GCN2 Modulator Compounds

Abstract

The present invention relates to compounds of formula (I) and formula (Ia) or stereoisomers, tautomers, or pharma- ceutically acceptable salts thereof, wherein the variables are defined herein, and their use in the treatment, prevention, amelioration, control, or reduction of risk of disorders associated with general regulatory non-inhibitory 2 (GCN2).

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 329,281, filed April 8, 2022, and U.S. Provisional Application No. 63 / 329,282, filed April 8, 2022, both of which are incorporated by reference in their entireties.

[0002] FIELD OF THEINVENTION This application relates to novel compounds and their use as general control non-repressible 2 (GCN2) modulators. The compounds described herein may be useful in treating or preventing diseases in which GCN2 is involved. [Background technology]

[0003] background Diverse cellular conditions and stresses activate a broadly conserved signaling pathway termed the integrated stress response (ISR) pathway. Activation of the ISR can induce cell cycle arrest, differentiation, amino acid biosynthesis and transport pathways, compensatory adaptation or apoptosis, depending on the cell type and the initiating stress.

[0004] General regulatory non-repressible 2 (GCN2) is one of four stress kinases in the ISR pathway that senses amino acid availability and regulates gene expression in response to amino acid starvation, UV irradiation, viral infection, proteasome inhibition, hypoxia, glucose deprivation, and oxidative stress. In mammals, GCN2 is also called EIF2AK4 (eukaryotic translation initiation factor 2 alpha kinase 4).

[0005] GCN2 contains a eukaryotic kinase domain, a pseudokinase domain, and a histidyl-tRNA synthetase (HisRS)-related domain that binds uncharged tRNAs with higher affinity than charged tRNAs. Sequences at both the N- and C-termini of GCN2 have been shown to be important for efficient sensitization of starvation signals. The C-terminal lysine residues are also required for tRNA binding and kinase activity, and residues at the very tip of the C-terminal region have been shown to contribute to the ribosome-binding ability of GCN2, which is important for translational control.

[0006] In eukaryotes, the mechanism of recognition of essential amino acid deficiency follows a conserved general regulatory system in which uncharged transfer RNA first induces the autophosphorylation of GCN2 and then the phosphorylation of eukaryotic initiation factor 2α (eIF2α), leading to a decrease in total protein synthesis and therefore to a decrease in the overall utilization of amino acids. Concomitantly, stress-responsive mRNAs and upstream open reading frames (uORFs), including ATF4, CHOP, GADD34 and β-secretase BACE-1, are translated more efficiently when eIF2α is phosphorylated, leading to increased amino acid biosynthesis and transport pathways. The GCN2-mediated translation program controls the host response to infection, immunization, inflammation and responses to other physiological and pathological processes. A prominent subset of genes upregulated by ATF4 are involved in amino acid import and metabolism, and a hallmark of ATF4- / - cells is impaired amino acid metabolism. Summary of the Invention [Problem to be solved by the invention]

[0007] Therefore, modulation of general control non-repressible 2 (GCN2) offers a therapeutic strategy for many diseases. [Means for solving the problem]

[0008] Summary of the Invention The present invention provides compounds that have activity as general control non-repressible 2 (GCN2) modulators.

[0009] In one embodiment, the present invention relates to a compound represented by formula (I): [ka] [During the ceremony, R 1 , R 2 , R 3 and R 4 H, halo and C 1-3 independently selected from the group consisting of alkyl; R 5 is H or C 1-3 is alkyl; R 6 , R 7 and R 8 H, halo, C 1-6 Alkyl and C 1-6 alkoxy, wherein C 1-6 Alkyl is optionally substituted with OH; 1-6 The alkoxy is optionally C 1-6 Alkoxy or NR 10 R 11 is replaced by; R 9 is H, C 1-6 Alkyl, C 5-6 cycloalkyl or 4-6 membered heterocyclyl, where C 1-6 Alkyl is NR 10 R 11 is replaced by C 5-6 Cycloalkyl and 4-6 membered heterocyclyl are oxo, NR 10 R 11 , -C(O)NR 10 R 11 and optionally NR 10 R 11 C replaced with 1-6 optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl; R 10 and R 11 are independently H or C 1-6 C optionally substituted with alkoxy 1-3 is alkyl; and X, Y and Q are independently C, CH or N; However, R 9 is H and X and Y are C or CH, then R 6 , R 7 and R 8 At least one of the following is C 1-6 Alkoxy, where C 1-6 Alkoxy is C 1-6 Alkoxy or NR 10 R 11 is replaced by. or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof.

[0010] In one embodiment, R 9 is H, C 1-6 Alkyl, C 5-6 cycloalkyl or 5- or 6-membered heterocyclyl, where C 1-6 Alkyl is NR 10 R 11 is replaced by C 5-6 Cycloalkyl and 5- or 6-membered heterocyclyl are oxo, NR 10 R 11 , -C(O)NR 10 R 11 and optionally NR 10 R 11 C replaced with 1-6 and optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl.

[0011] In another aspect, the present invention relates to a compound of formula (Ia) [ka] [During the ceremony, Ra 1 and Ra 4 is a halo; Ra 2 and Ra 3 H, halo and C 1-3 independently selected from the group consisting of alkyl; Ra 5 is H or C1-3 is alkyl; Ra 6 , R 7 and R 8 H, halo, C 1-6 Alkyl and C 1-6 alkoxy, wherein C 1-6 Alkyl and C 1-6 The alkoxy is optionally substituted with OH; Ra 9 is H, C 5-6 cycloalkyl or 5- or 6-membered heterocyclyl, where C 5-6 cycloalkyl and 5- or 6-membered heterocyclyl are optionally substituted with OH; and Q is C, CH or N. or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof.

[0012] The compounds of the present invention may be used as GCN2 modulators. The compounds of the present invention may be used as GCN2 inhibitors. The compounds of the present invention may be used as GCN2 antagonists. The compounds of the present invention may be used as GCN2 agonists. The compounds of the present invention may be used to treat diseases or disorders characterized by activation of GCN2. The compounds of the present invention may be used to manufacture medicaments. The compounds or medicaments may be used to treat, prevent, alleviate, control, or reduce the risk of diseases or disorders in which GCN2 is involved. The compounds of the present invention may be used as a single agent or in combination with one or more additional pharmaceutical agents. The additional pharmaceutical agents may include radiation therapy, chemotherapy, immunotherapy, or tumor microenvironment modulating agents. The compounds of the present invention may be useful for treating cancer, neurodegenerative diseases, chronic infections, or conditions or symptoms related thereto. The compounds of the present invention are useful in treating breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, renal cancer, lung cancer, melanoma, fibrosarcoma, osteosarcoma, connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, gastrointestinal cancer, adenocarcinoma, hepatocellular carcinoma, thyroid cancer, multiple myeloma, secretory cell carcinoma, myelodysplastic syndromes, myeloproliferative neoplasms, malignant glioma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia, chronic myeloid leukemia, hair follicle cancer, leukemia ... It may be useful in treating Leigh cell leukemia, benign monoclonal gammopathy (MGUS), plasmacytoma, lymphoplasmacytic lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, large granular lymphocytic leukemia, B cell prolymphocytic leukemia, T cell prolymphocytic leukemia, small cell lung cancer, malignant pleural mesothelioma, squamous cell carcinoma of the head and neck, glioblastoma multiforme, sarcoma, childhood neuroblastoma, or conditions related thereto. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Detailed Description of the Invention The present invention relates to novel compounds. The present invention also relates to the use of the novel compounds as modulators of GCN2. The present invention further relates to the use of the novel compounds in the manufacture of a medicament for use as a GCN2 modulator.

[0014] The invention further relates to compounds, compositions and medicaments which may be useful in the treatment of cancer, neurodegenerative diseases, chronic infections or conditions or symptoms associated therewith.

[0015] In one embodiment, the compound of formula (I) [ka] [During the ceremony, R 1 , R 2 , R 3 and R 4 H, halo and C 1-3 independently selected from the group consisting of alkyl; R 5 is H or C 1-3 is alkyl; R 6 , R 7 and R 8 H, halo, C 1-6 Alkyl and C 1-6 alkoxy, wherein C 1-6 Alkyl is optionally substituted with OH; 1-6 The alkoxy is optionally C 1-6 Alkoxy or NR 10 R 11 is replaced by; R 9 is H, C 1-6 Alkyl, C 5-6 cycloalkyl or 4-6 membered heterocyclyl, where C 1-6 Alkyl is NR 10 R 11 is replaced by C 5-6 Cycloalkyl and 4-6 membered heterocyclyl are oxo, NR 10 R 11 , -C(O)NR 10 R 11 and optionally NR 10 R 11 C replaced with 1-6 optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl; R 10 and R11 are independently H or C 1-6 C optionally substituted with alkoxy 1-3 is alkyl; and X, Y and Q are independently C, CH or N; However, R 9 is H and X and Y are C or CH, then R 6 , R 7 and R 8 At least one of the following is C 1-6 Alkoxy, where C 1-6 Alkoxy is C 1-6 Alkoxy or NR 10 R 11 is replaced by. or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof is provided.

[0016] In the description herein, every description, variation, embodiment or aspect of a part may be combined with every description, variation, embodiment or aspect of any other part to the same extent as if each and every combination of descriptions was specifically and individually listed.

[0017] In one embodiment, R 2 and R 3 is H.

