Substituted heterocyclic compound derivatives and pharmaceutical uses thereof

Abstract

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.

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-step kinase Greatwall (GWL) promotes the inactivation of the phosphatase PP2A / B55delta, which targets CDK phosphorylation sites (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)). Arpp19, a substrate of Greatwall kinase, inhibits protein phosphatase 2A to control mitosis (Science 330 1673-1677). pENSA and pARPP19 are substrates of PP2A / B55, and they bind tightly to the complex and undergo dephosphorylation at a very slow rate, thereby inhibiting the catalytic activity of PP2A / B55 through "unfair competition" (Williams et al., (2014)). Greatwall-phosphorylated Ensosulfine is both an inhibitor and a substrate of PP2A-B55 heterotrimers. (eLife 3:e01695.) Entry of cells 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 their activities are combined to allow MASTL activity to 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 is initiated by APC / C-dependent ubiquitination of CCNB1, followed by proteasomal degradation. This attenuates CDK1 activity, ultimately deactivating MASTL and increasing PP2A / B55 phosphatase activity, which is necessary for timely mitotic exit. 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). Inhibition 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. Overexpression of MASTL has been reported in 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 colorectal cancer (Eur. Rev. Med. Pharmacol. Sci. 21 2413-2420) and colon 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 (Vera 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 frequently 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 rapid-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). Therapeutic opportunities Normal colon cells do not express MASTL or express it only at very low levels, which is a key factor in the cell proliferation window. Depletion of MASTL in HCT-116 cells induced G2 / M arrest, apoptosis induction through modulation of anti-apoptotic proteins (Survivin and Bcl-xL, possibly through Gsk3β activation), and importantly, growth reduction in vivo. In addition to directly affecting HCT-116 cell proliferation, MASTL-induced modulation of anti-apoptotic proteins also increased their sensitivity to 5-FU treatment. MASTL has been shown to be a key factor in the development 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 lead hit that senses cells by irradiation. Such effects were not observed in primary human fibroblasts, suggesting the possibility of selective sensitization of tumor cells over non-transformed cells (Nagel et al., (2015)). A genome-wide siRNA screen identifies the radiosensitizing effect of downregulation of MASTL and FOXM1 in NSCLC (Mol. Cancer Ther. 14 1434-1444). A similar effect was 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 flow cytometry 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 DNA damage repair pathways and mitosis, MASTL plays a role in regulating PP2A activity during interphase (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 megakaryocytopoiesis. More recently, it has been shown that such point mutations in MASTL do not induce decreased activity as originally thought, but rather exhibit gain-of-function alterations that induce 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. Summary of the Invention [Problem to be solved by the invention]

[0007] Therefore, there is a need for MASTL inhibitors that are expected to provide beneficial therapeutic effects in, for example, cancer treatment. [Means for solving the problem]

[0008] According to the present invention, there is provided a compound of formula (I) below, or a pharmaceutically acceptable salt thereof: JPEG2025541224000001.jpg70168In the above formula, The H ring in formula (I) is a carbon atom * 1 or * Concatenated with 2; Z is -NR 1 R 2 or -CN; R 1 and R 2 are each independently H, D and C 1-6 alkyl, wherein said C 1-6 The alkyl is optionally partially or fully deuterated; R 3 are each independently a halogen, C 1-6 selected from alkyl and amino; X 1 is N and X 2 is CR 4 or X 1 is C and X 2 is NR 5 and; X 3 is CH or N; R 4 , H, NR X1 R X2 , -OH and C 1-6 alkyl; R 5 is H and C 1-6 alkyl, where R 4 or R 5 The above C 1-6 The alkyl group is optionally partially or fully deuterated; L 1 is a bond or NR 6 , O, and S; R 6 is H, C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-6cycloalkyl; Here, the C 3-6 Cycloalkyl is ═O, halogen, 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 7 R 8 ]p-, p is an integer from 1 to 4; R 7 and R 8 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 7 and R 8 L 2 are attached together to the same carbon atom in C 3-6 forming a cycloalkyl or 3- to 6-membered heterocyclyl, Here, the C 1-4 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; Q 1 is C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; where C 6-10 Aryl and 5- to 10-membered heteroaryl may be one or more R 9 optionally replaced by; Each R 9 are independently halogen, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-6 Haloalkyl, -OR 10 , -S(O) x R 10 , -N(R 10 )2, -C(O)R 10 , -OC(O)R 10 , -C(O)OR 10 , -NR 10 C(O)R 10 , -NR 10 C(O)OR 10 , -C(O)N(R 10 )2, -OC(O)N(R 10 )2, -NR 10 SO2R 10 , -SO2N(R 10 )2, and -NR 10 C(O)N(R 10 )2 is selected; Here, the C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl is a group consisting of one or more R 11 optionally replaced by; Here, each R 10 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl; Here, each R 11 are independently halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl and NR X1 R X2 Selected from; where R X1 and R X2 are each independently H, and C optionally substituted with OH or 3- to 6-membered heterocyclyl; 1-4 Alkyl, -OC 1-6 Alkyl, -C(O)-C 1-6 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; n is an integer from 0 to 4; and x is an integer from 0 to 3, where R 4 or R 5 C is not hydrogenated or deuterated 1-6 When it is alkyl, Z is -CN or -NR 1 R 2 and where R 1 and R 2 At least one of the following is D or partially or fully deuterated C 1-6 It is alkyl.

[0009] The present invention also provides a compound represented by the following formula (II) or a pharmaceutically acceptable salt thereof: JPEG2025541224000002.jpg56128In the above formula, The H ring in formula (II) is a carbon atom * 1 or * Concatenated with 2; R 1 and R 2 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 haloalkyl; R 3 are each independently a halogen, C 1-6 selected from alkyl and amino; X 1 is N and X 2 is CR 4 or X 1 is C and X 2 is NR 5 and; X 3 is CH or N; R 4 and R 5 are each independently H, halogen, CN, or C 1-6 Alkyl and C 1-6 haloalkyl; L 1is a bond or NR 6 , O, and S; R 6 is H, C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-6 cycloalkyl; Here, the C 3-6 Cycloalkyl is ═O, halogen, 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 7 R 8 ]p-, p is an integer from 1 to 4; R 7 and R 8 are independently H, C 1-4 Alkyl, C 6-10 Aryl, COO-C 1-6 Alkyl, NR X1 R X2 , C(O)NR X1 R X3 and 5- to 10-membered heteroaryl; where L 2 R 7 and R 8 At least one of them is not H, Said C 1-4 Alkyl is 3- to 6-membered cycloalkyl, C 4-8 Alkyl, or NR X1 R X2 is replaced by; Q 1 is C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; where C 6-10 Aryl and 5- to 10-membered heteroaryl may be one or more R 9 optionally replaced by; Each R 9are independently halogen, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR 10 , -S(O) x R 10 , -N(R 10 )2, -C(O)R 10 , -OC(O)R 10 , -C(O)OR 10 , -NR 10 C(O)R 10 , -NR 10 C(O)OR 10 , -C(O)N(R 10 )2, -OC(O)N(R 10 )2, -NR 10 SO2R 10 , -SO2N(R 10 )2, and -NR 10 C(O)N(R 10 )2 is selected; Here, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Haloalkyl is one or more R 11 optionally replaced by; Here, each R 10 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl; Here, each R 11 are independently halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, NR X1 R X2 and C(O)NR X1 R X2 Selected from; where R X1 and R X2 are each independently H, OH, or C optionally substituted with 3- to 6-membered heterocyclyl; 1-4 Alkyl, OH, -OC 1-6 Alkyl, -C(O)-C 1-6alkyl, 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; where R X3 OH and OC 1-6 alkyl; n is an integer from 0 to 4; and x is an integer of 0 to 3.

[0010] The present invention also provides a compound represented by the following chemical formula (III) or a pharmaceutically acceptable salt thereof: JPEG2025541224000003.jpg52128In the above formula, The H ring in formula (III) is a carbon atom * 1 or * Concatenated with 2; R 1 and R 2 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 haloalkyl; R 3 are each independently a halogen, C 1-6 selected from alkyl and amino; X 1 is N and X 2 is CR 4 or X 1 is C and X 2 is NR 5 and; X 3 is CH or N; R 4 and R 5 are each independently H, halogen, CN, or C 1-6 Alkyl and C 1-6 haloalkyl; L 1 is a bond or NR 6, O, and S; R 6 is H, C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-6 cycloalkyl; Here, the C 1-4 The alkyl is optionally partially or fully deuterated; Here, the C 3-6 Cycloalkyl is ═O, halogen, 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 7 R 8 ]p-, p is an integer from 1 to 4; R 7 and R 8 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 7 and R 8 L 2 are attached together to the same carbon atom in C 3-6 forming a cycloalkyl or 3- to 6-membered heterocyclyl, Here, the C 1-4 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; Q 1 is C 6-10 selected from aryl and 5- to 10-membered heteroaryl; where C 6-10 Aryl and 5- to 10-membered heteroaryl may be one or more R 9 optionally replaced by; Each R9 are independently halogen, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, -OR 10 , -S(O)xR 10 , -N(R 10 )2, -C(O)R 10 , -OC(O)R 10 , -C(O)OR 10 , -NR 10 C(O)R 10 , -NR 10 C(O)OR 10 , -C(O)N(R 10 )2, -OC(O)N(R 10 )2, -NR 10 SO2R 10 , -SO2N(R 10 )2, and -NR 10 C(O)N(R 10 )2 is selected; Here, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl may be one or more R 11 optionally replaced by; Here, the C 1-6 The alkyl is optionally partially or fully deuterated; Here, each R 10 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl; Here, each R 11 are independently halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl and NR X1 R X2 Selected from; where R X1 and R X2are each independently H, OH, or C optionally substituted with 3- to 6-membered heterocyclyl; 1-4 Alkyl, -OC 1-6 Alkyl, -C(O)-C 1-6 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; n is an integer from 0 to 4; and x is an integer from 0 to 3; Here, Q 1 There are one or more R 9 is not replaced by or Q 1 One or more R 9 any one of C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or partially or fully deuterated C 1-6 When it is not alkyl, R 6 is a partially or fully deuterated C 1-4 It is alkyl.

[0011] The present invention also provides a compound of the following chemical formula (IV) or a pharmaceutically acceptable salt thereof: JPEG2025541224000004.jpg53128

[0012] Here, the R 1 and R 2 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 haloalkyl; R 3 are each independently a halogen, C 1-6 selected from alkyl and amino; X 1 is N and X 2 is CR 4 or X 1 is C and X 2 is NR 5 and; X 3 is CH or N; R 4 , R 5 and R 12 are each independently H, halogen, CN, or C 1-6 Alkyl and C 1-6 haloalkyl; where X 1 If is N, then X 4 is N and X 5 is CH or X 4 is CH and X 5 is N; where X 1 If C, then X 4 and X 5 are both CH; Here, the R 4 and R 5 C 1-6 The alkyl is optionally partially or fully deuterated; L 1 is a bond or NR 6 , O, and S; R 6 is H, C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-6 cycloalkyl; Here, the C 3-6 Cycloalkyl is ═O, halogen, 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 7 R 8 ]p-, p is an integer from 1 to 4; R 7 and R 8 are independently H, C 1-4 Alkyl, C1-4 Haloalkyl, OH, COOH, C(O)NR X1 R X2 , and C 3-6 cycloalkyl or R 7 and R 8 L 2 are attached together to the same carbon atom in C 3-6 forming a cycloalkyl or 3- to 6-membered heterocyclyl, Here, the C 1-4 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; Q 1 is C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; where C 6-10 Aryl and 5- to 10-membered heteroaryl may be one or more R 9 optionally replaced by; Each R 9 are independently halogen, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR 10 , -S(O) x R 10 , -N(R 10 )2, -C(O)R 10 , -OC(O)R 10 , -C(O)OR 10 , -NR 10 C(O)R 10 , -NR 10 C(O)OR 10 , -C(O)N(R 10 )2, -OC(O)N(R 10 )2, -NR 10 SO2R 10 , -SO2N(R10 )2, and -NR 10 C(O)N(R 10 )2 is selected; Here, the C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl is a group consisting of one or more R 11 optionally replaced by; Here, each R 10 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl; Here, each R 11 are independently halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl and NR X1 R X2 Selected from; where R X1 and R X2 are each independently H, OH, or C optionally substituted with 3- to 6-membered heterocyclyl; 1-4 Alkyl, -OC 1-6 Alkyl, -C(O)-C 1-6 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; n is an integer from 0 to 4; and x is an integer of 0 to 3.

[0013] The present invention also provides Compound Nos. 1-239 listed in Table 1 herein, or a pharmaceutically acceptable salt thereof. [Effects of the Invention]

[0014] 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.

[0015] 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).

[0016] The present invention also provides a compound or a pharmaceutically acceptable salt thereof for use in treating a disease in which PD-L1 expression is dependent on interferon.

[0017] 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.

[0018] 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.

[0019] In certain embodiments, the compounds of the present invention are for use in the treatment of cancer.

[0020] In certain embodiments, the compounds of the invention are for use in treating cancers that overexpress MASTL, ie, cancers 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).

[0021] 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.

[0022] In certain embodiments, the metabolic disorder may be insulin resistance, diabetes, or obesity. Symptoms and conditions associated with the metabolic disorder 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).

[0023] In certain embodiments, the compounds of the present invention are for use in treating a platelet disorder, such as thrombocytopenia.

[0024] 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

[0025] definition As used in the specification and claims, the following terms have the following meanings unless otherwise specified.

[0026] The term "treat" or "treatment" refers to indications of successful treatment or amelioration of a disease, pathology, or condition, including alleviation; relief; reduction of symptoms or making the condition or state more tolerable to the patient; slowing of the rate of regression or decline; making the end point of regression 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).

[0027] 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.

[0028] As defined herein, the terms "inhibition," "inhibit," "inhibiting," and the like, in connection with protein-inhibitor (e.g., antagonist) interactions, refer to negatively affecting (e.g., decreasing) the activity or functional level of a protein (e.g., a component of MASTL) relative to the activity or functional level of the protein pathway in the absence of the inhibitor. In some embodiments, inhibition refers to a decrease in a disease or disease symptom (e.g., cancer associated with increased MASTL activity). In some embodiments, inhibition refers to a decrease in the activity level of a signaling pathway or signaling pathway associated with MASTL. Thus, inhibition may include, at least in part, partially or completely blocking a stimulus; reducing, preventing, or delaying activation; inactivating, desensitizing, or down-regulating signal transduction or enzymatic 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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] Term C m-n is a term that refers to a group having m to n carbon atoms.

[0033] 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 1-6Alkylene can be -CH-, -CHCH-, -CHCH(CH)-, -CHCHCH-, or -CHCH(CH)CH-. Alkyl and alkylene groups can be unsubstituted or substituted 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.

[0034] The term “C 1-6 haloalkyl”, e.g., “C 1-4 "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 1-6 Haloalkyl 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).

[0035] 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 unsubstituted or substituted with one or more substituents. Possible substituents are described herein. For example, the substituents can be those of an alkyl group, as described above.

[0036] 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. Also, an alkynylene group can 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 unsubstituted or substituted with one or more substituents. Possible substituents are described herein. For example, the substituents can be those of an alkyl group, as described above.

[0037] The term “C3-12 "Cycloalkyl" includes saturated hydrocarbon ring systems containing 3 to 12 carbon atoms. Cycloalkyl groups may be monocyclic 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.

[0038] The term “C 3-12 "Cycloalkenyl" includes hydrocarbon ring systems containing 3 to 12 carbon atoms and at least one double bond (e.g., one or two double bonds). Cycloalkenyl groups can be monocyclic or fused, bridged, or spiro hydrocarbon ring systems. For example, C 3-12 The cycloalkenyl may be cyclobutenyl, cyclopentenyl, cyclohexenyl.

[0039] The terms "heterocyclyl," "heterocyclic," or "heterocycle" include non-aromatic saturated or partially saturated monocyclic 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 heterocyclic rings may contain 7 to 12 member 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 to 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 may be formed with one or two double bonds. This applies particularly to monocyclic rings having 5 to 7 members. The double bond is generally between two carbon atoms, but may be between a carbon atom and a nitrogen atom. Bicyclic systems may 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 may share a bridgehead, i.e., the rings are connected to each other through two non-adjacent carbon or nitrogen atoms (bridged ring systems). 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, etc. 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. Heterocycles containing sulfur also include sulfur-oxidized heterocycles containing SO or SO groups. 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 heterocyclic ring may be linked to another 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 a ring nitrogen. For example, L. 1 Reference to "heterocyclylene," which may appear as: refers to a divalent "heterocyclyl," for example, 3,2-morpholinylene.

[0040] 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.

[0041] The term "spiro bicyclic ring system" includes ring systems in which two rings share one common spiro carbon atom, i.e., a 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.

[0042] "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-C m-n"Alkyl" groups are defined in the same manner.

[0043] -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.

[0044] The term "aromatic," when applied to a substituent in its entirety, includes monocyclic or polycyclic ring systems having 4n+2 electrons in a complex π-system within the ring or ring system, with all atoms contributing to the complex π-system lying in the same plane.

[0045] The term "aryl" includes aromatic hydrocarbon ring systems. The ring systems have 4n+2 electrons in the 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.

[0046] The term "heteroaryl" refers to an aromatic mono- or bicyclic ring containing one or more (e.g., 1 to 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.

[0047] 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, such as fused 5- and 6-membered rings or bicycle 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. Typically, the number of basic nitrogen atoms present in a heteroaryl group, including optional amino group substitutions on the ring, will be fewer than five.

[0048] 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 bicyclic or polycyclic ring systems in which at least one ring is aromatic and the other ring(s) may be non-aromatic, saturated, or partially saturated, and at least one ring contains 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.

[0049] 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.

[0050] Examples of 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0051] Specific examples of particular bicyclic heteroaryl groups containing a 6-membered ring fused to a 5-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adenylyl, guanylyl), indazolyl, benzodioxolyl, pyrrolopyridine, and pyrazolopyridinyl groups.

[0052] Specific examples of 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.

[0053] The term "oxo" or "=O" as used herein means an oxygen that is double bonded to a carbon atom.

[0054] The term "optionally substituted" includes groups, structures, or molecules that are substituted and groups, structures, or molecules that are not substituted.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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 X1 R X2A group such as -NRR' can form: JPEG2025541224000005.jpg25150

[0059] Similarly, an -NRR' group within a substituent may form a carbonyl-linked 4- to 6-membered heterocyclyl, for example, a -C(O)NRR' group may be formed as follows: JPEG2025541224000006.jpg32128

[0060] The -NRR' groups in substituents such as -OC(O)NRR', -SO2NRR' and -NRC(O)NRR', - may similarly form 4- to 6-membered heterocyclyls in these substituents.

[0061] "Compounds of the invention" means any compound disclosed generally or specifically herein. Thus, compounds of the invention include compounds of formula (I), (II), (III), or (IV) and compounds of the Examples.

[0062] A bond ending in JPEG2025541224000007.jpg8128 or "*" indicates that the bond is connected to another atom not shown in the structure. A bond that ends within a ring structure but does not terminate at an atom of the ring structure indicates that the bond may be connected to any of the atoms of the ring structure as allowed by valence.

[0063] It should be understood that features, integers, traits, compounds, chemical moieties, or groups described in connection with a particular aspect, embodiment, or example of the invention are applicable to other aspects, embodiments, or examples 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 the disclosed methods or processes, can be combined in any combination, except where at least some of such features and / or steps are mutually exclusive. The invention is not limited to the detailed description of the foregoing examples. The 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.

[0064] The reader is reminded of all documents and literature in connection with this application, filed contemporaneously with or prior to this application, and published as presented herein, the contents of which are hereby incorporated by reference.

[0065] 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.

[0066] A suitable or preferred feature of any compound of the invention may also be a suitable feature of any other aspect.

[0067] 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.

[0068] 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, glucuronate, 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.

[0069] Suitable base salts are formed from bases which form non-toxic salts.

[0070] 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).

[0071] 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.

[0072] 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.

[0073] 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 different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of the asymmetric center and described by the Cahn and Prelog 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 may 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 partial stereoisomeric mixture or a single partial stereoisomer. The compound of the present invention can exist as a single stereoisomer or can be a mixture of stereoisomers, e.g., 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 partial 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.

[0074] 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.

[0075] 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.

[0076] 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 by chromatography, typically using HPLC, on an asymmetric resin with a mobile phase composed of a hydrocarbon, typically heptane or hexane, containing, by volume, 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.

[0077] Alternatively, the racemate (or racemic precursor) may 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 may be separated by chromatography and / or fractional crystallization, and one or both of the partial stereoisomers may be converted into the corresponding pure enantiomer by means well known to those skilled in the art.

[0078] When any racemate is crystallized, two other types can be determined. The first type is the racemate (actually a 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.

[0079] 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).

[0080] 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), 1 1 C. 1 3 C. 1 4 C. 1 5 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.

[0081] 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.

[0082] 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 reduce 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, 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 It may form an alkyl group.

[0083] 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.

[0084] 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.

[0085] 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, a compound of the present invention may 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. JPEG2025541224000008.jpg25128

[0086] Amino-substituted triazines can exhibit hindered rotation about the SP2 carbon-N bond, producing partially rotamers (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.

[0087] 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.

[0088] 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 can 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 biocleavable ester derivatives that can be formed at a carboxyl or hydroxy group of the compounds of the present invention, and biocleavable amide derivatives that can be formed at a carboxyl or amino group of the compounds of the present invention.

[0089] 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 may be metabolically produced compounds.

[0090] Suitable pharmaceutically acceptable pro-drugs of the compounds of the present invention are those pro-drugs that, based on sound medical judgment, are suitable for administration to the human or animal body without undesirable pharmacological activity and undue toxicity.

[0091] 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);

[0092] 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.

[0093] Suitable pharmaceutically acceptable prodrugs of compounds of general formula I having a carboxyl group are, for example, biocleavable esters. 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 1-6C such as alkoxymethyl esters and pivaloyloxymethyl 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 prodrugs 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 hydroxy groups include inorganic esters such as phosphate esters (including phosphoric acid amide cyclic esters). Additionally, suitable pharmaceutically acceptable ester-forming groups for hydroxy groups 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 1-4 Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include α-acyloxyalkyl groups, such as acetoxymethyl and pivaloyloxymethyl.

[0094] Suitable pharmaceutically acceptable pro-drugs of compounds of the 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.

[0095] Suitable pharmaceutically acceptable prodrugs 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.

[0096] compound In some embodiments, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof: JPEG2025541224000009.jpg53128In the above formula, The H ring in formula (I) is a carbon atom * 1 or * Concatenated with 2; Z is -NR 1 R 2or -CN; R 1 and R 2 are each independently H, D and C 1-6 alkyl, wherein said C 1-6 The alkyl is optionally partially or fully deuterated; R 3 are each independently a halogen, C 1-6 selected from alkyl and amino; X 1 is N and X 2 is CR 4 or X 1 is C and X 2 is NR 5 and; X 3 is CH or N; R 4 , H, NR X1 R X2 , -OH and C 1-6 alkyl; R 5 is H and C 1-6 alkyl, where R 4 or R 5 The above C 1-6 The alkyl group is optionally partially or fully deuterated; L 1 is a bond or NR 6 , O, and S; R 6 is H, C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-6 cycloalkyl; Here, the C 3-6 Cycloalkyl is ═O, halogen, 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 7 R 8 ]p-, where p is an integer from 1 to 4; R 7 and R 8 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 7 and R 8 L 2 are attached together to the same carbon atom in C 3-6 forming a cycloalkyl or 3- to 6-membered heterocyclyl, Here, the C 1-4 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; Q 1 is C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; where C 6-10 Aryl and 5- to 10-membered heteroaryl may be one or more R 9 optionally replaced by; Each R 9 are independently halogen, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR 10 , -S(O) x R 10 , -N(R 10 )2, -C(O)R 10 , -OC(O)R 10 , -C(O)OR 10 , -NR 10 C(O)R 10 , -NR 10 C(O)OR10 , -C(O)N(R 10 )2, -OC(O)N(R 10 )2, -NR 10 SO2R 10 , -SO2N(R 10 )2, and -NR 10 C(O)N(R 10 )2 is selected; Here, the C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl is a group consisting of one or more R 11 optionally replaced by; Here, each R 10 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl; Here, each R 11 are independently halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl and NR X1 R X2 where R is selected from X1 and R X2 are each independently H, and C optionally substituted with OH or 3- to 6-membered heterocyclyl; 1-4 Alkyl, -OC 1-6 Alkyl, -C(O)-C 1-6 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; n is an integer from 0 to 4; and x is an integer from 0 to 3, where R 4 or R 5 C is not hydrogenated or deuterated 1-6 When it is alkyl, Z is -CN or -NR 1 R 2 and where R 1 and R 2At least one of the following is D or partially or fully deuterated C 1-6 It is alkyl.

[0097] In some embodiments, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof: In the above formula, The H ring in formula (I) is a carbon atom * 1 or * Concatenated with 2; Z is -NR 1 R 2 or -CN; R 1 and R 2 are each independently H, D and C 1-6 alkyl, wherein said C 1-6 The alkyl is optionally partially or fully deuterated; R 3 are each independently a halogen, C 1-6 selected from alkyl and amino; X 1 is N and X 2 is CR 4 or X 1 is C and X 2 is NR 5 and; X 3 is CH or N; R 4 , H, NR X1 R X2 , -OH and C 1-6 alkyl; R 5 is H and C 1-6 alkyl, where R 4 or R 5 The above C 1-6 The alkyl is optionally partially or fully deuterated; L 1 is a bond or NR 6 , O, and S; R 6 is H, C 1-4Alkyl, and C 1-4 haloalkyl; L 2 is a bond or -[CR 7 R 8 ]p-, where p is an integer from 1 to 4; R 7 and R 8 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 7 and R 8 L 2 are attached together to the same carbon atom in C 3-6 forming a cycloalkyl or 3- to 6-membered heterocyclyl, Here, the C 1-4 Alkyl is OH, OC 1-4 Alkyl, or halogen or C 1-6 C optionally substituted with haloalkyl 6-10 optionally substituted with aryl; Q 1 is C 3-12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; where C 6-10 Aryl and 5- to 10-membered heteroaryl may be one or more R 9 optionally replaced by; Each R 9 are independently halogen, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )2, -C(O)R 10 , -OC(O)R 10 , -C(O)OR 10 , -NR 10 C(O)R10 , -NR 10 C(O)OR 10 , -C(O)N(R 10 )2 and -OC(O)N(R 10 )2 is selected; Here, the C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl is a group consisting of one or more R 11 optionally replaced by; Here, each R 10 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl; Here, each R 11 are independently halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl and NR X1 R X2 where R is selected from X1 and R X2 are each independently H, and C optionally substituted with OH or 3- to 6-membered heterocyclyl; 1-4 Alkyl, -OC 1-6 Alkyl, -C(O)-C 1-6 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; n is an integer from 0 to 4; and x is an integer from 0 to 3; where R 4 or R 5 C is not hydrogenated or deuterated 1-6 When it is alkyl, Z is -CN or -NR 1 R 2 and where R 1 and R 2 At least one of the following is D or partially or fully deuterated C 1-6 It is alkyl.

[0098] In some embodiments, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof: In the above formula, The H ring in formula (I) is a carbon atom * 1 or * Concatenated with 2; Z is -NR 1 R 2 or -CN; R 1 and R 2 are each independently H, D and C 1-6 alkyl, wherein said C 1-6 The alkyl is optionally partially or fully deuterated; R 3 are each independently a halogen, C 1-6 selected from alkyl and amino; X 1 is N and X 2 is CR 4 or X 1 is C and X 2 is NR 5 and; X 3 is CH or N; R 4 , H, NR X1 R X2 , -OH and C 1-6 alkyl; R 5 is H and C 1-6 alkyl, where R 4 or R 5 The above C 1-6 The alkyl is optionally partially or fully deuterated; L 1 is a bond or NR 6 , O, and S; R 6 is H, C 1-4 Alkyl and C 1-4 haloalkyl; L 2is a bond or -[CR 7 R 8 ]p-, where p is an integer from 1 to 4; R 7 and R 8 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 7 and R 8 L 2 are attached together to the same carbon atom in C 3-6 forming a cycloalkyl or 3- to 6-membered heterocyclyl, Here, the C 1-4 Alkyl is OH, OC 1-4 Alkyl, or halogen or C 1-6 C optionally substituted with haloalkyl 6-10 optionally substituted with aryl; Q 1 is C 3-12 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; where C 6-10 Aryl and 5- to 10-membered heteroaryl may be one or more R 9 optionally replaced by; Each R 9 are independently halogen, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )2, -C(O)R 10 , -OC(O)R 10 , -C(O)OR 10 , -NR 10 C(O)R 10 , -NR 10 C(O)OR 10 , -C(O)N(R 10 )2 and -OC(O)N(R10 )2 is selected; Here, the C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl is a group consisting of one or more R 11 optionally replaced by; Here, each R 10 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl; Here, each R 11 are independently halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl and NR X1 R X2 where R is selected from X1 and R X2 are each independently H, or C optionally substituted with OH or 3- to 6-membered heterocyclyl; 1-4 Is it alkyl; n is an integer from 0 to 4; and x is an integer from 0 to 3; where R 4 or R 5 is H or undeuterated C 1-6 When Z is alkyl, it is -CN or -NR 1 R 2 and where R 1 and R 2 At least one of the following is D or partially or fully deuterated C 1-6 It is alkyl.

[0099] In some embodiments, there is provided a compound of formula (II) or a pharmaceutically acceptable salt thereof: JPEG2025541224000010.jpg56128In the above formula, The H ring in formula (II) is a carbon atom * 1 or * Concatenated with 2; R 1 and R 2 are independently H, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 haloalkyl; R 3 are each independently a halogen, C 1-6 selected from alkyl and amino; X 1 is N and X 2 is CR 4 or X 1 is C and X 2 is NR 5 and; X 3 is CH or N; R 4 and R 5 are each independently H, halogen, CN, or C 1-6 Alkyl and C 1-6 haloalkyl; L 1 is a bond or NR 6 , O, and S; R 6 is H, C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-6 cycloalkyl; Here, the C 3-6 Cycloalkyl is ═O, halogen, 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 7 R 8 ]p-, p is an integer from 1 to 4; R 7 and R 8 are independently H, C 1-4 Alkyl, C 6-10 Aryl, COO-C 1-6 Alkyl, NR X1 R X2 , C(O)NRX1 R X3 and 5- to 10-membered heteroaryl; where L 2 R 7 and R 8 At least one of them is not H, Said C 1-4 Alkyl is 3- to 6-membered cycloalkyl, C 4-8 Alkyl, or NR X1 R X2 is replaced by; Q 1 is C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; where C 6-10 Aryl and 5- to 10-membered heteroaryl may be one or more R 9 optionally replaced by; Each R 9 are independently halogen, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR 10 , -S(O) x R 10 , -N(R 10 )2, -C(O)R 10 , -OC(O)R 10 , -C(O)OR 10 , -NR 10 C(O)R 10 , -NR 10 C(O)OR 10 , -C(O)N(R 10 )2, -OC(O)N(R 10 )2, -NR 10 SO2R 10 , -SO2N(R 10 )2, and -NR 10 C(O)N(R 10 )2 is selected; Here, the C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl and C 1-6 Haloalkyl is one or more R 11 optionally replaced by; Here, each R 10 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl; Here, each R 11 are independently halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, NR X1 R X2 and C(O)NR X1 R X2 Selected from; where R X1 and R X2 are each independently H, OH, or C optionally substituted with 3- to 6-membered heterocyclyl; 1-4 Alkyl, OH, -OC 1-6 Alkyl, -C(O)-C 1-6 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; where R X3 OH and OC 1-6 alkyl; n is an integer from 0 to 4; and x is an integer of 0 to 3.

