Pyridone and pyrimidinone inhibitors of hematopoietic progenitor kinase 1

Abstract

The present invention relates to compounds of formula (I), which can be used to modulate the activity of HPK-1 protein, thereby treating cancer, viral infections and immune-mediated disorders. JPEG2025539086000282.jpg54149

Description

Detailed Description of the Invention

[0001] The present invention relates to compounds and methods useful for inhibiting hematopoietic progenitor kinase 1 (HPK-1, MAP4K1). Accordingly, the inhibitors may be for use in the treatment of diseases such as cancer and viral infections. The invention extends to the compounds themselves, pharmaceutical compositions, methods of making the compounds, and methods of inhibiting HPK-1 protein.

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

[0003] Immuno-oncology plays an increasingly important role in cancer treatment by recruiting immune cells to recognize and ultimately eliminate cancer cells. Recently, significant advances have been made in monoclonal antibodies targeting T cell inhibitory checkpoints, such as CTLA-4, PD1, and PD-L1, and these have been remarkably successful in promoting durable anti-tumor responses in patients (Lee et al., Molecules, 2019, 24, 1190-1205).

[0004] In a productive immune response against tumors, the release of tumor antigens engages antigen receptors on immune cells, including dendritic cells and antigen-presenting cells, ultimately priming and activating T cells. These antigen-specific T cells migrate to the tumor site, infiltrate the tumor, and kill the target cancer cells that comprise the tumor (Chen and Mellman, Immunity, 2013, 39, 1–10). However, the delicate balance of this process can be disrupted by mechanisms designed to evade detection by the immune system and circumvent normal immune surveillance. Response rates to checkpoint inhibitor treatment vary depending on the type of cancer targeted and appear to be sensitive to suppressive factors in the tumor microenvironment, which can lead to impaired T cell effector function and resistance to treatment (Sharma et al., Cell, 2017, 168, 707–723). Antibody treatments are also limited to targeting only extracellular inhibitory checkpoints / negative regulators; accessing intracellular targets requires different modalities, such as cell-permeable small molecules.

[0005] Therefore, alternative means of modulating immune responses, particularly T cell immune responses, are needed 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 the negative regulation of T cell responses against tumors (Adams et al., Nat. Rev. Drug Disc., 2015, 14, 603-622; Weinmann, ChemMedChem, 2016, 11, 450-466; Sasikumar et al., BioDrugs, 2018, 32, 481-497).

[0007] HPK-1 has been investigated as a potential immuno-oncology target due to its restricted cellular expression in hematopoietic cells such as T cells, B cells, macrophages, dendritic cells, neutrophils, and mast cells (Kiefer et al., EMBO J., 1996, 15, 7013-7025). It has been shown to negatively regulate T cell and dendritic cell function. HPK-1 knockout (KO) mouse studies have confirmed its role in regulating T cell activation, with HPK-1 KO or kinase activity-deficient mice exhibiting enhanced antigen presentation, increased ERK1 / 2 activation, and being able to mount enhanced 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). More 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 caused by the prostaglandin E2 and adenosine pathways (Wang et al., PLoS One, 2020, 15, e0243145). Another potent small molecule has also been shown to suppress tumor growth in the MC38 mouse syngeneic tumor model and the CT26 mouse tumor explant model when combined with an anti-PD1 antibody (You et al., J. Immunother. Cancer, 2021, 9, e001402). These data clearly demonstrate that loss of HPK-1 functional activity, both by genetic deletion and pharmacological inhibition, promoted T cell activation and antitumor effects in preclinical models.

[0008] T cell activation involves several enzymes, including kinases that signal activation. HPK-1 kinase activity is expressed in T 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), transforming growth factor receptor (TGF-PR) (Wang et al., J. Biol. Chem., 1997, 272, 22771-22775), PGE2 receptor EP2, and E receptor EP3. It is induced by activation of P4 (Ikegami et al., J. Immunol., 2001, 166, 4689-4696), LPS receptor (Alzabin et al., J. Immunol., 2009, 182, 6187-6194), and by 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). HPK-1 activation, signaling, and immunobiology have been recently reviewed by Sawasdikosol et al. (eLife, 2020, 9, e55122). HPK-1 is fully activated by ZAP-70 phosphorylation at Tyr379 and autophosphorylation at Thr165 and Ser171 (Sauer et al., Mol. Cell. Biol., 2005, 25, 2364-2383). Upon catalytic activation, 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. Chem., 2012, 287, 34091-34100). Negative regulation of B cells works in a very similar way (Sauer et al., J. Biol. Chem., 2001, 276, 45207-45216; Wang et al., J. Biol. Chem., 2012, 287, 11037-11048).

[0009] The structure of the HPK-1 kinase domain was recently elucidated in the apo form and in co-structure with a small molecule ligand (Wu et al., Structure, 2019, 27, 125-133; Johnson et al., J. Biol. Chem., 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 intrinsically 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 segment exhibits a well-conserved dimerization interface.

[0010] Several small molecule inhibitors of HPK-1 have been reported, but they are not primarily HPK-1 inhibitors but rather act as off-targets. 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 resulting in weaker off-target activity. Subsequently, several more potent HPK-1 inhibitors with varying degrees of HPK-1 enzymatic potency, cell-based potency, and kinase selectivity have been described in the literature (You et al., J. Immunother. Cancer, 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).

[0011] Therefore, there is still a need in the art for improved therapies for treating diseases such as cancer, which may be resistant to conventional therapeutic approaches.Immunologic strategies show promise for cancer treatment, and there is a need in the art to develop improved compositions and methods.In particular, there is a need for potent and selective small molecule inhibitors of HPK-1, as well as methods for treating diseases that can benefit from such inhibition.

[0012] Pyridone inhibitors of kinases are known in the literature. For example, Georges et al. (WO 2009024332) describe pyridone amide inhibitors of focal adhesion kinase (FAK), Bryan et al. (ACS Med. Chem. Letts., 2016, 7, 100-104) describe 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) detail synthetic methods for producing pyridone amides. None of these reports provide any HPK-1 activity data. The first two reports describe specific substituents, particularly 4-aminophenyl substituents, designed to optimize activity at FAK and EGFR, respectively, which are not preferred for HPK-1 activity. The present inventors have discovered that certain substituted pyridone carboxamides are potent and selective inhibitors of HPK-1.

[0013] According to a first aspect of the present invention there is provided a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomer or polymorph thereof:

[0014] [ka] [In the formula, X is CH or N; Z is phenyl or 5- or 6-membered heteroaryl, where phenyl or heteroaryl is selected from halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, CN, OR 8 , S.R. 8 , SOR 8 , SO2R 8 , SO2NR 8 R 9 , C.O.R. 8 , COOR 8 ,CONR 8 R 9 , N.R. 8 COR 9 , N.R. 8 SO2R 9 , N.R. 8 R 9 , optionally substituted 3- to 10-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 6~10 Aryl or optionally substituted C 3~9 cycloalkyl, and / or wherein adjacent substituents of phenyl or heteroaryl, together with the atoms to which they are attached, may form an optionally substituted 3- to 6-membered heterocycle or an optionally substituted 5- or 6-membered heteroaryl; R 1 ~R 7 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, CN, OR 10 , S.R. 8 , SOR 8 , SO2R 8 , SO2NR 8 R 9 , C.O.R. 10 , COOR 8 ,CONR 10 R 11 , N.R. 10 COR 11 , N.R. 10 SO2R 11 , N.R. 10 R11 , optionally substituted C3-C6 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted 5-10 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 they are attached form a C=O group, an optionally substituted C3-C6 cycloalkyl or an optionally substituted 3-8 membered heterocyclyl, and / or R 3 and R 5 together with the C atom to which they are attached form an optionally substituted C3-C6 cycloalkyl or an optionally substituted 3-8 membered heterocyclyl; R 8 and R 9 are independently hydrogen, optionally substituted C1-C 12 Alkyl, optionally substituted C-C 12 Alkenyl, optionally substituted C-C 12 Alkynyl, optionally substituted C 6~12 aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, and optionally substituted 5-10 membered heteroaryl; 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 3-8 membered heterocyclyl, and optionally substituted 5-10 membered heteroaryl.

[0015] In a second aspect of the present invention, there is provided a pharmaceutical composition comprising a compound according to the first aspect, or a pharmaceutically acceptable salt, solvate, tautomer or polymorph thereof, and a pharmaceutically acceptable vehicle.

[0016] The present invention also provides, in a third aspect, a process for producing a composition according to the second aspect, comprising contacting a therapeutically effective amount of a compound of the first aspect, or a pharmaceutically acceptable salt, solvate, tautomer or polymorph thereof, with a pharmaceutically acceptable vehicle.

[0017] We have found that compounds of the present invention are useful in therapy or as medicines.

[0018] Thus, in a fourth aspect, there is provided a compound of formula (I), or a pharmaceutically acceptable complex, salt, solvate, tautomer or polymorph thereof, or a composition of the second aspect, for use in therapy.

[0019] The present inventors have found that compounds of formula (I) are effective in modulating the activity of HPK-1.

[0020] Thus, in a fifth aspect, there is provided a compound of formula (I), or a pharmaceutically acceptable complex, salt, solvate, tautomer or polymorph thereof, or a composition of the second aspect, for use in modulating the activity of HPK-1 protein.

[0021] In a sixth aspect, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomer or polymorph thereof in the manufacture of a medicament for modulating the activity of HPK-1 protein.

[0022] In a seventh aspect, there is provided a method of modulating the activity of HPK-1 protein, 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, tautomer or polymorph thereof, or a composition of the second aspect.

[0023] Preferably, the compounds of formula (I) are for use in inhibiting or antagonizing HPK-1 protein.

[0024] It will be understood that an "inhibitor," as it relates to a ligand and HPK-1, includes a molecule, combination of molecules, or complex that inhibits, antagonizes, suppresses, downregulates, and / or desensitizes HPK-1. An "inhibitor" includes any reagent that inhibits constitutive activity of HPK-1. Constitutive activity is that which is evident in the absence of ligand / HPK-1 interaction. An "inhibitor" also includes any reagent that inhibits or prevents stimulated (or regulated) activity of HPK-1.

[0025] The compounds of the present invention, and pharmaceutically related compositions thereof, are useful for treating a variety of diseases, disorders and conditions associated with the regulation of signal transduction pathways involving HPK-1.

[0026] By administering a compound of the present invention that inhibits HPK-1 protein, an enhanced immune response may be evident in a subject in need thereof. This enhanced immune response may include a T cell population that exhibits enhanced priming, activation, migration, proliferation, survival, and cytolytic activity compared to before administration of the compound or pharmaceutical composition. T cell activation is characterized by increased levels of secreted cytokines, such as IFNγ and IL-2, or an increased number of CD8 T cells compared to before 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 subject's antigen-presenting cells undergo accelerated maturation and activation compared to before administration of the compound or pharmaceutical composition. In certain aspects of this embodiment, the antigen-presenting cells are dendritic cells.

[0027] The compounds of the invention bind directly to HPK-1 protein and inhibit its kinase activity. In certain embodiments, the compounds of the invention reduce, inhibit, antagonize, or otherwise attenuate HPK-1-mediated phosphorylation of SLP76 and / or Gads.

[0028] The compounds of the present invention may or may not be specific inhibitors of HPK-1. A specific HPK-1 inhibitor reduces the biological activity of HPK-1 by an amount that is statistically greater than the inhibitory effect of an inhibitor 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 IC of the HPK-1 inhibitor against HPK-1 is 50 IC of HPK-1 inhibitors against different types of kinases 50 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001% or less of the above.

[0029] Any method known in the art for measuring the kinase activity of HPK-1 can be used to determine whether HPK-1 is inhibited, including in vitro enzymatic kinase assays, immunoblotting with 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 measuring downstream biological effects of HPK-1 kinase activity, e.g., T cell or B cell activation.

[0030] The compounds of the present invention can be used to treat diseases, disorders, and conditions associated with the regulation of signal transduction pathways involving HPK-1. These diseases, disorders, and conditions are pathological conditions in which HPK-1 activity is required for the development or maintenance of the pathological condition. In certain embodiments, the pathological condition is cancer.

[0031] The compounds of the present invention can be used to treat diseases resulting from 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 result in ineffective control of pathogens or tumors. Examples of diseases resulting from T cell dysfunction include unresolved acute infection, chronic infection, and cancer.

[0032] Inhibiting the HPK-1 protein can treat, ameliorate, or prevent cancer, viral infections, and immune-mediated disorders.

[0033] Thus, in an eighth aspect, there is provided a compound of formula (I), or a pharmaceutically acceptable complex, salt, solvate, tautomer or polymorph thereof, or a composition of the second aspect, for use in the treatment, amelioration or prevention of a disease selected from cancer, viral infection and immune-mediated disorders.

[0034] Preferably, the treatment, amelioration or prevention comprises inhibiting the HPK-1 protein.

[0035] In a ninth aspect, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomer or polymorph thereof in the manufacture of a medicament for treating, ameliorating or preventing a disease selected from cancer, a viral infection and an immune-mediated disorder.

[0036] In a tenth aspect, there is provided a method of treating, ameliorating or preventing a disease selected from cancer, viral infection and immune-mediated disorders, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable complex, salt, solvate, tautomer or polymorph thereof, or a composition of the second aspect.

[0037] It can be understood that the term "preventing" can mean "reducing the likelihood of."

[0038] In an eleventh aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomer or polymorph thereof for use in modulating the activity of HPK-1 protein.

[0039] [ka] wherein X is CH or N; Z is phenyl or 5- or 6-membered heteroaryl, where phenyl or heteroaryl is selected from halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, CN, OR 8 , S.R. 8 , SOR 8 , SO2R 8 , SO2NR 8 R 9 , C.O.R. 8 , COOR 8 ,CONR 8 R 9 , N.R. 8 COR 9 , N.R. 8 SO2R 9 , N.R. 8 R 9 , optionally substituted 3- to 10-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 6~10 Aryl or optionally substituted C 3~9 cycloalkyl, and / or wherein adjacent substituents of phenyl or heteroaryl, together with the atoms to which they are attached, may form an optionally substituted 3- to 6-membered heterocycle or an optionally substituted 5- or 6-membered heteroaryl; R 1 ~R 7 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, CN, OR 10 , S.R. 8 , SOR 8 , SO2R 8 , SO2NR 8 R 9 , C.O.R. 10 , COOR 8 ,CONR 10 R 11 , N.R. 10 COR 11 , N.R. 10 SO2R11 , N.R. 10 R 11 , optionally substituted C3-C6 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted 5-10 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 they are attached form a C=O group, an optionally substituted C3-C6 cycloalkyl or an optionally substituted 3-8 membered heterocyclyl, and / or R 3 and R 5 together with the C atom to which they are attached form an optionally substituted C3-C6 cycloalkyl or an optionally substituted 3-8 membered heterocyclyl; R 8 and R 9 are independently hydrogen, optionally substituted C1-C 12 Alkyl, optionally substituted C-C 12 Alkenyl, optionally substituted C-C 12 Alkynyl, optionally substituted C 6~12 aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, and optionally substituted 5-10 membered heteroaryl; 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 3-8 membered heterocyclyl, and optionally substituted 5-10 membered heteroaryl.

[0040] In some embodiments, the compounds of the present invention can be used to treat viral infections in a subject in need thereof, hi some embodiments, the compounds of the present invention can be used as adjuvants to enhance the effectiveness of vaccination.

[0041] The viral disease may be hepatitis B, hepatitis C or HIV.

[0042] In one preferred embodiment, the disease is cancer, which 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.

[0043] In some embodiments, cancers treatable using 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, renal cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer), hematological cancers (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 said cancers.

[0044] In some embodiments, HPK-1 inhibitors can be used to treat tumors that produce PGE2 (COX-2-overexpressing tumors) and / or adenosine (CD73 and CD39-overexpressing tumors). COX-2 overexpression has been detected in several tumors, such as colorectal cancer, breast cancer, pancreatic cancer, and lung cancer. CD73 is upregulated in various cancers, including those of the colon, lung, pancreas, and ovary.

[0045] In an alternative preferred embodiment, the disease is a viral infection, which may be hepatitis B, hepatitis C virus (HCV) infection, or human immunodeficiency virus (HIV) infection.

[0046] Unless the context indicates otherwise, the following definitions are used in connection with the compounds of the invention.

[0047] Throughout the description and claims of this specification, the word "comprise" and other forms of the word, such as "comprising" and "comprises," mean including but not limited to, and are not intended to exclude, for example, other additives, components, integers, or steps.

[0048] As used in this description 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 mixtures of two or more such compositions.

[0049] "Optional" or "optionally" means that the subsequently described event, action, or circumstance may or may not occur, and that the description includes examples when the event, action, or circumstance occurs and examples when the event, action, or circumstance does not occur.

[0050] The term "alkyl," as used herein, unless otherwise specified, refers to a saturated linear or branched hydrocarbon. In certain embodiments, an alkyl group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, an alkyl group contains 1 to 6 carbon atoms, i.e., C1-C6 alkyl. C1-C6 alkyl includes, for example, methyl, ethyl, n-propyl (1-propyl) and isopropyl (2-propyl, 1-methylethyl), butyl, pentyl, hexyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. In alternative embodiments, an alkyl group contains 1 to 3 carbon atoms, i.e., C1-C3 alkyl. An alkyl group can be unsubstituted or substituted with halogen, oxo, CN, OR, or substituted with any of the following: 16 , S.R. 16 , SOR 16 , SO2R 16 , C.O.R. 16 , COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 , N.R. 16 R 17 , optionally substituted C 6~12 Aryl, optionally substituted C 3~6 The optionally substituted C1-C6 alkyl may be substituted with one or more of cycloalkyl, an optionally substituted 3- to 6-membered heterocycle, or an optionally substituted 5- to 10-membered heteroaryl. Thus, an optionally substituted C1-C6 alkyl may be substituted with an optionally substituted C1-C6 haloalkyl, i.e., an alkyl group substituted with at least one halogen and oxo, CN, OR, or the like. 16 , S.R. 16 , SOR 16 , SO2R 16 , C.O.R. 16 , COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 , N.R. 16 R 17 , optionally substituted C 6~12 Aryl, optionally substituted C 3~6It will be understood that the optionally substituted C1-C6 alkyl may be further substituted with one or more of cycloalkyl, optionally substituted 3-6 membered heterocycle, or optionally substituted 5-10 membered heteroaryl. The optionally substituted C1-C6 alkyl may be polyfluoroalkyl, preferably C1-C3 polyfluoroalkyl, most preferably CF3.

[0051] 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 3-8 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

[0052] The term "halo" or "halogen" includes fluoro (-F), chloro (-Cl), bromo (-Br) and iodo (-I).

[0053] The term "polyfluoroalkyl" may refer to a C1-C3 alkyl group in which two or more hydrogen atoms are replaced by fluorine atoms. This term may also 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.

[0054] "Alkenyl" refers to an olefinically unsaturated hydrocarbon group that can be unbranched or branched. In certain embodiments, an alkenyl group has 2 to 6 carbons, i.e., the alkenyl group is a C2-C6 alkenyl. C2-C6 alkenyl includes, for example, vinyl, allyl, propenyl, butenyl, pentenyl, and hexenyl. In alternative embodiments, the alkenyl group has 2 to 3 carbons, i.e., the alkenyl group is a C2-C3 alkenyl. An alkenyl group can be unsubstituted or optionally substituted with C2-C6 alkynyl, halogen, oxo, CN, OR 16 , S.R. 16 , SOR 16 , SO2R 16 , C.O.R. 16 , COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 , N.R. 16 R 17 , optionally substituted C 6~12 Aryl, optionally substituted C 3~6 R may be substituted with one or more of cycloalkyl, optionally substituted 3- to 6-membered heterocycle, or optionally substituted 5- to 10-membered heteroaryl. 16 and R 17 may be as defined above.

[0055] "Alkynyl" refers to an acetylenically unsaturated hydrocarbon group that can be unbranched or branched. In certain embodiments, an alkynyl group has 2 to 6 carbons, i.e., the alkynyl group is a C2-C6 alkynyl. C2-C6 alkynyl includes, for example, propargyl, propynyl, butynyl, pentynyl, and hexynyl. In alternative embodiments, the alkynyl group has 2 to 3 carbons, i.e., the alkynyl group is a C2-C3 alkynyl. An alkynyl group can be unsubstituted or optionally substituted with C2-C6 alkenyl, halogen, oxo, CN, OR, or the like. 16 , S.R. 16 , SOR 16 , SO2R 16 , C.O.R. 16, COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 , N.R. 16 R 17 , optionally substituted C 6~12 Aryl, optionally substituted C 3~6 R may be substituted with one or more of cycloalkyl, optionally substituted 3- to 6-membered heterocycle, or optionally substituted 5- to 10-membered heteroaryl. 16 and R 17 may be as defined above.

[0056] "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 groups can be unsubstituted or optionally substituted, such as C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, oxo, CN, OR 16 , S.R. 16 , SOR 16 , SO2R 16 , C.O.R. 16 , COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 , N.R. 16 R 17 , optionally substituted C 6~12 Aryl, optionally substituted C 3~6 R may be substituted with one or more of cycloalkyl, optionally substituted 3- to 6-membered heterocycle, or optionally substituted 5- to 10-membered heteroaryl. 16 and R 17 may be as defined above.

[0057] "Heteroaryl," unless otherwise specified, 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, the group is considered to be a heteroaryl group if one or both rings contain at least one ring atom that is a heteroatom. In some embodiments, a heteroaryl 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 may contain 1, 2, 3, or 4 heteroatoms. Examples of 5- to 10-membered heteroaryl groups 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 heteroaryl groups include those in which a phenyl, pyridine, pyrimidine, pyrazine, or pyridazine ring is fused to a 5- or 6-membered monocyclic heteroaryl ring. Heteroaryl groups can be unsubstituted or optionally substituted with C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, oxo, CN, OR 16 , S.R. 16 , SOR 16 , SO2R 16 , C.O.R. 16 , COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 , N.R.16 R 17 , optionally substituted C 6~12 Aryl, optionally substituted C 3~6 R may be substituted with one or more of cycloalkyl, optionally substituted 3- to 6-membered heterocycle, or optionally substituted 5- to 10-membered heteroaryl. 16 and R 17 may be as defined above.

[0058] "Heterocycle" or "heterocyclyl," unless otherwise specified, 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, the heterocycle is a 3- to 6-membered monocyclic molecule 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. 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, oxirene, thiirane, pyrroline, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine, 1,2,3,6-tetrahydropyridin-1-yl, tetrahydropyran, pyran, morpholine, piperazine, thiane, thiine, piperazine, azepane, diazepane, and oxazine. Heterocyclic groups can be unsubstituted or optionally substituted with C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, oxo, CN, OR 16 , S.R. 16 , SOR 16 , SO2R 16 , C.O.R. 16 , COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 , N.R. 16 R 17 , optionally substituted C 6~12Aryl, optionally substituted C 3~6 R may be substituted with one or more of cycloalkyl, optionally substituted 3- to 6-membered heterocycle, or optionally substituted 5- to 10-membered heteroaryl. 16 and R 17 may be as defined above.

[0059] "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. In an aryl group, all of the ring atoms are understood to be carbon. C6-C 12 Examples of aryl groups include, but are not limited to, phenyl, α-naphthyl, β-naphthyl, biphenyl, tetrahydronaphthyl, and indanyl. An optionally substituted aryl group may be an optionally substituted phenyl group. An optionally substituted aryl group may be unsubstituted or optionally substituted with C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, CN, OR 16 , S.R. 16 , SOR 16 , SO2R 16 , C.O.R. 16 , COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 , N.R. 16 R 17 , optionally substituted C 6~12 Aryl, optionally substituted C 3~6 R may be substituted with one or more of cycloalkyl, optionally substituted 3- to 6-membered heterocycle, or optionally substituted 5- to 10-membered heteroaryl. 16 and R 17 may be as defined above.

[0060] As used herein, the term "bicyclic" or "bicyclic" refers to a molecule featuring two rings. Similarly, as used herein, "tricyclic" refers to a molecule featuring three rings. Similarly, as used herein, "polycyclic" refers to a molecule featuring three or more rings. In each case, the rings may be optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or combinations thereof. In one embodiment, the rings are fused across a bond between two atoms. A moiety formed by fusion shares a bond between the rings and may be referred to as "fused." In another embodiment, a moiety is formed by fusing two rings across a series of atoms in the rings to form a bridgehead. Similarly, a "bridge" is an unbranched chain of one or more atoms connecting two bridgeheads of a bicyclic or polycyclic compound. In another embodiment, the molecule is a "spiro" or "spirocyclic" moiety. A spirocyclic group may be a C3-C6 cycloalkyl or a monocyclic or bicyclic 3- to 8-membered heterocycle bonded via a single carbon atom of the spirocyclic moiety to a single carbon atom of the carbocyclic or heterocyclic moiety. In one embodiment, a spirocyclic group is a cycloalkyl and bonded to another cycloalkyl. In another embodiment, a spirocyclic group is a cycloalkyl and bonded to a heterocyclyl. In a further embodiment, a spirocyclic group is a heterocyclyl and bonded to another heterocyclyl. In yet another embodiment, a spirocyclic group is a heterocyclyl and bonded to a cycloalkyl.

[0061] 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 3-8 membered heterocyclyl, and optionally substituted 5-10 membered heteroaryl.

