WO2018195075A1

WO2018195075A1 - Compounds, compositions and methods of use

Info

Publication number: WO2018195075A1
Application number: PCT/US2018/027969
Authority: WO
Inventors: Duane A. Burnett; Joseph P. Vacca
Original assignee: Aquinnah Pharmaceuticals Inc
Current assignee: Aquinnah Pharmaceuticals Inc
Priority date: 2017-04-19
Filing date: 2018-04-17
Publication date: 2018-10-25
Anticipated expiration: 2019-10-19

Abstract

Herein, compounds, compositions and methods for modulating inclusion formation and stress granules in cells related to the onset of neurodegenerative diseases, musculoskeletal diseases, cancer, ophthalmological diseases, and viral infections are described.

Description

COMPOUNDS, COMPOSITIONS AND METHODS OF USE

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority to and the benefit of U.S. Provisional Application No. 62/487, 180, filed on April 19, 2017, the entire contents of which are incorporated by reference herein.

FIELD OF THE INVENTION

The invention relates to compounds, compositions and methods for modulating inclusion formation and stress granules in cells, and for treatment of neurodegenerative diseases, musculoskeletal diseases, cancer, ophthalmological diseases, and viral infections.

BACKGROUND OF THE INVENTION

One of the hallmarks of many neurodegenerative diseases is the accumulation of protein inclusions in the brain and central nervous system. These inclusions are insoluble aggregates of proteins and other cellular components that cause damage to cells and result in impaired function. Proteins such as tau, a-synuclein, huntingtin and β-amyloid have all been found to form inclusions in the brain and are linked to the development of a number of neurodegenerative diseases, including Alzheimer's disease and Huntington's disease. Recently, the TDP-43 protein was identified as one of the major components of protein inclusions that typify the

neurogenerative diseases Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Dementia with ubiquitin inclusions (FTLD-U) (Ash, P.E., et al. (2010) Hum Mol Genet 19(16):3206-3218; Hanson, K.A., et al. (2010) J Biol Chem 285: 11068-11072; Li, Y., et al. (2010) Proc Natl Acad Sci U.S.A. 107(7):3169-3174; Neumann, M., et al. (2006) Science 314: 130-133; Tsai, K.J., et al. (2010) J Exp Med 207: 1661-1673; Wils, H., et al. (2010) Proc Natl Acad Sci U.S.A. 170:3858-3863). Abnormalities in TDP-43 biology appear to be sufficient to cause neurodegenerative disease, as studies have indicated that mutations in TDP-43 occur in familial ALS (Barmada, S.J., et al. (2010) J N euro sci 30:639-649; Gitcho, M.A., et al. (2008) Ann Neurol 63(4): 535-538; Johnson, B.S., et al. (2009) / Biol Chem 284:20329-20339; Ling, S.C., et al. (2010) Proc Natl Acad Sci U.S.A. 107: 13318-13323; Sreedharan, J., et al. (2008) Science 319: 1668-1672). In addition, TDP-43 has been found to play a role in the stress granule machinery (Colombrita, C, et al. (2009) J Neurochem 111(4): 1051-1061; Liu-Yesucevitz, L., et al. (2010) PLoS One 5(10):el3250). Analysis of the biology of the major proteins that accumulate in other neurodegenerative diseases has lead to major advances in our understanding of the pathophysiology of TDP-43 inclusions as well as the development of new drug discovery platforms.

Currently, it is believed that aggregates that accumulate in neurodegenerative diseases like ALS, FTLD-U, Parkinson's disease and Huntington's disease accumulate slowly and are very difficult to disaggregate or perhaps can't be disaggregated. Thus, there is a need in the art for compositions and methods that can rapidly disaggregate stress granules and/or inhbibt their formation altogether.

SUMMARY OF THE INVENTION

In one aspect, the invention provides a compound of Formula (I):

Formula (I)

or a pharmaceutically acceptable salt thereof, wherein each of the variables above are described herein, for example, in the detailed description below.

In another aspect, the invention provides methods for treatment of a neurodegenerative disease or disorder, a musculoskeletal disease or disorder, a cancer, an ophthalmological disease or disorder (e.g., a retinal disease or disorder), and/or a viral infection in a subject, the method comprising administering a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) to a subject in need thereof.

In another aspect, the invention provides methods of diagnosing a neurodegenerative disease in a subject, the method comprising administering a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) to the subject. For use in diagnosis, the compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) can be modified with a label.

In another aspect, the invention provides methods of modulating stress granules comprising contacting a cell with a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)). In another aspect, the invention provides methods of modulating TDP-43 inclusion formation comprising contacting a cell with a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)).

In another aspect, the invention provides a method of screening for modulators of TDP- 43 aggregation comprising contacting a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) with the cell that expresses TDP-43 and develops spontaneous inclusions.

