Preparation of substituted 1,2-diaminoheterocyclic compound derivatives and their pharmaceutical use

Abstract

The present invention relates to compounds that are microtubule-associated serine / threonine-like kinase (MASTL) inhibitors and the use of the compounds for the treatment of diseases and medical conditions mediated by MASTL, such as the treatment of cancer and other target-related diseases.

Description

[Technical Field]

[0001] The present invention relates to compounds that are inhibitors of microtubule-associated serine / threonine-like kinase (MASTL), and the use of such compounds in the treatment of diseases and medical conditions mediated by MASTL, such as the treatment of cancer and other target-related diseases. [Background technology]

[0002] Microtubule-associated serine / threonine kinase homolog (MASTL), also known as Greatwall kinase (GWL), is a member of the AGC kinase family that regulates the mitotic phosphatase complex PP2A / B55. MASTL is located on human chromosome 10p12.1 and encodes an 850-amino acid protein. MASTL is unique among kinases because it contains an approximately 500-amino acid insertion between kinase subdomains VII and VIII, which correspond to the activation loop. The protein regulates mitotic entry and exit through its ability to inactivate the phosphatase PP2A / B55 (Castilho et al., 2009). The M phase kinase Greatwall (GWL) promotes inactivation of PP2A / B55delta, a phosphatase directed against CDK phosphosites (Mol. Biol. Cell. 20(22):4777-89). MASTL indirectly inhibits phosphatases through phosphorylation of ENSA and ARPP19 at S67 and S62 (pENSA / pARPP19), respectively (Gharbi-Ayachi et al., (2010). The substrate of Greatwall kinase, Arpp19, controls mitosis by inhibiting protein phosphatase 2A. (Science 330 1673-1677)). pENSA and pARPP19 are substrates of PP2A / B55, bind tightly to the complex, and inhibit the complex by undergoing dephosphorylation at an extremely slow rate, thereby suppressing the catalytic activity of PP2A / B55 through "unfair competition" (Williams et al., (2014). Greatwall-phosphorylated endosulfine is both an inhibitor and a substrate of PP2A-B55 heterotrimers. (eLife 3:e01695)).Cell entry into mitosis is regulated by a rapid increase in the phosphorylation of various substrates by CDK1 / CCNB1, which is accompanied by a decrease in the activity of PP2A / B55. MASTL is a substrate of CDK1 / CCNB1, and these activities combine to ensure that MASTL activity reaches its peak during mitosis. MASTL activity is essential for regulating mitotic exit by delaying the increase in PP2A / B55 activity until chromosome segregation is complete. Anaphase entry begins with APC / C-dependent ubiquitination of CCNB1, followed by its degradation by the proteasome. This attenuates CDK1 activity, ultimately inactivating MASTL and increasing the activity of PP2A / B55 phosphatases, which are necessary for timely exit from mitosis. Temporal regulation of PP2A / B55 reactivation by the PP2A-B55-ENSA / ARPP19-MASTL pathway is essential for orderly cytokinesis after chromosome segregation (Cundell et al., (2013). The BEG (PP2A-B55 / ENSA / Greatwall) pathway ensures cytokinesis follows chromosome separation. (Mol. Cell 52 393-405)). Suppression of MASTL kinase activity leads to premature cytokinesis, resulting in chromosome segregation defects and aneuploidy.

[0003] MASTL is known to be essential for cell cycle progression during embryogenesis in various organisms, including mice, frogs, and fruit flies. In mice, it remains essential for up to one year after birth, after which its loss (total deletion) is tolerated (Belen Sanz Castillo: Role of MASTL in mammals: Molecular functions and physiological relevance, 2017). Furthermore, an siRNA screen identified MASTL as a gene that can specifically suppress the proliferation of transformed (thyroid cancer) cells but not non-transformed cells (Anania et al., (2015) Identification of thyroid tumor cell vulnerabilities through a siRNA-based functional screening. (Oncotarget 6, 34629-34648)). These studies suggest that the nature of MASTL is not universal but is limited to early developmental steps in the embryo and organism. Furthermore, this study shows that some cancer cells revert to a state similar to the embryonic cell cycle state (where MASTL activity is essential), making their cell cycle regulatory mechanisms sensitive to MASTL loss. Ultimately, inhibitors of MASTL kinase have an excellent therapeutic scope, with broad applicability across a variety of cancers; therefore, MASTL is an ideal target for cancer therapy.

[0004] Many studies have demonstrated that MASTL plays an important role in cancer development. MASTL overexpression has been shown to be a potential prognostic indicator of breast (Alvarez-Fernandez et al. (2017)), oral cavity (Wang et al. (2014) Mastl kinase, a promising therapeutic target, promotes cancer recurrence. (Oncotarget 5 11479-11489)), and stomach (Sun et al. (2017) Mastl overexpression is associated with epithelial to mesenchymal transition and predicts a poor clinical outcome in gastric cancer. (Oncol. Lett. 14 7283-7287) Therapeutic relevance of the PP2A-B55 inhibitory kinase MASTL / Greatwall in breast cancer. (Cell Death Differ. 25, 828-840; Zhuge et al. (2017)). MASTL is a potential poor prognostic indicator in ER+ breast cancer. It has been identified in a variety of human tumors, including colon and rectal cancer (Eur. Rev. Med. Pharmacol. Sci. 21 2413-2420) and colorectal cancer (Vera et al., (2015)). Greatwall promotes cell transformation by hyperactivating AKT in human malignancies (eLife 4, e10115). Mouse xenograft studies using doxycycline-inducible knockout of MASTL by CRISPR / Cas9 in MDA-MB-231 cells showed a significant reduction in tumor size when MASTL was depleted compared to control animals. MASTL protein expression levels correlated with the aggressiveness of ER+ breast cancer and predicted poor patient survival (Alvarez-Fernandez et al., (2018)).Therapeutic relevance of the PP2A-B55 inhibitory kinase MASTL / Greatwall in breast cancer. (Cell Death Differ. 25 828-840)). Upregulation of MASTL is associated with cancer progression in head and neck tumors and is often associated with more aggressive forms of the disease. (Wang et al., (2014)). Mastl kinase, a promising therapeutic target, promotes cancer recurrence. (Oncotarget 5, 11479-11489)). Through a high-throughput siRNA screen in BCPAP thyroid cancer, vulnerability to MASTL loss was identified, which resulted in a significant decrease in cell proliferation. (Anania et al. (2015)). In colorectal cancer, upregulation of MASTL correlates with decreased patient survival and can act as a prognostic biomarker for potential disease aggressiveness (Uppada et al., (2018)). MASTL induces colon cancer progression and chemoresistance by promoting Wnt / β-catenin signaling. (Mol. Cancer 17:111). Supporting a therapeutic window, normal colonocytes do not express MASTL or express it only at very low levels. Depletion of MASTL in HCT-116 cells resulted in G2 / M arrest, apoptosis induction through modulation of anti-apoptotic proteins (Survivin and Bcl-xL, possibly through Gsk3β activation), and, importantly, in vivo. In vivo growth reduction was induced. Regulation of anti-apoptotic proteins by MASTL induction not only directly affected HCT-116 cell proliferation, but also increased their sensitivity to 5-FU treatment. MASTL is a novel inhibitor of acute myeloid leukemia (Tzelepis et al. (2016)).A CRISPR dropout screen identifies genetic vulnerabilities and therapeutic targets in acute myeloid leukemia (Cell Rep. 17, 1193-1205), and has illuminated potential new therapeutic targets for many cancers, such as head and neck squamous cell carcinoma (Wang et al., 2014), and thyroid cancer (Anania et al., 2015).

[0005] In addition to its role as a regulator of the G2 / M checkpoint, MASTL can deactivate checkpoint signaling and aid in recovery from DNA damage, supporting its role in the potential effects of DNA-damaging agents (Peng et al., (2010) "A novel role for greatwall kinase in recovery from DNA damage." (Cell Cycle 9 4364-4369)). An unbiased genome-wide siRNA loss-of-function screen in NSCLC cells identified MASTL as a key hit that sensitizes cells to radiation. This effect was not observed in primary human fibroblasts, indicating the possibility of selective sensitization of tumor cells over non-transformed cells (Nagel et al., (2015) "Genome-wide siRNA screen identifies the radiosensitizing effect of downregulation of MASTL and FOXM1 in NSCLC." (Mol. Cancer Ther. 14 1434-1444)). Similar effects were observed in a xenograft tumor model of UM-SSC-11-B cells derived from cisplatin-refractory head and neck squamous cell carcinoma (Wang et al., 2014). MASTL deficiency resensitized the cells to cisplatin treatment. Further parenchymal cell analysis studies in UM-SSC-11-B cells showed an increase in the sub-G1 population and induction of apoptosis, whereas MASTL-depleted normal oral keratinocyte OKF4 cells were resistant to apoptosis, regardless of cisplatin treatment.

[0006] Besides its role in cancer through regulation of damage repair pathways and mitosis, MASTL plays a role in regulating PP2A activity during interphase (Belen Sanz Castillo, 2017). Point mutations in the MASTL gene have been shown to cause autosomal dominant thrombocytopenia (Drachman et al., Autosomal dominant thrombocytopenia: incomplete megakaryocyte differentiation and linkage to human chromosome 10. (Blood. 2000;96:118-125.), providing evidence for a role for MASTL in megakaryocytic cells. More recently, it has been shown that such point mutations in MASTL do not induce decreased activity as originally thought, but rather exhibit a gain-of-function alteration that induces decreased PP2A activity accompanied by increased phosphorylation of Cdk and PP2A substrates (Hurtado et al., (2018) Thrombocytopenia-associated mutations in Ser / Thr kinase MASTL deregulate actin cytoskeletal dynamics in platelets. (J Clin Invest. 128(12):5351-5367). Therefore, MASTL inhibitors, through their effects on the PI3K / AKT pathway and cytoskeleton regulation, may hold therapeutic potential in the treatment of platelet disorders, including metabolic diseases (such as diabetes and obesity) and the rare genetic disease MASTL-associated thrombocytopenia, respectively. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Mol.Biol.Cell.20(22):4777-89 [Non-patent document 2] Science 330 1673-1677 [Non-patent document 3] Mol.Cell 52 393-405 Summary of the Invention [Problem to be solved by the invention]

[0008] Therefore, there is a need for MASTL inhibitors that are expected to provide beneficial therapeutic effects, for example, in cancer treatment. [Means for solving the problem]

[0009] According to the present invention, there is provided a compound of the following general formula (I) or a pharmaceutically acceptable salt thereof: [ka] (I) In the formula: The H ring in general formula (I) is a carbon atom *1 or *2 and concatenated; R 1 is H, C 1-6 Alkyl and C 1-6 haloalkyl; R 2 is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and Q 3 -L 3 wherein C is selected from 1-6 The alkyl group may be one or more R 6 optionally substituted with substituents; L 3 are combined or C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 alkynylene; Q 3 is C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, C 6-12 aryl, and 5- or 6-membered heteroaryl; Here, the C 3-6Cycloalkyl and 3- to 6-membered heterocyclyl may be substituted with one or more R 7 optionally replaced by Here, the C 6-12 Aryl and 5- or 6-membered heteroaryl can be selected from one or more R 8 optionally replaced by; R 3 are independently halo, C 1-6 selected from alkyl and amino; X1 is N and X2 is CR 4 or X1 is C and X2 is NR 5 and; X3 is C or N; R 4 H, halo, CN, C 1-6 Alkyl and C 1-6 haloalkyl; R 5 is H, C 1-6 Alkyl, Q 4 -L 4 - selected from Here, the C 1-6 The alkyl group may be one or more R 9 optionally replaced by L 4 is a bond or C 1-4 is alkylene; Q 4 is C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, C 6-12 aryl, and 5- or 6-membered heteroaryl; Here, the C 3-6 Cycloalkyl and 3- to 6-membered heterocyclyl may be substituted with one or more R 10 and wherein C is optionally substituted with 6-12 Aryl and 5- or 6-membered heteroaryl may be substituted with one or more R 11 optionally replaced by; L 1 is a bond or NR 12 , O, S and Q 5 is selected from R12 is H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-C 1-4 Alkyl and C 1-4 Alkyl-OR A5 is selected from Here, the C 3-6 Cycloalkyl and C 3-6 Cycloalkyl-C 1-4 Alkyl is ═O, halo, C 1-4 Alkyl and C 1-4 optionally substituted with one or more substituents selected from haloalkyl; Q 5 is a 4- to 6-membered heterocyclylene containing one ring nitrogen atom and optionally one ring atom selected from O, S and N, wherein Q 5 Q 5 is connected to the H ring of the general formula (I) by a ring carbon or ring nitrogen atom in Here, Q 5 =O, halo, C 1-4 Alkyl and C 1-4 optionally substituted with one or more substituents selected from haloalkyl; L 2 is a bond or -[CR 13 R 14 ] p - and p is an integer from 1 to 4; R 13 and R 14 are independently H, C 1-4 Alkyl, C 1-4 Haloalkyl, OH, COOH, C(O)NR X1 R X2 , and C 3-6 cycloalkyl or R 13 and R 14 L 2 are both attached to the same carbon atom in 3-6 forming a cycloalkyl or 3- to 6-membered heterocyclyl, Here, the C1-4 Alkyl is OH, OC 1-4 alkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, or halogen or C 1-6 C optionally substituted with haloalkyl 6-10 optionally substituted with aryl; where R X1 and R X2 is independently H, OH, or C optionally substituted with 3- to 6-membered heterocyclyl; 1-4 alkyl, and 5- to 10-membered heteroaryl, or R X1 and R X2 are attached together to the same nitrogen atom to form a 3- to 6-membered heterocyclyl; Here, the C 3-6 Cycloalkyl or 3- to 6-membered heterocyclyl is ═O, halo, C 1-4 Alkyl and C 1-4 optionally substituted with one or more substituents selected from haloalkyl; Q 1 is C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3- to 12-membered heterocyclyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, COOH, C(O)NR Z1 R Z2 , and C(O)OC 1-6 alkyl; Here, each R Z1 and R Z2 are each independently H, OH, C 3-6 Cycloalkyl, C 6-10 C optionally substituted with aryl or 5- to 10-membered heteroaryl 1-6 alkyl; or R Z1 and R Z2 are attached together to the same nitrogen atom to form a 3- to 6-membered heterocyclyl; Here, the C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl and 3- to 12-membered heterocyclyl may be substituted with one or more R 15optionally replaced by Here, the C 6-10 Aryl and 5- to 10-membered heteroaryl may be one or more R 16 optionally replaced by; Each R 15 are independently halo, =O, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR 17 , -S(O) x1 R 17 , -NR 17 R B1 , -C(O)R 17 , -OC(O)R 17 , -C(O)OR 17 , -NR B1 C(O)R 17 , -NR B1 C(O)OR 17 , -C(O)NR 17 R B1 , -OC(O)NR 17 R B1 , -NR B1 SO2R 17 , -SO2NR 17 R B1 and -NR A1 C(O)NR 17 R B1 is selected from Here, the C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl is a group consisting of one or more R 18 optionally replaced by R 17 is H, C 1-6 Alkyl and C 1-6 haloalkyl, wherein said C 1-6 The alkyl group may be one or more R 19 optionally replaced by; Each R 16 are independently halo, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Haloalkyl, -OR 20 , -S(O) x2 R 20 , -NR 20 R B2 , -C(O)R 20 , -OC(O)R 20 , -C(O)OR 20 , -NR B2 C(O)R 20 , -NR B2 C(O)OR 20 , -C(O)NR 20 R B2 , -OC(O)NR 20 R B2 , -NR B2 SO2R 20 , -SO2NR 20 R B2 and -NR A2 C(O)NR 20 R B2 is selected from Here, the C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl is a group consisting of one or more R 21 optionally replaced by where R 20 is H, C 1-6 Alkyl and C 1-6 haloalkyl, wherein said C 1-6 The alkyl group may be one or more R 22 optionally replaced by; R 6 , R 7 , R 9 , R 10 , R 18 , R 19 , R 21 and R 22 are each independently halo, =O, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR A3 , -S(O) x3 R A4 , -NR A3 R B3 , -C(O)R A3 , -OC(O)R A3 , -C(O)ORA3 , -NR B3 C(O)R A3 , -NR B3 C(O)OR A3 , -C(O)NR A3 R B3 , -NR B4 SO2R A3 and -SO2NR A3 R B3 Selected from; R 8 and R 11 are each independently halo, =O, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR A4 , -S(O) x4 R A4 , -NR A4 R B4 , -C(O)R A4 , -OC(O)R A4 , -C(O)OR A4 , -NR B4 C(O)R A4 , -NR B4 C(O)OR A4 , -C(O)NR A4 R B4 , -NR B4 SO2R A4 and -SO2NR A4 R B4 Selected from; R 1A , R 1B , R A2 , R B2 , R A3 , R B3 , R A4 , R B4 and R A5 are independently H, C 1-4 Alkyl and C 1-4 haloalkyl; or any -NR A3 R B3 , -NR A4 R B4 , -NR 17 R B1 or -NR 20 R B2may form a 4- to 6-membered heterocyclyl within the substituent, wherein the 4- to 6-membered heterocyclyl is selected from halo, ═O, C 1-4 Alkyl and C 1-4 optionally substituted with one or more substituents selected from haloalkyl; n is an integer from 0 to 4; and x1, x2, x3 and x4 are each independently selected from 0, 1 or 2. [Effects of the Invention]

[0010] The present invention also provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0011] The present invention also provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical, in some embodiments, for the treatment of a medical condition or disease mediated by microtubule associated serine / threonine-like kinase (MASTL).

[0012] The present invention also provides a method for treating a medical condition or disease mediated by MASTL in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0013] In certain embodiments, the compounds of the present invention are for use in treating proliferative disorders, e.g., cancer. In certain embodiments, the compounds of the present invention are for use in preventing or inhibiting cancer progression, e.g., through preventing or inhibiting cancer cell migration, cancer cell invasion, and / or cancer metastasis.

[0014] In certain embodiments, the compounds of the present invention are for use in the treatment of cancer.

[0015] In certain embodiments, the compounds of the invention are for use in treating cancers that overexpress MASTL.

[0016] In certain embodiments, the compounds of the invention are for use in the treatment of cancer selected from breast, ovarian, lung, colon, prostate, oral cavity, stomach, adrenal cortex, pancreas, kidney, sarcoma, liver, endometrial, thyroid, head or neck, brain (e.g., glioma), melanoma (e.g., ocular melanoma), and hematological cancers (e.g., leukemias such as AML, lymphoma, myeloma, and multiple myeloma).

[0017] In certain embodiments, the compounds of the invention are for use in the treatment or prevention of a metabolic disorder or a symptom or condition associated with a metabolic disorder.

[0018] In certain embodiments, the metabolic disorder may be insulin resistance, diabetes, or obesity. Symptoms and conditions associated with metabolic disorders may include one or more of elevated blood sugar, elevated cholesterol, elevated triglyceride levels, heart disease, stroke, high blood pressure, and increased risk of blood clots (e.g., deep vein thrombosis).

[0019] In certain embodiments, the compounds of the present invention are for use in treating a platelet disorder, such as thrombocytopenia.

[0020] The compounds of the present invention may be used alone or in combination with one or more anti-cancer agents and / or radiation therapy, as described herein. DETAILED DESCRIPTION OF THE INVENTION

[0021] definition As used in the specification and claims, the following terms have the following meanings unless otherwise specified.

[0022] The term "treat" or "treatment" refers to indications of successful treatment or amelioration of a disease, pathology, or condition, including palliative care; relief; reduction in symptoms or making the condition or state more tolerable to the patient; slowing the rate of degeneration or decline; making the end point of degeneration less debilitating; and objective or subjective parameters that improve the patient's physical or mental well-being. For example, certain methods herein treat cancer by reducing the symptoms of the cancer, which are known or can be determined by one of ordinary skill in the art. The term "treat" and its variants include prevention of the condition, state, or disease (e.g., preventing the onset of one or more symptoms of a cancer associated with MASTL).

[0023] The term "associated with" or "associated with" refers to a substance or substance activity or function associated with a disease (e.g., cancer) that is caused (in whole or in part) by the disease (e.g., cancer) or that the symptoms of the disease are caused (in whole or in part) by the substance or substance activity or function. For example, symptoms of a disease or condition associated with MASTL pathway activity can be symptoms that arise (in whole or in part) from increased activity levels of the MASTL protein pathway. As used herein, something described as associated with a disease can be a target for treatment of the disease if it is a causative agent. For example, a disease associated with increased activity levels of MASTL can be treated with an agent (e.g., a compound described herein) that is effective in reducing MASTL activity levels.

[0024] As defined herein, the terms "inhibition," "inhibit," "inhibiting," and the like, in reference to protein-inhibitor (e.g., antagonist) interactions, refer to a negative effect on the activity or level of function of a protein (e.g., a component of MASTL) relative to the activity or level of function of the protein pathway in the absence of the inhibitor. In some embodiments, inhibition refers to a reduction in a disease or disease symptom (e.g., cancer associated with increased activity of MASTL). In some embodiments, inhibition refers to a reduction in the activity level of a signaling pathway or signaling pathway associated with MASTL. Thus, inhibition may include, at least in part, partially or fully blocking a stimulus; reducing, preventing, or delaying activation; inactivating, desensitizing, or down-regulating signal transduction or enzyme activity or the amount of a protein (e.g., MASTL). Inhibition may include, at least in part, partially or totally reducing stimulation, reducing activation, modulating signal transduction or enzymatic activity, or levels of other proteins, or deactivating, desensitizing, or down-regulating the amount of proteins (e.g., components of the MASTL protein pathway) that can modulate cell survival, cell proliferation, or cell motility compared to non-diseased controls.

[0025] Throughout the description and claims of this specification, the words "comprise" and "contain" and variations thereof mean "including but not limited to" and are not intended to exclude other moieties, additives, components, integers or steps.

[0026] Throughout the description and claims of this specification, the singular includes the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification must be understood to contemplate the plural as well as the singular, unless the context otherwise requires.

[0027] The term "halo" or "halogen" refers to one of the halogens in Group 17 of the periodic table. In particular, the term refers to fluorine, chlorine, bromine, and iodine. Preferably, the term refers to fluorine or chlorine.

[0028] Term C m-n is a term that refers to a group having m to n carbon atoms.

[0029] The term “C 1-6 "Alkyl" is a term that refers to a linear or branched hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. 1-4 "Alkyl" refers to a group containing up to four carbon atoms. An alkylene group is a divalent alkyl group, which in turn may be linear or branched and has two points of attachment to the remainder of the molecule. An alkylene group may also be, for example, one of the alkyl groups described in this paragraph. For example, C 1-6 Alkylene can be -CH-, -CHCH-, -CHCH(CH)-, -CHCHCH-, or -CHCH(CH)CH-. Alkyl and alkylene groups can be substituted or unsubstituted with one or more substituents. Possible substituents are described herein. For example, alkyl or alkylene group substituents can be halogen, such as fluorine, chlorine, bromine, and iodine, OH, C-C alkoxy, -NR'R'' amino, where R' and R'' are independently H or alkyl. Other substituents for alkyl groups can alternatively be used.

[0030] The term “C 1-6 "Haloalkyl," e.g., "C1-4 haloalkyl," refers to a hydrocarbon chain substituted with at least one halogen atom, selected independently at each occurrence, such as fluorine, chlorine, bromine, and iodine. The halogen atom may be located at any position on the hydrocarbon chain. For example, C 1-6Haloalkyl can refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl (e.g., 1-chloromethyl and 2-chloroethyl), trichloroethyl (e.g., 1,2,2-trichloroethyl and 2,2,2-trichloroethyl), fluoroethyl (e.g., 1-fluoromethyl and 2-fluoroethyl), trifluoroethyl (e.g., 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl), chloropropyl, trichloropropyl, fluoropropyl, and trifluoropropyl. Haloalkyl groups can be, for example, -CX, -CHX, -CHCX, -CHCHX, or -CX(CH)CH, where X is halo (e.g., F, Cl, Br, or I). Fluoroalkyl groups are hydrocarbon chains substituted with at least one fluorine atom (e.g., -CF, -CHF, -CHCF, or -CHCHF).

[0031] The term “C 2-6 "Alkenyl" includes a branched or linear hydrocarbon chain having at least one double bond and 2, 3, 4, 5, or 6 carbon atoms. The double bond may be present in the E or Z isomer. The double bond may be present in any possible position on the hydrocarbon chain. For example, "C 2-6 "Alkenyl" can be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, and hexadienyl. An alkenylene group is a divalent alkenyl group, which in turn can be linear or branched and has two points of attachment to the remainder of the molecule. An alkenylene group can also be, for example, one of the alkenyl groups described in this paragraph. For example, an alkenylene can be -CH=CH-, -CHCH=CH-, -CH(CH)CH=CH-, or -CHCH=CH-. Alkenyl and alkenylene groups can be substituted or unsubstituted with one or more substituents. Possible substituents are described herein. For example, substituents can be those of alkyl groups described above.

[0032] The term “C 2-6"Alkynyl" includes a branched or linear hydrocarbon chain having at least one triple bond and 2, 3, 4, 5, or 6 carbon atoms. The triple bond may be present at any possible position on the hydrocarbon chain. For example, "C 2-6 "Alkynyl" can be ethynyl, propynyl, butynyl, pentynyl, and hexynyl. An alkynylene group is a divalent alkynyl group, which in turn can be linear or branched and has two points of attachment to the remainder of the molecule. An alkynylene group can also be, for example, one of the alkynyl groups described in this paragraph. For example, an alkynylene can be -C≡C-, -CHC≡C-, -CHC≡CCH-, -CH(CH)CH≡C-, or -CHC≡CCH. An alkynyl or alkynylene group can be substituted or unsubstituted with one or more substituents. Possible substituents are described herein. For example, the substituents can be those of an alkyl group, as described above.

[0033] The term “C 3-12 "Cycloalkyl" includes saturated hydrocarbon ring systems containing from 3 to 12 carbon atoms. Cycloalkyl groups may be single ring or fused, bridged, or spiro saturated hydrocarbon ring systems. The term "C 3-6 "Cycloalkyl" includes saturated hydrocarbon ring systems containing 3, 4, 5, or 6 carbon atoms. For example, C3-C 12 Cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane (norbornane), bicyclo[2.2.2]octane, or tricyclo[3.3.1.1]decane (adamantyl). For example, "C3-C6 cycloalkyl" can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.1.1]hexane, or bicyclo[1.1.1]pentane. Preferably, "C3-C6 cycloalkyl" can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0034] The term “C 3-12"Cycloalkenyl" includes hydrocarbon ring systems containing 3 to 12 carbon atoms and at least one double bond (e.g., 1 or 2 double bonds). Cycloalkenyl groups can be single ring or fused, bridged, or spiro hydrocarbon ring systems. For example, C 3-12 The cycloalkenyl may be cyclobutenyl, cyclopentenyl, or cyclohexenyl.

[0035] The terms "heterocyclyl," "heterocyclic," or "heterocycle" include non-aromatic saturated or partially saturated single-ring or fused, bridged, or spiro bicyclic heterocyclic ring systems. Monocyclic heterocyclic rings may contain 1 to 5 (preferably 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur and 3 to 12 (preferably 3 to 7) ring atoms. Bicyclic heterocycles may contain 7 to 12-membered atoms in the ring. Bicyclic heterocyclic rings may be fused, spiro, or bridged ring systems. Heterocyclyl groups may be 3- to 9- (e.g., 3- to 7-) membered non-aromatic monocyclic or bicyclic saturated or partially saturated groups containing 3-12, e.g., 1, 2, or 3 heteroatoms independently selected from O, S, and N in the ring system (in other words, 1, 2, or 3 ring atoms selected from O, S, and N forming the ring system). Partially saturated means that the ring can be formed with one or two double bonds. This applies particularly to monocyclic rings having 5 to 7 members. The double bond is typically between two carbon atoms, but may also be between a carbon atom and a nitrogen atom. Bicyclic rings can be spiro-fused, i.e., the rings are connected to each other through a single carbon atom; vicinal-fused, i.e., the rings are connected to each other through two adjacent carbon or nitrogen atoms; or they can share a bridgehead, i.e., the rings are connected to each other through two non-adjacent carbon or nitrogen atoms (bridged ring system). Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, and dioxanyl, as well as substituted cyclic ethers. Heterocycles containing at least one nitrogen in a ring position include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, tetrahydropyridinyl, homopiperidinyl, homopiperazinyl, 2,5-diaza-bicyclo[2.2.1]heptanyl, and the like.Common sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepin. Other heterocycles include dihydrooxathiolyl, tetrahydrooxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. Sulfur-containing heterocycles also include oxidized sulfur heterocycles containing an SO or SO group. For example, sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl, such as tetrahydrothienyl 1,1-dioxide and thiomorpholinyl 1,1-dioxide, are included. Suitable values ​​for heterocyclyl groups containing one or two oxo (=O) are, for example, 2-oxopyrrolidinyl, 2-oxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. In particular, the heterocyclyl group is a saturated monocyclic 3- to 7-membered heterocyclyl containing one, two or three heteroatoms selected from nitrogen, oxygen or sulfur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As can be understood by those skilled in the art, any heterocycle can be linked to a different group via any suitable atom, such as a carbon or nitrogen atom. For example, the term "piperidino" or "morpholino" refers to a piperidin-1-yl or morpholin-4-yl ring linked via the ring nitrogen. For example, L. 1 Reference to "heterocyclylene", which may be represented by: refers to a divalent "heterocyclyl", for example, 3,2-morpholinylene.

[0036] The term "bridged ring system" includes ring systems in which two rings share two or more atoms, as seen, for example, in Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 131-133, 1992. Preferably, the bridge is formed between two non-adjacent carbon or nitrogen atoms in the ring system. The bridge connecting the bridge head atoms may be a bond and may contain one or more atoms. Examples of bridged heterocyclyl ring systems include aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane, and quinuclidine.

[0037] The term "spirobicyclic ring system" includes ring systems in which two rings share one common spiro carbon atom, i.e., the heterocyclic ring is linked to an additional carbocyclic or heterocyclic ring through one common spiro carbon atom. Examples of spirocyclic ring systems include 3,8-diaza-bicyclo[3.2.1]octane, 2,5-diaza-bicyclo[2.2.1]heptane, 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 6-oxa-2-azaspiro[3.4]octane, 2,7-diaza-spiro[4.4]nonane, 2-azaspiro[3.5]nonane, 2-oxa-7-azaspiro[3.5]nonane, and 2-oxa-6-azaspiro[3.5]nonane.

[0038] "Heterocyclyl-C m-n "Alkyl" is C m-n and heterocyclyl groups covalently bonded to alkylene groups, both of which are defined herein; where heterocyclyl-C m-n The alkyl group is linked to the rest of the molecule through a carbon atom in the alkylene group. m-n alkyl, heteroaryl-C m-n Alkyl" and "Cycloalkyl-Cm-n "Alkyl" is defined in the same manner.

[0039] -NRR replaced by "-C m-n "C" substituted by alkyl and -OR m-n Alkyl" is similar to C m-n refers to an -NRR'' or -OR'' group covalently bonded to an alkylene group, where the group is connected to the remainder of the molecule through a carbon atom within the alkylene group.

[0040] The term "aromatic," when applied to the substituent as a whole, includes monocyclic or polycyclic ring systems having 4n+2 electrons in the complex π-system within the ring or ring system, with all atoms contributing to the complex π-system lying in the same plane.

[0041] The term "aryl" includes aromatic hydrocarbon ring systems. The ring systems have 4n+2 electrons in a complex π-system within the ring, with all atoms contributing to the complex π-system lying in the same plane. For example, "aryl" can be phenyl and naphthyl. The aryl system itself can be substituted with other groups.

[0042] The term "heteroaryl" refers to an aromatic mono- or bicyclic ring containing one or more (e.g., 1-4, particularly 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. The ring or ring system has 4n+2 electrons in a complex pi-system, with all atoms contributing to the complex pi-system lying in the same plane.

[0043] Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 12 ring members, more typically 5 to 10 ring members. Heteroaryl groups can be, for example, 5- or 6-membered monocyclic rings or 9- or 10-membered bicyclic rings, e.g., fused 5- and 6-membered rings or bicyclic structures formed by two fused 6-membered rings. Each ring can contain about four heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, heteroaryl rings contain up to three heteroatoms, more typically up to two, e.g., a single heteroatom. In one embodiment, a heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in a heteroaryl ring can be basic, as in the case of imidazole or pyridine, or essentially non-basic, as in the case of indole or pyrrole nitrogens. Generally, the number of basic nitrogen atoms present in a heteroaryl group, including optional ring amino group substitutions, will be fewer than five.

[0044] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, and benzofurazanyl. These include quinolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzoisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 1H-pyrazolo[4,3-d]oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, and imidazo[1,2-b][1,2,4]triazinyl. Examples of heteroaryl groups containing at least one nitrogen atom in a ring position include pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, and pteridinyl. "Heteroaryl" also includes partially aromatic bi- or polycyclic ring systems which are non-aromatic, saturated, or partially saturated when at least one ring is aromatic and one or more other rings contain one or more heteroatoms selected from nitrogen, oxygen, or sulfur.Examples of partially aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzothienyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl, and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl.

[0045] Examples of 5-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

[0046] Examples of 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0047] Examples of particular bicyclic heteroaryl groups containing a 6-membered ring fused to a 5-membered ring include, but are not limited to, benzofuranyl, benzothiopenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adenylyl, guanylyl), indazolyl, benzodioxolyl, pyrrolopyridine, and pyrazolopyridinyl groups.

[0048] Examples of particular bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolidinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

[0049] The term "oxo" or "=O" as used herein means an oxygen that is double bonded to a carbon atom.

[0050] The term "optionally substituted" includes groups, structures, or molecules that are substituted and groups, structures, or molecules that are not substituted.

[0051] Where optional substituents are selected from "one or more" groups, this definition should be understood to include all substituents selected from one of the specified groups or substituents selected from two or more of the specified groups.

[0052] When a residue is substituted, the substitution may occur anywhere within the residue that is chemically feasible and consistent with the valency requirements of the atom. The residue may be substituted with one or more substituents, e.g., 1, 2, 3, or 4 substituents; optionally, one or two substituents are present in a group. When two or more substituents are present, the substituents may be the same or different.

[0053] Substituents are present only at chemically feasible positions, and those of ordinary skill in the art can determine (experimentally or theoretically) which substitutions are chemically feasible and which are not, without undue effort.

[0054] Ortho, meta and para substitutions are terms that are well known in the art. Without a doubt, an "ortho" substitution can refer to a simple group, such as the fluoro group in the example below, or to a bond terminal. [ka] Any other part of the molecule shown is a substitution pattern in which adjacent carbons have substituents. [ka] A "meta" substitution is a substitution pattern in which two substituents are located on carbons one carbon away from each other, i.e., there is one carbon atom between the substituted carbons. In other words, one substituent is located on the second atom from the one bearing a substituent. For example, the following group is meta-substituted: [ka] "Para" substitution is a substitution pattern in which two substituents are located on carbons separated by two carbon atoms, i.e., there are two carbon atoms between the substituted carbons. In other words, there is another substituent on the third atom from the atom bearing the substituent. For example, the following group is para-substituted: [ka] Reference to an -NRR' group forming a 4- to 6-membered heterocyclyl means that R and R' together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl group. For example, -NR A1 R B1 , -NR A4 R B4 , -NR A5 R B5 , -NR 17 R B2 or -NR 20 R B3 A group such as -NRR' can be formed as follows: [ka] Similarly, the -NRR' group within the substituent may form a carbonyl-linked 4- to 6-membered heterocyclyl, for example, a -C(O)NRR' group can be formed as follows: [ka] -NRR' in substituents such as -OC(O)NRR', -SO2NRR' and -NRC(O)NRR', - may similarly form 4- to 6-membered heterocyclyl in these substituents.

[0055] "Compounds of the invention" means any compound disclosed generally or specifically herein. Thus, compounds of the invention include compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) and compounds of the Examples.

[0056] [ka] or a bond ending in "*" indicates that the bond is connected to another atom not shown in the structure. A bond that ends within a cyclic structure but does not terminate at an atom of the ring structure indicates that the bond can be connected to any of the atoms of the ring structure as allowed by the valences.

[0057] It should be understood that features, integers, traits, compounds, chemical moieties, or groups described in connection with any embodiment or illustration of the present invention are applicable to any other embodiment or illustration described herein, except to the extent that they cannot be used in conjunction with one another. All features disclosed herein (including the accompanying claims, abstract, and drawings), and / or all steps of any disclosed method or process, can be combined in any combination, except where at least some of such features and / or steps are mutually exclusive. The present invention is not limited to the detailed description of the foregoing embodiments. The present invention extends to any novel feature or any novel combination of features disclosed herein (including the accompanying claims, abstract, and drawings), or any novel feature or any novel combination of steps of any disclosed method or process.

[0058] The reader is reminded of all documents and literature in connection with this application, filed contemporaneously herewith or prior thereto, and published as presented herein, the contents of which are hereby incorporated by reference.

[0059] The various functional groups and substituents comprising the compounds of the present invention are generally selected so that the molecular weight of the compound does not exceed 1000. More typically, the molecular weight of the compound will be less than 750, e.g., less than 700, or less than 650, or less than 600, and more preferably less than 550.

[0060] A suitable or preferred feature of any compound of the invention may also be a suitable feature of any other aspect.

[0061] The present invention contemplates pharmaceutically acceptable salts of the compounds of the present invention. These may include acid addition and base salts of the compounds. These may be acid addition and base salts of the compounds.

[0062] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronic acid, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 1,5-naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, saccharate, stearate, succinate, tartrate, tosylate, and trifluoroacetate.

[0063] Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts. Hemisalts of acids and bases may form, for example, hemisulfate and hemicalcium salts. For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002).

[0064] Pharmaceutically acceptable salts of the compounds of the present invention can be prepared, for example, by one or more of the following methods: (i) reacting a compound of the present invention with a desired acid or base; (ii) removing an acid- or base-labile protecting group from a suitable precursor of a compound of the invention, or ring-opening a suitable cyclic precursor, e.g., a lactone or lactam, using a desired acid or base; or (iii) Conversion of one salt of a compound of the invention into another by reaction with an appropriate acid or base or by a suitable ion exchange column.

[0065] Such methods are generally carried out in solution. The salts produced can be precipitated and recovered by filtration or by evaporation of the solvent. The degree of ionization of the salts produced can vary from completely ionized to almost non-ionized.

[0066] Compounds that have the same molecular formula but differ in the nature or sequence of atomic bonding or the arrangement of their atoms in space are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "partial stereoisomers," and those that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, when it is bonded to four other groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of the asymmetric center and described by Cahn and Prelog's R- and S-ordering rules or the way molecules rotate the plane of polarized light and are designated as right- and left-handed (i.e., as (+)- or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture." When a compound of the present invention has two or more stereocenters, a combination of (R) and (S) stereoisomers is contemplated. The combination of (R) and (S) stereoisomers can produce a stereoisomeric mixture or a single stereoisomer. The compound of the present invention can exist as a single stereoisomer or can be a mixture of stereoisomers, such as a racemic mixture, other enantiomeric mixtures, and partial stereoisomeric mixtures. When the mixture is an enantiomeric mixture, the enantiomeric excess can be any one of those disclosed above. When the compound is a single stereoisomer, the compound can contain other stereoisomers or enantiomers as impurities. Thus, a single stereoisomer need not necessarily have 100% enantiomeric excess (ee) or partial stereoisomeric excess (de), but can have about 85%, e.g., at least 90%, at least 95%, or at least 99% of the isomer.

[0067] The compounds of the present invention may have one or more asymmetric centers, and therefore, such compounds can be produced as individual (R)- or (S)-stereoisomers or mixtures thereof. Unless otherwise specified, the description or name of a particular compound in the specification and claims is intended to include all individual enantiomers and mixtures thereof, racemic or otherwise. Methods for the determination of stereochemistry and separation of stereoisomers are well known in the art, for example, by synthesis from optically active starting materials or resolution of racemic forms (see discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present invention may have centers of geometric isomerism (E- and Z-isomers). The present invention should be understood to include all optical, regioisomers, and geometric isomers and mixtures thereof that possess MASTL inhibitor activity.

[0068] Z / E (eg, cis / trans) isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0069] Conventional techniques for the preparation / separation of individual enantiomers, if necessary, include chiral synthesis from suitable optically pure precursors or resolution of the isomers (or isomers of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). Thus, the chiral compounds of the present invention (and their chiral precursors) can be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase composed of a hydrocarbon, typically heptane or hexane, containing 0-50% isopropanol, typically 2-20%, and, as a specific example, 0-5% alkylamine, e.g., 0.1% diethylamine. Concentration of the eluate provides the enriched mixture.

[0070] Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound, for example, an alcohol, or, if the compound of the invention contains an acidic or basic moiety, with a base or acid, such as 1-phenylethylamine or tartaric acid. The resulting mixture of partial stereoisomers can be separated by chromatography and / or fractional crystallization, and one or both of the partial stereoisomers can be converted into the corresponding pure enantiomers by means well known to those skilled in the art.