[0100] In some embodiments, there is provided a compound of formula (II) or a pharmaceutically acceptable salt thereof: In the above formula, The H ring in formula (II) is a carbon atom * 1 or * Concatenated with 2; R 1 and R 2 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl; R3 are each independently a halogen, C 1-6 selected from alkyl and amino; X 1 is N and X 2 is CR 4 or X 1 is C and X 2 is NR 5 and; X 3 is CH or N; R 4 and R 5 are each independently H, halogen, CN, or C 1-6 Alkyl and C 1-6 haloalkyl; L 1 is a bond or NR 6 , O, and S; R 6 is H, C 1-4 Alkyl and C 1-4 haloalkyl; L 2 is a bond or -[CR 7 R 8 ]p-, where p is an integer from 1 to 4; R 7 and R 8 are independently H, C 1-4 Alkyl, C 6-10 Aryl, COO-C 1-6 Alkyl, NR X1 R X2 , C(O)NR X1 R X3 and 5- to 10-membered heteroaryl; where L 2 R 7 and R 8 At least one of them is not H, Said C 1-4 Alkyl is 3- to 6-membered cycloalkyl, C 4-8 Alkyl, or NR X1 R X2is replaced by; Q 1 is C 3-12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; where C 6-10 Aryl and 5- to 10-membered heteroaryl may be one or more R 9 optionally replaced by; Each R 9 are independently halogen, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )2, -C(O)R 10 , -OC(O)R 10 , -C(O)OR 10 , -NR 10 C(O)R 10 , -NR 10 C(O)OR 10 , -C(O)N(R 10 )2 and -OC(O)N(R 10 )2 is selected; Here, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Haloalkyl is one or more R 11 optionally replaced by; Here, each R 10 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl; Here, each R 11 are independently halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, NR X1 R X2 and C(O)NR X1 R X2 Selected from; where R X1 and R X2are each independently H, OH, or C optionally substituted with 3- to 6-membered heterocyclyl; 1-4 Alkyl, OH, -OC 1-6 Alkyl, -C(O)-C 1-6 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; where R X3 OH and OC 1-6 alkyl; n is an integer from 0 to 4; and x is an integer of 0 to 3.

[0101] In some embodiments, there is provided a compound of formula (II) or a pharmaceutically acceptable salt thereof: In the above formula, The H ring in formula (II) is a carbon atom * 1 or * Concatenated with 2; R 1 and R 2 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl; R 3 are each independently a halogen, C 1-6 selected from alkyl and amino; X 1 is N and X 2 is CR 4 or X 1 is C and X 2 is NR 5 and; X 3 is CH or N; R 4 and R 5 are each independently H, halogen, CN, or C 1-6 Alkyl and C 1-6 haloalkyl; L 1is a bond or NR 6 , O, and S; R 6 is H, C 1-4 Alkyl and C 1-4 haloalkyl; L 2 is a bond or -[CR 7 R 8 ]p-, where p is an integer from 1 to 4; R 7 and R 8 are independently H, C 1-4 Alkyl, C 6-10 Aryl, COO-C 1-6 Alkyl, NR X1 R X2 , C(O)NR X1 R X3 and 5- to 10-membered heteroaryl; where L 2 R 7 and R 8 At least one of them is not H, Said C 1-4 Alkyl is 3- to 6-membered cycloalkyl, C 4-8 Alkyl, or NR X1 R X2 is replaced by; Q 1 is C 3-12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; where C 6-10 Aryl and 5- to 10-membered heteroaryl may be one or more R 9 optionally replaced by; Each R 9 are independently halogen, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )2, -C(O)R10 , -OC(O)R 10 , -C(O)OR 10 , -NR 10 C(O)R 10 , -NR 10 C(O)OR 10 , -C(O)N(R 10 )2 and -OC(O)N(R 10 )2 is selected; Here, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Haloalkyl is one or more R 11 optionally replaced by; Here, each R 10 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl; Here, each R 11 are independently halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, NR X1 R X2 and C(O)NR X1 R X2 where R is selected from X1 and R X2 are each independently H, OH, or C optionally substituted with 3- to 6-membered heterocyclyl; 1-4 Alkyl, OH, -OC 1-6 Alkyl and -C(O)-C 1-6 alkyl; where R X3 OH and OC 1-6 alkyl; n is an integer from 0 to 4; and x is an integer of 0 to 3.

[0102] In one preferred embodiment, the compound of formula (II) is JPEG2025541224000011.jpg41138

[0103] In one embodiment, there is provided a compound of formula (III) or a pharmaceutically acceptable salt thereof: JPEG2025541224000012.jpg52128In the above formula, The H ring in formula (III) is a carbon atom * 1 or * Concatenated with 2; R 1 and R 2 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 haloalkyl; R 3 are each independently a halogen, C 1-6 selected from alkyl and amino; X 1 is N and X 2 is CR 4 or X 1 is C and X 2 is NR 5 and; X 3 is CH or N; R 4 and R 5 are each independently H, halogen, CN, or C 1-6 Alkyl and C 1-6 haloalkyl; L 1 is a bond or NR 6 , O, and S; R 6 is H, C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-6 cycloalkyl; Here, the C 1-4 The alkyl is optionally partially or fully deuterated; Here, the C 3-6 Cycloalkyl is ═O, halogen, C 1-4 Alkyl and C 1-4optionally substituted with one or more substituents selected from haloalkyl; L 2 is a bond or -[CR 7 R 8 ]p-, where p is an integer from 1 to 4; R 7 and R 8 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 7 and R 8 L 2 are attached together to the same carbon atom in C 3-6 forming a cycloalkyl or 3- to 6-membered heterocyclyl, Here, the C 1-4 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; Q 1 is C 6-10 selected from aryl and 5- to 10-membered heteroaryl; where C 6-10 Aryl and 5- to 10-membered heteroaryl may be one or more R 9 optionally replaced by; Each R 9 are independently halogen, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, -OR 10 , -S(O)xR 10 , -N(R 10 )2, -C(O)R 10 , -OC(O)R 10, -C(O)OR 10 , -NR 10 C(O)R 10 , -NR 10 C(O)OR 10 , -C(O)N(R 10 )2, -OC(O)N(R 10 )2, -NR 10 SO2R 10 , -SO2N(R 10 )2, and -NR 10 C(O)N(R 10 )2 is selected; Here, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl may be one or more R 11 optionally replaced by; Here, the C 1-6 The alkyl is optionally partially or fully deuterated; Here, each R 10 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl; Here, each R 11 are independently halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl and NR X1 R X2 Selected from; where R X1 and R X2 are each independently H, OH, or C optionally substituted with 3- to 6-membered heterocyclyl; 1-4 Alkyl, -OC 1-6 Alkyl, -C(O)-C 1-6 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; n is an integer from 0 to 4; and x is an integer from 0 to 3; Here, Q 1 There are one or more R 9 is not replaced by or Q 1 One or more R 9 one of which is C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or partially or fully deuterated C 1-6 When it is not alkyl, R 6 is a partially or fully deuterated C 1-4 It is alkyl.

[0104] In one embodiment, there is provided a compound of formula (III) or a pharmaceutically acceptable salt thereof: In the above formula, The H ring in formula (III) is a carbon atom * 1 or * Concatenated with 2; R 1 and R 2 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 haloalkyl; R 3 are each independently a halogen, C 1-6 selected from alkyl and amino; X 1 is N and X 2 is CR 4 or X 1 is C and X 2 is NR 5 and; X 3 is CH or N; R 4 and R 5 are each independently H, halogen, CN, or C 1-6 Alkyl and C 1-6 haloalkyl; L 1 is a bond or NR 6and; R 6 is H, C 1-4 Alkyl and C 1-4 haloalkyl; Here, the C 1-4 The alkyl is optionally partially or fully deuterated; L 2 is a bond or -[CR 7 R 8 ]p-, where p is an integer from 1 to 4; R 7 and R 8 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 7 and R 8 L 2 are attached together to the same carbon atom in C 3-6 forming a cycloalkyl or 3- to 6-membered heterocyclyl, Here, the C 1-4 Alkyl is OH, OC 1-4 Alkyl, or halogen or C 1-6 C optionally substituted with haloalkyl 6-10 optionally substituted with aryl; Q 1 is C 6-10 selected from aryl and 5- to 10-membered heteroaryl; where C 6-10 Aryl and 5- to 10-membered heteroaryl may be one or more R 9 optionally replaced by; Each R 9 are independently halogen, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, -OR 10, -N(R 10 )2, -C(O)R 10 , -OC(O)R 10 , -C(O)OR 10 , -NR 10 C(O)R 10 , -NR 10 C(O)OR 10 , -C(O)N(R 10 )2 and -OC(O)N(R 10 )2 is selected; Here, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl may be one or more R 11 optionally replaced by; Here, the C 1-6 The alkyl is optionally partially or fully deuterated; Here, each R 10 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl; Here, each R 11 are independently halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl and NR X1 R X2 Selected from; where R X1 and R X2 are each independently H, OH, or C optionally substituted with 3- to 6-membered heterocyclyl; 1-4 Alkyl, -OC 1-6 Alkyl, -C(O)-C 1-6 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; n is an integer from 0 to 4; and x is an integer from 0 to 3; Here, Q 1 There are one or more R 9is not replaced by or Q 1 One or more R 9 one of which is C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or partially or fully deuterated C 1-6 When it is not alkyl, R 6 is a partially or fully deuterated C 1-4 It is alkyl.

[0105] In one embodiment, there is provided a compound of formula (III) or a pharmaceutically acceptable salt thereof: In the above formula, The H ring in formula (III) is a carbon atom * 1 or * Concatenated with 2; R 1 and R 2 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 haloalkyl; R 3 are each independently a halogen, C 1-6 selected from alkyl and amino; X 1 is N and X 2 is CR 4 or X 1 is C and X 2 is NR 5 and; X 3 is CH or N; R 4 and R 5 are each independently H, halogen, CN, or C 1-6 Alkyl and C 1-6 haloalkyl; L 1 is a bond or NR 6 and; R 6 is H, C1-4 Alkyl and C 1-4 haloalkyl; Here, the C 1-4 The alkyl is optionally partially or fully deuterated; L 2 is a bond or -[CR 7 R 8 ]p-, where p is an integer from 1 to 4; R 7 and R 8 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 7 and R 8 L 2 are attached together to the same carbon atom in C 3-6 forming a cycloalkyl or 3- to 6-membered heterocyclyl, Here, the C 1-4 Alkyl is OH, OC 1-4 Alkyl, or halogen or C 1-6 C optionally substituted with haloalkyl 6-10 optionally substituted with aryl; Q 1 is C 6-10 selected from aryl and 5- to 10-membered heteroaryl; where C 6-10 Aryl and 5- to 10-membered heteroaryl may be one or more R 9 optionally replaced by; Each R 9 are independently halogen, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, -OR 10 , -N(R 10 )2, -C(O)R10 , -OC(O)R 10 , -C(O)OR 10 , -NR 10 C(O)R 10 , -NR 10 C(O)OR 10 , -C(O)N(R 10 )2 and -OC(O)N(R 10 )2 is selected; Here, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl may be one or more R 11 optionally replaced by; Here, the C 1-6 The alkyl is optionally partially or fully deuterated; Here, each R 10 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl; Here, each R 11 are independently halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl and NR X1 R X2 Selected from; where R X1 and R X2 are each independently H, OH, or C optionally substituted with 3- to 6-membered heterocyclyl; 1-4 alkyl; n is an integer from 0 to 4; and x is an integer from 0 to 3; Here, Q 1 There are one or more R 9 is not replaced by or Q 1 One or more R 9 one of which is C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or partially or fully deuterated C 1-6 When it is not alkyl, R 6 is a partially or fully deuterated C 1-4 It is alkyl.

[0106] In one embodiment, there is provided a compound of formula (IV) below, or a pharmaceutically acceptable salt thereof: JPEG2025541224000013.jpg53128

[0107] Here, the R 1 and R 2 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 haloalkyl; R 3 are each independently a halogen, C 1-6 selected from alkyl and amino; X 1 is N and X 2 is CR 4 or X 1 is C and X 2 is NR 5 and; X 3 is CH or N; R 4 , R 5 and R 12 are each independently H, halogen, CN, or C 1-6 Alkyl and C 1-6 haloalkyl; where X 1 If is N, then X 4 is N and X 5 is CH or X 4 is CH and X 5 is N; where X 1 If C, then X 4 and X 5 are both CH; Here, the R4 and R 5 C 1-6 The alkyl is optionally partially or fully deuterated; L 1 is a bond or NR 6 , O, and S; R 6 is H, C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-6 cycloalkyl; Here, the C 3-6 Cycloalkyl is ═O, halogen, 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 7 R 8 ]p-, where p is an integer from 1 to 4; R 7 and R 8 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 7 and R 8 L 2 are attached together to the same carbon atom in C 3-6 forming a cycloalkyl or 3- to 6-membered heterocyclyl, Here, the C 1-4 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; Q 1 is C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3- to 12-membered heterocyclyl, C 6-10aryl, and 5- to 10-membered heteroaryl; where C 6-10 Aryl and 5- to 10-membered heteroaryl may be one or more R 9 optionally replaced by; Each R 9 are independently halogen, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR 10 , -S(O) x R 10 , -N(R 10 )2, -C(O)R 10 , -OC(O)R 10 , -C(O)OR 10 , -NR 10 C(O)R 10 , -NR 10 C(O)OR 10 , -C(O)N(R 10 )2, -OC(O)N(R 10 )2, -NR 10 SO2R 10 , -SO2N(R 10 )2, and -NR 10 C(O)N(R 10 )2 is selected; Here, the C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl is a group consisting of one or more R 11 optionally replaced by; Here, each R 10 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl; Here, each R 11 are independently halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl and NR X1 R X2 Selected from; where R X1 and R X2are each independently H, OH, or C optionally substituted with 3- to 6-membered heterocyclyl; 1-4 Alkyl, -OC 1-6 Alkyl, -C(O)-C 1-6 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; n is an integer from 0 to 4; and x is an integer of 0 to 3.

[0108] In one embodiment, there is provided a compound of formula (IV) or a pharmaceutically acceptable salt thereof: Here, the R 1 and R 2 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 haloalkyl; R 3 are each independently a halogen, C 1-6 selected from alkyl and amino; X 1 is N and X 2 is CR 4 or X 1 is C and X 2 is NR 5 and; X 3 is CH or N; R 4 , R 5 and R 12 are each independently H, halogen, CN, or C 1-6 Alkyl and C 1-6 haloalkyl; where X 1 If is N, then X 4 is N and X 5 is CH or X 4 is CH and X5 is N; where X 1 If C, then X 4 and X 5 are both CH; Here, the R 4 and R 5 C 1-6 The alkyl is optionally partially or fully deuterated; L 1 is a bond or NR 6 and; R 6 is H, C 1-4 Alkyl and C 1-4 haloalkyl; L 2 is a bond or -[CR 7 R 8 ]p-, where p is an integer from 1 to 4; R 7 and R 8 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 7 and R 8 L 2 are attached together to the same carbon atom in C 3-6 forming a cycloalkyl or 3- to 6-membered heterocyclyl, Here, the C 1-4 Alkyl is OH, OC 1-4 Alkyl, or halogen or C 1-6 C optionally substituted with haloalkyl 6-10 optionally substituted with aryl; Q 1 is C 3-12 Cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; where C 6-10Aryl and 5- to 10-membered heteroaryl may be one or more R 9 optionally replaced by; Each R 9 are independently halogen, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )2, -C(O)R 10 , -OC(O)R 10 , -C(O)OR 10 , -NR 10 C(O)R 10 , -NR 10 C(O)OR 10 , -C(O)N(R 10 )2 and -OC(O)N(R 10 )2 is selected; Here, the C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl is a group consisting of one or more R 11 optionally replaced by; Here, each R 10 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl; Here, each R 11 are independently halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl and NR X1 R X2 Selected from; where R X1 and R X2 are each independently H, OH, or C optionally substituted with 3- to 6-membered heterocyclyl; 1-4 Alkyl, -OC 1-6 Alkyl, -C(O)-C 1-6 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; n is an integer from 0 to 4; and x is an integer of 0 to 3.

[0109] In one embodiment, there is provided a compound of formula (IV) or a pharmaceutically acceptable salt thereof: Here, the R 1 and R 2 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 haloalkyl; R 3 are each independently a halogen, C 1-6 selected from alkyl and amino; X 1 is N and X 2 is CR 4 or X 1 is C and X 2 is NR 5 and; X 3 is CH or N; R 4 , R 5 and R 12 are each independently H, halogen, CN, or C 1-6 Alkyl and C 1-6 haloalkyl; where X 1 If is N, then X 4 is N and X 5 is CH or X 4 is CH and X 5 is N; where X 1 If C, then X 4 and X 5 are both CH; Here, the R 4 and R 5 C 1-6 The alkyl is optionally partially or fully deuterated; L 1is a bond or NR 6 and; R 6 is H, C 1-4 Alkyl or C 1-4 haloalkyl; L 2 is a bond or -[CR 7 R 8 ]p-, where p is an integer from 1 to 4; R 7 and R 8 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 7 and R 8 L 2 are attached together to the same carbon atom in C 3-6 forming a cycloalkyl or 3- to 6-membered heterocyclyl, Here, the C 1-4 Alkyl is OH, OC 1-4 Alkyl, or halogen or C 1-6 C optionally substituted with haloalkyl 6-10 optionally substituted with aryl; Q 1 is C 3-12 Cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; where C 6-10 Aryl and 5- to 10-membered heteroaryl may be one or more R 9 optionally replaced by; Each R 9 are independently halogen, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )2, -C(O)R 10 , -OC(O)R10 , -C(O)OR 10 , -NR 10 C(O)R 10 , -NR 10 C(O)OR 10 , -C(O)N(R 10 )2 and -OC(O)N(R 10 )2 is selected; Here, the C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl is a group consisting of one or more R 11 optionally replaced by; Here, each R 10 are independently H, C 1-6 Alkyl and C 1-6 haloalkyl; Here, each R 11 are independently halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Haloalkyl and NR X1 R X2 Selected from; where R X1 and R X2 are each independently H, or C optionally substituted with OH or 3- to 6-membered heterocyclyl; 1-4 alkyl; n is an integer from 0 to 4; and x is an integer of 0 to 3.

[0110] In one preferred embodiment, the compound of formula (IV) is JPEG2025541224000014.jpg21128

[0111] In a preferred embodiment, a compound of formula (I), (II) or (III) JPEG2025541224000015.jpg76147

[0112] JPEG2025541224000016.jpg93148

[0113] JPEG2025541224000017.jpg109148

[0114] In a preferred embodiment, -L in the compound of formula (I), (II), (III) or (IV) 1 -L 2 -Q 1 The group may be selected from one of the following structures: JPEG2025541224000018.jpg121147JPEG2025541224000019.jpg133147JPEG2025541224000020.jpg152147JPEG2025541224000021.jpg200147

[0115] In still other embodiments, there is provided a compound selected from any one of Compound Nos. 1 to 239 listed in Table 1 herein, or a pharmaceutically acceptable salt or precursor thereof.

[0116] [Table 1] JPEG2025541224000023.jpg220156JPEG2025541224000024.jpg221156JPEG2025541224 000025.jpg228154JPEG2025541224000026.jpg222156JPEG2025541224000027.jpg22215 6JPEG2025541224000028.jpg231156JPEG2025541224000029.jpg225156JPEG2025541224 000030.jpg223156JPEG2025541224000031.jpg227156JPEG2025541224000032.jpg29156

[0117] 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.

[0118] 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.

[0119] 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 or oily solutions for intravenous, subcutaneous, intramuscular or intraperitoneal administration or suppositories for rectal administration).

[0120] The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may, for example, contain one or more coloring, sweetening, flavoring and / or preservative agents.

[0121] 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.

[0122] 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.

[0123] The magnitude of the dose of the compounds of the 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.

[0124] 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.

[0125] 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 is used. Preferably, the compounds of the present invention are administered orally, for example, in tablet or capsule dosage form. Orally administered daily doses may be, for example, a total daily dose 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 contains 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.

[0126] 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.

[0127] 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 microtubule-associated serine / threonine-like kinase (MASTL).

[0128] 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 in which PD-L1 expression is dependent on interferon.

[0129] CN 116942819 discloses the use of MASTL inhibitors to prepare drugs for treating tumors whose PD-L1 expression is dependent on interferon. MASTL Kinase Inhibitor-1 (MKI-1) significantly suppressed the upregulation of interferon-induced PD-L1 expression in breast cancer MDA-MB-468 cells, effectively enhancing the antitumor function of T cells. However, it had no effect on the expression of tumor cells (breast cancer MDA-MB-231 cells) that express high levels of PD-L1 but are not affected by interferon.

[0130] In some embodiments, the disease in which PD-L1 expression is dependent on interferon is a proliferative disease. In some embodiments, the proliferative disease is cancer, and optionally the cancer is selected from breast cancer, ovarian cancer, lung cancer, colorectal cancer, prostate cancer, oral cancer, gastric cancer, adrenocortical carcinoma, pancreatic cancer, kidney cancer, sarcoma, liver cancer, endometrial cancer, thyroid cancer, head and neck cancer, brain cancer (e.g., glioma), melanoma (e.g., ocular melanoma), and blood cancer (e.g., leukemia such as AML, lymphoma, myeloma, and multiple myeloma).

[0131] 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 MASTL.

[0132] 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.

[0133] 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.

[0134] The MASTL-mediated medical condition disease may be any of the diseases or medical conditions listed in this application, such as a proliferative disorder, in particular cancer.

[0135] 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, mouse, dog, cat, primate, or horse.

[0136] 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 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.

[0137] 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)). Depletion of MASTL has been shown to increase the radiosensitivity of breast cancer cells and reduce the formation of radioresistant breast cancer cells, suggesting the 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 be relatively nontoxic.

[0138] In certain embodiments, the compounds of the present invention are for use in the treatment of proliferative disorders, including cancer and benign proliferative disorders.

[0139] 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.

[0140] In certain embodiments, the compounds of the present invention are for use in the treatment of cancer.

[0141] In certain embodiments, the compounds of the present invention are for use in treating cancers that overexpress MASTL. The compounds of the present invention may be useful in treating and / or preventing, for example:

[0142] Carcinomas include tumors derived from stratified squamous epithelium (squamous cell carcinomas) and tumors arising within organs or glands (adenocarcinomas), 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 (including, but not limited to, colon and rectal cancer), anal cancer, gastric cancer, lung cancer (including but not limited to small cell carcinoma and non-small cell carcinoma, 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 ovarian epithelial carcinoma or intestinal liquid tumors, surface epithelial tumors including endometrioid tumors and mucinous cystadenocarcinoma, 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, myeloma), germ cell tumors, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, Renal carcinoma (including but not limited to renal cell carcinoma, clear cell carcinoma, and Wilms' tumor), medullary 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, papillary-interstitial carcinoma, uterine clear cell carcinoma, uterine fibroids and leiomyosarcoma, mixed Mullerian tumor), testicular cancer, osteosarcoma, epithelial carcinoma, sarcomatoid carcinoma, nasopharyngeal carcinoma, laryngeal carcinoma; oral and oropharyngeal squamous cell carcinoma.

[0143] Sarcomas, including: 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 (neural connective tissue found in the brain); myxosarcoma (primitive embryonic connective tissue); chordoma, endothelioma, lymphangiosarcoma, lymphangioendosarcoma, synovioma, Ewing's sarcoma, mesenchymoma and mixed mesodermal tumors (mixed connective tissue type) and other soft tissue sarcomas.

[0144] Solid tumors of the nervous system include medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, and schwannoma.

[0145] melanoma, uveal melanoma and retinoblastoma; Myeloma and multiple myeloma include myeloma-related conditions, including light chain myeloma, non-secretory myeloma, plasmacytoma, amyloidosis, smoldering multiple myeloma (SMM), immunoglobulin D myeloma, immunoglobulin E myeloma, and monoclonal gammopathy of undetermined significance (MGUS).

[0146] Myeloid and granulocytic leukemias (malignancies of the myeloid and granulocytic leukemia lineage, e.g., acute myeloid leukemia (AML)); lymphoid, lymphocytic, and lymphoblastic leukemias (malignancies of the lymphocytic and lymphocytic blood lineage); polycythemia vera and polycythemia (malignancies of various blood cell products, but predominantly erythrocytes); hematopoietic tumors, including myelofibrosis; and Lymphoma, including Hodgkin's and non-Hodgkin's lymphoma.

[0147] 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.

[0148] 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).

[0149] 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 protein Ki-67); luminal B breast cancer (hormone-receptor positive (estrogen-receptor and / or progesterone-receptor positive) and high levels of Ki-67, HER2-positive or HER2-negative); 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 defined in Table 1 of Dai et al., Am. J. Cancer Research. 2015;5(10):2929-2943).

[0150] 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.

[0151] In one embodiment, the compounds of the invention provide an anti-cancer effect 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, an inhibition of cell migration, an inhibition or prevention of tumor invasion and / or a prevention or prevention of metastasis.

[0152] The compounds of the present invention can be used to prevent or inhibit the progression of cancer. The compounds of the present invention may be used to slow, delay, or halt the progression of cancer. Cancer progression is generally determined by assigning a stage to the cancer. Staging is generally carried out by assigning a number from I to IV to the cancer, with I representing isolated cancer and IV representing an advanced stage of disease in which the cancer has metastasized to other organs. The stage is generally determined by taking into account the size of the tumor, whether it has involved adjacent organs, the number of lymph nodes involved, and whether the cancer has metastasized. Preventing or inhibiting cancer progression is particularly important for preventing the spread of cancer. For example, cancer may progress from stage I to stage II, in which it spreads locally, or from stage III to stage IV, in which it has metastasized to other organs.

[0153] 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.

[0154] The compounds of the invention may be for use in preventing or inhibiting the development of second primary cancers.

[0155] 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 from the start of treatment or may develop resistance during treatment.

[0156] The compounds of the present invention are intended to be used in the treatment of cancer, wherein the cancer is a recurrent cancer that can occur locally, adjacently, or at a distant site. A recurrent cancer is a cancer that recurs after a period in which the cancer cannot be detected after initial treatment. The same cancer can recur in the same tissue or in another part of the body.

[0157] The compounds of the invention may be for use in preventing or inhibiting the recurrence of cancer.

[0158] The compounds of the invention may be for use in the treatment of cancer, wherein the cancer is a metastatic or secondary cancer.

[0159] The compounds of the present invention may be used to prevent or inhibit cancer metastasis. The treatment for metastatic cancer may be the same as or different from the treatment previously used to treat the primary tumor. For example, in certain embodiments, the primary tumor may be surgically removed, and the compounds of the present invention may be 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 improve the effectiveness of cancer treatment and maximize the length and depth of remission. Any combination therapy disclosed herein may be used with the compounds of the present invention.

[0160] 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 may 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 located in a tissue different from 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.

[0161] Benign proliferative disorders The compound of the present invention, or a pharmaceutically acceptable salt thereof, may be used to treat a benign proliferative disease. The benign disease may be a benign tumor, such as hemangioma, hepatocellular adenoma (HCA), cavernous hemangioma, focal nodular hyperplasia, acoustic neuroma, neurofibroma, bile duct adenoma, bile duct cystadenoma, fibroma, lipoma, leiomyoma, mesothelioma, teratoma, myxoma, nodular regenerative hyperplasia, trachoma, pyogenic granuloma, mole, uterine fibroid, thyroid adenoma, adrenal cortical adenoma, or pituitary adenoma.

[0162] 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).

[0163] 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.

[0164] The metabolic disorder may be a glucose metabolic disorder or a weight disorder.

[0165] The term "dysglycemia" includes any disorder 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 diseases, disorders and conditions such as: hyperglycemia, type 2 diabetes, gestational diabetes, type 1 diabetes, insulin resistance, impaired glucose tolerance, hyperinsulinemia, dysglycemia, pre-diabetes, other metabolic disorders (e.g., metabolic syndrome), and obesity.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] 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 individual, 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 are considered normal weight; adults with a BMI between -25 and -29.9 kg / m are considered overweight (pre-obese); and adults with a BMI of -30 kg / m or greater are considered obese. Thus, in some embodiments, the weight disorder is obesity.

[0170] 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, and diabetic cardiomyopathy.

[0171] 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.

[0172] 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.

[0173] In certain embodiments, the compounds of the present invention are for use in treating a platelet disorder, such as thrombocytopenia.

[0174] 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.

[0175] 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.

[0176] In some embodiments, the compounds of the present invention are used in combination with one or more anti-cancer agents and / or radiation therapy.

[0177] 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)). MASTL kinase, a promising therapeutic target, promotes cancer recurrence (Oncotarget 5 11479-11489; Nagel et al., (2015)). Genome-wide siRNA screens confirm the radiation-reducing effects of downregulating MASTL and FOXM1 in NSCLC (Mol. Cancer Ther. 14 1434-1444; Uppada et al. (2018)). MASTL promotes Wnt / β-catenin signaling to induce colorectal cancer progression and chemoresistance (Mol. Cancer 17:111; Yoon et al., (2018)). MASTL inhibition promotes mitotic catastrophe through PP2A activation to inhibit cancer growth and radioresistance in breast cancer cells.BMC Cancer 18:716).

[0178] 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.

[0179] 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, triethylenethiopheneamine, carmustine, lomustine, streptozocin, and dacarbazine); antimetabolites ( antifolates and hydroxyureas such as gemcitabine, 5-fluorouracil, and tegafur; antifolates such as raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine; antibiotics (e.g., anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitogens, thiazolinone); mycin-C, dactinomycin, and mithramycin); antimitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, taxoids such as taxol and taxotere, and polokinase 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, mitoxin, thiazolinone ... xantrone and camptothecin; bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol™), nab-paclitaxel (albumin-bound paclitaxel), docetaxel, mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferons (especially IFN-alpha), etoposide, teniposide, DNA-dimethylating 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 inhibitors of 5α-reductase 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)-kissin, EGFR family tyrosine kinase inhibitors such as nazolin-4-amine (CI1033), 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; modules of protein regulators of cellular apoptosis 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, CSF-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; (v) antiangiogenic agents that inhibit the effects of vascular endothelial growth factor, such as 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 that replace genes such as abnormal p53 or abnormal BRCA1 or BRCA2; (vii) immunotherapeutic approaches, e.g., 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); gp100; dendritic cell-based vaccines (Ad.p53 such as DCs; toll-like receptor (TLR) modulators, e.g., TLR-7 or TLR-9 agonists; PD-1, PD-L1, PD-L2, and CTLA-4-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; also, anti-CTLA-4 antibodies (such as ipilimumab); antibody therapies such as CAR-T cell therapies; and (viii) cytotoxic agents, such as fludaribine (fludara), cladribine, pentostatin (Nipent™); (ix) targeted therapies, such as PI3K inhibitors, e.g., idelalisib and perifosine; SMAC (second mitochondrial-mediated activator of caspases) mimetics, and also known as inhibitor of apoptosis protein (IAP) antagonists (IAP antagonists). Such agonists inhibit IAPs, such as XIAP, cIAP1, and cIAP2, and redirect the cell's 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 Therapeutics), and HGS1029 (Human Genome Sciences); 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 PEGPH2O.

[0180] The additional anti-cancer agent may be in a single formulation or in one or more of the additional formulations described herein.

[0181] 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).

[0182] 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).

[0183] Therapeutic agents for the treatment or prevention of metabolic disorders may include one or more of the following: (i) diabetes medications, 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).

[0184] 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.

[0185] 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" means administered simultaneously. In another embodiment of the invention, "combination" means administered separately. In an additional embodiment of the invention, "combination" means administered sequentially. If administration is sequential or separate, the beneficial effect of the combination should not be lost by delaying the administration of the second component.

