GCN2 inhibitors and uses thereof

Abstract

To provide compounds, compositions thereof, and methods of using the same.SOLUTION: The present invention relates to compounds and methods useful for inhibiting General amino acid Control Non-derepressible 2 kinase ("GCN2"). In another aspect, the invention also provides pharmaceutically acceptable compositions comprising the compounds of the present invention, and methods of using the compositions in treatment of various disorders.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Citation of Related Applications This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 62 / 623,299, filed January 29, 2018, the contents of which are incorporated herein by reference in their entirety. Technical field of the invention

[0002] The present invention relates to compounds and methods useful for inhibiting General Amino Acid Control Non-derepressible 2 kinase ("GCN2"). The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention, and methods of using the compositions in the treatment of various disorders. [Background technology]

[0003] Background of the Invention GCN2 (general amino acid control essential 2) is a ubiquitously expressed protein kinase involved in the cellular response to amino acid deficiency in eukaryotes (Castilho et al., 2014). Cellular deficiency of one or more amino acids leads to the accumulation of uncharged cognate transfer RNAs (tRNAs), which are directly bound by GCN2, resulting in kinase activation and phosphorylation of eukaryotic initiation factor 2α (eIF2α) at ​​serine 51 (Wek et al., 1989; Dong et al., 2000). Phosphorylation of eIF2α leads to the initiation of protein translation, which causes a decrease in translation of most mRNAs and results in an overall decrease in amino acid availability. Concomitantly, eIF2α phosphorylation increases translation of a specific subset of mRNAs containing specific upstream open reading frames in their 5'-untranslated regions (5'-UTRs), such as the mammalian transcription factor ATF4 (Vattem and Wek, 2004), which promotes restoration of protein homeostasis. Thus, GCN2 is a critical determinant of the developmental fate of cells in response to amino acid depletion.

[0004] Induction of cellular responses to amino acid depletion has emerged as an important mechanism for regulating the mammalian immune system, particularly in certain disease settings, including cancer and autoimmunity. Various immunosuppressive cell types involved in controlling immune responses in these settings, including tolerogenic dendritic cells, myeloid-derived suppressor cells (MDSCs), tolerogenic / M2 macrophages, and cancer cells themselves, have been reported to use amino acid depletion to suppress T cell responses (Munn et al., 2004; Munn et al., 2005; Rodriguez et al., 2010; Whyte et al., 2011; Uyttenhove et al., 2003). This is achieved by intracellular transport of amino acids combined with overexpression of amino acid catabolic enzymes within these cells, such as the tryptophan-arginine catabolic enzymes indoleamine 2,3 dioxygenase (IDO) and tryptophan 2,3 dioxygenase (TDO), and the arginine catabolic enzymes arginase 1 and 2 (ARG1, ARG2). As a result, these cells, wherever present, can reduce the local extracellular concentration of specific amino acids and thus induce GCN2 activity in nearby T cells in an antigen-specific manner (Munn et al., 2004). In murine systems, both in vitro and in vivo, depletion of local concentrations of tryptophan or arginine (e.g., by dendritic cells expressing IDO or ARG1) has been reported to induce T cell proliferation arrest and anergy in a GCN2-dependent manner (Munn et al., 2005; Rodriguez et al., 2007; Fletcher et al., 2015). Furthermore, the induction and / or maintenance of MDSCs and immunosuppressive regulatory T cells (T-regs) may also depend on GCN2 activity under amino acid depletion conditions (Fletcher et al., 2015; Fallarino et al., 2006). Finally, other studies have suggested that activation of GCN2 by IDO in tolerogenic macrophages is a key mechanism for suppressing systemic autoimmune responses to apoptotic cells (Ravishankar et al., 2015).These findings implicate GCN2 as a potentially important effector of the immunosuppressive effects of amino acid wasting associated with various disease states.

[0005] Early-stage cancers need to evade host anti-cancer immunity in order to grow (Corthay, 2014). This can be achieved by modulating tumor antigen presentation and / or by actively suppressing immune attack using tumor immune evasion mechanisms. High expression of amino acid catabolic enzymes, such as IDO and ARG1, has been observed across a large population of cancer patients with various tumor types, both in the cancer cells themselves and in immunosuppressed host cell types that accumulate in tumors, tumor-draining lymph nodes, and / or peripheral circulation (Uyttenhove et al., 2003; Pilotte et al., 2012; Zea et al., 2005). Thus, amino acid wasting may be a potent and widespread immune evasion mechanism that anti-cancer immunity can restore. Consistent with this, amino acid wasting in both tumors and tumor-draining lymph nodes has been established as a resistance mechanism to existing immuno-oncology agents, including checkpoint receptor-blocking antibodies, in several syngeneic mouse tumor models (Holmgaard et al., 2013; Spranger et al., 2014). Based on this, inhibitors of IDO and TDO are currently undergoing cancer clinical trials, and inhibitors of additional amino acid catabolases are in preclinical development. Therefore, inhibitors of GCN2 may also be useful for cancer treatment by disrupting the nodal effector signaling of amino acid wasting in the immune system and establishing anti-cancer immune responses. Genetic ablation of GCN2 is well tolerated in mice under standard growth conditions (Zhang et al., 2002), and GCN2 inhibition may have broader utility than inhibitors of individual amino acid catabolases because GCN2 responds to the wasting of several different amino acids.

[0006] Furthermore, activation and overexpression of GCN2 have been observed in various human tumors compared with normal tissues (Ye et al., 2010; Wang et al., 2013). GCN2 depletion reduced the growth of mouse embryonic fibroblasts and human cancer cells in vitro under severe amino acid or glucose depletion conditions and blocked the growth of human tumor xenografts in mice (Ye et al., 2010). Therefore, GCN2 inhibitors may have direct anticancer effects due to the frequent disruption of nutrient supply in the tumor microenvironment.

[0007] For these reasons, there is a need for the development of potent and selective inhibitors of GCN2 for the treatment of cancer, either as single agents or in combination with, for example, anti-CTLA4 and anti-PD1 / PD-L1 checkpoint blocking antibodies. Summary of the Invention [Means for solving the problem]

[0008] Summary of the Invention It has now been found that compounds of the present invention, and pharmaceutically acceptable compositions thereof, are effective as inhibitors of GCN2 kinase. Such compounds have the general formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0009] The compounds of the present invention and pharmaceutically acceptable compositions thereof are useful for treating a variety of diseases, disorders, or conditions associated with the regulation of signal transduction pathways involving GCN2 kinase, including those described herein.

[0010] The compounds provided by this invention are also useful for the study of the GCN2 enzyme in biological and pathological phenomena; for the study of intracellular signaling pathways occurring in body tissues; and for the comparative evaluation, in vitro or in vivo, of new GCN2 inhibitors or other regulators of kinases, signaling pathways, and cytokine levels. In an embodiment of the present invention, for example, the following items are provided: (Item 1) Formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein the compound is of formula I: Ring A is a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8- to 10-membered bicyclic aromatic carbocyclic ring, a 4- to 8-membered partially unsaturated monocyclic heterocyclic ring optionally fused to a 5- to 6-membered aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 12-membered partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7- to 12-membered partially unsaturated spirocyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. a 7- to 12-membered partially unsaturated bicyclic heterocyclic ring having one to four heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 7- to 12-membered partially unsaturated bridged bicyclic heterocyclic ring having one to two heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 5- to 6-membered monocyclic heteroaromatic ring having one to four heteroatoms independently selected from nitrogen, oxygen, or sulfur; an 8- to 10-membered bicyclic heteroaromatic ring having one to five heteroatoms independently selected from nitrogen, oxygen, or sulfur; or Het, where Het is a 4- to 8-membered saturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 12-membered saturated spirocyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 12-membered saturated bicyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7- to 12-membered saturated bridged bicyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring B is [ka] and; Ring C is [ka] and; Each R is independently hydrogen or C 1~6 an optionally substituted group selected from aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8- to 10-membered bicyclic aromatic carbocyclic ring, 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or Two R groups may optionally be joined together to form a divalent C 2~4 Forming an alkylene chain; two R groups, optionally taken together with the atoms between them, form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R' is independently hydrogen or C optionally substituted with halogen. 1~3 is an aliphatic group; R1 each independently represents hydrogen, halogen, —CN, —NO2, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)S(O)2R, —C(O)N═S(O)(R)2, —N(R)2, —N(R)C(O)R, —N(R)C(O)N(R)2, —N(R)C(O)OR, —N(R)S(O)2R, —N(R)S(O)2N(R)2, — OR, -ON(R)SOR, -P(O)(R), -SR, -S(O)R, -S(O)R, -S(O)(NH)R, -S(O)N(R), -S(NH)(O)OH, -N=S(O)(R), -C(R)S(=O)(=NH)R, -C(R)NHSOCH, -CD, -CDN(R)S(O)R, or R; or: 2 R's 1 the groups optionally taken together form =O, =NH or =NS(O)R; or 2 R's 1 The groups may be optionally joined together to form a divalent C 2~4 Forming an alkylene chain; R 2 are independently hydrogen, halogen, —CN, —C(O)N(R′)2, —OR′, —N(R′)2, —S(O)2R, —S(O)2N(R)2, —O-phenyl, or an optionally substituted group, wherein the optionally substituted group is C 1~3 selected from a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, or sulfur, or a 4- to 8-membered saturated monocyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 3 is hydrogen, halogen, —CN, —OR′, —N(R′)2, or an optionally substituted group, and the optionally substituted group is C 1~3 selected from aliphatic, phenyl, or 5- to 6-membered monocyclic heteroaromatic rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 4is hydrogen, halogen, —CN, —OR, —N═S(O)(R), —N(R), or an optionally substituted group, and the optionally substituted group is C 1~3 selected from a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, nitrogen, oxygen, or sulfur, or a 7- to 12-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, or 2; p is 0 or 1; and q is 0 or 1; compound. (Item 2) The compound according to item 1, wherein ring A is Het. (Item 3) Ring B is [ka] Item 1. The compound according to item 1, (Item 4) Ring C is [ka] [ka] Item 1. The compound according to item 1, (Item 5) R 1each independently represents hydrogen, halogen, —CN, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)S(O)2R, —C(O)N═S(O)(R)2, —N(R)2, —N(R)C(O)R, —N(R)C(O)N(R)2, —N(R)C(O)OR, —N(R)S(O)2R, —N(R)S(O)2N(R)2, —OR, —O Item 1. The compound according to item 1, wherein N(R)SOR, -P(O)(R), -SR, -S(O)R, -S(O)R, -S(O)(NH)R, -S(O)N(R), -S(NH)(O)OH, -N=S(O)(R), -C(R)S(=O)(=NH)R, -C(R)NHSOCH, -CD, -CDN(R)S(O)R, or R. (Item 6) R 2 are each independently hydrogen, halogen, —CN, —C(O)N(R′)2, —OR′, —N(R′)2, or an optionally substituted group, and the optionally substituted group is C 1~3 The compound according to item 1, wherein the heteroatom is selected from aliphatic or 5- to 6-membered monocyclic heteroaromatic rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. (Item 7) R 3 is hydrogen, halogen, —CN, —OR′, —N(R′)2, or an optionally substituted group, and the optionally substituted group is C 1~3 The compound according to item 1, wherein the heteroatom is selected from aliphatic or 5- to 6-membered monocyclic heteroaromatic rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. (Item 8) R 4 is hydrogen, halogen, —CN, —OR, —N(R)2, or an optionally substituted group, and the optionally substituted group is C 1~3The compound according to item 1, wherein the heterocyclic ring is selected from a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, nitrogen, oxygen, or sulfur, or a 7- to 12-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. (Item 9) Ring B is [ka] and ring C is [ka] Item 1. The compound according to item 1, (Item 10) Formula Xa, Xb, or Xc: [ka] or a pharmaceutically acceptable salt thereof. (Item 11) Ring B is [ka] and C is [ka] Item 1. The compound according to item 1, (Item 12) Formula XVII-a, XVII-b, or XVII-c: [ka] or a pharmaceutically acceptable salt thereof. (Item 13) Formula XXIX-a, XXIX-b, or XXIX-c: [ka] or a pharmaceutically acceptable salt thereof. (Item 14) 14. The compound according to any one of items 1 to 13, wherein m is 1, 2, 3, 4 or 5, in particular 1, 2 or 3. (Item 15) The compound according to Item 1, wherein the compound is selected from the compounds illustrated in Tables 1 to 4. (Item 16) A pharmaceutical composition comprising a compound according to any one of items 1 to 15, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. (Item 17) A method of inhibiting GCN2 in a patient or a biological sample, comprising administering to the patient or contacting with the biological sample a compound according to any one of items 1 to 15, or a pharmaceutical composition thereof. (Item 18) 16. A method of treating a GCN2-mediated disorder, disease, or condition in a patient, comprising administering to the patient a compound according to any one of items 1 to 15, or a pharmaceutical composition thereof. (Item 19) 19. The method of claim 18, wherein the GCN2-mediated disorder, disease, or condition is selected from the group consisting of an inflammatory condition, an immunological condition, an autoimmune condition, an allergic condition, a rheumatic condition, a thrombotic condition, a cancer, an infection, a neurodegenerative disease, a degenerative disease, a neuroinflammatory disease, a cardiovascular disease, and a metabolic condition. (Item 20) 20. The method of item 19, wherein the cancer is a solid tumor, wherein the solid tumor is selected from the group consisting of solid tumors of epithelial, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid, intestinal, liver, brain, prostate, genitourinary tract, lymphatic system, stomach, larynx, bone including chondrosarcoma and Ewing's sarcoma, germ cell including fetal tissue tumors, and / or lung tumors, monocytic leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma, neurofibroma, angiosarcoma, breast cancer, and / or malignant melanoma, and tumors of the blood and immune system. (Item 21) 20. The method of item 19, wherein the autoimmune condition is rheumatoid arthritis, systemic lupus, multiple sclerosis, psoriasis, Sjogren's syndrome or transplant organ rejection. (Item 22) 20. The method of claim 19, wherein the metabolic condition is diabetes. (Item 23) 20. The method of claim 19, wherein the degenerative disease is osteoarthritis. (Item 24) 20. The method of claim 19, wherein the inflammatory condition is asthma, inflammatory bowel disease, or giant cell arthritis. (Item 25) 20. The method of item 19, wherein the cardiovascular disease is an ischemic injury. (Item 26) 20. The method of item 19, wherein the neurodegenerative disease is Alzheimer's disease, Down's syndrome, Hereditary cerebral hemorrhage with amyloidosis - Dutch type, cerebral amyloid angiopathy, Creutzfeldt-Jakob disease, frontotemporal dementia, Huntington's disease, or Parkinson's disease. (Item 27) 20. The method of item 19, wherein the infection is caused by a mycobacterium, including Leishmania, M. leprae, M. tuberculosis and / or M. avium, a malaria parasite, a human immunodeficiency virus, an Epstein-Barr virus, a herpes simplex virus, or a hepatitis C virus. (Item 28) 20. The method of claim 18, wherein the GCN2-mediated disorder, disease, or condition is cancer, and the method further comprises administering a second agent for the treatment of cancer. DETAILED DESCRIPTION OF THE INVENTION

[0011] Detailed Description of Specific Embodiments 1. General Description of Certain Embodiments of the Invention: The compounds of the present invention and compositions thereof are useful as inhibitors of GCN2 protein kinase. In some embodiments, provided compounds inhibit GCN2.

[0012] In certain embodiments, the present invention provides compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein the compound is of formula I: Ring A is a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8- to 10-membered bicyclic aromatic carbocyclic ring, a 4- to 8-membered partially unsaturated monocyclic heterocyclic ring optionally fused to a 5- to 6-membered aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 12-membered partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7- to 12-membered partially unsaturated spirocyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. a 7- to 12-membered partially unsaturated bicyclic heterocyclic ring having one to four heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 7- to 12-membered partially unsaturated bridged bicyclic heterocyclic ring having one to two heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 5- to 6-membered monocyclic heteroaromatic ring having one to four heteroatoms independently selected from nitrogen, oxygen, or sulfur; an 8- to 10-membered bicyclic heteroaromatic ring having one to five heteroatoms independently selected from nitrogen, oxygen, or sulfur; or Het, where Het is a 4- to 8-membered saturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 12-membered saturated spirocyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 12-membered saturated bicyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7- to 12-membered saturated bridged bicyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring B is [ka] and; Ring C is [ka] [ka] and; Each R is independently hydrogen or C 1~6 an optionally substituted group selected from aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8- to 10-membered bicyclic aromatic carbocyclic ring, 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or Two R groups may optionally be joined together to form a divalent C 2~4 Forming an alkylene chain; two R groups, optionally taken together with the atoms between them, form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R' is independently hydrogen or C optionally substituted with halogen. 1~3 is an aliphatic group; R 1each independently represents hydrogen, halogen, —CN, —NO2, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)S(O)2R, —C(O)N═S(O)(R)2, —N(R)2, —N(R)C(O)R, —N(R)C(O)N(R)2, —N(R)C(O)OR, —N(R)S(O)2R, —N(R)S(O)2N(R)2, — OR, -ON(R)SOR, -P(O)(R), -SR, -S(O)R, -S(O)R, -S(O)(NH)R, -S(O)N(R), -S(NH)(O)OH, -N=S(O)(R), -C(R)S(=O)(=NH)R, -C(R)NHSOCH, -CD, -CDN(R)S(O)R, or R; or: 2 R's 1 the groups optionally taken together form =O, =NH or =NS(O)R; or 2 R's 1 The groups may be optionally joined together to form a divalent C 2~4 Forming an alkylene chain; R 2 are independently hydrogen, halogen, —CN, —C(O)N(R′)2, —OR′, —N(R′)2, —S(O)2R, —S(O)2N(R)2, —O-phenyl, or an optionally substituted group, wherein the optionally substituted group is C 1~3 selected from a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, or sulfur, or a 4- to 8-membered saturated monocyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 3 is hydrogen, halogen, —CN, —OR′, —N(R′)2, or an optionally substituted group, and the optionally substituted group is C 1~3 selected from aliphatic, phenyl, or 5- to 6-membered monocyclic heteroaromatic rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 4is hydrogen, halogen, —CN, —OR, —N═S(O)(R), —N(R), or an optionally substituted group, and the optionally substituted group is C 1~3 selected from a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, nitrogen, oxygen, or sulfur, or a 7- to 12-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, or 2; p is 0 or 1; and q is 0 or 1. 2. Compounds and definitions:

[0013] The compounds of the present invention include those generally described herein and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of the present invention, chemical elements are identified according to the Handbook of Chemistry and Physics, 75th Edition, Periodic Table of the Elements, CAS Edition. Furthermore, general principles of organic chemistry are described in "Organic Chemistry," the entire contents of which are incorporated herein by reference. "Advanced Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5th ed., eds. Smith, M.B. and March, J., John Wiley & Sons, New York: 2001.

[0014] The terms "aliphatic" or "aliphatic group," as used herein, mean a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic (also referred to herein as "carbocycle," "alicyclic," or "cycloalkyl"), which has one point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and which has one point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl groups, alkenyl groups, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0015] As used herein, the term "bridged bicyclic" refers to any bicyclic ring system having at least one bridge, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated. As defined by IUPAC, a "bridge" is an unbranched chain of atoms, or an atomic or valence bond, connecting two bridgeheads, where a "bridgehead" is any skeletal atom of the ring system attached to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups shown below, each attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more substituents, such as those shown for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclic groups include: [ka] [ka]

[0016] The term "lower alkyl" refers to a straight or branched C 1~4 refers to an alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0017] The term "lower haloalkyl" refers to a straight or branched C alkyl group substituted with one or more halogen atoms. 1~4 Refers to an alkyl group.

[0018] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon, the quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocyclic ring, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl) means one or more of:

[0019] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0020] As used herein, the term "divalent saturated or unsaturated, linear or branched C 1~8 (or C 1~6 ) Hydrocarbon chain" refers to divalent alkylene, alkenylene, and alkynylene chains, which may be straight or branched, as defined herein.

[0021] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH) n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms have been replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0022] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0023] As used herein, the term "cyclopropylenyl" refers to a divalent cyclopropyl group, having the following structure: [ka]

[0024] The term "halogen" means F, Cl, Br or I.

[0025] The term "aryl," used alone or as part of a larger moiety, such as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, in which at least one ring in the system is aromatic, and in which each ring in the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring." In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. Similarly, the term "aryl," as used herein, also includes within its scope groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0026] The terms "heteroaryl" and "heteroar-," used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy," refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, with 6, 10, or 14 pi-electrons shared in the cyclic arrangement, and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-," as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently are optionally substituted.

[0027] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety, either saturated or partially unsaturated, having, in addition to carbon atoms, one or more, preferably 1 to 4, heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + It may also be NR (as in N-substituted pyrrolidinyl).

[0028] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of these ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0029] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as defined herein.

[0030] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to a compound that is not substantially altered when subjected to conditions that allow for its production, detection, and, in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein.

[0031] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently: halogen; -(CH) 0~4 R ○ ;-(CH2) 0~4 OR ○ ;-O(CH2) 0~4 R ○ , -O-(CH2) 0~4 C(O)OR ○ ;-(CH2) 0~4 CH(OR ○ )2;-(CH2) 0~4 SR ○ ;-(CH2) 0~4 Ph (this is R○ -(CH2) 0~4 O(CH2) 0~1 Ph (this is R ○ -CH=CHPh (which can be substituted with R ○ -(CH2) 0~4 O(CH2) 0~1 -pyridyl (this is R ○ -NO2; -CN; -N3; ​​-(CH2) 0~4 N(R ○ )2;-(CH2) 0~4 N(R ○ )C(O)R ○ ;-N(R ○ )C(S)R ○ ;-(CH2) 0~4 N(R ○ )C(O)N(R ○ )2;-N(R ○ )C(S)N(R ○ )2;-(CH2) 0~4 N(R ○ )C(O)OR ○ ;-N(R ○ )N(R ○ )C(O)R ○ ;-N(R ○ )N(R ○ )C(O)N(R ○ )2;-N(R ○ )N(R ○ )C(O)OR ○ ;-(CH2) 0~4 C(O)R ○ ;-C(S)R ○ ;-(CH2) 0~4 C(O)OR ○ ;-(CH2) 0~4 C(O)SR ○ ;-(CH2) 0~4 C(O)OSi(R ○ )3;-(CH2) 0~4 OC(O)R ○ ;-OC(O)(CH2) 0~4 SR, -SC(S)SR ○ ;-(CH2) 0~4 SC(O)R ○ ;-(CH2) 0~4 C(O)N(R○ )2;-C(S)N(R ○ )2;-C(S)SR ○ ;-(CH2) 0~4 OC(O)N(R ○ )2;-C(O)N(OR ○ )R ○ ;-C(O)C(O)R ○ ;-C(O)CH2C(O)R ○ ;-C(NOR ○ )R ○ ;-(CH2) 0~4 SSR ○ ;-(CH2) 0~4 S(O)2R ○ ;-(CH2) 0~4 S(O)2OR ○ ;-(CH2) 0~4 OS(O)2R ○ ;-S(O)2N(R ○ )2;-(CH2) 0~4 S(O)R ○ ;-(CH2) 0~4 S(O)(NR ○ )R ○ ;-N(R ○ )S(O)2N(R ○ )2;-N(R ○ )S(O)2R ○ ;-N(R ○ )S(O)(NR ○ )(R ○ )2;-N(OR ○ )R ○ ;-N=S(O)(R ○ )2;-N(OR ○ )SO2R ○ ;-C(NH)N(R ○ )2;-P(O)2R ○ ;-P(O)(R ○ )2;-OP(O)(R ○ )2;-OP(O)(OR ○ )2;-Si(R ○ )3;-(C 1~4 straight or branched chain alkylene)ON(R ○ )2; or -(C 1~4 straight or branched chain alkylene)C(O)ON(R ○ )2, where each R○ may be substituted as defined below and independently represent hydrogen, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2- (a 5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definitions, R ○ two independent occurrences of together with the atom(s) between them form a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which can be substituted as defined below.