Still other objects and advantages of the invention will become apparent to those of skill in the art from the disclosure herein, which is simply illustrative and not restrictive. Thus, other embodiments will be recognized by the skilled artisan without departing from the spirit and scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease or Charcot disease, is a fatal neurodegenerative disease that occurs with an incidence of approximately 1/100,000 (Mitchell, J.D. and Borasio, G.D., (2007) Lancet 369:2031-41). There is currently no therapy for ALS, and the average survival rate of patients from the onset of the disease is roughly four years. ALS presents with motor weakness in the distal limbs that rapidly progresses proximally (Mitchell, J.D. and Borasio, G.D., (2007) Lancet 369:2031-41; Lambrechts, D.E., et al. (2004) Trends Mol Med 10:275-282). Studies over the past decade have indicated that TDP- 43 is the major protein that accumulates in affected motor neurons in sporadic ALS (Neumann, M., et al. (2006) Science 314: 130-133). The causes of sporadic ALS are not known, but identification of the major pathological species accumulating in the spinal cord of ALS patients represents a seminal advance for ALS research. To date, TDP-43 is the only protein that has been both genetically and pathologically linked with sporadic ALS, which represents the predominant form of the disease. Multiple papers have identified mutations in TDP-43 associated with sporadic and familial ALS (Sreedharan, J., et al. (2008) Science 319: 1668-1672; Gitcho, M.A., et al. (2008) Ann Neurol 63(4):535-538; Neumann, M., et al. (2006) Science 314: 130-133). Inhibitors of cell death and inclusions linked to TDP-43 represent a novel therapeutic approach to ALS, and may also elucidate the biochemical pathway linked to the formation of TDP-43 inclusions (Boyd, J.B., et al. (2014) J Biomol Screen 19(l):44-56). As such, TDP-43 represents one of the most promising targets for pharmacotherapy of ALS.

TDP-43 is a nuclear RNA binding protein that translocates to the cytoplasm in times of cellular stress, where it forms cytoplasmic inclusions. These inclusions then colocalize with reversible protein-mRNA aggregates termed "stress granules" (SGs) (Anderson P. and Kedersha, N. (2008) Trends Biochem Sci 33: 141-150; Kedersha, N. and Anderson, P. (2002) Biochem Soc Trans 30:963-969; Lagier-Tourenne, C, et al. (2010) Hum Mol Genet 19:R46-R64). Under many stress-inducing conditions (e.g. , arsenite treatment, nutrient deprivation), TDP-43 co- localization with SGs approaches 100%. The reversible nature of SG-based aggregation offers a biological pathway that can be applied to reverse the pathology and toxicity associated with TDP-43 inclusion formation. Studies show that agents that inhibit SG formation also inhibit formation of TDP-43 inclusions (Liu-Yesucevitz, L., et al. (2010) PLoS One 5(10):el3250). The relationship between TDP-43 and stress granules is important because it provides a novel approach for dispersing TDP-43 inclusions using physiological pathways that normally regulate this reversible process, rather than direct physical disruption of protein aggregation by a small molecule pharmaceutical. Investigating the particular elements of the SG pathway that regulate TDP-43 inclusion formation can identify selective approaches for therapeutic intervention to delay or halt the progression of disease. Stress granule biology also regulates autophagy and apoptosis, both of which are linked to neurodegeneration. Hence, compounds inhibiting TDP-43 aggregation may play a role in inhibiting neurodegeneration.

Modulators of TDP-43 Inclusions and Stress Granules

Accordingly, in one aspect, the invention provides a compound of Formula (I):

Formula (I)

or a pharmaceutically acceptable salt thereof, wherein Ring A is heterocyclyl, aryl, or heteroaryl; X is C(R ) or N; L¹ is a bond or Ci-C₆ alkylene; L² is Ci-C₆ alkylene optionally substituted with 1-5 R⁵; R¹ is hydrogen, halo or -OR^A; R² is Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ heteroalkyl, or Ci-C₆ haloalkyl; each R³ is independently Ci-C₆ alkyl, halo, cyano, or oxo, wherein each alkyl is optionally substituted with 1-8 R⁶; each R⁴ is independently Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ heteroalkyl, Ci-C₆ haloalkyl, halo, or -OR^A, wherein each alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with 1-5 R⁷; each R⁵ is independently Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ heteroalkyl, Ci-C₆ haloalkyl, halo, cyano, cycloalkyl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with 1-8 R⁸; or two R⁵ are taken together with the atoms to which they are attached to form a ring optionally substituted with 1-8 R⁸; each R^A is independently hydrogen or Ci-C₆ alkyl; each R⁶ , R⁷, and R⁸ is independently d- C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ heteroalkyl, Ci-C₆ haloalkyl, halo, cyano, oxo, cycloalkyl, or heterocyclyl; each of n and o is indepedendently 0 or 1, wherein the sum of n + o is not greater than 1; q is independently 0, 1, 2, 3, 4, 5, or 6; and p is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

In some embodiments, Ring A is aryl (e.g., monocyclic aryl). In some embodiments,

Ring A is phenyl

). In some embodiments, Ring A is phenyl and q is 0 or 1. In some embodiments, R⁴ is halo (e.g., fluoro) or -OR^A (e.g., -OCH³). In some embodiments, R⁴ is halo (e.g., fluoro). In some embodiments, R⁴ is -OR^A, (e.g., -OCH₃).

In some embodiments, Ring A is heteroaryl. In some embodiments, Ring A is a monocyclic heteroaryl. In some embodiments, Ring A is a nitrogen-containing heteroaryl. In some embodiments Ring A is a 6-membered heteroaryl. In some embodiments, Ring A is

pyridyl (e.g.,

In some embodiments, Ring A is pyridyl and q is 0.

In some embodiments, Ring A is heterocyclyl. In some embodiments, Ring A is a monocyclic heterocyclyl. In some embodiments, Ring A is an oxygen-containing heterocyclyl. In some embodiments Ring A is a 4-membered heterocyclyl. In some embodiments, Ring A is

oxetanyl (e.g.,

). In some embodiments, Ring A is oxetanyl and q is 0.

In some embodiments, X is CR¹ (e.g., CH). In some embodiments, X is N.