[0186] 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 combined amount is a "therapeutically effective amount" if, when combined, it is sufficient to reduce or completely alleviate the symptoms or other adverse effects of the disease; treat the disease; reverse, completely halt, or slow the progression of the disease; or reduce the risk of worsening the disease. Generally, such amounts can be determined by one of 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.

[0187] 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.

[0188] 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.

[0189] 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.

[0190] 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.

[0191] 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 treatments are well known and commercially available.

[0192] 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.

[0193] 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.

[0194] biological analysis The biological effect of a compound can be assessed using one of the assays described in the Examples herein.

[0195] In certain embodiments, compounds have a pIC of 7.0 or less in the MASTLwt activity assay described in the Examples. 50 It has.

[0196] synthesis The compounds of the present invention can be prepared using methods similar to the general synthetic methods described in the Examples. In the description of the synthetic methods set forth below and in the description of the referenced synthetic methods used to prepare starting materials, it should be understood that all reaction conditions suggested, including the choice of solvent, reaction environment, reaction temperature, duration of experiment, and work procedure, can be selected by those skilled in the art.

[0197] It is understood by those skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions employed.

[0198] Necessary starting materials can be obtained by standard procedures of organic chemistry. The preparation of such starting materials is illustrated by the following representative process variants and the accompanying examples. Alternatively, necessary starting materials can be obtained through analogous procedures that are within the ordinary skill of an organic chemist.

[0199] In the steps defined below, during the synthesis of the compounds of the invention or of particular starting materials, it will be appreciated that it may be desirable to protect certain substituents to prevent these undesired reactions. The skilled chemist will recognize when such protection is required and how to place and subsequently remove protecting groups.

[0200] Examples of protecting groups can be found in one of many general references on the subject, such as "Protective Groups in Organic Synthesis" by Theodora Green (publisher: John Wiley & Sons). Protecting groups can be removed by methods described in the literature or by any convenient method known to skilled chemists to be suitable for removing the protecting group in question, with such method being chosen so as to remove the protecting group with minimal interference with groups elsewhere in the molecule.

[0201] 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.

[0202] 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 with 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, for example, by treatment with a suitable acid such as sulfuric or phosphoric acid or trifluoroacetic acid, and allylmethoxycarbonyl groups such as benzyloxycarbonyl groups may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon or by treatment with a Lewis acid such as BF3.OE2. 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.

[0203] 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 such as 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 such as benzyl groups can be removed by hydrogenation over a catalyst, e.g., palladium-on-carbon.

[0204] 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 base 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.

[0205] The resin can also be used as a protecting group. [Example]

[0206] As used herein, the abbreviations have the following meanings: Aq. = aqueous solution 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 = propylphosphonic 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

[0207] material and method Unless otherwise specified herein, solvents, reagents, and starting materials were purchased from commercial suppliers. All reactions were carried out at room temperature unless otherwise specified. Flash column chromatography was performed using an ISCO Combiflash Nextgen or Biotage Selekt with packed columns filled with Merck silica gel 60 (40-63 μm) or C18 flash silica.

[0208] 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 50 mm × 4.6 mm column using water and acetonitrile acidified with 0.1% formic acid at a rate of 1.5 mL / min and detected at 254 nm.

[0209] The following methods were used: Method 1: 4 minute method The gradient used 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 used 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: 5 minute method The gradient used 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

[0210] chemical synthesis Microwave reactions were carried out using a Biotage Robot 60+ microwave reactor.

[0211] Intermediate A1 JPEG2025541224000033.jpg241286-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyrimidine Step 1: N-[(5-bromopyrimidin-2-yl)methyl]acetamide To a solution of (5-bromopyrimidin-2-yl)methanamine (3.23 g, 17.16 mmol) in DCM (30 mL) was added EtN (5.21 g, 51.48 mmol, 7.17 mL) and acetyl chloride (2.69 g, 34.32 mmol) dropwise at 0 °C. After the addition, the mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with HO (50 mL) and extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (40 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give N-[(5-bromopyrimidin-2-yl)methyl]acetamide (2.44 g, 53.84% yield) as a yellow solid. MS(ESI) m / z=232.0 [M+H]+.

[0212] Step 2: 3-Bromo-6-methyl-imidazo[1,5-a]pyrimidine A mixture of N-[(5-bromopyrimidin-2-yl)methyl]acetamide (2.64 g, 11.48 mmol) and POC13 (5.28 g, 34.43 mmol, 3.20 mL) in toluene (25 mL) was degassed and purged with N. The mixture was stirred at 110 °C under N for 12 h. The reaction mixture was diluted with HO (50 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with brine (40 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 3-bromo-6-methyl-imidazo[1,5-a]pyrimidine (0.65 g, 26.02% yield) as a yellow solid. MS(ESI) m / z=212.0 [M+H]+.

[0213] Step 3: 6-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyrimidine A mixture of 3-bromo-6-methyl-imidazo[1,5-a]pyrimidine (200 mg, 943.19 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.40 g, 9.43 mmol), AcOK (277.70 mg, 2.83 mmol), and Pd(dppf)Cl (34.51 mg, 47.16 μmol) in dioxane (3 mL) was degassed and purged with N, after which the mixture was stirred at 100 °C under N atmosphere for 5 h. The reaction mixture was concentrated under reduced pressure to give a yellow solid, 6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyrimidine (2.67 g, crude material). MS(ESI)m / z=178.0[boronic acid+H]+.

[0214] Intermediate A2 JPEG2025541224000034.jpg271286-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridin-3-ol Step 1: 6-Bromoimidazo[1,5-a]pyridin-3-ol To a solution of (5-bromo-2-pyridyl)methanamine (3 g, 13.42 mmol) in DCM (60 mL) was added a solution of NaHCO (3.38 g, 40.27 mmol) in HO (30 mL) and a solution of triphosgene (3.98 g, 13.42 mmol) in DCM (60 mL) dropwise at 0 °C. The mixture was then stirred at 25 °C under a N atmosphere for 3 h. The aqueous layer was separated and extracted with DCM (50 mL × 3). The organic layer was washed with brine (50 mL), dried over NaSO, and concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography to give 6-bromoimidazo[1,5-a]pyridin-3-ol (640 mg, 22.38% yield) as a yellow solid. MS(ESI) m / z=213.1 [M+H]+.

[0215] Step 2: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridin-3-ol To a stirred solution of 6-bromoimidazo[1,5-a]pyridin-3-ol (300 mg, 1.41 mmol) in 1,4-dioxane (4 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (429.13 mg, 1.69 mmol), AcOK (276.42 mg, 2.82 mmol), and Pd(dppf)Cl (115.00 mg, 140.82 μmol) under a N atmosphere, and the reaction mixture was stirred at 110 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridin-3-ol (300 mg crude) as a yellow solid. MS(ESI)m / z=161.1[boronic acid+H]+.

[0216] Intermediate A3 JPEG2025541224000035.jpg291281-Fluoro-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine Step 1: 6-Bromo-1-fluoro-3-methyl-imidazo[1,5-a]pyridine To a solution of 6-bromo-3-methyl-imidazo[1,5-a]pyridine (250 mg, 1.18 mmol) in DMF (5 mL) was added 1-fluoro-2,4,6-trimethyl-pyridin-1-ium; tetrafluoroborate (537.72 mg, 2.37 mmol). After the addition, the mixture was stirred at 60 °C for 1 hour, and then 1-fluoro-2,4,6-trimethyl-pyridin-1-ium; tetrafluoroborate (537.72 mg, 2.37 mmol) was added. After the addition, the mixture was stirred at 60 °C for 1 hour, and then 1-fluoro-2,4,6-trimethyl-pyridin-1-ium; tetrafluoroborate (537.72 mg, 2.37 mmol) was added. The mixture was stirred at 60 °C for 10 hours under a N atmosphere. The reaction mixture was quenched by the addition of HO (5 mL). The residue was purified by column chromatography to give 6-bromo-1-fluoro-3-methyl-imidazo[1,5-a]pyridine (43 mg, 187.73 μmol, 15.85% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6)δ=8.35 (s, 1H), 7.42 (d, 1H), 6.70 (d, 1H), 2.52 (s, 3H)

[0217] Step 2: 1-Fluoro-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine To a solution of 6-bromo-1-fluoro-3-methyl-imidazo[1,5-a]pyridine (88 mg, 384.20 μmol) in dioxane (2 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (117.08 mg, 461.04 μmol), KOAc (75.41 mg, 768.40 μmol), and Pd(dppf)Cl2 (15.69 mg, 19.21 μmol). The mixture was stirred at 110 °C under a N2 atmosphere for 12 hours. The mixture was filtered and concentrated under reduced pressure to give a residue. After adding a small amount of DCM (0.5 mL) to the residue, the suspension was filtered through a Celite pad, and the filter cake was washed with petroleum ether (5 mL). The combined filtrates were concentrated to dryness to give the crude product, 1-fluoro-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine (130 mg crude) as a brown oil. 1H NMR (400 MHz, , DMSO-d6)δ=8.05 (s, 1H), 7.37 (dd, 1H), 6.69 (d, 1H), 2.56 (s, 3H), 1.31 (s, 12H)

[0218] Intermediate A4 JPEG2025541224000036.jpg241286-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trideuteriomethyl)indazole Step 1: 6-Bromo-1-(trideuteriomethyl)indazole

[0219] To a stirred solution of 6-bromo-1H-indazole (20 g, 101.51 mmol) in THF (240 mL) was added 60% NaH (4.47 g, 111.66 mmol) at 0 °C, followed by trideuterio(iodo)methane (21.61 g, 152.26 mmol), and the reaction mixture was stirred at 20 °C for 2 h under a N atmosphere. The reaction mixture was quenched by the addition of HO (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash silica gel chromatography to give 6-bromo-1-(trideuteriomethyl)indazole (11.6 g, 53.38% yield) as a red oil. MS(ESI) m / z=214.1 [M+H]+.

[0220] Step 2: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trideuteriomethyl)indazole To a stirred solution of 6-bromo-1-(trideuteriomethyl)indazole (10.6 g, 49.51 mmol) in 1,4-dioxane (206 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (15.09 g, 59.42 mmol), AcOK (9.72 g, 99.03 mmol), and Pd(dppf)Cl (4.04 g, 4.95 mmol) under a N atmosphere, and the reaction mixture was stirred at 110 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trideuteriomethyl)indazole (11.4 g, 88.16% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6)δ=8.06 (d, 1H), 7.94 (d, 1H), 7.74 (dd, 1H), 7.40 (d, 1H), 1.32 (s, 12H).

[0221] General synthetic approach to intermediate B JPEG2025541224000037.jpg68143N-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridin-3-amine Step 1: 1-[(5-bromo-2-pyridyl)methyl]-3-methyl-thiourea To a stirred solution of (5-bromo-2-pyridyl)methanamine (2 g, 8.95 mmol) in DCM (20 mL) was added DIPEA (2.31 g, 17.90 mmol) and methylimino(thioxo)methane (654.30 mg, 8.95 mmol), and the reaction mixture was stirred at 15 °C under a N atmosphere for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography to give 1-[(5-bromo-2-pyridyl)methyl]-3-methyl-thiourea (2.13 g, 91.49% yield) as a green solid. MS(ESI) m / z=261.5 [M+H]+.

[0222] Step 2: 6-Bromo-N-methyl-imidazo[1,5-a]pyridin-3-amine To a stirred solution of 1-[(5-bromo-2-pyridyl)methyl]-3-methyl-thiourea (2.13 g, 8.19 mmol) in DCM (18 mL) and DMF (6 mL) was added DIPEA (2.12 g, 16.37 mmol) and EDCI (2.35 g, 12.28 mmol), and the reaction mixture was stirred at 15 °C under a N atmosphere for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography to give 6-bromo-N-methyl-imidazo[1,5-a]pyridin-3-amine (1.3 g, 70.23% yield) as a green solid. MS(ESI) m / z=226.1 [M+H]+.

[0223] Step 3: N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridin-3-amine To a stirred solution of 6-bromo-N-methyl-imidazo[1,5-a]pyridin-3-amine (1.3 g, 5.75 mmol) in dioxane (30 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.75 g, 6.90 mmol), AcOK (1.13 g, 11.50 mmol), and Pd(dppf)Cl (469.60 mg, 575.04 μmol), and the reaction mixture was stirred at 110° C. under a N atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridin-3-amine (597 mg, 2.19 mmol, 38.01% yield) as a green solid. 1H NMR (400 MHz, DMSO-d6)δ=8.06 (s, 1H), 7.93 (s, 1H), 7.16 (d, 1H), 6.86 (s, 1H), 6.48-6.44 (m, 1H), 6.42 (d, 1H), 2.88 (d, 3H), 1.29 (s, 12H). JPEG2025541224000038.jpg30144

[0224] A general synthetic approach to intermediate C (imidazole amines) JPEG2025541224000039.jpg76140(R or S)-1-(2-(trifluoromethyl)-1H-imidazol-4-yl)propan-1-amine Step 1: Trimethyl-[2-[[2-(trifluoromethyl)imidazol-1-yl]methoxy]ethyl]silane A mixture of 2-(trifluoromethyl)-1H-imidazole (3.00 g, 22.05 mmol) in THF (60 mL) was degassed and purged with N three times. 60% NaH (3.53 g, 88.19 mmol) was added to the mixture and stirred at 0 °C for 2 h under N atmosphere. SEM-Cl (4.41 g, 26.46 mmol) was then added at 0 °C and stirred at 25 °C for 2 h. The reaction mixture was diluted with HO (80 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give trimethyl-[2-[[2-(trifluoromethyl)imidazol-1-yl]methoxy]ethyl]silane (7 g, 95.37% yield) as a yellow oil. 1H NMR (400 MHz, CDC13)δ=7.21 (d, 1H), 7.15 (d, 1H), 5.42 (s, 2H), 3.57-3.51 (m, 2H), 0.92-0.84 (m, 2H), 0.00 (s, 9H).

[0225] Step 2: 2-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazole-4-carbaldehyde To a mixture of trimethyl-[2-[[2-(trifluoromethyl)imidazol-1-yl]methoxy]ethyl]silane (5.7 g, 21.40 mmol) in THF (60 mL) was added n-BuLi (2.5 M, 10.27 mL) and stirred at −78 °C for 0.5 h under N2 atmosphere. DMF (9.39 g, 128.41 mmol) was then added to the reaction and stirred at −78 °C for 1 h. The reaction mixture was quenched with aqueous NH4Cl (100 mL) at 0 °C and extracted with EtOAc (80 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give 2-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazole-4-carbaldehyde (4.7 g, 63.42% yield) as a white oil. 1H NMR (400 MHz, CDCl3)δ=9.92 (s, 1H), 7.87 (s, 1H), 5.88 (s, 2H), 3.65-3.60 (m, 2H), 0.96-0.91 (m, 2H), 0.00 (s, 9H).

[0226] Step 3: (NE,R)-2-Methyl-N-[[2-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]methylene]propane-2-sulfinamide To a solution of 2-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazole-4-carbaldehyde (2.3 g, 7.81 mmol) in THF (50 mL) was added Ti(OEt) (8.91 g, 39.07 mmol) and (R)-2-methylpropane-2-sulfinamide (4.74 g, 39.07 mmol). The mixture was stirred at 80 °C for 3 h. The reaction mixture was quenched with HO (10 mL) at 25 °C, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give (NE, R)-2-methyl-N-[[2-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]methylene]propane-2-sulfinamide (2.2 g, 67.28% yield) as a white oil. 1H NMR (400 MHz, CD3OD)δ=8.61 (s, 1H), 7.83 (s, 1H), 5.96 (d, 1H), 5.87 (d, 1H), 3.62 (t, 2H), 1.28 (s, 9H), 0.95-0.85 (m, 2H), -0.03 (s, 9H).

[0227] Step 4: (R)-2-methyl-N-((S or R)-1-(2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)propyl)propane-2-sulfinamide A solution of (NE,R)-2-methyl-N-[[2-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]methylene]propane-2-sulfinamide (500 mg, 1.26 mmol) in THF (5 mL) was added to a solution of EtMgBr (3 M, 10 mL) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by the addition of aqueous NHCl (60 mL) at 25 °C and filtered with EtOAc (40 mL × 3). The combined organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give (R)-2-methyl-N-((S or R)-1-(2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)propyl)propane-2-sulfinamide (200 mg, 33.47% yield) as a beige oil. 1H NMR (400 MHz, CD3OD)δ=7.19 (s, 1H), 5.64 (d, 1H), 5.48 (d, 1H), 4.49 (t, 1H), 3.65-3.55 (m, 2H), 2.03 (t, 2H), 1.19 (s, 9H), 1.02 (t, 3H), 0.96-0.88 (m, 2H), 0.00 (s, 9H)

[0228] Step 5: (S or R)-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propan-1-amine To a solution of (R)-2-methyl-N-((S or R)-1-(2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)propyl)propane-2-sulfinamide (160 mg, 374.18 μmol) in DCM (1.5 mL) was added HCl / dioxane (4 M, 0.5 mL). The mixture was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a residue which was not further purified to give (S or R)-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propan-1-amine (85 mg, crude) as a colorless oil. MS(ESI) m / z=192.2 [M−H]−. JPEG2025541224000040.jpg152144

[0229] General synthetic approach to intermediate D (indazole amines) JPEG2025541224000041.jpg76145(1S or 1R)-1-[1-(difluoromethyl)pyrazol-3-yl]-2-methyl-propan-1-amine Step 1: tert-butyl N-[(1S or 1R)-1-[methoxy(methyl)carbamoyl]-2-methyl-propyl]carbamate To a solution of (2S or 2R)-2-(tert-butoxycarbonylamino)-3-methyl-butyric acid (5 g, 23.01 mmol) in DMF (50 mL) was added EDCI (4.85 g, 25.32 mmol) and HOBt (3.42 g, 25.32 mmol) at 0 °C, followed by N-methoxymethanamine hydrochloride (2.47 g, 25.32 mmol) and TEA (2.56 g, 25.32 mmol) at 15 °C and stirring under N atmosphere at 15 °C for 16 h. Concentration under reduced pressure gave the crude product. The crude product was purified by flash silica gel chromatography to give tert-butyl N-[(1S or 1R)-1-[methoxy(methyl)carbamoyl]-2-methyl-propyl]carbamate (6.1 g, crude material) as a yellow solid. 1H NMR (400 MHz, CDCl3)δ=5.13 (d, 1H), 4.57 (br s, 1H), 3.77 (s, 3H), 3.21 (s, 3H), 2.04-1.92 (m, 1H), 1.43 (s, 9H), 0.95 (d, 3H), 0.90 (d, 3H).

[0230] Step 2: tert-butyl (R)-(2-methyl-4-oxohex-5-yn-3-yl)carbamate To a solution of tert-butyl N-[(1S or 1R)-1-[methoxy(methyl)carbamoyl]-2-methyl-propyl]carbamate (6 g, 23.05 mmol) in THF (10 mL) was added bromo(ethynyl)magnesium (0.5 M, 230.48 mL in THF) under N2 atmosphere at 78 °C for 1 h and stirred at 30 °C under N2 atmosphere for 16 h. The THF was evaporated in vacuo, and the aqueous residue was extracted with EtOAc (100 mL). The combined organic phases were washed with saturated aqueous NaHCO3 (15 mL) and brine (15 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl (R or S)-(2-methyl-4-oxohex-5-yn-3-yl)carbamate (5.46 g, crude) as a brown oil. 1H NMR (400 MHz, CDCl3)δ=5.04 (br d, 1H), 4.40 (dd, 1H), 3.37 (s, 1H), 2.46 (m, 1H), 1.45 (s, 9H), 1.05 (d, 3H), 0.84 (d, 3H).

[0231] Step 3: tert-butyl N-[(1S or 1R)-2-methyl-1-(1H-pyrazol-3-yl)propyl]carbamate To a solution of tert-butyl (R or S)-(2-methyl-4-oxohex-5-yn-3-yl)carbamate (5.46 g, 24.24 mmol) in EtOH (100 mL) was added NH2NH2.HO (2.48 g, 48.47 mmol) at 80 °C, and the mixture was stirred at 80 °C under a N2 atmosphere for 0.5 h. The suspension was filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography to give tert-butyl N-[(1S or 1R)-2-methyl-1-(1H-pyrazol-3-yl)propyl]carbamate (2.2 g, 37.93% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3)δ=7.51 (d, J=1.6 Hz, 1H), 6.16 (br s, 1H), 5.35 (d, J=5.6 Hz, 1H), 4.64 (d, J=6.8 Hz, 1H), 2.14 (br d, J=6.0 Hz, 1H), 0.92 (dd, J=16.0, 6.8 Hz, 6H).

[0232] Step 4: tert-butyl N-[(1S or 1R)-1-[1-(difluoromethyl)pyrazol-3-yl]-2-methyl-propyl]carbamate To a solution of tert-butyl N-[(1S or 1R)-2-methyl-1-(1H-pyrazol-3-yl)propyl]carbamate (2 g, 8.36 mmol) and KF (1.46 g, 25.07 mmol) in MeCN (30 mL) was added 1-[[bromo(difluoro)methyl]-ethoxy-phosphoryl]oxyethane (2.68 g, 10.03 mmol). The mixture was stirred at 30 °C under a N atmosphere for 12 h. The reaction mixture was diluted with water (50 mL), and the resulting mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, and then concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give a white solid tert-butyl N-[(1S or 1R)-1-[1-(difluoromethyl)pyrazol-3-yl]-2-methyl-propyl]carbamate (440 mg, 18.20% yield). 1H NMR (400 MHz, CDCl3)δ=7.73 (d, J=2.4 Hz, 1H), 7.14 (t, J=61.2 Hz, 1H), 6.30 (d, J=2.4 Hz, 1H), 5.15 (br s, 1H), 4.67 (br s, 1H), 2.14-2.10 (m, 1H), 1.49-1.42 (s, 9H), 0.90 (d, J=6.8 Hz, 6H).

[0233] Step 5: (1S or 1R)-1-[1-(difluoromethyl)pyrazol-3-yl]-2-methyl-propan-1-amine To a solution of tert-butyl N-[(1S or 1R)-1-[1-(difluoromethyl)pyrazol-3-yl]-2-methyl-propyl]carbamate (440 mg, 1.52 mmol) in 1,4-dioxane (8 mL) was added HCl / dioxane (8 mL, 4 M) at 15° C. and stirred under N atmosphere at 15° C. for 16 h. Concentration under reduced pressure gave (1S or 1R)-1-[1-(difluoromethyl)pyrazol-3-yl]-2-methyl-propan-1-amine (330.3 mg, crude) as a white solid. 1H NMR (400 MHz, DMSO-d6))δ=8.68 (br s, 3H), 8.31 (d, J=2.8 Hz, 1H), 7.84 (t, J=60.0 Hz, 1H), 6.72 (d, J=2.8 Hz, 1H), 4.15 (br s, 1H), 2.29-2.17 (m, 1H), 0.96 (d, J=6.8 Hz, 3H), 0.80 (d, J=6.8 Hz, 3H). JPEG2025541224000042.jpg51140

[0234] Intermediate E JPEG2025541224000043.jpg30128 tert-Butyl (2-(1-(2-aminoethyl)-1H-pyrazol-3-yl)propan-2-yl)carbamate Step 1: tert-butyl N-[2-methoxy(methyl)amino]-1,1-dimethyl-2-oxo-ethyl]carbamate To a stirred solution of 2-(tert-butoxycarbonylamino)-2-methyl-propanoic acid (91 mg, 447.76 μmol), N-methoxymethanamine (52.41 mg, 537.31 μmol), DMAP (65.64 g, 537.31 μmol), and DIPEA (69.44 mg, 537.31 μmol) in DCM (2 mL) was added DCC (110.86 mg, 537.31 μmol), and the mixture was stirred at 20 °C for 16 h. The mixture was filtered to remove precipitated N,N'-dicyclohexylurea, and the filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (20 mL) and washed with 10% aqueous citric acid (20 mL × 3), 10% aqueous NaHCO (10 mL), and saturated aqueous sodium chloride (20 mL × 3), followed by drying over anhydrous NaSO. The residue was purified by flash silica gel chromatography to give tert-butyl N-[2-[methoxy(methyl)amino]-1,1-dimethyl-2-oxo-ethyl]carbamate (105 mg, 76.17% yield) as a white solid. MS(ESI) m / z=247.1 [M+H]+.

[0235] Step 2: tert-Butyl N-[1,1-dimethyl-2-oxo-but-3-ynyl]carbamate To a solution of tert-butyl N-[2-[methoxy(methyl)amino]-1,1-dimethyl-2-oxo-ethyl]carbamate (32 mg, 129.92 μmol) in THF (5 mL) was added bromo(ethynyl)magnesium (0.5 M, 1.04 mL) dropwise at −78 °C, and the mixture was stirred at 25 °C under a N atmosphere for 24 h. The reaction mixture was quenched by the addition of HO (5 mL) at 30 °C and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give tert-butyl N-(1,1-dimethyl-2-oxo-but-3-ynyl)carbamate (45 mg, crude) as a yellow solid. MS(ESI) m / z=156.1 [M-tBu+H]+.

[0236] Step 3: tert-butyl N-[1-methyl-1-(1H-pyrazol-3-yl)ethyl]carbamate To a solution of tert-butyl N-(1,1-dimethyl-2-oxobut-3-ynyl)carbamate (44 mg, 208.28 μmol) in EtOH (5 mL) was added NHNH.H0 (24.53 mg, 416.55 μmol), and the mixture was stirred at 80 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to remove EtOH and residual NH.H0 at 30 °C. The residue was diluted with H0 (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography to give tert-butyl N-[1-methyl-1-(1H-pyrazol-3-yl)ethyl]carbamate (17 mg, 20.65% yield) as a yellow oil. MS(ESI) m / z=226.1 [M+H]+.

[0237] Step 4: tert-butyl N-[1-[1-[2-(benzyloxycarbonylamino)ethyl]pyrazol-3-yl]-1-methyl-ethyl]carbamate To a solution of tert-butyl N-[1-methyl-1-(1H-pyrazol-3-yl)ethyl]carbamate (305 mg, 1.35 mmol) in THF (8 mL) was added NaH (108.30 mg, 2.71 mmol, 60% purity) at 0 °C and stirred at 20 °C for 0.5 h. Benzyl N-(2-bromoethyl)carbamate (419.33 mg, 1.62 mmol) was then added under a N atmosphere at 20 °C for 12 h. The reaction mixture was quenched by the addition of water (10 mL) at 25 °C, and the mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography to give tert-butyl N-[1-[1-[2-(benzyloxycarbonylamino)ethyl]pyrazol-3-yl]-1-methyl-ethyl]carbamate (78 mg, 14.31% yield) as a white solid. MS(ESI) m / z=402.9 [M+H]+.

[0238] Step 5: tert-butyl (2-(1-(2-aminoethyl)-1H-pyrazol-3-yl)propan-2-yl)carbamate Concentrated HCl (1.27 g, 12.56 mmol, 1.25 mL, 36% purity) was added to tert-butyl N-[1-[1-[2-(benzyloxycarbonylamino)ethyl]pyrazol-3-yl]-1-methyl-ethyl]carbamate (15 mg, 28.49 μmol) and stirred at 30° C. under N atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography to give tert-butyl (2-(1-(2-aminoethyl)-1H-pyrazol-3-yl)propan-2-yl)carbamate (2.2 mg, 19.68% yield) as a yellow solid. MS(ESI) m / z=269.1 [M+H]+.

[0239] A general synthetic approach to intermediate F (oxadiazole amines) JPEG2025541224000044.jpg74140(1S or 1R)-2-methyl-1-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]propan-1-amine Step 1: tert-butyl N-[(1S or 1R)-2-methyl-1-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]propyl]carbamate To a solution of (2S or 2R)-2-(tert-butoxycarbonylamino)-3-methyl-butyric acid (300 mg, 1.38 mmol) in DMF (5 mL) was added CDI (335.85 mg, 2.07 mmol), and the mixture was stirred at 25 °C for 1 h. 2,2,2-Trifluoro-N-hydroxy-acetamidine (265.23 mg, 2.07 mmol) was then added and stirred at 25 °C for 16 h. The mixture was stirred at 110 °C under microwave irradiation for 4 h. The reaction was concentrated under reduced pressure to give the residue. The crude product was purified by column chromatography to give tert-butyl N-[(1S or 1R)-2-methyl-1-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]propyl]carbamate (110 mg, 21.89% yield) as a yellow solid. 1H NMR (400 MHz DMSO-d6)δ= 7.90 (d, J=7.6 Hz, 1H), 4.78 (t, J=7.6 Hz, 1H), 2.27-2.11 (m, 1H), 1.38 (s, 9H), 0.95 (d, J=6.8 Hz, 3H), 0.86 (d, J=6.8 Hz, 3H).

[0240] Step 2: (1S or 1R)-2-methyl-1-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]propan-1-amine

[0241] To a solution of tert-butyl N-[(1S or 1R)-2-methyl-1-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]propyl]carbamate (100 mg, 323.33 μmol) in DCM (5 mL) was added HCl / dioxane (4 M, 2.5 mL), and the mixture was stirred for 2 h at 25° C. The mixture was concentrated under reduced pressure to give (1S or 1R)-2-methyl-1-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]propan-1-amine (210 mg, crude) as a yellow solid. MS(ESI) m / z=210.1 [M+H]+. JPEG2025541224000045.jpg27142

[0242] General synthetic approach to intermediate G (pyridinamine) JPEG2025541224000046.jpg44142(1R or 1S)-1-(5-fluoro-2-pyridyl)ethanamine Step 1: (NE, R, or S)—N-[(5-fluoro-2-pyridyl)methylene]-2-methyl-propane-2-sulfinamide To a solution of 5-fluoropyridine-2-carbaldehyde (13.5 g, 107.91 mmol) in THF (150 mL) was added tetraisopropoxytitanium (122.68 g, 431.65 mmol, 127.39 mL) and (R)-2-methylpropane-2-sulfinamide (26.16 g, 215.83 mmol). The mixture was stirred at 50 °C for 3 h. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give (NE, R, or S)—N-[(5-fluoro-2-pyridyl)methylene]-2-methyl-propane-2-sulfinamide (20.2 g, 73.80% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6)δ=8.74 (d, J=2.4 Hz, 1H), 8.46 (s, 1H), 8.17 (dd, J=8.8, 4.8 Hz, 1H), 7.91 (dt, J=8.8, 2.8 Hz, 1H), 1.18 (s, 9H).

[0243] Step 2: (R)—N-[(1R or 1S)-1-(5-fluoro-2-pyridyl)ethyl]-2-methyl-propane-2-sulfinamide To a solution of (NE, R, or S)—N-[(5-fluoro-2-pyridyl)methylene]-2-methyl-propane-2-sulfinamide (1 g, 4.38 mmol) in THF (20 mL) was added MeMgBr (1 M, 105.13 mL) at −78 °C, and the mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched by the addition of NH 4 Cl (100 mL) at 25 °C, diluted with EtOAc (100 mL), and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the residue. The crude product was purified by column chromatography to give (R)-N-[(1R or 1S)-1-(5-fluoro-2-pyridyl)ethyl]-2-methyl-propane-2-sulfinamide (0.5 g, 39.71% yield) as a yellow oil. MS(ESI) m / z=273.1 [M+H]+.

