Substituted heterocyclic compound derivative and pharmaceutical application thereof

Abstract

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

Description

Technical Field

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

[0002] Microtubule-associated serine / threonine kinase-like (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 a protein of 850 amino acids. It is unique among kinases in that it contains an insertion of approximately 500 amino acids between kinase subdomains VII and VIII, corresponding to the activation loop. The protein regulates entry and exit from mitosis through its ability to inactivate the phosphatase PP2A / B55 (Castilho et al., (2009). The M phase kinase Greatwall (Gwl) promotes inactivation of PP2A / B55delta, a phosphatase directed against CDKphosphosites. (Mol. Biol. Cell. 20(22):4777-89)). MASTL indirectly inhibits the phosphatase by phosphorylating ENSA and ARPP19 (pENSA / pARPP19) at S67 and S62, respectively (Gharbi-Ayachi et al., (2010). Thesubstrate of Greatwall kinase, Arpp19, controls mitosis by inhibiting proteinphosphatase 2A. (Science 330 1673-1677)). pENSA and pARPP19 are substrates of PP2A / B55 that inhibit the complex by binding tightly to it and undergoing dephosphorylation at a very slow rate, thereby inhibiting the catalytic activity of PP2A / B55 through "unfair competition" (Williams et al., (2014). Greatwall-phosphorylated Endosulfineis both an inhibitor and a substrate of PP2A-B55 heterotrimers. (eLife3:e01695.)). Entry into cell mitosis is controlled by a rapid increase in phosphorylation of a large number of substrates caused by CDK1 / CCNB1, which is accompanied by a decrease in PP2A / B55 activity. MASTL is a substrate of CDK1 / CCNB1, and the combination of their activities ensures that MASTL activity peaks during mitosis. MASTL activity is crucial for coordinating exit from mitosis by delaying the increase in PP2A / B55 activity until chromosome segregation is complete. APC / C-dependent ubiquitination of CCNB1, followed by its degradation by the proteasome, initiates entry into anaphase.This weakens CDK1 activity, leading to the eventual inactivation of MASTL and an increase in the activity of the PP2A / B55 phosphatase required for timely exit from mitosis. Temporal control of PP2A / B55 reactivation via the PP2A-B55-ENSA / ARPP19-MASTL pathway is crucial for orderly cytokinesis following 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 will result in premature cytokinesis, causing chromosome segregation defects and aneuploidy.

[0003] MASTL has been shown to be essential for cell cycle progression during embryogenesis in many organisms, including mice, frogs, and flies. In mice, MASTL remains essential for up to a year after birth, after which its loss (complete ablation) is tolerated (Belén Sanz Castillo: Role of MASTL in mammals: Molecular functions and physiological relevance, 2017). Additionally, siRNA screens have identified MASTL as a gene that specifically inhibits 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 importance of MASTL is not universal and is restricted to the embryonic and early developmental stages of organisms. Furthermore, studies have shown that the cell cycle control mechanisms in some cancer cells have reverted to a state similar to that of the embryonic cell cycle (where MASTL activity is essential), making them sensitive to MASTL loss. Therefore, MASTL kinase inhibitors will have broad applicability in a variety of cancers, along with a favorable therapeutic window, and are thus ideal targets for cancer therapy.

[0004] Numerous studies have shown that MASTL plays a key role in cancer development. Overexpression of MASTL has been identified in a range of other human tumors, including breast tumors ( et al., (2017)), oral tumors (Wang et al., (2014). Mastl kinase, a promising therapeutic target, promotes cancer recurrence. (Oncotarget 5 11479 - 11489.)), and gastric tumors (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 (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 - induced CRISPR / Cas9 knockout of MASTL in MDA - MB - 231 cells showed that tumor size decreased significantly when MASTL was depleted relative to control animals. In ER+ breast cancer, the expression level of MASTL protein is associated with invasiveness and is a predictor of low patient survival rate ( et al., (2018). Therapeutic relevance of the PP2A-B55 inhibitory kinase MASTL / Greatwall in breast cancer. (Cell Death Differ. 25, 828-840)). Upregulation of MASTL is associated with cancer progression in head and neck tumors and is often associated with more aggressive forms of the disease (Wang et al., (2014). Mastl kinase, a promising therapeutic target, promotes cancer recurrence. (Oncotarget 5, 11479-11489)). High-throughput siRNA screening of BCPAP thyroid cancer identified vulnerabilities to MASTL loss, which led to a significant reduction in cell proliferation (Anania et al., (2015)). In colorectal cancer, upregulation of MASTL is associated with low patient survival and can serve 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)). To support a therapeutic window, normal colonocytes do not express MASTL or express it only at very low levels. Depletion of MASTL in HCT-116 cells led to G2 / M arrest, induced apoptosis by regulating anti-apoptotic proteins (Survivin and Bcl-xL, possibly through Gsk3β activation), and significantly reduced growth in vivo. In addition to having a direct effect on HCT-116 cell proliferation, MASTL-derived regulation of anti-apoptotic proteins also led to increased sensitivity to 5-FU treatment. MASTL has been highlighted as a potential new therapeutic target in several cancers, such as 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.)), 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 also inactivates checkpoint signaling and aids in the recovery from DNA damage, thus supporting a role in potentiating the 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 performed in NSCLC cells identified MASTL as a major hit that sensitizes cells to radiation. This effect was not observed in primary human fibroblasts, suggesting the possibility of selectively sensitizing tumor cells rather than untransformed cells (Nagel et al., (2015). Genome-wide siRNA Screen identifies the radiosensitizing effect of downregulation of MASTL and FOXM1 in NSCLC. (Mol. Cancer Ther. 14 1434-1444)). A similar effect was observed in a xenograft tumor model of UM-SSC-11-B cells derived from a cisplatin-resistant head and neck squamous cell carcinoma (Wang et al., 2014). MASTL depletion resensitizes cells to cisplatin treatment. Additional flow cytometry studies performed in UM-SSC-11-B cells showed an increase in the sub-G1 population and induction of apoptosis, while MASTL-depleted normal oral keratinocyte OKF4 cells resisted cell death with or without cisplatin treatment.

[0006] In addition to the role MASTL plays in cancer by regulating DNA damage repair pathways and mitosis, it also plays a role in regulating PP2A activity during interphase (Belén Sanz Castillo, 2017). The discovery that point mutations in the MASTL gene cause autosomal dominant thrombocytopenia (Drachman et al., Autosomal dominant thrombocytopenia: incomplete megakaryocyte differentiation and linkage to human chromosome 10. (Blood. 2000; 96:118 - 125.)) provides evidence for the role of MASTL in megakaryocytopoeisis. More recently, it has been found that such point mutations in MASTL do not result in reduced activity as initially thought, but rather are associated with increased phosphorylation of Cdk and PP2A substrates, indicating a gain-of-function alteration that leads to reduced PP2A activity (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)). Thus, MASTL inhibitors may have therapeutic potential in treating metabolic diseases such as diabetes and obesity and platelet disorders, including the rare genetic disease MASTL-associated thrombocytopenia, through their regulatory effects on the PI3K / AKT pathway and the cytoskeleton, respectively.

[0007] Accordingly, there is a need to anticipate MASTL inhibitors that provide beneficial therapeutic effects, such as in cancer treatment. SUMMARY OF THE INVENTION

[0008] According to the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0009]

[0010] wherein the H ring in formula (I) is bonded to a carbon atom * 1 or * 2;

[0011] Z is -NR 1 R 2 or -CN;

[0012] R 1 and R2 Independently selected from: H, D, and C 1-6 alkyl

[0013] wherein said C 1-6 alkyl is optionally partially or fully deuterated;

[0014] R 3 each independently selected from: halogen, C 1-6 alkyl, and amino;

[0015] X1 is N and X2 is CR 4 , or X1 is C and X2 is NR 5 ;

[0016] X3 is CH or N;

[0017] R 4 selected from: H, NR X1 R X2 ,-OH, and C 1-6 alkyl;

[0018] R 5 selected from: H and C 1-6 alkyl,

[0019] wherein R 4 or R 5 the C 1-6 alkyl on is optionally partially or fully deuterated;

[0020] L 1 is a bond or selected from: NR 6 , O, and S;

[0021] R 6 selected from H, C 1-4 alkyl, C 1-4 haloalkyl, and C 3-6 cycloalkyl,

[0022] wherein 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;

[0023] L 2 is a bond or -[CR 7 R 8 p-;

[0024] p is an integer from 1 to 4;

[0025] R 7 and R 8 each independently selected from: H, C 1-4 alkyl, and C1-4 haloalkyl, OH, COOH, C(O)NR X1 R X2 and C 3-6 cycloalkyl, or R 7 and R 8 are attached to the same carbon atom in L 2 to form, together, a C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group,

[0026] wherein said C 1-4 alkyl is optionally substituted with: OH, O-C 1-4 alkyl, a 3- to 6-membered heterocyclic group, a 5- to 10-membered heteroaryl or a C 1-6 aryl optionally substituted with halogen or C 6-10 haloalkyl;

[0027] Q 1 is selected from: C 3-12 cycloalkyl, C 3-12 cycloalkenyl, a 3- to 12-membered heterocyclic group, C 6-10 aryl and a 5- to 10-membered heteroaryl;

[0028] wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more R 9 substituents;

[0029] each R 9 is independently selected from: 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;

[0030] Wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted by one or more R 11 ; and

[0031] wherein each R 10 is independently selected from: H, C 1-6 alkyl, and C 1-6 haloalkyl;

[0032] wherein each R 11 is independently selected from: halogen, -CN, -NO2, C 1-4 alkyl, C 1-4 haloalkyl, and NR X1 R X2 ; wherein R X1 and R X2 are independently selected from: H, C 1-4 alkyl optionally substituted by OH or a 3- to 6-membered heterocyclic group, -OC 1-6 alkyl, -C(O)-C 1-6 alkyl, and a 5- to 10-membered heteroaryl, or R X1 and R X2 are attached to the same nitrogen atom and together form a 3- to 6-membered heterocyclic group;

[0033] n is an integer from 0 to 4; and

[0034] x is an integer from 0 to 3;

[0035] wherein when R 4 or R 5 is H or an undehydrogenated C 1-6 alkyl, then

[0036] Z is -CN, or

[0037] -NR 1 R 2 wherein at least one of R 1 and R 2 is D or a partially or fully deuterated C 1-6 alkyl.

[0038] In addition, according to the present invention, there is provided a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0039]

[0040] wherein the H ring in formula (II) is bonded to a carbon atom *1 or *2 ;

[0041] R 1 and R2 independently selected from: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl;

[0042] R 3 each independently selected from: halogen, C 1-6 alkyl and amino;

[0043] X1 is N and X2 is CR 4 , or X1 is C and X2 is NR 5 ;

[0044] X3 is CH or N;

[0045] R 4 and R 5 independently selected from: H, halogen, CN, C 1-6 alkyl and C 1-6 haloalkyl;

[0046] L 1 is a bond or selected from: NR 6 , O and S;

[0047] R 6 selected from H, C 1-4 alkyl, C 1-4 haloalkyl and C 3-6 cycloalkyl,

[0048] wherein said 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;

[0049] L 2 is a bond or -[CR 7 R 8 p-;

[0050] p is an integer from 1 to 4;

[0051] R 7 and R 8 each independently selected from: 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;

[0052] wherein the R in L 2 ​7 and R 8 at least one of which is not H, and

[0053] said C 1-4 alkyl is substituted by a 3- to 6-membered cycloalkyl group, C 4-8 alkyl or NR X1 R X2 substituted;

[0054] Q 1 is selected from: C 3-12 cycloalkyl, C 3-12 cycloalkenyl, a 3- to 12-membered heterocyclic group, C 6-10 aryl and a 5- to 10-membered heteroaryl;

[0055] wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted by one or more R 9 substituted;

[0056] each R 9 is independently selected from: 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,

[0057] wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl are optionally substituted by one or more R 11 substituted; and

[0058] wherein each R 10 is independently selected from: H, C 1-6Alkyl and C 1-6 haloalkyl;

[0059] wherein each R 11 is independently selected from: halogen, -CN, -NO2, C 1-4 alkyl, C 1-4 haloalkyl, NR X1 R X2 and C(O)NR X1 R X2 ; wherein R X1 and R X2 are independently selected from: H, C 1-4 alkyl optionally substituted by OH or a 3- to 6-membered heterocyclic group, OH, -OC 1-6 alkyl, -C(O)-C 1-6 alkyl and a 5- to 10-membered heteroaryl, or R X1 and R X2 are attached to the same nitrogen atom and together form a 3- to 6-membered heterocyclic group;

[0060] wherein R X3 is selected from: OH and O-C 1-6 alkyl;

[0061] n is an integer from 0 to 4; and

[0062] x is an integer from 0 to 3.

[0063] In addition, according to the present invention, there is provided a compound of formula (III) or a pharmaceutically acceptable salt thereof:

[0064]

[0065] wherein the H ring in formula (III) is bonded to carbon atom * 1 or * 2;

[0066] R 1 and R 2 are independently selected from: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl;

[0067] R 3 are each independently selected from: halogen, C 1-6 alkyl and amino;

[0068] X1 is N and X2 is CR 4 , or X1 is C and X2 is NR 5 ;

[0069] X3 is CH or N;

[0070] R 4 and R 5 are each independently selected from: H, halogen, CN, C 1-6 alkyl, and C 1-6 haloalkyl;

[0071] L 1 is a bond or is selected from: NR 6 , O, and S;

[0072] R 6 is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, and C 3-6 cycloalkyl,

[0073] wherein said C 1-4 alkyl is optionally partially or fully deuterated;

[0074] wherein said 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;

[0075] L 2 is a bond or -[CR 7 R 8 p-;

[0076] p is an integer from 1 to 4;

[0077] R 7 and R 8 are each independently selected from: H, C 1-4 alkyl, and C 1-4 haloalkyl, OH, COOH, C(O)NR X1 R X2 and C 3-6 cycloalkyl, or R 7 and R 8 are attached to the same carbon atom in L 2 to form a C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group,

[0078] wherein said C 1-4 alkyl is optionally substituted with: OH, O-C 1-4 alkyl, a 3- to 6-membered heterocyclic group, a 5- to 10-membered heteroaryl, or an optionally halogen- or C 1-6 haloalkyl-substituted C 6-10 aryl;

[0079] Q 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl;

[0080] Wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted by one or more R 9 substituents;

[0081] Each R 9 is independently selected from: 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 heterocyclic group, 5- to 10-membered heteroaryl, -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;

[0082] Wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclic group and 5- to 10-membered heteroaryl are optionally substituted by one or more R 11 substituents;

[0083] Wherein said C 1-6 alkyl is optionally partially or fully deuterated;

[0084] Wherein each R 10 is independently selected from: H, C 1-6 alkyl and C 1-6 haloalkyl;

[0085] Wherein each R 11 is independently selected from: halogen, -CN, -NO2, C 1-4 alkyl, C 1-4 haloalkyl and NR X1 R X2 ;

[0086] wherein R X1 and R X2 are independently selected from: H, C 1-4 alkyl optionally substituted with OH or a 3- to 6-membered heterocyclic group, -OC 1-6 alkyl, -C(O)-C 1-6 alkyl and 5- to 10-membered heteroaryl, or R X1 and R X2 are attached to the same nitrogen atom and together form a 3- to 6-membered heterocyclic group;

[0087] n is an integer from 0 to 4; and

[0088] x is an integer from 0 to 3;

[0089] wherein when Q 1 is not substituted with one or more R 9 or

[0090] when any one of the one or more R 1 on Q 9 is not C3-C6 cycloalkyl, 5- to 10-membered heterocyclic group, 5- to 10-membered heteroaryl or partially or fully deuterated C 1-6 alkyl, then

[0091] R 6 is partially or fully deuterated C 1-4 alkyl.

[0092] In addition, according to the present invention, there is provided a compound of formula (IV) or a pharmaceutically acceptable salt thereof:

[0093]

[0094] wherein R 1 and R 2 are independently selected from: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl;

[0095] R 3 are each independently selected from: halogen, C 1-6 alkyl and amino;

[0096] X1 is N and X2 is CR 4 or X1 is C and X2 is NR 5 ;

[0097] X3 is CH or N;

[0098] R 4 、R 5 and R 12Independently selected from: H, halogen, CN, C 1-6 alkyl and C 1-6 haloalkyl;

[0099] wherein when X1 is N, then

[0100] X 4 is N and X 5 is CH, or X 4 is CH and X 5 is N; and

[0101] wherein when X1 is C, then X4 and X5 are both CH;

[0102] wherein R 4 or R 5 on the said C 1-6 alkyl is optionally partially or fully deuterated;

[0103] L 1 is a bond or selected from: NR 6 、O and S;

[0104] R 6 is selected from H, C 1-4 alkyl, C 1-4 haloalkyl and C 3-6 cycloalkyl,

[0105] wherein the said C 3-6 cycloalkyl is optionally substituted by one or more substituents selected from: =O, halogen, C 1-4 alkyl and C 1-4 haloalkyl;

[0106] L 2 is a bond or -[CR 7 R 8 p-,

[0107] where p is an integer from 1 to 4;

[0108] R 7 and R 8 are each independently selected from: H, C 1-4 alkyl and C 1-4 haloalkyl, OH, COOH, C(O)NR X1 R X2 and C 3-6 cycloalkyl, or R 7 and R 8 are attached to the same carbon atom in L 2 to form C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group,

[0109] wherein the said C 1-4The alkyl group is optionally substituted with: OH, O-C 1-4 alkyl group, 3- to 6-membered heterocyclic group, 5- to 10-membered heteroaryl group, or C 1-6 aryl group optionally substituted with halogen or C 6-10 haloalkyl group;

[0110] Q 1 selected from C 3-12 cycloalkyl group, C 3-12 cycloalkenyl group, 3- to 12-membered heterocyclic group, C 6-10 aryl group and 5- to 10-membered heteroaryl group;

[0111] wherein the C 6-10 aryl group and 5- to 10-membered heteroaryl group are optionally substituted with one or more R 9 substituents;

[0112] Each R 9 is independently selected from: halogen, -CN, -NO2, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 haloalkyl group, -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,

[0113] wherein the C 1-6 alkyl group, C 2-6 alkenyl group and C 2-6 alkynyl group are optionally substituted with one or more R 11 substituents,

[0114] where each R 10 is independently selected from: H, C 1-6 alkyl group and C 1-6 haloalkyl group;

[0115] where each R 11Independently selected from: halogen, -CN, -NO2, C 1-4 alkyl, C 1-4 haloalkyl and NR X1 R X2 ;

[0116] wherein R X1 and R X2 are independently selected from: H, C 1-4 alkyl optionally substituted by OH or a 3- to 6-membered heterocyclic group, -OC 1-6 alkyl, -C(O)-C 1-6 alkyl and 5- to 10-membered heteroaryl, or R X1 and R X2 are attached to the same nitrogen atom and together form a 3- to 6-membered heterocyclic group;

[0117] n is an integer from 0 to 4; and

[0118] x is an integer from 0 to 3.

[0119] In addition, according to the present invention, there are provided compound numbers 1-239 listed in Table 1 of this specification, or pharmaceutically acceptable salts thereof.

[0120] There is also provided a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0121] There is also provided a compound of the present invention or a pharmaceutically acceptable salt thereof for use as a drug. In some embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat a disease or medical condition mediated by microtubule-associated serine / threonine-like kinase (MASTL).

[0122] There is also provided a compound of the present invention or a pharmaceutically acceptable salt thereof for treating a disease in which PD-L1 expression is interferon-dependent.

[0123] There is also provided 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 present invention or a pharmaceutically acceptable salt thereof.

[0124] In certain embodiments, the compounds of the present invention are used to treat proliferative diseases, such as cancer. In certain embodiments, the compounds of the present invention are used to prevent or inhibit cancer progression, such as by preventing or inhibiting cancer cell migration, cancer cell invasion, and / or preventing or inhibiting cancer metastasis.

[0125] In certain embodiments, the compounds of the present invention are used to treat cancer.

[0126] In certain embodiments, the compounds of the invention are used to treat cancers overexpressing MASTL. In certain embodiments, the compounds of the invention are used to treat cancers selected from the following: 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., uveal melanoma), and blood cancers (e.g., leukemia such as AML, lymphoma, myeloma, and multiple myeloma).

[0127] In certain embodiments, the compounds of the invention are used to treat or prevent metabolic disorders, or symptoms or conditions associated with metabolic diseases.

[0128] In certain embodiments, the metabolic disorder can be insulin resistance, diabetes, or obesity. Symptoms and conditions associated with the metabolic disorder can include one or more of the following: elevated blood glucose, elevated cholesterol, elevated triglyceride levels, heart disease, stroke, hypertension, and increased risk of blood clots (e.g., deep vein thrombosis).

[0129] In certain embodiments, the compounds of the invention are used to treat platelet disorders, such as thrombocytopenia.

[0130] The compounds of the invention can be used alone or in combination with one or more anti-cancer agents and / or radiotherapy as described herein. Detailed Description

[0131] Definitions

[0132] Unless otherwise indicated, the following terms used in the specification and claims have the following meanings set forth below.

[0133] The term "treat" or "treatment" refers to any indication of successful treatment or amelioration of a disease, pathology, or condition, including any objective or subjective parameter such as elimination; remission; alleviation of symptoms or making the pathology or condition more tolerable to the patient; slowing the rate of degeneration or decline; making the end point of degeneration less debilitating; or improving the physical or mental health of the patient. For example, certain methods herein treat cancer by alleviating cancer symptoms. The symptoms of cancer are known or can be determined by one of ordinary skill in the art. The term "treat" and its inflected forms include preventing a pathology, condition, or disease (e.g., preventing the development of one or more symptoms of a cancer associated with MASTL).

[0134] The term "associated with" or "associated" in the context of a substance or substance activity or function associated with a disease (such as cancer) means that the disease (such as cancer) is (wholly or in part) caused by the substance or substance activity or function, or the symptoms of the disease are (wholly or in part) caused by the substance or substance activity or function. For example, the symptoms of a disease or condition associated with MASTL pathway activity may be (wholly or in part) symptoms caused by an increased level of MASTL protein pathway activity. As used herein, a substance described as being associated with a disease, if it is a causative agent, can be a target for the treatment of the disease. For example, a disease associated with an increased level of MASTL activity can be treated with an agent (such as a compound described herein) that effectively reduces the level of MASTL activity.

[0135] As defined herein, the term "inhibit" when referring to a protein-inhibitor (such as an antagonist) interaction means a negative effect (such as a decrease) on the activity or function level of a protein (such as a component of MASTL) protein pathway relative to the activity or function level of the protein pathway in the absence of the inhibitor. In some embodiments, inhibition refers to a reduction in a disease or disease symptom (such as cancer) associated with an increased level of MASTL activity. In some embodiments, inhibition refers to a decrease in the activity level of a signal transduction pathway or signaling pathway associated with MASTL. Thus, inhibition can at least in part include, partially or completely blocking a stimulus, reducing, preventing or delaying activation, or inactivating, desensitizing or downregulating signal transduction or enzyme activity or the amount of a protein (such as MASTL). Inhibition can at least in part include, partially or completely reducing a stimulus, reducing activation, or inactivating, desensitizing or downregulating signal transduction or enzyme activity or the amount of a protein (such as a component of the MASTL protein pathway), which protein can regulate the level of another protein or regulate cell survival, cell proliferation or cell motility relative to a non-disease control.

[0136] Throughout the description and claims of this specification, the words "comprise" and "comprising" and their variants mean "including but not limited to", and they are not intended to (and do not) exclude other parts, additives, ingredients, wholes or steps. Throughout the description and claims of this specification, the singular includes the plural unless the context otherwise requires. In particular, in the case of using an indefinite article, the specification should be understood to contemplate both the plural and the singular unless the context otherwise requires.

[0137] The term "halo" or "halogen" refers to one of the halogens in Group 17 of the periodic table. The term particularly refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine.

[0138] The term C m-n refers to a group having from m to n carbon atoms.

[0139] The term "C1-6 "Alkyl" refers to a straight-chain or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. "C 1-4 "Alkyl" also refers to such a group containing up to 4 carbon atoms. An alkylene is a divalent alkyl group, which can also be straight-chain or branched and has two connection points to the rest of the molecule. In addition, the alkylene can correspond to, for example, one of the alkyl groups listed in this paragraph. For example, C 1-6 The alkylene can be -CH2-, -CH2CH2-, -CH2CH(CH3)-, -CH2CH2CH2- or -CH2CH(CH3)CH2-. The alkyl and alkylene groups can be unsubstituted or substituted by one or more substituents. The possible substituents are described herein. For example, the substituents of the alkyl or alkylene group can be halogen (such as fluorine, chlorine, bromine and iodine), OH, C1-C4 alkoxy, -NR'R" amino, where R′ and R″ are independently H or alkyl. Or other substituents of the alkyl group can be used.

[0140] The term "C 1-6 "Halogenated alkyl", such as "C 1-4 "Halogenated alkyl" refers to a hydrocarbon chain substituted by at least one halogen atom independently selected from, for example, fluorine, chlorine, bromine and iodine each time it appears. The halogen atom can be present at any position on the hydrocarbon chain. For example, C 1-6 The halogenated alkyl can refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl (such as 1-chloroethyl and 2-chloroethyl), trichloroethyl (such as 1,2,2-trichloroethyl, 2,2,2-trichloroethyl), fluoroethyl (such as 1-fluoroethyl and 2-fluoroethyl), trifluoroethyl (such as 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl), chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl. The halogenated alkyl can be, for example, -CX3, -CHX2, -CH2CX3, -CH2CHX2 or -CX(CH3)CH3, where X is halogen (such as F, Cl, Br or I). Fluoroalkyl, that is, a hydrocarbon chain substituted by at least one fluorine atom (such as -CF3, -CHF2, -CH2CF3 or -CH2CHF2).

[0141] The term "C 2-6 "Alkenyl" includes a branched or straight-chain hydrocarbon chain containing at least one double bond and having 2, 3, 4, 5 or 6 carbon atoms. The double bond can exist as an E or Z isomer. The double bond can be at any possible position on the hydrocarbon chain. For example, "C 2-6"Alkenyl" can be vinyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, and hexadienyl. Alkenylene is a divalent alkenyl, which can also be straight-chain or branched-chain and has two connection points to the rest of the molecule. In addition, alkenylene can correspond to one of the alkenyls listed in this paragraph, for example. For example, alkenylene can be -CH=CH-, -CH2CH=CH-, -CH(CH3)CH=CH-, or -CH2CH=CH-. Alkenyl and alkenylene can be unsubstituted or substituted by one or more substituents. The possible substituents are described herein. For example, the substituents can be those described above as alkyl substituents.

[0142] The term "C 2-6 Alkynyl" includes a branched or straight-chain hydrocarbon chain containing at least one triple bond and having 2, 3, 4, 5, or 6 carbon atoms. The triple bond can be at any possible position in the hydrocarbon chain. For example, "C 2-6 Alkynyl" can be ethynyl, propynyl, butynyl, pentynyl, and hexynyl. Alkynylene is a divalent alkynyl, which can also be straight-chain or branched-chain and has two connection points to the rest of the molecule. In addition, alkynylene can correspond to one of the alkynyls listed in this paragraph, for example. For example, alkynylene can be -C≡C-, -CH2C≡C-, -CH2C≡CCH2-, -CH(CH3)CH≡C-, or -CH2C≡CCH3. Alkynyl and alkynylene can be unsubstituted or substituted by one or more substituents. The possible substituents are described herein. For example, the substituents can be those described above as alkyl substituents.

[0143] The term "C 3-12 Cycloalkyl" includes a saturated hydrocarbon ring system containing 3 to 12 carbon atoms. Cycloalkyl can be a monocyclic or fused, bridged, or spiro saturated hydrocarbon ring system. The term "C 3-6 Cycloalkyl" includes a saturated hydrocarbon ring system 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. Suitably, "C3-C6 cycloalkyl" can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0144] The term "C 3-12 Cycloalkenyl" includes a hydrocarbon ring system containing 3 to 12 carbon atoms and at least one double bond (e.g., 1 or 2 double bonds). Cycloalkenyl can be a monocyclic or fused, bridged, or spiro hydrocarbon ring system. For example, C3-12 The cycloalkenyl group can be cyclobutenyl, cyclopentenyl, or cyclohexenyl.