In some embodiments, L¹ is a bond. In some embodiments, L¹ is Ci-C₆ alkylene (e.g., Q alkylene).

In some embodiments, L² is Ci-C₂ alkylene (e.g., ethylene or methylene). In some embodiments, L² is C₂ alkylene (e.g., ethylene). In some embodiments, L² is Ci alkylene (methylene). In some embodiments, L² is substituted with 1-5 R⁵. In some embodiments, each R⁵ is independently Ci-C₆ alkyl or halo. In some embodiments, R⁵ is Ci-C₆ alkyl (e.g., methyl). In some embodiments, R⁵ is halo (e.g., fluoro). In some embodiments, two R⁵ are taken together with the atoms to which they are attached to form a ring (e.g., cycloalkyl or heterocyclyl). In some embodiments, two R⁵ are taken together with the atoms to which they are attached to form a cycloalkyl ring (e.g., cyclopropyl). In some embodiments, two R⁵ are taken together with the atoms to which they are attached to form a heterocyclyl ring (e.g., oxetanyl).

In some embodiments, L¹ is a bond and L² is Ci-C₂ alkylene (e.g., ethylene or methylene). In some embodiments, L¹ is Ci alkylene and L² is Ci-C₂ alkylene (e.g., ethylene or methylene.

In some embodiments, R² is Ci-C₆ alkyl or Ci-C₆ haloalkyl. In some embodiments, R² is Ci-C₆ alkyl (e.g., Ci-C₂ alkyl, e.g., ethyl). In some embodiments, R² is Ci-C₆ haloalkyl (e.g., C_\- C₂ haloalkyl, e.g., -CH₂CF₃).

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, o is 0. In some embodiments, o is 1.

In some embodiments, n is 0 and o is 0. In some embodiments, n is 1 and o is 0. In some embodiments, n is 0 and o is 1.

In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 1, and R³ is oxo.

In some embodiments, the compound of Formula compound of Formula (I-a):

Formula (I-a)

or a pharmaceutically acceptable salt, wherein Ring A is phenyl, pyridyl, or oxetanyl; X is CH or N; L¹ is a bond or methylene; L² is Ci-C₂ alkylene optionally substituted with 1-5 R⁵; R² is ethyl or -CH₂CF₃; R³ is oxo; each R⁴ is independently fluoro or -OCH₃; each R⁵ is independently methyl or fluoro; or two R⁵ are taken together with the atoms to which they are attached to form cyclopropyl or oxetanyl; each of n and o is indepedendently 0 or 1, wherein the sum of n + o is not greater than 1 ; q is independently 0 or 1 ; and p is 0 or 1. In some embodiments, the compound of Formula (I) or Formula (I-a) is selected from:

In some embodiments, the compound of Formula (I) is a compound of Formula (I-b):

Formula (I-b)

or a pharmaceutically acceptable salt thereof, wherein L¹ is Ci-C₆ alkylene; L² is Ci-C₆ alkylene substituted with 1-5 R⁵; R² is Ci-C₆ alkyl or Ci-C₆ haloalkyl; each R³ is independently Ci-C₆ alkyl, halo, cyano, or oxo, wherein each alkyl is optionally substituted with 1-8 R⁶; each R⁴ is independently Ci-C₆ alkyl, C2-C₆ alkenyl, C2-C₆ alkynyl, Ci-C₆ heteroalkyl, Ci-C₆ haloalkyl, halo, or -OR^A, wherein each alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with 1-5 R⁷; each R⁵ is independently Ci-C₆ alkyl, C2-C₆ alkenyl, C2-C₆ alkynyl, Ci-C₆ heteroalkyl, Ci-C₆ haloalkyl, halo, cyano, cycloalkyl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with 1-8 R⁸; or two R⁵ are taken together with the atoms to which they are attached to form a ring optionally substituted with 1-8 R⁸; each R^A is independently hydrogen or Ci-C₆ alkyl; each R⁶ , R⁷, and R⁸ is independently Ci-C₆ alkyl, C2-C₆ alkenyl, C2-C₆ alkynyl, Ci-C₆ heteroalkyl, Ci-C₆ haloalkyl, halo, cyano, oxo, cycloalkyl, or heterocyclyl; each of n and o is

indepedendently 0 or 1, wherein the sum of n + o is equal to 1 ; q is independently 0, 1, 2, 3, 4, 5, or 6; and p is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

In some embodiments, q is 0 or 1. In some embodiments, q is 1. In some embodiments, R⁴ is halo (e.g., fluoro) or -OR^A (e.g., -OCH). In some embodiments, R⁴ is halo (e.g., fluoro). In some embodiments, R⁴ is -OR^A, (e.g., -OCH₃).

In some embodiments, L¹ is Ci-C₆ alkylene (e.g., Ci alkylene).

In some embodiments, L² is Ci-C₂ alkylene (e.g., ethylene or methylene). In some embodiments, L² is C2 alkylene (e.g., ethylene). In some embodiments, L² is Ci alkylene (methylene).

In some embodiments, L² is substituted with 1-5 R⁵. In some embodiments, R⁵ is Ci-C₆ alkyl (e.g., methyl). In some embodiments, two R⁵ are taken together with the atoms to which they are attached to form a ring (e.g., cycloalkyl or heterocyclyl). In some embodiments, two R⁵ are taken together with the atoms to which they are attached to form a cycloalkyl ring (e.g., cyclopropyl). In some embodiments, two R⁵ are taken together with the atoms to which they are attached to form a heterocyclyl ring (e.g., oxetanyl). In some embodiments, L¹ is Ci alkylene and L² is Ci-C₂ alkylene (e.g., ethylene or methylene.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, o is 0. In some embodiments, o is 1.