[0244] Step 3: (1R or 1S)-1-(5-fluoro-2-pyridyl)ethanamine To a solution of (R)-N-[(1R or 1S)-1-(5-fluoro-2-pyridyl)ethyl]-2-methyl-propane-2-sulfinamide (0.5 g, 2.05 mmol) in DCM (5 mL) was added HCl / dioxane (4 M, 2.5 mL). The mixture was stirred at 25° C. for 3 h. The reaction mixture was concentrated under reduced pressure to give (1R or 1S)-1-(5-fluoro-2-pyridyl)ethanamine (0.45 g, 100% yield) as a white solid. MS(ESI) m / z=141.0 [M+H]+. JPEG2025541224000047.jpg70144

[0245] Intermediate H JPEG2025541224000048.jpg271282-[2-(trifluoromethyl)-1H-imidazol-4-yl]propan-2-amine Step 1: 2-(trifluoromethyl)-1-((2-(trimethylsilyl) To a solution of 60% NaH (646.64 mg, 16.17 mmol) in THF (40 mL) was added 2-(trifluoromethyl)-1H-imidazole (2 g, 14.70 mmol) at 0 °C and stirred for 30 min. SEM-Cl (2.70 g, 16.17 mmol, 2.86 mL) was added dropwise to the mixture at 0 °C. The mixture was warmed to 20 °C and stirred for 2 h. The reaction mixture was quenched by the addition of HO (50 mL) at 0 °C, extracted with EtOAc (120 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography to give 2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (3.1 g, 77.61% yield) as a white liquid. 1H NMR (400 MHz, CHLOROFORM-d)δ=7.15 (d, J=1.2 Hz, 1H), 7.08 (d, J=1.2 Hz, 1H), 5.36 (s, 2H), 3.48 (t, J=8.4 Hz, 2H), 0.87 (t, J=8.0 Hz, 2H), 0.07 (s, 9H).

[0246] Step 2: 2-[[4-Bromo-2-(trifluoromethyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane To a solution of 2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (2 g, 7.51 mmol) in CHCl (20 mL) and DMF (20 mL) was added NBS (1.47 g, 8.26 mmol) dropwise at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure at 20 °C and extracted with EtOAc (100 mL × 3) and HO (30 mL). The combined organic layers were washed with brine (30 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography to give 2-[[4-bromo-2-(trifluoromethyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane (1.64 g, 59.46% yield) as a white oil. 1H NMR (400 MHz, CHLOROFORM-d) δ=5.45(s, 2H), 3.62(t, J=8.8 Hz, 2H), 0.99(t, J=8.4 Hz, 2H), 0.05(s, 9H).

[0247] Step 3: 2-[[4-(1-ethoxyvinyl)-2-(trifluoromethyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane A mixture of 2-[[4-bromo-2-(trifluoromethyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane (1.3 g, 3.77 mmol), tributyl(1-ethoxyvinyl)stannane (2.04 g, 5.65 mmol, 1.91 mL) in 1,4-dioxane (30 mL) was degassed and purged with N. After that, Pd(PPh) (435.14 mg, 376.56 μmol) was added to the mixture and stirred at 100 °C for 16 h under N. The reaction mixture was cooled to 20 °C, diluted with HO (30 mL), and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give 2-[[4-(1-ethoxyvinyl)-2-(trifluoromethyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane (2.7 g, crude) as a black oil, which was used immediately in the next step without further purification. LCMS m / z(ESI+) 337.1 [M+H]+.

[0248] Step 4: 1-[2-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]ethanone A mixture of 2-[[4-(1-ethoxyvinyl)-2-(trifluoromethyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane (2.7 g, 8.03 mmol) in THF (10 mL) and HCl (2 M, 20.77 mL) was stirred at 20 °C for 3 h. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give 1-[2-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]ethanone (1 g, 38.79% yield) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d)δ=7.81 (s, 1H), 5.44 (s, 2H), 3.55 (t, J=8.4 Hz, 2H), 2.59 (s, 3H), 0.94 (t, J=8.0 Hz, 2H), 0.002 (s, 9H).

[0249] Step 5: 2-[2-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]propan-2-ol To a solution of 1-[2-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]ethanone (11 g, 35.67 mmol) in THF (250 mL) was added MeMgBr (3 M, 35.67 mL, 3 eq) at −78 °C, and the mixture was stirred at 25 °C for 16 h under N2 atmosphere. The mixture was poured into cold (0 °C) saturated NH4Cl solution (500 mL) and stirred for 1 h. THF was evaporated in vacuo (35 °C), and the aqueous layer was extracted with EtOAc (500 mL). The combined organic phase was washed successively with saturated aqueous NaHCO3 solution (100 mL) and brine (100 mL × 3), dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated in vacuo. The residue was purified by flash silica gel chromatography to give 2-[2-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]propan-2-ol (9 g, 77.77% yield) as a yellow oil. MS(ESI) m / z 325.1 [M+H]+.

[0250] Step 6: 2-chloro-N-[1-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]ethyl]acetamide A mixture of 2-[2-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]propan-2-ol (4.2 g, 12.95 mmol, 1 eq) and 2-chloroacetonitrile (10 mL) in AcOH (6.22 g, 103.57 mmol, 5.93 mL, 8 eq) was cooled to 0 °C in an ice bath before adding H2SO4 (11.43 g, 116.52 mmol, 6.21 mL, 9 eq). The reaction was warmed to 25 °C and stirred for 18 h. The reaction mixture was quenched by the addition of 500 mL of 1 M NaOH at 30 °C and extracted with EtOAc (500 mL × 3). The combined organic layers were washed with 100 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography to give 2-chloro-N-[1-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]ethyl]acetamide (6.5 g, 88.44% yield) as a yellow solid. MS(ESI) m / z 270.1 [M+H]+.

[0251] Step 7: 2-[2-(trifluoromethyl)-1H-imidazol-4-yl]propan-2-amine To a solution of 2-chloro-N-[1-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]ethyl]acetamide (2 g, 7.42 mmol, 1 eq) in EtOH (20 mL) was added thiourea (677.51 mg, 8.90 mmol) and acetic acid (8.02 g, 133.51 mmol, 7.64 mL, 18 eq) at 25 °C. The mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched by the addition of 100 mL of 1 M NaOH at 30 °C and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the residue. A yellow solid of 2-[2-(trifluoromethyl)-1H-imidazol-4-yl]propan-2-amine hydrochloride (1.1 g, yield 33.01%) was obtained. LCMS m / z(ESI+) 194.1 [M+H]+.

[0252] Intermediate I JPEG2025541224000049.jpg271282-(2,3-Dichlorophenyl)-1-(1H-imidazol-4-yl)ethan-1-amine Step 1: 2-(2,3-dichlorophenyl)-N-methoxy-N-methyl-acetamide To a solution of 2-(2,3-dichlorophenyl)acetic acid (5 g, 24.39 mmol) and N-methoxymethanamine hydrochloride (2.85 g, 29.26 mmol) in DCM (50 mL) was added HATU (18.54 g, 48.77 mmol) and DIEA (15.76 g, 121.93 mmol) at 15 °C. The mixture was stirred at 15 °C under a N atmosphere for 12 h. The mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography to give 2-(2,3-dichlorophenyl)-N-methoxy-N-methyl-acetamide (5.02 g, 82.97% yield) as a purple solid. MS(ESI) m / z=247.6 [M+H]+.

[0253] Step 2: 2-(2,3-dichlorophenyl)-1-(1-tritylimidazol-4-yl)ethanone To a solution of 4-iodo-1-trityl-imidazole (9.5 g, 21.77 mmol) in DCM (160 mL) was added EtMgBr (3 M in THF, 7.26 mL) under N2 at -10 °C and stirred for 1 h at -10 °C under N2. To a solution of 2-(2,3-dichlorophenyl)-N-methoxy-N-methyl-acetamide (4.59 g, 18.51 mmol) in DCM (60 mL) was added the mixture under N2 at -10 °C and stirred for 12 h at 15 °C under N2. The mixture was poured into cold (0 °C) saturated aqueous NH4Cl (100 mL) and stirred for 1 h. The combined organic phase was washed with saturated aqueous NaHCO3 (50 mL) and brine (30 mL × 3), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography to give 2-(2,3-dichlorophenyl)-1-(1-tritylimidazol-4-yl)ethanone (3.28 g, 30.28% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6)δ=7.66 (d, J=1.2 Hz, 1H), 7.58 (d, J=1.2 Hz, 1H), 7.54 (dd, J=7.6, 1.6 Hz, 1H), 7.46-7.40 (m, 9H), 7.37-7.34 (m, 1H), 7.33-7.29 (m, 1H), 7.24-7.15 (m, 6H), 4.50 (s, 2H).

[0254] Step 3: 2-(2,3-dichlorophenyl)-1-(1-tritylimidazol-4-yl)ethanamine To a solution of 2-(2,3-dichlorophenyl)-1-(1-tritylimidazol-4-yl)ethanone (1 g, 2.01 mmol) in MeOH (20 mL) was added NaBHCN (189.51 mg, 3.02 mmol) and NHOAc (1.55 g, 20.10 mmol) at 15 °C. The reaction mixture was heated at 70 °C and stirred under a N atmosphere for 12 h. The mixture was poured into cold (0 °C) saturated aqueous NHCl solution (50 mL) and stirred for 1 h. The mixture was extracted with EtOAc (50 mL), and the combined organic phases were washed with brine (15 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography to give 2-(2,3-dichlorophenyl)-1-(1-tritylimidazol-4-yl)ethanamine (330 mg, 32.93% yield) as a yellow solid. MS(ESI) m / z=499.7 [M+3H]+.

[0255] Step 4: 2-(2,3-dichlorophenyl)-1-(1H-imidazol-4-yl)ethan-1-amine To a solution of 2-(2,3-dichlorophenyl)-1-(1-tritylimidazol-4-yl)ethanamine (0.33 g, 179.89 μmol) in MeOH (2 mL) was added HCl (1.84 g, 2.52 mmol, 1.80 mL, 1 M) at 20 °C. The mixture was stirred at 50 °C under a N atmosphere for 2 h. The mixture was concentrated under reduced pressure to give the crude product. 2-(2,3-dichlorophenyl)-1-(1H-imidazol-4-yl)ethan-1-amine (22.15 mg, 36.8% yield) was obtained as a yellow solid. MS(ESI) m / z=256.1 [M+H]+.

[0256] Intermediate J JPEG2025541224000050.jpg271282-(2,3-Dichlorophenyl)-1-(1,2,4-oxadiazol-5-yl)ethan-1-amine Step 1: tert-butyl (1-amino-3-(2,3-dichlorophenyl)-1-oxopropan-2-yl)carbamate To a stirred solution of 2-((tert-butoxycarbonyl)amino)-3-(2,3-dichlorophenyl)propanoic acid (693 mg, 2.07 mmol) in DMF (10 mL) was added EDCI (596.28 mg, 3.11 mmol) and HOBt (420.30 mg, 3.11 mmol), followed by DIEA (804.01 mg, 6.22 mmol) and NHCl (166.38 mg, 3.11 mmol). The reaction mixture was stirred at 15 °C under a N atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to remove DMF. The crude product was purified by column chromatography to give tert-butyl (1-amino-3-(2,3-dichlorophenyl)-1-oxopropan-2-yl)carbamate (418 mg, 60.50% yield) as a beige solid. MS(ESI) m / z=233.0 [M-Boc+H]+.

[0257] Step 2: tert-butyl (Z)-(3-(2,3-dichlorophenyl)-1-(((dimethylamino)methylene)amino)-1-oxopropan-2-yl)carbamate To a stirred solution of tert-butyl (1-amino-3-(2,3-dichlorophenyl)-1-oxopropan-2-yl)carbamate (318 mg, 954.35 μmol) in DCM (12 mL) was added 1,1-dimethoxy-N,N-dimethyl-methanamine (147.84 mg, 1.24 mmol). The reaction mixture was stirred at 45° C. under a N atmosphere for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The product was tert-butyl (Z)-(3-(2,3-dichlorophenyl)-1-(((dimethylamino)methylene)amino)-1-oxopropan-2-yl)carbamate (544 mg, 100%) as a colorless oil. MS(ESI) m / z=388.0 [M+H]+.

[0258] Step 3: tert-butyl (2-(2,3-dichlorophenyl)-1-(1,2,4-oxadiazol-5-yl)ethyl)carbamate To a stirred solution of tert-butyl (Z)-(3-(2,3-dichlorophenyl)-1-(((dimethylamino)methylene)amino)-1-oxopropan-2-yl)carbamate (370 mg, 952.90 μmol) in EtOH (15 mL) was added hydroxylamine hydrochloride (132.44 mg, 1.91 mmol). The reaction mixture was stirred at 75° C. under a N atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography to give tert-butyl (2-(2,3-dichlorophenyl)-1-(1,2,4-oxadiazol-5-yl)ethyl)carbamate (202 mg, 59.18% yield) as a beige solid. MS(ESI) m / z=302.0 [M-tBu+H]+.

[0259] Step 4: 2-(2,3-dichlorophenyl)-1-(1,2,4-oxadiazol-5-yl)ethan-1-amine To a stirred solution of tert-butyl (2-(2,3-dichlorophenyl)-1-(1,2,4-oxadiazol-5-yl)ethyl)carbamate (110 mg, 307.07 μmol) in HFIP (10 mL) was added 4-methylbenzenesulfonic acid (211.52 mg, 1.23 mmol). The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography to give 2-(2,3-dichlorophenyl)-1-(1,2,4-oxadiazol-5-yl)ethan-1-amine (114.2 mg) as a beige solid. MS(ESI) m / z=258.0 [M+H]+.

[0260] Intermediate K JPEG2025541224000051.jpg38128(R or S)-1-(1-(difluoromethyl)-1H-pyrazol-3-yl)propane-1,3-diamine Step 1: (R or S)-4-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)butyric acid To a stirred solution of (2R or 2S)-4-amino-2-((tert-butoxycarbonyl)amino)butyric acid (10 g, 45.82 mmol) in acetone (125 mL) was added aqueous NaHCO (1.1 M, 125.00 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 10 min under a N atmosphere. Then, benzyl carbonochloridate (9.38 g, 55.00 mmol) in toluene (3 mL) was added, and the reaction mixture was stirred at 15 °C for 12 h under a N atmosphere. The reaction mixture was concentrated under reduced pressure to give (R or S)-4-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)butyric acid (16.14 g, 100% yield). MS(ESI) m / z=375.0 [M+Na]+.

[0261] Step 2: tert-butyl N-[(1R or 1S)-3-(benzyloxycarbonylamino)-1-[methoxy(methyl)carbamoyl]propyl]carbamate To a solution of (R or S)-4-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)butyric acid (12 g, 34.05 mmol) in DMF (20 mL) was added EDCI (7.18 g, 37.46 mmol) and HOBt (5.06 g, 37.46 mmol) at 0 °C. Then, N-methoxymethanamine hydrochloride (3.65 g, 37.46 mmol) and TEA (3.79 g, 37.46 mmol) were added to the mixture, which was stirred at 15 °C under a N atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give tert-butyl N-[(1R or 1S)-3-(benzyloxycarbonylamino)-1-[methoxy(methyl)carbamoyl]propyl]carbamate (8.7 g, 64.60% yield) as a yellow oil. MS(ESI) m / z=395.8 [M+H]+.

[0262] Step 3: tert-butyl N-[(1R or 1S)-1-[2-(benzyloxycarbonylamino)ethyl]-2-oxo-propyl]carbamate To a solution of tert-butyl N-[(1R or 1S)-3-(benzyloxycarbonylamino)-1-[methoxy(methyl)carbamoyl]propyl]carbamate (6 g, 15.17 mmol) in THF (60 mL) was added bromo(methyl)magnesium (3 M diethyl ether, 15.17 mL) at −78 °C under N atmosphere for 1 h, followed by stirring at 30 °C under N for 16 h. The mixture was poured into saturated aqueous NH4Cl (20 mL) at 0 °C and stirred for 1 h. The mixture was then extracted with EtOAc (300 mL × 2). The combined organic phase was washed with saturated aqueous NaHCO3 (15 mL) and brine (15 mL × 3), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl N-[(1R or 1S)-1-[2-(benzyloxycarbonylamino)ethyl]-2-oxo-propyl]carbamate (4.67 g, crude material) as a yellow oil. MS(ESI)m / z=no desired mass.

[0263] Step 4: tert-Butyl N-[(E, 1R, or 1S)-1-[2-(benzyloxycarbonylamino)ethyl]-4-(dimethylamino)-2-oxo-but-3-enyl]carbamate To a solution of tert-butyl N-[(1R or 1S)-1-[2-(benzyloxycarbonylamino)ethyl]-2-oxo-propyl]carbamate (4.67 g, 13.33 mmol) in MeCN (50 mL) was added DMF-DMA (3.18 g, 26.65 mmol). The reaction mixture was stirred at 85 °C under a N atmosphere for 12 h. The mixture was concentrated under reduced pressure to give tert-butyl N-[(E, 1R or 1S)-1-[2-(benzyloxycarbonylamino)ethyl]-4-(dimethylamino)-2-oxo-but-3-enyl]carbamate (5 g, crude) as a yellow oil. MS(ESI)m / z=no desired mass.

[0264] Step 5: tert-butyl N-[(1R or 1S)-3-(benzyloxycarbonylamino)-1-(1H-pyrazol-3-yl)propyl]carbamate To a solution of tert-butyl N-[(E, 1R, or 1S)-1-[2-(benzyloxycarbonylamino)ethyl]-4-(dimethylamino)-2-oxobut-3-enyl]carbamate (5 g, 12.33 mmol) in EtOH (80 mL) was added hydrazine hydrate (1.26 g, 24.66 mmol) at 80 °C and stirred at 80 °C for 0.5 h under a N atmosphere. The reaction mixture was quenched by the addition of H O (30 mL). The reaction mixture was concentrated under reduced pressure to remove EtOH and then extracted with EtOAc (100 mL × 3). The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give tert-butyl N-[(1R or 1S)-3-(benzyloxycarbonylamino)-1-(1H-pyrazol-3-yl)propyl]carbamate (420 mg, yield 9.10%) as a yellow oil. MS(ESI) m / z=375.2 [M+H]+.

[0265] Step 6: tert-butyl N-[(1R or 1S)-3-(benzyloxycarbonylamino)-1-[1-(difluoromethyl)pyrazol-3-yl]propyl]carbamate To a solution of tert-butyl N-[(1R or 1S)-3-(benzyloxycarbonylamino)-1-(1H-pyrazol-3-yl)propyl]carbamate (150 mg, 400.61 μmol) and KF (69.82 mg, 1.20 mmol) in MeCN (3 mL) was added 1-[[bromo(difluoro)methyl]-ethoxy-phosphoryl]oxyethane (128.36 mg, 480.73 μmol). The mixture was stirred at 50 °C under a N atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give tert-butyl N-[(1R or 1S)-3-(benzyloxycarbonylamino)-1-[1-(difluoromethyl)pyrazol-3-yl]propyl]carbamate (42 mg, 24.70% yield) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ=8.04 (s, 1H), 7.59-7.34 (m, 5H), 7.33-7.20 (m, 1H), 7.18-7.00 (m, 1H), 6.53 (s, 1H), 5.17 (s, 2H), 4.96 (s, 2H), 2.23-2.00 (m, 2H), 1.54 (s, 9H).

[0266] Step 7: (R or S)-1-(1-(difluoromethyl)-1H-pyrazol-3-yl)propane-1,3-diamine To a solution of tert-butyl N-[(1R or 1S)-3-(benzyloxycarbonylamino)-1-[1-(difluoromethyl)pyrazol-3-yl]propyl]carbamate (82 mg, 193.20 μmol) in 1,4-dioxane (3 mL) was added HCl (5 mL) at 15° C. and stirred under N atmosphere at 15° C. for 16 h. Concentration under reduced pressure gave (R or S)-1-(1-(difluoromethyl)-1H-pyrazol-3-yl)propane-1,3-diamine (36.7 mg, crude) as a yellow oil. MS(ESI) m / z=325.2 [M+H]+.

[0267] Intermediate L JPEG2025541224000052.jpg191282-(4-chloro-2,3-difluoro-phenyl)ethanamine Step 1: tert-butyl N-[2-(4-chloro-2,3-difluoro-phenyl)ethyl]carbamate To a solution of 1-bromo-4-chloro-2,3-difluorobenzene (1 g, 4.40 mmol), potassium; 2-(tert-butoxycarbonylamino)ethyl-trifluoroboranide (1.10 g, 4.40 mmol) in toluene (36 mL) and HO (6 mL) was added CsCO (4.30 g, 13.19 mmol), Pd(OAc) (98.71 mg, 439.69 μmol), and dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (205.17 mg, 439.69 μmol) under N atmosphere at 100 °C for 12 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL) and NaCl. S After drying over O, filtration, and concentration under reduced pressure gave a residue that was purified by flash silica gel chromatography to give tert-butyl N-[2-(4-chloro-2,3-difluoro-phenyl)ethyl]carbamate (960 mg, 74.84% yield) as a yellow oil. 1H NMR (400 MHz, CHCl3-d) δ=7.15-7.05 (m, 1H), 6.91 (t,J=7.2 Hz, 1H), 3.34 (d,J=6.4 Hz, 2H), 2.84 (t,J=6.4 Hz, 2H), 1.41 (s, 9H).

[0268] Step 2: 2-(4-chloro-2,3-difluoro-phenyl)ethanamine To a solution of tert-butyl N-[2-(4-chloro-2,3-difluoro-phenyl)ethyl]carbamate (960 mg, 3.29 mmol) in dioxane (12 mL) was added HCl / dioxane (4 M, 12 mL). The mixture was stirred under N2 atmosphere at 25 °C for 4 h. The reaction mixture was concentrated under reduced pressure to give the crude product 2-(4-chloro-2,3-difluoro-phenyl)ethanamine (750 mg, crude material) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.21 (br s, 2H), 7.50-7.35 (m, 1H), 7.32-7.14 (m, 1H), 3.10-2.95 (m, 4H).

[0269] Intermediate M JPEG2025541224000053.jpg271285-(1-amino-1-methyl-ethyl)-2-(difluoromethyl)pyrazol-3-amine Step 1: tert-butyl N-(3-cyano-1,1-dimethyl-2-oxo-propyl)carbamate To a solution of CHCN (5.10 g, 124.27 mmol) in THF (100 mL) was added dropwise NaHMDS (1 M, 124.27 mL) at −78 °C. After the addition, the mixture was stirred at −50 °C for 20 minutes, and then methyl 2-(tert-butoxycarbonylamino)-2-methyl-propanoate (9 g, 41.42 mmol) in THF (100 mL) was added dropwise at −78 °C. The resulting mixture was stirred at −50 °C for 1 hour. To the mixture was added CHCOOH (7.96 g, 132.56 mmol) at −78 °C. The reaction mixture was concentrated under reduced pressure to give tert-butyl N-(3-cyano-1,1-dimethyl-2-oxo-propyl)carbamate (7 g, crude) as a dark brown solid. MS(ESI) m / z=227.1 [M+H]+.

[0270] Step 2: tert-butyl N-[1-(5-amino-1H-pyrazol-3-yl)-1-methyl-ethyl]carbamate To a solution of tert-butyl N-(3-cyano-1,1-dimethyl-2-oxopropyl)carbamate (7 g, 30.94 mmol) in EtOH (100 mL) was added CHCOOH (5.57 g, 92.81 mmol) and N2H4·HO (5.47 g, 92.81 mmol) at 0 °C. The mixture was stirred at 25 °C for 24 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give tert-butyl N-[1-(5-amino-1H-pyrazol-3-yl)-1-methyl-ethyl]carbamate (3.5 g, 37.66% yield) as a yellow oil. MS(ESI) m / z=141.2.

[0271] Step 3: tert-butyl N-[1-[5-amino-1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]carbamate To a solution of 1-[[bromo(difluoro)methyl]-ethoxy-phosphoryl]oxyethane (1.17 g, 4.37 mmol) and KF (483.56 mg, 8.32 mmol) in MeCN (15 mL) was added tert-butyl N-[1-(5-amino-1H-pyrazol-3-yl)-1-methyl-ethyl]carbamate (1 g, 4.16 mmol) under N atmosphere at 20 °C. The mixture was stirred at 20 °C for 18 h. The reaction mixture was diluted with HO (30 mL) and then extracted with DCM (40 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography to give tert-butyl N-[1-[5-amino-1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]carbamate (355 mg, 22.33% yield) as a white solid. MS(ESI) m / z=291.2 [M+H]+.

[0272] Step 4: 5-(1-amino-1-methyl-ethyl)-2-(difluoromethyl)pyrazol-3-amine A mixture of tert-butyl N-[1-[5-amino-1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]carbamate (355 mg, 1.22 mmol) and HCl / dioxane (4 M, 2.60 mL) in DCM (6 mL) was stirred for 18 h at 25° C. The reaction mixture was concentrated under reduced pressure to give 5-(1-amino-1-methyl-ethyl)-2-(difluoromethyl)pyrazol-3-amine (360 mg, crude) as a white solid. MS(ESI) m / z=191.1 [M+H]+.

[0273] Intermediate N JPEG2025541224000054.jpg30128(1S or 1R)-2-methyl-1-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]propan-1-amine Step 1: tert-butyl N-[(1S or 1R)-1-(hydrazinecarbonyl)-2-methyl-propyl]carbamate To a solution of methyl (2S or 2R)-2-(tert-butoxycarbonylamino)-3-methyl-butyrate (8 g, 34.59 mmol) in MeOH (80 mL) was added hydrazine hydrate (5.19 g, 103.77 mmol, 5.04 mL), and the reaction mixture was stirred at 85 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was dissolved in DCM (100 mL) and extracted with DCM (100 mL × 3) and water (100 mL). The combined organic phases were washed with brine (120 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product (12.2 g, 100% yield). 1H NMR (400 MHz, DMSO-d6) δ=9.04 (s, 1H), 6.63 (d, J=8.8 Hz, 1H), 4.22 (s, 2H), 3.69 (t, J=8.4 Hz, 1H), 1.88-1.82 (m, 1H), 1.38 (s, 9H), 0.86-0.80 (m, 6H).

[0274] Step 2: tert-butyl N-[(1S or 1R)-2-methyl-1-[[(2,2,2-trifluoroacetyl)amino]carbamoyl]propyl]carbamate To a solution of tert-butyl N-[(1S or 1R)-1-(hydrazinecarbonyl)-2-methyl-propyl]carbamate (2.0 g, 8.65 mmol) and DIEA (2.24 g, 17.29 mmol, 3.01 mL) in DCM (20 mL) was added (CFCO)O (2.18 g, 10.38 mmol, 1.44 mL) dropwise at 0 °C, and the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into water (30 mL) and extracted with DCM (50 mL × 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give tert-butyl N-[(1S or 1R)-2-methyl-1-[[(2,2,2-trifluoroacetyl)amino]carbamoyl]propyl]carbamate (2.47 g, crude) as a colorless oil. LCMS m / z(ESI+) 271.1 [M+H]+.

[0275] Step 3: tert-butyl N-[(1S or 1R)-2-methyl-1-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]propyl]carbamate To a solution of tert-butyl N-[(1S or 1R)-2-methyl-1-[[(2,2,2-trifluoroacetyl)amino]carbamoyl]propyl]carbamate (1.5 g, 4.58 mmol) in THF (30 mL) was added Burgess reagent (4.37 g, 18.33 mmol) at 25 °C, and the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography to give tert-butyl N-[(1S or 1R)-2-methyl-1-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]propyl]carbamate (1.1 g, 72.95% yield) as a yellow oil. LCMS m / z(ESI+) 254.0 [M+H]+.

[0276] Step 4: (1S or 1R)-2-methyl-1-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]propan-1-amine A mixture of tert-butyl N-[(1S)-2-methyl-1-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]propyl]carbamate (100 mg, 323.33 μmol) in HFIP (1 mL) was stirred in a microwave at 150° C. for 1 h. The reaction was concentrated under reduced pressure to give a residue that afforded (1S or 1R)-2-methyl-1-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]propan-1-amine (67 mg, crude) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ=3.92 (d, J=6.4 Hz, 1H), 2.05-1.91 (m, 1H), 0.92 (d, J=6.7 Hz, 3H), 0.84 (d, J=6.8 Hz, 3H).

[0277] General synthetic method for target compound A JPEG2025541224000055.jpg210144

[0278] Example 1 JPEG2025541224000056.jpg37128N2-(2-(1-(difluoromethyl)-1H-pyrazol-3-yl)propan-2-yl)-6-(6-methylimidazo[1,5-a]pyrimidin-3-yl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) Step 1: 6-chloro-N2-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-1,3,5-triazine-2,4-diamine A mixture of 2-[1-(difluoromethyl)pyrazol-3-yl]propan-2-amine (Intermediate D2, 200.12 mg, 945.57 μmol), 4,6-dichloro-1,3,5-triazin-2-amine (130 mg, 787.97 μmol), and DIPEA (408 mg, 3.15 mmol) in 1,4-dioxane (8 mL) was degassed and purged with N, and the mixture was stirred at 90 °C under N atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give 6-chloro-N-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-1,3,5-triazine-2,4-diamine (160 mg, 46.80% yield) as a white solid. MS(ESI) m / z=304.1 [M+H]+.

[0279] Step 2: N2-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-(6-methylimidazo[1,5-a]pyrimidin-3-yl)-1,3,5-triazine-2,4-diamine A mixture of 6-chloro-N-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-1,3,5-triazine-2,4-diamine (50 mg, 164.64 μmol), 6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyrimidine (Intermediate A1, 2.67 g, 10.30 mmol), KPO (87.37 mg, 411.59 μmol), and ditert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (10.73 mg, 16.46 μmol) in THF (10 mL) and HO (1 mL) was degassed and purged with N, and the mixture was stirred at 90 °C under N atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to give compound N2-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-(6-methylimidazo[1,5-a]pyrimidin-3-yl)-1,3,5-triazine-2,4-diamine (6.0 mg, 4.55% yield) as a yellow solid. MS (ESI) m / z=401.0 [M+H]+. 1H NMR (400 MHz, Methanol-d4):δ=8.96 (t, 2H), 7.90 (d, J=2.8 Hz, 1H), 7.59-7.24 (m, 2H), 6.46 (d, J=2.8 Hz, 1H), 2.71 (br s, 3H), 1.82 (s, 6H).

[0280] Example 2 JPEG2025541224000057.jpg431286-(3-Methylimidazo[1,5-a]pyridin-6-yl)-N2-[phenyl-[2-(trifluoromethyl)-1H-imidazol-4-yl]methyl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) LCMS m / z (ESI+) 466.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6)δ=8.72 (s, 1H), 8.35 (br s, 1H), 7.41 (d, J=1.6 Hz, 1H), 7.39 (s, 2H), 7.36-7.31 (m, 1H), 7.27 (t, J=7.6 Hz, 2H), 7.21-7.16 (m, 1H), 6.98 (br s, 1H), 6.56 (br s, 3H), 5.74 (s, 1H), 2.63 (s, 3H).

[0281] Example 3 JPEG2025541224000058.jpg26128 Methyl (S or R)-2-((2-amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)pyrimidin-4-yl)amino)-3-(2,3-dichlorophenyl)propanoic acid (general synthesis method for target compound A) LCMS m / z (ESI+) 471.0 [M+H]+. 1H NMR (400 MHz, Methanol-d4):δ=8.54 (s, 1H), 7.57 (d, J=9.6 Hz, 1H), 7.43 (dd, J=8.0, 1.6 Hz, 1H), 7.33 (s, 1H), 7.30-7.28 (m, 1H), 7.24-7.18 (m, 1H), 7.15 (d, J=10.4 Hz, 1H), 6.31 (br s, 1H), 5.13-5.12 (m, 1H), 3.74 (s, 3H), 3.49 (dd, J=14.0, 6.0 Hz, 1H), 3.26 (dd, J=14.0, 8.8 Hz, 1H), 2.71 (s, 3H).