[0071] When any racemate is crystallized, two other types can be determined. The first type is the racemate (actually the racemate) mentioned above, in which one homogeneous form of crystals containing the two enantiomers in equimolar amounts is produced. The second type is a racemic mixture or composite in which two forms of crystals are produced in equimolar amounts, each containing a single enantiomer.

[0072] The two crystalline forms present in a racemic mixture have identical physical properties, but may have different physical properties compared to the actual racemate. Racemic mixtures can be separated by conventional techniques well known to those skilled in the art. See, for example, "Stereochemistry of Organic Compounds" by EL Eliel and SH Wilen (Wiley, 1994).

[0073] The compounds and salts described herein may be isotopically labeled (or "radiolabeled"). Thus, one or more atoms are replaced with atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of radionuclides that may be incorporated include: 2 H (also written as "D" for deuterium), 3 H (also written as "T" for tritium), 11 C. 13 C. 14 C. 15 O. 17 O.18 O. 13 N, 15 N, 18 F, 36 Cl, 123 I, 25 I, 32 P, 35 The radionuclide used will depend on the specific application of the radiolabeled derivative in question. For example, for in-vitro competition assays, 3 H or 14 C is often useful. For radio-imaging applications, 11 C or 18 F is often useful. In some embodiments, the radionuclide is 3 H. In some embodiments, the radionuclide is 14 C. In some embodiments, the radionuclide is 11 C. And in some embodiments, the radionuclide is 18 It's F.

[0074] Isotopically labeled compounds can be prepared by processes similar to those described, using conventional techniques generally known to those skilled in the art or substituting the appropriate isotopically labeled reagent for a previously used non-labeled reagent.

[0075] Selective substitution of deuterium for hydrogen in a compound can modulate the metabolism of the compound, the PK / PD properties of the compound, and / or the toxicity of the compound. For example, deuteration can increase the half-life or decrease the solubility of the compound in vivo. Deuteration can also reduce the formation of toxic metabolites, improving safety and durability. The present invention should be understood to include deuterated derivatives of compounds of general formula (I). As used herein, the term deuterated derivative refers to a compound of the present invention in which at least one hydrogen atom at a specific position is replaced with deuterium. For example, C 1-4 -One or more hydrogen atoms of the alkyl group are replaced with deuterium to form a deuterated C 1-4- may form an alkyl group.

[0076] Certain compounds of the present invention may exist in solvated as well as undissolved forms, such as, for example, hydrated forms, and it should be understood that the present invention encompasses all such solvated forms that possess MASTL inhibitory activity.

[0077] Additionally, certain compounds of the present invention may exhibit polymorphism, and it should be understood that the present invention encompasses all such forms that possess MASTL inhibitory activity.

[0078] The compounds of the present invention can exist in many different tautomeric forms, and reference to a compound of the present invention includes all such forms. Without question, the compounds of the present invention can exist in one of many tautomeric forms, and if only one is specifically described or presented, all others are nevertheless included in the compounds of the present invention. Examples of tautomeric forms include keto-, enol-, and enolate-forms, such as the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro. [ka]

[0079] Amino-substituted triazines can exhibit hindered rotation about the SP2 carbon-N bond, generating regioisomers (blocked rotamers) (Amm et al. (1998), Mag. Reson. Chem. 36 587-596). Reference to compounds of the present invention includes all blocked rotamer forms of such compounds.

[0080] The in vivo effects of the compounds of the invention may be exerted in part by one or more metabolites formed in the human or animal body following administration of the compounds of the invention.

[0081] Furthermore, it should be understood that suitable pharmaceutically acceptable pro-drugs of the compounds of general formula (I) also form an aspect of the present invention. Accordingly, the compounds of the present invention include pro-drug forms of the compounds, and the compounds of the present invention can be administered in the form of pro-drugs (i.e., compounds that are broken down in the human or animal body to release the compounds of the present invention). Pro-drugs may be used to alter the physical and / or pharmacokinetic properties of the compounds of the present invention. Pro-drugs can be formed when the compounds of the present invention contain a suitable group or substituent to which a property-modifying group can be attached. Examples of pro-drugs include biotransferable ester derivatives that can be formed at carboxyl or hydroxy groups in the compounds of the present invention and biocleavable amide derivatives that can be formed at carboxyl or amino groups in the compounds of the present invention.

[0082] Thus, the present invention includes the compounds of the present invention as defined herein when made available by organic synthesis and when made available in the human or animal body by cleavage of their pro-drugs. Thus, the present invention includes compounds of general formula (I) produced by organic synthetic means and compounds produced in the human or animal body by metabolism of precursor compounds; in other words, compounds of general formula (I) may be synthetically produced compounds or compounds produced by metabolism.

[0083] Suitable pharmaceutically acceptable pro-drugs of the compounds of the present invention are programmed drugs that, based on sound medical judgment, are suitable for administration to the human or animal body without undesirable pharmacological activity and undue toxicity.

[0084] Examples of various forms of pro-drugs have been described in the following documents: a)Methods in Enzymology, Vol.42, p.309-396, edited by K.Widder, et al.(Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c)A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.Bundgaard, Chapter 5 "Design and Application of Pro-drugs", by H.Bundgaard p.113-191(1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N.Kakeya, et al., Chem.Pharm.Bull., 32, 692(1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACSSymposium Series, Volume 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

[0085] Suitable pharmaceutically acceptable program-drugs of compounds of general formula I having a carboxyl group are, for example, biocleavable esters. The biocleavable esters of the present invention containing a carboxyl group are, for example, pharmaceutically acceptable esters that are cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters for carboxy include C methyl, ethyl, and tert-butyl.1-6 C such as alkyl esters and methoxymethyl esters 1-6 C such as alkoxymethyl esters and pivalooxymethyl esters 1-6 C such as alkanoyloxymethyl esters, 3-butaridyl esters, cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters 3-8 Cycloalkylcarbonyloxy-C 1-6 alkyl esters, 2-oxo-1,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester, and C such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters 1-6 Alkoxycarbonyloxy-C 1-6 Suitable pharmaceutically acceptable program-drugs of the compounds of the present invention having a hydroxy group include, for example, biocleavable esters or ethers thereof. Biocleavable esters or ethers of the compounds of the present invention containing a hydroxy group are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body to produce the parent hydroxy group compound. Suitable pharmaceutically acceptable ester-forming groups for the hydroxy group include inorganic esters such as phosphate esters (including cyclic esters of phosphoric acid amides). Furthermore, suitable pharmaceutically acceptable ester-forming groups for the hydroxy group include C alkyl esters such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 1-10 Alkanoyl group, ethoxycarbonyl group, N,N-(C 1-6 C such as alkyl) 2-carbamoyl group, 2-dialkylaminoacetyl group and 2-carboxyacetyl group 1-10 Examples of ring substitutions on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C 1-4Suitable pharmaceutically acceptable ether-forming groups for a hydroxy group include α-acyloxyalkyl groups, such as acetoxymethyl and pivaloxymethyl.

[0086] Suitable pharmaceutically acceptable prodrugs of the compounds of the present invention having a carboxyl group include, for example, amines such as ammonia, C methylamine, 1-4 Alkylamines, dimethylamines (C 1-4 C alkyl)2 amines, N-ethyl-N-methylamine or diethylamine, 2-methoxyethylamine 1-4 Alkoxy-C 2-4 Phenyl-C alkylamines, such as benzylamine 1-4 Amides formed with alkylamines and amino acids such as glycine or their esters, for example biocleavable amides.

[0087] Suitable pharmaceutically acceptable program drugs of the compounds of the present invention having an amino group are, for example, biocleavable amides or carbamate derivatives thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example, C acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. 1-10 Examples of ring substitutions on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C 1-4 Suitable pharmaceutically acceptable carbamates from an amino group include, for example, acyloxyalkoxycarbonyl and benzyloxycarbonyl groups.

[0088] compound In some embodiments, the compound of general formula (I) is a compound of general formula (II), or a pharmaceutically acceptable salt thereof: [ka] (II)

[0089] In some embodiments, the compound of general formula (I) is a compound of general formula (III), or a pharmaceutically acceptable salt thereof: [ka] (III)

[0090] In some embodiments, the compound of general formula (I) is a compound of general formula (IV), or a pharmaceutically acceptable salt thereof: [ka] (IV)

[0091] In some embodiments, the compound of general formula (I) is a compound of general formula (V), or a pharmaceutically acceptable salt thereof: [ka] (V)

[0092] In some embodiments, the compound of general formula (I) is a compound of general formula (VI), or a pharmaceutically acceptable salt thereof: [ka] (VI)

[0093] In some embodiments, the compound of general formula (I) is a compound of general formula (VII), or a pharmaceutically acceptable salt thereof: [ka] (VII)

[0094] In some embodiments, the compound of general formula (I) is a compound of general formula (VIII), or a pharmaceutically acceptable salt thereof: [ka] (VIII)

[0095] In some embodiments, the compound of general formula (I) is a compound of general formula (IX), or a pharmaceutically acceptable salt thereof: [ka] (IX)

[0096] In some embodiments, the compound of general formula (I) is a compound of general formula (X), or a pharmaceutically acceptable salt thereof: [ka] (X)

[0097] In some embodiments, the compound of general formula (I) is a compound of general formula (XI), or a pharmaceutically acceptable salt thereof: [ka] (XI)

[0098] In some embodiments, the compound of general formula (I) is a compound of general formula (XII), or a pharmaceutically acceptable salt thereof: [ka] (XII)

[0099] In some embodiments, the compound of general formula (I) is a compound of general formula (XIII), or a pharmaceutically acceptable salt thereof: [ka] (XIII)

[0100] In some embodiments, the compound of general formula (I) is a compound of general formula (XIV), or a pharmaceutically acceptable salt thereof: [ka] (XIV)

[0101] In yet another embodiment, the present invention provides a compound selected from any one of the examples herein, or a pharmaceutically acceptable salt or precursor thereof.

[0102] Certain compounds of the present invention exhibited IC values ​​in the MASTL activity assay described in the Examples. 50 is less than 2mM, 1.5mM, 1mM, 750nM, 500nM, 250nM, 200nM, 150nM, 100nM, 90nM, 80nM, 70nM, 60nM, 50mM, 40nM, 30mM, 20nM, 15nM, 10nM, 8nM, 5nM, 4nM, 3nM, 2nM or 1nM.

[0103] In some embodiments, compounds of the present invention include, for example, compounds of general formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV) or a pharmaceutically acceptable salt thereof, wherein each R 1 , R 2 , R 3 , L 1 , L 2 and Q 1 has any one of the following meanings 1 to 96:

[0104] 1.R 1 is H.

[0105] 2.R 1 and R 2 are both H.

[0106] 3.R 1 is H and R 2 is C 1-6 alkyl, optionally C 1-6 The alkyl is substituted by one or more R6 substituents as defined above.

[0107] 4.R 1 is H and R 2 is C 1-6 alkyl, where C 1-6 The alkyl group may be one or more R 6 optionally substituted with substituents, R 6 Halo, =O, -OR A3 , -SR A4 , C(O)R A3 , -OC(O)R A3 , -C(O)OR A3 , -S(O)2R A4 and -NR A3 R B3 is selected from.

[0108] 5.R 1 is H and R 2 is C 1-6 alkyl, preferably R 2 is methyl.

[0109] 6.R 1 is H and R 2 Q 3 -L 3 where: L 3 is a bond or C 1-6 alkylene, preferably L 3 is methylene and Q 3 is as defined above.

[0110] 7.R 1 is H and R 2 Q 3 -L 3 where: L 3 is a bond or C 1-6 alkylene, preferably L 3 is methylene; Q 3 is C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl, optionally with one or more R 7 is replaced by

[0111] 8.R 1 is H and R 2 Q 3 -L 3 where: L 3 is a bond or C 1-6 alkylene, preferably L 3 is methylene; Q 3 is a 3- to 6-membered heterocyclyl, and one or more R 7 is optionally replaced by

[0112] 9.R 1 is H and R 2 Q 3 -L 3 where: L 3 is a bond or C 1-6 alkylene, preferably L 3 is methylene; Q 3 is C 6-12 aryl or 5- or 6-membered heteroaryl, preferably Q 3 is a C6 aryl, and one or more R 8 is optionally replaced by

[0113] 10.R 1 is H and R 2 Q 3 -L 3 where: L 3 is methylene; Q 3 is a C6 aryl, and optionally one or more R 8 is replaced by

[0114] 11.R 1 and R 2 is as defined in any one of 6 to 8 above, and each R 7 Halo, =O, -CN, -NO2, C 1-4 Alkyl, C 1-4Haloalkyl, -OR A3 and -C(O)R A3 are independently selected from, where R A3 is as defined above.

[0115] 12.R 1 and R 2 is as defined in any one of 6 to 8 above, wherein each R 7 is a halo (e.g., F).

[0116] 13.R 1 and R 2 is as defined in any one of 6, 9, or 10 above, and each R 8 Halo, =O, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR A4 , and -C(O)R A4 are independently selected from, where R A4 is as defined above.

[0117] 14.R 1 and R 2 is as defined in any one of 9 or 10 above, wherein each R 8 is a halo (e.g., F).

[0118] 15.n is 0.

[0119] 16.n is 1.

[0120] 17. Each R 3 is a halo, where optionally each R 3 is independently selected from fluoro and chloro.

[0121] 18. Each R 3 is C 1-6 alkyl, where optionally each R 3 is methyl.

[0122] 19. Each R 3 is an amino.

[0123] 20.n is 1 and R 3 is fluoro.

[0124] 21. In the compounds of general formula III, IV, V, VI and VII, R 3 is attached to the 3-, 4- and / or 7-position of the indazole ring.

[0125] 22. In the compounds of general formulae VIII, IX, X, XI, XII, XIII and XIV, the group of general formula is: [ka] selected from one of the following structures: [ka] 23.R 4 or R 5 is H.

[0126] 24.R 4 or R 5 is C 1-6 It is alkyl and optionally methyl.

[0127] 25.R 4 is CN.

[0128] 26.R 5 is the Q defined above. 4 -L 4 -It is.

[0129] 27.R 5 Q 4 -L 4 -, where L 4 is a bond, and Q 4 is C 3-6 Cycloalkyl; 3- to 6-membered heterocyclyl; C 6-12aryl; and 5- or 6-membered heteroaryl.

[0130] 28.R 5 Q 4 -L 4 -, where L 4 is a bond, and Q 4 is a 5- or 6-membered heterocyclyl containing an oxygen atom.

[0131] 29.R 5 Q 4 -L 4 -, where L 4 is a bond, and Q 4 is selected from the following: [ka]

[0132] 30.R 5 Q 4 -L 4 -, where L 4 is C 1-4 is alkylene, and Q 4 is C 3-6 Cycloalkyl; 3- to 6-membered heterocyclyl; C 6-12 aryl; and 5- or 6-membered heteroaryl.

[0133] 31. In any one of the compounds of general formulae IV, VI, VII, IX, XI, XII, XIII and XIV, R 4 or R 5 is H or C 1-6 alkyl, where optionally R 4 or R 5 is methyl and n is 0.

[0134] 32. In any one of the compounds of general formulae IV, VI, VII, IX, XI, XII, XIII and XIV, R 4 or R 5 is H or C 1-6 alkyl, where optionally R4 or R 5 is methyl, n is 1, and R 3 is halo, preferably fluoro.

[0135] 33.R 1 is H and R 2 is C 1-6 alkyl, preferably R 2 is methyl and R 4 or R 5 is H and n is 0.

[0136] 34.R 1 and R 2 is as defined by any one of 3 to 8 above, and R 4 or R 5 is H and n is 0.

[0137] 35.R 1 and R 2 is as defined by any one of 3 to 9 above, and R 4 or R 5 is H, n is 1, and R 3 is halo, preferably fluoro.

[0138] 36.R 1 and R 2 is as defined by any one of 3 to 9 above, and R 4 or R 5 is H or methyl, n is 0 or 1, and R 3 is halo, preferably fluoro.

[0139] 37.L 1 is O or S. Preferably, L 1 is O.

[0140] 38.L 1 is a bond.

[0141] 39.L 1 is NR12 where R 12 is C 3-6 Cycloalkyl, C 1-4 Alkyl and -C 1-4 Alkyl-OR A5 For example, R 12 is H, C 3-4 Cycloalkyl and C 1-3 alkyl (eg, methyl or ethyl).

[0142] 40.L 1 is NR 12 where R 12 is C 3-6 Cycloalkyl, for example, C3 cycloalkyl.

[0143] 41.L 1 is NH.

[0144] 42.L 1 is NR 12 where R 12 is -CH3.

[0145] 43.L 1 Q 5 where Q 5 is as defined above.

[0146] 44.L 1 Q 5 where Q 5 is a 4- to 6-membered heterocyclylene containing a nitrogen atom and one or two additional heteroatoms independently selected from N, O and S. Optionally, Q 5 Q 5 is bonded to the H ring of general formula (I) by the ring nitrogen atom in

[0147] 45.L 1 Q 5 where Q 5 is a 4- to 6-membered heterocyclylene containing one ring nitrogen atom and one oxygen atom, where Q 5 Q5 is bonded to the H ring of general formula (I) by the ring nitrogen atom of

[0148] 46.L 2 is a bond.

[0149] 47.L 2 is defined above as -[CR 13 R 14 ] p is.

[0150] 48.L 2 is -[CR 13 R 14 ] p where R 13 and R 14 are each independently H and C 1-4 alkyl (e.g., methyl, CH3).

[0151] 49.L 2 is -[CR 13 R 14 ] p where p is an integer from 1 to 2, and R 13 and R 14 are independently H, C 1-4 Alkyl, C 1-4 Haloalkyl, OH, COOH, C(O)NR X1 R X2 , and C 3-6 cycloalkyl, or L 2 R attached to the same carbon atom in 13 and R 14 Both are C 3-6 In some embodiments, C forms a cycloalkyl. 1-4 Alkyl is OH, OC 1-4 alkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, or C 6-10 In some embodiments, the C is optionally substituted with aryl. 6-10 Aryl is a halogen or C 1-6 Optionally substituted haloalkyl.

[0152] 50.L 2 is -[CR 13 R 14 ] p where p is 1 and R 13 and R 14 are all H or C 1-4 alkyl. For example, R 13 and R 14 may both be methyl (CH3).

[0153] 51.L 2 is -C(CH3)2CH2- or -CH2C(CH3)2- or -CH2CH2-.

[0154] 52.L 2 is -[CR 13 R 14 ] p where R 13 and R 14 L 2 C is attached to the same carbon atom in 3-6 Together they form a cycloalkyl or a 3- to 6-membered heterocyclyl. In some embodiments, R 13 and R 14 L 2 and R are attached to the same carbon atom and together form a C cycloalkyl (i.e., cyclopropyl) or a C cycloalkyl (i.e., cyclobutyl). 13 and R 14 L 2 and together form a 3-6-membered heterocyclyl such as an oxiranyl or oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl group. In such embodiments, p may be 1.

[0155] 53.R X1 and R X2 are independently H, C 1-4 alkyl and 5- to 10-membered heteroaryl, or R X1 and R X2are attached together to the same nitrogen atom to form a 3- to 6-membered heterocyclyl. 1-4 The alkyl is optionally substituted by OH or 3- to 6-membered heterocyclyl.

[0156] 54.L 1 and L 2 None of these is a bond.

[0157] 55.-L 1 -L 2 - is arbitrarily selected from the following structures: [ka]

[0158] 56.Q 1 is a 5- to 10-membered heteroaryl group, preferably a 5- or 6-membered heteroaryl group, wherein the heteroaryl group contains one or two heteroatoms independently selected from O, N and S, and wherein optionally the heteroaryl group contains one or more R as defined above. 16 is replaced by

[0159] 57.Q 1 is C 6-10 aryl, preferably C aryl, optionally one or more R as defined above 16 is replaced by

[0160] 58.Q 1 is an 8-, 9-, or 10-membered bicyclic heteroaryl group composed of one, two, or three heteroatoms. The heteroatoms may be independently selected from O, N, and S. In some embodiments, the bicyclic heteroaryl group comprises a 5- or 6-membered heterocyclo-fused C5 or C6 aryl ring. In certain embodiments, the 5- or 6-membered heterocycle contains a single heteroatom, such as an oxygen atom. Optionally, the bicyclic heteroaryl group may comprise one or more R as defined above. 16 is replaced by

[0161] 59.Q 1 is C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3- to 12-membered heterocyclyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, COOH, C(O)NR Z1 R Z2 , and C(O)OC 1-6 alkyl. Each R Z1 and R Z2 is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; or R Z1 and R Z2 are attached to the same nitrogen atom and together form a 3- to 6-membered heterocyclyl. 1-6 The alkyl is optionally substituted with OH.

[0162] 60.Q 1 is as defined in 56, 57, 58 or 59 above, wherein the heteroaryl or aryl group is selected from one, two or three R 16 is replaced by R 16 is halo (preferably chloro and / or fluoro), C 1-6 Alkyl, C 1-6 haloalkyl.

[0163] 61.Q 1 is as defined in any one of 56 to 60 above, and one or more R 16 where at least one R 16 is a C such as methyl, ethyl, propyl (e.g., isopropyl) or butyl (e.g., t-butyl). 1-6 alkyl. Optionally, C 1-6 Alkyl is one or more R as defined above. 21 In some embodiments, the C 1-6The alkyl group may be one or more R 21 where at least one R 21 is -NR A3 R B3 Preferably, -NR A3 R B3 forms a 5- or 6-membered heterocyclyl group. 1-6 Alkyl is one or more of -OR 20 substituted by a group, where R 20 is H or C, such as methyl, ethyl, or propyl (e.g., isopropyl). 1-6 It is alkyl, preferably methyl.

[0164] 62.Q 1 is as defined in any one of 56 to 61 above, and one or more R 16 where at least one R 16 is a halo or C 1-6 haloalkyl, e.g., Q 1 is one, two or three R 16 In certain embodiments, each R 16 is optionally selected from chloro, fluoro, CHF2, CF3, chloroform, CCl3, CH2CF3, and CH2CCl3. In some embodiments, Q 1 is one, two or three R 16 where each R 16 is optionally selected from fluoro or chloro.

[0165] 63.Q 1 is as defined in any one of 56 to 62 above, and two or more R 16 where at least one R 16 is halo (e.g., fluoro or chloro), and at least one R 16 is C 1-6 In some embodiments, C is alkyl. 1-6 Alkyl is one or more of -OR 20substituted by a group, where R 20 is H or C, such as methyl, ethyl, or propyl (e.g., isopropyl). 1-6 It is alkyl, preferably methyl.

[0166] 64.Q 1 is a 3- to 12-membered heterocyclyl group, preferably a 5- to 6-membered heterocyclyl group. Optionally, the heterocyclyl group may be further comprised of one or more R 15 In some embodiments, R 15 is C 1-6 It is an alkyl group.

[0167] 65.Q 1 is one or more R 15 C optionally substituted by 3-12 Cycloalkyl, C 3-12 cycloalkenyl and 3- to 12-membered heterocyclyl, where each R 15 Ha, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, and OR 17 are independently selected from, where C 1-6 The alkyl group may be one or more R 18 optionally replaced by Here, each R 17 is H and C 1-6 independently selected from alkyl; Here, each R 18 Halo, -NR A3 R B3 and OR A3 are independently selected from; Here, each R A3 is H and C 1-4 alkyl, or —NR , forming a 4- to 6-membered heterocyclyl; A3 R B3 It may be.

[0168] 66.Q 1 is one or more R 16 C optionally substituted by6-10 aryl or 5- to 10-membered heteroaryl, where each R 16 Ha, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl and OR 20 is selected from, where C 1-6 The alkyl may optionally be one or more R 21 is replaced by Here, each R 20 is H and C 1-6 independently selected from alkyl; Here, each R 21 Halo, -NR A3 R B3 and OR A3 are independently selected from; Here, each R A3 is H and C 1-4 independently selected from alkyl, or -NR A3 R B3 may form a 4- to 6-membered heterocyclyl.

[0169] 67.Q 1 is a 5- to 10-membered heteroaryl, C 6-10 Aryl, C 3-12 cycloalkyl or 3- to 12-membered heterocyclyl; wherein optionally said 5- to 10-membered heteroaryl or C 6-10 Aryl is one or more R 16 is replaced by Here, optionally, the C 3-12 Cycloalkyl or 3- to 12-membered heterocyclyl may be one or more R 15 is replaced by Here, each R 15 or R 16 is halo (preferably F and / or Cl); C 1-6Haloalkyl (preferably CHF2, CF3, CH2CF3, CHCl2, CCl3, CH2CCl3); methyl, ethyl, propyl (e.g., isopropyl), butyl (e.g., t-butyl), methoxy, methoxymethyl, methoxyethyl, and 5-membered heterocyclosubstituted C 1-4 alkyl.

[0170] 68.Q 1 is selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, furyl, thiazolyl, thiopenyl, oxazolyl, isoxazolyl, and isothiazolyl.

[0171] 69.Q 1 is pyrazolyl.

[0172] 70.Q 1 is pyridinyl.

[0173] 71.Q 1 is triazolyl.

[0174] 72.Q 1 is C 6-10 In some embodiments, Q is an aryl group. 1 is a phenyl group.

[0175] 73.Q 1 is an aryl or heteroaryl as defined in any one of 68 to 72 above, wherein the aryl or heteroaryl is selected from one or more R 16 where each R 16 Ha, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl and OR 20 are independently selected from, where optionally C 1-6 Alkyl is R 21 is replaced by Here, each R 20 is H and C 1-6independently selected from alkyl; Here, each R 21 Halo, -NR A3 R B3 and OR A3 are independently selected from; Here, each R A3 is H and C 1-4 independently selected from alkyl, or -NR A3 R B3 may form a 4- to 6-membered heterocyclyl.

[0176] 74.Q 1 is as defined in any one of 56 to 73 above, and Q 1 Q 1 -L by the ring carbon 1 -L 2 - is bonded to

[0177] 75.Q 1 is as follows: [ka] Here, ring A is -L 1 -L 2 - is a 5- or 6-membered heteroaryl containing a ring nitrogen and one or more heteroatoms independently selected from O, S, and N, positioned ortho to the bond to -, wherein optionally the heteroaryl is selected from one or more R 16 is replaced by Q 1 Examples include: [ka]

[0178] 76.Q 1 has a structure selected from the following: [ka] where R 15 and R 16is as defined above and x is 0, 1, 2 or 3. Optionally, R 15 or R 16 is halo (preferably chloro and / or fluoro), C 1-6 Alkyl, C 1-6 haloalkyl.

[0179] 77.Q 1 is defined by 75 or 76 above, where each R 16 Ha, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl or OR 20 are independently selected from, where optionally C 1-6 The alkyl group may be one or more R 21 is replaced by Here, each R 20 is H and C 1-6 independently selected from alkyl; Here, each R 21 Halo, -NR A3 R B3 and OR A3 are independently selected from; Here, each R A3 is H and C 1-4 independently selected from alkyl, or -NR A3 R B3 may form a 4- to 6-membered heterocyclyl.

[0180] 78.Q 1 is defined by 76 above, where each R 15 Ha, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl and OR 17 are independently selected from, where optionally C 1-6 The alkyl group may be one or more R 18 is replaced by Here, each R 17 is H and C 1-6 independently selected from alkyl; Here, each R 18Halo, -NR A3 R B3 and OR A3 are independently selected from; Here, each R A3 is H and C 1-4 independently selected from alkyl, or -NR A3 R B3 may form a 4- to 6-membered heterocyclyl.

[0181] 79.Q 1 has a structure selected from the following: [ka] JPEG2024522201000031.jpg90126

[0182] 80.L 1 is O; L 2 is as defined by any one of 44 to 53 above; Q 1 is as defined by any one of 56 to 79 above. In some embodiments, Q 1 is any of the structures shown in 79 above.

[0183] 81.L 1 Q 5 where Q 5 is a 4- to 6-membered heterocyclylene containing one ring nitrogen atom and one O atom, where Q 5 Q 5 is connected to the H ring of general formula (I) by a ring nitrogen atom within the L 2 is as defined by any one of 44 to 53 above; Q 1 is as defined by any one of 56 to 79 above. In some embodiments, Q 1 is any of the structures shown in 79 above.

[0184] 82.L 1 Q 5 where Q 5 is a 4- to 6-membered heterocyclylene containing one ring nitrogen atom and one O atom, where Q 5 Q 5 is connected to the H ring of general formula (I) by a ring nitrogen atom within the L 2 is -[CR 13 R 14 ] p where p is 1 and R 13 and R 14 are both H; Q 1 is as defined by any one of 56 to 79 above; preferably, Q 1 is any of the structures shown in 79 above.

[0185] 83.L 1 is NR 12 where R 12 is methyl; L 2 is as defined by any one of 44 to 53 above; Q 1 is as defined by any one of 56 to 79 above. In some embodiments, Q 1 is any of the structures shown in 79 above.

[0186] 84.L 1 is NR 12 where R 12 is C 1-4 alkyl (e.g., methyl or ethyl); L 2 is -[CR 13 R 14 ] p where p is 1 and R 13 and R 14 are H, respectively; Q 1is as defined by any one of 56 to 79 above; preferably, Q 1 is any of the structures shown in 79 above.

[0187] 85.L 1 is NR 12 where R 12 is C 1-4 alkyl (e.g., methyl or ethyl); L 2 is -[CR 13 R 14 ] p where p is 2 and R 13 and R 14 are H, respectively; Q 1 is as defined by any one of 56 to 9 above; preferably, Q 1 is any of the structures shown in 79 above.

[0188] 86.L 1 is NR 12 where R 12 is C 3-6 cycloalkyl, for example, C cycloalkyl; L 2 is -[CR 13 R 14 ] p where p is 2 and R 13 and R 14 are H, respectively; Q 1 is as defined by any one of 56 to 79 above; preferably, Q 1 is any of the structures shown in 79 above.

[0189] 87. In compounds of general formula VII, XII or XIV: R 13 and R 14 is H and C 1-4 Q are independently selected from alkyl; 1is as defined by any one of 56 to 79 above.

[0190] 88. In compounds of general formula VII, XII or XIV: R 13 and R 14 are both H or methyl; Q 1 is any of the structures shown in 79 above.

[0191] 89. In compounds of general formula VII, XII or XIV: R 13 and R 14 is C 3-6 together form a cycloalkyl, preferably a cyclopropyl or cyclobutyl group; Q 1 is as defined in any one of 56 to 79 above; preferably, Q 1 is any of the structures shown in 79 above.

[0192] 90.L 1 is H; L 2 is -[CR 13 R 14 ] p where p is 2 and R 13 and R 14 are H, respectively; Q 1 is as defined by any one of 56 to 79 above; preferably, Q 1 is any of the structures shown in 79 above.

[0193] 91.L 1 is H; L 2 is -[CR 13 R 14 ] p where p is 2 and R 13 are both CH3 and R 14 are both H; Q 1is as defined by any one of 56 to 79 above; preferably, Q 1 is any of the structures shown in 79 above.

[0194] 92.L 2 is a bond, and Q 1 is a 5- to 10-membered heteroaryl group. 1 is an 8-, 9-, or 10-membered bicyclic heteroaryl group containing one, two, or three heteroatoms. In some embodiments, the bicyclic heteroaryl group comprises a 5- or 6-membered heterocyclo-fused C5 or C6 aryl ring. In certain embodiments, the 5- or 6-membered heterocycle contains a single heteroatom, such as an oxygen atom. Optionally, the bicyclic heteroaryl group may comprise one or more R 16 is replaced by

[0195] 93.L 1 and L 2 has one of the structures shown in 54 above, and Q 1 is as defined by any one of 56 to 79 above; preferably, Q 1 is any of the structures shown in 77 above.

[0196] 94.Q 1 is as defined in any one of 56 to 79 above, wherein L 1 , O, NR 12 or S and L 2 is a bond, and Q 1 Q 1 -L by the ring carbon 1 -L 2 - is bonded to

[0197] 95.Q 1 is as defined in any one of 56 to 79 above, wherein L 2 is -[CR 13 R 14 ] pand p is 2, 3 or 4, where Q 1 is connected by the ring nitrogen -L 1 -L 2 -. Optionally, L 1 is NH or NR 12 where R 12 is C 3-6 cycloalkyl (e.g., cyclopropyl) or C 1-4 alkyl (for example, methyl or ethyl).

[0198] 96.-L 1 -L 2 -Q 1 is selected from one of the following structures: [ka] JPEG2024522201000033.jpg124127JPEG2024522201000034.jpg111127JPEG2024522201000035.jpg166126

[0199] 97. In compounds of general formula VII, XII or XIV: R 4 or R 5 is H, C 1-6 Alkyl or Q 4 -L 4 - selected from, where L 4 is a bond, and Q 4 is C 3-6 Cycloalkyl; 3- to 6-membered heterocyclyl; C 6-12 aryl; 5- or 6-membered heteroaryl, preferably wherein Q 4 is a 3- to 6-membered heterocyclyl, for example a 6-membered heterocyclyl; n is 0 or 1; When n is 1, R 3 is halo, preferably fluoro; R 13 and R 14 is H, C 1-4 Alkyl and C1-4 haloalkyl, or R 13 and R 14 L 2 are attached to the same carbon atom at C 3-6 together form a cycloalkyl or a 3- to 6-membered heterocyclyl, where C 3-6 Cycloalkyl or 3- to 6-membered heterocyclyl is ═O, halo, C 1-4 Alkyl and C 1-4 optionally substituted with one or more substituents selected from haloalkyl; Q 1 is as defined by any one of 56 to 79 above, and preferably Q 1 is any of the structures shown in 79 above.

[0200] 98. In compounds of general formula VII, XII, or XIV: R 4 or R 5 is H and C 1-6 alkyl (e.g., methyl); n is 0 or 1; When n is 1, R 3 is halo, preferably fluoro; R 13 and R 14 is H, C 1-4 Alkyl and C 1-4 haloalkyl, or R 13 and R 14 L 2 are attached to the same carbon atom at C 3-6 Cycloalkyl, preferably C 3-4 together form a cycloalkyl; Q 1 is a 5- to 10-membered heteroaryl, C 6-10 Aryl, C 3-12 cycloalkyl or 3- to 12-membered heterocyclyl; wherein optionally 5- to 10-membered heteroaryl or C 6-10Aryl is one or more R 16 is replaced by Here, arbitrarily, C 3-12 Cycloalkyl or 3- to 12-membered heterocyclyl may be one or more R 15 is replaced by Here, each R 15 is halo (preferably chloro and / or fluoro), C 1-6 Alkyl, C 1-6 Haloalkyl and OR 17 are independently selected from, where optionally C 1-6 The alkyl group may be one or more R 18 is replaced by Each R 16 is halo (preferably chloro and / or fluoro), C 1-6 Alkyl, C 1-6 Haloalkyl and OR 20 and optionally wherein C 1-6 The alkyl group may be one or more R 21 is replaced by where R 17 and R 20 H and C 1-6 are each independently selected from alkyl; where R 18 and R 21 Halo, -NR A3 R B3 and OR A3 are independently selected from; Here, each R A3 H and C 1-4 alkyl, or —NR A3 R B3 may form a 4- to 6-membered heterocyclyl.

[0201] 99. Compounds of general formula VII, XII or XIV: R 4 or R 5 H and C 1-6 alkyl (e.g., methyl); n is 0 or 1; When n is 1, R 3 is halo, preferably fluoro; R 13 and R 14 is H, C 1-4 Alkyl and C 1-4 haloalkyl, or R 13 and R 14 L 2 are attached to the same carbon atom at C 3-6 Cycloalkyl, preferably C 3-4 together form a cycloalkyl; Q 1 is a 5- to 10-membered heteroaryl, C 6-10 Aryl, C 3-12 cycloalkyl or 3- to 12-membered heterocyclyl; wherein optionally 5- to 10-membered heteroaryl or C 6-10 Aryl is one or more R 16 is replaced by Here, arbitrarily, C 3-12 Cycloalkyl or 3- to 12-membered heterocyclyl may be one or more R 15 is replaced by where R 15 or R 16 is halo (preferably F and / or Cl); C 1-6 Haloalkyl (preferably CHF2, CF3, CH2CF3, CHCl, CCl3, CH2CCl3); methyl, ethyl, propyl (e.g., isopropyl), butyl (e.g., t-butyl), methoxy, methoxymethyl, methoxyethyl, and 5-membered heterocyclosubstituted C 1-4 alkyl.

[0202] 100. In the compound defined by any one of 35 to 79 above: R 4 or R 5 is H or methyl; n is 0 or 1, and if n is 1, R 3is halo, preferably F; R 1 and R 2 is as defined by any one of 1 to 14 above.

[0203] In some embodiments, the compound of the invention is any one of the compounds selected in Table 1, or a pharmaceutically acceptable salt thereof.

[0204] [Table 1] JPEG2024522201000037.jpg179118JPEG2024522201000038.jpg161118JPEG2024522 201000039.jpg173117JPEG2024522201000040.jpg162119JPEG2024522201000041.j pg181120JPEG2024522201000042.jpg154117JPEG2024522201000043.jpg181120JPE G2024522201000044.jpg171117JPEG2024522201000045.jpg171116JPEG20245222010 00046.jpg169118JPEG2024522201000047.jpg156117JPEG2024522201000048.jpg16 2118JPEG2024522201000049.jpg147118JPEG2024522201000050.jpg152115JPEG202 4522201000051.jpg179119JPEG2024522201000052.jpg157118JPEG20245222010000 53.jpg168122JPEG2024522201000054.jpg163120JPEG2024522201000055.jpg193118

[0205] In certain embodiments, the present invention provides a compound selected from any one of the embodiments herein, or a pharmaceutically acceptable salt thereof.

[0206] Pharmaceutical Composition In yet another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0207] Conventional procedures for the selection and preparation of suitable pharmaceutical compositions are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs", MEAulton, Churchill Livingstone, 1988.

[0208] The compositions of the invention may be in a form suitable for oral use (e.g., tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., creams, ointments, gels or aqueous or oily solutions or suspensions), administration by inhalation (e.g., finely divided powders or liquid aerosols), administration by inhalant (e.g., finely divided powders) or parenteral administration (e.g., sterile aqueous solutions for intravenous, subcutaneous, intramuscular or intraperitoneal administration or suppositories for rectal administration).

[0209] The compositions of the present invention can be prepared in a conventional manner using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and / or preservative agents.

[0210] An effective amount of a compound of this invention for use in treating a disease is an amount sufficient to cause a warm-blooded animal, especially a human, to symptomatically alleviate or slow the progression of the disease.

[0211] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will vary depending on the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain from 0.1 mg to 0.5 g (more suitably, 0.5 to 100 mg, e.g., 1 to 30 mg) of active agent formulated in any appropriate and convenient manner, and the amount of excipient may vary from about 5 to about 98% by weight of the total composition.

[0212] The magnitude of the dose of the compounds of the present invention administered for therapeutic or prophylactic purposes will vary according to well-known medical principles depending on the nature and severity of the disease, the age and sex of the animal or patient, and the route of administration.

[0213] When the compounds of the present invention are used for therapeutic or prophylactic purposes, they are generally administered in a range of daily dosages, for example, selected from 0.1 mg / kg to 100 mg / kg, 1 mg / kg to 750 mg / kg, 1 mg / kg to 600 mg / kg, 1 mg / kg to 550 mg / kg, 1 mg / kg to 75 mg / kg, 1 mg / kg to 50 mg / kg, 1 mg / kg to 20 mg / kg, or 5 mg / kg to 10 mg / kg, and if necessary, administered in divided doses.

[0214] Generally, lower dosages are administered when parenteral routes are used. Thus, for example, for intravenous, subcutaneous, intramuscular, or intraperitoneal administration, dosages in the range of 0.1 mg / kg to 30 mg / kg of body weight are generally used. In certain embodiments, the compounds of the present invention are administered intravenously at a daily dose of, for example, 1 mg / kg to 750 mg / kg, 1 mg / kg to 600 mg / kg, 1 mg / kg to 550 mg / kg, or 5 mg / kg to 550 mg / kg, e.g., approximately 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 180, 200, 225, 250, 275, 300, 350, 400, 450, 500, 540, 550, or 575 mg / kg. Similarly, for administration by inhalation, a dose in the range of, for example, 0.05 mg / kg to 25 mg / kg body weight should be used. Preferably, the compounds of the present invention are administered orally, for example, in tablet or capsule dosage form. The daily oral dosage may be, for example, a total daily dosage selected from 1 mg to 1000 mg, 5 mg to 1000 mg, 10 mg to 750 mg, or 25 mg to 500 mg. Typically, a unit dosage form will contain approximately 0.5 mg to 0.5 g of the compound of the present invention. In certain embodiments, the compounds of the present invention are administered parenterally, for example, by intravenous administration. In certain other embodiments, the compounds of the present invention are administered orally.

[0215] Therapeutic Uses and Applications According to another aspect, the present invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0216] A further aspect of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or medical condition mediated by serine / threonine-like kinase (MASTL).