[0145] The terms "heterocyclic group", "heterocyclic", or "heterocycle" include non-aromatic saturated or partially saturated monocyclic or fused, bridged, or spiro bicyclic heterocyclic systems. The monocyclic heterocycle may contain about 3 to 12 (suitably 3 to 7) ring atoms, having 1 to 5 (suitably 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur in the ring. The bicyclic heterocycle may contain 7 to 12 member atoms in the ring. The bicyclic heterocycle may be a fused, spiro, or bridged ring system. The heterocyclic group may be a 3-12, such as 3 to 9 (e.g., 3 to 7)-membered non-aromatic monocyclic or bicyclic saturated or partially saturated group, containing 1, 2, or 3 heteroatoms independently selected from O, S, and N in the ring system (in other words, 1, 2, or 3 of the atoms forming the ring system are selected from O, S, and N). Partially saturated means that the ring may contain one or two double bonds. This applies especially to monocycles having 5 to 7 members. The double bonds are usually between two carbon atoms, but may also be between a carbon atom and a nitrogen atom. The bicyclic system may be spiro-fused, i.e., the rings are connected to each other through a single carbon atom; ortho-fused, i.e., the rings are connected to each other through two adjacent carbon atoms or nitrogen atoms; or they may share a bridgehead, i.e., the rings are connected to each other through two non-adjacent carbon atoms or nitrogen atoms (bridged ring system). Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycles containing at least one nitrogen in the ring position include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, tetrahydropyridyl, homopiperidinyl, homopiperazinyl, 2,5-diaza-bicyclo[2.2.1]heptyl, etc. Typical sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepine. Other heterocycles include dihydrooxathiolyl, tetrahydrooxazolyl, tetrahydrooxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For sulfur-containing heterocycles, it also includes sulfur-oxidized heterocycles containing SO or SO2 groups. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl, such as tetrahydrothiophene 1,1-dioxide and thiomorpholine 1,1-dioxide. Suitable values for heterocyclic groups bearing 1 or 2 oxo (=O) groups are, for example, 2-oxopyrrolidinyl, 2-oxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl, or 2,6-dioxopiperidinyl.Specific heterocyclic groups are saturated monocyclic 3- to 7-membered heterocyclic groups containing 1, 2 or 3 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 will be understood by those skilled in the art, any heterocycle can be attached to another group through any suitable atom (such as through a carbon or nitrogen atom). For example, the term "piperidino" or "morpholino" refers to a piperidin-1-yl or morpholin-4-yl ring attached through the ring nitrogen. When referring to a "heterocyclic subunit", for example, it can be represented by L. 1 What is represented is a divalent "heterocyclic group", such as 3,2-morpholinyl subunit.

[0146] The term "bridged ring system" includes ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 131-133, 1992. Suitably, the bridge is formed between two non-adjacent carbon or nitrogen atoms in the ring system. The bridge connecting the bridgehead atoms can be a bond or contain one or more atoms. Examples of bridged heterocyclic group ring systems include azabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, azabicyclo[2.2.2]octane, azabicyclo[3.2.1]octane and quinuclidine.

[0147] The term "spirobicyclic system" includes ring systems in which two ring systems share a common spiro carbon atom, that is, the heterocycle is attached to another carbocyclic or heterocyclic ring through a single common spiro carbon atom. Examples of spiro systems include 3,8-diazabicyclo[3.2.1]octane, 2,5-diazabicyclo[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-diazaspiro[4.4]nonane, 2-azaspiro[3.5]nonane, 2-oxa-7-azaspiro[3.5]nonane and 2-oxa-6-azaspiro[3.5]nonane.

[0148] "heterocyclic group-C m-n alkyl" includes a heterocyclic group covalently attached to C m-n alkylene, both of which are defined herein; and wherein the heterocyclic group-C m-n alkyl is attached to the rest of the molecule through a carbon atom in the alkylene. The group "aryl-C m-n"alkyl", "heteroaryl-C m-n "alkyl" and "cycloalkyl-C m-n "alkyl" are defined in the same manner.

[0149] "-C m-n "alkyl" substituted by -NRR" and "C m-n "alkyl" also refers to an -NRR" or -OR" group covalently linked to a C m-n alkylidene, wherein the group is attached to the rest of the molecule through a carbon atom in the alkylidene.

[0150] The term "aromatic" when applied to a substituent as a whole includes monocyclic or polycyclic systems having 4n + 2 electrons in the conjugated π-system within the ring or ring system, where all atoms contributing to the conjugated π-system are in the same plane.

[0151] The term "aryl" includes aromatic hydrocarbon ring systems. The ring system has 4n + 2 electrons in the conjugated π-system within the ring, where all atoms contributing to the conjugated π-system are in the same plane. For example, "aryl" can be phenyl and naphthyl. The aryl system itself can be substituted by other groups.

[0152] The term "heteroaryl" includes aromatic monocyclic or bicyclic rings containing one or more (e.g., 1 - 4, especially 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. The ring or ring system has 4n + 2 electrons in the conjugated π-system, where all atoms contributing to the conjugated π-system are in the same plane.

[0153] Examples of heteroaryl are monocyclic and bicyclic groups having 5 - 12 ring members, more usually 5 - 10 ring members. Heteroaryl can be, for example, 5 - or 6 - membered monocycles or 9 - or 10 - membered bicyclic rings, such as a bicyclic structure formed by fused 5 - and 6 - membered rings or two fused 6 - membered rings. Each ring can contain up to about 4 heteroatoms, usually selected from nitrogen, sulfur, and oxygen. Typically, the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, e.g., a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atom in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or substantially non - basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in the heteroaryl, including any amino substituents on the ring, will be less than five.

[0154] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, benzofuryl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzoisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furyl, 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 containing at least one nitrogen in the ring positions include pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl and pteridinyl. "Heteroaryl" also includes partially aromatic bicyclic or polycyclic systems where at least one ring is an aromatic ring and one or more other rings are non-aromatic, saturated or partially saturated rings provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of partially aromatic heteroaryl include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzothienyl, dihydrobenzofuryl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuryl, 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.

[0155] Examples of five-membered heteroaryl include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl.

[0156] Examples of six-membered heteroaryl include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0157] Specific examples of bicyclic heteroaryls containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, pyrrolopyridine, and pyrazolopyridyl.

[0158] Specific examples of bicyclic heteroaryls containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolinyl, benzoxazinyl, benzodiazinyl, pyridinopyridyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl.

[0159] As used herein, the term “oxo” or “=O” refers to an oxygen double-bonded to a carbon atom.

[0160] The term “optionally substituted” includes substituted and unsubstituted groups, structures, or molecules.

[0161] When an optional substituent is selected from “one or more” groups, it is understood that the definition includes all substituents selected from one designated group or substituents selected from two or more designated groups.

[0162] When a moiety is substituted, it can be substituted at any position of the moiety where it is chemically possible and valence requirements are met. The moiety can be substituted with one or more substituents, e.g., 1, 2, 3, or 4 substituents; optionally, 1 or 2 substituents on a group. In the case of two or more substituents, the substituents can be the same or different.

[0163] Substituents are present only at positions where they are chemically possible, and those skilled in the art can determine (experimentally or theoretically) which substitutions are chemically possible and which are not without undue effort.

[0164] Reference to the -NRR’ group forming a 4- to 6-membered heterocyclic group means that R and R’ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic group. For example, -NRR’ such as -NR X1 R X2 The group can form:

[0165]

[0166] Similarly, the -NRR’ group within a substituent can form a carbonyl-linked 4- to 6-membered heterocyclic group, e.g., the -C(O)NRR’ group can form:

[0167]

[0168] The -NRR' groups in substituents such as -OC(O)NRR', -SO2NRR' and -NRC(O)NRR' can similarly form 4- to 6-membered heterocyclic groups in these substituents.

[0169] The phrase "compounds of the invention" refers to those compounds disclosed herein, both generically and specifically. Thus, compounds of the invention include compounds of formula (I), (II), (III) or (IV) as well as the compounds in the Examples.

[0170] by A bond ending in ' or '*' indicates that the bond is attached to another atom not shown in the structure. A bond that ends inside a ring structure and does not end on an atom in the ring structure indicates that the bond may be attached to any atom in the ring structure if valence permits.

[0171] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all steps of any method or process so disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any foregoing embodiments. The invention extends to any novel one or any novel combination of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one or any novel combination of the steps of any method or process so disclosed.

[0172] The reader's attention is directed to all papers and documents related to the present application which are filed concurrently with or prior to the present specification, which are disclosed to the public with the present specification, and the contents of all these papers and documents are incorporated herein by reference.

[0173] The various functional groups and substituents making up the compounds of the 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, such as less than 700, or less than 650, or less than 600, or more preferably less than 550.

[0174] Suitable or preferred features of any compound of the invention may also be suitable features of any other aspect.

[0175] The present invention contemplates pharmaceutically acceptable salts of the compounds of the present invention. These can include acid addition salts and base salts of the compounds. These can be acid addition salts and base salts of the compounds.

[0176] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, edisylate, esylate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hippurate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 1,5-naphthalenedisulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, saccharate, stearate, succinate, tartrate, tosylate, and trifluoroacetate.

[0177] Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts. Hemisalts of acids and bases can also be formed, such as hemisulfates and hemicalcium salts. For a review of suitable salts, see “Handbook of Pharmaceutical Salts: Properties, Selection, and Use”, by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0178] Pharmaceutically acceptable salts of the compounds of the present invention can be prepared, for example, by one or more of the following methods:

[0179] (i) reacting a compound of the present invention with the desired acid or base;

[0180] (ii) removing an acid- or base-labile protecting group from a suitable precursor of the compound of the present invention, or by ring-opening of a suitable cyclic precursor such as a lactone or lactam with the desired acid or base; or

[0181] (iii) converting one salt of a compound of the present invention to another salt by reaction with a suitable acid or base or by passage through a suitable ion exchange column.

[0182] These methods are generally carried out in solution. The resulting salt can be precipitated and collected by filtration, or can be recovered by evaporation of the solvent. The degree of ionization of the resulting salt can range from fully ionized to almost non-ionized.

[0183] Compounds that have the same molecular formula, but differ in the nature or sequence of bonding of their atoms or in 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 "diastereoisomers", and stereoisomers whose mirror images do not overlap are called "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S- ranking rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light, and are designated as dextrorotatory or levorotatory (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal amounts of enantiomers is called a "racemic mixture". When the compounds of the present invention have two or more stereocenters, any combination of (R) and (S) stereoisomers is considered. Combinations of (R) and (S) stereoisomers can result in mixtures of diastereoisomers or a single diastereoisomer. The compounds of the present invention can exist in the form of a single stereoisomer or can be a mixture of stereoisomers, such as a racemic mixture and other enantiomeric mixtures, as well as mixtures of diastereoisomers. When the mixture is a mixture of enantiomers, the enantiomeric excess can be any of those disclosed above. When the compound is a single stereoisomer, the compound may still contain other diastereoisomers or enantiomers as impurities. Thus, a single stereoisomer does not necessarily have a 100% enantiomeric excess (e.e.) or diastereomeric excess (d.e.), but can have an e.e. or d.e. of at least about 85%, for example at least 90%, at least 95% or at least 99%.

[0184] The compounds of the present invention may have one or more asymmetric centers; thus, such compounds can be produced in the form of individual (R)- or (S)-stereoisomers or mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include its individual enantiomers and mixtures thereof, racemic or otherwise. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry", 4th Edition, J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of the racemic form. Some compounds of the present invention may have geometric isomeric centers (E- and Z-isomers). It is to be understood that the present invention encompasses all enantiomers, diastereomers and geometric isomers having MASTL inhibitory activity and mixtures thereof.

[0185] Z / E (e.g., cis / trans) isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0186] Conventional techniques for preparing / separating individual enantiomers, when necessary, include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). Thus, chiral compounds of the present invention (and their chiral precursors) can be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0 to 50% by volume of isopropanol, typically 2% to 20%, and for specific instances, containing 0 to 5% by volume of an alkylamine, such as 0.1% diethylamine. Concentration of the eluate provides an enriched mixture.

[0187] Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound, such as an alcohol, or, in the case where the compound of the present invention contains an acidic or basic moiety, with a base or acid such as 1-phenylethylamine or tartaric acid. The resulting mixture of diastereomers can be separated by chromatography and / or fractional crystallization, and one or both of the diastereomers can be converted to the corresponding pure enantiomers by methods well known to the skilled person.

[0188] When any racemate crystallizes, two different types of crystals are possible. The first type is the racemic compound (true racemate) mentioned above, in which a single uniform form of crystal is produced, containing equimolar amounts of the two enantiomers. The second type is a racemic mixture or conglomerate, in which two forms of crystals are produced in equimolar amounts, each crystal containing a single enantiomer.

[0189] Although the two crystal types present in a racemic mixture have the same physical properties, they may have different physical properties compared to a true racemate. Racemic mixtures can be separated by conventional techniques known to those skilled in the art, for example, see “Stereochemistry of Organic Compounds”, by E.L. Eliel and S.H. Wilen (Wiley, 1994).

[0190] The compounds and salts described in this specification may be isotopically labeled (or “radioactively labeled”). Thus, one or more atoms are replaced by atoms having an atomic weight or mass number different from the atomic weight or mass number typically found in nature. Examples of radionuclides that can be incorporated include 2 H (also written as “D” for deuterium), 3 H (also written as “T” for tritium), 11 C, 13 C, 14 C, 15 O, 17 O, 18 O, 13 N, 15 N, 18 F, 36 Cl, 123 I, 25 I, 32 P, 35 S, etc. The radionuclide used will depend on the specific application of the radiolabeled derivative. For example, for in vitro competitive assays, 3 H or 14 C are generally useful. For radioimaging applications, 11 C or 18 F are generally 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. In some embodiments, the radionuclide is 18 F.

[0191] Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described, using appropriate isotopically labeled reagents in place of the previously used non-labeled reagents.

[0192] The selective replacement of hydrogen by deuterium in a compound can modulate the metabolism of the compound, the PK / PD properties of the compound, and / or the toxicity of the compound. For example, deuteration can increase the half-life or decrease the clearance of the compound in the body. Deuteration can also inhibit the formation of toxic metabolites, thereby improving safety and tolerance. It should be understood that the present invention includes deuterated derivatives of the compounds of formula (I). As used herein, the term deuterated derivative refers to a compound of the present invention in which at least one hydrogen atom is replaced by deuterium at a specific position. For example, one or more hydrogen atoms in a C 1-4 -alkyl can be replaced by deuterium to form a deuterated C 1-4 -alkyl.

[0193] Certain compounds of the present invention can exist in solvated and non-solvated forms, such as hydrated forms. It should be understood that the present invention includes all such solvated forms having MASTL inhibitory activity.

[0194] It should also be understood that certain compounds of the present invention may exhibit polymorphism, and the present invention includes all such forms having MASTL inhibitory activity.

[0195] The compounds of the present invention can exist in many different tautomeric forms, and the mention of the compounds of the present invention includes all such forms. For the sake of clarity, when a compound can exist in one of several tautomeric forms and only one is specifically described or shown, all other forms are 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 (shown below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro.

[0196]

[0197] Amino-substituted triazines can exhibit hindered rotation around the SP2 carbon-N bond, resulting in diastereoisomers (closed rotamers) (Amm et al. (1998), Mag.Reson.Chem. 36 587-596). The mention of the compounds of the present invention includes all such closed rotamer forms of the compound.

[0198] The in vivo action of the compounds of the present invention can be exerted in part through one or more metabolites formed in a human or animal body after administration of the compounds of the present invention.

[0199] It should also be understood that suitable pharmaceutically acceptable prodrugs of the compounds of formula (I) also form an aspect of the present invention. Accordingly, the compounds of the present invention include prodrug forms of the compounds, and the compounds of the present invention may be administered in the form of a prodrug (i.e., a compound that releases the compound of the present invention in the human or animal body). Prodrugs can be used to modify the physical properties and / or pharmacokinetic properties of the compounds of the present invention. When the compounds of the present invention contain suitable groups or substituents, prodrugs can be formed, and the modifying groups can be attached to such groups or substituents. Examples of prodrugs include in vivo cleavable ester derivatives that can be formed at the carboxyl or hydroxyl groups of the compounds of the present invention, and in vivo cleavable amide derivatives that can be formed at the carboxyl or amino groups of the compounds of the present invention.

[0200] Accordingly, the present invention includes those compounds of the present invention as defined herein when obtained by organic synthesis and when obtained in the human or animal body by cleavage of their prodrugs. Accordingly, the present invention includes those compounds of formula (I) produced by organic synthesis methods, and also includes such compounds produced in the human or animal body by metabolism of precursor compounds, i.e., the compounds of formula (I) can be synthetically produced compounds or metabolically produced compounds.

[0201] Suitable pharmaceutically acceptable prodrugs of the compounds of the present invention are prodrugs based on sound medical judgment, which are suitable for administration to the human or animal body without undesirable pharmacological activity and excessive toxicity.

[0202] Various forms of prodrugs have been described, for example, in the following documents:

[0203] a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder et al. (Academic Press, 1985);

[0204] b) Design of Pro-drugs, edited by H. Bundgaard (Elsevier, 1985);

[0205] c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Pro-drugs", written by H. Bundgaard, p. 113-191 (1991);

[0206] d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

[0207] e) H. Bundgaard et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);

[0208] f) N. Kakeya et al., Chem. Pharm. Bull., 32, 692 (1984);

[0209] g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", A.C.S. Symposium Series, Volume 14; and

[0210] h) E. Roche (ed.), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

[0211] Suitable pharmaceutically acceptable prodrugs of the compounds of formula I having a carboxyl group are, for example, their in vivo cleavable esters. The in vivo cleavable esters of the compounds of the invention containing a carboxyl group are, for example, pharmaceutically acceptable esters which cleave in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters of the carboxyl group include C 1-6 alkyl esters (such as methyl ester, ethyl ester and tert-butyl ester), C 1-6 alkoxymethyl esters (such as methoxymethyl ester), C 1-6 alkanoyloxymethyl esters (such as pivaloyloxymethyl ester), 3-phthalidyl ester, C 3-8 cycloalkylcarbonyloxy-C 1-6 alkyl esters (such as cyclopentylcarbonyloxymethyl ester and 1-cyclohexylcarbonyloxyethyl ester), 2-oxo-1,3-dioxolene methyl esters (such as 5-methyl-2-oxo-1,3-dioxolene-4-yl methyl ester) and C 1-6 alkoxycarbonyloxy-C 1-6 alkyl esters (such as methoxycarbonyloxymethyl ester and 1-methoxycarbonyloxyethyl ester). Suitable pharmaceutically acceptable prodrugs of the compounds of the invention having a hydroxyl group are, for example, their in vivo cleavable esters or ethers. The in vivo cleavable esters or ethers of the compounds of the invention containing a hydroxyl group are, for example, pharmaceutically acceptable esters or ethers which cleave in the human or animal body to produce the parent hydroxyl compound. Suitable pharmaceutically acceptable ester-forming groups for the hydroxyl group include inorganic esters, such as phosphate esters (including aminophosphoric acid cyclic esters). Other suitable pharmaceutically acceptable ester-forming groups for the hydroxyl group include C 1-10 alkanoyl groups (such as acetyl group, benzoyl group, phenylacetyl group and substituted benzoyl groups and phenylacetyl groups), C 1-10Alkoxycarbonyl (such as ethoxycarbonyl), N,N-(C 1-6 alkyl)2-carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl. Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C 1-4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for the hydroxyl group include α-acyloxyalkyl, such as acetoxymethyl and pivaloyloxymethyl.

[0212] Suitable pharmaceutically acceptable prodrugs of the compounds of the invention having a carboxyl group are, for example, their in vivo cleavable amides, such as amides formed with amines, said amines such as ammonia, C 1-4 alkylamine (such as methylamine), (C 1-4 alkyl)2-amine (such as dimethylamine, N-ethyl-N-methylamine or diethylamine), C 1-4 alkoxy-C 2-4 alkylamine (such as 2-methoxyethylamine), phenyl-C 1-4 alkylamine (such as benzylamine) and amino acids (such as glycine) or their esters.

[0213] Suitable pharmaceutically acceptable prodrugs of the compounds of the invention having an amino group are, for example, their in vivo cleavable amide or carbamate derivatives. Suitable pharmaceutically acceptable amides from the amino group include, for example, amides formed by C 1-10 alkanoyl, said C 1-10 alkanoyl such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl. Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C 1-4 alkyl)piperazin-1-ylmethyl.

[0214] Suitable pharmaceutically acceptable carbamates from the amino group include, for example, acyloxyalkoxycarbonyl and benzyloxycarbonyl.

[0215] Compound

[0216] In some embodiments, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0217]

[0218] wherein the H ring bond in formula (I) is bonded to a carbon atom *1 or *2 on;

[0219] Z is -NR 1 R 2or -CN;

[0220] R 1 and R 2 are independently selected from: H, D, and C 1-6 alkyl;

[0221] wherein said C 1-6 alkyl is optionally partially or fully deuterated;

[0222] R 3 are each independently selected from: halogen, C 1-6 alkyl, and amino;

[0223] X1 is N and X2 is CR 4 , or X1 is C and X2 is NR 5 ;

[0224] X3 is CH or N;

[0225] R 4 is selected from: H, NR X1 R X2 、-OH, and C 1-6 alkyl;

[0226] R 5 is selected from: H and C 1-6 alkyl,

[0227] wherein R 4 or R 5 the C 1-6 alkyl on is optionally partially or fully deuterated;

[0228] L 1 is a bond or is selected from: NR 6 、O, and S;

[0229] R 6 is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, and C 3-6 cycloalkyl,

[0230] wherein said C 3-6 cycloalkyl is optionally substituted by one or more substituents selected from: =O, halogen, C 1-4 alkyl, and C 1-4 haloalkyl;

[0231] L 2 is a bond or -[CR 7 R 8 p-,

[0232] where p is an integer from 1 to 4;

[0233] R 7 and R8 Each independently selected from: H, C 1-4 alkyl and C 1-4 haloalkyl, OH, COOH, C(O)NR X1 R X2 and C 3-6 cycloalkyl, or R 7 and R 8 are attached to the same carbon atom on L 2 to form together a C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group,

[0234] wherein said C 1-4 alkyl is optionally substituted by: OH, O-C 1-4 alkyl, a 3- to 6-membered heterocyclic group, a 5- to 10-membered heteroaryl or a C 1-6 aryl optionally substituted by halogen or C 6-10 haloalkyl;

[0235] Q 1 selected from: C 3-12 cycloalkyl, C 3-12 cycloalkenyl, a 3- to 12-membered heterocyclic group, C 6-10 aryl and a 5- to 10-membered heteroaryl;

[0236] wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted by one or more R 9 substituents;

[0237] Each R 9 is independently selected from: 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(R10 ) 2;

[0238] wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are optionally substituted by one or more R 11 ; and

[0239] wherein each R 10 is independently selected from: H, C 1-6 alkyl, and C 1-6 haloalkyl;

[0240] wherein each R 11 is independently selected from: halogen, -CN, -NO2, C 1-4 alkyl, C 1-4 haloalkyl, and NR X1 R X2 ; wherein R X1 and R X2 are independently selected from: H, C 1-4 alkyl optionally substituted by OH or a 3- to 6-membered heterocyclic group, -OC 1-6 alkyl, -C(O)-C 1-6 alkyl, and 5- to 10-membered heteroaryl, or R X1 and R X2 are attached to the same nitrogen atom and together form a 3- to 6-membered heterocyclic group;

[0241] n is an integer from 0 to 4; and

[0242] x is an integer from 0 to 3;

[0243] wherein when R 4 or R 5 is H or an undehydrogenated C 1-6 alkyl, then

[0244] Z is -CN, or

[0245] -NR 1 R 2 wherein at least one of R 1 and R 2 is D or a partially or fully deuterated C 1-6 alkyl.

[0246] In some embodiments, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0247] wherein the H ring in formula (I) is bonded to a carbon atom *1 or *2 ;

[0248] Z is -NR 1 R2 or -CN;

[0249] R 1 and R 2 are each independently selected from: H, D, and C 1-6 alkyl;

[0250] wherein said C 1-6 alkyl is optionally partially or fully deuterated;

[0251] R 3 are each independently selected from: halogen, C 1-6 alkyl, and amino;

[0252] X1 is N and X2 is CR 4 , or X1 is C and X2 is NR 5 ;

[0253] X3 is CH or N;

[0254] R 4 is selected from: H, NR X1 R X2 、-OH, and C 1-6 alkyl;

[0255] R 5 is selected from: H and C 1-6 alkyl,

[0256] wherein R 4 or R 5 on the C 1-6 alkyl is optionally partially or fully deuterated;

[0257] L 1 is a bond or is selected from: NR 6 、O, and S;

[0258] R 6 is selected from H, C 1-4 alkyl, and C 1-4 haloalkyl;

[0259] L 2 is a bond or -[CR 7 R 8 p-,

[0260] where p is an integer from 1 to 4;

[0261] R 7 and R 8 are each independently selected from: H, C 1-4 alkyl, and C 1-4 haloalkyl, OH, COOH, C(O)NR X1 R X2 and C 3-6Cycloalkyl, or R 7 and R 8 are attached to the same carbon atom in L 2 to form, together, a C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group,

[0262] wherein said C 1-4 alkyl is optionally substituted by: OH, O-C 1-4 alkyl or C optionally substituted by halogen or C 1-6 haloalkyl-substituted C 6-10 aryl;

[0263] Q 1 is selected from: C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0264] wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted by one or more R 9 substituents;

[0265] Each R 9 is independently selected from: 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;

[0266] wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted by one or more R 11 substituents; and

[0267] wherein each R 10 is independently selected from: H, C 1-6 alkyl and C 1-6 haloalkyl;

[0268] wherein each R 11 is independently selected from: halogen, -CN, -NO2, C1-4 alkyl, C 1-4 haloalkyl, and NR X1 R X2 ; wherein R X1 and R X2 are independently selected from: H, C 1-4 alkyl optionally substituted with OH or a 3- to 6-membered heterocyclic group, -OC 1-6 alkyl, -C(O)-C 1-6 alkyl, and 5- to 10-membered heteroaryl, or R X1 and R X2 are attached to the same nitrogen atom and together form a 3- to 6-membered heterocyclic group;

[0269] n is an integer from 0 to 4; and

[0270] x is an integer from 0 to 3;

[0271] wherein when R 4 or R 5 is H or undeuterated C 1-6 alkyl, then

[0272] Z is -CN, or

[0273] -NR 1 R 2 wherein at least one of R 1 and R 2 is D or partially or fully deuterated C 1-6 alkyl.