[0282] Example 4 JPEG2025541224000059.jpg27128 Methyl (2S or 2R)-2-[[4-amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazin-2-yl]amino]-3-(2,3-dichlorophenyl)propanoic acid (general synthesis method for target compound A) LCMS m / z (ESI+) 472.0 [M+H] + . 1H NMR (400 MHz, Methanol-d4)δ=8.84 (br s, 1H), 8.25 (s, 1H), 7.62-7.40 (m, 2H), 7.33-7.25 (m, 2H), 7.23-7.16 (m, 1H), 7.15-7.04 (m, 1H), 5.27-5.14 (m, 1H), 3.80-3.67 (m, 3H), 3.64-3.45 (m, 1H), 3.27-3.10 (m, 1H), 2.81-2.63 (m, 3H).

[0283] Example 5 JPEG2025541224000060.jpg441286-(3-Methylimidazo[1,5-a]pyridin-6-yl)-N2-(trideuteriomethyl)-N4-[(1R or 1S)-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound B) Step 1: 4,6-Dichloro-N-(trideuteriomethyl)-1,3,5-triazin-2-amine 2,4,6-Trichloro-1,3,5-triazine (2 g, 10.85 mmol) was dissolved in THF (20 mL) and cooled to -70 °C. DIPEA (2.80 g, 21.69 mmol) and trideuteriomethanamine hydrochloride (764.99 mg, 10.85 mmol) were added to the reaction mixture, which was stirred at -70 °C for 1 h and warmed to 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography to give 4,6-dichloro-N-(trideuteriomethyl)-1,3,5-triazin-2-amine (1.2 g, 46.20% yield) as a white solid. MS(ESI) m / z=182.1 [M+H]+.

[0284] Step 2: 6-chloro-N2-(trideuteriomethyl)-N4-[(1R or 1S)-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine To a solution of 4,6-dichloro-N-(trideuteriomethyl)-1,3,5-triazin-2-amine (100 mg, 549.37 μmol) and (1R or 1S)-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propan-1-amine (106.12 mg, 462.14 μmol) in n-BuOH (5 mL) was added DIPEA (213.01 mg, 1.65 mmol). The mixture was stirred at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give 6-chloro-N2-(trideuteriomethyl)-N4-[(1R or 1S)-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (155 mg, 74.96% yield) as a white solid. MS(ESI) m / z=339.2 [M+H]+.

[0285] Step 3: 6-(3-methylimidazo[1,5-a]pyridin-6-yl)-N2-(trideuteriomethyl)-N4-[(1R or 1S)-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine 6-chloro-N2-(trideuteriomethyl)-N4-[(1R or 1S)-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (150 mg, 442.83 μmol), 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-diazinediamine)- A mixture of (oxaborolan-2-yl)imidazo[1,5-a]pyridine (228.61 mg, 885.65 μmol), ditert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (14.43 mg, 22.14 μmol), and KPO (187.99 mg, 885.65 μmol) was degassed and purged with N, and the mixture was stirred at 90 °C for 12 h. The reaction was concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography to give 6-(3-methylimidazo[1,5-a]pyridin-6-yl)-N2-(trideuteriomethyl)-N4-[(1R or 1S)-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (12.2 mg, 6.34% yield) as a yellow solid. MS (ESI) m / z 435.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ=8.82 (s, 1H), 7.52 (s, 2H), 7.28 (s, 1H), 7.16 (s, 2H), 7.00 (br s, 2H), 5.15 (s, 1H), 2.65 (s, 3H), 1.96-1.85 (m, 2H), 0.92 (t, J=7.6 Hz, 3H).

[0286] Example 6 JPEG2025541224000061.jpg42128(S or R)-N2-(methyl-d3)-N4-(2-methyl-1-(2-(trifluoromethyl)-1H-imidazol-4-yl)propyl)-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound B) MS (ESI) m / z 449.2 [M+H] + . 1H NMR (400 MHz, Methanol-d4) δ=8.89 (s, 1H), 8.18 (s, 1H), 7.61 (s, 1H), 7.49 (d, J=9.6 Hz, 1H), 7.30 (s, 1H), 7.19 (br s, 1H), 5.25-5.08 (m, 1H), 2.71 (s, 3H), 2.24 (s, 1H), 0.99 (m, 6H).

[0287] Example 7A and Example 7B JPEG2025541224000062.jpg33128N4-[(1S or 1R)-2-cyclopropyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]ethyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound B) 7A MS (ESI) m / z 444.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6)δ=13.06 (s, 1H), 8.90 (s, 1H), 7.54 (s, 2H), 7.38 (s, 2H), 7.23-7.14 (m, 1H), 6.81 (br s, 2H), 5.96-5.78 (m, 1H), 5.40-5.10 (m, 1H), 5.07-5.01 (m, 1H), 5.00-4.89 (m, 1H), 2.65 (s, 3H), 2.14-2.08 (m, 2H), 2.03-1.94 (m, 2H).

[0288] 7B LCMS m / z (ESI+) 444.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6)δ=11.60 (s, 1H), 8.81 (s, 1H), 7.56 (s, 2H), 7.28 (s, 2H), 7.18 (s, 1H), 6.70 (br s, 2H), 5.91-5.81 (m, 1H), 5.37-5.15 (m, 1H), 5.04 (d, J=1.6 Hz, 1H), 5.00-4.95 (m, 1H), 2.65 (s, 3H), 2.14-2.07 (m, 2H), 2.04-1.95 (m, 2H).

[0289] Example 8 JPEG2025541224000063.jpg321286-(1H-indazol-5-yl)-N4-[(1R or 1S)-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound C) Step 1: 6-chloro-N4-[(1R or 1S)-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine To a solution of (1R or 1S)-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propan-1-amine (248.45 mg, 1.08 mmol) and 4,6-dichloro-1,3,5-triazin-2-amine (170 mg, 1.03 mmol) in i-PrOH (6 mL) was added DIPEA (532.69 mg, 4.12 mmol). The mixture was stirred at 90 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give 6-chloro-N4-[(1R or 1S)-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (589 mg, 100% yield) as a yellow oil. MS(ESI) m / z=322.0 [M+H]+.

[0290] Step 2: 6-(1-tetrahydropyran-2-ylindazol-5-yl)-N4-[(1R or 1S)-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine To a solution of 6-chloro-N-[(1R or 1S)-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (520 mg, 1.62 mmol) and 1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (1.06 g, 3.23 mmol) in THF (7 mL) and HO (0.7 mL) was added KPO (1.03 g, 4.85 mmol), ditert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (105.35 mg, 161.65 μmol). After degassing and purging with N, the mixture was stirred at 90 °C under a N atmosphere for 12 h. The reaction mixture was diluted with HO (10 mL) and extracted with dichloromethane (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give 6-(1-tetrahydropyran-2-ylindazol-5-yl)-N-[(1R or 1S)-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (173.2 mg, 21.32% yield) as a yellow oil. MS(ESI) m / z=488.2 [M+H]+.

[0291] Step 3: 6-(1H-indazol-5-yl)-N4-[(1R or 1S)-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine To a solution of 6-(1-tetrahydropyran-2-ylindazol-5-yl)-N4-[(1R or 1S)-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (173 mg, 354.89 μmol) in DCM (3 mL) was added TFA (1.54 g, 13.51 mmol). The mixture was stirred at 25 °C for 4 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give a white solid of 6-(1H-indazol-5-yl)-N4-[(1R or 1S)-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (69.7 mg, 48.69% yield). LCMS m / z (ESI+) 404.0 [M+H] + . 1H NMR (400 MHz, Methanol-d4):δ=8.71 (br s, 1H), 8.32-8.22 (m, 2H), 7.75-7.68 (m, 1H), 7.29 (s, 1H), 5.49-5.43 (m, 1H), 2.15-1.99 (m, 2H), 1.12-1.02 (m, 3H).

[0292] Example 9 JPEG2025541224000064.jpg37128N2-(2-(1-(difluoromethyl)-1H-pyrazol-3-yl)propan-2-yl)-6-(1-(methyl-d3)-1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) LCMS m / z (ESI+) 403.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ=8.34 (br s, 1H), 8.07-8.02 (m, 1H), 8.02-7.97 (m, 1H), 7.93 (br s, 1H), 7.87-7.51 (m, 2H), 7.01 (br s, 1H), 6.62-6.36 (m, 3H), 1.78 (s, 6H).

[0293] Example 10 JPEG2025541224000065.jpg371286-(3-aminoimidazo[1,5-a]pyridin-6-yl)-N2-(2-(1-(difluoromethyl)-1H-pyrazol-3-yl)propan-2-yl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound C)

[0294] Step 1: 6-chloro-N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-1,3,5-triazine-2,4-diamine To a solution of 2-[1-(difluoromethyl)pyrazol-3-yl]propan-2-amine (Intermediate D2, 2 g, 9.45 mmol, HCl) and 4,6-dichloro-1,3,5-triazin-2-amine (1.56 g, 9.45 mmol) in i-PrOH (20 mL) was added DIPEA (3.66 g, 28.35 mmol), and the mixture was stirred at 90 °C for 16 h. The reaction was concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography to give 6-chloro-N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-1,3,5-triazine-2,4-diamine (1.8 g, 43.28% yield) as a bright yellow solid. MS(ESI) m / z=304.0 [M+H]+.

[0295] Step 2: 6-(3-aminoimidazo[1,5-a]pyridin-6-yl)-N2-(2-(1-(difluoromethyl)-1H-pyrazol-3-yl)propan-2-yl)-1,3,5-triazine-2,4-diamine To a solution of 6-chloro-N-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-1,3,5-triazine-2,4-diamine (1.27 g, 4.17 mmol) in THF (67.5 mL) and HO (6.75 mL) was added N-[(4-methoxyphenyl)methyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridin-3-amine (1.9 g, 5.01 mmol), ditert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (272.09 mg, 417.48 μmol), and KCO (1.15 g, 8.35 mmol), and the reaction mixture was stirred at 75 °C under a N atmosphere for 12 h. The reaction was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give a brown solid, N2-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-[3-[(4-methoxyphenyl)methylamino]imidazo[1,5-a]pyridin-6-yl]-1,3,5-triazine-2,4-diamine (1.03 g, 47.40% yield). MS(ESI) m / z=521.2 [M+H]+.

[0296] Step 3: 6-(3-aminoimidazo[1,5-a]pyridin-6-yl)-N2-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-1,3,5-triazine-2,4-diamine A solution of N2-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-[3-[(4-methoxyphenyl)methylamino]imidazo[1,5-a]pyridin-6-yl]-1,3,5-triazine-2,4-diamine (2 g, 3.84 mmol) in TFA (20 mL) was stirred at 15 °C for 6 h. The reaction was filtered and then concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography to give 6-(3-aminoimidazo[1,5-a]pyridin-6-yl)-N2-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-1,3,5-triazine-2,4-diamine (410 mg, 26.65% yield) as a yellow solid. MS (ESI) m / z=401.1 [M+H]+. 1H NMR (400 MHz, Methanol-d4) δ=9.11-8.69 (m, 1H), 7.90 (br s, 1H), 7.60-7.13 (m, 4H), 6.46 (s, 1H), 1.81 (s, 6H).

[0297] Example 11 JPEG2025541224000066.jpg371286-(3-aminoimidazo[1,5-a]pyridin-6-yl)-N2-(2-(2-(trifluoromethyl)-1H-imidazol-4-yl)propan-2-yl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound C) LCMS m / z (ESI+) 419.2 [M+H]+. 1H NMR (400 MHz, METHANOL-d4) 8=9.03-8.44 (m, 1H), 8.25 (br s, 1H), 7.72-7.34 (m, 4H), 7.33-7.25 (m, 1H), 7.24-6.77 (m, 1H), 1.93-1.62 (m, 6H).

[0298] Example 12 JPEG2025541224000067.jpg361284-((2-(1-(difluoromethyl)-1H-pyrazol-3-yl)propan-2-yl)amino)-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2-carbonitrile (general synthesis method for target compound E) Step 1: 4,6-Dichloro-N-(2-(1-(difluoromethyl)-1H-pyrazol-3-yl)propan-2-yl)-1,3,5-triazin-2-amine To a stirred solution of 2-[1-(difluoromethyl)pyrazol-3-yl]propan-2-amine (165 mg, 779.63 μmol) in THF (4 mL) at −70° C. under N atmosphere was added DIPEA (201.52 mg, 1.56 mmol) and 2,4,6-trichloro-1,3,5-triazine (129.39 mg, 701.66 μmol) and the reaction mixture was stirred at −70° C. under N atmosphere for 1 h and then warmed to 15° C. under N atmosphere for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography to give 4,6-dichloro-N-(2-(1-(difluoromethyl)-1H-pyrazol-3-yl)propan-2-yl)-1,3,5-triazin-2-amine (180 mg, 557.05 μmol) as a beige solid. MS(ESI) m / z=323.0 [M+H]+.

[0299] Step 2: 4-chloro-N-(2-(1-(difluoromethyl)-1H-pyrazol-3-yl)propan-2-yl)-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazin-2-amine To a solution of 4,6-dichloro-N-(2-(1-(difluoromethyl)-1H-pyrazol-3-yl)propan-2-yl)-1,3,5-triazin-2-amine (150 mg, 464.21 μmol) and 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine (143.79 mg, 557.05 μmol) in THF (1.5 mL) and HO (1.5 mL) was added KPO (197.07 mg, 928.42 μmol) and ditert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (15.13 mg, 23.21 μmol). The mixture was stirred at 60 °C for 6 h. The reaction was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give 4-chloro-N-(2-(1-(difluoromethyl)-1H-pyrazol-3-yl)propan-2-yl)-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazin-2-amine (45 mg, 107.44 μmol, 23.15% yield) as a green solid. MS(ESI) m / z=419.1 [M+H]+.

[0300] Step 3: 4-((2-(1-(difluoromethyl)-1H-pyrazol-3-yl)propan-2-yl)amino)-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2-carbonitrile A mixture of 4-chloro-N-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazin-2-amine (45 mg, 107.44 μmol), tetrabutylammonium cyanide (31.73 mg, 118.19 μmol), and DABCO (14.46 mg, 128.93 μmol) in MeCN (1 mL) was degassed and purged with N, and the mixture was stirred under N at 15° C. for 16 h. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give a yellow solid, 4-((2-(1-(difluoromethyl)-1H-pyrazol-3-yl)propan-2-yl)amino)-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2-carbonitrile (19.74 mg, 44.83% yield). MS (ESI) m / z=410.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6)δ=9.48-9.25 (m, 1H), 9.04-8.80 (m, 1H), 8.14-8.03 (m, 1H), 7.93-7.57 (m, 3H), 7.18 (d, J=9.6 Hz, 1H), 6.48-8.41 (m, 1H), 2.88-2.78 (m, 3H), 1.73 (s, 6H).

[0301] Example 13 JPEG2025541224000068.jpg38128N2-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-(3-methylimidazo[1,5-a]pyrazin-6-yl)-1,3,5-triazine-2,4-diamine

[0302] Step 1: N-[(5-bromopyrazin-2-yl)methyl]acetamide To a stirred solution of (5-bromopyrazin-2-yl)methanamine (20 g, 74.37 mmol) in DCM (600 mL) was added EtN (22.58 g, 223.10 mmol). Then, acetyl chloride (11.68 g, 148.73 mmol) was added slowly at 0 °C, and the reaction mixture was stirred at 15 °C for 16 h. The reaction mixture was poured into water (300 mL) and extracted with DCM (500 mL × 3). The combined organic layers were washed with brine (500 mL × 2), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product N-[(5-bromopyrazin-2-yl)methyl]acetamide (15 g, 87.67% yield) as a brown solid. MS(ESI) m / z 230.1 [M+H]+.

[0303] Step 2: 6-Bromo-3-methyl-imidazo[1,5-a]pyrazine To a stirred solution of N-[(5-bromopyrazin-2-yl)methyl]acetamide (19 g, 82.59 mmol) and 2-methoxypyridine (18.02 g, 165.17 mmol) in DCM (370 mL) at 0 °C, TFAA (34.69 g, 165.17 mmol) was added, and the reaction mixture was stirred at 15 °C under a N atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography to give 6-bromo-3-methyl-imidazo[1,5-a]pyrazine (3.3 g, 18.84% yield) as a beige solid. MS(ESI) m / z 211.9[M+H]+.

[0304] Step 3: Tributyl-(3-methylimidazo[1,5-a]pyrazin-6-yl)stannane To a solution of 6-bromo-3-methyl-imidazo[1,5-a]pyrazine (500 mg, 2.36 mmol) in dioxane (10 mL) was added Pd(dba) (215.92 mg, 235.80 μmol), dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane (193.60 mg, 471.59 μmol), NaCO (749.76 mg, 7.07 mmol), and hexabutylditin (HEXABUTYLDITIN) (2.74 g, 4.72 mmol, 2.36 mL) under N atmosphere, and the reaction mixture was stirred at 110 °C for 12 h under N atmosphere. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography to give tributyl-(3-methylimidazo[1,5-a]pyrazin-6-yl)stannane (113 mg, 11.35% yield) as a yellow oil. MS(ESI) m / z=424.0 [M+H]+.

[0305] Step 4: N2-(2-(1-(difluoromethyl)-1H-pyrazol-3-yl)propan-2-yl)-6-(3-methylimidazo[1,5-a]pyrazin-6-yl)-1,3,5-triazine-2,4-diamine A stirred solution of tributyl-(3-methylimidazo[1,5-a]pyrazin-6-yl)stannane (60 mg, 142.11 μmol), 6-chloro-N-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-1,3,5-triazine-2,4-diamine (Example 10-1, 43.16 mg, 142.11 μmol), and Pd(PPh) (16.42 mg, 14.21 μmol) was transferred to a microwave tube in DMSO (4 mL). The sealed tube was heated in a microwave oven at 160 °C for 2 h. The crude product was purified by column chromatography to give a white solid, N2-(2-(1-(difluoromethyl)-1H-pyrazol-3-yl)propan-2-yl)-6-(3-methylimidazo[1,5-a]pyrazin-6-yl)-1,3,5-triazine-2,4-diamine (1.31 mg, 2.30% yield). MS (ESI) m / z=401.2 [M+H]+. 1H NMR (400 MHz, Methanol-d4)δ=9.10 (d, J=3.6 Hz, 2 H), 7.98 (d, J=2.4 Hz, 1H), 7.94 (s, 1H), 7.42 (t, J=59.6 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 2.80 (s, 3H), 1.87 (s, 6H).

[0306] Example 14 JPEG2025541224000069.jpg351284-(3-Methylimidazo[1,5-a]pyridin-6-yl)-6-[[1-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]ethyl]amino]-1,3,5-triazine-2-carbonitrile (general synthesis method for target compound E) MS (ESI) m / z=428.2 [M+H]+. 1H NMR (400 MHz, CD3CN)δ=9.10-8.54 (m, 1H), 7.67-7.57 (m, 1H), 7.57-7.48 (m, 1H), 7.46-7.37 (m, 1H), 7.29-7.15 (m, 1H), 2.83-2.79 (m, 3H), 1.82-1.78 (m, 6H).

[0307] Example 15 JPEG2025541224000070.jpg25128(2S)-2-[[4-cyano-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazin-2-yl]amino]-3-(2,3-dichlorophenyl)propanoic acid (general synthesis method for target compound E) MS (ESI) m / z=468.1 [M+H]+.

[0308] 1H NMR (400 MHz, DMSO-d6)δ=13.25 (br s, 1H), 9.26 (t, J=8.0 Hz, 1H), 8.94-8.82 (m, 1H), 7.62-7.42 (m, 1H),7.54-7.17 (m, 5H), 5.10-4.75 (m, 1H), 3.58-3.46 (m, 1H), 3.20-3.16 (m, 1H), 2.75-2.65 (m, 3H). Example 16 JPEG2025541224000071.jpg26128

[0309] N4-[2-amino-2-(2,3-dichlorophenyl)ethyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)pyrimidine-2,4-diamine (general synthesis method for target compound A) MS (ESI) m / z=428.1 [M+H]+.

[0310] 1H NMR (400 MHz, Methanol-d4)δ=8.84 (s, 1H), 7.87-7.79 (m, 2H), 7.71-7.59 (m, 2H), 7.49 (t, J=8.0 Hz, 1H), 7.28 (dd, J=9.6, 0.8 Hz, 1H), 6.50 (s, 1H), 5.29 (t, J=6.4 Hz, 1H), 4.17-4.00 (m, 2H), 2.90 (s, 3H). Example 17 JPEG2025541224000072.jpg28128

[0311] N4-[2-(2,3-dichlorophenyl)-2-(methylamino)ethyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)pyrimidine-2,4-diamine (general synthesis method for target compound A) MS (ESI) m / z=442.1 [M+H]+.

[0312] 1H NMR (400 MHz, DMSO-d6)δ=8.56 (s, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.60-7.52 (m, 2H), 7.46-7.39 (m, 1H), 7.27 (s, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.02 (br s, 1H), 6.31 (s, 1H), 6.10 (br s, 2H), 4.37 (br s, 1H), 3.80-3.36 (m, 3H), 2.64 (s, 3H), 2.24 (s, 3H). Example 18 JPEG2025541224000073.jpg33128

[0313] N-[2-[[2-amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)pyrimidin-4-yl]amino]-1-(2,3-dichlorophenyl)ethyl]acetamide

[0314] To a solution of N4-[2-amino-2-(2,3-dichlorophenyl)ethyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)pyrimidine-2,4-diamine (Example 16, 26 mg, 60.70 μmol) in DCM (5 mL) was added DIEA (15.69 mg, 121.41 μmol) and (2,5-dioxopyrrolidin-1-yl)acetate (38.15 mg, 242.81 μmol). The mixture was stirred at 15° C. under a N2 atmosphere for 12 hours. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give a yellow solid of N-[2-[[2-amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)pyrimidin-4-yl]amino]-1-(2,3-dichlorophenyl)ethyl]acetamide (9.01 mg, 30.28% yield). MS (ESI) m / z=470.1 [M+H]+.

[0315] 1H NMR (400 MHz, Methanol-d4)δ=8.86 (s, 1H), 7.87-7.74 (m, 2H), 7.50 (t, J=8.0 Hz, 2H), 7.35 (t, J=8.0 Hz, 1H), 7.26 (d, J=9.6 Hz, 1H), 6.46 (s, 1H), 5.73 (t, J=6.8 Hz, 1H), 3.89 (d, J=6.8 Hz, 2H), 2.91 (s, 3H), 2.01 (s, 3H). Example 19 JPEG2025541224000074.jpg32128

[0316] N-[2-[[2-amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)pyrimidin-4-yl]amino]-1-(2,3-dichlorophenyl)ethyl]-N-methyl-acetamide

[0317] To a stirred solution of N-[2-(2,3-dichlorophenyl)-2-(methylamino)ethyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)pyrimidine-2,4-diamine (Example 17, 100 mg, 226.07 μmol) in DCM (4 mL) was added (2,5-dioxopyrrolidin-1-yl)acetate (355.21 mg, 2.26 mmol) and DIEA (175.31 mg, 1.36 mmol), and the reaction mixture was stirred under a N atmosphere at 15° C. for 24 h. The reaction mixture was concentrated under reduced pressure to remove DCM. The crude product was purified by column chromatography to give a white solid N-[2-[[2-amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)pyrimidin-4-yl]amino]-1-(2,3-dichlorophenyl)ethyl]-N-methyl-acetamide (16.78 mg, 15.32% yield). MS (ESI) m / z=484.2 [M+H]+.

[0318] 1H NMR (400 MHz, Methanol-d4)δ=8.86-8.78 (m, 1H), 7.88-7.79 (m, 2H), 7.67-7.58 (m, 1H), 7.54 (d, J=7.6 Hz, 1H), 7.44-7.38 (m, 1H), 7.28 (d, J=10.0 Hz, 1H), 6.39 (s, 1H), 6.31-6.27 (m, 1H), 4.18-4.07 (m, 2H), 2.93-2.87 (m, 3H), 2.78-2.66 (m, 3H), 2.35-2.07 (m, 3H). Example 20 JPEG2025541224000075.jpg33128

[0319] (2S or 2R)-2-[[4-amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazin-2-yl]amino]-3-(2,3-dichlorophenyl)-N-methoxy-propanamide

[0320] Step 1: tert-butyl N-[(1S or 1R)-1-[(2,3-dichlorophenyl)methyl]-2-(methoxyamino)-2-oxo-ethyl]carbamate

[0321] To a stirred solution of (2S or 2R)-2-(tert-butoxycarbonylamino)-3-(2,3-dichlorophenyl)propanoic acid (140 mg, 418.92 μmol) in DCM (2 mL) was added O-methylhydroxyamine (69.97 mg, 837.84 μmol), DIPEA (162.42 mg, 1.26 mmol), EDCI (120.46 mg, 628.38 μmol), and HOBt (84.91 mg, 628.38 μmol) under a N atmosphere at 0 °C, and the reaction mixture was stirred at 15 °C under a N atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography to give tert-butyl N-[(1S or 1R)-1-[(2,3-dichlorophenyl)methyl]-2-(methoxyamino)-2-oxo-ethyl]carbamate (140 mg, 92.00% yield) as a white solid. MS(ESI)m / z=306.9[M-tBu +H]+. Step 2: (2S or 2R)-2-amino-3-(2,3-dichlorophenyl)-N-methoxy-propanamide

[0322] A reaction mixture of a stirred solution of tert-butyl N-[(1S or 1R)-1-[(2,3-dichlorophenyl)methyl]-2-(methoxyamino)-2-oxo-ethyl]carbamate (180 mg, 495.55 μmol) in HCl / dioxane (2 mL, 4 M) and dioxane (2 mL) was stirred under a N atmosphere at 15° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give (2S or 2R)-2-amino-3-(2,3-dichlorophenyl)-N-methoxy-propanamide (140 mg, 94.30% yield) as a beige solid. MS(ESI) m / z=263.1 [M+H]+.

[0323] Step 3: (2S or 2R)-2-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-3-(2,3-dichlorophenyl)-N-methoxy-propanamide

[0324] To a stirred solution of (2S or 2R)-2-amino-3-(2,3-dichlorophenyl)-N-methoxy-propanamide (148 mg, 494.02 μmol) in i-PrOH (3 mL) was added DIEA (191.54 mg, 1.48 mmol) and 4,6-dichloro-1,3,5-triazin-2-amine (97.81 mg, 592.83 μmol), and the reaction mixture was stirred at 90 °C under a N atmosphere for 4 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography to give (2S or 2R)-2-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-3-(2,3-dichlorophenyl)-N-methoxy-propanamide (149 mg, 77.01% yield) as a beige solid. MS(ESI) m / z=392.9 [M+2+H]+.

[0325] Step 4: (2S or 2R)-2-[[4-amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazin-2-yl]amino]-3-(2,3-dichlorophenyl)-N-methoxy-propanamide

[0326] To a solution of (2S or 2R)-2-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-3-(2,3-dichlorophenyl)-N-methoxy-propanamide (20 mg, 51.07 μmol) and 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine (19.77 mg, 76.60 μmol) in THF (1 mL) and HO (0.1 mL) was added KCO (14.12 mg, 102.13 μmol) and ditert-butyl(cyclopentyl)phosphane; dichloropalladium; and iron (3.33 mg, 5.11 μmol). The reaction mixture was stirred at 75 °C under a N atmosphere for 4 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography to give (2S or 2R)-2-[[4-amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazin-2-yl]amino]-3-(2,3-dichlorophenyl)-N-methoxy-propanamide (1.84 mg, 7.39% yield) as a yellow solid. MS (ESI) m / z=487.1 [M+H]+.

[0327] 1H NMR (400 MHz, Methanol-d4)δ=9.16-8.97 (m, 1H), 8.03-7.94 (m, 1H), 7.92 (s, 1H), 7.80 (dd, J=10.0, 1.2 Hz, 1H), 7.46-7.11 (m, 3H), 5.01-4.77 (m, 1H), 3.64-3.56 (m, 3H), 3.50-3.35 (m, 1H), 3.26-3.16 (m, 1H), 3.05-2.94 (m, 3H). Example 21 JPEG2025541224000076.jpg26128

[0328] N4-[(1S or 1R)-2-(2,3-dichlorophenyl)-1-(1H-tetrazol-5-yl)ethyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine

[0329] Step 1: (2S or 2R)-2-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-3-(2,3-dichlorophenyl)propanamide

[0330] To a solution of (2S or 2R)-2-amino-3-(2,3-dichlorophenyl)propanamide (700 mg, 3.00 mmol) in i-PrOH (14 mL) was added 4,6-dichloro-1,3,5-triazin-2-amine (495.45 mg, 3.00 mmol) and DIPEA (1.16 g, 9.01 mmol). The reaction was stirred at 90 °C under a N atmosphere for 6 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give (2S or 2R)-2-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-3-(2,3-dichlorophenyl)propanamide (650 mg, 1.80 mmol, 59.86% yield) as a colorless oil. MS(ESI) m / z=362.8 [M+H]+.

[0331] Step 2: (2S or 2R)-2-[[4-amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazin-2-yl]amino]-3-(2,3-dichlorophenyl)propanamide

[0332] To a solution of (2S or 2R)-2-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-3-(2,3-dichlorophenyl)propanamide (650 mg, 1.80 mmol) in THF (6.5 mL) and HO (0.65 mL) was added 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine (556.77 mg, 2.16 mmol), KCO (496.86 mg, 3.59 mmol), and ditert-butyl(cyclopentyl)phosphane; dichloropalladium; and iron (117.15 mg, 179.75 μmol). The mixture was stirred at 75 °C under a N atmosphere for 3 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography to give the product (2S or 2R)-2-[[4-amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazin-2-yl]amino]-3-(2,3-dichlorophenyl)propanamide (234 mg, 28.47% yield) as a yellow solid. MS(ESI) m / z=457.0 [M+H]+.

[0333] Step 3: (2S or 2R)-2-[[4-amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazin-2-yl]amino]-3-(2,3-dichlorophenyl)propanenitrile

[0334] To a solution of (2S or 2R)-2-[[4-amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazin-2-yl]amino]-3-(2,3-dichlorophenyl)propanamide (100 mg, 218.67 μmol) in DCM (3 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl-azanide (416.88 mg, 1.75 mmol). The mixture was stirred at 45° C. under a N atmosphere for 16 h. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give the product (2S or 2R)-2-[[4-amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazin-2-yl]amino]-3-(2,3-dichlorophenyl)propanenitrile (120 mg, 62.46% yield) as a yellow solid. MS(ESI) m / z=439.1 [M+H]+.

[0335] Step 4: N4-[(1S or 1R)-2-(2,3-dichlorophenyl)-1-(1H-tetrazol-5-yl)ethyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine

[0336] To a solution of (2S or 2R)-2-[[4-amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazin-2-yl]amino]-3-(2,3-dichlorophenyl)propanenitrile (30 mg, 68.29 μmol) in toluene (3 mL) was added AcOH (41.01 mg, 682.90 μmol), EtN (69.10 mg, 682.90 μmol), and NaN (44.40 mg, 682.90 μmol). The mixture was stirred at 100 °C under a N atmosphere for 12 h. The mixture was concentrated to give the crude product. The crude product was purified by column chromatography to give the product N4-[(1S or 1R)-2-(2,3-dichlorophenyl)-1-(1H-tetrazol-5-yl)ethyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine (6.6 mg, 20.04% yield) as a yellow solid. MS (ESI) m / z=482.1 [M+H]+.

[0337] 1H NMR (400 MHz, Methanol-d4)δ=9.16-8.79 (m, 1H), 8.08-7.69 (m, 3H), 7.48-7.02 (m, 3H), 6.16-5.87 (m, 1H), 3.89-3.67 (m, 1H), 3.57-3.44 (m, 1H) 3.10-2.88 (m, 3H). Example 22 JPEG2025541224000077.jpg27128

[0338] N4-[2-(2,3-dichlorophenyl)-1-(1-tritylimidazol-4-yl)ethyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) MS (ESI) m / z=480.0 [M+H]+.

