 to R 5 Group and / or R 6 and R 7 Together with the C atom to which it is bound, it forms a C=O group.

[0262] In some embodiments, a pair of adjacent R 1 to R 7 The group is combined with the atoms to which it is attached to form an optionally substituted 3 to 6 membered heterocyclic ring, an optionally substituted 5 or 6 membered heteroaryl, an optionally substituted 3 to 6 membered cycloalkyl or an optionally substituted phenyl. More preferably, in some embodiments, a pair of adjacent R 1 to R 5 The group is combined with the atoms to which it is attached to form an optionally substituted 5- or 6-membered heterocyclic ring, an optionally substituted 5- or 6-membered heteroaryl group, or an optionally substituted phenyl group. 1 to R 5 The heterocyclic ring, heteroaryl, cycloalkyl or phenyl formed by the group may be unsubstituted or substituted by one or more of the following: optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, oxo, CN, OR 16 SR 16 、SOR 16 、SO2R16 、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 or NR 16 R 17 .

[0263] R 16 and R 17 may be independently selected from the group consisting of: H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C 6-12 Aryl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3- to 6-membered heterocyclic ring, or optionally substituted 5- to 10-membered heteroaryl. 16 and R 17 R may be each independently selected from the group consisting of H, an optionally halogenated C1-C6 alkyl group, an optionally halogenated C2-C6 alkenyl group or an optionally halogenated C2-C6 alkynyl group. 16 and R 17 R 16 and R 17 Both are H.

[0264] More preferably, a pair of adjacent R 1 to R 5 The heterocyclic ring, heteroaryl, cycloalkyl or phenyl group formed by the group may be unsubstituted or substituted by one or more of the following: C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, halogen, oxo, OH and NH2. Most preferably, the group is formed by a pair of adjacent R 1 to R 5 The heterocyclic ring, heteroaryl, cycloalkyl or phenyl group formed by the group may be unsubstituted or substituted with one or more of methyl, fluoro and oxo.

[0265] In some embodiments, Y has formula (a). In some embodiments, X 1 It's CR 1 , X 2 It's CR 2 , X 3 It's CR 3 , and X 4 It's CR 4 In some embodiments, X 1 It is N, X 2 It's CR 2 , X 3 It's CR 3 , and X4 It's CR 4 In some embodiments, X 1 It's CR 1 , X 2 It is N, X 3 It's CR 3 , and X 4 It's CR 4 In some embodiments, X 1 It's CR 1 , X 2 It's CR 2 , X 3 is N, and X 4 It's CR 4 In some embodiments, X 1 It's CR 1 , X 2 It's CR 2 , X 3 It's CR 3 , and X 4 is N. In some embodiments, X 1 It is N, X 2 It is N, X 3 It's CR 3 , and X 4 It's CR 4 In some embodiments, X 1 It's CR 1 , X 2 It is N, X 3 It's CR 3 , and X 4 is N. Therefore, Y can be In X 1 It's CR 1 , X 2 It's CR 2 , X 3 Say CR 3 And X 4 It's CR 4 In the embodiment, preferably, one or more pairs of adjacent R 1 to R 5 The group is combined with the atoms to which it is attached to form an optionally substituted 3 to 6 membered heterocycle, an optionally substituted 5 or 6 membered heteroaryl, an optionally substituted 3 to 6 membered cycloalkyl or an optionally substituted phenyl. In embodiments where Y is a bicyclic group, Y may be In some embodiments, Y may be

[0266]

[0267] In some embodiments, Y has formula (b). L may be NR 6 .X 1 Can be CR 1 .X 2 Can be CR 2 .X 4 Can be CR 4 Therefore, Y can be In embodiments where Y is a bicyclic group, Y may be In some embodiments, Y may be

[0268] In some embodiments, Y has formula (c). L may be NR 6 or S. X 1 Can be CR 1 , X 2 Can be CR 2 , and X 3 Can be CR 3 Alternatively, X 1 Can be N, X 2 Can be CR 2 , and X 3 Can be CR 3 Alternatively, X 1 Can be CR 1 , X 2 Can be N, and X 3 Can be CR 3 Alternatively, X 1 Can be CR 1 , X 2 Can be CR 2 , and X 3 Can be N. Therefore, Y can be In embodiments where Y is a bicyclic group, Y may be In some embodiments, Y may be

[0269] In some embodiments, Y has formula (d) or (e). L can be O, NR 6 or CR 6 R 7 Therefore, Y can be

[0270] In embodiments where Y is a bicyclic group, Y may be In some embodiments, Y may be In a preferred embodiment, Y is not cyclohexyl or 4-aminocyclohexyl.

[0271] In some embodiments, Y has formula (f), (g) or (h). Thus, Y may be

[0272] Z may be a substituted phenyl group or a substituted pyridyl group.

[0273] In a preferred configuration, the adjacent substituents of the phenyl or 5 or 6 membered heteroaryl Z are linked together with the C atoms of the phenyl or heteroaryl to which they are attached to form a 5 or 6 membered heterocyclic or heteroaromatic group. It should be understood that in these embodiments, the group Z is an optionally substituted fused group. A preferred fused group Z is an optionally substituted tetrahydroquinoline or an optionally substituted tetrahydroisoquinoline. Optional substituents include, but are not limited to, C 1-6 More preferably, the optional substituent is CH3 or F.

[0274] In another preferred configuration, the phenyl group or the 5- or 6-membered heteroaryl group Z is substituted by an optionally substituted 3- to 10-membered heterocyclyl group or an optionally substituted 5- to 10-membered heteroaryl group, and the phenyl group or the 5- or 6-membered heteroaryl group may be further optionally substituted by one or more substituents selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, CN, OR 8 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 8 、COOR 8 、CONR 8 R 9 NR 8 COR 9 NR 8 SO2R 9 and NR 8 R 9, each of which is optionally substituted with one or more substituents. In some embodiments, phenyl or 5 or 6 membered heteroaryl Z is substituted with an optionally substituted 5 to 10 membered heterocyclyl or an optionally substituted 5 to 10 membered heteroaryl, and phenyl or 5 or 6 membered heteroaryl may further be optionally substituted with halogen. In some embodiments, phenyl or 5 or 6 membered heteroaryl Z is substituted with an optionally substituted 5 to 7 membered heterocyclyl or an optionally substituted 5 or 6 membered heteroaryl, and phenyl or 5 or 6 membered heteroaryl may further be optionally substituted with halogen. Halogen may be fluorine. Heterocyclyl or heteroaryl (which is a substituent on the Z group) may be unsubstituted or substituted with one or more optional substituents selected from the group consisting of: optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C 3-6 Cycloalkyl, halogen, oxo, CN, OR 16 SR 16 、SOR 16 、SO2R 16 、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 or NR 16 R 17 More preferably, the heterocyclyl or heteroaryl (which is a substituent on the Z group) may be unsubstituted or substituted with one or more substituents selected from the group consisting of optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C 3-6 Cycloalkyl, halogen, oxo, COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 or NR 16 R 17 . Alkyl groups can be OR 16 and NR 16 R 17 Replace. R 16 and R 17 Can be as defined above. In some embodiments, R 16 and R 17 and alkyl, wherein the alkyl radicals are selected from the group consisting of H, C1-C3 alkyl, or an optionally halogenated 5- or 6-membered heterocycle.

[0275] Preferably the group Z has the formula:

[0276]

[0277] where X 5 、X 6 、X 7 and X 8 Each independently selected from N and CR 11 , provided that X 5 、X 6 、X 7 and X 8 Only one of them is N; R 11 is independently H or halogen at each occurrence, preferably F; and A is selected from optionally substituted C1-C6 alkyl, COR 8 、COOR 8 、CONR 8 R 9 NR 8 COR 9 NR 8 R 9 , optionally substituted 3- to 10-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl. 8 and R 9 R is independently hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3 to 8 membered heterocyclyl, or optionally substituted 5 to 10 membered heteroaryl. More preferably, R 8 and R 9 is independently hydrogen, optionally substituted C1-C3 alkyl or optionally substituted 5 or 6 membered heterocyclyl. Alkyl may be unsubstituted or substituted by halogen, OR 16 or NR 16 R 17 One or more of R 16 and R 17 Can be as defined above. In some embodiments, R 16 and R 17 Can independently be H or C1-C3 alkyl.

[0278] In a preferred embodiment, heterocyclyl or heteroaryl (which is a substituent on the Z group, which may optionally be A in the above formula) is an optionally substituted 5- or 6-membered heterocyclyl or an optionally substituted 5- or 6-membered heteroaryl. In a preferred embodiment, heterocyclyl or heteroaryl (which is a substituent on the Z group, which may optionally be A in the above formula) is an optionally substituted 6-membered heterocyclyl or an optionally substituted 6-membered heteroaryl.

[0279] The heterocyclic or heteroaryl group (which is a substituent on the Z group, which may optionally be A in the above formula) may be unsubstituted or substituted by one or more of the following: optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, oxo, CN, OR 16 SR 16 、SOR 16 、SO2R 16 、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 NR 16 R 17 , optionally substituted C 6-12 Aryl, optionally substituted C 3-6 Non-adjacent substituent pairs of cycloalkyl, optionally substituted 3 to 6 membered heterocycle or optionally substituted 5 to 10 membered heteroaryl, or 3 to 8 membered heterocyclyl can be combined to form a bridged group. More preferably, the optionally substituted heterocyclyl or optionally substituted heteroaryl (which is a substituent on the Z group, which may optionally be A in the above formula) may be unsubstituted or substituted with one or more of the following: optionally substituted C1-C3 alkyl, halogen, oxo, COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 or NR 16 R 17 , or non-adjacent pairs of substituents of a 3- to 8-membered heterocyclic group may be combined to form a bridge group. Even more preferably, the heterocyclic group or heteroaryl (which is a substituent on the Z group, which may optionally be A in the above formula) may be unsubstituted or substituted with one or more of the following: optionally substituted C1-C3 alkyl, fluorine, COR 16 or CONR 16 R 17 , or non-adjacent substituent pairs of 3 to 8 membered heterocyclic groups can be combined to form a bridge group. The alkyl group can be unsubstituted or substituted with halogen, OR 16 or NR 16 R 17 One or more of R 16 and R 17 Can be as defined above. In some embodiments, R 16 and R 17 may be independently selected from the group consisting of: H, optionally substituted C1-C3 alkyl, optionally substituted C 3-6cycloalkyl, an optionally substituted 3- to 6-membered heterocycle, or an optionally substituted 5- to 10-membered heteroaryl. 16 and R 17 Each is independently selected from the group consisting of H, methyl and an optionally halogenated 5- or 6-membered heterocycle. Preferably, the bridging group is an optionally substituted methylene or ethylene group.

[0280] Preferably the heteroaryl group (which is a substituent on the Z group, which may optionally be A in the above formula) is pyridyl, pyrazolyl or oxazolyl.

[0281] Preferably the heterocyclic group (which is a substituent on the Z group, which may optionally be A in the above formula) is a group of formula (i) or (j):

[0282]

[0283] in:

[0284] T is N and M is NR 13 , CR 14 R 15 , O, S or SO2; or T is CR 18 , and M is NR 13 , O, S or SO2;

[0285] Q is C(R 12 )2, and n is 1 or 2;

[0286] R 12 is independently at each occurrence H, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-6 Cycloalkyl, OR 19 ; or NR 19 R 20 ; and / or two R bound to adjacent carbon atoms 12 The groups may be linked to form a fused group A or to two R groups bonded to non-adjacent carbon atoms. 12 The groups can be connected to form a bicyclic bridging group A;

[0287] R 13 is H, optionally substituted C1-C6 alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, COR 19 or CONR 19 R 20 ;

[0288] R 14 and R 15 are each independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C3-C6 cycloalkyl, OR 19 and NR 19 R 20 , or R 14 and R 15 The C atoms to which they are all bound may be linked together to form an optionally substituted 3- to 6-membered heterocyclic group or an optionally substituted C 3-6 Cycloalkyl;

[0289] R 18 is hydrogen or optionally substituted C1-C6 alkyl; and

[0290] R 19 and R 20 are each independently H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 3- to 6-membered heterocyclyl.

[0291] In some embodiments, n is 1.

[0292] In some embodiments, T is N and M is NR 13 In some embodiments, T is CR 18 , and M is NR 13 .

[0293] R 13 It can be H, optionally substituted C1-C6 alkyl, C 3-6 Cycloalkyl, COR 19 or CONR 19 R 20 . R 19 and R 20 may be each independently H, optionally substituted C 1-3 alkyl or an optionally substituted 5- or 6-membered heterocyclic group. More preferably, R 19 and R 20 are each independently H, optionally substituted C 1-3 Alkyl or an optionally halogenated 5 or 6 membered heterocyclic group. The alkyl group may be unsubstituted or substituted by halogen, oxo, CN, OR 16 or NR 16 R 17 One or more of R16 and R 17 May be as defined above. Preferably, R 16 and R 17 is H or CH3. 13 Can be CH3, CH2CH3, CH2CH2OH, CH2CH2OCH3,

[0294] In some embodiments, T is N and M is CR 14 R 15 .

[0295] R 14 and R 15 may be independently selected from hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C3-C6 cycloalkyl, OR 19 -and-NR 19 R 20 , or R 14 and R 15 The C atoms to which they are all bound may be linked together to form an optionally substituted 3- to 6-membered heterocyclic group. 14 and R 15 are each independently selected from hydrogen, halogen, optionally substituted C1-C3 alkyl and NR 19 R 20 , or R 14 and R 15 They may be joined together to form an optionally substituted 3- to 6-membered heterocyclic group. 19 and R 20 may each independently be H or optionally substituted C 1-3 Preferably, R 19 and R 20 Each is H. R 14 and R 15 can be independently H, F, NH2 or R 14 and R 15 They can be linked together with the C atoms to which they are all bound to form a 5-membered heterocyclic group.

[0296] In some embodiments, T is N, and M is O or SO2.

[0297] Preferably, R 18 It's hydrogen.

[0298] Preferably, R 12 is independently H, halogen or optionally substituted C 1-3 Alkyl; and / or two R bound to non-adjacent carbon atoms 12 More preferably, R12 H at each occurrence; and / or two R bound to non-adjacent carbon atoms 12 The groups are connected to form a bicyclic bridging group.

[0299] Exemplary bridging groups have the formula:

[0300]

[0301] The group A or heterocyclyl or heteroaryl may be the only substituent of phenyl or pyridyl Z, or one or more other substituents may be present. When present, the one or more other substituents may be selected from halogen; Ak; -OH; -OAk; -NH2; -NHAk; NAk2; optionally substituted heteroaryl; and optionally substituted heterocyclyl, wherein Ak is independently C at each occurrence. 1-6 Alkyl or C 3-6 The one or more other substituents are preferably halogen, more preferably F.

[0302] In some embodiments, the phenyl group or the 5- or 6-membered heteroaryl group Z is further substituted by halogen, preferably further substituted by fluorine.

[0303] Z can be

[0304]

[0305]

[0306] All features described herein (including any accompanying claims, abstract, and drawings) and / or all steps of any method or process so disclosed may be combined with any of the above aspects in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive.

[0307] General solution

[0308] General Solution 1

[0309] Compounds of formula (I) can be prepared from compounds of formula (II) under the demethylation conditions described below.

[0310]

[0311] Typically, demethylation is carried out in an acidic reaction mixture using, for example, H2SO4 or HCl aqueous solution in the presence or absence of a cosolvent (such as dioxane, ether or alcohol) and typically at elevated temperatures. Alternatively, a nucleophilic bromine source may also be used as a demethylating agent, such as by using BBr3, LiBr / pTSA or HBr aqueous solution in the presence or absence of a cosolvent (such as dioxane, DMF or ether) and heating at 60 to 100°C for demethylation. Compounds of formula (II) may be synthesized by those skilled in the art according to the method described below.

[0312] General Solution 2

[0313] The compound of formula (I) can also be prepared by reacting a compound of formula (III) with an amine of formula (IV) using the S N Ar reaction preparation.

[0314]

[0315] The amine of formula (IV) replaces the halogen atom, such as chlorine atom, in the pyridone intermediate (III). N The Ar reaction can employ any reaction conditions known in the art, typically using an excess of pure amine at elevated temperature. Alternatively, and particularly for volatile or noble amines, the amine is dissolved in a suitable solvent such as EtOH, DIPEA, or NMM along with a separate base (typically EtN, DIPEA, or NMM). i PrOH, n BuOH or t In the presence of a precipitate, the mixture is stirred at 80 to 120° C. in BuOH and heated at 80 to 120° C. for up to 24 hours. In the event that any component may have limited solubility, a phase transfer catalyst such as TBAI in a suitable solvent such as toluene or xylene with a suitable base such as Et N, DIPEA or NMM may also be employed. Amines of formula (IV) are commercially available or can be synthesized by one skilled in the art.

[0316] General Solution 3

[0317] Compounds of formula (I) can also be prepared from compounds of formula (V) and amines of formula (VI) in an amide bond forming reaction as described below.

[0318]

[0319] Typical conditions employ the use of a suitable organic base and a suitable coupling agent to activate the carboxylic acid of the compound of formula (V). Preferred coupling agents are EDCI with HOBt, T3P, HATU, HBTU, or BOP. Preferred organic bases include DIPEA or TEA in a suitable organic solvent such as DCM, DMF, DMA, THF, MeOH, or MeCN. The reaction can be shaken or stirred at room temperature, typically for up to 24 hours. Compounds of formula (VI) are commercially available or can be synthesized by those skilled in the art.

[0320] General Solution 4

[0321] Compounds of formula (IX) can be prepared from formaldehyde compounds of formula (VII) and amines of formula (VI) according to the sequence described below.

[0322]

[0323] The oxidation of aldehyde (VII) to the corresponding acid (VIII) is typically performed with a strong oxidizing agent such as KMnO4, sodium perborate or methyltrioxorhenium in a suitable solvent such as pyridine, water, acetic acid or methanol, typically at room temperature for 1 to 24 hours. It will be appreciated that aldehydes of formula (VII) can also be converted to acids of formula (VIII) via the corresponding ester intermediate using methods known to those skilled in the art, such as reactions with Br2 and alcoholic solvents. Acid (VIII) can then be converted to amides of formula (IX) using methods similar to those described in General Scheme 3. Thus, preferred amide coupling agents are EDCI with HOBt, T3P, HATU, HBTU, or BOP. Preferably, the organic base is DIPEA or TEA in a suitable organic solvent such as DCM, DMF, DMA, THF, MeOH or MeCN. Compounds of formula (IX) can also be prepared from the corresponding acid via an acid chloride route using a chlorinating agent such as SOCl2, SO2Cl2, POCl3 or POCl5. The reaction may be shaken or stirred at room temperature and is typically continued for up to 24 hours.Compounds of formula (VI) are commercially available or can be synthesized by one skilled in the art.

[0324] General Solution 5

[0325] Compounds of formula (II) and (III) can be prepared from compounds of formula (IX) according to the sequences described below.

[0326]

[0327] The compound of formula (IX) can be subjected to a Buchwald amination reaction with an amine of suitable formula (IV) to provide an amine of formula (II). The Buchwald reaction is carried out at elevated temperatures, typically at 60 to 110° C., with a suitable base such as DIPEA, TEA, NaOtBu, Cs2CO3, Na2CO3 or NaH and a suitable solvent such as n-BuOH, t-BuOH, 1,4-dioxane or EtOH. Suitable transition metal catalysts for the reaction include Pd2(dba)3, Pd(dppf)Cl2, Pd(OAc)2 or Pd(dba)Cl2, and suitable ligands such as dppf, BINAP, Xantphos or S-Phos, and the reaction is typically carried out for 12 to 24 hours.

[0328] Compounds of formula (IX) can be directly subjected to demethylation reactions using conditions similar to those described in general scheme 1. Thus, demethylation of (IX) is typically performed in an acidic reaction mixture using, for example, aqueous H2SO4 or HCl in the presence or absence of a cosolvent such as 1,4-dioxane, ether or alcohol, and typically at elevated temperatures. Alternatively, a nucleophilic bromine source can also be used as a demethylating agent, for example by using aqueous BBr3, LiBr / pTSA or HBr in the presence or absence of a cosolvent such as 1,4-dioxane, DMF or ether, and heating at 60 to 100°C to provide pyridones of formula (III).

[0329] General Solution 6

[0330] Compounds of formula (V) can be prepared from compounds of formula (VIII) via compounds of formula (X) according to the sequence described below.

[0331]

[0332] The compound of formula (VIII) can be converted to the corresponding pyridone of formula (X) in a demethylation reaction similar to the demethylation reaction described in general scheme 1. Thus, the reaction is typically carried out with or without a co-solvent (such as 1,4-dioxane or ether) and typically at 60 to 100° C. using aqueous HCl for 6 to 24 hours. During the demethylation reaction, the iodo group of (VIII) is typically observed to be replaced by chlorine to give the product compound of formula (X). The acid of formula (X) can then be reacted with an amine of formula (IV) under conditions similar to those described in general scheme 2. N Ar reaction. Therefore, the amine is dissolved in a suitable solvent (such as EtOH, i PrOH, n BuOH ort BuOH) and the mixture is heated at 80 to 120° C. for up to 24 hours to obtain the amine product of formula (V). In the case where any component may have limited solubility, a phase transfer catalyst such as TBAI in a suitable solvent (such as toluene or xylene) containing a suitable base (such as EtN, DIPEA or NMM) may also be employed. Amines of formula (IV) are commercially available or can be synthesized by one skilled in the art.

[0333] General Solution 7

[0334] A compound of formula (II) can be converted into a different compound of formula (II) via a compound of formula (XI) according to the sequence described below.