[0217] Also provided is the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or medical condition mediated by serine / threonine-like kinase (MASTL).

[0218] Also provided is a method for treating a disease or medical condition mediated by MASTL in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0219] The following paragraphs provide criteria for the application of the compounds of the present invention, or pharmaceutically acceptable salts thereof, for use in treating specific diseases or conditions. Any reference herein to a compound for a specific use should be understood to be intended for (i) the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating the disease or condition in question; and (ii) a method of treating a disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0220] The MASTL-mediated medical condition disease can be any of the diseases or medical conditions listed in this application, such as a proliferative disorder, in particular cancer.

[0221] The subject to which the compounds of the present invention are administered may be a warm-blooded mammal, such as a human or animal. In certain embodiments, the subject or patient is a human. In other embodiments, the subject is an animal, such as a rat, dog, cat, primate, or horse.

[0222] The association of MASTL with human and animal diseases is clearly set forth in the background of the present invention. The contents of this specification and related references are intended to provide further support for the therapeutic use of the compounds of the present invention. Such supporting evidence linking MASTL to diseases and conditions also forms part of the disclosure for the utility of the compounds of the present invention in treating and preventing the medical conditions described herein.

[0223] Proliferative disorders MASTL has been shown to play a role in many diseases, including various cancers, and there is growing interest in using MASTL inhibitors as a therapeutic strategy (Marzec and Burgess, The Oncogenic Functions of MASTL Kinase, Front Cell Dev. Biol. (2018);6:162). This is supported by the observation that MASTL inhibition can reduce tumor growth in vitro and in vivo (Wang et al., (2014), Vera et al., (2015), Anania et al., (2015), Alvarez-Fernandez et al., (2018)). MASTL depletion has been shown to increase the radiosensitivity of breast cancer cells and reduce the formation of radioresistant breast cancer cells, suggesting a therapeutic combination of MASTL inhibitors and radiation therapy (Yoon et al., "MASTL inhibition promotes mitotic catastrophe through PP2A activation to inhibit cancer growth and radioresistance in breast cancer cells," BMC Cancer (2018) 18, 716). Knockdown of MASTL has also been shown to reduce the viability of thyroid cancer cells without significantly affecting normal cell proliferation (Anania et al., 2015), suggesting that MASTL inhibitors may also be relatively nontoxic.

[0224] In certain embodiments, the compounds of the present invention are for use in the treatment of proliferative disorders, including cancer and benign proliferative disorders.

[0225] cancer In certain embodiments, the compounds of the invention are for use in preventing or inhibiting cancer progression, for example, through preventing or inhibiting cancer cell migration, cancer cell invasion and / or cancer metastasis.

[0226] In certain embodiments, the compounds of the present invention are for use in the treatment of cancer.

[0227] In certain embodiments, the compounds of the invention are for use in treating cancers that overexpress MASTL.

[0228] The compounds of the present invention may be useful in the treatment and / or prevention of, for example: Carcinomas include tumors derived from stratified squamous epithelium (squamous cell carcinoma) and tumors arising within organs or glands (adenocarcinoma), such as breast, colon, lung, prostate, ovarian, esophageal cancer (including, but not limited to, esophageal adenocarcinoma and squamous cell carcinoma), basal-like breast cancer, basal cell carcinoma (a form of skin cancer), squamous cell carcinoma (various tissues), head and neck carcinoma (including, but not limited to, squamous cell carcinoma), gastric carcinoma (including, but not limited to, gastric adenocarcinoma and gastrointestinal stromal tumor), signet ring cell carcinoma, bladder carcinoma (including transitional cell carcinoma (malignant neoplasm of the bladder)), bronchial carcinoma, colorectal cancer (colon cancer and rectal cancer), anal cancer, gastric cancer, lung cancer (including but not limited to small cell carcinoma and non-small cell carcinoma of the lung, lung adenocarcinoma, squamous cell carcinoma, large cell carcinoma, bronchoalveolar carcinoma and mesothelioma), neuroendocrine tumors (including but not limited to carcinoids of the gastrointestinal tract, breast and other organs), adrenocortical carcinoma, thyroid cancer, pancreatic cancer, breast cancer (including but not limited to ductal carcinoma, lobular carcinoma, inflammatory breast carcinoma, clear cell carcinoma and mucinous carcinoma), (including but not limited to intestinal liquid tumors, endometrioid tumors and mucinous cystadenocarcinoma, ovarian epithelial or surface epithelial tumors including sex cord-stromal tumors), liver and bile duct carcinoma (including but not limited to hepatocellular carcinoma, cholangiocarcinoma and hemangioma), prostate cancer, adenocarcinoma, brain tumors (including but not limited to glioma, glioblastoma, myeloid tumor), germ cell tumors, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, kidney pancreatic carcinoma (including but not limited to renal cell carcinoma, clear cell carcinoma, Wilms' tumor), bone marrow carcinoma, ductal carcinoma in situ or bile duct carcinoma, choriocarcinoma, seminoma, germ cell carcinoma, cervical cancer, uterine carcinoma (including but not limited to endometrial adenocarcinoma, uterine papillary-intestinal carcinoma, uterine clear cell carcinoma, uterine fibroids and leiomyosarcoma, mixed Müllerian tumor), testicular cancer, osteogenic carcinoma, epithelial carcinoma, sarcomatoid carcinoma, nasopharyngeal carcinoma, laryngeal carcinoma; oral and nasopharyngeal squamous cell carcinoma; Sarcomas include osteosarcoma and osteogenic sarcoma (bone); chondrosarcoma (cartilage); leiomyosarcoma (smooth muscle); rhabdomyosarcoma (skeletal muscle); mesothelioma and mesothelioma (membrane lining of body cavities); fibrosarcoma (fibrous tissue); angiosarcoma and hemangioendothelioma (blood vessels); liposarcoma (fatty tissue); glioblastoma and astrocytoma (genetic connective tissue found in the brain); myosarcoma (primitive embryonic connective tissue); chordoma, endothelioma, lymphangiosarcoma, lymphangioendosarcoma, synovioma, Ewing's sarcoma, mesenchymal and mesodermal tumors (mixed connective tissue type) and other soft tissue sarcomas; solid tumors of the nervous system, including medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, and schwannoma; melanoma, uveal melanoma and retinoblastoma; Myeloma and multiple myeloma, including conditions associated with myeloma, including light chain myeloma, non-secretory myeloma, plasmacytoma, amyloidosis, smoldering multiple myeloma (SMM), immunoglobulin D myeloma, immunoglobulin E myeloma, and monoclonal gammathyroid effectiveness (MGUS); Myeloid and granulocytic leukemias (malignancies of the myeloid and granulocytic leukemia lineage (e.g., acute myeloid leukemia)); lymphoid, lymphocytic, and lymphoblastic leukemias (malignancies of the lymphoid and lymphocytic blood lineage); and polycystic and erythroid products (malignancies of various blood products, but predominantly erythrocytes); hematopoiesis, including myelofibrosis; and Lymphoma, including Hodgkin's and non-Hodgkin's lymphoma.

[0229] In some embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, are for use in treating a solid tumor, such as any one of the solid tumors described above.

[0230] In certain embodiments, the compounds of the invention are for use in the treatment of cancer selected from breast, ovarian, lung, colon, prostate, oral cavity, stomach, adrenal cortex, pancreas, kidney, sarcoma, liver, endometrial, thyroid, head or neck, brain (glioma), melanoma (e.g., ocular melanoma), and hematological cancers (e.g., leukemias such as AML, lymphoma, myeloma, and multiple myeloma).

[0231] In yet another embodiment, the compound of the invention, or a pharmaceutically acceptable salt thereof, is for use in treating breast cancer selected from luminal A breast cancer (hormone-receptor positive (estrogen-receptor and / or progesterone-receptor positive), HER2-negative, and low levels of the protein Ki-67); luminal B breast cancer (hormone-receptor positive (estrogen-receptor and / or progesterone-receptor positive) and HER2-positive or HER2-negative with high levels of Ki-67); triple-negative breast cancer (i.e., the tumor is estrogen receptor-negative, progesterone receptor-negative, and HER2-negative); HER2-positive breast cancer, or normal-like breast cancer (classifications as defined in Table 1 of Dai et al. Am. J. Cancer Research. 2015;5(10):2929-2943).

[0232] In one embodiment, the compound of the invention, or a pharmaceutically acceptable salt thereof, is for use in treating a cancer selected from pancreatic cancer, triple-negative breast cancer (i.e., the tumor is estrogen receptor negative, progesterone receptor negative, and HER2 negative), hormone-refractory prostate cancer, and non-small cell lung cancer.

[0233] The compounds of the present invention provide anti-cancer effects against cancer (e.g., any of the cancers disclosed herein) selected from one or more of an anti-proliferative effect, a pro-apoptotic effect, an anti-mitotic effect, an anti-angiogenic effect, inhibition of cell migration, inhibition or prevention of tumor invasion and / or prevention or inhibition of metastasis.

[0234] The compounds of the present invention can be used to prevent or inhibit cancer progression. The compounds of the present invention may be used to slow, delay, or halt cancer progression. Cancer progression is generally determined by assigning stages to cancer. The stages are generally numbered from I to IV, with I representing isolated cancer and IV representing the stage of disease progression in which the cancer has metastasized to other organs. The stages generally take into account the size of the tumor, whether adjacent organs have been affected, whether lymph nodes have metastasized, etc. Preventing or inhibiting cancer progression is particularly important for preventing cancer spread, for example, from stage I to stage II, in which cancer spreads locally, or from stage III to stage IV, in which cancer metastasizes to other organs.

[0235] The compounds of the invention may be for use in the treatment of cancer, wherein the cancer is a primary cancer, which may be a second primary cancer.

[0236] The compounds of the invention may be for use in preventing or inhibiting the development of second primary cancers.

[0237] The compounds of the invention may be for use in treating cancers that are refractory (resistant) to anti-cancer drugs (e.g., chemotherapy) and / or radiation therapy. The cancer may be resistant initially to treatment or may develop resistance during treatment.

[0238] The compounds of the present invention are intended to be used in the treatment of cancer, wherein the cancer is a recurrent cancer, which may be local, regional or distant. A recurrent cancer is a cancer that recurs after a period of time in which the cancer cannot be found after initial treatment. The same cancer can recur in the same tissue or in another part of the body.

[0239] The compounds of the invention may be for use in preventing or inhibiting the recurrence of cancer.

[0240] The compounds of the invention may be for use in the treatment of cancer, wherein the cancer is a metastatic or secondary cancer.

[0241] The compounds of the present invention may be used to prevent or inhibit cancer metastasis. The treatment for metastatic cancer may be the same or different from the treatment previously used to treat the primary tumor. For example, in certain embodiments, the primary tumor may be surgically resected, and the compounds of the present invention are used to prevent the spread of cancer cells that remain after surgery or that have already escaped from the primary tumor. In other embodiments, the primary tumor may be treated using radiation therapy. In other embodiments, the primary tumor may be treated with chemotherapy. Combination therapies are commonly used to treat cancer, generally to maximize the length and depth of remission. Any combination therapy disclosed herein may be used with the compounds of the present invention.

[0242] If a primary tumor has already metastasized and a secondary tumor has formed, the compounds of the present invention may be used to treat the secondary tumor. This can include both treating the secondary tumor and preventing secondary tumor metastasis. Reference to metastasis herein is intended to encompass metastasis of any tumor disclosed herein. Generally, the secondary tumor will be in a different tissue than the primary tumor. For example, the secondary tumor may be a secondary bone tumor. In certain embodiments, the compounds of the present invention are intended for use in treating secondary bone tumors, e.g., secondary bone tumors where the primary tumor is a breast or prostate tumor.

[0243] Benign proliferative disorders The compounds of the present invention, or pharmaceutically acceptable salts thereof, may be used to treat benign proliferative diseases. The benign diseases may be benign tumors, such as hemangioma, hepatocellular adenoma (HCA), cavernous hemangioma, focal nodular hyperplasia, acoustic neuroma, neurofibroma, bile duct adenoma, cholangiocytoma, fibroma, lipoma, myoma, mesothelioma, teratoma, myxoma, nodular regenerative hyperplasia, trachoma, pyogenic granuloma, mole, uterine fibroid, thyroid adenoma, adrenal cortical adenoma, or pituitary adenoma.

[0244] In some embodiments, the benign proliferative disease is a hyperproliferative skin disorder, including psoriasis, warts, keratoacanthoma, seborrhea, ichthyosis, actinic keratosis, Bowen's disease, papilloma, seborrheic keratosis, eczema, atopic dermatitis, keloids, and epidermolysis bullosa (EB).

[0245] Other diseases and conditions In certain embodiments, the compounds of the invention are for use in the treatment or prevention of metabolic disorders, or symptoms or conditions associated with metabolic disorders.

[0246] The metabolic disorder may be a glucose metabolism disorder or a weight disorder.

[0247] The term "glucose metabolism disorder" includes all disorders characterized by a clinical symptom or combination of clinical symptoms associated with elevated levels of glucose and / or elevated levels of insulin in healthy individuals and related subjects. Elevated glucose and / or insulin levels can be manifested in the following diseases, disorders and conditions, among others: hyperglycemia, type 2 diabetes, gestational diabetes, type 1 diabetes, insulin resistance, impaired glucose tolerance, hyperinsulinemia, impaired glucose metabolism, pre-diabetes, other metabolic disorders (such as metabolic syndrome), and obesity.

[0248] The term "insulin resistance," as used herein, refers to a condition in which normal amounts of insulin fail to produce normal physiological or molecular responses.

[0249] The term "hyperglycemia," as used herein, refers to a condition in which high amounts of glucose circulate in the plasma of a healthy individual. Hyperglycemia can be diagnosed using methods known in the art, including measuring fasting blood glucose levels.

[0250] The term "hyperinsulinemia," as used herein, refers to a condition in which circulating insulin levels are elevated in conjunction with elevated or normal blood glucose levels. Hyperinsulinemia can be caused by insulin resistance associated with dyslipidemia, such as high triglycerides, high cholesterol, high low-density lipoprotein (LDL), and low high-density lipoprotein (HDL); high uric acid levels; polycystic ovary syndrome; type 2 diabetes; and obesity. Hyperinsulinemia can be diagnosed when plasma insulin levels are 2 μg / ml or higher.

[0251] The term "weight disorder" refers to a condition associated with excessive weight and / or increased appetite. Various parameters are used to determine whether a subject is overweight compared to a healthy person, including the subject's age, height, sex, and health status. For example, a subject can be considered overweight or obese by assessing the subject's body mass index (BMI), which is calculated by dividing the subject's height by their weight. Adults with a BMI ranging from -18.5 to -24.9 kg / m can be considered normal weight; adults with a BMI between -25 and -29.9 kg / m can be considered overweight (pre-obese); and adults with a BMI of -30 kg / m or greater can be considered obese. Thus, in some embodiments, the weight disorder is obesity.

[0252] Thus, symptoms and conditions associated with metabolic disorders may include, but are not limited to, increased blood sugar (hyperglycemia), decreased insulin production, metabolic syndrome, increased cholesterol, increased triglyceride levels, heart disease, stroke, high blood pressure, increased risk of blood clots (e.g., deep vein thrombosis), diabetes, metabolic acidosis, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, and the like.

[0253] The term "metabolic syndrome" refers to a cluster of related traits, including, but not limited to, hyperinsulinemia, abnormal glucose tolerance, fat redistribution to the abdominal or upper body compartment, hypertension, abnormal fiber breakdown, and dyslipidemia, which are characterized by elevated triglycerides, low high-density lipoprotein (HDL) cholesterol, and elevated low-density lipoprotein (LDL) particles. Subjects with metabolic syndrome are at risk for developing type 2 diabetes and / or other disorders, such as atherosclerosis.

[0254] The compounds of the invention may be used to prevent or inhibit the progression or symptoms of metabolic disorders or conditions associated therewith. For example, the compounds of the invention may lower blood glucose, insulin, triglyceride, or cholesterol levels to ranges found in healthy subjects; reduce weight; improve glucose tolerance, energy expenditure, or insulin sensitivity; delay the onset or progression of diabetes; reduce blood pressure; and / or reduce the risk of blood clots, heart disease, or stroke.

[0255] In certain embodiments, the compounds of the present invention are for use in treating a platelet disorder, such as thrombocytopenia.

[0256] The compounds of the present invention may be used alone or in combination with one or more anti-cancer agents and / or radiation therapy, as described herein.

[0257] Combination therapy The compounds of the present invention may be used alone to provide a therapeutic effect. The compounds of the present invention may also be used in conjunction with one or more additional therapies.

[0258] In some embodiments, the compounds of the present invention are used in combination with one or more anti-cancer agents and / or radiation therapy.

[0259] The rationale for this is based on results showing that overexpression of MASTL is associated with resistance to cisplatin ( Wang et al., 2014 ) by accelerating checkpoint recovery ( Wong et al., 2016 ). Conversely, knockdown of MASTL has been observed to sensitize cancer cells to cisplatin, radiation therapy, and 5-fluorouracil (5FU) in various cancer types (Wang et al., (2014)). Serine / threonine kinase (MASTL kinase), a promising therapeutic target, promotes cancer recurrence (Oncotarget511479-11489; Nagel et al., (2015)). Genome-wide siRNA screens confirm the radiation-reducing effects of downregulating MASTL and FOXM1 in NSCLC (Mol. Cancer Ther.141434-1444; Uppada et al. (2018)). MASTL promotes Wnt / β-catenin signaling to induce colorectal cancer progression and chemoresistance (Mol. Cancer17:111; Yoon et al., (2018)). MASTL inhibition promotes mitotic catastrophe through PP2A activation to inhibit cancer growth and radioresistance in breast cancer cells.BMC Cancer18:716).

[0260] Therefore, the compounds of the present invention can be used to prevent or reduce cellular resistance to anti-cancer drugs, including chemotherapeutic agents and radiation therapy.

[0261] Such chemotherapy may include one or more of the following classes of anti-cancer drugs: (i) Antiproliferative / antineoplastic drugs and combinations thereof, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, uracil mustard, bendamustine, melphalan, chlorambucil, chlormethine, busulfan, temozolomide, nitrosoureas, ifosfamide, melphalan, pipobroman, triethylene-melamine, triethylenethiophosphoramide, carmustine, rhodanese, antimetabolites (e.g., fluoropyrimidines such as gemcitabine and 5-fluorouracil and tegafur, antifolates and hydroxyureas such as raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine); antibiotics (e.g., adriamycin, anthracyclines such as ampicillin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin); antimitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, taxoids such as taxol and taxotere, and polo kinase inhibitors); proteasome inhibitors, e.g., carfilzomib and Bortezomib; interferon therapeutic agents; and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, irinotecan, mitoxantrone, and camptothecin); bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol®), nab-paclitaxel (albumin-bound paclitaxel), docetaxel, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferons (especially IFN-alpha), etoposide, teniposide, DNA-demethylating agents (e.g., azacitidine or decitabine);and histone deacetylase (HDAC) inhibitors (e.g., vorinostat, MS-275, panobinostat, romidepsin, valproic acid, mocetinostat (MGCD0103), and pracinostat SB939); (ii) Cytostatic agents such as antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxifene), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or agonists (e.g., goserelin, leuprorelin, and buserelin), progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorozole, and exemestane), and 5α-reductase inhibitors such as finasteride; and navelbine, CPT-11, anastrozole, letrozole, capecitabine, reloxafam, cyclophosphamide, ifosfamide, and droloxafine; (iii) anti-invasive agents, such as dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function, or antibodies against heparanase; (iv) inhibitors of growth factor function: for example, such inhibitors include growth factor antibodies and growth factor receptor antibodies, such as the anti-erbB2 antibody trastuzumab [Herceptin®], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (e.g., gefitinib, erlotinib, 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI1 033), EGFR family tyrosine kinase inhibitors such as afatinib, vandetanib, osimertinib, and rociletinib), erbB2 tyrosine kinase inhibitors such as lapatinib and antibodies against costimulatory molecules such as CTLA-4, 4-IBB, and PD-I, or antibodies against cytokines (IL-10, TGF-beta); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; modulators of protein regulators of cell apoptosis (e.g., Bcl-2 inhibitors); inhibitors of the platelet-derived growth factor family such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (e.g., farnesyltransferase inhibitors, Ras / Raf signaling inhibitors such as sorafenib, tipifarnib, and lonafarnib), inhibitors of cell signaling via MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CS F-1R kinase inhibitors, IGF receptor kinase inhibitors, for example, dalotuzumab; cyclin-dependent kinase inhibitors such as Aurora kinase inhibitors and CDK2 and / or CDK4 inhibitors; CCR2, CCR4 or CCR6 antagonists; RAF kinase inhibitors such as those described in WO2006043090, WO2009077766, WO2011092469 or WO2015075483; and Hedgehog inhibitors, for example, vismodegib.

[0262] (v) antiangiogenic agents that inhibit the effects of vascular endothelial growth factor (e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin™)); thalidomide; lenalidomide; and VEGF receptor tyrosine kinase inhibitors such as vandetanib, vatalanib, sunitinib, axitinib, pazopanib, and cabozantinib; (vi) gene therapy approaches, including approaches to replace abnormal genes, such as, for example, abnormal p53 or abnormal BRCA1 or BRCA2; (vii) for example, alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®) and ofatumumab; interferons such as interferon alpha; interleukins such as IL-2 (aldesleukins); interleukin inhibitors, e.g., IRAK4 inhibitors; cancer vaccines, including prophylactic and therapeutic vaccines such as HPV vaccines, e.g., Gardasil, Cervarix, Oncophage, and Sipuleucel-T (Provenge); cgp100; dendritic cell-based vaccines (Ad.p53 toll-like receptor modulators, such as TLR-7 or TLR-9 agonists; PD-1, PD-L1, PD-L2, and CTL4-A modulators (e.g., nivolumab), antibodies, and vaccines; other IDO inhibitors (such as indoximod); anti-PD-1 monoclonal antibodies (such as MK-3475 and nivolumab); anti-PDL1 monoclonal antibodies (such as MEDI-4736 and RG-7446); anti-PDL2 monoclonal antibodies; and gene therapy approaches, including antibody therapies, such as anti-CTLA-4 antibodies (such as ipilumumab), CAR-T cell therapy; and (viii) cytotoxic agents such as, for example, fludaribine (fludara), cladribine, pentostatin (Nipent™); (ix) Targeted therapies, such as PI3K inhibitors, e.g., idelalisib and perifosine, SMAC (second mitochondrial-induced activator of caspases) mimetics, also known as IAP (Inhibitor of Apoptosis Proteins) antagonists (IAP antagonists). Such agonists inhibit IAPs, such as XIAP, cIAP1, and cIAP2, thereby resetting the apoptotic pathway. Specific SMAC mimetics include birinapant (TL32711, TetraLogic Pharmaceuticals), LCL161 (Novartis), AEG40730 (Aegera Therapeutics), SM-164 (University of Michigan), LBW242 (Novartis), ML101 (Sanford-Burnham Medical Research Institute), AT-406 (Ascenta Therapeutics / University of Michigan), GDC-0917 (Genentech), AEG35156 (Aegera Therapeutic), and HGS1029 (Human Genome Sciences); and agents that target the ubiquitin proteasome system (UPS), such as bortezomib, carfilzomib, marizomib (NPI-0052), and MLN9708; CXCR4 antagonists, such as plerixafor or BL-8040; (x) PARP inhibitors, such as niraparib (MK-4827), talazoparib (BMN-673), veliparib (ABT-888); olaparib, CEP 9722, and BGB-290 (xi) chimeric antigen receptors, anticancer vaccines and arginase inhibitors; (xii) hyaluronan-degrading agents, such as the hyaluronidase enzyme PEGPH20 The additional anti-cancer agent may be in a single formulation or in one or more of the additional formulations described herein.

[0263] Specific anticancer agents that may be used with the compounds of the present invention include, for example, paclitaxel (including nab-paclitaxel), gemcitabine, oxaliplatin, irinotecan, leucovorin, and 5-fluorouracil. In some embodiments, the additional anticancer agent is selected from capecitabine, gemcitabine, and 5-fluorouracil (5FU).

[0264] In some embodiments, the compounds of the present invention may be used in conjunction with one or more therapies for the treatment or prevention of metabolic disorders, including therapeutic agents, LDL apheresis, dietary restriction, and / or surgery (e.g., bariatric surgery).

[0265] Therapeutic agents for the treatment or prevention of metabolic disorders may include one or more of the following: (i) diabetes treatments, such as metformin, sulfonylureas (e.g., glyburide, glipizide, and glimepiride), meglitinides (e.g., repaglinide and nateglinide), thiazolidinediones (e.g., rosiglitazone and pioglitazone), DPP-4 inhibitors (e.g., sitagliptin, saxagliptin, and linagliptin), GLP-1 receptor agonists (e.g., exenatide, liraglutide, and semaglutide), SGLT2 inhibitors (e.g., canagliprozin, dapagliflozin, and empagliflozin), insulins (e.g., long-acting insulins such as insulin detemir or insulin detemir), and aspirin; (ii) cholesterol-lowering agents, such as statins (e.g., atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin); cholesterol absorption inhibitors (e.g., ezetimibe); PCSK9 inhibitors (e.g., Repatha and Praluent); (iii) triglyceride-lowering agents, such as statins, fibrates, nicotinic acid, and omega-3 fatty acids; (iv) anticoagulants, e.g., anticoagulants (e.g., heparin, warfarin, rivaroxaban, dabigatran, apixaban, edoxaban, enoxaparin, fondaparinux); (v) antihypertensive agents, for example, diuretics (e.g., thiazide diuretics such as chlorthalidone, chlorothiazide, hydrochlorothiazide, indapamide, and metolazone; potassium-sparing diuretics such as amiloride, spironolactone, and triamterene; loop diuretics such as bumetanide, furosemide, and torsemide; combined diuretics such as amiloride hydrochloride / hydrochlorothiazide, spironolactone / hydrochlorothiazide, and triamterene / hydrochlorothiazide), beta-blockers (e.g., acebutolol, atenolol, betaxolol, bisoprolol, bisoprolol / hydrochlorothiazide, metoprolol tartrate, metoprolol succinate, nadolol, pindolol, propranolol, solotol, and timolol), ACE inhibitors (e.g., benazepril, kebutopril, enalapril, folic acid, sinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril), angiotensin II receptor blockers (ARBs) (e.g., candesartan, eprosartan, irbesartan, losartan, telmisartan, valsartan), calcium channel blockers (e.g., amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil), alpha-blockers (e.g., doxazosin, prazosin, terazosin), alpha-beta blockers (e.g., carvedilol, labetalol), central agonists (e.g., methyldopa, clonidine, guanfacine), vasodilators (e.g., hydralazine, minoxidil), aldosterone receptor antagonists (e.g., eplerenone, spironolactone), direct renin inhibitors (e.g., aliskiren).

[0266] Such combination treatment may be achieved by the simultaneous, sequential or separate administration of the individual components of the treatment. Such combination products employ compounds of this invention within the therapeutically effective dosage ranges described herein, as well as other pharmaceutically effective dosage ranges.

[0267] When the term "combination" is used herein, it should be understood to refer to simultaneous, separate, or sequential administration. In one embodiment of the invention, "combination" refers to simultaneous administration. In another embodiment of the invention, "combination" refers to separate administration. In additional embodiments of the invention, "combination" refers to sequential administration. When administration is sequential or separate, the beneficial effect of the combination should not be lost by delaying the administration of the second component.

[0268] In some embodiments where combination therapy is used, the amount of the compound of the present invention and the amount of the other pharmaceutically active agent, when combined, are therapeutically effective to treat the target disease in a patient. In this context, a "therapeutically effective amount" is sufficient if the combined amount is sufficient to reduce or completely alleviate the symptoms or other adverse effects of the disease; to overcome the disease; to reverse, completely halt, or slow the progression of the disease; or to reduce the risk of the disease worsening. Generally, such amounts can be determined by one of ordinary skill in the art based on the dosage ranges for the compounds of the present invention described herein and the established or otherwise published dosage ranges for the other pharmaceutically active compound.

[0269] According to a further embodiment of the present invention there is provided a compound of the present invention as defined herein and an additional anti-cancer agent as defined herein for use in the joint treatment of cancer.

[0270] According to a further embodiment of the present invention there is provided a pharmaceutical product comprising a compound of the present invention as defined herein and an additional anti-cancer agent as defined herein for the co-treatment of cancer.

[0271] According to a further embodiment of the present invention, there is provided a method of treating a human or animal subject suffering from cancer, comprising the step of administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, simultaneously, sequentially or separately with an additional anti-cancer agent as defined herein.

[0272] According to a further embodiment of the present invention there is provided a compound of the present invention or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, either simultaneously, sequentially or separately with an additional anti-cancer agent as defined above.

[0273] The compounds of the present invention may be used in conjunction with radiation therapy. Suitable radiation therapy includes, for example, X-ray therapy, proton beam therapy, or electron beam therapy. Radiation therapy can also be used, for example, 131 I, 32 P, 90 Y, 89 Sr, 153 Sm also 223 This may involve the use of radionuclide preparations such as Ra. Such radionuclide treatment methods are well known and commercially available.

[0274] According to a further embodiment of the present invention there is provided a compound of the present invention, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of cancer in conjunction with radiation therapy.

[0275] According to a further embodiment of the present invention, there is provided a method for treating a human or animal subject suffering from cancer, comprising the step of administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, simultaneously, sequentially or separately with radiation therapy.

[0276] Biological Assays The biological effect of a compound can be assessed using one of the assays described in the Examples herein.

[0277] In certain embodiments, compounds have a pIC of 7.0 or less in the MASTLwt activity assay described in the Examples. 50 It has.

[0278] Synthesis The compounds of the present invention can be prepared using methods similar to the general synthetic methods described in the Examples. In the descriptions of the synthetic methods described below and the descriptions of the reference synthetic methods used to prepare starting materials, it should be understood that all reaction conditions proposed, including the selection of solvents, reaction pressure, reaction temperature, duration of experiments, and work procedures, can be selected by those skilled in the art.

[0279] One skilled in the art of organic synthesis understands that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions.

[0280] Necessary starting materials can be obtained by standard procedures of organic chemistry. The preparation of such starting materials is illustrated within the following representative process variants and accompanying examples. Alternatively, necessary starting materials can be obtained through procedures analogous to those illustrated, within the ordinary skill of an organic chemist.

[0281] It will be appreciated that during the synthesis of the compounds of the invention, or of particular starting materials, in the steps defined below, it may be desirable to protect certain substituents to prevent these undesired reactions, and the skilled chemist will recognize when such protection is required and how to place or subsequently remove such protecting groups.

[0282] For examples of protecting groups, see, for example, 'Protective Groups in Organic Synthesis' by Theodora Green (publisher: John Wiley & Sons), among many other general works on the subject. Protecting groups can be removed by any convenient method known to skilled chemists to be suitable for removing the protecting group in question, chosen to effect removal of the protecting group while minimizing interference with groups elsewhere in the molecule.

[0283] Thus, if reactants contain groups such as amino, carboxy or hydroxy, it may be preferable to protect the group in some of the reactions mentioned herein.

[0284] For example, suitable protecting groups for amino or alkylamino groups are, for example, acyl groups, e.g., alkanoyl groups such as acetyl or trifluoroacetyl, alkoxycarbonyl groups, e.g., methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl groups, allylmethoxycarbonyl groups, e.g., benzyloxycarbonyl, or aroyl groups, e.g., benzoyl. The deprotection conditions for protecting groups necessarily vary depending on the choice of protecting group. Thus, for example, acyl groups, such as alkanoyl or alkoxycarbonyl groups or aroyl groups, can be removed by hydrolysis using a suitable base, e.g., an alkali metal hydroxide, e.g., lithium or sodium hydroxide. Alternatively, acyl groups such as tert-butoxycarbonyl groups may be removed by treatment with a suitable acid, for example, sulfur or phosphoric acid or trifluoroacetic acid, and allylmethoxycarbonyl groups such as benzyloxycarbonyl groups may be removed by hydrogenation over a catalyst such as palladium-on-carbon or by treatment with a Lewis acid such as BF3.OEt2. A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example, dimethylaminopropylamine, or hydrazine.

[0285] Suitable protecting groups for hydroxy groups include, for example, acyl groups, e.g., alkanoyl groups such as acetyl, aroyl groups such as benzoyl, or arylmethyl groups such as benzyl. The deprotection conditions for such protecting groups necessarily vary depending on the choice of protecting group. Thus, for example, acyl groups, e.g., alkanoyl or aroyl groups, can be removed by hydrolysis with a suitable salt, e.g., an alkali metal hydroxide, e.g., lithium or sodium hydroxide, or ammonia. Alternatively, arylmethyl groups, e.g., benzyl groups, can be removed by hydrogenation over a catalyst, e.g., palladium-on-carbon.

[0286] Suitable protecting groups for carboxyl groups are, for example, esterifying groups, such as methyl or ethyl groups, which may be removed by hydrolysis with a salt such as sodium hydroxide, or, for example, t-butyl groups, which may be removed by treatment with an acid, for example, an organic acid such as trifluoroacetic acid, or, for example, benzyl groups, which may be removed by hydrogenation over a catalyst such as palladium on carbon.

[0287] The resin can also be used as a protecting group.

[0288] Example Throughout this specification, such abbreviations have the following meanings: Aq. = aqueous DCM = dichloromethane DMF = N,N-dimethylformamide DMSO = dimethyl sulfoxide Et = ethyl EtOAc = ethyl acetate h = time MeOH = methanol Me = methyl min = minutes mol = mole cPr = cyclopropyl iPr = Isopropyl Rt = Retention time RT = Room temperature Sat. = Saturated THF = tetrahydrofuran T3P = propyl phosphonic anhydride DIEA = N,N-diisopropylethylamine Et3N = triethylamine HOBt = 1-hydroxybenzotriazole hydrate NH4Cl = ammonium chloride EDCI·HCl = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride EtOH = ethanol NaOAc = sodium acetate NaHCO3 = sodium bicarbonate NaOH = sodium hydroxide KF = potassium fluoride MeMgBr = methylmagnesium bromide NaBH3CN = sodium cyanoborohydride NH3 = ammonia HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate NBS = N-bromosuccinimide NH2NH2·H2O = hydrazine monohydrate H3PO4 = phosphoric acid Na2SO4 = sodium sulfate MeCN = acetonitrile

[0289] material and method Unless otherwise specified herein, solvents, reagents, and starting materials were purchased and used from conventional suppliers. All reactions were carried out at room temperature unless otherwise specified. Flash column chromatography was performed using an ISCO Combiflash RF Flash or Biotage Isolera Prime on Merck silica gel 60 (40-63 μm) or silica-filled packed columns.

[0290] LCMS LCMS data were recorded on a Waters 2695 HPLC using a Waters 2487 UV detector and a Thermo LCQ ESI-MS. Samples were eluted through a Phenomenex Luna 3μ C18 50mm × 4.6mm column using water and acetonitrile acidified with 0.1% formic acid at 1.5mL / min and detected at 254nm.

[0291] The following methods were used: Method 1: 4 minute method The gradient applied is: Time (min) % Water + 0.1% Formic Acid % Acetonitrile + 0.1% Formic Acid 0.0 65 35 3.5 10 90 3.9 10 90 4.0 65 35 Method 2: 5 minute method The gradient applied is: Time (min) % Water + 0.1% Formic Acid % Acetonitrile + 0.1% Formic Acid 0.0 90 10 0.5 90 10 4.0 10 90 4.7 10 90 4.8 65 35 5.0 65 35 Method 3: 10 minute method The gradient applied is: Time (min) % Water + 0.1% Formic Acid % Acetonitrile + 0.1% Formic Acid 0.0 95 5 8.0 5 95 8.5 5 95 9.0 95 5 9.5 95 5 LCMS (MDAP) data were recorded on a Shimadzu Prominence Series coupled to an LCMS-2020 ESI and APCI mass spectrometer. Samples were eluted through a Phenomenex Gemini 5μ C18 110Å 250 mm × 4.6 mm column using water and acetonitrile acidified with 0.1% formic acid at 1 mL / min and detected at 254 nm.

[0292] The following methods were used: Method 4:5-95 analytical method The gradient applied is: Time (min) % Water + 0.1% Formic Acid % Acetonitrile + 0.1% Formic Acid 0.0 95 5 1.0 95 5 21.0 5 95 25.0 5 95 30.0 70 30 Method 5:30-90 Analysis method The gradient applied is: Time (min) % Water + 0.1% Formic Acid % Acetonitrile + 0.1% Formic Acid 0.0 70 30 1.0 70 30 21.0 10 90 25.0 10 90 30.0 70 30 Method 6:5-95 Analysis Method (8 minutes) The gradient applied is: Time (min) % Water + 0.1% Formic Acid % Acetonitrile + 0.1% Formic Acid 0.0 95 5 0.5 95 5 5.5 5 95 7.0 5 95 7.5 70 30 Method 7:5-95 Analysis Method (5 minutes) The gradient applied is: Time (min) % Water + 0.1% Formic Acid % Acetonitrile + 0.1% Formic Acid 0.0 95 5 0.5 95 5 5.5 5 95 7.0 5 95 7.5 95 5 UPLC-MS was performed on a Waters Acquity UPLD system consisting of an Acquity I-Class Sample Manager-FL, an Acquity I-Class Binary Solvent Manager, and an Acquity UPLC Column Manager. UV detection was performed using an Acquity UPLC PDA detector (scanning from 210 nm to 400 nm) while mass detection was performed using an Acquity QDa detector (mass scanning from 100-1250 Da, simultaneous positive and negative modes). Analytes were separated using a Waters Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 μm).

[0293] Method 8 (basic 2 minutes) The gradient applied is: Time (min) 0.1% ammonia in water 0.1% ammonia in acetonitrile 0.00 95 5 0.25 95 5 1.25 5 95 1.55 5 95 1.65 95 5 2.00 95 5 Method 9 (basic 4 minutes) The gradient applied is: Time (min) 0.1% ammonia in water 0.1% ammonia in acetonitrile 0.00 95 5 0.25 95 5 2.75 5 95 3.25 5 95 3.35 95 5 4.00 95 5 Mass Directed Purification was performed using a Phenomenex Gemini 5μ C18 250 mm × 21.2 mm column through a Shimadzu Prominence Series coupled to an LCMS-2020 ESI and APCI mass spectrometer using water and acetonitrile acidified with 0.1% formic acid at 15 mL / min with detection at 254 nm.

[0294] The gradient applied is: Time (min) % Water + 0.1% Formic Acid % Acetonitrile + 0.1% Formic Acid 0.0 95 5 1.0 95 5 21.0 5 95 25.0 5 95 30.0 70 30 NMR NMR was also used to characterize the final compounds. NMR spectra were recorded at 500 MHz on a Varian VNMRS 500 MHz spectrometer (25 °C), a Bruker Avanced 400 MHz NMR spectrometer, or a Varian VNMRS 600 MHz spectrometer using residual isotopic solvents (chloroform, δH = 7.27 ppm, DMSO δH = 2.50 ppm, methanol δH = 3.31 ppm) as an internal standard. Chemical shifts are expressed in parts per million (ppm). Coupling constants (J) are reported in Hertz.

[0295] Many triazine compounds, including rotamers and / or tautomers, exhibited complex NMR structures, which were analyzed using variable temperature (Vt) NMR from 90 to 120 °C with the expected patterns.

[0296] chemical synthesis Microwave reactions were carried out using a Biotage Initiator 8+ microwave reactor.

[0297] General synthesis method A [ka] Step 1. 4-Chloro-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazin-2-amine (Intermediate X) (1 mol eq.) was added to a mixture of N,N-diisopropylethylamine (5-10 mol eq.) and an appropriate amount of amine (1.8-2.0 mol eq.) in 1,4-dioxane at room temperature. The reaction mixture was heated at 80-120 °C for 2 h to 7 days and then concentrated to dryness under reduced pressure. The crude material was purified by flash chromatography to afford the THP-protected product 1.

[0298] Step 2. A solution of the THP-protected product I from step 1 in 1,4-dioxane / methanol (1:1) was treated with 4 M HCl in 1,4-dioxane at room temperature. The reaction mixture was heated in a sealed vial at 25-120 °C for 1-24 h. After concentrating the reaction mixture to dryness under reduced pressure, the crude material was purified by flash chromatography to give the desired product II.

[0299] General synthesis method B [ka] Step 1: To a stirred solution of 2-amino-4,6-dichlorotriazine in 1,4-dioxane was added N,N-diisopropylmethylamine, followed by the appropriate amount of amine. The resulting mixture was stirred at room temperature for 12 hours. The volatiles were removed under reduced pressure, and the crude material was purified by silica chromatography to give product III.

[0300] Step 2: A stirred solution of product III, tripotassium phosphate, bis[2-(di-tert-butylphosphanyl)cyclopenta-2,4-dien-1-yl]iron, a palladium catalyst such as dichloropalladium, and water in tetrahydrofuran was first degassed by bubbling N2 directly through the solution. The mixture was heated to 80°C, and a solution of 1-tetrahydropyran-2-yl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (Intermediate V) in THF was added. The reaction mixture was then stirred at 60-100°C for 2-24 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the crude material was purified by flash column chromatography to obtain product I.