[0062] R 1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, CN, OR 10 , S.R. 8 , SOR 8 , SO2R 8 , SO2NR 8 R 9 , C.O.R. 10 , COOR 8 ,CONR 10 R 11 , N.R. 10 COR 11 , N.R. 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 may be independently hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, or optionally substituted C2-C3 alkynyl. More preferably, R 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, most preferably methyl. 10 and R 11 may be independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl. More preferably, R 10 and R 11are 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, most preferably methyl. Thus, R 1 may be hydrogen, methyl, CN, or OCH3.

[0063] R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, CN, OR 10 , S.R. 8 , SOR 8 , SO2R 8 , SO2NR 8 R 9 , C.O.R. 10 , COOR 8 ,CONR 10 R 11 , N.R. 10 COR 11 , N.R. 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 ~R 11 is R 1 Most preferably, R 2 is hydrogen.

[0064] R 3and R 4 are independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, CN, OR 10 , S.R. 8 , SOR 8 , SO2R 8 , SO2NR 8 R 9 , C.O.R. 10 , COOR 8 ,CONR 10 R 11 , N.R. 10 COR 11 , N.R. 10 SO2R 11 , N.R. 10 R 11 , optionally substituted C3-C6 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl or optionally substituted phenyl, or R 3 and R 4 may be taken together with the C atom to which they are attached to form a C=O group, an optionally substituted C3-C6 cycloalkyl or an optionally substituted 3-8 membered heterocyclyl. More preferably, R 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 3-8 membered heterocyclyl, or R 3 and R 4 may be taken together with the C atom to which they are attached to form an optionally substituted C3-C6 cycloalkyl or an optionally substituted 3-8 membered heterocyclyl. Even more preferably, R 3 and R 4 are independently hydrogen, C1-C3 alkyl or halogen, or R 3 and R 4may form a C3-C6 cycloalkyl together with the C atom to which they are attached. 8 ~R 11 is R 1 Most preferably, R 3 and R 4 are independently hydrogen, methyl, ethyl, i-propyl or fluorine, or R 3 and R 4 together with the C atom to which they are attached to form a cyclopropyl.

[0065] R 5 and R 6 are independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, CN, OR 10 , S.R. 8 , SOR 8 , SO2R 8 , SO2NR 8 R 9 , C.O.R. 10 , COOR 8 ,CONR 10 R 11 , N.R. 10 COR 11 , N.R. 10 SO2R 11 , N.R. 10 R 11 , optionally substituted C3-C6 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl or optionally substituted phenyl, or R 5 and R 6 may be taken together with the C atom to which they are attached to form a C=O group, an optionally substituted C3-C6 cycloalkyl or an optionally substituted 3-8 membered heterocyclyl. More preferably, R 5 and R 6 are independently hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, halogen, CN, OR10 , optionally substituted C3-C6 cycloalkyl or optionally substituted 3-8 membered heterocyclyl, or R 5 and R 6 may form a C=O group together with the C atom to which they are attached. Even more preferably, R 5 and R 6 are independently hydrogen, C1-C3 alkyl or halogen, or R 5 and R 6 may form a C=O group together with the C atom to which they are attached. 8 ~R 11 is R 1 Most preferably, R 5 and R 6 is hydrogen or R 5 and R 6 together with the C atom to which they are attached to form a C=O group.

[0066] R 7 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, CN, OR 10 , S.R. 8 , SOR 8 , SO2R 8 , SO2NR 8 R 9 , C.O.R. 10 , COOR 8 ,CONR 10 R 11 , N.R. 10 COR 11 , N.R. 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 7is hydrogen, C1-C3 alkyl, CN or OR 10 R 8 ~R 11 is R 1 Most preferably, R 7 is hydrogen or methyl.

[0067] Therefore, Y is [ka] may be.

[0068] Z may be a substituted phenyl, substituted pyrazole, or substituted pyridinyl group.

[0069] In one preferred arrangement, adjacent substituents of a phenyl or 5- or 6-membered heteroaryl group Z are linked together with the C atoms of the phenyl or heteroaryl group to which they are attached to form a 5- or 6-membered heterocyclic or heteroaromatic group. It will be understood that in these embodiments, the group Z is an optionally substituted fused group. Furthermore, adjacent substituents of a heterocyclic or heteroaryl group, together with the atoms to which they are attached, may form a further optionally substituted 3- to 6-membered heterocycle or a further optionally substituted 5- or 6-membered heteroaryl. Thus, the optionally substituted fused group may be an optionally substituted bicyclic fused group or an optionally substituted tricyclic fused group. The optionally substituted bicyclic or tricyclic fused group may be an optionally substituted 8- to 14-membered heterocyclic or heteroaromatic group. In some embodiments, Z is an optionally substituted bicyclic fused group, an optionally substituted 9- or 10-membered heterocyclic or heteroaromatic group. In alternative embodiments, Z is an optionally substituted tricyclic fused group, an optionally substituted 12- to 14-membered heterocyclic 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 optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, oxo, CN, OR 16 , S.R. 16 , SOR 16, SO2R 16 , C.O.R. 16 , COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 , N.R. 16 R 17 , optionally substituted C 6~12 Aryl, optionally substituted C 3~6 The fused group may be substituted with one or more of an optionally substituted cycloalkyl, an optionally substituted 3- to 6-membered heterocycle, or an optionally substituted 5- to 10-membered heteroaryl. More preferably, the fused group is unsubstituted or optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, halogen, oxo, CN, OR 16 , S.R. 16 , SOR 16 , SO2R 16 , C.O.R. 16 , COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 or NR 16 R 17 Most preferably, the fused group is unsubstituted or 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, an optionally substituted alkenyl, or an optionally substituted alkynyl, the alkyl, alkenyl, or alkynyl may be unsubstituted or may be substituted with one or more of halogen, oxo, CN, OR 16 , S.R. 16 , SOR 16 , SO2R 16 , C.O.R. 16 , COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 and NR 16 R17 More preferably, the alkyl, alkenyl or alkynyl is unsubstituted or is substituted with one or more of OR 16 It is replaced by R 16 and R 17 may be as defined above. Preferably, R 16 and R 17 are independently H, optionally substituted C 1~3 Alkyl or optionally substituted C 3~6 It may also be cycloalkyl, where the alkyl or cycloalkyl is unsubstituted or substituted with halogen or OH. Most preferably, R 16 and R 17 are independently H, methyl, and optionally substituted cyclopropyl, where cyclopropyl is optionally substituted with fluorine. The fused group may be unsubstituted or substituted with between 1 and 6 substituents. More preferably, the fused group is unsubstituted or substituted with 1, 2, or 3 substituents. Optional substituents include, without limitation, C1-C6 alkyl or F. More preferably, the optional substituent is CH3 or F. In the most preferred embodiment, the fused group is unsubstituted or substituted with methyl, ethyl, [ka] , OH, OCH3, oxo or [ka] is substituted with one or more of:

[0070] Preferred groups Z are of the formula: [ka] [where, X 5 , X 6 , X 7 and X 8 is X5 , X 6 , X 7 and X 8 N and CR on the condition that only one of 21 are independently selected from R 21 is independently at each occurrence H or halogen, preferably F; A is optionally substituted C1-C6 alkyl; COR 8 , COOR 8 ,CONR 8 R 9 , N.R. 8 COR 9 , N.R. 8 R 9 , optionally substituted 3- to 10-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl. 8 and R 9 may independently be 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 3-8 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. More preferably, R 8 and R 9 are independently hydrogen, optionally substituted C1-C3 alkyl, or optionally substituted 5- or 6-membered heterocyclyl. Alkyl may be unsubstituted or may be substituted with halogen, OR 16 or NR 16 R 17 R 16 and R 17 may be as defined above. In some embodiments, R 16 and R 17 may independently be H or C1-C3 alkyl.

[0071] An alternative preferred group Z is of the formula: [ka] [In the formula, X 5 , X 6 , X 7 and X 8 is X 5 , X 6 , X 7 and X 8 N or CR, provided that only one of 21 and R 21 is independently selected from H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, CN, OR 8 , S.R. 8 , SOR 8 , SO2R 8 , SO2NR 8 R 9 , C.O.R. 8 , COOR 8 ,CONR 8 R 9 , N.R. 8 COR 9 , N.R. 8 SO2R 9 , N.R. 8 R 9 , optionally substituted 3- to 6-membered heterocyclyl, optionally substituted 5- or 6-membered heteroaryl, optionally substituted C 6~10 Aryl or optionally substituted C 3~9 is cycloalkyl, A is optionally substituted C1-C6 alkyl, OR 8 , SO2R 8 , SO2NR 8 R 9 , C.O.R. 8 , COOR 8 ,CONR 8 R 9 , N.R. 8 COR 9 , N.R. 8 SO2R 9 , N.R. 8 R 9 , optionally substituted 3- to 10-membered heterocyclyl and optionally substituted 5- to 10-membered heteroaryl.

[0072] In some embodiments, X 5 , X 6 , X 7 and X 8 All are CR 21 is.

[0073] In an alternative embodiment, X 5 , X 7 and X 8 All are CR 21 and X 6 is N.

[0074] In one embodiment, the phenyl or 5- or 6-membered heteroaryl group Z is selected from the group consisting of optionally substituted 3- to 10-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C 6~10 Aryl or optionally substituted C 3~9 It can be understood that optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or optionally substituted cycloalkyl may be group A in the above formula. In some embodiments, the phenyl or 5- or 6-membered heteroaryl group Z is substituted with optionally substituted 3- to 10-membered heterocyclyl or optionally substituted 5- to 10-membered heteroaryl.

[0075] A preferred optionally substituted heteroaryl group which is optionally a substituent on the group Z, which may be A in the above formula, is optionally substituted pyridinyl, optionally substituted pyrazolyl, optionally substituted oxazolyl or optionally substituted 2H-1,2,3-triazolyl. A preferred heteroaryl group which is optionally a substituent on the group Z, which may be A in the above formula, is pyridyl, pyrazolyl or oxazolyl.

[0076] 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 octahydropyrrolo[1,2-a]pyrazinyl, optionally substituted octahydroimidazo[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.

[0077] Preferred heterocyclyl groups which are substituents on the Z group, which may optionally be A in the above formula, are of formula (i) or (j): [ka] [In the formula, T is N and M is NR 13 , C.R. 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 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 , S.R. 16 , SOR 16 , SO2R 16 , C.O.R.16 , COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 , N.R. 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 / or two R 12 The group may define an oxo group, or two R 12 The groups may be linked to form a fused group, or two R 12 the groups may be linked to form a bicyclic bridged 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 , S.R. 16 , SOR 16 , SO2R 16 , C.O.R. 16 , COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 , N.R. 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 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 , S.R. 16 , SOR 16, SO2R 16 , C.O.R. 16 , COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 , N.R. 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.

[0078] Preferred heterocyclyl groups which are substituents on the Z group, which may optionally be A in the above formula, are of formula (i) or (j): [ka] [In the formula, T is N and M is NR 13 , C.R. 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 1 or 2; R 12 is, at each occurrence, independently selected from 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 bonded to adjacent carbon atoms 12 The groups may be linked to form a fused group, or two R 12 the groups may be linked to form a bicyclic bridged group; R 13is 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 and R 14 and R 15 is 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 are linked together with the C atoms to which they are both attached to form an optionally substituted 3- to 6-membered heterocyclyl or an optionally substituted C 3~6 may form a cycloalkyl, R 18 is hydrogen or optionally substituted C1-C6 alkyl, R 19 and R 20 each independently represents 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 group, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 3- to 6-membered heterocyclyl.

[0079] The heterocyclyl or heteroaryl substituent on the Z group may be unsubstituted or 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 , S.R. 16 , SOR 16 , SO2R 16 , C.O.R. 16 , COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 or NR 16 R 17 and optionally substituted with one or more optional substituents which may be selected from the group consisting of: More preferably, the heterocyclyl or heteroaryl substituent on the Z group is unsubstituted or 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 , N.R. 16 COR 17 or NR 16 R 17 The alkyl may be optionally substituted with one or more substituents selected from the group consisting of OR 16 and NR 16 R 17 may be substituted with R 16 and R 17 may be as defined above. In some embodiments, R 16 and R 17 may each independently be selected from the group consisting of H, C1-C3 alkyl, or an optionally halogenated 5- or 6-membered heterocycle.

[0080] Heterocyclyl, heteroaryl, aryl or cycloalkyl, which are substituents on the Z group and may be group A in the above formula, may be unsubstituted or 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 , S.R. 16 , SOR 16 , SO2R 16 , C.O.R. 16 , COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 , N.R. 16 R 17 , optionally substituted C 6~12 Aryl, optionally substituted C 3~6 The group R 12 , R 13 , R 14 and / or R 15 It will be understood that R 13 , R 14 and / or R 15 may be H or a substituent as defined below. Similarly, R 12 is H or a substituent as defined below, and / or two R 12 The group may define an oxo group, or two R 12 The groups may be linked to form a fused group, or two R 12 The groups may be linked to form a bicyclic bridging group. Most preferably, these substituents are groups R 13 or R 14More preferably, the heterocyclyl, heteroaryl, aryl or cycloalkyl substituent on the Z group is unsubstituted or optionally substituted C1-C6 alkyl, oxo, CN, OR 16 , SO2R 16 , C.O.R. 16 , COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 , N.R. 16 R 17 , optionally substituted C 3~6 R may be substituted with one or more substituents selected from the group consisting of cycloalkyl, an optionally substituted 3- to 6-membered heterocycle, or an optionally substituted 5- or 6-membered heteroaryl. 16 and R 17 may be as defined above. Preferably, R 16 and R 17 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. More preferably, R 16 and R 17 are 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 the heterocyclyl, heteroaryl, aryl, or cycloalkyl substituent on the Z group is directly or indirectly substituted with optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, the alkyl, alkenyl, or alkynyl may be unsubstituted or may be substituted with halogen, oxo, CN, OR 16a , S.R. 16a , SOR 16a , SO2R 16a , C.O.R. 16a , COOR 16a ,CONR 16a R 17a , N.R. 16a COR17a , N.R. 16a R 17a , optionally substituted C 6~12 Aryl, optionally substituted C 3~6 and optionally substituted with one or more of cycloalkyl, an optionally substituted 3- to 6-membered heterocycle, or an optionally substituted 5- to 10-membered heteroaryl. More preferably, the alkyl, alkenyl, or alkynyl is unsubstituted or is selected from the group consisting of fluoro, OR, 16a , SO2R 16a , optionally substituted C 3~6 R is substituted with one or more of cycloalkyl, optionally substituted 4- to 6-membered heterocycle, or optionally substituted 5- or 6-membered heteroaryl. 16a and R 17a is the above R 16 and R 17 More preferably, R 16a and R 17a are 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 the heterocyclyl, heteroaryl, aryl or cycloalkyl substituent on the Z group is directly or indirectly substituted with optionally substituted cycloalkyl, optionally substituted heterocycle or optionally substituted heteroaryl, the cycloalkyl, heterocycle or heteroaryl may be unsubstituted or optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, oxo, CN, OR 16b , S.R. 16b , SOR 16b , SO2R 16b , C.O.R. 16b , COOR 16b ,CONR 16b R 17b , N.R. 16b COR 17b or NR 16bR 17b More preferably, the cycloalkyl, heterocycle, or heteroaryl is unsubstituted or 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 C1-C3 alkyl optionally substituted with fluoro, OH, or OCH3, fluoro, oxo, or CONR 16b R 17b R 16b and R 17b is the above R 16 and R 17 More preferably, R 16b and R 17b are 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. Heterocyclyl, heteroaryl, aryl, or cycloalkyl can be understood to be indirectly substituted with a group when it has a substituent containing that group. In embodiments where aryl or cycloalkyl is a substituent on the Z group, preferably the aryl or cycloalkyl is unsubstituted. In embodiments where heterocyclyl or heteroaryl is a substituent on the Z group, preferably the heterocyclyl or heteroaryl is substituted. Preferably, the heterocyclyl or heteroaryl has one, two, or three substituents, and most preferably has one substituent. Most preferably, the heterocyclyl or heteroaryl that is a substituent on the Z group is unsubstituted or is selected from the group consisting of methyl, ethyl, [ka] , oxo, CN, OH, OCH3, [ka] and optionally substituted with one or more substituents optionally selected from the group consisting of:

[0081] Therefore, R 13 , R 14 and R 15 are independently H, methyl, ethyl, [ka] , oxo, CN, OH, OCH3, [ka] M may be CR 14 R 15 In embodiments where R 15 may be H, and R 14 may be as defined above.

[0082] In another embodiment, the phenyl or 5- or 6-membered heteroaryl group Z is not directly substituted with 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 group Z is not directly substituted with halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, CN, OR 8 , S.R. 8 , SOR 8 , SO2R 8 , SO2NR 8 R 9 , C.O.R. 8 , COOR 8 ,CONR 8 R 9 , N.R. 8 COR 9 , N.R.8 SO2R 9 and NR 8 R 9 and R is substituted with one or more substituents selected from the group consisting of: It can be understood that these substituents may also be the group A. More preferably, the phenyl or 5- or 6-membered heteroaryl group Z is substituted with one or more substituents selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, OR 8 , SO2R 8 , SO2NR 8 R 9 , C.O.R. 8 , COOR 8 ,CONR 8 R 9 , N.R. 8 SO2R 9 and NR 8 R 9 Most preferably, the phenyl or 5- or 6-membered heteroaryl group Z is substituted with one or more substituents selected from the group consisting of optionally substituted C1-C3 alkyl, OR 8 , SO2R 8 , SO2NR 8 R 9 , C.O.R. 8 ,CONR 8 R 9 , N.R. 8 SO2R 9 and NR 8 R 9 R is substituted with one or more substituents selected from the group consisting of 8 and R 9 are independently hydrogen, optionally substituted C1-C 12 Alkyl, optionally substituted C 6~12 aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, and optionally substituted 5-10 membered heteroaryl. More preferably, R 8 and R 9 are independently hydrogen, optionally substituted C1-C 10alkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. Most preferably, R 8 and R 9 may be H, optionally substituted C1-C8 alkyl, cyclopropyl, optionally substituted 5- or 6-membered heterocycle, or optionally substituted phenyl. The alkyl group may be unsubstituted or may be substituted with halogen, oxo, CN, OR 16 , S.R. 16 , SOR 16 , SO2R 16 , C.O.R. 16 , COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 , N.R. 16 R 17 , optionally substituted C 6~12 Aryl, optionally substituted C 3~6 The alkyl group may be substituted with one or more of cycloalkyl, an optionally substituted 3- to 6-membered heterocycle, or an optionally substituted 5- to 10-membered heteroaryl. More preferably, the alkyl group is unsubstituted or is substituted with a halogen, OR 16 , N.R. 16 R 17 , optionally substituted phenyl, optionally substituted C 3~6 R is substituted with one or more of cycloalkyl, optionally substituted 3- to 6-membered heterocycle, or optionally substituted 5- or 6-membered heteroaryl. 16 and R 17 is preferably H or C 1~3 Most preferably, the alkyl group is unsubstituted or substituted with one or more of F, OH, N(CH), N(CHCH), an optionally substituted 5- or 6-membered heterocycle, an optionally substituted 5- or 6-membered heteroaryl, or an optionally substituted phenyl. 8 or R 9is an optionally substituted cycloalkyl, an optionally substituted heterocycle, or an optionally substituted heteroaryl, or an alkyl group is substituted with 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 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 , S.R. 16 , SOR 16 , SO2R 16 , C.O.R. 16 , COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 , N.R. 16 R 17 , optionally substituted C 6~12 Aryl, optionally substituted C 3~6 It may be substituted with one or more of 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 is unsubstituted or 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 CH, OCH, and / or oxo. R 8 or R 9is an optionally substituted aryl, or when the alkyl group is substituted with an optionally substituted aryl, the optionally substituted aryl may be unsubstituted or optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, CN, OR 16 , S.R. 16 , SOR 16 , SO2R 16 , C.O.R. 16 , COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 , N.R. 16 R 17 , optionally substituted C 6~12 Aryl, optionally substituted C 3~6 Optionally substituted with one or more of cycloalkyl, optionally substituted 3- to 6-membered heterocycle, or optionally substituted 5- to 10-membered heteroaryl. Most preferably, the optionally substituted aryl is unsubstituted or 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 with one or more of CH3 and / or OCH3. Phenyl or a 5- or 6-membered heteroaryl group Z is CH3, CH2CF3, CF3, [ka] may be substituted with one or more substituents selected from the group consisting of:

[0083] In a preferred embodiment, the heterocyclyl or heteroaryl that 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, the heterocyclyl or heteroaryl that 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.

[0084] The heterocyclyl or heteroaryl group, which is optionally a substituent on the Z group, which may be A in the above formula, may be unsubstituted or optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, oxo, CN, OR 16 , S.R. 16 , SOR 16 , SO2R 16 , C.O.R. 16 , COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 , N.R. 16 R 17 , optionally substituted C 6~12 Aryl, optionally substituted C 3~6 The optionally substituted heterocyclyl or optionally substituted heteroaryl may be unsubstituted or may be substituted with one or more of an optionally substituted C1-C3 alkyl, halogen, oxo, C0R, C1-C3 alkyl, or C1-C3 alkyl. 16 , COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 or NR 16 R 17or pairs of non-adjacent substituents of the 3- to 8-membered heterocyclyl may combine to form a bridging group. Even more preferably, the heterocyclyl or heteroaryl group that is a substituent on the Z group, which may optionally be A in the above formula, may be unsubstituted or may be optionally substituted with one or more of C1-C3 alkyl, fluorine, COR 16 or CONR 16 R 17 or pairs of non-adjacent substituents on the 3- to 8-membered heterocyclyl may combine to form a bridging group. The alkyl may be unsubstituted or may be substituted with one or more of halogen, OR 16 or NR 16 R 17 R 16 and R 17 may be as defined above. In some embodiments, R 16 and R 17 is H, optionally substituted C1-C3 alkyl, optionally substituted C 3~6 cycloalkyl, optionally substituted 3- to 6-membered heterocycle, or optionally substituted 5- to 10-membered heteroaryl. 16 and R 17 are each 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.

[0085] n can be 1 or 2. In some embodiments, n is 1.

[0086] In some embodiments, T is N and M is NR 13 In some embodiments, T is CR 18 and M is NR 13 is.

[0087] R 13 is H, optionally substituted C1-C6 alkyl, C3~6 Cycloalkyl, COR 19 or CONR 19 R 20 R 19 and R 20 are each independently H, optionally substituted C 1~3 It may be alkyl or an optionally substituted 5- or 6-membered heterocyclyl. More preferably, R 19 and R 20 each independently represents H, optionally substituted C 1~3 Alkyl or an optionally halogenated 5- or 6-membered heterocyclyl. Alkyl may be unsubstituted or may be substituted with halogen, oxo, CN, OR 16 or NR 16 R 17 R 16 and R 17 may be as defined above.

[0088] Preferably, R 16 and R 17 is H or CH3. R 13 are CH3, CH2CH3, [ka] , CH2CH2OH, CH2CH2OCH3, [ka] may be.

[0089] In some embodiments, T is N and M is CR 14 R 15 is.

[0090] R 14 and R 15 is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C3-C6 cycloalkyl, OR 19 - and -NR 19 R20 or R 14 and R 15 may be joined together with the C atoms to which they are both attached to form an optionally substituted 3- to 6-membered heterocyclyl. More preferably, R 14 and R 15 is hydrogen, halogen, optionally substituted C1-C3 alkyl and NR 19 R 20 or R 14 and R 15 may be linked together with the C atoms to which they are both attached to form an optionally substituted 3- to 6-membered heterocyclyl. 19 and R 20 are each independently H or optionally substituted C 1~3 It may be alkyl. Preferably, R 19 and R 20 are H. R 14 and R 15 may each independently be H, F, NH, or R 14 and R 15 may be joined together with the C atom to which they are both attached to form a 5-membered heterocyclyl.

[0091] In some embodiments, T is N and M is O or SO2.

[0092] Preferably, R 18 is hydrogen.

[0093] Preferably, R 12 is, at each occurrence, independently H, halogen, or optionally substituted C 1~3 alkyl and / or two R attached to the same carbon atom 12 groups define an oxo group and / or two R 12 More preferably, R 12is H or CH3 at each occurrence, and / or two R 12 groups define an oxo group and / or two R 12 The groups are linked to form a bicyclic bridged group.

[0094] Exemplary bridging groups have the formula: [ka] It has.

[0095] The group A or heterocyclyl or heteroaryl group may be the only substituent on the phenyl or pyridyl group Z, or one or more further substituents may be present. When present, the one or more further substituents may be selected from halogen, Ak, -OH, -OAk, -NH2, -NHAk, NAk2, optionally substituted heteroaryl, and optionally substituted heterocyclyl, where Ak at each occurrence is independently C 1~6 Alkyl group or C 3~6 The one or more further substituents are preferably halogen, more preferably F.

[0096] A phenyl or 5- or 6-membered heteroaryl group may not contain any further substituents. Thus, each R 21 may be H.