[0335]

[0336] This sequence is generally applicable to compounds of formula (II), wherein Y is a protecting group known to those skilled in the art. For example, if the protecting group is p-methoxybenzyl or dimethoxybenzyl, the group Y can be removed with an acidic reagent (such as TFA, trifluoromethanesulfonic acid or HCl) in a suitable solvent (such as DCM, dioxane, DCE or toluene) with or without heating for 1 to 48 hours at a temperature between 20 and 80 ° C to obtain a primary amine of formula (XI). These amines can then be used to carry out a Buchwald amination reaction with a halide of a suitable formula (XII) using similar conditions to those described in general scheme 5 to obtain a secondary amine of formula (II). Therefore, at high temperatures, suitable bases such as DIPEA, TEA, NaOtBu, Cs2CO3, Na2CO3 or NaH and suitable solvents such as n-BuOH, t-BuOH, 1,4-dioxane, toluene or EtOH are typically reacted at 60 to 110 ° C. Suitable transition metal catalysts for the reaction include Pd2(dba)3, Pd(dppf)Cl2, Pd(OAc)2 or Pd(dba)Cl2, and suitable ligands such as dppf, BINAP, Xantphos or S-Phos, and the reaction is typically carried out for 12 to 24 hours. Preferred reagents include BrettPhos-Pd-G3 catalyst systems. The halides of formula (XII) are commercially available or can be synthesized by those skilled in the art.

[0337] General Solution 8

[0338] Compounds of formula (XIII) can be converted into different compounds of formula (II) via compounds of formula (XIV) and (XV) according to the sequence described below.

[0339]

[0340] Compounds of formula (XIII) can be subjected to a Buchwald amination reaction with an amine of formula (IV) using conditions similar to those described in general scheme 5 to obtain amines of formula (XIV). Thus, the reaction is carried out at elevated temperatures, typically at 60 to 110° C., with a suitable base such as DIPEA, TEA, NaOtBu, Cs2CO3, Na2CO3 or NaH and a suitable solvent such as n-BuOH, t-BuOH, 1,4-dioxane, toluene or EtOH. Suitable transition metal catalysts for the reaction include Pd2(dba)3, Pd(dppf)Cl2, Pd(OAc)2 or Pd(dba)Cl2, and suitable ligands such as dppf, BINAP, Xantphos or S-Phos, and the reaction is typically carried out for 12 to 24 hours. Amines of formula (IV) are commercially available or can be synthesized by those skilled in the art. The obtained compound of formula (XIV) can then undergo ester hydrolysis, which typically uses a suitable alkali metal or base to hydrolyze the ester and provide an acid of formula (XV). Suitable alkali metal or base can be LiOH, KOH, NaOH or K CO , and the reaction is typically carried out in an aqueous solution or in a mixture of a solvent (such as water, THF, MeOH or EtOH) at room temperature for 1 to 48 hours. Then, the acid of obtained formula (XV) can be subjected to amide bond formation reaction using conditions similar to those described in general scheme 3 with an amine of suitable formula (VI). Typical conditions employ the use of a suitable organic base and a suitable coupling agent to activate the carboxylic acid. Preferred coupling agents are EDCI with HOBt, T P, HATU, HBTU, or BOP. Preferred organic bases are included in DIPEA or TEA in suitable organic solvents such as DCM, DMF, DMA, THF, MeOH or MeCN. The reaction can be shaken or stirred at room temperature, typically continuing up to 24 hours. Compounds of formula (VI) are commercially available or can be synthesized by one skilled in the art to give products of formula (II).

[0341] General synthesis procedure

[0342] General Program 1

[0343]

[0344] Method a:

[0345] At 0 to 5 ° C, formula (II) compound (1.0eq) is dissolved in 1,4-dioxane (13mL / mmol) containing 4M HCl, and the resulting reaction mixture is refluxed for 2 to 6 hours. The reaction progress is monitored by TLC or / and LCMS. After completion, the solvent is evaporated under reduced pressure to obtain a crude product, which is purified by grinding with an ether-pentane mixture or column chromatography to obtain a solid formula (I) compound (yield 7-80%).

[0346] Method b:

[0347] To a stirred solution of the compound of formula (II) (1.0 eq) in DMF (9 mL / mmol) was added PTSA.HO (5.0 eq) at room temperature, followed by LiBr (5.0 eq), and the resulting reaction mixture was stirred at 100 to 120 ° C for 10 to 15 minutes. The reaction was confirmed to be complete by UPLC-MS or / and TLC. Subsequently, the reaction mass was diluted with chilled water and extracted with DCM containing 5-15% methanol. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain a crude product, which was purified by column chromatography or preparative HPLC to obtain the compound of formula (I) as a solid (yield 7-80%).

[0348] Method c:

[0349] At 0 to 5 ° C, HBr (40%, 6 mL / mmol) was added dropwise to a stirred solution of compound of formula (II) (1.0 eq, 0.295 mmol) in 1,4-dioxane (6 mL / mmol). The entire reaction mixture was stirred overnight at 75 to 80 ° C. The reaction progress was checked by LCMS, and after completion, the solvent and excess HBr were evaporated in vacuo using acetonitrile by azeotropic distillation, and the remaining residue was washed with diethyl ether to obtain a crude product, which was purified by column chromatography to obtain a compound of formula (I) as a solid (yield 10-65%).

[0350] General Program 2

[0351]

[0352] To a stirred solution of the compound of formula (III) (1.0 eq) in n-butanol or t-BuOH or toluene (11 mL / mmol) is added N,N-diisopropylethylamine or TEA (15.0 eq), and the mixture is stirred at room temperature for 10-20 minutes. Subsequently, the compound of formula (IV) (1.5 eq) is added to the reaction vessel. The resulting reaction mixture is stirred at 100 to 120 ° C for 10-16 hours. The reaction progress is monitored by LCMS / TLC, and after the reaction is complete, the solvent is evaporated under reduced pressure to obtain a crude material, which is purified by column chromatography or preparative reverse phase HPLC to obtain a compound of formula (I) as a solid (yield 10-65%).

[0353] General Program 3

[0354]

[0355] Method a:

[0356] At room temperature, HATU (1.5 eq) and TEA (3.0 eq.1) were added to a stirred solution of the compound of formula (V) (1.0 eq) in THF (3.5 mL / mmol) and a few drops of DMF, and the resulting reaction mixture was stirred at room temperature for 10-15 minutes. Subsequently, the compound of formula (VI) Z-NH2 (1.2 eq) was added to the reaction vessel, and the mixture was stirred at room temperature for 2-5 hours. The reaction progress was monitored by TLC and LCMS, and TLC and LCMS confirmed the formation of the desired product. Subsequently, the reaction mixture was evaporated in vacuo to obtain a residue, which was diluted with DCM containing 5-10% MeOH and repeatedly washed with water and brine. The organic portion was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a crude product, which was purified by Combi flash column chromatography using 5-10% MeOH in DCM as an eluent to obtain the compound of formula (I) as a solid (yield 10-80%).

[0357] Method b:

[0358] To the stirred solution of formula (V) compound (1.0eq) in toluene (6.5mL / mmol), POCl is added (0.30mL / mmol), and the combined mixture is refluxed for 2-4 hours, to obtain the corresponding acid chloride intermediate. Subsequently, the solvent is evaporated in vacuo, and the crude acid chloride is dissolved in DCM (6.5mL / mmol), and triethylamine (5.0eq) is added at 0 to 5°C, followed by addition of formula (VI) compound Z-NH (1.5eq). The gained reaction mixture is stirred at room temperature for 10-16 hours. Reaction process is monitored by LCMS or / and TLC, and after completion, the solvent is evaporated in vacuo to obtain a crude product, which is purified by column chromatography or preparative HPLC to obtain a solid formula (I) compound (yield 5-65%).

[0359] General Program 4

[0360]

[0361] Method a:

[0362] At 0 to 5 ° C, to a stirred solution of the compound of formula (VII) (1.0 eq) in a mixture of tert-butanol (5.2 mL / mmol) and water (2.6 mL / mmol) was added 2-methyl-2-butene (3.0 eq), followed by sodium dihydrogen phosphate (2.5 eq) and sodium chlorite (2.0 eq), and the entire mixture was stirred at 0 to 5 ° C for 1-2 hours. The reaction progress was monitored by LCMS, and after completion, the reaction mass was quenched with 1N formic acid solution. The product was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a compound of formula (VIII) as a solid (yield 70-80%).

[0363] Method b:

[0364] At 0 to 5 ° C, KMnO4 (1.0 eq) was added to a stirred solution of compound of formula (VII) (1.0 eq) in pyridine aqueous solution (50%, 5.2 mL / mmol) in batches. The resulting reaction mixture was stirred at room temperature for 1-2 hours. The reaction progress was monitored by TLC / LCMS, and after completion, the reaction mixture was filtered and washed with acetonitrile and water. The filtrate was distilled under reduced pressure using excess acetonitrile to obtain a crude product, which was purified by wet grinding with diethyl ether to obtain a compound of formula (VIII) (yield 65-85%) in the form of its potassium salt.

[0365] General Program 5

[0366]

[0367] To a stirred solution of compound (IX) (1.0 eq) in 1,4-dioxane (15 mL / mmol) was added compound (IV) Y-NH2 (1.2 eq) and Cs2CO3 (3.0 eq) in a sealed tube. The combined reaction mixture was degassed with a nitrogen balloon for 10-20 minutes. Subsequently, Pd2(dba)3 (0.1 eq) and Xantphos (0.2 eq) were added to the reaction vessel, and the resulting reaction mixture was stirred at 100 ° C overnight. The reaction progress was monitored by LCMS / TLC, and after completion, the reaction mixture was diluted with water and extracted with DCM containing 10% methanol. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain a crude product, which was purified by silica gel column chromatography using 3-5% methanol in DCM as an eluent to obtain a solid compound (yield 70-80%).

[0368] General Program 6

[0369]

[0370] At 0 to 5 ° C, TFA (2 mL / mmol) was added dropwise to a stirred solution of compound of formula (II) (1.0 eq) in DCE (8 mL / mmol), and the combined mixture was stirred at room temperature overnight. The reaction process was monitored by LCMS / TLC, and after completion, the reaction mixture was evaporated to dryness to obtain a residue, which was neutralized with TEA and extracted with DCM containing 15% methanol. The combined organic layer was washed with salt water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain a crude product, which was purified by silica gel column chromatography using 5-10% methanol in DCM as an eluent to obtain a solid compound of formula (XI) (yield 70-75%).

[0371] General Program 7

[0372]

[0373] To a stirred solution of the compound of formula (XI) (1.0 eq) in toluene (40 mL / mmol) was added the compound of formula (XII) (1.2 eq), followed by the addition of NaO t The reaction mixture was purged with a nitrogen balloon for 10-20 minutes. Then, BretPhos-Pd-G3 (0.2 eq) was added to the reaction vessel and the resulting reaction mixture was stirred at 100 ° C overnight. The reaction progress was monitored by LCMS / TLC, and after completion, the reaction mixture was diluted with water and extracted with DCM containing 10% methanol. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain a crude compound, which was purified by silica gel column chromatography using 4-5% methanol in DCM as eluent to obtain a solid compound of formula (II) (yield 40-50%).

[0374] General Program 8

[0375]

[0376] To a stirred solution of the compound of formula (XIV) (1.0 eq, 2.1 mmol) in THF (2 mL / mmol) was added a solution of LiOH.HO (4.0 eq) in water (1 mL / mmol) at room temperature, followed by addition of MeOH (2 mL / mmol) and stirring overnight at room temperature. The reaction progress was monitored by UPLC-MS / TLC, which showed the formation of the desired product. The reaction mixture was then concentrated in vacuo and slightly acidified with citric acid solution to obtain a white solid precipitate, which was filtered and washed with water, then washed with hexane and dried in vacuo to obtain the compound of formula (XV) as a solid (yield 70-80%).

[0377] General purification and analytical methods

[0378] All final compounds were purified by Combi-flash or preparative HPLC purification and analyzed for purity and product identity by UPLC or LCMS according to one of the following conditions.

[0379] Preparative HPLC

[0380] Preparative HPLC was performed on a Waters automated purification instrument using a YMC Triart C18 column (250 x 20 mm, 5 μm) or a phenylhexyl column (250 x 21.2 mm, 5 μm) operated between ambient temperature and 50°C with a flow rate of 16.0-50.0 mL / min.

[0381] Mobile phase 1: A = water containing 20 mM ammonium bicarbonate, B = acetonitrile; gradient profile: the mobile phase composition was initially 80% A and 20% B, then changed to 60% A and 40% B after 3 minutes, then changed to 30% A and 70% B after 20 minutes, then changed to 5% A and 95% B after 21 minutes, maintained at this composition for 1 minute for column washing, and then returned to the initial composition and maintained for 3 minutes.

[0382] Mobile phase 2: A = water with 10 mM ammonium acetate, B = acetonitrile; gradient profile: initial mobile phase composition was 90% A and 10% B, then changed to 70% A and 30% B after 2 minutes, then changed to 20% A and 80% B after 20 minutes, then changed to 5% A and 95% B after 21 minutes, maintained at this composition for 1 minute for column washing, then returned to the initial composition and maintained for 3 minutes.

[0383] LCMS method

[0384] General 5-minute method: Zorbax Extend C18 column (50 x 4.6 mm, 5 μm) operated at ambient temperature with a flow rate of 1.2 mL / min. Mobile phase: A = water containing 10 mM ammonium acetate, B = acetonitrile; Gradient profile: 90% A and 10% B to 70% A and 30% B over 1.5 minutes, then to 10% A and 90% B over 3.0 minutes, maintaining this composition for 1.0 minute, and finally returning to the starting composition for 2.0 minutes.

[0385] UPLC method

[0386] UPLC was performed at ambient temperature on a Waters automated purification instrument using a Zorbax Extend C18 column (50 x 4.6 mm, 5 μm) with a flow rate of 1.5 ml / min.

[0387] Mobile phase 1: A = water with 5 mM ammonium acetate, B = 90:10 acetonitrile / water with 5 mM ammonium acetate; gradient profile: 95% A and 5% B to 65% A and 35% B over 2 minutes, then to 10% A and 90% B over 3.0 minutes, maintained at this composition for 4.0 minutes, and finally returned to the starting composition for 5.0 minutes.

[0388] Mobile phase 2: A = water with 0.05% formic acid, B = acetonitrile; gradient profile: 98% A and 2% B, hold for 1 minute, then 90% A and 10% B, hold for 1 minute, then 2% A and 98% B, hold for 2 minutes, then return to the starting composition, hold for 3 minutes.

[0389] Examples

[0390] Nuclear magnetic resonance (NMR) spectra were consistent with the proposed structures in all cases. Characteristic chemical shifts (δ) are given relative to tetramethylsilane ( 1 H-NMR) parts per million downfield and relative to trichlorofluoromethane ( 19 F NMR) parts per million upfield are given as follows: for example, s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The following abbreviations for common solvents are used: CDCl3, deuterochloroform; d6-DMSO, deuterodimethylsulfoxide; and CD3OD, deuteromethanol.

[0391] Mass spectra, MS (m / z), were recorded using electrospray ionization (ESI). Where appropriate and unless otherwise stated, m / z data provided are for isotopes 19 F. 35 Cl, 79 Br and127 I.

[0392] All chemicals, reagents and solvents were purchased from commercial sources and used without further purification.Unless otherwise noted, all reactions were carried out under a nitrogen atmosphere.

[0393] Flash column chromatography was performed using prepacked silica gel cartridges on a Combi-Flash platform. Preparative HPLC purification was performed according to the General Purification and Analytical Methods described above. Thin layer chromatography (TLC) was performed on Merck Silica Gel 60 plates (5729). Unless otherwise stated, all final compounds were >95% pure as determined by LCMS or UPLC analysis as described in the General Purification and Analytical Methods above.

[0394] Example 45: 4-((8-Methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4- (4-Methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

[0395]

[0396] Example 45 was prepared according to the methods described in General Procedures 1 to 7 and the methods described below.

[0397] Preparation 1: 4-chloro-N-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide .HCl

[0398]

[0399] Step 1: 4-iodo-2-methoxynicotinic acid

[0400]

[0401] At 0 to 5 ° C, to a stirred solution of commercially available 4-iodo-2-methoxynicotinaldehyde (5.0 g, 19.01 mmol) in a mixture of tert-butanol (100 mL) and water (50 mL) was added 2-methyl-2-butene (6.03 mL, 57.03 mmol), followed by sodium dihydrogen phosphate (6.55 g, 47.52 mmol) and sodium chlorite (3.43 g, 38.02 mmol), and the combined mixture was stirred at 0 to 5 ° C for 1 hour. The reaction progress was monitored by LCMS, and after completion, the reaction mass was quenched with 1N formic acid solution and the product was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (4.2 g, 79.17% yield) as an off-white solid. LCMS m / z: 280.0 [M + H].

[0402] Step 2: 4-iodo-2-methoxy-N-(4-(4-methylpiperazin-1-yl)phenyl)nicotinamide

[0403]

[0404] To a stirred solution of 4-iodo-2-methoxynicotinic acid (Preparation-1, Step-1) (4.0 g, 14.33 mmol) in THF (50 mL) and a few drops of DMF was added HATU (8.17 g, 21.50 mmol) and TEA (5.90 mL, 43.01 mmol) at room temperature, and the resulting reaction mixture was stirred at room temperature for 10-15 minutes. Next, commercially available 4-(4-methylpiperazin-1-yl)aniline (3.29 g, 17.20 mmol) was added to the reaction vessel and the mixture was stirred at room temperature for 2-3 hours. TLC and LCMS showed that the desired product was completely formed. Subsequently, the reaction mixture was evaporated in vacuo to give a residue, which was diluted with 5-10% MeOH / DCM and washed repeatedly with water and brine. The organic portion was dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product, which was purified by Combi flash column chromatography using 5-10% MeOH in DCM as eluent to afford the title compound as an off-white solid (5.0 g, 77.1% yield). LCMS m / z: 452.8 [M+H].

[0405] Step 3: 4-Chloro-N-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide .HCl

[0406]

[0407] 4-Iodo-2-methoxy-N-(4-(4-methylpiperazin-1-yl)phenyl)nicotinamide (Preparation-1, Step-2) (500 mg, 1.11 mmol) was dissolved in 1,4-dioxane (15 mL) containing 4M HCl at 0-5°C and the reaction mixture was refluxed for 2 hours. TLC and LCMS showed the formation of the desired product, so the solvent was evaporated under reduced pressure to give a crude solid product, which was purified by trituration with an ether-pentane mixture and dried under vacuum to give the title compound as an off-white solid (250 mg, 65.17% yield). LCMS m / z: 347.18 [M+H].

[0408] Preparation 2: 8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-amine

[0409]

[0410] Step 1: Ethyl 2-((5-bromo-4-methyl-3-nitropyridin-2-yl)oxy)acetate

[0411]

[0412] To a stirred solution of commercially available 5- bromo- 2- chloro- 4- methyl -3- nitropyridine (25.0g, 99.41mmol) in acetonitrile (400mL) is added oven-dried potassium carbonate (41.21g, 298.26mmol) and ethyl glycolate (28.22mL, 298.26mmol). The resulting reaction mass is heated at 80 DEG C for 12 hours under a nitrogen atmosphere. The reaction progress is monitored by LCMS / TLC, and after the completion of the reaction, the resulting reaction mass is cooled to room temperature, filtered through a sintering funnel and the filtrate is evaporated in vacuo to obtain a crude material, which is purified by column chromatography using 5-7% ethyl acetate in hexane as an eluent to obtain the title compound (15.0g, 47.0% yield) as a pale white solid compound. LCMS m / z:318.8[M+H].

[0413] Step 2: 7-Bromo-8-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

[0414]

[0415] A stirred solution of ethyl 2-((5-bromo-4-methyl-3-nitropyridin-2-yl)oxy)acetate (Preparation-2, Step-1) (25.0 g, 78.34 mmol) in methanol (300.0 mL) was charged into a clean, dry standard oscillation vessel and purged with argon, followed by the addition of glacial acetic acid (20.0 mL) and subsequently Raney nickel (about 13.12 g). The entire mixture was again purged with argon for 10 minutes and hydrogenated at room temperature under 40 psi of hydrogen for 12 hours. TLC showed complete consumption of the starting material and the formation of the desired product along with some uncyclized intermediate amine-ester. The reaction mixture was filtered through a short bed of celite, and after washing the bed of celite several times, the filtrate was concentrated in vacuo to give a crude material, which was dissolved in a round-bottom flask (500 mL) and to which was added ethanol (150 mL) followed by glacial acetic acid (30 mL). The resulting reaction mixture was heated at 80°C for 12 hours and the solvent was evaporated in vacuo to give the crude product, which was purified by washing with MTBE and pentane to afford the title compound as an off-white solid (13.3 g, 70% yield). LCMS m / z: 243.0 [M+H].

[0416] Step 3: 7-Bromo-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine

[0417]

[0418] To a stirred solution of 7-bromo-8-methyl-1H-pyrido[2,3-b][1,4]oxazine-2(3H)-one (preparation-2, step-2) (10.0 g, 41.32 mmol) in THF was added BH3.THF solution (170.0 mL) dropwise at 0 to 5 ° C. under a nitrogen atmosphere. Then, the mixture was heated at 70 ° C for 3 hours. After completion (confirmed by TLC), the reaction mixture was cooled to room temperature and quenched by adding MeOH (200 mL) followed by concentrated HCl. The mixture was concentrated in vacuo to obtain a crude material, which was basified with NaHCO3 aqueous solution and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo to obtain the title compound (7.5 g, 80% yield) as an off-white crude solid, which was used in the next step as is without any further purification. LCMS m / z: 228.8 [M+H].