[0032] R ○ (R ○ Suitable monovalent substituents on the ring formed by two independent occurrences of (a ring formed by two independent occurrences of together with the atom between them) are independently halogen, -(CH2) 0~2 R ● ,-(Halo R ● ), -(CH2) 0~2 OH, -(CH2) 0~2 OR ● , -(CH2) 0~2 CH(OR ● )2;-O(HaloR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● , -(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● , -(CH2) 0~2 SR ● , -(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● , -(CH2) 0~2 N(R ● )2, -NO2, -Si(R ● )3, -OSi(R ● )3, -C(O)SR ● , -(C 1~4straight or branched chain alkylene)C(O)OR ● , or -SSR ● where each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. ○ Suitable divalent substituents on a saturated carbon atom of include ═O and ═S.

[0033] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include: ═O, ═S, ═NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , =NSO2R * , -O(C(R * 2)) 2~3 O-, or -S(C(R * 2)) 2~3 S-. Here R * Each independent occurrence of may be hydrogen, C, which may be substituted as defined below. 1~6 and an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having an aliphatic or 0-4 heteroatom independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to a vicinal substitutable carbon of an "optionally substituted" group include -O(CR * 2) 2~3 O-, where R * Each independent occurrence of may be hydrogen, C, which may be substituted as defined below. 1~6It is selected from an aliphatic or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0034] R * Suitable substituents on the aliphatic group include halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -N(R ● )2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0035] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -N(R † )2, -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)2N(R † )2, -C(S)N(R † )2, -C(NH)N(R † )2, or -N(R † )S(O)2R † where each R † are independently hydrogen, C which may be substituted as defined below 1~6an aliphatic, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definitions, R † two independent occurrences of together with the atom(s) between them form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0036] R † Suitable substituents on the aliphatic group are independently halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -N(R ● )2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0037] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, Vol. 66, pp. 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Examples of salts that may be used include phosphate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0038] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N +(C 1~4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additionally, pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0039] Unless otherwise specified, structures depicted herein are also intended to include all isomers of the structure (e.g., enantiomers, diastereomeric isomers, and geometric (or conformational) isomers), e.g., R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E stereoisomers. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the present invention. Unless otherwise specified, all tautomers of the compounds of the present invention are within the scope of the present invention. Furthermore, unless otherwise specified, structures depicted herein are also intended to include compounds which differ only by the presence of one or more isotopically enriched atoms. For example, replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure, including the replacement of a carbon with a C-rich carbon, are within the scope of the invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents according to the invention. In certain embodiments, the R of provided compounds x contains one or more deuterium atoms.

[0040] As used herein, the term "inhibitor" is defined as a compound that binds to and / or inhibits GCN2 with measurable affinity. In certain embodiments, an inhibitor has an IC of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. 50 and / or have a binding constant.

[0041] The compounds of the present invention can be tethered to a detectable moiety. It is understood that such compounds are useful as imaging agents. Those skilled in the art will recognize that a detectable moiety can be attached to a provided compound via a suitable substituent. As used herein, the term "suitable substituent" refers to a moiety that can be covalently linked to a detectable moiety. Such moieties are well known to those skilled in the art and include, for example, groups containing carbonate, amino, thiol, or hydroxyl moieties, to name a few. It is understood that such moieties can be attached directly to a provided compound or via a tethering group such as a bivalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties can be attached via click chemistry. In some embodiments, such moieties can be attached via 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst. Methods using click chemistry are known in the art and include those described by Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17, 52-57.

[0042] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and refers to any moiety that can be detected, such as primary and secondary labels. Radioisotopes (e.g., tritium, 32 P, 33 P, 35 S, or 14C), primary labels, such as mass tags and fluorescent labels, are signal-generating reporter groups that can be detected without further modification. Detectable moieties also include luminescent and phosphorescent groups.

[0043] As used herein, the term "secondary label" refers to moieties such as biotin and various protein antigens that require the presence of a secondary intermediate to generate a detectable signal. For biotin, the secondary intermediate may include a streptavidin-enzyme conjugate. For antigen labels, the secondary intermediate may include an antibody-enzyme conjugate. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of non-radioactive fluorescence resonance energy transfer (FRET), and the second group generates the signal that is detected.

[0044] As used herein, the terms "fluorescent label," "fluorescent dye," and "fluorophore" refer to a moiety that absorbs light energy at a defined excitation wavelength and emits light energy at a different wavelength. Examples of fluorescent labels include Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660, and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY530 / 550, BODIPY558 / 568, BODIPY564 / 570, BODIPY576 / 589, BODIPY581 / 591, BODIPY630 / 650, BODIPY650 / 665), carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), dansyl, dapoxyl, dialkylaminocoumarin, 4',5'-dichloro-2',7'-dimethoxy-fluorescein, DM-NERF, eosin, erythrosine, fluorescein, FAM, hydrochloride Examples of suitable dyes include, but are not limited to, roxycoumarin, IRDyes (IRD40, IRD700, IRD800), JOE, Lissamine rhodamine B, Marina Blue, methoxycoumarin, naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, pyrene, rhodamine B, rhodamine 6G, rhodamine green, rhodamine red, rhodol green, 2',4',5',7'-tetra-bromosulfone-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, and Texas Red-X.

[0045] As used herein, the term "mass tag" refers to any moiety that can be uniquely detected by its mass using mass spectrometry (MS) detection technology.Examples of mass tag include electrophoretic release tags such as N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipeconic acid, 4'-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone and their derivatives.The synthesis and usefulness of these mass tags are described in U.S. Patent No. 4,650,750, U.S. Patent No. 4,709,016, U.S. Patent No. 5,360,8191, U.S. Patent No. 5,516,931, U.S. Patent No. 5,602,273, U.S. Patent No. 5,604,104, U.S. Patent No. 5,610,020 and U.S. Patent No. 5,650,270. Other examples of mass tags include, but are not limited to, nucleotides of various lengths and base compositions, dideoxynucleotides, oligonucleotides, oligopeptides, oligosaccharides, and other synthetic polymers of various lengths and monomer compositions. A wide variety of organic molecules (biomolecules or synthetic compounds), both neutral and charged, in the appropriate mass range (100-2000 daltons) may be used as mass tags.

[0046] The terms "measurable affinity" and "measurably inhibit," as used herein, mean that there is a measurable change in GCN2 protein kinase activity between a sample containing a compound of the present invention or a composition thereof and GCN2 protein kinase and an equivalent sample containing GCN2 protein kinase in the absence of said compound or composition thereof. 3. Description of Exemplary Embodiments:

[0047] As noted above, in certain embodiments, the present invention provides compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein the compound is of formula I: Ring A is a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8- to 10-membered bicyclic aromatic carbocyclic ring, a 4- to 8-membered partially unsaturated monocyclic heterocyclic ring optionally fused to a 5- to 6-membered aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 12-membered partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7- to 12-membered partially unsaturated spirocyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. a 7- to 12-membered partially unsaturated bicyclic heterocyclic ring having one to four heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 7- to 12-membered partially unsaturated bridged bicyclic heterocyclic ring having one to two heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 5- to 6-membered monocyclic heteroaromatic ring having one to four heteroatoms independently selected from nitrogen, oxygen, or sulfur; an 8- to 10-membered bicyclic heteroaromatic ring having one to five heteroatoms independently selected from nitrogen, oxygen, or sulfur; or Het, where Het is a 4- to 8-membered saturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 12-membered saturated spirocyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 12-membered saturated bicyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7- to 12-membered saturated bridged bicyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring B is [ka] and; Ring C is [ka] and; Each R is independently hydrogen or C1~6 an optionally substituted group selected from aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8- to 10-membered bicyclic aromatic carbocyclic ring, 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or Two R groups may optionally be joined together to form a divalent C 2~4 Forming an alkylene chain; two R groups, optionally taken together with the atoms between them, form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Each R' is independently hydrogen or C optionally substituted with halogen. 1~3 is an aliphatic group; R 1 each independently represents hydrogen, halogen, —CN, —NO2, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)S(O)2R, —C(O)N═S(O)(R)2, —N(R)2, —N(R)C(O)R, —N(R)C(O)N(R)2, —N(R)C(O)OR, —N(R)S(O)2R, —N(R)S(O)2N(R)2, — OR, -ON(R)SOR, -P(O)(R), -SR, -S(O)R, -S(O)R, -S(O)(NH)R, -S(O)N(R), -S(NH)(O)OH, -N=S(O)(R), -C(R)S(=O)(=NH)R, -C(R)NHSOCH, -CD, -CDN(R)S(O)R, or R; or: 2 R's 1 the groups optionally taken together form =O, =NH or =NS(O)R; or 2 R's 1 The groups may be optionally joined together to form a divalent C 2~4Forming an alkylene chain; R 2 are independently hydrogen, halogen, —CN, —C(O)N(R′)2, —OR′, —N(R′)2, —S(O)2R, —S(O)2N(R)2, —O-phenyl, or an optionally substituted group, wherein the optionally substituted group is C 1~3 selected from a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, or sulfur, or a 4- to 8-membered saturated monocyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 3 is hydrogen, halogen, —CN, —OR′, —N(R′)2, or an optionally substituted group, and the optionally substituted group is C 1~3 selected from aliphatic, phenyl, or 5- to 6-membered monocyclic heteroaromatic rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 4 is hydrogen, halogen, —CN, —OR, —N═S(O)(R), —N(R), or an optionally substituted group, and the optionally substituted group is C 1~3 selected from a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, nitrogen, oxygen, or sulfur, or a 7- to 12-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, or 2; p is 0 or 1; and q is 0 or 1.

[0048] As defined above and described herein, ring A is a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8- to 10-membered bicyclic aromatic carbocyclic ring, a 4- to 8-membered partially unsaturated monocyclic heterocyclic ring optionally fused to a 5- to 6-membered aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 12-membered partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. a 7- to 12-membered partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 7- to 12-membered partially unsaturated bicyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 7- to 12-membered partially unsaturated bridged bicyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 5- or 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0049] In some embodiments, ring A is a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, ring A is phenyl. In some embodiments, ring A is an 8- to 10-membered bicyclic aromatic carbocyclic ring. In some embodiments, ring A is a 4- to 8-membered partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally fused to a 5- to 6-membered aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring A is a 7- to 12-membered partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring A is a 7- to 12-membered partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring A is a 7- to 12-membered partially unsaturated bicyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring A is a 7- to 12-membered partially unsaturated bridged bicyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring A is a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring A is an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0050] In some embodiments, ring A is Het. In some embodiments, ring A is a 4- to 8-membered saturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring A is a 7- to 12-membered saturated spirocyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring A is a 7- to 12-membered saturated bicyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring A is a 7- to 12-membered saturated bridged bicyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0051] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] is.

[0052] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] is.

[0053] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] is.

[0054] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] is.

[0055] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] is.

[0056] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] is.

[0057] In some embodiments, ring A is selected from those depicted in Tables 1-4 below.

[0058] As defined above and described herein, Ring B is [ka] is.

[0059] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] is.

[0060] In some embodiments, Ring B is selected from those depicted in Tables 1-4 below.

[0061] As defined above and described herein, Ring C is [ka] [ka] is.

[0062] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] is.

[0063] In some embodiments, Ring C is selected from those depicted in Tables 1-4 below.

[0064] As defined above and described herein, each R is independently hydrogen or C 1~6an optionally substituted group selected from aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8- to 10-membered bicyclic aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R groups optionally taken together form a divalent C 2~4 form an alkylene chain; or two R groups, optionally taken together with the atoms between them, form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0065] In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C 1~6 In some embodiments, R is an optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted 8- to 10-membered bicyclic aromatic carbocyclic ring. In some embodiments, R is an optionally substituted 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is an optionally substituted 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is an optionally substituted 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, two R groups optionally taken together form a divalent C 2~4form an alkylene chain. In some embodiments, two R groups, optionally taken together with the atoms between them, form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0066] In some embodiments, R is selected from those depicted in Tables 1-4 below.

[0067] Each R' is independently hydrogen, or C optionally substituted with halogen, as defined above and described herein. 1~3 It is an aliphatic group.

[0068] In some embodiments, R' is hydrogen. In some embodiments, R' is C optionally substituted with halogen. 1~3 It is an aliphatic group.

[0069] In some embodiments, R' is selected from those depicted in Tables 1-4 below.

[0070] As defined above and described herein, R 1 each independently represents hydrogen, halogen, —CN, —NO2, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)S(O)2R, —C(O)N═S(O)(R)2, —N(R)2, —N(R)C(O)R, —N(R)C(O)N(R)2, —N(R)C(O)OR, —N(R)S(O)2R, —N(R)S(O)2N(R)2, —OR , -ON(R)S0R, -P(O)(R), -SR, -S(O)R, -S(O)R, -S(O)(NH)R, -S(O)N(R), -S(NH)(O)OH, -N=S(O)(R), -C(R)S(=O)(=NH)R, -C(R)NHSOCH, -CD, -CDN(R)S(O)R, or R; or two R 1 The groups optionally join to form =O, =NH, or =NS(O)R; or two R 1The groups may be optionally joined together to form a divalent C 2~4 Forms an alkylene chain.

[0071] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is halogen. In some embodiments, R 1 is -CN. In some embodiments, R 1 is —NO. In some embodiments, R 1 is —C(O)R. In some embodiments, R 1 is —C(O)OR. In some embodiments, R 1 is —C(O)N(R). In some embodiments, R 1 is —C(O)N(R)S(O)R. In some embodiments, R 1 is —C(O)N═S(O)(R). In some embodiments, R 1 is -N(R). In some embodiments, R 1 is —N(R)C(O)R. In some embodiments, R 1 is —N(R)C(O)N(R). In some embodiments, R 1 is —N(R)C(O)OR. In some embodiments, R 1 is —N(R)S(O)R. In some embodiments, R 1 is —N(R)S(O)N(R). In some embodiments, R 1 In some embodiments, R 1 is -ON(R)SO2R. In some embodiments, R 1 is -P(O)(R). In some embodiments, R 1 In some embodiments, R 1 is -S(O)R. In some embodiments, R 1 is —S(O)R. In some embodiments, R 1is —S(O)(NH)R. In some embodiments, R 1 is —S(O)N(R). In some embodiments, R 1 is —S(NH)(O)OH. In some embodiments, R 1 is -N=S(O)(R). In some embodiments, R 1 is —C(R)S(═O)(═NH)R. In some embodiments, R 1 is —C(R)2NHSO2CH3. In some embodiments, R 1 is -CD3. In some embodiments, R 1 is -CD2N(R)S(O)2R. In some embodiments, R 1 is R. In some embodiments, two R 1 The groups optionally join to form =O, =NH, or =NS(O)R. In some embodiments, two R 1 The groups may be optionally joined together to form a divalent C 2~4 Forms an alkylene chain.

[0072] In some embodiments, R 1 is fluoro. In some embodiments, R 1 is chloro. In some embodiments, R 1 is methyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 is —OH. In some embodiments, R 1 is —OCH. In some embodiments, R 1 is —CHOH. In some embodiments, R 1 is —CHCN. In some embodiments, R 1 is —CF. In some embodiments, R 1 is —CH 2 NH 2 . In some embodiments, R 1 is —COOH. In some embodiments, R 1 is -NH2.

[0073] In some embodiments, two R 1 The group forms ═O. In some embodiments, two R 1 The group forms =NH. In some embodiments, two R 1 The groups form =NSO2CH3. In some embodiments, two R 1 The base is [ka] Form.

[0074] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0075] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0076] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0077] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0078] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0079] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0080] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0081] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0082] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0083] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0084] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0085] In some embodiments, R1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0086] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0087] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0088] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0089] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0090] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0091] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0092] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0093] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0094] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0095] In some embodiments, R 1 teeth, [ka] In some embodiments, R1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0096] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0097] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is.

[0098] In some embodiments, R 1 is selected from those illustrated in Tables 1 to 4 below.

[0099] As defined above and described herein, R 2 Each of R 2 are independently hydrogen, halogen, —CN, —C(O)N(R′)2, —OR′, —N(R′)2, —S(O)2R, —S(O)2N(R)2, —O-phenyl, or an optionally substituted group, wherein the optionally substituted group is C 1~3 A 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, or sulfur, or a 4- to 8-membered saturated monocyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0100] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is halogen. In some embodiments, R 2 is -CN. In some embodiments, R 2 is —C(O)N(R′). In some embodiments, R 2 is -OR'. In some embodiments, R 2 is -N(R'). In some embodiments, R 2 is —S(O)R. In some embodiments, R 2 is —S(O)N(R). In some embodiments, R 2 is —O-phenyl. In some embodiments, R 2 is replaced by C 1~3 In some embodiments, R 2 is optionally substituted phenyl. In some embodiments, R 2is an optionally substituted 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 2 is an optionally substituted 4- to 8-membered saturated monocyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0101] In some embodiments, R 2 is fluoro. In some embodiments, R 2 is chloro. In some embodiments, R 2 is bromo. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is —CF. In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] is.

[0102] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] is.

[0103] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] is.

[0104] In some embodiments, R2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] is.

[0105] In some embodiments, R 2 is selected from those illustrated in Tables 1 to 4 below.

[0106] As defined above and described herein, R 3 is hydrogen, halogen, —CN, —OR′, —N(R′)2, or an optionally substituted group, and the optionally substituted group is C 1~3 It is selected from aliphatic, phenyl, or a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0107] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is halogen. In some embodiments, R 3 is -CN. In some embodiments, R 3is -OR'. In some embodiments, R 3 is -N(R'). In some embodiments, R 3 is replaced by C 1~3 In some embodiments, R 3 is optionally substituted phenyl. In some embodiments, R 3 is an optionally substituted 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0108] In some embodiments, R 3 is selected from those illustrated in Tables 1 to 4 below.

[0109] As defined above and described herein, R 4 is hydrogen, halogen, —CN, —OR, —N═S(O)(R), —N(R), or an optionally substituted group, and the optionally substituted group is C 1~3 A 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, nitrogen, oxygen, or sulfur, or a 7- to 12-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0110] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is halogen. In some embodiments, R 4 is -CN. In some embodiments, R 4 In some embodiments, R 4 is -N=S(O)(R). In some embodiments, R 4 is -N(R). In some embodiments, R 4 is replaced by C 1~3In some embodiments, R 4 is an optionally substituted 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 4 is an optionally substituted 7- to 12-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0111] In some embodiments, R 4 is fluoro. In some embodiments, R 4 is chloro. In some embodiments, R 4 is methyl. In some embodiments, R 4 is —CF. In some embodiments, R 4 is —OH. In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] is.

[0112] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] is.

[0113] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] is.

[0114] In some embodiments, R 4 is selected from those illustrated in Tables 1 to 4 below.

[0115] As defined above and described herein, m is 0, 1, 2, 3, 4, or 5.

[0116] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5.

[0117] In some embodiments, m is 1, 2, or 3.

[0118] In some embodiments, m is selected from those depicted in Tables 1-4 below.

[0119] As defined above and described herein, n is 0, 1, or 2.

[0120] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0121] In some embodiments, n is selected from those depicted in Tables 1-4 below.

[0122] As defined above and described herein, p is 0 or 1.

[0123] In some embodiments, p is 0. In some embodiments, p is 1.

[0124] In some embodiments, p is selected from those depicted in Tables 1-4 below.

[0125] As defined above and described herein, q is 0 or 1.

[0126] In some embodiments, q is 0. In some embodiments, q is 1.

[0127] In some embodiments, q is selected from those depicted in Tables 1-4 below.

[0128] In certain embodiments, the present invention provides compounds wherein ring B is [ka] which results in formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring C, R 1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0129] In certain embodiments, the present invention provides compounds wherein ring B is [ka] which results in formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring C, R 1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0130] In certain embodiments, the present invention provides compounds wherein ring B is [ka] which gives rise to formula IV: [ka] or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring C, R 1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0131] In certain embodiments, the present invention provides compounds wherein ring B is [ka] which gives rise to formula V: [ka] or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring C, R1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0132] In certain embodiments, the present invention provides compounds wherein ring A is Het and ring B is [ka] which gives rise to formula VI: [ka] or a pharmaceutically acceptable salt thereof, wherein rings C, R 1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0133] In certain embodiments, the present invention provides compounds wherein ring A is Het and ring B is [ka] and the ring C is [ka] which gives the compound of formula VII: [ka] or a pharmaceutically acceptable salt thereof, wherein Het, R 1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0134] In certain embodiments, the present invention provides compounds wherein ring A is piperidinyl, piperazinyl, or morpholinyl and ring B is [ka] and the ring C is [ka] which results in compounds of formula VIII-a, VIII-b, or VIII-c, respectively: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0135] In certain embodiments, the present invention provides compounds wherein ring A is Het and ring B is [ka] and the ring C is [ka] which gives the compound of formula IX: [ka] or a pharmaceutically acceptable salt thereof, wherein Het, R 1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0136] In certain embodiments, the present invention provides compounds wherein ring A is piperidinyl, piperazinyl, or morpholinyl and ring B is [ka] and the ring C is [ka] which gives the formula Xa, Xb, or Xc, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0137] In certain embodiments, the present invention provides compounds wherein ring A is Het and ring B is [ka] and the ring C is [ka] which gives rise to formula XI: [ka] or a pharmaceutically acceptable salt thereof, wherein Het, R 1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0138] In certain embodiments, the present invention provides compounds wherein ring A is piperidinyl, piperazinyl, or morpholinyl and ring B is [ka] and the ring C is [ka] which gives the compounds of formula XII-a, XII-b, or XII-c, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0139] In certain embodiments, the present invention provides compounds wherein ring A is Het and ring B is [ka] and the ring C is [ka] which gives the compound of formula XIII: [ka] or a pharmaceutically acceptable salt thereof, wherein Het, R 1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0140] In certain embodiments, the present invention provides compounds wherein ring A is piperidinyl, piperazinyl, or morpholinyl and ring B is [ka] and the ring C is [ka] which gives the formula XIV-a, XIV-b, or XIV-c, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0141] In certain embodiments, the present invention provides compounds wherein ring A is Het and ring B is [ka] which gives Equation XV: [ka] or a pharmaceutically acceptable salt thereof, wherein rings C, R 1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0142] In certain embodiments, the present invention provides compounds wherein ring A is Het and ring B is [ka] and the ring C is [ka] which gives formula XVI: [ka] or a pharmaceutically acceptable salt thereof, wherein Het, R 1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0143] In certain embodiments, the present invention provides compounds wherein ring A is piperidinyl, piperazinyl, or morpholinyl and ring B is [ka] and the ring C is [ka] which gives rise to the formula XVII-a, XVII-b, or XVII-c, respectively: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0144] In certain embodiments, the present invention provides compounds wherein ring A is Het and ring B is [ka] and the ring C is [ka] which gives the compound of formula XVIII: [ka] or a pharmaceutically acceptable salt thereof, wherein Het, R 1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0145] In certain embodiments, the present invention provides compounds wherein ring A is piperidinyl, piperazinyl, or morpholinyl and ring B is [ka] and the ring C is [ka] which gives formula XIX-a, XIX-b, or XIX-c, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0146] In certain embodiments, the present invention provides compounds wherein ring A is Het and ring B is [ka] and the ring C is [ka] This gives the formula XX: [ka] or a pharmaceutically acceptable salt thereof, wherein Het, R 1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0147] In certain embodiments, the present invention provides compounds wherein ring A is piperidinyl, piperazinyl, or morpholinyl and ring B is [ka] and the ring C is [ka] which gives rise to the formula XXI-a, XXI-b, or XXI-c, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0148] In certain embodiments, the present invention provides compounds wherein ring A is Het and ring B is [ka] and the ring C is [ka] which gives the compound of formula XXII: [ka] or a pharmaceutically acceptable salt thereof, wherein Het, R 1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0149] In certain embodiments, the present invention provides compounds wherein ring A is piperidinyl, piperazinyl, or morpholinyl and ring B is [ka] and the ring C is [ka] and thereby forming a compound of formula XXIII-a, XXIII-b, or XXIII-c, respectively: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0150] In certain embodiments, the present invention provides compounds wherein ring A is Het, thereby providing compounds of formula XXIV: [ka] or a pharmaceutically acceptable salt thereof, wherein Het, ring B, ring C, R 1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0151] In certain embodiments, the present invention provides compounds wherein ring A is Het and ring C is [ka] which gives Equation XXV: [ka] or a pharmaceutically acceptable salt thereof, wherein Het, ring B, R 1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0152] In certain embodiments, the present invention provides compounds wherein ring A is Het and ring C is [ka] which gives the compound of formula XXVI: [ka] or a pharmaceutically acceptable salt thereof, wherein Het, ring B, R 1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0153] In certain embodiments, the present invention provides compounds wherein ring A is Het and ring C is [ka] which gives the compound of formula XXVII: [ka] or a pharmaceutically acceptable salt thereof, wherein Het, ring B, R 1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0154] In certain embodiments, the present invention provides compounds wherein ring A is Het and ring C is [ka] which gives the compound of formula XXVIII: [ka] or a pharmaceutically acceptable salt thereof, wherein Het, ring B, R 1 , R 2 , R 3 , R 4 Each of m, n, p, and q, both alone and in combination, is as defined above and described herein.