[0339] 1H NMR (400 MHz, DMSO-d6) δ=15.22 (br s, 1H), 14.74 (br s, 1H), 9.21-9.00 (m, 2H), 8.78 (br d, 1H), 8.10 (s, 1H), 7.93-7.86 (m, 1H), 7.78 (s, 1H), 7.76-7.64 (m, 1H), 7.63-7.40 (m, 2H), 7.35 (m, 1H), 7.31-7.16 (m, 1H), 7.22-7.15 (m, 1H), 6.06-6.03 (m, 0.5H), 5.60-5.57 (m, 0.5H), 3.57-3.35 (m, 2H), 3.06-2.90 (m, 3H). Example 23 JPEG2025541224000078.jpg27128

[0340] N2-(2-(2,3-dichlorophenyl)-1-(1,2,4-oxadiazol-5-yl)ethyl)-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) MS (ESI) m / z=482.1 [M+H]+.

[0341] 1H NMR (400 MHz, DMSO-d6) δ=9.24 (br s, 2H), 8.91 (s, 1H), 7.96 (br s, 1H), 7.86 (br d, 2H), 7.80 (d, 1H), 7.63 (d, 1 H), 7.32 (dd, 1H), 7.27-7.21 (m, 1H), 7.20-7.13 (m, 1H), 5.14 (t, 1H), 3.65-3.73 (m, 1H), 3.40-3.32 (m, 1H), 2.87 (s, 3H). Example 24 JPEG2025541224000079.jpg32128

[0342] 6-(1H-indazol-5-yl)-N4-[(1R or 1S)-2-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound C) MS (ESI) m / z =418.2 [M+H]+.

[0343] 1H NMR (400 MHz, DMSO-d6) δ=13.43 (s, 1H), 8.78 (s, 1H), 8.63-8.38 (m, 1H), 8.37-8.31 (m, 1H), 8.31-8.02 (m, 2H), 7.67-8.00 (m, 2H), 7.66-7.39 (m, 1H), 7.35 (s, 1H), 5.22-5.00 (m, 1H), 2.27 (m, 1H), 1.01-0.93 (m, 3H), 0.90-0.83 (m, 3H). Example 25 JPEG2025541224000080.jpg39128

[0344] N2-[(1R or 1S)-3-amino-1-[1-(difluoromethyl)pyrazol-3-yl]propyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) MS (ESI) m / z=415.1 [M+H]+.

[0345] 1H NMR (400 MHz, DMSO-d6)δ=9.15 (s, 1H), 8.38-8.04 (m, 5H), 7.96 (s, 1H), 7.90-7.58 (m, 3H), 7.30 (br s, 1H), 6.60 (d, 1H), 5.60-5.25 (m, 1H), 2.97 (s, 3H), 2.93 (d, 2H), 2.45-2.19 (m, 2H). Example 26 JPEG2025541224000081.jpg37128

[0346] N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-(1H-indazol-5-yl)-N2-methyl-1,3,5-triazine-2,4-diamine (general synthesis method for target compound D) Step 1: 4,6-Dichloro-N-methyl-1,3,5-triazin-2-amine

[0347] A solution of 2,4,6-trichloro-1,3,5-triazine (3 g, 16.27 mmol) in THF (20 mL) was cooled to -70 °C. DIPEA (4.21 g, 32.54 mmol) and methanamine (1.10 g, 16.27 mmol) were added to the reaction mixture, which was stirred at -70 °C for 1 h and warmed to 15 °C under a N atmosphere for 11 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give 4,6-dichloro-N-methyl-1,3,5-triazin-2-amine (5.03 g, 86.36% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ = 9.01 (br s, 1H), 2.83 (s, 3H).

[0348] Step 2: 6-chloro-N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-N2-methyl-1,3,5-triazine-2,4-diamine

[0349] To a solution of 4,6-dichloro-N-methyl-1,3,5-triazine-2-amine (169.16 mg, 945.00 μmol) and 2-[1-(difluoromethyl)pyrazol-3-yl]propan-2-amine (200 mg, 945.00 μmol) in i-PrOH (6 mL) was added DIPEA (366.40 mg, 2.84 mmol), and the mixture was stirred at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give 6-chloro-N-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-N-methyl-1,3,5-triazine-2,4-diamine (205 mg, 68.28% yield) as a white solid.

[0350] 1H NMR (400 MHz, DMSO-d6) δ=8.11 (s, 1H), 8.02 (d, 1H), 7.86-7.55 (m, 2H), 6.32 (d, 1H), 2.41 (d, 3H), 1.64 (s, 6H).

[0351] Step 3: N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-N2-methyl-6-(1-tetrahydropyran-2-ylindazol-5-yl)-1,3,5-triazine-2,4-diamine

[0352] To a stirred solution of 6-chloro-N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-N2-methyl-1,3,5-triazine-2,4-diamine (205 mg, 645.21 μmol) in THF (2 mL) and HO (0.2 mL) was added 1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (317. Ditert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (42.05 mg, 64.52 μmol), ditert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (42.05 mg, 64.52 μmol), and KCO (178.34 mg, 1.29 mmol) were added, and the reaction mixture was stirred at 75 °C under a N atmosphere for 12 hours. The reaction was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give a yellow solid, N-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-N-methyl-6-(1-tetrahydropyran-2-ylindazol-5-yl)-1,3,5-triazine-2,4-diamine (170 mg, 54.49% yield). MS(ESI) m / z=484.1 [M+H]+.

[0353] Step 4: N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-(1H-indazol-5-yl)-N2-methyl-1,3,5-triazine-2,4-diamine

[0354] To a solution of N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-N2-methyl-6-(1-tetrahydropyran-2-ylindazol-5-yl)-1,3,5-triazine-2,4-diamine (160 mg, 330.91 μmol) in DCM (5 mL) was added TFA (2.17 g, 19.01 mmol). The mixture was stirred under N2 at 15 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by column chromatography to give N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-(1H-indazol-5-yl)-N2-methyl-1,3,5-triazine-2,4-diamine (47.01 mg, 35.57% yield) as a white solid. MS (ESI) m / z=399.7 [M+H]+.

[0355] 1H NMR (400 MHz, DMSO-d6)δ=8.59 (br s, 1H), 8.25-8.09 (m, 2H), 8.00 (d, 1H), 7.70 (t, 1H), 7.54 (d, 1H), 7.19 (br s, 2H), 6.45 (d, 1H), 2.81 (s, 3H), 1.79 (s, 6H). Example 27 JPEG2025541224000082.jpg36128

[0356] N4-[(1R or 1S)-1-[1-(difluoromethyl)pyrazol-3-yl]-2-methyl-propyl]-6-(1H-indazol-5-yl)-N2-methyl-1,3,5-triazine-2,4-diamine (general synthesis method for target compound D) MS (ESI) m / z=414.2[M+H]+.

[0357] 1H NMR (400 MHz, METHANOL-d4)δ=8.79-8.61 (m, 1H), 8.27 (s, 1H), 8.16 (dd, 1H), 8.08-8.01 (m, 1H), 7.73 (d, 1H), 7.46 (t, 1H), 6.56 (d, 1H), 5.39-5.22 (m, 1H), 3.08 (s, 3H), 2.40-2.29 (m, 1H), 1.09 (d, 3H), 0.99 (d, 3H). Example 28 JPEG2025541224000083.jpg34128

[0358] N4-[(1R or 1S)-2-Methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-6-[1-(trideuteriomethyl)indazol-6-yl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) MS (ESI) m / z=435.2 [M+H]+.

[0359] 1H NMR (400 MHz, CD3OD)δ=8.55-8.49 (m, 1H), 8.14 (s, 1H), 8.05-7.85 (m, 2H), 7.35-7.23 (m, 1H), 5.39-5.08 (m, 1H), 2.48-2.22 (m, 1H), 1.11-1.04 (m, 3H), 1.01-0.94 (m, 3H). Example 29A & Example 29B JPEG2025541224000084.jpg39128

[0360] N4-[(1S or 1R)-1-[1-(difluoromethyl)pyrazol-3-yl]-2-methyl-propyl]-N2-(trideuteriomethyl)-6-[1-(trideuteriomethyl)indazol-6-yl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound B) 29A MS (ESI) m / z=434.2 [M+H]+.

[0361] 1H NMR (400 MHz, Methanol-d4)δ=8.44 (s, 1H), 8.13 (s, 1H), 8.04 (d, 1H), 7.98 (m, 2H), 7.46 (t, 1H), 6.56 (d, 1H), 5.40 (m, 1H), 2.40 (m, 1H), 1.09 (d, 3H), 0.98 (d, 3H). 29B MS (ESI) m / z=434.3 [M+H]+.

[0362] 1H NMR:(400 MHz, DMSO-d6)δ=8.48 (s, 1H), 8.20 (m, 3H), 7.93 (m, 3H), 7.49 (br s, 1H), 6.60 (d, 1 H), 5.20 (br s, 1H), 2.25 (m, 1 H), 1.01 (d, 3H), 0.90 (d, 3H). Example 30 JPEG2025541224000085.jpg38128

[0363] 6-(3-aminoimidazo[1,5-a]pyridin-6-yl)-N2-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-N4-(trideuteriomethyl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound D) MS (ESI) m / z=418.2 [M+H]+.

[0364] 1H NMR (400 MHz, Methanol-d4) δ=8.72 (m, 1H), 8.01 (m, 1H), 7.55 (m, 2H), 7.22 (m, 2H), 6.48 (s, 1H), 1.83 (s, 6H). Example 31 JPEG2025541224000086.jpg39128

[0365] 6-(1-Methylindazol-6-yl)-N4-[(1R)-2-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-N2-(trideuteriomethyl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound B) MS (ESI) m / z=449.2 [M+H]+.

[0366] 1H NMR (400 MHz, Methanol-d4)δ=8.51 (m, 1H), 8.12 (s, 1H), 8.00 (m, 2H), 7.31 (s, 1H), 5.35 (m, 1H), 4.17 (s, 3H), 2.42 (m, 1H), 1.09 (d, 3H), 0.98 (d, 3H). Example 32 JPEG2025541224000087.jpg33128

[0367] N4-[(R or S)-cyclopropyl-[2-(trifluoromethyl)-1H-imidazol-4-yl]methyl]-6-(1H-indazol-5-yl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound B) MS (ESI) m / z =416.1 [M+H]+.

[0368] 1H NMR (400 MHz, CD3OD) δ=8.78 (m, 1H), 8.12 (s, 1H), 8.16 (d, 1H), 7.81 (m, 1H), 7.41 (m, 1H), 4.79 (m, 1H), 1.58 (m, 1H), 0.76 (m, 2H), 0.62 (m, 1H), 0.49 (m, 1H). Example 33 JPEG2025541224000088.jpg36128

[0369] N4-[(R)-cyclopropyl-[1-(difluoromethyl)pyrazol-3-yl]methyl]-6-(1H-indazol-5-yl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound B) MS (ESI) m / z=398.2 [M+H]+.

[0370] 1H NMR (400 MHz, CD3OD)δ=8.69 (s, 1H), 8.27 (s, 1H), 8.21 (m, 1H), 8.02 (s, 1H), 7.76 (m, 1H), 7.45 (t, 1H), 6.62 (d, 1H), 4.81 (d, 1H), 1.52 (m, 1H), 0.76 (m, 2H), 0.62 (m, 2H). Example 34 JPEG2025541224000089.jpg37128

[0371] 6-(1-methylindazol-5-yl)-N4-[(1R)-2-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) MS (ESI) m / z=432.2 [M+H]+.

[0372] 1H NMR (400 MHz, DMSO-d6)δ=8.73 (m, 1H), 8.38 (m, 1H), 8.19 (d, 1H), 7.67 (d, J=9.2 Hz, 1H), 7.43 (m, 2H), 6.93 (m, 2H), 5.25 (m, 1H), 4.07 (s, 3H), 2.25 (m, 1H), 0.98 (m, 3H), 0.84 (m, 3H). Example 35 JPEG2025541224000090.jpg38128

[0373] 6-(3-methyl-1H-indazol-5-yl)-N4-[(1R)-2-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) MS (ESI) m / z=432.2 [M+H]+.

[0374] 1H NMR (400 MHz, CD3OD) δ=8.68 (m, 1H), 8.30 (m, 1H), 7.62 (d, 1H), 7.28 (s, 1H), 5.34 (m, 1H), 2.64 (s, 3H), 2.39 (m, 1H), 1.07 (m, 3H), 0.97 (m, 3H). Example 36 JPEG2025541224000091.jpg24128

[0375] N2-[2-(6-fluoro-2-pyridyl)-1,1-dimethyl-ethyl]-6-[1-(trideuteriomethyl)indazol-6-yl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) MS (ESI) m / z=396.2 [M+H]+.

[0376] 1H NMR (400 MHz, CD3OD) δ=8.68 (m, 1H), 8.30 (m, 2H), 7.87 (m, 2H), 7.14 (m, 1H), 6.87 (br d, 1H), 3.42 (s, 2H), 1.51 (s, 6H). Example 37 JPEG2025541224000092.jpg35128

[0377] N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-[1-(methylamino)indazol-6-yl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) MS (ESI) m / z=415.2 [M+H]+.

[0378] 1H NMR (400 MHz, Methanol-d4) δ=9.01 (m, 1H), 7.90 (s, 1H), 7.61 (m, 4H), 6.45 (s, 1H), 3.17 (s, 3H), 1.82 (s, 6H). Example 38 JPEG2025541224000093.jpg37128

[0379] 6-[4-amino-6-[[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]amino]-1,3,5-triazin-2-yl]imidazo[1,5-a]pyridin-3-ol (general synthesis method for target compound A) MS (ESI) m / z=402.1 [M+H]+.

[0380] 1H NMR (400 MHz, Methanol-d4)δ=8.60 (m, 1H), 7.94 (s, 1H), 7.68 (m, 1H), 7.09 (m, 3H), 6.51 (s, 1H), 1.83 (s, 6H). Example 39 JPEG2025541224000094.jpg35128

[0381] N2-[1-methyl-1-[4-(trifluoromethyl)thiazol-2-yl]ethyl]-6-[1-(trideuteriomethyl)indazol-6-yl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) MS (ESI) m / z=438.1 [M+H]+.

[0382] 1H NMR (400 MHz, Methanol-d4)δ=8.55 (m, 1H), 8.18 (m, 2H), 7.94 (br s, 1H), 7.81 (m, 1H), 1.95 (s, 6H). Example 40 JPEG2025541224000095.jpg25128

[0383] N4-[1,1-dimethyl-2-[3-(trifluoromethyl)pyrazol-1-yl]ethyl]-6-[1-(trideuteriomethyl)indazol-6-yl]pyrimidine-2,4-diamine (general synthesis method for target compound A) MS (ESI) m / z=434.2 [M+H]+.

[0384] 1H NMR (400 MHz, CD3OD) δ=8.13 (s, 1H), 8.01 (m, 2H), 7.67 (s, 1H), 7.44 (d, 1H), 6.59 (d, 1H), 6.40 (s, 1H), 4.84 (s, 2H), 1.52 (s, 6H). Example 41 JPEG2025541224000096.jpg25128

[0385] 6-(3-aminoimidazo[1,5-a]pyridin-6-yl)-N2-[2-(2,3-dichlorophenyl)-1,1-dimethyl-ethyl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound B) MS (ESI) m / z =443.1 [M+H]+.

[0386] 1H NMR (400 MHz, DMSO-d6) δ=8.94 (m, 1H), 8.33 (s, 2H), 7.50 (m, 3H), 7.38 (s, 1H), 7.26 (t, 1H), 7.13 (s, 1H), 7.05 (m, 2H), 6.87 (m, 1H), 3.52 (s, 2H), 1.39 (s, 6H). Example 42 JPEG2025541224000097.jpg26128

[0387] 6-(3-aminoimidazo[1,5-a]pyridin-6-yl)-N2-[2-(4-chloro-2,3-difluoro-phenyl)ethyl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound B) MS (ESI) m / z=417.2 [M+H]+.

[0388] 1H NMR (400 MHz, CD3OD) δ=8.92 (s, 1H), 7.60 (m, 1H), 7.44 (m, 1H), 7.25 (d, 1H), 7.21 (m, 1H), 7.12 (m, 1H), 3.82 (t, 1H), 3.69 (t, 1H), 3.01 (t, 2H). Example 43 JPEG2025541224000098.jpg37128

[0389] 6-(1H-indazol-5-yl)-N4-[(1S or 1R)-3-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]butyl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound B) MS (ESI) m / z =432.4 [M+H]+.

[0390] 1H NMR (400 MHz, DMSO-d6) δ=13.37 (m, 2H), 8.75 (d, 1H), 8.35 (m, 1H), 8.21 (s, 1H), 7.57 (d, 1H), 7.50 (m, 1H), 7.26 (m, 1H), 6.81 (br s, 1H), 6.68 (br s, 1H), 5.48 (m, 1H), 1.78 (br s, 1H), 1.69 (m, 1H), 0.96 (m, 6H). Example 44 JPEG2025541224000099.jpg31128

[0391] 6-(1,3-Dimethylindazol-6-yl)-N2-[(1R or 1S)-2-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (General synthesis method for target compound A) MS (ESI) m / z=446.2 [M+H]+.

[0392] 1H NMR (400 MHz, Methanol-d4) δ=8.43 (m, 1H), 7.99 (m, 2H), 7.32 (m, 1H), 5.42 (m, 1H), 4.15 (m, 3H), 2.59 (s, 3H), 2.45 (m, 1H), 1.14 (m, 3H), 1.01 (m, 3H). Example 45 JPEG2025541224000100.jpg33128

[0393] 6-(3-Fluoro-1-methyl-indazol-6-yl)-N2-[(1R or 1S)-2-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (General synthesis method for target compound A) MS (ESI) m / z=450.2 [M+H]+.

[0394] 1H NMR (400 MHz, DMSO-d6) δ=8.42 (br s, 1H), 8.11 (br d, 1H), 8.04-7.79 (m, 2H), 7.72-7.37 (m, 1H), 7.36-7.13 (m, 2H), 5.24-4.97 (m, 1H), 4.02-3.98 (m, 3H), 2.29-2.16 (m, 1H), 0.99-0.91 (m, 3H), 0.89-0.81 (m, 3H). Example 46 JPEG2025541224000101.jpg36128

[0395] 6-(1-methyl-1H-indazol-5-yl)-N2-(2-(2-(trifluoromethyl)-1H-imidazol-4-yl)propan-2-yl)-1,3,5-triazine-2,4-diamine MS (ESI) m / z=399.9 [M+H]+.

[0396] 1H NMR (400MHz, DMSO-d6):δ=8.52 (br s, 1H), 8.19-8.11 (m, 2H), 8.03 (d, 1H), 7.73 (t, 1H), 7.64 (br d, 1H), 7.58 (s, 1H), 7.05 (br s, 2H), 6.47 (s, 1H), 4.07 (s, 3H), 1.79 (s, 6H). Example 47A JPEG2025541224000102.jpg35128

[0397] (R or S)—N2-(1-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2-methylpropyl)-6-(1-methyl-1H-indazol-5-yl)-1,3,5-triazine-2,4-diamine MS (ESI) m / z=414.2 [M+H]+.

[0398] 1H NMR (400MHz, DMSO-d6):δ=8.71 (s, 1H), 8.29 (br d, 1H), 8.20 (s, 1H), 8.09 (br s, 1H), 7.79 (t, 1H), 7.76-7.62 (m, 2H), 7.02 (br s, 2H), 6.56 (d, 1H), 5.43-5.01 (m, 1H), 4.08 (s, 3H), 2.33-2.08 (m, 1H), 0.99 (d, 3H), 0.88 (d, 3H). Example 48 JPEG2025541224000103.jpg35128

[0399] N2-(2-(1-(difluoromethyl)-1H-pyrazol-3-yl)propan-2-yl)-6-(1-methyl-1H-indazol-5-yl)-1,3,5-triazine-2,4-diamine MS (ESI) m / z=399.9 [M+H]+.

[0400] 1H NMR (400MHz, DMSO-d6):δ=8.52 (br s, 1H), 8.19-8.11 (m, 2H), 8.03 (d, 1H), 7.73 (t, 1H), 7.64 (br d, 1H), 7.58 (s, 1H), 7.05 (br s, 2H), 6.47 (s, 1H), 4.07 (s, 3H), 1.79 (s, 6H). Example 135 JPEG2025541224000104.jpg37128

[0401] N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-N2-methyl-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound B) MS (ESI) m / z 414.2 [M+H]+.

[0402] 1H NMR (400 MHz, DMSO-d6) δ=8.70 (s, 1H), 7.98 (d, 1H), 7.48 (t, 1H), 7.49-7.42 (m, 1H), 7.39 (br s, 1H), 7.26 (s, 1H), 7.22-6.88 (m, 2H), 6.42 (d, 1H), 3.05 (s, 3H), 2.63 (s, 3H), 1.77-1.75 (s, 6H). Example 136A & Example 136B JPEG2025541224000105.jpg29128

[0403] N2-[(1R or 1S)-1-(5-fluoro-2-pyridyl)-2-methyl-propyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) 136A MS (ESI) m / z 393.0 [M+H] + .

[0404] 1H NMR (400 MHz, Methanol-d4) δ=8.85 (d, 1H), 8.44-8.42 (m, 1H), 8.22 (s, 1H), 7.61-7.48 (m, 4H), 7.30 (s, 1H), 5.11-5.03 (m, 1H), 2.72 (d, 3H), 2.30-2.24 (m, 1H), 1.07-1.03 (m, 3H), 0.90-0.86 (m, 3H). 136B MS (ESI) m / z=392.9 [M+H]+.

[0405] 1H NMR (400 MHz, Methanol-d4) δ=8.85 (d, 1H), 8.44-8.42 (m, 1H), 7.61-7.31 (m, 4H), 7.29 (s, 1H), 5.09 (dd, 1H), 2.71 (d, 3H), 2.30-2.24 (m, 1H), 1.07-1.03 (m, 3H), 0.90-0.86 (m, 3H). Example 137 JPEG2025541224000106.jpg27128

[0406] (2S or 2R)-2-[[4-amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazin-2-yl]amino]-3-(2,3-difluorophenyl)propanoic acid (general synthesis method for target compound A) MS (ESI) m / z 426.2 [M+H] + .

[0407] 1H NMR (400 MHz, DMSO-d6) δ=8.80 (s, 1H), 8.13 (s, 1H), 7.57-7.41 (m, 2H), 7.28 (s, 1H), 7.25-7.00 (m, 4H), 6.68 (br s, 2H), 4.82 (br d, 1H), 3.32-3.28 (m, 2H), 2.65 (s, 3H). Example 138 JPEG2025541224000107.jpg26128

[0408] (2S or 2R)-3-(2,3-dichlorophenyl)-2-[[4-(methylamino)-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazin-2-yl]amino]propanoic acid (general synthesis method for target compound B) MS (ESI) m / z 472.1 [M+H] + .

[0409] 1H NMR (400 MHz, DMSO-d6) δ=8.78 (s, 1H), 7.57-7.50 (m, 1H), 7.49-7.31 (m, 4H), 7.31-7.18 (m, 2H), 7.14 (br s, 1H), 4.91 (br s, 1H), 3.47-3.42 (m, 1H), 3.28-3.17 (m, 1H), 2.84 (br s, 3H), 2.66 (s, 3H). Example 139 JPEG2025541224000108.jpg30128

[0410] N2-[(1R or 1S)-1-(5-fluoro-2-pyridyl)ethyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) MS (ESI) m / z 364.9 [M+H] + .

[0411] 1H NMR (400 MHz, Methanol-d4) δ=8.85 (m, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 7.62-7.47 (m, 4H), 7.29 (s, 1H), 5.36-5.26 (m, 1H), 2.70 (s, 3H), 1.55 (d, 3H). Example 140 JPEG2025541224000109.jpg29128

[0412] N2-[(1R or 1S)-1-(5-fluoro-2-pyridyl)propyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) MS (ESI) m / z 378.9 [M+H] + .

[0413] 1H NMR (400 MHz, Methanol-d4) δ=8.76 (m, 1H), 8.41 (d, J=7.6 Hz, 1H), 8.23 ​​(s, 1H), 7.57-7.50 (m, 4H), 7.28 (s, 1H), 5.20-5.04 (m, 1H), 2.69 (s, 3H), 2.07-1.81 (m, 2H), 1.04-0.93 (m, 3H). Example 141A & Example 141B JPEG2025541224000110.jpg29128

[0414] N2-[(1R or 1S)-1-(6-fluoro-3-pyridyl)propyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) 141A MS (ESI) m / z 379.2 [M+H] + .

[0415] 1H NMR (400 MHz, DMSO-d6) δ=8.77 (s, 1H), 8.30 (s, 1H), 8.02 (dt, 1H), 7.65 (s, 1H), 7.55-7.45 (m, 2H), 7.28 (s, 1H), 7.10 (dd, 1H), 6.64 (s, 2H), 5.04 (s, 1H), 2.66 (s, 3H), 2.01-1.76 (m, 2H), 0.93 (t, 3H). 141B LCMS m / z (ESI+) 379.2 [M+H] + .

[0416] 1H NMR (400 MHz, DMSO-d6) δ=8.77 (s, 1H), 8.30 (s, 1H), 8.02 (dt, 1H), 7.65 (s, 1H), 7.55-7.45 (m, 2H), 7.28 (s, 1H), 7.10 (dd, 1H), 6.64 (s, 2H), 5.04 (s, 1H), 2.66 (s, 3H), 2.01-1.76 (m, 2H), 0.93 (t, 3H). Example 142A & Example 142B JPEG2025541224000111.jpg37128

[0417] 6-(3-Methylimidazo[1,5-a]pyridin-6-yl)-N2-[(1R or 1S)-2-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) 142A LCMS (ESI) m / z=432.0 [M+H]+.

[0418] 1H NMR (400 MHz, DMSO-d6) δ=8.81 (s, 1H), 8.19 (s, 1H), 7.52 (s, 2H), 7.28 (s, 1H), 7.21 (br s, 1H), 7.17-6.94 (m, 1H), 6.65 (br s, 2H), 5.09 (br s, 1H), 2.65 (s, 3H), 2.22 (qd, 1H), 0.96 (d, 3H), 0.87 (d, 3H). 142B LCMS m / z (ESI+) 432.3 [M+H] + .

[0419] 1H NMR (400 MHz, DMSO-d6) δ=8.81 (s, 1H), 8.16 (s, 1H), 7.52 (d, 2H), 7.28 (s, 1H), 7.21 (br s, 1H), 7.10 (br s, 1H), 6.64 (br s, 2H), 5.09 (br s, 1H), 2.65 (s, 3H), 2.22 (qd, 1H), 0.96 (d, 3H), 0.87 (d, 3H). Example 143A & Example 143B JPEG2025541224000112.jpg26128

[0420] (1R or 1S)-1-(2,3-dichlorophenyl)-2-[[2-(methylamino)-6-(3-methylimidazo[1,5-a]pyridin-6-yl)pyrimidin-4-yl]amino]ethanol (general synthesis method for target compound B) 143A LCMS m / z (ESI+) 443.1 [M+H] + .

[0421] 1H NMR (400 MHz, Methanol-d4) δ=8.54 (s, 1H), 7.59 (d, 1H), 7.51 (d, 1H), 7.43 (d, 1H), 7.34-7.24 (m, 2H), 7.19 (d, 1H), 6.21 (s, 1H), 5.32 (m, 1H), 3.88-3.58 (m, 1H), 3.69 (s, 1H), 2.96 (s, 3H), 2.68 (s, 3H). 143B LCMS m / z (ESI+) 443.1 [M+H] + .

[0422] 1H NMR (400 MHz, Methanol-d4):δ=8.57 (s, 1H), 7.62 (dd, 1H), 7.54 (d, 1H), 7.44 (dd, 1H), 7.33-7.29 (m, 2H), 7.19 (d, 1H), 6.24 (s, 1H), 5.35 (dd, 1H), 3.84-3.67 (m, 2H), 2.98 (s, 3H), 2.71 (s, 3H). Example 144 JPEG2025541224000113.jpg25128

[0423] (2R or 2S)-2-[[2-amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)pyrimidin-4-yl]amino]-3-(2,3-difluorophenyl)propanoic acid (general synthesis method for target compound A) LCMS m / z (ESI+) 425.0 [M+H] + .

[0424] 1H NMR (400 MHz, DMSO-d6) δ=8.53 (s, 1H), 8.14 (s, 1H), 7.53 (d, 1H), 7.26 (s, 1H), 7.24-7.17 (m, 2H), 7.17-7.04 (m, 3H), 6.97 (br s, 1H), 6.37 (s, 1H), 5.89 (s, 1H), 4.84 (br s, 1H), 3.30-3.12 (m, 2H), 2.64 (s, 3H). Example 145 JPEG2025541224000114.jpg27128

[0425] (2R or 2S)-3-(2,3-dichlorophenyl)-2-[[2-(methylamino)-6-(3-methylimidazo[1,5-a]pyridin-6-yl)pyrimidin-4-yl]amino]propanoic acid (general synthesis method for target compound B) LCMS m / z (ESI+) 471.0 [M+H]+ .

[0426] 1H NMR (400 MHz, DMSO-d6):δ=8.52 (s, 1H), 7.52 (d, 1H), 7.43 (d, 1H), 7.37 (d, 1H), 7.29-7.21 (m, 2H), 7.16 (d, 1H), 6.93 (s, 1H), 6.27 (s, 1H), 6.17 (s, 1H), 4.88 (s, 1H), 3.35-3.31 (m, 2H), 2.81 (d, 3H), 2.63 (s, 3H). Example 146A & Example 146B JPEG2025541224000115.jpg24128

[0427] (1S or 1R)-[[4-amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazin-2-yl]amino]-1-(2,3-dichlorophenyl)ethanol (general synthesis method for target compound A) 146A LCMS m / z (ESI+) 429.9 [M+H] + .

[0428] 1H NMR (400 MHz, Methanol-d4) δ=8.87 (s, 1H), 7.71-7.41 (m, 3H), 7.34-7.26 (m, 2H), 7.23-7.13 (m, 1H), 5.33 (d, 1H), 3.82-3.70 (m, 1H), 3.66-3.55 (m, 1H), 2.85-2.66 (s, 3H). 146B LCMS m / z (ESI+) 429.9 [M+H] + .

[0429] 1H NMR (400 MHz, Methanol-d4) δ=8.87 (s, 1H), 7.67-7.40 (m, 3H), 7.36-7.25 (m, 2H), 7.24-7.12 (m, 1H), 5.33 (d, 1H), 3.82-3.70 (m, 1H), 3.62 (dd, 1H), 2.73 (s, 3H). Example 147 JPEG2025541224000116.jpg36128

[0430] 6-(1-Fluoro-3-methyl-imidazo[1,5-a]pyridin-6-yl)-N2-[(1R)-2-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine LCMS m / z=450.2 [M+H]+.

[0431] 1H NMR (400 MHz, CD3OD) δ=8.77 (s, 1H), 7.48 (d, 1H), 7.38 (d, 1H), 7.24-7.03 (m, 1H), 5.23-5.10 (m, 1H), 2.63 (s, 3H), 2.40-2.05 (m, 1H), 1.08-0.97 (m, 3H), 0.96-0.87 (m, 3H). Example 148 JPEG2025541224000117.jpg25128

[0432] (2S or 2R)-2-[[2-amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)pyrimidin-4-yl]amino]-3-(2,3-dichlorophenyl)propanamide (general synthesis method for target compound A) LCMS m / z (ESI+) 456.1 [M+H] + .