[0419] Step 4: tert-Butyl 7-bromo-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate

[0420]

[0421] At room temperature, under a nitrogen atmosphere, triethylamine (46.23 mL, 328.94 mmol), DMAP (8.03 g, 65.78 mmol) and Boc-anhydride (60.52 mL, 263.15 mmol) were added to a stirred solution of 7-bromo-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (Preparation-2, Step-3) (15.0 g, 65.78 mmol) in DCE (200 mL) under nitrogen atmosphere. The reaction mass was heated at 70 ° C for 16 hours. The reaction progress was monitored by LCMS / TLC, and after the reaction was complete, water was added and the organic matter was extracted with ethyl acetate. The combined organic layer was washed with water, then washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a crude compound, which was purified by column chromatography using 20-30% ethyl acetate in hexane to give the title compound (9.7 g, 45% yield) as an off-white solid. LCMS m / z: 329.0 [M+H].

[0422] Step 5: 7-((4-methoxybenzyl)amino)-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxadiazole tert-Butyl oxazine-1-carboxylate

[0423]

[0424] To a stirred solution of tert-butyl 7-bromo-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (Preparation-2, Step-4) (200 mg, 0.61 mmol) in 1,4-dioxane was added 4-methoxybenzylamine (0.16 mL, 1.22 mmol) and cesium carbonate (497 mg, 1.524 mmol). The resulting reaction mixture was degassed with nitrogen for 20 minutes, followed by the addition of BrettphosPdG3 (112 mg, 0.12 mmol) and the mixture was degassed again for 10 minutes. The entire reaction mass was heated at 100 ° C for 16 hours. The reaction progress was monitored by LCMS / TLC, and upon completion, the mixture was filtered through a bed of celite, washed with ethyl acetate, and the combined washings were concentrated under reduced pressure to give a crude product, which was purified by column chromatography using 30-40% ethyl acetate in hexanes as eluent to afford the title compound (120 mg, 51.06% yield) as a pale yellow solid. LCMS m / z: 386 [M+H].

[0425] Step 6: 8-Methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-amine.TFA

[0426]

[0427] A solution of tert-butyl 7-((4-methoxybenzyl)amino)-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (Preparation-2, Step-5) (120 mg, 0.31 mmol) in TFA (4 mL) was stirred at room temperature for 2 hours. After completion of the reaction (monitored by LCMS), the reaction mixture was evaporated in vacuo to give the title compound (130 mg, crude) as a TFA salt, which was used as is in the next step without further purification. LCMS m / z: 166 [M+H].

[0428] Preparation 3: 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4- (4-Methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (Example 45)

[0429]

[0430] To a stirred solution of 4-chloro-N-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide.HCl (Preparation-1, Step-2) (150 mg, 0.43 mmol) in n-butanol (5 mL) was added N,N-diisopropylethylamine (1.13 mL, 6.50 mmol), and the entire reaction was stirred at room temperature for 20 minutes. Subsequently, 8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-amine.TFA (Preparation-2, Step-6) (126 mg, 0.65 mmol) was added to the reaction mixture, and the entire reaction was stirred at 120° C. for 16 hours. The reaction progress was monitored by LCMS / TLC, and after completion of the reaction, the solvent was evaporated under reduced pressure to give a crude product, which was purified by preparative reverse phase HPLC to afford the title compound as a white solid (25 mg, yield 9.14%, qualitative HPLC purity normalized by area 99.22%). 1 HNMR (400MHz; DMSO-d6): δ1.92(s,3H),2.21(s,3H),2.43-2.45(m,4H),3.07-3.09(m,4H),3.31(bs,2H),4.25(t,J=3.8Hz,2H),5.55(d,J=7.36Hz, 1H),5.79(s,1H),6.90(d,J=8.8Hz,2H),7.27(d,J=7.6Hz,1H),7.30(s,1 H),7.46(d,J=8.8Hz,2H),11.35(s,1H),11.90(s,1H),12.86(s,1H); LCMS m / z:476.46[M+H].

[0431] Example 167: N-(4-(4-cyclopropylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido)phenyl)- [2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide

[0432]

[0433] Example 167 was prepared according to the methods described in General Procedures 1 to 7 and the methods described below.

[0434] Preparation 9: 8-Methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-amine dihydrochloride

[0435]

[0436] Step 1: 7-Bromo-8-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

[0437]

[0438] To a stirred solution of commercially available 3-amino-5-bromo-4-methylpyridin-2-ol (50.0 g, 0.246 mol) in acetonitrile (1.0 L) was added 2-chloroacetyl chloride (55.66 g, 0.495 mol) in an ice bath at 0-5 ° C. Then, after stirring for 2-5 minutes, K2CO3 (85.4 g, 0.618 mol, 2.5 eq) was added and the combined mixture was slowly warmed to room temperature for 3 hours. After 3 hours, the reaction vessel was transferred to an oil bath and the contents were refluxed at approximately 90 ° C. for 3 hours. LC-MS showed complete consumption of 3-amino-5-bromo-4-methylpyridin-2-ol and formation of the acylated intermediate. An additional 2.5 equivalents of K2CO3 (85.4 g, 0.618 mmol, 2.5 eq) were added to the reaction mixture in 0.5 equivalent increments to bring the pH to approximately 8. In the mixture of 4-nitro-2-oxo-1-oxo-2-oxo-4-oxo-2 ...

[0439] Step 2: 7-Bromo-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine

[0440]

[0441] To a stirred solution of 7-bromo-8-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (Preparation 9, Step 1) (54 g, 0.222 mol) in anhydrous THF (0.27 L, 5 V) was added BH 3 .THF solution (0.98 L, 0.888 mol, 0.9 M in THF) dropwise via a dropping funnel at 0-5 ° C under an inert atmosphere, and the combined mixture was further stirred for 15 minutes. The resulting reaction mixture was allowed to warm to room temperature, and then the reaction vessel was transferred to a preheated oil bath and the contents were stirred at 70 ° C for 8 hours. The reaction progress was monitored by LC-MS until complete consumption of the starting material and formation of the desired product were observed. The reaction mass was cooled to room temperature and then transferred to an ice bath and quenched by dropwise addition of ice-cold MeOH (0.27 L, 5 V) followed by 1N HCl (0.98 L), and the entire reaction was further stirred overnight. The reaction progress was monitored by LC-MS, which confirmed the formation of the desired product along with trace impurities. After completion of the reaction, the solvent was evaporated from the reaction mixture under reduced pressure to yield a residue, which was cooled in an ice bath and neutralized with a saturated solution of NaHCO₃ (3 L) to a pH of approximately 8. The neutralized material was diluted with water (1.0 L) and extracted with EtOAc (2 x 2.5 L). The combined organic layers were washed with brine (2.0 L), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to yield a crude product (48.0 g). This was purified by column chromatography on silica gel (60-120 mesh) (200 g slurry and 2.5 kg column bed) using 10-50% EtOAc in DCM as the eluent to yield the title compound (44.5 g). This material was again dissolved in ethyl acetate (0.9 L), followed by the addition of activated carbon (2.2 g) and stirred at room temperature for 30 minutes. The charcoal was filtered through a bed of celite, the bed was washed with ethyl acetate (0.1 L) and the resulting filtrate was evaporated in vacuo to give the title compound as a white solid (44.0 g, 86.8% yield, 99% HPLC purity). LCMS m / z: 229.0 [M+H].

[0442] Step 3: tert-Butyl (8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)carbamate

[0443]

[0444] At room temperature, CsCO(177.79g, 0.55mol) and 7-bromo-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (preparation 9, step 2) (50.0g, 0.218mol) were added to a stirred solution of tert-butyl carbamate (63.9g, 0.546mol) in 1,4-dioxane (1.0L). The reaction mixture was purged with nitrogen for 30 minutes. Brettphos-Pd-G3 (5.94g, 0.007mol) was added and the mixture was purged with nitrogen again for 15 minutes. The resulting reaction mixture was transferred to a preheated oil bath and stirred for 3 hours at 105°C under an inert atmosphere. The reaction progress was monitored by LC-MS, and after completion, the reaction mixture was cooled to room temperature, filtered through a bed of diatomaceous earth and the bed was washed with 1,4-dioxane (200mL). The filtrate was also combined with the filtrate from another 75 g batch reaction and concentrated under reduced pressure to give a residue, which was diluted with water (2.0 L) and extracted with EtOAc (2 x 2.5 L). The combined organic layers were washed with brine (2 x 2.0 L), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude product (250 g), which was purified by 60-120 mesh silica gel column chromatography (500 g slurry and 5 kg column bed) using 5-50% EtOAc in DCM as eluent to give the title compound as a light yellow solid (135 g, 93% yield, 99% HPLC purity). LCMS m / z: 266.24 [M+H].

[0445] Step 4: 8-Methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-amine dihydrochloride

[0446]

[0447] At ice-cold temperature, to a stirred suspension of (8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-yl)tert-butyl carbamate (preparation 9, step 3) (135.0 g, 0.508 mol) in 1,4-dioxane (1.38 L) was added 1,4-dioxane (1.38 L) containing 4M HCl, and the combined mixture was stirred at room temperature for 2 hours. As 4M HCl was added, the suspension began to dissolve and lumps began to appear in the reaction mixture. Slowly, the lumps decomposed and the reaction mixture became a thick suspension. After stirring at room temperature for 2 hours, LC-MS and TLC confirmed that the reaction was complete, with the starting material completely exhausted. The solvent from the reaction mixture was evaporated under reduced pressure to obtain a crude material, which was wet-ground with heptane, filtered and dried in vacuo at 40 ° C for 30 minutes to give the title compound (119.0 g, 99% yield, 99% HPLC purity) as a light brown solid. LCMS m / z: 166.14 [M+H].

[0448] Preparation 10: 4-(4-cyclopropylpiperazin-1-yl)aniline-methane

[0449]

[0450] Step 1: 1-cyclopropyl-4-(4-nitrophenyl)piperazine

[0451]

[0452] To a stirred solution of commercially available 1-cyclopropylpiperazine (107.33 g, 0.9 mol) in DMF (1.0 L) was added K2CO3 (293.83 g, 2.12 mol) and the resulting reaction mixture was stirred at room temperature for 10 minutes. Commercially available 1-fluoro-4-nitrobenzene (100.0 g, 0.709 mol) was added to the reaction mixture, followed by stirring for 3 hours at 80 ° C. The reaction process was monitored by HPLC and TLC. After the starting material was completely exhausted, the reaction mixture was cooled to room temperature and quenched with ice-cold water (5.0 L). The resulting suspension was stirred at room temperature for 30 minutes. The precipitated solid was filtered and washed with water (2.5 L) until the pH of the filtrate became neutral. Finally, the solid was washed with n-heptane (1.0 L) and dried at 50 ° C in a vacuum oven for 16 hours to obtain the title compound (172.0 g, yield 98%, HPLC purity 98.83%) as a yellow solid. LCMS m / z: 248.18 [M+H].

[0453] Step 2: 4-(4-cyclopropylpiperazin-1-yl)aniline

[0454]

[0455] A stirred solution of 1-cyclopropyl-4-(4-nitrophenyl)piperazine (Preparation 10, Step 1) (6.0 g, 0.024 mol) in ethyl acetate (60 mL) was purged with nitrogen, followed by addition of 10% Pd / C (50% wet product; 1.2 g, 20% w / w) under an inert atmosphere, and the mixture was maintained at room temperature under hydrogen balloon pressure for 24 hours. The reaction progress was monitored by UPLC and TLC. After complete depletion of the starting material, the reaction mixture was filtered through a bed of celite under an inert atmosphere, and the bed was washed with ethyl acetate (15 mL) under a nitrogen atmosphere. The filtrate was evaporated under reduced pressure to give the title compound (5.105 g, 98% yield, 77.49% HPLC purity) as a light brown solid. LCMS m / z: 218.2 [M+H].

[0456] Preparation 11: N-(4-(4-cyclopropylpiperazin-1-yl)phenyl)-4-iodo-2-methoxynicotinamide

[0457]

[0458] Step 1: 4-iodo-2-methoxynicotinic acid

[0459]

[0460] To a stirred solution of commercially available 4-iodo-2-methoxynicotinaldehyde (50.0 g, 0.19 mol) in t-BuOH (1.0 L) was added portionwise an aqueous solution of NaHPO (114.0 g, 0.95 mol) and NaClO (55.85 g, 0.6 mol) at 0 to 5°C over 30 minutes. After the addition was complete, the reaction mixture was maintained at 0 to 5°C for 2 hours. The progress of the reaction was monitored by HPLC and TLC. After complete consumption of the starting material, the reaction mixture was quenched with an aqueous solution of NaSO (250.0 g in 1.0 L of water) at 0 to 5°C, during which an exotherm of up to approximately 10°C was observed, and the color of the mixture changed from yellow to light green. A saturated solution of KCO (500 mL) was then added to make the reaction mass alkaline (pH = 14). The basic aqueous solution was washed with EtOAc (1.0 L) and acidified (pH = 2) using 12N HCl (500 mL) at 5-10°C. Finally, the compound was extracted with ethyl acetate (2 x 2.0 L) containing 20% t-BuOH. The combined organic layers were dried over anhydrous NaSO, filtered, and evaporated under reduced pressure to afford the title compound (50.0 g, 94% yield, 99% HPLC purity) as a white solid. LCMS m / z: 279.94 [M+H].

[0461] Step 2: N-(4-(4-cyclopropylpiperazin-1-yl)phenyl)-4-iodo-2-methoxynicotinamide

[0462]

[0463] To a stirred solution of 4-iodo-2-methoxynicotinic acid (Preparation 11, Step 1) (100.0 g, 0.358 mol) in DMF (1.0 L) was added HATU (204.4 g, 0.538 mol) at room temperature, followed by dropwise addition of triethylamine (149.3 mL, 1.07 mol), and the combined mixture was stirred at room temperature for 10 minutes. Furthermore, 4-(4-cyclopropylpiperazin-1-yl)aniline (Preparation 10, Step 2) (125.6 g, 0.573 mol) was added and the resulting reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by UPLC and TLC. After complete depletion of the starting material, the reaction mixture was poured into ice-cold water (4.0 L) and stirred for 30 minutes. The precipitated solid was filtered and washed with water until the pH of the filtrate became neutral. The solid was then dried in a vacuum oven at 50° C. for 16 hours to afford the title compound as a light brown solid (160.0 g, 94% yield, 99% HPLC purity). LCMS m / z: 479.16 [M+H].

[0464] Preparation 12: Step 1: N-(4-(4-cyclopropylpiperazin-1-yl)phenyl)-2-methoxy-4-(8-methyl-2,3-diol)-1-yl)-1-nitro-2-nitro-4-nitro-2-nitro-2-nitro-3-nitro-4 ... Hydrogen-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)nicotinamide

[0465]

[0466] To a stirred solution of N-(4-(4-cyclopropylpiperazin-1-yl)phenyl)-4-iodo-2-methoxynicotinamide (Preparation 11, Step 2) (35.0 g, 0.073 mol) in 1,4-dioxane (0.35 L) was added K3PO4 (62.13 g, 0.29 mol) and 8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-amine dihydrochloride (Preparation 9, Step 4) (18.2 g, 0.077 mol) at room temperature. The reaction mixture was purged with nitrogen for 30 minutes. Thereafter, Pd2(dba)3 (2.01 g, 0.0022 mol) and Xantphos (2.54 g, 0.0044 mol) were added thereto. The resulting reaction mixture was transferred to a preheated oil bath and stirred at 105°C under an inert atmosphere for 3 hours. The reaction process is monitored by LCMS, and after completion, the reaction mixture is cooled to room temperature and filtered through a diatomaceous earth bed, and the bed is washed with DCM (0.2L). The filtrate is concentrated under reduced pressure to obtain the residue (45.0g) in the form of a yellow solid, the residue is diluted with water (0.7L) and extracted with DCM (2 × 0.7L). The organic layer merged is washed with salt water (0.5L), through anhydrous Na2SO4 drying, filtered and concentrated under reduced pressure to obtain a crude product (38.0g), by silica gel column chromatography [90.0g slurries (60 to 120 mesh silica gel) and 1.35kg column bed (100 to 200 mesh)], using the 2-2.5% MeOH in DCM as eluent [using 0.5% (total silica used) triethylamine to make silica gel alkaline] it is purified, to obtain the title compound (31.0g, yield 63%, HPLC purity 98.72%) in the form of a yellow solid. LCMS m / z: 516.35 [M+H].

[0467] Step 2: N-(4-(4-cyclopropylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2, 3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide (Example 167)

[0468]

[0469] A stirred solution of N-(4-(4-cyclopropylpiperazin-1-yl)phenyl)-2-methoxy-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)nicotinamide (Preparation 12, Step 1) (12.5 g, 0.024 mol) in 4M HCl-1,4-dioxane (0.25 L) was heated at 80°C for 1 hour. Initially, the compound was dissolved in 4M HCl in 1,4-dioxane, but as the temperature reached 80°C, lumps appeared in the reaction mixture. Slowly, the lumps decomposed and the reaction mixture became a thick suspension. The progress of the reaction was monitored by LCMS. After complete consumption of the starting material, the solvent from the reaction mixture was evaporated under reduced pressure to obtain a residue as a light yellow solid, which was dissolved in Milli-Q water (0.75 L, 60 V) and washed with ethyl acetate (2 x 0.3 L, HPLC grade). The acidic aqueous layer was transferred to a 2 L RBF and cooled to 0 to 5 ° C by external cooling with an ice-salt mixture while neutralizing the solution by dropwise addition of a saturated NaHCO solution [0.2 L, 16 V (saturated NaHCO was filtered through a sintered funnel before use)]. After neutralization, the pH of the solution was approximately 7-8, and a solid compound precipitated from the solution, which was stirred at room temperature for 30 minutes. The solid was then filtered using a Buchner funnel and washed with water until the pH of the filtrate became neutral. Finally, a heptane (0.1 L) wash was performed to obtain a wet cake (17.0 g, HPLC purity 97%) as a pale yellow solid.

[0470] Crystallization 1:The wet product (17.0 g, 0.034 mol) was dissolved in DCM (2.5 L, 200 V, HPLC grade) and refluxed to ensure maximum dissolution, followed by addition of Mili-Q water (0.6 L) and filtering the entire reaction through a cotton plug. The solid collected on the cotton was washed with DCM (0.1 L) and mixed with the main original layer. The layers were separated, and the organic portion was washed with brine (0.6 L), dried over anhydrous sodium sulfate, filtered, and transferred to a 3-neck 5 L round-bottom flask. Activated carbon (0.6 g) was added and the combined mixture was refluxed for 30 minutes. The carbon was filtered through a bed of celite, and the bed was washed with DCM (0.525 L, total DCM used was 250 V). Heptane [1.1 L, (1 / 3 volume total DCM)] was slowly added to this clear yellow solution through a dropping funnel and the entire reaction was refluxed. The clear solution became slightly turbid, and the mixture was stirred at room temperature overnight. The suspension was cooled to 0 to 5 ° C with an external ice-salt mixture, kept for 1 hour, and filtered through a Buchner funnel. Finally, the combined wet cake was washed with n-heptane (2 × 0.1 L) and blotted dry for 1 hour. The solid was dried overnight at 50 ° C in a vacuum oven to obtain the title compound (28.0 g, 76% yield, 99.78% HPLC purity) as a light yellow solid.

[0471] Crystallization 2: The wet product (10 g) was dissolved in DMA (160 mL) at 50 ° C, followed by addition of charcoal (500 mg) and the entire reaction mixture was stirred at 50 ° C for 45 minutes. The mixture was filtered through a bed of diatomaceous earth (15 g), and the bed was washed with hot DMA (5 × 20 mL). The filtrate was collected and chilled water (420 mL) was added dropwise at 4-5 ° C to obtain a precipitate, and the suspension was kept cool for 3 hours. The suspension was filtered and washed with water (420 mL). The wet cake was slurry washed with water (2 × 300 mL), blotted for 4 hours, and finally dried in a vacuum oven at 50 ° C for 18 hours, then dried at 75 ° C for 10 hours to obtain the title compound (8.55 g, HPLC purity 99.02%) as a light yellow solid. 1H NMR (400MHz; DMSO-d6): δ0.43-0.46(m,2H),0.84-0.88(m,2H),1.62-1.67(m,1H),1 .93(s,3H),2.67(t,J=4.84Hz,4H),3.05(t,J=4.56Hz,4H),3.33(s,2H),4.26(t,J= 4.12Hz,2H),5.54-5.57(m,1H),5.81(s,1H),6.90(d,J=9.08Hz,2H),7.26-7.30(m, 2H),7.47(d,J=9.0Hz,2H),11.35(d,J=6.0Hz,1H),11.91(s,1H),12.85(s,1H); LCMS m / z:502.22[M+H].

[0472] Example 168: N-(3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8- 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydro Pyridine-3-carboxamide

[0473]

[0474] Example 168 was prepared according to the methods described in General Procedures 1 to 7 and the methods described below.

[0475] Preparation 13: 3-Methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-amine

[0476]

[0477] Step 1: tert-Butyl 3-(hydroxymethyl)piperazine-1-carboxylate

[0478]

[0479] At 0 to 5 ° C, to a stirred solution of commercially available piperazine-1,3-dicarboxylic acid 1- (tert-butyl) ester 3-methyl ester (1000mg, 4.093mmol) in anhydrous THF (10mL) was added 1M LiAlH4 in THF (4.912mL, 4.912mmol), and the reaction mass was stirred at this temperature for 2 hours. The reaction progress was monitored by TLC, and after completion, the reaction mass was quenched by dropwise addition of saturated sodium sulfate solution and stirred at room temperature for another 1 hour. The aqueous solution was filtered through a bed of diatomaceous earth. The filtrate was evaporated in vacuo to obtain the title compound (1050mg, crude material) as a slightly yellow solid, which was used in the next step without any further purification. LCMS m / z: 217.10 [M+H].