[0155] In certain embodiments, the present invention provides a compound wherein n is 1, p is 1, q is 1, and R 2 is -CF3 and R 3 is hydrogen and R 4 is hydrogen, ring A is piperidinyl, piperazinyl, or morpholinyl, and ring B is [ka] and the ring C is [ka] which gives rise to the formula XXIX-a, XXIX-b, or XXIX-c, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 and m, both alone and in combination, are as defined above and described herein.

[0156] Exemplary compounds of the present invention are set forth in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11]

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 2-1

Table 2-2

Table 3-1

Table 3-2

Table 3-3

Table 3-4

Table 3-5

Table 3-6

Table 3-7

Table 3-8

Table 3-9

Table 3-10

Table 3-11

Table 3-12

Table 3-13

Table 3-14

Table 3-15

Table 3-16

Table 3-17

Table 3-18

Table 3-19

Table 3-20

Table 3-21

Table 3-22

Table 3-23

Table 3-24

Table 3-25

Table 3-26

Table 3-27

Table 3-28

Table 3-29

Table 3-30

Table 3-31

Table 3-32

Table 3-33

Table 3-34

Table 3-35

Table 3-36

Table 3-37

Table 3-38

Table 3-39

Table 3-40

Table 3-41

Table 3-42

Table 3-43

Table 3-44

Table 3-45

Table 3-46

Table 3-47

Table 3-48

Table 3-49

Table 3-50

Table 3-51

Table 3-52

Table 3-53

Table 3-54

Table 3-55

Table 3-56

Table 3-57

[0157] In some embodiments, the present invention provides a compound shown in Tables 1-4 above, or a pharmaceutically acceptable salt thereof.

[0158] In certain embodiments, the present invention provides a complex comprising GCN2 and an inhibitor. 4. General Methods for Obtaining the Compounds:

[0159] The compounds of the invention may generally be prepared or isolated by synthetic and / or semi-synthetic methods known to those skilled in the art for similar compounds, as well as by methods detailed in the Examples herein.

[0160] In the following schemes, where a particular protecting group ("PG"), leaving group ("LG"), or transformation condition is illustrated, one of skill in the art will understand that other protecting groups, leaving groups, and transformation conditions are also suitable and contemplated. Such groups and transformations are described in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M.B. Smith and J. March, 5th Edition, John Wiley & Sons, 2001; Comprehensive Organic Transformations, R.C. Larock, 2nd Edition, John Wiley & Sons, 1999; and Protecting Groups in Organic Synthesis, T.W. Greene and Described in detail in PGM Wuts, 3rd Edition, John Wiley & Sons, 1999.

[0161] As used herein, the phrase "leaving group" (LG) includes, but is not limited to, halogen (e.g., fluoride, chloride, bromide, iodide), sulfonate (e.g., mesylate, tosylate, benzenesulfonate, brosylate, disylate, triflate), diazonium, and the like.

[0162] As used herein, the phrase "oxygen protecting group" includes, for example, carbonyl protecting groups, hydroxyl protecting groups, and the like. Hydroxyl protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference in its entirety. Examples of suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates. Specific examples include formates, benzoylformates, chloroacetates, trifluoroacetates, methoxyacetates, triphenylmethoxyacetates, p-chlorophenoxyacetates, 3-phenylpropionates, 4-oxopentanoates, 4,4-(ethylenedithio)pentanoates, pivalates (trimethylacetyl), crotonates, 4-methoxycrotonates, benzoates, p-benylbenzoates, 2,4,6-trimethylbenzoates, carbonates (methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl). Examples of such silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives.Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers. Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.

[0163] Amino-protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference in its entirety. Suitable amino-protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allylamines, amides, and the like. Examples of such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.

[0164] In certain embodiments, compounds of formula II of the present invention are generally prepared according to the following Schemes 1-17:

[0165] Scheme 1: Ring C is a pyrimidine and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula II, wherein is hydrogen, n is 1, p is 1, and q is 1. [ka]

[0166] In the above scheme 1, rings A and R 1 , R 2 Each of m is as defined above and below, and in the classes and subclasses described herein.

[0167] Scheme 2: Ring C is a pyrimidine and R 2 is -CHF2, and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula II, wherein is hydrogen, n is 1, p is 1, and q is 1. [ka]

[0168] In the above scheme 2, rings A and R 1 Each of m is as defined above and below, and in the classes and subclasses described herein.

[0169] Scheme 3: Ring C is pyridine and R 3 General scheme for the preparation of compounds of formula II, wherein is hydrogen, n is 1, and q is 1. [ka]

[0170] In the above scheme 3, rings A and R 1 , R 2 , R 4 Each of m, p, and m is as defined above and below, and in the classes and subclasses described herein.

[0171] Scheme 4: Ring A is pyridine and R 3 General scheme for the preparation of compounds of formula II, wherein is hydrogen, n is 1, and q is 1. [ka]

[0172] In the above scheme 4, rings A and R 1 , R 2 , R 4 Each of m, p, and m is as defined above and below, and in the classes and subclasses described herein.

[0173] Scheme 5: Ring C is pyridine and R 2 is -CHF2, and R 3 General scheme for the preparation of compounds of formula II, wherein is hydrogen, n is 1, and q is 1. [ka]

[0174] In the above scheme 5, rings A and R 1 , R 4 Each of m, p, and m is as defined above and below, and in the classes and subclasses described herein.

[0175] Scheme 6: Ring C is pyridine and R 2 is -CHF2, and R 3 General scheme for the preparation of compounds of formula II, wherein is hydrogen, n is 1, and q is 1. [ka]

[0176] In the above scheme 6, rings A and R 1 , R 4 Each of m, p, and m is as defined above and below, and in the classes and subclasses described herein.

[0177] Scheme 7: Ring C is pyridine and R 2 is -CHF2, and R 3General scheme for the preparation of compounds of formula II, wherein is hydrogen, n is 1, and q is 1. [ka]

[0178] In the above scheme 7, rings A and R 1 , R 4 Each of m, p, and m is as defined above and below, and in the classes and subclasses described herein.

[0179] Scheme 8: Ring C is pyridine and R 2 is -CHF2, and R 3 General scheme for the preparation of compounds of formula II, wherein is hydrogen, n is 1, and q is 1. [ka]

[0180] In the above scheme 8, ring A, R 1 , R 4 Each of m, p, and m is as defined above and below, and in the classes and subclasses described herein.

[0181] Scheme 9: Ring C is pyridine and R 2 is -CHF2, and R 3 General scheme for the preparation of compounds of formula II, wherein is hydrogen, n is 1, p is 1, and q is 1. [ka]

[0182] In the above Scheme 9, rings A and R 1 , R 4 Each of m is as defined above and below, and in the classes and subclasses described herein.

[0183] Scheme 10: Ring C is pyridine and R 2 is -CHF2, and R 3 General scheme for the preparation of compounds of formula II, wherein is hydrogen, n is 1, and q is 1. [ka]

[0184] In the above scheme 10, rings A and R 1 , R 4 Each of m, p, and m is as defined above and below, and in the classes and subclasses described herein.

[0185] Scheme 11: Ring C is phenyl and R 2 is -CHF2, and R 3 General scheme for the preparation of compounds of formula II, wherein is hydrogen, n is 1, and q is 1. [ka]

[0186] In the above scheme 11, rings A and R 1 , R 4 Each of m, p, and m is as defined above and below, and in the classes and subclasses described herein.

[0187] Scheme 12: Ring C is phenyl and R 2 is -CHF2, and R 3 General scheme for the preparation of compounds of formula II, wherein is hydrogen, n is 1, and q is 1. [ka]

[0188] In the above scheme 12, rings A and R 1 , R 4Each of m, p, and m is as defined above and below, and in the classes and subclasses described herein.

[0189] Scheme 13: Ring C is pyridine and R 2 is -OCF2H, and R 3 General scheme for the preparation of compounds of formula II, wherein is hydrogen, n is 1, and q is 1. [ka]

[0190] In the above scheme 13, rings A and R 1 , R 4 Each of m, p, and m is as defined above and below, and in the classes and subclasses described herein.

[0191] Scheme 14: Ring C is pyridine and R 2 is -CF3 and R 3 General scheme for the preparation of compounds of formula II, wherein is hydrogen, n is 1, and q is 1. [ka]

[0192] In the above Scheme 14, rings A and R 1 , R 4 Each of m, p, and m is as defined above and below, and in the classes and subclasses described herein.

[0193] Scheme 15: Ring C is pyridine and R 2 is -CHF2, and R 3 General scheme for the preparation of compounds of formula II, wherein is hydrogen, n is 1, and q is 1. [ka]

[0194] In the above scheme 15, rings A and R 1 , R 4 Each of m, p, and m is as defined above and below, and in the classes and subclasses described herein.

[0195] Scheme 16: Ring C is a pyrimidine and R 2 is -Cl and R 3 General scheme for the preparation of compounds of formula II, wherein is hydrogen, n is 1, and q is 1. [ka]

[0196] In the above scheme 16, rings A and R 1 , R 4 Each of m, p, and m is as defined above and below, and in the classes and subclasses described herein.

[0197] Scheme 17: Ring C is a pyrimidine and R 2 is -CHF2, and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula II, wherein is hydrogen, n is 1, p is 1, and q is 1. [ka]

[0198] In the above Scheme 17, rings A and R 1 Each of m is as defined above and below, and in the classes and subclasses described herein.

[0199] Scheme 18: Ring C is a pyrimidine attached to the bicyclic core from the 4-position and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula III, wherein is hydrogen, p is 1, and q is 1. [ka]

[0200] In the above scheme 18, rings A and R 1 , R 2 Each of m, m, and n is as defined above and below, and in the classes and subclasses described herein.

[0201] Scheme 19: Ring C is a pyrimidine attached to the bicyclic core from the 4-position and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula III, wherein is hydrogen, p is 1, and q is 1. [ka]

[0202] In the above scheme 19, ring A, R 1 , R 2 Each of m, m, and n is as defined above and below, and in the classes and subclasses described herein.

[0203] Scheme 20: Ring C is a pyrimidine attached to the bicyclic core from the 4-position and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula III, wherein is hydrogen, p is 1, and q is 1. [ka]

[0204] In the above scheme 20, rings A and R 1 , R 2 Each of m, m, and n is as defined above and below, and in the classes and subclasses described herein.

[0205] Scheme 21: Ring C is a pyridine attached to the bicyclic core from the 4-position and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula III, wherein is hydrogen, p is 1, and q is 1. [ka]

[0206] In the above scheme 21, rings A and R 1 , R 2 Each of m, m, and n is as defined above and below, and in the classes and subclasses described herein.

[0207] Scheme 22: Ring C is pyrimidine and R 3 General scheme for the preparation of compounds of formula III, wherein is hydrogen and q is 1. [ka]

[0208] In the above scheme 22, rings A and R 1 , R 2 , R 4 , m, n, and p are each as defined above and below, and in the classes and subclasses described herein.

[0209] Scheme 23: Ring C is pyridin-4-yl further substituted at the 2-position, and R 3 General scheme for the preparation of compounds of formula III, wherein is hydrogen and q is 1. [ka]

[0210] In the above scheme 23, rings A and R 1 , R 2 , R 4, m, n, and p are each as defined above and below, and in the classes and subclasses described herein.

[0211] Scheme 24: Ring C is a pyridine introduced by cross-coupling reaction, and R 3 General scheme for the preparation of compounds of formula III, wherein is hydrogen and q is 1. [ka]

[0212] In the above Scheme 24, rings A and R 1 , R 2 , R 4 , m, n, and p are each as defined above and below, and in the classes and subclasses described herein.

[0213] Scheme 25: Ring C is a pyridine introduced by CH activation and R 3 General scheme for the preparation of compounds of formula III, wherein is hydrogen and q is 1. [ka]

[0214] In the above Scheme 25, rings A and R 1 , R 2 , R 4 , m, n, and p are each as defined above and below, and in the classes and subclasses described herein.

[0215] Scheme 26: Ring C is pyrimidine and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula IV, wherein is hydrogen, p is 1, and q is 1. [ka]

[0216] In the above Scheme 26, rings A and R 1 , R 2 Each of m, m, and n is as defined above and below, and in the classes and subclasses described herein.

[0217] Scheme 27: Ring C is pyridine and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula IV, wherein is hydrogen, p is 1, and q is 1. [ka]

[0218] In the above Scheme 27, rings A and R 1 , R 2 Each of m, m, and n is as defined above and below, and in the classes and subclasses described herein.

[0219] Scheme 28: Ring C is pyrimidine and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula IV, wherein is hydrogen, p is 1, and q is 1. [ka]

[0220] In the above scheme 28, rings A and R 1 , R 2 Each of m, m, and n is as defined above and below, and in the classes and subclasses described herein.

[0221] Scheme 29: Ring C is pyrimidine and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula IV, wherein is hydrogen, p is 1, and q is 1. [ka]

[0222] In the above scheme 29, ring A, R 1 , R 2 Each of m, m, and n is as defined above and below, and in the classes and subclasses described herein.

[0223] Scheme 30: Ring C is a pyrimidine and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula IV, wherein is hydrogen, p is 1, and q is 1. [ka]

[0224] In the above Scheme 30, rings A and R 1 , R 2 Each of m, m, and n is as defined above and below, and in the classes and subclasses described herein.

[0225] Scheme 31: Ring C is a pyrimidine and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula IV, wherein is hydrogen, n is 1, p is 1, and q is 1. [ka]

[0226] In the above Scheme 31, rings A and R 1 , R 2 Each of m is as defined above and below, and in the classes and subclasses described herein.

[0227] Scheme 32: Ring C is pyrimidine and R 2 is -C(O)NH2 and R 3 is hydrogen and R4 General scheme for the preparation of compounds of formula IV, wherein is hydrogen, n is 1, p is 1, and q is 1. [ka]

[0228] In the above Scheme 32, rings A and R 1 Each of m is as defined above and below, and in the classes and subclasses described herein.

[0229] Scheme 33: Ring C is 5-fluoropyrimidine and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula IV, wherein is hydrogen, n is 1, p is 1, and q is 1. [ka]

[0230] In the above Scheme 33, rings A and R 1 , R 2 Each of m is as defined above and below, and in the classes and subclasses described herein.

[0231] Scheme 34: Ring C is 6-chloropyrimidine and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula IV, wherein is hydrogen, n is 1, p is 1, and q is 1. [ka]

[0232] In the above Scheme 34, rings A and R 1 , R 2 Each of m is as defined above and below, and in the classes and subclasses described herein.

[0233] Scheme 35: Ring C is a 6-substituted pyrimidine and R 3 General scheme for the preparation of compounds of formula IV, wherein is hydrogen, n is 1, p is 1, and q is 1. [ka]

[0234] In the above Scheme 35, rings A and R 1 , R 2 , R 4 Each of m is as defined above and below, and in the classes and subclasses described herein.

[0235] Scheme 36: Ring C is 6-methylpyrimidine and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula IV, wherein is methyl, n is 1, p is 1, and q is 1. [ka]

[0236] In the above Scheme 36, rings A and R 1 , R 2 Each of m is as defined above and below, and in the classes and subclasses described herein.

[0237] Scheme 37: Ring C is pyrimidine and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula IV, wherein is hydrogen, n is 1, p is 1, and q is 1. [ka]

[0238] In the above Scheme 37, rings A and R 1 , R 2Each of m is as defined above and below, and in the classes and subclasses described herein.

[0239] Scheme 38: Ring C is pyridine and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula IV, wherein is hydrogen, n is 1, p is 1, and q is 1. [ka]

[0240] In the above Scheme 38, rings A and R 1 , R 2 Each of m is as defined above and below, and in the classes and subclasses described herein.

[0241] Scheme 39: Ring C is pyridine and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula IV, wherein is hydrogen, n is 1, p is 1, and q is 1. [ka]

[0242] In the above Scheme 39, rings A and R 1 , R 2 Each of m is as defined above and below, and in the classes and subclasses described herein.

[0243] Scheme 40: Ring C is pyridine and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula IV, wherein is hydrogen, n is 1, p is 1, and q is 1. [ka]

[0244] In the above Scheme 40, rings A and R 1 , R 2 Each of m is as defined above and below, and in the classes and subclasses described herein.

[0245] Scheme 41: Ring C is pyridine and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula IV, wherein is hydrogen, n is 1, p is 1, and q is 1. [ka]

[0246] In the above Scheme 41, rings A and R 1 , R 2 Each of m is as defined above and below, and in the classes and subclasses described herein.

[0247] Scheme 42: Ring C is pyrimidine and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula IV, wherein is hydrogen, n is 1, p is 1, and q is 1. [ka]

[0248] In the above Scheme 42, rings A and R 1 , R 2 Each of m is as defined above and below, and in the classes and subclasses described herein.

[0249] Scheme 43: Ring C is pyrimidine and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula IV, wherein is hydrogen, n is 1, p is 1, and q is 1. [ka]

[0250] In the above Scheme 43, rings A and R 1 , R 2 Each of m is as defined above and below, and in the classes and subclasses described herein.

[0251] Scheme 44: Ring C is pyridazine and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula IV, wherein is hydrogen, n is 1, p is 1, and q is 1. [ka]

[0252] In the above Scheme 44, rings A and R 1 , R 2 Each of m is as defined above and below, and in the classes and subclasses described herein.

[0253] Scheme 45: Ring C is pyridazine and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula IV, wherein is hydrogen, n is 1, p is 1, and q is 1. [ka]

[0254] In the above Scheme 45, rings A and R 1 , R 2 Each of m is as defined above and below, and in the classes and subclasses described herein.

[0255] Scheme 46: Ring C is pyridine and R 3 is hydrogen and R 4General scheme for the preparation of compounds of formula IV, wherein is hydrogen, n is 1, p is 1, and q is 1. [ka]

[0256] In the above Scheme 46, rings A and R 1 , R 2 Each of m is as defined above and below, and in the classes and subclasses described herein.

[0257] Scheme 47: Ring C is pyridine and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula IV, wherein is fluoro, n is 1, p is 1, and q is 1. [ka]

[0258] In the above Scheme 47, rings A and R 1 , R 2 Each of m is as defined above and below, and in the classes and subclasses described herein.

[0259] Scheme 48: Ring C is a pyrimidine and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula IV, wherein is fluoro, n is 1, p is 1, and q is 1. [ka]

[0260] In the above Scheme 48, rings A and R 1 , R 2 Each of m is as defined above and below, and in the classes and subclasses described herein.

[0261] Scheme 49: Ring C is a pyrimidine and R 2 is -CF2CH3 and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula IV, wherein is hydrogen, n is 1, p is 1, and q is 1. [ka]

[0262] In the above Scheme 49, rings A and R 1 Each of m is as defined above and below, and in the classes and subclasses described herein.

[0263] Scheme 50: Ring C is a pyrimidine attached to the bicyclic core from the 2-position and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula V, wherein is hydrogen, n is 1, p is 1, and q is 1. [ka]

[0264] In the above scheme 50, rings A and R 1 , R 2 Each of m is as defined above and below, and in the classes and subclasses described herein.

[0265] Scheme 51: Ring C is a pyrimidine attached to the bicyclic core from the 2-position and R 2 is -CF2H and R 3 is hydrogen and R 4 General scheme for the preparation of compounds of formula V, wherein is hydrogen, n is 1, p is 1, and q is 1. [ka]

[0266] In the above Scheme 51, rings A and R 1 Each of m is as defined above and below, and in the classes and subclasses described herein.

[0267] Those skilled in the art will appreciate that compounds of Formulas I-V may contain one or more stereocenters and may exist as racemates or diastereomeric mixtures. Those skilled in the art will also appreciate that there are numerous methods known in the art for separating isomers to obtain stereoenriched or stereopure isomers of these compounds, including, but not limited to, HPLC, chiral HPLC, fractional crystallization of diastereomeric salts, kinetic enzymatic analysis (e.g., with lipases or esterases of fungal, bacterial, or animal origin), and formation of covalent diastereomeric derivatives using enantiomerically enriched reagents.

[0268] Those skilled in the art will recognize that various functional groups present in the compounds of the present invention, such as aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens, and nitriles, can be interconverted by techniques well known in the art, including, but not limited to, reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration. March's Advanced Organic Chemistry, 5th Edition, eds. Smith, MB, and March, J., John Wiley & Sons, New York: 2001, which is incorporated herein by reference in its entirety. Such interconversions may require one or more of the techniques described above, and certain methods for synthesizing the compounds of the present invention are described below in examples. 5. Uses, Formulation and Administration a. Pharmaceutically acceptable compositions

[0269] According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in the composition of the present invention is effective to measurably inhibit GCN2 protein kinase or a mutant thereof in a biological sample or a patient. In certain embodiments, the amount of compound in the composition of the present invention is effective to measurably inhibit GCN2 protein kinase or a mutant thereof in a biological sample or a patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0270] The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0271] The term " pharmaceutically acceptable carrier, adjuvant or vehicle " refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound that is formulated together. Pharmaceutically acceptable carrier, adjuvant or vehicle that can be used in the composition of the present invention includes, but is not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, etc.), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol and wool fat.

[0272] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, the compound of the invention, or an inhibitory active metabolite or residue thereof.

[0273] As used herein, the term "inhibitorily active metabolite or residue thereof" means that the metabolite or residue thereof is also an inhibitor of GCN2 protein kinase or a mutant thereof.

[0274] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term "parenteral," as used herein, includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present invention can be aqueous or oleaginous suspensions. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0275] For this purpose, any non-irritating fixed oil can be used, including synthetic mono- or diglycerides.Fatty acids such as oleic acid and its glyceride derivatives are useful for preparing injections, as are natural pharmaceutically acceptable oils, particularly polyoxyethylated olive oil or castor oil.These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions.Other commonly used surfactants, such as Tweens, Spans and other emulsifiers, or bioavailability enhancers, which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms, can also be used for formulation purposes.

[0276] The pharmaceutically acceptable composition of the present invention can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions.For tablets intended for oral use, commonly used carriers include lactose and corn starch.Lubricants such as magnesium stearate are also usually added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.When aqueous suspension is required for oral use, active ingredient is combined with emulsifier and suspending agent.If desired, certain sweeteners, flavorings or colorings can also be added.

[0277] Alternatively, the pharmaceutically acceptable compositions of the present invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thereby melting in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0278] The pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0279] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical transdermal patches may also be used.

[0280] For topical application, provided pharmaceutically acceptable compositions can be formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water.Alternatively, provided pharmaceutically acceptable compositions can be formulated into a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0281] For ophthalmic use, the provided pharmaceutically acceptable compositions may be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or preferably as a solution in isotonic, pH-adjusted, sterile saline, with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[0282] The pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation, and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0283] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0284] The amount of the compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration, etc. Preferably, provided compositions should be formulated so that a dosage of between 0.01 and 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0285] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the invention in a composition will also depend on the particular compound in the composition. b. Uses of the Compounds and Pharmaceutically Acceptable Compositions

[0286] The compounds and compositions described herein are generally useful for inhibiting GCN2 protein kinase activity.