[0097] Alternatively, the phenyl or 5- or 6-membered heteroaryl group may be 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 , S.R. 8 , SOR 8 , SO2R 8 , SO2NR 8 R 9 , C.O.R. 8 , COOR 8 ,CONR 8 R 9 , N.R.8 COR 9 , N.R. 8 SO2R 9 , N.R. 8 R 9 , optionally substituted 3- to 6-membered heterocyclyl, or optionally substituted 5- or 6-membered heteroaryl. These substituents may be substituted by one or more R 21 It can be understood that the further R in the above formula may be a group. 21 The group may be H. Thus, each R 21 may be H or a substituent as defined below. A phenyl or 5- or 6-membered heteroaryl group may be 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 , S.R. 8 , SOR 8 , SO2R 8 , SO2NR 8 R 9 , C.O.R. 8 , COOR 8 ,CONR 8 R 9 , N.R. 8 COR 9 , N.R. 8 SO2R 9 and NR 8 R 9 R may be further optionally substituted with one or more substituents selected from the group consisting of 8 and R 9 may independently be 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 the phenyl or 5- or 6-membered heteroaryl group is further substituted with optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, the alkyl, alkenyl, or alkynyl may be unsubstituted or may be substituted with halogen, oxo, CN, OR 16 , S.R. 16 , SOR 16 , SO2R 16 , C.O.R. 16 , COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 and NR 16 R 17 More preferably, the alkyl, alkenyl or alkynyl is unsubstituted or substituted with fluorine, OR 16 and NR 16 R 17 It is replaced by R 16 and R 17 may be as defined above. Preferably, R 16 and R 17 may independently be 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 group Z is 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 3~6In some embodiments, the phenyl or 5- or 6-membered heteroaryl group 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 group may not contain any further substituents. Alternatively, the phenyl or 5- or 6-membered heteroaryl group may be substituted with halogen, optionally substituted C1-C3 alkyl, CN, OR 8 , COOR 8 ,CONR 8 R 9 , N.R. 8 R 9 or 5- or 6-membered heteroaryl. The phenyl or 5- or 6-membered heteroaryl group may be further optionally substituted with a halogen. In some embodiments, the phenyl or 5- or 6-membered heteroaryl group Z is substituted with an optionally substituted 5- to 7-membered heterocyclyl, an optionally substituted 5- or 6-membered heteroaryl, phenyl, or cyclohexyl. In some embodiments, the phenyl or 5- or 6-membered heteroaryl group Z is substituted with an optionally substituted 5- to 7-membered heterocyclyl or an optionally substituted 5- or 6-membered heteroaryl. The phenyl or 5- or 6-membered heteroaryl group may not contain any further substituents. Alternatively, the phenyl or 5- or 6-membered heteroaryl group may be further optionally substituted with a halogen. The halogen may be fluorine. In some embodiments, the phenyl or 5- or 6-membered heteroaryl group Z is substituted with an optionally substituted heterocyclyl or an optionally substituted heteroaryl and is selected from the group consisting 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 [ka] Thus, each R 21 are independently 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 [ka] may be.

[0098] In some embodiments, the phenyl or 5- or 6-membered heteroaryl group Z is further substituted with halogen, preferably fluorine.

[0099] Z is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] may be.

[0100] It will be appreciated that the compounds described above may exist as enantiomeric and diastereomeric pairs, which are also further embodiments of the present invention.

[0101] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC).

[0102] Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, if the compound of formula (I) contains an acidic or basic moiety, with 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 diastereoisomers can be converted into the corresponding pure enantiomer(s) by means well known to those skilled in the art.

[0103] The chiral compounds of the invention (and their chiral precursors) may be obtained in enantiomerically enriched form by chromatography, typically HPLC, on an asymmetric resin using a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0-50% by volume, typically 2%-20% isopropanol, and 0-5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate provides an enriched mixture.

[0104] Mixtures of stereoisomers can be separated by conventional techniques known to those skilled in the art, see, for example, "Stereochemistry of Organic Compounds" by EL Eliel and SH Wilen (Wiley, New York, 1994).

[0105] It will be understood that the compounds described herein, or pharmaceutically acceptable salts, solvates, tautomers or polymorphs thereof, may be used in medicines which may be used in monotherapy (i.e., use of the compound alone) to inhibit HPK-1 protein and / or to treat, ameliorate or prevent disease.

[0106] Alternatively, the compounds or pharmaceutically acceptable salts, solvates, tautomers or polymorphs thereof may be used as an adjunct to or in combination with known therapies to inhibit HPK-1 protein and / or to treat, ameliorate or prevent disease.

[0107] Thus, in one embodiment, a second therapeutic agent may be administered with the compound of Formula (I). The compound of Formula (I) may be administered before, after, and / or together with the second therapeutic agent. The second therapeutic agent may comprise an antiviral agent, an anti-inflammatory agent, conventional chemotherapy, an anti-cancer vaccine and / or hormonal therapy, or an anti-proliferative compound. Alternatively or additionally, the second therapeutic agent may comprise 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), a PD-L1 inhibitor (such as durvalumab, avelumab, and atezolidinib). The therapeutic agent may include an anti-cancer agent such as ribozyme, ribozyme inhibitor, ribozyme agonist ...Antiproliferative compounds include aromatase inhibitors (formestane, anastrozole), antiestrogens (tamoxifen, raloxifene, fulvestrant), topoisomerase inhibitors (camptothecin, irinotecan, doxorubicin, mitoxantrone, etoposide, epirubicin), and microtubule-active compounds (paclitaxel). Docetaxel, vinblastine, vincristine, discodermolide, colchicine, epothilone), alkylating agents (ifosfamide, cyclophosphamide), histone deacetylase inhibitors (SAHA), anti-cancer metabolites (5-fluorouracil, gemcitabine, 5-azacytidine, methotrexate, pemetrexed), cyclooxygenase inhibitors (celecoxib, rofecoxib, valdecoxib), MMP inhibitors, mTOR inhibitors (sirolimus), platin compounds (cisplatin, oxaliplatin), kinase inhibitors (imatinib, sunitinib, nilotinib, dasatinib, Herceptin, Irene), These include, but are not limited to, vasodilators (e.g., cyclosporine, cyclosporine, cyclosporine), steroids (e.g. ...Additionally, the second therapy can be adefovir, tenofovir disoproxil fumarate plus emtricitabine (Truvada), tenofovir disoproxil fumarate (Viread), entecavir, lamivudine, tenofovir alafenamide, telbivudine, clevudine, emtricitabine, pegylated interferon alfa 2b, multiferon, interferon alfa 1b, interferon alfa 2b, pegylated interferon alfa 2a, interferon alfa n1, ribavirin, interferon beta 1a, bioferon, interferon alfa 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 These may include 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.

[0108] Methods for co-administration with additional therapeutic agents 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 and Wilkins, Philadelphia, PA; Chabner and Longo (eds.), Cancer Chemotherapy and Biotherapy, 2001, Lippincott, Williams and Wilkins, Philadelphia, PA).

[0109] In one embodiment, the disease is cancer and a chemotherapeutic agent may be administered with the compound of Formula (I). The chemotherapeutic agent may further be selected from the group consisting of cancer vaccines, targeted drugs, targeted antibodies, antibody fragments, antimetabolites, anti-neoplastic agents, antifolates, toxins, alkylating agents, DNA strand breakers, DNA minor groove binders, pyrimidine analogs, ribonucleotide reductase inhibitors, tubulin interacting agents, antihormones, immunomodulators, anti-adrenal agents, cytokines, radiation therapy, cell therapy, cell ablative therapy such as B cell ablative therapy, and hormone therapy. Alternatively or additionally, the chemotherapeutic agent may include abiraterone, altretamine, anhydrovinblastine, auristatin, bexarotene, bicalutamide, bleomycin, cachectin, cemadotin, chlorambucil, cyclophosphamide, docetaxol, doxetaxel, carboplatin, cysplatin, cytarabine, dactinomycin, daunorubicin, decitabine, doxorubicin, etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea, streptozocin, mitomycin, methotrexate, taxanes, tamoxifen, vinblastine, vincristine, and / or vindesine.

[0110] Complexes of compounds of Formula (I) can be understood to be multicomponent complexes in which the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes may be other than salts or solvates. Complexes of this type include clathrates (drug-host inclusion complexes) and cocrystals. The latter are typically defined as crystalline complexes of neutral molecular components bound to each other through non-covalent interactions, but they can also be complexes of neutral molecules with salts. Cocrystals may be prepared by melt crystallization, by recrystallization from solvents, or by physically grinding the components together—see O. Almarsson and MJ Zaworotko (2004), Chem Commun, 17, 1889-1896, incorporated herein by reference. For a general review of multicomponent complexes, see Haleblian (August 1975), J Pharm Sci, 64(8), 1269-1288, incorporated herein by reference.

[0111] The term "pharmaceutically acceptable salt" may be understood to refer to any salt of a compound described herein that retains its biological properties and is not toxic or otherwise undesirable for pharmaceutical use. Such salts may be derived from a variety of organic and inorganic counterions well known in the art.Such salts include, but are not limited to, (1) 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, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, and methanesulfonic acid. Sulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexyl sulfuric acid or (2) base addition salts formed when an acidic proton present in the parent compound is coordinated by (a) a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or an alkali metal or alkaline earth metal hydroxide, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, lithium hydroxide, zinc hydroxide, and barium hydroxide, ammonia, or (b) 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'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like.

[0112] Pharmaceutically acceptable salts include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, as well as, when the compound contains a basic functional group, hydrohalides, e.g., hydrochlorides, hydrobromides, and hydroiodides, carbonates or bicarbonates, sulfates or bisulfates, borates, phosphates, hydrogen phosphates, dihydrogen phosphates, pyroglutamate, saccharates, stearates, sulfamate, nitrates, orotates, oxalates, palmitates, pamoates, and the like. , acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, tannate, tartrate, tosylate, sorbate, ascorbate, malate, maleate, fumarate, tartrate, camsylate, citrate, cyclamate, benzoate, isethionate, esylate, formate, 3-(4-hydroxybenzoyl)benzoate, Picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), methylsulfate, naphthylate, 2-napsylate, nicotinate, ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2. The salts may include salts of non-toxic organic or inorganic acids such as 2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethyl acetate, tert-butyl acetate, lauryl sulfate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate, and xinafoate.

[0113] Hemisalts of acids and bases may also be made, such as hemisulfate salts. Those skilled in the art will recognize that such salts include those wherein the counterion is optically active, such as D-lactate, or racemic, such as DL-tartrate.

[0114] For a review of suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, Weinheim, Germany, 2002).

[0115] Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of the following three methods: (i) by reacting a compound of formula (I) with a desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound of formula (I) using a desired acid or base; or (iii) By converting one salt of a compound of formula (I) to another by reaction with an appropriate acid or base or by suitable ion exchange columns.

[0116] All three reactions are typically carried out in solution. The resulting salts can precipitate and be collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization in the resulting salts can vary from completely ionized to nearly non-ionized.

[0117] The term "solvate" can be understood to refer to a compound described herein or a salt thereof, further comprising a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When 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, for example, DO, d6-acetone, and d6-DMSO.

[0118] A currently accepted classification system for organic hydrates defines isolated site, channel, or metal ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by KR Morris (HG Brittain, ed., Marcel Dekker, 1995), incorporated herein by reference. Isolated site hydrates are hydrates in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules are in lattice channels where they are next to other water molecules. In metal ion coordinated hydrates, the water molecules are bound to the metal ion.

[0119] 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 such cases, non-stoichiometry will become the norm.

[0120] The compounds of the present invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline, including polymorphs of said crystalline materials. The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and, depending on temperature, may exhibit the physical properties of either a solid or a liquid. Typically, such materials do not give rise to distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as liquids. Upon heating, a transition from solid to liquid properties occurs, characterized by a change of state, typically second-order ("glass transition"). The term "crystalline" refers to a solid phase in which the material has an ordered internal structure at the molecular level and gives rise to a distinctive X-ray diffraction pattern with distinct peaks. When heated sufficiently, such materials will also exhibit the properties of a liquid, but the transition from solid to liquid is characterized by a phase change, typically first-order ("melting point").

[0121] The compounds of the present invention may exist in a mesomorphic state (mesophase or liquid crystal) when exposed to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Liquid crystallinity resulting from a change in temperature is described as "thermotropic," and liquid crystallinity resulting from the addition of a second component, such as water or another solvent, is described as "lyotropic." Compounds with the potential to form lyotropic mesophases are described as "amphiphilic," and those with ionic (-COO) - Na + , -COO - K + , or -SO3 - Na + etc.) or non-ionic (-N - N + They consist of molecules with polar head groups (e.g., (CH3)3). For further information, see Crystals and the Polarizing Microscope, 4th Edition, by N.H. Hartshorne and A. Stuart (Edward Arnold, 1970), which is incorporated herein by reference.

[0122] The compound of formula (I) can be combined in a composition that has several different forms, depending particularly on the method that the composition is to be used.Thus, for example, the composition can be in the form of powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, micelle solution, transdermal patch, liposome suspension, or any other suitable form that can be administered to humans or animals that need treatment.It will be understood that the pharmaceutical vehicle according to the present invention should be well tolerated by the subject that it is given to.

[0123] Medicaments containing the compounds described herein may be used in several ways. Suitable modes of administration include oral, intratumoral, parenteral, topical, inhalation / intranasal, rectal / intravaginal, and ocular / aural administration.

[0124] Formulations suitable for the aforementioned modes of administration may be formulated for immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release.

[0125] The compounds of the present invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be used, so that the compound enters the bloodstream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing microparticles, liquids, or powders, lozenges (including liquid-filled lozenges), chewable tablets, multi- and nanoparticulates, gels, solid solutions, liposomes, films, ovules, sprays, liquid formulations, and buccal / mucoadhesive patches.

[0126] Liquid formulations include suspensions, solutions, syrups and elixirs. These formulations may be used as fillers for 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 emulsifying agents and / or suspending agents. Liquid formulations can also be prepared by the reconstitution of a solid, for example, from a sachet.

[0127] The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described by Liang and Chen (2001) in Expert Opinion in Therapeutic Patents, 11(6), 981-986.

[0128] For tablet dosage forms, depending on the dosage, the drug may comprise 1% to 80% by weight of the dosage form, more typically 5% to 60% by weight of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant will comprise 1% to 25% by weight of the dosage form, preferably 5% to 20% by weight.

[0129] Binders are commonly used to impart cohesion to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Tablets can also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dicalcium phosphate dihydrate.

[0130] Tablets may also optionally include surfactants such as sodium lauryl sulfate and polysorbate 80, and lubricants such as silicon dioxide and talc. When present, surfactants may comprise from 0.2% to 5% by weight of the tablet, and lubricants may comprise from 0.2% to 1% by weight of the tablet.

[0131] Tablets also typically contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants generally comprise 0.25% to 10% by weight of the tablet, preferably 0.5% to 3%. Other possible ingredients include antioxidants, colorants, flavorings, preservatives, and taste-masking agents.

[0132] 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 to form tablets. Tablet blends, or portions of blends, may alternatively be wet-granulated, dry-granulated, or melt-granulated, melt-congealed, or extruded prior to tableting. The final formulation may comprise one or more layers, may be coated or uncoated, or may even be encapsulated. Tablet formulations are discussed in "Pharmaceutical Dosage Forms: Tablets," Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

[0133] Modified release formulations suitable for 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. (2001) Pharmaceutical Technology Online, 25(2), 1-14. The use of chewing gum to achieve controlled release is described in WO 00 / 35298.

[0134] The compounds of the present invention may be administered directly into the bloodstream, into muscles, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

[0135] Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of 3 to 9), although for some applications parenteral formulations may be more suitably formulated as sterile non-aqueous solutions or as a dry form to be used in conjunction with a suitable vehicle such as sterile pyrogen-free water.

[0136] The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well-known to those skilled in the art.

[0137] The solubility of the compounds of formula (I) used in the preparation of parenteral solutions can be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents. Formulations for parenteral administration may be formulated for immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release. Thus, the compounds of the present invention may be formulated as solid, semisolid, or thixotropic liquids for administration as implanted depots that provide modified release of the active compound. Examples of such formulations include drug-coated stents and poly(dl-lactic-coglycolic) acid (PGLA) microspheres.

[0138] The compounds of the present invention may be administered topically to the skin or mucosa, i.e., dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be incorporated—see, for example, J Pharm Sci, 88(10), 955-958, by Finnin and Morgan (October 1999).

[0139] Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (eg Powderject™, Bioject™, etc.) injection.

[0140] The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder from a dry powder inhaler (alone, in admixtures, e.g., with lactose in a dry blend, or as mixed-component particles, e.g., mixed with a phospholipid such as phosphatidylcholine), or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably one that uses electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of 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 include a bioadhesive agent, e.g., chitosan or cyclodextrin.

[0141] The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound(s) of the invention, for example, in ethanol, aqueous ethanol, or an alternative agent suitable for dispersing, solubilizing, or extending the release of the active agent, propellant(s) as a solvent, and an optional surfactant, such as sorbitan trioleate, oleic acid, or oligolactic acid.

[0142] Prior to use in a dry powder or suspension formulation, 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 comminuting method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to produce nanoparticles, high pressure homogenization, or spray drying.

[0143] Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters, and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the invention, a suitable powder base such as lactose or starch, and a performance modifier such as L-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0144] Solution formulations suitable for use in atomizers that use electrohydrodynamics to generate a fine mist may contain 1 μg to 20 mg of a compound of the invention per actuation, and actuation volumes may vary from 1 μl to 100 μl. A typical formulation may include a compound of formula (I), propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that may be used in place of propylene glycol include glycerol and polyethylene glycol.

[0145] Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled / intranasal administration.

[0146] In the case of dry powder inhalers and aerosols, the dosage unit is determined by a valve which delivers a metered amount. Units according to the invention are typically arranged to administer a metered dose or "puff" containing 1 μg to 100 mg of a compound of formula (I). The total daily dose will typically be in the range of 1 μg to 200 mg, which may be administered in a single dose or, more commonly, as divided doses throughout the day.

[0147] The compounds of the invention may also 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.

[0148] The compounds of the present invention may be administered directly to the eye or ear, typically in the form of droplets of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g., absorbent gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, wafers, lenses, and microparticulate or vesicular systems such as niosomes or liposomes. Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose-based polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers such as gellan gum, may also be incorporated, along with preservatives such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

[0149] The compounds of the present invention may 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 may be administered via intratumoral injection. A typical injection solution consists of propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that may be used instead of propylene glycol include glycerol and polyethylene glycol.

[0150] The compounds of the present invention may be combined with soluble macromolecular entities such as cyclodextrins and suitable derivatives thereof or polyethylene glycol-containing polymers to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability for use in any of the aforementioned modes of administration.

[0151] Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, cyclodextrins may be used as auxiliary additives, i.e., as carriers, diluents, or solubilizers. The most commonly used for these purposes are alpha-, beta-, and gamma-cyclodextrins, examples of which can be found in International Patent Application Nos. WO 91 / 11172, WO 94 / 02518, and WO 98 / 55148.

[0152] It will be understood that the amount of compound required is determined by the biological activity and bioavailability of the compound, which in turn depends on the mode of administration, the physicochemical properties of the compound, and whether the compound is used as a monotherapy or in a combination therapy. The frequency of administration will also be affected by the half-life of the compound in the subject being treated. The optimal dosage to be administered can be determined by one skilled in the art and will vary depending on the specific compound being used, the strength of the pharmaceutical composition, the mode of administration, and the progression of the disease. Additional factors depending on the specific subject being treated, including the subject's age, weight, sex, diet, and time of administration, will result in the need to adjust the dosage. In this regard, the amount of compound in the composition of the present invention is sufficient to measurably inhibit HPK-1 or a mutant thereof in a biological sample or patient.

[0153] Generally, for administration to humans, the total daily dose of the compounds of the present invention is typically in the range of 1 mg to 1 g, e.g., 100 μg to 10 g, such as 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 single or divided doses and, at the physician's discretion, may fall outside the typical ranges described herein. These dosages are based on an average human subject weighing approximately 60 kg to 70 kg. A physician will be able to readily determine dosages for subjects whose weight falls outside this range, such as infants and the elderly.

[0154] However, it is understood by those skilled in the art that for agents that modulate the immune system, both the dosage and frequency of administration may differ from those of more conventional therapies. In particular, for agents that stimulate the immune system, for example, through modulation of HPK-1, the agent may be administered in small doses very infrequently, for example, twice a week, weekly, or monthly. Smaller doses may also be effective when administered topically to small areas of the skin.

[0155] The compounds may be administered before, during or after the onset of the disease to be treated.

[0156] Known procedures, such as those conventionally used by the pharmaceutical industry (e.g., in vivo experiments, clinical trials, etc.), can be used to generate specific formulations containing the compounds according to the invention and to formulate precise treatment regimens (such as the daily dose and frequency of administration of the compounds).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.

[0157] Thus, in a tenth aspect of the present invention, there is provided a pharmaceutical composition comprising a compound according to the first aspect, or a pharmaceutically acceptable salt, solvate, tautomer or polymorph thereof, and a pharmaceutically acceptable vehicle.

[0158] The present invention also provides, in an eleventh aspect, a process for producing a composition according to the tenth aspect, comprising contacting a therapeutically effective amount of a compound of the first aspect, or a pharmaceutically acceptable salt, solvate, tautomer or polymorph thereof, with a pharmaceutically acceptable vehicle.

[0159] A "subject" may be a vertebrate, a mammal, or a domestic animal. Thus, the compounds, compositions, and medicaments according to the present invention may be used to treat any mammal, such as livestock (e.g., horses), pets, or in other veterinary applications. Most preferably, however, the subject is a human.

[0160] A "therapeutically effective amount" of a compound is any amount that, when administered to a subject, is the amount of drug needed to treat a target disease or produce a desired effect, i.e., modulate HPK-1 protein.

[0161] For example, the therapeutically effective amount of the compound used may be about 0.01 mg to about 800 mg, preferably about 0.01 mg to about 500 mg. It is preferred that the amount of the compound is about 0.1 mg to about 250 mg, most preferably about 0.1 mg to about 20 mg.

[0162] A "pharmaceutically acceptable vehicle" as referred to herein is any known compound or combination of known compounds known to those skilled in the art to be useful in formulating pharmaceutical compositions.

[0163] In one embodiment, the pharmaceutically acceptable vehicle may be solid, and the composition may be in the form of a powder or tablet. A solid pharmaceutically acceptable vehicle may contain one or more substances that may also act as flavoring agents, lubricants, solubilizers, suspending agents, pigments, fillers, glidants, compression aids, inert binders, sweeteners, preservatives, pigments, coatings, or tablet disintegrants. The vehicle may also be an encapsulating material. In powders, the vehicle is a finely divided solid mixed with the finely divided active agent of the present invention (i.e., a compound according to the first, second, third, or sixth aspect). In tablets, the active compound may be mixed in suitable proportions with a vehicle having the necessary compression properties and compressed into the desired shape and size. Powders and tablets preferably contain up to 99% of the active compound. Suitable solid vehicles include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting point waxes, and ion exchange resins, hi another embodiment, the pharmaceutical vehicle may be a gel and the composition may be in the form of a cream or the like.

[0164] However, the pharmaceutical vehicle may also be liquid, and the pharmaceutical composition may be in the form of a solution. Liquid vehicles are used in the preparation of solutions, suspensions, emulsions, syrups, elixirs, and pressurized compositions. The compounds according to the present invention may be dissolved or suspended in a pharmaceutically acceptable liquid vehicle, such as water, an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat. The liquid vehicle may contain other suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, colorants, viscosity adjusters, stabilizers, or osmolality adjusters. Suitable examples of liquid vehicles for oral and parenteral administration include water (water partially containing additives such as those described above, e.g., cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and peanut oil). For parenteral administration, the vehicle may also be an oily ester, such as ethyl oleate and isopropyl myristate. Sterile liquid vehicles are useful in sterile liquid form compositions for parenteral administration. The liquid vehicle for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.

[0165] Liquid pharmaceutical compositions that are sterile solutions or suspensions can be utilized by injection, for example, intramuscular, intrathecal, epidural, intraperitoneal, intravenous, and especially subcutaneous injection. The compounds may also be prepared as sterile solid compositions that can be dissolved or suspended at the time of administration using sterile water, physiological saline, or other appropriate sterile injectable medium.

[0166] The compounds and compositions of the present invention may be administered in the form of a sterile solution or suspension containing other solutes or suspending agents (e.g., sufficient saline or glucose to make the solution isotonic), bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleic acid ester of sorbitol and its anhydrides, copolymerized with ethylene oxide), and the like. Compounds used in accordance with the present invention can also be administered orally in either liquid or solid composition form. Compositions suitable for oral administration include solid forms such as pills, capsules, granules, tablets, and powders, and liquid forms such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.

[0167] Also included within the scope of the present invention are soft drugs or prodrugs, which are compounds of formula (I) containing metabolically or hydrolytically unstable moieties that are converted in vivo to inactive derivatives. Processes by which active drug substances are converted to 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.

[0168] Those skilled in the art will recognize that active drug substances may be converted into prodrugs, which are metabolically unstable derivatives that are converted to active drug substances in the body. Also included within the scope of the present invention are prodrugs, which are compounds of formula (I) containing metabolically or hydrolytically unstable moieties that are converted to active drugs of formula (I) in vivo. Processes by which prodrugs are converted to active drug substances include, but are not limited to, ester hydrolysis, phosphate ester 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. Accordingly, the prodrug moieties may include 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 enable the drug substance to be administered by an alternative route of administration, for example as an intravenous solution.

[0169] The compounds included herein can also be used as active components of proteolysis-targeting chimeric molecules (PROTACs). Inspired by the normal use of the ubiquitin-proteasome system (UPS) by cells to maintain intracellular homeostasis, PROTACs utilize the endogenous ubiquitination machinery to recognize and degrade proteins tagged with a ligand that has affinity for that protein. PROTAC molecules are bifunctional and consist of three main components: a protein targeting moiety (PTM), a linker (L), and a moiety that targets and recruits the E3 ubiquitinylation ligase complex (ULM) to degrade the target protein. It will be understood that the compounds of the present invention may also be used as the PTM component.