[0274] In some embodiments, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0275] wherein the H ring in formula (I) is bonded to a carbon atom *1 or *2 ;

[0276] Z is -NR 1 R 2 or -CN;

[0277] R 1 and R 2 are independently selected from: H, D, and C 1-6 alkyl;

[0278] wherein the C 1-6 alkyl is optionally partially or fully deuterated;

[0279] R 3 are each independently selected from: halogen, C 1-6 alkyl, and amino;

[0280] X1 is N and X2 is CR 4or X1 is C and X2 is NR 5 ;

[0281] X3 is CH or N;

[0282] R 4 is selected from: H, NR X1 R X2 , -OH and C 1-6 alkyl;

[0283] R 5 is selected from: H and C 1-6 alkyl,

[0284] wherein R 4 or R 5 the C 1-6 alkyl is optionally partially or fully deuterated;

[0285] L 1 is a bond or is selected from: NR 6 , O and S;

[0286] R 6 is selected from H, C 1-4 alkyl and C 1-4 haloalkyl;

[0287] L 2 is a bond or -[CR 7 R 8 p-,

[0288] where p is an integer from 1 to 4;

[0289] R 7 and R 8 are each independently selected from: H, C 1-4 alkyl and C 1-4 haloalkyl, OH, COOH, C(O)NR X1 R X2 and C 3-6 cycloalkyl, or R 7 and R 8 are attached to the same carbon atom in L 2 to form C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group,

[0290] wherein the C 1-4 alkyl is optionally substituted with: OH, O-C 1-4 alkyl or C 1-6 aryl optionally substituted with halogen or C 6-10 haloalkyl;

[0291] Q 1 is selected from: C 3-12 cycloalkyl, C6-10 Aryl and 5- to 10-membered heteroaryl;

[0292] wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted by one or more R 9 substituents;

[0293] each R 9 is independently selected from: 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;

[0294] wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted by one or more R 11 substituents; and

[0295] wherein each R 10 is independently selected from: H, C 1-6 alkyl and C 1-6 haloalkyl;

[0296] wherein each R 11 is independently selected from: halogen, -CN, -NO2, C 1-4 alkyl, C 1-4 haloalkyl and NR X1 R X2 ; wherein R X1 and R X2 are independently selected from: H, C 1-4 alkyl optionally substituted by OH or a 3- to 6-membered heterocyclic group;

[0297] n is an integer from 0 to 4; and

[0298] x is an integer from 0 to 3;

[0299] wherein when R 4 or R 5 is H or an undehydrogenated C 1-6When the alkyl group is

[0300] Z is -CN, or

[0301] -NR 1 R 2 , where R 1 and R 2 at least one of which is D or a partially or fully deuterated C 1-6 alkyl group.

[0302] In some embodiments, there is provided a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0303]

[0304] wherein the H ring in formula (II) is bonded to a carbon atom *1 or *2 ;

[0305] R 1 and R 2 are independently selected from: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl;

[0306] R 3 each independently selected from: halogen, C 1-6 alkyl, and amino;

[0307] X1 is N and X2 is CR 4 , or X1 is C and X2 is NR 5 ;

[0308] X3 is CH or N;

[0309] R 4 and R 5 are independently selected from: H, halogen, CN, C 1-6 alkyl, and C 1-6 haloalkyl;

[0310] L 1 is a bond or selected from: NR 6 , O, and S;

[0311] R 6 is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, and C 3-6 cycloalkyl,

[0312] wherein the C 3-6 cycloalkyl is optionally substituted with one or more substituents selected from: =O, halogen, C 1-4Alkyl and C 1-4 haloalkyl;

[0313] L 2 is a bond or -[CR 7 R 8 p-;

[0314] p is an integer from 1 to 4;

[0315] R 7 and R 8 are each independently selected from: 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;

[0316] wherein at least one of the Rs in L 2 is not H, and 7 and R 8 in

[0317] said C 1-4 alkyl is substituted by 3- to 6-membered cycloalkyl, C 4-8 alkyl or NR X1 R X2 ;

[0318] Q 1 is selected from: C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3- to 12-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0319] wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted by one or more Rs 9 ;

[0320] each R 9 is independently selected from: 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)R10 、-NR 10 C(O)OR 10 、-C(O)N(R 10 )2、-OC(O)N(R 10 )2.-NR 10 S02R 10 、-SO2N(R 10 )2 and -NR 10 C(O)N(R 10 )2;

[0321] Wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 The haloalkyl group is optionally substituted with one or more R 11 Replace, and

[0322] Each R 10 Independently selected from: H, C 1-6 Alkyl and C 1-6 Haloalkyl;

[0323] Each R 11 Independently selected from: halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, NR X1 R X2 and C(O)NR X1 R X2 ; where R X1 and R X2 are independently selected from: H, C optionally substituted by OH or a 3 to 6 membered heterocyclic group 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 to the same nitrogen atom and together form a 3- to 6-membered heterocyclic group;

[0324] Where R X3 Selected from: OH and OC 1-6 alkyl;

[0325] n is an integer from 0 to 4; and

[0326] x is an integer from 0 to 3.

[0327] In some embodiments, a compound of formula (II) or a pharmaceutically acceptable salt thereof is provided:

[0328] Wherein the H ring in formula (II) is bonded to a carbon atom *1 or*2 above;

[0329] R 1 and R 2 are each independently selected from: H, C 1-6 alkyl and C 1-6 haloalkyl;

[0330] R 3 are each independently selected from: halogen, C 1-6 alkyl and amino;

[0331] X1 is N and X2 is CR 4 , or X1 is C and X2 is NR 5 ;

[0332] X3 is CH or N;

[0333] R 4 and R 5 are each independently selected from: H, halogen, CN, C 1-6 alkyl and C 1-6 haloalkyl;

[0334] L 1 is a bond or is selected from: NR 6 , O and S;

[0335] R 6 is selected from H, C 1-4 alkyl and C 1-4 haloalkyl;

[0336] L 2 is a bond or -[CR 7 R 8 p-;

[0337] wherein p is an integer from 1 to 4;

[0338] R 7 and R 8 are each independently selected from: 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;

[0339] wherein at least one of the R 2 in L 7 and the R 8 in is not H; and

[0340] the C 1-4 alkyl is substituted by 3- to 6-membered cycloalkyl, C4-8 alkyl or NR X1 R X2 substituted;

[0341] Q 1 selected from: C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0342] wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted by one or more R 9 substituted;

[0343] each R 9 is independently selected from: 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,

[0344] wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl are optionally substituted by one or more R 11 substituted, and

[0345] wherein each R 10 is independently selected from: H, C 1-6 alkyl and C 1-6 haloalkyl;

[0346] wherein each R 11 is independently selected from: halogen, -CN, -NO2, C 1-4 alkyl, C 1-4 haloalkyl, NR X1 R X2 and C(O)NR X1 R X2 ; wherein R X1 and R X2Independently selected from: H, C optionally substituted with OH or a 3- to 6-membered heterocyclic group 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 to the same nitrogen atom and together form a 3- to 6-membered heterocyclic group;

[0347] wherein R X3 is selected from: OH and O-C 1-6 alkyl;

[0348] n is an integer from 0 to 4; and

[0349] x is an integer from 0 to 3.

[0350] In some embodiments, there is provided a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0351] wherein the H ring in formula (II) is bonded to a carbon atom *1 or *2 ;

[0352] R 1 and R 2 are independently selected from: H, C 1-6 alkyl and C 1-6 haloalkyl;

[0353] R 3 are each independently selected from: halogen, C 1-6 alkyl and amino;

[0354] X1 is N and X2 is CR 4 , or X1 is C and X2 is NR 5 ;

[0355] X3 is CH or N;

[0356] R 4 and R 5 are independently selected from: H, halogen, CN, C 1-6 alkyl and C 1-6 haloalkyl;

[0357] L 1 is a bond or selected from: NR 6 , O and S;

[0358] R 6 is selected from H, C 1-4 alkyl and C 1-4 haloalkyl;

[0359] L 2 is a bond or -[CR7 R 8 p-;

[0360] where p is an integer from 1 to 4;

[0361] R 7 and R 8 are each independently selected from: 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;

[0362] wherein at least one of the R 2 in L 7 and the R 8 in is not H; and

[0363] the C 1-4 alkyl is substituted with a 3- to 6-membered cycloalkyl, C 4-8 alkyl or NR X1 R X2 ;

[0364] Q 1 is selected from: C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0365] wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more R 9 ;

[0366] each R 9 is independently selected from: 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,

[0367] wherein the C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and C 1-6 Haloalkyl is optionally substituted by one or more R 11 substituents, and

[0368] wherein each R 10 is independently selected from: H, C 1-6 alkyl, and C 1-6 haloalkyl;

[0369] wherein each R 11 is independently selected from: halogen, -CN, -NO2, C 1-4 alkyl, C 1-4 haloalkyl, NR X1 R X2 and C(O)NR X1 R X2 ; where R X1 and R X2 are independently selected from: H, C 1-4 alkyl optionally substituted by OH or a 3- to 6-membered heterocyclic group, OH, -OC 1-6 alkyl, and -C(O)-C 1-6 alkyl;

[0370] wherein R X3 is selected from: OH and O-C 1-6 alkyl;

[0371] n is an integer from 0 to 4; and

[0372] x is an integer from 0 to 3.

[0373] In some preferred embodiments, the compounds of formula (II) may not include

[0374] In some embodiments, there is provided a compound of formula (III) or a pharmaceutically acceptable salt thereof:

[0375]

[0376] wherein the H ring in formula (III) is bonded to a carbon atom *1 or *2 ;

[0377] R 1 and R 2 are independently selected from: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl;

[0378] R 3 are each independently selected from: halogen, C 1-6 alkyl, and amino;

[0379] X1 is N and X2 is CR 4 , or X1 is C and X2 is NR 5 ;

[0380] X3 is CH or N;

[0381] R 4 and R 5 are independently selected from: H, halogen, CN, C 1-6 alkyl, and C 1-6 haloalkyl;

[0382] L 1 is a bond or is selected from: NR 6 , O, and S;

[0383] R 6 is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, and C 3-6 cycloalkyl,

[0384] wherein the C 1-4 alkyl is optionally partially or fully deuterated;

[0385] wherein 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;

[0386] L 2 is a bond or -[CR 7 R 8 p-,

[0387] where p is an integer from 1 to 4;

[0388] R 7 and R 8 are each independently selected from: H, C 1-4 alkyl, and C 1-4 haloalkyl, OH, COOH, C(O)NR X1 R X2 and C 3-6 cycloalkyl, or R 7 and R 8 are attached to the same carbon atom in L 2 to form a C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group,

[0389] wherein the C1-4 The alkyl group is optionally substituted with: OH, O-C 1-4 alkyl group, 3- to 6-membered heterocyclic group, 5- to 10-membered heteroaryl group, or C 1-6 aryl group substituted with haloalkyl; 6-10 aryl group;

[0390] Q 1 selected from C 6-10 aryl group and 5- to 10-membered heteroaryl group;

[0391] wherein the C 6-10 aryl group and 5- to 10-membered heteroaryl group are optionally substituted with one or more R 9 substituents;

[0392] Each R 9 is independently selected from: halogen, -CN, -NO2, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 haloalkyl group, C3-C6 cycloalkyl group, 5- to 10-membered heterocyclic group, 5- to 10-membered heteroaryl group, -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,

[0393] wherein the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C3-C6 cycloalkyl group, 5- to 10-membered heterocyclic group and 5- to 10-membered heteroaryl group are optionally substituted with one or more R 11 substituents,

[0394] wherein the C 1-6 alkyl group is optionally partially or fully deuterated;

[0395] wherein each R 10 is independently selected from: H, C1-6 alkyl and C 1-6 haloalkyl;

[0396] wherein each R 11 is independently selected from: halogen, -CN, -NO2, C 1-4 alkyl, C 1-4 haloalkyl and NR X1 R X2 ;

[0397] wherein R X1 and R X2 are independently selected from: H, C 1-4 alkyl optionally substituted with OH or a 3- to 6-membered heterocyclic group, -OC 1-6 alkyl, -C(O)-C 1-6 alkyl and 5- to 10-membered heteroaryl, or R X1 and R X2 are attached to the same nitrogen atom and together form a 3- to 6-membered heterocyclic group; and

[0398] n is an integer from 0 to 4; and

[0399] x is an integer from 0 to 3;

[0400] wherein when Q 1 is not substituted by one or more R 9 s, or

[0401] when any one of the one or more R 1 s on Q 9 is not C3-C6 cycloalkyl, 5- to 10-membered heterocyclic group, 5- to 10-membered heteroaryl or partially or fully deuterated C 1-6 alkyl, then

[0402] R 6 is partially or fully deuterated C 1-4 alkyl.

[0403] In some embodiments, there is provided a compound of formula (III) or a pharmaceutically acceptable salt thereof:

[0404] wherein the H ring in formula (III) is bonded to a carbon atom *1 or *2 ;

[0405] R 1 and R 2 are independently selected from: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl;

[0406] R 3Each independently selected from: halogen, C 1-6 alkyl and amino;

[0407] X1 is N and X2 is CR 4 or X1 is C and X2 is NR 5 ;

[0408] X3 is CH or N;

[0409] R 4 and R 5 are independently selected from: H, halogen, CN, C 1-6 alkyl and C 1-6 haloalkyl;

[0410] L 1 is a bond or NR 6 ;

[0411] R 6 is selected from H, C 1-4 alkyl and C 1-4 haloalkyl,

[0412] wherein the C 1-4 alkyl is optionally partially or fully deuterated;

[0413] L 2 is a bond or -[CR 7 R 8 p-,

[0414] where p is an integer from 1 to 4;

[0415] R 7 and R 8 are each independently selected from: H, C 1-4 alkyl and C 1-4 haloalkyl, OH, COOH, C(O)NR X1 R X2 and C 3-6 cycloalkyl, or R 7 and R 8 are attached to the same carbon atom in L 2 to form C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group,

[0416] wherein the C 1-4 alkyl is optionally substituted by: OH, O-C 1-4 alkyl or C 1-6 aryl optionally substituted by halogen or C 6-10 haloalkyl;

[0417] Q 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl;

[0418] wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted by one or more R 9 substituents;

[0419] each R 9 is independently selected from: 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 heterocyclic group, 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,

[0420] wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclic group and 5- to 10-membered heteroaryl are optionally substituted by one or more R 11 substituents,

[0421] wherein said C 1-6 alkyl is optionally partially or fully deuterated;

[0422] wherein each R 10 is independently selected from: H, C 1-6 alkyl and C 1-6 haloalkyl;

[0423] wherein each R 11 is independently selected from: halogen, -CN, -NO2, C 1-4 alkyl, C 1-4 haloalkyl and NR X1 R X2 ;

[0424] wherein R X1 and R X2 are independently selected from: H, C 1-4 alkyl optionally substituted by OH or a 3- to 6-membered heterocyclic group, -OC 1-6 alkyl, -C(O)-C 1-6An alkyl group and a 5- to 10-membered heteroaryl group, or R X1 and R X2 are attached to the same nitrogen atom and together form a 3- to 6-membered heterocyclic group; and

[0425] n is an integer from 0 to 4; and

[0426] x is an integer from 0 to 3;

[0427] wherein when Q 1 is not substituted by one or more R 9 or

[0428] when one or more of the R 1 on Q 9 is not a C3-C6 cycloalkyl group, a 5- to 10-membered heterocyclic group, a 5- to 10-membered heteroaryl group or a partially or fully deuterated C 1-6 alkyl group, then

[0429] R 6 is a partially or fully deuterated C 1-4 alkyl group.

[0430] In some embodiments, there is provided a compound of formula (III) or a pharmaceutically acceptable salt thereof:

[0431] wherein the H ring bond in formula (III) is bonded to a carbon atom *1 or *2 ;

[0432] R 1 and R 2 are independently selected from: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl;

[0433] R 3 are each independently selected from: halogen, C 1-6 alkyl and amino;

[0434] X1 is N and X2 is CR 4 or X1 is C and X2 is NR 5 ;

[0435] X3 is CH or N;

[0436] R 4 and R 5 are independently selected from: H, halogen, CN, C 1-6 alkyl and C 1-6 haloalkyl;

[0437] L 1 is a bond or NR6 ;

[0438] R 6 is selected from H, C 1-4 alkyl and C 1-4 haloalkyl,

[0439] wherein said C 1-4 alkyl is optionally partially or fully deuterated;

[0440] L 2 is a bond or -[CR 7 R 8 p-,

[0441] where p is an integer from 1 to 4;

[0442] R 7 and R 8 are each independently selected from: H, C 1-4 alkyl and C 1-4 haloalkyl, OH, COOH, C(O)NR X1 R X2 and C 3-6 cycloalkyl, or R 7 and R 8 are attached to the same carbon atom in L 2 to form C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group,

[0443] wherein said C 1-4 alkyl is optionally substituted with: OH, O-C 1-4 alkyl or C optionally substituted with halogen or C 1-6 haloalkyl-substituted C 6-10 aryl;

[0444] Q 1 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl;

[0445] wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more R 9 substituents;

[0446] Each R 9 is independently selected from: 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 heterocyclic group, 5- to 10-membered heteroaryl, -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,

[0447] wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclic group, and 5- to 10-membered heteroaryl are optionally substituted with one or more R 11 substituents,

[0448] wherein said C 1-6 alkyl is optionally partially or fully deuterated;

[0449] wherein each R 10 is independently selected from: H, C 1-6 alkyl, and C 1-6 haloalkyl;

[0450] wherein each R 11 is independently selected from: halogen, -CN, -NO2, C 1-4 alkyl, C 1-4 haloalkyl, and NR X1 R X2 ;

[0451] wherein R X1 and R X2 are independently selected from: H, C 1-4 alkyl optionally substituted with OH or a 3- to 6-membered heterocyclic group; and

[0452] n is an integer from 0 to 4; and

[0453] x is an integer from 0 to 3;

[0454] wherein when Q 1 is not substituted with one or more R 9 substituents, or

[0455] when any one of the one or more R 1 substituents on Q 9 is not C3-C6 cycloalkyl, 5- to 10-membered heterocyclic group, 5- to 10-membered heteroaryl, or partially or fully deuterated C 1-6 alkyl, then

[0456] R 6 is partially or fully deuterated C 1-4 alkyl.

[0457] In some embodiments, a compound of formula (IV) or a pharmaceutically acceptable salt thereof is provided:

[0458]

[0459] wherein R 1 and R 2 are independently selected from: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl;

[0460] R 3 are each independently selected from: halogen, C 1-6 alkyl, and amino;

[0461] X1 is N and X2 is CR 4 , or X1 is C and X2 is NR 5 ;

[0462] X3 is CH or N;

[0463] R 4 、R 5 and R 12 are independently selected from: H, halogen, CN, C 1-6 alkyl, and C 1-6 haloalkyl;

[0464] wherein when X1 is N, then

[0465] X4 is N and X5 is CH, or X4 is CH and X5 is N; and

[0466] wherein when X1 is C, then X4 and X5 are both CH;

[0467] wherein the C 4 or C 5 alkyl on R 1-6 is optionally partially or fully deuterated;

[0468] L 1 is a bond or is selected from: NR 6 、O, and S,

[0469] R 6 is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, and C 3-6 cycloalkyl,

[0470] wherein the C 3-6 cycloalkyl is optionally substituted with one or more substituents selected from: ═O, halogen, C 1-4 alkyl, and C1-4 Halogenated alkyl;

[0471] L 2 is a bond or -[CR 7 R 8 p-,

[0472] wherein p is an integer from 1 to 4;

[0473] R 7 and R 8 are each independently selected from: H, C 1-4 alkyl and C 1-4 halogenated alkyl, OH, COOH, C(O)NR X1 R X2 and C 3-6 cycloalkyl, or R 7 and R 8 are attached to the same carbon atom in L 2 to form together C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group,

[0474] wherein the C 1-4 alkyl is optionally substituted by: OH, O-C 1-4 alkyl, a 3- to 6-membered heterocyclic group, a 5- to 10-membered heteroaryl or a C 1-6 halogenated alkyl-substituted C 6-10 aryl;

[0475] Q 1 is selected from C 3-12 cycloalkyl, C 3-12 cycloalkenyl, a 3- to 12-membered heterocyclic group, C 6-10 aryl and a 5- to 10-membered heteroaryl;

[0476] wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted by one or more R 9 substituents;

[0477] Each R 9 is independently selected from: halogen, -CN, -NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenated alkyl, -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)R10 、-NR 10 C(O)OR 10 、-C(O)N(R 10 )2、-OC(O)N(R 10 )2.-NR 10 S02R 10 、-SO2N(R 10 )2 and -NR 10 C(O)N(R 10 )2,

[0478] Wherein C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 The alkynyl group is optionally substituted with one or more R 11 replace,

[0479] Each R 10 Independently selected from: H, C 1-6 Alkyl and C 1-6 Haloalkyl;

[0480] Each R 11 Independently selected from: halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl and NR X1 R X2 ;

[0481] Where R X1 and R X2 are independently selected from: H, C optionally substituted by OH or a 3 to 6 membered heterocyclic group 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 to the same nitrogen atom and together form a 3- to 6-membered heterocyclic group;

[0482] n is an integer from 0 to 4; and

[0483] x is an integer from 0 to 3.

[0484] In some embodiments, a compound of formula (IV) or a pharmaceutically acceptable salt thereof is provided:

[0485] Where R 1 and R 2 Independently selected from: H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Haloalkyl;

[0486] R 3 are each independently selected from: halogen, C 1-6 alkyl, and amino;

[0487] X1 is N and X2 is CR 4 , or X1 is C and X2 is NR 5 ;

[0488] X3 is CH or N;

[0489] R 4 , R 5 and R 12 are independently selected from: H, halogen, CN, C 1-6 alkyl, and C 1-6 haloalkyl;

[0490] wherein when X1 is N, then

[0491] X4 is N and X5 is CH, or X4 is CH and X5 is N; and

[0492] wherein when X1 is C, then X4 and X5 are both CH;

[0493] wherein R 4 or R 5 the C 1-6 alkyl on is optionally partially or fully deuterated;

[0494] L 1 is a bond or NR 6 ,

[0495] R 6 is selected from H, C 1-4 alkyl, and C 1-4 haloalkyl;

[0496] L 2 is a bond or -[CR 7 R 8 p-,

[0497] where p is an integer from 1 to 4;

[0498] R 7 and R 8 are each independently selected from: H, C 1-4 alkyl, and C 1-4 haloalkyl, OH, COOH, C(O)NR X1 R X2 and C 3-6 cycloalkyl, or R 7 and R 8 are attached to the same carbon atom in L 2 to form C 3-6cycloalkyl or 3- to 6-membered heterocyclic group,

[0499] wherein said C 1-4 alkyl is optionally substituted with: OH, O-C 1-4 alkyl or C 1-6 aryl optionally substituted with halogen or C 6-10 haloalkyl;

[0500] Q 1 is selected from C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0501] wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more R 9 substituents;

[0502] each R 9 is independently selected from: 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,

[0503] wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted with one or more R 11 substituents,

[0504] wherein each R 10 is independently selected from: H, C 1-6 alkyl and C 1-6 haloalkyl;

[0505] wherein each R 11 is independently selected from: halogen, -CN, -NO2, C 1-4 alkyl, C 1-4 haloalkyl and NR X1 R X2 ;

[0506] Where R X1 and R X2 are independently selected from: H, C optionally substituted by OH or a 3 to 6 membered heterocyclic group 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 to the same nitrogen atom and together form a 3- to 6-membered heterocyclic group;

[0507] n is an integer from 0 to 4; and

[0508] x is an integer from 0 to 3.

[0509] In some embodiments, a compound of formula (IV) or a pharmaceutically acceptable salt thereof is provided:

[0510] Where R 1 and R 2 Independently selected from: H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Haloalkyl;

[0511] R 3 Each independently selected from: halogen, C 1-6 Alkyl and amino groups;

[0512] X1 is N and X2 is CR 4 , or X1 is C and X2 is NR 5 ;

[0513] X3 is CH or N;

[0514] R 4 , R 5 and R 12 Independently selected from: H, halogen, CN, C 1-6 Alkyl and C 1-6 Haloalkyl;

[0515] When X1 is N, then

[0516] X4 is N and X5 is CH, or X4 is CH and X5 is N; and

[0517] When X1 is C, then X4 and X5 are both CH;

[0518] Where R 4 or R 5 On the C 1-6 The alkyl group is optionally partially or fully deuterated;

[0519] L1 is a bond or NR 6 ,

[0520] R 6 is selected from H, C 1-4 alkyl and C 1-4 haloalkyl;

[0521] L 2 is a bond or -[CR 7 R 8 p-,

[0522] wherein p is an integer from 1 to 4;

[0523] R 7 and R 8 are each independently selected from: H, C 1-4 alkyl and C 1-4 haloalkyl, OH, COOH, C(O)NR X1 R X2 and C 3-6 cycloalkyl, or R 7 and R 8 are attached to the same carbon atom in L 2 to form together a C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group,

[0524] wherein the C 1-4 alkyl is optionally substituted by: OH, O-C 1-4 alkyl or C optionally substituted by halogen or C 1-6 haloalkyl-substituted C 6-10 aryl;

[0525] Q 1 is selected from C 3-12 cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl;

[0526] wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted by one or more R 9 substituents;

[0527] Each R 9 is independently selected from: 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 , -NR10 C(O)R 10 、 -NR 10 C(O)OR 10 、 -C(O)N(R 10 )2 and -OC(O)N(R 10 )2,

[0528] wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted by one or more R 11 substituents,

[0529] wherein each R 10 is independently selected from: H, C 1-6 alkyl and C 1-6 haloalkyl;

[0530] wherein each R 11 is independently selected from: halogen, -CN, -NO2, C 1-4 alkyl, C 1-4 haloalkyl and NR X1 R X2 ;

[0531] wherein R X1 and R X2 are independently selected from: H, C 1-4 alkyl optionally substituted by OH or a 3 - to 6 - membered heterocyclic group;

[0532] n is an integer from 0 to 4; and

[0533] x is an integer from 0 to 3.

[0534] In some preferred embodiments, the compounds of formula (IV) may not include

[0535] the compounds of formula (I), (II) or (III) may be selected from any of the following structures:

[0536]

[0537] In some preferred embodiments, the group in the compounds of formula (IV) may be selected from any of the following structures:

[0538]

[0539] In some preferred embodiments, the group It may be selected from any one of the following structures:

[0540]

[0541] In some preferred embodiments, the group -L in the compounds of formula (I), (II), (III) or (IV) 1 -L 2 -Q 1 may be selected from any one of the following structures:

[0542]

[0543]

[0544]

[0545]

[0546] In another embodiment, there is provided a compound selected from any one of Compound Nos. 1-239 listed in Table 1 herein, or a pharmaceutically acceptable salt or prodrug thereof.

[0547] [Table 1]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559] Pharmaceutical composition

[0560] According to 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.

[0561] Conventional methods for selecting and preparing suitable pharmaceutical compositions are described, for example, in “Pharmaceuticals - The Science of Dosage Form Designs”, M.E. Aulton, Churchill Livingstone, 1988.

[0562] The compositions of the present invention can be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), in a form suitable for topical use (e.g., as creams, ointments, gels or aqueous or oily solutions or suspensions), in a form suitable for administration by inhalation (e.g., as fine powders or liquid aerosols), in a form suitable for administration by insufflation (e.g., as fine powders) or in a form suitable for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular or intraperitoneal administration, or as suppositories for rectal administration).

[0563] The compositions of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions for oral use can contain, for example, one or more colorants, sweeteners, flavorants and / or preservatives.

[0564] An effective amount of the compounds of the present invention for treating a condition is an amount sufficient to alleviate the symptoms of the condition or slow the progression of the condition in warm - blooded animals, particularly humans, for the condition in question.

[0565] The amount of the active ingredient combined with one or more excipients to produce a single dosage form must vary depending on the host to be treated and the particular route of administration. For example, a preparation for oral administration to humans typically contains, for example, from 0.1 mg to 0.5 g (more suitably from 0.5 to 100 mg, e.g., 1 to 30 mg) of the active agent, together with a suitable and convenient amount of excipients, the amount of excipients being from about 5% to about 98% of the total weight of the composition.

[0566] In accordance with well - known medical principles, the dosage size of the compounds of the present invention for therapeutic or prophylactic purposes will naturally vary according to the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0567] When the compounds of the present invention are used for therapeutic or prophylactic purposes, the daily dose range typically administered is, for example, a daily dose of 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 body weight, administered in divided doses if necessary. Generally, when the parenteral route is employed, a lower dose will be administered. Thus, for example, for intravenous, subcutaneous, intramuscular or intraperitoneal administration, the dose range typically used is, for example, from 0.1 mg / kg to 30 mg / kg body weight. In certain embodiments, the compounds of the present invention are administered intravenously at a daily dose of, for example, from 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, for example, at about 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 will be used. Suitably, the compounds of the present invention are administered orally, for example, in the form of tablets or capsules. The daily oral dose can 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. Generally, the unit dosage form will contain from about 0.5 mg to 0.5 g of the compound of the present invention. In one specific embodiment, the compound of the present invention is administered parenterally, for example, by intravenous administration. In another specific embodiment, the compound of the present invention is administered orally.

[0568] Therapeutic uses and applications

[0569] According to another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use as a medicament.