[0287] The activity of the compounds utilized in this invention as inhibitors of GCN2, or a mutant thereof, may be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine inhibition of either the phosphorylation activity and / or subsequent functional consequences or ATPase activity of activated GCN2 or its mutants. Alternative in vitro assays quantitate the ability of inhibitors to bind to GCN2. Inhibitor binding can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / GCN2 complex, and determining the amount of bound radiolabel. Alternatively, inhibitor binding can be determined by performing a competition experiment in which a new inhibitor is incubated with GCN2 bound to a known radioligand. Detailed conditions for assaying compounds utilized as inhibitors of GCN2 or its mutants in this invention are described in the Examples below.

[0288] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder as described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to susceptible individuals prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have been cured, e.g., to prevent or delay their recurrence.

[0289] The provided compounds are inhibitors of one or more GCN2s and are therefore useful for treating one or more disorders associated with the activity of GCN2. Accordingly, in certain embodiments, the present invention provides a method for treating a GCN2-mediated disorder, comprising administering to a patient in need thereof a compound of the present invention or a pharmaceutically acceptable composition thereof.

[0290] As used herein, the term "GCN2-mediated" disorder, disease, and / or condition means any disease or other aggravating condition in which GCN2 or a mutant thereof is known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which GCN2 or a mutant thereof is known to play a role.

[0291] In some embodiments, the present invention provides methods for treating one or more disorders, diseases, and / or conditions, wherein the disorder, disease, or condition is selected from the group consisting of an inflammatory condition, an immunological condition, an autoimmune condition, an allergic condition, a rheumatic condition, a thrombotic condition, a cancer, an infection, a neurodegenerative disease, a degenerative disease, a neuroinflammatory disease, a cardiovascular disease, and a metabolic condition.

[0292] In some embodiments, the cancer to be treated is a solid tumor or a tumor of the blood and immune system.

[0293] In some embodiments, the cancer is a solid tumor, wherein the solid tumor originates from the group of epithelial, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid, intestinal, liver, brain, prostate, genitourinary tract, lymphatic system, stomach, larynx, bone (including chondrosarcoma and Ewing's sarcoma), germ cell (including fetal tissue tumors), and / or lung tumors, monocytic leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma, neurofibroma, angiosarcoma, breast cancer, and / or malignant melanoma.

[0294] In some embodiments, the autoimmune condition is rheumatoid arthritis, systemic lupus, multiple sclerosis, psoriasis, Sjogren's syndrome, or transplant organ rejection.

[0295] In some embodiments, the metabolic condition is diabetes.

[0296] In some embodiments, the degenerative disease is osteoarthritis.

[0297] In some embodiments, the inflammatory condition is asthma, inflammatory bowel disease, or giant cell arteritis.

[0298] In some embodiments, the cardiovascular disease is an ischemic injury.

[0299] In some embodiments, the neurodegenerative disease is Alzheimer's disease, Down's syndrome, Hereditary cerebral hemorrhage with amyloidosis - Dutch type, cerebral amyloid angiopathy, Creutzfeldt-Jakob disease, frontotemporal dementia, Huntington's disease, or Parkinson's disease.

[0300] In some embodiments, the infection is caused by leishmania, mycobacteria (including M. leprae, M. tuberculosis and / or M. avium), malaria parasites, human immunodeficiency virus, Epstein-Barr virus, herpes simplex virus, or hepatitis C virus.

[0301] The invention further provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, for the preparation of a medicament for the treatment of an inflammatory condition, an immunological condition, an autoimmune condition, an allergic condition, a rheumatic condition, a thrombotic condition, a cancer, an infection, a neurodegenerative disease, a degenerative disease, a neuroinflammatory disease, a cardiovascular disease, or a metabolic condition. c. Combination therapy

[0302] Depending on the particular condition, or disease, being treated, additional therapeutic agents, which are normally administered to treat that condition, can be administered in combination with the compounds and compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."

[0303] In certain embodiments, the provided combinations, or compositions thereof, are administered in combination with another therapeutic agent.

[0304] Examples of drugs with which the combinations of this invention may be combined include, but are not limited to: drugs for treating Alzheimer's disease, such as Aricept® and Excelon®; drugs for treating HIV, such as ritonavir; drugs for treating Parkinson's disease, such as L-DOPA / carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; drugs for treating multiple sclerosis (MS), such as beta interferons (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; drugs for treating asthma, such as albuterol and Singulair®; drugs for treating schizophrenia, such as Zyprexa, Risperdal, Seroquel, and haloperidol; anti-inflammatory drugs, such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants, such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors, such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents agents); agents for treating cardiovascular disease, such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease, such as corticosteroids, cholestyramine, interferons, and antivirals; agents for treating blood disorders, such as corticosteroids, anti-leukemia agents, and growth factors; agents that prolong or improve pharmacokinetics, such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic degradation) and CYP3A4 inhibitors (e.g., ketokenozole and ritonavir), and agents for treating immune deficiency disorders, such as gamma globulins.

[0305] In certain embodiments, the combination therapy of the invention, or a pharmaceutically acceptable composition thereof, is administered in combination with a monoclonal antibody or siRNA therapeutic agent.

[0306] These additional agents may be administered separately from the combination therapy provided, as part of a multiple dose regimen. Alternatively, these agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition. When administered as part of a multiple dose regimen, the two active agents may be given simultaneously, sequentially, or within a period of each other, usually within 5 hours of each other.

[0307] As used herein, the terms "combination," "in combination," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the invention. For example, a combination of the invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form.

[0308] The amount of additional therapeutic agent present in the compositions of the invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions of the present disclosure will range from about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0309] In one embodiment, the present invention provides a composition comprising a compound of Formula I and one or more additional therapeutic agents. The therapeutic agents can be administered together with the compound of Formula I, or before or after the administration of the compound of Formula I. Suitable therapeutic agents are described in more detail below. In certain embodiments, the compound of Formula I can be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, the compound of formula I can be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after the therapeutic agent.

[0310] In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder, or condition by administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biological agents, such as, for example, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib), colchicine (Colcrys®), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone), probenecid, allopurinol, febuxostat, etc. (febuxostat) (Uloric®), sulfasalazine (Azulfidine®), antimalarials (e.g., hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®)), methotrexate (Rheumatrex®), gold salts (e.g., gold thioglucose (Solganal®), gold thiomalate (Myochrysine®), and auranofin (Ridaura®) )), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), and "anti-TNF" agents (e.g., etanercept (Enbrel®), infliximab (Remicade®), golimumab (Gibberish®), fluconazole (Fenix ​​... Mabs (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), "anti-IL-1" agents (e.g., anakinra (Kineret®) and rilonacept (Arcalyst®)), canakinumab (Ilaris®), anti-Jak inhibitors (e.g., tofacitinib), antibodies (e.g., rituximab (Rituxan®)), "anti-T cell" agents (e.g.,Abatacept (Orencia®), “anti-IL-6” agents (e.g., tocilizumab (Actemra®)), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies (e.g., tanezumab), anticoagulants (e.g., heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®)), antidiarrheal drugs (e.g., diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders (e.g., cholestyramine), alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives (e.g., milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®), anticholinergics or antispasmodics (e.g., dicyclomine (Bentyl®)), Singulair®, beta-2 agonists (e.g., albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®)), anticholinergics (e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids (e.g., beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), and flunisolide (Aerobid®)), Afviar®, Symbicort®, Dulera®,Cromolyn sodium (Intal®), methylxanthines (e.g., theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline), IgE antibodies (e.g., omalizumab (Xolair®)), nucleoside reverse transcriptase inhibitors (e.g., zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®) ), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors (e.g., delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (nev airapine (Viramune®) and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors (e.g., tenofovir (Viread®)), protease inhibitors (e.g., amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), trademark), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitors (e.g., enfuvirtide (Fuzeon®) and maraviroc (Selzentry®)), integrase inhibitors (e.g., raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®),vincristine (Oncovin®), bortezomib (Velcade®), and dexamethasone (Decadron®) in combination with lenalidomide (Revlimid®), or any combination or combinations thereof.

[0311] In another embodiment, the present invention provides a method of treating gout, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib), colchicine (Colcrys®), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone), probenecid, allopurinol, febuxostat (Uloric®).

[0312] In another embodiment, the present invention provides a method of treating rheumatoid arthritis, comprising administering to a patient in need thereof a compound of Formula I and nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone), sulfasalazine (Azulfidine®), antimalarials ( For example, hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts (e.g., gold thioglucose (Solganal®), gold thiomalate (Myochrysine®), and auranofin (Ridaura®)), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imura®), n®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), and "anti-TNF" agents (e.g., etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®), and adalimumab (Humira®)), "anti-IL-1" agents (e.g., anakinra (Kineret®) and rilonacept (Arcalyst®)), antibodies (e.g., rituximab (Rituxan®)), "anti-T cell" agents (e.g., abatacept (Orencia®)), and "anti-IL-6" agents (e.g., tocilizumab (Actemra®)).

[0313] In some embodiments, the present invention provides a method of treating osteoarthritis, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), and monoclonal antibodies (e.g., tanezumab).

[0314] In some embodiments, the present invention provides a method of treating systemic lupus erythematosus, comprising administering to a patient in need thereof a compound of Formula I and acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone), antimalarials (e.g., hydroxychloroquine (Plaq), and administering one or more additional therapeutic agents selected from fluticasone (fluconazole), fluoxetine ...

[0315] In some embodiments, the present invention provides a method of treating inflammatory bowel disease, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from mesalamine (Asacol®), sulfasalazine (Azulfidine®), antidiarrheals (e.g., diphenoxylate (Lomotil®) and loperamide (Imodium®)), bile acid binders (e.g., cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®)), laxatives (e.g., milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®), and anticholinergics or antispasmodics (e.g., dicyclomine (Bentyl®)), anti-TNF therapeutics, steroids, and antibiotics (e.g., Flagyl or ciprofloxacin).

[0316] In some embodiments, the present invention provides a method of treating asthma by administering to a patient in need thereof a compound of Formula I and one or more of Singulair®, beta-2 agonists (e.g., albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®)), anticholinergics (e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®)), inhaled corticosteroids (e.g., prednisone, prednisolone, beclomethasone dipropionate), or steroids (e.g., benzodiazepines, benzodiazepines, benzotriazolone ... and administering one or more additional therapeutic agents selected from fluticasone (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®), cromolyn sodium (Intal®), methylxanthines (e.g., theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline), and IgE antibodies (e.g., omalizumab (Xolair®)).

[0317] In some embodiments, the present invention provides a method of treating COPD, comprising administering to a patient in need thereof a compound of Formula I and a beta-2 agonist (e.g., albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®)), an anticholinergic (e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®)), a methylxanthine (e.g., theophylline (Th and aminophylline), inhaled corticosteroids (e.g., prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®).

[0318] In some embodiments, the present invention provides methods of treating HIV, comprising administering to a patient in need thereof a compound of Formula I and a nucleoside reverse transcriptase inhibitor (e.g., zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®)). , lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors (e.g., delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®), and etravirine (Intelence®)), nucleoside reverse transcriptase inhibitors (e.g., tenofovir (Viread®)), protease inhibitors (e.g., amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Nor vir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®)), entry inhibitors (e.g., enfuvirtide (Fuzeon®) and maraviroc (Selzentry®)), integrase inhibitors (e.g., raltegravir (Isentress®), and combinations thereof).

[0319] In another embodiment, the present invention provides a method of treating a hematological malignancy, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0320] In another embodiment, the present invention provides a method of treating a solid tumor, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0321] In another embodiment, the present invention provides a method of treating a hematological malignancy, comprising administering to a patient in need thereof a compound of Formula I and a hedgehog (Hh) signaling pathway inhibitor. In some embodiments, the hematological malignancy is DLBCL (Ramirez et al., "Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma," Leuk. Res. (2012), published online July 17, and incorporated herein by reference in its entirety).

[0322] In another embodiment, the present invention provides a method of treating diffuse large B-cell lymphoma (DLBCL), comprising administering to a patient in need thereof the compound of Formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and combinations thereof.

[0323] In another embodiment, the present invention provides a method of treating multiple myeloma, comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from bortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, in combination with lenalidomide (Revlimid®).

[0324] In another embodiment, the invention provides a method of treating Waldenstrom's macroglobulinemia, comprising administering to a patient in need thereof the compound of Formula I and one or more additional therapeutic agents selected from chlorambucil (Leukeran®), cyclophosphamide (Cytoxan®, Neosar®), fludarabine (Fludara®), cladribine (Leustatin®), rituximab (Rituxan®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, and a SYK inhibitor.

[0325] In some embodiments, the present invention provides a method of treating Alzheimer's disease, comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from donepezil (Aricept®), rivastigmine (Excelon®), galantamine (Razadyne®), tacrine (Cognex®), and memantine (Namenda®).

[0326] In another embodiment, the present invention provides a method of treating organ transplant rejection or graft-versus-host disease, comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from steroids, cyclosporine, FK506, rapamycin, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, and SYK inhibitors.

[0327] In another embodiment, the present invention provides a method for treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I and a BTK inhibitor, wherein the disease is selected from the group consisting of inflammatory bowel disease, arthritis, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, and inflammatory bowel disease (IGD). thyroiditis), Graves' disease, autoimmune thyroiditis, Sjögren's syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barré syndrome, acute disseminated cerebrospinal meningitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia , Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, autonomic neuropathy, membranous glomerular nephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, hyperproliferative disorders, rejection of transplanted organs or tissues, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplants, blood transfusions, anaphylaxis, allergies (e.g., to plant pollen, latex, drugs, food, insect venom, animal hair, animal dander, house dust mites, or cockroach calyx) calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis abscess, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitisMyocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, B-cell proliferative disorders (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Walde's lymphoma M. Lundstrom's macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, or lymphomatoid granulomatosis, breast cancer, prostate cancer, or cancer of the mast cells (e.g., mastocytoma, mast cell leukemia, mastocytoma) alveolar sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, bone and joint diseases (including but not limited to rheumatoid arthritis, seronegative spondyloarthritis (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastases), thromboembolic disorders (e.g., myocardial infarction, angina pectoris, re-occlusion after angioplasty, restenosis after angioplasty, re-occlusion after aortocoronary artery bypass, restenosis after aortocoronary artery bypass, stroke, transient ischemia, peripheral arterial occlusive disorder , pulmonary embolism, deep vein thrombosis), inflammatory pelvic disease, urethritis, sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis (cholocystitis), agammaglobulinemia, psoriasis, allergies, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandulardisease) (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, metastatic carcinoma of the liver, leukemia, and rheumatoid arthritis. In some embodiments, the disease is selected from osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom's macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behcet's disease, scleroderma, mycosis fungoides, acute inflammatory responses (e.g., acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease.

[0328] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, comprising the step of administering to a patient in need thereof a compound of Formula I and a PI3K inhibitor, wherein the disease is selected from cancer, a neurodegenative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, a pathological immune condition involving T-cell activation, a cardiovascular disorder, and a CNS disorder.

[0329] In another embodiment, the invention provides a method of treating or lessening the severity of a disease, comprising the step of administering to a patient in need thereof a compound of Formula I and a PI3K inhibitor, wherein the disease is a benign or malignant tumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid gland, sarcoma, glioblastoma, neuroblastoma, multiple myeloma or gastrointestinal cancer, particularly colon cancer or colorectal adenoma or head and neck tumor, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasia, intraepithelial neoplasia, character), adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma (including, for example, non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (also called Hodgkin or Hodgkin's disease)), breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or leukemia, Cowden syndrome, Lhermitte-Dudos disease Diseases including Banayan-Zonana syndrome or diseases in which the PI3K / PKB pathway is abnormally activated, asthma of any type or onset, including both intrinsic (non-allergic) and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitis asthma, exercise-induced asthma, occupational asthma and asthma induced after bacterial infection, acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, chronic obstructive airway disease or chronic obstructive lung diseasedisease (COPD, COAD or COLD) (including associated chronic bronchitis or dyspnea), emphysema, and exacerbations of airway overactivity as a result of other medications (especially other inhaled medications), bronchitis of any type or occurrence (including but not limited to acute, arachidic, catarrhal, croupus, chronic or tuberculous bronchitis), pneumoconiosis of any type or occurrence (an inflammatory, generally occupational, lung disease, whether chronic or acute, frequently associated with airway obstruction and caused by repeated inhalation of dust) (including, for example, aluminum lung disease, anthracosis, asbestosis, stone disease, ptilosis, siderosis, silicosis, tabacosis and byssinosis), Loffler's syndromesyndrome), eosinophilic pneumonia, parasitic (especially metazoan) infestations (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophil-related disorders affecting the airways caused by eosinophilic granulomas and drug reactions, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid diseases affecting the nose, including acne, lupus erythematosus, pemphigus, epidermolysis bullosa acquisita, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, allergic rhinitis, and inflammatory diseases involving an autoimmune response or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell aplasia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma (sclerodoma), Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal conjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, and The present invention provides methods for treating a neurodegenerative disease selected from glomerulonephritis (with or without nephrotic syndrome (including, for example, idiopathic nephrotic syndrome or minimal change nephropathy)), restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, as well as neurodegenerative diseases caused by trauma, glutamate neurotoxicity, and hypoxia.

[0330] The compounds and compositions of the present invention can be administered in any amount and via any route effective for treating or reducing the severity of cancer, autoimmune disorders, proliferative disorders, inflammatory disorders, neurodegenerative or psychiatric disorders, schizophrenia, bone-related disorders, liver disease, or cardiac disorders. The exact amount required will vary from subject to subject, depending on the subject's race, age, and general condition, the severity of the infection, the specific drug, its mode of administration, and the like. The compounds of the present invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The term "dosage unit form" as used herein refers to a physically discrete unit of drug appropriate for the patient being treated. However, it will be understood that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder, the activity of the specific compound used, the specific composition used, the patient's age, weight, general health, sex, and diet, the time of administration, the route of administration, and the rate of excretion of the specific compound used, the duration of treatment, drugs used in combination with or concomitantly with the specific compound used, and similar factors well known in the medical field. The term "patient," as used herein, means an animal, preferably a mammal, and most preferably a human.

[0331] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intravesically, intravaginally, intraperitoneally, topically (such as by powders, ointments, or drops), buccally, as an oral spray or nasal drops, etc., depending on the severity of the infection being treated. In certain embodiments, the compounds of the present invention can be administered orally or parenterally, one or more times per day, at dosage levels of about 0.01 mg / kg to about 50 mg / kg of subject's body weight, and preferably about 1 mg / kg to about 25 mg / kg of subject's body weight per day, to obtain the desired therapeutic effect.

[0332] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active compounds, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions can also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0333] Injectable preparations, such as injectable aqueous or oleaginous sterile suspensions, can be formulated using suitable dispersing or wetting agents and suspending agents according to known techniques. Sterile injectable preparations can also be injectable sterile solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating, fixed oil can be used, including synthetic mono- or diglycerides. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectable preparations.

[0334] Injectable preparations can be sterilized prior to use, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other injectable sterile medium.

[0335] To prolong the effect of the compounds of the present invention, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The absorption rate of the compound then depends on its dissolution rate, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of parenterally administered compound forms can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms can be made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. The release rate of the compound can be controlled depending on the ratio of compound to polymer and the nature of the specific polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0336] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound of the invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.

[0337] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) humectants, such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents, such as kaolin and bentonite clay; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0338] Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical compounding art. They may optionally contain opacifying agents, and they can also be composed so as to release the active ingredient(s) solely, or preferentially, in a certain part of the intestinal tract, optionally with a delay. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0339] The active compound can also be in microencapsulated form with one or more excipients as described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical compounding art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also contain, as is common practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, these dosage forms may also contain buffering agents. They may optionally contain opacifying agents, and they may be composed to release the active ingredient(s) singly or preferentially in a certain part of the intestinal tract, optionally with a delay. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0340] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers, as may be required. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0341] According to one embodiment, the present invention relates to a method of inhibiting protein kinase activity in a biological sample, comprising the step of contacting said biological sample with a compound of the present invention, or a composition comprising said compound.

[0342] According to another embodiment, the present invention relates to a method for inhibiting the activity of GCN2 or a mutant thereof in a biological sample, comprising the step of contacting said biological sample with a compound of the present invention, or a composition comprising said compound.

[0343] The term "biological sample," as used herein, includes, but is not limited to, cell cultures or extracts thereof; biopsies obtained from mammals or extracts thereof; and blood, saliva, urine, stool, semen, tears, or other bodily fluids or extracts thereof.

[0344] Inhibition of the activity of a protein kinase or GCN2 protein kinase, or a variant thereof, in a biological sample is useful for a variety of purposes known to those skilled in the art, including, but not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological assays.

[0345] Another embodiment of the invention relates to a method of inhibiting protein kinase activity in a patient, comprising administering to said patient a compound of the present invention, or a composition comprising said compound.

[0346] According to another embodiment, the present invention provides a method for treating a disorder mediated by GCN2 or a mutant thereof in a patient in need thereof, comprising administering to said patient a compound according to the present invention or a pharmaceutically acceptable composition thereof, such disorders being as described in detail herein.

[0347] Depending on the particular condition, or disease, being treated, additional therapeutic agents, which are normally administered to treat that condition, may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."

[0348] The compounds of the present invention can also be used to advantage in combination with other antiproliferative compounds, including, but not limited to, aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule-active compounds, alkylating compounds, histone deacetylase inhibitors, compounds that induce cell differentiation processes, cyclooxygenase inhibitors, MMP inhibitors, mTOR inhibitors, antineoplastic antimetabolites, platinum compounds, compounds that target / reduce protein or lipid kinase activity, and even antiangiogenic compounds, compounds that target, reduce or inhibit protein or lipid phosphatase activity, gonadorelin agonists, antiandrogens, methionine aminopeptides, etc. enzyme inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target Flt-3 and decrease or inhibit its activity; Hsp90 inhibitors (17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (Conforma Therapeutics); temozolomide (Temodal®); kinesin spindle protein inhibitors (such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine / chlorpromazine from CombinatoRx); MEK inhibitors (such as ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 and leucovorin from Pfizer). The term "aromatase inhibitor", as used herein, relates to a compound that inhibits estrogen production, for example the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.The term includes, but is not limited to, steroids, especially atamestane, exemestane, and formestane, and nonsteroids, especially aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole. Exemestane is marketed under the trade name Aromasin™. Formestane is marketed under the trade name Lentaron™. Fadrozole is marketed under the trade name Afema™. Anastrozole is marketed under the trade name Arimidex™. Letrozole is marketed under the trade name Femara™ or Femar™. Aminoglutethimide is marketed under the trade name Orimeten™. Combinations of the present invention containing a chemotherapeutic agent that is an aromatase inhibitor are particularly useful for the treatment of hormone receptor-positive tumors, such as breast tumors.

[0349] The term "antiestrogen," as used herein, refers to a compound that antagonizes the action of estrogen at the estrogen receptor level. This term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen is marketed under the trade name Nolvadex™. Raloxifene hydrochloride is marketed under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. The combination of the present invention, which includes a chemotherapeutic agent that is an anti-estrogen, is particularly useful for treating estrogen receptor-positive tumors, such as breast tumors.

[0350] The term "antiandrogen," as used herein, refers to any substance capable of inhibiting the biological action of androgen hormones, including, but not limited to, bicalutamide (Casodex™). The term "gonadorelin agonist," as used herein, includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin can be administered under the brand name Zoladex™.

[0351] In some embodiments, the one or more other therapeutic agents is an androgen receptor inhibitor. Approved androgen receptor inhibitors useful in the present invention include enzalutamide (Xtandi®, Astellas / Medivation). Approved inhibitors of androgen synthesis include abiraterone (Zytiga®, Centocor / Ortho); approved gonadotropin-releasing hormone (GnRH) receptor antagonists (degalarix, Firmagon®, Ferring Pharmaceuticals).

[0352] In some embodiments, the one or more other therapeutic agents are selective estrogen receptor modulators (SERMs), which interfere with the synthesis or activity of estrogen. Approved SERMs useful in the present invention include raloxifene (Evista®, Eli Lilly).