[0480] Step 2: tert-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid Butyl ester

[0481]

[0482] To a stirred solution of tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (preparation 13, step 1) (780 mg, 3.606 mmol) in DMSO (10 mL) was added commercially available 1,2-difluoro-4-nitrobenzene (745.87 mg, 4.688 mmol), followed by KOH (627.30 mg, 11.179 mmol), and all reactants were stirred at 30 ° C for 18 hours. The reaction progress was monitored by LCMS, and after completion, the reactant was diluted with chilled water and extracted with DCM containing 10% methanol. The combined organic layer was distilled off to obtain a crude compound, which was purified by silica gel column chromatography using methanol and DCM as eluents to obtain the title compound (280 mg, 99% yield) as a yellow semi-solid. LCMS m / z: 336.11 [M+H].

[0483] Step 3: 8-Nitro-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine.HCl

[0484]

[0485] To a stirred solution of tert-butyl 8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (Preparation 13, Step 2) (280 mg, 0.834 mmol) in 1,4-dioxane (3 mL) was added 4M HCl-dioxane (3 mL) at 0 to 5° C., and the resulting reaction mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS, and after completion, the reaction mixture was evaporated in vacuo to afford the title compound (270 mg, crude) as a slightly yellow solid, which was used in the next step without further purification. LCMS m / z: 236.02 [M+H].

[0486] Step 4: 3-Methyl-8-nitro-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine

[0487]

[0488] To a stirred solution of 8-nitro-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine.HCl (Preparation 13, Step 3) (270 mg, 1.148 mmol) in MeOH (5 mL) was added a 40% solution of formaldehyde (0.430 mL, 5.739 mmol) and NaBH3CN (129.83 mg, 2.066 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by UPLC-MS, and after completion, the reaction mixture was diluted with water and extracted with DCM containing 10% methanol. The combined organic layers were evaporated in vacuo to give the title compound (235 mg, crude material) as a slightly yellow semi-solid, which was used in the next step without any further purification. LCMS m / z: 250.05 [M+H].

[0489] Step 5: 3-Methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-amine

[0490]

[0491] To a stirred solution of 3-methyl-8-nitro-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine (Preparation 13, Step 4) (225 mg, 0.903 mmol) in ethanol (5 mL) was added Fe powder (252.02 mg, 4.513 mmol), followed by a solution of NH4Cl (241.41 mg, 4.513 mmol) in water (1 mL). The resulting reaction mixture was refluxed at 85 ° C for 2 hours. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was diluted with water (20 mL) and extracted with a solution of 10% methanol in DCM (2×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound, which was purified by Combi-flash using 4% methanol in DCM as eluent to afford the title compound (180 mg, 90% yield) as a light brown viscous liquid. LCMS m / z: 220.06 [M+H].

[0492] Preparation 14: Step 1: 4-iodo-2-methoxy-N-(3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino [1,2-d][1,4]oxazin-8-yl)nicotinamide

[0493]

[0494] To a stirred solution of 4-iodo-2-methoxynicotinic acid (Preparation 11, Step 1) (170 mg, 0.609 mmol) in THF (10 mL) was added HATU (278.05 mg, 0.731 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 15 minutes. Subsequently, DIPEA (0.319 mL, 1.828 mmol) and 3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-amine (Preparation 13, Step 5) (133.54 mg, 0.609 mmol) were added to the reaction vessel and the entire reaction was stirred at room temperature for 18 hours. The reaction progress was monitored by TLC / LC-MS, and upon completion, the reaction mixture was diluted with water (20 mL) and extracted with DCM (2×100 mL) containing 10% methanol. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel (12 g) Combi-flash column using 5% MeOH in DCM as eluent to afford the title compound (150 mg, 51% yield, 98% HPLC purity) as a light brown viscous liquid. LCMS m / z: 481.04 [M+H].

[0495] Step 2: 4-iodo-N-(3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine- 8-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride

[0496]

[0497] A stirred suspension of 4-iodo-2-methoxy-N-(3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)nicotinamide (Preparation 14, Step 1) (140 mg, 0.291 mmol) in 4M HCl in dioxane (5 mL) was heated at 80° C. for 2 hours. After completion of the reaction (monitored by LCMS), the reaction mass was evaporated in vacuo to give the title compound (140 mg, crude) as a slightly yellow sticky solid, which was used in the next step without further purification. LCMS m / z: 375.05 [M+H].

[0498] Step 3: N-(3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)- 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine- 3-Formamide (Example 168)

[0499]

[0500] To a stirred solution of 4-iodo-N-(3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride (Preparation 14, Step 2) (140 mg, 0.421 mmol) in n-BuOH (10 mL) was added 8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-amine dihydrochloride (Preparation 9, Step 4) (83.40 mg, 0.505 mmol) at room temperature, followed by DIPEA (0.367 mL, 2.103 mmol). The resulting reaction mixture was stirred at 110 ° C for 18 hours. The reaction progress was monitored by LC-MS, and after completion, the reaction mixture was diluted with water (25 mL) and extracted with a 10% methanol solution in DCM (2×100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to afford the title compound as a brown solid (25 mg, 13% yield, 96.82% HPLC purity). 1 H NMR (500MHz; DMSO-d6): δ1.67(t,J=10.65Hz,1H),1.92(s,3H),2.05-2.10(m,2H),2.21(s,3H),2.57-2.63 (m,2H),2.78(d,J=10.0Hz,1H),2.85(d,J=10.6Hz,1H),2.99(t,J=9.65Hz,1H),3.65(d,J=11.35H,1H),3.8 9(t,J=9.45Hz,1H),4.21-4.26(m,3H),5.55(d,J=7.45Hz,1H),5.81(s,1H),6.81(d,J=8.8Hz,1H),6.92-6. 94(m,1H),7.14(d,J=2.25Hz,1H),7.28(t,J=10.05Hz,2H),11.31(s,1H),11.88(s,1H),12.82(s,1H); LCMS m / z:504.29[M+H].

[0501] Example 363: 4-((8-Methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N- (4-(4-(6-methylpyridin-3-yl)piperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

[0502]

[0503] Example 363 was prepared according to the methods described in General Procedures 1 to 7 and the methods described below.

[0504] Preparation 15: 4-(4-(6-methylpyridin-3-yl)piperazin-1-yl)aniline

[0505]

[0506] Step 1: 1-(6-methylpyridin-3-yl)-4-(4-nitrophenyl)piperazine

[0507]

[0508] To a degassed solution of commercially available 1-(4-nitrophenyl)piperazine (300 mg, 1.43 mmol) in 1,4-dioxane (5 mL) was added 5-bromo-2-methyl-pyridine (296 mg, 1.72 mmol), t To the mixture of BuONa (402 mg, 3.58 mmol), BrettPhos (154 mg, 0.29 mmol) and Brettphos-Pd-G3 (130 mg, 0.14 mmol) was added. The resulting mixture was heated at 100 ° C under a nitrogen atmosphere for 16 hours. The reaction progress was monitored by LCMS, and after completion, the reaction mixture was cooled to room temperature and filtered through a celite bed. The filtrate was evaporated under reduced pressure to obtain a crude product, which was then purified by column chromatography to obtain the title compound (400 mg, 93.5% yield) as a yellow solid. LCMS m / z: 299.1 [M + H].

[0509] Step 2: 4-(4-(6-methylpyridin-3-yl)piperazin-1-yl)aniline

[0510]

[0511] To a stirred solution of 1-(6-methylpyridin-3-yl)-4-(4-nitrophenyl)piperazine (Preparation 15, Step 1) (250 mg, 0.88 mmol) in methanol (5 mL) was added 10% Pd-C (50 mg) at room temperature under an inert atmosphere, and the reaction mixture was placed under a hydrogen balloon for 2 hours. TLC and LC-MS confirmed the completion of the reaction, after which the reaction mass was filtered through a short bed of celite and the filtrate was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography to afford the title compound as an off-white solid (200 mg, 85% yield). LCMS m / z: 269.2 [M+H].

[0512] Preparation 16: 2-methoxy-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino Niacin

[0513]

[0514] Step 1: 4-iodo-2-methoxynicotinate methyl ester

[0515]

[0516] To a stirred solution of commercially available 4-iodo-2-methoxynicotinic acid (300 mg, 1.075 mmol) in DMF (6 mL) was added K2CO3 (371.50 mg, 2.688 mmol) at ice-cold temperature, followed by addition of MeI (0.1 mL, 1.613 mmol), and the entire reaction mixture was stirred at room temperature for 2 hours. UPLC and TLC showed that the desired substance had been formed and the starting material was completely exhausted. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was purified by Combi flash chromatography on silica gel (12.0 g) using 20% ethyl acetate in hexane as eluent to give the title compound (190 mg, 60% yield) as an off-white solid. LCMS m / z: 294.02 [M+H].

[0517] Step 2: 2-methoxy-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino methyl nicotinate

[0518]

[0519] To a stirred solution of 8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-amine dihydrochloride (Preparation 9, Step 4) (121.64 mg, 0.737 mmol) in 1,4-dioxane (15 mL) was added CsCO (1000.81 mg, 3.072 mmol) followed by methyl 4-iodo-2-methoxynicotinate (Preparation 16, Step 1) (180 mg, 0.614 mmol) at room temperature. The resulting mixture was degassed for 15 minutes before the addition of Pd(dba) (56.22 mg, 0.0614 mmol) and XPhos (71.05 mg, 0.1228 mmol) and the entire reaction was further stirred at 100 ° C overnight. LCMS and TLC showed that the desired compound had formed and the starting material was completely consumed. The crude mixture was diluted with water and extracted with 10% methanol in DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo to afford the crude product, which was purified by Combi-flash to afford the title compound as a white solid (150 mg, 77% yield). LCMS m / z: 331.22 [M+H].

[0520] Step 3: 2-methoxy-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino Niacin

[0521]

[0522] To a stirred solution of methyl 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxylate (Preparation 16, Step 2) (140 mg, 0.424 mmol) in THF (2 mL) and MeOH (1 mL) was added LiOH.HO (89 mg, 2.12 mmol) dissolved in HO (1 mL) and the whole reaction was stirred at room temperature for 4 hours. UPLC and TLC showed that the desired material had formed and the starting material was completely consumed. The solvent was evaporated in vacuo to obtain the crude product, which was diluted with a small amount of water and the pH of the mixture was adjusted to about 5 by slowly adding citric acid solution. The resulting material was diluted with water and extracted with 10% methanol in DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give the title compound (130 mg, crude), which was used in the next step without any further purification. LCMS m / z: 317.19 [M+H].

[0523] Preparation 17: Step 1: 2-Methoxy-4-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine- 7-yl)amino)-N-(4-(4-(6-methylpyridin-3-yl)piperazin-1-yl)phenyl)nicotinamide

[0524]

[0525] To a stirred solution of 2-methoxy-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)nicotinic acid (Preparation 16, Step 3) (100 mg, 0.32 mmol) in DMF (3 mL) was added DIPEA (0.17 mL, 0.95 mmol) and HATU (360 mg, 0.95 mmol) and the whole was stirred at room temperature for 30 minutes. Next, 4-(4-(6-methylpyridin-3-yl)piperazin-1-yl)aniline (Preparation 15, Step 2) (84.8 mg, 0.32 mmol) was added to the reaction vessel and stirring was continued at room temperature for 16 hours. The reaction progress was monitored by LCMS, and upon completion, the reaction mass was quenched with ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product, which was purified by column chromatography to afford the title compound as a brown solid (100 mg, 55.8% yield). LCMS m / z: 567.3 [M+H].

[0526] Step 2: 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4- (4-(6-methylpyridin-3-yl)piperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (Example 363)

[0527]

[0528] To a stirred solution of 2-methoxy-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-(6-methylpyridin-3-yl)piperazin-1-yl)phenyl)nicotinamide (Preparation 17, Step 1) (40 mg, 0.07 mmol) in DMF (2 mL) was added LiCl (14.9 mg, 0.35 mmol) and pTSA (67.2 mg, 0.35 mmol) at room temperature under an inert atmosphere. The resulting reaction mixture was stirred at 80 °C for 16 h. The reaction progress was monitored by LCMS, and upon completion, the reaction mass was directly purified by preparative HPLC to afford the title compound (12 mg, 30.8% yield, 99.65% HPLC purity) as an off-white solid. 1 H NMR (400 MHz; DMSO-d6): δ 1.93 (s, 3H), 2.36 (s, 3H), 3.25-3.31 (m, 10H, combined with DMSO water), 4.25 (s, 2H), 5.56 (d, J = 7.36 Hz, 1H), 5.79 (s, 1H), 6.99 (d, J = 8.96 Hz, 2H), 7.10 (d, J = 8.4 Hz, 1H), 7.26-7.33 (m, 3H), 7.51 (d, J = 8.88 Hz, 2H), 8.21 (s, 1H), 11.34 (s, 1H), 11.90 (s, 1H), 12.87 (s, 1H); LCMS m / z: 553.2 [M+H].

[0529] Example 371: 4-((8-Methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo- Substituted-N-(4-(4-(thiazol-2-yl)piperazin-1-yl)phenyl)-1,2-dihydropyridine-3-carboxamide

[0530]

[0531] Example 371 was prepared according to the methods described in General Procedures 1 to 7 and the methods described below.

[0532] Preparation 18: 4-(4-(thiazol-2-yl)piperazin-1-yl)aniline

[0533]

[0534] Step 1: 2-(4-(4-nitrophenyl)piperazin-1-yl)thiazole

[0535]

[0536] To a stirred solution of commercially available 1- fluoro-4-nitro-benzene (400 mg, 2.34 mmol) in DMF (10 mL) was added KCO (978 mg, 7.09 mmol) and commercially available 2-piperazine-1-ylthiazole (400 mg, 2.84 mmol) and continued stirring at room temperature for 16 hours. LCMS confirmed product formation. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain the title compound (500 mg, 72.9% yield) as a yellow solid. LCMS m / z: 291.0 [M+H].

[0537] Step 2: 4-(4-(thiazol-2-yl)piperazin-1-yl)aniline

[0538]

[0539] To a stirred solution of 2-(4-(4-nitrophenyl)piperazin-1-yl)thiazole (Preparation 18, Step 1) (250 mg, 0.877 mmol) in methanol (5 mL) was added 10% Pd-C (50 mg) at room temperature under an inert atmosphere. The resulting mixture was stirred at room temperature for 2 hours. LCMS confirmed the formation of the product. The reaction mass was filtered through a short bed of celite and the filtrate was evaporated under reduced pressure to give the title compound (210 mg, 92% yield) as a solid, which was used in the next step without any further purification. LCMS m / z: 261.1 [M+H].

[0540] Preparation 19: 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxazin- Substituted-N-(4-(4-(thiazol-2-yl)piperazin-1-yl)phenyl)-1,2-dihydropyridine-3-carboxamide (Example 371)

[0541]

[0542] The title compound was prepared using exactly the same procedure as described in Preparation 17, Steps 1 to 2, where the coupling amine was 4-(4-(thiazol-2-yl)piperazin-1-yl)aniline (Preparation 18, Step 2). HPLC purity: 99.10%; 1H NMR (400 MHz; DMSO-d6): δ 1.93 (s, 3H), 3.23 (t, J = 5.12 Hz, 4H), 3.33 (s, 2H, combined with DMSO water) 3.53 (t, J = 4.8 Hz, 4H), 4.24 (d, J = 3.65 Hz, 2H), 5.55 (d, J = 7.4 Hz, 1H), 5.81 (s, 1H), 6.88 (d, J = 3. 6Hz,1H),6.99(d,J=9.04Hz,2H),7.19(d,J=3.6Hz,1H),7.29(d,J=11.92Hz,2H),7.51(d,J =8.92Hz, 2H), 11.37 (d, J = 7.56Hz, 1H), 11.89 (s, 1H), 12.89 (s, 1H); LCMSm / z: 545.39[M+H].

[0543] Example 197: 4-((3,8-Dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino 1-Methyl-2-piperidin-1-yl)-N-(4-(2-(methoxymethyl)-4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

[0544]

[0545] Example 197 was prepared according to the methods described in General Procedures 1 to 7 and the methods described below.

[0546] Preparation 20: 4-(2-(methoxymethyl)-4-methylpiperazin-1-yl)aniline

[0547]

[0548] Step 1: tert-Butyl 3-(hydroxymethyl)-4-(4-nitrophenyl)piperazine-1-carboxylate

[0549]

[0550] To a stirred solution of commercially available 1-fluoro-4-nitrobenzene (500 mg, 0.046 mmol) in DMSO (8 mL) was added tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (Preparation 13, Step 1) (342.51 mg, 2.427 mmol) at room temperature, followed by KOH (389.15 mg, 6.935 mmol), which was then further stirred at 30 ° C for 18 hours. The reaction progress was monitored by TLC / LCMS, and after completion, the reaction mixture was diluted with chilled water (20 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was purified by Combi-flash using 3% MeOH-DCM as eluent to give the title compound (415 mg, 51% yield) as a light brown viscous liquid. LCMS m / z: 338.12 [M+H].

[0551] Step 2: 2-(Methoxymethyl)-4-methyl-1-(4-nitrophenyl)piperazine

[0552]

[0553] To a stirred solution of tert-butyl 3-(hydroxymethyl)-4-(4-nitrophenyl)piperazine-1-carboxylate (Preparation 20, Step 1) (400 mg, 1.186 mmol) in 1,4-dioxane (4 mL) was added 4M HCl in dioxane (4 mL) at 0 to 5° C. and the whole was stirred at 30° C. for 5 hours. The reaction progress was monitored by LC-MS, and upon completion, the solvent was evaporated to dryness to give the intermediate (1-(4-nitrophenyl)piperazin-2-yl)methanol hydrochloride (432 g, crude) as a yellow solid, which was dissolved in MeOH (5 mL) and 40% formaldehyde solution (0.66 mL, 8.851 mmol) and added with NaBH 3 CN (200.23 mg, 3.186 mmol) at room temperature. The resulting mixture was stirred at room temperature for 18 hours. The reaction progress was monitored by UPLC-MS, and upon completion, the reaction mixture was diluted with water (20 mL) and extracted with a 10% methanol in DCM solution (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by Combi-flash using 4% MeOH in DCM as eluent to give the title compound (235 mg, 50% yield) as a light brown viscous liquid. LCMS m / z: 266.09 [M+H].

[0554] Step 3: 4-(2-(methoxymethyl)-4-methylpiperazin-1-yl)aniline

[0555]

[0556] To a stirred solution of 2-(methoxymethyl)-4-methyl-1-(4-nitrophenyl)piperazine (Preparation 20, Step 2) (200 mg, 0.754 mmol) in EtOH (8 mL) was added Fe powder (210.47 mg, 3.769 mmol) and aqueous NH4Cl solution (201.61 mg, 3.769 mmol in 1 mL of water) at room temperature. The resulting reaction mixture was refluxed at 80 ° C for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, diluted with water (20 mL) and extracted with a 10% methanol solution in DCM (2×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (250 mg, crude material) as a brown sticky solid, which was used in the next step without further purification. LCMS m / z: 236.31 [M+H].

[0557] Preparation 21: 3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-amine.2HCl

[0558]

[0559] Step 1: N-(5-bromo-2-hydroxy-4-methylpyridin-3-yl)-2-chloropropionamide

[0560]

[0561] To a stirred solution of commercially available 3-amino-5-bromo-4-methylpyridin-2-ol (2000 mg, 9.852 mmol) in THF (50 mL) was added TEA (4.15 mL, 29.556 mmol) at 0 to 5 ° C. Subsequently, 2-chloropropionyl chloride (1.17 mL, 11.822 mmol) was added dropwise and the resulting reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC and LC-MS, and TLC and LC-MS showed that the starting material was converted into the desired product. The reaction mixture was diluted with water (200 mL) and extracted with a DCM solution (10 × 100 mL) containing 10% methanol. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (3.0 g, crude material) as a pale white solid, which was used in the next step without any further purification. LCMS m / z: 292.84 [M+H].

[0562] Step 2: 7-Bromo-3,8-dimethyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

[0563]

[0564] To a stirred solution of N-(5-bromo-2-hydroxy-4-methylpyridin-3-yl)-2-chloropropionamide (Preparation 21, Step 1) (6000 mg, 20.439 mmol) in DMF (60 mL) was added KCO (8474 mg, 61.318 mmol) and the entire reaction was stirred at room temperature for a few minutes and then heated at 70 ° C overnight. The progress of the reaction was monitored by TLC and LC-MS, which showed that the starting material was converted to the desired product. The reaction mixture was poured into chilled water (300 mL) and stirred for 30 minutes to produce a solid precipitate, which was collected in a Buchner funnel and washed with hexane, sucked dry for 30 minutes, and then oven-dried overnight to give the title compound (4.1 g, crude material) as a light brown solid, which was used in the next step without further purification. LCMS m / z: 256.94 [M+H].

[0565] Step 3: 7-Bromo-3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine

[0566]

[0567] By 7- bromo -3,8- dimethyl -1H- pyrido [2,3-b] [1,4] oxazine -2 (3H) -one (preparation 21, step 2) (2970mg, 11.552mmol) in BH3.THF (46.2mL, 1M in THF) in a stirring solution was stirred at 0 to 5 ° C for a few minutes, then stirred at room temperature for 3 hours. After the reaction was completed (monitored by LC-MS and TLC), MeOH (100mL) was added dropwise until bubbling stopped to quench the reaction mixture, followed by 1N HCl (46.2mL) and stirred for another hour. Next, MeOH was evaporated under reduced pressure to obtain a residue, which was neutralized with a saturated NaHCO3 aqueous solution. Then, it was diluted with water (200mL) and extracted with EtOAc (4 × 200mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give the crude product, which was purified by silica gel (80 g) column chromatography using 5-7% ethyl acetate in DCM as eluent to afford the title compound (2.1 g, 75% yield) as a white solid. LCMS m / z: 242 [M+H].