[0018] In one embodiment, R 6 , R 7 and R 8 At least one of R is not H. 6 , R 7 and R 8 One of them is Halo, C 1-6 Alkyl and C 1-6 alkoxy, wherein C 1-6 Alkyl is optionally substituted with OH; 1-6 The alkoxy is optionally C 1-6 Alkoxy or NR 10 R 11 is replaced by R 6 , R7 and R 8 The remainder of R is H. In some embodiments, R 6 , R 7 and R 8 The two are halo, C 1-6 Alkyl and C 1-6 alkoxy, wherein C 1-6 Alkyl is optionally substituted with OH; 1-6 The alkoxy is optionally C 1-6 Alkoxy or NR 10 R 11 and the remainder are H. In one embodiment, R 6 , R 7 and R 8 are each independently halo, C 1-6 Alkyl and C 1-6 alkoxy, wherein C 1-6 Alkyl is optionally substituted with OH; 1-6 The alkoxy is optionally C 1-6 Alkoxy or NR 10 R 11 has been replaced with.

[0019] In one embodiment, the moiety: [ka] teeth: [ka] In some embodiments, the moiety is selected from the group consisting of [ka] It is.

[0020] In one embodiment, R 9 is H. In some embodiments, R 9 is NR 10 R 11 C replaced with 1-6 In one embodiment, R 9is C 5-6 cycloalkyl or 4-6 membered heterocyclyl, where C 5-6 Cycloalkyl and 4-6 membered heterocyclyl are oxo, NR 10 R 11 , -C(O)NR 10 R 11 and optionally NR 10 R 11 C replaced with 1-6 In one embodiment, R is optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, 9 teeth [ka] In one embodiment, R 9 teeth [ka] where R 12 is NR 10 R 11 , -C(O)NR 10 R 11 or optionally NR 10 R 11 C replaced with 1-6 alkyl.

[0021] In certain embodiments, X, Y or both are N.

[0022] In one embodiment, the compound of formula (II) [ka] [During the ceremony, R 1 , R 2 , R 3 and R 4 H, halo and C 1-3 independently selected from the group consisting of alkyl; R 5 is H or C 1-3 is alkyl; R 6 , R7 and R 8 H, halo, C 1-6 Alkyl and C 1-6 alkoxy, wherein C 1-6 Alkyl is optionally substituted with OH; 1-6 The alkoxy is optionally C 1-6 Alkoxy or NR 10 R 11 is replaced by; R 9 is H, C 1-6 Alkyl, C 5-6 cycloalkyl or 4-6 membered heterocyclyl, where C 1-6 Alkyl is NR 10 R 11 is replaced by C 5-6 Cycloalkyl and 4-6 membered heterocyclyl are oxo, NR 10 R 11 , -C(O)NR 10 R 11 and optionally NR 10 R 11 C replaced with 1-6 optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl; R 10 and R 11 are independently H or C 1-6 C optionally substituted with alkoxy 1-3 It is alkyl. or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof is provided.

[0023] In one embodiment, the compound of formula (III) [ka] [During the ceremony, R 1 , R 2 , R 3 and R 4 H, halo and C 1-3 independently selected from the group consisting of alkyl; R5 is H or C 1-3 is alkyl; R 6 , R 7 and R 8 H, halo, C 1-6 Alkyl and C 1-6 alkoxy, wherein C 1-6 Alkyl is optionally substituted with OH; 1-6 The alkoxy is optionally C 1-6 Alkoxy or NR 10 R 11 is replaced by; R 9 is H, C 1-6 Alkyl, C 5-6 cycloalkyl or 4-6 membered heterocyclyl, where C 1-6 Alkyl is NR 10 R 11 is replaced by C 5-6 Cycloalkyl and 4-6 membered heterocyclyl are oxo, NR 10 R 11 , -C(O)NR 10 R 11 and optionally NR 10 R 11 C replaced with 1-6 optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl; R 10 and R 11 are independently H or C 1-6 C optionally substituted with alkoxy 1-3 It is alkyl. or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof is provided.

[0024] The compound can be selected from any one of the exemplary compounds shown in Table 1, a stereoisomer, a tautomer, or a pharma- ceutically acceptable salt thereof.

[0025] In certain embodiments, the compound is selected from the group consisting of the following, or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof: [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11]

[0026] In another embodiment, the compound of formula (Ia) [ka] [During the ceremony, Ra 1 and Ra 4 is a halo; Ra 2 and Ra 3 H, halo and C 1-3 independently selected from the group consisting of alkyl; Ra 5 is H or C 1-3 is alkyl; Ra 6 , R 7 and R8 H, halo, C 1-6 Alkyl and C 1-6 alkoxy, wherein C 1-6 Alkyl and C 1-6 The alkoxy is optionally substituted with OH; Ra 9 is H, C 5-6 cycloalkyl or 5- or 6-membered heterocyclyl, where C 5-6 Cycloalkyl and 5- or 6-membered heterocyclyl are optionally substituted with OH; and Q is C, CH or N. or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof is provided.

[0027] In the description herein, every description, variation, embodiment or aspect of a part may be combined with every description, variation, embodiment or aspect of any other part to the same extent as if each and every combination of descriptions was specifically and individually listed.

[0028] In one embodiment, Ra 2 and Ra 3 is H.

[0029] In one embodiment, Ra 5 is C 1-3 Alkyl (eg, methyl and ethyl).

[0030] In one embodiment, Ra 6 , Ra 7 and Ra 8 is not H. In some embodiments, the moiety: [ka] teeth: [ka] is selected from the group consisting of:

[0031] In some embodiments, the moiety is [ka] It is.

[0032] In one embodiment, Ra 9 is H. In some embodiments, Ra 9 is C 5-6 cycloalkyl or 5- or 6-membered heterocyclyl, where C 5-6 Cycloalkyl and 5- or 6-membered heterocyclyl are optionally substituted with OH. In some embodiments, Ra 9 teeth [ka] It is.

[0033] In one embodiment, Ra 9 is H and Q is N.

[0034] In certain embodiments, the compound of formula (IIa) [ka] [During the ceremony, Ra 1 and Ra 4 is a halo; Ra 5 is H or C 1-3 is alkyl; Ra 6 , Ra 7 and Ra 8 H, halo, C 1-6 Alkyl and C 1-6 alkoxy, wherein C 1-6 Alkyl and C 1-6 The alkoxy is optionally substituted with OH; Ra 9 teeth [ka] and Q is C, CH or N. or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof is provided.

[0035] In certain embodiments, the compound of formula (IIIa) [ka] [During the ceremony, Ra 1 and Ra 4 is a halo; Ra 6 , Ra 7 and Ra 8 H, halo, C 1-6 Alkyl and C 1-6 alkoxy, wherein C 1-6 Alkyl and C 1-6 The alkoxy is optionally substituted with OH; Ra 9 is H, C 5-6 cycloalkyl or 5- or 6-membered heterocyclyl, where C 5-6 Cycloalkyl and 5- or 6-membered heterocyclyl are optionally substituted with OH; and Q is C, CH or N. or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof is provided.

[0036] The compound of formula (Ia) and some of its derivatives or synthetic intermediates can be prepared by synthetic methods known to those skilled in the art.In some embodiments, the present invention provides a method for preparing the compound defined by formula (Ia) above.Some compounds of the present invention can be prepared according to the method described in WO2021 / 165346.

[0037] For the GCN2 enzyme assay, test compounds were prepared at appropriate concentrations in DMSO solution. IC 50 Values ​​were calculated from the remaining activity using the read-out conversion ratio.

[0038] The compound can be selected from any one of the exemplary compounds shown in Table 1a, a stereoisomer, a tautomer, or a pharma- ceutically acceptable salt thereof.

[0039] In certain embodiments, the compound is selected from the group consisting of the following, or a stereoisomer, tautomer, or pharma- ceutically acceptable salt thereof: [Table 12] [Table 13] [Table 14] [Table 15]

[0040] Treatment A further embodiment of the present invention relates to a compound of formula (1) or a salt thereof or a pharmaceutical composition comprising a compound of formula (1) as a GCN2 modulator. The compounds of the present invention may be used as GCN2 modulators. The compounds of the present invention may be used as GCN2 inhibitors, antagonists or agonists. The compounds of the present invention may be used to treat diseases or disorders characterized by activation of GCN2.

[0041] The compounds of the invention may be used to treat cancer, neurodegenerative diseases, chronic infections or conditions or symptoms related thereto.

[0042] The compounds of the present invention can be used to treat cancer. In some embodiments, the compounds of the present invention are used to treat breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, renal cancer, lung cancer, melanoma, fibrosarcoma, osteosarcoma, connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, gastrointestinal cancer, adenocarcinoma, hepatocellular carcinoma, thyroid cancer, multiple myeloma, secretory cell carcinoma, myelodysplastic syndrome, myeloproliferative neoplasm, malignant glioma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia, chronic myelogenous leukemia. , hairy cell leukemia, benign monoclonal gammopathy (MGUS), plasmacytoma, lymphoplasmacytic lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, large granular lymphocytic leukemia, B-cell prolymphocytic leukemia, T-cell prolymphocytic leukemia, small cell lung cancer, malignant pleural mesothelioma, squamous cell carcinoma of the head and neck, glioblastoma multiforme, sarcoma, childhood neuroblastoma, or a condition or symptom related thereto.

[0043] In certain embodiments, the compounds and compositions detailed herein are used as modulators of GCN2. Provided herein are methods of treating a disease in an individual comprising administering an effective amount of a compound of Formula (I) and Formula (Ia) or any embodiment, variation or aspect thereof.