[0353] The term "topoisomerase I inhibitors" as used herein includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analog 9-nitrocamptothecin, and the macromolecule camptothecin conjugate PNU-166148. Irinotecan can be administered, for example, in the form marketed, for example, under the trademark Camptosar™. Topotecan is marketed under the trademark Hycamptin™.

[0354] The term "topoisomerase II inhibitors," as used herein, includes, but is not limited to, doxorubicin (including liposomal formulations such as Caelyx™), daunorubicin, epirubicin, anthracyclines such as idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is marketed under the trade name Etopophos™. Teniposide is marketed under the trade name VM26-Bristol. Doxorubicin is marketed under the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketed under the trade name Farmorubicin™. Idarubicin is marketed under the trade name Zavedos™. Mitoxantrone is marketed under the trade name Novantron.

[0355] The term "microtubule activators" refers to microtubule stabilizing compounds, microtubule destabilizing compounds, and microtubule polymerization inhibitors, including, but not limited to, taxanes such as paclitaxel and docetaxel; vinca alkaloids such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolide; coticin and epothilones and their derivatives. Paclitaxel is marketed under the trade name Taxol™. Docetaxel is marketed under the trade name Taxotere™. Vinblastine sulfate is marketed under the trade name Vinblastin RP™. Vincristine sulfate is marketed under the trade name Farmistin™.

[0356] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name Cyclostin™. Ifosfamide is marketed under the trade name Holoxan™.

[0357] The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit histone deacetylase and which possess antiproliferative activity, including but not limited to suberoylanilide hydroxamic acid (SAHA).

[0358] The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds (such as 5-azacytidine and decitabine), methotrexate and edatrexate, and folate antagonists (such as pemetrexed). Capecitabine is marketed under the trade name Xeloda™. Gemcitabine is marketed under the trade name Gemzar™.

[0359] The term "platinum compound" as used herein includes, but is not limited to, carboplatin, cisplatin, cisplatinum, and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark Carboplat™. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark Eloxatin™.

[0360] The term "compounds that target / increase protein or lipid kinase activity; or protein or lipid phosphatase activity; or even anti-angiogenic compounds", as used herein, includes, but is not limited to, a) compounds that target platelet-derived growth factor receptor (PDGFR) and reduce or inhibit its activity, such as compounds that inhibit the PDGF receptor, especially N-phenyl-2-pyrimidine-amine derivatives such as imatinib, SU101, SU6668 and GFB-111, b) compounds that target fibroblast growth factor receptor (FGFR) and reduce or inhibit its activity, c) compounds that target insulin-like growth factor receptor I (IGF-IR) and reduce or inhibit its activity, especially compounds that inhibit the kinase activity of the IGF-I receptor, or compounds that target the IGF-IR and reduce or inhibit its activity, such as antibodies that target the IGF-I receptor or the extracellular domain of the growth factor receptor. d) compounds that target the Trk receptor tyrosine kinase family and reduce or inhibit their activity, or ephrin B4 inhibitors; e) compounds that target the AxI receptor tyrosine kinase family and reduce or inhibit their activity; f) compounds that target the Ret receptor tyrosine kinase and reduce or inhibit its activity; g) compounds that target the Kit / SCFR receptor tyrosine kinase, such as imatinib, and reduce or inhibit its activity; h) compounds that target the c-Kit receptor tyrosine kinase, such as imatinib, and reduce or inhibit its activity; Compounds that target the tyrosine kinase family and decrease or inhibit its activity, in particular compounds that target the c-kit receptor tyrosine kinase, which is part of the PDGFR family, such as compounds that inhibit the c-Kit receptor, such as imatinib, i) N-phenyl-2-pyrimidine-amine derivatives such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC680410; PD173955 from ParkeDavis;or dasatinib (BMS-354825), j) compounds that target and reduce or inhibit the activity of members of the c-Abl family, their gene fusion products (e.g., BCR-Abl kinase) and mutants, such as compounds that target and reduce or inhibit the activity of c-Abl family members and their gene fusion products, such as dasatinib (BMS-354825); j) compounds that target and reduce or inhibit the activity of members of the cyclin-dependent kinase family (CDK), including members of the protein kinase C (PKC) and Raf families of serine / threonine kinases, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, TYK2, BTK and TEC families, and / or staurosporine derivatives such as midostaurin (further exemplary compounds include UCN-01, safingol, BAY4 3-9006, bryostatin 1, perifosine; llmofosine; RO318220 and RO320432; GO6976; lsis3521; LY333531 / LY379196; isoquinoline compounds; FTIs; PD184352 or QAN697 (P13K inhibitors) or AT7519 (CDK inhibitors), k) imatinib mesylate (Gleevec™) or Tyrphostins (tyrphostin A23 / RG-50810; AG99; tyrphostin AG213; tyrphostin AG1748; tyrphostin AG490; tyrphostin B44; tyrphostin B44 (+) enantiomer; tyrphostin AG555; AG494; tyrphostin AG556, AG957, etc.) and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;l) compounds that target, reduce or inhibit the activity of protein tyrosine kinase inhibitors, such as compounds that target, reduce or inhibit the activity of protein tyrosine kinase inhibitors, including compounds that target, reduce or inhibit the activity of protein tyrosine kinase inhibitors, including NSC680410, adaphostin; l) compounds that target, reduce or inhibit the activity of epidermal growth factor receptor family, in particular compounds, proteins or antibodies that inhibit members of the EGF receptor tyrosine kinase family, such as EGF receptor, ErbB2, ErbB3 and ErbB4, or that bind to EGF or EGF-related ligands, CP358774, ZD1839, ZM105180;targeting the epidermal growth factor family of receptor tyrosine kinases (EGFR1, ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and variants thereof, such as trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3 and 7H-pyrrolo-[2,3-d]pyrimidine derivatives, m) compounds that target c-Met and reduce or inhibit its activity, particularly compounds that inhibit the kinase activity of the c-Met receptor, or compounds that target the c-Met receptor and reduce or inhibit its activity, such as antibodies that target the extracellular domain of c-Met or that bind to HGF; n) compounds that target c-Met receptor and reduce or inhibit its activity, including but not limited to, PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofa o) compounds that target one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK) and decrease or inhibit their kinase activity, including citinib and ruxolitinib, including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictorelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765 and idelalisib; , compounds that target PI3 kinase (PI3K) and decrease or inhibit its kinase activity, and q) protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as compounds that target, decrease or inhibit the signaling action of the Hedgehog protein (Hh) or Smoothened receptor (SMO) pathway, including, but not limited to, cyclopamine, vismodegib, itraconazole, erismodegib and IPI-926 (salidegib);

[0361] The term "PI3K inhibitor," as used herein, includes, but is not limited to, compounds that have inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, including, but not limited to, PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors useful in the present invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictorelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[0362] The term "BTK inhibitor," as used herein, includes, but is not limited to, compounds that have inhibitory activity against Bruton's tyrosine kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

[0363] The term "SYK inhibitor" as used herein includes, but is not limited to, compounds that have inhibitory activity against spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0364] Further examples of BTK inhibitory compounds, and conditions treatable by such compounds in combination with the compounds of the present invention, can be found in WO2008039218 and WO2011090760, which are incorporated by reference in their entireties.

[0365] Further examples of SYK inhibitory compounds, and conditions treatable by such compounds in combination with the compounds of the present invention, can be found in WO2003063794, WO2005007623 and WO2006078846, which are incorporated herein by reference in their entireties.

[0366] Further examples of PI3K inhibitory compounds, and conditions treatable by such compounds in combination with the compounds of the present invention, can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554 and WO2007044729, which are incorporated by reference in their entireties.

[0367] Further examples of JAK inhibitory compounds, and conditions treatable by such compounds in combination with the compounds of the present invention, can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, which are incorporated by reference in their entireties.

[0368] Additional anti-angiogenic compounds include compounds that have another mechanism for their activity, for example unrelated to protein or lipid kinase inhibition, such as thalidomide (Thalomid™) and TNP-470.

[0369] Examples of proteasome inhibitors useful in combination with the compounds of the invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0370] Compounds which target protein or lipid phosphatases, decreasing or inhibiting their activity are, for example, inhibitors of phosphatase 1, phosphatase 2A or CDC25 (such as okadaic acid or a derivative thereof).

[0371] Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, α-, γ-, or δ-tocopherol, or α-, γ-, or δ-tocotrienol.

[0372] The term cyclooxygenase inhibitors, as used herein, includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives (such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acids (such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid, lumiracoxib, etc.).

[0373] The term "bisphosphonate," as used herein, includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etridonic acid is marketed under the trade name Didronel™. Clodronic acid is marketed under the trade name Bonefos™. Tiludronic acid is marketed under the trade name Skelid™. Pamidronic acid is marketed under the trade name Aredia™. Alendronic acid is marketed under the trade name Fosamax™. Ibandronic acid is marketed under the trade name Bondranat™. Risedronic acid is marketed under the trade name Actonel™. Zoledronic acid is marketed under the trade name Zometa™. The term "mTOR inhibitors" relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

[0374] The term "heparanase inhibitor," as used herein, refers to a compound that targets, decreases, or inhibits heparin sulfate degradation. This term includes, but is not limited to, PI-88. The term "biological response modifier," as used herein, refers to a lymphokine or interferon.

[0375] The term "inhibitor of Ras oncogenic isoforms", such as H-Ras, K-Ras or N-Ras, as used herein refers to compounds that target Ras and reduce or inhibit its tumor activity, such as "farnesyltransferase inhibitors" such as L-744832, DK8G557 or R115777 (Zarnestra™).The term "telomerase inhibitor", as used herein, refers to compounds that target telomerase and reduce or inhibit its activity.The compound that targets telomerase and reduces or inhibits its activity is particularly a compound that inhibits telomerase receptor, such as telomestatin.

[0376] The term "methionine aminopeptidase inhibitor" as used herein refers to a compound that targets methionine aminopeptidase and reduces or inhibits its activity. Compounds that target methionine aminopeptidase and reduces or inhibits its activity include, but are not limited to, bengamide or its derivatives.

[0377] The term "proteasome inhibitor" as used herein refers to a compound that targets the proteasome, reduces or inhibits its activity. Compounds that target the proteasome, reduces or inhibits its activity include, but are not limited to, bortezomib (Velcade™) and MLN341.

[0378] The term "matrix metalloproteinase inhibitors" or ("MMP" inhibitors), as used herein, includes, but is not limited to, collagen peptidomimetic inhibitors and non-peptidomimetic inhibitors, tetracycline derivatives, such as the hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), metastat (NSC683551), BMS-279251, BAY12-9566, TAA211, MMI270B or AAJ996.

[0379] The term "compounds used in the treatment of hematological malignancies," as used herein, includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target FMS-like tyrosine kinase receptor (Flt-3R) and decrease or inhibit its activity; interferon, 1-β-D-arabinofuransylcytosine (ara-c), and bisulfan; and ALK inhibitors, which are compounds that target, decrease or inhibit anaplastic lymphoma kinase.

[0380] Compounds that target the FMS-like tyrosine kinase receptor (Flt-3R) and reduce or inhibit its activity are compounds, proteins, or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248, and MLN518, among others.

[0381] The term "HSP90 inhibitor," as used herein, includes, but is not limited to, compounds that target, decrease, or inhibit the intrinsic ATPase activity of HSP90; compounds that degrade, target, decrease, or inhibit HSP90 client proteins via the ubiquitin-proteasome pathway. Compounds that target, decrease, or inhibit the intrinsic ATPase activity of HSP90 include, among others, compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG), geldanamycin derivatives, other geldanamycin-related compounds; radicicol, and HDAC inhibitors.

[0382] The term "antiproliferative antibody" as used herein includes, but is not limited to, trastuzumab (Herceptin™), trastuzumab-DM1, erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40), and 2C4 antibodies. Antibody refers to intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.

[0383] For the treatment of acute myeloid leukemia (AML), the compound of the present invention can be used in combination with standard leukemia therapy, especially in combination with the therapy used for the treatment of AML.In particular, the compound of the present invention can be administered in combination with other drugs useful for the treatment of AML, such as farnesyltransferase inhibitors and / or daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum and PKC412.

[0384] Other anti-leukemia compounds include, for example, the pyrimidine analog Ara-C, which is a 2'-alpha-hydroxyribose (arabinoside) derivative of deoxycytidine.Similarly, hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate are purine analogs.Compounds that target, reduce or inhibit the activity of histone deacetylase (HDAC) inhibitors, such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA), inhibit the activity of enzymes known as histone deacetylases. Specific HDAC inhibitors include compounds disclosed in US 6,552,065, including but not limited to MS275, SAHA, FK228 (formerly FR901228), trichostatin A, and N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propanamide or its pharmaceutically acceptable salt and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide or its pharmaceutically acceptable salt, especially lactate. Somatostatin receptor antagonists, as used herein, refer to compounds that target, manipulate, or inhibit somatostatin receptors, such as octreotide and SOM230. Techniques that damage tumor cells refer to techniques such as ionizing radiation. The term "ionizing radiation," referred to above and hereafter, means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is delivered in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, Principles and Practice of Oncology, Devita et al. (eds.), 4th ed., Vol. 1, pp. 248-275 (1993).

[0385] Similarly, EDG binders and ribonucleotide reductase inhibitors are included. The term "EDG binders" as used herein refers to a class of immunosuppressants that modulate lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitors" refers to pyrimidine or purine nucleoside analogs, including but not limited to fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with an ara-C agonist for ALL), and / or pentostatin. Ribonucleotide reductase inhibitors are, in particular, hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0386] Also included are VEGF compounds, proteins or monoclonal antibodies such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin™; Endostatin™; anthranilic acid amide; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies such as rhuMAb and RHUFab, VEGF aptamers such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, Angiozyme (RPI4610) and bevacizumab (Avastin™), among others.

[0387] Photodynamic therapy, as used herein, refers to a treatment that uses certain chemicals known as photosensitive compounds to treat or prevent cancer. Examples of photodynamic therapy include treatment with compounds such as Visudyne™ and porfimer sodium.

[0388] Angiogenic antisteroids, as used herein, refer to compounds that block or inhibit angiogenesis, such as, for example, anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocortisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, and dextasazone.

[0389] Corticosteroid-containing implants refer to compounds such as fluocinolone and dextasazone.

[0390] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormone compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanisms of action.

[0391] The compounds of the present invention are also useful as co-therapeutic compounds for use in combination with other drug substances, such as anti-inflammatory, bronchodilator, or antihistamine drug substances, particularly in the treatment of obstructive or inflammatory airway diseases such as those mentioned hereinabove, e.g., as enhancers of the therapeutic activity of such drugs or as a means of reducing the required dosage or potential side effects of such drugs. The compounds of the present invention may be mixed with other drug substances in a given pharmaceutical composition, or may be administered separately from, before, simultaneously with, or after the other drug substances. Thus, the present invention includes combinations of the compounds of the present invention as described hereinabove with anti-inflammatory, bronchodilator, antihistamine, or antitussive drug substances, wherein the compounds of the present invention and the drug substances are in the same or different pharmaceutical compositions.

[0392] Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids (e.g., budesonide, beclomethasone dipropionate, fluticasone propionate, ciclesonide, or mometasone furoate); non-steroidal glucocorticoid receptor agonists; LTB4 antagonists (e.g., LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247); LTD4 antagonists (e.g., montelukast and zafirlukast); PDE4 inhibitors (e.g., cilomilast (Ariflo® GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Allofylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID™ CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo)); A2a agonists; A2b antagonists; and beta-2 adrenoceptor agonists (e.g., albuterol (salbutamol), metaproterenol, terbutaline, salmeterol Suitable bronchodilator drugs include anticholinergic or antimuscarinic compounds, especially ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate.

[0393] Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratadine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine.

[0394] Other useful combinations of the compounds of the invention with anti-inflammatory drugs are with antagonists of chemokine receptors, such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, in particular CCR-5 antagonists, such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, and Takeda antagonists, such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium chloride (TAK-770).

[0395] In some embodiments, the one or more other therapeutic agents is a poly ADP-ribose polymerase (PARP) inhibitor. In some embodiments, the PARP inhibitor is selected from olaparib (Lynparza®, AstraZeneca); rucaparib (Rubraca®, Clovis Oncology); niraparib (Zejula®, Tesaro); talazoparib (MDV3800 / BMN 673 / LT00673, Medivation / Pfizer / Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).

[0396] The term "Bcl-2 inhibitors," as used herein, includes, but is not limited to, compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including, but not limited to, ABT-199, ABT-731, ABT-737, apogossypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and its analogs), dual Bcl-2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), genasense (G3139), HA14-1 (and its analogs; see WO2008118802), navitoclax (and its analogs, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and its analogs, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), and venetoclax. In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic agent. In some embodiments, the Bcl-2 inhibitor is a peptidomimetic.

[0397] In some embodiments, the one or more other therapeutic agents are inhibitors of anti-apoptotic proteins, such as BCL-2. Approved anti-apoptotic agents that can be used in the present invention include venetoclax (Venclexta®, AbbVie / Genentech); and blinatumomab (Blincyto®, Amgen). Other therapeutic agents that target apoptotic proteins that are undergoing clinical trials and can be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

[0398] The structures of the active compounds identified by code numbers, generic names or trade names can be taken from the actual edition of the standard abstract "The Merck Index" or from databases such as Patents International (eg IMS World Publications).

[0399] The compounds of the present invention may also be used in combination with known therapeutic processes, such as the administration of hormones or radiation. In certain embodiments, provided compounds are used as radiosensitizers, particularly to treat tumors that are poorly sensitive to radiation therapy.

[0400] The compounds of the present invention can be administered alone or in combination with one or more other therapeutic compounds. Possible combination therapy can be in the form of a fixed combination, or the compounds of the present invention and one or more other therapeutic compounds can be administered at different times or independently, or a fixed combination can be administered in combination with one or more other therapeutic compounds. The compounds of the present invention can also be administered for tumor treatment in combination with other or additional, inter alia, chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof. Long-term treatment, as described above, is equally possible in the context of other treatment strategies, as well as adjuvant therapy. Another possible treatment is, for example, treatment to maintain the patient's condition after tumor regression or even after chemopreventive treatment in at-risk patients.

[0401] These additional agents may be administered separately from the composition containing the compound of the present invention as part of a multiple dose regimen. Alternatively, these agents may be part of a single dosage form, mixed together with the compound of the present invention in a single composition. When administered as part of a multiple dose regimen, the two active agents may be provided simultaneously, sequentially, or within a period of each other, usually within 5 hours of each other.

[0402] As used herein, the terms "combination," "combined," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a compound of the present invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or may be administered together in a single dosage form. Thus, the present invention provides a single dosage form comprising a compound of the present invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0403] The amount of either the compounds of the present invention and additional therapeutic agent (in compositions containing such additional therapeutic agents) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, the compositions of the present invention should be formulated so that a dosage of the compound of the present invention that is between 0.01 and 100 mg / kg body weight / day can be administered.

[0404] In compositions containing an additional therapeutic agent, such additional therapeutic agent and the compound of the present invention may act synergistically. Thus, the amount of additional therapeutic agent in such compositions will be less than the amount that would be required in a monotherapy utilizing only that therapeutic agent. In such compositions, a dosage of the additional therapeutic agent between 0.01 and 1,000 μg / kg body weight / day can be administered.

[0405] The amount of additional therapeutic agent present in the compositions of the present invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the disclosed compositions will be in the range of about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0406] The compounds of the present invention or pharmaceutical compositions thereof can also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents, and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices are at risk of clot formation or platelet activation. These undesirable effects can be prevented or reduced by pre-coating these devices with a pharmaceutically acceptable composition containing a kinase inhibitor. An implantable device coated with the compounds of the present invention is another embodiment of the present invention. Exemplary Immuno-Oncology Agents

[0407] In some embodiments, the one or more other therapeutic agents are immuno-oncology agents. As used herein, the term "immuno-oncology agent" refers to an agent that is effective for enhancing, stimulating, and / or upregulating the immune response in a subject. In some embodiments, the administration of an immuno-oncology agent with a compound of the present invention has a synergistic effect in the treatment of cancer.

[0408] The tumor immunotherapeutic agent may be, for example, a small molecule drug, an antibody, or a biological or small molecule. Examples of biological tumor immunotherapeutic agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the monoclonal antibody is a humanized or human antibody.

[0409] In some embodiments, the immuno-oncology agent is either (i) an agonist of a stimulatory (including costimulatory) receptor or (ii) an antagonist of an inhibitory (including co-inhibitory) signal on a T cell, both of which result in amplification of the antigen-specific T cell response.

[0410] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory or costimulatory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, and OP G, RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / D Contains R3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0411] In some embodiments, the tumor immunomodulator is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation to stimulate an immune response.

[0412] In some embodiments, the combination of a compound of the present invention with an immuno-oncology agent may stimulate a T cell response. In some embodiments, the immuno-oncology agent is (i) an antagonist (e.g., an immune checkpoint inhibitor) of a protein that inhibits T cell activation (e.g., CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin-9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4); or (ii) an agonist of a protein that stimulates T cell activation (e.g., B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H).

[0413] In some embodiments, the immuno-oncology agent is an antagonist of an inhibitory receptor on NK cells or an agonist of an activating receptor on NK cells. In some embodiments, the immuno-oncology agent is an antagonist of KIR, such as lirilumab.

[0414] In some embodiments, the immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes, including, but not limited to, a CSF-1R antagonist (e.g., a CSF-1R antagonist antibody, such as RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (WO11 / 140249; WO13169264; WO14 / 036357)).

[0415] In some embodiments, the immuno-oncology agent is selected from agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling via inhibitory receptors, antagonists, and one or more agents that systemically increase the frequency of anti-tumor T cells, agents that overcome different immunosuppressive pathways within the tumor microenvironment (e.g., blocking the engagement of inhibitory receptors (e.g., PD-L1 / PD-1 interactions), depleting or inhibiting Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibiting metabolic enzymes such as IDO, or reversing / preventing T cell energy or exhaustion), and agents that induce innate immune activation and / or inflammation at the tumor site.

[0416] In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist. In some embodiments, the CTLA-4 antagonist is an antagonistic CTLA-4 antibody. In some embodiments, the antagonistic CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab.

[0417] In some embodiments, the immuno-oncology agent is a PD-1 antagonist. In some embodiments, the PD-1 antagonist is administered by injection. In some embodiments, the immuno-oncology agent is an antibody or antigen-binding portion thereof that specifically binds to the programmed cell death-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, the PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments, the antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO 2012 / 145493). In some embodiments, the immuno-oncology agent can be pidilizumab (CT-011). In some embodiments, the immuno-oncology agent is a recombinant protein called AMP-224, which consists of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1.

[0418] In some embodiments, the immuno-oncology agent is a PD-L1 antagonist. In some embodiments, the PD-L1 antagonist is an antagonistic PD-L1 antibody. In some embodiments, the PD-L1 antibody is MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), or MSB0010718C (WO2013 / 79174).

[0419] In some embodiments, the immuno-oncology agent is a LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is an antagonistic LAG-3 antibody. In some embodiments, the LAG-3 antibody is BMS-986016 (WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (WO08 / 132601, WO009 / 44273).

[0420] In some embodiments, the immuno-oncology agent is a CD137 (4-1BB) agonist. In some embodiments, the CD137 (4-1BB) agonist is an agonistic CD137 antibody. In some embodiments, the CD137 antibody is urelumab or PF-05082566 (WO12 / 32433).

[0421] In some embodiments, the immuno-oncology agent is a GITR agonist. In some embodiments, the GITR agonist is an agonistic GITR antibody. In some embodiments, the GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO006 / 105021, WO009 / 009116), or MK-4166 (WO11 / 028683).

[0422] In some embodiments, the immuno-oncology agent is an indoleamine (2,3)-dioxygenase (IDO) antagonist. In some embodiments, the IDO antagonist is selected from epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmatinib (INC280, Novartis); GDC-0919 (Genentech / Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906 / KD108 (Phytoceutica); an enzyme that breaks down kynurenine (Kynase, Kyn Therapeutics); and NLG-919 (WO09 / 73620, WO009 / 1156652, WO11 / 56652, WO12 / 142237).