[0568] Step 4: tert-Butyl 7-bromo-3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate

[0569]

[0570] To a stirred solution of 7-bromo-3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (Preparation 21, Step 3) (2100 mg, 8.638 mmol) in THF (42 mL) was added 1.3 M LiHMDS (9.96 mL, 1.5 eq) at 0-5 ° C under an inert atmosphere. Then, Boc-anhydride (3.96 mL, 17.277 mmol) was added to the reaction vessel and stirring was continued at room temperature for 7 hours. The reaction progress was monitored by TLC / LCMS, and after completion, the reaction mixture was diluted with water and extracted with EtOAc (8 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was purified by column chromatography using 25-30% EtOAc in hexane as eluent to give the title compound (2.4 g, 81% yield) as a pale white solid. LCMS m / z: 342.92 [M+H].

[0571] Step 5: 7-((tert-Butoxycarbonyl)amino)-3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1, 4] tert-Butyl oxazine-1-carboxylate

[0572]

[0573] At room temperature, Cs2CO3 (6569 mg, 20.16 mmol) and 7-bromo-3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester (preparation 21, step 4) (2306 mg, 6.721 mmol) were added to a stirred solution of Boc-amine (1574 mg, 13.442 mmol) in 1,4-dioxane (46 mL). The resulting reaction mixture was purged with nitrogen for 20 minutes. Subsequently, Brettphos-Pd-G3 (1218 mg, 1.344 mmol) was added to the reaction vessel and all reactants were stirred at 105 ° C for 3 hours. The reaction progress was monitored by LCMS, and after completion, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (6 × 200 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the crude product, which was purified by column chromatography using 25% EtOAc in DCM as eluent to afford the title compound as a brown solid (2100 mg, 82% yield). LCMS m / z: 380.40 [M+H].

[0574] Step 6: 3,8-Dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-amine.2HCl

[0575]

[0576] A solution of tert-butyl 7-((tert-butoxycarbonyl)amino)-3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (Preparation 21, Step 5) (1900 mg, 5.013 mmol) in 2M HCl in dioxane (38 mL) was stirred at room temperature for 4 hours. The reaction progress was monitored by LCMS, and upon completion, the solvent was evaporated in vacuo to give a residue that was triturated with diethyl ether and dried to give the title compound as a light brown solid (1330 mg, crude). LCMS m / z: 180.22 [M+H].

[0577] Preparation 22: Step 1: 4-iodo-2-methoxy-N-(4-(2-(methoxymethyl)-4-methylpiperazin-1-yl)phenyl) Niacinamide

[0578]

[0579] To a stirred solution of 4-iodo-2-methoxynicotinic acid (Preparation 11, Step 1) (280 mg, 1.004 mmol) in THF (10 mL) was added HBTU (456.82 mg, 1.205 mmol) and stirred at room temperature for 15 minutes. Next, DIPEA (0.525 mL, 3.011 mmol) and 4-(2-(methoxymethyl)-4-methylpiperazin-1-yl)aniline (Preparation 20, Step 3) (236.22 mg, 1.004 mmol) were added to the reaction vessel and the entire reaction was stirred at room temperature for an additional 18 hours. The reaction progress was monitored by LC-MS, and upon completion, the reaction mixture was diluted with water (20 mL) and extracted with 10% methanol in DCM (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by Combi-flash using 4% MeOH in DCM as eluent to afford the title compound as a light brown sticky solid (155 mg, 37% yield). LCMS m / z: 497.16 [M+H].

[0580] Step 2: 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2- Methoxy-N-(4-(2-(methoxymethyl)-4-methylpiperazin-1-yl)phenyl)nicotinamide

[0581]

[0582] To a stirred solution of 4-iodo-2-methoxy-N-(4-(2-(methoxymethyl)-4-methylpiperazin-1-yl)phenyl)nicotinamide (Preparation 22, Step 1) (145 mg, 0.292 mmol) in 1,4-dioxane (10 mL) was added 3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-amine.2HCl (Preparation 21, Step 6) (62.827 mg, 0.351 mmol) followed by CsCO (428.32 mg, 1.315 mmol) at room temperature. This mixture was purged with nitrogen for 15 minutes before the addition of Pd(dba) (26.75 mg, 0.029 mmol) and Xantphos (33.81 mg, 0.058 mmol) to the reaction vessel and heated at 100° C. overnight. The reaction progress was monitored by TLC / LC-MS, and upon completion, the reaction mixture was diluted with water (20 mL) and extracted with a 10% methanol in DCM solution (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by Combi-flash using 4-5% MeOH-DCM as eluent to afford the title compound (140 mg, 87% yield) as a brown, sticky solid. LCMS m / z: 548.38 [M+H].

[0583] Step 3: 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N- (4-(2-(Methoxymethyl)-4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (Example 197)

[0584]

[0585] A stirred suspension of 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-methoxy-N-(4-(2-(methoxymethyl)-4-methylpiperazin-1-yl)phenyl)nicotinamide (Preparation 22, Step 2) (130 mg, 0.237 mmol) in 4M HCl in dioxane (5 mL) was stirred at 80° C. for 3 hours. The reaction progress was monitored by LC-MS, and after completion, the reaction mixture was distilled off to obtain the crude product, which was purified by preparative HPLC to give the title compound as a white solid (20 mg, 16% yield). HPLC purity: 99.84%; 1 H NMR (500MHz; DMSO-d6): δ1.26(d,J=6.25Hz,3H),1.84-1.88(m,4H),1.97-2.01(m,1H),2.13-2.18(m,1H),2.19(s,3H ),2.29-2.33(m,1H),2.47-2.50(m,1H),2.59-2.62(m,1H),2.69-2.71(m,1H),2.86-2.91(m,1H),3.24(s,3H),3.31-3 .39(m,1H),3.75-3.78(m,1H),4.00-4.03(m,1H),4.16-4.18(m,1H),5.47-5.49(m,1H),5.75(s,1H),6.86(d,J=8.95 Hz,2H),7.21-7.24(m,2H),7.46(d,J=8.95Hz,2H),11.31(s,1H),11.79(s,1H),12.85(s,1H); LCMSm / z:534.35[M+H].

[0586] Example 263: N-(3-amino-4-(4-methylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrrolidone)- 2-oxo-1,2-dihydropyridine-3-carboxamide

[0587]

[0588] Example 263 was prepared according to the methods described in General Procedures 1 to 7 and the methods described below.

[0589] Preparation 23: Step 1: 4-iodo-2-methoxy-N-(4-(4-methylpiperazin-1-yl)-3-nitrophenyl)nicotinamide

[0590]

[0591] Thionyl chloride (0.10mL, 1.41mmol) is added to the stirred solution of 4- iodo- 2- methoxynicotinic acid (preparation 11, step 1) (200mg, 0.71mmol) in DCM (5mL) and all reactants are stirred at 45 DEG C for 1 hour. Subsequently, reactant is cooled to room temperature and concentrated in vacuo to obtain corresponding crude acid chloride, which is dissolved in DCM (5mL) and DIPEA (0.38mL, 2.14mmol) is added, followed by dropwise addition of commercially available 4- (4- methylpiperazine -1- bases) -3- nitro-aniline (202mg, 0.85mmol) in DCM (2mL) at 0 to 5 DEG C. Gained reaction mixture is stirred at room temperature for 16 hours. Reaction process is monitored by LCMS, and after completion, reaction mixture is quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product, which was purified by column chromatography to afford the title compound as an off-white solid (250 mg, 71% yield). LCMS m / z: 497.97 [M+H].

[0592] Step 2: 4-chloro-N-(4-(4-methylpiperazin-1-yl)-3-nitrophenyl)-2-oxo-1,2-dihydropyridine-3- Formamide

[0593]

[0594] A mixture of 4-iodo-2-methoxy-N-(4-(4-methylpiperazin-1-yl)-3-nitrophenyl)nicotinamide (Preparation 23, Step 1) (250 mg, 0.503 mmol) in 4M HCl in dioxane (5 mL) was stirred at 80° C. for 2 hours. The reaction was then monitored by LCMS, and upon completion, the reaction mixture was evaporated under reduced pressure to give a residue, which was triturated with diethyl ether to give the title compound as a brown solid (200 mg, crude), which was used in the next step without further purification. LCMS m / z: 392.1 [M+H].

[0595] Step 3: 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4- (4-Methylpiperazin-1-yl)-3-nitrophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

[0596]

[0597] To a stirred solution of 4-chloro-N-(4-(4-methylpiperazin-1-yl)-3-nitrophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (Preparation 23, Step 2) (200 mg, 0.51 mmol) in n-BuOH (4 mL) was added DIPEA (0.27 mL, 1.53 mmol) and 8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-amine.2HCl (Preparation 9, Step 4) (101 mg, 0.61 mmol) at room temperature. The resulting reaction mixture was stirred at 120 ° C. in a sealed tube for 16 hours. The reaction progress was checked by LC-MS, and then the solvent was evaporated in vacuo to give the crude product, which was purified by silica gel (100-200 mesh) column chromatography to give the title compound (130 mg, 48.9% yield) as an off-white solid. LCMS m / z: 521.2 [M+H].

[0598] Preparation 24: N-(3-amino-4-(4-methylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyridine (2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide (Example 263)

[0599]

[0600] To a stirred solution of 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-methylpiperazin-1-yl)-3-nitrophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (Preparation 23, Step 3) (100 mg, 0.19 mmol) in methanol (5 mL) was added 10% Pd-C (30 mg) under inert atmosphere and the whole was stirred under hydrogen balloon pressure for 2 hours. The progress of the reaction was monitored by LC-MS, and after completion, the reaction mixture was filtered through a short bed of celite and the bed was washed with 10% MeOH-DCM. The filtrate was then concentrated under reduced pressure to obtain the crude compound, which was purified by preparative HPLC to afford the title compound as an off-white solid (13 mg, 14% yield). HPLC purity: 99.82%; 1H NMR (400MHz; DMSO-d6): δ1.92(s,3H),2.22(s,3H),2.76(s,4H),3.31(s,4H),4.25(s,2H),4.77(s,2H),5.55(d,J=7.4Hz,1H),5.7 9(s,1H),6.77-6.85(m,2H),7.03(d,J=2.08Hz,1H),7.24-7.30(m,2H),11.33(d,J=6.08Hz,1H),11.93(s,1H),12.77(s,1H); LCMS m / z:491.34[M+H].

[0601] Example 132: 4-((8-Methoxy-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N- (4-(4-Methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

[0602]

[0603] Example 132 was prepared according to the methods described in General Procedures 1 to 7 and the methods described below.

[0604] Preparation 25: tert-Butyl 7-bromo-8-methoxy-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate

[0605]

[0606] Step 1: 5-Bromo-2-chloro-4-methoxy-3-nitropyridine

[0607]

[0608] To a stirred solution of commercially available 5-bromo-2,4-dichloro-3-nitropyridine (1650 mg, 6.069 mol) in MeOH (20 mL) was added NaOMe (327.84 mg, 6.069 mmol) at room temperature and the combined reaction mixture was stirred for 2 hours at 60° C. The progress of the reaction was monitored by TLC and LCMS, and upon completion, the solvent was evaporated to dryness in vacuo to obtain a residue, which was purified by silica gel Combi-flash using ethyl acetate and hexane as eluents to afford the title compound (1550 mg, 95% yield) as a slightly yellow liquid.

[0609] Step 2: Methyl 2-((5-bromo-4-methoxy-3-nitropyridin-2-yl)oxy)acetate

[0610]

[0611] To a stirred solution of methyl 2-hydroxyacetate (3132.22 mg, 34.772 mmol) in acetonitrile (60 mL) was added KCO (4805.78 mg, 34.772 mmol) and after 10 minutes, at room temperature, 5-bromo-2-chloro-4-methoxy-3-nitropyridine (preparation 25, step 1) (3100 mg, 11.591 mmol) was added to the reaction mixture. The resulting mixture was stirred overnight at 80 ° C. The reaction progress was monitored by TLC and LCMS, and after completion, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was evaporated in vacuo to dryness to obtain a crude compound, which was purified by silica gel Combi-flash using ethyl acetate and hexane as eluents to obtain the title compound (360 mg, 10% yield) as a slightly yellowish sticky solid. LCMS m / z: 320.98 [M+H].

[0612] Step 3: 7-Bromo-8-methoxy-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

[0613]

[0614] To a stirred solution of methyl 2-((5-bromo-4-methoxy-3-nitropyridin-2-yl)oxy)acetate (Preparation 25, Step 2) (360 mg, 1.121 mmol) in AcOH (5 mL) was added Fe powder (250.43 mg, 4.484 mmol) at room temperature, and the reaction mixture was refluxed at 90 ° C for 1.5 hours. LCMS and TLC showed that the desired product had been formed. Acetic acid was evaporated in vacuo to give a residue, which was neutralized with saturated sodium bicarbonate solution and diluted with water. The aqueous material was extracted and neutralized with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the title compound (300 mg, crude material) as a white solid, which was used in the next step without any further purification. LCMS m / z: 258.94 [M+H].

[0615] Step 4: 7-Bromo-8-methoxy-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine

[0616]

[0617] In a reaction vial, a suspension of 7-bromo-8-methoxy-1H-pyrido[2,3-b][1,4]oxazine-2(3H)-one (Preparation 25, Step 3) (300 mg, 1.158 mmol) in 0.9M BH3-THF solution (6.43 mL, 5.790 mmol) was stirred at room temperature for 2 hours at 0-5 ° C. The reaction progress was monitored by TLC and LCMS, and after completion, the reaction mass was quenched with methanol and subsequently quenched with 1N HCl (0.2 mL). After 1 hour, the reaction mass was evaporated to dryness in vacuo, neutralized with saturated sodium bicarbonate solution and diluted with water. The aqueous material was neutralized by extraction with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the title compound (360 mg, crude material) as a slightly yellow viscous liquid, which was used in the next step without any further purification. LCMS m / z: 244.96 [M+H].

[0618] Step 5: tert-Butyl 7-bromo-8-methoxy-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate

[0619]

[0620] At room temperature, TEA (1.02mL, 7.340mmol), DMAP (179.34mg, 1.468mmol) and Boc-anhydride (1.349mL, 5.878mmol) are added to a stirred solution of 7-bromo-8-methoxy-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (preparation 25, step 4) (360mg, 1.468mmol) in DCE (10mL). The resulting reaction mixture is stirred at room temperature for 6 hours. The reaction progress is monitored by TLC and LCMS, and after completion, the reaction mass is diluted with water and extracted with ethyl acetate. The combined organic layer is distilled off to obtain a crude product, which is purified by silica gel Combi-flash using ethyl acetate and hexane as eluents to obtain the title compound (300mg, 59% yield) as a slightly yellowish viscous solid. LCMS m / z:345.06[M+H].

[0621] Preparation 26: 4-amino-2-methoxy-N-(4-(4-methylpiperazin-1-yl)phenyl)nicotinamide

[0622]

[0623] Step 1: (2-methoxy-3-((4-(4-methylpiperazin-1-yl)phenyl)carbamoyl)pyridin-4-yl)amino Tert-butyl ester

[0624]

[0625] To a stirred solution of 4-iodo-2-methoxy-N-(4-(4-methylpiperazin-1-yl)phenyl)nicotinamide (Preparation 1, Step 2) (353 mg, 0.780 mmol) in dioxane (10 mL) was added tert-butyl carbamate (182.78 mg, 1.560 mmol) followed by CsCO (635.3 mg, 1.949 mmol) at room temperature. The resulting reaction mixture was purged with nitrogen for 15 minutes. Pd(dba) (71.42 mg, 0.077 mmol) and Xantphos (90.26 mg, 0.155 mmol) were then added to the reaction vessel and heated at 105 °C overnight. The reaction progress was monitored by TLC and LCMS, and upon completion, the reaction mixture was diluted with water and extracted with a 10% MeOH solution in DCM (5 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude compound, which was purified by silica gel column (12 g) Combi-flash using 3-4% MeOH in DCM as eluent to afford the title compound (315 mg, 49% yield) as a sticky solid. LCMS m / z: 442.55 [M+H].

[0626] Step 2: 4-amino-2-methoxy-N-(4-(4-methylpiperazin-1-yl)phenyl)nicotinamide

[0627]

[0628] Under ice cooling, to a stirred solution of tert-butyl (2-methoxy-3-((4-(4-methylpiperazin-1-yl)phenyl)carbamoyl)pyridin-4-yl)carbamate (Preparation 26, Step 1) (300 mg, 0.679 mmol) in DCE (6 mL) was added TFA (1.2 mL) and the combined mixture was stirred for a few minutes. It was then slowly warmed to room temperature for 2 hours. The reaction progress was monitored by TLC and LCMS, which showed that the starting material was converted into the desired product and a demethylated product as a small amount of impurity. The reaction mixture was diluted with water and neutralized with saturated sodium bicarbonate solution. The product was extracted with 10% MeOH in DCM (3×100 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silica gel column (12 g) Combi-flash using 7-9% MeOH in DCM as eluent to afford the title compound (191 mg, 82% yield) as a yellow sticky solid. LCMS m / z: 342.13 [M+H].

[0629] Preparation 27: Step 1: 8-methoxy-7-((2-methoxy-3-((4-(4-methylpiperazin-1-yl)phenyl)carbamyl tert-Butyl (4-(2-(2-methyl-1-pyridin-4-yl)amino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate)

[0630]

[0631] To a stirred solution of 4-amino-2-methoxy-N-(4-(4-methylpiperazin-1-yl)phenyl)nicotinamide (Preparation 26, Step 2) (80 mg, 0.234 mmol) in toluene (10 mL) was added tert-butyl 7-bromo-8-methoxy-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (Preparation 25, Step 5) (96.80 mg, 0.281 mmol) and NaO at room temperature. t To the reaction mixture was added Bu (56.33 mg, 0.586 mmol). The resulting reaction mixture was purged with nitrogen for 15 minutes, after which BrettPhos-Pd-G3 (42.51 mg, 0.047 mmol) was added to the reaction vessel and the entire reaction was heated at 100 ° C overnight. The reaction progress was checked by LCMS, and after completion, the reaction mass was diluted with water and extracted with DCM containing 10% methanol. The combined organic layers were distilled off to obtain the crude compound, which was purified by silica gel Combi-flash to obtain the title compound (200 mg, crude material) as a brown viscous liquid. LCMS m / z: 606.27 [M+H].

[0632] Step 2: 4-((8-methoxy-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N- (4-(4-Methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (Example 132)

[0633]

[0634] To a stirred solution of tert-butyl 8-methoxy-7-((2-methoxy-3-((4-(4-methylpiperazin-1-yl)phenyl)carbamoyl)pyridin-4-yl)amino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (Preparation 27, Step 1) (30 mg, 0.049 mmol) in DMF (3 mL) was added PTSA.HO (9.41 mg, 0.049 mmol) followed by LiBr (4.25 mg, 0.049 mmol). The entire reaction was heated at 65 °C for 40 minutes. LCMS showed the formation of the desired material. Upon completion, the reaction mixture was diluted with water and extracted with 10% MeOH in DCM. The combined organic layers were evaporated under reduced pressure to give the demethylated crude compound tert-butyl 8-methoxy-7-((2-methoxy-3-((4-(4-methylpiperazin-1-yl)phenyl)carbamoyl)pyridin-4-yl)amino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (66 mg, crude material) as a brown sticky solid, which was suspended in DCM (2 mL) containing 20% TFA and stirred at room temperature under an inert atmosphere for 3 hours. The reaction progress was monitored by LCMS, and after completion, the solvent was evaporated under reduced pressure to give a crude product, which was purified by preparative HPLC to give the title compound (2.8 mg, 11% yield) as a white solid. HPLC purity: 95.24%; 1 H NMR (500MHz; DMSO-d6): δ2.17(s,3H),2.43(s,4H),3.03(s,4H),3.22(d,J=3.7Hz,2H),3.62(s,3H),4.21(t,J=3.85Hz,2H),5.68(d,J=7.1Hz, 1H),5.84(s,1H),6.85(d,J=9.05Hz,2H),7.23-7.26(m,2H),7.40(d,J=9.0Hz,2H),11.35(d,J=5.95Hz,1H),11.93(s,1H),12.80(s,1H); LCMS m / z:492.25[M+H].

[0635] Example 163: N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-((8-methyl-2,3-dihydro-1H-pyrrolidone)- 2-oxo-1,2-dihydropyridine-3-carboxamide

[0636]

[0637] Example 132 was prepared according to the methods described in General Procedures 1 to 7 and the methods described below.

[0638] Preparation 28: 2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-amine.TFA

[0639]

[0640] Step 1: 7-Bromo-1,2,3,4-tetrahydroisoquinoline

[0641]

[0642] A suspension of commercially available 7-bromo-1,4-dihydroisoquinolin-3(2H)-one (340 mg, 1.503 mmol) in 0.9 M BH3-THF solution (5.01 mL, 4.511 mmol) was stirred at room temperature for 1 hour at 0-5 ° C., followed by heating at 60 ° C. for 1 hour. The reaction progress was monitored by TLC and LCMS, and after completion, it was quenched with methanol, subsequently quenched with 1 N HCl and neutralized with saturated sodium bicarbonate solution. The aqueous material was extracted with DCM containing 10% methanol and the combined organic layers were concentrated in vacuo to give a crude compound, which was purified on silica gel using methanol in DCM as an eluent to give the title compound (460 mg, crude material) as a slightly yellow solid. LCMS m / z: 211.92 [M+H].