[0570] Another aspect of the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for the treatment of diseases or medical conditions mediated by microtubule-associated serine / threonine-like kinase (MASTL).

[0571] Another aspect of the present invention further provides a compound of the present invention or a pharmaceutically acceptable salt thereof for the treatment of diseases in which PD-L1 expression is interferon-dependent.

[0572] CN 116942819 discloses the use of MASTL inhibitors in the preparation of a medicament for treating tumors in which PD-L1 expression is interferon-dependent. MASTL Kinase Inhibitor-1 (MKI-1) has a significant inhibitory effect on the upregulation of interferon-induced PD-L1 expression (breast cancer MDA-MB-468 cells), and can effectively enhance the anti-tumor function of T cells; while it is unlikely to affect the expression of tumor cells (breast cancer MDA-MB-231 cells) with high-level PD-L1 expression and not affected by interferon.

[0573] In some embodiments, the disease in which PD-L1 expression is interferon-dependent is a proliferative disease. In some embodiments, the proliferative disease is cancer, optionally, wherein the cancer is selected from: breast cancer, ovarian cancer, lung cancer, colorectal cancer, prostate cancer, oral cancer, gastric cancer, adrenocortical cancer, pancreatic cancer, kidney cancer, sarcoma, liver cancer, endometrial cancer, thyroid cancer, head and neck cancer, brain cancer (such as glioma), melanoma (such as uveal melanoma) and blood cancers (such as leukemia such as AML, lymphoma, myeloma and multiple myeloma).

[0574] Also provided is the use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease or medical condition mediated by MASTL.

[0575] 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 present invention or a pharmaceutically acceptable salt thereof.

[0576] In the following parts of the present application, reference is made to a compound of the present invention or a pharmaceutically acceptable salt thereof for treating certain diseases or medical conditions. It should be understood that the compounds mentioned herein for specific uses are also intended to refer to (i) the use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating the disease or medical condition; and (ii) a method for treating the disease or medical condition in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0577] The disease or medical condition mediated by MASTL can be any disease or medical condition listed in the present application, such as a proliferative disease, especially cancer.

[0578] The subject to which the compound of the present invention is administered can be a warm-blooded mammal, such as a human or an animal. In a specific embodiment, the subject or patient is a human. In other embodiments, the subject is an animal, such as a rat, a mouse, a dog, a cat, a primate or a horse.

[0579] The association of MASTL with human and animal diseases has been described in the background of the present invention. The present disclosure and related references provide further support for the therapeutic use of the compounds of the present invention. Accordingly, the supporting references that link MASTL to diseases and conditions also form part of the disclosure of the use of the compounds of the present invention in the treatment and prevention of the medical conditions described herein.

[0580] Proliferative diseases

[0581] MASTL has been shown to play a role in many diseases, including various cancers, and there is increasing 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 a therapeutic combination of MASTL inhibitors with radiotherapy (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 found 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 non-toxic.

[0582] In certain embodiments, the compounds of the present invention are used for the treatment of proliferative diseases, including cancer and benign proliferative diseases.

[0583] Cancer

[0584] In certain embodiments, the compounds of the present invention are used to prevent or inhibit cancer progression, for example, by preventing or inhibiting cancer cell migration, cancer cell invasion, and / or preventing or inhibiting cancer metastasis.

[0585] In certain embodiments, the compounds of the present invention are used for the treatment of cancer.

[0586] In certain embodiments, the compounds of the invention are used to treat cancers overexpressing MASTL. The compounds of the invention can be used for treatment and / or prevention, for example:

[0587] Cancer , including, for example, tumors derived from stratified squamous epithelium (squamous cell carcinoma) and tumors occurring in organs or glands (adenocarcinoma). Examples include breast cancer, colon cancer, lung cancer, prostate cancer, ovarian cancer, esophageal cancer (including but not limited to esophageal adenocarcinoma and squamous cell carcinoma), basal-like breast cancer, basal cell carcinoma (a type of skin cancer), squamous cell carcinoma (of various tissues), head and neck cancer (including but not limited to squamous cell carcinoma), gastric cancer (including but not limited to gastric adenocarcinoma, gastrointestinal stromal tumor), signet ring cell carcinoma, bladder cancer (including transitional cell carcinoma (a type of bladder malignancy)), bronchial carcinoma, colorectal cancer (including but not limited to colon cancer and rectal cancer), anal cancer, gastric cancer, lung cancer (including but not limited to small cell lung cancer and non-small cell lung cancer, lung adenocarcinoma, squamous cell carcinoma, large cell carcinoma, bronchioloalveolar 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 cancer, clear cell carcinoma, mucinous carcinoma), ovarian cancer (including but not limited to ovarian epithelial or surface epithelial stromal tumors, including serous tumors, endometrioid tumors, and mucinous cystadenocarcinoma, sex cord-stromal tumors), liver and bile duct cancer (including but not limited to hepatocellular carcinoma, cholangiocarcinoma, and hemangioma), prostate cancer, adenocarcinoma, brain tumors (including but not limited to glioma, glioblastoma, and medulloblastoma), germ cell tumor, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, kidney cancer (including but not limited to renal cell carcinoma, clear cell carcinoma, and Wilms tumor), medullary carcinoma, ductal carcinoma in situ or cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, cervical cancer, uterine cancer (including but not limited to endometrial adenocarcinoma, uterine papillary serous carcinoma, uterine clear cell carcinoma, uterine sarcoma, and leiomyosarcoma, Mullerian mixed tumor), testicular cancer, osteogenic carcinoma, epithelial cell carcinoma, sarcomatoid carcinoma, nasopharyngeal carcinoma, laryngeal cancer; oral and oropharyngeal squamous cell carcinoma;

[0588] Sarcoma , including: osteosarcoma and osteogenic sarcoma (bone); chondrosarcoma (cartilage); leiomyosarcoma (smooth muscle); rhabdomyosarcoma (skeletal muscle); mesotheliosarcoma and mesothelioma (inner layer of the body cavity membrane); fibrosarcoma (fibrous tissue); angiosarcoma and hemangioendothelioma (blood vessels); liposarcoma (adipose tissue); glioma and astrocytoma (neurogenic connective tissue found in the brain); myxosarcoma (primitive embryonic connective tissue); chordoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, Ewing sarcoma, mesenchymal and mixed mesodermal tumors (mixed connective tissue types), and other soft tissue sarcomas;

[0589] Solid tumors of the nervous system , including medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, and schwannoma;

[0590] Melanoma, uveal melanoma, and retinoblastoma;

[0591] Myeloma and multiple myeloma , including light chain myeloma, non-secretory myeloma, plasmacytoma, amyloidosis, smoldering multiple myeloma (SMM), immunoglobulin D myeloma, immunoglobulin E myeloma, and myeloma-related conditions, including monoclonal gammopathy of undetermined significance (MGUS);

[0592] Hematopoietic system tumors , including: myeloid and granulocytic leukemia (malignant tumors of the myeloid and granulocytic white blood cell series, such as acute myeloid leukemia (AML)); lymphoid, lymphocytic, and lymphoblastic leukemia (malignant tumors of the lymphoid and lymphocytic blood cell series); polycythemia vera and erythrocytosis (malignant tumors of various blood cell products, but predominantly red blood cells); myelofibrosis; and

[0593] Lymphoma , including: Hodgkin lymphoma and non-Hodgkin lymphoma.

[0594] In some embodiments, the compounds of the present invention or their pharmaceutically acceptable salts are used for the treatment of solid tumors, such as any of the solid tumors listed above.

[0595] In certain embodiments, the compounds of the present invention are used for the treatment of cancers selected from: breast cancer, ovarian cancer, lung cancer, colorectal cancer, prostate cancer, oral cancer, gastric cancer, adrenocortical cancer, pancreatic cancer, kidney cancer, sarcoma, liver cancer, endometrial cancer, thyroid cancer, head and neck cancer, brain cancer (such as glioma), melanoma (such as uveal melanoma), and blood cancers (such as leukemia like AML, lymphoma, myeloma, and multiple myeloma).

[0596] In another embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof are used for the treatment of breast cancer selected from: Luminal A breast cancer (hormone receptor positive (estrogen receptor and / or progesterone receptor positive), HER2 negative and low levels of the protein Ki-67); Luminal B breast cancer (hormone receptor positive (estrogen receptor and / or progesterone receptor positive), HER2 positive or HER2 negative, and having high levels of Ki-67); triple negative breast cancer (i.e., the tumor is estrogen receptor negative, progesterone receptor negative and HER2 negative); HER2 positive breast cancer or normal-like breast cancer (classified as defined in Table 1 of Dai et al., Am. J. Cancer Res. 2015; 5(10):2929-2943).

[0597] In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof are used for the treatment of cancers 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.

[0598] In an embodiment, the compounds of the invention provide an anti-cancer effect on cancers (such as any of the cancers disclosed herein), said anti-cancer effect being selected from one or more of anti-proliferative effect, pro-apoptotic effect, anti-mitotic effect, anti-angiogenic effect, inhibition of cell migration, inhibition or prevention of tumor invasion and / or prevention or inhibition of metastasis.

[0599] The compounds of the invention can be used for preventing or inhibiting the progression of cancer. The compounds of the invention can be used for slowing, delaying or preventing cancer progression. The progression of cancer is generally determined by assigning a stage to the cancer. Staging is generally done by assigning a number from I to IV to the cancer, where I is an isolated cancer and IV is the advanced stage of the disease, at which time the cancer has spread to other organs. Staging generally takes into account the size of the tumor, whether it has invaded adjacent organs, the number of lymph nodes to which it has spread, and whether the cancer has metastasized. Preventing or inhibiting the progression of cancer is particularly important for preventing the spread of cancer, such as progression from stage I to stage II, at which time the cancer spreads locally, or from stage III to stage IV, at which time the cancer metastasizes to other organs.

[0600] The compounds of the invention can be used for the treatment of cancer, wherein the cancer is a primary cancer, which can be a second primary cancer.

[0601] The compounds of the invention can be used for preventing or inhibiting the occurrence of a second primary cancer.

[0602] The compounds of the present invention can be used for treating cancers which are refractory (resistant) to anti-cancer agents (e.g., chemotherapy) and / or radiotherapy. The cancer may be resistant at the start of treatment or may become resistant during the course of treatment.

[0603] The compounds of the present invention can be used for treating cancers which are recurrent cancers, which can be local, regional or distant. A recurrent cancer is a cancer that recurs after initial treatment and after a period of time during which the cancer was undetectable. The same cancer may recur in the same tissue or in different parts of the body.

[0604] The compounds of the present invention can be used for preventing or inhibiting the recurrence of cancer.

[0605] The compounds of the present invention can be used for treating cancers which are metastatic or secondary cancers.

[0606] The compounds of the present invention can be used for preventing or inhibiting cancer metastasis. The treatment of metastatic cancers can be the same as or different from the therapy previously used to treat the primary tumor. For example, in certain embodiments, the primary tumor can be surgically removed and the compounds of the present invention are used to prevent the spread of cancer cells that may remain after surgery or have escaped from the primary tumor. In other embodiments, radiotherapy can be used to treat the primary tumor. In other embodiments, the primary tumor can be treated by chemotherapy. Combination therapies are commonly used to treat cancers to improve treatment and generally to maximize the length and depth of remission. Any combination therapy disclosed herein can be used in combination with the compounds of the present invention.

[0607] When the primary tumor has metastasized and secondary tumors have formed, the compounds of the present invention can be used for treating the secondary tumors. This may involve the treatment of the secondary tumors and the prevention of metastasis of the secondary tumors. The metastasis referred to herein is intended to include the metastasis of any tumor disclosed herein. Generally, the secondary tumors will be located in a tissue different from the primary tumor. For example, the secondary tumor can be a secondary tumor in bone. In a specific embodiment, the compounds of the present invention are used for treating secondary tumors in bone, such as for treating secondary bone tumors, where the primary tumor is a breast or prostate tumor.

[0608] Benign proliferative diseases

[0609] The compounds of the present invention or their pharmaceutically acceptable salts can be used for the treatment of benign proliferative diseases. Benign diseases can be benign tumors, such as hemangioma, hepatocellular adenoma, cavernous hemangioma, focal nodular hyperplasia, acoustic neuroma, neurofibroma, bile duct adenoma, bile duct cystanoma, fibroma, lipoma, leiomyoma, mesothelioma, teratoma, myxoma, nodular regenerative hyperplasia, trachoma, pyogenic granuloma, mole, uterine fibroids, thyroid adenoma, adrenal cortical adenoma or pituitary adenoma.

[0610] In some embodiments, the benign proliferative disease is an overproliferative skin disease. Benign overproliferative skin diseases include psoriasis, common warts, keratoacanthoma, seborrhea, ichthyosis, actinic keratosis, Bowen’s Disease, papilloma, seborrheic keratosis, eczema, atopic dermatitis, keloid and epidermolysis bullosa (EB).

[0611] Other diseases and conditions

[0612] In certain embodiments, the compounds of the present invention are used for the treatment or prevention of metabolic disorders, or symptoms or conditions associated with metabolic disorders.

[0613] The metabolic disorder can be a glucose metabolism disorder or a weight disorder.

[0614] The term “glucose metabolism disorder” includes any disorder characterized by a clinical symptom or combination of clinical symptoms associated with elevated glucose levels and / or elevated insulin levels in a subject relative to a healthy individual. Elevated glucose and / or insulin levels may be manifested in the following diseases, disorders and conditions: hyperglycemia, type II diabetes, gestational diabetes, type I diabetes, insulin resistance, impaired glucose tolerance, hyperinsulinemia, abnormal glucose metabolism, prediabetes, other metabolic disorders (such as metabolic syndrome) and obesity, etc.

[0615] As used herein, the term “insulin resistance” refers to a condition in which a normal amount of insulin does not produce a normal physiological or molecular response.

[0616] As used herein, the term “hyperglycemia” refers to a condition in which the amount of glucose circulating in the plasma of a subject is elevated relative to a healthy individual. Hyperglycemia can be diagnosed using methods known in the art, including measuring fasting blood glucose levels.

[0617] As used herein, the term "hyperinsulinemia" refers to a condition in which circulating insulin levels increase in response to 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 II diabetes, and obesity. Hyperinsulinemia can be diagnosed as a plasma insulin level higher than about 2 μl / ml.

[0618] The phrase "weight disorder" refers to a condition associated with overweight and / or increased appetite. Various parameters are used to determine whether a subject is overweight compared to a reference healthy individual, including the subject's age, height, gender, 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 weight in kilograms by the subject's height in meters. Adults with a BMI in the range of -18.5 to -24.9 kg / m are considered to have a normal weight; adults with a BMI between -25 and -29.9 kg / m can be considered overweight (pre-obese); and adults with a BMI of -30 kg / m or higher can be considered obese. Thus, in some embodiments, the weight disorder is obesity.

[0619] Accordingly, symptoms and conditions associated with metabolic disorders can include, but are not limited to, elevated blood glucose (hyperglycemia), reduced insulin production, metabolic syndrome, elevated cholesterol, elevated triglyceride levels, heart disease, stroke, hypertension, increased risk of blood clots (e.g., deep vein thrombosis), glycosuria, metabolic acidosis, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, and diabetic cardiomyopathy.

[0620] The term "metabolic syndrome" refers to a cluster of related characteristics, including but not limited to hyperinsulinemia, impaired glucose tolerance, redistribution of fat to the abdominal or upper body compartments, hypertension, fibrinolytic disorders, and dyslipidemia characterized by high triglycerides, low high-density lipoprotein (HDL)-cholesterol, and high small dense low-density lipoprotein (LDL) particles. Subjects with metabolic syndrome are at risk of developing type II diabetes and / or other conditions (e.g., atherosclerosis).

[0621] The compounds of the present invention can be used to prevent or inhibit the progression or symptoms of metabolic disorders or conditions associated therewith. For example, the compounds of the present invention can reduce blood glucose, insulin, triglyceride, or cholesterol levels to ranges found in healthy subjects; reduce body 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 thrombosis, heart disease, or stroke.

[0622] In certain embodiments, the compounds of the invention are used for treating platelet disorders, such as thrombocytopenia.

[0623] The compounds of the invention can be used alone or in combination with one or more anticancer agents and / or radiotherapy as described herein.

[0624] Combination therapy

[0625] The compounds of the invention can be used alone to provide a therapeutic effect. The compounds of the invention can also be used in combination with one or more other therapies.

[0626] In some embodiments, the compounds of the invention are used in combination with one or more anticancer agents and / or radiotherapy.

[0627] The underlying rationale is based on results showing that overexpression of MASTL is associated with cisplatin resistance by accelerating checkpoint recovery (Wong et al., 2016), and (Wang et al., 2014). Conversely, in some cancer types, knockdown of MASTL has been observed to sensitize cancer cells to cisplatin, radiotherapy, and 5-fluorouracil (5FU) (Wang et al. (2014). Mastl kinase, a promising therapeutic target, promotes cancer recurrence. Oncotarget 5 11479-11489; Nagel et al. (2015). Genome-wide siRNA Screen identifies the radiosensitizing effect of downregulation of MASTL and FOXM1 in NSCLC. Mol. Cancer Ther. 14 1434-1444; Uppada et al. (2018). MASTL induces colon cancer progression and chemoresistance by promoting Wnt / β-catenin signaling. 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).

[0628] Thus, the compounds of the present invention can be used to prevent or reduce the resistance of cells to anti-cancer agents (including chemotherapeutic agents, radiotherapy).

[0629] Such chemotherapy can include one or more anti-cancer agents of the following categories:

[0630] (i) Anti-proliferative / anti-tumor drugs and their combinations, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, uracil mustard, bendamustine, melphalan, chlorambucil, chlormethine, busulfan, temozolomide, nitrosoureas, ifosfamide, melphalan, pipobroman, triethylenemelamine, triethylenethiophosphoramide, carmustine, lomustine, streptozocin, and dacarbazine); antimetabolites (e.g., gemcitabine and antifolates, such as fluoropyrimidines, such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytarabine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, gemcitabine, and hydroxyurea); antibiotics (e.g., anthracycline antibiotics, such as doxorubicin, bleomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitomycin-C, actinomycin, and mithramycin); anti-mitotic agents (e.g., vinca alkaloids, such as vincristine, vinblastine, vindesine, and vinorelbine, and taxanes, such as paclitaxel and docetaxel, and multi-kinase inhibitors); proteasome inhibitors, such as carfilzomib and bortezomib; interferon therapy; and topoisomerase inhibitors (e.g., epipodophyllotoxins, such as etoposide and teniposide, amsacrine, topotecan, irinotecan, mitoxantrone, and camptothecin); bleomycin, actinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol TM ), nab-paclitaxel (albumin-bound paclitaxel), docetaxel, mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferon (especially IFN-α), etoposide, teniposide, DNA demethylating agents (e.g., azacitidine or decitabine); and histone deacetylase (HDAC) inhibitors (e.g., vorinostat, MS-275, panobinostat, romidepsin, valproic acid, mocetinostat (MGCD0103), and pracinostat SB939);

[0631] (ii) Cytostatic agents, such as anti-estrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxyfene), anti-androgens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole, and exemestane), and 5α-reductase inhibitors, such as finasteride; and vinorelbine, CPT-11, anastrozole, letrazole, capecitabine, reloxafme, cyclophosphamide, ifosfamide, and droloxafine;

[0632] (iii) Anti-invasive agents, such as dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, urokinase plasminogen activator receptor function inhibitors, or heparanase antibodies;

[0633] (iv) Growth factor function inhibitors: For example, such inhibitors include growth factor antibodies and growth factor receptor antibodies, such as the anti-erbB2 antibody trastuzumab [Herceptin TM, anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors such as gefitinib, erlotinib, 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), afatinib, vandetanib, osimertinib, and roxitinib), erbB2 tyrosine kinase inhibitors such as lapatinib), and antibodies to costimulatory molecules such as CTLA-4, 4-1BB, and PD-1, or antibodies to cytokines (IL-10, TGF-β); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; regulators of regulators of apoptosis protein regulators (e.g., Bcl-2 inhibitors); inhibitors of the platelet-derived growth factor family such as imatinib and / or nilotinib (AMN 107); inhibitors of serine / threonine kinases (e.g., Ras / Raf signaling inhibitors such as farnesyltransferase inhibitors, 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 such as daclizumab; aurora kinase inhibitors and cyclin-dependent kinase inhibitors such as 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 such as vismodegib.

[0634] (v) Anti-angiogenic agents, such as those that inhibit the action of vascular endothelial growth factor, [e.g., anti-vascular endothelial growth factor antibody bevacizumab (Avastin TM )]; thalidomide; lenalidomide; and, for example, VEGF receptor tyrosine kinase inhibitors such as vandetanib, vatalanib, sunitinib, axitinib, pazopanib, and cabozantinib;

[0635] (vi) Gene therapy, including, for example, methods of replacing abnormal genes (such as abnormal p53 or abnormal BRCA1 or BRCA2);

[0636] (vii) Immunotherapy, including, for example, antibody therapy such as alemtuzumab, rituximab, ibritumomab, tositumomab Ofatumumab; interferons, such as interferon alpha; interleukins, such as IL-2 (aldesleukin); interleukin inhibitors, such as IRAK4 inhibitors; cancer vaccines, including prophylactic and therapeutic vaccines, such as HPV vaccines, such as Gardasil, Cervarix, Oncophage, and Sipuleucel-T (Provenge); gp100; dendritic cell-based vaccines (such as Ad.p53 DC); toll-like receptor modulators, such as TLR-7 or TLR-9 agonists; PD-1, PD-L1, PD-L2, and CTLA4-A modulators (such as nivolumab), antibodies, and vaccines; other IDO inhibitors (such as indomethacin); anti-PD-1 monoclonal antibodies (such as MK-3475 and nivolumab); anti-PDL1 monoclonal antibodies (such as MEDI-4736 and RG-7446); anti-PDL2 monoclonal antibodies; and anti-CTLA-4 antibodies (such as ipilimumab), CAR-T cell therapy; and

[0637] (viii) cytotoxic agents, such as fludarabine (fludara), cladribine, pentostatin (Nipent TM );

[0638] (ix) targeted therapies, such as PI3K inhibitors, such as idelalisib and perifosine; SMAC (second mitochondria-derived activator of caspases) mimetics, also known as inhibitor of apoptosis protein (IAP) antagonists (IAP antagonists). These agents inhibit IAPs, such as XIAP, cIAP1, and cIAP2, thus reconstituting the apoptotic pathway. Specific SMAC mimetics include Birinapant (TL32711, TetraLogic Pharmaceuticals), LCL161 (Novartis), AEG40730 (Aegera Therapeutics), SM-164 (University of Michigan), LBW242 (Novartis), ML101 (Sanford-Burnham Medical Research Institute), AT-406 (Ascenta Therapeutics / University of Michigan), GDC-0917 (Genentech), AEG35156 (Aegera Therapeutics), and HGS1029 (Human Genome Sciences); and agents targeting the ubiquitin proteasome system (UPS), such as bortezomib, carfilzomib, marizomib (NPI-0052), and MLN9708; CXCR4 antagonists, such as plerixafor or BL-8040;

[0639] (x) PARP inhibitors, such as niraparib (MK-4827), talazoparib (BMN-673), veliparib (ABT-888); olaparib, CEP 9722, and BGB-290;

[0640] (xi) Chimeric antigen receptors, anti-cancer vaccines, and arginase inhibitors;

[0641] (xii) Agents that degrade hyaluronic acid, such as hyaluronidase PEGPH20.

[0642] Other anti-cancer agents can be a single agent or one or more of the other agents listed herein.

[0643] Specific anti-cancer agents that can 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 other anti-cancer agent is selected from capecitabine, gemcitabine, and 5-fluorouracil (5FU).

[0644] In some embodiments, the compounds of the present invention are used in combination with one or more therapies for treating or preventing metabolic disorders, said therapies including therapeutic agents, LDL apheresis, dietary restriction, and / or surgery (such as bariatric surgery).

[0645] Therapeutic agents for treating or preventing metabolic disorders can include one or more agents from the following categories:

[0646] (i) Diabetes treatment, such as metformin, sulfonylureas (such as glibenclamide, glipizide, and glimepiride), meglitinides (such as repaglinide and nateglinide), thiazolidinediones (such as rosiglitazone and pioglitazone), DPP-4 inhibitors (such as sitagliptin, saxagliptin, and linagliptin), GLP-1 receptor agonists (such as exenatide, liraglutide, and semaglutide), SGLT2 inhibitors (such as canagliflozin, dapagliflozin, and empagliflozin), insulin (such as long-acting insulin, such as insulin glargine or insulin detemir), and aspirin;

[0647] (ii) Cholesterol-lowering agents, such as statins (such as atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin); cholesterol absorption inhibitors (such as ezetimibe); PCSK9 inhibitors (such as evolocumab and alirocumab);

[0648] (iii) Triglyceride-lowering agents, such as statins, fibrates, niacin, and omega-3 fatty acids;

[0649] (iv) Anticoagulants, such as anticoagulants (e.g., heparin, warfarin, rivaroxaban, dabigatran, apixaban, edoxaban, enoxaparin, fondaparinux);

[0650] (v) Hypotensive agents, such as 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, torsemide; combination diuretics such as amiloride hydrochloride / hydrochlorothiazide, spironolactone / hydrochlorothiazide, triamterene / hydrochlorothiazide), β-blockers (e.g., acebutolol, atenolol, betaxolol, bisoprolol, bisoprolol / hydrochlorothiazide, metoprolol tartrate, metoprolol succinate, nadolol, pindolol, propranolol, solotol, timolol), ACE inhibitors (e.g., benazepril, captopril, enalapril, fosinopril, 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), α-blockers (e.g., doxazosin, prazosin, terazosin), α-β-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).

[0651] This combination therapy can be achieved by simultaneously, sequentially, or separately administering the individual components of the treatment. This combination product uses the compounds of the present invention within the therapeutically effective dose range described above and other pharmaceutically active agents within the approved dose range.

[0652] As used herein, when the term "combination" is used, it should be understood to mean simultaneous, separate, or sequential administration. In one aspect of the present invention, "combination" means simultaneous administration. In another aspect of the present invention, "combination" means separate administration. In another aspect of the present invention, "combination" means sequential administration. When administered sequentially or separately, the delayed administration of the second component should not result in the loss of the beneficial effects of the combination.

[0653] In some embodiments using combination therapy, when combined, the amounts of the compounds of the invention and the amounts of other pharmaceutically active agents are therapeutically effective for treating the target disorder in a patient. As used herein, they are "therapeutically effective amounts" if, when combined, the combined amounts are sufficient to alleviate or completely relieve the symptoms or other adverse effects of the disorder; cure the disorder; reverse, completely stop or slow the progression of the disorder; or reduce the risk of worsening of the disorder. Generally, such amounts can be determined by those skilled in the art, for example, starting from the dosage ranges of the compounds of the invention described in this specification and the approved or published dosage ranges of other pharmaceutically active compounds.

[0654] According to another aspect of the invention, there is provided a compound of the invention as defined above and another anti-cancer agent as defined above for use in combination therapy of cancer.

[0655] According to another aspect of the invention, there is provided a pharmaceutical product comprising a compound of the invention as defined above and another anti-cancer agent as defined above for use in combination therapy of cancer.

[0656] According to another aspect of the invention, there is provided a method of treating a human or animal subject suffering from cancer, the method comprising administering a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof and another anti-cancer agent as defined above to the subject simultaneously, sequentially or separately.

[0657] According to another aspect of the invention, there is provided a compound of the invention or a pharmaceutically acceptable salt thereof for use simultaneously, sequentially or separately with another anti-cancer agent as defined above in the treatment of cancer.

[0658] The compounds of the invention can also be used in combination with radiotherapy. Suitable radiotherapy includes, for example, X-ray therapy, proton beam therapy or electron beam therapy. Radiotherapy can also include the use of radiopharmaceutical preparations, such as 131 I, 32 P, 90 Y, 89 Sr, 153 Sm or 223 Ra. Such radionuclide therapy is well known and commercially available.

[0659] According to another aspect of the invention, there is provided a compound of the invention or a pharmaceutically acceptable salt thereof as defined above for use in combination with radiotherapy in the treatment of cancer.