[0433] 1H NMR (400 MHz, Methanol-d4):δ=8.54 (s, 1H), 7.57 (d, 1H), 7.42-7.40 (m, 1H), 7.33-7.32 (m, 2H), 7.22-7.14 (m, 2H), 6.30 (br s, 1H), 3.50-3.45 (m, 1H), 3.25-3.21 (m, 1H), 2.71 (s, 3H). Example 149A & Example 149B JPEG2025541224000118.jpg38128

[0434] N2-Methyl-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-N4-[(1S or 1R)-2-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound B) 149A LCMS m / z (ESI+) 446.2 [M+H] + .

[0435] 1H NMR (400 MHz, Methanol-d4):δ=8.91 (br s, 1H), 7.62 (br s, 1H), 7.50 (br d, 1H), 7.30 (s, 1H), 7.21 (br s, 1H), 5.30-5.13 (m, 1H), 3.01 (br s, 3H), 2.71 (s, 3H), 2.25 (br s, 1H), 1.11-0.90 (m, 6H). 149B LCMS m / z (ESI+) 446.2 [M+H] + .

[0436] 1H NMR (400 MHz, DMSO-d6) δ=8.82 (s, 1H), 7.53 (s, 2H), 7.31-6.91 (m, 4H), 5.11 (br s, 1H), 2.88 (br s, 3 H), 2.66 (s, 3H), 2.25-2.19 (m, 1H), 0.97 (br d, J=6.8 Hz, 3H), 0.87 (d, 3H). Example 150 JPEG2025541224000119.jpg40128

[0437] 6-(3-Methylimidazo[1,5-a]pyridin-6-yl)-N4-[(1S)-2-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]pyrimidine-2,4-diamine (General synthesis method for target compound A) LCMS m / z (ESI+) 431.1 [M+H] + .

[0438] 1H NMR (400 MHz, Methanol-d4) δ=9.04 (s, 1H), 8.00 (s, 1H), 7.93 (d, 1H), 7.44 (d, 1H), 7.29 (s, 1H), 6.67 (s, 1H), 5.24 (d, 1H), 3.04 (s, 3H), 2.46-2.24 (m, 1H), 1.05 (d, 3H), 0.95 (d, 3H). Example 151 JPEG2025541224000120.jpg37128

[0439] 6-(3-Methylimidazo[1,5-a]pyridin-6-yl)-N4-[[2-(trifluoromethyl)-1H-imidazol-4-yl]methyl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) LCMS m / z (ESI+) 390.0 [M+H] + .

[0440] 1H NMR (400 MHz, DMSO-d6):δ=13.12 (br s, 1H), 8.81 (s, 1H), 7.52 (s, 2H), 7.36 (br s, 1H), 7.28 (s, 1H), 7.18 (br s, 1H), 6.70 (br s, 2H), 4.53 (br s, 2H), 2.65 (s, 3H). Examples 152A & 152B JPEG2025541224000121.jpg36128

[0441] 6-(3-Methylimidazo[1,5-a]pyridin-6-yl)-N4-[(1S or 1R)-3-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]butyl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) 152A LCMS m / z (ESI+) 456.2 [M+H] + .

[0442] 1H NMR (400 MHz, DMSO-d6):δ=7.12 (s, 1H), 5.63 (d, 1H), 5.51 - 5.36 (m, 2H), 4.49 (q, 1H), 3.51 (d, 2H), 1.87-1.71 (m, 2H), 1.69-1.62 (m, 1H), 1.07 (s, 9H), 0.94-0.84 (m, 8H), -0.04 (m, 9H). 152B LCMS m / z (ESI+) 446.2 [M+H] + .

[0443] 1H NMR (400 MHz, Methanol-d4):δ=8.90 (s, 1H), 7.68 - 7.56 (m, 1H), 7.49 (br d, 1H), 7.28 (s, 1H), 7.16 (m, 1H), 5.62-5.27 (m, 1H), 2.69 (s, 3H), 1.91-1.59 (m, 3H), 1.01 (d, 6H). Examples 153A & 153B JPEG2025541224000122.jpg39128

[0444] N4-[(S or R)-cyclohexyl-[2-(trifluoromethyl)-1H-imidazol-4-yl]methyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) 153A LCMS m / z (ESI+) 472.2 [M +H]+.

[0445] 1H NMR (400 MHz, DMSO-d6):δ=13.14 (br s, 1H), 8.81 (s, 1H), 8.13 (s, 1H), 7.52 (s, 2H), 7.28 (br s, 3H), 6.66 (br s, 2H), 5.08 (br s, 1H), 2.65 (s, 3H), 1.89-1.56 (m, 6H), 1.29-1.15 (m, 3H), 1.08-0.89 (m, 2H). 153B LCMS m / z (ESI+) 472.2 [M+H] + .

[0446] 1H NMR (400 MHz, DMSO-d6):δ=13.08 (br s, 1H), 8.81 (s, 1H), 8.14 (s, 1H), 7.52 (s, 2H), 7.35-6.95 (m, 3H), 6.67 (br s, 2H), 5.09 (br s, 1H), 2.65 (s, 3H), 1.94-1.49 (m, 6H), 1.30-0.90 (m, 5H). Example 154 JPEG2025541224000123.jpg36128

[0447] N4-[(S or R)-cyclopropyl-[2-(trifluoromethyl)-1H-imidazol-4-yl]methyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) LCMS m / z (ESI+) 430.0 [M+H] + .

[0448] 1H NMR (400 MHz, Methanol-d4):δ=8.92 (br s, 1H), 8.15 (s, 1H), 7.69-7.58 (m, 1H), 7.55-7.46 (m, 1H), 7.32 (s, 1H), 7.23 (br s, 1H), 4.96 (br s, 1H), 2.72 (s, 3H), 1.38 (br s, 1H), 0.76- 0.35 (m, 4H). Example 155A & Example 155B JPEG2025541224000124.jpg32128

[0449] 6-(3-Methylimidazo[1,5-a]pyridin-6-yl)-N4-[(1S or 1R)-2-methyl-1-(2-methyl-1H-imidazol-4-yl)propyl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) 155A LCMS m / z (ESI+) 378.2 [M+H] + .

[0450] 1H NMR (400 MHz, Methanol-d4):δ=9.11 (br s, 1H), 8.06-8.00 (m, 1H), 7.91 (s, 1H), 7.82 (d, 1H), 7.37 (br s, 1H), 5.36-4.93 (m, 1H), 3.02 (s, 3H), 2.63 (s, 3H), 2.34-2.24 (m, 1H), 1.11 (d, 3H), 1.03 (br d, 3H). 155B LCMS m / z (ESI+) 378.2 [M+H] + .

[0451] 1H NMR (400 MHz, Methanol-d4):δ=9.10 (br s, 1H), 8.04-8.01 (m, 1H), 7.90 (s, 1H), 7.86-7.79 (m, 1H), 7.32-7.29 (m, 1H), 5.32-4.96 (m, 1H), 2.99 (s, 3H), 2.63 (s, 3H), 2.33-2.23 (m, 1H), 1.11 (br d, 3H), 1.03 (br d, J=6.4 Hz, 3H). Example 156 JPEG2025541224000125.jpg33128

[0452] 6-(1H-indazol-6-yl)-N4-[(1R or 1S)-2-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine LCMS m / z (ESI+) 418.1 [M+H] + .

[0453] 1H NMR (400 MHz, Methanol-d4):δ=8.50 (br s, 1H), 8.19 (br s, 1H), 7.97-7.94 (m, 2H), 7.32 (s, 1H), 5.41-5.12 (m, 1H), 2.37 (br s, 1H), 1.09 (br s, 3H), 0.99 (br s, 3H). Example 157 JPEG2025541224000126.jpg31128

[0454] 6-(1H-indazol-6-yl)-N4-[(1S or 1R)-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound C) LCMS m / z (ESI+) 404.2 [M+H] + .

[0455] 1H NMR (400 MHz, Methanol-d4):δ=8.35 (br s, 1H), 8.12-8.08 (m, 1H), 7.89 (d, 1H), 7.80 (d, 1H), 7.19 (s, 1H), 5.20-5.02 (m, 1H), 2.06-1.85 (m, 2H), 1.00-0.90 (m, 3H). Example 158 JPEG2025541224000127.jpg36128

[0456] 6-(3-Methylimidazo[1,5-a]pyridin-6-yl)-N4-[(1S or 1R)-2-methyl-1-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]propyl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) LCMS m / z (ESI+) 434.1 [M+H] + .

[0457] 1H NMR (400 MHz, METHANOL-d4) δ=9.07-8.75 (m, 1H), 8.45 (s, 1H), 7.76-7.40 (m, 2H), 7.32 (s, 1H), 5.54-5.28 (m, 1H), 2.74 (d, 3H), 2.53-2.36 (m, 1H), 1.18 (dd, 3H), 1.05 (d, 3H). Example 159 JPEG2025541224000128.jpg37128

[0458] 6-(3-Methylimidazo[1,5-a]pyridin-6-yl)-N4-[[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) LCMS m / z (ESI+) 392.0 [M+H] + .

[0459] 1H NMR (400 MHz, Methanol-d4) δ=9.02-8.78 (m, 1H), 8.20 (s, 1H), 7.71-7.41 (m, 2H), 7.30 (s, 1H), 4.97 (s, 2H), 2.71 (s, 3H). Example 160 JPEG2025541224000129.jpg37128

[0460] 6-(3-Methylimidazo[1,5-a]pyridin-6-yl)-N4-[1-methyl-1-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]ethyl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) LCMS m / z (ESI+) 420.0 [M+H] + .

[0461] 1H NMR (400 MHz, METHANOL-d4) δ=8.72 (s, 1H), 7.42 (s, 1H), 7.29 (s, 1H), 7.20 (s, 1H), 2.71 (s, 3H), 1.89 (s, 6H). Example 161 JPEG2025541224000130.jpg38128

[0462] N4-methyl-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-N4-[(1S or 1R)-2-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine

[0463] To a solution of 6-(3-methylimidazo[1,5-a]pyridin-6-yl)-N2-[(1R or 1S)-2-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (Examples 144A & 144B, 170 mg, 394.04 μmol) in THF (2 mL) was added 60% NaH (18.91 mg, 788.08 μmol) at 0°C and stirred for 1 hour. Then, MeI (104.87 mg, 738.82 μmol, 97.27 μL) was added dropwise to the mixture at 0°C. The mixture was warmed to 25°C and stirred for 1 hour. The reaction mixture was diluted with HO (100 mL) and filtered to remove insoluble material. The filtrate was extracted with EtOAc (100 mL × 3). The organic layer was then washed with brine (50 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give N4-methyl-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-N4-[(1S or 1R)-2-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (62.48 mg, 35.6% yield) as a yellow oil. LCMS m / z (ESI+) 446.1 [M+H] + .

[0464] 1H NMR (400 MHz, DMSO-d6):δ=13.29 (s, 1H), 8.84 (s, 1H), 8.14 (s, 1H), 7.64-7.47 (m, 2H), 7.29 (br s, 2H), 6.67 (br s, 2H), 5.96-5.60 (m, 1H), 2.82 (br s, 3H), 2.66 (s, 3H), 2.59-2.53 (m, 1H), 0.93 (br d, 6H). Example 162 JPEG2025541224000131.jpg37128

[0465] N4-[(2-chloro-3-fluoro-phenyl)methyl]-N4-methyl-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) LCMS m / z (ESI+) 398.1 [M+H] + .

[0466] 1H NMR (400 MHz, DMSO-d6) δ=8.81 (s, 1H), 7.53 (br s, 2H), 7.41-7.28 (m, 3H), 7.09 (d, 1H), 6.79 (s, 2H), 5.04 (s, 2H), 3.24 (s, 3H), 2.65 (s, 3H). Example 163 JPEG2025541224000132.jpg38128

[0467] N4-[(3-chloro-2-fluoro-phenyl)methyl]-N4-methyl-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) LCMS m / z (ESI+) 398.1 [M+H]+.

[0468] 1H NMR (400 MHz, DMSO-d6) δ=8.81 (s, 1H), 8.16 (s, 1H), 7.51 (s, 2H), 7.46 (t, 1H), 7.33-7.23 (m, 2H), 7.21-7.13 (m, 1H), 6.75 (s, 2H), 4.99 (s, 2H), 3.20 (s, 3H), 2.64 (s, 3H). Example 164 JPEG2025541224000133.jpg35128

[0469] N4-Methyl-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-N4-[[2-(trifluoromethyl)-1H-imidazol-4-yl]methyl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) LCMS m / z (ESI+) 404.2 [M+H]+.

[0470] 1H NMR (400 MHz, DMSO-d6):δ=11.45 (s, 1H), 8.84 (d, 1H), 7.61-7.47 (m, 2H), 7.28 (s, 1H), 7.19 (s, 1H), 6.71 (s, 2H), 4.83 (br s, 2H), 3.18 (br s, 3H), 2.65 (m, 3H). Example 165 JPEG2025541224000134.jpg37128

[0471] 6-(3-methylimidazo[1,5-a]pyridin-6-yl)-N4-[(1S or 1R)-2-methyl-1-[1-methyl-2-(trifluoromethyl)imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine

[0472] To a solution of 6-(3-methylimidazo[1,5-a]pyridin-6-yl)-N2-[(1R or 1S)-2-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (Examples 144A & 144B, 170 mg, 394.04 μmol) in THF (2 mL) was added 60% NaH (18.91 mg, 788.08 μmol) at 0°C and stirred for 1 h. Then, MeI (104.87 mg, 738.82 μmol, 97.27 μL) was added dropwise to the mixture at 0°C. The mixture was warmed to 25°C and stirred for 1 h. The reaction mixture was diluted with HO (100 mL) and filtered to remove insoluble material. The filtrate was extracted with EtOAc (100 mL × 3). The organic layer was then washed with brine (50 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give 6-(3-methylimidazo[1,5-a]pyridin-6-yl)-N-[(1S or 1R)-2-methyl-1-[1-methyl-2-(trifluoromethyl)imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (94.95 mg, 54.1% yield) as a yellow oil. LCMS m / z (ESI+) 446.3 [M+H] + .

[0473] 1H NMR (400 MHz, Methanol-d4):δ=8.91 (br s, 1H), 8.37 (br s, 1H), 7.67-7.58 (m, 1H), 7.54-7.48 (m, 1H), 7.31 (s, 1H), 7.26-7.21 (m, 1H), 5.21-4.98 (m, 1H), 3.81 (s, 3H), 2.76-2.67 (m, 3H), 2.30-2.17 (m, 1H), 1.04-0.98 (m, 3H), 0.97-0.91 (m, 3H). Example 166 JPEG2025541224000135.jpg37128

[0474] 6-(3-Methylimidazo[1,5-a]pyridin-6-yl)-N4-[(1S or 1R)-2-methyl-1-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]propyl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) LCMS m / z (ESI+) 434.1 [M+H]+.

[0475] 1H NMR (400 MHz, DMSO-d6) δ=8.77 (s, 1H), 8.30 (s, 1H), 7.86 (s, 1H), 7.53-7.50 (m, 1H), 7.44 (s, 1H), 7.27 (s, 1H), 6.78 (s, 2H), 5.32 (t, J=7.2 Hz, 1H), 2.65 (s, 3H), 2.43-2.41 (m, 1H), 1.09 (d, 3H), 0.99 (d, 3H). Example 167 JPEG2025541224000136.jpg35128

[0476] N4-[(1R or 1S)-1-[1-(difluoromethyl)pyrazol-3-yl]-2-methyl-propyl]-6-(1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound C) MS (ESI) m / z=400.1 [M+H] + .

[0477] 1H NMR (400 MHz, Methanol-d4):δ=8.50 (br s, 1H), 8.19 (br s, 1H), 8.05-7.91 (m, 3H), 7.47 (t, 1H), 6.57 (d, 1H), 5.39-4.92 (m, 1H), 2.32 (dd, 1H), 1.13-1.05 (m, 3H), 1.02-0.93 (m, 3H). Example 168 JPEG2025541224000137.jpg29128

[0478] 6-[(1R or 1S)-1-[[4-amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazin-2-yl]amino]-2-methyl-propyl]pyridine-3-carbonitrile (general synthesis method for target compound A) MS (ESI) m / z=400.2 [M+H]+.

[0479] 1H NMR (400 MHz, Methanol-d4) δ=8.85 (d, 1H), 8.44-8.42 (m, 1H), 8.22 (s, 1H), 7.61-7.51 (m, 4H), 7.32 (s, 1H), 5.11-5.03 (m, 1H), 2.74 (d, 3H), 2.30-2.24 (m, 1H), 1.06-1.02 (m, 3H), 0.89-0.85 (m, 3H). Example 169 JPEG2025541224000138.jpg36128

[0480] N4-methyl-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-N4-[(1S or 1R)-2-methyl-1-[1-methyl-2-(trifluoromethyl)imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine

[0481] To a solution of 6-(3-methylimidazo[1,5-a]pyridin-6-yl)-N2-[(1R or 1S)-2-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (Examples 144A & 144B, 200 mg, 463.57 μmol) in THF (2 mL) was added 60% NaH (22.25 mg, 927.75 μmol) at 0°C and stirred for 1 h. Then, MeI (123.37 mg, 869.20 μmol) was added dropwise to the mixture at 0°C. The mixture was warmed to 25°C and stirred for 1 h. The reaction mixture was diluted with HO (100 mL) and filtered to remove insoluble material. The filtrate was extracted with EtOAc (100 mL × 3). The organic layer was then washed with brine (50 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography to give N-methyl-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-N-[(1S or 1R)-2-methyl-1-[1-methyl-2-(trifluoromethyl)imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (59.64 mg, 28.1% yield) as a yellow oil. MS (ESI) m / z=460.3 [M+H]+.

[0482] 1H NMR (400 MHz, Methanol-d4):δ=8.95 (br s, 1H), 8.35 (br s, 1H), 7.75-7.61 (m, 1H), 7.59-7.46 (m, 1H), 7.38-7.26 (m, 2H), 5.98-5.64 (m, 1H), 3.82 (s, 3H), 3.10 (br s, 3H), 2.72 (d, 3H), 2.64-2.51 (m, 1H), 1.02-0.89 (m, 6H). Example 170A & Example 170B JPEG2025541224000139.jpg27128

[0483] (2R or 2S)-2-[[4-amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazin-2-yl]amino]-3-(2,3-dichlorophenyl)propanamide (general synthesis method for target compound A) 170A MS (ESI) m / z=457.0 [M+H] + .

[0484] 1H NMR (400 MHz, METHANOL-d4) δ=8.93-8.84 (m, 1H), 7.60-7.46 (m, 2H), 7.42-7.31 (m, 1H), 7.29 (s, 1H), 7.24 (d, 1H), 7.20-7.06 (m, 1H), 5.21 (dd, 1H), 3.59-3.46 (m, 1H), 3.24-3.02 (m, 1H), 2.86-2.68 (m, 3H). 170B MS (ESI) m / z=457.0 [M+H]+.

[0485] 1H NMR (400 MHz, DMSO-d6) δ=8.98-8.75 (m, 1H), 7.99 (s, 1H), 7.85-7.71 (m, 3H), 7.61-7.16 (m, 6H), 7.05 (br s, 1H), 5.01-4.68 (m, 1H), 3.45-3.01 (m, 2H), 2.92-2.82 (m, 3H). Example 171 JPEG2025541224000140.jpg37128

[0486] N4-[(1R or 1S)-1-[1-(difluoromethyl)pyrazol-3-yl]-2-methyl-propyl]-6-(1H-indazol-6-yl)-N2-methyl-1,3,5-triazine-2,4-diamine (general synthesis method for target compound D) MS (ESI) m / z=414.1 [M+H]+.

[0487] 1H NMR (400 MHz, DMSO-d6):δ=13.14 (s, 1H), 8.54 (s, 1H), 8.12-8.05 (m, 3H), 7.80 (d, 1H), 7.70 (t, 1H), 7.48-6.92 (m, 2H), 6.61 (d, 1H), 5.24-5.16 (m, 1H), 2.90 (br s, 3H), 2.35-2.18 (m, 1H), 1.01 (d, 3H), 0.89 (d, 3H). Example 172 JPEG2025541224000141.jpg37128

[0488] N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-N2-methyl-6-(1-methylindazol-6-yl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound B) MS (ESI) m / z=414.2 [M+H]+.

[0489] 1H NMR (400 MHz DMSO-d6) δ=8.37 (s, 1H), 8.04 (s, 1H), 7.99 (d, 2H), 7.86-7.57 (m, 2H), 7.25-6.82 (m, 2H), 6.43 (d, 1H), 4.07 (s, 3H), 2.92-2.58 (m, 3H), 1.77 (s, 6H). Example 173 JPEG2025541224000142.jpg36128

[0490] N4-[(1R or 1S)-1-[1-(difluoromethyl)pyrazol-3-yl]-2-methyl-propyl]-N2-methyl-6-(1-methylindazol-6-yl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound B) MS (ESI) m / z=428.2 [M+H]+.

[0491] 1H NMR (400 MHz, DMSO-d6) δ=8.52 (s, 1H), 8.14 (d, 1H), 8.10-8.02 (m, 2H), 7.87-7.79 (m, 1H), 7.75-7.53 (m, 1H), 7.28 (s, 1H), 7.03 (s, 1H), 6.62 (d, 1H), 5.22 (s, 1H), 4.13 (s, 3H), 2.93 (s, 3H), 2.25 (m, 1H), 1.03 (d, 3H), 0.91 (d, 3H). Example 174 JPEG2025541224000143.jpg37128

[0492] 6-(1-methylindazol-6-yl)-N4-[1-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]ethyl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) MS (ESI) m / z=418.2 [M+H]+.

[0493] 1H NMR (400 MHz, METHANOL-d4) δ=8.66-8.22 (m, 1H), 8.02 (s, 2H), 7.75 (s, 1H), 7.25 (s, 1H), 4.12 (s, 3H), 1.83 (s, 6H). Example 175 JPEG2025541224000144.jpg33128

[0494] N2-[1-[1-(2-aminoethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) MS (ESI) m / z=393.2 [M+H]+.

[0495] 1H NMR (Methanol-d4) δ=9.62 (br s, 0.5H), 9.14 (br s, 0.5H), 8.03 (d, 1H), 7.98-7.84 (m, 2H), 7.69-7.67 (m, 1H), 6.57-6.26 (m, 1H), 4.48-4.44 (m, 2H), 3.57-3.38 (m, 2H), 3.12-2.98 (m, 3H), 1.92 (s, 6H). Example 176 JPEG2025541224000145.jpg37128

[0496] 6-(1-methylindazol-6-yl)-N4-[(1R or 1S)-2-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) MS (ESI) m / z=432.3 [M+H]+.

[0497] 1H NMR (METHANOL-d4) δ=8.51 (s, 1H), 8.35 (s, 1H), 8.18-8.07 (m, 1H), 8.04 (s, 1H), 7.79 (d, 1H), 7.18 (br s, 1H), 5.35-5.04 (m, 1H), 4.14 (s, 3H), 2.30-2.22 (m, 1H), 1.07-0.93 (m, 6H). Example 177 JPEG2025541224000146.jpg35128

[0498] N4-[1-[5-amino-1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) MS (ESI) m / z=415.2 [M+H]+.

[0499] 1H NMR (400 MHz, DMSO-d6):δ=8.75 (s, 1H), 7.58-7.32 (m, 3H), 7.28 (s, 1H), 6.89 (br s, 1H), 6.54 (br s, 2H), 5.51 (br s, 2H), 5.33 (s, 1H), 2.64 (s, 3H), 1.70 (s, 6H). Example 178 JPEG2025541224000147.jpg32128

[0500] N2-[(1R or 1S)-1-[5-(aminomethyl)-2-pyridyl]-2-methyl-propyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) MS (ESI) m / z=404.2 [M+H] + .

[0501] 1H NMR (400 MHz, METHANOL-d4) δ=8.97-8.81 (m, 1H), 8.57 (s, 1H), 7.85 (d, 1H), 7.69-7.57 (m, 1H), 7.56-7.47 (m, 2H), 7.31 (d, 1H), 5.04 (s, 1H), 3.98 (d, 2H), 2.74 (d, 3H), 2.39-2.08 (m, 1H), 1.09 (dd, 3H), 0.94-0.90 (m, 3H). Example 179 JPEG2025541224000148.jpg35128

[0502] 6-(1H-indazol-6-yl)-N4-[(1R or 1S)-3-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]butyl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound C) MS (ESI) m / z =432.2 [M+H]+.

[0503] 1H NMR (DMSO-d6) δ=13.32 (br s, 2H), 8.57-8.46 (m, 1H), 8.16-8.03 (m, 2H), 7.81 (dd, J=8.4, 3.6 Hz, 1H), 7.63-7.34 (m, 1H), 7.23 (br d, J=7.6 Hz, 1H), 6.73-7.00 (m, 2H), 5.60-5.15 (m, 1H) 1.89-1.76 (m, 1H), 1.73-1.58 (m, 2H), 0.97-0.92 (m, 6H). Examples 180A & 180B JPEG2025541224000149.jpg36128

[0504] 6-(1-methylindazol-6-yl)-N4-[(1R or 1S)-3-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]butyl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) 180A MS (ESI) m / z =446.5 [M+H]+.

[0505] 1H NMR (400 MHz, Methanol-d4)δ=8.55-8.44 (m, 1H), 8.19-8.14 (m, 1H), 8.04-7.89 (m, 2H), 7.33-7.28 (m, 1H), 5.74-5.40 (m, 1H), 4.20 (s, 3H), 1.99-1.86 (m, 2H), 1.74 (m, 1H), 1.12-1.01 (m, 6H). 180B MS (ESI) m / z =446.2 [M+H]+.

[0506] 1H NMR (400 MHz, DMSO-d6)δ=13.46-13.29 (m, 1H), 8.48 (s, 1H), 8.12-8.07 (m, 2H), 7.81-7.79 (m, 1H), 7.64-7.45 (m, 1H), 7.40-7.19 (m, 1H), 6.91 (s, 1H), 6.71 (br s, 1H), 5.45-5.22 (m, 1H), 4.09 (s, 3H), 1.81-1.75 (m, 1H), 1.73-1.66 (m, 2H), 0.96-0.93 (m, 6H). Example 181 JPEG2025541224000150.jpg37128

[0507] 6-(1,3-dimethylimidazo[1,5-a]pyridin-6-yl)-N2-[(1S or 1R)-2-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (general synthesis method for target compound A) MS (ESI) m / z =446.2 [M+H]+.

[0508] 1H NMR (400 MHz, DMSO-d6) δ=8.87-8.83 (m, 1H), 7.90-7.86 (m, 1H), 7.77-7.59 (m, 2H), 7.26 (s, 1H), 7.14 (s, 1H),7.09 (br s, 1H), 5.18-4.99 (m, 1H), 2.90-2.84 (m, 3H), 2.59-2.58 (m, 3H), 2.28-2.12 (m, 1H), 0.96-0.93 (m, 3H) 0.86-0.83 (m, 3H). biological analysis material and method MASTL activity analysis

[0509] Wild-type human active MASTL (154 pM) was incubated with a biotin-tagged 40-mer ENSA peptide (10 nM), experimental compounds, and ATP (18 μM) in assay buffer (50 mM HEPES, 100 mM NaCl, 0.1 mM EGTA, 10 mM MgCl2, 0.01% Tween-20, 0.5 mM TCEP, pH 7.5) for 60 min at room temperature. Experimental compounds were assayed using a 12-point dose range consisting of 0, a DMSO control, and 10 consecutive doses of 0.0005, 0.002, 0.005, 0.014, 0.04, 0.12, 0.37, 1.11, 3.33, and 10 μM. The DMSO concentration was the same for all samples (1%). The reaction was terminated by adding an equal volume of detection buffer (assay buffer + 267.5 pM Ab-K, 1.25 nM SA-D2, 20 mM EDTA, and 400 mM KF) to a final volume of 20 μl and incubated at room temperature for 60 min. Activity was measured using a plate reader (PerkinElmer EnSight) based on the FRET signal generated between SA-D2 (streptavidin-D2) and Ab-K (anti-phospho-serine 67 ENSA antibody conjugated to cryptate (rabbit polyclonal, using standard technology from a commercial supplier)). HTRF reagents (CisBio) were prepared according to the manufacturer's recommendations. The 40-mer biotin-tagged ENSA peptide (synthesized by Bionics) used was based on serine 67 of ENSA (YPSLGQKPGGSDFLMKRLQKGQKYFDSGDYNMAKAKMKNK). result The results of the MASTL activity assay are shown in Table 2 below:

[0510] [Table 2] JPEG2025541224000152.jpg232128JPEG2025541224000153.jpg232128JPEG2025541224000154.jpg63137

Claims

1. The H ring of the chemical formula (I) is a carbon atom ＊ 1 or ＊ It is linked to 2; Z is -NR １ R ２ or -CN; R １ and R ２ These are H, D, and C, respectively, independently. １－６ Selected from alkyl groups, Here, C １－６ Alkyls are optionally partially or completely deuterated; R ３ is each independently selected from halogen, C １－６ 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 CH or N; R ４ H, NR Ｘ１ R Ｘ２ , -OH and C １－６ Selected from alkyl groups; R ５ H and C １－６ Selected from alkyl groups, Here, R ４ or R ５ C １－６ Alkyl groups are optionally partially or completely deuterated; L １ is a bond or NR ６ Selected from O and S; R ６ H, C １－４ Alkyl, C １－４ Haloalkyl and CC ３－６ Selected from cycloalkyl groups, Here, C ３－６ Cycloalkyl groups consist of =O, halogen, and 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 ７ R ８ ]p-, Here, p is an integer between 1 and 4; R ７ and R ８ 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 ７ and R ８ is L ２ They are attached together to the same carbon atom within, C ３－６ Forming cycloalkyl or 3-6 membered heterocyclines, 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; Q １ C ３－１２ Cycloalkyl, C ３－１２ Cycloalkenyl, 3- to 12-membered heterocyclyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls; Here, C ６－１０ Aryls and 5- to 10-membered heteroaryls are one or more R ９ It is arbitrarily replaced by; Each R ９ is independently halogen, -CN, -NO ２ , C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, -OR １０ , -S(O) ｘ R １０ , -N(R １０ ), ２ , -C(O)R １０ [[ID=2罢译]4]], -OC(O)R １０ , -C(O)OR １０ , -NR １０ C(O)R １０ , -NR １０ C(O)OR １０ , -C(O)N(R １０ ), ２ ,-OC(O)N(R １０ ), ２ , -NR １０ SO ２ R １０ , -SO ２ N(R １０ ), ２ , and -NR １０ C(O)N(R １０ ), ２ and is selected from; Here, C １－６ Alkyl, C ２－６ Alkenyl and C ２－６ Alkinyl contains one or more R １１ It is arbitrarily replaced by; Here, each R １０ is independently selected from H, C １－６ alkyl and C １－６ haloalkyl; Here, each R １１ These are, independently, halogen, -CN, and -NO ２ , C １－４ Alkyl, C １－４ Haloalkyl and NR Ｘ１ R Ｘ２ Selected from; where R Ｘ１ and R Ｘ２ Each of these is independently a C molecule optionally substituted with H, OH, or a 3- to 6-membered heterocycline. １－４ Alkyl, -OC １－６ Alkyl, -C(O)-C １－６ Selected from alkyl and 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; n is an integer from 0 to 4; and x is an integer between 0 and 3; Here, R ４ or R ５ is H or undeuterated C １－６ When it is alkyl, Z is -CN or -NR １ R ２ And, Here, R １ and R ２ At least one of them is D or partially or completely deuterated C １－６ A compound of chemical formula (I) that is alkyl, or a pharmaceutically acceptable salt thereof.