[0170] Thus, according to a further aspect, there is provided a PROTAC of formula (II) or a pharmaceutically acceptable salt, solvate, tautomer or polymorph thereof. PTM-L-ULM (II) wherein PTM is a protein targeting moiety and is a compound of formula (I): L is a linker, ULM is an E3 ubiquitinylation ligase complex. Suitable linkers and E3 ubiquitinylation ligase complexes are known in the art.

[0171] The compound of formula (I) may be attached to a linker through the group Z. Thus, the group Z may be as defined above except that a hydrogen atom has been removed from the group Z, making the group divalent.

[0172] Thus, the PROTAC of formula (II) preferably has the formula (IIa): [ka] It is a PROTAC.

[0173] The scope of the present invention includes all pharmaceutically acceptable isotopically labeled compounds of the present invention in which 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 predominant in nature.

[0174] Examples of isotopes suitable for inclusion in compounds of the present invention include: 2 H and 3 Hydrogen such as H 11 C. 13 C and 14 Carbon, such as C 36 chlorine such as Cl, 18 Fluorine such as F, 123 I and 125 Iodine, such as I 13 N and 15 Nitrogen such as N 15 O. 17 O and 18 Oxygen, such as O 32 Phosphorus such as P, 35 Contains sulfur isotopes such as S.

[0175] Certain isotopically labeled compounds of the present invention, for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. 3 H, and carbon-14, i.e. 14 C are particularly useful for this purpose given their ease of incorporation and rapid means of detection. 2 Substitution with isotopes such as H may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferable in certain situations. 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0176] 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 Preparations, using appropriate isotopically labeled reagents in place of conventionally used non-labeled reagents. According to a further embodiment, the compound of formula (I): [ka] [In the formula, Y is a formula (a) to (h): [ka] is selected from X is N or CH; X 1 is N or CR 1 and X 2 is N or CR 2 and X 3 is N or CR 3 and X 4 is N or CR 4 and L is O, S, NR 6 or CR 6 R 7 and Z is phenyl or 5- or 6-membered heteroaryl, where phenyl or heteroaryl is selected from halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, CN, OR 8 , S.R. 8 , SOR 8 , SO2R 8 , SO2NR 8 R 9 , C.O.R. 8 , COOR 8 ,CONR 8 R 9 , N.R. 8 COR 9 , N.R. 8 SO2R 9 , N.R. 8 R 9 , optionally substituted 3- to 10-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl; and / or wherein adjacent substituents of phenyl or heteroaryl, together with the atoms to which they are attached, may form an optionally substituted 3- to 6-membered heterocycle or an optionally substituted 5- or 6-membered heteroaryl; R 1 ~R 7 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, CN, OR 10 , S.R. 8 , SOR 8 , SO2R 8 , SO2NR 8 R 9 , C.O.R. 10 , COOR 8 ,CONR 10 R 11 , N.R. 10 COR11 , N.R. 10 SO2R 11 , N.R. 10 R 11 , optionally substituted C3-C6 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl or optionally substituted phenyl, and / or adjacent R 1 ~R 7 one or more pairs of groups together with the atom to which they are attached 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, and / or R on the same C atom 1 ~R 5 Pairs of groups and / or R 6 and R 7 together with the C atom to which they are attached to form a C=O group, 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 3-8 membered heterocyclyl, and optionally substituted 5-10 membered heteroaryl; 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 3-8 membered heterocyclyl, and optionally substituted 5-10 membered heteroaryl; b is 0, 1, 2, 3 or 4. or a pharmaceutically acceptable complex, salt, solvate, tautomer or polymorph thereof, is provided, However, the compound is [ka] [ka] [ka] isn't it.

[0177] Preferred fused groups Y include the following groups: For simplicity, each of these groups is exemplified without substituents, but where applicable, each ring of these fused groups may independently be unsubstituted or may be substituted with R 1 ~R 7 It will be understood that the group may be substituted with one or more substituents independently selected from the non-H groups of: [ka] [ka] [ka]

[0178] The bicyclic group Y is preferably unsubstituted or contains one or more substituents R 1 , preferably a group of the following formula, optionally substituted with OH: [ka]

[0179] Preferred substituents for groups of formulae (a) to (h) are: 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 1~6Perfluoroalkyl, C 1~6 perfluoroalkoxy; CN; -NHC(=O)Ak; -NHC(=O)Ar; -NHSO2Ak; halogen, preferably F or Cl; optionally substituted phenyl; optionally substituted pyridyl; and unsubstituted or containing one or more substituents, such as one or more C 1~6 heterocyclic groups of N and C ring atoms substituted with alkyl groups, e.g., pyrrolidinyl, piperidinyl, or piperazinyl, wherein each occurrence of Ak is independently selected from C 1~6 Alkyl group or C 3~6 is a cycloalkyl group, and Ar is an aryl or heteroaryl group that is unsubstituted or substituted with one or more substituents.

[0180] Ar is preferably selected from phenyl and 5- or 6-membered heteroaryl, with ring atoms selected from C atoms, N atoms, and optionally O or S atoms. Ar may be unsubstituted or may contain one or more substituents, for example, C 1~6 Alkyl, C 1~6 It may be substituted with one or more groups selected from alkoxy, F, Cl, NO2 and CN.

[0181] As explained above, Y is selected from formulas (a) to (h).

[0182] R 1 ~R 7 are independently hydrogen, optionally substituted C1-C6 alkyl, halogen, CN, OR 10 , C.O.R. 10 , COOR 8 ,CONR 10 R 11 , N.R. 10 COR 11 , N.R. 10 SO2R 11 , N.R. 10 R 11, optionally substituted C3-C6 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl or optionally substituted phenyl, and / or adjacent R 1 ~R 7 One or more pairs of groups together with the atom to which they are attached may 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, and / or R on the same C atom 1 ~R 5 Pairs of groups and / or R 6 and R 7 may form a C=O group together with the C atom to which they are attached. 1 ~R 7 are independently hydrogen, optionally substituted C1-C3 alkyl, halogen, CN, OR 10 , C.O.R. 10 ,CONR 10 R 11 , N.R. 10 COR 11 , N.R. 10 SO2R 11 , N.R. 10 R 11 , optionally substituted C3-C6 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl or optionally substituted phenyl, and / or adjacent R 1 ~R 7 One or more pairs of groups together with the atom to which they are attached may 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, and / or R on the same C atom 1 ~R 5 Pairs of groups and / or R 6 and R 7 may form a C=O group together with the C atom to which they are attached. 8 and R9 may 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 may be unsubstituted or substituted with one or more of halogen, OH, or OCH3. The or each cycloalkyl, heterocyclyl, or heteroaryl may be unsubstituted or substituted with halogen, C 1~3 It may be substituted with one or more of alkyl, OH and oxo, more preferably the or each cycloalkyl, heterocyclyl or heteroaryl may be unsubstituted or substituted with Cl, CH or oxo.

[0183] R 1 ~R 7 are independently hydrogen, methyl, CF3, CH2OH, F, Cl, CN, OH, OCH3, OCF3, COCH3, CONH2, NHCOCH3, [ka] or phenyl, and / or adjacent R 1 ~R 7 one or more pairs of groups together with the atom to which they are attached 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, and / or R on the same C atom 1 ~R 5 Pairs of groups and / or R 6 and R 7 together with the C atom to which they are attached to form a C=O group.

[0184] In some embodiments, adjacent R 1~R 7 The pair of groups, together with the atoms to which they are attached, 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. More preferably, in some embodiments, adjacent R 1 ~R 5 The pair of groups, together with the atoms to which they are attached, form an optionally substituted 5- or 6-membered heterocycle, an optionally substituted 5- or 6-membered heteroaryl, or an optionally substituted phenyl. 1 ~R 5 The heterocycle, heteroaryl, cycloalkyl or phenyl formed by the pair of groups may be unsubstituted or 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 , S.R. 16 , SOR 16 , SO2R 16 , C.O.R. 16 , COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 or NR 16 R 17 may be substituted with one or more of:

[0185] R 16 and R 17 is 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 R may be independently selected from the group consisting of cycloalkyl, optionally substituted 3- to 6-membered heterocycle, or optionally substituted 5- to 10-membered heteroaryl. 16 and R 17R may each independently be selected from the group consisting of H, optionally halogenated C1-C6 alkyl, optionally halogenated C2-C6 alkenyl, or optionally halogenated C2-C6 alkynyl. 16 and R 17 may each independently be H or methyl. In some embodiments, R 16 and R 17 are both H.

[0186] More preferably, adjacent R 1 ~R 5 The heterocycle, heteroaryl, cycloalkyl or phenyl formed by the pair of groups may be unsubstituted or substituted with one or more of C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, halogen, oxo, OH and NH2. Most preferably, adjacent R 1 ~R 5 The heterocycle, heteroaryl, cycloalkyl or phenyl formed by the pair of groups may be unsubstituted or substituted with one or more of methyl, fluorine and oxo.

[0187] In some embodiments, Y has the formula (a). 1 is CR 1 and X 2 is CR 2 and X 3 is CR 3 and X 4 is CR 4 In some embodiments, X 1 is N and X 2 is CR 2 and X 3 is CR 3 and X 4 is CR 4 In some embodiments, X 1 is CR 1 and X 2 is N and X 3 is CR 3 and X4 is CR 4 In some embodiments, X 1 is CR 1 and X 2 is CR 2 and X 3 is N and X 4 is CR 4 In some embodiments, X 1 is CR 1 and X 2 is CR 2 and X 3 is CR 3 and X 4 is N. In some embodiments, X 1 is N and X 2 is N and X 3 is CR 3 and X 4 is CR 4 In some embodiments, X 1 is CR 1 and X 2 is N and X 3 is CR 3 and X 4 is N. Therefore, Y is [ka] X 1 is CR 1 and X 2 is CR 2 and X 3 is CR 3 and X 4 is CR 4 In the embodiment, preferably, adjacent R 1 ~R 5 One or more pairs of groups, together with the atoms to which they are attached, 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 is: [ka] In some embodiments, Y may be [ka] may be.

[0188] In some embodiments, Y has the formula (b): L is NR 6 X 1 is CR 1 X 2 is CR 2 X 4 is CR 4 Therefore, Y may be [ka] In embodiments where Y is a bicyclic group, Y may be [ka] In some embodiments, Y may be [ka] may be.

[0189] In some embodiments, Y has the formula (c): L is NR 6 Or it may be S. X 1 is CR 1 X may be 2 is CR 2 X may be 3 is CR 3 Alternatively, X 1 may be N, and X 2 is CR 2 X may be 3 is CR 3 Alternatively, X1 is CR 1 X may be 2 may be N, and X 3 is CR 3 Alternatively, X 1 is CR 1 X may be 2 is CR 2 X may be 3 may be N. Therefore, Y is [ka] In embodiments where Y is a bicyclic group, Y may be [ka] In some embodiments, Y may be [ka] may be.

[0190] In some embodiments, Y has the formula (d) or (e). L is O, NR 6 or CR 6 R 7 Therefore, Y may be [ka] In embodiments where Y is a bicyclic group, Y may be [ka] In some embodiments, Y may be [ka] In a preferred embodiment, Y is not cyclohexyl or 4-aminocyclohexyl.

[0191] In some embodiments, Y has the formula (f), (g), or (h). Thus, Y is: [ka] may be.

[0192] Z may be a substituted phenyl or substituted pyridinyl group.

[0193] In one preferred arrangement, adjacent substituents of a phenyl or 5- or 6-membered heteroaryl group Z are linked together with the C atoms of the phenyl or heteroaryl group to which they are attached to form a 5- or 6-membered heterocyclic or heteroaromatic group. In these embodiments, it will be understood that 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, without limitation, C 1~6 alkyl or F. More preferably, the optional substituent is CH or F.

[0194] In another preferred arrangement, the phenyl or 5- or 6-membered heteroaryl group Z is substituted with an optionally substituted 3- to 10-membered heterocyclyl or an optionally substituted 5- to 10-membered heteroaryl, and the phenyl or 5- or 6-membered heteroaryl group is optionally substituted with one or more substituents, such as halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, CN, OR 8 , S.R. 8 , SOR 8 , SO2R 8 , SO2NR 8 R 9 , C.O.R. 8 , COOR 8 ,CONR 8 R 9 , N.R. 8COR 9 , N.R. 8 SO2R 9 and NR 8 R 9 and optionally substituted with one or more substituents selected from the group consisting of: In some embodiments, the phenyl or 5- or 6-membered heteroaryl group Z is substituted with an optionally substituted 5- to 10-membered heterocyclyl or an optionally substituted 5- to 10-membered heteroaryl, and the phenyl or phenyl or 5- or 6-membered heteroaryl group may be further optionally substituted with a halogen. In some embodiments, the phenyl or 5- or 6-membered heteroaryl group Z is substituted with an optionally substituted 5- to 7-membered heterocyclyl or an optionally substituted 5- or 6-membered heteroaryl, and the phenyl or phenyl or 5- or 6-membered heteroaryl group may be further optionally substituted with a halogen. The halogen may be fluorine. The heterocyclyl or heteroaryl substituent on the Z group may be unsubstituted or 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 , S.R. 16 , SOR 16 , SO2R 16 , C.O.R. 16 , COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 or NR 16 R 17 and optionally substituted with one or more optional substituents which may be selected from the group consisting of: More preferably, the heterocyclyl or heteroaryl substituent on the Z group is unsubstituted or optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C 3~6 Cycloalkyl, halogen, oxo, COR16 , COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 or NR 16 R 17 The alkyl may be optionally substituted with one or more substituents selected from the group consisting of OR 16 and NR 16 R 17 may be substituted with R 16 and R 17 may be as defined above. In some embodiments, R 16 and R 17 may each independently be selected from the group consisting of H, C1-C3 alkyl, or an optionally halogenated 5- or 6-membered heterocycle.

[0195] Preferred groups Z are of the formula: [ka] [where, X 5 , X 6 , X 7 and X 8 is X 5 , X 6 , X 7 and X 8 N and CR on the condition that only one of 11 are independently selected from R 11 is independently at each occurrence H or halogen, preferably F; A is optionally substituted C1-C6 alkyl; COR 8 , COOR 8 ,CONR 8 R 9 , N.R. 8 COR 9 , N.R. 8 R 9 , optionally substituted 3- to 10-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl. 8 and R 9may independently be 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 3-8 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. More preferably, R 8 and R 9 are independently hydrogen, optionally substituted C1-C3 alkyl, or optionally substituted 5- or 6-membered heterocyclyl. Alkyl may be unsubstituted or may be substituted with halogen, OR 16 or NR 16 R 17 R 16 and R 17 may be as defined above. In some embodiments, R 16 and R 17 may independently be H or C1-C3 alkyl.

[0196] In a preferred embodiment, the heterocyclyl or heteroaryl that 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, the heterocyclyl or heteroaryl that 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.

[0197] The heterocyclyl or heteroaryl group, which is optionally a substituent on the Z group, which may be A in the above formula, may be unsubstituted or optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, oxo, CN, OR 16 , S.R. 16 , SOR 16 , SO2R 16 , C.O.R. 16 , COOR16 ,CONR 16 R 17 , N.R. 16 COR 17 , N.R. 16 R 17 , optionally substituted C 6~12 Aryl, optionally substituted C 3~6 The optionally substituted heterocyclyl or optionally substituted heteroaryl may be unsubstituted or may be substituted with one or more of an optionally substituted C1-C3 alkyl, halogen, oxo, C0R, C1-C3 alkyl, or C1-C3 alkyl. 16 , COOR 16 ,CONR 16 R 17 , N.R. 16 COR 17 or NR 16 R 17 or pairs of non-adjacent substituents of the 3- to 8-membered heterocyclyl may combine to form a bridging group. Even more preferably, the heterocyclyl or heteroaryl group that is a substituent on the Z group, which may optionally be A in the above formula, may be unsubstituted or may be optionally substituted with one or more of C1-C3 alkyl, fluorine, COR 16 or CONR 16 R 17 or pairs of non-adjacent substituents on the 3- to 8-membered heterocyclyl may combine to form a bridging group. The alkyl may be unsubstituted or may be substituted with one or more of halogen, OR 16 or NR 16 R 17 R 16 and R 17 may be as defined above. In some embodiments, R 16 and R 17is H, optionally substituted C1-C3 alkyl, optionally substituted C 3~6 cycloalkyl, optionally substituted 3- to 6-membered heterocycle, or optionally substituted 5- to 10-membered heteroaryl. 16 and R 17 are each 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.

[0198] Preferred heteroaryl groups which are optional substituents on the Z group which may be A in the above formula are pyridyl, pyrazolyl or oxazolyl.

[0199] Preferred heterocyclyl groups which are substituents on the Z group, which may optionally be A in the above formula, are of formula (i) or (j): [ka] [In the formula, T is N and M is NR 13 , C.R. 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 1 or 2; R 12 is, at each occurrence, independently selected from 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 bonded to adjacent carbon atoms 12The groups may be linked to form a fused group A, or two R groups attached to non-adjacent carbon atoms may be linked to form a fused group A. 12 groups may be linked to form a bicyclic bridging group A; 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 and R 14 and R 15 is 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 are linked together with the C atoms to which they are both attached to form an optionally substituted 3- to 6-membered heterocyclyl or an optionally substituted C 3~6 may form a cycloalkyl, R 18 is hydrogen or optionally substituted C1-C6 alkyl, R 19 and R 20 each independently represents 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 group, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 3- to 6-membered heterocyclyl.

[0200] In some embodiments, n is 1.

[0201] In some embodiments, T is N and M is NR 13 In some embodiments, T is CR 18 and M is NR 13 is.

[0202] R 13 is H, optionally substituted C1-C6 alkyl, C 3~6 Cycloalkyl, COR 19 or CONR 19 R 20 R 19 and R 20 are each independently H, optionally substituted C 1~3 It may be alkyl or an optionally substituted 5- or 6-membered heterocyclyl. More preferably, R 19 and R 20 each independently represents H, optionally substituted C 1~3 Alkyl or an optionally halogenated 5- or 6-membered heterocyclyl. Alkyl may be unsubstituted or may be substituted with halogen, oxo, CN, OR 16 or NR 16 R 17 R 16 and R 17 may be as defined above. Preferably, R 16 and R 17 is H or CH3. R 13 are CH3, CH2CH3, [ka] may be.

[0203] In some embodiments, T is N and M is CR 14 R 15 is.

[0204] R 14 and R15 is 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 may be joined together with the C atoms to which they are both attached to form an optionally substituted 3- to 6-membered heterocyclyl. More preferably, R 14 and R 15 is hydrogen, halogen, optionally substituted C1-C3 alkyl and NR 19 R 20 or R 14 and R 15 may be joined together with the C atoms to which they are both attached to form an optionally substituted 3- to 6-membered heterocyclyl. 19 and R 20 are each independently H or optionally substituted C 1~3 It may be alkyl. Preferably, R 19 and R 20 are H. R 14 and R 15 may each independently be H, F, NH, or R 14 and R 15 may be joined together with the C atom to which they are both attached to form a 5-membered heterocyclyl.

[0205] In some embodiments, T is N and M is O or SO2.

[0206] Preferably, R 18 is hydrogen.

[0207] Preferably, R 12 is, at each occurrence, independently H, halogen, or optionally substituted C 1~3 alkyl and / or two R attached to non-adjacent carbon atoms 12More preferably, R 12 is H at each occurrence, and / or two R attached to non-adjacent carbon atoms 12 The groups are linked to form a bicyclic bridged group.

[0208] Exemplary bridging groups have the formula: [ka] It has.

[0209] The group A or heterocyclyl or heteroaryl group may be the only substituent on the phenyl or pyridyl group Z, or one or more further substituents may be present. When present, the one or more further substituents may be selected from halogen, Ak, -OH, -OAk, -NH2, -NHAk, NAk2, optionally substituted heteroaryl, and optionally substituted heterocyclyl, where Ak at each occurrence is independently C 1~6 Alkyl group or C 3~6 The one or more further substituents are preferably halogen, more preferably F.

[0210] In some embodiments, the phenyl or 5- or 6-membered heteroaryl group Z is further substituted with halogen, preferably fluorine.

[0211] Z is [ka] may be.

[0212] All of the features described in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination with any of the above aspects, except combinations in which at least some of such features and / or steps are mutually exclusive.

[0213] General scheme General Scheme 1 Compounds of formula (I) may be prepared from compounds of formula (II) under demethylation conditions as described below. [ka] The demethylation reaction is typically carried out in an acidic reaction mixture, typically at elevated temperatures, using, for example, aqueous H2SO4 or HCl, with or without a cosolvent such as dioxane, ether, or alcohol. Alternatively, a nucleophilic bromine source can be used as the demethylation reagent, for example, by using BBr3, LiBr / pTSA, or aqueous HBr with or without a cosolvent such as dioxane, DMF, or ether under heating at 60-100°C. Compounds of formula (II) may be synthesized by one skilled in the art according to the methods described below.

[0214] General Scheme 2 Compounds of formula (I) may also be prepared by the procedure described below. N It may be prepared from a compound of formula (III) with an amine of formula (IV) using the Ar reaction. [ka] The amine of formula (IV) replaces a halogen atom, such as a chlorine atom, from the pyridone intermediate (III). N The Ar reaction may use any of the reaction conditions known in the art, typically using an excess of neat amine at elevated temperatures. Alternatively, for particularly volatile or precious amines, the amine may be reacted with EtOH, with another base, typically EtN, DIPEA, or NMM. i PrOH, n BuOH or tThe amine is dissolved in a suitable solvent, such as BuOH, and the mixture is heated at 80-120°C for up to 24 hours. If the solubility of any component may be limited, a phase transfer catalyst, such as TBAI in a suitable solvent, such as toluene or xylene, with a suitable base, such as EtN, DIPEA, or NMM, may also be used. Amines of formula (IV) are commercially available or may be synthesized by one skilled in the art.

[0215] General Scheme 3 Compounds of formula (I) may also be prepared from compounds of formula (V) using amines of formula (VI) in an amide bond forming reaction as described below. [ka] Typical conditions utilize activation of the carboxylic acid of a compound of formula (V) using a suitable organic base and a suitable coupling agent. Preferred coupling agents are either HOBt, T3P, HATU, HBTU, or EDCI with BOP. Preferred organic bases include either DIPEA or TEA in a suitable organic solvent such as DCM, DMF, DMA, THF, MeOH, or MeCN. The reaction may be shaken or stirred at room temperature, typically for up to 24 hours. Compounds of formula (VI) are commercially available or may be synthesized by one skilled in the art.

[0216] General Scheme 4 Compounds of formula (IX) may be prepared from carbaldehyde compounds of formula (VII) and amines of formula (VI) in the sequence described below. [ka] Oxidation of aldehyde (VII) to the corresponding acid (VIII) is typically carried out using a strong oxidizing agent such as KMnO, 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 the aldehyde of formula (VII) may also be converted to the acid of formula (VIII) via the corresponding ester intermediate using reactions known to those skilled in the art, such as those using Br and alcoholic solvents. The acid (VIII) may then be converted to the amide of formula (IX) using methods similar to those described in General Scheme 3. Accordingly, preferred amide coupling agents are either HOBt, T3P, HATU, HBTU, or EDCI with BOP. Preferred organic bases include either 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 the acid chloride route using a chlorinating reagent such as SOCl, SOCl, POCl, or POCl. The reaction may be shaken or stirred at room temperature, typically for up to 24 hours. Compounds of formula (VI) are commercially available or may be synthesized by one skilled in the art.

[0217] General Scheme 5 Compounds of formula (II) and (III) may be prepared from compounds of formula (IX) according to the sequence described below. [ka] Compounds of formula (IX) may undergo a Buchwald amination reaction with a suitable amine of formula (IV) to give amines of formula (II). The Buchwald reaction is carried out at elevated temperatures, typically 60-110°C, using a suitable base such as DIPEA, TEA, NaOtBu, CsCO, NaCO, 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 Pd(dba), Pd(dppf)Cl, Pd(OAc), or Pd(dba)Cl with a suitable ligand such as dppf, BINAP, Xantphos, or S-Phos, and the reaction is typically carried out for 12-24 hours.

[0218] Compounds of formula (IX) may undergo a direct demethylation reaction using conditions similar to those described in general Scheme 1. Thus, demethylation of (IX) is typically carried out in an acidic reaction mixture, typically at elevated temperatures, using, for example, aqueous H2SO4 or HCl, with or without a co-solvent such as 1,4-dioxane, ether, or alcohol. Alternatively, a nucleophilic bromine source can be used as the demethylation reagent, for example, by using BBr3, LiBr / pTSA, or aqueous HBr with or without a co-solvent such as 1,4-dioxane, DMF, or ether under heating at 60-100°C, to provide pyridones of formula (III).

[0219] General Scheme 6 Compounds of formula (V) may be prepared from compounds of formula (VIII) via compounds of formula (X) according to the sequence described below. [ka] Compounds of formula (VIII) may be converted to the corresponding pyridone of formula (X) in a demethylation reaction similar to that described in general Scheme 1. Thus, the reaction is typically carried out using aqueous HCl, with or without a co-solvent such as 1,4-dioxane or ether, typically at 60-100°C for 6-24 hours. During the demethylation reaction, it is typically observed that the iodine group of (VIII) is replaced by chloride to give the product compound of formula (X). The acid of formula (X) can then be converted to a S-type pyridone with an amine of formula (IV) under conditions similar to those described in general Scheme 2. N Thus, amines can be reacted with EtOH, with another base, typically EtN, DIPEA, or NMM. i PrOH, n BuOH or t The amine is dissolved in a suitable solvent, such as BuOH, and the mixture is heated at 80-120°C for up to 24 hours to give the amine product of formula (V). If the solubility of either component may be limited, a phase transfer catalyst, such as TBAI in a suitable solvent, such as toluene or xylene, with a suitable base, such as EtN, DIPEA, or NMM, may also be used. Amines of formula (IV) are commercially available or may be synthesized by one skilled in the art.