[0423] In some embodiments, the immuno-oncology agent is an OX40 agonist. In some embodiments, the OX40 agonist is an agonistic OX40 antibody. In some embodiments, the OX40 antibody is MEDI-6383 or MEDI-6469.

[0424] In some embodiments, the immuno-oncology agent is an OX40L antagonist. In some embodiments, the OX40L antagonist is an antagonistic OX40 antibody. In some embodiments, the OX40L antagonist is RG-7888 (WO06 / 029879).

[0425] In some embodiments, the immuno-oncology agent is a CD40 agonist. In some embodiments, the CD40 agonist is an agonistic CD40 antibody. In some embodiments, the immuno-oncology agent is a CD40 antagonist. In some embodiments, the CD40 antagonist is an antagonistic CD40 antibody. In some embodiments, the CD40 antibody is lucatumumab or dacetuzumab.

[0426] In some embodiments, the immuno-oncology agent is a CD27 agonist. In some embodiments, the CD27 agonist is an agonistic CD27 antibody. In some embodiments, the CD27 antibody is varlilumab.

[0427] In some embodiments, the tumor immunomodulator is MGA271 (against B7H3) (WO11 / 109400).

[0428] In some embodiments, the immuno-oncology agent is selected from the group consisting of abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

[0429] In some embodiments, the tumor immunotherapy agent is an immunostimulatory agent. For example, antibodies that block the PD-1 and PD-L1 inhibitory axis can liberate activated tumor-reactive T cells and have been shown in clinical trials to induce durable anti-tumor responses in an increasing number of tumor histologies, including some tumor types not previously considered susceptible to immunotherapy. See, for example, Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al. (2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (Opdivo®, Bristol-Myers Squibb, also known as ONO-4538, MDX1106, and BMS-936558) has shown the potential to improve overall survival in patients with RCC who have experienced disease progression during or after previous antiangiogenic therapy.

[0430] In some embodiments, the immunomodulatory therapeutic agent specifically induces apoptosis of tumor cells. Approved immunomodulatory therapeutic agents that can be used in the present invention include pomalidomide (Pomalyst®, Celgene); lenalidomide (Revlimid®, Celgene); ingenol mebutate (Picato®, LEO Pharma).

[0431] In other embodiments, the immunomodulatory therapeutic agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T (Provenge®, Dendreon / Valeant Pharmaceuticals), which is approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec (Imlygic®, BioVex / Amgen, formerly known as T-VEC), a genetically modified oncolytic virus therapy approved for the treatment of unresectable cutaneous, subcutaneous, and nodal disease of melanoma.In some embodiments, the immuno-oncology agent is an oncolytic virotherapy such as PexaVec / JX-594 (SillaJen / formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-) deficient vaccinia virus engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); Reolysin® (Oncolytics) Biotech) (a mutant of respiratory enterovirus (reovirus) that does not replicate in cells that are not activated by RAS in a number of cancers, including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head and neck squamous cell carcinoma (NCT01166542); pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer (NSCLC) (NCT00861627); metastatic or advanced epithelial cancers, such as ovarian cancer (NCT02028117), colorectal cancer, bladder cancer, head and neck squamous cell carcinoma, and salivary gland cancer (NCT02636036) Enadenotusilev (NG-348, PsiOxus, formerly known as ColoAd1) (an adenovirus engineered to express full-length CD80 and an antibody fragment specific for the T-cell receptor CD3 protein) in tumors; ONCOS-102 (Targovax / formerly Oncos) (an adenovirus engineered to express GM-CSF) in melanoma (NCT03003676) and peritoneal disease, colorectal cancer, or ovarian cancer (NCT02963831); GL-ONC1 (GLV-1h68 / GLV-1h153, Genelux) GmbH) (vaccinia viruses engineered to express beta-galactosidase (beta-gal) / beta-glucoronidase or beta-gal / human sodium iodide symporter (hNIS) were investigated in peritoneal carcinomatosis (NCT01443260); fallopian tube cancer, ovarian cancer (NCT02759588), respectively); or CG0070 (Cold Genesys) (adenovirus engineered to express GM-CSF) in bladder cancer (NCT02365818).

[0432] In some embodiments, the immuno-oncology agents include JX-929 (SillaJen / formerly Jennerex Biotherapeutics) (a TK- and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase, capable of converting the prodrug 5-fluorocytosine to the cytotoxic drug 5-fluorouracil); TG01 and TG02 (Targovax / formerly Oncos) (peptide-based immunotherapeutics targeting refractory RAS mutations); and TILT-123 (TILT Biotherapeutics) (an engineered adenovirus designated Ad5 / 3-E2F-delta24-hTNFα-IRES-hIL20); and VSV-GP (ViraTherapeutics) (an engineered adenovirus engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV) and targeting antigen-specific CD8 + The virus is selected from vesicular stomatitis virus (VSV), which can be further engineered to express antigens designed to enhance T cell responses.

[0433] In some embodiments, the tumor immunotherapeutic agent is a T cell that has been engineered to express a chimeric antigen receptor, or CAR. Such T cells that have been engineered to express a chimeric antigen receptor are called CAR-T cells.

[0434] CARs are constructed that consist of a binding domain, which can be derived from a single-chain variable fragment (scFv) derived from a monoclonal antibody specific for a cell surface antigen, which is a natural ligand, and fused to an endodomain that is the functional end of a T cell receptor (TCR), such as the CD3-zeta signaling domain derived from the TCR, which can generate an activation signal in T lymphocytes. Upon binding to an antigen, such a CAR links to an endogenous signaling pathway in effector cells, generating an activation signal similar to that initiated by the TCR complex.

[0435] For example, in some embodiments, the CAR-T cells are one of those described in U.S. Pat. No. 8,906,682 (June, incorporated herein by reference in its entirety), which discloses CAR-T cells engineered to include an extracellular domain having an antigen-binding domain (such as a domain that binds to CD19) fused to the intracellular signaling domain of the T cell antigen receptor complex zeta chain (such as CD3-zeta). When expressed in T cells, CARs can redirect antigen recognition based on antigen-binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. Over 200 clinical trials are currently underway using CAR-T cells in a wide range of indications [https: / / clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors&pg=1].

[0436] In some embodiments, the immunostimulatory agent is an activator of retinoic acid receptor-related orphan receptor gamma (RORγt). RORγt is a transcription factor that plays a key role in the differentiation and maintenance of type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells, as well as in the differentiation of IL-17-expressing innate immune cell subsets, such as NK cells. In some embodiments, the activator is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).

[0437] In some embodiments, the immunostimulatory agent is a toll-like receptor (TLR) agonist or activator. Suitable TLR activators include TLR9 agonists or activators, such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG currently being investigated for follicular B-cell and other lymphomas (NCT02254772). TLR8 agonists or activators that can be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals), which is currently being investigated for head and neck squamous cell carcinoma (NCT02124850) and ovarian cancer (NCT02431559).

[0438] Other immuno-oncology agents that can be used in the present invention include urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; varilumab (CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), an anti-OX40 monoclonal antibody; lirilumab (IPH2102 / BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca), an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; MK-4166 (Merck & Co., Inc.), an anti-KIR monoclonal antibody; Co.), and anti-GITR monoclonal antibody.

[0439] In some embodiments, the immunostimulatory agent is selected from elotuzumab, mifamurtide, an agonist or activator of a toll-like receptor, and an activator of RORγt.

[0440] In some embodiments, the immunostimulatory therapeutic agent is recombinant human interleukin-15 (rhIL-15). rhIL-15 is being tested in the clinic as a therapeutic agent for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888), and leukemia (NCT02689453). In some embodiments, the immunostimulatory agent is recombinant human interleukin-12 (rhIL-12). In some embodiments, the IL-15-based immunotherapeutic agent is heterodimeric IL-15 (hetIL-15, Novartis / Admune), a fusion complex consisting of a synthetic form of endogenous IL-15 complexed to the soluble IL-15 binding protein IL-15 receptor alpha chain (IL15:sIL-15RA), which is being tested in Phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer, and head and neck squamous cell carcinoma (NCT02452268). In some embodiments, the recombinant human interleukin-12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124.

[0441] In some embodiments, the immuno-oncology agent is selected from those described in Jerry L. Adams et al., "Big opportunities for small molecules in immuno-oncology," Cancer Therapy 2015, Vol. 14, pages 603-622, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is selected from the examples described in Table 1 of Jerry L. Adams et al. In some embodiments, the immuno-oncology agent is a small molecule that targets an immuno-oncology target selected from those listed in Table 2 of Jerry L. Adams et al. In some embodiments, the immuno-oncology agent is a small molecule agent selected from those listed in Table 2 of Jerry L. Adams et al.

[0442] In some embodiments, the immuno-oncology agent is selected from the small molecule immuno-oncology agents described in Peter L. Toogood, "Small molecule immuno-oncology therapeutic agents," Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, pages 319-329, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is an agent that targets a pathway described in Peter L. Toogood.

[0443] In some embodiments, the tumor immunoagent is selected from those described in Sandra L. Ross et al., "Bispecific T cell engager (BiTE®) antibody constructs can mediate bystander tumor cell killing," PLoS ONE 12(8):e0183390, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the tumor immunoagent is a bispecific T cell engager (BiTE®) antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct is a CD19 / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct is an EGFR / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells, which release cytokines that induce upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells, which results in the induction of bystander cell lysis. In some embodiments, the bystander cells are within a solid tumor. In some embodiments, the lysing bystander cells are in the vicinity of the BiTE®-activated T cells. In some embodiments, the bystander cells comprise tumor-associated antigen (TAA)-negative cancer cells. In some embodiments, the bystander cells comprise EGFR-negative cancer cells. In some embodiments, the tumor immunotherapy agent is an antibody that blocks the PD-L1 / PD1 axis and / or CTLA4. In some embodiments, the tumor immunotherapy agent is ex vivo expanded tumor-infiltrating T cells.In some embodiments, the tumor immunotherapeutic agent is a bispecific antibody construct or a chimeric antibody receptor (CAR) that directly links T cells to tumor-associated surface antigens (TAAs). Exemplary Immune Checkpoint Inhibitors

[0444] In some embodiments, the immuno-oncology agent is an immune checkpoint inhibitor as described herein.

[0445] The term " checkpoint inhibitor " as used herein refers to an agent that is useful for preventing cancer cells from evading the immune system of patients.One of the main mechanisms of anti-tumor immune destruction is known as " T cell exhaustion ", which is caused by long-term exposure to antigen, which leads to the upregulation of inhibitory receptors.These inhibitory receptors act as immune checkpoints to prevent indiscriminate immune responses.

[0446] PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), B- and T-lymphocyte attenuator (BTLA; CD272), T-cell immunoglobulin and mucin domain-3 (Tim-3), and lymphocyte-activation gene-3 (Lag-3; CD223) are often referred to as checkpoint regulators. They act as molecular “gatekeepers” that allow extracellular information to dictate whether cell cycle progression and other intracellular signaling processes should proceed.

[0447] In some embodiments, the immune checkpoint inhibitor is an antibody to PD-1, which binds to the programmed death 1 receptor (PD-1) and prevents this receptor from binding to the inhibitory ligand PDL-1, thus abolishing the tumor's ability to suppress the host's anti-tumor immune response.

[0448] In one aspect, the checkpoint inhibitor is a biological therapeutic agent or a small molecule. In another aspect, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein, or a combination thereof. In a further aspect, the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or a combination thereof. In additional aspects, the checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, a ligand of the B-7 family, or a combination thereof. In some aspects, the checkpoint inhibitor is an immunostimulant, a T cell growth factor, an interleukin, an antibody, a vaccine, or a combination thereof. In further aspects, the interleukin is IL-7 or IL-15. In certain aspects, the interleukin is glycosylated IL-7. In additional aspects, the vaccine is a dendritic cell (DC) vaccine.

[0449] Checkpoint inhibitors include any agent that blocks or inhibits an inhibitory pathway of the immune system in a statistically significant manner. Such inhibitors can include small molecule inhibitors, or can include antibodies or antigen-binding fragments thereof that bind to and block or inhibit immune checkpoint receptors, or antibodies that bind to and block or inhibit immune checkpoint receptor ligands. Exemplary immune checkpoint molecules that can be targeted for blockage or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belonging to the CD2 family of molecules), and NK, gamma delta, and memory CD8.+ (expressed on all αβ T cells), CD160 (also called BY55), CGEN-15049, CHK1 and CHK2 kinases, A2aR, and various B-7 family ligands. B7 family ligands include, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6, and B7-H7. Checkpoint inhibitors include antibodies or antigen-binding fragments thereof, other binding proteins, biotherapeutics, or small molecules that bind to and block or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, and CGEN-15049. Exemplary immune checkpoint inhibitors include tremelimumab (CTLA-4 blocking antibody) (anti-OX40), PD-L1 monoclonal antibody (anti-B7-H1; MEDI4736), MK-3475 (PD-1 blocker), nivolumab (anti-PD1 antibody), CT-011 (anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody), BMS-936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody), MSB0010718C (anti-PDL1 antibody), and ipilimumab (anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to, PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86, and TIM-3.

[0450] In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In some embodiments, the checkpoint inhibitor is selected from the group consisting of nivolumab (Opdivo®), ipilimumab (Yervoy®), and pembrolizumab (Keytruda®). In some embodiments, the checkpoint inhibitor is selected from nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck); ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb); durvalumab (anti-PD-L1 antibody, Imfinzi®, AstraZeneca); and atezolizumab (anti-PD-L1 antibody, Tecentriq®, Genentech).

[0451] In some embodiments, the checkpoint inhibitor is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (Keytruda®), or tremelimumab.

[0452] In some embodiments, the immune checkpoint inhibitor is REGN2810 (Regeneron) (an anti-PD-1 antibody studied in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376)); pidilizumab (CureTech) (an antibody that binds to PD-1, also known as CT-011), which is in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab (Bavencio®, Pfizer / Merck), which is in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer). KGaA) (also known as MSB0010718C, a fully human IgG1 anti-PD-L1 antibody); or PDR001 (Novartis), an inhibitory antibody that binds to PD-1, which is in clinical trials for non-small cell lung cancer, melanoma, triple-negative breast cancer, and advanced or metastatic solid tumors. Tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that has been investigated in clinical trials for several indications, including mesothelioma, colorectal cancer, renal cancer, breast cancer, lung and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial carcinoma, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody currently being investigated in a Phase 1 clinical trial for advanced solid tumors (NCT02694822).

[0453] In some embodiments, the checkpoint inhibitor is an inhibitor of T cell immunoglobulin mucin-containing protein-3 (TIM-3). TIM-3 inhibitors that can be used in the present invention include TSR-022, LY3321367, and MBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody currently being investigated in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody currently being investigated in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody currently being investigated in advanced malignancies (NCT02608268).

[0454] In some embodiments, the checkpoint inhibitor is an inhibitor of T cell immunoreceptor with Ig and ITIM domains, i.e., TIGIT, an immunoreceptor on certain T cells and NK cells. TIGIT inhibitors that can be used in the present invention include BMS-986207 (Bristol-Myers Squibb), anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428).

[0455] In some embodiments, the checkpoint inhibitor is an inhibitor of lymphocyte activation gene-3 (LAG-3). LAG-3 inhibitors that can be used in the present invention include BMS-986016, REGN3767, and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is currently being investigated in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron) is also an anti-LAG-3 antibody and is currently being investigated in malignant tumors (NCT03005782). IMP321 (Immutep SA) is a LAG-3-Ig fusion protein and is being investigated in melanoma (NCT02676869); adenocarcinoma (NCT02614833); and metastatic breast cancer (NCT00349934).

[0456] Checkpoint inhibitors that can be used in the present invention include OX40 agonists. OX40 agonists currently being investigated in clinical trials include PF-04518600 / PF-8600 (Pfizer) (agonistic anti-OX40 antibodies) in metastatic kidney cancer (NCT03092856) and advanced cancers and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck) (agonistic anti-OX40 antibody) in a Phase 1 cancer clinical trial (NCT02528357); MCT02318394 and NCT02705482 in advanced solid tumors. These include EDI0562 (Medimmune / AstraZeneca) (agonistic anti-OX40 antibody); MEDI6469 (agonistic anti-OX40 antibody) (Medimmune / AstraZeneca) in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155), and metastatic prostate cancer (NCT01303705); and BMS-986178 (Bristol-Myers Squibb) (agonistic anti-OX40 antibody) in advanced cancers (NCT02737475).

[0457] The checkpoint inhibitor that can be used in the present invention includes CD137 (also known as 4-1BB) agonist.The CD137 agonist that is currently being investigated in clinical trials includes utomilumab (PF-05082566, Pfizer) (agonistic anti-CD137 antibody) in diffuse large B-cell lymphoma (NCT02951156) and advanced cancer and neoplasm (NCT02554812 and NCT05082566); Urelumab (BMS-663513, Bristol-Myers Squibb) (agonistic anti-CD137 antibody) in melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981).

[0458] The checkpoint inhibitors that can be used in the present invention include CD27 agonists.CD27 agonists currently being investigated in clinical trials include varlilumab (CDX-1127, Celldex Therapeutics) (agonistic anti-CD27 antibody) in squamous cell head and neck cancer, ovarian cancer, colorectal cancer, renal cell carcinoma and glioblastoma (NCT02335918), lymphoma (NCT01460134), and glioma and astrocytoma (NCT02924038).

[0459] Checkpoint inhibitors that can be used in the present invention include glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists. GITR agonists currently being investigated in clinical trials include TRX518 (Leap Therapeutics) (agonistic anti-GITR antibody) in melanoma and other malignant solid tumors (NCT01239134 and NCT02628574); GWN323 (Novartis) (agonistic anti-GITR antibody) in solid tumors and lymphomas (NCT02740270); INCAGN01876 (Incyte / Agenus) (agonistic anti-GITR antibody) in advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck) (agonistic anti-GITR antibody) in solid tumors (NCT02132754), and MEDI1873 (Medimmune / AstraZeneca) (human IgG1) in advanced solid tumors (NCT02583165). agonistic hexameric GITR ligand molecules having an Fc domain.

[0460] Checkpoint inhibitors that can be used in the present invention include inducible T cell costimulatory agent (ICOS, also known as CD278) agonists. ICOS agonists currently being investigated in clinical trials include MEDI-570 (Medimmune) (agonistic anti-ICOS antibody) in lymphoma (NCT02520791); GSK3359609 (Merck) (agonistic anti-ICOS antibody) in a phase 1 trial (NCT02723955); and JTX-2011 (Jounce Therapeutics) (agonistic anti-ICOS antibody) in a phase 1 trial (NCT02904226).

[0461] Checkpoint inhibitors that can be used in the present invention include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors currently being investigated in clinical trials include lirilumab (IPH2102 / BMS-986015, Innate Pharma / Bristol-Myers Squibb), an anti-KIR antibody, in leukemia (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma), in myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to the long cytoplasmic tail three domain (KIR3DL2), in lymphoma (NCT02593045).

[0462] Checkpoint inhibitors that can be used in the present invention include CD47 inhibitors of the interaction between CD47 and signal regulatory protein alpha (SIRPa). CD47 / SIRPa inhibitors currently being investigated in clinical trials include ALX-148 (Alexo Therapeutics), in a Phase 1 trial (NCT03013218), an antagonistic variant of (SIRPa) that binds to CD47 and blocks CD47 / SIRPa-mediated signaling; TTI-621 (SIRPa-Fc, Trillium Therapeutics), in Phase 1 clinical trials (NCT02890368 and NCT02663518), a soluble recombinant fusion protein generated by linking the N-terminal CD47-binding domain of SIRPa to the Fc domain of human IgG1, which binds to human CD47 and blocks human CD47 from its "do not eat me" message. These include CC-90002 (Celgene), an anti-CD47 antibody, in leukemia (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.), in colorectal neoplasia and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338), and lymphoma (NCT02953509).

[0463] Checkpoint inhibitors that can be used in the present invention include CD73 inhibitors. CD73 inhibitors currently being investigated in clinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody, in solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody, in solid tumors (NCT02754141).

[0464] Checkpoint inhibitors that can be used in the present invention include agonists of the stimulator of interferon genes protein (STING, also known as transmembrane protein 173 or TMEM173). STING agonists currently being investigated in clinical trials include MK-1454 (Merck), an agonistic synthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU-S100 (MIW815, Aduro Biotech / Novartis), an agonistic synthetic cyclic dinucleotide, in Phase 1 trials (NCT02675439 and NCT03172936).

[0465] Checkpoint inhibitors that can be used in the present invention include CSF1R inhibitors. CSF1R inhibitors currently being investigated in clinical trials include pexidartinib (PLX3397, Plexxikon) (a CSF1R small molecule inhibitor) in colorectal cancer, pancreatic cancer, metastatic and advanced cancers (NCT02777710), melanoma, non-small cell lung cancer, squamous cell head and neck cancer, gastrointestinal stromal tumor (GIST), and ovarian cancer (NCT02452424); and pancreatic cancer (NCT03153410), melanoma (NCT031012 54) and solid tumors (NCT02718911); IMC-CS4 (LY3022855, Lilly) (anti-CSF-1R antibody); and BLZ945 (4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylic acid methylamide, Novartis) (an orally available inhibitor of CSF1R) in advanced solid tumors (NCT02829723).

[0466] Checkpoint inhibitors that can be used in the present invention include NKG2A receptor inhibitors. NKG2A receptor inhibitors currently being investigated in clinical trials include monalizumab (IPH2201, Innate Pharma), an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).

[0467] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab. [Example]

[0468] Example As illustrated in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures: While the general methods illustrate the synthesis of certain compounds of the present invention, it will be understood that the following general methods, and other methods known to those of skill in the art, are applicable to all compounds as described herein, and each subclass and species of these compounds.

[0469] Preparation 1: 2-(1H-pyrazol-4-yl)morpholine A1. [ka]

[0470] A mixture of tert-butyl 2-(2-oxoethyl)morpholine-4-carboxylate (5.77 g, 25 mmol) and DMF-DMA (6.7 mL, 50 mmol) in DMF (50 mL) was stirred at 80° C. for 17 hours. The reaction mixture was cooled to ambient temperature, and the solvent was removed in vacuo. The residue was taken up in EtOH (100 mL), and hydrazine hydrate (1.3 mL, 26.5 mmol) was added with stirring at ambient temperature. After 3 hours, the solvent was removed in vacuo, and the residue was purified by column chromatography (silica, eluting with a gradient of PE / EtOAc) to give tert-butyl 2-(1H-pyrazol-4-yl)morpholine-4-carboxylate (2.35 g, 37%) as a yellow solid. 1H NMR (500 MHz, chloroform-d) δ 7.63 (s, 2H), 4.52 (dd, 1H), 4.12 (br s, 1H), 3.97–3.90 (m, 2H), 3.68 (td, 1H), 3.05 (d, 2H), 1.51 (s, 9H); MS m / z: 254.1 (M+H) + .

[0471] 3M HCl in MeOH (45 mL of 3M, 135 mmol) was added to a stirred solution of tert-butyl 2-(1H-pyrazol-4-yl)morpholine-4-carboxylate (2.35 g, 9.3 mmol) in DCM (75 mL), and the reaction was heated under reflux for 5 hours. The reaction was cooled to ambient temperature, and the solvent was removed in vacuo. The residue was dissolved in a minimum amount of DCM / MeOH and loaded onto an ion-exchange cartridge. The cartridge was washed with a mixture of MeOH / DCM, which was discarded. The product was eluted by washing with 2M NH3 in MeOH / DCM. The solvent was removed in vacuo to give 2-(1H-pyrazol-4-yl)morpholine A1 (1.27 g, 89%) as an orange solid, which was carried on to the next reaction without further purification; 1 H NMR (500 MHz, chloroform-d) δ 7.60 (s, 2H), 4.56 (dd, 1H), 3.98 (ddd, 1H), 3.77 (td, 1H), 3.11 (dd, 1H), 3.00 (td, 1H), 2.93 - 2.88 (m, 2H); MS m / z: 154.2 (M+H) + .