In some embodiments, n is 1 and o is 0. In some embodiments, n is 0 and o is 1.

In some embodiments, p is 0.

, or a pharmaceutically acceptable salt thereof.

In some embo ound of Formula (I-c):

Formula (I-c)

or a pharmaceutically acceptable salt thereof, wherein X is QR¹) or N; L¹ is a bond or Ci- alkylene; L² is Ci-C₆ alkylene optionally substituted with 1-5 R⁵; R¹ is hydrogen, halo, or each R³ is independently Ci-C₆ alkyl, halo, cyano, or oxo, wherein each alkyl is optionally substituted with 1-8 R⁶; each R⁴ is independently Ci-C₆ alkyl, C2-C₆ alkenyl, C2-C₆ alkynyl, Ci- C₆ heteroalkyl, Ci-C₆ haloalkyl, halo, or -OR^A, wherein each alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with 1-5 R⁷; each R⁵ is independently Ci-C₆ alkyl, C2-C₆ alkenyl, C2-C₆ alkynyl, Ci-C₆ heteroalkyl, Ci-C₆ haloalkyl, halo, cyano, cycloalkyl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with 1-8 R⁸; or two R⁵ are taken together with the atoms to which they are attached to form a ring optionally substituted with 1-8 R⁸; each R^A is

independently hydrogen or Ci-C₆ alkyl; each R⁶ , R⁷, and R⁸ is independently Ci-C₆ alkyl, C2-C₆ alkenyl, C2-C₆ alkynyl, Ci-C₆ heteroalkyl, Ci-C₆ haloalkyl, halo, cyano, oxo, cycloalkyl, or heterocyclyl; each of n and o is indepedendently 0 or 1, wherein the sum of n + o is not greater than 1; q is independently 0, 1, 2, 3, 4, 5, or 6; and p is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

In some embodiments, q is 0 or 1. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, R⁴ is halo (e.g., fluoro) or -OR^A (e.g., -OCH). In some embodiments, R⁴ is halo (e.g., fluoro). In some embodiments, R⁴ is -OR^A, (e.g., -OCH₃).

In some embodiments, X is CR¹ (e.g., CH). In some embodiments, X is N.

In some embodiments, L¹ is a bond. In some embodiments, L¹ is Ci-C₆ alkylene (e.g., Ci alkylene).

In some embodiments, L² is substituted with 1-5 R⁵. In some embodiments, each R⁵ is independently Ci-C₆ alkyl or halo. In some embodiments, R⁵ is Ci-C₆ alkyl (e.g., methyl). In some embodiments, R⁵ is halo (e.g., fluoro). In some embodiments, two R⁵ are taken together with the atoms to which they are attached to form a ring (e.g., cycloalkyl or heterocyclyl). In some embodiments, two R⁵ are taken together with the atoms to which they are attached to form a cycloalkyl ring (e.g., cyclopropyl). In some embodiments, two R⁵ are taken together with the atoms to which they are attached to form a heterocyclyl ring (e.g., oxetanyl).

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, o is 0. In some embodiments, o is 1. In some embodiments, n is 0 and o is 0. In some embodiments, n is 1 and o is 0. In some embodiments, n is 0 and o is 1.

In some embodiments, the compound of Formula (I-c) is selected from:

In another aspect, the invention provides a pharmaceutical composition comprising a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) or a

pharmaceutically acceptable salt thereof in a mixture with a pharmaceutically acceptable excipient, diluent or carrier.

In another aspect, the invention provides a method of modulating stress granule formation, the method comprising contacting a cell with a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)). In some embodiments, stress granule formation is inhibited. In some embodiments, the stress granule is disaggregated. In some embodiments, stress granule formation is stimulated.

In some embodiments, a compound of Formula (I) (e.g., a compound of Formula (I-a), (I- b), or (I-c)) inhibits the formation of a stress granule. The compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) can inhibit the formation of a stress granule by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% (i.e., complete inhibition) relative to a control.

In some embodiments, a compound Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) disaggregates a stress granule. The compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) can disperses or disaggregate a stress granule by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% (i.e., complete dispersal) relative to a control.

In some embodiments, the stress granule comprises tar DNA binding protein-43 (TDP- 43), T-cell intracellular antigen 1 (TIA- 1), TIA1 cytotoxic granule-associated RNA binding protein-like 1 (TIAR, TIAL1), GTPase activating protein binding protein 1 (G3BP-1), GTPase activating protein binding protein 2 (G3BP-2), tris tetraprolin (TTP, ZFP36), fused in sarcoma (FUS), or fragile X mental retardation protein (FMRP, FMR1).

In some embodiments, the stress granule comprises tar DNA binding protein-43 (TDP- 43), T-cell intracellular antigen 1 (TIA-1), TIA1 cytotoxic granule-associated RNA binding protein-like 1 (TIAR, TIAL1), GTPase activating protein binding protein 1 (G3BP-1), GTPase activating protein binding protein 2 (G3BP-2), fused in sarcoma (FUS), or fragile X mental retardation protein (FMRP, FMR1).

In some embodiments, the stress granule comprises tar DNA binding protein-43 (TDP- 43), T-cell intracellular antigen 1 (TIA-1), TIA1 cytotoxic granule-associated RNA binding protein-like 1 (TIAR, TIAL1), GTPase activating protein binding protein 1 (G3BP-1), GTPase activating protein binding protein 2 (G3BP-2), or fused in sarcoma (FUS).