[0660] According to another aspect of the invention, there is provided a method of treating a human or animal subject suffering from cancer, the method comprising administering a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof and radiotherapy to the subject simultaneously, sequentially or separately.

[0661] Biological assays

[0662] One or more of the assay methods described in the embodiments herein can be used to evaluate the biological effects of a compound.

[0663] In certain embodiments, in the MASTLwt activity assay described in the examples, the pIC 50 of the compound is 7.0 or less.

[0664] Synthesis

[0665] 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 following synthetic methods and the reference synthetic methods for preparing the starting materials, it should be understood that those skilled in the art can select all the proposed reaction conditions, including the choice of solvents, reaction atmospheres, reaction temperatures, experiment durations, and post-treatment steps.

[0666] Those skilled in the art of organic synthesis will understand that the functional groups present on different parts of the molecule must be compatible with the reagents and reaction conditions used.

[0667] The necessary starting materials can be obtained by standard procedures of organic chemistry. The preparation of such starting materials incorporates the following representative method variations and is described in the appended examples. Alternatively, the necessary starting materials can be obtained by procedures similar to those described within the ordinary skill of an organic chemist.

[0668] It should be understood that during the process of synthesizing the compounds of the present invention in the methods defined below, or during the synthesis of certain starting materials, it may be necessary to protect certain substituents to prevent them from undergoing undesired reactions. Skilled chemists will understand when such protection is required and how to place such protecting groups in the appropriate positions and then remove them.

[0669] For examples of protecting groups, see one of the numerous general textbooks on the subject, e.g., ‘Protective Groups in Organic Synthesis’, by Theodora Green (Publisher: John Wiley & Sons). The protecting groups can be removed by any convenient method described in the literature or known to skilled chemists that is suitable for removing the protecting group in question, and such a method is selected so as to effect the removal of the protecting group with minimal interference to the groups elsewhere in the molecule.

[0670] Thus, if the reactants include groups such as, for example, amino, carboxyl, or hydroxyl groups, it may be necessary to protect such groups in some of the reactions mentioned herein.

[0671] For example, suitable protecting groups for an amino or alkylamino group are, for example, acyl groups such as alkanoyl groups like acetyl or trifluoroacetyl, alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl or tert - butoxycarbonyl, arylmethoxycarbonyl groups such as benzyloxycarbonyl, or aroyl groups such as benzoyl. The deprotection conditions for the above - mentioned protecting groups must vary with the choice of the protecting group. Thus, for example, an acyl group such as an alkanoyl group, an alkoxycarbonyl group or an aroyl group can be removed by hydrolysis, for example, with a suitable base such as an alkali metal hydroxide (such as lithium hydroxide or sodium hydroxide). Alternatively, an acyl group such as tert - butoxycarbonyl can be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and an arylmethoxycarbonyl group such as benzyloxycarbonyl can be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid such as BF3·OEt2. Suitable alternative protecting groups for a primary amino group are, for example, phthaloyl groups, which can be removed by treatment with an alkylamine such as dimethylaminopropylamine, or with hydrazine.

[0672] Suitable protecting groups for a hydroxyl group are, for example, acyl groups (such as alkanoyl groups like acetyl, aroyl groups like benzoyl) or arylmethyl groups (such as benzyl). The deprotection conditions for the above - mentioned protecting groups will have to vary with the choice of the protecting group. Thus, for example, an acyl group such as an alkanoyl group or an aroyl group can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide (such as lithium hydroxide or sodium hydroxide) or ammonia. Alternatively, an arylmethyl group such as benzyl can be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0673] Suitable protecting groups for a carboxyl group are, for example, esterifying groups such as methyl or ethyl, which can be removed by hydrolysis, for example, with a base such as sodium hydroxide, or, for example, tert - butyl, which can be removed by treatment with an acid such as an organic acid (such as trifluoroacetic acid), or, for example, benzyl, which can be removed by hydrogenation over a catalyst such as palladium on carbon.

[0674] Resins can also be used as protecting groups.

[0675] Examples

[0676] Throughout this specification, these abbreviations have the following meanings:

[0677] Aq. = aqueous solution DCM = dichloromethane

[0678] DMF = N,N - dimethylformamide DMSO = dimethyl sulfoxide

[0679] Et = ethyl EtOAc = ethyl acetate

[0680] h = hour MeOH = methanol

[0681] Me = methyl min = minute

[0682] mol = mole, cPr = cyclopropyl

[0683] iPr = isopropyl, Rt = retention time

[0684] RT = room temperature, Sat. = saturated

[0685] THF = tetrahydrofuran, T3P = propylphosphonic anhydride

[0686] DIEA = N,N - diisopropylethylamine, Et3N = triethylamine

[0687] HOBt = 1 - hydroxybenzotriazole hydrate, NH4Cl = ammonium chloride

[0688] EDCIHCl = 1 - ethyl - 3 - (3 - dimethylaminopropyl)carbodiimide hydrochloride

[0689] EtOH = ethanol, NaOAc = sodium acetate

[0690] NaHCO3 = sodium bicarbonate, NaOH = sodium hydroxide

[0691] KF = potassium fluoride, MeMgBr = methylmagnesium bromide

[0692] NaBH3CN = sodium cyanoborohydride, NH3 = ammonia

[0693] HATU = 1 - [bis(dimethylamino)methylene] - 1H - 1,2,3 - triazolo[4,5 - b]pyridinium 3 - oxide hexafluorophosphate

[0694] NBS = N - bromosuccinimide, NH2NH2·H2O = hydrazine monohydrate

[0695] H3PO4 = phosphoric acid, Na2SO4 = sodium sulfate

[0696] MeCN = acetonitrile

[0697] Materials and Methods

[0698] Unless otherwise stated, solvents, reagents, and starting materials were purchased from commercial suppliers and used as received. Unless otherwise stated, all reactions were carried out at RT. Flash column chromatography was performed on an ISCO Combiflash Nextgen or Biotage Selekt using pre - packed columns filled with Merck flash silica 60 (40 - 63 μm) or C18 flash silica.

[0699] LCMS

[0700] LCMS data was recorded on a Waters 2695 HPLC using a Waters 2487 UV detector and a Thermo LCQ ESI-MS. Samples were eluted through a Phenomenex Luna 3μ C18 50mm×4.6mm column with water and acetonitrile acidified with 0.1% formic acid at 1.5 mL / min and detected at 254 nm.

[0701] The following methods were used:

[0702] Method 1 : 4-minute method

[0703] The gradient employed was:

[0704]

[0705] Method 2 : 5-minute method

[0706] The gradient employed was:

[0707]

[0708] Method 3 : 10-minute method

[0709] The gradient employed was:

[0710]

[0711] Chemical synthesis

[0712] Microwave reactions were carried out using a Biotage Robot 60+ microwave reactor.

[0713] Intermediate A1

[0714]

[0715] 6-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyrimidine

[0716] Step 1: N-[(5-Bromopyrimidin-2-yl)methyl]acetamide

[0717] At 0 °C, Et3N (5.21 g, 51.48 mmol, 7.17 mL) and acetyl chloride (2.69 g, 34.32 mmol) were added dropwise to a solution of (5-bromopyrimidin-2-yl)methanamine (3.23 g, 17.16 mmol) in DCM (30 mL). After addition, the mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with H2O (50 mL) and extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (40 mL × 3), dried over anhydrous Na2SO4, 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.

[0718] MS(ESI) m / z = 232.0 [M+H]+.

[0719] Step 2: 3-Bromo-6-methyl-imidazo[1,5-a]pyrimidine

[0720] A mixture of N-[(5-bromopyrimidin-2-yl)methyl]acetamide (2.64 g, 11.48 mmol), POCl3 (5.28 g, 34.43 mmol, 3.20 mL) in toluene (25 mL) was degassed and purged with N2, then the mixture was stirred at 110 °C under N2 for 12 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with brine (40 mL × 3), dried over anhydrous Na2SO4, 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.

[0721] MS(ESI) m / z = 212.0 [M+H]+.

[0722] Step 3: 6-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyrimidine

[0723] A mixture of 3-bromo-6-methylimidazo[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)Cl2 (34.51 mg, 47.16 μmol) in dioxane (3 mL) was degassed and purged with N2, and then the mixture was stirred at 100 °C under N2 for 5 h. The reaction mixture was concentrated under reduced pressure to give 6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyrimidine (2.67 g, crude product) as a yellow solid.

[0724] MS(ESI) m / z = 178.0 [boronic acid + H]+.

[0725] Intermediate A2

[0726]

[0727] 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridin-3-ol

[0728] Step 1: 6-Bromoimidazo[1,5-a]pyridin-3-ol

[0729] At 0 °C, a solution of NaHCO3 (3.38 g, 40.27 mmol) in H2O (30 mL) and a solution of triphosgene (3.98 g, 13.42 mmol) in DCM (60 mL) were added dropwise to a solution of (5-bromo-2-pyridyl)methanamine (3 g, 13.42 mmol) in DCM (60 mL), and then the mixture was stirred at 25 °C under N2 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 Na2SO4 and concentrated under reduced pressure to give a 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.

[0730] MS(ESI) m / z = 213.1 [M + H]+.

[0731] Step 2: 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridin-3-ol

[0732] Under N2, 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)Cl2 (115.00 mg, 140.82 μmol) were added to a stirred solution of 6-bromoimidazo[1,5-a]pyridin-3-ol (300 mg, 1.41 mmol) in 1,4-dioxane (4 mL), 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 product) as a yellow solid.

[0733] MS(ESI) m / z = 161.1 [boronic acid + H]+.

[0734] Intermediate A3

[0735]

[0736] 1-Fluoro-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine

[0737] Step 1: 6-Bromo-1-fluoro-3-methyl-imidazo[1,5-a]pyridine

[0738] 1-Fluoro-2,4,6-trimethyl-pyridin-1-ium; tetrafluoroborate (537.72 mg, 2.37 mmol) was added to a solution of 6-bromo-3-methyl-imidazo[1,5-a]pyridine (250 mg, 1.18 mmol) in DMF (5 mL). After addition, the mixture was stirred at 60 °C for 1 h, then 1-Fluoro-2,4,6-trimethyl-pyridin-1-ium; tetrafluoroborate (537.72 mg, 2.37 mmol) was added. After addition, the mixture was stirred at 60 °C for 1 h, then 1-Fluoro-2,4,6-trimethyl-pyridin-1-ium; tetrafluoroborate (537.72 mg, 2.37 mmol) was added. The mixture was stirred at N2, 60 °C for 10 h. The reaction mixture was quenched by the addition of H2O (5 mL). The residue was purified by column chromatography to give the product 6-bromo-1-fluoro-3-methyl-imidazo[1,5-a]pyridine (43 mg, 187.73 μmol, 15.85% yield) as a yellow solid.

[0739] 1H NMR (400 MHz, DMSO-d6) δ = 8.35 (s, 1H), 7.42 (d, 1H), 6.70 (d, 1H), 2.52 (s, 3H).

[0740] Step 2: 1-Fluoro-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine

[0741] 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 N2 atmosphere for 12 h. The mixture was filtered and then concentrated under reduced pressure to give a residue. A small amount of DCM (0.5 mL) was added to the residue, and then the suspension was filtered through a pad of diatomaceous earth 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 product), as a brown oil.

[0742] 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).

[0743] Intermediate A4

[0744]

[0745] 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trideuteriomethyl)indazole

[0746] Step 1: 6-Bromo-1-(trideuteriomethyl)indazole

[0747] At 0 °C, 60% NaH (4.47 g, 111.66 mmol) was added to a stirred solution of 6-bromo-1H-indazole (20 g, 101.51 mmol) in THF (240 mL), then tri-deuterated (iodo)methane (21.61 g, 152.26 mmol) was added, and the reaction mixture was stirred at 20 °C under N2 for 2 h. The reaction mixture was quenched with H2O (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-(tri-deuteromethyl)indazole (11.6 g, 53.38% yield) as a red oil.

[0748] MS(ESI) m / z = 214.1 [M+H]+.

[0749] Step 2: 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tri-deuteromethyl)indazole

[0750] Under N2, 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)Cl2 (4.04 g, 4.95 mmol) were added to a stirred solution of 6-bromo-1-(tri-deuteromethyl)indazole (10.6 g, 49.51 mmol) in 1,4-dioxane (206 mL), 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-(tri-deuteromethyl)indazole (11.4 g, 88.16% yield) as an off-white solid.

[0751] 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).

[0752] General method for Intermediate B

[0753]

[0754] Intermediate B1

[0755]

[0756] N-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridin-3-amine

[0757] Step 1: 1-[(5-Bromo-2-pyridyl)methyl]-3-methyl-thiourea

[0758] 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(thio)methane (654.30 mg, 8.95 mmol), and the reaction mixture was stirred at 15 °C under N2 for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue 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.

[0759] MS(ESI) m / z = 261.5 [M+H]+.

[0760] Step 2: 6-Bromo-N-methyl-imidazo[1,5-a]pyridin-3-amine

[0761] To a stirred solution of 1-[(5-bromo-2-pyridyl)methyl]-3-methyl-thiourea (2.13 g, 8.95 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 N2 for 16 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-bromo-N-methyl-imidazo[1,5-a]pyridin-3-amine (1.3 g, 70.23% yield) as a green solid.

[0762] MS(ESI) m / z = 226.1 [M+H]+.

[0763] Step 3: N-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridin-3-amine

[0764] To a stirred solution of 6-bromo-N-methylimidazo[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)Cl2 (469.60 mg, 575.04 μmol), and the reaction mixture was stirred at 110 °C under N2 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.

[0765] 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).

[0766]

[0767] General procedure for Intermediate C (imidazole amine)

[0768]

[0769] Intermediate C1A

[0770]

[0771] (R or S)-1-(2-(trifluoromethyl)-1H-imidazol-4-yl)propan-1-amine

[0772] Step 1: Trimethyl-[2-[[2-(trifluoromethyl)imidazol-1-yl]methoxy]ethyl]silane

[0773] A mixture of 2-(trifluoromethyl)-1H-imidazole (3.00 g, 22.05 mmol) in THF (60 mL) was degassed and purged with N2 three times. Then, 60% NaH (3.53 g, 88.19 mmol) was added to the mixture, and the mixture was stirred at 0 °C under N2 for 2 h. Then, SEM-Cl (4.41 g, 26.46 mmol) was added at 0 °C, and the mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H2O (80 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a 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.

[0774] 1H NMR (400 MHz, CDCl3): 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).

[0775] Step 2: 2-(Trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazole-4-carbaldehyde

[0776] n-BuLi (2.5 M, 10.27 mL) was added to a mixture of trimethyl-[2-[[2-(trifluoromethyl)imidazol-1-yl]methoxy]ethyl]silane (5.7 g, 21.40 mmol) in THF (60 mL), and the mixture was stirred at -78 °C under N2 for 0.5 h. Then, DMF (9.39 g, 128.41 mmol) was added to the reaction mixture and stirred at -78 °C for 1 h. The reaction mixture was quenched by adding an aqueous NH4Cl solution (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 obtain a 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.

[0777] 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).

[0778] Step 3: (NE,R)-2-Methyl-N-[[2-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]methylene]propane-2-sulfinamide

[0779] 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)4 (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 H2O (10 mL) at 25 °C, then 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.

[0780] 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).

[0781] 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

[0782] At 0 °C, to a solution of EtMgBr (3 M, 10 mL) was added (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). The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by adding aqueous NH4Cl solution (60 mL) at 25 °C and extracted with EtOAc (40 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a 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 an off-white oil.

[0783] 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)

[0784] Step 5: (S or R)-1-[2-(Trifluoromethyl)-1H-imidazol-4-yl]propan-1-amine

[0785] 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. The residue was obtained without further purification and (S or R)-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propan-1-amine (85 mg, crude product) as a colorless oil.

[0786] MS (ESI) m / z = 192.2 [M - H]-.

[0787]

[0788] General method for Intermediate D (Indazole amine)

[0789]

[0790] Intermediate D1A

[0791]

[0792] (1S or 1R)-1-[1-(Difluoromethyl)pyrazol-3-yl]-2-methyl-propan-1-amine

[0793] Step 1: tert-Butyl N-[(1S or 1R)-1-[Methoxy(methyl)carbamoyl]-2-methyl-propyl]carbamate

[0794] At 0 °C, to a solution of (2S or 2R)-2-(tert-butoxycarbonylamino)-3-methylbutyric 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), then at 15 °C, N-methoxymethanamine; hydrochloride (2.47 g, 25.32 mmol) and TEA (2.56 g, 25.32 mmol) were added, and the mixture was stirred at 15 °C under a N2 atmosphere for 16 h. The mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel chromatography to obtain tert-butyl N-[(1S or 1R)-1-[methoxy(methyl)carbamoyl]-2-methylpropyl]carbamate (6.1 g, crude product), as a yellow solid.

[0795] 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).

[0796] Step 2: tert-butyl (R)-(2-methyl-4-oxohex-5-yn-3-yl)carbamate

[0797] At -78 °C under N2, to a solution of tert-butyl N-[(1S or 1R)-1-[methoxy(methyl)carbamoyl]-2-methylpropyl]carbamate (6 g, 23.05 mmol) in THF (10 mL) was added bromo(ethynyl)magnesium (0.5 M, 230.48 mL, in THF) over 1 h, then the mixture was stirred at 30 °C under a N2 atmosphere for 16 h. 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 the filtrate was concentrated under reduced pressure to obtain tert-butyl (R or S)-(2-methyl-4-oxohex-5-yn-3-yl)carbamate (5.46 g, crude product), as a brown oil.

[0798] 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).

[0799] Step 3: tert-butyl N-[(1S or 1R)-2-methyl-1-(1H-pyrazol-3-yl)propyl]carbamate

[0800] At 80 °C, hydrazine hydrate (2.48 g, 48.47 mmol) was added 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), and the mixture was stirred at 80 °C under N2 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.

[0801] 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).

[0802] Step 4: tert-Butyl N-[(1S or 1R)-1-[1-(difluoromethyl)pyrazol-3-yl]-2-methylpropyl]carbamate

[0803] 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]oxirane (2.68 g, 10.03 mmol). The mixture was stirred at 30 °C under N2 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 Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give tert-butyl N-[(1S or 1R)-1-[1-(difluoromethyl)pyrazol-3-yl]-2-methylpropyl]carbamate (440 mg, 18.20% yield) as a white solid.

[0804] 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).

[0805] Step 5: (1S or 1R)-1-[1-(difluoromethyl)pyrazol-3-yl]-2-methyl-propan-1-amine

[0806] At 15 °C, HCl / dioxane (8 mL, 4 M) was added 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), and the mixture was stirred at N2, 15 °C for 16 h. The mixture was concentrated under reduced pressure to obtain (1S or 1R)-1-[1-(difluoromethyl)pyrazol-3-yl]-2-methyl-propan-1-amine (330.3 mg, crude product), which was a white solid.

[0807] 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).

[0808]

[0809] Intermediate E

[0810]

[0811] tert-Butyl (2-(1-(2-aminoethyl)-1H-pyrazol-3-yl)propan-2-yl)carbamate

[0812] Step 1: Obtain tert-butyl N-[2-[methoxy(methyl)amino]-1,1-dimethyl-2-oxo-ethyl]carbamate

[0813] To a stirred mixture 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), 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 the precipitated N,N'-dicyclohexylurea, and the filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (20 mL), washed with 10% aqueous citric acid solution (20 mL×3), 10% aqueous NaHCO3 solution (10 mL) and saturated aqueous sodium chloride solution (20 mL×3), and dried over anhydrous Na2SO4. 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.

[0814] MS(ESI) m / z = 247.1 [M+H]+.

[0815] Step 2: Obtain tert-butyl N-(1,1-dimethyl-2-oxo-but-3-ynyl)carbamate

[0816] At -78 °C, 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 dropwise with bromo(ethynyl)magnesium (0.5 M, 1.04 mL), and the mixture was stirred at N2, 25 °C for 24 h. The reaction mixture was quenched by the addition of H2O (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 Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl N-(1,1-dimethyl-2-oxo-but-3-ynyl)carbamate (45 mg, crude product) as a yellow solid.

[0817] MS(ESI) m / z = 156.1 [M-tBu+H]+.

[0818] Step 3: tert-butyl N-[1-methyl-1-(1H-pyrazol-3-yl)ethyl]carbamate

[0819] To a solution of tert-butyl N-(1,1-dimethyl-2-oxo-but-3-ynyl)carbamate (44 mg, 208.28 μmol) in EtOH (5 mL) was added NH2NH2·H2O (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 N2H4·H2O at 30 °C. The residue was diluted with H2O (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a 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.

[0820] MS(ESI) m / z = 226.1 [M+H]+.

[0821] Step 4: tert-butyl N-[1-[1-[2-(benzyloxycarbonylamino)ethyl]pyrazol-3-yl]-1-methylethyl]carbamate

[0822] At 0 °C, 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), and the mixture was stirred at 20 °C for 0.5 h, then N-(2-bromoethyl)carbamic acid benzyl ester (419.33 mg, 1.62 mmol) was added at 20 °C under N2. The reaction mixture was quenched by adding water (10 mL) at 25 °C, and then the mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography to give tert-butyl N-[1-[1-[2-(benzyloxycarbonylamino)ethyl]pyrazol-3-yl]-1-methylethyl]carbamate (78 mg, 14.31% yield) as a white solid.

[0823] MS(ESI) m / z = 402.9 [M+H]+.

[0824] Step 5: tert-butyl (2-(1-(2-aminoethyl)-1H-pyrazol-3-yl)propan-2-yl)carbamate

[0825] Concentrated hydrochloric acid (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-methylethyl]carbamate (15 mg, 28.49 μmol), and the mixture was stirred at 30 °C under N2 for 12 h. The reaction mixture was concentrated under reduced pressure to obtain a 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.

[0826] MS(ESI) m / z = 269.1 [M+H]+.

[0827] General method for Intermediate F (oxadiazole amine)

[0828]

[0829] Intermediate F1A

[0830]

[0831] (1S or 1R)-2-methyl-1-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]propan-1-amine

[0832] Step 1: tert-Butyl N-[(1S or 1R)-2-methyl-1-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]propyl]carbamate

[0833] To a solution of (2S or 2R)-2-(tert-butoxycarbonylamino)-3-methylbutyric 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. Then 2,2,2-trifluoro-N-hydroxy-acetamidine (265.23 mg, 2.07 mmol) was added and the mixture was stirred at 25 °C for 16 h. The mixture was stirred in a microwave at 110 °C for 4 h. The reaction mixture was concentrated under reduced pressure to obtain a 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.

[0834] 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).

[0835] Step 2: (1S or 1R)-2-methyl-1-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]propan-1-amine

[0836] 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 at 25 °C for 2 h. 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 product) as a yellow solid.

[0837] MS (ESI) m / z = 210.1 [M + H]+.

[0838]

[0839] General method for Intermediate G (pyridineamine)

[0840]

[0841] Intermediate G1

[0842]

[0843] (1R or 1S)-1-(5-fluoro-2-pyridyl)ethanamine

[0844] Step 1: (NE,R or S)-N-[(5-fluoro-2-pyridyl)methylene]-2-methyl-propan-2-sulfinamide

[0845] To a solution of 5-fluoropyridine-2-carbaldehyde (13.5 g, 107.91 mmol) in THF (150 mL) was added titanium(IV) isopropoxide (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 mixture 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-methylpropane-2-sulfinamide (20.2 g, 73.80% yield) as a yellow oil.

[0846] 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).

[0847] Step 2: (R)-N-[(1R or 1S)-1-(5-fluoro-2-pyridyl)ethyl]-2-methylpropane-2-sulfinamide

[0848] At -78 °C, MeMgBr (1 M, 105.13 mL) was added to a solution of (NE,R or S)-N-[(5-fluoro-2-pyridyl)methylene]-2-methylpropane-2-sulfinamide (1 g, 4.38 mmol) in THF (20 mL). The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched by the addition of NH4Cl (100 mL) at 25 °C, then 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 Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography to give (R)-N-[(1R or 1S)-1-(5-fluoro-2-pyridyl)ethyl]-2-methylpropane-2-sulfinamide (0.5 g, 39.71% yield) as a yellow oil.

[0849] MS (ESI) m / z = 273.1 [M+H]+.

[0850] Step 3: (1R or 1S)-1-(5-fluoro-2-pyridyl)ethanamine

[0851] 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 afford (1R or 1S)-1-(5-fluoro-2-pyridyl)ethylamine (0.45 g, 100% yield) as a white solid.

[0852] MS(ESI) m / z = 141.0 [M+H]+.

[0853]

[0854] Intermediate H

[0855]

[0856] 2-[2-(trifluoromethyl)-1H-imidazol-4-yl]propan-2-amine

[0857] Step 1: 2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

[0858] At 0 °C, 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), and the mixture was stirred for 30 min. At 0 °C, SEM-Cl (2.70 g, 16.17 mmol, 2.86 mL) was added dropwise to the mixture. The mixture was warmed to 20 °C and stirred for 2 h. The reaction mixture was quenched by the addition of H2O (50 mL) at 0 °C, extracted with EtOAc (120 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica chromatography to afford 2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (3.1 g, 77.61% yield) as a white liquid.

[0859] 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).

[0860] Step 2: 2-[[4-bromo-2-(trifluoromethyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane

[0861] At 25 °C, NBS (1.47 g, 8.26 mmol) was added dropwise to a solution of 2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (2 g, 7.51 mmol) in CHCl3 (20 mL) and DMF (20 mL) over 16 h. At 20 °C, the reaction mixture was concentrated under reduced pressure and extracted with EtOAc (100 mL × 3) and H2O (30 mL). The combined organic layers were washed with brine (30 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a 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.

[0862] 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).

[0863] Step 3: 2-[[4-(1-Ethoxyvinyl)-2-(trifluoromethyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane

[0864] 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 N2, then Pd(PPh3)4 (435.14 mg, 376.56 μmol) was added to the mixture and stirred at 100 °C under N2 for 16 h. The reaction mixture was cooled to 20 °C, then diluted with H2O (30 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over Na2SO4, 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 product) as a black oil, which was used directly in the next step without further purification.

[0865] LCMS m / z (ESI+) 337.1 [M+H]+.

[0866] Step 4: 1-[2-(Trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]ethanone

[0867] At 20 °C, 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 for 3 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, 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.

[0868] 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).

[0869] Step 5: 2-[2-(Trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]propan-2-ol

[0870] At -78 °C, MeMgBr (3 M, 35.67 mL, 3 equiv) was added to a solution of 1-[2-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]ethanone (11 g, 35.67 mmol) in THF (250 mL), and then the mixture was stirred at 25 °C under N2 for 16 h. 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 phases were washed successively with saturated aqueous NaHCO3 (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.

[0871] MS (ESI) m / z 325.1 [M+H]+.

[0872] Step 6: 2-Chloro-N-[1-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]ethyl]acetamide

[0873] A mixture of 2-[2-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]propan-2-ol (4.2 g, 12.95 mmol, 1 equiv) and 2-chloroacetonitrile (10 mL) in AcOH (6.22 g, 103.57 mmol, 5.93 mL, 8 equiv) was cooled to 0 °C in an ice bath, and then H2SO4 (11.43 g, 116.52 mmol, 6.21 mL, 9 equiv) was added. The reaction mixture was warmed to 25 °C and stirred for 18 h. The reaction mixture was quenched by adding 500 mL of NaOH (1 M) 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 a 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.

[0874] MS(ESI) m / z 270.1 [M+H]+.

[0875] Step 7: 2-[2-(trifluoromethyl)-1H-imidazol-4-yl]propan-2-amine

[0876] At 25 °C, thiourea (677.51 mg, 8.90 mmol) and acetic acid (8.02 g, 133.51 mmol, 7.64 mL, 18 equiv) were added to a solution of 2-chloro-N-[1-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]ethyl]acetamide (2 g, 7.42 mmol, 1 equiv) in EtOH (20 mL). The mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched by adding 100 mL of NaOH (1 M) at 30 °C and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with 100 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. 2-[2-(trifluoromethyl)-1H-imidazol-4-yl]propan-2-amine hydrochloride (1.1 g, 33.01% yield) was obtained as a yellow solid.