[0044] It has been found that GCN2 can be used as an immune regulator. GCN2 senses tryptophan and L-arginine depletion. Indoleamine 2,3-dioxygenase (IDO) is a potent immunomodulatory enzyme that mediates the conversion of the essential amino acid tryptophan (Trp) to kynurenine, and its expression enables some macrophages and dendritic cells (DCs) to inhibit T cell proliferation (Grohmann et al., 2003; Mellor and Munn, 2004). IDO and subsequent tryptophan starvation trigger a GCN2-dependent stress signaling pathway that induces profound anergy in response to T cells. GCN2 knockout cells are refractory to IDO-induced cell cycle arrest and anergy. IDO-expressing plasmacytoid DCs are found in tumor-draining lymph nodes and activate the GCN2 kinase pathway in response to T cells. T cells with targeted disruption of GCN2 are insensitive to IDO-mediated suppression of proliferation (Munn et al., 2005). GCN2 activation through the accumulation of uncharged tRNA leads to inhibition of CD8+ effector T cells and increased generation and activation of regulatory T cells.

[0045] IFN-γ is a cytokine that is mostly produced by activated T and NK cells and has complex actions on immune and non-immune cells. IFN-γ has an important role in inflammation and is therefore particularly relevant in transplantation and autoimmune diseases. IFN-γ induces Trp metabolism, which subsequently activates GCN2 kinase, leading to phosphorylation of eIF2α, an activator of autophagy. Conversely, Trp supplementation reduces activation of the GCN2-eIF2α pathway and inhibits autophagy. Moreover, targeting GCN2 expression by RNA interference also inhibits IFN-γ-induced autophagy (Fougeray et al., 2012).

[0046] GCN2 plays a central role in the regulation of cell cycle arrest induced by L-arginine (L-Arg) starvation. L-Arg is a non-essential amino acid that plays a central role in the regulation of immune responses (Bronte and Zanovello, 2005). In tumor-infiltrating myeloid cells, L-Arg is converted to urea and ornithine by arginase I and arginase II, and is oxidized to citrulline and nitric oxide by the inducible form of nitric oxide synthase. Thus, L-Arg is severely reduced in cancer patients, after liver transplantation or severe trauma due to increased production of arginase I (Zea et al., 2005; Roth et al., 1994; Angele et al., 1999). Increased arginase activity is frequently observed in patients with breast, prostate, lung and colon cancer (Cederbaum et al., 2004). The result is reduced T-cell proliferation and impaired T-cell function. GCN2 knockout T cells showed no reduction in proliferation in the absence of L-Arg ( Rodriguez et al., 2006 ).

[0047] GCN2 activation via L-Arg depletion has also been shown to occur in astrocytes, similar to how activation of GCN2 kinase in response to Trp depletion by IDO mediates growth arrest and induction of T cell anergy. L-Arg consumption by arginase 1 in tumor-conditioned cells mediates GCN2 kinase-dependent cell cycle arrest at the G0-G1 phase and downregulation of the ζ chain of the TCR / CD3 complex in antigen-activated T cells (Rodriguez et al., 2002).

[0048] Activation of GCN2 via amino acid deficient conditions promotes macrophage inflammation and mortality in a mouse model of sepsis. GCN2 knockout macrophages exhibited significantly reduced cytokine gene expression following lipopolysaccharide (LPS) stimulation. When monocytic lineage-specific GCN2 knockout mice were challenged with a lethal dose of LPS, the mice showed a reduced inflammatory response, with reduced IL-6 and IL-12 expression that correlated with a significant reduction in animal mortality (Liu et al., 2014).

[0049] In certain embodiments, provided herein are methods for treating a disease mediated by the GCN2 pathway in an individual, comprising administering to the individual an effective amount of a compound of Formula (I) or Formula (Ia) or a pharma- ceutical acceptable salt thereof.

[0050] In certain embodiments, provided herein are methods for treating a disease characterized by activation of the GCN2 pathway in an individual, comprising administering to the individual an effective amount of a compound of Formula (I) or Formula (Ia) or a pharma- ceutical acceptable salt thereof.

[0051] In some embodiments, a method of treating a disease in an individual is provided herein, wherein the individual has a low amino acid level. In some embodiments, the individual has a low non-essential amino acid level. In some embodiments, the individual has a low L-arginine level. In some embodiments, the individual has a low L-tryptophan level. In some embodiments, the disease is caused by low levels of L-arginine in a particular tissue or cell type, such as a tumor or immune cell. In some embodiments, the disease is caused by low levels of L-tryptophan in a particular tissue or cell type, such as a tumor or immune cell. In some embodiments, the L-tryptophan level is less than 200 μM, less than 100 μM, less than 75 μM, less than 50 μM, or less than 25 μM. In some embodiments, the L-tryptophan level is between 10 μM and 75 μM. In some embodiments, the L-arginine level is less than 200 μM, less than 100 μM, less than 75 μM, less than 50 μM, or less than 25 μM. In some embodiments, the L-arginine level is between 10 μM and 75 μM.

[0052] Also provided herein is a method for treating disease in an individual, wherein the disease is related to overexpression of GCN2.In some embodiments, provided herein is a method for treating disease in an individual, wherein the disease is related to activation of GCN2.In some embodiments, GCN2 is overexpressed and / or activated in certain tissues or cell types, such as tumors or immune cells.

[0053] In some embodiments, the methods provided herein inhibit a stress response in a cell. In some embodiments, the stress response is involved in cancer cell protection. In some embodiments, the stress response is associated with amino acid starvation. In some embodiments, the stress response is an unfolded protein response. In some embodiments, the stress response is an ER stress response.

[0054] In some embodiments, the methods provided herein decrease phosphorylation of GCN2. In some embodiments, downstream signaling by GCN2 is decreased. In some embodiments, phosphorylation of eIF2a kinase is decreased.

[0055] It has also been shown that persistent parasitic or viral infection is associated with local induction of IDO expression, which influences the activation of appropriate immune responses. It has also been shown that cutaneous Leishmania sylvestris infection stimulated IDO expression in local lymph nodes. Induced IDO attenuated the T cell stimulatory function of dendritic cells and suppressed local T cell responses to foreign and nominally parasitic antigens (Makala et al., 2011).

[0056] A role for IDO in leprosy was also demonstrated: an increased number of IDO-expressing macrophages / dendritic cells was found in lepromatous compared to borderline reactive patients. Furthermore, increased IDO message was found in M. leprae-stimulated peripheral blood mononuclear cells. These data suggest that chronic M. leprae infection activates the inhibitory molecule IDO, which then contributes to the specific immune suppression observed in lepromatous leprosy (de Souza et al., 2011).

[0057] It has been described that HIV inhibits CD4+ T cell proliferation through induction of IDO in plasmacytoid dendritic cells, and in vitro inhibition of IDO results in increased CD4(+) T cell proliferative responses of peripheral blood mononuclear cells from HIV-infected patients ( Boasso et al., 2007 ).

[0058] Therefore, the inhibitors of IDO / GCN2 pathway disclosed herein can be used to enhance immune response against chronic and persistent infection.In some embodiments, the compounds or salts thereof described herein or compositions described herein can be used in a method for treating or preventing viral infection.In some embodiments, the viral infection is African swine fever virus, dengue virus, enterovirus, hepatitis B virus, hepatitis C virus, influenza virus, tick-borne encephalitis virus or West Nile virus infection.In some embodiments, the viral infection is caused by a virus that activates GCN2 in infected cells.

[0059] The fundamental mechanism of nutritional stress management mediated by the GCN2 pathway functions primarily to couple cell proliferation to amino acid availability (Zhang et al., 2002).

[0060] In the tumor microenvironment, abnormal development of the vasculature leads to inadequate blood supply and glucose and amino acid deprivation. Both amino acid and glucose deprivation, a stress found in solid tumors, activates GCN2 to upregulate ATF4 target genes involved in amino acid synthesis and transport. GCN2 activation / overexpression and increased phospho-eIF2α compared to normal tissues were found in human and mouse tumors, and abrogation of ATF4 or GCN2 expression significantly inhibited tumor growth in vivo (Ye et al., 2010).

[0061] ATF4 is required in tumor cells for homeostasis of amino acid metabolism, and activation of the GCN2-ATF4-asparagine synthetase (ASNS) pathway promotes tumor cell survival under nutrient (amino acid or glucose) deprivation. The GCN2-eIF2α pathway is activated in various human and mouse tumor tissues. Depletion of ATF4 or GCN2 severely inhibits tumor growth in vivo. Together, these results suggest that the GCN2-ATF4-ASNS pathway is a promising target for tumor therapy.

[0062] Tumor xenograft studies of head and neck squamous cell carcinoma (HNSCC) or fibrosarcoma (HT1080) cell lines with GCN2 deficiency prevented tumor growth and survival (Ye et al., 2010; Wang et al., 2013). Furthermore, in response to vemurafenib, BRAF-mutated melanoma and colorectal cancer cells rapidly induced the ISR as a cytoprotective mechanism via GCN2 activation. Vemurafenib-induced ISR, an event independent of downstream MEK inhibition, was specifically abrogated by silencing of GCN2, but not other eIF2α kinases. Interestingly, siRNA-silenced ATF4 sensitized BRAF-mutated melanoma cells to vemurafenib. Thus, GCN2-mediated ISR may promote cellular adaptation to vemurafenib-induced stress and provide insight into the development of drug resistance ( Nagasawa et al., 2017 ).

[0063] It has been reported that amino acid deprivation, glucose deprivation and hypoxia promote tumor growth and angiogenesis via the GCN2 / eIF2α / ATF4 pathway (Wang et al., 2013). GCN2 expression is elevated in human tumors to overcome the stress associated with amino acid deprivation by stimulating vascular endothelial growth factor (VEGF)-mediated angiogenesis.

[0064] Leukemic cells lack the ability to synthesize asparagine. Hence, asparaginase, which functions by depleting asparagine and glutamine, is the treatment of first line for B-cell derived acute lymphoblastic leukemia (B-ALL) (Terwilliger et al., 2017). Treatment with asparaginase activates the GCN2 pathway in some leukemic cells, which has been shown to be a mechanism by which tumor cells deal with nutrient stress by restoring chemotherapy amino acid deprivation (Lough et al., 2018). Inhibition of GCN2 sensitizes cancer cells with low basal expression of asparagine synthetase (ASNS) to the anti-leukemic drug asparaginase (Nakamura et al., 2018). Hence, GCN2 inhibitors could be explored as monotherapy or in combination with asparaginase.