[0301] Step 3: A solution of product I in methyl alcohol was treated with 4 M HCl in 1,4-dioxane at 60 °C for 2-16 h. The resulting suspension was filtered, and the filtered solid was washed with a solvent such as 1,4-dioxane, ethyl acetate, and / or diethyl ether. The solid material was purified by flash column chromatography to give the desired product II.

[0302] Method C [ka] A solution of Intermediate Z in NMP was treated with an appropriate amount of amine and N,N-diisopropylethylamine, and the reaction mixture was stirred at 90° C. for 2 hours to 3 days. The reaction was allowed to cool to room temperature and then purified by flash silica chromatography or diluted with 9:1 DMSO:water and purified by preparative HPLC.

[0303] General synthesis method D [ka] Step 1: A stirred solution of 2-amino-4,6-dichlorotriazine in 1,4-dioxane was added to N,N-diisopropylethylamine, followed by the appropriate amount of amine. The resulting mixture was stirred at room temperature for 12 hours or heated in a microwave oven for 1-2 hours. After removing the volatiles under reduced pressure, the crude material was purified by silica chromatography to give product III.

[0304] Step 2: A stirred solution of product III, intermediate WY, tripotassium phosphate, bis[2-(di-tert-butylphosphanyl)cyclopenta-2,4-dien-1-yl]iron, a palladium catalyst such as dichloropalladium, and water in tetrahydrofuran was degassed by bubbling N2 directly through the solution. The mixture was heated at 90-120 °C for 2-24 h. The reaction mixture was concentrated to dryness under reduced pressure, and the crude material was purified by flash column chromatography to give product IV.

[0305] Alternatively, intermediate WY is synthesized in situ. [ka] Step 2: A palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) was added to a degassed solution of appropriately substituted 6-bromoimidazo[1,5-a]pyridine, potassium acetate, and bis(pinacolato)diboron, and the mixture was heated at 90-120 °C for 6-24 hours. After the mixture was cooled to room temperature, product III, bis[2-(di-tert-butylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; a second palladium catalyst such as dichloropalladium, and potassium tribasic were added. The mixture was heated at 70-120 °C for 8-24 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the crude material was purified by flash column chromatography to give product IV.

[0306] General synthesis method E [ka] Methylimidazopyridinyltriazineamine, a pyrimidine amine in 1,4-dioxane, was added to the substituted amine and DIEA. The reaction mixture was then heated to 90-120°C and stirred for 10-20 hours. The reaction mixture was concentrated under reduced pressure to leave a residue, which was purified by preparative HPLC to obtain the target compound.

[0307] General synthesis method F [ka] Step 1 After cooling the solution of amino acid, EtN, and HOBt in anhydrous DCM to 0 °C, EDCI HCl was added and stirred at 20-50 °C for 30 min. N-Methoxymethanamine was then added and stirred at 20-50 °C for an additional 10-20 h. The crude product was purified by recrystallization.

[0308] Step 2 The (methoxy(methyl)amino)carbamate in THF was cooled to -78°C under nitrogen, and bromo(ethynyl)magnesium was added dropwise. The mixture was then stirred at -78°C for 1 hour. The mixture was then heated to 20-50°C and stirred for an additional 10-20 hours. The residue was purified by silica gel column chromatography to obtain the target compound.

[0309] Step 3 t-Butyl carbamate (2.6 g, 11.64 mmol) was dissolved in ethanol, NH2NH2·H2O was added, and the mixture was heated at 50-80 °C for 30 min-1 h, then cooled to 20 °C for 0.5-2 h. The residue was purified by silica gel column chromatography to obtain the compound.

[0310] Step 4 KF and tert-butyl pyrazole carbamate were combined in a flask under N2, and then acetonitrile was added followed by 1-[[bromo(difluoro)methyl]-ethoxy-phosphoryl]oxyethane. The reaction mixture was stirred at 20-50 °C for 10-20 h. The residue was purified by silica gel column chromatography to obtain the target compound.

[0311] Step 5 To a solution of difluoromethylpyrazole carbamate in DCM was added HCl / 1,4-dioxane and the reaction mixture was stirred at 20-30° C. for 10-20 hours. The residue was diluted with 1M NaOH and the organic phase was extracted. The mixture was evaporated under reduced pressure.

[0312] Step 6 To a solution of methylimidazopyridinyltriazineamine, key intermediate 2 and DIEA were added in 1,4-dioxane in a microwave tube. The sealed tube was heated in a microwave oven at 100-120 °C for 1-5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give the target compound.

[0313] Example 1 6-(1H-indazol-6-yl)-N2-[1-[6-(trifluoromethyl)-2-pyridyl]cyclopropyl]-1,3,5-triazine-2,4-diamine hydrochloride [ka] Example 1 was synthesized by general synthesis method A.

[0314] Step 1: 6-(1-tetrahydropyran-2-ylindazol-6-yl)-N4-[1-[6-(trifluoromethyl)-2-pyridyl]cyclopropyl]-1,3,5-triazine-2,4-diamine 4-Chloro-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazin-2-amine (Intermediate X) (69 mg, 0.21 mmol) was added to a mixture of 1-[6-(trifluoromethyl)-2-pyridyl]cyclopropanamine (Intermediate H) (76 mg, 0.38 mmol) and N,N-diisopropylethylamine (0.36 mL, 2.09 mmol) in 1,4-dioxane (7 mL) at 25 °C. The reaction mixture was heated at 120 °C for 5 days and concentrated to dryness under reduced pressure. The crude material was purified by flash chromatography (25 g silica eluted with a gradient of 0-70% EtOAc in hexanes) to afford the title compound (64 mg, 0.12 mmol, 59% yield).

[0315] Step 2: 6-(1H-indazol-6-yl)-N2-[1-[6-(trifluoromethyl)-2-pyridyl]cyclopropyl]-1,3,5-triazine-2,4-diamine hydrochloride 6-(1-tetrahydropyran-2-ylindazol-6-yl)-N2-[1-[6-(trifluoromethyl)-2-pyridyl]cyclopropyl]-1,3,5-triazine-2,4-diamine (59 mg, 0.12 mmol) in 1,4-dioxane (5 mL) and methyl alcohol (5 mL) were added to 4 M HCl in 1,4-dioxane (1.19 mL, 4.75 mmol) at 25 °C. The reaction mixture was heated in a sealed vial at 60 °C for 9 h. The reaction mixture was concentrated to dryness under reduced pressure. The crude material was purified by flash chromatography (25 g silica eluting with a gradient of 0-1% methanol in EtOAc) to give the title compound (23 mg, 0.05 mmol, 41% yield). 1H NMR (399 MHz, DMSO-d6, VT 90℃) δ 13.01 (s, 1H), 8.42 (s, 1H), 8.04 (s, 1H), 7.92 - 7.85 (m, 2H), 7.77 - 7.67 (m, 1H), 7.64 (d, J = LCMS-MDAP Rt = 19.18 min >95% (Method 4) m / z (ESI + ) 413.20 [M+H] + .

[0316] Example 2 6-(1H-indazol-6-yl)-N2-[1-[1-(2-methoxyethyl)pyrazol-3-yl]cyclopropyl]-1,3,5-triazine-2,4-diamine [ka] Synthesized by general synthetic method A using the following reagents and conditions: Step 1: Intermediate X (60 mg, 0.18 mmol), 1-[1-(2-methoxyethyl)pyrazol-3-yl]cyclopropanamine (Intermediate E) (89 mg, 0.49 mmol), N,N-diisopropylethylamine (0.16 mL, 0.91 mmol) and 1,4-dioxane (6 mL) were heated at 90 °C for 72 h.

[0317] Step 2: N2-[1-[1-(2-methoxyethyl)pyrazol-3-yl]cyclopropyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (52 mg, 0.11 mmol), 1,4-dioxane (4.5 mL), and methyl alcohol (4.5 mL) and 4 M HCl in 1,4-dioxane (1.1 mL, 4.37 mmol) were heated at 60 °C for 10 h. Purification by flash chromatography afforded the title compound (16 mg, 0.04 mmol, 37% yield).

[0318] 1 H NMR (399 MHz, DMSO-d6, VT 90℃) δ 13.00 (s, 1H), 8.46 (s, 1H), 8.10 - 7.99 (m, 2H), 7.73 (d, J = 8.5 Hz, 1H), 7.53 (s, 1H), 7.40 (d, J = 2.2 Hz, 1H), 6.42 (s, 2H), 6.04 (d, J = 2.2 Hz, 1H), 4.10 (t, J = 5.5 Hz, 2H), 3.62 (t, J = 5.5 Hz, 2H), 3.17 (s, 3H), 1.23 (dt, J = 21.9, 2.7 Hz, 4H). LCMS MDAP Rt = 12.95 min, >98% (Method 4); m / z (ESI + ) 392.20 [M+H] + .

[0319] Example 3 4-[3-[(2,3-dichlorophenyl)methyl]morpholin-4-yl]-6-(1H-indazol-6-yl)-1,3,5-triazin-2-amine hydrochloride [ka] Synthesized by general synthetic method A using the following reagents and conditions: Step 1: Intermediate X (6.5 mg, 0.02 mmol), 3-[(2,3-dichlorophenyl)methyl]morpholine (Intermediate P) (7.3 mg, 0.03 mmol), N,N-diisopropylethylamine (0.01 mL, 0.04 mmol), and 1,4-dioxane (0.5 mL). The reaction mixture was heated in a microwave at 120 °C for 2 h.

[0320] Step 2: 4-[3-[(2,3-dichlorophenyl)methyl]morpholin-4-yl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazin-2-amine (0.02 mmol), 4 M HCl in 1,4-dioxane was heated at 60° C. for 16 h. Purification by flash chromatography gave the title compound. 1 H NMR (399 MHz, DMSO-d6) (VT at 90°C) δ 8.42 (s, 1H), 8.05 (d, J = 1.0 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.73 (dd, J = 8.7, 0.9 Hz, 1H), 7.52 - 7.45 (m, 1H), 7.36 - 7.23 (m, 3H), 7.12 (t, J = 7.9 Hz, 1H), 6.48 (s, 2H), 5.14 (s, 1H), 4.50 (d, J = 11.2 Hz, 1H), 3.97 (d, J = 9.3 Hz, 1H), 3.78 - 3.67 (m, 3H), 3.60 - 3.36 (m, 2H), 2.93 (d, J = 6.7 Hz, 1H). LCMS-LCQ Rt = 6.06 min, 95% (Method 3); m / z (ESI + ) 456.42 [M+H] + .

[0321] Example 4 6-(1H-indazol-6-yl)-N2-[1-methyl-1-[6-(trifluoromethyl)-2-pyridyl]ethyl]-1,3,5-triazine-2,4-diamine hydrochloride [ka] Synthesized by general synthetic method A using the following reagents and conditions: Step 1: Intermediate X (55 mg, 0.17 mmol), 2-[6-(trifluoromethyl)-2-pyridyl]propan-2-amine hydrochloride (Intermediate K) (60 mg, 0.25 mmol), N,N-diisopropylethylamine (0.29 mL, 1.66 mmol), and 1,4-dioxane (5.5 mL) were heated at 120 °C for 4 days.

[0322] Step 2: N2-[1-methyl-1-[6-(trifluoromethyl)-2-pyridyl]ethyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (39 mg, 0.08 mmol), 1,4-dioxane (3.2 mL), methyl alcohol (3.2 mL), and 4 M HCl in 1,4-dioxane (0.78 mL, 3.13 mmol) were heated at 60 °C for 10 h. Purification by flash chromatography afforded the title compound (19.5 mg, 0.0400 mmol, 54% yield). 1 H NMR (399 MHz, DMSO-d6, VT 90℃) δ 8.29 (s, 1H), 8.02 (d, J = 1.1 Hz, 1H), 7.93 (t, J = 7.9 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.60 (d, J = 7.5 Hz, 2H), 7.29 (s, 1H), 6.36 (s, 2H), 1.77 (s, 6H). LCMS MDAP Rt = 18.16, >98% (Method 4); m / z (ESI + ) 415.2 [M+H] + .

[0323] Example 5 N2-(4-fluoro-2,3-dihydrobenzofuran-3-yl)-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Synthesized by general synthetic method A using the following reagents and conditions: Step 1: Intermediate X (50 mg, 0.15 mmol), 4-fluoro-2,3-dihydro-1-benzofuran-3-amine hydrochloride (47 mg, 0.25 mmol), N,N-diisopropylethylamine (0.18 mL, 1.06 mmol) and 1,4-dioxane (12 mL) were heated at 80 °C for 4 days.

[0324] Step 2: N2-(4-Fluoro-2,3-dihydrobenzofuran-3-yl)-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (57 mg, 0.13 mmol), 1,4-dioxane (5 mL), methyl alcohol (5 mL), and 4 M HCl in 1,4-dioxane (1.27 mL, 5.1 mmol) were heated at 60° C. for 12 h. Purification by flash chromatography afforded the title compound (26 mg, 0.07 mmol, 53% yield). 1 H NMR (399 MHz, DMSO-d6, VT 90℃) δ 8.48 (d, J = 1.2 Hz, 1H), 8.05 (d, J = 1.1 Hz, 1H), 8.03 (d, J = 1.3 Hz, 1H), 7.75 (dd, J = 8.5, 0.9 Hz, 1H), 7.60 (s, 1H), 7.22 (td, J = 8.2, 5.9 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 6.63 (t, J = 8.7 Hz, 1H), 6.58 (s, 2H), 6.13 - 5.95 (m, 1H), 4.81 (t, J = 9.1 Hz, 1H), 4.43 (dd, J = 9.6, 5.0 Hz, 1H). LCMS-LCQ Rt = 5.18, >95% (Method 3); m / z (ESI + ) 364.11 [M+H] + .

[0325] Example 6 6-(1H-indazol-6-yl)-N2-[1-(2-pyridyl)cyclopropyl]-1,3,5-triazine-2,4-diamine [ka] Synthesized by general synthetic method A using the following reagents and conditions: Step 1: Intermediate X (40 mg, 0.12 mmol), 1-(pyridin-2-yl)cyclopropan-1-amine (40 mg, 0.30 mmol), N,N-diisopropylethylamine (0.13 mL, 0.76 mmol) and 1,4-dioxane (4 mL) were heated at 100 °C for 7 days.

[0326] Step 2: N2-[1-(2-pyridyl)cyclopropyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (52 mg, 0.12 mmol), 1,4-dioxane (5 mL), methyl alcohol (5 mL), and 4 M HCl in 1,4-dioxane (1.21 mL, 4.83 mmol) were heated at 60° C. for 12 h. Purification by flash chromatography afforded the title compound (17 mg, 0.04 mmol, 36% yield). 1H NMR (600 MHz, DMSO-d6) δ 13.29 (s, 0.57H), 13.18 (s, 0.34H), 8.48 (s, 1H), 8.44 (d, J = 4.8 Hz, 0.31H), 8.42 - 8.37 (m, 0.56H), 8.28 (s, 0.31H), 8.14 (s, 1H), 8.10 (s, 0.63H), 8.08 - 7.98 (m, 0.46H), 7.83 (d, J = 8.6 Hz, 0.30H), 7.79 (d, J = 8.5 Hz, 0.55H), 7.67 (d, J = 8.5 Hz, 0.31H), 7.63 (t, J = 7.7 Hz, 0.50H), 7.59 (t, J = 7.7 Hz, 0.29H), 7.32 (t, J = 7.4 Hz, 1H), 7.14 - 7.03 (m, 1H), 6.84 (s, 2H), 1.63 - 1.57 (m, 1H), 1.53 (q, J = 4.2 Hz, 1H), 1.34 - 1.25 (m, 2H), 1.21 (s, 0.18H). LCMS MDAP Rt = 11.04 min, >97% (Method 4); m / z (ESI + ) 345.1 [M+H] + .

[0327] Example 7 N2-(2,3-dihydrobenzofuran-3-ylmethyl)-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Synthesized by general synthetic method A using the following reagents and conditions: Step 1: Intermediate X (54 mg, 0.16 mmol), 2,3-dihydro-1-benzofuran-3-ylmethanamine (40 mg, 0.27 mmol), N,N-diisopropylethylamine (0.14 mL, 0.82 mmol) and 1,4-dioxane (13 mL) were heated at 60° C. for 72 hours.

[0328] Step 2: N2-(2,3-Dihydrobenzofuran-3-ylmethyl)-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (52 mg, 0.12 mmol), methyl alcohol (5 mL), and 4 M HCl in 1,4-dioxane (1.17 mL, 4.69 mmol) were heated at 60° C. for 14 h. Purification by flash chromatography afforded the title compound (27 mg, 0.07 mmol, 63% yield). 1 H NMR (600 MHz, DMSO-d6) δ 13.26 (s, 1H), 8.49 (s, 0.45H), 8.46 (s, 0.60H), 8.09 (s, 1H), 8.07 (d, J = 8.5 Hz, 0.37H), 8.02 (d, J = 8.5 Hz, 0.61H), 7.78 (t, J = 7.9 Hz, 1H), 7.59 (t, J = 5.5 Hz, 0.69H), 7.41 (t, J = 6.1 Hz, 0.48H), 7.32 (d, J = 7.3 Hz, 0.49H), 7.27 (d, J = 7.3Hz, 0.65H), 7.10 (t, J = 7.8 Hz, 1H), 6.90 (s, 2H), 6.83 (q, J = 7.7 Hz, 1H), 6.76 (t, J = 8.5 Hz, 1H), 4.55 (t, J = 9.0 Hz, 1H), 4.49 - 4.43 (m, 0.48H), 4.43 - 4.38 (m, 0.70H), 3.84 - 3.72 (m, 1H), 3.74 - 3.66 (m, 1H), 3.62 - 3.53 (m, 0.55H), 3.52 - 3.44 (m, 0.41H), 3.43 - 3.34 (m, 0.59H). LCMS MDAP Rt = 15.4 min, >98% (Method 4); m / z (ESI + ) 360.1 [M+H] + .

[0329] Example 8 6-(1H-indazol-6-yl)-N2-[[6-(trifluoromethyl)-2-pyridyl]methyl]-1,3,5-triazine-2,4-diamine [ka] Synthesized by general synthetic method A using the following reagents and conditions: Step 1: Intermediate X (50 mg, 0.15 mmol), [6-(trifluoromethyl)pyridin-2-yl]methanamine (44 mg, 0.25 mmol), N,N-diisopropylethylamine (0.13 mL, 0.76 mmol) and 1,4-dioxane (5 mL) were heated at 60 °C for 48 h.

[0330] Step 2: 6-(1-tetrahydropyran-2-ylindazol-6-yl)-N-[[6-(trifluoromethyl)-2-pyridyl]methyl]-1,3,5-triazine-2,4-diamine (64 mg, 0.14 mmol), methyl alcohol (9 mL), and 4 M HCl in 1,4-dioxane (1.36 mL, 5.44 mmol) were heated at 60° C. for 13 h. Purification by flash chromatography gave the title compound (5 mg, 0.01 mmol, 9%). 1 H NMR (600 MHz, DMSO-d6) δ 13.48 - 13.04 (m, 1H), 8.49 (s, 0.50H), 8.40 (s, 0.36H), 8.10 (s, 1H), 8.09 - 7.99 (m, 1H), 7.98 (t, J = 6.4 Hz, 1H), 7.90 (d, J = 8.5 Hz, 0.56H), 7.84 - 7.60 (m, 2H), 7.10 - 6.74 (m, 2H), 4.75 (d, J = 6.1 Hz, 1H), 4.67 (d, J = 6.2 Hz, 1H). LCMS LCQ, Rt = 5.08 min >95% (Method 3); m / z (ESI + ) 387.34 [M+H] + .

[0331] Example 9 N2-Cyclopropyl-N2-[2-(2,3-dichlorophenyl)ethyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Synthesized by general synthetic method A using the following reagents and conditions: Step 1: Intermediate X (30 mg, 0.09 mmol), N-[2-(2,3-dichlorophenyl)ethyl]cyclopropanamine (31 mg, 0.14 mmol), N,N-diisopropylethylamine (0.04 mL, 0.23 mmol) and 1,4-dioxane (3 mL) were heated at 60 °C for 5 days.

[0332] Step 2: N-Cyclopropyl-N-[2-(2,3-dichlorophenyl)ethyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (40 mg, 0.08 mmol), 1,4-dioxane (5 mL), methyl alcohol (5 mL), and 4 M HCl in 1,4-dioxane (0.76 mL, 3.05 mmol) were heated at 60° C. for 14 h. Purification by flash chromatography afforded the title compound (20 mg, 0.04 mmol, 58% yield). 1 H NMR (399 MHz, DMSO-d6, VT 90℃) δ 8.51 (s, 1H), 8.10 - 8.02 (m, 2H), 7.75 (d, J = 8.3 Hz, 1H), 7.41 (dd, J = 7.9, 1.6 Hz, 1H), 7.32 (dd, J = 7.7, 1.7 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 6.51 (s, 2H), 3.87 (t, J = 7.2 Hz, 2H), 3.13 (t, J = 7.3 Hz, 2H), 2.86 - 2.68 (m, 1H), 0.93 - 0.76 (m, 2H), 0.76 - 0.54 (m, 2H). LCMS LCQ Rt = 7.03 min, >98% (Method 3); m / z (ESI+ ) 440 / 442 (Cl isotopes) [M+H] + .

[0333] Example 10 N2-[2-(2,3-dichlorophenyl)ethyl]-N2-ethyl-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Synthesized by general synthetic method A using the following reagents and conditions: Step 1: Intermediate X (52 mg, 0.16 mmol), 2-(2,3-dichlorophenyl)-N-ethyl-ethanamine (56 mg, 0.26 mmol), N,N-diisopropylethylamine (0.14 mL, 0.79 mmol) and 1,4-dioxane (6 mL) were heated at 60 °C for 20 h.

[0334] Step 2: N-[2-(2,3-dichlorophenyl)ethyl]-N-ethyl-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (63 mg, 0.12 mmol), methyl alcohol (4 mL), and 4 M HCl in 1,4-dioxane (1.23 mL, 4.92 mmol) were heated at 60° C. for 16 h. Purification by flash chromatography afforded the title compound (39 mg, 0.09 mmol, 72% yield). 1H NMR (600 MHz, DMSO-d6) δ 13.26 (s, 1H), 8.49 (s, 0.42H), 8.46 (s,0.59H), 8.10 (s, 1H), 8.08 - 7.98 (m, 1H), 7.78 (dd, J = 8.5, 3.4 Hz, 1H), 7.50 (d, J = 8.0 Hz, 0.37H), 7.42 (t, J = 7.8 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.31 - 7.24 (m, 1H), 6.83 (s, 2H), 3.88 (t, J = 7.2 Hz, 1H), 3.71 (t, J = 7.6 Hz, 1H), 3.63 (t, J = 7.1 Hz, 1H), 3.55 (q, J = 7.0 Hz, 1H), 3.13 (t, J = 7.3 Hz, 1H), 3.09 (t, J = 7.7 Hz, 1H), 1.15 (t, J = 7.1 Hz, 1H), 1.10 (t, J = 7.0 Hz, 2H). LCMS MDAP, Rt = 18.96 min, >97% (Method 4); m / z (ESI + ) 428 / 430 (Cl isotopes) [M+H] + .

[0335] Example 11 6-(1H-indazol-6-yl)-N2-[2-[3-(trifluoromethyl)pyrazol-1-yl]ethyl]-1,3,5-triazine-2,4-diamine [ka] Synthesized by general synthetic method A using the following reagents and conditions: Step 1: Intermediate X (60 mg, 0.18 mmol), 2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]ethan-1-amine (54 mg, 0.30 mmol), N,N-diisopropylethylamine (0.11 mL, 0.63 mmol) and 1,4-dioxane (3.6 mL) were heated at 60 °C for 24 h.

[0336] Step 2: 6-(1-tetrahydropyran-2-ylindazol-6-yl)-N-[2-[3-(trifluoromethyl)pyrazol-1-yl]ethyl]-1,3,5-triazine-2,4-diamine (67 mg, 0.14 mmol), methyl alcohol (3.5 mL), and 4 M HCl in 1,4-dioxane (1.4 mL, 5.6 mmol) were heated at 60° C. for 16 h. Purification by flash chromatography afforded the title compound (22 mg, 0.0500 mmol, 38% yield). 1 H NMR (600 MHz, DMSO-d6) δ 13.25 (s, 1H), 8.48 (s, 0.38H), 8.44 (s, 0.49H), 8.12 - 8.08 (m, 1H), 8.06 (d, J = 8.5 Hz, 0.41H), 8.00 (d, J = 8.5 Hz, 0.53H), 7.94 (s, 0.54H), 7.91 (s, 0.42H), 7.81 - 7.71 (m, 1H), 7.43 (t, J = 5.7 Hz, 0.59H), 7.20 (t, J = 5.2 Hz, 0.20H), 6.93 (s, 1H), 6.78 (s, 1H), 6.68 (s, 0.41H), 6.63 (s, 0.38H), 4.43 (t, J = 5.5 Hz, 1H), 4.39 (t, J = 6.4 Hz, 1H), 3.79 (q, J = 6.1 Hz, 1H), 3.68 (q, J = 6.2 Hz, 1H). LCMS MDAP Rt = 15.09 min, >95% (Method 4); m / z (ESI + ) 390 [M+H] + .

[0337] Example 12 6-(1H-indazol-6-yl)-N2-[1-methyl-1-(2-pyridyl)ethyl]-1,3,5-triazine-2,4-diamine hydrochloride [ka] Synthesized by general synthetic method A using the following reagents and conditions: Step 1: Intermediate X (200 mg, 0.60 mmol), 2-(2-pyridyl)-2-propylamine (135 mg, 1 mmol), N,N-diisopropylethylamine (0.32 mL, 1.81 mmol) and 1,4-dioxane (20 mL) were heated at 100° C. for 4 days.

[0338] Step 2: N2-[1-methyl-1-(2-pyridyl)ethyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (105 mg, 0.24 mmol), 1,4-dioxane (10 mL), methyl alcohol (10 mL), and 4 M HCl in 1,4-dioxane (2.44 mL, 9.76 mmol) were heated at 60° C. for 12 h. Purification by flash chromatography afforded the title compound (93 mg, 0.24 mmol, 97% yield). 1 H NMR (600 MHz, DMSO-d6) δ 13.37 (s, 0.36H), 13.30 (s, 0.66H), 8.56 (s, 1H), 8.50 (s, 0.43H), 8.07 (s, 1.11H), 8.03 (s, 0.76H), 7.82 - 7.52 (m, 3H), 7.46 (d, J = 8.1 Hz, 1H), 7.19 (s, 0.39H), 7.13 (s, 0.68H), 6.90 - 6.36 (m, 2H), 1.73 (s, 6H). LCMS MDAP Rt = 10.22 min, >97% (Method 4); m / z (ESI + ) 371.1 [M+H] + .

[0339] Example 13 N2-[(2,3-dichlorophenyl)methyl]-6-(1H-indazol-6-yl)-N2-methyl-1,3,5-triazine-2,4-diamine [ka] Synthesized by general synthetic method A using the following reagents and conditions: Step 1: Intermediate X (50 mg, 0.15 mmol), (2,3-dichlorophenyl)methyl](methyl)amine hydrochloride (41 mg, 0.18 mmol), N,N-diisopropylethylamine (0.08 mL, 0.45 mmol), and 1,4-dioxane (2 mL) were heated at 60 °C for 20 h.

[0340] Step 2: N-[(2,3-dichlorophenyl)methyl]-N-methyl-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (69 mg, 0.14 mmol), methanol (1 mL), and 4 M HCl in 1,4-dioxane (3 mL, 12 mmol) were stirred at room temperature for 90 min. Purification by flash chromatography afforded the title compound (17 mg, 0.04 mmol, 29%). 1 H NMR (600 MHz, DMSO-d6) δ 13.27 (s, 0.5H), 13.20 (s, 0.5H), 8.55 (s, 0.5H), 8.38 (s, 0.5H), 8.12 (d, J = 8.9 Hz, 1H), 8.07 (s, 0.4H), 7.92 (d, J = 8.6 Hz, 0.6H), 7.81 (d, J = 8.4 Hz, 0.5H), 7.73 (d, J = 8.6 Hz, 0.5H), 7.55 - 7.52 (m, 1H), 7.33 (q, J = 8.1 Hz, 1H), 7.11 (d, J = 7.7 Hz, 0.5H), 7.08 - 7.03 (m, 1.5H), 6.93 (s, 2H), 5.08 (s, 1H), 4.92 (s, 1H), 3.28 (s, 0.3H), 3.12 (s, 1.6H). LCMS-MDAP Rt = 18.89 min, >95% (Method 4); m / z (ESI + ) 401.95, 399.95 (Cl isotopes) [M+H] + .

[0341] Example 14 6-(1H-indazol-6-yl)-N2-[2-(3-methylpyrazol-1-yl)ethyl]-1,3,5-triazine-2,4-diamine [ka] Synthesized by general synthetic method A using the following reagents and conditions: Step 1: Intermediate X (60 mg, 0.18 mmol), 2-(3-methyl-1H-pyrazol-1-yl)ethan-1-amine (37 mg, 0.30 mmol), N,N-diisopropylethylamine (0.08 mL, 0.45 mmol) and 1,4-dioxane (3.5 mL) were heated at 60 °C for 40 h.

[0342] Step 2: N2-[2-(3-methylpyrazol-1-yl)ethyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (72 mg, 0.17 mmol), methyl alcohol (5 mL), and 4 M HCl in 1,4-dioxane (1.72 mL, 6.87 mmol) were heated at 60° C. for 16 h. Purification by flash chromatography gave the title compound (37 mg, 0.11 mmol, 62%). 1H NMR (600 MHz, DMSO-d6) δ 13.26 (s, 1H), 8.49 (s, 0.37H), 8.44 (s, 0.47H), 8.16 - 8.04 (m, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.83 - 7.71 (m, 1H), 7.55 (s, 0.55H), 7.52 (s, 0.42H), 7.34 (t, J = 5.6 Hz, 0.58H), 7.13 (t, J = 5.6 Hz, 0.44H), 6.93 (s, 1H), 6.79 (s, 1H), 5.97 (s, 0.52H), 5.94 (s, 0.37H), 4.23 (t, J = 6.1 Hz, 1H), 4.19 (t, J = 6.6 Hz, 1H), 3.73 (q, J = 6.2 Hz, 1H), 3.62 (q, J = 6.3 Hz, 1H), 2.13 (s, 2H), 2.11 (s, 1H). LCMS MDAP Rt = 12.43 min, >97% (Method 4); m / z (ESI + ) 336 [M+H] + .

[0343] Example 15 6-(1H-indazol-6-yl)-N2-[2-(4-methylpyrazol-1-yl)ethyl]-1,3,5-triazine-2,4-diamine [ka] Synthesized by general synthetic method A using the following reagents and conditions: Step 1: Intermediate X (50 mg, 0.15 mmol), 2-(4-methyl-1H-pyrazol-1-yl)ethan-1-amine (21.76 mg, 0.17 mmol), N,N-diisopropylethylamine (0.07 mL, 0.38 mmol) and 1,4-dioxane (3 mL) were heated at 60 °C for 40 h.

[0344] Step 2: N2-[2-(4-methylpyrazol-1-yl)ethyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (50 mg, 0.12 mmol), methyl alcohol (3 mL), and 4 M HCl in 1,4-dioxane (0.89 mL, 3.58 mmol) were heated at 60° C. for 21 h. Purification by flash chromatography afforded the title compound (50 mg, 0.12 mmol, 51%). 1 H NMR (600 MHz, DMSO-d6) δ 13.26 (s, 1H), 8.49 (s, 0.36H), 8.44 (s, 0.46H), 8.14 - 8.04 (m, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.83 - 7.73 (m, 1H), 7.46 (d, J = 9.3 Hz, 1H), 7.33 (t, J = 5.8 Hz, 0.59H), 7.22 (s, 1H), 7.13 (t, J = 5.8 Hz, 0.43H), 6.94 (s, 1H), 6.78 (s, 1H), 4.25 (t, J = 6.5 Hz, 1H), 4.20 (t, J = 6.1 Hz, 1H), 3.72 (q, J = 6.4 Hz, 1H), 3.62 (q, J = 6.3 Hz, 1H), 1.97 (s, 2H), 1.94 (s, 1H). LCMS MDAP Rt = 12.55 min, >98% (Method 4); m / z (ESI + ) 336 [M+H] + .

[0345] Example 16 N2-[2-(3-chloro-2-pyridyl)ethyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine hydrochloride [ka] Synthesized by general synthetic method A using the following reagents and conditions: Step 1: Intermediate X (75 mg, 0.23 mmol), 2-(3-chloro-2-pyridyl)ethylammonium chloride (53 mg, 0.27 mmol), N,N-diisopropylethylamine (0.1 mL, 0.57 mmol), and 1,4-dioxane (4.5 mL) were heated at 60° C. for 12 hours.

[0346] Step 2: N2-[2-(3-chloro-2-pyridyl)ethyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (50 mg, 0.11 mmol), methyl alcohol (1 mL), and 4 M HCl in 1,4-dioxane (0.83 mL, 3.33 mmol) were heated at 60° C. for 18 h. Filtration afforded the title compound (30 mg, 0.08 mmol, 70% yield). 1 H NMR (399 MHz, DMSO-d6, VT 90℃) δ 8.52 (s, 1H), 8.49 - 8.42 (m, 1H), 8.15 (s, 1H), 7.98 (dt, J = 9.4, 1.7 Hz, 1H), 7.91 - 7.85 (m, 1H), 7.85 - 7.78 (m, 1H), 7.30 - 7.20 (m, 1H), 3.94 - 3.79 (m, 2H), 3.24 (t, J = 7.1 Hz, 2H). LCMS MDAP Rt = 14.07 min, 70% (Method 4); + ) 367.1 [M+H] + .

[0347] Example 17 N4-[(2,3-dichlorophenyl)methyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Synthesized by general synthetic method A using the following reagents and conditions: Step 1: Intermediate X (60 mg, 0.18 mmol), 1-(2,3-dichlorophenyl)methanamine (0.03 mL, 0.22 mmol), N,N-diisopropylethylamine (0.09 mL, 0.54 mmol), and 1,4-dioxane (1 mL) were heated at 60° C. for 16 hours.

[0348] Step 2: N4-[(2,3-dichlorophenyl)methyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (85 mg, 0.18 mmol), 1.25 M HCl in methanol (0.87 mL, 1.08 mmol), and 4 M HCl in 1,4-dioxane (0.9 mL, 3.61 mmol) were stirred at room temperature for 1 h. Purification by flash chromatography (silica, eluting with a 0-10% methanol in DCM gradient) and homogenization with diethyl ether afforded the title compound (2.2 mg, 0.01 mmol, 3%). 1 H NMR (600 MHz, DMSO-d6) δ 13.29 (s, 0.6H), 13.22 (s, 0.4H), 8.48 (s, 0.6H), 8.41 (s, 0.4H), 8.13 - 8.01 (m, 1H), 8.00 - 7.83 (m, 1H), 7.76 (dd, J = 28.6, 9.0 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.45 - 7.17 (m, 2H), 7.07 - 6.74 (m, 2H), 4.72 (d, J = 6.2 Hz, 0.8H), 4.58 (d, J = 6.2 Hz, 1.2H).LCMS MDAP Rt = 17.41 min (Method 4); m / z (ESI + ) 385.90 [M+H] + .

[0349] Example 18 N2-[2-(2,3-dichlorophenyl)ethyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Synthesized by general synthetic method A using the following reagents and conditions: Step 1: Intermediate X (125 mg, 0.38 mmol), 2-(2,3-dichlorophenyl)ethanamine (83 mg, 0.43 mmol), N,N-diisopropylethylamine (0.16 mL, 0.94 mmol) and 1,4-dioxane (2 mL) were heated at 60° C. for 2 hours.

[0350] Step 2: N2-[2-(2,3-dichlorophenyl)ethyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (65 mg, 0.13 mmol), 1.25 M HCl in methanol (1 mL, 1.34 mmol), and 4 M HCl in 1,4-dioxane (1 mL, 4 mmol) were heated at 60 °C for 3 h. Purification by flash chromatography (silica, eluting with a gradient of 0-10% methanol in DCM) gave the title compound (23 mg, 0.05 mmol, 41% yield). 1H NMR - (500MHz, D6-DMSO) δH 13.25 (s, 1H), 8.47 (s, 0.5H*), 8.44 (s, 0.5H*) 8.09 (s, 0.5H*), 8.04 (d, 8.6 Hz, 0.5H*), 8.00 (d, J = 8.6 Hz, 0.5H*), 7.77 (t, J = 8.6 Hz, 1H), 7.49 (d, J = 7.6 Hz, 0.5H*), 7.47-7.40 (m, 1H), 7.36 (d, 7.6 Hz, 0.5H*) 7.33-7.21 (m, 2H), 6.94-6.81 (br, 1.5H*), 6.78-6.69 (br, 1H), 3.65 (q, J = 6.5 Hz, 1H), 3.52 (q, J = 6.8 Hz), 3.10-3.02 (m, 2H) (*unusual splitting resolved on VT-NMR at 90℃). LCMS Rt = 5.76 min, >95% (Method 3) 5-95% Acetonitrile:Water (0.1% Formic)); m / z (ESI + ) 400.14 [M+H] + .

[0351] Example 19 6-(1H-indazol-6-yl)-N2-methyl-N2-[1-(1-methylpyrazol-3-yl)cyclopropyl]-1,3,5-triazine-2,4-diamine [ka] Synthesized using general method B: Step 1: 6-chloro-N4-methyl-N4-[1-(1-methylpyrazol-3-yl)cyclopropyl]-1,3,5-triazine-2,4-diamine N-Methyl-1-(1-methylpyrazol-3-yl)cyclopropanamine (Intermediate D) (100 mg, 0.67 mmol) was suspended in 1,4-dioxane (4 mL), and 2-amino-4,6-dichlorotriazine (100 mg, 0.61 mmol) was added, followed by N,N-diisopropylethylamine (0.32 mL, 1.82 mmol). The mixture was heated at 90°C for 12 hours. After evaporation of the solvent under reduced pressure to dryness, the crude material was purified by flash column chromatography (silica eluting with a gradient of 0-10% methanol in DCM) to afford the title compound (55 mg, 0.19 mmol, 31% yield) as a white solid. LCMS-LCQ Rt = 3.00 min (Method 2); m / z (ESI + )280.19, 282.20 (Cl isotope) [M+H] + . Step 2: N4-Methyl-N4-[1-(1-methylpyrazol-3-yl)cyclopropyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine A stirred solution of 6-chloro-N4-methyl-N4-[1-(1-methylpyrazol-3-yl)cyclopropyl]-1,3,5-triazine-2,4-diamine (38 mg, 0.14 mmol), tripotassium phosphate (86 mg, 0.41 mmol), and bis[2-(di-tert-butylphosphenyl)cyclopenta-2,4-dien-1-yl]iron;dichloropalladium (9 mg, 0.01 mmol) in tetrahydrofuran (5 mL) and water (0.5 mL) was degassed by bubbling N directly into the solution. After heating the mixture at 80° C., a solution of 1-tetrahydropyran-2-yl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (Intermediate V) (111 mg, 0.34 mmol) in THF (4 mL) was added and the reaction was stirred for 12 h at 80° C. The mixture was concentrated to dryness under reduced pressure, and the crude material was purified by flash column chromatography (silica gel, eluting with a gradient of 30 to 100% EtOAc in petroleum ether) to afford the title compound (40 mg, 0.09 mmol, 63% yield) as a white solid. 1H NMR (399 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.11 (d, J= 8.5 Hz, 1H), 7.76 (d,J= 8.5 Hz, 1H), 7.38 (d,J= 2.2 Hz, 1H), 6.59 - 6.42 (m, 3H), 5.93 (d, J= 2.1 Hz, 1H), 5.80 (d, J= 9.1 Hz, 1H), 3.88 (d, J= 11.2 Hz, 1H), 3.76 - 3.65 (m, 4H), 3.22 (s, 3H), 2.46 - 2.33 (m, 1H), 2.13 - 1.96 (m, 2H), 1.86 - 1.68 (m, 1H), 1.65 - 1.54 (m, 2H), 1.47 - 1.30 (m, 4H); LCMS MDAP Rt = 16.58 min (Method 4); m / z (ESI + ) 446.3 [M+H] + . Step 3: 6-(1H-indazol-6-yl)-N2-methyl-N2-[1-(1-methylpyrazol-3-yl)cyclopropyl]-1,3,5-triazine-2,4-diamine A solution of N2-methyl-N2-[1-(1-methylpyrazol-3-yl)cyclopropyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (40 mg, 0.09 mmol) in methyl alcohol (1 mL) and 4 M HCl (0.22 mL, 0.90 mmol) in 1,4-dioxane was heated at 40° C. for 16 h. The resulting suspension was filtered, and the filtered solid was washed with diethyl ether and petroleum ether and then dried in an oven at 50° C. for 2 h to obtain the title compound. 1H NMR (399 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.14 (s, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 6.03 (d, J = 2.2 Hz, 1H), 3.74 (s, 3H), 3.32 (s, 3H), 1.46 (d, J = 4.2 Hz, 4H). LCMS MDAP Rt = 13.45 min (Method 4); m / z (ESI + ) 362.2 [M+H] + .