[0220] General Scheme 7 A compound of formula (II) may be converted to a different compound of formula (II) via a compound of formula (XI) according to the sequence described below. [ka] This sequence typically applies to compounds of formula (II) where Y is a protecting group known to those skilled in the art. For example, if the protecting group is para-methoxybenzyl or dimethoxybenzyl, the group Y may be removed with an acidic reagent such as TFA, triflic acid, or HCl in a suitable solvent such as DCM, dioxane, DCE, or toluene, with or without heating at a temperature between 20 and 80°C for 1 to 48 hours, to give primary amines of formula (XI). These amines may then be used in a Buchwald amination reaction with a suitable halide of formula (XII) using conditions similar to those described in general Scheme 5 to give secondary amines of formula (II). Thus, the reaction is carried out at elevated temperatures, typically 60 to 110°C, using a suitable base such as DIPEA, TEA, NaOtBu, CsCO, NaCO, 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 Pd(dba) with a suitable ligand such as dppf, BINAP, Xantphos, or S-Phos, Pd(dppf)Cl, Pd(OAc) or Pd(dba)Cl, and the reaction is typically carried out for 12-24 hours. Preferred reagents include the BrettPhos-Pd-G3 catalyst system. Halides of formula (XII) are commercially available or may be synthesized by one skilled in the art.

[0221] General Scheme 8 A compound of formula (XIII) may be converted to a different compound of formula (II) via compounds of formula (XIV) and (XV) according to the sequence described below. [ka] Compounds of formula (XIII) may undergo a Buchwald amination reaction with a suitable amine of formula (IV) using conditions similar to those described in general Scheme 5 to provide amines of formula (XIV). Thus, the reaction is carried out at elevated temperatures, typically 60-110°C, using a suitable base such as DIPEA, TEA, NaOtBu, CsCO, NaCO, 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 Pd(dba), Pd(dppf)Cl, Pd(OAc), or Pd(dba)Cl with a suitable ligand such as dppf, BINAP, Xantphos, or S-Phos, and the reaction is typically carried out for 12-24 hours. Amines of formula (IV) are commercially available or may be synthesized by one skilled in the art. The resulting compound of formula (XIV) may then undergo an ester hydrolysis reaction, typically using a suitable alkali or base, to hydrolyze the ester and provide an acid of formula (XV). Suitable alkalis or bases may be LiOH, KOH, NaOH, or K2CO3, and the reaction is typically carried out in aqueous solution or a mixture of solvents such as water, THF, MeOH, or EtOH at room temperature for 1 to 48 hours. The resulting acid of formula (XV) may then undergo an amide bond formation reaction with a suitable amine of formula (VI) using conditions similar to those described in general Scheme 3. Typical conditions utilize activation of the carboxylic acid using a suitable organic base and a suitable coupling agent. Preferred coupling agents are either HOBt, T3P, HATU, HBTU, or EDCI with BOP. Preferred organic bases include either DIPEA or TEA in a suitable organic solvent such as DCM, DMF, DMA, THF, MeOH, or MeCN. The reaction may be shaken or stirred at room temperature, typically for up to 24 hours. Compounds of formula (VI) are commercially available or may be synthesised by one skilled in the art to give products of formula (II).

[0222] General synthetic procedure General Procedure 1 [ka]

[0223] Method a: Compounds of formula (II) (1.0 equiv.) were taken in 4 M HCl in 1,4-dioxane (13 mL / mmol) at 0-5°C, and the resulting reaction mixture was refluxed for 2-6 h. The progress of the reaction was monitored by TLC and / or LCMS. After completion, the solvent was evaporated under reduced pressure to give the crude product, which was purified by trituration with ether-pentane mixtures or column chromatography to give compounds of formula (I) (yields 7-80%) as solids.

[0224] Method b: To a stirred solution of compound of formula (II) (1.0 equiv.) in DMF (9 mL / mmol) at room temperature, PTSA.HO (5.0 equiv.) was added, followed by LiBr (5.0 equiv.), and the resulting reaction mixture was stirred at 100-120 °C for 10-15 min. Completion of the reaction was confirmed by UPLC-MS and / or TLC. The reaction mass was then diluted with cold water and extracted with 5-15% methanol in DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was purified by column chromatography or prep-HPLC to give compound of formula (I) (7-80% yield) as a solid.

[0225] Method c: To a stirred solution of compound of formula (II) (1.0 equiv. 0.295 mmol) in 1,4-dioxane (6 mL / mmol) was added HBr (40%, 6 mL / mmol) dropwise at 0-5°C. The whole was stirred at 75-80°C overnight. The progress of the reaction was monitored by LCMS, and upon completion, the solvent and excess HBr were evaporated in vacuo by azeotropic distillation using acetonitrile, and the remaining residue was washed with diethyl ether to give the crude product, which was purified by column chromatography to give compound of formula (I) (yield 10-65%) as a solid.

[0226] General Procedure 2 [ka] To a stirred solution of compound of formula (III) (1.0 equiv.) in n-butanol, t-BuOH, or toluene (11 mL / mmol), N,N-diisopropylethylamine or TEA (15.0 equiv.) was added, and the mixture was stirred at room temperature for 10-20 minutes. Then, compound of formula (IV) (1.5 equiv.) was added to the reaction vessel. The resulting reaction mixture was stirred at 100-120 °C for 10-16 hours. The reaction progress was monitored by LCMS / TLC, and upon completion, the solvent was evaporated under reduced pressure to give a crude mass, which was purified by column chromatography or preparative reverse-phase HPLC to give compound of formula (I) (10-65% yield) as a solid.

[0227] General Procedure 3 [ka]

[0228] Method a: To a stirred solution of compound (V) (1.0 equiv.) in THF (3.5 mL / mmol) and a few drops of DMF, HATU (1.5 equiv.) and TEA (3.0 equiv.) were added at room temperature, and the resulting reaction mixture was stirred at room temperature for 10–15 min. Then, compound (VI) Z-NH2 (1.2 equiv.) was added to the reaction vessel, and the mixture was stirred at room temperature for 2–5 h. The reaction progress was monitored by TLC and LCMS, which confirmed the formation of the desired product. The reaction mixture was then evaporated in vacuo to give a residue, which was diluted with 5–10% MeOH in DCM and washed repeatedly with water and brine. The organic portion was dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product, which was purified by Combi-flash column chromatography using 5–10% MeOH in DCM as the eluent to give compound (I) (10–80% yield) as a solid.

[0229] Method b: To a stirred solution of compound of formula (V) (1.0 equiv.) in toluene (6.5 mL / mmol), POCl3 (0.30 mL / mmol) was added, and the combined mixture was refluxed for 2-4 h to give the corresponding acid chloride intermediate. The solvent was then evaporated under vacuum, and the crude acid chloride was taken up in DCM (6.5 mL / mmol). At 0-5 °C, triethylamine (5.0 equiv.) was added, followed by compound of formula (VI) Z-NH2 (1.5 equiv.). The resulting reaction mixture was stirred at room temperature for 10-16 h. The reaction progress was monitored by LCMS and / or TLC. Upon completion, the solvent was evaporated under vacuum to give the crude product, which was purified by column chromatography or prep-HPLC to give compound of formula (I) (5-65% yield) as a solid.

[0230] General Procedure 4 [ka]

[0231] Method a: To a stirred solution of compound of formula (VII) (1.0 equiv.) in a mixture of tert-butanol (5.2 mL / mmol) and water (2.6 mL / mmol) at 0-5°C, 2-methyl-2-butene (3.0 equiv.) was added, followed by sodium dihydrogen phosphate (2.5 equiv.) and sodium chlorite (2.0 equiv.), and the whole mixture was stirred at 0-5°C for 1-2 h. The reaction progress was monitored by LCMS, and upon completion, the reaction mass was quenched with 1N formic acid solution. The product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give compound of formula (VIII) (70-80% yield) as a solid.

[0232] Method b: To a stirred solution of compound of formula (VII) (1.0 equiv.) in aqueous pyridine (50%, 5.2 mL / mmol) at 0-5°C, KMnO4 (1.0 equiv.) was added portionwise. The resulting reaction mixture was stirred at room temperature for 1-2 h. The reaction progress was monitored by TLC / LCMS. Upon completion, the reaction mixture was filtered and washed with acetonitrile and water. The filtrate was distilled under reduced pressure using excess acetonitrile to give the crude product, which was purified by trituration with diethyl ether to give compound of formula (VIII) (65-85% yield) as its potassium salt.

[0233] General Step 5 [ka] To a stirred solution of compound of formula (IX) (1.0 equiv.) in 1,4-dioxane (15 mL / mmol) in a sealed tube was added compound of formula (IV) Y-NH (1.2 equiv.) and CsCO (3.0 equiv.). The combined reaction mixture was degassed for 10-20 minutes using a nitrogen balloon. Pd(dba) (0.1 equiv.) and Xantphos (0.2 equiv.) were then 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 upon completion, the reaction mixture was diluted with water and extracted with 10% methanol in DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product, which was purified by column chromatography on silica gel using 3-5% methanol in DCM as the eluent to give the compound of formula (II) (yield 70-80%) as a solid.

[0234] General Procedure 6 [ka] To a stirred solution of compound of formula (II) (1.0 equiv.) in DCE (8 mL / mmol) at 0-5°C, TFA (2 mL / mmol) was added dropwise, and the combined mixture was stirred at room temperature overnight. The reaction progress was monitored by LCMS / TLC. Upon completion, the reaction mixture was evaporated to dryness to give a residue, which was neutralized with TEA and extracted with 15% methanol in DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product, which was purified by column chromatography on silica gel using 5-10% methanol in DCM as the eluent to give compound of formula (XI) (70-75% yield) as a solid.

[0235] General Procedure 7 [ka] To a stirred solution of compound of formula (XI) (1.0 equivalent) in toluene (40 mL / mmol) was added compound of formula (XII) (1.2 equivalents), followed by NaO t Bu (2.5 equiv.) was added. The reaction mixture was purged with a nitrogen balloon for 10-20 minutes. BretPhos-Pd-G3 (0.2 equiv.) was then added to the reaction vessel, and the resulting reaction mixture was stirred at 100 °C overnight. The reaction progress was monitored by LCMS / TLC. Upon completion, the reaction mixture was diluted with water and extracted with 10% methanol in DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude compound, which was purified by column chromatography on silica gel using 4-5% methanol in DCM as the eluent to give the compound of formula (II) (40-50% yield) as a solid.

[0236] General Procedure 8 [ka] To a stirred solution of compound of formula (XIV) (1.0 equiv., 2.1 mmol) in THF (2 mL / mmol) at room temperature, a solution of LiOH.HO (4.0 equiv.) in water (1 mL / mmol) was added, followed by MeOH (2 mL / mmol), and the whole was stirred at room temperature overnight. The reaction progress was monitored by UPLC-MS / TLC, which indicated the formation of the desired product. The reaction mixture was then concentrated in vacuo and slightly acidified with a solution of citric acid to give a white solid precipitate, which was filtered, washed with water, then hexane, and dried under vacuum to give compound of formula (XV) (70-80% yield) as a solid.

[0237] General purification and analytical methods All final compounds were purified by either Combi-flash or prep-HPLC purification and analyzed for purity and product identity by UPLC or LCMS according to one of the following conditions.

[0238] Prep-HPLC Preparative HPLC was performed on a Waters autopurifier using either a YMC Triart C18 column (250 × 20 mm, 5 μm) or a phenylhexyl column (250 × 21.2 mm, 5 μm) operated between ambient and 50 °C at flow rates of 16.0–50.0 mL / min.

[0239] Mobile phase 1: A = 20 mM ammonium bicarbonate in water, B = acetonitrile; gradient profile: initial composition of mobile phase 80% A and 20% B, then to 60% A and 40% B after 3 min, then to 30% A and 70% B after 20 min, then to 5% A and 95% B after 21 min, held at this composition for 1 min for column wash, then returned to the initial composition over 3 min.

[0240] Mobile phase 2: A = 10 mM ammonium acetate in water, B = acetonitrile; gradient profile: initial composition of mobile phase 90% A and 10% B, then to 70% A and 30% B after 2 min, then to 20% A and 80% B after 20 min, then to 5% A and 95% B after 21 min, held at this composition for 1 min for column washing, then returned to the initial composition over 3 min.

[0241] LCMS method Typical 5-minute method: Zorbax Extend C18 column (50 × 4.6 mm, 5 μm) operated at ambient temperature and a flow rate of 1.2 mL / min. Mobile phase: A = 10 mM ammonium acetate in water, B = acetonitrile; gradient profile: 90% A and 10% B to 70% A and 30% B in 1.5 min, then to 10% A and 90% B in 3.0 min, held at this composition for 1.0 min, and finally returned to the initial composition over 2.0 min.

[0242] UPLC method UPLC was performed on a Waters autopurifier using a Zorbax Extend C18 column (50 x 4.6 mm, 5 μm) at ambient temperature and a flow rate of 1.5 ml / min.

[0243] Mobile phase 1: A = 5 mM ammonium acetate in water, B = 5 mM ammonium acetate in 90:10 acetonitrile / water; gradient profile: 95% A and 5% B to 65% A and 35% B in 2 min, then to 10% A and 90% B in 3.0 min, held at this composition for 4.0 min, and finally returned to the initial composition over 5.0 min.

[0244] Mobile phase 2: A = 0.05% formic acid in water, B = acetonitrile; gradient profile from 98% A and 2% B over 1 min, then 90% A and 10% B over 1 min, then 2% A and 98% B over 2 min, then return to initial composition over 3 min. [Example]

[0245] Nuclear magnetic resonance (NMR) spectra were consistent with the proposed structures in all cases. Characteristic chemical shifts (δ) are given in parts per million downfield (δ) from tetramethylsilane (TMS) using conventional abbreviations for the designations of major peaks: e.g., s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; 1 H-NMR) and parts per million high field from trichloro-fluoro-methane ( 19 For common solvents, the following abbreviations are used: CDCl3, deuterochloroform; d6-DMSO, deuterodimethylsulfoxide; and CD3OD, deuteromethanol.

[0246] Mass spectra, MS (m / z), were recorded using electrospray ionization (ESI). Where relevant and unless otherwise stated, the m / z data given are isotopic. 19 F, 35 Cl, 79 Br and 127 It is about I.

[0247] All chemicals, reagents and solvents were purchased from commercial sources and used without further purification. All reactions were carried out under a nitrogen atmosphere unless otherwise noted.

[0248] Flash column chromatography was performed using prepacked silica gel cartridges on a Combi-Flash platform. Prep-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 noted, all final compounds were greater than 95% pure as judged by the LCMS or UPLC analytical methods described in the general purification and analytical methods above.

[0249] 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 [ka] Example 45 was prepared according to the methods described in General Procedures 1-7 and as described below.

[0250] Preparation 1: 4-chloro-N-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide.HCl [ka]

[0251] Step 1: 4-Iodo-2-methoxynicotinic acid [ka] 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) at 0-5 °C, 2-methyl-2-butene (6.03 mL, 57.03 mmol) was added, 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 0-5 °C for 1 h. The reaction progress was monitored by LCMS. Upon completion, the reaction mass was quenched with 1N formic acid solution, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to afford the title compound (4.2 g, 79.17% yield) as an off-white solid. LCMS m / z: 280.0 [M+H].

[0252] Step 2: 4-iodo-2-methoxy-N-(4-(4-methylpiperazin-1-yl)phenyl)nicotinamide [ka] 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, HATU (8.17 g, 21.50 mmol) and TEA (5.90 mL, 43.01 mmol) were added at room temperature, and the resulting reaction mixture was stirred at room temperature for 10–15 min. Then, 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 h. TLC and LCMS indicated complete formation of the desired product. The reaction mixture was then 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 under vacuum to give the crude product, which was purified by Combi-flash column chromatography using 5-10% MeOH in DCM as the eluent to give the title compound (5.0 g, 77.1% yield) as an off-white solid. LCMS m / z: 452.8 [M+H].

[0253] Step 3: 4-chloro-N-(4-(4-methylpiperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide.HCl [ka] 4-Iodo-2-methoxy-N-(4-(4-methylpiperazin-1-yl)phenyl)nicotinamide (Preparation-1, Step-2) (500 mg, 1.11 mmol) was taken up in 4M HCl in 1,4-dioxane (15 mL) at 0-5°C, and the reaction mixture was refluxed for 2 hours. TLC and LCMS indicated the formation of the desired product, so the solvent was evaporated under reduced pressure to give a solid crude product, which was purified by trituration with an ether-pentane mixture and dried under vacuum to give the title compound (250 mg, 65.17% yield) as an off-white solid. LCMS m / z: 347.18 [M+H].

[0254] Preparation 2: 8-Methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-amine [ka]

[0255] Step 1: Ethyl 2-((5-bromo-4-methyl-3-nitropyridin-2-yl)oxy)acetate [ka] To a stirred solution of commercially available 5-bromo-2-chloro-4-methyl-3-nitropyridine (25.0 g, 99.41 mmol) in acetonitrile (400 mL) was added oven-dried potassium carbonate (41.21 g, 298.26 mmol) and ethyl glycolate (28.22 mL, 298.26 mmol). The resulting reaction mass was heated at 80 °C under a nitrogen atmosphere for 12 hours. The reaction progress was monitored by LCMS / TLC. Upon completion of the reaction, it was cooled to room temperature, filtered through a sintered funnel, and the filtrate was evaporated in vacuo to give the crude material, which was purified via column chromatography using 5-7% ethyl acetate in hexane as the eluent to give the title compound (15.0 g, 47.0% yield) as an off-white solid compound. LCMS m / z: 318.8 [M+H].

[0256] Step 2: 7-Bromo-8-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one [ka] 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 placed in a clean, dry Parr shaker vessel and purged with argon. Then, glacial acetic acid (20.0 mL) was added, followed by Raney Ni (approximately 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 formation of the desired product along with some uncyclized intermediate amine-ester. The reaction mixture was filtered through a short bed of Celite. After washing the Celite bed several times, the resulting filtrate was concentrated in vacuo to give the crude material, which was taken up in a round-bottom flask (500 mL). ethanol (150 mL) followed by glacial acetic acid (30 mL) were added to it. The resulting reaction mixture was heated at 80° C. for 12 hours and the solvent was evaporated in vacuo to give a crude product which was purified by washing with MTBE and pentane to give the title compound (13.3 g, 70% yield) as an off-white solid. LCMS m / z: 243.0 [M+H].

[0257] Step 3: 7-Bromo-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine [ka] To a stirred solution of 7-bromo-8-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (Preparation-2, Step-2) (10.0 g, 41.32 mmol) in THF under a nitrogen atmosphere at 0-5 °C, BH3.THF solution (170.0 mL) was added dropwise. The mixture was then heated at 70 °C for 3 h. 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 give the crude material, which was basified with aqueous NaHCO3 solution and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated in vacuo to give the title compound (7.5 g, 80% yield) as a crude off-white solid, which was used as such in the next step without further purification. LCMS m / z: 228.8 [M+H].

[0258] Step 4: tert-Butyl 7-bromo-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate [ka] 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) was added triethylamine (46.23 mL, 328.94 mmol), DMAP (8.03 g, 65.78 mmol), and Boc-anhydride (60.52 mL, 263.15 mmol) at room temperature under nitrogen atmosphere. The reaction mass was heated at 70 °C for 16 h. The reaction progress was monitored by LCMS / TLC, and after completion of the reaction, water was added and the organics were extracted with ethyl acetate. The combined organic layers were washed with water, followed by brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the 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].

[0259] Step 5: tert-Butyl 7-((4-methoxybenzyl)amino)-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate [ka] 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, then BrettphosPdG3 (112 mg, 0.12 mmol) was added 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 the crude product, which was purified by column chromatography using 30-40% ethyl acetate in hexane as the eluent to give the title compound (120 mg, 51.06% yield) as a pale yellow solid. LCMS m / z: 386 [M+H].

[0260] Step 6: 8-Methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-amine.TFA [ka] 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 its TFA salt, which was used as such in the next step without further purification. LCMS m / z: 166 [M+H].

[0261] 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) [ka] 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 whole was stirred at room temperature for 20 minutes. Then, 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 whole was stirred at 120 °C for 16 hours. The progress of the reaction was monitored by LCMS / TLC, and after completion of the reaction, the solvent was evaporated under reduced pressure to give the crude product, which was purified by preparative reverse-phase HPLC to give the title compound (25 mg, 9.14% yield, qualitative HPLC purity by area normalization 99.22%) as a white solid. 1 H NMR (400 MHz; DMSO-d6): δ 1.92 (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 = 3.8 Hz, 2H), 5.55 (d, J = 7.36 Hz, 1H), 5.79 (s,1H), 6.90 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 7.6 Hz, 1H), 7.30 (s, 1H), 7.46 (d,J = 8.8 Hz, 2H), 11.35 (s, 1H), 11.90 (s, 1H), 12.86 (s, 1H); LCMS m / z: 476.46[M+H].

[0262] Example 167: 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 [ka] Example 167 was prepared according to the methods described in General Procedures 1-7 and as described below.

[0263] Preparation 9: 8-Methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-amine dihydrochloride [ka]

[0264] Step 1: 7-Bromo-8-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one [ka]

[0265] 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) in an ice bath at 0-5 °C, 2-chloroacetyl chloride (55.66 g, 0.495 mol) was added. After 2-5 min of stirring, K2CO3 (85.4 g, 0.618 mol, 2.5 equiv.) was added, and the combined mixture was allowed to warm slowly to room temperature for 3 h. After 3 h, the reaction vessel was transferred to an oil bath, and the contents were refluxed at approximately 90 °C for 3 h. LC-MS indicated complete consumption of 3-amino-5-bromo-4-methylpyridin-2-ol and formation of the acylated intermediate. An additional 2.5 equiv. of K2CO3 (85.4 g, 0.618 mmol, 2.5 equiv.) was added in 0.5 equiv. increments to the reaction mixture to bring the pH to approximately 8. The resulting reaction mixture was then stirred at reflux for 16 hours. Complete consumption of the intermediate was confirmed by LC-MS. The reaction mixture was cooled to room temperature, the solvent was decanted, and concentrated under reduced pressure to give a crude material, which was quenched with ice-cold water (1.0 L) to maintain an internal temperature of 5-10 °C. The resulting suspension was stirred for 30 minutes and filtered. The remaining reaction mass was diluted with additional ice-cold water (1.0 L). The resulting suspension was stirred for 30 minutes and filtered through the same Buchner funnel. The filter cake was washed with ice-cold water until the pH of the filtrate was neutral. The resulting wet material was dried overnight in a vacuum oven at 50 °C to give the title compound (53.0 g, 88.5% yield, 97% purity by HPLC) as a white solid. LCMS m / z: 242.97 [M+H].

[0266] Step 2: 7-Bromo-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine [ka] 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 dry THF (0.27 L, 5 V) was added BH3.THF solution (0.98 L, 0.888 mol, 0.9 M solution in THF) dropwise via addition funnel at 0-5 °C under an inert atmosphere, and the combined mixture was further stirred for 15 min. 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 h. 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, 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 whole was further stirred overnight. The progress of the reaction was monitored by LC-MS, which confirmed the formation of the desired product along with traces of impurities. After completion of the reaction, the solvent was evaporated from the reaction mixture under reduced pressure to give a residue, which was cooled in an ice bath and neutralized with saturated NaHCO3 solution (3 L) to achieve a pH of about 8. The neutralized mass was diluted with water (1.0 L) and extracted with EtOAc (2 x 2.5 L). The combined organic layers were washed with brine solution (2.0 L), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product (48.0 g), which was purified by column chromatography on silica gel (60-120 mesh) (200 g for the slurry and 2.5 kg for the column bed) using 10-50% EtOAc in DCM as the eluent to give the title compound (44.5 g). This material was redissolved in ethyl acetate (0.9 L), followed by the addition of activated carbon (2.2 g) and stirring at room temperature for 30 minutes. The activated carbon 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 (44.0 g, 86.8% yield, 99% purity by HPLC) as a white solid. LCMS m / z: 229.0 [M+H].

[0267] Step 3: tert-Butyl (8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)carbamate [ka] To a stirred solution of tert-butyl carbamate (63.9 g, 0.546 mol) in 1,4-dioxane (1.0 L) at room temperature was added CsCO (177.79 g, 0.55 mol) and 7-bromo-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (Preparation 9, Step 2) (50.0 g, 0.218 mol). The reaction mixture was purged with nitrogen gas for 30 minutes. Brettphos-Pd-G (5.94 g, 0.007 mol) was added, and the mixture was again purged with nitrogen gas for 15 minutes. 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 progress was monitored by LC-MS. Upon completion, the reaction mixture was cooled to room temperature and filtered through a bed of Celite, rinsing the bed with 1,4-dioxane (200 mL). The filtrate was combined with that from another 75 g batch reaction and concentrated under reduced pressure to give a residue that was diluted with water (2.0 L) and extracted with EtOAc (2 × 2.5 L). The combined organic layers were washed with brine (2 × 2.0 L), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product (250 g), which was purified by column chromatography on 60–120 mesh silica gel (500 g for the slurry and 5 kg for the column bed) using 5–50% EtOAc in DCM as the eluent to give the title compound (135 g, 93% yield, 99% purity by HPLC) as a pale yellow solid. LCMS m / z: 266.24 [M+H].