In some embodiments, the stress granule comprises tar DNA binding protein-43 (TDP- 43).

In some embodiments, the stress granule comprises T-cell intracellular antigen 1 (TIA-1).

In some embodiments, the stress granule comprises TIA-1 cytotoxic granule-associated RNA binding protein-like 1 (TIAR, TIAL1).

In some embodiments, the stress granule comprises GTPase activating protein binding protein 1 (G3BP-1).

In some embodiments, the stress granule comprises GTPase activating protein binding protein 2 (G3BP-2).

In some embodiments, the stress granule comprises tris tetraprolin (TTP, ZFP36).

In some embodiments, the stress granule comprises fused in sarcoma (FUS).

In some embodiments, the stress granule comprises fragile X mental retardation protein (FMRP, FMR1).

In another aspect, the invention provides a method of modulating TDP-43 inclusion formation, the method comprising contacting a cell with a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)). In some embodiments, TDP-43 inclusion formation is inhibited. In some embodiments, the TDP-43 inclusion is disaggregated. In some

embodiments, TDP-43 inclusion formation is stimulated.

In some embodiments, a compound of Formula (I) (e.g., a compound of Formula (I-a), (I- b), or (I-c)) inhibits the formation of a TDP-43 inclusion. The compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) can inhibit the formation of a TDP-43 inclusion by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% (i.e., complete inhibition) relative to a control.

In some embodiments, a compound of Formula (I) (e.g., a compound of Formula (I-a), (I- b), or (I-c)) disaggregates a TDP-43 inclusion. The compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) can disperses or disaggregate a TDP-43 inclusion by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% (i.e., complete dispersal) relative to a control.

In another aspect, the invention provides a method for treatment of a neurodegenerative disease or disorder, a musculoskeletal disease or disorder, a cancer, an ophthalmological disease or disorder (e.g., a retinal disease or disorder), and/or a viral infection, the method comprising administering an effective amount of a compound of Formula (I) (e.g., a compound of Formula

(I-a), (I-b), or (I-c)) to a subject in need thereof.

In some embodiments, the methods are performed in a subject suffering from a neurodegenerative disease or disorder, a musculoskeletal disease or disorder, a cancer, an ophthalmological disease or disorder (e.g., a retinal disease or disorder), and/or a viral infection.

In some embodiments, the methods are performed in a subject suffering from a neurodegenerative disease or disorder. In some embodiments, the methods are performed in a subject suffering from a musculoskeletal disease or disorder. In some embodiments, the methods are performed in a subject suffering from a cancer. In some embodiments, the methods are performed in a subject suffering from an ophthalmological disease or disorder (e.g., a retinal disease or disorder). In some embodiments, the methods are performed in a subject suffering from a viral infection or viral infections.

In some embodiments, the methods comprise administering a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) to a subject in need thereof. In some embodiments, the subject is a mammal. In some embodiments, the subject is a nematode. In some embodiments, the subject is human.

In some embodiments, the methods further comprise the step of diagnosing the subject with a neurodegenerative disease or disorder, a musculoskeletal disease or disorder, a cancer, an ophthalmological disease or disorder (e.g., a retinal disease or disorder), or a viral infection prior to administration of a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)). In some embodiments, the methods further comprise the step of diagnosing the subject with a neurodegenerative disease or disorder prior to administration of a compound of Formula

(I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)). In some embodiments, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, frontotemporal dementia (FTD), FTLD-U, FTD caused by mutations in the progranulin protein or tau protein (e.g., progranulin-deficient FTLD), frontotemporal dementia with inclusion body myopathy (IBMPFD), frontotemporal dementia with motor neuron disease, amyotrophic lateral sclerosis (ALS), Huntington' s disease (HD), Huntington's chorea, prion diseases (e.g., Creutzfeld-Jacob disease, bovine spongiform encephalopathy, Kuru, and scrapie), Lewy Body disease, diffuse Lewy body disease (DLBD), polyglutamine (poly Q) -repeat diseases, trinucleotide repeat diseases, cerebral degenerative diseases, presenile dementia, senile dementia, Parkinsonism linked to chromosome 17 (FTDP- 17), progressive supranuclear palsy (PSP), progressive bulbar palsy (PBP), psuedobulbar palsy, spinal and bulbar muscular atrophy (SBMA), primary lateral sclerosis, Pick's disease, primary progressive aphasia, corticobasal dementia, HIV-associated dementia, Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies, Down's syndrome, multiple system atrophy, spinal muscular atrophy (SMA, e.g., SMA Type I (e.g., Werdnig-Hoffmann disease), SMA Type II, SMA Type III (e.g., Kugelberg-Welander disease), and congenital SMA with arthrogryposis), progressive spinobulbar muscular atrophy (e.g., Kennedy disease), post- polio syndrome (PPS), spinocerebellar ataxia, pantothenate kinase-associated neurodegeneration (PANK), spinal degenerative disease/motor neuron degenerative diseases, upper motor neuron disorder, lower motor neuron disorder, age-related disorders and dementias, Hallervorden-Spatz syndrome, cerebral infarction, cerebral trauma, chronic traumatic encephalopathy, transient ischemic attack, Lytigo-bodig (amyotrophic lateral sclerosis-parkinsonism dementia), Guam- Parkinsonism dementia, hippocampal sclerosis, corticobasal degeneration, Alexander disease, Apler' s disease, Krabbe's disease, neuroborreliosis, neurosyphilis, Sandhoff disease, Tay-Sachs disease, Schilder' s disease, Batten disease, Cockayne syndrome, Kearns-Sayre syndrome, Gerstmann-Straussler-Scheinker syndrome and other transmissible spongiform

encephalopathies, hereditary spastic paraparesis, Leigh' s syndrome, demyelinating diseases, neuronal ceroid lipofuscinoses, epilepsy, tremors, depression, mania, anxiety and anxiety disorders, sleep disorders (e.g., narcolepsy, fatal familial insomnia), acute brain injuries (e.g., stroke, head injury) autism, other diseases or disorders relating to the aberrant expression of TDP-43 and altered proteostasis, and any combination thereof.