[0352] Example 20 N2-[1-(2-chloro-3-fluoro-phenyl)cyclopropyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Synthesized using general method B: Step 1: 6-chloro-N4-[1-(2-chloro-3-fluoro-phenyl)cyclopropyl]-1,3,5-triazine-2,4-diamine To a stirred solution of 2-amino-4,6-dichlorotriazine (506 mg, 3.0 mmol), N,N-diisopropylethylamine (1.34 mL, 7.68 mmol) in 1,4-dioxane (15 mL) was added, followed by 1-(2-chloro-3-fluorophenyl)cyclopropanamine (570 mg, 3.07 mmol). The resulting mixture was stirred at room temperature for 12 h. The reaction mixture was evaporated to dryness under reduced pressure, and the crude material was purified by chromatography (silica, eluting with a 50-100% EtOAc gradient in petroleum ether) to afford the title compound (600 mg, 1.81 mmol, 59% yield) as a white powder. 1H NMR (600 MHz, DMSO-d6) δ 8.40 (d, J= 102.2 Hz, 1H), 7.79 - 7.47 (m, 1H), 7.32 (s, 1H), 7.30 - 7.18 (m, 2H), 7.10 (d, J= 98.6 Hz, 1H), 1.21 - 1.14 (m, 2H), 1.12 - 1.04 (m, 2H). Step 2: N4-[1-(2-chloro-3-fluoro-phenyl)cyclopropyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine A stirred solution of 6-chloro-N4-[1-(2-chloro-3-fluoro-phenyl)cyclopropyl]-1,3,5-triazine-2,4-diamine (70 mg, 0.22 mmol), tripotassium phosphate (142 mg, 0.67 mmol), and bis[2-(di-tert-butylphosphanyl)cyclopenta-2,4-dien-1-yl]iron;dichloropalladium (14.5 mg, 0.02 mmol) in tetrahydrofuran (5 mL) and water (0.5 mL) was degassed by bubbling N directly into the solution. After heating the mixture to 80°C, a solution of 1-tetrahydropyran-2-yl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (Intermediate V) (183 mg, 0.56 mmol) in THF (5 mL) was added and the reaction was stirred at 80°C for 12 hours. The mixture was concentrated to dryness, and the crude material was purified by flash column chromatography (silica, eluting with a gradient of 30-100% EtOAc in petroleum ether) to afford the title compound (75 mg, 0.15 mmol, 67% yield) as a white solid. LCMS-LCQ Rt = 3.50 min (Method 1); m / z (ESI + ) 480.27 [M+H] + . Step 3: N2-[1-(2-chloro-3-fluoro-phenyl)cyclopropyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine A solution of N2-[1-(2-chloro-3-fluorophenyl)cyclopropyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (75 mg, 0.16 mmol) in methyl alcohol (1 mL) and 4 M HCl in 1,4-dioxane (0.4 mL, 1.56 mmol) was heated at 40° C. for 16 h. The resulting suspension was filtered, washed with diethyl ether and petroleum ether, and dried in an oven at 50° C. for 2 h to give the title compound (55 mg, 0.14 mmol, 88%). 1 H NMR (399 MHz, DMSO-d6, VT 90℃) δ 8.48 (s, 1H), 8.11 (s, 1H), 7.97 (d, J= 8.7 Hz, 1H), 7.81 (dd, J= 17.6, 8.1 Hz, 2H), 7.31 (q, J= 7.5, LCMS MDAP Rt = 18.32 min (Method 4); m / z (ESI + ) 396.1 [M+H].

[0353] Example 21 N2-[(3-chloro-5-methyl-2-pyridyl)methyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Synthesized using general method B: Step 1: 6-chloro-N4-[(3-chloro-5-methyl-2-pyridyl)methyl]-1,3,5-triazine-2,4-diamine N,N-Diisopropylethylamine (0.43 mL, 2.49 mmol) was added to a suspension of 2-amino-4,6-dichlorotriazine (90 mg, 0.55 mmol) and (3-chloro-5-methyl-2-pyridyl)methanamine (78 mg, 0.50 mmol) in 1,4-dioxane (2 mL). The reaction mixture was stirred at room temperature for 16 h and then partitioned between ethyl acetate and water. The organic phase was separated, dried (MgSO), filtered, and concentrated to dryness under reduced pressure. The residue was dry-loaded onto Celite and purified by flash silica chromatography eluting with a gradient of 0-5% methanol in DCM to afford the title compound (44 mg, 0.15 mmol, 29%) as a white solid. 1 H NMR (600 MHz, chloroform-d) δ 8.26 (s, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.16 - 6.90 (m, 1H), 5.53 - 5.09 (m, 2H), 4.78 - 4.61 (m, 2H), 2.33 (s, 3H). LCMS MDAP Rt = 2.51 min (Method 6); m / z (ESI + ) 284.85 [M+H] + . Step 2: N2-[(3-chloro-5-methyl-2-pyridyl)methyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine Bis[2-(di-tert-butylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloropalladium (5.0 mg, 0.01 mmol) was added to a degassed mixture of 1-tetrahydropyran-2-yl-6-(4,4,5,5-tetramethyl-1,3,2-dioxycyclolan-2-yl)indazole (Intermediate V) (60 mg, 0.19 mmol), 6-chloro-N2-[(3-chloro-5-methyl-2-pyridyl)methyl]-1,3,5-triazine-2,4-diamine (44 mg, 0.15 mmol), and tripotassium phosphate (98 mg, 0.46 mmol) in tetrahydrofuran (1 mL) and water (0.25 mL). The reaction mixture was heated at 60°C for 16 hours, cooled to room temperature, and filtered through a Celite pad. The Celite pad was washed successively with ethyl acetate and water. The organic phase of the filtrate was separated, then washed with brine, dried (MgSO), filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash silica chromatography eluting with 0-10% methanol in DCM. The product containing fractions were collected and concentrated under reduced pressure, then further purified by flash silica chromatography eluting with a gradient of 0-60% ethyl acetate in petroleum ether. The title compound was obtained as a white solid, which was used directly in the next step.

[0354] Step 3: N2-[(3-chloro-5-methyl-2-pyridyl)methyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine N2-[(3-chloro-5-methyl-2-pyridyl)methyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (26 mg, 0.06 mmol) was dissolved in methanol (1 mL) and 4 M HCl in 1,4-dioxane (2 mL) was added. The resulting solution was stirred at room temperature for 2 hours and concentrated to dryness under reduced pressure. The residue was purified by flash silica chromatography eluting with a gradient of 0-15% methanol in ethyl acetate to afford the title compound (12 mg, 0.03 mmol, 20% yield) as an off-white solid. 1H NMR (399 MHz, DMSO-d6) (VT at 90℃) δ 13.01 (s, 1H), 8.49 (s, 1H), 8.32 (s, 1H), 8.07 - 7.99 (m, 2H), 7.77 - 7.69 (m, 2H), 7.06 (s, 1H), 6.53 (s, 2H), 4.75 (d,J =5.4 Hz, 2H), 2.28 (s, 3H). LCMS MDAP Rt = 14.78 min (Method 4); m / z (ESI + ) 367.1 [M+H] + .

[0355] Example 22 N2-[1-[1-(difluoromethyl)pyrazol-3-yl]cyclopropyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Synthesized using general method B: Step 1: 6-chloro-N4-[1-[1-(difluoromethyl)pyrazol-3-yl]cyclopropyl]-1,3,5-triazine-2,4-diamine 2-Amino-4,6-dichlorotriazine (322 mg, 1.95 mmol), [1-[1-(difluoromethyl)pyrazol-3-yl]cyclopropyl]ammonium chloride (Intermediate G) (273 mg, 1.3 mmol), and N,N-diisopropylethylamine (0.45 mL, 2.6 mmol) were dissolved in 1,4-dioxane (20 mL) and the reaction mixture was stirred for 48 h. The reaction mixture was dry-loaded directly onto Celite and purified by flash silica chromatography eluting with a 0-100% ethyl acetate in petroleum ether gradient to afford the title compound (187 mg, 0.59 mmol, 45% yield) as a white solid. 1H NMR (600 MHz, chloroform-d) δ 7.66 (d, J = 2.7 Hz, 1H), 7.06 (t, J = 60.9 Hz, 1H), 6.35 - 6.25 (m, 1H), 6.06 (s, 1H), 5.26 (m, 2H), 1.48 - 1.44 (m, 2H), 1.31 - 1.28 (m, 2H). LCMS LCQ Rt = 4.58 min (Method 3); m / z (ESI + ) 302.22 [M+H] + . Step 2: N4-[1-[1-(difluoromethyl)pyrazol-3-yl]cyclopropyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine Bis[2-(di-tert-butylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloropalladium (8 mg, 0.01 mmol) was added to a suspension of 6-chloro-N4-[1-[1-(difluoromethyl)pyrazol-3-yl]cyclopropyl]-1,3,5-triazine-2,4-diamine (189 mg, 0.63 mmol), 1-tetrahydropyran-2-yl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (Intermediate V) (247 mg, 0.75 mmol), and tripotassium phosphate (266 mg, 1.25 mmol) in tetrahydrofuran (8 mL) and water (2 mL). The two-phase mixture was degassed with nitrogen for 5 minutes, then sealed and heated at 80 °C for 16 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and brine. The organic phase was separated, dried (MgSO), filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash silica chromatography eluting with a gradient of 0-100% ethyl acetate in petroleum ether to afford the title compound (204 mg, 0.41 mmol, 66% yield) as a colorless oil. 1H NMR (600 MHz, chloroform-d) δ 8.71 - 8.51 (m, 1H), 8.12 - 8.03 (m, 1H), 7.76 - 7.60 (m, 2H), 7.08 (t, J = 60.9 Hz, 1H), 6.53 - 6.17 (m, 2H), 5.88 - 5.70 (m, 1H), 5.58 - 5.33 (m, 2H), 4.08 - 3.97 (m, 1H), 3.81 - 3.67 (m, 1H), 2.60 (s, 1H), 2.20 - 2.10 (m, 1H), 2.08 - 2.03 (m, 1H), 1.81 - 1.68 (m, 3H), 1.67 - 1.59 (m, 1H), 1.58 - 1.46 (m, 2H), 1.43 - 1.31 (m, 2H). LCMS LCQ Rt = 6.11 min (Method 3); m / z (ESI + ) 468.29 [M+H] + . Step 3: N2-[1-[1-(difluoromethyl)pyrazol-3-yl]cyclopropyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine N2-[1-[1-(difluoromethyl)pyrazol-3-yl]cyclopropyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (204 mg, 0.44 mmol) was dissolved in 1,4-dioxane (10 mL) and then added to 4 M HCl in 1,4-dioxane (5.5 mL, 21.8 mmol). The reaction mixture was stirred at room temperature for 16 h, then diluted with diethyl ether (10 mL), and the resulting precipitate was collected by filtration. The solid was dried under vacuum to give the title compound (125 mg, 0.28 mmol, 65% yield). 1H NMR (399 MHz, DMSO-d6) (VT at 90℃) δ 9.34 (s, 2H), 8.59 (s, 1H), 8.18 (s, 1H), 8.09 - 7.86 (m, 3H), 7.62 (t, J = 59.8 Hz, 1H), 6.44 (d, J = 2.7 Hz, 1H), 3.58 (s, 1H), 1.42 (dd, J = 6.3, 4.3 Hz, 4H). LCMS MDAP Rt = 10.253 min, 96% (Method 5); + ) 384.2 [M+H] + .

[0356] Example 23 N2-[1-(2,3-difluorophenyl)cyclopropyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Synthesized using general method B: Step 1: 6-chloro-N4-[1-(2,3-difluorophenyl)cyclopropyl]-1,3,5-triazine-2,4-diamine 2-Amino-4,6-dichlorotriazine (240 mg, 1.45 mmol) in 1,4-dioxane (3.5 mL) was added to N,N-diisopropylethylamine (0.63 mL, 3.64 mmol), followed by 1-(2,3-difluorophenyl)cyclopropanamine (Intermediate J) (120 mg, 0.71 mmol). The resulting mixture was stirred at room temperature for 12 h. The solvent was removed under reduced pressure, and the crude material was purified by flash chromatography (silica gel, eluting with a 50-100% EtOAc gradient in petroleum ether) to afford the title compound (150 mg, 0.48 mmol, 67% yield) as a white powder. 1 H NMR (600 MHz, chloroform-d) δ 7.30 (dt, J = 75.5, 7.1 Hz, 1H), 7.04 - 6.88 (m, 2H), 2.89 (s, 3H), 1.27 - 1.16 (m, 4H). Step 2: N4-[1-(2,3-difluorophenyl)cyclopropyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine A stirred solution of 6-chloro-N4-[1-(2,3-difluorophenyl)cyclopropyl]-1,3,5-triazine-2,4-diamine (75 mg, 0.25 mmol), potassium phosphate tripotassium (158 mg, 0.75 mmol), and bis[2-(di-tert-butylphosphenyl)cyclopenta-2,4-dien-1-yl]iron; dichloropalladium (16 mg, 0.02 mmol) in tetrahydrofuran (5 mL) and water (0.5 mL) was degassed by bubbling N2 directly through the solution. The mixture was heated to 80 °C, and then a solution of 1-tetrahydropyran-2-yl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (Intermediate V) (204 mg, 0.62 mmol) in THF (4 mL) was added. The reaction was stirred at 80 °C for 12 h. The reaction mixture was concentrated to dryness under reduced pressure, and the crude material was purified by flash column chromatography (silica gel, eluting with a gradient of 30-100% EtOAc in petroleum ether) to afford the title compound (80 mg, 0.17 mmol, 69% yield) as a white solid. LCMS MDAP Rt = 3.21 min (Method 6); m / z (ESI + ) 464.15 [M+H] + . Step 3: N2-[1-(2,3-difluorophenyl)cyclopropyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine A solution of N2-[1-(2,3-difluorophenyl)cyclopropyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (80 mg, 0.17 mmol) in methyl alcohol (1 mL) and 4 M HCl in 1,4-dioxane (0.4 mL, 1.73 mmol) was heated at 40° C. for 16 h. The precipitate formed was filtered, washed with diethyl ether and petroleum ether, and then dried in an oven at 50° C. for 2 h to give the title compound (53 mg, 0.13 mmol, 65% yield). 1 H NMR (399 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.54 (s, 1H), 8.14 (d, J = 1.0 Hz, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.88 (dd, J = 8.6, 0.9 Hz, 1H), 7.62 - 7.43 (m, 1H), 7.28 - 7.16 (m, 1H), 7.16 - 7.09 (m, 1H), 1.35 (s, 4H). LCMS-MDAP Rt = 2.97 min (Method 6); m / z (ESI + ) 380.05 [M+H] + .

[0357] Example 24 N2-[(2-chloro-3-fluoro-phenyl)methyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Synthesized using general method B: Step 1: 6-chloro-N4-[(2-chloro-3-fluoro-phenyl)methyl]-1,3,5-triazine-2,4-diamine 2-Amino-4,6-dichlorotriazine (1.0 g, 6.0 mmol) was added to a solution of N,N-diisopropylethylamine (2.64 mL, 15.15 mmol) and 2-chloro-3-fluorobenzylamine (0.97 g, 6.0 mmol) in 1,4-dioxane (60 mL) and stirred for 20 h at 25° C. The reaction mixture was dry-loaded directly onto Celite and purified by flash chromatography on silica (40 g) eluting with a gradient of 0-5% methanol in DCM to give the title compound (0.75 g, 2.56 mmol, 42% yield). 1 H NMR (600 MHz, DMSO-d6) δ 8.26 (t, J = 6.3 Hz, 0.66H), 8.12 (t, J = 6.2 Hz, 0.27H), 7.41 - 7.18 (m, 4H), 7.16 - 7.07 (m, 1H), 4.58 - 4.42 (m, 2H). LCMS MDAP Rt = 3.36 min, >98% (Method 7); m / z (ESI + ) 288 / 290 [M+H] + . Step 2: N4-[(2-chloro-3-fluoro-phenyl)methyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine A mixture of 6-chloro-N4-[(2-chloro-3-fluorophenyl)methyl]-1,3,5-triazine-2,4-diamine (250 mg, 0.87 mmol), 1-tetrahydropyran-2-yl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (Intermediate V) (570 mg, 1.74 mmol), and potassium phosphate tribasic (553 mg, 2.6 mmol) in tetrahydrofuran (12 mL) and water (1.2 mL) was degassed for 5 min. Bis[2-(di-tert-butylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloropalladium (56.55 mg, 0.09 mmol) was added, and the reaction mixture was degassed for 5 min and then immediately heated to 65 °C in a sealed vessel. The reaction mixture was stirred at 65 °C for 2.5 h, then loaded directly onto Celite and flash chromatographed on Si02 (24 g) eluting with a 0-100% EtOAc gradient in petroleum ether to afford the title compound (266 mg, 0.56 mmol, 64% yield). 1 H NMR (600 MHz, DMSO-d6) δ 8.57 (s, 0.66H), 8.48 (s, 0.46H), 8.20 - 8.10 (m, 1.60H), 8.06 (d, J = 8.5 Hz, 0.43H), 7.94 (t, J = 6.3 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 8.5 Hz, 0.47H), 7.48 - 7.18 (m, 3H), 7.07 - 6.75 (m, 2H), 5.90 (d, J = 8.7 Hz, 0.70H), 5.80 (d, J = 9.4 Hz, 0.49H), 4.83 - 4.67 (m, 1H), 4.62 (d, J = 5.9 Hz, 1H), 3.94 - 3.82 (m, 1H), 3.81 - 3.64 (m, 1H), 2.48 - 2.35 (m, 1H), 2.16 - 2.00 (m, 2H), 1.78 (s, 1H), 1.61 (s, 2H). LCMS MDAP Rt = 6.26 min, >95% (Method 7); m / z (ESI +) 454 / 456 [M+H] + . Step 3: N2-[(2-chloro-3-fluoro-phenyl)methyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine A solution of N2-[(2-chloro-3-fluorophenyl)methyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (264 mg, 0.58 mmol) in methyl alcohol (15 mL) and 4 M HCl in 1,4-dioxane (6 mL, 23 mmol) was heated at 60 °C for 20 h. The reaction mixture was concentrated under reduced pressure, and the crude material was dissolved in methanol and eluted on an SCX-2 cartridge (2 × 10 g) with 2 M NH3 in methanol (with DCM for improved solubility). Fractions were concentrated under reduced pressure, and the crude material was purified by flash chromatography on Si02 eluting with a 0-30% methanol in DCM gradient to afford the title compound (250 mg, 0.64 mmol, 80% yield). 1 H NMR (600 MHz, DMSO-d6) δ 13.28 (s, 0.53H), 13.23 (s, 0.34H), 8.48 (s, 0.46H), 8.42 (s, 0.30H), 8.13 - 8.01 (m, 1H), 7.97 (d, J = 8.5 Hz, 0.31H), 7.89 (t, J = 6.2 Hz, 1H), 7.79 (d, J = 8.5 Hz, 0.50H), 7.74 (d, J = 8.3 Hz, 1H), 7.38 - 7.16 (m, 3H), 6.92 (s, 2H), 4.72 (d, J = 6.1 Hz, 1H), 4.59 (d, J = 6.1 Hz, 1H). LCMS MDAP Rt = 23.4 min; >95% (Method 4); m / z (ESI + ) 370 / 372 [M+H] + .

[0358] Example 25 N4-[1-(2,3-difluorophenyl)-1-methyl-ethyl]-6-imidazo[1,5-a]pyridin-6-yl-1,3,5-triazine-2,4-diamine [ka] Synthesized by general method D: Step 1: 6-chloro-N4-[1-(2,3-difluorophenyl)-1-methyl-ethyl]-1,3,5-triazine-2,4-diamine 2-Amino-4,6-dichlorotriazine (300 mg, 1.82 mmol) was dissolved in 1,4-dioxane (10.5 mL), followed by the addition of 2-(2,3-difluorophenyl)propan-2-amine hydrochloride (Intermediate N) (0.2 mL, 2.04 mmol) and N,N-diisopropylethylamine (1.11 mL, 6.36 mmol). The mixture was heated in a microwave at 150 °C for 1 h. The reaction mixture was partitioned between DCM and water. The organic phase was separated, dried (hydrophobic frit), and concentrated under reduced pressure. The crude material was homogenized with diethyl ether and filtered to give the title compound (511 mg, 1.45 mmol, 80% yield) as a white solid. 1 H NMR (600 MHz, chloroform-d) δ 7.19 - 6.81 (m, 3H), 5.81 (s, 1H), 5.41 - 4.81 (m, 2H), 1.80 (s, 6H). Step 2: N4-[1-(2,3-difluorophenyl)-1-methyl-ethyl]-6-imidazo[1,5-a]pyridin-6-yl-1,3,5-triazine-2,4-diamine [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (12 mg, 0.02 mmol) was added to a degassed suspension of 6-bromoimidazo[1,5-a]pyridine (75 mg, 0.38 mmol), bis(pinacolato)diboron (110 mg, 0.4300 mmol), and potassium acetate (66 mg, 0.67 mmol) in tetrahydrofuran (2 mL). The reaction mixture was sealed and heated at 80°C overnight, then cooled to room temperature, and 6-chloro-N4-[1-(2,3-difluorophenyl)-1-methyl-ethyl]-1,3,5-triazine-2,4-diamine (100 mg, 0.33 mmol), potassium phosphate tripotassium (213 mg, 1.0 mmol), and bis[2-(di-tert-butylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloropalladium (4.35 mg, 0.01 mmol) were added. The reaction mixture was diluted with water (0.2 mL) and tetrahydrofuran (2 mL), sealed, and heated at 85°C for 16 hours. The reaction mixture was allowed to cool to room temperature and then partitioned between ethyl acetate and aqueous potassium carbonate. The organic phase was separated, dried (MgSO4), filtered, and concentrated to dryness under reduced pressure. The residue was purified by aminosilica chromatography eluting with a gradient of 65-100% ethyl acetate in petroleum ether to give the title compound (22.7 mg, 0.06 mmol, 17%) as a pale yellow solid. 1H NMR (399 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.37 (s, 1H), 7.44 (d, J = 9.5 Hz, 1H), 7.32 - 7.01 (m, 7H), 6.25 (s, 1H), 1.80 (s, 6H). LCMS LCQ Rt = 4.64 min (Method 3); m / z (ESI + ) 382.29 [M+H] + .

[0359] Example 26 N4-[1-(2,3-dichlorophenyl)-1-methyl-ethyl]-6-imidazo[1,5-a]pyridin-6-yl-1,3,5-triazine-2,4-diamine [ka] Synthesized by general method D: Step 1: 6-chloro-N4-[1-(2,3-dichlorophenyl)-1-methyl-ethyl]-1,3,5-triazine-2,4-diamine A solution of 2-(2,3-dichlorophenyl)propan-2-amine hydrochloride (Intermediate M) (0.2 mL, 2.04 mmol) and 2-amino-4,6-dichlorotriazine (300 mg, 1.82 mmol) in 1,4-dioxane (10.5 mL) was added to N,N-diisopropylethylamine (1.11 mL, 6.36 mmol), and the mixture was heated in a microwave at 150 °C for 1 h. The mixture was cooled to room temperature and partitioned between DCM and water. The organic phase was separated (hydrophobic frit) and concentrated to dryness under reduced pressure. The residue was homogenized with petroleum ether to give the title compound (648 mg, 1.66 mmol, 91% yield) as a white solid. 1 H NMR (600 MHz, chloroform-d) δ 7.51 - 7.35 (m, 2H), 7.16 (m, 1H), 5.91 (s, 1H), 5.34 - 4.64 (m, 2H), 1.86 (s, 6H). Step 2: N4-[1-(2,3-dichlorophenyl)-1-methyl-ethyl]-6-imidazo[1,5-a]pyridin-6-yl-1,3,5-triazine-2,4-diamine [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg, 0.02 mmol) was added to a degassed suspension of 6-bromoimidazo[1,5-a]pyridine (68 mg, 0.35 mmol), bis(pinacolato)diboron (100 mg, 0.39 mmol), and potassium acetate (59 mg, 0.60 mmol) in tetrahydrofuran (2 mL). The reaction was sealed and heated at 80 °C for 16 h. The reaction mixture was cooled to room temperature, and 6-chloro-N4-[1-(2,3-dichlorophenyl)-1-methyl-ethyl]-1,3,5-triazine-2,4-diamine (100 mg, 0.30 mmol), tripotassium phosphate (191 mg, 0.90 mmol), bis[2-(di-tert-butylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloropalladium (4 mg, 0.01 mmol) were added. The reaction mixture was diluted with water (0.20 mL) and tetrahydrofuran (2.0 mL), sealed, and heated at 85 °C for 16 hours. The reaction mixture was partitioned between ethyl acetate and aqueous potassium carbonate solution. The organic phase was separated, dried (MgSO4), filtered, and concentrated in vacuo. The residue was first purified by flash silica chromatography eluting with a gradient of 0-10% methanol in DCM, and then by flash amino silica chromatography eluting with a gradient of 65-100% ethyl acetate in petroleum ether to afford the title compound (10.7 mg, 0.02 mmol, 8% yield) as a pale yellow solid. 1 H NMR (600 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.57 - 7.37 (m, 4H), 7.31 (s, 1H), 7.05 (d, J = 9.6 Hz, 1H), 6.67 (s, 2H), 1.79 (s, 6H). LCMS-LCQ Rt = 5.14 min (Method 3); m / z (ESI + ) 414.23 [M+H] + .

[0360] Example 27 N4-[1-(2,3-dichlorophenyl)-1-methyl-ethyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Synthesized using general method B: Step 1: 1-Tetrahydropyran-2-yl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)indazole (Intermediate V) (148 mg, 0.45 mmol), 6-chloro-N4-[1-(2,3-dichlorophenyl)-1-methyl-ethyl]-1,3,5-triazine-2,4-diamine (Step 1 of Example 6) (100 mg, 0.30 mmol), and potassium phosphate tripotassium (191 mg, 0.90 mmol) were mixed in tetrahydrofuran (1.5 mL) and water (0.15 mL). The mixture was degassed for 5 minutes and added to bis[2-(di-tert-butylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloropalladium (20 mg, 0.03 mmol). The mixture was degassed for 5 min and then heated in a microwave at 120° C. for 1 h. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by flash column chromatography on silica eluting with a gradient of 10–50% ethyl acetate in petroleum ether to give the tetrahydropyranyl-protected product as a white solid, which was readily deprotected in the next step.

[0361] Step 2: The product from Step 1 was dissolved in methyl alcohol (3 mL) and 4 M HCl in 1,4-dioxane (2.25 mL, 9.02 mmol) was added. The solution was heated at 60 °C for 2 h and then evaporated to dryness under reduced pressure. The resulting oil was purified by passing through an SCX-2 cartridge, first washing with methanol, and then eluting the product with 3 M NH3 in methanol to give the title compound (38 mg, 0.08 mmol, 27% yield) as a white solid. 1H NMR (399 MHz, DMSO-d6) (VT at 90℃) δ 12.95 (s, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.77 - 7.61 (m, 3H), 7.46 (d, J = 4.4 Hz, 2H), 7.10 (s, 1H), 6.27 (s, 2H), 1.91 (s, 6H). LCMS MDAP Rt = 16.83 (Method 4); m / z (ESI + ) 413.90 [M+H] + .

[0362] Example 28 N2-[1-(2,3-difluorophenyl)-1-methyl-ethyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Synthesized using general method B: Step 1: N4-[1-(2,3-difluorophenyl)-1-methyl-ethyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine A stirred solution of 6-chloro-N4-[1-(2,3-difluorophenyl)-1-methyl-ethyl]-1,3,5-triazine-2,4-diamine (Example 25, Step 1) (100 mg, 0.33 mmol), tripotassium phosphate (212 mg, 1.0 mmol), and bis[2-(di-tert-butylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloropalladium (22 mg, 0.03 mmol) in tetrahydrofuran (5 mL) and water (0.5 mL) was degassed by bubbling N directly into the solution. After heating the mixture to 80° C., a solution of 1-tetrahydropyran-2-yl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (Intermediate V) (274 mg, 0.83 mmol) in THF (4 mL) was added, and the reaction mixture was stirred for 12 h at 80° C. The reaction mixture was concentrated to dryness under reduced pressure, and the crude material was purified by flash column chromatography on silica eluting with a 30-100% EtOAc gradient in petroleum ether to afford the title compound (92 mg, 0.20 mmol, 59% yield) as a white solid. 1 H NMR (399 MHz, DMSO-d6) δ 8.37 (s, 1H), 8.08 (s, 1H), 7.89 (s, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.35 - 7.04 (m, 4H), 6.39 (s, 2H), 5.85 LCMS LCQ Rt = 4.40 min (Method 2); m / z (ESI + ) 466.26 [M+H] + . Step 2: N2-[1-(2,3-difluorophenyl)-1-methyl-ethyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine A solution of N2-[1-(2,3-difluorophenyl)-1-methyl-ethyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (90 mg, 0.19 mmol) in methyl alcohol (1 mL) and 4 M HCl (0.48 mL, 1.93 mmol) in 1,4-dioxane was heated at 40 °C for 16 h. The resulting precipitate was filtered, washed with diethyl ether and petroleum ether, and dried in an oven at 50 °C for 2 h to give the title compound (65 mg, 0.17 mmol, 87% yield). 1 H NMR (399 MHz, DMSO-d6, VT 90℃) δ 8.34 (s, 1H), 8.12 (s, 1H), 7.80 (s, 2H), 7.31 (s, 1H), 7.21 (dt, J = 9.5, 3.7 Hz, 2H), 1.85 (d, J = 1.1 Hz, 6H); LCMS MDAP Rt = 16.70 (Method 4); m / z (ESI + ) 382.10 [M+H] + .

[0363] Example 29 N4-[(2,3-dichlorophenyl)methyl]-6-imidazo[1,5-a]pyridin-6-yl-1,3,5-triazine-2,4-diamine [ka] Synthesized by general method D: Step 1: 6-chloro-N4-[(2,3-dichlorophenyl)methyl]-1,3,5-triazine-2,4-diamine 2-Amino-4,6-dichlorotriazine (500 mg, 3.0 mmol) was added to a pre-stirred solution of 1-(2,3-dichlorophenyl)methanamine (0.48 mL, 3.64 mmol) and N,N-diisopropylethylamine (1.3 mL, 7.6 mmol) in 1,4-dioxane (15 mL). The reaction mixture was stirred at room temperature for 3 h, then dry-loaded directly onto Celite and purified by flash silica chromatography eluting with a 0-100% ethyl acetate in petroleum ether gradient to afford the title compound (716 mg, 2.23 mmol, 74% yield) as a white solid. 1 H NMR (600 MHz, DMSO-d6) δ 8.30 (t, J = 6.2 Hz, 0.7H), 8.15 (t, J = 6.2 Hz, 0.3H), 7.59 - 7.51 (d, 1H), 7.42 - 7.23 (m, 4H), 4.56-4.49 (m, 2H). LCMS MDAP Rt = 19.46 min (Method 4); m / z (ESI + ) 305.8 [M+H] + . Step 2: N4-[(2,3-dichlorophenyl)methyl]-6-imidazo[1,5-a]pyridin-6-yl-1,3,5-triazine-2,4-diamine [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (12 mg, 0.02 mmol) was added to a degassed suspension of bis(pinacolato)diboron (108 mg, 0.43 mmol), 6-bromoimidazo[1,5-a]pyridine (74 mg, 0.38 mmol), and potassium acetate (64 mg, 0.66 mmol) in tetrahydrofuran (2 mL). The reaction was sealed and heated at 80 °C overnight. The reaction mixture was cooled to room temperature, and 6-chloro-N4-[(2,3-dichlorophenyl)methyl]-1,3,5-triazine-2,4-diamine (100 mg, 0.33 mmol), tripotassium phosphate (209 mg, 0.99 mmol), and bis[2-(di-tert-butylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloropalladium (4.3 mg, 0.01 mmol) were added. The reaction mixture was diluted with water (0.2 mL) and tetrahydrofuran (2 mL), sealed, and heated at 80 °C for 4 h. After cooling to room temperature, the reaction mixture was diluted with DCM, dry-loaded onto Celite, and directly purified by flash silica chromatography eluting with a 0-10% methanol in DCM gradient to provide a tan solid product. Further purification was accomplished using reverse-phase preparative MDAP LCMS eluting with a 30-95% acetonitrile gradient in water with a formic acid (0.1%) modifier gradient over 32 min to afford the title compound (26 mg, 0.06 mmol, 19% yield) as a pale yellow solid. 1 H NMR (600 MHz, DMSO-d6) δ 9.22 - 9.01 (m, 1H), 8.64 - 8.43 (m, 1H), 7.89 (t, J = 6.3 Hz, 0.6H), 7.81 - 7.75 (m, 0.4H), 7.62 - 7.21 (m, 5H), 7.17 - 6.55 (m, 3H), 4.71 (d, J = 6.2 Hz, 0.8H), 4.57 (d, J = 6.3 Hz, 1.2H). LCMS MDAP Rt = 14.92 min (Method 4); + ) 385.85 [M+H] + .

[0364] Example 30 N4-[(2,3-difluorophenyl)methyl]-6-imidazo[1,5-a]pyridin-6-yl-1,3,5-triazine-2,4-diamine [ka] Synthesized by general method D: Step 1: 6-chloro-N4-[(2,3-difluorophenyl)methyl]-1,3,5-triazine-2,4-diamine RW-2196-22 2-Amino-4,6-dichlorotriazine (500 mg, 3.0 mmol) was added to a stirred solution of 2,3-difluorobenzylamine (0.43 mL, 3.64 mmol) and N,N-diisopropylethylamine (1.32 mL, 7.58 mmol) in 1,4-dioxane (15 mL). The reaction was stirred at room temperature for 3 h, then dry-loaded onto Celite and purified by flash silica chromatography eluting with a gradient of 0-10% methanol in DCM to afford the title compound (577 mg, 2.02 mmol, 67% yield). 1 H NMR (600 MHz, DMSO-d6) δ 8.25 (t, J = 6.2 Hz, 0.65H), 8.10 (t, J = 6.2 Hz, 0.35H), 7.44 - 7.06 (m, 5H), 4.54 - 4.43 (m, 2H). LCMS MDAP Rt = 2.29 min (Method 6); m / z (ESI + ) 271.9 [M+H] + . Step 2: N4-[(2,3-difluorophenyl)methyl]-6-imidazo[1,5-a]pyridin-6-yl-1,3,5-triazine-2,4-diamine 1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13.5 mg, 0.02 mmol) was added to a degassed suspension of bis(pinacolato)diboron (121 mg, 0.48 mmol), 6-bromoimidazo[1,5-a]pyridine (83 mg, 0.42 mmol), and potassium acetate (72 mg, 0.74 mmol). The reaction was sealed and heated at 80°C overnight. After cooling to room temperature, 6-chloro-N4-[(2,3-difluorophenyl)methyl]-1,3,5-triazine-2,4-diamine (100 mg, 0.37 mmol), potassium phosphate tripotassium (234 mg, 1.1 mmol), and bis[2-(di-tert-butylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloropalladium (4.8 mg, 0.01 mmol) were added. The reaction mixture was diluted with tetrahydrofuran (2 mL) and water (0.2 mL) and heated at 80°C for 16 hours. After cooling to room temperature, the reaction mixture was dry-loaded directly onto Celite and purified by flash silica chromatography, eluting with a gradient of 0-10% methanol in DCM. The isolated material was first eluted with petroleum ether and then further purified by aminosilica chromatography eluting with a gradient of 0-10% methanol in DCM to afford the title compound (39 mg, 0.1 mmol, 28% yield) as a yellow solid. 1 H NMR (600 MHz, DMSO-d6) δ 9.18 - 9.07 (m, 1H), 8.59 - 8.48 (m, 1H), 7.89 - 7.85 (m, 0.6H), 7.77 - 7.73 (m, 0.4H), 7.59 - 7.47 (m, 2H), 7.40 - 7.31 (m, 1H), 7.30 - 7.12 (m, 3H), 6.94 (s, 1H), 6.84 (s, 1H), 4.68 (d, J = 6.2 Hz, 0.9H), 4.58 (d, J = 6.2 Hz, 1.1H). LCMS MDAP Rt = 2.16 min (Method 6); m / z (ESI + ) 353.95 [M+H] + .

[0365] Example 31 N4-[2-(2,3-dichlorophenyl)ethyl]-6-imidazo[1,5-a]pyridin-6-yl-1,3,5-triazine-2,4-diamine [ka] Synthesized by general method D: Step 1: 6-chloro-N4-[2-(2,3-dichlorophenyl)ethyl]-1,3,5-triazine-2,4-diamine RW-2196-24 The title compound was synthesized using the same method as in Example 30, Step 1, except that 2,3-difluorobenzylamine was replaced with 2-(2,3-dichlorophenyl)ethanamine to afford the product as a white solid. 1 H NMR (600 MHz, DMSO-d6) δ 7.80 (t, J = 5.7 Hz, 0.7H), 7.63 (t, J = 5.7 Hz, 0.3H), 7.55 - 7.41 (m, 1H), 7.37 - 7.20 (m, 3H), 7.20 - 6.98 (br m, 1H), 3.44 (q, J = 6.7 Hz, 2H), 3.04 - 2.88 (m, 2H). LCMS LCQ Rt = 10.30 min (Method 3); m / z (ESI + ) 318.15 [M+H] + . Step 2: N4-[2-(2,3-dichlorophenyl)ethyl]-6-imidazo[1,5-a]pyridin-6-yl-1,3,5-triazine-2,4-diamine The title compound was synthesized using the same method as in Example 29, Step 2, except that 6-chloro-N4-[(2,3-dichlorophenyl)methyl]-1,3,5-triazine-2,4-diamine was replaced with 6-chloro-N4-[2-(2,3-dichlorophenyl)ethyl]-1,3,5-triazine-2,4-diamine to afford the product (23 mg) as a pale yellow solid. 1H NMR (600 MHz, DMSO-d6) δ 9.11 (s, 0.5H), 9.07 (s, 0.5H), 8.54 (d, J = 7.3 Hz, 1H), 7.69 - 7.10 (m, 7H), 6.89 (s, 1H), 6.71 (s, 1H), 3.65 (q, J = 6.7 Hz, 1H), 3.52 (q, J = 6.7 Hz, 1H), 3.08 - 2.98 (m, 2H). LCMS MDAP Rt = 14.94 min (Method 4); m / z (ESI + ) 399.90 [M+H] + .

[0366] Example 32 N4-[1-[1-(difluoromethyl)pyrazol-3-yl]cyclopropyl]-6-(1-methylindazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Synthesized by general method D: A stirred solution of 6-chloro-N4-[1-[1-(difluoromethyl)pyrazol-3-yl]cyclopropyl]-1,3,5-triazine-2,4-diamine (Example 22, Step 1) (50 mg, 0.17 mmol), potassium phosphate tripotassium (70 mg, 0.33 mmol), and bis[2-(di-tert-butylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloropalladium (6 mg, 0.01 mmol) in tetrahydrofuran (5 mL) and water (0.5 mL) was degassed by bubbling N2 directly through the solution. After heating the mixture to 80 °C, 1-methyl-1H-indazole-6-boronic acid (44 mg, 0.25 mmol) in THF (4 mL) was added, and the reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated to dryness under reduced pressure, and the crude material was purified by flash column chromatography (silica gel, eluting with a gradient of 30-100% EtOAc in petroleum ether). The solid was homogenized with a mixture of diethyl ether and petroleum ether to afford the title compound (15 mg, 0.04 mmol, 22% yield) as an off-white solid. 1 H NMR (399 MHz, DMSO-d6, VT 90℃) δ 8.42 (s, 1H), 8.11 - 7.99 (m, 2H), 7.93 (d, J = 2.7 Hz, 1H), 7.80 - 7.36 (m, 3H), 6.52 (s, 2H), 6.35 (d, J = 2.7 Hz, 1H), 4.06 (s, 3H), 1.36 (p, J = 4.9, 4.1 Hz, 2H), 1.33 - 1.25 (m, 2H). LCMS MDAP Rt = 16.15 min (Method 4); m / z (ESI + ) 398.2 [M+H] + .