[0268] Step 4: 8-Methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-amine dihydrochloride [ka] To a stirred suspension of tert-butyl (8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)carbamate (Preparation 9, Step 3) (135.0 g, 0.508 mol) in 1,4-dioxane (1.38 L) was added 4 M HCl in 1,4-dioxane (1.38 L) at ice-cold temperature, and the combined mixture was allowed to stir at room temperature for 2 hours. Upon addition of the 4 M HCl, the suspension began to dissolve, and clumps began to appear in the reaction mixture. Slowly, the clumps broke down, and the reaction mixture became a thick suspension. After stirring at room temperature for 2 hours, LC-MS and TLC confirmed the reaction was complete, with the starting material being completely consumed. The solvent from the reaction mixture was evaporated under reduced pressure to give a crude material which was triturated with heptane, filtered and dried in vacuo at 40° C. for 30 minutes to give the title compound (119.0 g, 99% yield, 99% purity by HPLC) as a light brown solid. LCMS m / z: 166.14 [M+H].

[0269] Preparation 10: 4-(4-cyclopropylpiperazin-1-yl)aniline-methane [ka]

[0270] Step 1: 1-Cyclopropyl-4-(4-nitrophenyl)piperazine [ka] 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, which was then stirred at 80 °C for 3 hours. The progress of the reaction was monitored by HPLC and TLC. After complete consumption of the starting material, 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 was neutral. Finally, the solid was washed with n-heptane (1.0 L) and dried in a vacuum oven at 50° C. for 16 h to give the title compound (172.0 g, 98% yield, 98.83% purity by HPLC) as a yellow solid. LCMS m / z: 248.18 [M+H].

[0271] Step 2: 4-(4-cyclopropylpiperazin-1-yl)aniline [ka] 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 and, under an inert atmosphere, was followed by the addition of 10% Pd / C (50% wet; 1.2 g, 20% w / w), and the mixture was maintained at room temperature under hydrogen balloon pressure for 24 h. The reaction progress was monitored by UPLC and TLC. After complete consumption 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 gas atmosphere. The filtrate was evaporated under reduced pressure to give the title compound (5.105 g, 98% yield, 77.49% purity by HPLC) as a light brown solid. LCMS m / z: 218.2 [M+H].

[0272] Preparation 11: N-(4-(4-cyclopropylpiperazin-1-yl)phenyl)-4-iodo-2-methoxynicotinamide [ka]

[0273] Step 1: 4-Iodo-2-methoxynicotinic acid [ka] 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 an aqueous solution of NaH2PO4 (114.0 g, 0.95 mol) and NaClO2 (55.85 g, 0.6 mol) in portions over 30 min at 0-5 °C. After the addition was complete, the reaction mixture was held at 0-5 °C for 2 h. The reaction progress was monitored by HPLC and TLC. After complete consumption of the starting material, the reaction mixture was quenched with an aqueous solution of Na2SO3 (250.0 g in 1.0 L of water) at 0-5 °C, during which an exotherm was observed up to approximately 10 °C and the color of the mixture changed from yellow to pale green. A saturated solution of K2CO3 (500 mL) was then added to make the reaction mass basic (pH = 14). The basic aqueous solution was washed with EtOAc (1.0 L) and acidified (pH = 2) using 12 N HCl (500 mL) at 5-10 °C. Finally, the compound was extracted using 20% ​​t-BuOH in ethyl acetate (2 x 2.0 L). The combined organic layers were dried over anhydrous NaSO, filtered, and evaporated under reduced pressure to give the title compound (50.0 g, 94% yield, 99% purity by HPLC) as a white solid. LCMS m / z: 279.94 [M+H].

[0274] Step 2: N-(4-(4-cyclopropylpiperazin-1-yl)phenyl)-4-iodo-2-methoxynicotinamide [ka] 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), followed by the dropwise addition of triethylamine (149.3 mL, 1.07 mol) at room temperature. The combined mixture was stirred at room temperature for 10 min. Further addition of 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 h. The reaction progress was monitored by UPLC and TLC. After complete consumption of the starting material, the reaction mixture was poured into ice-cold water (4.0 L) and stirred for 30 min. The precipitated solid was filtered and washed with water until the pH of the filtrate was neutral. The solid was then dried in a vacuum oven at 50° C. for 16 hours to give the title compound (160.0 g, 94% yield, 99% purity by HPLC) as a light brown solid. LCMS m / z: 479.16 [M+H].

[0275] Preparation 12: Step 1: 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 [ka] 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 KPO (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 gas for 30 minutes. Pd(dba) (2.01 g, 0.0022 mol) and Xantphos (2.54 g, 0.0044 mol) were then added. 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 progress was monitored by LCMS. Upon completion, the reaction mixture was cooled to room temperature, filtered through a bed of Celite, and the bed was washed with DCM (0.2 L). The filtrate was concentrated under reduced pressure to give the residue (45.0 g) as a yellow solid, which was diluted with water (0.7 L) and extracted with DCM (2 × 0.7 L). The combined organic layers were washed with brine (0.5 L), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product (38.0 g), which was purified by column chromatography on silica gel [90.0 g (60–120 mesh silica gel) in a slurry and 1.35 kg (100–200 mesh) in a column bed] using 2–2.5% MeOH in DCM as the eluent [silica gel was made basic using 0.5% triethylamine (of the total silica used)] to give the title compound (31.0 g, 63% yield, 98.72% purity by HPLC) as a yellow solid. LCMS m / z: 516.35 [M+H].

[0276] 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) [ka] 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 4 M HCl-1,4-dioxane (0.25 L) was heated at 80 °C for 1 h. Initially, the compound was dissolved in 4 M HCl in 1,4-dioxane, but when the temperature reached 80 °C, clumps appeared in the reaction mixture. Slowly, the clumps collapsed, 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 give the residue as a pale yellow solid, which was dissolved in Milli-Q water (0.75 L, 60 V) and washed with ethyl acetate (2 × 0.3 L, HPLC grade). The acidic aqueous layer was transferred to a 2 L RBF and cooled to 0-5 °C with external cooling using an ice-salt mixture while the solution was neutralized dropwise with a saturated solution of NaHCO3 [0.2 L, 16V (saturated NaHCO3 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 left stirring at room temperature for 30 min. The solid was then filtered off using a Buchner funnel and washed with water until the pH of the filtrate was neutral. A final heptane (0.1 L) wash yielded a wet cake (17.0 g, 97% pure by HPLC) as a pale yellow solid.

[0277] Crystallization 1:The wet product (17.0 g, 0.034 mol) was dissolved in DCM (2.5 L, 200V, HPLC grade) and refluxed to maximize dissolution. Then, Milli-Q water (0.6 L) was added, and the whole was filtered through a cotton plug. The solid collected on the cotton was washed with DCM (0.1 L) and combined with the original main 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 three-neck 5 L round-bottom flask. Activated carbon (0.6 g) was added, and the combined mixture was refluxed for 30 minutes. The activated carbon was filtered through a bed of Celite, and the bed was washed with DCM (0.525 L; total DCM used was 250V). To this clear, yellow solution, heptane [1.1 L, (1 / 3 volume of total DCM)] was slowly added via a dropping funnel, and the whole was refluxed. The clear solution became slightly cloudy, and the mixture was left stirring at room temperature overnight. The suspension was cooled to 0-5 °C with an external ice-salt mixture for 1 h and filtered through a Buchner funnel. Finally, the combined wet cake was washed with n-heptane (2 x 0.1 L) and left to suction dry for 1 h. The solid was dried in a vacuum oven at 50 °C overnight to give the title compound (28.0 g, 76% yield, 99.78% purity by HPLC) as a pale yellow solid.

[0278] Crystallization 2: The wet product (10 g) was dissolved in DMA (160 mL) at 50 °C, then charcoal (500 mg) was added, and the whole was stirred at 50 °C for 45 min. The mixture was filtered through a bed of Celite (15 g), and the bed was washed with hot DMA (5 × 20 mL). The filtrate was collected, and cold water (420 mL) was added dropwise at 4–5 °C to give a precipitate, and the suspension was kept cold for 3 h. The suspension was filtered and washed with water (420 mL). The wet cake was slurry washed with water (2 × 300 mL), sucked dry for 4 h, and finally dried in a vacuum oven at 50 °C for 18 h and then at 75 °C for 10 h to give the title compound (8.55 g, 99.02% purity by HPLC) as a pale yellow solid. 1H NMR (400 MHz; DMSO-d6): δ 0.43-0.46 (m, 2H), 0.84-0.88 (m, 2H), 1.62-1.67 (m, 1H), 1.93 (s,3H), 2.67 (t, J = 4.84 Hz, 4H), 3.05 (t, J = 4.56 Hz, 4H), 3.33 (s, 2H), 4.26(t, J = 4.12 Hz, 2H), 5.54-5.57 (m, 1H), 5.81 (s, 1H), 6.90 (d, J = 9.08 Hz,2H), 7.26-7.30 (m, 2H), 7.47 (d, J = 9.0 Hz, 2H), 11.35 (d, J = 6.0 Hz, 1H),11.91 (s, 1H), 12.85 (s, 1H); LCMS m / z: 502.22 [M+H].

[0279] Example 168: 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 [ka]

[0280] Example 168 was prepared according to the methods described in General Procedures 1-7 and as described below.

[0281] Preparation 13: 3-Methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-amine [ka]

[0282] Step 1: tert-Butyl 3-(hydroxymethyl)piperazine-1-carboxylate [ka] To a stirred solution of commercially available 1-(tert-butyl) 3-methylpiperazine-1,3-dicarboxylate (1000 mg, 4.093 mmol) in dry THF (10 mL) was added a 1 M solution of LiAlH in THF (4.912 mL, 4.912 mmol) at 0-5 °C, and the reaction mass was stirred at this temperature for 2 h. The reaction progress was monitored by TLC, and after completion, it was quenched by dropwise addition of a saturated solution of sodium sulfate and further stirred at room temperature for 1 h. The aqueous solution was filtered through a bed of Celite. The filtrate was evaporated in vacuo to give the title compound (1050 mg, crude) as a yellowish solid, which was used in the next step without further purification. LCMS m / z: 217.10 [M+H].

[0283] Step 2: tert-Butyl 8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate [ka] 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 the whole was stirred at 30 °C for 18 h. The reaction progress was monitored by LCMS, and upon completion, it was diluted with cold water and extracted with 10% methanol in DCM. The combined organic layers were evaporated to give the crude compound, which was purified by column chromatography on a silica gel bed using methanol and DCM as eluents to give the title compound (280 mg, 99% yield) as a yellow semi-solid. LCMS m / z: 336.11 [M+H].

[0284] Step 3: 8-Nitro-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine.HCl [ka] 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 4 M HCl-dioxane (3 mL) at 0-5 °C, and the resulting reaction mixture was stirred at room temperature for 3 h. The reaction was monitored by LCMS, and upon completion, it was evaporated in vacuo to give the title compound (270 mg, crude) as a yellowish solid, which was used in the next step without further purification. LCMS m / z: 236.02 [M+H].

[0285] Step 4: 3-Methyl-8-nitro-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine [ka] 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) at room temperature was added a 40% solution of formaldehyde (0.430 mL, 5.739 mmol) and NaBHCN (129.83 mg, 2.066 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by UPLC-MS, and upon completion, it was diluted with water and extracted with 10% methanol in DCM. The combined organic layers were evaporated in vacuo to give the title compound (235 mg, crude) as a yellowish semi-solid, which was used in the next step without further purification. LCMS m / z: 250.05 [M+H].

[0286] Step 5: 3-Methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-amine [ka] 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 NH4Cl (241.41 mg, 4.513 mmol) as a solution in water (1 mL). The resulting reaction mixture was refluxed at 85 °C for 2 h. The reaction progress was monitored by TLC and LC-MS. Upon completion, the reaction mixture was diluted with water (20 mL) and extracted with 10% methanol in DCM solution (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 the eluent to give the title compound (180 mg, 90% yield) as a pale brown viscous liquid. LCMS m / z: 220.06 [M+H].

[0287] 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 [ka] 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. 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 then added to the reaction vessel, and the whole was stirred at room temperature for 18 hours. The progress of the reaction was monitored by TLC / LC-MS. Upon completion, the reaction mixture was diluted with water (20 mL) and extracted with 10% methanol in DCM (2 × 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 on a silica gel (12 g) column using 5% MeOH in DCM as the eluent to give the title compound (150 mg, 51% yield, 98% HPLC purity) as a light brown viscous liquid. LCMS m / z: 481.04 [M+H].

[0288] Step 2: 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 [ka] 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 4 M HCl in dioxane (5 mL) was heated at 80 °C for 2 h. 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 yellowish sticky solid, which was used in the next step without further purification. LCMS m / z: 375.05 [M+H].

[0289] 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-carboxamide (Example 168) [ka] 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) followed by DIPEA (0.367 mL, 2.103 mmol) at room temperature. The resulting reaction mixture was stirred at 110 °C for 18 h. The reaction progress was monitored by LC-MS, and upon completion, the reaction mixture was diluted with water (25 mL) and extracted with 10% methanol in DCM solution (2 x 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 prep-HPLC to give the title compound (25 mg, 13% yield, 96.82% purity by HPLC) as a brown solid. 1 H NMR (500 MHz; DMSO-d6): δ 1.67 (t, J = 10.65 Hz, 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 = 10.0 Hz, 1H), 2.85 (d, J = 10.6 Hz,1H), 2.99 (t, J = 9.65 Hz, 1H), 3.65 (d, J = 11.35H, 1H), 3.89 (t, J = 9.45 Hz,1H), 4.21-4.26 (m, 3H), 5.55 (d, J = 7.45 Hz, 1H), 5.81 (s, 1H), 6.81 (d, J =8.8 Hz, 1H), 6.92-6.94 (m, 1H), 7.14 (d, J = 2.25 Hz, 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].

[0290] 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 [ka] Example 363 was prepared according to the methods described in General Procedures 1-7 and as described below.

[0291] Preparation 15: 4-(4-(6-methylpyridin-3-yl)piperazin-1-yl)aniline [ka]

[0292] Step 1: 1-(6-methylpyridin-3-yl)-4-(4-nitrophenyl)piperazine [ka] 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) at room temperature. t BuONa (402 mg, 3.58 mmol), BrettPhos (154 mg, 0.29 mmol), and Brettphos-Pd-G3 (130 mg, 0.14 mmol) were added. The resulting mixture was heated at 100° C. under a nitrogen atmosphere for 16 hours. The reaction progress was monitored by LCMS, and upon completion, the reaction mixture was cooled to room temperature and filtered through a bed of celite. The filtrate was evaporated under reduced pressure to give the crude product, which was then purified by column chromatography to give the title compound (400 mg, 93.5% yield) as a yellow solid. LCMS m / z: 299.1 [M+H].

[0293] Step 2: 4-(4-(6-methylpyridin-3-yl)piperazin-1-yl)aniline [ka] 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 then placed under hydrogen balloon pressure for 2 hours. TLC and LC-MS confirmed the reaction was complete, after which the reaction mass was filtered through a short bed of Celite, and the filtrate was evaporated under reduced pressure to give the crude product, which was purified by column chromatography to give the title compound (200 mg, 85% yield) as an off-white solid. LCMS m / z: 269.2 [M+H].

[0294] Preparation 16: 2-Methoxy-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)nicotinic acid [ka]

[0295] Step 1: Methyl 4-iodo-2-methoxynicotinate [ka] To a stirred solution of commercially available 4-iodo-2-methoxynicotinic acid (300 mg, 1.075 mmol) in DMF (6 mL) was added KCO (371.50 mg, 2.688 mmol) followed by MeI (0.1 mL, 1.613 mmol) at ice-cold temperature, and the whole was stirred at room temperature for 2 hours. UPLC and TLC showed that the desired mass was formed, and the starting material was completely consumed. The reaction mixture was diluted with 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 the crude product, which was purified by Combi-flash chromatography on silica gel (12.0 g) using 20% ​​ethyl acetate in hexane as the eluent to give the title compound (190 mg, 60% yield) as an off-white solid. LCMS m / z: 294.02 [M+H].

[0296] Step 2: Methyl 2-methoxy-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)nicotinate [ka] 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 min, then Pd(dba) (56.22 mg, 0.0614 mmol) and XPhos (71.05 mg, 0.1228 mmol) were added, and the whole was further stirred at 100 °C overnight. LCMS and TLC showed the desired compound had formed, with the starting material being completely consumed. The crude mixture was diluted with water and extracted with 10% methanol in DCM. The combined organic layers were dried over anhydrous NaSO, filtered, and evaporated in vacuo to give the crude product, which was purified by Combi-flash to give the title compound (150 mg, 77% yield) as a white solid. LCMS m / z: 331.22 [M+H].

[0297] Step 3: 2-Methoxy-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)nicotinic acid [ka] 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 was stirred at room temperature for 4 h. UPLC and TLC showed that the desired mass was formed, and the starting material was completely consumed. The solvent was evaporated in vacuo to give the crude product, which was diluted with a small amount of water, and the pH of the mixture was adjusted to approximately 5 by slow addition of citric acid solution. The resulting mass 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 further purification. LCMS m / z: 317.19 [M+H].

[0298] Preparation 17, Step 1: 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 [ka] 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. Then, 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 progress of the reaction was monitored by LCMS, and after 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 give the crude product, which was purified by column chromatography to give the title compound (100 mg, 55.8% yield) as a brown solid. LCMS m / z: 567.3 [M+H].

[0299] 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) [ka] 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 prep-HPLC to afford the title compound (12 mg, 30.8% yield, 99.65% purity by HPLC) as an off-white solid. 1H NMR (400 MHz; DMSO-d6): δ 1.93 (s, 3H), 2.36 (s, 3H), 3.25-3.31 (m, 10H, consistent 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 = 8.88Hz, 2H), 8.21 (s, 1H), 11.34 (s, 1H), 11.90 (s, 1H), 12.87 (s, 1H); LCMS m / z: 553.2 [M+H].

[0300] Example 371: 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 [ka] Example 371 was prepared according to the methods described in General Procedures 1-7 and as described below.

[0301] Preparation 18: 4-(4-(thiazol-2-yl)piperazin-1-yl)aniline [ka]

[0302] Step 1: 2-(4-(4-nitrophenyl)piperazin-1-yl)thiazole [ka] To a stirred solution of commercially available 1-fluoro-4-nitro-benzene (400 mg, 2.34 mmol) in DMF (10 mL) was added K2CO3 (978 mg, 7.09 mmol) and commercially available 2-piperazin-1-ylthiazole (400 mg, 2.84 mmol), and stirring was continued at room temperature for 16 h. LCMS confirmed the formation of the product. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography to give the title compound (500 mg, 72.9% yield) as a yellow solid. LCMS m / z: 291.0 [M+H].

[0303] Step 2: 4-(4-(thiazol-2-yl)piperazin-1-yl)aniline [ka] 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 further purification. LCMS m / z: 261.1 [M+H].

[0304] Preparation 19: 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 (Example 371) [ka] The title compound was prepared using exactly the same method described in Preparation 17, Steps 1-2, 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, consistent 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 = 3.6 Hz, 1H), 6.99 (d, J = 9.04Hz, 2H), 7.19 (d, J = 3.6 Hz, 1H), 7.29 (d, J = 11.92 Hz, 2H), 7.51 (d, J LCMSm / z: 545.39 [M+H].

[0305] Example 197: 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 [ka] Example 197 was prepared according to the methods described in General Procedures 1-7 and as described below.

[0306] Preparation 20: 4-(2-(methoxymethyl)-4-methylpiperazin-1-yl)aniline [ka]

[0307] Step 1: tert-Butyl 3-(hydroxymethyl)-4-(4-nitrophenyl)piperazine-1-carboxylate [ka] To a stirred solution of commercially available 1-fluoro-4-nitrobenzene (500 mg, 0.046 mmol) in DMSO (8 mL) at room temperature was added tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (Preparation 13, Step 1) (342.51 mg, 2.427 mmol), followed by KOH (389.15 mg, 6.935 mmol), which was then further stirred at 30 °C for 18 h. The reaction progress was monitored by TLC / LCMS, and upon completion, the reaction mixture was diluted with cold 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 the crude product, which was purified by Combi-flash using 3% MeOH-DCM as the eluent to give the title compound (415 mg, 51% yield) as a light brown, viscous liquid. LCMS m / z: 338.12 [M+H].

[0308] Step 2: 2-(Methoxymethyl)-4-methyl-1-(4-nitrophenyl)piperazine [ka] 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 4 M HCl in dioxane (4 mL) at 0-5 °C, and the whole was stirred at 30 °C for 5 h. 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 added at room temperature with a 40% solution of formaldehyde (0.66 mL, 8.851 mmol) along with NaBHCN (200.23 mg, 3.186 mmol). The resulting mixture was stirred at room temperature for 18 h. The reaction progress was monitored by UPLC-MS, and upon completion, the reaction mixture was diluted with water (20 mL) and extracted with 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 the eluent to give the title compound (235 mg, 50% yield) as a light brown viscous liquid. LCMS m / z: 266.09 [M+H].

[0309] Step 3: 4-(2-(methoxymethyl)-4-methylpiperazin-1-yl)aniline [ka] 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) at room temperature 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). The resulting reaction mixture was refluxed at 80 °C for 2 h. After completion of the reaction, it was cooled to room temperature, diluted with water (20 mL), and extracted with 10% methanol in DCM solution (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) as a brown sticky solid, which was used in the next step without further purification. LCMS m / z: 236.31 [M+H].

[0310] Preparation 21: 3,8-Dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-amine.2HCl [ka]

[0311] Step 1: N-(5-bromo-2-hydroxy-4-methylpyridin-3-yl)-2-chloropropanamide [ka] 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 0-5 °C. 2-Chloropropanoyl chloride (1.17 mL, 11.822 mmol) was then added dropwise, and the resulting reaction mixture was stirred at room temperature for 3 h. The reaction progress was monitored by TLC and LC-MS, which indicated the conversion of the starting material to the desired product. The reaction mixture was diluted with water (200 mL) and extracted with 10% methanol in DCM solution (10 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (3.0 g, crude) as a pale white solid, which was used in the next step without further purification. LCMS m / z: 292.84 [M+H].

[0312] Step 2: 7-Bromo-3,8-dimethyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one [ka] To a stirred solution of N-(5-bromo-2-hydroxy-4-methylpyridin-3-yl)-2-chloropropanamide (Preparation 21, Step 1) (6000 mg, 20.439 mmol) in DMF (60 mL) was added KCO (8474 mg, 61.318 mmol), and the whole was stirred at room temperature for several minutes and then heated at 70 °C overnight. The progress of the reaction was monitored by TLC and LC-MS, which indicated the conversion of the starting material to the desired product. The reaction mixture was poured into cold water (300 mL) and stirred for 30 minutes to produce a solid precipitate, which was collected in a Buchner funnel, washed with hexane, and dried under suction for 30 minutes, followed by oven drying overnight to afford the title compound (4.1 g, crude) as a light brown solid, which was used in the next step without further purification. LCMS m / z: 256.94 [M+H].

[0313] Step 3: 7-Bromo-3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine [ka] A stirred solution of 7-bromo-3,8-dimethyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (Preparation 21, Step 2) (2970 mg, 11.552 mmol) in BH3.THF (46.2 mL, 1 M solution in THF) was stirred at 0-5 °C for several minutes, then at room temperature for 3 h. After completion of the reaction (monitored by LC-MS and TLC), the reaction mixture was quenched by the dropwise addition of MeOH (100 mL) until effervescence ceased, followed by the addition of 1 N HCl (46.2 mL) and further stirring for 1 h. The MeOH was then evaporated under reduced pressure to give a residue that was neutralized with a saturated aqueous solution of NaHCO3. It was then diluted with water (200 mL) and extracted with EtOAc (4 × 200 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated in vacuo to give the crude product, which was purified by column chromatography on silica gel (80 g) using 5-7% ethyl acetate in DCM as the eluent to give the title compound (2.1 g, 75% yield) as a white solid. LCMS m / z: 242 [M+H].

[0314] Step 4: tert-Butyl 7-bromo-3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate [ka] 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 equiv.) under an inert atmosphere at 0-5 °C. Boc-anhydride (3.96 mL, 17.277 mmol) was then added to the reaction vessel, and stirring was continued at room temperature for 7 h. The reaction progress was monitored by TLC / LCMS. Upon 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 the crude product, which was purified by column chromatography using 25-30% EtOAc in hexanes as the eluent to give the title compound (2.4 g, 81% yield) as an off-white solid. LCMS m / z: 342.92 [M+H].

[0315] Step 5: tert-Butyl 7-((tert-butoxycarbonyl)amino)-3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate [ka] To a stirred solution of Boc-amine (1574 mg, 13.442 mmol) in 1,4-dioxane (46 mL) at room temperature was added CsCO (6569 mg, 20.16 mmol) and tert-butyl 7-bromo-3,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (Preparation 21, Step 4) (2306 mg, 6.721 mmol). The resulting reaction mixture was purged with nitrogen for 20 minutes. Brettphos-Pd-G (1218 mg, 1.344 mmol) was then added to the reaction vessel, and the whole was stirred at 105 °C for 3 hours. The reaction progress was monitored by LCMS, and upon 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 give the crude product, which was purified by column chromatography using 25% EtOAc in DCM as the eluent to give the title compound (2100 mg, 82% yield) as a brown solid. LCMS m / z: 380.40 [M+H].