[0877] LCMS m / z(ESI+) 194.1 [M+H]+.

[0878] Intermediate I

[0879]

[0880] 2-(2,3-dichlorophenyl)-1-(1H-imidazol-4-yl)ethan-1-amine

[0881] Step 1: 2-(2,3-Dichlorophenyl)-N-methoxy-N-methyl-acetamide

[0882] At 15 °C, HATU (18.54 g, 48.77 mmol) and DIEA (15.76 g, 121.93 mmol) were added 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). The mixture was stirred at N2, 15 °C for 12 h. The mixture was concentrated under reduced pressure to give a 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.

[0883] MS(ESI) m / z = 247.6 [M+H]+.

[0884] Step 2: 2-(2,3-Dichlorophenyl)-1-(1-tritylimidazol-4-yl)ethanone

[0885] At -10 °C under N2 atmosphere, EtMgBr (3 M in THF, 7.26 mL) was added to a solution of 4-iodo-1-tritylimidazole (9.5 g, 21.77 mmol) in DCM (160 mL), and the mixture was stirred at -10 °C, N2 for 1 h. At -10 °C under N2 atmosphere, a solution of 2-(2,3-dichlorophenyl)-N-methoxy-N-methyl-acetamide (4.59 g, 18.51 mmol) in DCM (60 mL) was added to the mixture, and the mixture was stirred at 15 °C, N2 for 12 h. The mixture was poured into cold (0 °C) saturated aqueous NH4Cl solution (100 mL) and stirred for 1 h. The combined organic phases were washed with saturated aqueous NaHCO3 solution (50 mL) and brine (30 mL × 3), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a 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.

[0886] 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).

[0887] Step 3: 2-(2,3-Dichlorophenyl)-1-(1-tritylimidazol-4-yl)ethanamine

[0888] At 15 °C, NaBH3CN (189.51 mg, 3.02 mmol) and NH4OAc (1.55 g, 20.10 mmol) were added to a solution of 2-(2,3-dichlorophenyl)-1-(1-tritylimidazol-4-yl)ethanone (1 g, 2.01 mmol) in MeOH (20 mL). Then the reaction mixture was heated to 70 °C and stirred for 12 h under a N2 atmosphere. The mixture was poured into cold (0 °C) saturated aqueous NH4Cl solution (50 mL) and stirred for 1 h. Then the mixture was extracted with EtOAc (50 mL), and the combined organic phases were washed with brine (15 mL × 3), dried over Na2SO4, filtered, and the filtrate was concentrated under 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.

[0889] MS (ESI) m / z = 499.7 [M+3H]+.

[0890] Step 4: 2-(2,3-Dichlorophenyl)-1-(1H-imidazol-4-yl)ethan-1-amine

[0891] At 20 °C, HCl (1.84 g, 2.52 mmol, 1.80 mL, 1 M) was added to a solution of 2-(2,3-dichlorophenyl)-1-(1-tritylimidazol-4-yl)ethanamine (0.33 g, 179.89 μmol) in MeOH (2 mL). Then the mixture was stirred at 50 °C under N2 for 2 h. The mixture was concentrated under reduced pressure to give the crude product, and 2-(2,3-dichlorophenyl)-1-(1H-imidazol-4-yl)ethan-1-amine (22.15 mg, 36.8% yield) was obtained as a yellow solid.

[0892] MS (ESI) m / z = 256.1 [M+H]+.

[0893] Intermediate J

[0894]

[0895] 2-(2,3-Dichlorophenyl)-1-(1,2,4-oxadiazol-5-yl)ethan-1-amine

[0896] Step 1: tert-Butyl (1-amino-3-(2,3-dichlorophenyl)-1-oxopropan-2-yl)carbamate

[0897] 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 NH4Cl (166.38 mg, 3.11 mmol). The reaction mixture was stirred at 15 °C under a N2 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 an off-white solid.

[0898] MS(ESI) m / z = 233.0 [M - Boc + H]+.

[0899] Step 2: (Z)-(3-(2,3-dichlorophenyl)-1-(((dimethylamino)methylene)amino)-1-oxopropan-2-yl)carbamate

[0900] 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-dimethylmethanamine (147.84 mg, 1.24 mmol). The reaction mixture was stirred at 45 °C under a N2 atmosphere for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The product (Z)-(3-(2,3-dichlorophenyl)-1-(((dimethylamino)methylene)amino)-1-oxopropan-2-yl)carbamate (544 mg, 100%) was obtained as a colorless oil.

[0901] MS(ESI) m / z = 388.0 [M + H]+.

[0902] Step 3: tert-butyl (2-(2,3-dichlorophenyl)-1-(1,2,4-oxadiazol-5-yl)ethyl)carbamate

[0903] 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 N2 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 2-(2,3-dichlorophenyl)-1-(1,2,4-oxadiazol-5-yl)ethyl)carbamate (202 mg, 59.18% yield) as an off-white solid.

[0904] MS(ESI) m / z = 302.0 [M-tBu+H]+.

[0905] Step 4: 2-(2,3-dichlorophenyl)-1-(1,2,4-oxadiazol-5-yl)ethan-1-amine

[0906] 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 an off-white solid.

[0907] MS(ESI) m / z = 258.0 [M+H]+.

[0908] Intermediate K

[0909]

[0910] (R or S)-1-(1-(difluoromethyl)-1H-pyrazol-3-yl)propane-1,3-diamine

[0911] Step 1: (R or S)-4-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)butanoic acid

[0912] At 0 °C, an aqueous solution of NaHCO3 (1.1 M, 125.00 mL) was added to a stirred solution of (2R or 2S)-4-amino-2-(tert-butoxycarbonylamino)butyric acid (10 g, 45.82 mmol) in acetone (125 mL), and the reaction mixture was stirred at 0 °C under a N2 atmosphere for 10 min. Then benzyl chloroformate (9.38 g, 55.00 mmol) in toluene (3 mL) was added, and the reaction mixture was stirred at 15 °C under a N2 atmosphere for 12 h. 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).

[0913] MS(ESI) m / z = 375.0 [M+Na]+.

[0914] Step 2: tert-Butyl N-[(1R or 1S)-3-(benzyloxycarbonylamino)-1-[methoxy(methyl)carbamoyl]propyl]carbamate

[0915] At 0 °C, EDCI (7.18 g, 37.46 mmol) and HOBt (5.06 g, 37.46 mmol) were added 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). Then N-methoxymethanamine; hydrochloride (3.65 g, 37.46 mmol) and TEA (3.79 g, 37.46 mmol) were added to the mixture, and the mixture was stirred at 15 °C under N2 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.

[0916] MS(ESI) m / z = 395.8 [M+H]+.

[0917] Step 3: tert-Butyl N-[(1R or 1S)-1-[2-(benzyloxycarbonylamino)ethyl]-2-oxopropyl]carbamate

[0918] At -78 °C, under N2, bromo(methyl)magnesium (3 M in diethyl ether, 15.17 mL) was added 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) over 1 h, and then the mixture was stirred at 30 °C under N2 for 16 h. At 0 °C, the mixture was poured into saturated aqueous NH4Cl solution (20 mL) and stirred for 1 h. The mixture was then extracted with EtOAc (300 mL × 2). The combined organic phases were washed with saturated aqueous NaHCO3 solution (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-oxopropyl]carbamate (4.67 g, crude product) as a yellow oil.

[0919] MS (ESI) m / z = no expected mass.

[0920] Step 4: tert-butyl N-[(E,1R or 1S)-1-[2-(benzyloxycarbonylamino)ethyl]-4-(dimethylamino)-2-oxo-but-3-enyl]carbamate

[0921] DMF-DMA (3.18 g, 26.65 mmol) was added to a solution of tert-butyl N-[(1R or 1S)-1-[2-(benzyloxycarbonylamino)ethyl]-2-oxopropyl]carbamate (4.67 g, 13.33 mmol) in MeCN (50 mL). The reaction mixture was stirred at 85 °C under N2 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 product) as a yellow oil.

[0922] MS (ESI) m / z = no expected mass.

[0923] Step 5: tert-butyl N-[(1R or 1S)-3-(benzyloxycarbonylamino)-1-(1H-pyrazol-3-yl)propyl]carbamate

[0924] At 80 °C, hydrazine hydrate (1.26 g, 24.66 mmol) was added to a solution of tert-butyl N-[(E,1R or 1S)-1-[2-(benzyloxycarbonylamino)ethyl]-4-(dimethylamino)-2-oxo-but-3-enyl]carbamate (5 g, 12.33 mmol) in EtOH (80 mL), and the mixture was stirred at 80 °C under N2 for 0.5 h. The reaction mixture was quenched by the addition of H2O (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 Na2SO4, filtered, and concentrated under reduced pressure to give a 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, 9.10% yield) as a yellow oil.

[0925] MS(ESI) m / z = 375.2 [M+H]+.

[0926] Step 6: tert-butyl N-[(1R or 1S)-3-(benzyloxycarbonylamino)-1-[1-(difluoromethyl)pyrazol-3-yl]propyl]carbamate

[0927] 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]oxirane (128.36 mg, 480.73 μmol). The mixture was stirred at 50 °C under N2 for 12 h. The reaction mixture was concentrated under reduced pressure to give a 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.

[0928] 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).

[0929] Step 7: (R or S)-1-(1-(difluoromethyl)-1H-pyrazol-3-yl)propane-1,3-diamine

[0930] At 15 °C, HCl (5 mL) was added to a solution of tert-butyl N-[(1R or 1S)-3-(benzyloxycarbonylamino)-1-[1-(difluoromethyl)-1H-pyrazol-3-yl]propyl]carbamate (82 mg, 193.20 μmol) in 1,4-dioxane (3 mL), and the mixture was stirred at 15 °C under a N2 atmosphere for 16 h. The mixture was concentrated under reduced pressure to obtain (R or S)-1-(1-(difluoromethyl)-1H-pyrazol-3-yl)propane-1,3-diamine (36.7 mg, crude product) as a yellow oil.

[0931] MS(ESI) m / z = 325.2 [M+H]+.

[0932] Intermediate L

[0933]

[0934] 2-(4-Chloro-2,3-difluoro-phenyl)ethylamine

[0935] Step 1: tert-Butyl N-[2-(4-chloro-2,3-difluoro-phenyl)ethyl]carbamate

[0936] To a solution of 1-bromo-4-chloro-2,3-difluoro-benzene (1 g, 4.40 mmol), 2-(tert-butoxycarbonylamino)ethyl-trifluoroboranuide (1.10 g, 4.40 mmol) in toluene (36 mL) and H2O (6 mL) were added Cs2CO3 (4.30 g, 13.19 mmol), Pd(OAc)2 (98.71 mg, 439.69 μmol) and dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (205.17 mg, 439.69 μmol), and the mixture was stirred at 100 °C under N2 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), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain tert-butyl N-[2-(4-chloro-2,3-difluoro-phenyl)ethyl]carbamate (960 mg, 74.84% yield) as a yellow oil.

[0937] 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).

[0938] Step 2: 2-(4-Chloro-2,3-difluoro-phenyl)ethylamine

[0939] To a solution of tert-butyl N-[2-(4-chloro-2,3-difluorophenyl)ethyl]carbamate (960 mg, 3.29 mmol) in dioxane (12 mL) was added HCl / dioxane (4 M, 12 mL). The mixture was stirred at N2, 25 °C for 4 h. The reaction mixture was concentrated under reduced pressure to give the crude product 2-(4-chloro-2,3-difluorophenyl)ethylamine (750 mg, crude), as a white solid.

[0940] 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).

[0941] Intermediate M

[0942]

[0943] 5-(1-Amino-1-methylethyl)-2-(difluoromethyl)pyrazol-3-amine

[0944] Step 1: tert-Butyl N-(3-cyano-1,1-dimethyl-2-oxopropyl)carbamate

[0945] At -78 °C, NaHMDS (1 M, 124.27 mL) was added dropwise to a solution of CH3CN (5.10 g, 124.27 mmol) in THF (100 mL). After addition, the mixture was stirred at -50 °C for 20 min and then 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid methyl ester (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 h. CH3COOH (7.96 g, 132.56 mmol) was added to the mixture at -78 °C. The reaction mixture was concentrated under reduced pressure to give tert-Butyl N-(3-cyano-1,1-dimethyl-2-oxopropyl)carbamate (7 g, crude), as a dark brown solid.

[0946] MS (ESI) m / z = 227.1 [M+H]+.

[0947] Step 2: tert-Butyl N-[1-(5-amino-1H-pyrazol-3-yl)-1-methylethyl]carbamate

[0948] At 0 °C, acetic acid (5.57 g, 92.81 mmol) and hydrazine hydrate (5.47 g, 92.81 mmol) were added to a solution of tert-butyl N-(3-cyano-1,1-dimethyl-2-oxopropyl)carbamate (7 g, 30.94 mmol) in EtOH (100 mL). 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-methylethyl]carbamate (3.5 g, 37.66% yield) as a yellow oil.

[0949] MS(ESI) m / z = 141.2

[0950] Step 3: tert-butyl N-[1-[5-amino-1-(difluoromethyl)pyrazol-3-yl]-1-methylethyl]carbamate

[0951] At 20 °C under N2, tert-butyl N-[1-(5-amino-1H-pyrazol-3-yl)-1-methylethyl]carbamate (1 g, 4.16 mmol) was added 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). The mixture was stirred at 20 °C for 18 h. The reaction mixture was diluted with H2O (30 mL) and extracted with DCM (40 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over Na2SO4, filtered and 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-1-(difluoromethyl)pyrazol-3-yl]-1-methylethyl]carbamate (355 mg, 22.33% yield) as a white solid.

[0952] MS(ESI) m / z = 291.2 [M+H]+.

[0953] Step 4: 5-(1-amino-1-methylethyl)-2-(difluoromethyl)pyrazol-3-amine

[0954] A mixture of tert-butyl N-[1-[5-amino-1-(difluoromethyl)pyrazol-3-yl]-1-methylethyl]carbamate (355 mg, 1.22 mmol) and HCl / dioxane (4 M, 2.60 mL) in DCM (6 mL) was stirred at 25 °C for 18 h. The reaction mixture was concentrated under reduced pressure to give 5-(1-amino-1-methylethyl)-2-(difluoromethyl)pyrazol-3-amine (360 mg, crude product) as a white solid.

[0955] MS(ESI) m / z = 191.1 [M+H]+.

[0956] Intermediate N

[0957]

[0958] (1S or 1R)-2-methyl-1-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]propan-1-amine

[0959] Step 1: tert-Butyl N-[(1S or 1R)-1-(hydrazinecarbonyl)-2-methylpropyl]carbamate

[0960] Hydrazine hydrate (5.19 g, 103.77 mmol, 5.04 mL) was added to a solution of methyl (2S or 2R)-2-(tert-butoxycarbonylamino)-3-methylbutanoate (8 g, 34.59 mmol) in MeOH (80 mL), and then the reaction mixture was stirred at 85 °C for 12 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was dissolved in DCM (100 mL), then extracted with DCM (100 mL × 3) and water (100 mL), the combined organic phases were washed with brine (120 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product (12.2 g, 100% yield).

[0961] 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).

[0962] Step 2: tert-Butyl N-[(1S or 1R)-2-methyl-1-[[(2,2,2-trifluoroacetyl)amino]carbamoyl]propyl]carbamate

[0963] At 0 °C, (CF3CO)2O (2.18 g, 10.38 mmol, 1.44 mL) was added dropwise to a solution of tert-butyl N-[(1S or 1R)-1-(hydrazinocarbonyl)-2-methylpropyl]carbamate (2.0 g, 8.65 mmol) and DIEA (2.24 g, 17.29 mmol, 3.01 mL) in DCM (20 mL). The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into water (30 mL), extracted with DCM (50 mL × 3), the combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, 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 product), as a colorless oil.

[0964] LCMS m / z (ESI+) 271.1 [M+H]+.

[0965] Step 3: tert-Butyl N-[(1S or 1R)-2-methyl-1-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]propyl]carbamate

[0966] At 25 °C, Burgess reagent (4.37 g, 18.33 mmol) was added 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). The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into water (30 mL), extracted with EtOAc (50 mL × 3), the combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a 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.

[0967] LCMS m / z (ESI+) 254.0 [M+H]+.

[0968] Step 4: (1S or 1R)-2-Methyl-1-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]propan-1-amine

[0969] To a solution 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). The mixture was stirred in a microwave at 150 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue, yielding (1S or 1R)-2-methyl-1-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]propan-1-amine (67 mg, crude product), as a yellow oil.

[0970] 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).

[0971] General method for target compound A

[0972]

[0973] General method for target compound B

[0974]

[0975] General method for target compound C

[0976]

[0977] General method for target compound D

[0978]

[0979] General method for target compound E

[0980]

[0981] Example 1.

[0982]

[0983] N2-(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 method for target compound A)

[0984] Step 1: 6-Chloro-N2-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methylethyl]-1,3,5-triazine-2,4-diamine

[0985] 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 N2, and then the mixture was stirred at 90 °C under N2 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-N2-[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.

[0986] MS(ESI) m / z = 304.1 [M+H]+.

[0987] 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

[0988] A mixture of 6-chloro-N2-[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), K3PO4 (87.37 mg, 411.59 μmol), and di-tert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (10.73 mg, 16.46 μmol) in THF (10 mL) and H2O (1 mL) was degassed and purged with N2, and then the mixture was stirred at 90 °C under N2 for 12 h. The reaction mixture was concentrated under reduced pressure to give the 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.

[0989] MS(ESI) m / z = 401.0 [M+H]+.

[0990] 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).

[0991] Example 2

[0992]

[0993] 6-(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 method for target compound A)

[0994] LCMS m / z (ESI+) 466.0 [M+H] + .

[0995] 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).

[0996] Example 3

[0997]

[0998] (S or R)-Methyl 2-((2-amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)pyrimidin-4-yl)amino)-3-(2,3-dichlorophenyl)propionate (General method for target compound A)

[0999] LCMS m / z (ESI+) 471.0 [M+H] + .

[1000] 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).

[1001] Example 4

[1002]

[1003] (2S or 2R)-Methyl 2-[[4-amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazin-2-yl]amino]-3-(2,3-dichlorophenyl)propionate (General method for target compound A)

[1004] LCMS m / z (ESI+) 472.0 [M+H] + .

[1005] 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).

[1006] Example 5

[1007]

[1008] 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 (General method for target compound B)

[1009] Step 1: 4,6-Dichloro-N-(trideuteriomethyl)-1,3,5-triazin-2-amine

[1010] Dissolve 2,4,6-trichloro-1,3,5-triazine (2 g, 10.85 mmol) in THF (20 mL) and cool to -70 °C. Add DIPEA (2.80 g, 21.69 mmol) and trideuteriomethylamine; hydrochloride (764.99 mg, 10.85 mmol) to the reaction mixture, stir at -70 °C for 1 h, and allow it to warm to 25 °C and maintain for 12 h. Concentrate the reaction mixture under reduced pressure to obtain a residue. Purify the residue by flash silica gel chromatography to obtain 4,6-dichloro-N-(trideuteriomethyl)-1,3,5-triazin-2-amine (1.2 g, 46.20% yield) as a white solid.

[1011] MS (ESI) m / z = 182.1 [M+H]+

[1012] 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

[1013] 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 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to afford 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.

[1014] MS(ESI) m / z = 339.2 [M+H]+

[1015] 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

[1016] A mixture of 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-dioxaborolan-2-yl)imidazo[1,5-a]pyridine (228.61 mg, 885.65 μmol), di-tert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (14.43 mg, 22.14 μmol), K3PO4 (187.99 mg, 885.65 μmol) in THF (5 mL) and H2O (5 mL) was degassed and purged with N2, and then the mixture was stirred at 90 °C under N2 for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography to afford 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.

[1017] MS(ESI) m / z 435.2 [M+H] + .

[1018] 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).

[1019] Example 6

[1020]

[1021] (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 method for target compound B)

[1022] MS(ESI) m / z 449.2 [M+H] + .

[1023] 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).

[1024] Examples 7A and 7B

[1025]

[1026] N4-[(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 method for target compound B)

[1027] 7A

[1028] MS(ESI) m / z 444.2 [M+H] + .

[1029] 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).

[1030] 7B

[1031] LCMS m / z (ESI+) 444.2 [M + H] + .

[1032] 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).

[1033] Example 8

[1034]

[1035] 6-(1H-Indazol-5-yl)-N4-[(1R or 1S)-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine (general method for target compound C)

[1036] Step 1: 6-Chloro-N4-[(1R or 1S)-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-1,3,5-triazine-2,4-diamine

[1037] 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.

[1038] MS(ESI) m / z = 322.0 [M+H]+.

[1039] 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

[1040] To a solution of 6-chloro-N4-[(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 H2O (0.7 mL) was added K3PO4 (1.03 g, 4.85 mmol) and di-tert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (105.35 mg, 161.65 μmol) and the mixture was degassed and purged with N2, then stirred at 90 °C under N2 for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with dichloromethane (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, 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)-N4-[(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.

[1041] MS(ESI) m / z = 488.2 [M+H]+.

[1042] 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

[1043] 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 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 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) as a white solid.

[1044] LCMS m / z (ESI+) 404.0 [M+H] + .

[1045] 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).

[1046] Example 9

[1047]

[1048] N2-(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 method for target compound A)

[1049] LCMS m / z (ESI+) 403.1 [M+H] + .

[1050] 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)

[1051] Example 10

[1052]

[1053] 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 (General method for target compound C)

[1054] Step 1: 6-Chloro-N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methyl-ethyl]-1,3,5-triazine-2,4-diamine

[1055] 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-triazine-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 mixture was concentrated under reduced pressure to give a residue. The residue 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 pale yellow solid.

[1056] MS(ESI) m / z = 304.0 [M+H]+.

[1057] 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

[1058] To a stirred solution of 6-chloro-N4-[1-[1-(difluoromethyl)-1H-pyrazol-3-yl]-1-methylethyl]-1,3,5-triazine-2,4-diamine (1.27 g, 4.17 mmol) in THF (67.5 mL) and H2O (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), di-tert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (272.09 mg, 417.48 μmol) and K2CO3 (1.15 g, 8.35 mmol), and the reaction mixture was stirred at 75 °C under N2 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 N2-[1-[1-(difluoromethyl)-1H-pyrazol-3-yl]-1-methylethyl]-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) as a brown solid.

[1059] MS(ESI) m / z = 521.2 [M+H]+.

[1060] Step 3: 6-(3-Aminoimidazo[1,5-a]pyridin-6-yl)-N2-[1-[1-(difluoromethyl)-1H-pyrazol-3-yl]-1-methylethyl]-1,3,5-triazine-2,4-diamine

[1061] At 15 °C, to a solution of N2-[1-[1-(difluoromethyl)-1H-pyrazol-3-yl]-1-methylethyl]-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). The mixture was stirred at 15 °C for 6 h. The reaction was filtered and 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)-1H-pyrazol-3-yl]-1-methylethyl]-1,3,5-triazine-2,4-diamine (410 mg, 26.65% yield) as a yellow solid.

[1062] MS(ESI) m / z = 401.1 [M+H]+.

[1063] 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).

[1064] Example 11

[1065]

[1066] 6-(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 method for target compound C)

[1067] LCMS m / z (ESI+) 419.2 [M+H] + .

[1068] 1H NMR (400 MHz, methanol-d4) δ = 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)

[1069] Example 12

[1070]

[1071] 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 (General method for target compound E)

[1072] Step 1: 4,6-Dichloro-N-(2-(1-(difluoromethyl)-1H-pyrazol-3-yl)propan-2-yl)-1,3,5-triazin-2-amine

[1073] At -70 °C under N2, to a stirred solution of 2-[1-(difluoromethyl)pyrazol-3-yl]propan-2-amine (165 mg, 779.63 μmol) in THF (4 mL) 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 N2 for 1 h, then warmed to 15 °C under N2 and maintained for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue 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 an off-white solid.

[1074] MS(ESI) m / z = 323.0 [M+H]+.

[1075] 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

[1076] 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 H2O (1.5 mL) was added K3PO4 (197.07 mg, 928.42 μmol) and di-tert-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.

[1077] MS(ESI) m / z = 419.1 [M+H]+.

[1078] 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

[1079] A solution 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 N2, then the mixture was stirred at 15 °C under a N2 atmosphere for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 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) as a yellow solid.

[1080] MS (ESI) m / z = 410.3 [M+H]+.

[1081] 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).

[1082] Example 13

[1083]

[1084] N2-[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

[1085] Step 1: N-[(5-Bromopyrazin-2-yl)methyl]acetamide

[1086] To a stirred solution of (5-bromopyrazin-2-yl)methanamine (20 g, 74.37 mmol) in DCM (600 mL) was added Et3N (22.58 g, 223.10 mmol). Acetyl chloride (11.68 g, 148.73 mmol) was then added dropwise 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 Na2SO4 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.

[1087] MS (ESI) m / z 230.1 [M+H]+.

[1088] Step 2: 6-Bromo-3-methylimidazo[1,5-a]pyrazine

[1089] At 0 °C, TFAA (34.69 g, 165.17 mmol) was added 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), and the reaction mixture was stirred at 15 °C under N2 for 12 h. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography to give 6-bromo-3-methylimidazo[1,5-a]pyrazine (3.3 g, 18.84% yield) as an off-white solid.

[1090] MS (ESI) m / z 211.9 [M+H]+.

[1091] Step 3: Tributyl-(3-methylimidazo[1,5-a]pyrazin-6-yl)stannane

[1092] Under N2, Pd2(dba)3 (215.92 mg, 235.80 μmol), dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane (193.60 mg, 471.59 μmol), Na2CO3 (749.76 mg, 7.07 mmol) and hexabutylditin (2.74 g, 4.72 mmol, 2.36 mL) were added to a stirred solution of 6-bromo-3-methylimidazo[1,5-a]pyrazine (500 mg, 2.36 mmol) in dioxane (10 mL), and the reaction mixture was stirred at 110 °C under a N2 atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to give a 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.

[1093] MS(ESI) m / z = 424.0 [M+H]+.

[1094] 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

[1095] A stirred solution of tributyl-(3-methylimidazo[1,5-a]pyrazin-6-yl)stannane (60 mg, 142.11 μmol), 6-chloro-N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methylethyl]-1,3,5-triazine-2,4-diamine (Example 10-1, 43.16 mg, 142.11 μmol) and Pd(PPh3)4 (16.42 mg, 14.21 μmol) in DMSO (4 mL) was charged into a microwave tube. The sealed tube was heated at 160 °C under microwave for 2 h. The crude product was purified by column chromatography to give 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) as a white solid.

[1096] MS(ESI) m / z = 401.2 [M+H]+.

[1097] 1H NMR (400 MHz, methanol-d4) δ = 9.10 (d, J = 3.6 Hz, 2H), 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)

[1098] Example 14

[1099]

[1100] 4-(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 method for target compound E)

[1101] MS(ESI) m / z = 428.2 [M+H]+.

[1102] 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).

[1103] Example 15

[1104]

[1105] (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 method for target compound E)

[1106] MS(ESI) m / z = 468.1 [M+H]+.

[1107] 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).

[1108] Example 16

[1109]

[1110] N4-[2-Amino-2-(2,3-dichlorophenyl)ethyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)pyrimidine-2,4-diamine (General method for target compound A)

[1111] MS(ESI) m / z = 428.1 [M+H]+.

[1112] 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).

[1113] Example 17

[1114]

[1115] N4-[2-(2,3-Dichlorophenyl)-2-(methylamino)ethyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)pyrimidine-2,4-diamine (General method for target compound A)

[1116] MS(ESI) m / z = 442.1 [M+H]+.

[1117] 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).

[1118] Example 18

[1119]

[1120] N-[2-[[2-Amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)pyrimidin-4-yl]amino]-1-(2,3-dichlorophenyl)ethyl]acetamide

[1121] 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 N2 for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give the product N-[2-[[2-amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)pyrimidine-4-yl]amino]-1-(2,3-dichlorophenyl)ethyl]acetamide (9.01 mg, 30.28% yield) as a yellow solid.