[0472] Preparation 2: N-((6-methylmorpholin-2-yl)methyl)methanesulfonamide A2. [ka]

[0473] Di-tert-butyl dicarbonate (600 mg, 2.75 mmol) was added to a stirred solution of (6-methylmorpholin-2-yl)methanol (300 mg, 2.3 mmol) and EtN (835 μL, 6 mmol) in DCM (5 mL) at ambient temperature, and the reaction was stirred for 2 h. The reaction mixture was washed with 0.5 M HCl (1×), water (2×), and brine (1×). The combined organics were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica, eluting with a gradient of PE / EtOAc) to give tert-butyl cis-2-(hydroxymethyl)-6-methyl-morpholine-4-carboxylate (225 mg, 42%) as a colorless oil. 1 H NMR (500 MHz, chloroform-d) δ 3.90 (s, 2H), 3.73 - 3.68 (m, 1H), 3.64 - 3.55 (m, 3H), 2.67 (s, 1H), 2.49 (s, 1H), 1.94 (dd, 1H), 1.49 (s, 9H), 1.21 (d, 3H), and trans-2-(hydroxymethyl)-6-methyl tert-Butyl ethyl-morpholine-4-carboxylate (170 mg, 32%) as a colorless oil; 1 H NMR (500 MHz, chloroform-d) δ 4.00 - 3.96 (m, 1H), 3.90 (s, 1H), 3.72 (s, 1H), 3.66 - 3.49 (m, 3H), 3.38 (ddd, 1H), 3.15 (s, 1H), 1.98 - 1.82 (m, 1H), 1.49 (s, 9H), 1.23 (d, 3H).

[0474] To a solution of tert-butyl cis-2-(hydroxymethyl)-6-methyl-morpholine-4-carboxylate (225 mg, 1 mmol), tert-butyl N-methylsulfonylcarbamate (280 mg, 1.4 mmol), and PPh3 (760 mg, 3 mmol) in THF (10 mL) was added DEAD (330 μL, 2 mmol) dropwise, and the reaction mixture was stirred at ambient temperature under N2 for 18 h. The reaction mixture was concentrated in vacuo and purified by column chromatography to afford tert-butyl cis-2-[[tert-butoxycarbonyl(methylsulfonyl)amino]methyl]-6-methyl-morpholine-4-carboxylate as a colorless oil. This material was taken up in DCM (10 mL), and TFA (2 mL, 26 mmol) was added at ambient temperature. After 3 hours, the solvent was removed in vacuo, and the residue was azeotroped with DCM (twice) and diethyl ether (twice). The residue was taken up in MeOH and passed through an ion exchange cartridge, washing with a mixture of MeOH / DCM. The product was eluted with 2M NH3 in MeOH / DCM. The solvent was removed in vacuo to give cis-N-[(6-methylmorpholin-2-yl)methyl]methanesulfonamide A2 (173 mg, 85%) as a white solid, which was carried on to the next reaction without further purification. 1 H NMR (500 MHz, Loroform-d) δ 4.66 (br s, 1H), 3.59 - 3.49 (m, 2H), 3.17 (dd, 1H), 2.99 (dd, 1H), 2.90 (s, 3H), 2.78 (dd, 2H), 2.47 (dd, 1H), 2.35 (dd, 1H), 1.05 (d, 3H); MS m / z: 209 (M+H) + .

[0475] Preparation 3: N-((4,4-difluoropiperidin-3-yl)methyl)methanesulfonamide A3. [ka]

[0476] Methanesulfonyl chloride (200 μL, 2.6 mmol) was added to a solution of tert-butyl 3-(aminomethyl)-4,4-difluoro-piperidine-1-carboxylate (500 mg, 1.8 mmol) and EtN (400 μL, 2.9 mmol) in THF (11 mL) under N. The reaction mixture was stirred at ambient temperature for 3 h and then diluted with DCM and saturated aqueous NaHCO. The reaction was stirred for 10 min and then passed through a phase separation cartridge. The organic phase was concentrated and the residue was taken up in DCM / TFA (2 mL / 2 mL), stirred for 2 h and then concentrated. The residue was taken up in MeOH and passed through an ion exchange cartridge, washing with methanol and eluting the product with 2 M methanolic ammonia solution. The solution was concentrated in vacuo to give a white solid (450 mg) of N-((4,4-difluoropiperidin-3-yl)methyl)methanesulfonamide A3, which was carried on to the next reaction without further purification; 1 H NMR (500 MHz, DMSO-d6) δ 7.10 (t, 1H), 3.27 (ddd, 2H), 3.11 - 3.01 (m, 1H), 2.91-2.85 (m, 5H), 2.69 - 2.56 (m, 1H), 2.40 (dd, 1H), 2.08 - 1.86 (m, 2H), 1.84 - 1.66 (m, 1H).

[0477] Preparation 4: (S)-N-((6-oxopiperazin-2-yl)methyl)methanesulfonamide A4. [ka]

[0478] Benzyl chloroformate (1.2 mL, 8.5 mmol) was added to an ice-cold solution of (6S)-6-(hydroxymethyl)piperazin-2-one (800 mg, 6.15 mmol) and KCO (5.95 g, 43 mmol) in 20 mL of EtOAc / 20 mL of HO. The reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (NaSO), filtered, and concentrated in vacuo. The residue was purified by column chromatography to give benzyl (3S)-3-(hydroxymethyl)-5-oxo-piperazine-1-carboxylate as a colorless oil (700 mg, 43%); MS m / z: 265 (M+H). + .

[0479] DIAD (1.5 mL, 7.6 mmol) was added to an ice-cold solution of phthalimide (1.11 g, 7.6 mmol) and PPh3 (1.75 mL, 7.6 mmol) in DCM (10 mL) under N2. The solution was stirred for 10 min, and then (3S)-benzyl 3-(hydroxymethyl)-5-oxo-piperazine-1-carboxylate (500 mg, 1.9 mmol) was added. The solution was stirred for 18 h while gradually warming to ambient temperature. The solution was diluted with saturated aqueous NaHCO3. After stirring for 5 min, the layers were separated using a phase separation cartridge. The organic phase was concentrated in vacuo and the residue was purified by column chromatography (silica, eluting with a gradient of PE / EtOAc) to give benzyl (3R)-3-[(1,3-dioxoisoindolin-2-yl)methyl]-5-oxo-piperazine-1-carboxylate as an oil (700 mg, ca. 60% pure), which was carried on directly to the next step; MS m / z: 394 (M+H). + .

[0480] A mixture of (3R)-benzyl 3-[(1,3-dioxoisoindolin-2-yl)methyl]-5-oxo-piperazine-1-carboxylate (700 mg, 1.068 mmol) and hydrazine hydrate (100 μL, 2.04 mmol) in ethanol (5 mL) was heated under reflux for 5 h. The resulting suspension was filtered, and the white solid was washed thoroughly with ethanol. The ethanol solution was applied to an ion exchange cartridge, washing with methanol, and the product was then eluted with 2 M methanolic NH3 solution. The filtrate was concentrated to give (R)-benzyl 3-(aminomethyl)-5-oxopiperazine-1-carboxylate as a colorless oil, which was carried on directly to the next step (240 mg, 85%). MS m / z: 264 (M+H) + .

[0481] Methanesulfonyl chloride (100 μL, 1.3 mmol) was added to an ice-cold solution of (3R)-3-(aminomethyl)-5-oxo-piperazine-1-carboxylate (240 mg, 1 mmol) and EtN (200 μL, 1.4 mmol) in DCM (5 mL) under N. The solution was stirred for 3 h while gradually warming to ambient temperature. The reaction mixture was diluted with DCM and saturated aqueous NaHCO. After 5 min, the organic phase was isolated using a phase separation cartridge and then concentrated in vacuo. The residue was purified by column chromatography (silica, eluting with a gradient of PE / EtOAc) to give (3S)-3-(methanesulfonamidomethyl)-5-oxo-piperazine-1-carboxylate (233 mg, 75%) as a white foam, which was carried on directly to the next step; MS m / z: 342 (M+H). + .

[0482] A mixture of (3S)-benzyl 3-(methanesulfonamidomethyl)-5-oxo-piperazine-1-carboxylate (230 mg, 0.7 mmol), Pd(OAc) (60 mg, 0.3 mmol), EtSiH (500 μL, 3 mmol), and EtN (300 μL, 2 mmol) in DCM (5 mL) was stirred under N at ambient temperature for 2 h. The residue was passed through an ion exchange cartridge, washing with a mixture of MeOH / DCM, and the product was eluted with 2 M NH in MeOH / DCM. The solvent was removed in vacuo to give (S)—N-((6-oxopiperazin-2-yl)methyl)methanesulfonamide, A4, as a white solid (130 mg, 93%), which was carried on to the next reaction without further purification; MS m / z: 208 (M+H). + .

[0483] Preparation 5: (S)-Dimethyl((morpholin-2-ylmethyl)imino)-λ 6 -Sulfanone A5. [ka]

[0484] Sodium triacetoxyborohydride (1.26 g, 5.95 mmol) was added to a mixture of tert-butyl (2S)-2-formylmorpholine-4-carboxylate (320 mg, 1.5 mmol) and (methylsulfonimidoylmethane (165 mg, 1.8 mmol) in DCE (20 mL) and the reaction was stirred at ambient temperature for 60 h. The mixture was diluted with DCM and saturated aqueous NaHCO and stirred for 30 min. The layers were separated and the organic layer was washed with saturated aqueous NaHCO (twice), brine, dried (MgSO), filtered and concentrated in vacuo to give (S)-2-(((dimethyl(oxo)-λ 6 tert-Butyl (-sulfanylidene)amino)methyl)morpholine-4-carboxylate was obtained (343 mg); MS m / z: 293 (M+H) + .

[0485] The residue was taken up in DCM (10 mL) and TFA (5 mL) was added at ambient temperature. The mixture was stirred at ambient temperature for 17 hours. The solvent was removed in vacuo and the residue was azeotroped with DCM (twice) and diethyl ether (twice). The residue was passed through an ion exchange cartridge, washing with a MeOH / DCM mixture, and the product was eluted with 2M NH3 in a MeOH / DCM mixture. The solvent was removed in vacuo to give (S)-dimethyl((morpholin-2-ylmethyl)imino)-λ 6 -sulfanone A5 was obtained as a pale yellow oil (140 mg, 63%), which was carried on to the next reaction without further purification; 1 H NMR (500 MHz, DMSO-d6) δ 4.54 (s, 1H), 3.69 (ddd, 2H), 3.40 (td, 1H), 3.33 - 3.26 (m, 2H), 3.25 -3.23 (m, 1H), 2.96 (s, 3H), 2.81 -2.77 (m, 1H), 2.66 - 2.57 (m, 3H), 2.32 (dd, 1H); MS m / z: 193 (M+H) + .

[0486] Preparation 6: N-((5-ethyl-4,4-difluoropiperidin-3-yl)methyl)methanesulfonamide A6. [ka]

[0487] LiHMDS (5 mL of a 1 M solution, 5.0 mmol) was added dropwise to a solution of benzyl 3-ethyl-4-oxo-piperidine-1-carboxylate (1 g, 3.8 mmol) in THF (14 mL) cooled to −78° C. under N2. After 90 min, a solution of 2-(chloromethyl)isoindoline-1,3-dione (1.0 g, 5.1 mmol) in THF (2 mL) was added. The solution was stirred at 78° C. for 1 h, then at 0° C. for 1 h, and then quenched by the addition of saturated aqueous NH4Cl (approximately 2 mL). The reaction mixture was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica, eluting with a gradient of PE / EtOAc) to give benzyl 3-[(1,3-dioxoisoindolin-2-yl)methyl]-5-ethyl-4-oxo-piperidine-1-carboxylate as a colorless gum (1.1 g), which was carried on directly to the next step; MS m / z: 421 (M+H). + .

[0488] A mixture of benzyl 3-[(1,3-dioxoisoindolin-2-yl)methyl]-5-ethyl-4-oxo-piperidine-1-carboxylate (1.1 g, 2.6 mmol) and DAST (6 mL, 45 mmol) was stirred at 0 °C for 3 hours, then at ambient temperature for 16 hours. The reaction mixture was diluted with DCM and carefully quenched with saturated aqueous NaHCO. The layers were separated, and the organic phase was washed with brine, dried (NaSO), and concentrated in vacuo. The crude mixture was purified by column chromatography to give benzyl 3-((1,3-dioxoisoindolin-2-yl)methyl)-5-ethyl-4,4-difluoropiperidine-1-carboxylate as an off-white solid (200 mg, 17%); MS m / z: 423 (M+H). + .

[0489] This material was dissolved in EtOH (3 mL) and hydrazine hydrate (60 μL, 1.2 mmol) was added. The mixture was stirred under reflux for 24 h and then allowed to stand at ambient temperature for 36 h. The resulting suspension was diluted with methanol and passed through an ion exchange cartridge. The cartridge was washed with MeOH and the product was eluted with 2 M methanolic NH3 solution. The filtrate was concentrated to give benzyl 3-(aminomethyl)-5-ethyl-4,4-difluoropiperidine-1-carboxylate as a gum (115 mg); MS m / z: 313 (M+H). + .

[0490] This material was dissolved in DCM (3 mL) under N. EtN (100 μL, 0.7 mmol) was added and the solution was cooled in an ice bath. Methanesulfonyl chloride (50 μL, 0.6 mmol) was added dropwise and the reaction was stirred for 10 minutes. The cooling bath was removed and the mixture was stirred at ambient temperature for 10 minutes. The reaction was quenched with a few drops of saturated NaHCO and stirred for 5 minutes, then filtered through a phase separation cartridge and concentrated under reduced pressure to give benzyl 3-ethyl-4,4-difluoro-5-(methylsulfonamidomethyl)piperidine-1-carboxylate as a colorless oil (140 mg); MS m / z: 391 (M+H). + .

[0491] This material was dissolved in DCM (3 mL), and Pd(OAc) (35.23 mg, 0.2 mmol), EtN (176.0 μL, 1.3 mmol), and EtSiH (381.5 μL, 2.4 mmol) were added to the reaction mixture. The solution was stirred at ambient temperature for 1 h. The solution was poured onto an ion exchange cartridge, washing with methanol, and the product was eluted with 2 M methanolic NH solution. The filtrate was concentrated to give N-((5-ethyl-4,4-difluoropiperidin-3-yl)methyl)methanesulfonamide, A6, as a colorless gum (70 mg), which was carried on to the next reaction without further purification; MS m / z: 257 (M+H). + .

[0492] Preparation 7: N-((1,4-oxazepan-6-yl)methyl)methanesulfonamide A7. [ka]

[0493] Methanesulfonyl chloride (150 μL, 1.9 mmol) was added to a solution of tert-butyl 6-(aminomethyl)-1,4-oxazepane-4-carboxylate (300 mg, 1.3 mmol) and EtN (300 μL, 2.2 mmol) in DCM (5 mL) under N2 while cooling in an ice bath. The solution was stirred at ambient temperature for 2 h and then diluted with DCM. Saturated aqueous NaHCO3 was added, the mixture was stirred for 10 min, and the organic phase was isolated with a phase separation cartridge. The filtrate was concentrated in vacuo, and the residue was dissolved in DCM / TFA (1:1, 1 mL total) and stirred at ambient temperature for 2 h. The solution was concentrated in vacuo to give N-((1,4-oxazepan-6-yl)methyl)methanesulfonamide, A7, as a yellow oil (300 mg), which was carried on to the next reaction without purification, assuming the mono-TFA salt was isolated; MS m / z: 209 (M+H). + .

[0494] Preparation 8: 2-Methyl-6-(1H-pyrazol-4-yl)morpholine A8. [ka]

[0495] To a solution of 1-benzylpyrazole-4-carbaldehyde (2 g, 10.7 mmol) and nitromethane (7 mL, 129 mmol) cooled in an ice bath was added EtN (150 μL, 1.1 mmol). The mixture was stirred for 15 minutes with cooling and then at ambient temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (silica, eluted with a gradient of PE / EtOAc) to give 1-(1-benzylpyrazol-4-yl)-2-nitroethanol as a colorless oil (1 g, 37%), which was carried on directly to the next reaction; MS m / z: 248 (M+H). + .

[0496] A mixture of 1-(1-benzylpyrazol-4-yl)-2-nitro-ethanol (100 mg, 0.4 mmol), C-supported Pd, wet, Degussa (20 mg, 0.2 mmol) in methanol (4 mL) was stirred under a balloon of H at ambient temperature for 18 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give 2-amino-1-(1-benzylpyrazol-4-yl)ethanol as a colorless gum (90 mg), which was carried on directly to the next reaction; MS m / z: 218 (M+H). + .

[0497] 2-Bromopropanoyl bromide (114 mg, 0.5 mmol) was added to an ice-cold solution of 2-amino-1-(1-benzylpyrazol-4-yl)ethanol (100 mg, 0.5 mmol) and EtN (83 μL, 0.6 mmol) in DCM (4 mL) under N. The reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with DCM and washed with 2 M aqueous HCl, saturated aqueous NaHCO, and brine. The organic phase was dried (NaSO), filtered, and concentrated in vacuo to give a colorless oil. This material was dissolved in THF (3 mL), and the solution was cooled in an ice bath. Sodium hydride (37 mg, 60% dispersion in mineral oil, 0.9 mmol) was added, and the resulting suspension was stirred at ambient temperature for 2 h. The reaction was quenched with MeOH, then diluted with EtOAc and washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo to give a pale yellow gum (100 mg), MS m / z: 272 (M+H). + This was carried on directly to the next reaction without purification.

[0498] A mixture of 6-(1-benzylpyrazol-4-yl)-2-methyl-morpholin-3-one (100 mg, 0.4 mmol) and LiAlH (184 μL of 2 M, 0.4 mmol) in THF (3 mL) was stirred at 60 °C for 1 h. The resulting suspension was quenched with NaSO.10H O pellets and stirred for 30 min, then filtered. The filtrate was concentrated in vacuo, and the residue was dissolved in MeOH (2 mL). Three drops of concentrated HCl and C-supported Pd, wet, Degussa (20 mg, 0.02 mmol) were added to the solution. The reaction mixture was stirred at ambient temperature under a balloon of H for 18 h. The reaction mixture was poured onto an ion-exchange cartridge, washing with methanol, and the product was eluted with 2 M methanolic NH solution. The filtrate was concentrated in vacuo to give 2-methyl-6-(1H-pyrazol-4-yl)morpholine A8 (23 mg), which was carried on directly to the next reaction; MS m / z: 168 (M+H). + .

[0499] Preparation 9: N-((5,5-difluoropiperidin-3-yl)methyl)methanesulfonamide A9. [ka]

[0500] Methanesulfonyl chloride (151 μL, 2 mmol) was added to an ice-cold solution of tert-butyl 3,3-difluoro-5-(hydroxymethyl)piperidine-1-carboxylate (378 mg, 1.5 mmol) and EtN (314 μL, 2.3 mmol) in DCM (7 mL) under N. The solution was stirred for 18 h while gradually warming to ambient temperature. The reaction mixture was diluted with DCM and quenched with saturated aqueous NaHCO. After stirring for 15 min, the mixture was poured into a phase separation cartridge. The organic phase was concentrated in vacuo to give tert-butyl 3,3-difluoro-5-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (400 mg) as a colorless oil.

[0501] A portion of this material (100 mg, 0.3 mmol) was taken up in DMF (3 mL) under N and methanesulfonamide (100 mg, 1.1 mmol) and KCO (150 mg, 1.1 mmol) were added. The reaction mixture was stirred at ambient temperature for 18 h. The resulting suspension was stirred at 80 °C for 24 h, then diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried (NaSO), and concentrated in vacuo to give tert-butyl 3,3-difluoro-5-(methylsulfonamidomethyl)piperidine-1-carboxylate (150 mg) as a colorless oil.

[0502] This material was taken up in TFA (1.5 mL) / DCM (2 mL) and stirred at ambient temperature for 2 hours. The solution was concentrated in vacuo. The residue was taken up in MeOH and poured onto an ion exchange cartridge, washing with methanol, and the product was eluted with a 2M methanolic NH solution. The filtrate was concentrated in vacuo to give N-((5,5-difluoropiperidin-3-yl)methyl)methanesulfonamide A9 as a colorless oil (20 mg), which was carried on to the next reaction without further purification; MS m / z: 229 (M+H). + .

[0503] Preparation 10: (R)-N-((6,6-dimethylmorpholin-2-yl)methyl)methanesulfonamide A10. [ka]

[0504] Methanesulfonyl chloride (80 μL, 1 mmol) was added to a stirred suspension of tert-butyl (6S)-6-(aminomethyl)-2,2-dimethyl-morpholine-4-carboxylate (200 mg, 0.8 mmol) and EtN (175 μL, 1.3 mmol) in THF (10 mL) under an atmosphere of N, and the reaction was stirred at ambient temperature for 15 h. DMF (2 mL) was added to aid solubility, and the reaction was stirred at ambient temperature for an additional 3 h. The reaction was diluted with DCM and saturated aqueous NaHCO, and the reaction was stirred for 10 min. The layers were separated, and the aqueous layer was extracted with DCM (2×). The combined organic extracts were washed with brine (2×), dried (MgSO), filtered, and concentrated in vacuo to give a pale yellow oil (1 g); MS m / z: 323 (M+H). + .

[0505] This material was dissolved in DCM (5 mL) and TFA (0.5 mL) was added. The reaction mixture was stirred at ambient temperature for 4 hours and then concentrated in vacuo. The residue was azeotroped with DCM (twice) and diethyl ether (twice), then taken up in MeOH and passed through an ion exchange cartridge. The cartridge was washed with a mixture of MeOH / DCM, and the product was eluted by washing the cartridge with 2M NH3 in MeOH / DCM. The filtrate was concentrated in vacuo to give N-[[(2R)-6,6-dimethylmorpholin-2-yl]methyl]methanesulfonamide A10 (122 mg, 67%) as a colorless oil, which was carried on to the next reaction without further purification; 1 H NMR (500 MHz, chloroform-d) δ 4.65 (s, 1H), 3.87 - 3.82 (m, 1H), 3.22 (ddd, 1H), 3.03 - 2.99 (m, 1H), 2.99 (s, 3H), 2.87 (ddd, 1H), 2.67 (d, 1H), 2.59 (d, 1H), 2.51 (dd, 1H), 1.32 (s, 3H), 1.16 (s, 3H); MS m / z: 223 (M+H) + .

[0506] Preparation 11: N-((4-fluoropiperidin-3-yl)methyl)methanesulfonamide A11. [ka]

[0507] Methanesulfonyl chloride (100 μL, 1.3 mmol) was added to a solution of tert-butyl 3-(aminomethyl)-4-fluoro-piperidine-1-carboxylate (250 mg, 1.1 mmol) and EtN (200 μL, 1.4 mmol) in DCM (3 mL) while cooling in an ice bath. The solution was stirred at ambient temperature for 2 hours and then diluted with DCM. The mixture was washed with 2 M aqueous HCl, saturated aqueous NaHCO, and brine. The organic phase was dried (NaSO), filtered, and concentrated in vacuo.

[0508] The residue was taken up in DCM (2 mL) and TFA (2 mL, 26 mmol), stirred at ambient temperature for 1 h, and then concentrated in vacuo. The residue was diluted with MeOH and poured onto an ion exchange cartridge, washing with methanol, and the product was eluted with 2 M methanolic NH3 solution. The filtrate was concentrated in vacuo to give N-((4-fluoropiperidin-3-yl)methyl)methanesulfonamide A11, which was used without further purification.

[0509] Preparation 12: 2-(Methylsulfonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine A12. [ka]

[0510] NaH (79 mg of a 60% dispersion in mineral oil, 2 mmol) was added in one portion to a solution of tert-butyl 1,4,5,7-tetrahydropyrazolo[3,4-c]pyridine-6-carboxylate (400 mg, 1.8 mmol) in THF (7 mL) under N2 while cooling in an ice bath. After 15 min, methanesulfonyl chloride (166 μL, 2.2 mmol) was added to the solution. The reaction mixture was stirred for 18 h, during which time the temperature rose to ambient, then diluted with EtOAc and washed with 2 M aqueous NaOH and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo.