In some embodiments, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, frontotemporal dementia (FTD), FTLD-U, FTD caused by mutations in the progranulin protein or tau protein (e.g., progranulin-deficient FTLD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Huntington's chorea, Creutzfeld-Jacob disease, senile dementia, Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), Pick's disease, primary progressive aphasia, corticobasal dementia, Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies, Down's syndrome, multiple system atrophy, spinal muscular atrophy (SMA), spinocerebellar ataxia, spinal degenerative disease/motor neuron degenerative diseases, Hallervorden-Spatz syndrome, cerebral infarction, cerebral trauma, chronic traumatic encephalopathy, transient ischemic attack, Lytigo-bodig (amyotrophic lateral sclerosis-parkinsonism dementia), hippocampal sclerosis, corticobasal degeneration, Alexander disease, Cockayne syndrome, and any combination thereof.

In some embodiments, the neurodegenerative disease is frontotemporal dementia (FTD).

In some embodiments, the neurodegenerative disease is Alzheimer's disease or amyotrophic lateral sclerosis (ALS).

In some embodiments, the musculoskeletal disease is selected from the group consisting of muscular dystrophy, facioscapulohumeral muscular dystrophy (e.g., FSHD1 or FSHD2), Freidrich's ataxia, progressive muscular atrophy (PMA), mitochondrial encephalomyopathy

(MELAS), multiple sclerosis, inclusion body myopathy, inclusion body myositis (e.g., sporadic inclusion body myositis), post-polio muscular atrophy (PPMA), motor neuron disease, myotonia, myotonic dystrophy, sacropenia, multifocal motor neuropathy, inflammatory myopathies, paralysis, and other diseases or disorders relating to the aberrant expression of TDP-43 and altered proteostasis.

In some embodiments, compounds of Formula (I) (e.g., a compound of Formula (I-a), (I- b), or (I-c)) may be used to prevent or treat symptoms caused by or relating to said

musculoskeletal diseases, e.g., kyphosis, hypotonia, foot drop, motor dysfunctions, muscle weakness, muscle atrophy, neuron loss, muscle cramps, altered or aberrant gait, dystonias, astrocytosis (e.g., astrocytosis in the spinal cords), liver disease, respiratory disease or respiratory failure, inflammation, headache, and pain (e.g., back pain, neck pain, leg pain, or inflammatory pain).

In some embodiments, the cancer is selected from the group consisting of breast cancer, a melanoma, adrenal gland cancer, biliary tract cancer, bladder cancer, brain or central nervous system cancer, bronchus cancer, blastoma, carcinoma, a chondrosarcoma, cancer of the oral cavity or pharynx, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma, hepatic carcinoma, hepatoma, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, non-small cell lung cancer, ophthalmological cancer, osteosarcoma, ovarian cancer, pancreas cancer, peripheral nervous system cancer, prostate cancer, sarcoma, salivary gland cancer, small bowel or appendix cancer, small-cell lung cancer, squamous cell cancer, stomach cancer, testis cancer, thyroid cancer, urinary bladder cancer, uterine or endometrial cancer, vulval cancer, and any combination thereof.

In some embodiments, the cancer is selected from the group consisting of blastoma, carcinoma, a glioblastoma, hepatic carcinoma, lymphoma, leukemia, and any combination thereof.

In some embodiments, the cancer is selected from Hodgkin' s lymphoma or non- Hodgkin' s lymphoma. In some embodiments, the cancer is a non-Hodgkin' s lymphoma, selected from the group consisting of a B-cell lymphoma (e.g. , diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, marginal zone B-cell lymphomas, extranodal marginal B-cell lymphomas, mucosa-associated lymphoid tissue (MALT) lymphomas, modal marginal zone B-cell lymphoma, splenic marginal zone B- cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, Waldenstrom's

macroglobulinemia, hairy cell leukemia, and primary central nervous system (CNS) lymphoma) and a T-cell lymphoma (e.g. , precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, adult T-cell lymphoma (e.g. , smoldering adult T-cell lymphoma, chronic adult T-cell lymphoma, acute adult T-cell lymphoma, lymphomatous adult T-cell lymphoma), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma nasal type (ENKL), enteropathy-associated intestinal T-cell lymphoma (EATL) (e.g. , Type I EATL and Type II EATL), and anaplastic large cell lymphoma (ALCL)).

In some embodiments, the ophthalmological disease or disorder (e.g., retinal disease or disorder) is selected from macular degeneration (e.g. , age-related macular degeneration), diabetes retinopathy, histoplasmosis, macular hole, macular pucker, Bietti's crystalline dystrophy, retinal detachment, retinal thinning, retinoblastoma, retinopathy of prematurity,

Usher' s syndrome, vitreous detachment, Refsum disease, retinitis pigmentosa, onchocerciasis, choroideremia, Leber congenital amaurosis, retinoschisis (e.g. , juvenile retinoschisis), Stargardt disease, ophthalmoplegia, and the like.