[1122] MS(ESI) m / z = 470.1 [M+H]+.

[1123] 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).

[1124] Example 19

[1125]

[1126] N-[2-[[2-amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)pyrimidine-4-yl]amino]-1-(2,3-dichlorophenyl)ethyl]-N-methyl-acetamide

[1127] To a stirred solution of N4-[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 at 15 °C under N2 for 24 h. The reaction mixture was concentrated under reduced pressure to remove DCM. The crude product was purified by column chromatography to give N-[2-[[2-amino-6-(3-methylimidazo[1,5-a]pyridin-6-yl)pyrimidine-4-yl]amino]-1-(2,3-dichlorophenyl)ethyl]-N-methyl-acetamide (16.78 mg, 15.32% yield) as a white solid.

[1128] MS(ESI) m / z = 484.2 [M+H]+.

[1129] 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).

[1130] Example 20

[1131]

[1132] (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-propionamide

[1133] Step 1: tert-Butyl N-[(1S or 1R)-1-[(2,3-dichlorophenyl)methyl]-2-(methoxyamino)-2-oxo-ethyl]carbamate

[1134] At 0 °C under N2, 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-methylhydroxylamine (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), and the reaction mixture was stirred at 15 °C under N2 atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to give a 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.

[1135] MS(ESI) m / z = 306.9 [M-tBu+H]+.

[1136] Step 2: (2S or 2R)-2-Amino-3-(2,3-dichlorophenyl)-N-methoxy-propanamide

[1137] To 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), and the reaction mixture was stirred at 15 °C under N2 atmosphere 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 an off-white solid.

[1138] MS(ESI) m / z = 263.1 [M+H]+.

[1139] Step 3: (2S or 2R)-2-[(4-Amino-6-chloro-1,3,5-triazin-2-yl)amino]-3-(2,3-dichlorophenyl)-N-methoxy-propanamide

[1140] 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 N2 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 an off-white solid.

[1141] MS(ESI) m / z = 392.9 [M+2+H]+.

[1142] 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

[1143] 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 H2O (0.1 mL) was added K2CO3 (14.12 mg, 102.13 μmol) and di-tert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (3.33 mg, 5.11 μmol). The reaction mixture was stirred at 75 °C under N2 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.

[1144] MS(ESI) m / z = 487.1 [M+H]+.

[1145] 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).

[1146] Example 21

[1147]

[1148] 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

[1149] Step 1: (2S or 2R)-2-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-3-(2,3-dichlorophenyl)propanamide

[1150] 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 mixture was stirred at 90 °C under N2 atmosphere for 6 h. 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.

[1151] MS (ESI) m / z = 362.8 [M+H]+.

[1152] 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

[1153] 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 H2O (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), K2CO3 (496.86 mg, 3.59 mmol) and di-tert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (117.15 mg, 179.75 μmol). The mixture was stirred at 75 °C under N2 for 3 h. The reaction mixture was concentrated under reduced pressure to give a 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.

[1154] MS(ESI) m / z = 457.0 [M+H]+.

[1155] 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

[1156] 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-(triethylammonium) sulfonyl azide (416.88 mg, 1.75 mmol). The mixture was stirred at 45 °C under N2 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.

[1157] MS(ESI) m / z = 439.1 [M+H]+.

[1158] 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

[1159] 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), Et3N (69.10 mg, 682.90 μmol) and NaN3 (44.40 mg, 682.90 μmol). The mixture was stirred at 100 °C for 12 h under N2 atmosphere. 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.

[1160] MS(ESI) m / z = 482.1 [M+H]+.

[1161] 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).

[1162] Example 22

[1163]

[1164] 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 method for target compound A)

[1165] MS(ESI) m / z = 480.0 [M+H]+.

[1166] 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).

[1167] Example 23

[1168]

[1169] 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 method for target compound A)

[1170] MS (ESI) m / z = 482.1 [M + H]+.

[1171] 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, 1H), 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).

[1172] Example 24

[1173]

[1174] 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 method for target compound C)

[1175] MS (ESI) m / z = 418.2 [M + H]+.

[1176] 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).

[1177] Example 25

[1178]

[1179] 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 method for target compound A)

[1180] MS (ESI) m / z = 415.1 [M+H]+.

[1181] 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).

[1182] Example 26

[1183]

[1184] N4-[1-[1-(Difluoromethyl)pyrazol-3-yl]-1-methylethyl]-6-(1H-indazol-5-yl)-N2-methyl-1,3,5-triazine-2,4-diamine (General method for target compound D)

[1185] Step 1: 4,6-Dichloro-N-methyl-1,3,5-triazin-2-amine

[1186] 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 methylamine (1.10 g, 16.27 mmol) were added to the reaction mixture, and it was stirred at -70 °C for 1 h and then warmed to 15 °C and maintained at 15 °C for 11 h under a N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue 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 an off-white solid.

[1187] 1H NMR (400 MHz, DMSO-d6) δ = 9.01 (br s, 1H), 2.83 (s, 3H).

[1188] Step 2: 6-chloro-N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methylethyl]-N2-methyl-1,3,5-triazine-2,4-diamine

[1189] To a solution of 4,6-dichloro-N-methyl-1,3,5-triazin-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 then 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-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methylethyl]-N2-methyl-1,3,5-triazine-2,4-diamine (205 mg, 68.28% yield) as a white solid.

[1190] 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).

[1191] Step 3: N4-[1-[1-(difluoromethyl)pyrazol-3-yl]-1-methylethyl]-N2-methyl-6-(1-tetrahydropyran-2-ylindazol-5-yl)-1,3,5-triazine-2,4-diamine

[1192] To a stirred solution of 6-chloro-N4-[1-[1-(difluoromethyl)-1H-pyrazol-3-yl]-1-methylethyl]-N2-methyl-1,3,5-triazine-2,4-diamine (205 mg, 645.21 μmol) in THF (2 mL) and H2O (0.2 mL) was added 1-(tetrahydropyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (317.65 mg, 967.82 μmol), di-tert-butyl(cyclopentyl)phosphane; dichloropalladium; ferrous (42.05 mg, 64.52 μmol), di-tert-butyl(cyclopentyl)phosphane; dichloropalladium; ferrous (42.05 mg, 64.52 μmol) and K2CO3 (178.34 mg, 1.29 mmol), and the reaction mixture was stirred at 75 °C under N2 atmosphere for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give N4-[1-[1-(difluoromethyl)-1H-pyrazol-3-yl]-1-methylethyl]-N2-methyl-6-(1-(tetrahydropyran-2-yl)-1H-indazol-5-yl)-1,3,5-triazine-2,4-diamine (170 mg, 54.49% yield) as a yellow solid.

[1193] MS (ESI) m / z = 484.1 [M+H]+.

[1194] Step 4: N4-[1-[1-(Difluoromethyl)-1H-pyrazol-3-yl]-1-methylethyl]-6-(1H-indazol-5-yl)-N2-methyl-1,3,5-triazine-2,4-diamine

[1195] To a solution of N4-[1-[1-(difluoromethyl)-1H-pyrazol-3-yl]-1-methylethyl]-N2-methyl-6-(1-(tetrahydropyran-2-yl)-1H-indazol-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 at 15 °C under N2 for 12 h. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography to give N4-[1-[1-(difluoromethyl)-1H-pyrazol-3-yl]-1-methylethyl]-6-(1H-indazol-5-yl)-N2-methyl-1,3,5-triazine-2,4-diamine (47.01 mg, 35.57% yield) as a white solid.

[1196] MS (ESI) m / z = 399.7 [M+H]+.

[1197] 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).

[1198] Example 27

[1199]

[1200] 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 method for target compound D)

[1201] MS (ESI) m / z = 414.2 [M + H]+.

[1202] 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).

[1203] Example 28

[1204]

[1205] 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 method for target compound A)

[1206] MS (ESI) m / z = 435.2 [M + H]+.

[1207] 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).

[1208] Example 29A & Example 29B

[1209]

[1210] 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 method for target compound B)

[1211] 29A

[1212] MS(ESI) m / z = 434.2 [M+H]+.

[1213] 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).

[1214] 29B

[1215] MS(ESI) m / z = 434.3 [M+H]+.

[1216] 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, 1H), 5.20 (br s, 1H), 2.25 (m, 1H), 1.01 (d, 3H), 0.90 (d, 3H).

[1217] Example 30

[1218]

[1219] 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 method for target compound D)

[1220] MS(ESI) m / z = 418.2 [M+H]+.

[1221] 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).

[1222] Example 31

[1223]

[1224] 6-(1-Methyl-1H-indazol-6-yl)-N4-[(1R)-2-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]propyl]-N2-(trideuteriomethyl)-1,3,5-triazine-2,4-diamine (General method for target compound B)

[1225] MS(ESI) m / z = 449.2 [M+H]+.

[1226] *13461H 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).

[1227] Example 32

[1228]

[1229] 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 method for target compound B)

[1230] MS(ESI) m / z = 416.1 [M+H]+.

[1231] 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).

[1232] Example 33

[1233]

[1234] N4-[(R)-Cyclopropyl-[1-(difluoromethyl)-1H-pyrazol-3-yl]methyl]-6-(1H-indazol-5-yl)-1,3,5-triazine-2,4-diamine (General method for target compound B)

[1235] MS(ESI) m / z = 398.2 [M+H]+.

[1236] 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).

[1237] Example 34

[1238]

[1239] 6-(1-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 method for target compound A)

[1240] MS (ESI) m / z = 432.2 [M+H]+.

[1241] 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).

[1242] Example 35

[1243]

[1244] 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 method for target compound A)

[1245] MS (ESI) m / z = 432.2 [M+H]+.

[1246] 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).

[1247] Example 36

[1248]

[1249] N2-[2-(6-Fluoro-2-pyridinyl)-1,1-dimethylethyl]-6-[1-(trideuteriomethyl)-1H-indazol-6-yl]-1,3,5-triazine-2,4-diamine (General method for target compound A)

[1250] MS(ESI) m / z = 396.2 [M+H]+.

[1251] 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).

[1252] Example 37

[1253]

[1254] N4-[1-[1-(Difluoromethyl)-1H-pyrazol-3-yl]-1-methylethyl]-6-[1-(methylamino)-1H-indazol-6-yl]-1,3,5-triazine-2,4-diamine (General method for target compound A)

[1255] MS(ESI) m / z = 415.2 [M+H]+.

[1256] 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).

[1257] Example 38

[1258]

[1259] 6-[4-Amino-6-[[1-[1-(difluoromethyl)-1H-pyrazol-3-yl]-1-methylethyl]amino]-1,3,5-triazin-2-yl]imidazo[1,5-a]pyridin-3-ol (General method for target compound A)

[1260] MS(ESI) m / z = 402.1 [M+H]+.

[1261] 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).

[1262] Example 39

[1263]

[1264] N2-[1-Methyl-1-[4-(trifluoromethyl)thiazol-2-yl]ethyl]-6-[1-(trideuteriomethyl)indazol-6-yl]-1,3,5-triazine-2,4-diamine (General method for target compound A)

[1265] MS(ESI) m / z = 438.1 [M+H]+.

[1266] 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).

[1267] Example 40

[1268]

[1269] N4-[1,1-Dimethyl-2-[3-(trifluoromethyl)pyrazol-1-yl]ethyl]-6-[1-(trideuteriomethyl)indazol-6-yl]pyrimidine-2,4-diamine (General method for target compound A)

[1270] MS(ESI) m / z = 434.2 [M+H]+.

[1271] 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).

[1272] Example 41

[1273]

[1274] 6-(3-Aminoimidazo[1,5-a]pyridin-6-yl)-N2-[2-(2,3-dichlorophenyl)-1,1-dimethylethyl]-1,3,5-triazine-2,4-diamine (General method for target compound B)

[1275] MS(ESI) m / z = 443.1 [M+H]+.

[1276] 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).

[1277] Example 42

[1278]

[1279] 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 method for target compound B)

[1280] MS (ESI) m / z = 417.2 [M+H]+.

[1281] 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).

[1282] Example 43

[1283]

[1284] 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 method for target compound B)

[1285] MS (ESI) m / z = 432.4 [M+H]+.

[1286] 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).

[1287] Example 44

[1288]

[1289] 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 method for target compound A)

[1290] MS(ESI) m / z = 446.2 [M+H]+.

[1291] 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).

[1292] Example 45

[1293]

[1294] 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 method for target compound A)

[1295] MS(ESI) m / z = 450.2 [M+H]+.

[1296] 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).

[1297] Example 46

[1298]

[1299] 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

[1300] MS(ESI) m / z = 399.9 [M+H]+.

[1301] 1H NMR (400 MHz, 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).

[1302] Example 47A

[1303]

[1304] (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

[1305] MS(ESI) m / z = 414.2 [M + H]+.

[1306] 1H NMR (400 MHz, DMSO-d6): δ = 8.71 (s, 1H), 8.29 (br d, 1H), 8.20 (s, 1H), 8.09 (brs, 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).

[1307] Example 48

[1308]

[1309] 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

[1310] MS(ESI) m / z = 399.9 [M + H]+.

[1311] 1H NMR (400 MHz, 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).

[1312] Example 135

[1313]

[1314] 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 method for target compound B)

[1315] MS(ESI) m / z 414.2 [M+H]+.

[1316] 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).

[1317] Example 136A & Example 136B

[1318]

[1319] 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 method for target compound A)

[1320] 136A

[1321] MS(ESI) m / z 393.0 [M+H] + .

[1322] 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).

[1323] 136B

[1324] MS(ESI) m / z = 392.9 [M+H]+.

[1325] 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).

[1326] Example 137

[1327]

[1328] (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 method for target compound A)

[1329] MS (ESI) m / z 426.2 [M+H] + .

[1330] 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).

[1331] Example 138

[1332]

[1333] (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 method for target compound B)

[1334] MS (ESI) m / z 472.1 [M+H] + .

[1335] 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).

[1336] Example 139

[1337]

[1338] 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 method for target compound A)

[1339] MS(ESI) m / z 364.9 [M+H] + .

[1340] 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).

[1341] Example 140

[1342]

[1343] 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 method for target compound A)

[1344] MS(ESI) m / z 378.9 [M+H] + .

[1345] 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).

[1346] Example 141A & Example 141B

[1347]

[1348] 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 method for target compound A)

[1349] 141A

[1350] MS(ESI) m / z 379.2 [M+H] + .

[1351] 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).

[1352] 141B

[1353] LCMS m / z (ESI+) 379.2 [M+H] + .

[1354] 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).

[1355] Example 142A & Example 142B

[1356]

[1357] 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 method for target compound A)

[1358] 142A

[1359] LCMS (ESI) m / z = 432.0 [M+H]+.

[1360] 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).

[1361] 142B

[1362] LCMS m / z (ESI+) 432.3 [M+H] + .

[1363] 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).

[1364] Example 143A & Example 143B

[1365]

[1366] (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 method for target compound B)

[1367] 143A

[1368] LCMS m / z (ESI+) 443.1 [M+H] + .

[1369] 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).

[1370] 143B

[1371] LCMS m / z (ESI+) 443.1 [M+H] + .

[1372] 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).

[1373] Example 144

[1374]

[1375] (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 method for target compound A)

[1376] LCMS m / z (ESI+) 425.0 [M+H] + .

[1377] 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).

[1378] Example 145

[1379]

[1380] (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 method for target compound B)

[1381] LCMS m / z (ESI+) 471.0 [M+H] + .

[1382] 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).

[1383] Example 146A & Example 146B

[1384]

[1385] (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 method for target compound A)

[1386] 146A

[1387] LCMS m / z (ESI+) 429.9 [M + H] + .

[1388] 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).

[1389] 146B

[1390] LCMS m / z (ESI+) 429.9 [M + H] + .

[1391] 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).

[1392] Example 147

[1393]

[1394] 6-(1-Fluoro-3-methylimidazo[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

[1395] LCMS m / z = 450.2 [M+H]+.

[1396] 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).

[1397] Example 148

[1398]

[1399] (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 method for target compound A)

[1400] LCMS m / z (ESI+) 456.1 [M+H] + .

[1401] 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).

[1402] Example 149A & Example 149B

[1403]

[1404] 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 method for target compound B)

[1405] 149A

[1406] LCMS m / z (ESI+) 446.2 [M+H] + .

[1407] 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).

[1408] 149B

[1409] LCMS m / z (ESI+) 446.2 [M+H] + .

[1410] 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, 3H), 2.66 (s, 3H), 2.25 - 2.19 (m, 1H), 0.97 (br d, J=6.8 Hz, 3H), 0.87 (d, 3H).

[1411] Example 150

[1412]

[1413] 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 method for target compound A)

[1414] LCMS m / z (ESI+) 431.1 [M+H] + .

[1415] 1H NMR (400 MHz, methanol = 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).

[1416] Example 151

[1417]

[1418] 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 method for target compound A)

[1419] LCMS m / z (ESI+) 390.0 [M+H] + .

[1420] 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).

[1421] Example 152A & 152B

[1422]

[1423] 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 method for target compound A)

[1424] 152A

[1425] LCMS m / z (ESI+) 456.2 [M+H] + .

[1426] 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).

[1427] 152B

[1428] LCMS m / z (ESI+) 446.2 [M+H] + .

[1429] 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).

[1430] Example 153A & 153B

[1431]

[1432] 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 method for target compound A)

[1433] 153A

[1434] LCMS m / z (ESI+) 472.2 [M + H]+.

[1435] 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).

[1436] 153B

[1437] LCMS m / z (ESI+) 472.2 [M + H] + .

[1438] 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).

[1439] Example 154

[1440]

[1441] 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 method for target compound A)

[1442] LCMS m / z (ESI+) 430.0 [M+H] + .

[1443] 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).

[1444] Example 155A & Example 155B

[1445]

[1446] 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 method for target compound A)

[1447] 155A

[1448] LCMS m / z (ESI+) 378.2 [M+H] + .

[1449] 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).

[1450] 155B

[1451] LCMS m / z (ESI+) 378.2 [M+H] + .

[1452] 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).

[1453] Example 156

[1454]

[1455] 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

[1456] LCMS m / z (ESI+) 418.1 [M + H] + .

[1457] 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).

[1458] Example 157

[1459]

[1460] 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 method for target compound C)

[1461] LCMS m / z (ESI+) 404.2 [M + H] + .

[1462] 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).

[1463] Example 158

[1464]

[1465] 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 method of target compound A)

[1466] LCMS m / z (ESI+) 434.1 [M+H] + .

[1467] 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).

[1468] Example 159

[1469]

[1470] 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 method of target compound A)

[1471] LCMS m / z (ESI+) 392.0 [M+H] + .

[1472] 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).

[1473] Example 160

[1474]

[1475] 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 method of target compound A)

[1476] LCMS m / z (ESI+) 420.0 [M+H] + .

[1477] 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).

[1478] Example 161

[1479]

[1480] 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

[1481] At 0 °C, 60% NaH (18.91 mg, 788.08 μmol) was added 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), and the mixture was stirred for 1 h. Then, at 0 °C, MeI (104.87 mg, 738.82 μmol, 97.27 μL) was added dropwise to the mixture. The mixture was warmed to 25 °C and stirred for 1 h. The reaction mixture was diluted with H2O (100 mL) and filtered to remove insolubles. The filtrate was extracted with EtOAc (100 mL × 3). Then the organic layer was washed with brine (50 mL × 3), dried over anhydrous Na2SO4, 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.

[1482] LCMS m / z (ESI+) 446.1 [M+H] + .

[1483] 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).

[1484] Example 162

[1485]

[1486] 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 method for target compound A)

[1487] LCMS m / z (ESI+) 398.1 [M+H] + .

[1488] 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).

[1489] Example 163

[1490]

[1491] 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 method for target compound A)

[1492] LCMS m / z (ESI+) 398.1 [M+H]+.

[1493] 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).

[1494] Example 164

[1495]

[1496] 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 method for target compound A)

[1497] LCMS m / z (ESI+) 404.2 [M+H]+.

[1498] 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).

[1499] Example 165

[1500]

[1501] 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

[1502] At 0 °C, 60% NaH (18.91 mg, 788.08 μmol) was added 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), and the mixture was stirred for 1 h. Then, at 0 °C, MeI (104.87 mg, 738.82 μmol, 97.27 μL) was added dropwise to the mixture. The mixture was warmed to 25 °C and stirred for 1 h. The reaction mixture was diluted with H2O (100 mL) and filtered to remove insolubles. The filtrate was extracted with EtOAc (100 mL × 3). Then the organic layer was washed with brine (50 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to give 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 (94.95 mg, 54.1% yield) as a yellow oil.

[1503] LCMS m / z (ESI+) 446.3 [M+H] + .

[1504] 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).

[1505] Example 166

[1506]

[1507] 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 method for target compound A)

[1508] LCMS m / z (ESI+) 434.1 [M+H]+.

[1509] 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).

[1510] Example 167

[1511]

[1512] 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 method for target compound C)

[1513] MS (ESI) m / z = 400.1 [M + H] + .

[1514] 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).

[1515] Example 168

[1516]

[1517] 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 method for target compound A)

[1518] MS (ESI) m / z = 400.2 [M + H]+.

[1519] 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).

[1520] Example 169

[1521]

[1522] 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

[1523] At 0 °C, 60% NaH (22.25 mg, 927.75 μmol) was added 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), and the mixture was stirred for 1 h. Then, at 0 °C, MeI (123.37 mg, 869.20 μmol) was added dropwise to the mixture. The mixture was warmed to 25 °C and stirred for 1 h. The reaction mixture was diluted with H2O (100 mL) and filtered to remove insolubles. The filtrate was extracted with EtOAc (100 mL × 3). Then the organic layer was washed with brine (50 mL × 3), dried over anhydrous Na2SO4, 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-[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.

[1524] MS (ESI) m / z = 460.3 [M + H]+.

[1525] 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).

[1526] Example 170A & Example 170B

[1527]

[1528] (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 method for target compound A)

[1529] 170A

[1530] MS (ESI) m / z = 457.0 [M + H] + .

[1531] 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).

[1532] 170B

[1533] MS (ESI) m / z = 457.0 [M + H]+.

[1534] 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).

[1535] Example 171

[1536]

[1537] 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 method for target compound D)

[1538] MS(ESI) m / z = 414.1 [M+H]+.

[1539] 1H NMR(400MHz, 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).

[1540] Example 172

[1541]

[1542] 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 method for target compound B)

[1543] MS(ESI) m / z = 414.2 [M+H]+.

[1544] 1H NMR(400MHz 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).

[1545] Example 173

[1546]

[1547] 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 method for target compound B)

[1548] MS(ESI) m / z = 428.2 [M+H]+.

[1549] 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).

[1550] Example 174

[1551]

[1552] 6-(1-Methyl-1H-indazol-6-yl)-N4-[1-methyl-1-[2-(trifluoromethyl)-1H-imidazol-4-yl]ethyl]-1,3,5-triazine-2,4-diamine (General method for target compound A)

[1553] MS (ESI) m / z = 418.2 [M + H]+.

[1554] 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).

[1555] Example 175

[1556]

[1557] N2-[1-[1-(2-Aminoethyl)-1H-pyrazol-3-yl]-1-methylethyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine (General method for target compound A)

[1558] MS (ESI) m / z = 393.2 [M + H]+.

[1559] 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).

[1560] Example 176

[1561]

[1562] 6-(1-Methyl-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 (General method for target compound A)

[1563] MS(ESI) m / z = 432.3 [M+H]+.

[1564] 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).

[1565] Example 177

[1566]

[1567] N4-[1-[5-Amino-1-(difluoromethyl)-1H-pyrazol-3-yl]-1-methylethyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine (General method for target compound A)

[1568] MS(ESI) m / z = 415.2 [M+H]+.

[1569] 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).

[1570] Example 178

[1571]

[1572] N2-[(1R or 1S)-1-[5-(Aminomethyl)-2-pyridinyl]-2-methylpropyl]-6-(3-methylimidazo[1,5-a]pyridin-6-yl)-1,3,5-triazine-2,4-diamine (General method for target compound A)

[1573] MS(ESI) m / z = 404.2 [M+H] + .

[1574] 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).

[1575] Example 179

[1576]

[1577] 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 method for target compound C)

[1578] MS(ESI) m / z = 432.2 [M+H]+.

[1579] 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).

[1580] Example 180A & 180B

[1581]

[1582] 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 method for target compound A)

[1583] 180A

[1584] MS(ESI) m / z = 446.5 [M+H]+.

[1585] 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).

[1586] 180B

[1587] MS (ESI) m / z = 446.2 [M + H]+.

[1588] 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).

[1589] Example 181

[1590]

[1591] 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 method for target compound A)

[1592] MS (ESI) m / z = 446.2 [M + H]+.

[1593] 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).

[1594] Biological assay

[1595] Materials and Methods

[1596] MASTL activity assay

[1597] At room temperature, wild-type human active MASTL (154 pM) was incubated with biotinylated 40-mer ENSA peptide (10 nM), the test compound, 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 minutes. The test compound was assayed using a 12-point dose range consisting of 0, 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 (1%) in all samples. 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) was added to terminate the reaction, bringing the final volume to 20 μl and maintaining it at room temperature for 60 min. Activity was measured using a microplate reader (PerkinElmer EnSight) via 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 techniques from commercial suppliers)). HTRF reagents (CisBio) were prepared according to the manufacturer's recommendations. The 40-mer biotinylated ENSA peptide used (synthesized by Bionics) was based on serine at approximately position 67 on ENSA (YPSLGQKPGGSDFLMKRLQKGQKYFDSGDYNMAKAKMKNK).

[1598] Results

[1599] The results of the MASTL activity assay are shown in Table 2 below:

[1600] [Table 2]

[1601] 0.001 μM < *** < 0.5 μM, 0.5 μM < ** < 1 μM, * > 1 μM

[1602]

[1603]

[1604]

[1605]

[1606]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein the H ring in formula (I) is bonded to a carbon atom *1 or *2 on; Z is -NR 1 R 2 or -CN; R 1 and R 2 are independently selected from: H, D, and C 1-6 alkyl; wherein said C 1-6 alkyl is optionally partially or fully deuterated; R 3 each independently selected from: halogen, C 1-6 alkyl, and amino; X1 is N and X2 is CR 4 or X1 is C and X2 is NR 5 ; X3 is CH or N; R 4 Selected from: H, NR X1 R X2 , -OH and C 1-6 alkyl; R 5 Selected from: H and C 1-6 alkyl group wherein R 4 or R 5 the C on 1-6 the alkyl is optionally partially or fully deuterated; L 1 is a bond or selected from: NR 6 , O, and S; R 6 selected from H, C 1-4 alkyl, C 1-4 haloalkyl, and C 3-6 cycloalkyl, Wherein said C 3-6 The cycloalkyl group is optionally substituted by one or more substituents selected from the following: =O, halogen, C 1-4 alkyl and C 1-4 haloalkyl; L 2 is a key or -[CR 7 R 8 p- wherein p is an integer from 1 to 4; R 7 and R 8 are each independently selected from: H, C 1-4 alkyl, and C 1-4 haloalkyl, OH, COOH, C(O)NR X1 R X2 and C 3-6 cycloalkyl, or R 7 and R 8 are attached to the same carbon atom in L 2 to form together a C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group, Wherein said C 1-4 alkyl is optionally substituted by: OH, O-C 1-4 alkyl, 3- to 6-membered heterocyclic group, 5- to 10-membered heteroaryl or C 1-6 aryl optionally substituted by halogen or C 6-10 haloalkyl; Q 1 Selected from: C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3- to 12-membered heterocyclic group, C 6-10 aryl, and 5- to 10-membered heteroaryl; Wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted with one or more R 9 substituents; Each R 9 is independently selected from: 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; wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted by one or more R 11 ; and Each R 10 is independently selected from: H, C 1-6 alkyl and C 1-6 haloalkyl; Each R 11 is independently selected from: halogen, -CN, -NO2, C 1-4 alkyl, C 1-4 haloalkyl, and NR X1 R X2 ; wherein R X1 and R X2 are independently selected from: H, C 1-4 alkyl optionally substituted by OH or a 3- to 6-membered heterocyclic group, -OC 1-6 alkyl, -C(O)-C 1-6 alkyl, and a 5- to 10-membered heteroaryl, or R X1 and R X2 are attached to the same nitrogen atom and together form a 3- to 6-membered heterocyclic group; n is an integer from 0 to 4; and x is an integer from 0 to 3; wherein when R 4 or R 5 is H or an undehydrogenated C 1-6 alkyl, then Z is -CN, or -NR 1 R 2 , wherein R 1 and R 2 at least one of which is D or a partially or fully deuterated C 1-6 alkyl group.