[0065] Without being bound to any particular theory, the GCN2-eIF2α-ATF4 pathway is important for maintaining metabolic homeostasis in tumor cells and thus represents a novel and attractive target for antitumor approaches.

[0066] The compounds disclosed herein as GCN2 modulators are useful in treating cancers including: colorectal cancer, gastrointestinal stromal tumors, lung cancer (e.g., small and non-small cell lung cancer, malignant mesothelioma, primary lung cancer), hematological cancers (e.g., multiple myeloma, leukemia (e.g., acute myeloid leukemia, acute lymphocytic leukemia, chronic leukemia), malignant lymphoma, Hodgkin's disease, non-Hodgkin's leukemia, chronic myeloproliferative disorders), cancer metastasis, precancerous lesions (e.g., bone marrow myelodysplastic syndrome), pancreatic cancer (e.g., pancreatic ductal carcinoma, pancreatic endocrine tumors), pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer (e.g., papillary adenocarcinoma, adenosquamous carcinoma), duodenal cancer, small intestinal cancer, breast cancer (e.g., intraductal carcinoma in situ, inflammatory breast cancer, invasive ductal carcinoma), ovarian cancer (e.g., The compound may be useful as a preventive or therapeutic agent for many GCN2-related diseases, such as ovarian epithelial cancer, ovarian germ cell tumor), testicular tumor, prostate cancer (e.g., hormone- and non-hormone-dependent prostate cancer, castration-resistant prostate cancer), liver cancer (e.g., hepatocellular carcinoma, primary liver cancer), extrahepatic bile duct cancer, thyroid cancer, kidney cancer (e.g., renal cell carcinoma, clear cell renal carcinoma), uterine cancer (e.g., cervical cancer, uterine body cancer, uterine sarcoma), brain tumor (e.g., glioma, glioblastoma, medulloblastoma, astrocytoma, pituitary adenoma), retinoblastoma, skin cancer (e.g., melanoma, basal cell carcinoma), sarcoma (e.g., rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma, osteosarcoma, spindle cell sarcoma), malignant bone tumor, and bladder cancer. In some embodiments, a compound or salt thereof described herein, or a composition described herein is used to treat breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, renal cancer, lung cancer, melanoma, fibrosarcoma, osteosarcoma, connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, gastrointestinal cancer or adenocarcinoma, hepatocellular carcinoma, thyroid cancer, multiple myeloma, secretory cell carcinoma, myelodysplastic syndromes, myeloproliferative neoplasms, malignant glioma, non-Hodgkin's disease, and / or myeloma. The present invention may be used in the treatment of cancers such as leukemia, ...In certain embodiments, the compounds, salts or compositions may be used in methods of treating metastatic renal cancer, chronic lymphocytic leukemia, pancreatic adenocarcinoma or non-small cell lung cancer.

[0067] GCN2 modulation provides the opportunity to disrupt tumor growth metabolism and at the same time enhance the efficacy of monotherapy or combination therapy with other anti-cancer drugs. In some embodiments, the compounds described herein or salts thereof or compositions described herein can be used to treat tumors in combination with other anti-cancer drugs, such as anti-neoplastic drugs, immune checkpoint inhibitors, or any other suitable anti-cancer drugs. Examples of immune checkpoint inhibitors include anti-PD-1, anti-PD-L1, anti-GITR, anti-OX-40, anti-LAG3, anti-TIM-3, anti-41BB, anti-CTLA-4 antibodies. Examples of anti-neoplastic drugs can include, for example, microtubule inhibitors, platinum coordination complexes, alkylating agents, topoisomerase II inhibitors, topoisomerase I inhibitors, antimetabolites, antibiotics, hormonal agents and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, proteasome inhibitors, and cancer metabolism inhibitors. Other anti-cancer agents may include one or more of an immunostimulant, an antibody or fragment thereof (e.g., an anti-CD20, anti-HER2, anti-CD52 or anti-VEGF antibody or fragment thereof) or an immunotoxin (e.g., an anti-CD33 antibody or fragment thereof, an anti-CD22 antibody or fragment thereof, a calicheamicin conjugate or a Pseudomonas exotoxin conjugate).

[0068] In some embodiments, the compound or salt thereof described herein or the composition described herein can be used in a method for treating cancer in an individual, wherein one or more of the cancer cells in the individual are dormant cancer cells.In some embodiments, one or more of the dormant cancer cells are disseminated tumor cells or circulating tumor cells.In some embodiments, one or more of the dormant cancer cells are disseminated tumor cells.

[0069] In some embodiments, the compound or salt thereof described herein or the composition described herein can be used in a method for treating cancer in an individual, where the individual has undergone a previous treatment. In some embodiments, the cancer is resistant or refractory to the previous treatment. In some embodiments, the cancer has progressed with the previous treatment. In this embodiment, the cancer is a recurrent cancer. In some embodiments, the previous treatment was with a ubiquitin-proteasome pathway inhibitor (e.g., bortezomib), a taxane (e.g., paclitaxel or docetaxel), a Cox-2 inhibitor (e.g., celecoxib), a platinum-based anti-neoplastic drug (e.g., cisplatin or oxaliplatin), an anthracycline (e.g., doxorubicin), a pyrimidine analog (e.g., 5-fluorouracil or gemcitabine), a topoisomerase inhibitor (e.g., etoposide), an mTOR inhibitor (e.g., rapamycin), an immune checkpoint inhibitor, or a drug used in immuno-oncology. In some embodiments, cancer is resistant to treatment with ubiquitin-proteasome pathway inhibitors (e.g., bortezomib), taxanes (e.g., paclitaxel or docetaxel), Cox-2 inhibitors (e.g., celecoxib), platinum-based antineoplastic drugs (e.g., cisplatin or oxaliplatin), anthracyclines (e.g., doxorubicin), pyrimidine analogs (e.g., 5-fluorouracil or gemcitabine), topoisomerase inhibitors (e.g., etoposide), mTOR inhibitors (e.g., rapamycin), immune checkpoint inhibitors or drugs used in immuno-oncology.In some embodiments, cancer is resistant to treatment with doxorubicin and / or rapamycin.

[0070] In some embodiments, administration of the compound, salt or composition reduces tumor growth, tumor growth or tumorigenicity in an individual. In some embodiments, the compound, salt or composition may be used in a method for reducing tumor growth, tumor growth or tumorigenicity in an individual in need of treatment. In some embodiments, tumor growth is slowed or stopped. In some embodiments, tumor growth is reduced by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%. In some embodiments, tumor size is reduced. In some embodiments, tumor size is reduced by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%. In some embodiments, tumor metastasis is prevented or slowed. In some embodiments, tumor growth, tumor growth or tumorigenicity is compared to tumor growth, tumor growth or tumorigenicity in the individual before administration of the compound, salt or composition. In some embodiments, tumor growth, tumor growth or tumorigenicity is compared to tumor growth, tumor growth or tumorigenicity in a similar individual or group of individuals. Methods for measuring tumor growth, tumor proliferation and tumorigenicity are known in the art, for example, by repeated imaging of an individual.

[0071] In certain embodiments, administration of the compound, salt or composition induces apoptosis of cancer cells, hi certain embodiments, apoptosis of cancer cells is increased by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% upon administration.

[0072] In certain embodiments, administration of the compound, salt or composition reduces CHOP induction, hi certain embodiments, CHOP induction is reduced by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% upon administration.

[0073] In certain embodiments, administration of the compound, salt or composition does not induce PERK activation. In certain embodiments, CHOP production by PERK is not inhibited by the administration.

[0074] It has recently been shown that hepatic GCN2 is activated in hepatic steatosis and that GCN2 deficiency protects against high-fat diet (HFD)-induced hepatic steatosis and insulin resistance, indicating that the role of GCN2 in regulating lipid metabolism is context-dependent.

[0075] After 12 weeks of high-fat diet (HFD) feeding, Gcn2- / - mice were significantly less obese than wild-type (WT) mice, and Gcn2- / - markedly attenuated HFD-induced liver dysfunction, hepatic steatosis, and insulin resistance. In the livers of HFD-fed mice, GCN2 deficiency resulted in higher levels of lipolysis genes, lower expression of genes related to fatty acid synthesis, transport, and lipid biosynthesis, and lower induction of oxidative stress. This study also reported that knockdown of GCN2 attenuated palmitate-induced steatosis, oxidative and ER stress, and changes in peroxisome proliferator-activated receptor gamma (PPARγ), fatty acid synthase, and metallothionein expression in HepG2 cells, while overexpression of GCN2 exacerbated them (Liu et al., 2018). These findings suggest that a strategy of inhibiting GCN2 activity in the liver may provide a novel approach to attenuate nonalcoholic fatty liver disease (NAFLD) progression.

[0076] When mice were maintained on a medium-fat (22 kcal% fat) diet during perinatal development, GCN2 deficiency reduced hepatic triglyceride stores ( Xu et al., 2013 ).

[0077] It was reported that GCN2 deficiency reduced cardiac dysfunction and hyperlipidemia in both type 1 diabetic (T1D) and type 2 diabetic (T2D) mice, and improved cardiac function in diabetic GCN2- / - mice correlated with reduced hypertrophy, fibrosis, lipid accumulation, oxidative stress, inflammation, and apoptosis. The pathological role of GCN2 in diabetic cardiomyopathy (DCM) was also verified in high glucose or palmitic acid treated H9C2 rat cardiomyoblast cell line (Feng et al., 2019).