[0643] Step 2: 7-Bromo-2-methyl-1,2,3,4-tetrahydroisoquinoline

[0644]

[0645] To a stirred solution of 7-bromo-1,2,3,4-tetrahydroisoquinoline (Preparation 28, Step 1) (460 mg, 1.428 mmol) in MeOH (10 mL) was added 40% formaldehyde solution (0.813 mL, 10.844 mmol) and NaBH3CN (245.33 mg, 3.904 mmol) at room temperature. After the addition was complete, the entire reaction was further stirred at room temperature for 16 hours. After completion of the reaction (checked by LCMS), the solvent was evaporated in vacuo to give a residue, which was purified by Combi-flash using 5% MeOH in DCM to give the title compound (475 mg, 97% yield) as a slightly yellowish sticky solid. LCMS m / z: 225.92 [M+H].

[0646] Step 3: N-(4-methoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine

[0647]

[0648] To a stirred solution of 7-bromo-2-methyl-1,2,3,4-tetrahydroisoquinoline (Preparation 28, Step 2) (475 mg, 2.100 mmol) in 1,4-dioxane (10 mL) was added (4-methoxyphenyl)methanamine (0.411 mL, 3.150 mmol) and NaO at room temperature. tTo the 4-thiazolinyl esters of 4-nitropropane-2-ol (5-nitropropane-2-ol)-1-nitropropane-2-ol (605.43mg, 6.300mmol). The obtained mixture was purged with nitrogen for 10 minutes. Then, Pd2(dba)3(192.36mg, 0.210mmol) and Brettphos (225.44mg, 0.420mmol) were added to the reaction mixture, and all reactants were heated at 100 DEG C for 18 hours. The reaction process was monitored by LCMS, and after completion, the reactant was diluted with water and extracted with DCM containing 10% methanol. The combined organic layer was distilled off to obtain a crude compound, which was purified on silica gel using the methanol in DCM as an eluent to obtain the title compound (355mg, 60% yield) as a brown solid. LCMS m / z:282.86[M+H].

[0649] Step 4: 2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-amine.TFA

[0650]

[0651] To a stirred solution of N-(4-methoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine (Preparation 28, Step 3) (345 mg, 1.221 mmol) in DCE (5 mL) was added TFA (1 mL) at 0 to 5° C., and the reaction mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS, and upon completion, the solvent was evaporated in vacuo to give the title compound (500 mg, crude) as a slightly black sticky solid, which was used in the next step without further purification. LCMS m / z: 163.27 [M+H].

[0652] Preparation 29: Step 1: 4-iodo-2-methoxy-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)nicotinamide

[0653]

[0654] To a stirred solution of 4-iodo-2-methoxynicotinic acid (Preparation 11, Step 1) (280 mg, 1.003 mmol) in THF (10 mL) was added HATU (457.97 mg, 1.204 mmol) and DIPEA (0.7 mL, 4.012 mmol) at room temperature, followed by 2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine.TFA (Preparation 28, Step 4) (195.27 mg, 1.204 mmol). The resulting reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction (checked by LCMS), the reaction mass was diluted with water and extracted with DCM containing 10% methanol. The combined organic layers were concentrated in vacuo to give the crude compound, which was purified on silica gel using methanol in DCM as eluent to give the title compound (185 mg) as a brown solid. LCMS m / z: 424.06 [M+H].

[0655] Step 2: 4-chloro-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-oxo-1,2-dihydropyridine-3-yl Formamide HCl

[0656]

[0657] A stirred suspension of 4-iodo-2-methoxy-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)nicotinamide (Preparation 29, Step 1) (165 mg, 0.390 mmol) in 4M HCl in dioxane (5 mL) was stirred at 80° C. for 18 hours. The reaction progress was monitored by LCMS, and upon completion, the solvent was evaporated in vacuo to give the title compound (135 mg, crude) as a brown semisolid, which was used in the next step without further purification. LCMS m / z: 318.07 [M+H].

[0658] Step 3: N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-(8-methyl-2,3-dihydro-1H-pyridine (2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide (Example 163)

[0659]

[0660] To a stirred suspension of 4-chloro-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide.HCl (Preparation 29, Step 2) (125 mg, 0.393 mmol) in t-BuOH (5 mL) was added 8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-amine dihydrochloride (Preparation 9, Step 4) (77.98 mg, 0.472 mmol) at room temperature, followed by DIPEA (0.35 mL, 1.965 mmol). The resulting reaction mixture was heated at 80 ° C for 18 hours. The reaction progress was monitored by LCMS, and after completion, the reaction mass was diluted with water and extracted with 10% methanol in DCM. The combined organic layers were evaporated in vacuo to give the crude product, which was purified on silica gel using methanol in DCM as eluent, followed by preparative HPLC to afford the title compound as a light brown solid (8 mg, 5% yield). HPLC purity: 99.18%; 1H NMR (500 MHz; DMSO-d6): δ 1.85 (s, 3H), 2.25 (s, 3H), 2.43 (s, 2H, combined in DMSO), 2.50 (t, J = 5.65 Hz, 2H), 2.70 (t, J = 5.25 Hz, 2H), 3.38 (s, 2H), 4.19 (s, 2H), 5.47 (d, J = 7.45 Hz, 1H), 5.75 (s, 1H), 6.98 (d, J = 8.7 Hz, 1H), 7.22 (d, J = 9.95 Hz, 2H), 7.28 (d, J = 6.75 Hz, 2H), 11.34 (s, 1H), 11.76 (s, 1H), 12.92 (s, 1H); LCMS m / z: 445.21 [MH].

[0661] Example 315: N-(4-(4-isobutyrylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido)phenyl)- [2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide

[0662]

[0663] Example 315 was prepared according to the methods described in General Procedures 1 to 7 and the methods described below.

[0664] Preparation 30: 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxazin- Substituted-N-(4-(piperazin-1-yl)phenyl)-1,2-dihydropyridine-3-carboxamide

[0665]

[0666] Step 1: tert-Butyl 4-(4-(4-iodo-2-methoxynicotinamido)phenyl)piperazine-1-carboxylate

[0667]

[0668] To a stirred solution of 4-iodo-2-methoxynicotinic acid (Preparation 11, Step 1) (2000 mg, 7.168 mmol) in THF (30 mL) was added HATU (4088.17 mg, 10.75 mmol), followed by DIPEA (3.68 mL, 21.50, mmol), and after 10 minutes commercially available tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (1789.56 mg, 6.451 mmol) was added to the reaction vessel. The entire reaction was stirred at room temperature for 12 hours. UPLC and TLC showed that the desired product had formed and the starting material was completely consumed. The reaction mixture was diluted with water and extracted with 15% methanol in DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered through a pad of celite and the filtrate evaporated in vacuo to afford the crude product, which was purified by Combi-flash (40 g column) using 60% ethyl acetate in hexanes as eluent to afford the title compound (3220 mg, 78% yield) as a black solid. LCMS m / z: 539.16 [M+H].

[0669] Step 2: 4-(4-(2-methoxy-4-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7- tert-Butyl)amino)nicotinamido)phenyl)piperazine-1-carboxylate

[0670]

[0671] To a stirred solution of tert-butyl 4-(4-(4-iodo-2-methoxynicotinamido)phenyl)piperazine-1-carboxylate (Preparation 30, Step 1) (153.28 mg, 0.929 mmol) in 1,4-dioxane (15 mL) was added CsCO (1514.03 mg, 4.647 mmol) at room temperature, followed by 8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-amine dihydrochloride (Preparation 9, Step 4) (500 mg, 0.929 mmol). The resulting reaction mixture was purged with nitrogen for 15 minutes, followed by the addition of Pd(dba) (85.06 mg, 0.0929 mmol) and Xantphos (107.56 mg, 0.1859 mmol) to the reaction vessel. The entire reaction was stirred at 100° C. under an inert atmosphere overnight. The 1-Hydroxy-2-oxo-1-oxo-2-oxo-4-oxo-6-nitro-1 ...

[0672] Step 3: 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo Substituted-N-(4-(piperazin-1-yl)phenyl)-1,2-dihydropyridine-3-carboxamide.HCl

[0673]

[0674] A suspension of tert-butyl 4-(4-(2-methoxy-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)nicotinamido)phenyl)piperazine-1-carboxylate (Preparation 30, Step 2) (500 mg, 0.869 mmol) in 4M HCl in dioxane (10 mL) was stirred at 80° C. for 3 hours. UPLC and TLC showed the desired material had formed and the starting material was completely consumed. The solvent in the reaction mixture was evaporated in vacuo to give the crude product, which was triturated with diethyl ether to give the title compound (570 mg, crude) as a yellow solid. LCMS m / z: 462.47 [M+H].

[0675] Preparation 31: N-(4-(4-isobutyrylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido)phenyl)-1H-pyrido- [2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide (Example 315)

[0676]

[0677] To a stirred solution of isobutyric acid (12 mg, 0.136 mmol) in DMF (4 mL) was added HATU (62.14 mg, 0.238 mmol) followed by DIPEA (0.119 mL, 0.681 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 10 minutes, followed by the addition of 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(4-(piperazin-1-yl)phenyl)-1,2-dihydropyridine-3-carboxamide.HCl (Preparation 30, Step 3) (69.14 mg, 0.150 mmol) to the reaction vessel and continued stirring at room temperature for 18 hours. The reaction progress was monitored by LCMS, and upon completion, the reaction mixture was diluted with water (20 mL) and extracted with a 10% methanol in DCM solution (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC to afford the title compound as a white solid (35 mg, 44% yield). HPLC purity: 99.26%; 1 H NMR (400MHz; DMSO-d6): δ1.02(d,J=6.72Hz,6H),1.93(s,3H),2.88-2.95(m,1 H),3.04-3.10(m,4H),3.33(9s,2H),3.60-3.64(m,4H),4.26(t,J=3.92Hz,2H ),5.56(d,J=7.4Hz,1H),5.81(s,1H),6.95(d,J=9.08Hz,2H),7.29(t,J=5.44 Hz, 2H), 7.50 (d, J = 9.0Hz, 2H), 11.37 (s, 1H), 11.89 (s, 1H), 12.92 (s, 1H); LCMS m / z:532.05[M+H].

[0678] Example 389: N-(3-Chloro-4-(4-ethylpiperazin-1-yl)-5-fluorophenyl)-4-((8-methyl-2,3-dihydro-1H- Pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide

[0679]

[0680] Example 389 was prepared according to the methods described in General Procedures 1 to 7 and the methods described below.

[0681] Preparation 32: 3-Chloro-4-(4-ethylpiperazin-1-yl)-5-fluoroaniline

[0682]

[0683] Step 1: 1-(2-chloro-6-fluoro-4-nitrophenyl)-4-ethylpiperazine

[0684]

[0685] At room temperature, 1-ethylpiperazine (194.75 mg, 1.705 mmol) was added to a stirred solution of commercially available 1-chloro-2,3-difluoro-5-nitrobenzene (300 mg, 1.55 mmol) in ACN (8 mL). The resulting reaction mixture was stirred at 80 ° C for 16 hours. The reaction progress was monitored by UPLC-MS, and after completion, the reaction mass was diluted with DCM containing 10% MeOH and washed with brine. The organic layer was concentrated in vacuo to obtain the title compound (486 mg, crude material) as a yellow viscous solid. LCMS m / z: 288.11 [M + H].

[0686] Step 2: 3-Chloro-4-(4-ethylpiperazin-1-yl)-5-fluoroaniline

[0687]

[0688] To a stirred solution of 1-(2-chloro-6-fluoro-4-nitrophenyl)-4-ethylpiperazine (Preparation 32, Step 1) (409 mg, 1.425 mmol) in a mixture of solvent EtOH (6 mL) and H2O (2 mL) was added Fe powder (397.73 mg, 7.123 mmol) followed by NHCl (380.99 mg, 7.123 mmol) at room temperature. The resulting reaction mixture was stirred at 80°C for 16 hours. The progress of the reaction was monitored by UPLC-MS, and upon completion, the reaction mixture was filtered through a bed of celite and the bed was washed with 10% MeOH in DCM. The filtrate was washed with water, then with brine and concentrated in vacuo to afford the title compound (422 mg, crude) as a yellow sticky solid. LCMS m / z: 258.11 [M+H].

[0689] Preparation 33: Step 1: N-(3-chloro-4-(4-ethylpiperazin-1-yl)-5-fluorophenyl)-4-iodo-2-methoxynicotinoyl amine

[0690]

[0691] To a stirred solution of 4-iodo-2-methoxynicotinic acid (Preparation 11, Step 1) (372 mg, 1.333 mmol) in THF (10 mL) was added HATU (760.37 mg, 1.999 mmol) followed by DIPEA (516.99 mg, 3.999 mmol) at room temperature and after 10 minutes 3-chloro-4-(4-ethylpiperazin-1-yl)-5-fluoroaniline (Preparation 32, Step 2) (343 mg, 1.333 mmol) was added to the reaction vessel and stirring was continued for 16 hours at room temperature. The progress of the reaction was monitored by UPLC-MS and upon completion, the reaction mass was diluted with 10% MeOH in DCM, washed with water, followed by brine and concentrated in vacuo to give the crude product, which was purified by column chromatography using 2-3% MeOH in DCM as eluent to afford the title compound (269 mg, 39% yield) as a yellow solid. LCMS m / z: 519.21 [M+H].

[0692] Step 2: N-(3-chloro-4-(4-ethylpiperazin-1-yl)-5-fluorophenyl)-2-methoxy-4-(8-methyl-2,3- dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)nicotinamide

[0693]

[0694] A stirred mixture of N-(3-chloro-4-(4-ethylpiperazin-1-yl)-5-fluorophenyl)-4-iodo-2-methoxynicotinamide (Preparation 33, Step 1) (200 mg, 0.386 mmol), 8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-amine dihydrochloride (Preparation 9, Step 4) (76.43 mg, 0.463 mmol) and CsCO (565.97 mg, 1.737 mmol) in dioxane (8 mL) was purged with nitrogen for 10 minutes, followed by the addition of Pd(dba) (35.35 mg, 0.039 mmol) and Xantphos (44.67 mg, 0.077 mmol) to the reaction vessel and the whole was heated at 100° C. for 16 hours. The reaction process was monitored by UPLC-MS, and after completion, the reaction mass was diluted with DCM containing 10% MeOH, filtered through a celite bed, and the bed was washed with MeOH-DCM. The filtrate was washed with water and then washed with brine. The organic layer was evaporated in vacuo to obtain a crude product, which was purified by column chromatography using 4-5% MeOH in DCM as an eluent to obtain the title compound (210 mg, 97% yield) as a dark yellow viscous liquid. LCMS m / z: 555.98 [M+H].

[0695] Step 3: N-(3-chloro-4-(4-ethylpiperazin-1-yl)-5-fluorophenyl)-4-((8-methyl-2,3-dihydro-1H-pyrrolidone)-1-yl)-5-fluorophenyl)-1- ... 2-oxo-1,2-dihydropyridine-3-carboxamide (Example 389)

[0696]

[0697] A suspension of N-(3-chloro-4-(4-ethylpiperazin-1-yl)-5-fluorophenyl)-2-methoxy-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)nicotinamide (Preparation 33, Step 2) (200 mg, 0.360 mmol) in 4M HCl-dioxane (6 mL) was stirred at 80° C. for 1 hour. After completion of the reaction (monitored by UPLC-MS), the solvent was evaporated in vacuo to obtain the crude compound, which was purified by preparative HPLC to afford the title compound as a light yellow solid (51 mg, 26% yield). HPLC purity: 99.85%; 1 H NMR (400 MHz; DMSO-d6): δ 1.04 (t, J = 7.16 Hz, 3H), 1.93 (s, 3H), 2.33-2.40 (m, 2H), 2.50-2.51 (m, 2H, combined with DMSO), 3.06 (s, 4H), 3.30-3.32 (m, 4H, combined with DMSO water), 4.26 (t, J = 4.0 Hz, 2H), 5.56 (d, J = 7.44 Hz, 1H), 5.81 (s, 1H), 7.32 (d, J = 5.28 Hz, 2H), 7.48-7.52 (m, 1H), 7.59 (d, J = 1.88 Hz, 1H), 11.45 (s, 1H), 11.60 (s, 1H), 13.26 (s, 1H); LCMS m / z:542.11[M+H].

[0698] Example 396: N-(4-(2-Hydroxypropan-2-yl)-1-methoxyisoquinolin-6-yl)-4-((8-methyl-2,3-dimethoxy)-1-methoxyisoquinolin-6-yl)- 1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide

[0699]

[0700] Example 396 was prepared according to the methods described in General Procedures 1 to 7 and the methods described below.

[0701] Preparation 34: 2-(6-amino-1-methoxyisoquinolin-4-yl)propan-2-ol

[0702]

[0703] Step 1: tert-Butyl (1-oxo-1,2-dihydroisoquinolin-6-yl)carbamate

[0704]

[0705] To a stirred suspension of commercially available 6-bromoisoquinolin-1(2H)-one (1120.25 mg, 5.00 mmol) in toluene (20 mL) was added tert-butyl carbamate (1464.25 mg, 12.50 mmol) and CsCO (4887.30 mg, 15.00 mmol) at room temperature. The resulting reaction mixture was purged with nitrogen for 10 minutes, followed by the addition of Brettphos-Pd-G (906.50 mg, 1.00 mmol) to the reaction vessel and the entire reaction heated at 100° C. for 16 hours. The reaction progress was monitored by LCMS, and upon completion, the reaction mixture was diluted with water and extracted with 10% MeOH in DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product, which was purified by Combi-flash using 2% MeOH in DCM as eluent to afford the title compound as a white solid (780 mg, 60% yield). LCMS m / z: 261.22 [M+H].

[0706] Step 2: tert-Butyl (4-iodo-1-oxo-1,2-dihydroisoquinolin-6-yl)carbamate

[0707]

[0708] To a stirred suspension of tert-butyl (1-oxo-1,2-dihydroisoquinolin-6-yl)carbamate (Preparation 34, Step 1) (780.87 mg, 3.00 mmol) in DCE (20 mL) was added 1-iodopyrrolidine-2,5-dione (742.43 mg, 3.30 mmol) and PTSA.HO (57.06 mg, 0.30 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction (checked by LCMS), the reaction mixture was treated with aqueous NaHSO (100 mL) and extracted with 10% MeOH in DCM. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (1004 mg, 86% yield) as an off-white solid, which was used in the next step without any further purification. LCMS m / z: 387.17 [M+H].

[0709] Step 3: tert-Butyl (4-iodo-1-methoxyisoquinolin-6-yl)carbamate

[0710]

[0711] To a stirred solution of tert-butyl (4-iodo-1-oxo-1,2-dihydroisoquinolin-6-yl)carbamate (Preparation 34, Step 2) (502.03 mg, 1.30 mmol) in toluene (20 mL) was added AgCO (3584.0 mg, 13.00 mmol) and MeI (0.40 mL, 6.50 mmol) in a sealed tube at room temperature. The entire reaction was stirred at 110 ° C for 16 hours. Conversion was confirmed by UP-LCMS, and the reaction mixture was then cooled to room temperature, diluted with ethyl acetate and passed through a bed of celite, which was further washed with ethyl acetate. The filtrate was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by Combi-flash using 5% EtOAc in hexane as eluent to give the title compound (440.23 mg, 85% yield) as a white solid. LCMS m / z: 401.18 [M + H].

[0712] Step 4: tert-Butyl (4-acetyl-1-methoxyisoquinolin-6-yl)carbamate

[0713]

[0714] To a stirred, degassed solution of (4-iodo-1-methoxyisoquinolin-6-yl)carbamic acid tert-butyl ester (Preparation 34, Step 3) (440.23 mg, 1.10 mmol), tributyl(1-ethoxyvinyl)stannane (595.89 mg, 1.65 mmol) and LiCl (139.88 mg, 3.30 mmol) in DMF (10 mL) was added Pd(PPh3)4 (127.11 mg, 0.11 mmol) in a sealed tube at room temperature. The resulting reaction mixture was stirred at 100 ° C for 16 hours. The progress of the reaction was monitored by UP-LCMS, and after completion, the reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was adsorbed on silica gel and gently rotated on a rotator at 40 ° C for 2 hours. UP-LCMS showed that the ether group was completely converted into the desired acetone group after rearrangement. The adsorbed complex was purified by Combi-flash using % EtOAc in hexanes as eluent to give the title compound as a white solid (284 mg, 81% yield). LCMS m / z: 317.19 [M+H].

[0715] Step 5: tert-Butyl (4-(2-hydroxypropan-2-yl)-1-methoxyisoquinolin-6-yl)carbamate

[0716]

[0717] To a stirred solution of tert-butyl (4-acetyl-1-methoxyisoquinolin-6-yl)carbamate (Preparation 34, Step 4) (474.21 mg, 1.50 mmol) in anhydrous THF (10 mL) was added methylmagnesium bromide (0.95 mL, 2.70 mmol) dropwise at 0-5 ° C. and the combined mixture was stirred at room temperature for 4 hours. Complete conversion was confirmed by UP-LCMS, and the reaction mixture was subsequently quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by Combi-flash using 30% EtOAc in hexane as eluent to give the title compound (265 mg, 88% yield) as a light yellow solid. LCMS m / z: 333.27 [M+H].