[0367] Example 33 N4-[1-[1-(difluoromethyl)pyrazol-3-yl]cyclopropyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized using the same method as in Example 32, except that 1-methyl-1H-indazole-6-boronic acid was replaced with 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine (Intermediate Y) to give the product as a yellow solid (32 mg, 0.08 mmol, 37% yield). 1 H NMR (399 MHz, DMSO-d6, VT 90℃) δ 8.72 (s, 1H), 7.91 (d, J = 2.6 Hz, 1H), 7.75 (s, 1H), 7.55 (t, J = 59.9 Hz, 1H), 7.45 (t, J = 8.4 Hz, 2H), 7.23 (d, J = 1.0 Hz, 1H), 6.53 (s, 2H), 6.31 (d, J = 2.7 Hz, 1H), 2.58 (s, 3H), 1.32 (q, J = 5.1, 3.9 Hz, 2H), 1.25 (dt, J = 5.7, 3.2 Hz, 2H). LCMS MDAP Rt = 11.65 min (Method 4); m / z (ESI + ) 398.2 [M+H] + .

[0368] Example 34 N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-imidazo[1,5-a]pyridin-6-yl-N4-methyl-1,3,5-triazine-2,4-diamine [ka] Synthesized by general method D: Step 1: 6-chloro-N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-N4-methyl-1,3,5-triazine-2,4-diamine 2-[1-(difluoromethyl)pyrazol-3-yl]-N-methyl-propan-2-amine (Intermediate O) (0.2 mL, 0.67 mmol) was suspended in 1,4-dioxane (3.5 mL) and 2-amino-4,6-dichlorotriazine (100 mg, 0.61 mmol) was added, followed by N,N-diisopropylethylamine (0.32 mL, 1.82 mmol). The mixture was heated at 90 °C in a microwave for 1 h. The reaction mixture was partitioned between DCM and HCl. The organic phase was separated, dried (hydrophobic frit), and concentrated in vacuo. The crude material was purified by flash column chromatography eluting with a gradient of 0-10% methanol in DCM. The isolated material was homogenized with diethyl ether and filtered to afford the title compound (10 mg, 0.0300 mmol, 5% yield) as a white solid.

[0369] Step 2: N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-imidazo[1,5-a]pyridin-6-yl-N4-methyl-1,3,5-triazine-2,4-diamine 6-Chloro-N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-N4-methyl-1,3,5-triazine-2,4-diamine (30 mg, 0.09 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine (Intermediate W) (49 mg, 0.14 mmol), and potassium phosphate tribasic (40 mg, 0.19 mmol) were dissolved in tetrahydrofuran (2 mL) and water (0.2 mL). The mixture was degassed with N for 5 minutes, and then bis[2-(di-tert-butylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloropalladium (3 mg, 0.004 mmol) was added. The mixture was degassed for another 2 minutes and then heated at 90 °C for 18 hours. The mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The crude material was purified by flash column chromatography eluting with a gradient of 0-10% methanol in ethyl acetate to give a pale brown solid. The solid was homogenized with diethyl ether to give the title compound (23 mg, 0.06 mmol, 60% yield) as an off-white solid.1 H NMR (399 MHz, DMSO-d6) (VT at 90) δ 8.79 (s, 1H), 8.47 (s, 1H), 7.97 (d, J = 2.7 Hz, 1H), 7.79 (t, J = 59.3 Hz, 1H), 7.46 (d, J = 9.5 Hz, 1H), 7.35 (s, 1H), 7.18 (d, J = 9.6 Hz, 1H), 6.78 (s, 2H), 6.29 (d, J = 2.6 Hz, 1H), 3.34 (s, 3H), 1.76 (s, 6H).

[0370] Example 35 N4-[1-[1-(difluoromethyl)pyrazol-3-yl]cyclopropyl]-6-imidazo[1,5-a]pyridin-6-yl-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized using the same method as in Example 32, except that 1-methyl-1H-indazole-6-boronic acid was replaced with 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine (Intermediate W) to give the title compound (31 mg) as an off-white solid. 1 H NMR (399 MHz, DMSO-d6) (VT at 90) δ 9.05 (s, 1H), 8.47 (s, 1H), 7.94 (d, J = 2.7 Hz, 1H), 7.75 (s, 1H), 7.59 (t, J = 59.9 Hz, 1H), 7.55 - 7.46 (m, 2H), 7.35 (s, 1H),6.52 (s, 2H), 6.34 (d, J = 2.7 Hz, 1H), 1.39 - 1.33 (m, 2H), 1.32 - 1.25 (m, 2H).

[0371] Example 36 N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-imidazo[1,5-a]pyridin-6-yl-1,3,5-triazine-2,4-diamine [ka] Step 1: 6-chloro-N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-1,3,5-triazine-2,4-diamine The title compound was synthesized using a method similar to that described in Example 34, except that 2-[1-(difluoromethyl)pyrazol-3-yl]-N-methyl-propan-2-amine (Intermediate O) was replaced with 2-[1-(difluoromethyl)pyrazol-3-yl]propan-2-amine (Intermediate L), to give the product as a white solid (242 mg, 0.78 mmol, 43% yield). 1 H NMR (399 MHz, DMSO-d6 VT at 90℃) δ 7.99 (d, J = 2.7 Hz, 1H), 7.64 (t, J = 59.9 Hz, 1H), 7.41 - 7.31 (m, 1H), 6.82 (s, 2H), 6.44 (d, J = 2.6 Hz, 1H), 1.71 (s, 6H). Step 2: N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-imidazo[1,5-a]pyridin-6-yl-1,3,5-triazine-2,4-diamine The title compound was synthesized using a method similar to Example 34, Step 2, except that 6-chloro-N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-N4-methyl-1,3,5-triazine-2,4-diamine was replaced with 6-chloro-N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-1,3,5-triazine-2,4-diamine to afford the product (118 mg) as a light brown solid. 1H NMR (399 MHz, DMSO-d6, VT 90℃) δ 8.94 (s, 1H), 8.44 (s, 1H), 7.99 (d, J = 2.7 Hz, 1H), 7.69 (t, J = 59.8 Hz, 1H), 7.49 (d, J = 9.3 Hz, 1H), 7.37 (d, J = 14.4 Hz, 2H), 6.96 (s, 1H), 6.45 (d, J = 2.6 Hz, 1H), 6.43 (s, 2H), 1.77 (s, 6H).

[0372] Example 37 N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine [ka] Substituting 6-chloro-N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-N4-methyl-1,3,5-triazine-2,4-diamine with 6-chloro-N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-1,3,5-triazine-2,4-diamine (Example 36, Step 1), 6-(4,4,5,5-tetramethyl-1 The title compound was synthesized using a method similar to Example 34, Step 2, except that 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine (Intermediate W) was replaced with 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine (Intermediate Y), which was further purified on an amino silica gel column (eluted with a 30-100% EtOAc gradient in petroleum ether) to afford the final product (26 mg, 0.06 mmol, 33% yield) as a yellow solid. 1H NMR (399 MHz, DMSO-d6, VT 90℃) δ 8.64 (s, 1H), 7.99 - 7.89 (m, 1H), 7.61 (t, J = 59.9 Hz, 1H), 7.42 (d, J = 9.5 Hz, 1H), 7.30 (d, J = 9.3 m / z Hz, 1H), 7.22 (s, 1H), 6.95 (s, 1H), 6.42 (s, 3H), 2.59 (d, J = 1.1 Hz, 3H), 1.74 (d, J = 1.4 Hz, 6H). (ESI + ) 400.05 [M+H] + .

[0373] Example 38 N4-[(2,3-dichlorophenyl)methyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized using a method similar to Example 34, Step 2, except that 6-chloro-N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-N4-methyl-1,3,5-triazine-2,4-diamine was replaced with 6-chloro-N4-[(2,3-dichlorophenyl)methyl]-1,3,5-triazine-2,4-diamine (Example 17, Step 1), and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine (Intermediate W) was replaced with 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine (Intermediate Y), which was extracted with 30-100% petroleum ether. Further purification on an amino silica gel column eluted with an EtOAc gradient gave the final product (10 mg, 0.02 mmol, 12% yield) as a yellow solid. LCMS MDAP Rt = 13.33 min (Method 4); m / z (ESI +) 399.90, 400.95, 401.90, 403.90 (2 x Cl isotopes) [M+H] + .

[0374] Example 39 N4-[1-(2,3-difluorophenyl)-1-methyl-ethyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized using a method similar to Example 34, Step 2, except that 6-chloro-N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-N4-methyl-1,3,5-triazine-2,4-diamine was replaced with 6-chloro-N4-[1-(2,3-difluorophenyl)-1-methyl-ethyl]-1,3,5-triazine-2,4-diamine (Example 25, Step 1), and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine (Intermediate W) was replaced with 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine (Intermediate Y), which was extracted with 30-100% petroleum ether. Further purification on an amino silica gel column eluted with an EtOAc gradient gave the final product (20 mg, 0.05 mmol, 25% yield) as a yellow solid. 1 H NMR (399 MHz, DMSO-d6, VT 90℃) δ 8.50 (s, 1H), 7.41 (d, J = 9.5 Hz, 1H), 7.24 (dd, J = 17.8, 7.0 Hz, 4H), 7.19 - 7.06 (m, 2H), 6.38 (s, 2H), 2.57 (s, 3H), 1.79 (d, J = 1.2 Hz, 6H). LCMS MDAP Rt = 12.80 min (Method 4); m / z (ESI + ) 395.95 [M+H] + .

[0375] Example 40 N4-[(2,3-difluorophenyl)methyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized using a method similar to Example 34, Step 2, except that 6-chloro-N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-N4-methyl-1,3,5-triazine-2,4-diamine was replaced with 6-chloro-N4-[2-(2,3-dichlorophenyl)ethyl]-1,3,5-triazine-2,4-diamine (Example 30, Step 1), and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine (Intermediate W) was replaced with 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine (Intermediate Y), which was purified by column chromatography on an amino silica gel column (30-100% petroleum ether). Further purification by elution with EtOAc gradient gave the final product (50 mg, 0.13 mmol, 59% yield) as a yellow solid. 1 H NMR (399 MHz, DMSO-d6, VT 90℃) δ 8.77 (s, 1H), 7.54 (d, J= 7.8 Hz, 2H), 7.47 (t, J= 1.4 Hz, 2H), 7.29 - 7.05 (m, 3H), 6.58 (s, 2H), 4.63 (d, J= 6.2 Hz, 2H), 2.61 (s, 3H). LCMS MDAP Rt = 12.46 min (Method 4); m / z (ESI + ) 367.95 [M+H] + .

[0376] Example 41 N2-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-(3-methyl-11H-indazol-5-yl)-1,3,5-triazine-2,4-diamine [ka] Step 1: N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-(3-methyl-1-tetrahydropyran-2-yl-indazol-5-yl)-1,3,5-triazine-2,4-diamine A stirred solution of 6-chloro-N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-1,3,5-triazine-2,4-diamine (Example 36, Step 1) (45 mg, 0.15 mmol), tripotassium phosphate (63 mg, 0.30 mmol), and bis[2-(di-tert-butylphosphanyl)cyclopenta-2,4-dien-1-yl]iron;dichloropalladium (5 mg, 0.010 mmol) in tetrahydrofuran (2.5 mL) and water (0.25 mL) was degassed by bubbling N directly into the solution. After heating the mixture to 80° C., a solution of 3-methyl-1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (Intermediate A) (76 mg, 0.22 mmol) in THF was added, and the reaction was stirred for 12 h at 80° C. The reaction mixture was concentrated to dryness under reduced pressure, and the crude material was purified by flash column chromatography (silica gel, eluting with a 30-100% EtOAc gradient in petroleum ether) to afford the title compound (50 mg, 0.10 mmol, 67% yield) as a pale yellow oil. 1H NMR (399 MHz, DMSO-d6, VT 90℃) δ 8.52 (s, 1H), 8.17 (d, J = 8.7 Hz, 1H), 7.97 (d, J = 2.7 Hz, 1H), 7.84 - 7.43 (m, 2H), 6.86 (s, 1H), 6.46 (d, J = 2.7 Hz, 1H), 6.35 (s, 2H), 5.73 (dd, J = 9.5, 2.7 Hz, 1H), 3.96 - 3.63 (m, 2H), 2.46 - 2.27 (m, 2H), 1.98 (s, 5H), 1.78 (s, 6H), 1.61 (dd, J = 8.6, 4.5 Hz, 2H). LCMS MDAP Rt = 17.22 min (Method 4); m / z (ESI + ) 484.3 [M+H] + . Step 2: N2-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-(3-methyl-1H-indazol-5-yl)-1,3,5-triazine-2,4-diamine N2-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-(3-methyl-1-tetrahydropyran-2-yl-indazol-5-yl)-1,3,5-triazine-2,4-diamine (50 mg, 0.10 mmol) in methyl alcohol (1 mL) and 4 M HCl (0.26 mL, 1.03 mmol) in 1,4-dioxane were heated at 40° C. for 16 h. The resulting precipitate was filtered, washed with diethyl ether and petroleum ether, and dried in an oven at 50° C. for 2 h to give the title compound (28 mg, 0.07 mmol, 66% yield). 1 H NMR (399 MHz, DMSO-d6, VT 90℃) δ 8.73 (s, 1H), 8.15 - 7.96 (m, 2H), 7.84 - 7.44 (m, 2H), 6.53 (s, 1H), 2.55 (s, 3H), 1.81 (s, 6H). LCMS MDAP Rt = 13.99 min (Method 4); m / z (ESI +) 400.2 [M+H] + .

[0377] Example 42 4-(3-benzylmorpholin-4-yl)-6-(1H-indazol-6-yl)-1,3,5-triazin-2-amine [ka] Synthesized by general synthesis method C: 3-Benzylmorpholine (35 mg, 0.20 mmol) was added to a suspension of 4-chloro-6-(1H-indazol-6-yl)-1,3,5-triazin-2-amine (Intermediate Z) (41 mg, 0.17 mmol) and N,N-diisopropylethylamine (0.09 mL, 0.50 mmol) in 1,4-dioxane (2 mL). The reaction mixture was heated at 60 °C for 4 h and then stirred at room temperature until the starting material was consumed. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase preparative MDAP LCMS eluting with 30-95% acetonitrile in water with a formic acid (0.1%) modifier gradient over 32 min. Relevant fractions were collected and concentrated to dryness under reduced pressure. The material was further dissolved in EtOAc (15 mL) and washed with saturated aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), then dried over MgSO4 and filtered under reduced pressure to give a tan solid.

[0378] 1H NMR (600 MHz, DMSO-d6) δ 13.43 (s, 1H), 8.50 (d, J = 6.1 Hz, 0.4H), 8.44 (s, 0.6H), 8.18 - 8.13 (m, 1H), 8.04 - 8.00 (m, 0.4H), 8.01 - 7.95 (m, 0.6H), 7.89 - 7.83 (m, 1H), 7.32 (t, 1H), 7.29 (d, J = 7.4 Hz, 2H), 7.20 (t, 2H), 7.10 - 7.07 (m, 1H), 5.04 (s, 1H), 4.72 (s, 0.5H), 4.64 (d, J = 13.7 Hz, 0.5H), 4.35 (d, J = 13.3 Hz, 1H), 3.98 (d, J = 10.9 Hz, 1H), 3.75 (d, J = 11.7 Hz, 1H), 3.61 (d, J = 11.8 Hz, 1H), 3.53 (d, J = 11.6 Hz, 1H), 3.11 - 3.06 (m, 1H), 2.99 (s, 1H), 2.86 (s, 1H).LCMS MDAP Rt = 17.04 min (Method 4); m / z (ESI+) 387.95 [M+H] + .

[0379] Example 43 N4-[2-(2,3-dichlorophenyl)ethyl]-6-(1H-indazol-6-yl)-N4-methyl-1,3,5-triazine-2,4-diamine [ka] Synthesized by general synthesis method C: 2-(2,3-Dichlorophenyl)-N-methyl-ethanamine; 2,2,2-trifluoroacetic acid (Intermediate Q) (62 mg, 0.19 mmol) was added to a suspension of 4-chloro-6-(1H-indazol-6-yl)-1,3,5-triazin-2-amine (Intermediate Z) (40 mg, 0.16 mmol) and N,N-diisopropylethylamine (0.08 mL, 0.49 mmol) in 1,4-dioxane (2 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by flash chromatography eluting with a gradient of 0-60% ethyl acetate in petroleum ether to afford the title compound (42 mg, 0.1 mmol, 59% yield) as a colorless solid. 1 H NMR (600 MHz, DMSO-d6) δ 13.26 (s, 0.5H), 13.24 (s, 0.5H), 8.50 (s, 0.3H), 8.44 (s, 0.6H), 8.09 (s, 1H), 8.07 (d, J= 8.3 Hz, 0.4H), 8.00 (d, J= 8.6 Hz, 0.6H), 7.77 (d, J= 8.3 Hz, 1H), 7.50 (d, J= 8.1 Hz, 0.3H), 7.38 (d, J= 7.8 Hz, 1H), 7.30 (d, J= 7.7 Hz, 1H), 7.22 (t ,J= 7.8 Hz, 1H), 6.84 (s, 2H), 3.97 (t, J= 7.1 Hz, 1H), 3.79 (t, J= 7.8 Hz, 1H), 3.27 (s, 1H), 3.15 (s, 1H), 3.10 (t, J= 7.0 Hz, 1H), 3.06 (s, 2H).. LCMS MDAP Rt = 17.38 min (Method 4); m / z (ESI + ) 415.85 / 413.9 [M+H] + .

[0380] Example 44 N4-[(2,3-difluorophenyl)methyl]-6-(1-methylindazol-5-yl)-1,3,5-triazine-2,4-diamine [ka] A solution of 6-chloro-N4-[(2,3-difluorophenyl)methyl]-1,3,5-triazine-2,4-diamine (Example 30, Step 1) (100 mg, 0.37 mmol) in tetrahydrofuran (3 mL) was added to bis[2-(di-tert-butylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloropalladium (12 mg, 0.02 mmol), and 1-methyl-1H-indazol-5-ylboronic acid (65 mg, 0.37 mmol). After degassing the reaction mixture with N2 bubbling for 3 minutes, potassium phosphate tribasic (156 mg, 0.74 mmol) was added, and the reaction mixture was heated at 85 °C for 16 hours under microwave irradiation. The reaction mixture was loaded directly onto silica and purified by flash chromatography eluting with a gradient of 2-3% methanol in DCM to afford the title compound (65 mg, 0.17 mmol, 46% yield). 1 H NMR (600 MHz, chloroform-d) δ 8.86 - 8.74 (m, 1H), 8.39 (d, J = 30.7 Hz, 1H), 8.05 (s, 1H), 7.39 (d, J = 8.9 Hz, 1H), 7.17 (s, 1H), 7.08 - 6.98 (m, 2H), 5.74 (s, 0.5H), 5.56 (s, 0.5H), 5.16 (d, J = 39.2 Hz, 2H), 4.86 (s, 1H), 4.72 (s, 1H), 4.09 (s, 3H). LCMS MDAP Rt = 2.51 min (Method 6); m / z (ESI+) 368.00 [M+H] + .

[0381] Example 45 N4-[(2,3-difluorophenyl)methyl]-6-(1H-indazol-5-yl)-1,3,5-triazine-2,4-diamine [ka] 6-Chloro-N4-[(2,3-difluorophenyl)methyl]-1,3,5-triazine-2,4-diamine (Example 30, Step 1) (100 mg, 0.37 mmol) in tetrahydrofuran (3 mL) was added to 1H-indazol-5-ylboronic acid (60 mg, 0.37 mmol) and cesium fluoride (112 mg, 0.74 mmol). The reaction mixture was degassed for 3 minutes with N2 bubbling, and tetrakis(triphenylphosphine)palladium(0) (21 mg, 0.02 mmol) was added. The resulting reaction mixture was heated in a microwave oven at 85 °C for 16 hours, then dry-loaded onto silica and purified by flash chromatography eluting with a gradient of 2-3% methanol in DCM to give the title compound (30 mg, 0.08 mmol, 22% yield) as an off-white solid. 1 H NMR (600 MHz, DMSO-d6) δ 13.52 - 12.98 (m, 1H), 8.70 (d, 1H), 8.31 - 8.22 (m, 1H), 8.17 (d, J = 13.6 Hz, 1H), 7.86 - 7.75 (m, 1H), 7.70 - 7.62 (m, 1H), 7.58 - 7.47 (m, 1H), 7.31 - 7.17 (m, 1H), 7.16 - 7.09 (m, 1H), 6.85 (s, 1H), 6.76 (s, 1H), 4.70 - 4.65 (m, 1H), 4.62 - 4.56 (m, 1H).LCMS MDAP Rt = 2.37 min (Method 6); m / z (ESI+) 354.00 [M+H] + .

[0382] Example 46 N4-[(2,3-difluorophenyl)methyl]-6-(1-methylindazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized in the same manner as in Example 44, except that 1-methyl-1H-indazol-5-ylboronic acid was replaced with (1-methylindazol-6-yl)boronic acid to give the desired product. 1 H NMR (600 MHz, chloroform-d) δ 8.50 - 8.42 (m, 1H), 8.19 - 8.07 (m, 1H), 7.99 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.22 - 7.13 (m, 1H), 7.11 - 6.99 (m, 2H), 5.68 (s, 0.5H), 5.55 (s, 0.5H), 5.18 (s, 1H), 5.10 (s, 1H), 4.86 (s, 1H), 4.74 (s, 1H), 4.14 (s, 3H).LCMS MDAP Rt = 2.70 min (Method 6); m / z (ESI+) 368.05 [M+H] + .

[0383] Example 47 N2-[(4-chloro-1-methyl-pyrazol-3-yl)methyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Step 1: 6-chloro-N2-[(4-chloro-1-methyl-1H-pyrazol-3-yl)methyl]-1,3,5-triazine-2,4-diamine) SDD146-1 N,N-Diisopropylethylamine (0.10 mL, 0.60 mmol) was added to a stirred suspension of 1-(4-chloro-1-methyl-1H-pyrazol-3-yl)methanamine hydrochloride (55 mg, 0.30 mmol) and dichloro-1,3,5-triazin-2-amine (50 mg, 0.30 mmol) in 1-methylpyrrolidin-2-one (0.6 mL) at 0° C. and stirred for 2 hours at 0° C. The reaction was quenched with water (5 mL) and stirred for 16 hours. The resulting precipitate was filtered, and the solid was dried under vacuum at 45° C. for 8 hours to give the title compound (52 mg, 0.19 mmol, 63% yield) as a colorless solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.88 (s, 1H), 7.52 - 6.95 (m, 2H), 4.60 - 4.29 (m, 2H), 3.77 (s, 3H). UPLCMS Rt = 0.80 min, 93% (Basic 2 min); m / z (ESI + ) 274 [M+H] + . Step 2: N2-[(4-chloro-1-methyl-pyrazol-3-yl)methyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine (1H-Indazol-6-yl)boronic acid (29 mg, 0.18 mmol), 6-chloro-N2-[(4-chloro-1-methyl-1H-pyrazol-3-yl)methyl]-1,3,5-triazine-2,4-diamine (50 mg, 0.18 mmol), and 3 M aqueous potassium carbonate (0.18 mL, 0.547 mmol) were added to a degassed mixture of 1,4-dioxane (1 mL) and water (0.07 mL). After degassing under nitrogen for 5 minutes, bis[2-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloromethane; and dichloropalladium (7.4 mg, 0.009 mmol) were added, and the reaction mixture was heated at 80 °C for 6 hours. The mixture was cooled to room temperature, diluted with DCM:methanol (8:2, 10 mL), and filtered through a pad of Celite / SiO. The filtrate was evaporated to dryness, and the crude material was purified by preparative HPLC. The fractions were collected and dried in vacuo at 40 °C to give a white solid. The material was further purified by flash silica chromatography, eluting with a gradient of 0-10% methanol in DCM, to give the title compound (5.8 mg, 0.016 mmol, 8.9% yield) as a colorless solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 8.87 - 8.35 (m, 1H), 8.19 - 7.74 (m, 4H), 7.50 - 7.31 (m, 1H), 6.99 - 6.61 (m, 2H), 4.77 -4.39 (m, 2H), 3.78 (s, 3H). UPLC-MS Rt = 1.27 min, 100% (4 min Basic); m / z (ESI + ) 356 [M+H] + .

[0384] Example 48 6-(1H-indazol-6-yl)-N2-[1-methyl-1-(6-methyl-2-pyridyl)ethyl]-1,3,5-triazine-2,4-diamine [ka] 4-Chloro-6-(1H-indazol-6-yl)-1,3,5-triazin-2-amine (Intermediate Z) (20 mg, 0.08 mmol) in NMP (0.30 mL) was added to 2-(6-methylpyridin-2-yl)propan-2-amine (Intermediate B) (31 mg, 0.20 mmol) and N,N-diisopropylethylamine (0.04 mL, 0.24 mmol), and the reaction was stirred at 90° C. for 20 hours. The reaction was cooled to room temperature, diluted with 9:1 DMSO:water, and purified by preparative HPLC. Fractions containing the desired compound were collected and concentrated to dryness under reduced pressure to give a light brown solid, which was homogenized twice with diethyl ether to give the title compound (3.2 mg, 11% yield). 1 H UPLC-MS Rt = 1.53 min, 100% (4 min Basic); m / z (ESI + ) 361.2 [M+H] + .

[0385] Example 49 N2-[(2-chloro-4-fluoro-phenyl)methyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Synthesized by general synthesis method C: 4-Chloro-6-(1H-indazol-6-yl)-1,3,5-triazin-2-amine (Intermediate Z) (30 mg, 0.12 mmol) in NMP (0.38 mL) was added to 1-(2-chloro-4-fluorophenyl)methanamine (0.04 mL, 0.30 mmol) and N,N-diisopropylethylamine (0.06 mL, 0.37 mmol), and the reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with 9:1 DMSO:water, and purified by preparative HPLC. Fractions containing the desired compound were collected and concentrated to dryness under reduced pressure to afford the title compound (4 mg, 9% yield) as an off-white solid. 1H NMR (DMSO-d6) δ: 13.31 (s, 1H), 8.48 (m, 1H), 8.16 - 7.97 (m, 2H), 7.92 - 7.69 (m, 1H), 7.43 (m, 2H), 7.21(m, 1H), 6.92 (m, 2H), 4.68 (s, 1H), 4.56 (d, J = 6.3 Hz, 1H). UPLC-MS Rt = 1.65 min, 96% (4 min Basic); m / z (ESI + ) 370.1 [M+H] + .

[0386] Example 50 N2-[(2-chloro-6-fluoro-phenyl)methyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized by Method C using the same method as in Example 49, except that 1-(2-chloro-4-fluorophenyl)methanamine was replaced with 1-(2-chloro-6-fluorophenyl)methanamine to give the desired product (3 mg, 5% yield) as an off-white solid. 1 H NMR (DMSO-d6) δ: 13.29 (s, 1H), 8.51 (m, 1H), 8.08 (m, 2H), 7.79 (d, J = 8.6 Hz, 1H), 7.55 (m, 1H), 7.37 (m, 2H), 7.26 (m, 1H), 6.86 (m, 2H), 4.74 (s, 1H), 4.64 (s, 1H). UPLC-MS Rt = 1.60 min, 100% (4 min Basic); m / z (ESI + ) 370.1 [M+H] + .

[0387] Example 51 N2-[(6-chloro-2,3-difluorophenyl)methyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized by Method C using the same method as in Example 49, except that 1-(2-chloro-4-fluorophenyl)methanamine was replaced with 1-(6-chloro-2,3-difluorophenyl)methanamine to give the desired compound (13.5 mg, 0.035 mmol, 43% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H), 8.66 -8.34 (m, 1H), 8.20 - 7.98 (m, 2H), 7.84 - 7.75 (m,1H), 7.74 - 7.30 (m, 3H), 7.21 - 6.59 (m, 2H), 4.81 -4.62 (m, 2H). UPLC-MS Rt = 1.61 min, 100% (4 min Basic); m / z (ESI + ) 388.1 [M+H] + .

[0388] Example 52 N2-[(2-chloro-4-methyl-phenyl)methyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized by Method C using the same method as in Example 49, except that 1-(2-chloro-4-fluorophenyl)methanamine was replaced with 1-(2-chloro-4-methylphenyl)methanamine, to afford the desired compound (9.0 mg, 0.025 mmol, 30% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.59 - 13.01 (m,1H), 8.75 - 8.26 (m, 1H), 8.26 - 7.94 (m, 2H), 7.92 -7.70 (m, 2H), 7.48 - 7.23 (m, 2H), 7.23 - 7.03 (m,1H), 7.03 - 6.65 (m, 2H), 4.80 - 4.33 (m, 2H), 2.32 -2.03 (m, 3H). UPLC-MS Rt = 1.72 min, 100% (4 min Basic); m / z (ESI + ) 366.1 [M+H] + .

[0389] Example 53 N2-[(5-chloro-2-pyridyl)methyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized by Method C using the same method as in Example 49, except that 1-(2-chloro-4-fluorophenyl)methanamine was replaced with 1-(5-chloropyridin-2-yl)methanamine, to give the desired compound (20 mg, 35% yield) as an off-white solid. 1 H NMR (DMSO-d6) δ: 13.30 (s, 1H), 8.57 (d, J = 8.3 Hz, 1H), 8.50 (s, 1H), 8.41 (s, 1H), 8.15 - 8.02 (m, 2H), 8.02 - 7.90 (m, 1H), 7.88 (d, J =8.4 Hz, 1H), 7.78 (dd, J = 20.0, 8.3 Hz, 2H), 7.39 (t, J = 9.2 Hz, 2H), 6.90 (d, J = 20.8 Hz, 3H), 4.71 (d, J = 6.0 Hz, 1H), 4.62 (d, J = 6.1 Hz, 2H). UPLC-MS Rt = 1.36 min, 95% (4 min Basic); m / z (ESI +) 353.1 [M+H] + .

[0390] Example 54 6-(1H-indazol-6-yl)-N2-[2-(6-methyl-2-pyridyl)ethyl]-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized by Method C using the same method as in Example 49, except that 1-(2-chloro-4-fluorophenyl)methanamine was replaced with 2-(6-methylpyridin-2-yl)ethan-1-amine to give the desired compound (19 mg, 34% yield) as an off-white solid. 1 H NMR (DMSO-d6) δ: 13.28 (s, 1H), 8.49 (d, J = 19.1 Hz, 1H), 8.23 ​​- 7.91 (m, 2H), 7.80 (t, J = 8.1 Hz, 1H), 7.59 (t, J = 7.8 Hz, 2H), 7.38 (d, J= 5.7 Hz, 1H), 7.19 (s, 0H), 7.14 - 7.01 (m, 2H), 6.90 (s, 1H), 6.74 (s, 1H), 3.74 (d, J = 6.7 Hz, 1H), 3.66 - 3.58 (m, 1H), 3.29 (s, 1H), 2.99(dt, J = 14.6, 7.5 Hz, 2H), 2.45 (s, 3H). UPLC-MS Rt = 1.29 min, 95% (4 min Basic); m / z (ESI + ) 347.1 [M+H] + .

[0391] Example 55 6-(1H-indazol-6-yl)-N2-[2-[5-(trifluoromethyl)-2-pyridyl]ethyl]-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized by Method C using the same method as in Example 49, except that 1-(2-chloro-4-fluorophenyl)methanamine was replaced with 2-[5-(trifluoromethyl)pyridin-2-yl]ethan-1-amine dihydrochloride to give the desired compound (21 mg, 35% yield) as an off-white solid. 1 H NMR (DMSO-d6) δ: 13.28 (s, 1H), 8.90 (d, J = 2.3 Hz, 1H), 8.47 (m, 1H), 8.18 - 7.97 (m, 3H), 7.79 (t, J = 7.3 Hz, 1H), 7.55 (t, J= 8.6 Hz, 1H), 7.42 (m, 0.5H), 7.23 (s, 0.5H), 6.83 (m, 2H), 3.80 (d, J = 6.4 Hz, 1H), 3.70 (d, J = 6.7 Hz, 1H), 3.23 - 3.06 (m,2H). UPLC-MS Rt = 1.48 min, 100% (4 min Basic); m / z (ESI + ) 401.2 [M+H] + .

[0392] Example 56 6-(1H-indazol-6-yl)-N2-[(1-propylpyrazol-3-yl)methyl]-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized by Method C using the same method as in Example 49, except that 1-(2-chloro-4-fluorophenyl)methanamine was replaced with 1-(1-propyl-1H-pyrazol-3-yl)methanamine to give the desired compound (2.4 mg, 4.2% yield) as an off-white solid. 1H NMR (DMSO-d6) δ: 13.27 (d, 1H), 8.51 (d, 1H), 8.08 (d, 2H), 7.79 (d, 1H), 7.54 (d, 2H), 6.85 (d, 2H), 6.17 (s, 1H), 4.57 (d, J = UPLC-MS Rt = 1.32 min, 96% (4 min Basic); m / z (ESI + ) 350.2 [M+H] + .

[0393] Example 57 N2-[(5-ethyl-2-pyridyl)methyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized by Method C using the same method as in Example 49, except that 1-(2-chloro-4-fluorophenyl)methanamine was replaced with 1-(5-ethylpyridin-2-yl)methanamine to give the desired compound (21 mg, 0.061 mmol, 37% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.66 - 12.96 (m, 1H), 8.51 - 8.43 (m, 2H), 8.17 -7.98 (m, 2H), 7.93 - 7.68 (m, 2H), 7.68 - 7.52 (m, 1H), 7.35 - 7.20 (m, 1H), 7.01-6.78 (m, 2H), 4.86 -4.48 (m, 2H), 2.80 - 2.56 (m, 2H), 1.67 - 0.52 (m, 3H). UPLC-MS Rt = 1.39 min, 97% (4 min Basic); m / z (ESI + ) 347.1 [M+H] + .

[0394] Example 58 6-(1H-indazol-6-yl)-N2-[(6-methyl-2-pyridyl)methyl]-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized by Method C using the same method as in Example 49, except that 1-(2-chloro-4-fluorophenyl)methanamine was replaced with 1-(6-methylpyridin-2-yl)methanamine to give the desired compound (20 mg, 0.060 mmol, 36.9% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.55 - 12.88 (m, 1H), 8.82 - 8.35 (m, 1H), 8.26 - 7.94 (m, 2H), 7.94 -7.75 (m, 2H), 7.75 - 7.46 (m, 2H), 7.46 - 7.03 (m, 4H), 7.03 - 6.65 (m, 2H), 5.00 - 4.44 (m, 2H). UPLC-MS Rt = 1.26 min, 100% (4 min Basic); m / z (ESI + ) 333.1 [M+H] + .

[0395] Example 59 6-(1H-indazol-6-yl)-N2-[[1-(2,2,2-trifluoroethyl)pyrazol-3-yl]methyl]-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized by Method C using the same method as in Example 49, except that 1-(2-chloro-4-fluorophenyl)methanamine was replaced with 1-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]methanamine to give the desired compound (21 mg, 0.053 mmol, 33% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.75 - 12.86 (m,1H), 8.66 - 8.41 (m, 1H), 8.18 - 7.98 (m, 2H), 7.91 -7.77 (m, 1H), 7.77 - 7.54 (m, 2H), 7.18 - 6.66 (m,2H), 6.56 - 6.20 (m, 1H), 5.08 (q, 2H), 4.78 - 4.27 (m,2H). UPLC-MS Rt = 1.31 min, 98% (4 min Basic); m / z (ESI + ) 390.1 [M+H] + .

[0396] Example 60 N2-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] To a solution of 4-chloro-6-(1H-indazol-6-yl)-1,3,5-triazin-2-amine (Intermediate Z) (79 mg, 0.32 mmol) in NMP (0.94 mL) was added 2-[1-(difluoromethyl)-1H-pyrazol-3-yl]propan-2-amine (Intermediate L) (206 mg, 0.80 mmol), followed by N,N-diisopropylethylamine (0.17 mL, 0.96 mmol), and the reaction mixture was heated at 90° C. for 9 days. The reaction mixture was diluted with a 9:1 DMSO:water mixture (2 mL), and the crude material was purified by preparative HPLC. The product-containing fractions were collected and concentrated to dryness under reduced pressure to afford the title compound (11 mg, 9% yield) as an off-white solid. 1 H NMR (DMSO-d6) δ: 13.50-13.06 (m, 1H), 8.72-8.22 (m, 1H), 8.22-7.55 (m, 5H), 7.33 (s, 1H), 6.94-6.19 (m, 3H), 1.74 (s, 6H). UPLC-MS Rt = 1.42 min, 97% (4 min Basic); m / z (ESI+ ) 386.1 [M+H] + .

[0397] Example 61 6-(1H-indazol-6-yl)-N2-[(1-isopropylpyrazol-3-yl)methyl]-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized by Method C using the same method as in Example 49, except that 1-(2-chloro-4-fluorophenyl)methanamine was replaced with 1-[1-(propan-2-yl)-1H-pyrazol-3-yl]methanamine to give the desired compound (32.5 mg, 0.093 mmol, 46% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.56 - 13.12 (m,1H), 8.71 - 8.33 (m, 1H), 8.28 - 7.95 (m, 2H), 7.94 -7.45 (m, 3H), 7.09 - 6.73 (m, 2H), 6.18 (s, 1H), 4.95 -4.49 (m, 2H), 4.49 - 4.29 (m, 1H), 1.40 (d, J = 6.7 Hz,6H). UPLC-MS Rt = 1.31 min, 100% (4 min Basic); m / z (ESI + ) 350.1 [M+H] + .

[0398] Example 62 6-(1H-indazol-6-yl)-N2-(2-pyrazol-1-ylethyl)-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized by Method C using the same method as in Example 49, except that 1-(2-chloro-4-fluorophenyl)methanamine was replaced with 2-(1H-pyrazol-1-yl)ethan-1-amine to give the desired compound (29 mg, 0.091 mmol, 45% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 8.55 -8.45 (m, 1H), 8.15 - 8.00 (m, 2H), 7.86 - 7.77 (m,1H), 7.76 - 7.72 (m, 1H), 7.49 - 7.44 (m, 1H), 7.42 -7.12 (m, 1H), 7.08 - 6.71 (m, 2H), 6.27 - 6.22 (m,1H), 4.39 - 4.29 (m, 2H), 3.72 - 3.66 (m, 2H). UPLC-MS Rt = 1.11 min, 100% (4 min Basic); m / z (ESI + ) 322.1 [M+H] + .

[0399] Example 63 N2-[2-(2,3-dichlorophenyl)-1,1-dimethyl-ethyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] To a solution of 4-chloro-6-(1H-indazol-6-yl)-1,3,5-triazin-2-amine (Intermediate Z) (50 mg, 0.20 mmol) in NMP (0.60 mL) was added 1-(2,3-dichlorophenyl)-2-methylpropan-2-amine (Intermediate T) (147 mg, 0.51 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.61 mmol). The reaction mixture was heated at 90 °C for 3 h and then at 170 °C for 72 h. The reaction mixture was cooled to room temperature, diluted with 9:1 DMSO:HO (2 mL), and purified by preparative HPLC. The product-containing fractions were collected and concentrated to dryness under reduced pressure to give the title compound (12 mg, 14% yield) as a white solid. 1 H NMR (DMSO-d6) δ: 13.30 (s, 1H), 8.51 (s, 1H), 8.10 (d, J = 16.5 Hz, 2H), 7.82 (s, 1H), 7.48 (dd, J = 8.0, 1.5 Hz, 1H), 7.25 (t, J = 7.8 Hz,1H), 7.12 (d, J = 7.8 Hz, 1H), 7.03 - 6.55 (m, 2H), 3.57 (d, J = 25.3 Hz, 2H), 1.42 (d, J = 16.0 Hz, 6H). UPLC-MS Rt = 2.07 min, 100% (4 min Basic); m / z (ESI + ) 428.1, 430.1, 431.1 (2 x Cl isotopes), [M+H] + .

[0400] Example 64 6-(1H-indazol-6-yl)-N2-[(4-methylthiazol-2-yl)methyl]-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized by Method C using the same method as in Example 49, except that 1-(2-chloro-4-fluorophenyl)methanamine was replaced with 1-(4-methyl-1,3-thiazol-2-yl)methanamine to give the desired compound (40 mg, 0.12 mmol, 58% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.50 - 13.08 (m, 1H), 8.51 (s, 1H), 8.32 - 8.04 (m,3H), 8.04 - 7.69 (m, 1H), 7.31 - 6.66 (m, 3H), 5.00 - 4.51 (m, 2H), 2.35 (s, 3H). UPLC-MS Rt = 1.24 min, 98% (4 min Basic); m / z (ESI + ) 339.1 [M+H] + .

[0401] Example 65 6-(1H-indazol-6-yl)-N2-[2-(2-methylthiazol-4-yl)ethyl]-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized by Method C using the same method as in Example 49, except that 1-(2-chloro-4-fluorophenyl)methanamine was replaced with 2-(2-methyl-1,3-thiazol-4-yl)ethan-1-amine to give the desired compound (45 mg, 0.128 mmol, 63% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 8.78 -8.32 (m, 1H), 8.32 - 7.97 (m, 2H), 7.92 - 7.69 (m, 1H), 7.55 - 7.15 (m, 2H), 7.01 - 6.50 (m, 2H), 3.81 -3.49 (m, 2H), 3.09 - 2.88 (m, 2H), 2.73 - 2.59 (m, 3H). UPLC-MS Rt = 1.28 min, 100% (4 min Basic); m / z (ESI + ) 353.1 [M+H] + .