In some embodiments, the ophthalmological disease or disorder (e.g., retinal disease or disorder) is selected from macular degeneration (e.g. , age-related macular degeneration), diabetes retinopathy, histoplasmosis, macular hole, macular pucker, Bietti's crystalline dystrophy, retinoblastoma, retinopathy of prematurity, Usher' s syndrome, Refsum disease, retinitis pigmentosa, onchocerciasis, choroideremia, Leber congenital amaurosis, retinoschisis (e.g. , juvenile retinoschisis), Stargardt disease, and the like. In some embodiments, the viral infection is caused by a virus selected from the group consisting of West Nile virus, respiratory syncytial virus (RSV), herpes simplex virus 1, herpes simplex virus 2, Epstein-Barr virus (EBV), hepatitis virus A, hepatitis virus B, hepatitis virus C, influenza viruses, chicken pox, avian flu viruses, smallpox, polio viruses, HIV- 1, HIV-2, Ebola virus, and any combination thereof.

In some embodiments, the viral infection is caused by a virus selected from the group consisting of herpes simplex virus 1, herpes simplex virus 2, Epstein-Barr virus (EBV), hepatitis virus A, hepatitis virus B, hepatitis virus C, HIV- 1, HIV-2, Ebola virus, and any combination thereof.

In some embodiments, the viral infection is HIV- 1 or HIV-2.

In some embodiments, the pathology of the neurodegenerative disease or disorder, musculoskeletal disease or disorder, cancer, ophthalmological disease or disorder (e.g., retinal disease or disorder), and/or viral infection comprises stress granules.

In some embodiments, pathology of the disease or disorder comprises stress granules. By comprising stress granules is meant that number of stress granules in a cell in the subject is changed relative to a control and/or healthy subject or relative to before onset of said disease or disorder. Exemplary diseases and disorders pathology of which incorporate stress granules include, but are not limited to, neurodegenerative diseases, musculoskeletal diseases, cancers, ophthalmological diseases (e.g., retinal diseases), and viral infections.

In another aspect, the invention provides methods of diagnosing a neurodegenerative disease, a musculoskeletal disease, a cancer, an ophthalmological disease (e.g., a retinal disease), or a viral infection in a subject, the method comprising administering a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) to the subject. In some embodiments, the invention provides methods of diagnosing a neurodegenerative disease in a subject, the method comprising administering a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) to the subject. For use in diagnosis, a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) can be modified with a label.

In another aspect, the invention provides methods of modulating stress granules comprising contacting a cell with a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)).

In another aspect, the invention provides methods of modulating TDP-43 inclusion formation comprising contacting a cell with a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)). In some embodiments, TDP-43 is inducibly expressed. In some embodiments, the cell line is a neuronal cell line.

In some embodiments, the cell is treated with a physiochemical stressor. In some embodiments, the physicochemical stressor is selected from arsenite, nutrient deprivation, heat shock, osmotic shock, a virus, genotoxic stress, radiation, oxidative stress, oxidative stress, a mitochondrial inhibitor, and an endoplasmic reticular stressor. In some embodiments, the physicochemical stressor is ultraviolet or x-ray radiation. In some embodiments, the physicochemical stressor is oxidative stress induced by FeCl₂ or CuCl₂ and a peroxide.

In yet another aspect, the invention provides a method of screening for modulators of TDP-43 aggregation comprising contacting a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) with a cell that expresses TDP-43 and develops spontaneous inclusions.

In some embodiments, the stress granule comprises TDP-43, i.e., is a TDP-43 inclusion. Accordingly, in some embodiments, a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) is a modulator of TDP-43 inclusions.

In another aspect, the invention provides a method of treating a B-cell or T-cell lymphoma, the method comprising administering a compound of Formula (I) to a subject in need thereof:

Formula (I) or a pharmaceutically acceptable salt thereof, wherein Ring A, X, L¹, L², R², R³, R⁴, n, o, p, q, and subvariables thereof are as described for Formula (I) herein.

In some embodiments, the B-cell or T-cell lymphoma is selected from the group consisting of diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, marginal zone B-cell lymphomas, extranodal marginal B-cell lymphomas, mucosa-associated lymphoid tissue (MALT) lymphomas, modal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, Waldenstrom' s macroglobulinemia, hairy cell leukemia, primary central nervous system (CNS) lymphoma, precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma, smoldering adult T-cell lymphoma, chronic adult T-cell lymphoma, acute adult T-cell lymphoma, lymphomatous adult T-cell lymphoma, angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma nasal type (ENKL), enteropathy- associated intestinal T-cell lymphoma (EATL), and anaplastic large cell lymphoma (ALCL). In another aspect, the invention provides a method of treating a neurodegenerative disease selected from the group consisting of frontotemporal dementia caused by mutations in the progranulin protein or tau protein (e.g., progranulin-deficient FTLD), frontotemporal dementia with inclusion body myopathy (IBMPFD), frontotemporal dementia with motor neuron disease , bovine spongiform encephalopathy, Kuru, scrapie, Lewy Body disease, diffuse Lewy body disease (DLBD), polyglutamine (polyQ)-repeat diseases, progressive bulbar palsy (PBP), psuedobulbar palsy, spinal and bulbar muscular atrophy (SBMA), primary lateral sclerosis, HIV- associated dementia, progressive spinobulbar muscular atrophy (e.g., Kennedy disease), post- polio syndrome (PPS), pantothenate kinase-associated neurodegeneration (PANK), Lytigo-bodig (amyotrophic lateral sclerosis-parkinsonism dementia), Guam-Parkinsonism dementia, hippocampal sclerosis, corticobasal degeneration, Alexander disease, Apler' s disease, Krabbe's disease, neuroborreliosis, neurosyphilis, Sandhoff disease, Tay-Sachs disease, Schilder's disease, Batten disease, Cockayne syndrome, Kearns-Sayre syndrome, Gerstmann-Straussler-Scheinker syndrome and other transmissible spongiform encephalopathies, hereditary spastic paraparesis, Leigh' s syndrome, demyelinating diseases, neuronal ceroid lipofuscinoses, epilepsy, tremors, depression, mania, anxiety and anxiety disorders, sleep disorders (e.g., narcolepsy, fatal familial insomnia), acute brain injuries (e.g., stroke, head injury) and autism, by administering a compound of Formula (I) to