2. The H ring in the above chemical formula (I) is a carbon atom. ＊ 1 or ＊ It is linked to 2; Z is -NR １ R ２ or -CN; R １ and R ２ These are H, D, and C, respectively, independently. １－６ Selected from alkyl, where C １－６ Alkyls are optionally partially or completely deuterated; R ３ These are, independently, halogen 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 CH or N; R ４ H, NR Ｘ１ R Ｘ２ , -OH and C １－６ Selected from alkyl groups; R ５ H and C １－６ Selected from alkyl groups, Here, R ４ or R ５ C １－６ Alkyls are optionally partially or completely deuterated; L １ is a bond or NR ６ Selected from O and S; R ６ H, C １－４ Alkyl and C １－４ Selected from haloalkyls, L ２ is a combination, or -[CR ７ R ８ ]p-, Here, p is an integer between 1 and 4; R ７ and R ８ 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 ７ and R ８ is L ２ They are attached together to the same carbon atom within, C ３－６ Forming cycloalkyl or 3-6 membered heterocyclines, Here, C １－４ Alkyl groups are OH, O-C １－４ Alkyl, or halogen, or C １－６ C optionally substituted with a haloalkyl group ６－１０ It can be arbitrarily replaced with an aryl; Q １ C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls; Here, C ６－１０ Aryls and 5- to 10-membered heteroaryls are one or more R ９ It is arbitrarily replaced by; Each R ９ These are, independently, halogen, -CN, and -NO ２ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, -OR １０ , -N(R １０ ) ２ , -C(O)R １０ , -OC(O)R １０ , -C(O)OR １０ , -NR １０ C(O)R １０ , -NR １０ C(O)OR １０ , -C(O)N(R １０ ) ２ and -OC(O)N(R １０ ) ２ Selected from; Here, C １－６ Alkyl, C ２－６ Alkenyl and C ２－６ Alkinyl contains one or more R １１ It is arbitrarily replaced by; Here, each R １０ These are H and C, independently. １－６ Alkyl and C １－６ Selected from haloalkyls; Here, each R １１ These are, independently, halogen, -CN, and -NO ２ , C １－４ Alkyl, C １－４ Haloalkyl and NR Ｘ１ R Ｘ２ Selected from; where R Ｘ１ and R Ｘ２ Each of these is independently a C molecule optionally substituted with H, OH, or a 3- to 6-membered heterocycline. １－４ Alkyl, -OC １－６ Alkyl, -C(O)-C １－６ Selected from alkyl and 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; n is an integer from 0 to 4; and x is an integer between 0 and 3; Here, R ４ or R ５ is H or undeuterated C １－６ When it is alkyl, Z is -CN or -NR １ R ２ And, Here, R １ and R ２ At least one of them is D or partially or completely deuterated C １－６ A compound of chemical formula (I) according to claim 1, which is alkyl, or a pharmaceutically acceptable salt thereof.

3. Here, the H ring in the above chemical formula (I) is a carbon atom. ＊ 1 or ＊ It is linked to 2; Z is -NR １ R ２ or -CN; R １ and R ２ These are H, D, and C, respectively, independently. １－６ Selected from alkyl groups, Here, C １－６ Alkyls are optionally partially or completely deuterated; R ３ These are, independently, halogen 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 CH or N; R ４ H, NR Ｘ１ R Ｘ２ , -OH and C １－６ Selected from alkyl groups; R ５ H and C １－６ Selected from alkyl, where R ４ or R ５ C １－６ Alkyls are optionally partially or completely deuterated; L １ is a bond or NR ６ Selected from O and S; R ６ H, C １－４ Alkyl and C １－４ Selected from haloalkyls, L ２ is a combination, or -[CR ７ R ８ ]p-, Here, p is an integer between 1 and 4; R ７ and R ８ 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 ７ and R ８ is L ２ They are attached together to the same carbon atom within, C ３－６ Forming cycloalkyl or 3-6 membered heterocyclines, Here, C １－４ Alkyl groups are OH, O-C １－４ Alkyl, or halogen, or C １－６ C optionally substituted with a haloalkyl group ６－１０ It can be arbitrarily replaced with an aryl; Q １ C ３－１２ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls; Here, C ６－１０ Aryls and 5- to 10-membered heteroaryls are one or more R ９ It is arbitrarily replaced by; Each R ９ These are, independently, halogen, -CN, and -NO ２ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, -OR １０ , -N(R １０ ) ２ , -C(O)R １０ , -OC(O)R １０ , -C(O)OR １０ , -NR １０ C(O)R １０ , -NR １０ C(O)OR １０ , -C(O)N(R １０ ) ２ and -OC(O)N(R １０ ) ２ Selected from; Here, C １－６ Alkyl, C ２－６ Alkenyl and C ２－６ Alkinyl contains one or more R １１ It is arbitrarily replaced by; Here, each R １０ These are H and C, independently. １－６ Alkyl and C １－６ Selected from haloalkyls; Here, each R １１ These are, independently, halogen, -CN, and -NO ２ , C １－４ Alkyl, C １－４ Haloalkyl and NR Ｘ１ R Ｘ２ Selected from; where R Ｘ１ and R Ｘ２ Each of these is independently a C atom optionally substituted with H, OH, or a 3- to 6-membered heterocycline. １－４ Selected from alkyl groups; n is an integer from 0 to 4; and x is an integer between 0 and 3; Here, R ４ or R ５ is H or undeuterated C １－６ When it is alkyl, Z is -CN or -NR １ R ２ And, Here, R １ and R ２ At least one of them is D or partially or completely deuterated C １－６ A compound of chemical formula (I) according to claim 1, which is alkyl, or a pharmaceutically acceptable salt thereof.

4. The H ring of chemical formula (II) is a carbon atom ＊ 1 or ＊ It is linked to 2; R １ and R ２ These are H and C, respectively, independently. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl and C １－６ Selected from haloalkyls; R ３ These are, independently, halogen 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 CH or N; R ４ and R ５ These are H, halogen, CN, and C, respectively, independently. １－６ Alkyl and C １－６ Selected from haloalkyls; L １ is a bond or NR ６ Selected from O and S; R ６ H, C １－４ Alkyl, C １－４ Haloalkyl and CC ３－６ Selected from cycloalkyl groups, Here, C ３－６ Cycloalkyl groups consist of =O, halogen, and 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 ７ R ８ ]p-, p is an integer between 1 and 4; R ７ and R ８ These are H and C, respectively, independently. １－４ Alkyl, C ６－１０ Ariel, COO-C １－６ Alkyl, NR Ｘ１ R Ｘ２ , C(O)NR Ｘ１ R Ｘ３ , and selected from 5- to 10-membered heteroaryls; Here, L ２ R ７ and R ８ At least one of them is not H, Said C １－４ Alkyl is a 3- to 6-membered cycloalkyl, C ４－８ Alkyl, or NR Ｘ１ R Ｘ２ Replaced by; Q １ C ３－１２ Cycloalkyl, C ３－１２ Cycloalkenyl, 3- to 12-membered heterocyclyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls; Here, C ６－１０ Aryls and 5- to 10-membered heteroaryls are one or more R ９ It is arbitrarily replaced by; Each R ９ These are, independently, halogen, -CN, and -NO ２ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, -OR １０ , -S(O) ｘ R １０ , -N(R １０ ) ２ , -C(O)R １０ , -OC(O)R １０ , -C(O)OR １０ , -NR １０ C(O)R １０ , -NR １０ C(O)OR １０ , -C(O)N(R １０ ) ２ , -OC(O)N(R １０ ) ２ , -NR １０ SO ２ R １０ , -SO ２ N(R) １０ ) ２ , and -NR １０ C(O)N(R) １０ ) ２ Selected from; Here, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl and C １－６ Haloalkyls are one or more R １１ It is arbitrarily replaced by; Here, each R １０ These are H and C, independently. １－６ Alkyl and C １－６ Selected from haloalkyls; Here, each R １１ These are, independently, halogen, -CN, and -NO ２ , C １－４ Alkyl, C １－４ Haloalkyl, NR Ｘ１ R Ｘ２ and C(O)NR Ｘ１ R Ｘ２ Selected from; where R Ｘ１ and R Ｘ２ Each of these is independently a C molecule optionally substituted with H, OH, or a 3- to 6-membered heterocycline. １－４ Alkyl, OH, -OC １－６ Alkyl, -C(O)-C １－６ Selected from alkyl and 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, R Ｘ３ OH and O-C １－６ Selected from alkyl groups; n is an integer from 0 to 4; and x is an integer between 0 and 3, the compound of chemical formula (II) or a pharmaceutically acceptable salt thereof.

5. Here, the H ring in the above chemical formula (II) is a carbon atom. ＊ 1 or ＊ It is linked to 2; R １ and R ２ These are H and C, respectively, independently. １－６ Alkyl and C １－６ Selected from haloalkyls; R ３ These are, independently, halogen 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 CH or N; R ４ and R ５ These are H, halogen, CN, and C, respectively, independently. １－６ Alkyl and C １－６ Selected from haloalkyls; L １ is a bond or NR ６ Selected from O and S; R ６ H, C １－４ Alkyl and C １－４ Selected from haloalkyls, L ２ is a combination, or -[CR ７ R ８ ]p-, Here, p is an integer between 1 and 4; R ７ and R ８ These are H and C, respectively, independently. １－４ Alkyl, C ６－１０ Ariel, COO-C １－６ Alkyl, NR Ｘ１ R Ｘ２ , C(O)NR Ｘ１ R Ｘ３ , and selected from 5- to 10-membered heteroaryls; Here, L ２ R ７ and R ８ At least one of them is not H, Said C １－４ Alkyl is a 3- to 6-membered cycloalkyl, C ４－８ Alkyl, or NR Ｘ１ R Ｘ２ Replaced by; Q １ C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls; Here, C ６－１０ Aryls and 5- to 10-membered heteroaryls are one or more R ９ It is arbitrarily replaced by; Each R ９ These are, independently, halogen, -CN, and -NO ２ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, -OR １０ , -N(R １０ ) ２ , -C(O)R １０ , -OC(O)R １０ , -C(O)OR １０ , -NR １０ C(O)R １０ , -NR １０ C(O)OR １０ , -C(O)N(R １０ ) ２ and -OC(O)N(R １０ ) ２ Selected from; Here, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl and C １－６ Haloalkyls are one or more R １１ It is arbitrarily replaced by; Here, each R １０ These are H and C, independently. １－６ Alkyl and C １－６ Selected from haloalkyls; Here, each R １１ These are, independently, halogen, -CN, and -NO ２ , C １－４ Alkyl, C １－４ Haloalkyl, NR Ｘ１ R Ｘ２ and C(O)NR Ｘ１ R Ｘ２ Selected from; where R Ｘ１ and R Ｘ２ Each of these is independently a C molecule optionally substituted with H, OH, or a 3- to 6-membered heterocycline. １－４ Alkyl, OH, -OC １－６ Alkyl, -C(O)-C １－６ Selected from alkyl and 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, R Ｘ３ OH and O-C １－６ Selected from alkyl groups; n is an integer from 0 to 4; and x is an integer from 0 to 3, wherein the compound of chemical formula (II) or a pharmaceutically acceptable salt thereof according to claim 4.

6. Here, the H ring in the above chemical formula (II) is a carbon atom. ＊ 1 or ＊ It is linked to 2; R １ and R ２ These are H and C, respectively, independently. １－６ Alkyl and C １－６ Selected from haloalkyls; R ３ These are, independently, halogen 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 CH or N; R ４ and R ５ These are H, halogen, CN, and C, respectively, independently. １－６ Alkyl and C １－６ Selected from haloalkyls; L １ is a bond or NR ６ Selected from O and S; R ６ H, C １－４ Alkyl and C １－４ Selected from haloalkyls, L ２ is a combination, or -[CR ７ R ８ ]p-, Here, p is an integer between 1 and 4; R ７ and R ８ These are H and C, respectively, independently. １－４ Alkyl, C ６－１０ Ariel, COO-C １－６ Alkyl, NR Ｘ１ R Ｘ２ , C(O)NR Ｘ１ R Ｘ３ , and selected from 5- to 10-membered heteroaryls; Here, L ２ R ７ and R ８ At least one of them is not H, Said C １－４ Alkyl is a 3- to 6-membered cycloalkyl, C ４－８ Alkyl, or NR Ｘ１ R Ｘ２ Replaced by; Q １ C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls; Here, C ６－１０ Aryls and 5- to 10-membered heteroaryls are one or more R ９ It is arbitrarily replaced by; Each R ９ These are, independently, halogen, -CN, and -NO ２ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, -OR １０ , -N(R １０ ) ２ , -C(O)R １０ , -OC(O)R １０ , -C(O)OR １０ , -NR １０ C(O)R １０ , -NR １０ C(O)OR １０ , -C(O)N(R １０ ) ２ and -OC(O)N(R １０ ) ２ Selected from; Here, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl and C １－６ Haloalkyls are one or more R １１ It is arbitrarily replaced by; Here, each R １０ These are H and C, independently. １－６ Alkyl and C １－６ Selected from haloalkyls; Here, each R １１ These are, independently, halogen, -CN, and -NO ２ , C １－４ Alkyl, C １－４ Haloalkyl, NR Ｘ１ R Ｘ２ and C(O)NR Ｘ１ R Ｘ２ Selected from; where R Ｘ１ and R Ｘ２ Each of these is independently a C molecule optionally substituted with H, OH, or a 3- to 6-membered heterocycline. １－４ Alkyl, OH, -OC １－６ Alkyl and -C(O)-C １－６ Selected from alkyl groups; Here, R Ｘ３ OH and O-C １－６ Selected from alkyl groups; n is an integer from 0 to 4; and x is an integer from 0 to 3, wherein the compound of chemical formula (II) or a pharmaceutically acceptable salt thereof according to claim 4.

7. Here, the H ring of chemical formula (III) is a carbon atom ＊ 1 or ＊ It is linked to 2; R １ and R ２ These are H and C, respectively, independently. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl and C １－６ Selected from haloalkyls; R ３ These are, independently, halogen 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 CH or N; R ４ and R ５ These are H, halogen, CN, and C, respectively, independently. １－６ Alkyl and C １－６ Selected from haloalkyls; L １ is a bond or NR ６ Selected from O and S; R ６ H, C １－４ Alkyl, C １－４ Haloalkyl and CC ３－６ Selected from cycloalkyl groups, Here, C １－４ Alkyls are optionally partially or completely deuterated; Here, C ３－６ Cycloalkyl groups consist of =O, halogen, and 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 ７ R ８ ]p-, Here, p is an integer between 1 and 4; R ７ and R ８ 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 ７ and R ８ is L ２ They are attached together to the same carbon atom within, C ３－６ Forming cycloalkyl or 3-6 membered heterocyclines, 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; Q １ C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls; Here, C ６－１０ Aryls and 5- to 10-membered heteroaryls are one or more R ９ It is arbitrarily replaced by; Each R ９ These are, independently, halogen, -CN, and -NO ２ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３ -C ６ Cycloalkyl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, -OR １０ , -S(O)xR １０ , -N(R １０ ) ２ , -C(O)R １０ , -OC(O)R １０ , -C(O)OR １０ , -NR １０ C(O)R １０ , -NR １０ C(O)OR １０ , -C(O)N(R １０ ) ２ , -OC(O)N(R １０ ) ２ , -NR １０ SO ２ R １０ , -SO ２ N(R) １０ ) ２ , and -NR １０ C(O)N(R) １０ ) ２ Selected from; Here, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３ -C ６ Cycloalkyls, 5- to 10-membered heterocyclyls, and 5- to 10-membered heteroaryls are one or more R １１ It is arbitrarily replaced by; Here, C １－６ Alkyls are optionally partially or completely deuterated; Here, each R １０ These are H and C, independently. １－６ Alkyl and C １－６ Selected from haloalkyls; Here, each R １１ These are, independently, halogen, -CN, and -NO ２ , C １－４ Alkyl, C １－４ Haloalkyl and NR Ｘ１ R Ｘ２ Selected from; Here, R Ｘ１ and R Ｘ２ Each of these is independently a C molecule optionally substituted with H, OH, or a 3- to 6-membered heterocycline. １－４ Alkyl, -OC １－６ Alkyl, -C(O)-C １－６ Selected from alkyl and 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; n is an integer from 0 to 4; and x is an integer between 0 and 3; Here, Q １ one or more types of R ９ It is not replaced by, or Q １ One or more R ９ One of them is C ３ -C ６ Cycloalkyl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or partially or completely deuterated C １－６ When it is not alkyl, R ６ C is partially or completely deuterated C １－４ A compound of chemical formula (III) that is alkyl, or a pharmaceutically acceptable salt thereof.

8. Here, the H ring in the chemical formula (III) is a carbon atom. ＊ 1 or ＊ It is linked to 2; R １ and R ２ These are H and C, respectively, independently. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl and C １－６ Selected from haloalkyls; R ３ These are, independently, halogen 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 CH or N; R ４ and R ５ These are H, halogen, CN, and C, respectively, independently. １－６ Alkyl and C １－６ Selected from haloalkyls; L １ is a bond or NR ６ And; R ６ H, C １－４ Alkyl and C １－４ Selected from haloalkyls, Here, C １－４ Alkyls are optionally partially or completely deuterated; L ２ is a combination, or -[CR ７ R ８ ]p-, Here, p is an integer between 1 and 4; R ７ and R ８ 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 ７ and R ８ is L ２ They are attached together to the same carbon atom within, C ３－６ Forming cycloalkyl or 3-6 membered heterocyclines, Here, C １－４ Alkyl groups are OH, O-C １－４ Alkyl, or halogen, or C １－６ C optionally substituted with a haloalkyl group ６－１０ It can be arbitrarily replaced with an aryl; Q １ C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls; Here, C ６－１０ Aryls and 5- to 10-membered heteroaryls are one or more R ９ It is arbitrarily replaced by; Each R ９ These are, independently, halogen, -CN, and -NO ２ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３ -C ６ Cycloalkyl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, -OR １０ , -N(R １０ ) ２ , -C(O)R １０ , -OC(O)R １０ , -C(O)OR １０ , -NR １０ C(O)R １０ , -NR １０ C(O)OR １０ , -C(O)N(R １０ ) ２ and -OC(O)N(R １０ ) ２ Selected from; Here, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３ -C ６ Cycloalkyls, 5- to 10-membered heterocyclyls, and 5- to 10-membered heteroaryls are one or more R １１ It is arbitrarily replaced by; Here, C １－６ Alkyls are optionally partially or completely deuterated; Here, each R １０ These are H and C, independently. １－６ Alkyl and C １－６ Selected from haloalkyls; Here, each R １１ These are, independently, halogen, -CN, and -NO ２ , C １－４ Alkyl, C １－４ Haloalkyl and NR Ｘ１ R Ｘ２ Selected from; where R Ｘ１ and R Ｘ２ Each of these is independently a C molecule optionally substituted with H, OH, or a 3- to 6-membered heterocycline. １－４ Alkyl, -OC １－６ Alkyl, -C(O)-C １－６ Selected from alkyl and 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; n is an integer from 0 to 4; and x is an integer between 0 and 3; Here, Q １ one or more types of R ９ It is not replaced by, or Q １ One or more R ９ One of them is C ３ -C ６ Cycloalkyl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or partially or completely deuterated C １－６ When it is not alkyl, R ６ C is partially or completely deuterated C １－４ A compound of chemical formula (III) according to claim 7, which is alkyl, or a pharmaceutically acceptable salt thereof.

9. Here, the H ring in the chemical formula (III) is a carbon atom. ＊ 1 or ＊ It is linked to 2; R １ and R ２ These are H and C, respectively, independently. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl and C １－６ Selected from haloalkyls; R ３ These are, independently, halogen 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 CH or N; R ４ and R ５ These are H, halogen, CN, and C, respectively, independently. １－６ Alkyl and C １－６ Selected from haloalkyls; L １ is a bond or NR ６ And; R ６ H, C １－４ Alkyl and C １－４ Selected from haloalkyls, Here, C １－４ Alkyls are optionally partially or completely deuterated; L ２ is a combination, or -[CR ７ R ８ ]p-, Here, p is an integer between 1 and 4; R ７ and R ８ 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 ７ and R ８ is L ２ They are attached together to the same carbon atom within, C ３－６ Forming cycloalkyl or 3-6 membered heterocyclines, Here, C １－４ Alkyl groups are OH, O-C １－４ Alkyl, or halogen, or C １－６ C optionally substituted with a haloalkyl group ６－１０ It can be arbitrarily replaced with an aryl; Q １ C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls; Here, C ６－１０ Aryls and 5- to 10-membered heteroaryls are one or more R ９ It is arbitrarily replaced by; Each R ９ is independently halogen, -CN, -NO ２ , C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３ -C ６ cycloalkyl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, -OR １０ , -N(R １０ ) ２ , -C(O)R １０ , -OC(O)R １０ , -C(O)OR １０ , -NR １０ C(O)R １０ , -NR １０ C(O)OR １０ , -C(O)N(R １０ ) ２ and -OC(O)N(R １０ ) ２ is selected from; Here, the C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３ -C ６ cycloalkyl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are optionally substituted with one or more R １１ ; Here, C １－６ Alkyls are optionally partially or completely deuterated; Here, each R １０ These are H and C, independently. １－６ Alkyl and C １－６ Selected from haloalkyls; Here, each R １１ These are, independently, halogen, -CN, and -NO ２ , C １－４ Alkyl, C １－４ Haloalkyl and NR Ｘ１ R Ｘ２ Selected from; where R Ｘ１ and R Ｘ２ Each of these is independently a C molecule optionally substituted with H, OH, or a 3- to 6-membered heterocycline. １－４ It is alkyl; n is an integer from 0 to 4; and x is an integer between 0 and 3; Here, Q １ one or more types of R ９ It is not replaced by, or Q １ One or more R ９ One of them is C ３ -C ６ Cycloalkyl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or partially or completely deuterated C １－６ When it is not alkyl, R ６ C is partially or completely deuterated C １－４ A compound of chemical formula (III) according to claim 7, which is alkyl, or a pharmaceutically acceptable salt thereof.

10. Here, R １ and R ２ These are H and C, respectively, independently. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl and C １－６ Selected from haloalkyls; R ３ These are, independently, halogen 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 CH or N; R ４ , R ５ and R １２ These are H, halogen, CN, and C, respectively, independently. １－６ Alkyl and C １－６ Selected from haloalkyls; Here, X １ If it is N, X ４ N is X ５ is CH or X ４ CH and X ５ is N; Here, X １ If C, then X ４ and X ５ All of them are CH; Here, R ４ and R ５ C １－６ Alkyls are optionally partially or completely deuterated; L １ is a bond or NR ６ Selected from O and S; R ６ H, C １－４ Alkyl, C １－４ Haloalkyl and CC ３－６ Selected from cycloalkyl groups, Here, the C ３－６ cycloalkyl is optionally substituted with one or more substituents selected from =O, halogen, C １－４ alkyl and C １－４ haloalkyl; L ２ is a combination, or -[CR ７ R ８ ]p-, Here, p is an integer between 1 and 4; R ７ and R ８ 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 ７ and R ８ is L ２ They are attached together to the same carbon atom within, C ３－６ Forming cycloalkyl or 3-6 membered heterocyclines, 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; Q １ C ３－１２ Cycloalkyl, C ３－１２ Cycloalkenyl, 3- to 12-membered heterocyclyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls; Here, C ６－１０ Aryls and 5- to 10-membered heteroaryls are one or more R ９ It is arbitrarily replaced by; Each R ９ These are, independently, halogen, -CN, and -NO ２ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, -OR １０ , -S(O) ｘ R １０ , -N(R １０ ) ２ , -C(O)R １０ , -OC(O)R １０ , -C(O)OR １０ , -NR １０ C(O)R １０ , -NR １０ C(O)OR １０ , -C(O)N(R １０ ) ２ , -OC(O)N(R １０ ) ２ , -NR １０ SO ２ R １０ , -SO ２ N(R) １０ ) ２ , and -NR １０ C(O)N(R) １０ ) ２ Selected from; Here, C １－６ Alkyl, C ２－６ Alkenyl and C ２－６ Alkinyl contains one or more R １１ It is arbitrarily replaced by; Here, each R １０ These are H and C, independently. １－６ Alkyl and C １－６ Selected from haloalkyls; Here, each R １１ These are, independently, halogen, -CN, and -NO ２ , C １－４ Alkyl, C １－４ Haloalkyl and NR Ｘ１ R Ｘ２ Selected from; Here, R Ｘ１ and R Ｘ２ Each of these is independently a C molecule optionally substituted with H, OH, or a 3- to 6-membered heterocycline. １－４ Alkyl, -OC １－６ Alkyl, -C(O)-C １－６ Selected from alkyl and 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; n is an integer from 0 to 4; and x is an integer between 0 and 3, representing the compound of chemical formula (IV) or a pharmaceutically acceptable salt thereof.

11. Here, R １ and R ２ These are H and C, respectively, independently. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl and C １－６ Selected from haloalkyls; R ３ These are, independently, halogen 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 CH or N; R ４ , R ５ and R １２ These are H, halogen, CN, and C, respectively, independently. １－６ Alki Lu and C １－６ Selected from haloalkyls; Here, X １ If it is N, X ４ N is X ５ is CH or X ４ CH and X ５ In N can be; Here, X １ If C, then X ４ and X ５ All of them are CH; Here, R ４ and R ５ C １－６ Alkyls are optionally partially or completely deuterated; L １ is a bond or NR ６ And; R ６ H, C １－４ Alkyl and C １－４ Selected from haloalkyls, L ２ is a combination, or -[CR ７ R ８ ]p-, Here, p is an integer between 1 and 4; R ７ and R ８ 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 ７ and R ８ is L ２ They are attached together to the same carbon atom within, C ３－６ Forming cycloalkyl or 3-6 membered heterocyclines, Here, C １－４ Alkyl groups are OH, O-C １－４ Alkyl, or halogen, or C １－６ C optionally substituted with a haloalkyl group ６－１０ It can be arbitrarily replaced with an aryl; Q １ C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls; Here, C ６－１０ Aryls and 5- to 10-membered heteroaryls are one or more R ９ It is arbitrarily replaced by; Each R ９ These are, independently, halogen, -CN, and -NO ２ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, -OR １０ , -N(R １０ ) ２ , -C(O)R １０ , -OC(O)R １０ , -C(O)OR １０ , -NR １０ C(O)R １０ , -NR １０ C(O)OR １０ , -C(O)N(R １０ ) ２ and -OC(O)N(R １０ ) ２ Selected from; Here, C １－６ Alkyl, C ２－６ Alkenyl and C ２－６ Alkinyl contains one or more R １１ It is arbitrarily replaced by; Here, each R １０ These are H and C, independently. １－６ Alkyl and C １－６ Selected from haloalkyls; Here, each R １１ These are, independently, halogen, -CN, and -NO ２ , C １－４ Alkyl, C １－４ Haloalkyl and NR Ｘ１ R Ｘ２ Selected from; Here, R Ｘ１ and R Ｘ２ Each of these is independently a C molecule optionally substituted with H, OH, or a 3- to 6-membered heterocycline. １－４ Alkyl, -OC １－６ Alkyl, -C(O)-C １－６ Selected from alkyl and 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; n is an integer from 0 to 4; and x is an integer from 0 to 3, the compound of chemical formula (IV) according to claim 10 or the drug thereof. A scientifically acceptable salt.

12. Here, R １ and R ２ These are H and C, respectively, independently. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl and C １－６ Selected from haloalkyls; R ３ These are, independently, halogen 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 CH or N; R ４ , R ５ and R １２ These are H, halogen, CN, and C, respectively, independently. １－６ Alkyl and C １－６ Selected from haloalkyls; Here, X １ If it is N, X ４ N is X ５ is CH or X ４ CH and X ５ is N; Here, X １ If C, then X ４ and X ５ All of them are CH; Here, R ４ and R ５ C １－６ Alkyls are optionally partially or completely deuterated; L １ is a bond or NR ６ And; R ６ H, C １－４ Alkyl or C １－４ Selected from haloalkyls, L ２ is a combination, or -[CR ７ R ８ ]p-, Here, p is an integer between 1 and 4; R ７ and R ８ 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 ７ and R ８ is L ２ They are attached together to the same carbon atom within, C ３－６ Forming cycloalkyl or 3-6 membered heterocyclines, Here, C １－４ Alkyl groups are OH, O-C １－４ Alkyl, or halogen, or C １－６ C optionally substituted with a haloalkyl group ６－１０ It can be arbitrarily replaced with an aryl; Q １ C ３－１２ Cycloalkyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls; Here, C ６－１０ Aryls and 5- to 10-membered heteroaryls are one or more R ９ It is arbitrarily replaced by; Each R ９ These are, independently, halogen, -CN, and -NO ２ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, -OR １０ , -N(R １０ ) ２ , -C(O)R １０ , -OC(O)R １０ , -C(O)OR １０ , -NR １０ C(O)R １０ , -NR １０ C(O)OR １０ , -C(O)N(R １０ ) ２ and -OC(O)N(R １０ ) ２ Selected from; Here, C １－６ Alkyl, C ２－６ Alkenyl and C ２－６ Alkinyl contains one or more R １１ It is arbitrarily replaced by; Here, each R １０ These are H and C, independently. １－６ Alkyl and C １－６ Selected from haloalkyls; Here, each R １１ These are, independently, halogen, -CN, and -NO ２ , C １－４ Alkyl, C １－４ Haloalkyl and NR Ｘ１ R Ｘ２ Selected from; Here, R Ｘ１ and R Ｘ２ Each of these is independently a C atom optionally substituted with H, OH, or a 3- to 6-membered heterocycline. １－４ It is alkyl; n is an integer from 0 to 4; and A compound of chemical formula (IV) according to claim 10 or a pharmaceutically acceptable salt thereof, wherein x is an integer from 0 to 3.

13.

14.

15.

16.

17.

18.

19.

20.

21. Here, -L １ -L ２ - Q １ The base is one of the following structures. The compound according to claim 1.

22. Here, -L １ -L ２ - Q １ The base is one of the following structures. The compound according to claim 4.

23. Here, -L １ -L ２ - Q １ The base is one of the following structures. The compound according to claim 7.

24. Here, -L １ -L ２ - Q １ The base is one of the following structures. The compound according to claim 10.

25. A compound or so selected from the group consisting of compounds 1 to 239 listed below. A pharmaceutically acceptable salt of [the substance].

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

27. A pharmaceutical composition according to claim 26 for use as a pharmaceutical.

28. The pharmaceutical composition according to claim 26, for use in the treatment of diseases or medical conditions mediated by microtubule-associated serine / threonine-like kinases (MASTLs).

29. The pharmaceutical composition according to claim 26, for use in the treatment of a disease in which PD-L1 expression is interferon-dependent.

30. A pharmaceutical composition according to claim 26, for use in the treatment of proliferative disorders, metabolic disorders, or symptoms or conditions associated with metabolic disorders, or platelet disorders, wherein the platelet disorder is optionally thrombocytopenia.

31. The pharmaceutical composition according to claim 30, wherein the proliferative disorder is cancer, and optionally, the cancer is selected from among 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).

32. The pharmaceutical composition according to claim 30, wherein the cancer is characterized by overexpression of MASTL.

33. The pharmaceutical composition according to claim 30, wherein the composition is administered together with one or more additional anticancer agents and / or radiotherapy.

34. The pharmaceutical composition according to claim 30, wherein the metabolic disorder is selected from insulin resistance, diabetes mellitus, or obesity, and the signs and symptoms associated with the metabolic disorder are selected from elevated blood glucose, elevated cholesterol, elevated triglyceride levels, heart disease, stroke, hypertension, and increased risk of thrombosis (e.g., deep vein thrombosis).

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