[0402] Example 66 N2-(2-Imidazo[2,1-b]thiazol-6-ylethyl)-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized by Method C using the same method as in Example 49, except that 1-(2-chloro-4-fluorophenyl)methanamine was replaced with 2-{imidazo[2,1-b][1,3]thiazol-6-yl}ethan-1-amine dihydrochloride to give the desired compound (41 mg, 0.11 mmol, 54% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.54 - 12.97 (m,1H), 8.77 - 8.33 (m, 1H), 8.20 - 8.01 (m, 2H), 7.93 -7.73 (m, 2H), 7.61 - 7.53 (m, 1H), 7.45 - 7.12 (m,2H), 7.07 - 6.64 (m, 2H), 3.83 - 3.51 (m, 2H), 3.05 -2.79 (m, 2H). UPLC-MS Rt = 1.08 min, 99% (4 min Basic); m / z (ESI + ) 378.1 [M+H] + .

[0403] Example 67 6-(1H-indazol-6-yl)-N2-[2-(4-methylthiazol-2-yl)ethyl]-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized by Method C using the same method as in Example 49, except that 1-(2-chloro-4-fluorophenyl)methanamine was replaced with 2-(4-methyl-1,3-thiazol-2-yl)ethan-1-amine to give the desired compound (40 mg, 0.114 mmol, 56% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 8.76 -8.33 (m, 1H), 8.21 - 7.96 (m, 2H), 7.90 - 7.67 (m, 1H), 7.52 - 7.21 (m, 1H), 7.21 - 7.04 (m, 1H), 6.95 (s, 1H), 6.80 (s, 1H), 3.91 - 3.55 (m, 2H), 3.31 - 3.13 (m, 2H), 2.34 (s, 3H). UPLC-MS Rt = 1.29 min, 97% (4 min Basic); m / z (ESI + ) 353.1 [M+H] + .

[0404] Example 68 N2-[[1-(difluoromethyl)pyrazol-3-yl]methyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized by Method C using the same method as in Example 49, except that 1-(2-chloro-4-fluorophenyl)methanamine was replaced with 1-[1-(difluoromethyl)-1H-pyrazol-3-yl]methanamine hydrochloride to give the desired compound (49 mg, 0.14 mmol, 61% yield) as an off-white solid.1 H NMR (400 MHz, DMSO-d6) δ 13.30 (s, 1H), 8.49 (s, 1H), 8.32 - 7.46 (m, 7H), 6.97 (s, 2H), 6.50 (s, 1H), 4.59 (d, J = 37.8 Hz, 2H). UPLC-MS Rt = 1.25 min, 99% (4 min Basic); m / z (ESI + ) 358.1 [M+H] + .

[0405] Example 69 6-(1H-indazol-6-yl)-N2-[2-(2-pyridyl)ethyl]-1,3,5-triazine-2,4-diamine [ka] Synthesized using general method B: Step 1: 6-chloro-N4-[2-(2-pyridyl)ethyl]-1,3,5-triazine-2,4-diamine To a stirred solution of 2-amino-4,6-dichlorotriazine (250 mg, 1.52 mmol) in 1,4-dioxane (9 mL) was added 2-(2-pyridyl)ethylamine (0.2 mL, 1.7 mmol), followed by N,N-diisopropylethylamine (0.66 mL, 3.79 mmol). The resulting mixture was stirred at room temperature for 12 h. The volatiles were removed under reduced pressure, and the crude material was purified by flash chromatography (silica gel, eluting with a 50-100% EtOAc gradient in petroleum ether) to afford the title compound (260 mg, 0.99 mmol, 65% yield) as a white powder. 1 H NMR (600 MHz, DMSO-d6) δ 8.46 (dt, J = 4.9, 1.4 Hz, 1H), 7.86 - 7.51 (m, 2H), 7.29 - 7.17 (m, 3H), 7.10 (d, J = 56.0 Hz, 1H), 3.58 - 3.51 (m, 2H), 2.95 - 2.88 (m, 2H). LCMS LCQ (Method 1) Rt = 0.48 min; m / z (ESI+ ) 251.08, 235.07(Cl isotopes) [M+H] + . Step 2: N4-[2-(2-pyridyl)ethyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine A stirred solution of 6-chloro-N4-[2-(2-pyridyl)ethyl]-1,3,5-triazine-2,4-diamine (100 mg, 0.40 mmol), potassium phosphate tripotassium (254 mg, 1.2 mmol), and bis[2-(di-tert-butylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloropalladium (26 mg, 0.04 mmol) in THF (5 mL) and water (0.5 mL) was degassed by bubbling N2 directly through the solution. After heating the mixture to 80 °C, a solution of 1-tetrahydropyran-2-yl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (Intermediate V) (327 mg, 1.0 mmol) in THF (4 mL) was added, and the mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated to dryness and the crude material was purified by flash column chromatography (silica gel, eluting with a gradient of 25-100% EtOAc in petroleum ether) to afford the title compound (120 mg, 0.27 mmol, 69% yield) as a white solid. LCMS MDAP (Method 6) Rt = 3.74 min; m / z (ESI + ) 417.10, [M+H] + . Step 3: 6-(1H-indazol-6-yl)-N2-[2-(2-pyridyl)ethyl]-1,3,5-triazine-2,4-diamine N2-[2-(2-pyridyl)ethyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (75 mg, 0.18 mmol) in methyl alcohol (1 mL) and 4 M HCl (1.35 mL, 5.4 mmol) in 1,4-dioxane were heated at 40° C. for 16 h. The resulting precipitate was filtered, washed with diethyl ether and petroleum ether, and dried in an oven at 50° C. for 2 h to give the title compound (50 mg, 0.15 mmol, 83% yield) as a white solid. 1 H NMR (399 MHz, DMSO-d6, VT 90℃) δ 8.67 (d, J = 5.6 Hz, 1H), 8.57 (s, 1H), 8.29 (t, J = 7.8 Hz, 1H), 8.16 (d, J = 1.0 Hz, 1H), 8.00 (d, J = LCMS LCQ Rt = 0.43 min (Method 1); m / z (ESI + ) 333.05 [M+H] + .

[0406] Example 70 N2-[(2,3-difluorophenyl)methyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] To a solution of 6-chloro-N4-[(2,3-difluorophenyl)methyl]-1,3,5-triazine-2,4-diamine (Example 30, Step 1) (650 mg, 2.4 mmol), (1H-indazol-6-yl)boronic acid (470 mg, 2.9 mmol), potassium carbonate (663 mg, 4.8 mmol) in 1,4-dioxane (8.0 mL), and water (2 mL) was added Pd(dppf)Cl2 (176 mg, 0.24 mmol), and the mixture was degassed for 5 minutes. The mixture was heated at 100 °C for 3 hours, then cooled to room temperature, filtered through a Celite pad, and washed with ethyl acetate (50 mL). The organic filtrate was washed successively with water (40 mL) and brine (40 mL), dried (Na2SO4), filtered, and concentrated to dryness under reduced pressure. The crude material was purified by flash column chromatography eluting with a gradient of 0-100% ethyl acetate in isohexane to afford the title compound (95 mg, 11% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.36 - 13.32 (m, 1H), 8.53 - 8.52 (m, 1H), 8.16 - 8.15 (m, 1H), 8.10 - 8.08 (m, 1H), 7.97 - 7.81 (m, 2H), 7.36 - 7.20 (m, 3H), 7.00 - 6.90 (br m, 2H), 4.75 - 4.65 (m , 2H). UPLC-MS Rt = 1.54 min, 98% (4 min Basic); m / z (ESI + ) 354.0 [M+H] + .

[0407] Example 71 N2-[1-(2,3-difluorophenyl)-1-methyl-ethyl]-6-(1H-indazol-6-yl)-N4-methyl-1,3,5-triazine-2,4-diamine [ka] Step 1: 4,6-Dichloro-N-[1-(2,3-difluorophenyl)-1-methyl-ethyl]-1,3,5-triazin-2-amine To a stirred solution of cyanuric chloride (300 mg, 1.63 mmol) in ethylene glycol dimethyl ether (10 mL) at −30° C. was added 2-(2,3-difluorophenyl)propan-2-amine (Intermediate N) (278 mg, 1.63 mmol) dropwise. The reaction mixture was stirred at −30° C. for 3 h and then at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with 1 N HCl (5 mL) and water (5 mL). The organic phase was dried (MgSO4) and concentrated to dryness under reduced pressure. The crude material was purified by flash column chromatography eluting with petroleum ether:ethyl acetate (6:4) to afford the title compound (248 mg, 0.7 mmol, 43% yield) as a clear gum. 1 H NMR (600 MHz, chloroform-d) δ 7.13 (ddt, J = 8.7, 7.1, 1.8 Hz, 1H), 7.10 - 7.03 (m, 2H), 6.30 (s, 1H), 1.84 (s, 6H). LCMS LCQ (method 3) Rt = 7.69 min; m / z (ESI + ) 318.84 [M+H] + . Step 2: 4-chloro-N-[1-(2,3-difluorophenyl)-1-methyl-ethyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazin-2-amine To a solution of 4,6-dichloro-N-[1-(2,3-difluorophenyl)-1-methyl-ethyl]-1,3,5-triazin-2-amine (240 mg, 0.75 mmol) in THF (6 mL) and water (1.2 mL) was added 1-tetrahydropyran-2-yl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (Intermediate V) (272 mg, 0.83 mmol) and potassium phosphate tribasic (400 mg, 1.88 mmol). The reaction mixture was degassed for 3 min with N2 gas bubbling, and bis[2-(di-tert-butylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloropalladium (24.5 mg, 0.04 mmol) was added and heated at 60 °C for 1 h. The reaction mixture was dry loaded onto silica and purified by flash column chromatography eluting with 1% methanol in DCM to afford the title compound (148 mg, 0.29 mmol, 39% yield) as a white solid. 1 H NMR (600 MHz, chloroform-d) δ 8.42 (s, 1H), 8.03 (s, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.28 (s, 1H), 7.06 (s, 1H), 6.15 (s, 1H), 5.78 (d, J = 9.4 Hz, 1H), 4.03 (d, J = 11.5 Hz, 1H), 3.81 (d, J = 10.6 Hz, 1H), 2.58 (d, J = 12.7 Hz, 1H), 2.22 - 2.14 (m, 1H), 2.06 (d, J = 13.4 Hz, 1H), 1.92 (d, J = 14.9 Hz, 6H), 1.79 (d, J = 11.5 Hz, 1H), 1.21 (s, 1H), 0.89 (dt, J = 18.1, 8.7 Hz, 1H); m / z (ESI + ) 485.05 [M+H] + . Step 3: N2-[1-(2,3-difluorophenyl)-1-methyl-ethyl]-6-(1H-indazol-6-yl)-N4-methyl-1,3,5-triazine-2,4-diamine 4-Chloro-N-[1-(2,3-difluorophenyl)-1-methyl-ethyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazin-2-amine (53 mg, 0.11 mmol) and methylamine (0.55 mL, 1.09 mmol) in tetrahydrofuran (0.5 mL) were stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was homogenized with petroleum ether. The pale yellow solid was treated with 4N HCl in 1,4-dioxane (0.5 mL) and stirred at 60° C. for 30 minutes. The resulting precipitate was filtered and washed with petroleum ether (3 mL). The solid obtained as the HCl salt of the desired product was treated with 5 mL of 35% aqueous ammonia, filtered, and washed with water. The crude material was purified by flash column chromatography eluting with a gradient of 40-50% ethyl acetate in petroleum ether to afford the title compound (16 mg, 0.04 mmol, 35% yield) as a white solid. 1H NMR (399 MHz, DMSO-d6, Vt 90℃) δ 8.31 (s, 1H), 8.01 (s, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.35 - 7.20 (m, 1H), 7.19 - 7.06 (m, 2H), 7.03 (s, 1H), 6.58 (s, 1H), 2.70 (s, 3H), 1.82 (s, 6H). LCMS MDAP Rt = 2.95 min (Method 6); m / z (ESI + ) 396.05 [M+H] + .

[0408] Example 72 6-Imidazo[1,5-a]pyridin-6-yl-N2-[1-methyl-1-(2-pyridyl)ethyl]-1,3,5-triazine-2,4-diamine [ka] N,N-Diisopropylethylamine (0.055 mL, 0.316 mmol) was added to a stirred solution of 2-(pyridin-2-yl)propan-2-amine (36 mg, 0.264 mmol) and 4-chloro-6-{imidazo[1,5-a]pyridin-6-yl}-1,3,5-triazin-2-amine (Intermediate C) (26 mg, 0.11 mmol) in 1-methylpyrrolidin-2-one (0.3 mL). The reaction mixture was heated at 90°C for 24 hours. The reaction mixture was diluted with DMSO:water (9:1) (2.0 mL) and purified by preparative HPLC. Pure fractions were collected, pooled, and evaporated to dryness to afford the title compound (19 mg, 0.055 mmol, 53% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.30 - 8.39 (m, 3H),7.99 - 6.99 (m, 7H), 6.73 (s, 2H), 1.73 (s, 6H). UPLC-MS Rt = 1.30 min, 98% (4 min Basic); + ) 347.2 [M+H] + .

[0409] Example 73 N2-[(2-chloro-3-fluoro-phenyl)methyl]-6-imidazo[1,5-a]pyridin-6-yl-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized using the same method as described in Example 72, except that 2-(pyridin-2-yl)propan-2-amine was replaced with 1-(2-chloro-3-fluorophenyl)methanamine to give the desired compound (17 mg 0.045 mmol, 43%) as a white solid. H NMR (400 MHz, DMSO-d) δ 9.16 (s, 1H), 8.61-8.48 (m, 1H), 8.02-7.74 (m, 1H), 7.71-7.16 (m, 6H), 7.09-6.81 (m, 2H), 5.13-4.37 (m, 2H). UPLC-MS Rt = 1.58 min, 98% (4 min Basic); m / z (ESI + ) 370.1 [M+H] + .

[0410] Example 74 N2-[[1-(difluoromethyl)pyrazol-3-yl]methyl]-6-imidazo[1,5-a]pyridin-6-yl-1,3,5-triazine-2,4-diaminediamine [ka] The title compound was synthesized using the same method as described in Example 72, except that 2-(pyridin-2-yl)propan-2-amine was replaced with 1-[1-(difluoromethyl)-1H-pyrazol-3-yl]methanamine, to afford the desired compound (24 mg 0.066 mmol, 63% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.38 - 8.88 (m, 1H), 8.77 - 8.43 (m, 1H), 8.13 (s, 1H), 7.99 - 7.41 (m, 4H), 7.39 (s, 1H), 7.10 - 6.74 (m, 2H), 6.56 - 6.24 (m, 1H), 4.76 - 4.15 (m, 2H). UPLC-MS Rt = 1.20 min, 99% (4 min Basic); m / z (ESI + ) 358.1 [M+H]+ .

[0411] Example 75 6-Imidazo[1,5-a]pyridin-6-yl-N2-[(1-propylpyrazol-3-yl)methyl]-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized using the same method as described in Example 72, except that 2-(pyridin-2-yl)propan-2-amine was replaced with 1-(1-propyl-1H-pyrazol-3-yl)methanamine to give the desired compound (24 mg 0.068 mmol, 64% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 0.5H), 9.13 s(0.5H), 8.58 (s, 1H), 7.68 - 7.44 (m, 4H), 7.39 (s, 1H),7.10 - 6.67 (m, 2H), 6.16 (s, 1H), 4.52 (dd, J = 42.1,5.6 Hz, 2H), 4.00 (t, J = 7.0 Hz, 2H), 1.76 (h, J = 7.3 Hz,2H), 0.83 (t, J = 6.4 Hz, 3H). UPLC-MS Rt = 1.28 min, 100% (4 min Basic); m / z (ESI + ) 350.1 [M+H] + .

[0412] Example 76 6-Imidazo[1,5-a]pyridin-6-yl-N2-[[1-(2,2,2-trifluoroethyl)pyrazol-3-yl]methyl]-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized using the same method as described in Example 72, except that 2-(pyridin-2-yl)propan-2-amine was replaced with 1-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]methanamine, to give the desired compound (19 mg, 0.050 mmol, 47% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.37 - 8.99 (m, 1H), 8.58 (s, 1H), 7.89 - 7.47 (m, 4H), 7.39 (s, 1H), 7.12 -6.70 (m, 2H), 6.31 (s, 1H), 5.07 (q, J = 9.2 Hz, 2H),4.69 - 4.31 (m, 2H). UPLC-MS Rt = 1.26 min, 100% (4 min Basic); m / z (ESI + ) 390.1 [M+H] + .

[0413] Example 77 6-Imidazo[1,5-a]pyridin-6-yl-N2-[(1-isopropylpyrazol-3-yl)methyl]-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized using the same method as described in Example 72, except that 2-(pyridin-2-yl)propan-2-amine was replaced with 1-[1-(propan-2-yl)-1H-pyrazol-3-yl]methanamine to give the desired compound (25 mg 0.070 mmol, 65% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.36 - 8.97 (m, 1H), 8.58 (s, 1H), 7.73 - 7.44 (m, 4H), 7.39 (s, 1H), 7.03 -6.68 (m, 2H), 6.16 (s, 1H), 4.68 - 4.30 (m, 3H), 1.40 (d, J = 6.7 Hz, 6H). UPLC-MS Rt = 1.27 min, 100% (4 min Basic); m / z (ESI + ) 350.1 [M+H] + .

[0414] Example 78 6-Imidazo[1,5-a]pyridin-6-yl-N2-(2-pyrazol-1-ylethyl)-1,3,5-triazine-2,4-diamine [ka] The title compound was synthesized using the same method as described in Example 72, except that 2-(pyridin-2-yl)propan-2-amine was replaced with 2-(1H-pyrazol-1-yl)ethan-1-amine to give the desired compound (37 mg, 70.2% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.41 - 8.98 (m, 1H), 8.58 (s, 1H), 7.83 - 7.65 (m, 1H), 7.65 - 7.52 (m, 2H),7.52 - 7.10 (m, 3H), 7.07 - 6.62 (m, 2H), 6.41 - 6.00(m, 1H), 4.53 - 4.24 (m, 2H), 3.87 - 3.57 (m, 2H). UPLC-MS Rt = 1.07 min, 98% (4 min Basic); m / z (ESI + ) 322.1 [M+H] + .

[0415] Example 79 N2-[(2,3-difluorophenyl)methyl]-6-(1H-indazol-6-yl)-N4-methyl-1,3,5-triazine-2,4-diamine [ka] Step 1: 4,6-Dichloro-N-[(2,3-difluorophenyl)methyl]-1,3,5-triazin-2-amine To a stirred solution of cyanuric chloride (2.0 g, 10.85 mmol) in ethylene glycol dimethyl ether (40 mL) at −30° C. was added 2,3-difluorobenzylamine (1.27 mL, 10.85 mmol) dropwise. The reaction mixture was then stirred at −30° C. for 3 h, followed by further stirring at room temperature for 30 min, at which point 1N HCl (5 mL) was added. The reaction mixture was partitioned between ethyl acetate (20 mL) and water (10 mL). The organic phase was dried (MgSO4) and evaporated to dryness under reduced pressure. The crude material was purified by flash column chromatography eluting with a gradient of 5–10% ethyl acetate in petroleum ether to afford the title compound (1.56 g, 5.09 mmol, 47% yield) as a pale yellow solid. 1 LCMS MDAP Rt = 3.04 min (Method 6); m / z (ESI + ) 292.85 [M+H] + . Step 2: 4-chloro-N-[(2,3-difluorophenyl)methyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazin-2-amine The title compound was synthesized using the same method as described in Example 71, Step 2, except that 4,6-dichloro-N-[1-(2,3-difluorophenyl)-1-methyl-ethyl]-1,3,5-triazin-2-amine was replaced with 4,6-dichloro-N-[(2,3-difluorophenyl)methyl]-1,3,5-triazin-2-amine to afford the desired compound (220 mg, 0.46 mmol, 37% yield) as a white solid. 1 H NMR (600 MHz, chloroform-d) δ 8.70 (s, 0.5H), 8.64 (s, 0.5H), 8.25 - 8.21 (m, 0.5H), 8.19 - 8.16 (m, 0.5H), 8.07 (d, J = 6.4 Hz, 1H), 7.77 (dd, J = 10.8, 8.5 Hz, 1H), 7.22 - 7.16 (m, 1H), 7.16 - 7.00 (m, 2H), 6.33 - 6.27 (m, 0.5H), 6.10 - 6.06 (m, 0.5H), 5.88 - 5.83 (m, 1H), 4.93 - 4.85 (m, 1H), 4.80 (d, J = 6.2 Hz, 1H), 4.08 - 4.02 (m, 1H), 3.86 - 3.78 (m, 1H), 2.66 - 2.57 (m, 1H), 2.21 - 2.14 (m, 1H), 2.12 - 2.04 (m, 1H), 1.88 - 1.72 (m, 2H), 1.70 - 1.64 (m, 1H). LCMS MDAP Rt = 3.48 min (Method 6); m / z (ESI + ) 457.0 [M+H] + . Step 3: N2-[(2,3-difluorophenyl)methyl]-6-(1H-indazol-6-yl)-N4-methyl-1,3,5-triazine-2,4-diamine The title compound was synthesized using the same method as described in Example 71, Step 3, except that 4-chloro-N-[1-(2,3-difluorophenyl)-1-methyl-ethyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazin-2-amine was replaced with 4-chloro-N-[(2,3-difluorophenyl)methyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazin-2-amine to obtain the desired compound (19 mg, 0.05 mmol, 45% yield). 1 H NMR (399 MHz, DMSO-d6, Vt 120℃) δ 8.49 (s, 1H), 8.26 - 7.94 (m, 2H), 7.73 (d, J = 8.5 Hz, 1H), 7.35 (s, 1H), 7.30 - 7.08 (m, 3H), 6.76 (s, 1H), 4.68 (d, J = 5.5 Hz, 2H). LCMS MDAP Rt = 16.93 min (Method 4); m / z (ESI + ) 367.95 [M+H] + .

[0416] Example 80 4-[(2,3-difluorophenyl)methoxy]-6-(1H-indazol-6-yl)-1,3,5-triazin-2-amine [ka] A solution of 4-chloro-6-(1H-indazol-6-yl)-1,3,5-triazin-2-amine (Intermediate Z) (23 mg, 0.09 mmol) in dry THF (2 mL) at 0 °C was treated with 2,3-difluorobenzyl alcohol (0.01 mL, 0.09 mmol) followed by potassium tert-butoxide (41 mg, 0.37 mmol). The yellow suspension was stirred at 0 °C for 1 h, then warmed to room temperature and stirred for 16 h. The reaction mixture was quenched with water (10 mL), and the product was extracted with ethyl acetate (2 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO), filtered, and concentrated under reduced pressure to give a brown oil. The crude material was purified by reverse-phase preparative MDAP LCMS eluting with 30-95% acetonitrile in water with a formic acid (0.1%) modifier gradient over 32 min. Relevant fractions were collected and concentrated to dryness under reduced pressure. The material was further dissolved in EtOAc (15 mL), washed with saturated aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried over MgSO4, filtered under reduced pressure, and concentrated to dryness under reduced pressure to afford the title compound (4.6 mg, 0.01 mmol, 13% yield) as an off-white solid. 1 H NMR (600 MHz, DMSO-d6) δ 13.35 (s, 1H), 8.51 (s, 1H), 8.13 (s, 1H), 8.06 (d, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 7.46 - 7.38 (m, 1H), 7.27 - 7.19 (m, 2H), 5.52 (s, 1H), 5.44 (s, 1H). LCMS MDAP Rt = 19.14 min (Method 4); + ) 354.85 [M+H] + .

[0417] Example 81 N2-[1-[1-(difluoromethyl)pyrazol-3-yl]cyclobutyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Synthesized using general method B: Step 1: 6-chloro-N4-[1-[1-(difluoromethyl)pyrazol-3-yl]cyclobutyl]-1,3,5-triazine-2,4-diamine N,N-Diisopropylethylamine (0.42 mL, 2.39 mmol) was added to a suspension of [1-[1-(difluoromethyl)pyrazol-3-yl]cyclobutyl]ammonium chloride (Intermediate AA) (214 mg, 0.96 mmol) and 2-amino-4,6-dichlorotriazine (237 mg, 1.44 mmol) in 1,4-dioxane (5 mL) and stirred at room temperature for 72 h. The reaction mixture was partitioned between EtOAc and water, and the organic phase was separated, washed with brine, dried (MgSO), and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, eluting with a gradient of 0-100% EtOAc in petroleum ether) to give a colorless oil that solidified upon standing as a pale yellow solid (90 mg, 0.26 mmol, 27% yield). The product was used in the next step without characterization.

[0418] Step 2: N4-[1-[1-(difluoromethyl)pyrazol-3-yl]cyclobutyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine 6-Chloro-N4-[1-[1-(difluoromethyl)pyrazol-3-yl]cyclobutyl]-1,3,5-triazine-2,4-diamine (45 mg, 0.14 mmol), 1-tetrahydropyran-2-yl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (Intermediate V) (70 mg, 0.21 mmol), and potassium phosphate tribasic (60 mg, 0.29 mmol) were dissolved in tetrahydrofuran (1 mL) and water (0.25 mL). Bis[2-(di-tert-butylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloropalladium (1.86 mg, 0.003 mmol) were added, and the reaction mixture was stirred at 85 °C overnight. The reaction mixture was passed through a pad of Celite, and the filtrate was partitioned between EtOAc and water. The organic phase was separated, dried (MgSO4), and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, eluting with a gradient of 0-100% EtOAc in petroleum ether) to give the title compound as a pale yellow oil (60 mg, 0.12 mmol, 83% yield). The product was used in the next step without characterization.

[0419] Step 3: N2-[1-[1-(difluoromethyl)pyrazol-3-yl]cyclobutyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine A solution of N2-[1-[1-(difluoromethyl)pyrazol-3-yl]cyclobutyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (60 mg, 0.12 mmol) in 1,4-dioxane (1.25 mL, 4.98 mmol) and 4 M HCl in MeOH (0.25 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was homogenized with EtOAc and petroleum ether, filtered, and collected to give the desired compound (43 mg, 0.090 mmol, 74% yield) as a pale yellow solid. 1 H NMR (399 MHz, DMSO-d 6,Vt 90℃) δ 8.42 (s, 1H), 8.09 (s, 1H), 8.00 - 7.86 (m, 2H), 7.82 - 7.50 (m, 3H), 6.49 (s, 1H), 2.74 - 2.59 (m, 4H), 2.05 - 1.93 (m, 2H). LCMS MDAP Rt = 15.92 min; >85% (Method 4); m / z (ESI + ) 398.05 [M+H] + .

[0420] Example 82 N4-[1-[1-(difluoromethyl)pyrazol-3-yl]cyclobutyl]-6-(1-methylindazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Synthesized by general method D: 6-Chloro-N4-[1-[1-(difluoromethyl)pyrazol-3-yl]cyclobutyl]-1,3,5-triazine-2,4-diamine (Example 81, Step 1) (45 mg, 0.14 mmol), 1-methyl-1H-indazole-6-boronic acid (38 mg, 0.21 mmol), and tripotassium phosphate (60 mg, 0.29 mmol) were dissolved in tetrahydrofuran (1 mL) and water (0.25 mL). Bis[2-(di-tert-butylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloropalladium (1.86 mg, 0.003 mmol) were added, and the reaction mixture was stirred at 85 °C overnight. The reaction mixture was passed through a Celite pad, and the filtrate was partitioned between EtOAc and water. The organic phase was separated, dried (MgSO4), and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, eluting with a gradient of 0-100% EtOAc in petroleum ether) to give the title compound as a pale yellow oil, which solidified upon standing as a pale yellow solid (42 mg, 0.10 mmol, 68% yield). 1H NMR (399 MHz, DMSO-d6, Vt 90 °C) δ 8.38 (s, 1H), 8.05 - 7.91 (m, 3H), 7.83 - 7.50 (m, 3H), 6.49 - 6.38 (m, 3H), 4.07 (s, 3H), 2.72 - 2.58 (m, 4H), 1.99 (s, 2H). LCMS MDAP Rt = 17.24 min; >95% (Method 4); m / z (ESI + ) 412.15 [M+H] + .

[0421] Example 83 6-(1H-indazol-6-yl)-N2-[1-methyl-1-[1-(2-pyrrolidin-1-ylethyl)pyrazol-3-yl]ethyl]-1,3,5-triazine-2,4-diamine hydrochloride [ka] Step 1: 2-[3-[1-[[4-amino-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazin-2-yl]amino]-1-methyl-ethyl]pyrazol-1-yl]ethanol A solution of 4-chloro-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazin-2-amine (Intermediate X) (125 mg, 0.38 mmol), N,N-diisopropylethylamine (0.2 mL, 1.13 mmol), and 2-[3-(1-amino-1-methyl-ethyl)pyrazol-1-yl]ethanol (Intermediate BG) (128 mg, 0.76 mmol) in 1,4-dioxane (23 mL) was conventionally heated at 90 °C for 5 days in a sealed microwave vial. The reaction mixture was concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, eluting with a 0-10% MeOH gradient in DCM) to afford the title compound (83 mg, 0.17 mmol, 45% yield) as a white solid. LCMS LCQ Rt = 4.67 min (Method 3); m / z (ESI + ) 464.04 [M+H] + . Step 2: N4-[1-[1-(2-chloroethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine 2-[3-[1-[[4-amino-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazin-2-yl]amino]-1-methyl-ethyl]pyrazol-1-yl]ethanol (80 mg, 0.17 mmol) in tetrahydrofuran (6 mL) and dichloromethane (6 mL) was added to thionyl chloride (0.13 mL, 1.73 mmol) at room temperature. The reaction mixture was refluxed for 15 hours and then concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, eluting with a gradient of 0-10% methanol in DCM) to afford the title compound (32 mg, 0.060 mmol, 35% yield) as an off-white solid. LCMS LCQ Rt = 5.83 min (Method 3); m / z (ESI+) 482.16 / 484.15 [M+H] + . Step 3: N4-[1-methyl-1-[1-(2-pyrrolidin-1-ylethyl)pyrazol-3-yl]ethyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine A mixture of N4-[1-[1-(2-chloroethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (30 mg, 0.060 mmol), pyrrolidine (0.13 mL, 1.56 mmol), and K2CO3 (21.5 mg, 0.16 mmol) in N,N-dimethylformamide (2.1 mL) was heated at 85 °C for 2 h in a sealed vial. The reaction mixture was concentrated to dryness under reduced pressure. The crude material was purified by flash chromatography (silica gel, eluting with a gradient of 0-30% methanol in DCM) to afford the title compound (28 mg, 0.05 mmol, 78% yield) as an off-white solid. LCMS LCQ Rt = 0.88 min (Method 3); m / z (ESI+) 517.19 [M+H] + . Step 4: 6-(1H-indazol-6-yl)-N2-[1-methyl-1-[1-(2-pyrrolidin-1-ylethyl)pyrazol-3-yl]ethyl]-1,3,5-triazine-2,4-diamine hydrochloride A solution of N2-[1-methyl-1-[1-(2-pyrrolidin-1-ylethyl)pyrazol-3-yl]ethyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (26 mg, 0.05 mmol) in 1,4-dioxane (2.5 mL) and methanol (2.5 mL) was added to 4 M HCl in 1,4-dioxane (0.19 mL, 0.75 mmol) at room temperature. The reaction mixture was heated in a sealed vial at 60 °C for 10 h and concentrated to dryness under reduced pressure. The crude material was purified by flash chromatography (silica gel, eluting with a gradient of 0-20% methanol in DCM) to afford the title compound (16 mg, 0.030 mmol, 64% yield) as a white solid. 1H NMR (399 MHz, DMSO-d6, Vt 90℃) δ 12.75 (s, 1H), 8.03 (s, 1H), 7.65 (s, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.24 LCMS LCQ Rt = 0.78 min; >95% (Method 3); m / z (ESI + ) 433.04 [M+H] + .

[0422] Example 84 N4-[1-[4-chloro-1-(difluoromethyl)pyrazol-3-yl]cyclopropyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Synthesized using general method B: Step 1: 6-chloro-N4-[1-[4-chloro-1-(difluoromethyl)pyrazol-3-yl]cyclopropyl]-1,3,5-triazine-2,4-diamine N,N-Diisopropylethylamine (0.13 mL, 0.74 mmol) was added to a solution of 1-[4-chloro-1-(difluoromethyl)pyrazol-3-yl]cyclopropanamine hydrochloride (Intermediate AB) (60 mg, 0.25 mmol) and 2-amino-4,6-dichlorotriazine (81 mg, 0.49 mmol) in 1,4-dioxane (2.5 mL), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between water and EtOAc, and the organic phase was separated, dried (MgSO), and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, eluting with a 0-60% EtOAc gradient in petroleum ether) to afford the title compound (65 mg, 0.18 mmol, 75% yield) as a white solid. 1H NMR (600 MHz, chloroform-d) δ 7.71 (s, 1H), 7.01 (t, J = 60.4 Hz, 1H), 6.06 (s, 1H), 5.33 (s, 2H), 1.53 - 1.47 (m, 2H), 1.27 - 1.24 (m, 2H). LCMS MDAP Rt = 18.41 min (Method 4); m / z (ESI+) 335.90 / 337.85 [M+H] + . Step 2: N4-[1-[4-chloro-1-(difluoromethyl)pyrazol-3-yl]cyclopropyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine Bis[2-(di-tert-butylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloropalladium (6.3 mg, 0.010 mmol) was added to a suspension of 1-tetrahydropyran-2-yl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (Intermediate V) (95.2 mg, 0.29 mmol), 6-chloro-N4-[1-[4-chloro-1-(difluoromethyl)pyrazol-3-yl]cyclopropyl]-1,3,5-triazine-2,4-diamine (65 mg, 0.19 mmol), and tripotassium phosphate (82 mg, 0.39 mmol) in tetrahydrofuran (2 mL) and water (0.50 mL). The reaction mixture was degassed under vacuum, purged with nitrogen, and then heated at 80 °C for 16 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The organic phase was dried (MgSO) and concentrated to dryness under reduced pressure. The residue was purified on flash silica gel (eluting with a gradient of 0-60% EtOAc in petroleum ether) to afford the title compound (94 mg, 0.18 mmol, 92% yield) as a colorless oil. 1H NMR (600 MHz, chloroform-d) δ 8.63 (d, J = 105.5 Hz, 1H), 8.13 (s, 1H), 8.04 (s, 1H), 7.78 - 7.64 (m, 1H), 7.04 (t, J = 60.6 Hz, 1H), 6.13 - 5.86 (m, 1H), 5.86 - 5.79 (m, 1H), 5.32 - 4.98 (m, 2H), 4.08 - 4.00 (m, 1H), 3.82 - 3.77 (m, 1H), 2.65 - 2.57 (m, 1H), 2.21 - 2.14 (m, 1H), 2.13 - 2.03 (m, 1H), 1.86 - 1.73 (m, 2H), 1.60 - 1.52 (m, 4H), 1.37 - 1.30 (m, 2H). LCMS MDAP Rt = 20.64 min (Method 4); m / z (ESI+) 502.15 [M+H] + . Step 3: N4-[1-[4-chloro-1-(difluoromethyl)pyrazol-3-yl]cyclopropyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine A solution of N4-[1-[4-chloro-1-(difluoromethyl)pyrazol-3-yl]cyclopropyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (94 mg, 0.19 mmol) in 1,4-dioxane (2.0 mL, 8.0 mmol) in methanol (0.50 mL) and 4 M HCl was stirred at room temperature for 72 h. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3, and the organic phase was separated, dried (MgSO4), and concentrated under reduced pressure. The residue was homogenized with EtOAc:petroleum ether (1:9), filtered, and collected to give the title compound (39 mg, 0.090 mmol, 47% yield) as a white solid. 1H NMR (399 MHz, DMSO-d6, Vt 90℃) δ 13.02 (s, 1H), 8.49 (s, 1H), 8.25 (s, 1H), 8.07 (s, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.77 - 7.46 (m, 3H), 6.46 (s, 2H), 1.51 - 1.45 (m, 2H), 1.33 - 1.27 (m, 2H). LCMS MDAP Rt = 16.76 min; >95% (Method 4); m / z (ESI + ) 418.05 [M+H] + .

[0423] Example 85 N2-[(2-fluoro-3-methoxy-phenyl)methyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Synthesized using general synthesis method A: Step 1: N4-[(2-fluoro-3-methoxy-phenyl)methyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine A mixture of 4-chloro-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazin-2-amine (Intermediate X) (50 mg, 0.15 mmol), 2-fluoro-3-methoxybenzylamine (39 mg, 0.25 mmol), and N,N-diisopropylethylamine (0.11 mL, 0.60 mmol) in 1,4-dioxane (7.5 mL) was heated at 80 °C for 18 h. The reaction mixture was concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, eluting with a 0-60% EtOAc gradient in petroleum ether) to afford the title compound (70 mg, 0.15 mmol, 98% yield) as a clear glass. LCMS LCQ Rt = 6.23 min (Method 3); m / z (ESI+) 450.19 [M+H] + . Step 2: N2-[(2-fluoro-3-methoxy-phenyl)methyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine N2-[(2-fluoro-3-methoxyphenyl)methyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (6 mg, 0.15 mmol) in 1,4-dioxane (3.0 mL) was added with 4 M HCl in 1,4-dioxane (0.57 mL, 2.27 mmol) at room temperature. The reaction mixture was conventionally heated in a sealed microwave vial at 60 °C for 11 h and then concentrated to dryness under reduced pressure. The crude material was purified by flash chromatography (silica gel, eluting with a gradient of 0-5% methanol in DCM) to afford the title compound (33 mg, 0.090 mmol, 58% yield) as a white solid. 1H NMR (399 MHz, DMSO-d6, Vt 90℃) δ 8.48 (s, 1H), 8.05 (s, 1H), 8.03 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.36 (s, 1H), 7.11 - 6.91 (m, 3H), 6.51 (s, 2H), 4.63 (d, J = 6.1 Hz, 2H), 3.82 (s, 3H). LCMS MDAP Rt = 15.83 min; >97% (Method 4); m / z (ESI + ) 366.05 [M+H] + .

[0424] Example 86 N2-[1-(1H-imidazol-4-yl)cyclopropyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine; 2,2,2-trifluoroacetate [ka] Synthesized using general method A: Step 1: 6-(1-tetrahydropyran-2-ylindazol-6-yl)-N4-[1-[1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]cyclopropyl]-1,3,5-triazine-2,4-diamine A mixture of 1-[1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]cyclopropanamine (Intermediate AC) (115 mg, 0.45 mmol) and 4-chloro-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazin-2-amine (Intermediate X) (50 mg, 0.15 mmol) in 1,4-dioxane (5 mL) was heated at 90 °C for 72 h. The reaction mixture was concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, eluting with a gradient of 0-20% methanol in EtOAc) to afford the title compound (85 mg, 0.15 mmol, 98% yield) as a pale brown solid. LCMS LCQ Rt = 5.31 min (Method 3); m / z (ESI+) 548.29 [M+H] + . Step 2: N2-[1-(1H-imidazol-4-yl)cyclopropyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine; 2,2,2-trifluoroacetate To a solution of 6-(1-tetrahydropyran-2-ylindazol-6-yl)-N2-[1-[1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]cyclopropyl]-1,3,5-triazine-2,4-diamine (83 mg, 0.15 mmol) in DCM (5.0 mL) was added trifluoroacetic acid (0.58 mL, 7.58 mmol). The reaction mixture was stirred at room temperature for 20 hours and then concentrated to dryness under reduced pressure. The crude material was purified by flash chromatography (silica gel, eluting with a gradient of 0-15% methanol in DCM) to afford the title compound (28 mg, 0.060 mmol, 39% yield) as an off-white solid. 1H NMR (399 MHz, DMSO-d6, Vt 90℃) δ 13.03 (s, 1H), 8.47 (s, 1H), 8.03 (d, J = 9.7 Hz, 2H), 7.73 (d, J = 8.6 Hz, 1H), 7.46 (s, 1H), 7.36 (s, 1H), 6.73 (s, 1H), 6.46 (s, 2H), 1.24 (s, 2H), 1.15 (s, 2H). LCMS MDAP Rt = 10.47 min; >95% (Method 4); m / z (ESI + ) 334.05 [M+H] + .