[0078] GCN2 deficiency attenuated transaortic constriction (TAC)-induced cardiac dysfunction and cardiomyocyte apoptosis by reducing cardiomyocyte apoptosis and myocardial oxidative stress. GCN2 activation impaired adaptive responses to congestive heart failure (Lu et al., 2014). After doxorubicin-induced cardiac dysfunction, Gcn2- / - mice developed less contractile dysfunction, myocardial fibrosis, apoptosis, and oxidative stress compared to WT mice. In the hearts of Dox-treated mice, GCN2 deficiency attenuated eIF2α phosphorylation and the induction of its downstream targets, activating transcription factor 4 (ATF4) and C / EBP homologous protein (CHOP), and preserved anti-apoptotic factors Bcl-2 and mitochondrial uncoupling protein-2 (UCP2) expression (Wang et al., 2018). These data suggest that a strategy to inhibit GCN2 activity in cardiomyocytes may provide a novel approach to attenuate Dox-related cardiotoxicity.

[0079] Thus, in some embodiments, the compounds described herein or salts thereof, or compositions described herein may be used to treat or prevent metabolic and cardiac diseases.

[0080] It was shown that GCN2 deletion attenuated denervation-induced muscle atrophy. GCN2 deficiency also significantly attenuated muscle mass loss in atrophied gastrocnemius and extensor digitorum longus muscles. Similar results were observed 14 days after denervation. Wheat germ agglutinin staining of muscle cryosections showed that myofiber size in GCN2-deficient TA muscles was well preserved in response to denervation (Guo et al., 2018). Furthermore, the deleterious effect of GCN2 in denervation-induced muscle atrophy was associated with FoxO3a activation, which upregulated genes involved in both the ubiquitin-proteasome pathway and autophagy in muscle atrophy (Sandri et al., 2004; Bertaggia et al., 2012; Wei et al., 2013; Guo et al., 2016).

[0081] Thus, in certain embodiments, a compound described herein or a salt thereof, or a composition described herein may be used to treat or prevent muscle atrophy.

[0082] The expression of long-lasting synaptic plasticity and long-term memory (LTM) requires protein synthesis that can be suppressed by phosphorylation of eIF2α. In mice lacking the EIF2α kinase GCN2, reduced phosphorylated eIF2α is associated with altered synaptic plasticity and memory. In GCN2-deficient mice with reduced levels of both EIF2α phosphorylation and ATF4, the thresholds for long-lasting long-term potentiation (L-LTP) and LTM in the hippocampus are lower and are associated with weakly conditioned spatial memory (Costa-Mattioli et al., 2005). This model is supported by increased ATF4 expression following treatment with Sal003, an eIF2α phosphatase inhibitor, which leads to impaired L-LTP and LTM function.

[0083] Thus, in some embodiments, a compound described herein or a salt thereof, or a composition described herein may be used to treat or prevent memory loss.

[0084] Increased phosphorylation of IF2α has been observed in the brains of Alzheimer's disease (AD) patients and AD model mice. Inhibition of GCN2 prevents amyloid-β-induced synaptic plasticity dysfunction by reducing eIF2α phosphorylation. Senile plaques consist mainly of β-amyloid peptide (Aβ) derived from amyloid precursor protein (APP), which undergoes proteolytic processing by β-secretase (BACE-1) and γ-secretase. It has also been reported that BACE-1 levels are translationally increased by eIF2α phosphorylation (O'Connor et al., 2008). GCN2 inhibition under such disease conditions promotes γ-secretase activation or BACE-1 induction, and the resulting Aβ accumulation and plaque formation in the brain provides a valuable avenue to combat or halt neurodegenerative disease progression.

[0085] GCN2 deletion prevented synaptic plasticity dysfunction and spatial memory deficits in mice expressing familial AD-associated mutations in amyloid precursor protein (APP) and presenilin-1 (PS1). PS1 is essential for γ-secretase activity, and GCN2 / eIF2α / ATF4 signaling has a key role in regulating γ-secretase activity in autophagy-impaired cells (Ohata et al., 2010).

[0086] Furthermore, hippocampal LTP deficits in APP-PS1 mice were normalized in APP-PS1 GCN2-deficient mice. The impairments in spatial learning and memory exhibited by APP-PS1 mice were prevented in APP-PS1 GCN2-deficient mice, as observed in the Morris water maze task with reduced escape latency, increased platform crossing, and target quadrant occupancy closer to that seen in wild-type mice (Ma et al., 2013). Collectively, these findings indicate that genetic ablation of the eIF2α kinase GCN2 prevents Alzheimer's disease-associated LTP failure and spatial memory dysfunction.

[0087] Thus, in some embodiments, a compound described herein or a salt thereof, or a composition described herein may be used to treat a neurodegenerative disease.

[0088] Angiogenesis, the formation of new blood vessels by endothelial cells (ECs), is an adaptive response to oxygen / nutrient deprivation sensed by GCN2 and orchestrated by vascular endothelial growth factor (VEGF) upon ischemia or exercise. Retinal and choroidal neovascularization is the major cause of vision loss in severe ocular diseases such as diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, and central and branch retinal vein occlusion. Amino acid restriction induces angiogenesis via GCN2 / ATF4 regulation of VEGF and hydrogen sulfide production (Longchamp et al., 2018).

[0089] Furthermore, retinal neovascularization is causally and dynamically linked to vascular degeneration, ischemia, and vascular remodeling in retinal tissue (Zhang et al., 2015). ATF4 has been shown to function as an oxygen sensor and interact with HIF-1α to regulate VEGF production (Zhong et al., 2012). Global knockout of ATF4 disrupts lens development and causes microphthalmia (Masuoka and Townes, 2002). Genetic inhibition of ATF4 activity attenuates diabetes-induced retinal inflammation and vascular leakage, suggesting that upregulation of ATF4 contributes to retinal inflammation and endothelial barrier dysfunction in diabetic retinopathy (Chen et al., 2012).

[0090] Thus, in some embodiments, a compound described herein or a salt thereof, or a composition described herein may be used to treat an ophthalmic disease.

[0091] Since there is accumulating evidence that GCN2 pathway strongly influences the function of immune system, the present invention encompasses the use of GCN2 modulators for the treatment or prevention of immune-related disorders.In some embodiments, the compounds described herein or their salts or compositions described herein can be used to treat or prevent immune-related disorders.In some embodiments, the compounds described herein or their salts or compositions described herein can be used to treat or prevent autoimmune diseases selected from the group consisting of arthritis, graft-versus-host disease, Crohn's disease, multiple sclerosis, lupus, type 1 diabetes, rheumatoid arthritis, Graves' disease, autoimmune hemolytic anemia, Wegener's granulomatosis, ankylosing spondylitis, aplastic anemia, Behcet's disease, hyper-IgE syndrome, idiopathic thrombocytopenic purpura, myasthenia gravis and psoriasis.

[0092] In certain embodiments, the compounds described herein or salts thereof, or compositions described herein may be used in transplantation procedures to treat organ rejection, myeloablative and non-myeloablative bone marrow graft rejection.

[0093] In some embodiments, the compounds described herein or their salts or compositions described herein can be used to inhibit the phosphorylation of GCN2.In some embodiments, the compounds described herein or their salts or compositions described herein can be used to promote protein synthesis recovery under amino acid starvation conditions.In some embodiments, the compounds described herein or their salts or compositions described herein can be used to enhance protein synthesis, and thus can be used for diseases or disorders mediated by reduced protein synthesis, such as muscle atrophy, muscular dystrophy, cachexia, synaptic plasticity and long-term memory, among others.

[0094] In accordance with the above disclosure, in some embodiments, the individual is a mammal. In some embodiments, the individual is a primate, cow, sheep, pig, horse, dog, cat, rabbit or rodent. In some embodiments, the individual is a human. In some embodiments, the individual has any of the diseases or disorders disclosed herein. In some embodiments, the individual is at risk of developing any of the diseases or disorders disclosed herein.

[0095] Also provided herein is the use of a compound described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein, in the manufacture of a medicament.In some embodiments, the manufacture of a medicament is for the treatment of a disorder or disease described herein.In some embodiments, the manufacture of a medicament is for the prevention and / or treatment of a disorder or disease mediated by the GCN2 pathway.

[0096] In some embodiments, the compounds or salts thereof described herein or the compositions described herein may be used in a method as a stand-alone treatment or a co-treatment with other symptomatic agents (e.g., agents that alleviate the lifelong symptoms of the treatment) and / or agents that target the etiology of the disorder. The compounds or compositions of the present invention may be used or administered in combination with a second therapeutic agent. The compounds or compositions of the present invention may be used or administered in combination with an anti-cancer agent, an anti-angiogenic agent, or an agent that targets immune checkpoint proteins. The compounds or compositions of the present invention may be used or administered in combination with a second therapeutic agent selected from PEG-arginase, asparaginase, anti-angiogenic factors, cysteinase, or sulfasalazine.

[0097] As provided herein, the compounds described herein or salts thereof and compositions described herein may be administered with an agent to treat any of the diseases and disorders disclosed herein. In some embodiments, the agent is an anti-angiogenic agent. In some embodiments, the agent is an anti-cancer agent. In some embodiments, the agent targets an immune checkpoint protein.

[0098] In some embodiments, (a) the compound described herein or a pharma- ceutically acceptable salt thereof or the pharmaceutical composition described herein and (b) the agent are administered sequentially, together, or simultaneously. In some embodiments, (a) the compound described herein or a pharma- ceutically acceptable salt thereof or the pharmaceutical composition described herein and (b) the agent are administered about 15 minutes or less apart, for example, about 10 minutes, 5 minutes, or 1 minute or less apart. In some embodiments, (a) the compound described herein or a pharma- ceutically acceptable salt thereof or the pharmaceutical composition described herein and (b) the agent are administered about 15 minutes or more apart, for example, about 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes or more apart. Either (a) the compound described herein or a pharma- ceutically acceptable salt thereof or the pharmaceutical composition described herein and (b) the agent may be administered first. In some embodiments, (a) the compound described herein or a pharma- ceutically acceptable salt thereof or the pharmaceutical composition described herein and (b) the agent are administered simultaneously.