[0511] The residue was taken up in DCM (3 mL) and TFA (2 mL), and the solution was stirred at ambient temperature for 2 hours, then concentrated in vacuo. The residue was diluted with MeOH and poured onto an ion exchange cartridge, washing with methanol, and the product was eluted with 2 M methanolic NH3 solution. The filtrate was concentrated in vacuo to give 2-(methylsulfonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine A12 as a colorless oil (240 mg, 67%), which was carried on to the next reaction without further purification; MS m / z: 202 (M+H).+ .

[0512] Preparation 13: Imino(methyl)(piperidin-3-ylmethyl)-λ 6 -Sulfanone A13. [ka]

[0513] tert-Butyl 3-[(methylsulfonimidoyl)methyl]piperidine-1-carboxylate (600 mg, 2.2 mmol) [see Preparation 35] was dissolved in DCM (3 mL) and TFA (1.7 mL, 22 mmol) was added. The mixture was stirred overnight at ambient temperature and then concentrated in vacuo. The residue was taken up in MeOH and loaded onto an ion exchange cartridge, and the product was eluted with 2 M methanolic ammonia solution. The filtrate was concentrated in vacuo to give imino(methyl)(piperidin-3-ylmethyl)-λ 6 -sulfanone A13 (250 mg, 65%) was obtained; 1 H NMR (500 MHz, methanol le-d4) δ 3.34 -3.24 (m, 1H), 3.19 - 3.10 (m, 2H), 3.10 - 3.07 (m, 3H), 3.05 - 2.97 (m, 1H), 2.60 (ddd, 1H), 2.52 - 2.43 (m, 1H), 2.30 - 2.18 (m, 1H), 2.08 (ddtd, 1H), 1.75 (dq, 1H), 1.61 (dtq, 1H),1.37 (dtd, 1H).

[0514] Preparation 14: 2-(1H-pyrazol-4-yl)piperazine A14. [ka]

[0515] A mixture of 2-(1H-pyrazol-4-yl)pyrazine (400 mg, 2.7 mmol) and PtO (100 mg, 0.4 mmol) in MeOH (15 mL) was shaken under 60 psi of H at ambient temperature for 18 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give 2-(1H-pyrazol-4-yl)piperazine A14 as a colorless oil, which was carried on directly to the next reaction without purification; MS m / z: 153 (M+H). + .

[0516] Preparation 15: N-((4,4-Difluoro-5,5-dimethylpiperidin-3-yl)methyl)methanesulfonamide A15. [ka]

[0517] (Bis(trimethylsilyl)amino)lithium (2.4 mL of a 1 M solution in THF, 2.4 mmol) was added dropwise to a solution of benzyl 3,3-dimethyl-4-oxo-piperidine-1-carboxylate (500 mg, 2 mmol) in THF (7 mL) at −78° C. under N. After 90 min, a solution of 2-(chloromethyl)isoindoline-1,3-dione (560 mg, 3 mmol) in THF (2 mL) was added. The reaction mixture was stirred for 1 h and then quenched by the addition of saturated aqueous NH₄Cl (approximately 2 mL). The reaction mixture was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (MgSO₄), filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica, eluting with a gradient of PE / EtOAc) and then by reverse phase chromatography (C18, MeCN / water-0.1% ammonium hydroxide as eluent) to give benzyl 5-[(1,3-dioxoisoindolin-2-yl)methyl]-3,3-dimethyl-4-oxo-piperidine-1-carboxylate as a colorless oil (180 mg, 21%); MS m / z: 421 (M+H). + .

[0518] DAST (450 μL, 3.4 mmol) was added dropwise to a solution of benzyl 5-[(1,3-dioxoisoindolin-2-yl)methyl]-3,3-dimethyl-4-oxo-piperidine-1-carboxylate (150 mg, 0.4 mmol) in DCM (3 mL) while cooling in an ice bath under N. After 5 min, the ice bath was removed, and the solution was stirred at ambient temperature for 22 h. An additional 0.45 mL of DAST was added to the reaction mixture. After 16 h, the reaction was quenched by careful addition of MeOH. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (silica, eluting with a gradient of PE / EtOAc) to give benzyl 5-((1,3-dioxoisoindolin-2-yl)methyl)-4,4-difluoro-3,3-dimethylpiperidine-1-carboxylate (60 mg, 34%); MS m / z: 443 (M+H). + .

[0519] The residue was taken up in EtOH (2.8 mL) and hydrazine hydrate (30 μL, 0.6 mmol) was added. The mixture was stirred under reflux for 16 h. The resulting suspension was diluted with methanol and loaded onto an ion exchange cartridge, washing with MeOH, and the product was eluted with 2 M methanolic NH3 solution. The filtrate was concentrated in vacuo to give the product as a pale yellow gum; MS m / z: 313 (M+H). + .

[0520] This material was dissolved in DCM (5 mL) under N2. Methanesulfonyl chloride (18 μL, 0.2 mmol) and Et3N (40 μL, 0.3 mmol) were added while cooling in an ice bath. After stirring for 5 min, the ice bath was removed, and the solution was stirred at ambient temperature for 2 h. The solution was diluted with DCM and washed with saturated aqueous NaHCO3. The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was taken up in DCM (3 mL). Pd(OAc)2 (20 mg, 0.1 mmol), Et3N (100 μL, 0.7 mmol), and triethylsilane (250 μL, 1.6 mmol) were added, and the reaction mixture was stirred at ambient temperature for 1 h. The solution was poured onto an ion exchange cartridge, washing with MeOH, and the product was then eluted with 2 M methanolic NH3 solution. The filtrate was concentrated in vacuo to give N-((4,4-difluoro-5,5-dimethylpiperidin-3-yl)methyl)methanesulfonamide A15 as a colorless gum (50 mg), which was carried on to the next reaction without further purification; MS m / z: 257 (M+H). + .

[0521] Preparation 16: (S)-N-((1-methyl-6-oxopiperazin-2-yl)methyl)methanesulfonamide A16. [ka]

[0522] NaH (30 mg of a 60% dispersion in mineral oil, 0.75 mmol) was added to a solution of benzyl (3R)-3-[(1,3-dioxoisoindolin-2-yl)methyl]-5-oxo-piperazine-1-carboxylate (200 mg, 0.5 mmol) in DMF (2 mL) under N2 while cooling in an ice bath. After 20 min, MeI (45 μL, 0.7 mmol) was added and the reaction mixture was stirred for 18 h, at which time the temperature rose to ambient. The reaction mixture was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica, eluted with DCM / EtOAc) to give (R)-benzyl 3-((1,3-dioxoisoindolin-2-yl)methyl)-4-methyl-5-oxopiperazine-1-carboxylate as a colorless oil (13 mg, 6%); MS m / z: 408 (M+H). + .

[0523] This material was taken up in EtOH (3 mL) and hydrazine hydrate (1 drop) was added. The reaction mixture was heated under reflux for 2 hours and then cooled to ambient temperature. The solution was loaded onto an ion exchange cartridge, washing with methanol, and the product was eluted with 2 M methanolic NH3 solution. The filtrate was concentrated in vacuo to give a yellow gum, which was taken up in DCM (2 mL). Et3N (45 μL, 0.3 mmol) was added, followed by methanesulfonyl chloride (15 μL, 0.2 mmol), and the reaction mixture was stirred at ambient temperature for 2 hours. The residue was diluted with DCM and saturated aqueous NaHCO3 and stirred for 5 minutes. The organic phase was isolated using a phase separation cartridge and then concentrated in vacuo; MS m / z: 356 (M+H). + .

[0524] The residue was taken up in DCM (2 mL) and EtSiH (50 μL, 0.3 mmol), EtN (45 μL, 0.3 mmol), and Pd(OAc) (4 mg, 0.02 mmol) were added. The resulting suspension was stirred at ambient temperature for 3 h, then diluted with methanol (3 mL) and loaded onto an ion-exchange cartridge. The cartridge was washed with methanol, and the product was eluted with a 2 M methanolic NH solution. The filtrate was concentrated in vacuo to give a brown gum (approximately 10 mg) containing (S)—N-((1-methyl-6-oxopiperazin-2-yl)methyl)methanesulfonamide A16; MS m / z: 222 (M+H). + This material was carried directly into the next reaction without further purification.

[0525] Preparation 17: N-((S)-morpholin-2-ylmethyl)methanesulfonimidamide A17. [ka]

[0526] N-Tosylmethanesulfonimidoyl chloride (297 mg, 3.7 mmol) was added to a solution of tert-butyl (2R)-2-(aminomethyl)morpholine-4-carboxylate (637 mg, 3 mmol) and EtN (868 μL, 6 mmol) in DCM (15 mL) while cooling in an ice bath under N. The ice bath was removed, and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with DCM and washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (MgSO), filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica, eluted with PE / EtOAc) to give tert-butyl (2S)-2-[[[S-methyl-N-(p-tolylsulfonyl)sulfonimidoyl]amino]methyl]morpholine-4-carboxylate as a colorless oil (400 mg, 30%); MS m / z: 446 (MH). - .

[0527] This material was dissolved in THF (10 mL) under argon. A sodium anthracene solution was freshly prepared by adding sodium pellets (270 mg, 12 mmol) to a suspension of anthracene (2.14 g, 12 mmol) in THF (30 mL) under argon. The suspension was stirred at ambient temperature for 3 h to give a dark blue / green solution. This solution was added dropwise to a solution of tert-butyl (2S)-2-[[[S-methyl-N-(p-tolylsulfonyl)sulfonimidoyl]amino]methyl]morpholine-4-carboxylate until the blue color persisted. After 15 min, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (2x). The combined organics were washed with brine and dried (Na2SO4), then filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, eluting with (EtOAc + 10% MeOH) / PE, gradient 5% to 100%). The product-containing fractions were combined and concentrated in vacuo. The residue was taken up in DCM (1 mL) and treated with TFA (0.5 mL). After stirring at ambient temperature for 3 hours, the reaction mixture was concentrated in vacuo to give N-((S)-morpholin-2-ylmethyl)methanesulfonimide amide A17 as a yellow oil (150 mg), which was carried on to the next reaction without further purification. 1 H NMR (500 MHz, DMSO-d6) δ 4.03 (m, 1H), 3.82 (m, 1H), 3.72 (m, 1H), 3.42 (s, 3H), 3.33-3.17 (m, 4H), 2.99 (m, 1H), 2.83 (m, 1H).

[0528] Preparation 18: N-(2-(piperidin-3-yl)propan-2-yl)methanesulfonamide A18. [ka]

[0529] Methanesulfonyl chloride (200 μL, 2.6 mmol) was added to a solution of 2-(3-pyridyl)propan-2-amine (250 mg, 1.8 mmol) and EtN (400 μL, 2.9 mmol) in DCM (4 mL) while cooling in an ice bath. After 5 min, the ice bath was removed and the solution was stirred at ambient temperature for 2 h. The solution was diluted with DCM and saturated aqueous NaHCO was added. The mixture was stirred at ambient temperature for 5 min. The organic phase was separated using a phase separation cartridge and concentrated in vacuo to give a pale yellow gum (350 mg, 90%), which was used directly in the next reaction; MS m / z: 215 (M+H). + .

[0530] A mixture of N-[1-methyl-1-(3-pyridyl)ethyl]methanesulfonamide (350 mg, 1.6 mmol), PtO (100 mg, 0.4 mmol), and HCl (5 mL of a 3 M solution in MeOH, 15 mmol) was shaken under 60 psi H pressure for 18 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give N-(2-(piperidin-3-yl)propan-2-yl)methanesulfonamide A18 as a colorless oil (400 mg, 98%), which was carried on to the next step without purification (assuming the mono-HCl salt); MS m / z: 221 (M+H). + .

[0531] Preparation 19: N-((5-methoxypiperidin-3-yl)methyl)methanesulfonamide A19. [ka]

[0532] Methanesulfonyl chloride (400 μL, 5.2 mmol) was added dropwise to a solution of (5-methoxy-3-pyridyl)methanamine (500 mg, 3.6 mmol) in DCM (10 mL) under N2 while cooling in an ice bath. The reaction mixture was stirred at ambient temperature for 2 h. The resulting suspension was diluted with DCM and saturated aqueous NaHCO3. After stirring for 5 min, the organic phase was isolated using a phase separation cartridge and concentrated in vacuo to give N-[(5-methoxy-3-pyridyl)methyl]methanesulfonamide as a brown oil (770 mg); MS m / z: 217 (M+H). + , which was carried directly into the next reaction.

[0533] A mixture of N-[(5-methoxy-3-pyridyl)methyl]methanesulfonamide (300 mg, 1.4 mmol), PtO (150 mg, 0.6 mmol), and HCl (15 mL of a 3 M solution in MeOH, 45 mmol) was shaken under 60 psi H pressure for 18 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give N-((5-methoxypiperidin-3-yl)methyl)methanesulfonamide A19 as a yellow oil, which was carried on directly to the next reaction without purification (assuming the mono-HCl salt); MS m / z: 223 (M+H). + .

[0534] Preparation 20: N-((2-methylpiperidin-3-yl)methyl)methanesulfonamide A20. [ka]

[0535] EtN (400 μL, 2.9 mmol) followed by methanesulfonyl chloride (200 μL, 2.6 mmol) was added to a solution of benzyl 3-(hydroxymethyl)-2-methyl-piperidine-1-carboxylate (500 mg, 1.9 mmol) in DCM (10 mL), and the mixture was stirred at ambient temperature for 18 h. The solution was diluted with DCM and saturated aqueous NaHCO. After stirring for 5 min, the organic phase was isolated using a phase separation cartridge and concentrated in vacuo; MS m / z: 342 (M+H). + The residue was dissolved in DMF (5 mL). Methanesulfonamide (600 mg, 6.3 mmol) and K2CO3 (1.0 g, 7.2 mmol) were added to the solution, which was stirred at 80 °C for 20 h. The resulting suspension was diluted with DCM and water. After stirring for 5 min, the organic phase was isolated using a phase separation cartridge and concentrated in vacuo. The residue was purified by column chromatography (silica, eluted with PE / EtOAc) to give benzyl 3-(methanesulfonamidomethyl)-2-methyl-piperidine-1-carboxylate as a pale yellow oil (210 mg, 33% over two steps); MS m / z: 341 (M+H) + .

[0536] A suspension of benzyl 3-(methanesulfonamidomethyl)-2-methyl-piperidine-1-carboxylate (210 mg, 0.6 mmol), EtSiH (300 μL, 1.9 mmol), Pd(OAc) (80 mg, 0.36 mmol), and EtN (200 μL, 1.4 mmol) in DCM (4 mL) was stirred at ambient temperature for 2 h. The resulting solution was diluted with MeOH and loaded onto an ion exchange cartridge, washing with MeOH, and the product was eluted with 2 M methanolic NH solution. The filtrate was concentrated in vacuo to give N-((2-methylpiperidin-3-yl)methyl)methanesulfonamide A20 as a brown oil (120 mg, 97%), which was carried on to the next reaction without further purification; MS m / z: 207 (M+H). + .

[0537] Preparation 21: N-(2-azaspiro[4.4]nonan-7-yl)methanesulfonamide A21. [ka]

[0538] tert-Butyl 8-oxo-2-azaspiro[4.4]nonane-2-carboxylate (100 mg, 0.4 mmol) and ammonium acetate (300 mg, 3.9 mmol) were stirred in methanol (2 mL) at ambient temperature for 3 hours. Sodium cyanoborohydride (26 mg, 0.4 mmol) was added, and the mixture was stirred at ambient temperature for 18 hours. The solution was loaded onto an ion exchange cartridge, washing with methanol, and the product was eluted with methanolic ammonia solution. The filtrate was concentrated in vacuo to give a colorless oil (60 mg). This material was taken up in DCM (3 mL), and EtN (70 μL, 0.5 mmol) was added, followed by methanesulfonyl chloride (30 μL, 0.4 mmol). After 1 hour, the solution was diluted with DCM and saturated aqueous NaHCO and stirred for 2 minutes. The organic phase was isolated using a phase separation cartridge and concentrated in vacuo. The residue was taken up in TFA (500 μL, 6.5 mmol) and DCM (3 mL) and stirred at ambient temperature for 18 h, then concentrated in vacuo to give N-(2-azaspiro[4.4]nonan-7-yl)methanesulfonamide A21 as a colorless oil, which was...

Claims

1. Formula I: 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein in formula I: Ring A is selected from the group consisting of a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8- to 10-membered bicyclic aromatic carbocyclic ring, a 4- to 8-membered partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally fused to a 5- to 6-membered aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 12-membered partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 7- to 12-membered partially unsaturated spirocyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. a 7- to 12-membered partially unsaturated bicyclic heterocyclic ring having one to four heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 7- to 12-membered partially unsaturated bridged bicyclic heterocyclic ring having one to two heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 5- to 6-membered monocyclic heteroaromatic ring having one to four heteroatoms independently selected from nitrogen, oxygen, or sulfur; an 8- to 10-membered bicyclic heteroaromatic ring having one to five heteroatoms independently selected from nitrogen, oxygen, or sulfur; or Het, where Het is a 4- to 8-membered saturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 12-membered saturated spirocyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7- to 12-membered saturated bicyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7- to 12-membered saturated bridged bicyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring B is 【Chemistry 2】 and Ring C is 【Chemistry 3】 and each R is independently hydrogen or an optionally substituted group selected from a C 1-6 aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8- to 10-membered bicyclic aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R groups optionally taken together form a divalent C 2-4 alkylene chain; or two R groups, optionally taken together with the atoms between them, form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R' is independently hydrogen or a C 1-3 aliphatic group optionally substituted with halogen; Each R 1 is independently hydrogen, halogen, —CN, —NO 2 , —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(O)N(R)S(O) 2 R, —C(O)N═S(O)(R) 2 , —N(R) 2 , —N(R)C(O)R, —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —N(R)S(O) 2 R, —N(R)S(O) 2 N(R) 2 , —OR, —ON(R)SO 2 R, —P(O)(R) 2 , —SR, —S(O)R, —S(O) 2 R, —S(O)(NH)R, —S(O) 2 N(R) 2 , —S(NH 2 ) 2 (O)OH, —N═S(O)(R) 2 , —C(R) 2 S(═O)(═NH)R, —C(R) 2 NHSO 2 CH 3 , —CD 3 , —CD 2 N(R)S(O) 2 R, or R; or: two R 1 groups optionally taken together form =O, =NH or =NS(O) 2 R; or two R 1 groups optionally taken together form a divalent C 2-4 alkylene chain; each R 2 is independently hydrogen, halogen, —CN, —C(O)N(R′) 2 , —OR′, —N(R′) 2 , —S(O) 2 R, —S(O) 2 N(R) 2 , —O-phenyl, or an optionally substituted group selected from a C 1-3 aliphatic, phenyl, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4- to 8-membered saturated monocyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 3 is hydrogen, halogen, —CN, —OR′, —N(R′) 2 , or an optionally substituted group selected from a C 1-3 aliphatic, phenyl, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 4 is hydrogen, halogen, —CN, —OR, —N═S(O)(R) 2 , —N(R) 2 , or an optionally substituted group selected from a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from C 1-3 aliphatic, nitrogen, oxygen, or sulfur, or a 7- to 12-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, or 2; p is 0 or 1; and q is 0 or 1; The compound or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is Het.

3. Ring C is 【Chemistry 4】 2. The compound of claim 1, wherein:

4. Each R 1 is independently hydrogen, halogen, -CN, -C(O)R, -C(O)OR, -C(O)N(R) 2 , -C(O)N(R)S(O) 2 R, -C(O)N=S(O)(R) 2 , -N(R) 2 , -N(R)C(O)R, -N(R)C(O)N(R) 2 , -N(R)C(O)OR, -N(R)S(O) 2 R, -N(R)S(O) 2 N(R) 2 , -OR, -ON(R)SO 2 R, -P(O)(R) 2 , -SR, -S(O)R, -S(O) 2 R, -S(O)(NH)R, -S(O) 2 N(R) 2 , -S(NH 2 ) 2 (O)OH, -N═S(O)(R) 2 , -C(R) 2 S(═O)(═NH)R, -C(R) 2 NHSO 2 CH 3 , -CD 3 , -CD 2 N(R)S(O) 2 R, or R, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently hydrogen, halogen, -CN, -C(O)N(R') 2 , -OR', -N(R') 2 , or an optionally substituted group, wherein the optionally substituted group is selected from a C 1-3 aliphatic or a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen, halogen, —CN, —OR′, —N(R′) 2 , or an optionally substituted group selected from a C 1-3 aliphatic or a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen, halogen, -CN, -OR, -N(R) 2 , or an optionally substituted group selected from a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from C 1-3 aliphatic, nitrogen, oxygen, or sulfur, or a 7- to 12-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

8. A compound represented by formula XII-a, XII-b, or XII-c: 【Chemistry 5】 10. The compound of claim 1, wherein:

9. A compound represented by formula XIV-a, XIV-b, or XIV-c: 【Chemistry 6】 2. The compound of claim 1, wherein:

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, 3, 4 or 5, particularly 1, 2 or 3.

11. The compound comprising: 【Chemistry 7-1】 【Chemistry 7-2】 【Chemistry 7-3】 【Chemistry 7-4】 【Chemistry 7-5】 【Chemistry 7-6】 【Hua 7-7】 【7-8】 【Chemistry 7-9】 【Chemistry 7-10】 【7-11】 【Chemistry 7-12】 【Chemistry 7-13】 【Chemistry 7-14】 【Chemistry 7-15】 【Chemistry 7-16】 【Chemistry 7-17】 【Chemistry 7-18】 【Chemistry 7-19】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

13. A composition for inhibiting GCN2 in a patient or biological sample, comprising a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

14. A composition for treating a GCN2-mediated disorder, disease, or condition, comprising a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

15. The composition of claim 14, wherein the GCN2-mediated disorder, disease, or condition is selected from the group consisting of an inflammatory condition, an immunological condition, an autoimmune condition, an allergic condition, a rheumatic condition, a thrombotic condition, a cancer, an infection, a neurodegenerative disease, a degenerative disease, a neuroinflammatory disease, a cardiovascular disease, and a metabolic condition.

16. The composition of claim 15, wherein the cancer is a solid tumor selected from the group consisting of solid tumors of epithelial, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid, intestinal, liver, brain, prostate, genitourinary tract, lymphatic system, stomach, larynx, bone including chondrosarcoma and Ewing's sarcoma, germ cell including fetal tissue tumors, and / or lung tumors, monocytic leukemia, lung adenocarcinoma, small cell lung cancer, pancreatic cancer, glioblastoma, neurofibroma, angiosarcoma, breast cancer, and / or malignant melanoma origin, and tumors of the blood and immune system.

17. The composition of claim 15, wherein the autoimmune condition is rheumatoid arthritis, systemic lupus, multiple sclerosis, psoriasis, Sjogren's syndrome or transplant organ rejection.

18. The composition described in claim 15, wherein the metabolic condition is diabetes.

19. The composition described in claim 15, wherein the degenerative disease is osteoarthritis.

20. The composition of claim 15, wherein the inflammatory condition is asthma, inflammatory bowel disease, or giant cell arthritis.

21. The composition described in claim 15, wherein the cardiovascular disease is an ischemic injury.

22. The composition of claim 15, wherein the neurodegenerative disease is Alzheimer's disease, Down's syndrome, Hereditary cerebral hemorrhage with amyloidosis - Dutch type, cerebral amyloid angiopathy, Creutzfeldt-Jakob disease, frontotemporal dementia, Huntington's disease, or Parkinson's disease.

23. The composition of claim 15, wherein the infection is caused by mycobacteria, including Leishmania, M. leprae, M. tuberculosis and / or M. avium, malaria parasites, human immunodeficiency virus, Epstein-Barr virus, herpes simplex virus, or hepatitis C virus.

24. The composition of claim 14, wherein the GCN2-mediated disorder, disease, or condition is cancer, and the composition is administered in combination with a second agent for the treatment of cancer.

Images