2. The compound according to claim 1, wherein the H ring in formula (I) is bonded to a carbon atom *1 or *2 thereon; Z is -NR 1 R 2 or -CN; R 1 and R 2 are independently selected from: H, D, and C 1-6 alkyl; wherein said C 1-6 alkyl is optionally partially or fully deuterated; R 3 each independently selected from: halogen, C 1-6 alkyl, and amino; X1 is N and X2 is CR 4 or X1 is C and X2 is NR 5 ; X3 is CH or N; R 4 Selected from: H, NR X1 R X2 , -OH and C 1-6 alkyl; R 5 Selected from: H and C 1-6 alkyl wherein R 4 or R 5 the C 1-6 alkyl group is optionally partially or fully deuterated; L 1 is a bond or selected from: NR 6 , O, and S; R 6 selected from H, C 1-4 alkyl and C 1-4 haloalkyl; L 2 is a key or -[CR 7 R 8 p- wherein p is an integer from 1 to 4; R 7 and R 8 are each independently selected from: H, C 1-4 alkyl, and C 1-4 haloalkyl, OH, COOH, C(O)NR X1 R X2 and C 3-6 cycloalkyl, or R 7 and R 8 are attached to the same carbon atom in L 2 to together form a C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group, Wherein said C 1-4 alkyl is optionally substituted by: OH, O-C 1-4 alkyl or C optionally substituted by halogen or 1-6 haloalkyl-substituted C 6-10 aryl; Q 1 Selected from: C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 aryl, and 5- to 10-membered heteroaryl; Wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted by one or more R 9 substituents; Each R 9 is independently selected from: 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; Wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted by one or more R 11 ; and where each R 10 is independently selected from: H, C 1-6 alkyl and C 1-6 haloalkyl; Each R 11 is independently selected from: halogen, -CN, -NO2, C 1-4 alkyl, C 1-4 haloalkyl, and NR X1 R X2 ; wherein R X1 and R X2 are independently selected from: H, C 1-4 alkyl optionally substituted with OH or a 3- to 6-membered heterocyclic group, -OC 1-6 alkyl, -C(O)-C 1-6 alkyl, and a 5- to 10-membered heteroaryl, or R X1 and R X2 are attached to the same nitrogen atom and together form a 3- to 6-membered heterocyclic group; n is an integer from 0 to 4; and x is an integer from 0 to 3; wherein when R 4 or R 5 is H or an undehydrogenated C 1-6 alkyl, then Z is -CN, or -NR 1 R 2 , where R 1 and R 2 in which at least one of them is D or a partially or fully deuterated C 1-6 alkyl group.

3. The compound according to claim 1, wherein the H ring in formula (I) is bonded to a carbon atom *1 or *2 thereon; Z is -NR 1 R 2 or -CN; R 1 and R 2 are independently selected from: H, D, and C 1-6 alkyl; wherein said C 1-6 alkyl is optionally partially or fully deuterated; R 3 each independently selected from: halogen, C 1-6 alkyl, and amino; X1 is N and X2 is CR 4 or X1 is C and X2 is NR 5 ; X3 is CH or N; R 4 Selected from: H, NR X1 R X2 , -OH and C 1-6 alkyl; R 5 Selected from: H and C 1-6 alkyl group wherein R 4 or R 5 the C on 1-6 the alkyl is optionally partially or fully deuterated; L 1 is a bond or selected from: NR 6 , O and S; R 6 selected from H, C 1-4 alkyl and C 1-4 haloalkyl; L 2 is a key or -[CR 7 R 8 p- wherein p is an integer from 1 to 4; R 7 and R 8 are each independently selected from: H, C 1-4 alkyl, and C 1-4 haloalkyl, OH, COOH, C(O)NR X1 R X2 and C 3-6 cycloalkyl, or R 7 and R 8 are attached to the same carbon atom in L 2 to together form a C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group, Wherein said C 1-4 alkyl is optionally substituted with: OH, O-C 1-4 alkyl or C optionally substituted with halogen or C 1-6 aryl substituted with haloalkyl; 6-10 aryl; Q 1 Selected from: C 3-12 cycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; Wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted with one or more R 9 substituents; Each R 9 is independently selected from: 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; Wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted by one or more R 11 ; and Each R 10 is independently selected from: H, C 1-6 alkyl and C 1-6 haloalkyl; where each R 11 is independently selected from: halogen, -CN, -NO2, C 1-4 alkyl, C 1-4 haloalkyl, and NR X1 R X2 ; where R X1 and R X2 are independently selected from: H, C 1-4 alkyl optionally substituted with OH or a 3- to 6-membered heterocyclic group; n is an integer from 0 to 4; and x is an integer from 0 to 3; wherein when R 4 or R 5 is H or an undehydrogenated C 1-6 alkyl, then Z is -CN, or -NR 1 R 2 , wherein R 1 and R 2 at least one of which is D or a partially or fully deuterated C 1-6 alkyl group.

4. A compound of formula (II) or a pharmaceutically acceptable salt thereof: wherein the H ring in formula (II) is bonded to a carbon atom *1 or *2 onto; R 1 and R 2 are independently selected from: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl; R 3 each independently selected from: halogen, C 1-6 alkyl, and amino; X1 is N and X2 is CR 4 or X1 is C and X2 is NR 5 ; X3 is CH or N; R 4 and R 5 are independently selected from: H, halogen, CN, C 1-6 alkyl and C 1-6 haloalkyl; L 1 is a bond or selected from: NR 6 , O and S; R 6 selected from H, C 1-4 alkyl, C 1-4 haloalkyl, and C 3-6 cycloalkyl, Wherein said C 3-6 The cycloalkyl group is optionally substituted by one or more substituents selected from the following: =O, halogen, C 1-4 alkyl and C 1-4 haloalkyl; L 2 is a key or -[CR 7 R 8 p-; p is an integer from 1 to 4; R 7 and R 8 each independently selected from: 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 the R in 7 and R 8 at least one of which is not H, and The said C 1-4 alkyl group is substituted by a 3- to 6-membered cycloalkyl group, a C 4-8 alkyl group or NR X1 R X2 ; Q 1 Selected from: C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3- to 12-membered heterocyclic group, C 6-10 aryl, and 5- to 10-membered heteroaryl; Wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted with one or more R 9 substituents; Each R 9 is independently selected from: 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, Wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl is optionally substituted by one or more R 11 substituents, and Each R 10 is independently selected from: H, C 1-6 alkyl, and C 1-6 haloalkyl; Each R 11 is independently selected from: halogen, -CN, -NO2, C 1-4 alkyl, C 1-4 haloalkyl, NR X1 R X2 and C(O)NR X1 R X2 ; wherein R X1 and R X2 are independently selected from: H, C 1-4 alkyl optionally substituted by OH or a 3- to 6-membered heterocyclic group, OH, -OC 1-6 alkyl, -C(O)-C 1-6 alkyl and a 5- to 10-membered heteroaryl, or R X1 and R X2 are attached to the same nitrogen atom and together form a 3- to 6-membered heterocyclic group; wherein R X3 is selected from: OH and O-C 1-6 alkyl; n is an integer from 0 to 4; and x is an integer from 0 to 3.

5. The compound according to claim 4, wherein the H ring in formula (II) is bonded to a carbon atom *1 or *2 on; R 1 and R 2 are independently selected from: H, C 1-6 alkyl, and C 1-6 haloalkyl; R 3 each independently selected from: halogen, C 1-6 alkyl, and amino; X1 is N and X2 is CR 4 or X1 is C and X2 is NR 5 ; X3 is CH or N; R 4 and R 5 are independently selected from: H, halogen, CN, C 1-6 alkyl and C 1-6 haloalkyl; L 1 is a bond or selected from: NR 6 , O, and S; R 6 selected from H, C 1-4 alkyl and C 1-4 haloalkyl; L 2 is a key or -[CR 7 R 8 p-; wherein p is an integer from 1 to 4; R 7 and R 8 each independently selected from: 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 the R in 7 and R 8 at least one of them is not H; and The said C 1-4 alkyl group is substituted by a 3- to 6-membered cycloalkyl group, a C 4-8 alkyl group or NR X1 R X2 ; Q 1 Selected from: C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 aryl, and 5- to 10-membered heteroaryl; Wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted with one or more R 9 substituents; Each R 9 is independently selected from: 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, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl is optionally substituted by one or more R 11 substituents, and where each R 10 is independently selected from: H, C 1-6 alkyl and C 1-6 haloalkyl; Each R 11 is independently selected from: halogen, -CN, -NO2, C 1-4 alkyl, C 1-4 haloalkyl, NR X1 R X2 and C(O)NR X1 R X2 ; wherein R X1 and R X2 are independently selected from: H, C 1-4 alkyl optionally substituted with OH or a 3- to 6-membered heterocyclic group, OH, -OC 1-6 alkyl, -C(O)-C 1-6 alkyl and a 5- to 10-membered heteroaryl, or R X1 and R X2 are attached to the same nitrogen atom and together form a 3- to 6-membered heterocyclic group; wherein R X3 is selected from: OH and O-C 1-6 alkyl; n is an integer from 0 to 4; and x is an integer from 0 to 3.

6. The compound according to claim 4, wherein the H ring in formula (II) is bonded to a carbon atom *1 or *2 onto; R 1 and R 2 are independently selected from: H, C 1-6 alkyl, and C 1-6 haloalkyl; R 3 each independently selected from: halogen, C 1-6 alkyl, and amino; X1 is N and X2 is CR 4 or X1 is C and X2 is NR 5 ; X3 is CH or N; R 4 and R 5 are independently selected from: H, halogen, CN, C 1-6 alkyl, and C 1-6 haloalkyl; L 1 is a bond or selected from: NR 6 , O and S; R 6 selected from H, C 1-4 alkyl, and C 1-4 haloalkyl; L 2 is a key or -[CR 7 R 8 p-; wherein p is an integer from 1 to 4; R 7 and R 8 each independently selected from: 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 in 7 and R 8 at least one of them is not H; and The said C 1-4 alkyl group is substituted by a 3- to 6-membered cycloalkyl group, a C 4-8 alkyl group or NR X1 R X2 ; Q 1 Selected from: C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; Wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted by one or more R 9 substituents; Each R 9 is independently selected from: 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, Wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl is optionally substituted by one or more R 11 substituents, and Each R 10 is independently selected from: H, C 1-6 alkyl, and C 1-6 haloalkyl; Each R 11 is independently selected from: halogen, -CN, -NO2, C 1-4 alkyl, C 1-4 haloalkyl, NR X1 R X2 and C(O)NR X1 R X2 ; wherein R X1 and R X2 are independently selected from: H, C 1-4 alkyl optionally substituted with OH or a 3- to 6-membered heterocyclic group, OH, -OC 1-6 alkyl and -C(O)-C 1-6 alkyl; wherein R X3 is selected from: OH and O-C 1-6 alkyl; n is an integer from 0 to 4; and x is an integer from 0 to 3.

7. A compound of formula (III) or a pharmaceutically acceptable salt thereof: wherein the H ring in formula (III) is bonded to a carbon atom *1 or *2 on; R 1 and R 2 are independently selected from: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl; R 3 each independently selected from: halogen, C 1-6 alkyl, and amino; X1 is N and X2 is CR 4 or X1 is C and X2 is NR 5 ; X3 is CH or N; R 4 and R 5 are independently selected from: H, halogen, CN, C 1-6 alkyl and C 1-6 haloalkyl; L 1 is a bond or selected from: NR 6 , O and S; R 6 selected from H, C 1-4 alkyl, C 1-4 haloalkyl, and C 3-6 cycloalkyl, wherein said C 1-4 alkyl is optionally partially or fully deuterated; Wherein said C 3-6 The cycloalkyl group is optionally substituted by one or more substituents selected from the following: =O, halogen, C 1-4 alkyl and C 1-4 haloalkyl; L 2 is a key or -[CR 7 R 8 p- wherein p is an integer from 1 to 4; R 7 and R 8 are each independently selected from: H, C 1-4 alkyl, and C 1-4 haloalkyl, OH, COOH, C(O)NR X1 R X2 and C 3-6 cycloalkyl, or R 7 and R 8 are attached to the same carbon atom in L 2 to form together a C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group, wherein said C 1-4 alkyl is optionally substituted with: OH, O-C 1-4 alkyl, 3- to 6-membered heterocyclic group, 5- to 10-membered heteroaryl or C 1-6 aryl optionally substituted with halogen or C 6-10 haloalkyl; Q 1 selected from C 6-10 aryl and 5- to 10-membered heteroaryl; Wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted with one or more R 9 substituents; Each R 9 is independently selected from: 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 heterocyclic group, 5- to 10-membered heteroaryl, -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, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclic group and 5- to 10-membered heteroaryl are optionally substituted by one or more R 11 substituents wherein said C 1-6 the alkyl group is optionally partially or fully deuterated; where each R 10 is independently selected from: H, C 1-6 alkyl and C 1-6 haloalkyl; where each R 11 is independently selected from: halogen, -CN, -NO2, C 1-4 alkyl, C 1-4 haloalkyl and NR X1 R X2 ; wherein R X1 and R X2 are independently selected from: H, C 1-4 alkyl optionally substituted with OH or a 3- to 6-membered heterocyclic group, -OC 1-6 alkyl, -C(O)-C 1-6 alkyl and 5- to 10-membered heteroaryl, or R X1 and R X2 are attached to the same nitrogen atom and together form a 3- to 6-membered heterocyclic group; and n is an integer from 0 to 4; and x is an integer from 0 to 3; where when Q 1 is not substituted by one or more Rs 9 or When Q 1 one or more Rs on 9 any of which is not C3-C6 cycloalkyl, 5- to 10-membered heterocyclic group, 5- to 10-membered heteroaryl or partially or fully deuterated C 1-6 alkyl, then R 6 is a partially or fully deuterated C 1-4 alkyl group.

8. The compound according to claim 7, wherein the H ring in formula (III) is bonded to a carbon atom *1 or *2 on; R 1 and R 2 are independently selected from: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl; R 3 each independently selected from: halogen, C 1-6 alkyl, and amino; X1 is N and X2 is CR 4 or X1 is C and X2 is NR 5 ; X3 is CH or N; R 4 and R 5 are independently selected from: H, halogen, CN, C 1-6 alkyl, and C 1-6 haloalkyl; L 1 is a key or NR 6 ; R 6 selected from H, C 1-4 alkyl, and C 1-4 haloalkyl, wherein said C 1-4 alkyl is optionally partially or fully deuterated; L 2 is a key or -[CR 7 R 8 p- wherein p is an integer from 1 to 4; R 7 and R 8 are each independently selected from: H, C 1-4 alkyl, and C 1-4 haloalkyl, OH, COOH, C(O)NR X1 R X2 and C 3-6 cycloalkyl, or R 7 and R 8 are attached to the same carbon atom in L 2 to form together a C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group, Wherein said C 1-4 alkyl is optionally substituted by: OH, O-C 1-4 alkyl or C optionally substituted by halogen or C 1-6 aryl substituted by haloalkyl; 6-10 aryl; Q 1 selected from C 6-10 aryl and 5- to 10-membered heteroaryl; Wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted by one or more R 9 substituents; Each R 9 is independently selected from: 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 heterocyclic group, 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, Wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclic group and 5- to 10-membered heteroaryl are optionally substituted by one or more R 11 substituted, wherein said C 1-6 alkyl is optionally partially or fully deuterated; where each R 10 is independently selected from: H, C 1-6 alkyl and C 1-6 haloalkyl; Each R 11 is independently selected from: halogen, -CN, -NO2, C 1-4 alkyl, C 1-4 haloalkyl, and NR X1 R X2 ; wherein R X1 and R X2 are independently selected from: H, C 1-4 alkyl optionally substituted with OH or a 3- to 6-membered heterocyclic group, -OC 1-6 alkyl, -C(O)-C 1-6 alkyl and 5- to 10-membered heteroaryl, or R X1 and R X2 are attached to the same nitrogen atom and together form a 3- to 6-membered heterocyclic group; and n is an integer from 0 to 4; and x is an integer from 0 to 3; wherein when Q 1 is not substituted by one or more R 9 , or When Q 1 one or more Rs on 9 any of which is not a C3-C6 cycloalkyl, 5- to 10-membered heterocyclic group, 5- to 10-membered heteroaryl or a partially or fully deuterated C 1-6 alkyl group, then R 6 is a partially or fully deuterated C 1-4 alkyl group.

9. The compound according to claim 7, wherein the H ring in formula (III) is bonded to a carbon atom *1 or *2 ; R 1 and R 2 are independently selected from: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl; R 3 each independently selected from: halogen, C 1-6 alkyl, and amino; X1 is N and X2 is CR 4 or X1 is C and X2 is NR 5 ; X3 is CH or N; R 4 and R 5 are independently selected from: H, halogen, CN, C 1-6 alkyl and C 1-6 haloalkyl; L 1 is a key or NR 6 ; R 6 selected from H, C 1-4 alkyl, and C 1-4 haloalkyl, wherein said C 1-4 alkyl is optionally partially or fully deuterated; L 2 is a key or -[CR 7 R 8 p- wherein p is an integer from 1 to 4; R 7 and R 8 each independently selected from: H, C 1-4 alkyl and C 1-4 haloalkyl, OH, COOH, C(O)NR X1 R X2 and C 3-6 cycloalkyl, or R 7 and R 8 are attached to the same carbon atom in L 2 to form together a C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group, wherein said C 1-4 alkyl is optionally substituted by: OH, O-C 1-4 alkyl or C optionally substituted by halogen or C 1-6 aryl substituted by haloalkyl; 6-10 aryl; Q 1 selected from C 6-10 aryl and 5- to 10-membered heteroaryl; Wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted by one or more R 9 substituents; Each R 9 is independently selected from: 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 heterocyclic group, 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, Wherein the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C3-C6 cycloalkyl group, 5- to 10-membered heterocyclic group and 5- to 10-membered heteroaryl group are optionally substituted by one or more R 11 substituents, wherein said C 1-6 alkyl is optionally partially or fully deuterated; Each R 10 is independently selected from: H, C 1-6 alkyl, and C 1-6 haloalkyl; Each R 11 is independently selected from: halogen, -CN, -NO2, C 1-4 alkyl, C 1-4 haloalkyl, and NR X1 R X2 ; wherein R X1 and R X2 are independently selected from: H, C 1-4 alkyl optionally substituted with OH or a 3- to 6-membered heterocyclic group; and n is an integer from 0 to 4; and x is an integer from 0 to 3; where when Q 1 is not substituted by one or more R 9 , or When Q 1 one or more Rs on 9 any of which is not a C3-C6 cycloalkyl, 5- to 10-membered heterocyclic group, 5- to 10-membered heteroaryl or partially or fully deuterated C 1-6 alkyl group, then R 6 is a partially or fully deuterated C 1-4 alkyl group.

10. A compound of formula (IV) or a pharmaceutically acceptable salt thereof: wherein R 1 and R 2 are independently selected from: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl; R 3 Each independently selected from: halogen, C 1-6 alkyl, and amino; X1 is N and X2 is CR 4 or X1 is C and X2 is NR 5 ; X3 is CH or N; R 4 、R 5 and R 12 are independently selected from: H, halogen, CN, C 1-6 alkyl and C 1-6 haloalkyl; wherein when X1 is N, then X4 is N and X5 is CH, or X4 is CH and X5 is N; and wherein when X1 is C, then X4 and X5 are both CH; wherein R 4 or R 5 the C on 1-6 the alkyl is optionally partially or fully deuterated; L 1 is a bond or selected from: NR 6 , O, and S, R 6 selected from H, C 1-4 alkyl, C 1-4 haloalkyl, and C 3-6 cycloalkyl, Wherein said C 3-6 The cycloalkyl group is optionally substituted by one or more substituents selected from the following: =O, halogen, C 1-4 alkyl and C 1-4 haloalkyl; L 2 is a key or -[CR 7 R 8 p- wherein p is an integer from 1 to 4; R 7 and R 8 are each independently selected from: H, C 1-4 alkyl, and C 1-4 haloalkyl, OH, COOH, C(O)NR X1 R X2 and C 3-6 cycloalkyl, or R 7 and R 8 are attached to the same carbon atom in L 2 to form together a C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group, Wherein said C 1-4 alkyl is optionally substituted by: OH, O-C 1-4 alkyl, a 3- to 6-membered heterocyclic group, a 5- to 10-membered heteroaryl group, or a C 1-6 aryl optionally substituted by halogen or C 6-10 haloalkyl; Q 1 selected from C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3- to 12-membered heterocyclic group, C 6-10 aryl, and 5- to 10-membered heteroaryl; Wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted with one or more R 9 substituents; Each R 9 is independently selected from: 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, Wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted by one or more R 11 substituents, Each R 10 is independently selected from: H, C 1-6 alkyl, and C 1-6 haloalkyl; Each R 11 is independently selected from: halogen, -CN, -NO2, C 1-4 alkyl, C 1-4 haloalkyl, and NR X1 R X2 ; wherein R X1 and R X2 are independently selected from: H, C 1-4 alkyl optionally substituted with OH or a 3- to 6-membered heterocyclic group, -OC 1-6 alkyl, -C(O)-C 1-6 alkyl and 5- to 10-membered heteroaryl, or R X1 and R X2 are attached to the same nitrogen atom and together form a 3- to 6-membered heterocyclic group; n is an integer from 0 to 4; and x is an integer from 0 to 3.

11. The compound according to claim 10, wherein R 1 and R 2 are independently selected from: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl; R 3 each independently selected from: halogen, C 1-6 alkyl, and amino; X1 is N and X2 is CR 4 or X1 is C and X2 is NR 5 ; X3 is CH or N; R 4 、 R 5 and R 12 are independently selected from: H, halogen, CN, C 1-6 alkyl, and C 1-6 haloalkyl; wherein when X1 is N, then X4 is N and X5 is CH, or X4 is CH and X5 is N; and wherein when X1 is C, then X4 and X5 are both CH; wherein R 4 or R 5 the C on 1-6 the alkyl is optionally partially or fully deuterated; L 1 is a key or NR 6 , R 6 selected from H, C 1-4 alkyl, and C 1-4 haloalkyl; L 2 is a key or -[CR 7 R 8 p- wherein p is an integer from 1 to 4; R 7 and R 8 are each independently selected from: H, C 1-4 alkyl, and C 1-4 haloalkyl, OH, COOH, C(O)NR X1 R X2 and C 3-6 cycloalkyl, or R 7 and R 8 are attached to the same carbon atom in L 2 to together form a C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group, wherein said C 1-4 alkyl is optionally substituted by: OH, O-C 1-4 alkyl or C optionally substituted by halogen or 1-6 haloalkyl-substituted C 6-10 aryl; Q 1 selected from C 3-12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl; Wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted by one or more R 9 substituents; Each R 9 is independently selected from: 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, wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are optionally substituted by one or more R 11 substituents, where each R 10 is independently selected from: H, C 1-6 alkyl, and C 1-6 haloalkyl; where each R 11 is independently selected from: halogen, -CN, -NO2, C 1-4 alkyl, C 1-4 haloalkyl, and NR X1 R X2 ; wherein R X1 and R X2 are independently selected from: H, C 1-4 alkyl optionally substituted with OH or a 3- to 6-membered heterocyclic group, -OC 1-6 alkyl, -C(O)-C 1-6 alkyl and 5- to 10-membered heteroaryl, or R X1 and R X2 are attached to the same nitrogen atom and together form a 3- to 6-membered heterocyclic group; n is an integer from 0 to 4; and x is an integer from 0 to 3.

12. The compound according to claim 10, wherein R 1 and R 2 are independently selected from: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl; R 3 each independently selected from: halogen, C 1-6 alkyl, and amino; X1 is N and X2 is CR 4 or X1 is C and X2 is NR 5 ; X3 is CH or N; R 4 、R 5 and R 12 are independently selected from: H, halogen, CN, C 1-6 alkyl and C 1-6 haloalkyl; wherein when X1 is N, then X4 is N and X5 is CH, or X4 is CH and X5 is N; and wherein when X1 is C, then X4 and X5 are both CH; wherein R 4 or R 5 the C on 1-6 the alkyl is optionally partially or fully deuterated; L 1 is a key or NR 6 , R 6 Selected from H, C 1-4 alkyl, and C 1-4 haloalkyl; L 2 is a key or -[CR 7 R 8 p- wherein p is an integer from 1 to 4; R 7 and R 8 are each independently selected from: H, C 1-4 alkyl, and C 1-4 haloalkyl, OH, COOH, C(O)NR X1 R X2 and C 3-6 cycloalkyl, or R 7 and R 8 are attached to the same carbon atom in L 2 to form together a C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group, Wherein said C 1-4 alkyl is optionally substituted by: OH, O-C 1-4 alkyl or C optionally substituted by halogen or C 1-6 aryl substituted by haloalkyl; 6-10 aryl; Q 1 selected from C 3-12 cycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; Wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted with one or more R 9 substituents; Each R 9 is independently selected from: 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, Wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted by one or more R 11 substituents, Each R 10 is independently selected from: H, C 1-6 alkyl, and C 1-6 haloalkyl; where each R 11 is independently selected from: halogen, -CN, -NO2, C 1-4 alkyl, C 1-4 haloalkyl, and NR X1 R X2 ; wherein R X1 and R X2 are independently selected from: H, C 1-4 alkyl optionally substituted by OH or a 3- to 6-membered heterocyclic group; n is an integer from 0 to 4; and x is an integer from 0 to 3.

13. The compound according to any one of claims 1, 4 and 7, wherein the group is selected from any one of the following structures:

14. The compound according to claim 10, wherein the group is selected from any one of the following structures:

15. The compound according to any one of claims 1, 4, 7 and 10, wherein the group is selected from any one of the following structures:

16. A compound according to any one of claims 1, 4, 7 and 10, wherein the group -L 1 -L 2 -Q 1 is selected from any one of the following structures:

17. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is any one selected from the group consisting of compound numbers 1 to 239 below:

18. A pharmaceutical composition comprising the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

19. The pharmaceutical composition according to claim 18, which is used as a medicine.

20. The pharmaceutical composition according to claim 18, which is used for treating a disease or medical condition mediated by microtubule-associated serine / threonine-like kinase (MASTL).

21. The pharmaceutical composition according to claim 18, which is used for treating a disease in which PD-L1 expression is interferon-dependent.

22. The pharmaceutical composition according to claim 18, which is used for treating a proliferative disease, a metabolic disorder or a symptom or condition associated with a metabolic disease, or a platelet disorder, optionally, wherein the platelet disorder is thrombocytopenia.

23. The pharmaceutical composition according to claim 22, wherein the proliferative disease is cancer, optionally, wherein the cancer is selected from: breast cancer, ovarian cancer, lung cancer, colorectal cancer, prostate cancer, oral cancer, gastric cancer, adrenocortical carcinoma, pancreatic cancer, renal cancer, sarcoma, liver cancer, endometrial cancer, thyroid cancer, head and neck cancer, brain cancer (such as glioma), melanoma (such as uveal melanoma) and blood cancer (such as leukemia, lymphoma, myeloma and multiple myeloma).

24. The pharmaceutical composition according to claim 22, wherein the cancer overexpresses MASTL.

25. The pharmaceutical composition according to claim 22, wherein the pharmaceutical composition is administered in combination with one or more other anti-cancer agents and / or radiotherapy.

26. The pharmaceutical composition according to claim 22, wherein the metabolic disorder is selected from insulin resistance, diabetes and obesity, or wherein the symptoms and conditions associated with the metabolic disorder are selected from: elevated blood glucose, elevated cholesterol, elevated triglyceride levels, heart disease, stroke, hypertension and increased risk of blood clots (such as deep vein thrombosis).

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