[0099] Provided herein is a method for enhancing an immune response in an individual, comprising administering to the individual (a) a compound described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein, and (b) an agent that targets an immune checkpoint protein. In some embodiments, the individual has cancer. In some embodiments, the enhanced immune response is directed toward tumor or cancer cells.

[0100] Also provided herein is a method of treating cancer in an individual in need thereof, comprising administering to the individual (a) a compound described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein, and (b) an agent that targets an immune checkpoint protein, wherein the individual's immune response is increased.

[0101] In some embodiments, the drug is an anticancer drug.In some embodiments, the anticancer drug is a ubiquitin-proteasome pathway inhibitor (e.g., bortezomib), a taxane (e.g., paclitaxel or docetaxel), a Cox-2 inhibitor (e.g., celecoxib), a platinum-based anti-neoplastic drug (e.g., cisplatin or oxaliplatin), an anthracycline (e.g., doxorubicin), a pyrimidine analog (e.g., 5-fluorouracil or gemcitabine), a topoisomerase inhibitor (e.g., etoposide) or a drug that modulates endoplasmic reticulum stress response or integrated stress response (e.g., IRE1 / XBP1 inhibitor or PERK inhibitor).In some embodiments, the anticancer drug is oxaliplatin, 5-fluorouracil or gemcitabine.In some embodiments, the anticancer drug is an immune checkpoint inhibitor or a drug used in immuno-oncology.

[0102] In certain embodiments, an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein is administered to an individual having cancer to increase sensitivity to one or more anti-cancer treatments.

[0103] In some embodiments, an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, is administered to an individual having cancer to enhance sensitivity to radiation. In some embodiments, provided herein is a method of treating cancer in an individual in need thereof, comprising administering to the individual (a) a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, and (b) radiation.

[0104] In some embodiments, an effective amount of the compound described herein or its pharmaceutically acceptable salt or the pharmaceutical composition described herein is administered to an individual with cancer to increase sensitivity to one or more anti-cancer drugs.In some embodiments, the anti-cancer drug is a ubiquitin-proteasome pathway inhibitor (e.g., bortezomib), a taxane (e.g., paclitaxel or docetaxel), a Cox-2 inhibitor (e.g., celecoxib), a platinum-based anti-neoplastic drug (e.g., cisplatin or oxaliplatin), an anthracycline (e.g., doxorubicin), a pyrimidine analog (e.g., 5-fluorouracil or gemcitabine), a topoisomerase inhibitor (e.g., etoposide) or a drug that modulates endoplasmic reticulum stress response or integrated stress response (e.g., IRE1 / XBP1 inhibitor or PERK inhibitor).In some embodiments, the anti-cancer drug is oxaliplatin, 5-fluorouracil or gemcitabine.In some embodiments, the anti-cancer drug is an immune checkpoint inhibitor or a drug used in immuno-oncology.

[0105] definition For the purposes of this application, the following definitions apply unless otherwise stated.

[0106] As used herein, the term "GCN2 modulator" refers to any compound that binds to and modulates the function of GCN2. The term "modulator" should be interpreted to include modulation by modalities including, but not limited to, antagonists, agonists, partial agonists, and inverse agonists.

[0107] The term "treatment" in relation to the use of any of the compounds described herein, including compounds of formula (1), is used to describe any form of intervention in which a compound is administered to an individual who has or is at risk of having or is likely to have the disease or disorder in question, such as cancer or an immunological disorder. Thus, the term "treatment" includes both preventative (prophylactic) treatment and treatment when measurable or detectable symptoms of the disease or disorder are present. Treatment also includes reducing one or more symptoms resulting from the disease or disorder, reducing the severity of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying the worsening of the disease or disorder), delaying the onset or recurrence of the disease or disorder, delaying or slowing the progression of the disease or disorder, improving the condition of the disease or disorder, providing remission (either partial or complete) of the disease or disorder, reducing the dosage of one or more other medications required to treat the disease or disorder, enhancing the effectiveness of other medications used to treat the disease or disorder, slowing the progression of the disease or disorder, improving the quality of life and / or extending the lifespan of a patient.

[0108] In some variations, treatment does not include prophylaxis. Thus, in some variations, treatment refers to the use of any of the compounds described herein, including compounds of formula (1), and is understood to be used to refer to any form of intervention in which a compound is administered to an individual who has, is at risk of, or is likely to have, the disease or disorder in question, such as cancer or an immunological disease.

[0109] "Individual" refers to a mammal, including humans and non-human mammals. Examples of individuals include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, an individual refers to a human.

[0110] The term "therapeutic effective amount" (e.g., in relation to a method of treating a disease or condition) refers to an amount of a compound that is effective to produce a desired therapeutic effect. For example, if the condition is pain, an effective therapeutic amount is an amount sufficient to provide a desired level of pain relief. The desired level of pain relief can be, for example, complete elimination of pain or a reduction in the severity of pain. In relation to treatment, if the condition is cancer, an effective therapeutic amount is an amount sufficient to reduce one or more symptoms associated with cancer, such as reducing tumor size or metastasis rate.

[0111] As used herein, "about" a parameter or value includes and describes the parameter or value itself. For example, "about X" includes and describes X itself.

[0112] Terms such as "alkyl," "alkoxy," and "halo" are all used in their ordinary sense (e.g., as defined in the IUPAC Gold Book) unless otherwise indicated. "Optionally substituted" as applied to a group means that the group can be substituted with one or more substituents, which can be the same or different, if substitution is desired.

[0113] As used herein, "heteroaryl" refers to an unsaturated aromatic cyclic group having 1-14 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen, and sulfur. Heteroaryl groups can have a single ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl), which condensed rings may or may not be aromatic. Particular heteroaryl groups are 5-14 membered rings having 1-12 annular carbon atoms and 1-6 annular heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-10 membered rings having 1-8 annular carbon atoms and 1-4 annular heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-, 6-, or 7-membered rings having 1-5 annular carbon atoms and 1-4 annular heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some variations, particular heteroaryl groups are monocyclic aromatic 5-, 6-, or 7-membered rings having 1-6 annular carbon atoms and 1-4 annular heteroatoms independently selected from nitrogen, oxygen, and sulfur. In other variations, certain heteroaryl groups are polycyclic aromatic rings having 1-12 ring carbon atoms and 1-6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. Heteroaryl groups may be fused to aryl, cycloalkyl, or heterocyclyl. In some variations, heteroaryl groups having more than one ring, at least one of which is aryl, cycloalkyl, or heterocyclyl, are bonded to the parent structure at an atom in the aromatic ring group having at least one ring heteroatom. Heteroaryl groups may be bonded to the parent structure at a ring carbon atom or a ring heteroatom.

[0114] As used herein, "heterocycle", "heterocyclic" or "heterocyclyl" refers to a saturated or unsaturated non-aromatic cyclic group having a single ring or multiple fused rings and having 1 to 14 annular carbon atoms and 1 to 6 annular heteroatoms, such as nitrogen, sulfur, or oxygen. In certain embodiments, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to provide N-oxide, -S(O)-, or -SO2- moieties. Heterocycles containing more than one ring may be fused, bridged, or spiro, or any combination thereof, but are other than heteroaryl. Heterocyclyl groups may be optionally substituted independently with one or more substituents described herein. Particular heterocyclyl groups are a 3- to 14-membered ring having 1 to 13 cyclic carbon atoms and 1 to 6 cyclic heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 12-membered ring having 1 to 11 cyclic carbon atoms and 1 to 6 cyclic heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 10-membered ring having 1 to 9 cyclic carbon atoms and 1 to 4 cyclic heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 8-membered ring having 1 to 7 cyclic carbon atoms and 1 to 4 cyclic heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 3- to 6-membered ring having 1 to 5 cyclic carbon atoms and 1 to 4 cyclic heteroatoms independently selected from nitrogen, oxygen and sulfur. In some variations, heterocyclyl includes a monocyclic 3-, 4-, 5-, 6-, or 7-membered ring having 1-2, 1-3, 1-4, 1-5, or 1-6 ring carbon atoms and 1-2, 1-3, or 1-4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In other variations, heterocyclyl includes a polycyclic non-aromatic ring having 1-12 ring carbon atoms and 1-6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. Heterocyclyl groups may be fused with an aryl, cycloalkyl, or heteroaryl. In some variations, heterocyclyl groups having more than one ring, with at least one ring being an aryl, cycloalkyl, or heteroaryl, are attached to the parent structure at an atom in the non-aromatic ring group having at least one heteroatom.

[0115] To the extent that any of the compounds described contain chiral centers, the invention extends to all optical isomers of such compounds, whether in the form of racemates or resolved enantiomers. Also provided herein are any and all stereoisomers of the compounds described herein, including, where applicable, geometric isomers (e.g., cis / trans isomers or E / Z isomers), enantiomers, diastereomers, or mixtures thereof in any ratio, including racemic mixtures.

[0116] The invention described herein relates to all crystalline forms, solvates and hydrates of any of the disclosed compounds, however prepared. If any of the disclosed compounds have an acid or basic center, such as a carboxylate or amino group, all salt forms of the compound are included herein. For pharmaceutical use, the salts must be considered as pharmaceutically acceptable salts.