[0718] Step 6: 2-(6-amino-1-methoxyisoquinolin-4-yl)propan-2-ol.HCl

[0719]

[0720] To a stirred solution of tert-butyl (4-(2-hydroxypropan-2-yl)-1-methoxyisoquinolin-6-yl)carbamate (Preparation 34, Step 5) (99.70 mg, 0.30 mmol) in dioxane (2 mL) was added 4 M HCl-dioxane (2 mL) under ice cooling, and the whole was stirred at room temperature for 16 hours. The reaction was confirmed complete by LCMS, after which the reaction mixture was concentrated under reduced pressure to give a residue, which was triturated with diethyl ether to give the title compound as a white solid (106 mg, crude). LCMS m / z: 233.27 [M+H].

[0721] Preparation 35: Step 1: 4-Chloro-2-oxo-1,2-dihydropyridine-3-carboxylic acid

[0722]

[0723] A suspension of 4-iodo-2-methoxynicotinic acid (Preparation 11, Step 1) (558.06 mg, 2 mmol) in dioxane (8 mL) containing 4 M HCl was stirred at 80 ° C for 2 hours. UP-LCMS and TLC showed that the starting material was completely converted to the desired product. The solvent in the reaction mixture was evaporated in vacuo to give a residue, which was triturated with diethyl ether to give the title compound (399 mg, crude material) as an off-white solid. LCMS m / z: 173.98 [M + H].

[0724] Step 2: 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo 1,2-dihydropyridine-3-carboxylic acid

[0725]

[0726] To a stirred suspension of 4-chloro-2-oxo-1,2-dihydropyridine-3-carboxylic acid (Preparation 35, Step 1) (399.16 mg, 2.00 mmol) in n-butanol (10 mL) was added 8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-amine dihydrochloride (Preparation 9, Step 4) (396.46 mg, 2.40 mmol) at room temperature, followed by DIPEA (2 mL, 12.00 mmol). The resulting reaction mixture was stirred at 130 ° C for 22 hours. The reaction progress was monitored by TLC and UP-LCMS, and after completion, the solvent was evaporated in vacuo to obtain a residue, which was triturated with diethyl ether to obtain the title compound (408 mg, 67% yield) as a slightly gray solid, which was used in the next step without any further purification. LCMS m / z: 303.15 [M + H].

[0727] Step 3: N-(4-(2-hydroxypropan-2-yl)-1-methoxyisoquinolin-6-yl)-4-((8-methyl-2,3-dihydro- 1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide (Example 396)

[0728]

[0729] To a stirred suspension of 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (Preparation 35, Step 2) (120.91 mg, 0.40 mmol) in DMF (3 mL) was added HATU (228.13 mg, 0.60 mmol), DIPEA (0.20 mL, 0.12 mmol) and 2-(6-amino-1-methoxyisoquinolin-4-yl)propan-2-ol.HCl (Preparation 34, Step 6) (92.91 mg, 0.40 mmol) at room temperature. The resulting reaction mixture was stirred at 50° C. for 16 hours. The reaction progress was monitored by TLC and UP-LCMS, and upon completion, the reaction mixture was poured into ice water and extracted with 10% MeOH in DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by Combi-flash using 10% MeOH in DCM as eluent, followed by preparative HPLC to give the title compound as a light yellow solid (5 mg, 3% yield). HPLC purity: 99.79%; 1H NMR (400MHz; DMSO-d6): δ1.68(s,6H),1.95(s,3H),3.32(s,2H),4.02(s,3H),4.27(s,2H),5.22(s,1H),5.57(d,J=7.28Hz,1H),5.84(s,1H),7.33 (t,J=4.24Hz,2H),7.87-7.90(m,1H),7.98(s,1H),8.18(d,J=4.24Hz,1H ),8.98(s,1H),11.46(d,J=6.04Hz,1H),11.78(s,1H),13.46(s,1H); LCMS m / z:517.33[M+H].

[0730] Example 198: 4-((3-Fluoro-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino 4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

[0731]

[0732] Example 198 was prepared according to the methods described in General Procedures 1 to 7 and the methods described below.

[0733] Preparation 36: Step 1: 7-((tert-Butoxycarbonyl)amino)-3-fluoro-8-methyl-2,3-dihydro-1H-pyrido[2, tert-Butyl 3-b][1,4]oxazine-1-carboxylate

[0734]

[0735] To a solution of commercially available 7-bromo-3-fluoro-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (100 mg, 0.41 mmol) in anhydrous THF (2 mL) was added LiHMDS (1 M, 0.61 mL) at room temperature, followed by the addition of Boc-anhydride (134 mg, 0.61 mmol). The resulting reaction mixture was refluxed for 6 hours. TLC showed that the reaction was complete. The reaction mixture was quenched with saturated ammonium chloride solution, and the organic layer was extracted with ethyl acetate. The combined organic layers were washed with water, then with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the Boc-protected intermediate (80 mg, 0.23 mmol), which was immediately dissolved in degassed dioxane (2 mL), and Boc-amine (135 mg, 1.16 mmol), Cs2CO3 (188 mg, 0.58 mmol), Brettphos (49.6 mg, 0.09 mmol) and Pd2(dba)3 (42.3 mg, 0.05 mmol) were added, and the entire reaction was heated at 110°C under a nitrogen atmosphere for 16 hours. The reaction progress was monitored by LCMS, and after completion, the reaction mixture was filtered through a celite bed and the filtrate was evaporated under reduced pressure to afford the crude product, which was purified by column chromatography to afford the title compound (50 mg, 56.4% yield) as an off-white solid. LCMS m / z: 384.0 [M+H].

[0736] Step 2: 4-((3-Fluoro-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)- N-(4-(4-Methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (Example 198)

[0737]

[0738] A suspension of tert-butyl 7-((tert-butoxycarbonyl)amino)-3-fluoro-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (Preparation 36, Step 1) (50 mg, 0.13 mmol) in 4M HCl-dioxane (1 mL) was stirred at 0 to 5°C for 1.5 hours. TLC showed that the reaction was complete, and the solvent was evaporated under reduced pressure to obtain a residue. The residue was immediately dissolved in n-butanol (1 mL) and DIPEA (0.15 mL, 0.86 mmol) and 4-chloro-N-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (Preparation 1, Step 3) (60 mg, 0.17 mmol) was added at room temperature. The resulting mixture was heated at 120°C for 16 hours. After completion of the reaction (monitored by TLC and LCMS), the solvent was evaporated in vacuo to obtain a residue, which was then purified by preparative HPLC to afford the title compound as a light brown solid (10 mg, 16% yield). HPLC purity: 99.76%; 1 H NMR (400MHz; DMSO-d6): δ1.98(s,3H),2.22(s,3H),2.45(s,4H),3.07-3.08(m,4H ),3.24(d,J=13.28Hz,1H),3.55(d,J=12.84Hz,1H),5.56(d,J=7.4Hz,1H),5.99( s,1H),6.28(s,0.5H),6.42(s,0.5H),6.91(d,J=8.88Hz,2H),7.28(t,J=6.84Hz, 1H),7.43-7.48(m,3H),11.38(d,J=6.08Hz,1H),11.98(s,1H),12.85(s,1H); LCMS m / z:394.30[M+H].

[0739] Example 137: N,N-dimethyl-4-(4-(4-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxadiazole (2-(2-oxo-1,2-dihydropyridine-3-carboxamido)phenyl)piperazine-1-carboxamide)

[0740]

[0741] Example 137 was prepared according to the methods described in General Procedures 1 to 7 and the methods described below.

[0742] Preparation 37: N,N-dimethyl-4-(4-(4-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxadiazole (4-(2-(2-oxo-1,2-dihydropyridine-3-carboxamido)phenyl)piperazine-1-carboxamide (Example 137)

[0743]

[0744] To a stirred solution of 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(4-(piperazin-1-yl)phenyl)-1,2-dihydropyridine-3-carboxamide.HCl (Preparation 30, Step 3) (70 mg, 0.15 mmol) in THF (2 mL) was added TEA (0.11 mL, 0.76 mmol) at 0-5°C, followed by dimethylcarbamoyl chloride (0.01 mL, 0.15 mmol) and the combined mixture was stirred at room temperature for another 3 hours. The reaction progress was monitored by LCMS, and after completion, the solvent was evaporated in vacuo to obtain the crude product, which was purified by preparative HPLC to afford the title compound (12 mg, 13% yield) as an off-white solid. HPLC purity: 99.64%; 1 H NMR (400 MHz; DMSO-d6): δ 1.93 (s, 3H), 2.77 (s, 6H), 3.08-3.10 (m, 4H), 3.22-3.25 (m, 4H), 3.32 (bs, 2H, combined in DMSO-H2O), 4.25 (s, 2H), 5.55 (d, J = 7.2 Hz, 1H), 5.79 (s, 1H), 6.94 (d, J = 8.8 Hz, 2H), 7.28 (t, J = 6.4 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H), 11.34 (s, 1H), 11.90 (s, 1H), 12.87 (s, 1H); LCMS m / z: 533.45 [M+H].

[0745] Example 271: N-(4-(1-Isopropyl-1H-pyrazol-5-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyridine (2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide

[0746]

[0747] Example 271 was prepared according to the methods described in General Procedures 1 to 7 and the methods described below.

[0748] Preparation 38: 4-chloro-N-(4-(1-isopropyl-1H-pyrazol-5-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-yl)- Formamide

[0749]

[0750] Step 1: 4-iodo-N-(4-(1-isopropyl-1H-pyrazol-5-yl)phenyl)-2-methoxynicotinamide

[0751]

[0752] To a stirred solution of commercially available 4-(1-isopropyl-1H-pyrazol-5-yl)aniline (100 mg, 0.49 mmol) in DCM (5 mL) was added DIPEA (0.432 mL, 2.48 mmol) and freshly prepared 4-iodo-2-methoxynicotinoyl chloride (369.40 mg, 1.24 mmol) at 0-5 ° C. The resulting reaction mixture was stirred at room temperature for 24 hours. After completion of the reaction (monitored by LCMS and TLC), the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by column chromatography using 2-5% MeOH in DCM to give the title compound (120 mg, 52.1% yield) as an off-white solid. LCMS m / z: 463.2 [M+H].

[0753] Step 2: 4-chloro-N-(4-(1-isopropyl-1H-pyrazol-5-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate Amide.HCl

[0754]

[0755] A suspension of 4-iodo-N-(4-(1-isopropyl-1H-pyrazol-5-yl)phenyl)-2-methoxynicotinamide (Preparation 38, Step 1) (120 mg, 0.259 mmol) in 6N aqueous HCl (3 mL) was refluxed for 16 h. After completion of the reaction (monitored by LCMS and TLC), the solvent was removed in vacuo to give the title compound (80 mg, crude) as an off-white solid.

[0756] Preparation 39: N-(4-(1-isopropyl-1H-pyrazol-5-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyridine (2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide (Example 271)

[0757]

[0758] To a stirred solution of 4-chloro-N-(4-(1-isopropyl-1H-pyrazol-5-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide.HCl (80 mg, 0.225 mmol) in n-BuOH (2 mL) was added DIPEA (0.12 mL, 0.67 mmol) followed by 8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-amine dihydrochloride (Preparation 9, Step 4) (73.95 mg, 0.45 mmol) at room temperature. The resulting reaction mixture was heated at 120 ° C for 16 hours. The reaction progress was monitored by LCMS, and upon completion, the solvent was removed in vacuo to give a residue, which was purified by preparative HPLC to give the title compound as a light brown solid (10 mg, 9% yield). HPLC purity: 99.89%; 1H NMR (400MHz; MeOD): δ1.43 (d, J = 6.64Hz, 6H), 2.03 (d, J = 9.36Hz, 3H), 3.44-3.47 (m, 2H), 4.35 (t, J = 4.28Hz, 2H), 4.57-4.63 (m, 1H), 5.73 (t, J = 7. 44Hz,1H),6.26(s,1H),7.24(d,J=7.6Hz,1H),7.34-7.38(m,3H),7.53(d ,J=1.8Hz,1H),7.80(d,J=8.44Hz,2H),11.96(s,1H),13.01(s,1H); LCMS m / z:486.35[M+H].

[0759] Example 126: 4-((8-Methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino 4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

[0760]

[0761] Example 126 was prepared according to the methods described in General Procedures 1 to 7 and the methods described below.

[0762] Preparation 40: 7-amino-8-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one.HCl

[0763]

[0764] Step 1: (8-Methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)carbamic acid tert-Butyl ester

[0765]

[0766] To a degassed solution of 7-bromo-8-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (Preparation 9, Step 1) (300 mg, 1.24 mmol) in dioxane (10 mL) was added tert-butyl carbamate (433 mg, 3.703 mmol), CsCO (1209 mg, 3.72 mmol), Brettphos (270 mg, 0.49 mmol) and tris(dibenzylideneacetone)dipalladium(0).CHCl (260 mg, 0.25 mmol) at room temperature. The resulting reaction mixture was heated at 110 ° C for 16 hours. The reaction progress was monitored by LCMS, and after completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to obtain the crude product, which was purified by column chromatography (70-100% ethyl acetate-hexane) to give the title compound (250 mg, 72.19% yield) as an off-white solid. LCMS m / z: 279.9 [M+H].

[0767] Step 2: 7-amino-8-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one.HCl

[0768]

[0769] A suspension of tert-butyl (8-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)carbamate (Preparation 40, Step 1) (60 mg, 0.21 mmol) in 4M HCl-dioxane (1 mL) was stirred at room temperature for 1 hour. After completion of the reaction (monitored by LCMS), the reaction mass was concentrated in vacuo to give the title compound (90 mg, crude) as an off-white solid.

[0770] Preparation 41: 4-((8-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino 4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (Example 126)

[0771]

[0772] To a stirred solution of 7-amino-8-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one.HCl (Preparation 40, Step 2) (90 mg, 0.503 mmol) in n-BuOH (2 mL) was added DIPEA (0.7 mL, 3.90 mmol) followed by 4-chloro-N-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (Preparation 1, Step 3) (70 mg, 0.39 mmol) at room temperature. The resulting mixture was stirred at 120 ° C for 16 hours. The reaction progress was monitored by LCMS, and after completion, the solvent was removed in vacuo to give a residue, which was purified by preparative HPLC to give the title compound as a white solid (12 mg, 5% yield). HPLC purity: 98.05%; 1 H NMR (400MHz; DMSO-d6): δ; 2.04 (s, 3H), 2.21 (s, 3H), 2.44-2.45 (m, 4H), 3.08 (s, 4H), 4.50 (s, 2H), 5.56 (d, J = 7.2Hz, 1 LCMS m / z:490.39[M+H].

[0773] The examples in the table below were prepared according to the methods described above in General Procedures 1 to 8 for the preparation of Examples 45, 126, 132, 137, 163, 167, 168, 197, 198, 263, 271, 315, 363, 371, 389, and 396, using the appropriate amines. In most cases, the amines were commercially available or synthesized by methods analogous to those described above. Purification was as described in the preceding methods.

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788]

[0789]

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806] Example 98: 4-((8-Methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4- (4-Methylpiperazin-1-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide

[0807]

[0808] Example 98 was prepared according to the methods described in General Procedures 1 to 3, 8 and the methods described below.

[0809] Preparation 6: 4-methoxy-6-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino 1-Methyl)pyrimidine-5-carboxylic acid

[0810]

[0811] Step 1: 4-Chloro-6-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyrimidine Methyl 5-pyridinecarboxylate

[0812]

[0813] At room temperature, to a stirred solution of commercially available 4,6-dichloropyrimidine-5-formic acid methyl ester (300 mg, 1.449 mmol) in t-BuOH (10 mL) was added 8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-amine.2HCl (preparation 9, step 4) (239.41 mg, 1.449 mmol) followed by DIPEA (1.262 mL, 7.246 mmol). The resulting reaction mixture was heated at 80 ° C for 18 hours. The reaction progress was monitored by LCMS, and after completion, the solvent was evaporated to dryness. Then, it was diluted with water and extracted with ethyl acetate. The combined organic layer was distilled off to obtain a crude compound, which was purified on a silica gel bed using ethyl acetate and hexane as eluents to obtain the title compound (90 mg, 18% yield) as a brown solid. LCMS m / z: 336.18 [M+H].

[0814] Step 2: 4-methoxy-6-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino 1-Methyl)pyrimidine-5-carboxylic acid

[0815]

[0816] To a stirred solution of 4-chloro-6-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyrimidine-5-carboxylic acid methyl ester (Preparation 6, Step 1) (90 mg, 0.268 mmol) in THF (3 mL) and methanol (1.5 mL) was added an aqueous solution of LiOH.HO (44.99 mg, 1.072 mmol, 1.5 mL of water) at room temperature. The entire reaction was stirred at room temperature overnight. The progress of the reaction was checked by LCMS, and after completion, the solvent was evaporated in vacuo to give a residue, which was diluted with water and the pH was adjusted with citric acid to make the solution acidic to obtain a solid precipitate. The precipitate was filtered, washed, and dried to give the title compound (65 mg, 76% yield) as an off-white solid. LCMS m / z: 318.21 [M+H].

[0817] Preparation 7: 4-methoxy-6-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino 4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-5-carboxamide

[0818]

[0819] To a stirred solution of 4-methoxy-6-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyrimidine-5-carboxylic acid (Preparation 6, Step 2) (55 mg, 0.173 mmol) in THF (3 mL) was added HATU (79.08 mg, 0.207 mmol) and after 15 minutes, DIPEA (0.090 mL, 0.519 mmol) and 4-(4-methylpiperazin-1-yl)aniline (39.70 mg, 0.207 mmol) were added to the reaction vessel. The resulting reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC / LC-MS, and upon completion, the reaction mass was diluted with water and extracted with 10% methanol in DCM. The combined organic layers were distilled off to obtain the crude product, which was purified on a silica gel bed using methanol and DCM as eluents to afford the title compound as an off-white sticky solid (85 mg, 100% yield). LCMS m / z: 491.35 [M+H].

[0820] Preparation 8: 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4- (4-Methylpiperazin-1-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (Example 98)

[0821]

[0822] A stirred suspension of 4-methoxy-6-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-5-carboxamide (Preparation 7) (75 mg, 0.394 mmol) in dioxane (3 mL) containing 4M HCl was stirred at 80° C. for 3 hours. The reaction progress was monitored by LCMS, and after completion, the solvent was evaporated in vacuo to give a residue, which was triturated with diethyl ether and finally purified by preparative HPLC to give the title compound as a yellow solid (18 mg, 25% yield). HPLC purity: 99.53%; 1 H NMR (500 MHz; DMSO-d6): δ 1.86 (s, 3H), 2.15 (s, 3H), 2.38 (s, 4H, combined with DMSO), 3.02 (s, 4H), 3.25 (s, 2H, combined with DMSO water) 4.16 (d, J = 3.65 Hz, 2H), 5.60 (s, 1H), 6.85 (d, J = 9.0 Hz, 2H), 7.36 (s, 1H), 7.40 (d, J = 8.9 Hz, 2H), 7.96 (s, 1H), 11.79 (s, 1H), 12.07 (s, 1H), 12.42 (bh, 1H); LCMS m / z: 477.43 [M+H].

[0823] The examples in the table below were prepared using the appropriate amines according to the methods described above for the preparation of Example 98 in General Procedures 1 to 8. Purification was as described in the previous methods.

[0824]

[0825] Biological tests

[0826] HPK-1 biochemical enzyme assay

[0827] Compound inhibitory potency was measured in an HPK-1 kinase inhibition assay. Briefly, recombinant full-length HPK-1 enzyme (6.8 nM) was incubated with 10 μM ATP and 12.5 μM porcine myelin basic protein (MBP) in 40 mM Tris.Cl pH 7.4 buffer containing 20 mM MgCl2, 50 μM DTT, and 0.1 mg / mL BSA at 25°C for 30 minutes in the presence of various concentrations of test compound or vehicle. The reaction was quenched and the reaction mixture was analyzed by an ADP-Glo kit that measures the ADP formed. The percentage of inhibition was calculated based on substrate conversion by considering the no enzyme control reaction as 100% inhibition and the vehicle-only reaction as 0% inhibition. Compounds were dissolved in DMSO and evaluated at 10 concentrations to determine the IC 50 value.

[0828] In the table below, A represents HPK-1IC 50 ≤10nM, B represents HPK-1 IC 50 >10nM but ≤100nM, and C indicates HPK-1 IC 50 >100nM but ≤1000nM.

[0829]

[0830]

Claims

1. A compound of formula (I): in: X is CH or N; Z is phenyl or 5- or 6-membered heteroaryl, wherein the phenyl or heteroaryl is substituted with one or more substituents selected from the group consisting of halogen, optionally substituted C 1- C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, CN, OR 8 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 8 、COOR 8 、CONR 8 R 9 NR 8 COR 9 NR 8 SO2R 9 NR 8 R 9 , an optionally substituted 3- to 10-membered heterocyclyl, an optionally substituted 5- to 10-membered heteroaryl, an optionally substituted C 6-10 Aryl or optionally substituted C 3-9 Cycloalkyl; and / or wherein adjacent substituents of the phenyl or heteroaryl groups may be combined together with the atoms to which they are attached to form an optionally substituted 3 to 6 membered heterocyclic ring or an optionally substituted 5 or 6 membered heteroaryl group; R 1 to R 7 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, CN, OR 10 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 10 、COOR 8 、CONR 10 R 11 NR 10 COR 11 NR 10 SO2R 11 NR 10 R 11 , optionally substituted C3-C6 cycloalkyl, optionally substituted 3 to 8 membered heterocyclyl, optionally substituted 5 to 10 membered heteroaryl or optionally substituted phenyl; and / or R 3 and R 4 and / or R 5 and R 6 Together with the C atom to which it is attached, it forms a C=O group, an optionally substituted C3-C6 cycloalkyl group or an optionally substituted 3- to 8-membered heterocyclyl group; and / or R 3 and R 5 Together with the C atom to which it is attached, it forms an optionally substituted C3-C6 cycloalkyl group or an optionally substituted 3- to 8-membered heterocyclic group; R 8 and R 9 are independently hydrogen, optionally substituted C1-C 12 Alkyl, optionally substituted C2-C 12 Alkenyl, optionally substituted C2-C 12 Alkynyl, optionally substituted C 6-12 aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl; and R 10 and R 11 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C 6-12 aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl; or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof.