[0316] Step 6: 3,8-Dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-amine.2HCl [ka] 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 2 M 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 (1330 mg, crude) as a light brown solid. LCMS m / z: 180.22 [M+H].

[0317] Preparation 22, Step 1: 4-Iodo-2-methoxy-N-(4-(2-(methoxymethyl)-4-methylpiperazin-1-yl)phenyl)nicotinamide [ka] 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. 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 then added to the reaction vessel, and the whole was further stirred at room temperature for 18 hours. The progress of the reaction was monitored by LC-MS, and upon completion, the reaction mixture was diluted with water (20 mL) and extracted with 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 the eluent to give the title compound (155 mg, 37% yield) as a light brown sticky solid. LCMS m / z: 497.16 [M+H].

[0318] 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 [ka] 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) at room temperature 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). The mixture was purged with nitrogen gas for 15 minutes, and then Pd(dba) (26.75 mg, 0.029 mmol) and Xantphos (33.81 mg, 0.058 mmol) were added to the reaction vessel and heated at 100 °C overnight. The reaction progress was monitored by TLC / LC-MS. Upon completion, the reaction mixture was diluted with water (20 mL) and extracted with 10% methanol in DCM solution (3 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 4-5% MeOH-DCM as the eluent to give the title compound (140 mg, 87% yield) as a brown sticky solid. LCMS m / z: 548.38 [M+H].

[0319] 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) [ka] 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 4 M HCl in dioxane (5 mL) was stirred at 80° C. for 3 h. The reaction progress was monitored by LC-MS, and upon completion, the reaction mixture was distilled off to give the crude product, which was purified by prep-HPLC to give the title compound (20 mg, 16% yield) as a white solid. HPLC purity: 99.84%; 1H NMR (500 MHz; DMSO-d6): δ 1.26 (d, J = 6.25 Hz, 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 = 8.95 Hz, 2H), 11.31 (s, 1H), 11.79 (s, 1H), 12.85 (s, 1H); LCMSm / z: 534.35 [M+H].

[0320] Example 263: 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 [ka] Example 263 was prepared according to the methods described in General Procedures 1-7 and as described below.

[0321] Preparation 23, Step 1: 4-Iodo-2-methoxy-N-(4-(4-methylpiperazin-1-yl)-3-nitrophenyl)nicotinamide [ka] To a stirred solution of 4-iodo-2-methoxynicotinic acid (Preparation 11, Step 1) (200 mg, 0.71 mmol) in DCM (5 mL) was added thionyl chloride (0.10 mL, 1.41 mmol), and the whole was stirred at 45 °C for 1 h. The reaction was then cooled to room temperature and concentrated in vacuo to give the corresponding crude acid chloride, which was dissolved in DCM (5 mL) and added dropwise at 0-5 °C with DIPEA (0.38 mL, 2.14 mmol), followed by a solution of commercially available 4-(4-methylpiperazin-1-yl)-3-nitroaniline (202 mg, 0.85 mmol) in DCM (2 mL). The resulting reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by LCMS, and upon completion, the reaction mixture was 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 give the crude product, which was purified by column chromatography to give the title compound (250 mg, 71% yield) as an off-white solid. LCMS m / z: 497.97 [M+H].

[0322] Step 2: 4-chloro-N-(4-(4-methylpiperazin-1-yl)-3-nitrophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] 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 4 M 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 (200 mg, crude) as a brown solid which was used in the next step without further purification. LCMS m / z: 392.1 [M+H].

[0323] 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 [ka] 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 in a sealed tube at 120 °C for 16 h. The progress of the reaction was confirmed by LC-MS, and then the solvent was evaporated in vacuo to give the crude product, which was purified by column chromatography on silica gel (100-200 mesh) to give the title compound (130 mg, 48.9% yield) as an off-white solid. LCMS m / z: 521.2 [M+H].

[0324] Preparation 24: 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 (Example 263) [ka] 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 an inert atmosphere, and the whole was stirred under hydrogen balloon pressure for 2 hours. The reaction progress was monitored by LC-MS, and upon 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 give the crude compound, which was purified by prep-HPLC to give the title compound (13 mg, 14% yield) as an off-white solid. HPLC purity: 99.82%; 1H NMR (400 MHz; DMSO-d6): δ 1.92 (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 = 7.4 Hz, 1H), 5.79 (s, 1H), 6.77-6.85 (m, 2H),7.03 (d, J = 2.08 Hz, 1H), 7.24-7.30 (m, 2H), 11.33 (d, J = 6.08 Hz, 1H), 11.93(s, 1H), 12.77 (s, 1H); LCMS m / z: 491.34 [M+H].

[0325] 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 [ka] Example 132 was prepared according to the methods described in General Procedures 1-7 and as described below.

[0326] Preparation 25: tert-Butyl 7-bromo-8-methoxy-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate [ka]

[0327] Step 1: 5-Bromo-2-chloro-4-methoxy-3-nitropyridine [ka] To a stirred solution of commercially available 5-bromo-2,4-dichloro-3-nitropyridine (1650 mg, 6.069 mol) in MeOH (20 mL) at room temperature was added NaOMe (327.84 mg, 6.069 mmol), and the combined reaction mixture was stirred for 2 h 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 give a residue, which was purified by Combi-flash on silica gel using ethyl acetate and hexane as eluents to give the title compound (1550 mg, 95% yield) as a yellowish liquid.

[0328] Step 2: Methyl 2-((5-bromo-4-methoxy-3-nitropyridin-2-yl)oxy)acetate [ka] 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, 5-bromo-2-chloro-4-methoxy-3-nitropyridine (Preparation 25, Step 1) (3100 mg, 11.591 mmol) was added to the reaction mixture at room temperature. The resulting mixture was stirred at 80 °C overnight. The progress of the reaction was monitored by TLC and LCMS, and upon completion, it was diluted with water and extracted with ethyl acetate. The combined organic layers were evaporated to dryness in vacuo to give the crude compound, which was purified by Combi-flash on silica gel using ethyl acetate and hexane as eluents to give the title compound (360 mg, 10% yield) as a yellowish sticky solid. LCMS m / z: 320.98 [M+H].

[0329] Step 3: 7-Bromo-8-methoxy-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one [ka] 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 then the reaction mixture was refluxed at 90° C. for 1.5 hours. LCMS and TLC showed that the desired product had formed. The acetic acid was evaporated in vacuo to give a residue that was neutralized with a saturated solution of sodium bicarbonate and diluted with water. The neutralized aqueous mass was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (300 mg, crude) as a white solid, which was used in the next step without further purification. LCMS m / z: 258.94 [M+H].

[0330] Step 4: 7-Bromo-8-methoxy-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine [ka] A suspension of 7-bromo-8-methoxy-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (Preparation 25, Step 3) (300 mg, 1.158 mmol) in 0.9 M BH3-THF solution (6.43 mL, 5.790 mmol) at 0-5 °C in a reaction vial was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mass was quenched with methanol followed by 1 N HCl (0.2 mL). After 1 hour, it was evaporated to dryness in vacuo, neutralized with a saturated solution of sodium bicarbonate, and diluted with water. The neutralized aqueous mass was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (360 mg, crude) as a yellowish viscous liquid, which was used in the next step without further purification. LCMS m / z: 244.96 [M+H].

[0331] Step 5: tert-Butyl 7-bromo-8-methoxy-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate [ka] To a stirred solution of 7-bromo-8-methoxy-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (Preparation 25, Step 4) (360 mg, 1.468 mmol) in DCE (10 mL) at room temperature was added TEA (1.02 mL, 7.340 mmol), DMAP (179.34 mg, 1.468 mmol), and Boc-anhydride (1.349 mL, 5.878 mmol). The resulting reaction mixture was stirred at room temperature for 6 hours. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layers were evaporated to give the crude product, which was purified by Combi-flash on silica gel using ethyl acetate and hexane as eluents to give the title compound (300 mg, 59% yield) as a yellowish sticky solid. LCMS m / z: 345.06 [M+H].

[0332] Preparation 26: 4-amino-2-methoxy-N-(4-(4-methylpiperazin-1-yl)phenyl)nicotinamide [ka]

[0333] Step 1: tert-butyl (2-methoxy-3-((4-(4-methylpiperazin-1-yl)phenyl)carbamoyl)pyridin-4-yl)carbamate [ka] 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) at room temperature was added tert-butyl carbamate (182.78 mg, 1.560 mmol), followed by CsCO (635.3 mg, 1.949 mmol). The resulting reaction mixture was purged with nitrogen gas 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, which was heated at 105 °C overnight. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was diluted with water and extracted with 10% MeOH in DCM solution (5 × 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 Combi-flash on a silica gel column (12 g) using 3-4% MeOH in DCM as the eluent to give the title compound (315 mg, 49% yield) as a sticky solid. LCMS m / z: 442.55 [M+H].

[0334] Step 2: 4-amino-2-methoxy-N-(4-(4-methylpiperazin-1-yl)phenyl)nicotinamide [ka] 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) with ice cooling and the combined mixture was stirred for several minutes before being allowed to warm slowly to room temperature over 2 hours. The reaction progress was monitored by TLC and LCMS, which indicated conversion of the starting material to the desired product with a small amount of demethylated product as an 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 x 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 Combi-flash on a silica gel column (12 g) using 7-9% MeOH in DCM as the eluent to give the title compound (191 mg, 82% yield) as a yellow sticky solid. LCMS m / z: 342.13 [M+H].

[0335] Preparation 27, Step 1: 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 [ka] 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. tBu (56.33 mg, 0.586 mmol) was added. 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 whole was heated at 100 °C overnight. The progress of the reaction was checked 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 to give the crude compound, which was purified by Combi-flash on silica gel to give the title compound (200 mg, crude) as a brown viscous liquid. LCMS m / z: 606.27 [M+H].

[0336] 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) [ka] 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 whole was heated at 65° C. for 40 min. LCMS showed the formation of the desired mass. After 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 crude demethylated 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) as a brown sticky solid, which was suspended in 20% TFA in DCM (2 mL) and stirred at room temperature under an inert atmosphere for 3 hours. The reaction progress was monitored by LCMS, and upon completion, the solvent was evaporated under reduced pressure to give the crude product, which was purified by prep-HPLC to give the title compound (2.8 mg, 11% yield) as a white solid. HPLC purity: 95.24%; 1 H NMR (500 MHz; DMSO-d6): δ 2.17 (s, 3H), 2.43 (s, 4H), 3.03 (s, 4H), 3.22 (d, J = 3.7 Hz, 2H),3.62 (s, 3H), 4.21 (t, J = 3.85 Hz, 2H), 5.68 (d, J = 7.1 Hz, 1H), 5.84 (s,1H), 6.85 (d, J = 9.05 Hz, 2H), 7.23-7.26 (m, 2H), 7.40 (d, J = 9.0 Hz, 2H),11.35 (d, J = 5.95 Hz, 1H), 11.93 (s, 1H), 12.80 (s, 1H); LCMS m / z: 492.25[M+H].

[0337] Example 163: 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 [ka] Example 132 was prepared according to the methods described in General Procedures 1-7 and as described below.

[0338] Preparation 28: 2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-amine.TFA [ka]

[0339] Step 1: 7-Bromo-1,2,3,4-tetrahydroisoquinoline [ka] 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) at 0-5 °C was stirred at room temperature for 1 h and then heated at 60 °C for 1 h. The reaction progress was monitored by TLC and LCMS. Upon completion, it was quenched with methanol, followed by 1 N HCl and neutralized with a saturated solution of sodium bicarbonate. The aqueous mass was extracted with 10% methanol in DCM, and the combined organic layers were concentrated in vacuo to give the crude compound, which was purified on silica gel using methanol in DCM as the eluent to give the title compound (460 mg, crude) as a yellowish solid. LCMS m / z: 211.92 [M+H].

[0340] Step 2: 7-Bromo-2-methyl-1,2,3,4-tetrahydroisoquinoline [ka] 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) at room temperature was added a 40% solution of formaldehyde (0.813 mL, 10.844 mmol) and NaBHCN (245.33 mg, 3.904 mmol). After the addition was complete, the whole was stirred at room temperature for an additional 16 hours. After completion of the reaction (confirmed 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 yellowish sticky solid. LCMS m / z: 225.92 [M+H].

[0341] Step 3: N-(4-Methoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine [ka] 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. t Bu (605.43 mg, 6.300 mmol) was added. The resulting mixture was purged with nitrogen gas for 10 minutes. Pd2(dba)3 (192.36 mg, 0.210 mmol) and Brettphos (225.44 mg, 0.420 mmol) were then added to the reaction mixture, and the whole was heated at 100 °C for 18 hours. The progress of the reaction was monitored by LCMS, and after completion, it was diluted with water and extracted with 10% methanol in DCM. The combined organic layers were evaporated to give the crude compound, which was purified on silica gel using methanol in DCM as the eluent to give the title compound (355 mg, 60% yield) as a brown solid. LCMS m / z: 282.86 [M+H].

[0342] Step 4: 2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-amine.TFA [ka] 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) at 0-5 °C, TFA (1 mL) was added and the reaction mixture was stirred at room temperature for 3 h. 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 dark sticky solid, which was used in the next step without further purification. LCMS m / z: 163.27 [M+H].

[0343] Preparation 29, Step 1: 4-Iodo-2-methoxy-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)nicotinamide [ka] To a stirred solution of 4-iodo-2-methoxynicotinic acid (Preparation 11, Step 1) (280 mg, 1.003 mmol) in THF (10 mL) at room temperature was added HATU (457.97 mg, 1.204 mmol) and DIPEA (0.7 mL, 4.012 mmol), 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 (confirmed by LCMS), the reaction mass was diluted with water and extracted with 10% methanol in DCM. The combined organic layers were concentrated in vacuo to give the crude compound, which was purified on silica gel using methanol in DCM as the eluent to give the title compound (185 mg) as a brown solid. LCMS m / z: 424.06 [M+H].

[0344] Step 2: 4-chloro-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide.HCl [ka] 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 4 M 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 semi-solid, which was used in the next step without further purification. LCMS m / z: 318.07 [M+H].

[0345] Step 3: 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 (Example 163) [ka] 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) followed by DIPEA (0.35 mL, 1.965 mmol) at room temperature. The resulting reaction mixture was heated at 80 °C for 18 h. The reaction progress was monitored by LCMS, and upon 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 prep-HPLC to give the title compound (8 mg, 5% yield) as a light brown solid. HPLC purity: 99.18%; 1H NMR (500 MHz; DMSO-d6): δ 1.85 (s, 3H), 2.25 (s, 3H), 2.43 (s, 2H matches 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 = 8.7Hz, 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].

[0346] Example 315: 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 [ka] Example 315 was prepared according to the methods described in General Procedures 1-7 and as described below.

[0347] Preparation 30: 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 [ka]

[0348] Step 1: tert-Butyl 4-(4-(4-iodo-2-methoxynicotinamido)phenyl)piperazine-1-carboxylate [ka] 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). After 10 min, commercially available tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (1789.56 mg, 6.451 mmol) was added to the reaction vessel. The whole was allowed to stir at room temperature for 12 h. UPLC and TLC showed that the desired product had formed, with the starting material being 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 was evaporated in vacuo to give the crude product, which was purified by Combi-flash (40 g column) using 60% ethyl acetate in hexane as the eluent to give the title compound (3220 mg, 78% yield) as a black solid. LCMS m / z: 539.16 [M+H].

[0349] Step 2: tert-Butyl 4-(4-(2-methoxy-4-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)nicotinamide)phenyl)piperazine-1-carboxylate [ka] 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) 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) at room temperature. The resulting reaction mixture was purged with nitrogen gas for 15 minutes, and then Pd(dba) (85.06 mg, 0.0929 mmol) and XantPhos (107.56 mg, 0.1859 mmol) were added to the reaction vessel. The whole was stirred overnight at 100 °C under an inert atmosphere. LCMS and TLC showed that the desired compound was formed, and the starting material was completely consumed. The reaction mass was cooled to room temperature, diluted with water, and extracted with 5-6% methanol in DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered through a bed of celite, and the filtrate was evaporated in vacuo to give the crude product, which was purified by Combi-flash (80 g column) using 10% methanol in DCM as the eluent to give the title compound (330 mg, 63% yield) as a yellow solid. LCMS m / z: 576.67 [M+H].

[0350] Step 3: 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 [ka] 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 4 M HCl in dioxane (10 mL) was stirred at 80 °C for 3 h. UPLC and TLC showed the desired mass had formed and the starting material had been completely consumed. The solvent from 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].

[0351] Preparation 31: 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 (Example 315) [ka] To a stirred solution of isobutyric acid (12 mg, 0.136 mmol) in DMF (4 mL) at room temperature was added HATU (62.14 mg, 0.238 mmol), followed by DIPEA (0.119 mL, 0.681 mmol). The resulting reaction mixture was stirred at room temperature for 10 minutes, and then 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) was added to the reaction vessel, and stirring was continued 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 10% methanol in DCM solution (2 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC to give the title compound (35 mg, 44% yield) as a white solid. HPLC purity: 99.26%; 1H NMR (400 MHz; DMSO-d6): δ 1.02 (d, J = 6.72 Hz, 6H), 1.93 (s, 3H), 2.88-2.95 (m, 1H),3.04-3.10 (m, 4H), 3.33 (9s, 2H), 3.60-3.64 (m, 4H), 4.26 (t, J = 3.92 Hz, 2H),5.56 (d, J = 7.4 Hz, 1H), 5.81 (s, 1H), 6.95 (d, J = 9.08 Hz, 2H), 7.29 (t, J =5.44 Hz, 2H), 7.50 (d, J = 9.0 Hz, 2H), 11.37 (s, 1H), 11.89 (s, 1H), 12.92 (s,1H); LCMS m / z: 532.05 [M+H].

[0352] 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 [ka] Example 389 was prepared according to the methods described in General Procedures 1-7 and as described below.

[0353] Preparation 32: 3-chloro-4-(4-ethylpiperazin-1-yl)-5-fluoroaniline [ka]

[0354] Step 1: 1-(2-chloro-6-fluoro-4-nitrophenyl)-4-ethylpiperazine [ka] To a stirred solution of commercially available 1-chloro-2,3-difluoro-5-nitrobenzene (300 mg, 1.55 mmol) in ACN (8 mL) was added 1-ethylpiperazine (194.75 mg, 1.705 mmol) at room temperature. The resulting reaction mixture was stirred at 80° C. for 16 hours. The reaction progress was monitored by UPLC-MS, and upon completion, the reaction mass was diluted with 10% MeOH in DCM and washed with brine. The organic layer was concentrated in vacuo to give the title compound (486 mg, crude) as a yellow sticky solid. LCMS m / z: 288.11 [M+H].

[0355] Step 2: 3-chloro-4-(4-ethylpiperazin-1-yl)-5-fluoroaniline [ka] 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 solvents EtOH (6 mL) and HO (2 mL) was added Fe powder (397.73 mg, 7.123 mmol) followed by NH4Cl (380.99 mg, 7.123 mmol) at room temperature. The resulting reaction mixture was allowed to stir at 80 °C for 16 h. The reaction progress was monitored by UPLC-MS. Upon completion, the reaction mixture was filtered through a bed of Celite and the bed was washed with 10% MeOH in DCM. The resulting filtrate was washed with water followed by brine and concentrated in vacuo to give the title compound (422 mg, crude) as a yellow sticky solid. LCMS m / z: 258.11 [M+H].

[0356] Preparation 33, Step 1: N-(3-chloro-4-(4-ethylpiperazin-1-yl)-5-fluorophenyl)-4-iodo-2-methoxynicotinamide [ka] To a stirred solution of 4-iodo-2-methoxynicotinic acid (Preparation 11, Step 1) (372 mg, 1.333 mmol) in THF (10 mL) at room temperature was added HATU (760.37 mg, 1.999 mmol), followed by DIPEA (516.99 mg, 3.999 mmol). After 10 min, 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 at room temperature for 16 h. The reaction progress was monitored by UPLC-MS. 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 the eluent to give the title compound (269 mg, 39% yield) as a yellow solid. LCMS m / z: 519.21 [M+H].

[0357] 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 [ka] 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 gas for 10 minutes, then Pd(dba) (35.35 mg, 0.039 mmol) and Xantphos (44.67 mg, 0.077 mmol) were added to the reaction vessel and the whole was heated at 100 °C for 16 hours. The progress of the reaction was monitored by UPLC-MS. Upon completion, the reaction mass was diluted with 10% MeOH in DCM, filtered through a bed of Celite, and the bed was washed with MeOH-DCM. The resulting filtrate was washed with water, followed by brine. The organic layer was evaporated in vacuo to give the crude product, which was purified by column chromatography using 4-5% MeOH in DCM as the eluent to give the title compound (210 mg, 97% yield) as a dark yellow viscous liquid. LCMS m / z: 555.98 [M+H].

[0358] Step 3: 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 (Example 389) [ka] 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 give the crude compound, which was purified by prep-HPLC to give the title compound (51 mg, 26% yield) as a pale yellow solid. HPLC purity: 99.85%; 1H 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 matched to DMSO water), 4.26 (t, J = 4.0Hz, 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].

[0359] Example 396: 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 [ka] Example 396 was prepared according to the methods described in General Procedures 1-7 and as described below.

[0360] Preparation 34: 2-(6-amino-1-methoxyisoquinolin-4-yl)propan-2-ol [ka]

[0361] Step 1: tert-butyl (1-oxo-1,2-dihydroisoquinolin-6-yl)carbamate [ka] 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 gas for 10 minutes, and then Brettphos-Pd-G (906.50 mg, 1.00 mmol) was added to the reaction vessel, and the whole was heated at 100 °C for 16 hours. The progress of the reaction 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 give the crude product, which was purified by Combi-flash using 2% MeOH in DCM as eluent to give the title compound (780 mg, 60% yield) as a white solid. LCMS m / z: 261.22 [M+H].

[0362] Step 2: tert-butyl (4-iodo-1-oxo-1,2-dihydroisoquinolin-6-yl)carbamate [ka] 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) at room temperature was added 1-iodopyrrolidine-2,5-dione (742.43 mg, 3.30 mmol) and PTSA.HO (57.06 mg, 0.30 mmol). The resulting reaction mixture was allowed to stir at room temperature for 2 hours. After completion of the reaction (confirmed by LCMS), the reaction mixture was treated with an aqueous solution of 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 afford the title compound (1004 mg, 86% yield) as an off-white solid, which was used in the next step without further purification. LCMS m / z: 387.17 [M+H].

[0363] Step 3: tert-butyl (4-iodo-1-methoxyisoquinolin-6-yl)carbamate [ka] 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 whole was stirred at 110 °C for 16 h. The 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 then 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 the eluent to give the title compound (440.23 mg, 85% yield) as a white solid. LCMS m / z: 401.18 [M+H].

[0364] Step 4: tert-butyl (4-acetyl-1-methoxyisoquinolin-6-yl)carbamate [ka] To a stirred, degassed solution of tert-butyl (4-iodo-1-methoxyisoquinolin-6-yl)carbamate (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 h. The reaction progress was monitored by UP-LCMS, and upon 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 onto silica gel and gently rotated on a rotary at 40 °C for 2 h. UP-LCMS showed complete conversion to the desired acetone group after rearrangement of the ether group. The adsorbed compound was purified by Combi-flash using 10% EtOAc in hexane as the eluent to give the title compound (284 mg, 81% yield) as a white solid. LCMS m / z: 317.19 [M+H].

[0365] Step 5: tert-butyl (4-(2-hydroxypropan-2-yl)-1-methoxyisoquinolin-6-yl)carbamate [ka] 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 dry THF (10 mL) was added dropwise methylmagnesium bromide (0.95 mL, 2.70 mmol) at 0-5 °C, and the combined mixture was allowed to stir at room temperature for 4 h. Complete conversion was confirmed by UP-LCMS, after which the reaction mixture was 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 hexanes as the eluent to give the title compound (265 mg, 88% yield) as a pale yellow solid. LCMS m / z: 333.27 [M+H].

[0366] Step 6: 2-(6-amino-1-methoxyisoquinolin-4-yl)propan-2-ol.HCl [ka] 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 4M HCl-dioxane (2 mL) with ice cooling, and the whole was allowed to stir at room temperature for 16 hours. Completion of the reaction was confirmed 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 (106 mg, crude) as a white solid. LCMS m / z: 233.27 [M+H].

[0367] Preparation 35, Step 1: 4-Chloro-2-oxo-1,2-dihydropyridine-3-carboxylic acid [ka] A suspension of 4-iodo-2-methoxynicotinic acid (Preparation 11, Step 1) (558.06 mg, 2 mmol) in 4 M HCl in dioxane (8 mL) was stirred at 80° C. for 2 hours. UP-LCMS and TLC showed complete conversion of the starting material to the desired product. The solvent from the reaction mixture was evaporated in vacuo to give a residue that was triturated with diethyl ether to give the title compound (399 mg, crude) as an off-white solid. LCMS m / z: 173.98 [M+H].

[0368] 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 [ka] 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) at room temperature 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), followed by DIPEA (2 mL, 12.00 mmol). The resulting reaction mixture was stirred at 130 °C for 22 h. The reaction progress was monitored by TLC and UP-LCMS. Upon completion, the solvent was evaporated in vacuo to give a residue that was triturated with diethyl ether to give the title compound (408 mg, 67% yield) as an off-white solid, which was used in the next step without further purification. LCMS m / z: 303.15 [M+H].