[0117] Particularly noteworthy salts or pharma- ceutically acceptable salts include acid addition salts and base addition salts. Such salts can be formed in a conventional manner, for example by reacting a compound in free acid or free base form with one or more equivalents of a suitable acid or base, optionally in a solvent or medium in which the salt is insoluble, followed by removing the solvent or medium by standard techniques, for example under reduced pressure, freeze-drying or filtration. Salts can also be prepared by exchanging a counterion of a compound in salt form with another counterion, for example using a suitable ion exchange resin.

[0118] Examples of pharma- ceutically acceptable salts include acid addition salts derived from mineral and organic acids and salts derived from metals such as sodium, magnesium, potassium and calcium.

[0119] Examples of acid addition salts are acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, arylsulfonic acids (e.g. benzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid and p-toluenesulfonic acid), ascorbic (e.g. L-ascorbic acid), L-aspartic acid, benzoic acid, 4-acetamidobenzoic acid, butyric acid, (+) camphoric acid, camphor-sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic (e.g. D-gluconic) acid, glucuronic (e.g. D-glucuronic acid, glutamic (e.g. L-glutamic) acid, α-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, lactic (e.g. (+)-L-lactic and (±)-DL-lactic) acid, lactobionic acid, maleic acid, malic (e.g. (-)-L-malic) acid, malonic acid, (±)-DL-mandelic acid, metaphosphoric acid, methanesulfonic acid, 1- Includes acid addition salts formed with hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric (e.g., (+)-L-tartaric) acid, thiocyanic acid, undecylenic acid, and valeric acid.

[0120] Also included are any solvates of the compounds and their salts.Preferred solvates are those formed by incorporating non-toxic pharma- ceutically acceptable solvent molecules (hereinafter referred to as solvating solvents) into the solid-state structure (e.g., crystalline structure) of the compounds of the present invention.Examples of such solvents include water, alcohols (e.g., ethanol, isopropanol and butanol) and dimethylsulfoxide.Solvates can be prepared by recrystallization of the compounds of the present invention with a solvent or a solvent mixture containing a solvating solvent.Whether solvates are formed in a given situation can be determined by subjecting the crystals of the compounds to analysis using well-known and standard techniques, such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and X-ray crystallography.

[0121] Solvates can be stoichiometric or non-stoichiometric solvates.Particular solvates can be hydrates, and examples of hydrates include hemihydrates, monohydrates and dihydrates.For more detailed description of solvates and the methods used for their preparation and characterization, see Bryn et al, Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3.

[0122] The term "pharmaceutical composition" in the context of the present invention means a composition that contains an active agent and further comprises one or more pharma- ceutically acceptable carriers suitable for administration to an individual. The composition may further comprise, depending on the nature of the administration method and administration form, ingredients selected from, for example, diluents, adjuvants, additives, vehicles, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, fragrances, antibacterial agents, antifungal agents, lubricants and dispersing agents. The composition may take the form of, for example, tablets, dragees, powders, elixirs, syrups, liquid preparations including suspensions, sprays, inhalants, tablets, lozenges, emulsions, solutions, cachets, granules, capsules and suppositories, as well as injectable liquid preparations including liposomal preparations.

[0123] The compounds of the invention may contain one or more isotopic substitutions, and the recitation of a particular element includes within its scope all isotopes of that element. For example, the recitation of hydrogen includes within its scope all isotopes of that element. 1 H, 2 H(D) and 3 H(T) within its scope. Similarly, the descriptions of carbon and oxygen are 12 C. 13 C and 14 C and 16 O and 18 O is included within its scope. In a similar manner, unless the context indicates otherwise, the description of a particular functional group also includes within its scope isotopic variations. For example, the description of an alkyl group such as an ethyl group or an alkoxy group such as a methoxy group also covers variations in which one or more of the hydrogen atoms of the group are in the form of a deuterium or tritium isotope, such as in an ethyl group (perdeuteroethyl group) in which all five hydrogen atoms are in the form of a deuterium isotope, or in a methoxy group (trideuteromethoxy group) in which all three hydrogen atoms are in the form of a deuterium isotope. Isotopes may be radioactive or non-radioactive.

[0124] Treatment dosage can vary according to the needs of the patient, the severity of the condition being treated and the compound being used.The determination of the appropriate dosage for a particular situation is within the skill of the art.Generally, treatment is started with a small dosage that is less than the optimal dose of the compound.Then, the dosage is increased by small increments until the optimal effect under the circumstances is reached.For convenience, if desired, the total daily dosage can be divided and administered in portions throughout the day.

[0125] The extent of the effective dosage of the compound will of course vary depending on the nature of the severity of the condition being treated and the particular compound and its route of administration. The selection of the appropriate dosage is within the ability of one of ordinary skill in the art without undue burden. In general, the daily dosage range can be about 10 μg to about 30 mg per kg of human and non-human animal body weight, preferably about 50 μg to about 30 mg per kg of human and non-human animal body weight, such as about 50 μg to about 10 mg per kg of human and non-human animal body weight, such as about 100 μg to about 30 mg per kg of human and non-human animal body weight, such as about 100 μg to about 10 mg per kg of human and non-human animal body weight, and most preferably about 100 μg to about 1 mg per kg of human and non-human animal body weight.

[0126] Pharmaceutical preparations While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (eg, formulation).

[0127] Thus, in one embodiment of the present invention, there is provided a pharmaceutical composition comprising at least one compound of formula (1) as defined above, together with at least one pharma- ceutically acceptable excipient.

[0128] The pharma- ceutically acceptable excipients may be selected, for example, from carriers (e.g., solid, liquid, or semi-solid carriers), adjuvants, diluents (e.g., solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and co-solvents), granulating agents, binders, flow aids, coating agents, release-controlling agents (e.g., release-suppressing or retarding polymers or waxes), binding agents, disintegrants, buffers, lubricants, preservatives, antifungal and antibacterial agents, antioxidants, buffers, tonicity adjusting agents, thickeners, flavors, sweeteners, dyes, plasticizers, taste-masking agents, stabilizers, or any other excipients conventionally used in pharmaceutical compositions.

[0129] As used herein, the term "pharmacologically acceptable" means a compound, substance, composition, and / or dosage form that is, within the scope of reasonable medical judgment, suitable for use in contact with the tissues of a subject (e.g., a human subject) without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each excipient must also be "acceptable" in terms of being compatible with the other ingredients of the formulation.

[0130] Pharmaceutical compositions containing compounds of formula (1) can be formulated by known techniques, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA. The pharmaceutical composition can be in any form suitable for oral, parenteral, intravenous, intramuscular, intrathecal, subcutaneous, topical, intranasal, intrabronchial, sublingual, buccal, ophthalmic, otic, rectal, vaginal or transdermal administration.

[0131] Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal patches.

[0132] The composition may be a tablet composition or a capsule composition. The tablet composition may contain a unit dose of the active compound together with an inert diluent or carrier, such as a sugar or sugar alcohol, such as lactose, sucrose, sorbitol or mannitol; and / or a non-sugar derived diluent, such as sodium carbonate, calcium phosphate, calcium carbonate or cellulose or its derivatives, such as microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, hydroxypropylmethylcellulose and starch, such as corn starch. The tablet may also contain components such as binding and granulating agents, such as polyvinylpyrrolidone, disintegrants (e.g., swellable cross-linked polymers such as cross-linked carboxymethylcellulose), lubricants (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffers (e.g., phosphate or citrate buffers) and effervescent agents, such as citric acid / bicarbonate mixtures. Such additives are well known and need not be described in detail here.

[0133] Tablets may be designed to release the drug upon contact with gastric fluids (fast dissolving tablets) or in a controlled manner over an extended period or in specific areas of the GI tract (controlled release tablets).

[0134] A pharmaceutical composition typically comprises about 1% (w / w) to about 95%, preferably % (w / w) active ingredient and 99% (w / w) to 5% (w / w) of a pharma- ceutically acceptable additive (e.g., as defined above) or a combination of such additives. Preferably, the composition comprises about 20% (w / w) to about 90% (w / w) active ingredient and 80% (w / w) to 10% of a pharma- ceutically acceptable additive or a combination of additives. A pharmaceutical composition comprises about 1% to about 95%, preferably about 20% to about 90%, active ingredient. The pharmaceutical composition of the present invention may be in unit dose form, such as, for example, in the form of ampoules, vials, suppositories, prefilled syringes, dragees, powders, tablets or capsules.

[0135] Tablets and capsules may, for example, contain 0-20% disintegrant, 0-5% lubricant, 0-5% flow aid and / or 0-99% (w / w) filler and / or extender (depending on drug dose). They may also contain 0-10% (w / w) polymer binder, 0-5% (w / w) antioxidant, 0-5% (w / w) pigment. Extended release tablets further typically contain 0-99% (w / w) release controlling (e.g. retarding) polymer (dose dependent). Film coats for tablets or capsules typically contain 0-10% (w / w) polymer, 0-3% (w / w) pigment and / or 0-2% (w / w) plasticizer.

[0136] The composition may be a parenteral composition. Parenteral formulations typically contain 0-20% (w / w) buffer, 0-50% (w / w) co-solvent and / or 0-99% (w / w) water for injection (WFI) (depending on the dose and whether it is lyophilized). Formulations for intramuscular depots may also contain 0-99% (w / w) oil.

[0137] Pharmaceutical formulations may be provided to the patient in "patient packs," usually blister packs, containing an entire course of treatment in one package.

[0138] The compound of formula (1) is generally provided in unit dosage form, and as such typically contains sufficient compound to provide a desired level of biological activity. For example, a formulation may contain 1 nanogram to 2 grams of active ingredient, e.g., 1 nanogram to 2 milligrams of active ingredient. Within these ranges, particular subranges of compound are 0.1 milligrams to 2 grams of active ingredient (more generally 10 milligrams to 1 gram, e.g., 50 milligrams to 500 milligrams) or 1 microgram to 20 milligrams (e.g., 1 microgram to 10 milligrams, e.g., 0.1 milligram to 2 milligrams of active ingredient).