[0425] Example 87 N2-[(2,3-difluoro-4-methoxy-phenyl)methyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Synthesized using general synthesis method A: Step 1: N4-[(2,3-difluoro-4-methoxy-phenyl)methyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine 4-Chloro-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazin-2-amine (Intermediate X) (50 mg, 0.15 mmol), 2,3-difluoro-4-methoxybenzylamine (43 mg, 0.25 mmol), and N,N-diisopropylethylamine (0.21 mL, 1.21 mmol) in 1,4-dioxane (7.5 mL) were heated at 80 °C for 24 h and then at 90 °C for 96 days. The reaction mixture was concentrated to dryness under reduced pressure. The crude material was purified by flash chromatography (silica gel, eluting with a 0-80% EtOAc gradient in petroleum ether) to afford the title compound (62 mg, 0.13 mmol, 83% yield) as a pale brown solid.

[0426] Step 2: N2-[(2,3-difluoro-4-methoxy-phenyl)methyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine To a solution of N2-[(2,3-difluoro-4-methoxyphenyl)methyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (60 mg, 0.13 mmol) in 1,4-dioxane (2.5 mL) and methanol (2.5 mL) was added 4 M HCl in 1,4-dioxane (0.48 mL, 1.93 mmol) at room temperature. The reaction mixture was heated at 60 °C for 11 h and then concentrated to dryness under reduced pressure. The crude material was purified by flash chromatography (silica gel, eluting with a gradient of 0-10% methanol in DCM) to afford the title compound (33 mg, 0.080 mmol, 64% yield) as an off-white solid. 1 H NMR (399 MHz, DMSO-d 6,Vt 90℃) δ 8.48 (s, 1H), 8.11 - 7.97 (m, 2H), 7.75 (d, J = 8.6 Hz, 1H), 7.39 (s, 1H), 7.17 (t, J = 8.1 Hz, 1H), 6.93 (t, J = 8.0 Hz, 1H), 6.52 (s, 2H), 4.59 (d, J = 6.0 Hz, 2H), 3.83 (s, 3H). LCMS MDAP Rt = 16.73 min; >95% (Method 4); m / z (ESI + ) 384.10 [M+H] + .

[0427] Example 88 N2-[(2,3-difluoro-4-methyl-phenyl)methyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Synthesized using general synthesis method A: Step 1: N4-[(2,3-difluoro-4-methyl-phenyl)methyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine A mixture of 4-chloro-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazin-2-amine (Intermediate X) (50 mg, 0.15 mmol), 2,3-difluoro-4-methylbenzylamine (39 mg, 0.25 mmol), and N,N-diisopropylethylamine (0.21 mL, 1.21 mmol) in 1,4-dioxane (7.5 mL) was heated at 80 °C for 23 h. The reaction mixture was concentrated to dryness under reduced pressure. The crude material was purified by flash chromatography (eluting with a 0-50% EtOAc in petroleum ether gradient) to afford the title compound (71 mg, 0.14 mmol, 94% yield) as a white gum. LCMS MDAP Rt = 21.48 min (Method 4); m / z (ESI+) 452.25 [M+H]+. Step 2: N2-[(2,3-difluoro-4-methyl-phenyl)methyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine To a solution of N2-[(2,3-difluoro-4-methyl-phenyl)methyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (67 mg, 0.15 mmol) in 1,4-dioxane (2.9 mL) and methanol (2.9 mL) was added 4 M HCl in 1,4-dioxane (0.56 mL, 2.23 mmol) at room temperature. The mixture was heated in a vial at 60 °C for 11 h and then concentrated to dryness under reduced pressure. The crude material was purified by flash chromatography (silica gel, eluting with a gradient of 0-10% methanol in DCM) to afford the title compound (34 mg, 0.090 mmol, 59% yield) as a white solid. 1H NMR (399 MHz, DMSO-d6, Vt 90℃) δ 8.48 (s, 1H), 8.14 - 7.96 (m, 2H), 7.75 (d, J = 8.5 Hz, 1H), 7.42 (s, 1H), 7.12 (t, J = 7.3 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 6.53 (s, 2H), 4.62 (d, J = 6.1 Hz, 2H), 2.23 (d, J = 2.2 Hz, 3H). LCMS MDAP Rt = 17.72 min; >95% (Method 4); m / z (ESI + ) 368.05 [M+H] + .

[0428] Example 89 N2-(6-fluoro-2,3-dihydrobenzofuran-3-yl)-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Synthesized using general synthesis method A: Step 1: N4-(6-fluoro-2,3-dihydrobenzofuran-3-yl)-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine A mixture of 4-chloro-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazin-2-amine (Intermediate X) (50 mg, 0.15 mmol), 6-fluoro-2,3-dihydro-1-benzofuran-3-amine hydrochloride (47 mg, 0.25 mmol), and N,N-diisopropylethylamine (0.21 mL, 1.21 mmol) in 1,4-dioxane (7.5 mL) was heated at 80° C. for 48 h. The reaction mixture was concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, eluting with a 0-50% EtOAc gradient in petroleum ether) to afford the title compound (60 mg, 0.13 mmol, 84% yield) as a white solid. LCMS MDAP Rt = 20.94 min (Method 4); m / z (ESI + ) 448.10 [M+H] + . Step 2: N2-(6-fluoro-2,3-dihydrobenzofuran-3-yl)-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine To a solution of N2-(6-fluoro-2,3-dihydrobenzofuran-3-yl)-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (56 mg, 0.12 mmol) in 1,4-dioxane (2.5 mL) and MeOH (2.5 mL) was added 4 M HCl in 1,4-dioxane (0.47 mL, 1.87 mmol) at room temperature. The reaction mixture was heated in a sealed vial at 60 °C for 11 h and then concentrated to dryness under reduced pressure. The crude material was purified by flash chromatography (silica gel, eluting with a gradient of 0-5% methanol in DCM) to afford the title compound (26 mg, 0.070 mmol, 55% yield) as a white solid. 1H NMR (399 MHz, DMSO-d6, Vt 90℃) δ 8.51 (s, 1H), 8.17 - 7.97 (m, 2H), 7.76 (d, J = 8.5 Hz, 1H), 7.51 (s, 1H), 7.39 (t, J = 6.5 Hz, 1H), 6.74 - 6.48 (m, 4H), 5.82 (s, 1H), 4.83 (t, J = 9.2 Hz, 1H), 4.50 (dd, J = 9.6, 5.4 Hz, 1H). LCMS MDAP Rt = 17.20 min; >95% (Method 4); m / z (ESI + ) 364.00 [M+H] + .

[0429] Example 90 N2-(4,6-difluoro-2,3-dihydrobenzofuran-3-yl)-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Synthesized using general synthesis method A: Step 1: N2-(4,6-difluoro-2,3-dihydrobenzofuran-3-yl)-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine A mixture of 4-chloro-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazin-2-amine (Intermediate X) (50 mg, 0.15 mmol), 4,6-difluoro-2,3-dihydro-1-benzofuran-3-amine hydrochloride (52 mg, 0.25 mmol), and N,N-diisopropylethylamine (0.21 mL, 1.21 mmol) in 1,4-dioxane (7.5 mL) was heated at 80 °C for 48 h. The reaction mixture was concentrated to dryness under reduced pressure and purified by flash chromatography (silica gel, eluting with a 0-50% EtOAc gradient in petroleum ether) to afford the title compound (67 mg, 0.14 mmol, 90% yield) as an off-white solid. LCMS MDAP Rt = 3.32 min (Method 7); m / z (ESI + ) 466.25 [M+H] + . Step 2: N2-(4,6-difluoro-2,3-dihydrobenzofuran-3-yl)-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine To a solution of N2-(4,6-difluoro-2,3-dihydrobenzofuran-3-yl)-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (65 mg, 0.14 mmol) in 1,4-dioxane (2.8 mL) and MeOH (2.8 mL) was added 4 M HCl in 1,4-dioxane (0.52 mL, 2.1 mmol) at room temperature. The reaction mixture was heated in a sealed vial at 60 °C for 11 h and then evaporated to dryness under reduced pressure. The crude material was purified by flash chromatography (silica gel, eluting with a gradient of 0-5% methanol in DCM) to afford the title compound (26 mg, 0.060 mmol, 46% yield) as a white solid. 1H NMR (399 MHz, DMSO-d6, Vt 90℃) δ 8.49 (s, 1H), 8.19 - 7.94 (m, 2H), 7.75 (d, J = 8.5 Hz, 1H), 7.64 (s, 1H), 6.67 - 6.47 (m, 4H), 5.98 (s, 1H), 4.86 (t, J = 9.1 Hz, 1H), 4.50 (dd, J = 9.7, 4.7 Hz, 1H). LCMS MDAP Rt = 17.76 min; >95% (Method 4); m / z (ESI + ) 382.00 [M+H] + .

[0430] Example 91 N2-[[2,3-Difluoro-4-(2-pyrrolidin-1-ylethoxy)phenyl]methyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine hydrochloride [ka] Step 1: 2-[4-[[[4-amino-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazin-2-yl]amino]methyl]-2,3-difluoro-phenoxy]ethanol A solution of 4-chloro-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazin-2-amine (Intermediate X) (68 mg, 0.21 mmol), 2-[4-(aminomethyl)-2,3-difluoro-phenoxy]ethanol (Intermediate BH) (50 mg, 0.25 mmol), and N,N-diisopropylethylamine (0.29 mL, 1.64 mmol) in 1,4-dioxane (7 mL) was heated at 80° C. for 4 h. The reaction mixture was loaded onto Celite and purified by flash chromatography (silica gel, eluting with a gradient of 0-5% methanol in DCM) to afford the title compound (81 mg, 0.15 mmol, 75% yield) as an off-white solid. 1H NMR (600 MHz, DMSO-d6) δ 8.56 (s, 0.47H), 8.52 (s, 1H), 8.17 - 8.12 (m, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.83 (t, J = 5.9 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.74 (t, J = 6.1 Hz, 0H), 7.19 - 7.07 (m, 1H), 7.05 - 6.90 (m, 2H), 6.83 (s, 1H), 5.95 - 5.78 (m, 1H), 4.87 (d, J = 21.2 Hz, 1H), 4.58 (d, J = 6.2 Hz, 1H), 4.51 (d, J = 6.1 Hz, 1H), 4.11 - 3.98 (m, 2H), 3.87 (t, J = 14.1 Hz, 1H), 3.75 - 3.62 (m, 3H), 2.45 - 2.35 (m, 1H), 2.08 - 1.94 (m, 2H), 1.83 - 1.69 (m, 1H), 1.58 (s, 2H). LCMS LCQ Rt = 5.63 min (Method 3); m / z (ESI+) 498.29 [M+H] + . Step 2: N4-[[4-(2-chloroethoxy)-2,3-difluoro-phenyl]methyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine To a solution of 2-[4-[[[4-amino-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazin-2-yl]amino]methyl]-2,3-difluoro-phenoxy]ethanol (39 mg, 0.080 mmol) in tetrahydrofuran (2.6 mL) and DCM (2.6 mL) was added thionyl chloride (0.09 mL, 1.41 mmol) at room temperature. The reaction mixture was heated to reflux for 38 hours and then concentrated to dryness under reduced pressure. The crude material was purified by flash chromatography (silica gel, eluting with a 0-100% EtOAc gradient in petroleum ether) to afford the title compound (22 mg, 0.040 mmol, 46% yield) as a pale brown solid. LCMS MDAP Rt = 21.68 min (Method 4); m / z (ESI + ) 516.15 / 518.10 [M+H] + . Step 3: N4-[[2,3-difluoro-4-(2-pyrrolidin-1-ylethoxy)phenyl]methyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine A mixture of N4-[[4-(2-chloroethoxy)-2,3-difluorophenyl]methyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (15 mg, 0.030 mmol), pyrrolidine (41 mg, 0.58 mmol), and potassium carbonate (10 mg, 0.070 mmol) in N,N-dimethylformamide (1 mL) was heated at 85° C. for 4.5 h. The reaction mixture was concentrated to dryness under reduced pressure, and the crude material was purified by flash chromatography (silica gel, eluting with a gradient of 0-5% methanol in DCM) to afford the title compound (9 mg, 0.010 mmol, 51% yield) as an off-white solid. LCMS MDAP Rt = 12.86 min (Method 4); m / z (ESI + ) 551.30 [M+H] + . Step 4: N2-[[2,3-difluoro-4-(2-pyrrolidin-1-ylethoxy)phenyl]methyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine hydrochloride To a solution of N2-[[2,3-difluoro-4-(2-pyrrolidin-1-ylethoxy)phenyl]methyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (9 mg, 0.020 mmol) in 1,4-dioxane (1.5 mL) and methanol (1.5 mL) was added 4 M HCl in 1,4-dioxane (0.06 mL, 0.25 mmol) at room temperature. The reaction mixture was heated at 60 °C for 11 h and then concentrated to dryness under reduced pressure. The crude material was purified by flash chromatography (silica gel, eluting with a gradient of 0-20% methanol in DCM) to afford the title compound (5 mg, 0.010 mmol, 58% yield) as a white solid. 1 H NMR (399 MHz, DMSO-d6, Vt 90℃) δ 13.16 (s, 1H), 8.49 (s, 1H), 8.13 - 7.97 (m, 2H), 7.75 (d, J = 8.5 Hz, 1H), 7.43 (s, 1H), 7.19 (t, J = LCMS MDAP Rt = 11.03 & 11.81 min; >95% (Method 4); m / z (ESI + ) 467.20 [M+H] + .

[0431] Example 92 6-(1H-indazol-6-yl)-N2-[(2-methylisoindolin-1-yl)methyl]-1,3,5-triazine-2,4-diamine hydrochloride [ka] Synthesized using general synthesis method A: Step 1: N4-[(2-methylisoindolin-1-yl)methyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine A mixture of 4-chloro-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazin-2-amine (Intermediate X) (25 mg, 0.080 mmol), (2-methyl-2,3-dihydro-1H-isoindol-1-yl)methanamine (20 mg, 0.12 mmol), and N,N-diisopropylethylamine (0.11 mL, 0.60 mmol) in 1,4-dioxane (3.5 mL) was heated at 80° C. for 24 h. The reaction mixture was loaded onto Celite and purified by flash chromatography (silica gel, eluting with a gradient of 0-5% methanol in DCM) to afford the title compound (25 mg, 0.050 mmol, 69% yield) as a pale brown solid. LCMS LCQ Rt = 0.92 min (Method 3); m / z (ESI+) 457.38 [M+H] + . Step 2: 6-(1H-indazol-6-yl)-N2-[(2-methylisoindolin-1-yl)methyl]-1,3,5-triazine-2,4-diamine hydrochloride To a solution of N2-[(2-methylisoindolin-1-yl)methyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (23 mg, 0.050 mmol) in 1,4-dioxane (1 mL) and methanol (1 mL) was added 4 M HCl in 1,4-dioxane (0.19 mL, 0.76 mmol) at room temperature. The reaction mixture was heated at 60 °C for 13 h and then concentrated to dryness under reduced pressure. The crude material was purified by flash chromatography (silica gel, eluting with a gradient of 0-10% methanol in DCM) to afford the title compound (21 mg, 0.050 mmol, 97% yield) as an off-white solid. 1H NMR (399 MHz, DMSO-d6, Vt 90℃) δ 13.04 (s, 1H), 8.49 (s, 1H), 8.11 - 7.97 (m, 2H), 7.75 (d, J = 8.6 Hz, 1H), 7.32 (s, 1H), 7.28 - 6.98 (m, 3H), 6.70 - 6.25 (m, 3H), 4.27 (s, 1H), 4.02 (s, 1H), 3.89 (s, 1H), 3.70 (s, 2H), 2.62 (s, 3H).

[0432] Example 93 N2-chroman-4-yl-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Synthesized using general synthesis method A: Step 1: N4-chroman-4-yl-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine A mixture of 4-chloro-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazin-2-amine (Intermediate X) (50 mg, 0.15 mmol), 3,4-dihydro-2H-1-benzopyran-4-amine (37 mg, 0.250 mmol), and N,N-diisopropylethylamine (0.21 mL, 1.21 mmol) in 1,4-dioxane (7 mL) was heated at 80 °C for 56 h. The reaction mixture was concentrated to dryness under reduced pressure, and the crude material was purified by flash chromatography (silica gel, eluting with a 0-70% EtOAc gradient in petroleum ether) to afford the title compound (73 mg, 0.15 mmol, 98% yield) as an off-white solid. LCMS MDAP Rt = 3.13 min (Method 7); m / z (ESI+) 444.20 [M+H] + . Step 2: N2-chroman-4-yl-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine To a solution of N2-chroman-4-yl-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (71 mg, 0.16 mmol) in 1,4-dioxane (3.2 mL) and methanol (3.2 mL) was added 4 M HCl in 1,4-dioxane (0.6 mL, 2.4 mmol) at room temperature. The reaction mixture was heated at 60 °C for 13 h and then concentrated to dryness under reduced pressure. The crude material was purified by flash chromatography (silica gel, eluting with a 0-5% MeOH gradient in DCM) to afford the title compound (35 mg, 0.090 mmol, 58% yield) as a white solid. 1 H NMR (399 MHz, DMSO-d6, Vt 90℃) δ 8.53 (s, 1H), 8.22 - 7.99 (m, 1H), 7.86 - 7.70 (m, 1H), 7.35 (s, 1H), 7.30 - 7.21 (m, 1H), 7.21 - 7.06 (m, 1H), 6.91 - 6.82 (m, 1H), 6.82 - 6.72 (m, 1H), 6.58 (s, 2H), 5.46 (s, 1H), 4.35 (s, 1H), 4.25 (s, 1H), 2.17 (s, 2H). LCMS MDAP Rt = 16.61 min (Method 4); m / z (ESI+) 360.10 [M+H] + .

[0433] Example 94 N2-chroman-3-yl-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Synthesized using general synthesis method A: Step 1: N4-chroman-3-yl-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine A mixture of 4-chloro-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazin-2-amine (Intermediate X) (50 mg, 0.15 mmol), 3,4-dihydro-2H-1-benzopyran-3-amine hydrochloride (46 mg, 0.25 mmol), and N,N-diisopropylethylamine (0.21 mL, 1.21 mmol) in 1,4-dioxane (12 mL) was heated at 80 °C for 72 h. The reaction mixture was loaded onto Celite and purified by flash chromatography (eluting with a 0-50% EtOAc in petroleum ether gradient) to afford the title compound (90 mg, 0.14 mmol, 94% yield) as an off-white solid. LCMS MDAP Rt = 3.31 min (Method 7); m / z (ESI+) 444.20 [M+H] + . Step 2: N2-chroman-3-yl-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine To a solution of N2-chroman-3-yl-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (88 mg, 0.20 mmol) in 1,4-dioxane (3.9 mL) and methanol (3.9 mL) was added 4 M HCl in 1,4-dioxane (0.74 mL, 2.98 mmol) at room temperature. The reaction mixture was heated at 60 °C for 13 h and then concentrated to dryness under reduced pressure. The crude material was purified by flash chromatography (silica gel, eluting with a 0-5% MeOH gradient in DCM) to afford the title compound (25 mg, 0.070 mmol, 33% yield) as a white solid. 1 H NMR (399 MHz, DMSO-d 6,Vt 90℃) δ 8.49 (s, 1H), 8.13 - 7.93 (m, 2H), 7.76 (d,J= 8.5 Hz, 1H), 7.08 (t,J= 7.0 Hz, 2H), 6.99 - 6.87 (m, 1H), 6.85 (t,J= 7.5 Hz, 1H), 6.78 (d,J= 8.3 Hz, 1H), 6.58 (s, 2H), 4.46 (s, 1H), 4.31 (d,J= 10.1 Hz, 1H), 3.91 (t,J= 9.4 Hz, 1H).

[0434] Example 95 N2-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-N4-[(2,3-difluorophenyl)methyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Step 1: 4,6-Dichloro-N-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-1,3,5-triazin-2-amine [1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]ammonium chloride (Intermediate L, HCl salt) (120 mg, 0.57 mmol) was added to a suspension of cyanuric chloride (110 mg, 0.60 mmol) and sodium carbonate (180 mg, 1.7 mmol) in diethyl ether (10 mL). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was loaded onto Celite and purified by flash chromatography (silica gel, eluted with a gradient of 30% EtOAc in petroleum ether) to give the desired compound (178 mg, 0.52 mmol, 92%) as a colorless oil. 1H NMR (600 MHz, chloroform-d) δ 7.77 (d, J= 2.7 Hz, 1H), 7.22 - 7.00 (m, 2H), 6.39 (d, J= 2.7 Hz, 1H), 3.69 (s, 2H), 1.81 (s, 6H). LCMS LCQ Rt = 6.77 min (Method 3); m / z (ESI+) 322.95 [M+H] + . Step 2: 4-chloro-N-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazin-2-amine Bis[2-(di-tert-butylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloropalladium (7.2 mg, 0.010 mmol) was added to a suspension of 1-tetrahydropyran-2-yl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (Intermediate V) (220 mg, 0.66 mmol), 4,6-dichloro-N-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-1,3,5-triazin-2-amine (178 mg, 0.55 mmol), and tripotassium phosphate (234 mg, 1.1 mmol) in tetrahydrofuran (8 mL). The biphasic mixture was degassed with N (10 min) and heated to 80 °C in a sealed vial for 2 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc and brine. The organic phase was separated, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, eluting with a gradient of 0-30% EtOAc in petroleum ether) to afford the title compound (119 mg, 0.22 mmol, 40% yield) as a pale yellow gum. LCMS LCQ Rt = 8.11 min (Method 3); m / z (ESI+) 489.19 [M+H] + . Step 3: N2-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-N4-[(2,3-difluorophenyl)methyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine 4-Chloro-N-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazin-2-amine (30 mg, 0.060 mmol) and 2,3-difluorobenzylamine (0.02 mL, 0.15 mmol) were dissolved in 1,4-dioxane (1 mL) and heated at 100° C. for 16 hours. After cooling to room temperature, 4 M HCl in 1,4-dioxane was added, and the reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was concentrated to dryness under reduced pressure and purified by flash chromatography (silica gel, eluting with a 0-50% EtOAc gradient in petroleum ether) to afford the title compound (8 mg, 0.010 mmol, 24% yield) as a white solid. 1 H NMR (399 MHz, DMSO-d 6, Vt 90℃) δ 13.03 (s, 1H), 8.43 (s, 1H), 8.07 (s, 1H), 7.95 (br m, 2H), 7.75 (d, J= 8.5 Hz, 1H), 7.64 (s, 1H), 7.48 (br m, 1H), 7.27 - 7.08 (m, 4H), 6.41 (s, 1H), 4.56 (s, 2H), 1.74 (s, 6H). LCMS MDAP Rt = 18.19 min; >95% (Method 5); m / z (ESI+) 512 [M+H] + .

[0435] Example 96 N2-[2-(2,3-dichlorophenyl)ethyl]-6-(1H-indazol-6-yl)-N2-(2-methoxyethyl)-1,3,5-triazine-2,4-diamine [ka] Synthesized using general synthesis method A: Step 1: N4-[2-(2,3-dichlorophenyl)ethyl]-N4-(2-methoxyethyl)-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine A mixture of 2-(2,3-dichlorophenyl)-N-(2-methoxyethyl)ethanamine (Intermediate AD) (57 mg, 0.23 mmol), 4-chloro-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazin-2-amine (Intermediate X) (46 mg, 0.14 mmol), and N,N-diisopropylethylamine (0.06 mL, 0.35 mmol) in 1,4-dioxane (2.8 mL) was heated at 60° C. for 44 h. The reaction mixture was dry-loaded onto Celite and purified by flash chromatography (silica gel, eluting with a 0-40% EtOAc gradient in petroleum ether) to afford the title compound (65 mg, 0.11 mmol, 78% yield) as a clear gum. 1H NMR (600 MHz, DMSO-d6) δ 8.58 (s, 0.35H), 8.53 (s, 0.58H), 8.17 - 8.13 (m, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.86 - 7.75 (m, 1H), 7.50 (d, J = 8.0 Hz, 0.31H), 7.44 - 7.39 (m, 1H), 7.33 (d, J = 7.4 Hz, 0.56H), 7.29 (t, J = 7.9 Hz, 0.16H), 7.23 (t, J = 7.8 Hz, 0.60H), 7.00 - 6.79 (m, 2H), 5.91 - 5.83 (m, 1H), 4.06 - 3.97 (m, 1H), 3.95 - 3.61 (m, 2H), 3.57 (t, J = 5.9 Hz, 0.75H), 3.52 (t, J = 5.9 Hz, 1.28H), 3.26 (s, 2H), 3.13 (t, J = 7.3 Hz, 1.33H), 3.09 (t, J = 7.6 Hz, 0.81H), 2.45 - 2.37 (m, 1H), 2.10 - 1.97 (m, 2H), 1.82 - 1.70 (m, 1H), 1.64 - 1.50 (m, 2H), 1.47 - 1.34 (m, 1H), 1.06 (s, 2H), 1.01 (s, 1H). LCMS LCQ Rt = 8.20 min (Method 3); m / z (ESI+) 542.28 [M+H] + . Step 2: N2-[2-(2,3-dichlorophenyl)ethyl]-6-(1H-indazol-6-yl)-N2-(2-methoxyethyl)-1,3,5-triazine-2,4-diamine A solution of N2-[2-(2,3-dichlorophenyl)ethyl]-N2-(2-methoxyethyl)-6-(1-tetrahydropyran-2-ylindazol-6-yl)-1,3,5-triazine-2,4-diamine (63 mg, 0.12 mmol) in methanol (4 mL) treated with 4 M HCl in 1,4-dioxane (1.16 mL, 4.65 mmol) was heated at 60 °C for 16 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in methanol and loaded onto an SCX-2 cartridge (10 g), and the product was eluted with 2 M NH3 in methanol (DCM was used to improve solubility). The eluate was concentrated to dryness under reduced pressure and purified by flash chromatography (silica gel, eluting with a 0-5% methanol in DCM gradient) to afford the title compound (37 mg, 0.080 mmol, 68% yield) as a white solid. 1 H NMR (600 MHz, DMSO-d6) δ 13.27 (s, 1H), 8.47 (d, J = 4.5 Hz, 1H), 8.10 (s, 1H), 8.07 - 8.01 (m, 1H), 7.79 (dd, J = 8.6, 2.4 Hz, 1H), 7.50 (d, J = 7.8 Hz, 0.31H), 7.42 (t, J = 8.2 Hz, 1H), 7.34 - 7.23 (m, 2H), 7.07 - 6.70 (m, 2H), 3.92 (t, J = 7.3 Hz, 1H), 3.81 - 3.71 (m, 2H), 3.66 (t, J = 5.9 Hz, 1H), 3.56 (t, J = 5.8 Hz, 1H), 3.50 (t, J = 5.9 Hz, 1H), 3.26 (s, 1H), 3.25 (s, 2H), 3.13 (t, J = 7.2 Hz, 1H), 3.09 (t, J = 7.7 Hz, 1H).

[0436] Example 97 N4-[1-[4-chloro-1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-(1-methylindazol-6-yl)-1,3,5-triazine-2,4-diamine [ka] Synthesized using general method B: Step 1: 6-chloro-N4-[1-[4-chloro-1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-1,3,5-triazine-2,4-diamine 2-Amino-4,6-dichlorotriazine (65 mg, 0.40 mmol) was suspended in 1,4-dioxane (1.5 mL), and N,N-diisopropylethylamine (0.14 mL, 0.79 mmol) was added, followed by [1-[4-chloro-1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]ammonium chloride intermediate BA (65 mg, 0.26 mmol). The mixture was heated at 60° C. for 12 hours. The crude material was purified by flash column chromatography (silica, eluting with a gradient of 0-10% methanol in DCM) to afford the title compound (20 mg, 0.06 mmol, 22% yield) as a white solid. Rt 3.51 min (Method 2); m / z (ESI + ) 337.86-339.88 [M+H] + . Step 2: N4-[1-[4-chloro-1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-(1-methylindazol-6-yl)-1,3,5-triazine-2,4-diamine A stirred solution of 6-chloro-N4-[1-[4-chloro-1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-1,3,5-triazine-2,4-diamine (30 mg, 0.09 mmol), potassium phosphate tripotassium (38 mg, 0.18 mmol), and bis[2-(di-tert-butylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloropalladium (2.9 mg, 0.006 mmol) in tetrahydrofuran (1 mL) and water (0.2 mL) was degassed by bubbling N2 directly through the solution for 5 min. The mixture was heated at 80 °C, and then 1-methyl-1H-indazole-6-boronic acid (23 mg, 0.13 mmol) in THF was added and the mixture was stirred for 12 h. After concentrating the reaction mixture to dryness, the crude material was purified by flash column chromatography (silica, eluting with a gradient of 30-100% ethyl acetate in petroleum ether) to afford the desired compound (8 mg, 0.02 mmol, 21% yield) as an off-white solid. 1 H NMR (399 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.85 - 7.45 (m, 3H), 7.04 (s, 1H), 6.33 (s, 2H), 4.03 (s, 3H), 1.77 (s, 6H). LCMS-MDAP Rt = 18.24 min (Method 4); m / z (ESI + ) 434.10-436.05 [M+H] + .

[0437] Example 98 6-(1H-indazol-6-yl)-N2-[(1-methylpyrrolidin-3-yl)m...

Claims

1. Compounds of the following general formula (I) or their pharmaceutically acceptable salts: 【Chemistry 1】 In the above formula, The H ring in general formula (I) is a carbon atom* １ or* ２ It is linked to; R １ H, C １－６ Alkyl and C １－６ Selected from haloalkyls; R ２ is selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, and C １－６ haloalkyl, and is selected from Here, C １－６ The alkyl group is optionally substituted with one or more R6 groups; R ３ These are, independently, Halo and C. １－６ Selected from alkyl and amino; X １ N is X ２ CR ４ is or X １ C is X ２ NR ５ And; X ３ is N; R ４ H, Halo, CN, C １－６ Alkyl and C １－６ Selected from haloalkyl groups, R ５ H, C １－６ Alkyl, Q ４ -L ４ - Selected from, Here, C １－６ Alkyl is one or more R ９ It is arbitrarily replaced with, L ４ is a bond, or C １－４ It is alkylene; Q ４ C ３－６ Cycloalkyl, 3- to 6-membered heterocyclyl, C ６－１２ Selected from aryls and 5- or 6-membered heteroaryls, Here, C ３－６ Cycloalkyls and 3- to 6-membered heterocyclines are one or more R １０ It is arbitrarily replaced by the C ６－１２ Aryls and 5- or 6-membered heteroaryls are one or more R １１ It is arbitrarily replaced by; L １ NR １２ , or O, R １２ H, C １－４ Alkyl, C １－４ Haloalkyl, C ３－６ Cycloalkyl, C ３－６ Cycloalkyl-C １－４ Alkyl and C １－４ Alkyl-OR Ａ５ Selected from, Here, C ３－６ Cycloalkyl and C ３－６ Cycloalkyl-C １－４ Alkyl is =O, halo, C １－４ Alkyl and C １－４ Optionally substituted with one or more substituted compounds selected from haloalkyl groups, L ２ is a combination, or -[CR １３ R １４ ] ｐ - and p is either 1 or 2; R １３ and R １４ These are H and C, respectively, independently. １－４ Alkyl, C １－４ Haloalkyl, OH, COOH, C(O)NR Ｘ１ R Ｘ２ , and C ３－６ Selected from cycloalkyl, or R １３ and R １４ is L ２ They are attached together to the same carbon atom within, and together C ３－６ Forming a cycloalkyl or 3-6-membered heterocycline, Here, C １－４ Alkyl groups are OH, O-C １－４ Alkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, or halogen or C １－６ C optionally substituted with a haloalkyl group ６－１０ It can be arbitrarily replaced with an aryl; Here, R Ｘ１ and R Ｘ２ This is independently a C that is optionally substituted with H;OH or a 3- to 6-membered heterocycline. １－４ Alkyl; selected from 5- to 10-membered heteroaryls, or R Ｘ１ and R Ｘ２ These are attached together to the same nitrogen atom, forming a 3- to 6-membered heterocycline; Here, C ３－６ Cycloalkyl or 3- to 6-membered heterocyclyls are =O, halo, C １－４ Alkyl and C １－４ Optionally substituted with one or more substituted compounds selected from haloalkyl groups; Q １ C ３－１２ Cycloalkyl, C ３－１２ Cycloalkenyl, 3- to 7-membered heterocyclyl, C ６－１０ Aryl, 5- to 9-membered heteroaryl, COOH, C(O)NR Ｚ１ R Ｚ２ , and C(O)O-C １－６ Selected from alkyl groups; Here, each R Ｚ１ and R Ｚ２ is independently selected from H; C1-6 alkyl optionally substituted with OH; C ３－６ cycloalkyl; C ６－１０ aryl; 5- to 10-membered heteroaryl; or R Ｚ１ and R Ｚ２ are attached together to the same nitrogen atom to form a 3- to 6-membered heterocyclyl; Here, C ３－１２ Cycloalkyl, C ３－１２ Cycloalkenyls and 3- to 7-membered heterocyclyls contain one or more R １５ It is arbitrarily replaced with, Here, the C ６－１０ aryl and 5- to 9-member heteroaryl are optionally substituted with one or more R １６ ; Each R １５ These are independently: halo, =O, -CN, -NO ２ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, -OR １７ , -S(O) ｘ１ R １７ , -NR １７ R Ｂ１ , -C(O)R １７ , -OC(O)R １７ , -C(O)OR １７ , -NR Ｂ１ C(O)R １７ , -NR Ｂ１ C(O)OR １７ , -C(O)NR １７ R Ｂ１ , -OC(O)NR １７ R Ｂ１ , -NR Ｂ１ SO ２ R １７ , -SO ２ NR １７ R Ｂ１ and -NR Ａ１ C(O)NR １７ R Ｂ１ Selected from: Here, C １－６ Alkyl, C ２－６ Alkenyl and C ２－６ Alkinyl contains one or more R １８ It is arbitrarily replaced with, R １７ H, C １－６ Alkyl and C １－６ Selected from haloalkyl, where C １－６ Alkyl is one or more R １９ It is arbitrarily replaced by; Each R １６ These are independently: Halo, -CN, -NO ２ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, -OR ２０ , -S(O) ｘ２ R ２０ , -NR ２０ R Ｂ２ , -C(O)R ２０ , -OC(O)R ２０ , -C(O)OR ２０ , -NR Ｂ２ C(O)R ２０ , -NR Ｂ２ C(O)OR ２０ , -C(O)NR ２０ R Ｂ２ , -OC(O)NR ２０ R Ｂ２ , -NR Ｂ２ SO ２ R ２０ , -SO ２ NR ２０ R Ｂ２ and -NR Ａ２ C(O)NR ２０ R Ｂ２ Selected from, Here, C １－６ Alkyl, C ２－６ Alkenyl and C ２－６ Alkinyl contains one or more R ２１ It is arbitrarily replaced with, Here, R ２０ H, C １－６ Alkyl and C １－６ Selected from haloalkyl, where C １－６ Alkyl is one or more R ２２ It is arbitrarily replaced by; R ６ , R ９ , R １０ , R １８ , R １９ , R ２１ and R ２２ These are, independently, Halo, =O, -CN, and -NO. ２ , C １－４ Alkyl, C １－４ Haloalkyl, -OR Ａ３ , -S(O) ｘ３ R Ａ４ , -NR Ａ３ R Ｂ３ , -C(O)R Ａ３ , -OC(O)R Ａ３ , -C(O)OR Ａ３ , -NR Ｂ３ C(O)R Ａ３ , -NR Ｂ３ C(O)OR Ａ３ , -C(O)NR Ａ３ R Ｂ３ , -NR Ｂ４ SO ２ R Ａ３ and -SO ２ N ＲＡ 3R Ｂ３ Selected from, R １１ H is, =O, -CN, -NO ２ , C １－４ Alkyl, C １－４ Haloalkyl, -OR Ａ４ , -S(O) ｘ４ R Ａ４ , -NR Ａ４ R Ｂ４ , -C(O)R Ａ４ , -OC(O)R Ａ４ , -C(O)OR Ａ４ , -NR Ｂ４ C(O)R Ａ４ , -NR Ｂ４ C(O)OR Ａ４ , -C(O)N ＲＡ 4R Ｂ４ , -NR Ｂ４ SO ２ R Ａ４ and -SO ２ NR Ａ４ R Ｂ４ Selected from, R １Ａ , R １Ｂ , R Ａ２ , R Ｂ２ , R Ａ３ , R Ｂ３ , R Ａ４ , R Ｂ４ and R Ａ５ These are H and C, respectively, independently. １－４ Alkyl and C １－４ Selected from haloalkyls, or any -NR Ａ３ R Ｂ３ , -NR Ａ４ R Ｂ４ , -NR １７ R Ｂ１ or -NR ２０ R Ｂ２ The substituted material may form a 4- to 6-membered heterocycline, where the 4- to 6-membered heterocycline is a halo, =O, C １－４ Alkyl and C １－４ Optionally substituted with one or more substituted compounds selected from haloalkyl groups; n is an integer from 0 to 4; and x1, x2, x3, and x4 are each independently selected from 0, 1, or 2.

2. Claim 1, selected from compounds of the following general formula (IV) or (IX). The compounds listed: 【Chemistry 2】 (IV) 【Transformation 3】 (IX) Here, R ３ , R ４ , R ５ , L １ , L ２ and Q １ This is as defined in claim 1.

3. Each R ３ This is a halo, and here, arbitrarily, each R ３ The compound according to claim 1, wherein is independently selected from fluoro and chloro.

4. R ４ or R ５ is H or C １－６ The compound according to claim 1, wherein it is alkyl and optionally methyl.

5. L １ NR １２ And R １２ C ３－６ Cycloalkyl, C １－４ Alkyl and -C １－４ Alkyl-OR Ａ５ Selected from, here, R Ａ５ The compound according to claim 1, wherein it is as defined in claim 1.

6. L １ The compound according to claim 1, wherein is NH.

7. L ２ is, -[CR １３ R １４ ] ｐ Here, p is an integer between 1 and 2, and R １３ and R １４ H and C １－４ Each alkyl group is independently selected, or R １３ and R １４ is, L ２ Attached to the same carbon atom within, C ３－６ The compound according to claim 1, wherein it together forms a cycloalkyl group.

8. L ２ The compound according to claim 1, wherein the bond is a combination.

9. The aforementioned Q １ is a 5- or 6-membered heteroaryl group comprising one or two heteroatoms independently selected from O, N, and S, wherein the heteroaryl group is optionally one or more R as defined in claim 1. １６ The compound according to claim 1, which is substituted by

10. Q １ The following applies: 【Chemistry 4】 Here, ring A is -L １ -L ２ A 5- or 6-membered heteroaryl comprising a ring nitrogen in the ortho position relative to the bond to - and one or more heteroatoms optionally independently selected from O, S and N, wherein the heteroaryl optionally comprises one or more R as defined in claim 1. １６ The compound according to claim 1, which is substituted by

11. Q １ C ６－１０ It is an aryl, and optionally one or more R as defined in claim 1. １６ The compound according to claim 1, which is substituted by

12. Q １ is an 8- or 9-membered bicyclic heteroaryl group comprising one, two, or three heteroatoms independently selected from O, N, and S, wherein the bicyclic heteroaryl group is optionally one or more R as defined in claim 1. １６ The compound according to claim 1, which is substituted by

13. Q １ The compound according to claim 1, having a structure selected from the following: 【Transformation 5】 The aforementioned R １５ and R １６ x is as defined in claim 1, where x is 0, 1, 2, or 3.

14. Q １ This is one, two, or three R １５ or R １６ It is replaced by, where R １５ or R １６ C is a halo (preferably chloro and / or fluoro), C １－６ Alkyl, C １－６ The compound according to claim 1, which is independently selected from haloalkyl groups.

15. A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds 1 to 229 listed below. Table 1

16. A pharmaceutical composition for use in the treatment of serine / threonine-like kinase (MASTL)-mediated diseases or medical conditions, comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

17. The pharmaceutical composition according to claim 16, wherein the disease or medical symptom is a proliferative disorder, a metabolic disorder, or a sign or symptom associated with a metabolic disorder, or a platelet disorder, where optionally the platelet disorder is thrombocytopenia.

18. The pharmaceutical composition according to claim 17, wherein the proliferative disorder is cancer, and wherein the cancer is optionally selected from among the cancers of the breast, ovary, lung, colon, prostate, oral cavity, stomach, adrenal cortex, pancreas, kidney, sarcoma, liver, endometrium, thyroid, head or neck, brain (e.g., glioma), melanoma (e.g., ocular melanoma), and hematological cancers (e.g., leukemia, lymphoma, myeloma, and multiple myeloma).

19. The pharmaceutical composition according to claim 18, wherein the cancer overexpresses MASTL.

20. The pharmaceutical composition according to claim 16, wherein the pharmaceutical composition is used in conjunction with one or more additional anticancer agents and / or radiotherapy.

21. The pharmaceutical composition according to claim 17, wherein the metabolic disorder is selected from insulin resistance, diabetes, or obesity, and the signs and symptoms associated with the metabolic disorder are selected from increased blood glucose, increased cholesterol, increased triglyceride levels, heart disease, stroke, hypertension, and increased risk of thrombosis (e.g., deep vein thrombosis).

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