2. The compound according to claim 1, wherein R 1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, CN, OR 10 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 10 、COOR 8 、CONR 10 R 11 NR 10 COR 11 NR 10 SO2R 11 or NR 10 R 11 .

3. The compound according to claim 1 or 2, wherein R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, CN, OR 10 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 10 、COOR 8 、CONR 10 R 11 NR 10 COR 11 NR 10 SO2R 11 or NR 10 R 11 .

4. A compound according to any one of the preceding claims, wherein R 3 and R 4 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, CN, OR 10 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 10 、COOR 8 、CONR 10 R 11 NR 10 COR 11 NR 10 SO2R 11 NR 10 R 11 , optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted phenyl, or R 3 and R 4 Together with the C atom to which it is attached, it forms a C═O group, an optionally substituted C 3 -C 6 cycloalkyl group, or an optionally substituted 3- to 8-membered heterocyclic group.

5. A compound according to any one of the preceding claims, wherein R 5 and R 6 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, CN, OR 10 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 10 、COOR 8 、CONR 10 R 11 NR 10 COR 11 NR 10 SO2R 11 NR 10 R 11 , optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted phenyl, or R 5 and R 6 Together with the C atom to which it is attached, it forms a C═O group, an optionally substituted C 3 -C 6 cycloalkyl group, or an optionally substituted 3- to 8-membered heterocyclic group.

6. A compound according to any one of the preceding claims, wherein R 7 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, CN, OR 10 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 10 、COOR 8 、CONR 10 R 11 NR 10 COR 11 NR 10 SO2R 11 or NR 10 R 11 .

7. A compound according to any one of the preceding claims, wherein: R 1 is hydrogen, methyl, CN or OCH3; R 2 It is hydrogen; R 3 and R 4 are independently hydrogen, methyl, ethyl, isopropyl or fluoro, or R 3 and R 4 Together with the C atom to which it is attached, it forms a cyclopropyl group; R 5 and R 6 is hydrogen, or R 5 and R 6 Together with the C atom to which it is bound, it forms a C=O group; and R 7 is hydrogen or methyl.

8. A compound according to any one of the preceding claims, wherein Z is substituted phenyl, substituted pyrazole or substituted pyridinyl.

9. The compound according to any one of the preceding claims, wherein adjacent substituents of the phenyl or 5- or 6-membered heteroaryl group Z are linked to the C atom of the phenyl or heteroaryl group to which they are attached to form a 5- or 6-membered heterocycle or heteroaromatic group, optionally wherein adjacent substituents of the heterocycle or heteroaryl group, together with the atom to which they are attached, combine to form another optionally substituted 3- to 6-membered heterocycle or another optionally substituted 5- or 6-membered heteroaryl group, such that the group Z is an optionally substituted bicyclic fused group or an optionally substituted tricyclic fused group.

10. The compound of claim 9, wherein the optionally substituted bicyclic or tricyclic fused group is an optionally substituted 8 to 14 membered heterocyclic or heteroaromatic group and is unsubstituted or substituted with one or more of the following: an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, halogen, oxo, CN, OR 16 SR 16 、SOR 16 、SO2R 16 、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 NR 16 R 17 , optionally substituted C 6-12 Aryl, optionally substituted C 3-6 cycloalkyl, an optionally substituted 3- to 6-membered heterocycle, or an optionally substituted 5- to 10-membered heteroaryl, and R 16 and R 17 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C 6-12 aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, or optionally substituted 5- to 10-membered heteroaryl.

11. The compound according to any one of claims 1 to 8, wherein Z has the formula: where X 5 、X 6 、X 7 and X 8 Is N or CR 21 , provided that X 5 、X 6 、X 7 and X 8 Only one of them is N; R 21 is independently at each occurrence H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, CN, OR 8 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 8 、COOR 8 、CONR 8 R 9 NR 8 COR 9 NR 8 SO2R 9 NR 8 R 9 , an optionally substituted 3- to 6-membered heterocyclyl, an optionally substituted 5- or 6-membered heteroaryl, an optionally substituted C 6-10 Aryl or optionally substituted C 3-9 cycloalkyl; and A is selected from optionally substituted C1-C6 alkyl, OR 8 、SO2R 8 、SO2NR 8 R 9 、COR 8 、COOR 8 、CONR 8 R 9 NR 8 COR 9 NR 8 SO2R 9 NR 8 R 9 , optionally substituted 3- to 10-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl.

12. The compound according to any one of claims 1 to 8, wherein the phenyl or 5- or 6-membered heteroaryl Z is substituted by an optionally substituted 3- to 10-membered heterocyclyl, an optionally substituted 5- to 10-membered heteroaryl, an optionally substituted C 6-10 Aryl or optionally substituted C 3-9 Cycloalkyl.

13. The compound according to claim 12, wherein the phenyl group or the 5- or 6-membered heteroaryl group Z is substituted by a heterocyclic group of formula (i) or (j): in: T is N and M is NR 13 , CR 14 R 15 , O, S or SO2; or T is CR 18 , and M is NR 13 , O, S or SO2; Q is C(R 12 )2, and n is 0, 1 or 2; R 12 is independently at each occurrence H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, oxo, CN, OR 16 SR 16 、SOR 16 、SO2R 16 、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 NR 16 R 17 , optionally substituted C 6-12 Aryl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3- to 6-membered heterocycle, or optionally substituted 5- to 10-membered heteroaryl; and / or two R bound to the same carbon 12 The group can define an oxo group, bound to two R atoms on adjacent carbon atoms. 12 The groups may be linked to form a fused group or bonded to two R 12 The groups can be linked to form a bicyclic bridging group; R 13 is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, oxo, CN, OR 16 SR 16 、SOR 16 、SO2R 16 、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 NR 16 R 17 , optionally substituted C 6-12 Aryl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3- to 6-membered heterocycle, or optionally substituted 5- to 10-membered heteroaryl; R 14 and R 15 Each is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, oxo, CN, OR 16 SR 16 、SOR 16 、SO2R 16 、COR 16 、COOR 16 、CONR 16 R 17 NR 16 COR 17 NR 16 R 17 , optionally substituted C 6-12 Aryl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3- to 6-membered heterocycle, or optionally substituted 5- to 10-membered heteroaryl.

14. The compound according to any one of claims 1 to 8, wherein the phenyl or 5- or 6-membered heteroaryl group Z is substituted by one or more substituents selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, CN, OR 8 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 8 、COOR 8 、CONR 8 R 9 NR 8 COR 9 NR 8 SO2R 9 and NR 8 R 9 .

15. The compound of claim 1, wherein the compound is: 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((1,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-Fluoro-4-(4-methylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(1-methylpiperidin-4-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-isopropylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(4-(pyridin-2-yl)phenyl)-1,2-dihydropyridine-3-carboxamide; 4-((8-methoxy-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-1,2-dihydropyridine-3-carboxamide; N-(3-Fluoro-4-(4-isopropylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-ethylpiperazin-1-yl)-3-fluorophenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-ethylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N,N-Dimethyl-4-(4-(4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenyl)piperazine-1-carboxamide; N-(4-(1,1-dioxothiomorpholino)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(4-(piperazin-1-yl)phenyl)-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(3,3-difluoropyrrolidine-1-carbonyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(1H-pyrazol-4-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(1H-pyrazol-3-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(oxazol-5-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-cyclopentylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(4-(pyridin-3-yl)phenyl)-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(4-(pyridin-4-yl)phenyl)-1,2-dihydropyridine-3-carboxamide; N-(4-(3-aminopiperidin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-aminopiperidin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-Dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4,4-difluoropiperidin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-cyclopropylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-isopropylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-4-((3,3,8-trimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)-2-oxo-4-((3,3,8-trimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-1,2-dihydropyridine-3-carboxamide; N-(4-(4-((1H-pyrazol-5-yl)methyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(3-hydroxypropyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(4-(4-((5-oxopyrrolidin-2-yl)methyl)piperazin-1-yl)phenyl)-1,2-dihydropyridine-3-carboxamide; N-(4-(4-isopropylpiperazin-1-yl)phenyl)-2-oxo-4-((3,3,8-trimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(2-cyanoethyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-cyclobutylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-Dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-(4-(4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenyl)-N,N-dimethylpiperazine-1-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(3-fluoro-4-(4-isopropylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(1-methyl-5-oxopyrrolidin-3-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(3-fluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(3-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-cyclopentylpiperazin-1-yl)phenyl)-4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3-ethyl-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3-Isopropyl-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-pyrido[2,3-b][1,4]oxazin]-7'-yl)amino)-N-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-cyano-4-(4-methylpiperazin-1-yl)phenyl)-4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-((1H-pyrazol-5-yl)methyl)piperazin-1-yl)phenyl)-4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-fluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(2-methyl-4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(2-(methoxymethyl)-4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3-Fluoro-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(3-methyl-4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(1-(2-methoxyethyl)piperidin-4-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-morpholinophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(2-Fluoro-4-(4-methylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-(dimethylcarbamoyl)-4-(4-methylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-((1-methylpiperidin-4-yl)amino)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(4-sulfamoylphenyl)-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-methylpiperazin-1-yl)-3-(4H-1,2,4-triazol-4-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(3-(2-hydroxypropan-2-yl)piperidin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(1-methylpiperidin-3-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-(4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamido)-2-(4-methylpiperazin-1-yl)benzoic acid; 1-(4-(4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenyl)piperidine-4-carboxylic acid; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(2-methyl-4-(methylsulfonamido)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(1-ethyl-3,3-dimethyl-2-oxoindolin-5-yl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; (S)-N-(4-(3,4-dimethylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; (R)-N-(4-(3,4-dimethylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(2-methyl-1H-benzo[d]imidazol-5-yl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-(3-(methylsulfonyl)propyl)piperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-(2-morpholinoethyl)piperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; (S)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(4-((2-oxooxazolidin-4-yl)methyl)phenyl)-1,2-dihydropyridine-3-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(N-cyclopropylsulfamoyl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-((1,1-dioxothiomorpholino)methyl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(4-(pyridin-4-ylmethyl)phenyl)-1,2-dihydropyridine-3-carboxamide; N-(1H-indazol-5-yl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(1H-indazol-6-yl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(2-(azetidin-3-yl)ethyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; (R)-N-(4-(2,4-dimethylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-carbamoylphenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(6-acetamidopyridin-3-yl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(Benzo[d][1,3]dioxol-5-yl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-((2-hydroxyethyl)sulfonyl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(1,2,3,4-tetrahydroquinolin-7-yl)-1,2-dihydropyridine-3-carboxamide; N-(4-(4-carbamoylpiperidin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(Benzo[d]thiazol-6-yl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(2-methylbenzo[d]thiazol-6-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(4-(4-propionylpiperazin-1-yl)phenyl)-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1,2-dihydropyridine-3-carboxamide; N-(4-(4-methoxyphenoxy)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(1,2,3,4-tetrahydroquinolin-6-yl)-1,2-dihydropyridine-3-carboxamide; N-(4-(1H-imidazol-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(1H-benzo[d]imidazol-6-yl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-1,2-dihydropyridine-3-carboxamide; N-(4-(4-cyclopentylpiperazin-1-yl)-3-fluorophenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-1,2-dihydropyridine-3-carboxamide; N-(3-chloro-4-(4-methylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-amino-4-(4-methylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; (S)-N-(4-(2,4-dimethylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-methyl-2-oxopiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(4-(3-oxopiperazin-1-yl)phenyl)-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-1,2-dihydropyridine-3-carboxamide; N-(3-bromo-4-(4-methylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(1-isopropyl-1H-pyrazol-5-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-methyl-3-oxopiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-Hydroxyquinoxalin-6-yl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(2-methoxyethyl)piperazin-1-yl)-3-methylphenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-fluoro-4-(1-(2-methoxyethyl)piperidin-4-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(3-methoxypropyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-hydroxypiperidin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(1-isopropylpiperidin-4-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-methylpiperidin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-((2-ethylhexyl)carbamoyl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(cyclopentanecarbonyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(2-methoxyacetyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(3-methoxypropionyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(4-(4-(pyridin-3-yl)piperazin-1-yl)phenyl)-1,2-dihydropyridine-3-carboxamide; N-methyl-4-(4-(4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenyl)piperazine-1-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(4-(4-(pyridin-4-yl)piperazin-1-yl)phenyl)-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(4-(4-(pyridin-2-yl)piperazin-1-yl)phenyl)-1,2-dihydropyridine-3-carboxamide; N-(2-methoxyethyl)-N-methyl-4-(4-(4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenyl)piperazine-1-carboxamide; N-(3-(dimethylamino)-4-(4-methylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-((1S,2S)-2-fluorocyclopropane-1-carbonyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-amino-4-(4-methylpiperazin-1-yl)phenyl)-4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(3-(methylamino)-4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamido)benzo[d]thiazol-6-yl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamido)benzo[d]thiazol-5-yl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(2-(dimethylamino)-2-oxoethyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((1H-indazol-3-yl)amino)-N-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-cyano-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(hydroxymethyl)-4-methylpiperidin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(1-hydroxyethyl)piperidin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(1H-pyrazole-5-carbonyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(3,3-dimethylcyclobutane-1-carbonyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-(2-methylcyclopropane-1-carbonyl)piperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-(1-methylcyclobutane-1-carbonyl)piperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-(3-methylcyclobutane-1-carbonyl)piperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-((1-methyl-1H-pyrazol-5-yl)methyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(2,2-dimethylcyclopropane-1-carbonyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(2-methoxy-2-methylpropyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-amino-4-(4-cyclopentylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(2-cyclopropylacetyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-chloro-4-(4-propionylpiperazin-1-yl)phenyl)-4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(cyclobutanecarbonyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-isobutyrylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(1-methyl-1H-pyrazole-5-carbonyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(3,3-dimethylazetidin-1-carbonyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(3,3-difluorocyclobutane-1-carbonyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(3,3-difluoroazetidine-1-carbonyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(2-azaspiro[3.3]heptane-2-carbonyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(1-methyl-1H-pyrazole-3-carbonyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; (R)-N-(4-(hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(4-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)phenyl)-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(azetidin-1-carbonyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(3-fluoro-4-(4-(4-isopropylpiperazin-1-yl)piperidin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; (S)-N-(4-(hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; (S)-N-(4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; (R)-N-(4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-cyclohexylphenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-([1,1'-biphenyl]-4-yl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-(2-methylbutanoyl)piperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(4-(4-(2,2,3,3-tetramethylcyclopropane-1-carbonyl)piperazin-1-yl)phenyl)-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-isobutyrylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(1-methyl-1H-pyrazol-3-yl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-(2-methylpyridin-3-yl)piperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(4-(4-(pyrimidin-5-yl)piperazin-1-yl)phenyl)-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-(2-methylpyridin-4-yl)piperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(4-(4-pivaloylpiperazin-1-yl)phenyl)-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(2-fluoro-2-methylpropanoyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; (S)-N-(4-(4-isobutyryl-3-methylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(2-methoxy-2-methylpropanoyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; (S)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(3-methyl-4-propionylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; (S)-N-(4-(4-(2-methoxyethyl)-3-methylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; (R)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(3-methyl-4-propionylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; (R)-N-(4-(4-(2-methoxyethyl)-3-methylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; (R)-N-(4-(4-isobutyryl-3-methylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; (S)-N-(4-(4-(2-methoxypropionyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(1-methoxypropan-2-yl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-cyanopiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; (R)-N-(4-(4-(2-methoxypropionyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-(methylalanyl)piperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-(1-methylcyclopropane-1-carbonyl)piperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-(1-methylpyrrolidin-3-carbonyl)piperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(2-hydroxy-2-methylpropionyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(dimethylalanyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; (S)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(4-(6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-ethylpiperazin-1-yl)-3-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(4-(4-propionylpiperazin-1-yl)phenyl)-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-(6-methylpyridin-3-yl)piperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(2-(methoxymethyl)pyridin-4-yl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N,N-Dimethyl-4-(4-(4-(4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenyl)piperazin-1-yl)picolinamide; N-(4-(4-(1-methyl-1H-imidazol-2-yl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(4-(4-(thiazol-4-yl)piperazin-1-yl)phenyl)-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(2-ethoxyethyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(2-methoxypropyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-isobutylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(4-(4-(thiazol-2-yl)piperazin-1-yl)phenyl)-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)phenyl)-4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-(1-methylazetidin-3-carbonyl)piperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(4-(6-oxooctahydro-2H-pyrido[1,2-a]pyrazin-2-yl)phenyl)-1,2-dihydropyridine-3-carboxamide; N-(4-(4-((dimethylamino)methyl)-4-hydroxypiperidin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-cyclopropylpiperazin-1-yl)-3-fluorophenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(2-methyl-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(1-(1H-pyrazol-5-yl)ethyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-(3-methyloxetan-3-yl)piperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(3-(N-methylisobutyramido)pyrrolidin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(6-azaspiro[2.5]oct-6-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(tert-butyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(1-isopropylpiperidin-4-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-ethylpiperazin-1-yl)-3-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-ethylpiperazin-1-yl)-3-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-Fluoro-4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-Dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-((dimethylamino)methyl)-4-hydroxypiperidin-1-yl)-3-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-chloro-4-(4-ethylpiperazin-1-yl)-5-fluorophenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-ethylpiperazin-1-yl)-3,5-difluorophenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-chloro-4-(4-cyclopropylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-((dimethylamino)methyl)-4-methoxypiperidin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-(Aminomethyl)-4-(4-methylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-(2-hydroxyethyl)-4-(4-methylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(3-aminopyrrolidin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(2-hydroxypropan-2-yl)-1-methoxyisoquinolin-6-yl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(2-(hydroxymethyl)pyrrolidin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(3-hydroxypyrrolidin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(4-(4-propylpiperazin-1-yl)phenyl)-1,2-dihydropyridine-3-carboxamide; N-(4-(4-cyclopropylpiperazin-1-yl)-3-methylphenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-cyclopropylpiperazin-1-yl)-3-ethoxyphenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-acetylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(3-hydroxypropionyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-isopropylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-isopropylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-(3-methoxypropyl)piperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-(1-methyl-1H-pyrazol-3-yl)piperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(2-(hydroxymethyl)-4-methylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-N-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-cyclopropylpiperidin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-2-oxo-1,2-dihydropyridine-3-carboxamide; 4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-N-(4-(4-methylpiperazin-1-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide; N-(4-(4-Isopropylpiperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxamide; or N-(4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxamide.

16. A PROTAC of formula (II): PTM-L-ULM (II), wherein PTM is a protein targeting moiety and is a compound of formula (I) according to any one of the preceding claims; L is a linker; and ULM is an E3 ubiquitin ligase complex.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, a PROTAC according to claim 16 or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof, and a pharmaceutically acceptable vehicle.

18. A compound of formula (I) according to any one of claims 1 to 15, a PROTAC according to claim 16, or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or a pharmaceutical composition according to claim 17, for use in therapy.

19. A compound of formula (I) according to any one of claims 1 to 15, a PROTAC according to claim 16 or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or a pharmaceutical composition according to claim 17 for use in modulating the activity of an HPK-1 protein.

20. A compound of formula (I) according to any one of claims 1 to 15, a PROTAC according to claim 16 or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or a pharmaceutical composition according to claim 17, for use in treating, ameliorating or preventing a disease selected from cancer, viral infection and immune-mediated disorders.

21. A compound of formula (I) for use in regulating the activity of HPK-1 protein: X is CH or N; Z is phenyl or 5- or 6-membered heteroaryl, wherein the phenyl or heteroaryl is substituted with one or more substituents selected from the group consisting of halogen, optionally substituted C 1- C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, CN, OR 8 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 8 、COOR 8 、CONR 8 R 9 NR 8 COR 9 NR 8 SO2R 9 NR 8 R 9 , an optionally substituted 3- to 10-membered heterocyclyl, an optionally substituted 5- to 10-membered heteroaryl, an optionally substituted C 6-10 Aryl or optionally substituted C 3-9 Cycloalkyl; and / or wherein adjacent substituents of the phenyl or heteroaryl groups may be combined together with the atoms to which they are attached to form an optionally substituted 3 to 6 membered heterocyclic ring or an optionally substituted 5 or 6 membered heteroaryl group; R 1 to R 7 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, CN, OR 10 SR 8 、SOR 8 、SO2R 8 、SO2NR 8 R 9 、COR 10 、COOR 8 、CONR 10 R 11 NR 10 COR 11 NR 10 SO2R 11 NR 10 R 11 , optionally substituted C3-C6 cycloalkyl, optionally substituted 3 to 8 membered heterocyclyl, optionally substituted 5 to 10 membered heteroaryl or optionally substituted phenyl; and / or R 3 and R 4 and / or R 5 and R 6 Together with the C atom to which it is attached, it forms a C=O group, an optionally substituted C3-C6 cycloalkyl group or an optionally substituted 3- to 8-membered heterocyclyl group; and / or R 3 and R 5 Together with the C atom to which it is attached, it forms an optionally substituted C3-C6 cycloalkyl or an optionally substituted 3- to 8-membered heterocyclyl; R 8 and R 9 are independently hydrogen, optionally substituted C1-C 12 Alkyl, optionally substituted C2-C 12 Alkenyl, optionally substituted C2-C 12 Alkynyl, optionally substituted C 6-12 aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl; and R 10 and R 11 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C 6-12 aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl; or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof.

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