[0369] 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) [ka] 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 allowed to stir 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 followed by prep-HPLC using 10% MeOH in DCM as eluent to give the title compound (5 mg, 3% yield) as a pale yellow solid. HPLC purity: 99.79%; 1 H NMR (400 MHz; DMSO-d6): δ 1.68 (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 = 7.28 Hz, 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 = 4.24 Hz, 1H), 8.98 (s,1H), 11.46 (d, J = 6.04 Hz, 1H), 11.78 (s, 1H), 13.46 (s, 1H); LCMS m / z: 517.33[M+H].

[0370] Example 198: 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 [ka] Example 198 was prepared according to the methods described in General Procedures 1-7 and as described below.

[0371] Preparation 36, Step 1: tert-Butyl 7-((tert-butoxycarbonyl)amino)-3-fluoro-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate [ka] 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 dry THF (2 mL) was added LiHMDS (1 M, 0.61 mL) followed by Boc-anhydride (134 mg, 0.61 mmol) at room temperature. The resulting reaction mixture was refluxed for 6 h. TLC showed 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, followed by brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give the Boc-protected intermediate (80 mg, 0.23 mmol), which was immediately taken up in degassed dioxane (2 mL) and Boc-amine (135 mg, 1.16 mmol), CsCO (188 mg, 0.58 mmol), Brettphos (49.6 mg, 0.09 mmol), and Pd(dba) (42.3 mg, 0.05 mmol) were added. The whole was heated at 110 °C under a nitrogen atmosphere for 16 h. The reaction progress was monitored by LCMS. Upon completion, the reaction mixture was filtered through a bed of Celite, and the filtrate was evaporated under reduced pressure to give the crude product, which was purified by column chromatography to give the title compound (50 mg, 56.4% yield) as an off-white solid. LCMS m / z: 384.0 [M+H].

[0372] 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) [ka] 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 4 M HCl-dioxane (1 mL) was stirred at 0-5 °C for 1.5 h. TLC indicated the reaction was complete, and the solvent was evaporated under reduced pressure to give a residue, which was immediately taken up in n-butanol (1 mL) and added with 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) at room temperature. The resulting mixture was heated at 120 °C for 16 h. After completion of the reaction (monitored by TLC and LCMS), the solvent was evaporated under vacuum to give a residue, which was then purified by prep-HPLC to give the title compound (10 mg, 16% yield) as a light brown solid. HPLC purity: 99.76%; 1 H NMR (400 MHz; DMSO-d6): δ 1.98 (s, 3H), 2.22 (s, 3H), 2.45 (s, 4H), 3.07-3.08 (m, 4H), 3.24(d, J = 13.28 Hz, 1H), 3.55 (d, J = 12.84 Hz, 1H), 5.56 (d, J = 7.4 Hz, 1H),5.99 (s, 1H), 6.28 (s, 0.5H), 6.42 (s, 0.5 H), 6.91 (d, J = 8.88 Hz, 2H), 7.28(t, J = 6.84 Hz, 1H), 7.43-7.48 (m, 3H), 11.38 (d, J = 6.08 Hz, 1H), 11.98 (s,1H), 12.85 (s, 1H); LCMS m / z: 394.30 [M+H].

[0373] Example 137: 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-carboxamide)phenyl)piperazine-1-carboxamide [ka] Example 137 was prepared according to the methods described in General Procedures 1-7 and as described below.

[0374] Preparation 37: 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-carboxamide)phenyl)piperazine-1-carboxamide (Example 137) [ka] 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) at 0-5 °C, TEA (0.11 mL, 0.76 mmol) was added, followed by dimethylcarbamoyl chloride (0.01 mL, 0.15 mmol), and the combined mixture was further stirred at room temperature for 3 h. The reaction progress was monitored by LCMS, and upon completion, the solvent was evaporated in vacuo to give the crude product, which was purified by prep-HPLC to give 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 matches 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].

[0375] Example 271: 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 [ka] Example 271 was prepared according to the methods described in General Procedures 1-7 and as described below.

[0376] Preparation 38: 4-chloro-N-(4-(1-isopropyl-1H-pyrazol-5-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide [ka]

[0377] Step 1: 4-iodo-N-(4-(1-isopropyl-1H-pyrazol-5-yl)phenyl)-2-methoxynicotinamide [ka] 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 h. After completion of the reaction (monitored by LCMS and TLC), the solvent was evaporated under reduced pressure to give the 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].

[0378] Step 2: 4-chloro-N-(4-(1-isopropyl-1H-pyrazol-5-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide.HCl [ka] 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 6 N aqueous HCl (3 mL) was refluxed for 16 hours. 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.

[0379] Preparation 39: 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 (Example 271) [ka] 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) at room temperature 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). 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 that was purified by prep-HPLC to give the title compound (10 mg, 9% yield) as a light brown solid. HPLC purity: 99.89%; 1 H NMR (400 MHz; MeOD): δ 1.43 (d, J = 6.64 Hz, 6H), 2.03 (d, J = 9.36 Hz, 3H), 3.44-3.47 (m,2H), 4.35 (t, J = 4.28 Hz, 2H), 4.57-4.63 (m, 1H), 5.73 (t, J = 7.44 Hz, 1H),6.26 (s, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.34-7.38 (m, 3H), 7.53 (d, J = 1.8 Hz,1H), 7.80 (d, J = 8.44 Hz, 2H), 11.96 (s, 1H), 13.01 (s, 1H); LCMS m / z: 486.35[M+H].

[0380] Example 126: 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 [ka] Example 126 was prepared according to the methods described in General Procedures 1-7 and as described below.

[0381] Preparation 40: 7-Amino-8-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one.HCl [ka]

[0382] Step 1: tert-butyl (8-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)carbamate [ka] 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 h. The reaction progress was monitored by LCMS, and upon completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give 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].

[0383] Step 2: 7-Amino-8-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one.HCl [ka] 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 4 M 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.

[0384] Preparation 41: 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 (Example 126) [ka] 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) at room temperature 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). The resulting mixture was stirred 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 that was purified by prep-HPLC to give the title compound (12 mg, 5% yield) as a white solid. HPLC purity: 98.05%; 1 H NMR (400 MHz; 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 = 7.2 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 7.2Hz, 1H), 7.42 (s, 1H), 7.47 (d, J = 8.8 Hz, 2H), 11.85 (s, 1H), 13.21 (s, 1H);LCMS m / z: 490.39 [M+H]. The examples in the following table were prepared according to the methods used above to prepare Examples 45, 126, 132, 137, 163, 167, 168, 197, 198, 263, 271, 315, 363, 371, 389, and 396 using the appropriate amine as described in General Procedures 1-8. In most cases, the amines were commercially available or synthesized by analogy with the methods described above. Purification was as described in the previous methods.

[0385] [Table 1] TIFF2025539086000209.tif209149 TIFF2025539086000210.tif202149 TIFF2025539086000211.tif202149 TIFF2025539086000212.tif202149 TIFF2025539086000213.tif195149 TIFF2025539086000214.tif216149 TIFF2025539086000215.tif216149 TIFF2025539086000216.tif209149 TIFF2025539086000217.tif216149 TIFF2025539086000218.tif174149 TIFF2025539086000219.tif181149 TIFF2025539086000220.tif174149 TIFF2025539086000221.tif181149 TIFF2025539086000222.tif216149 TIFF2025539086000223.tif209149 TIFF2025539086000224.tif209149 TIFF2025539086000225.tif216149 TIFF2025539086000226.tif209149 TIFF2025539086000227.tif209149 TIFF2025539086000228.tif209149 TIFF2025539086000229.tif216149 TIFF2025539086000230.tif209149 TIFF2025539086000231.tif188149 TIFF2025539086000232.tif202149 TIFF2025539086000233.tif202149 TIFF2025539086000234.tif202149 TIFF2025539086000235.tif216149 TIFF2025539086000236.tif209149 TIFF2025539086000237.tif202149 TIFF2025539086000238.tif209149 TIFF2025539086000239.tif216149 TIFF2025539086000240.tif216149 TIFF2025539086000241.tif174149 TIFF2025539086000242.tif188149 TIFF2025539086000243.tif216149 TIFF2025539086000244.tif195149 TIFF2025539086000245.tif216149 TIFF2025539086000246.tif181149 TIFF2025539086000247.tif195149 TIFF2025539086000248.tif181149 TIFF2025539086000249.tif216149 TIFF2025539086000250.tif209149 TIFF2025539086000251.tif216149 TIFF2025539086000252.tif181149 TIFF2025539086000253.tif209149 TIFF2025539086000254.tif209149 TIFF2025539086000255.tif188149 TIFF2025539086000256.tif216149 TIFF2025539086000257.tif188149 TIFF2025539086000258.tif209149 TIFF2025539086000259.tif188149 TIFF2025539086000260.tif181149 TIFF2025539086000261.tif209149 TIFF2025539086000262.tif216149 TIFF2025539086000263.tif216149 TIFF2025539086000264.tif209149 TIFF2025539086000265.tif209149 TIFF2025539086000266.tif174149 TIFF2025539086000267.tif85149

[0386] 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 [ka] Example 98 was prepared according to the methods described in General Procedures 1-3, 8 and below.

[0387] Preparation 6: 4-Methoxy-6-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyrimidine-5-carboxylic acid [ka]

[0388] Step 1: Methyl 4-chloro-6-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyrimidine-5-carboxylate [ka] To a stirred solution of commercially available methyl 4,6-dichloropyrimidine-5-carboxylate (300 mg, 1.449 mmol) in t-BuOH (10 mL) at room temperature was added 8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-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 upon completion, the solvent was evaporated to dryness. It was then diluted with water and extracted with ethyl acetate. The combined organic layers were evaporated to give the crude compound, which was purified on a silica gel bed using ethyl acetate and hexane as eluents to give the title compound (90 mg, 18% yield) as a brown solid. LCMS m / z: 336.18 [M+H].

[0389] Step 2: 4-Methoxy-6-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyrimidine-5-carboxylic acid [ka] To a stirred solution of methyl 4-chloro-6-((8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyrimidine-5-carboxylate (Preparation 6, Step 1) (90 mg, 0.268 mmol) in THF (3 mL) and methanol (1.5 mL) at room temperature was added an aqueous solution of LiOH.HO (44.99 mg, 1.072 mmol, 1.5 mL of water). The whole was stirred at room temperature overnight. The progress of the reaction was monitored by LCMS. Upon 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 acidify the solution, resulting in 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].

[0390] Preparation 7: 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 [ka] 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 min, 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 h. 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 evaporated to give the crude product, which was purified on a silica gel bed using methanol and DCM as eluents to give the title compound (85 mg, 100% yield) as an off-white sticky solid. LCMS m / z: 491.35 [M+H].

[0391] 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) [ka] 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 4 M HCl in dioxane (3 mL) was allowed to stir at 80° C. for 3 hours. The reaction progress was monitored by LCMS and upon completion, the solvent was evaporated in vacuo to give a residue which was triturated with diethyl ether and finally purified by prep-HPLC to give the title compound (18 mg, 25% yield) as a yellow solid. HPLC purity: 99.53%; 1H 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]. The examples in the following table were prepared following the method used above to prepare Example 98 using the appropriate amine as described in General Procedures 1-8. Purification was as described in the previous method.

[0392] [Table 2]

[0393] Biological Testing HPK-1 biochemical enzyme assay The inhibitory potency of compounds 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 the presence of various concentrations of test compound or vehicle in 40 mM Tris.Cl pH 7.4 buffer containing 20 mM MgCl, 50 μM DTT, and 0.1 mg / mL BSA for 30 minutes at 25°C. The reaction was quenched, and the reaction mixture was then analyzed using an ADP-Glo ​​kit, which measures the ADP produced. Percent inhibition was calculated from substrate conversion, considering no enzyme control reaction as 100% inhibition and vehicle-only reaction as 0% inhibition. Compounds were dissolved in DMSO and evaluated at 10 concentrations to determine the IC. 50 value was determined.

[0394] In the table below, A is HPK-1 IC 50B represents HPK-1 IC ≤ 10 nM 50 >10 nM but ≤100 nM, and C represents HPK-1 IC 50 represents >100nM but ≤1000nM.

[0395] [Table 3] TIFF2025539086000276.tif210149 TIFF2025539086000277.tif46149

Claims

1. A compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomer or polymorph thereof. 【Chemistry 1】 [In the formula, X is CH or N; Z is phenyl or 5- or 6-membered heteroaryl, wherein said phenyl or heteroaryl is selected from the group consisting of halogen, optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, CN, OR ８ , S.R. ８ , SOR ８ , S.O. ２ R ８ , S.O. ２ NR ８ R ９ , C.O.R. ８ , COOR ８ , C.O.R. ８ R ９ , N.R. ８ COR ９ , N.R. ８ SO ２ R ９ , N.R. ８ R ９ , optionally substituted 3- to 10-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C ６～１０ aryl or optionally substituted C ３～９ cycloalkyl, and / or wherein adjacent substituents of said phenyl or heteroaryl, together with the atoms to which they are attached, may form an optionally substituted 3- to 6-membered heterocycle or an optionally substituted 5- or 6-membered heteroaryl; R １ ~R ７ are independently hydrogen, optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, halogen, CN, OR １０ , S.R. ８ , SOR ８ , S.O. ２ R ８ , S.O. ２ NR ８ R ９ , C.O.R. １０ , COOR ８ , C.O.R. １０ R １１ , N.R. １０ COR １１ , N.R. １０ SO ２ R １１ , N.R. １０ R １１ , optionally substituted C ３ ~C ６ 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 they are attached, form a C=O group, an optionally substituted C ３ ~C ６ cycloalkyl or optionally substituted 3- to 8-membered heterocyclyl, and / or R ３ and R ５ together with the C atom to which they are attached, optionally substituted C ３ ~C ６ forming a cycloalkyl or an optionally substituted 3- to 8-membered heterocyclyl, R ８ and R ９ are independently hydrogen, optionally substituted C １ ~C １２ Alkyl, optionally substituted C ２ ~C １２ Alkenyl, optionally substituted C ２ ~C １２ Alkynyl, optionally substituted C ６～１２ Aryl, optionally substituted C ３ ~C ６ cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl; R １０ and R １１ are independently hydrogen, optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, optionally substituted C ６～１２ Aryl, optionally substituted C ３ ~C ６ cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl.

2. R １ is hydrogen, optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, halogen, CN, OR １０ , S.R. ８ , SOR ８ , S.O. ２ R ８ , S.O. ２ NR ８ R ９ , C.O.R. １０ , COOR ８ , C.O.R. １０ R １１ , N.R. １０ COR １１ , N.R. １０ SO ２ R １１ or NR １０ R １１ 2. The compound of claim 1, wherein:

3. R ２ is hydrogen, optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, halogen, CN, OR １０ , S.R. ８ , SOR ８ , S.O. ２ R ８ , S.O. ２ NR ８ R ９ , C.O.R. １０ , COOR ８ , C.O.R. １０ R １１ , N.R. １０ COR １１ , N.R. １０ SO ２ R １１ or NR １０ R １１ 3. The compound of claim 1 or claim 2, wherein:

4. R ３ and R ４ are independently hydrogen, optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, halogen, CN, OR １０ , S.R. ８ , SOR ８ , S.O. ２ R ８ , S.O. ２ NR ８ R ９ , C.O.R. １０ , COOR ８ , C.O.R. １０ R １１ , N.R. １０ COR １１ , N.R. １０ SO ２ R １１ , N.R. １０ R １１ , optionally substituted C ３ ~C ６ 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 they are attached, form a C=O group, an optionally substituted C ３ ~C ６ The compound according to any one of claims 1 to 3, which forms a cycloalkyl or an optionally substituted 3- to 8-membered heterocyclyl.

5. R ５ and R ６ are independently hydrogen, optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, halogen, CN, OR １０ , S.R. ８ , SOR ８ , S.O. ２ R ８ , S.O. ２ NR ８ R ９ , C.O.R. １０ , COOR ８ , C.O.R. １０ R １１ , N.R. １０ COR １１ , N.R. １０ SO ２ R １１ , N.R. １０ R １１ , optionally substituted C ３ ~C ６ 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 they are attached, form a C=O group, an optionally substituted C ３ ~C ６ The compound of any one of claims 1 to 4, which forms a cycloalkyl or an optionally substituted 3- to 8-membered heterocyclyl.

6. R ７ is hydrogen, optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, halogen, CN, OR １０ , S.R. ８ , SOR ８ , S.O. ２ R ８ , S.O. ２ NR ８ R ９ , C.O.R. １０ , COOR ８ , C.O.R. １０ R １１ , N.R. １０ COR １１ , N.R. １０ SO ２ R １１ or NR １０ R １１ The compound according to any one of claims 1 to 5,

7. R １ is hydrogen, methyl, CN or OCH ３ and R ２ is hydrogen, R ３ and R ４ are independently hydrogen, methyl, ethyl, i-propyl or fluorine, or R ３ and R ４ together with the C atom to which they are attached form a cyclopropyl, R ５ and R ６ is hydrogen, or R ５ and R ６ together with the C atom to which they are attached form a C=O group, R ７ The compound according to any one of claims 1 to 6, wherein is hydrogen or methyl.

8. The compound of any one of claims 1 to 7, wherein Z is a substituted phenyl, substituted pyrazole, or substituted pyridinyl group.

9. 9. The compound according to any one of claims 1 to 8, wherein adjacent substituents of the phenyl or 5- or 6-membered heteroaryl group Z are linked together with the C atoms of the phenyl or heteroaryl group to which they are attached to form a 5- or 6-membered heterocyclic or heteroaromatic group, and optionally adjacent substituents of the heterocyclic or heteroaryl group, together with the atoms to which they are attached, form a further optionally substituted 3- to 6-membered heterocycle or a further optionally substituted 5- or 6-membered heteroaryl, so that the group Z is an optionally substituted bicyclic fused group or an optionally substituted tricyclic fused group.

10. The optionally substituted bicyclic or tricyclic fused group is an optionally substituted 8- to 14-membered heterocyclic or heteroaromatic group, which is unsubstituted or optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, halogen, oxo, CN, OR １６ , S.R. １６ , SOR １６ , S.O. ２ R １６ , C.O.R. １６ , COOR １６ , C.O.R. １６ R １７ , N.R. １６ COR １７ , N.R. 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; １６ and R １７ are independently hydrogen, optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, optionally substituted C ６～１２ Aryl, optionally substituted C ３ ~C ６ The compound of claim 9, which is cycloalkyl, optionally substituted 3-8 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

11. Z is a group of the formula: 【Chemistry 2】 [In the formula, X ５ , X ６ , X ７ and X ８ is X ５ , X ６ , X ７ and X ８ N or CR, provided that only one of ２１ and R ２１ is, at each occurrence, independently H, halogen, optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, CN, OR ８ , S.R. ８ , SOR ８ , S.O. ２ R ８ , S.O. ２ NR ８ R ９ , C.O.R. ８ , COOR ８ , C.O.R. ８ R ９ , N.R. ８ COR ９ , N.R. ８ SO ２ R ９ , N.R. ８ R ９ , optionally substituted 3- to 6-membered heterocyclyl, optionally substituted 5- or 6-membered heteroaryl, optionally substituted C ６～１０ aryl or optionally substituted C ３～９ is cycloalkyl, A is optionally substituted C １ ~C ６ Alkyl, OR ８ , S.O. ２ R ８ , S.O. ２ NR ８ R ９ , C.O.R. ８ , COOR ８ , C.O.R. ８ R ９ , N.R. ８ COR ９ , N.R. ８ SO ２ R ９ , N.R. ８ R ９ 9. The compound of claim 1, wherein the aryl group is selected from the group consisting of an optionally substituted 3- to 10-membered heterocyclyl and an optionally substituted 5- to 10-membered heteroaryl.

12. The phenyl or 5- or 6-membered heteroaryl group Z is optionally substituted 3- to 10-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C ６～１０ aryl or optionally substituted C ３～９ The compound of any one of claims 1 to 8, which is substituted with cycloalkyl.

13. The phenyl or 5- or 6-membered heteroaryl group Z is of formula (i) or (j): 【Transformation 3】 [In the formula, T is N and M is NR １３ , C.R. １４ R １５ , O, S or SO ２ or T is CR １８ and M is NR １３ , O, S or SO ２ and Q is C(R １２ ) ２ and n is 0, 1 or 2; R １２ each occurrence independently represents H, optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, optionally substituted C １ ~C ６ Alkoxy, halogen, oxo, CN, OR １６ , S.R. １６ , SOR １６ , S.O. ２ R １６ , C.O.R. １６ , COOR １６ , C.O.R. １６ R １７ , N.R. １６ COR １７ , N.R. 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 １２ The group may define an oxo group, or two R １２ The groups may be linked to form a fused group, or two R １２ the groups may be linked to form a bicyclic bridged group; R １３ is H, optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, optionally substituted C １ ~C ６ Alkoxy, halogen, oxo, CN, OR １６ , S.R. １６ , SOR １６ , S.O. ２ R １６ , C.O.R. １６ , COOR １６ , C.O.R. １６ R １７ , N.R. １６ COR １７ , N.R. 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 is H, optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, optionally substituted C １ ~C ６ Alkoxy, halogen, oxo, CN, OR １６ , S.R. １６ , SOR １６ , S.O. ２ R １６ , C.O.R. １６ , COOR １６ , C.O.R. １６ R １７ , N.R. １６ COR １７ , N.R. 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 phenyl or 5- or 6-membered heteroaryl group Z is selected from the group consisting of halogen, optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, CN, OR ８ , S.R. ８ , SOR ８ , S.O. ２ R ８ , S.O. ２ NR ８ R ９ , C.O.R. ８ , COOR ８ , C.O.R. ８ R ９ , N.R. ８ COR ９ , N.R. ８ SO ２ R ９ and NR ８ R ９ The compound of any one of claims 1 to 8, substituted with one or more substituents selected from the group consisting of:

15. 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-dioxidothiomorpholino)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]octan-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]octan-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-dioxidothiomorpholino)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]octan-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]heptan-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-methoxypropanoyl)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-dimethylazetidine-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-(azetidine-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-methoxypropanoyl)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-methoxypropanoyl)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-methylpyrrolidine-3-carbonyl)piperazin-1-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(4-(4-(2-hydroxy-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; 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-methylazetidine-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]octan-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-hydroxypropanoyl)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 2. The compound of claim 1, wherein:

16. A PROTAC of formula (II). PTM-L-ULM (II) wherein PTM is a protein targeting moiety and is a compound of formula (I) as defined in any one of claims 1 to 15; L is a linker, ULM is an E3 ubiquitinylation ligase complex.]

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

18. 19. A compound of formula (I) as defined by any one of claims 1 to 15, a PROTAC as defined in claim 16, or a pharmaceutically acceptable complex, salt, solvate, tautomer or polymorph thereof, or a pharmaceutical composition as defined in claim 17, for use in therapy.

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

20. 19. A compound of formula (I) as defined by any one of claims 1 to 15, a PROTAC as defined in claim 16, or a pharmaceutically acceptable complex, salt, solvate, tautomer or polymorph thereof, or a pharmaceutical composition as defined in claim 17, for use in the treatment, amelioration or prevention of a disease selected from cancer, viral infection and immune-mediated disorder.

21. A compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomer or polymorph thereof for use in modulating the activity of HPK-1 protein. 【Chemistry 4】 wherein X is CH or N; Z is phenyl or 5- or 6-membered heteroaryl, wherein said phenyl or heteroaryl is selected from the group consisting of halogen, optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, CN, OR ８ , S.R. ８ , SOR ８ , S.O. ２ R ８ , S.O. ２ NR ８ R ９ , C.O.R. ８ , COOR ８ , C.O.R. ８ R ９ , N.R. ８ COR ９ , N.R. ８ SO ２ R ９ , N.R. ８ R ９ , optionally substituted 3- to 10-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C ６～１０ aryl or optionally substituted C ３～９ cycloalkyl, and / or wherein adjacent substituents of said phenyl or heteroaryl, together with the atoms to which they are attached, may form an optionally substituted 3- to 6-membered heterocycle or an optionally substituted 5- or 6-membered heteroaryl; R １ ~R ７ are independently hydrogen, optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, halogen, CN, OR １０ , S.R. ８ , SOR ８ , S.O. ２ R ８ , S.O. ２ NR ８ R ９ , C.O.R. １０ , COOR ８ , C.O.R. １０ R １１ , N.R. １０ COR １１ , N.R. １０ SO ２ R １１ , N.R. １０ R １１ , optionally substituted C ３ ~C ６ 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 they are attached, form a C=O group, an optionally substituted C ３ ~C ６ cycloalkyl or optionally substituted 3- to 8-membered heterocyclyl, and / or R ３ and R ５ together with the C atom to which they are attached, optionally substituted C ３ ~C ６ forming a cycloalkyl or an optionally substituted 3- to 8-membered heterocyclyl, R ８ and R ９ are independently hydrogen, optionally substituted C １ ~C １２ Alkyl, optionally substituted C ２ ~C １２ Alkenyl, optionally substituted C ２ ~C １２ Alkynyl, optionally substituted C ６～１２ Aryl, optionally substituted C ３ ~C ６ cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl; R １０ and R １１ are independently hydrogen, optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, optionally substituted C ６～１２ Aryl, optionally substituted C ３ ~C ６ cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl.

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