[0139] For oral compositions, a unit dosage form contains from 1 milligram to 2 grams, more typically from 10 milligrams to 1 gram, for example, 50 milligrams to 1 gram, for example, 100 milligrams to 1 gram of active compound.

[0140] The active compound is administered to a patient (e.g., a human or animal patient) in need thereof in an amount sufficient to achieve the desired therapeutic effect (an effective amount). The exact amount of the compound to be administered can be determined by the treating physician according to standard procedures. EXAMPLES

[0141] The present invention will now be described, but not limited to, with reference to the following examples. Certain compounds of formula (I) and formula (Ia) and their derivatives or synthetic intermediates can be prepared by synthetic methods known to those skilled in the art. In some embodiments, the present invention provides a method for preparing the compounds defined in formula (I) and formula (Ia) above. Certain compounds of the present invention can be prepared by the methods described in WO2021 / 165346.

[0142] Synthesis of (2R,4S)-4-((6-(3-((2,5-dichloro-3-(hydroxymethyl)phenyl)sulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)amino)-N-(2-methoxyethyl)pyrrolidine-2-carboxamide (compound 3) [ka]

[0143] Synthesis of 5-chloro-N-(2,4-dichloro-3-(2-(((1R,3R)-3-(((2-methoxyethyl)amino)methyl)cyclopentyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (compound 7) [ka]

[0144] Synthesis of (2R,4S)-4-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)amino)-N-(2-methoxyethyl)pyrrolidine-2-carboxamide (compound 15) [ka]

[0145] Synthesis of (1R,3R)-3-((6-(2,6-dichloro-3-((5-chloro-2-methoxypyridine)-3-sulfonamido)phenyl)quinazolin-2-yl)amino)cyclopentane-1-carboxamide (compound 16) [ka]

[0146] Synthesis of (R)-3-((6-(2,6-dichloro-3-((5-chloro-2-methoxypyridine)-3-sulfonamido)phenyl)quinazolin-2-yl)amino)-N-(2-methoxyethyl)pyrrolidine-1-carboxamide (Compound 18) [ka]

[0147] Synthesis of (1R,4R)-4-((6-(2,6-dichloro-3-((5-chloro-2-methoxypyridine)-3-sulfonamido)phenyl)quinazolin-2-yl)amino)-N-(2-methoxyethyl)cyclohexane-1-carboxamide (compound 21) [ka] [ka]

[0148] Synthesis of 5-chloro-N-(2,4-dichloro-3-(2-((1,1-dioxidotetrahydrothiophen-3-yl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (compound 27) [ka]

[0149] Synthesis of 5-chloro-N-(2,4-dichloro-3-(2-((2-(dimethylamino)ethyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (compound 30) [ka]

[0150] Synthesis of 2,5-dichloro-N-(3-(2-(((1R,4R)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-3-(hydroxymethyl)benzenesulfonamide (compound 53) [ka]

[0151] Synthesis of (1R,3R)-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2,6-difluorophenyl)-8-ethylquinazolin-2-yl)amino)-N-(2-methoxyethyl)cyclopentane-1-carboxamide (compound 54) [ka]

[0152] Synthesis of 2-chloro-N-(3-(2-(((1R,4R)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)benzenesulfonamide (Compound 70) [ka]

[0153] Synthesis of N-(3-(2-(((1R,4R)-4-aminocyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-2-chlorobenzenesulfonamide (Compound 71) [ka] [ka]

[0154] For the GCN2 enzyme assay, test compounds were prepared at appropriate concentrations in DMSO solution. IC 50 Values ​​were calculated from the remaining activity using the read-out conversion ratio. IC of example compounds 50 The values ​​are shown in Table 2. [Table 16]

Claims

1. Equation (Ia) 【Chemistry 1】 [During the ceremony, Ra １ and Ra ４ It is a halo; Ra ２ and Ra ３ H, Halo and C １－３ Independently selected from the group consisting of alkyls; Ra ５ is H or C １－３ It is alkyl; Ra ６ 、 Ra ７ 以及 Ra ８ 各自独立地选自H、卤素、C １－６ 烷基以及C １－６ 烷氧基组成的组,其中,C １－６ 烷基以及C １－６ 烷氧基可根据需要被OH取代; Ra ９ H, C ５－６ It is a cycloalkyl or a 5-membered or 6-membered heterocycline, where C ５－６ Cycloalkyl and 5-membered or 6-membered heterocyclyls are optionally substituted with OH groups; and Q is C, CH, or N. Compounds thereof or their stereoisomers, tautomers, or pharmaceutically acceptable salts.

2. Ra ２ and Ra ３ The compound according to claim 1, wherein H is present, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. 【Request Item 3】 【Chemistry 2】 but 【Transformation 3】 A compound according to claim 1, selected from the group consisting of the following, or its stereoisomer, tautomer, or pharmaceutically acceptable salt.

4. Ra ９ The compound according to claim 1, wherein H is present, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

5. Ra ９ C is substituted with OH as desired. ５－６ A cycloalkyl compound according to claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

6. Ra ９ The compound according to claim 1, wherein is a five-membered or six-membered heterocycline, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

7. Ra ９ but 【Chemistry 4】 The compound according to claim 1, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. 【Request Item 8】 【Chemistry 5】 [During the ceremony, R １ , R ２ , R ３ and R ４ H, Halo and C １－３ Independently selected from the group consisting of alkyls; R ５ is H or C １－３ It is alkyl; R ６ , R ７ and R ８ H, Haro, C １－６ Alkyl and C １－６ Independently selected from the group consisting of alkoxys, where C １－６ The alkyl group is optionally substituted with an OH group, C １－６ Alkoxy is C as desired １－６ Alkoxy or NR １０ R １１ It has been replaced with; R ９ H, C １－６ Alkyl, C ５－６ It is a cycloalkyl or a 4-6 member heterocycline, where C １－６ Alkyl is NR １０ R １１ It is replaced with C ５－６ Cycloalkyl and 4-6 membered heterocyclyls are oxo, NR １０ R １１ , -C(O)NR １０ R １１ and NR as requested １０ R １１ C is replaced by １－６ It is optionally substituted with one or two substituents independently selected from the group consisting of alkyl groups; R １０ and R １１ H or C １－６ C which is optionally substituted with an alkoxy １－３ It is alkyl; and X, Y, and Q are independently C, CH, or N. However, R ９ If H and X and Y are C or CH, then R ６ , R ７ and R ８ At least one of them is C １－６ It is an alkoxy, and here, C １－６ Alkoxy is C １－６ Alkoxy or NR １０ R １１ It has been replaced with [this]. Compounds thereof or their stereoisomers, tautomers, or pharmaceutically acceptable salts.

9. R ２ and R ３ The compound according to claim 8, wherein H is present, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. 【Request Item 10】 【Chemistry 6】 but 【Transformation 7】 A compound according to claim 8, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, selected from the group consisting of the above.

11. R ９ The compound according to claim 8, wherein H is present, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

12. R ９ NR １０ R １１ C is replaced by １－６ The compound according to claim 8, wherein it is an alkyl compound, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

13. R ９ C ５－６ It is a cycloalkyl or a 4-6 member heterocycline, where C ５－６ Cycloalkyl and 4-6 member heterocyclyl are oxo, NR １０ R １１ , -C(O)NR １０ R １１ and NR as requested １０ R １１ C is replaced by １－６ The compound according to claim 8, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, which are optionally substituted with one or two substituents independently selected from the group consisting of alkyl groups.

14. R ９ but 【Transformation 8】 The compound according to claim 8, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

15. R ９ but 【Chemistry 9】 and wherein R １２ is NR １０ R １１ , -C(O)NR １０ R １１ or optionally NR １０ R １１ and is selected from the group consisting of C １－６ alkyl, a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to claim 8.

16. The compound according to claim 8, wherein X is N, and its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof.

17. The compound according to claim 8, wherein Y is N, and its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof.

18. A compound selected from the compounds in Table 1 and Table 1a, or its stereoisomer, tautomer, or pharmaceutically acceptable salt: Table 1 Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 1a Table 12 Table 13 Table 14 Table 15

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for treating a disease or disorder characterized by activation of GCN2 in an individual requiring treatment.

21. The pharmaceutical composition according to claim 20, wherein the disease or disorder is cancer, neurodegenerative disease, or chronic infection.

22. The pharmaceutical composition according to claim 21, wherein the disease or disorder is cancer.

23. Cancers include breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, melanoma, fibrosarcoma, osteosarcoma, connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, gastrointestinal cancer, adenocarcinoma, hepatocellular carcinoma, thyroid cancer, multiple myeloma, secretory cell carcinoma, myelodysplastic syndrome, myeloproliferative neoplasm, malignant glioma, non-Hodgkin lymphoma, Hodgkin lymphoma, Burkitt lymphoma, chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy The pharmaceutical composition according to claim 22, wherein the patient is a cell leukemia, benign monoclonal gammaglobulinemia (MGUS), plasmacytoma, lymphoplasmacytic lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, large granular lymphocytic leukemia, B-cell prelymphocytic leukemia, T-cell prelymphocytic leukemia, small cell lung cancer, malignant pleural mesothelioma, squamous cell carcinoma of the head and neck, glioblastoma multiforme, sarcoma, or pediatric neuroblastoma.

24. The pharmaceutical composition according to claim 20, wherein a compound or its stereoisomer, tautomer, or pharmaceutically acceptable salt is administered in combination with a second therapeutic agent, wherein the second therapeutic agent is PEG-arginase, asparaginase, anti-angiogenic factor, cysteinase, or sulfasalazine.

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