In another aspect, the invention provides a method of treating a musculoskeletal disease by administering a compound of Formula (I) to a subject in need thereof:

In some embodiments, the musculoskeletal disease is selected from the group consisting of muscular dystrophy, facioscapulohumeral muscular dystrophy (e.g., FSHD1 or FSHD2), Freidrich' s ataxia, progressive muscular atrophy (PMA), mitochondrial encephalomyopathy (MELAS), multiple sclerosis, inclusion body myopathy, inclusion body myositis (e.g., sporadic inclusion body myositis), post-polio muscular atrophy (PPMA), motor neuron disease, myotonia, myotonic dystrophy, sacropenia, multifocal motor neuropathy, inflammatory myopathies, and paralysis.

In another aspect, the invention provides a method of treating an ophthalmological disease or disorder, the method comprising administering a compound of Formula (I) to a subject in need thereof:

In some embodiments, the ophthalmological disease (e.g., retinal disease)is selected from the group consisting of macular degeneration, age-related macular degeneration, diabetes retinopathy, histoplasmosis, macular hole, macular pucker, Bietti' s crystalline dystrophy, retinal detachment, retinal thinning, retinoblastoma, retinopathy of prematurity, Usher's syndrome, vitreous detachment, Refsum disease, retinitis pigmentosa, onchocerciasis, choroideremia, Leber congenital amaurosis, retinoschisis, juvenile retinoschisis, Stargardt disease, ophthalmoplegia, or any combination thereof.

In another aspect, the invention provides a method of treating a viral infection caused by the Ebola virus, the method comprising administering a compound of Formula (I) to a subject in need thereof:

In some embodiments, the subject is a mammal. In some embodiments, the subject is human.

In some embodiments, the method further comprises the step of diagnosing the subject with the neurodegenerative disease or disorder, musculoskeletal disease or disorder, cancer, ophthalmological disease or disorder, or viral infection prior to onset of said administration. In some embodiments, the pathology of said neurodegenerative disease or disorder, said musculoskeletal disease or disorder, said cancer, said ophthalmological disease or disorder, and said viral infection comprises stress granules. In some embodiments, the pathology of said neurodegenerative disease, said musculoskeletal disease or disorder, said cancer, said ophthalmological disease or disorder, and said viral infection comprises TDP-43 inclusions.

TDP-43 and other RNA-binding proteins function in both the nucleus and cytoplasm to process mRNA, e.g. , by splicing mRNA, cleaving mRNA introns, cleaving untranslated regions of mRNA or modifying protein translation at the synapse, axon, dendrite or soma. Therefore, targeting other proteins that function in an analogous manner to TDP-43 or by processing mRNA may also be beneficial to prevent and treat neurodegeneration resulting from disease. For instance, the fragile X mental retardation 1 (FMRP) protein is essential for normal cognitive development (Nakamoto, M., et al. (2007) Proc Natl Acad Sci U.S.A. 104: 15537-15542). The signaling systems that affect TDP-43 function might also affect this protein, thus improving cognitive function. This can be particularly important at the synapse where neurons

communicate. Without wishing to be bound by a theory, the signaling systems that compounds of Formula (I) target may also modify these processes, which play a role in neurodegeneration or mental health illnesses (e.g. , schizophrenia).

The cellular stress response follows a U-shaped curve. Overinduction of this pathway, such as observed in many neurodegenerative diseases, can be harmful for cells. However, a decreased stimulation of this pathway can also be harmful for cells, e.g. , in the case of an acute stress, such as a stroke. Thus, the appropriate action for some diseases is the inhibition of stress granule formation, while for other diseases, stimulation of stress granule formation is beneficial.

In some embodiments, the TDP-43 protein in a stress granule may be wild-type or a mutant form of TDP-43. In some embodiments, the mutant form of TDP-43 comprises an amino acid addition, deletion, or substitution, e.g., relative to the wild type sequence of TDP-43. In some embodiments, the mutant form of TDP-43 comprises an amino acid substitution relative to the wild type sequence, e.g., a G294A, A135T, Q331K, or Q343R substitution. In some embodiments, the TDP-43 protein in a stress granule comprises a post-translational modification, e.g., phosphorylation of an amino acid side chain, e.g., T103, S104, S409, or S410. In some embodiments, post-translational modification of the TDP-43 protein in a stress granule may be modulated by treatment with a compound of the invention. Methods of Treatment

Neurodegenerative diseases: Without wishing to be bound by a theory, compounds of Formula (I) can be used to delay the progression of neurodegenerative illnesses where the pathology incorporates stress granules. Such illnesses include ALS and frontotemporal dementia, in which TDP-43 is the predominant protein that accumulates to form the pathology. This group also includes Alzheimer' s disease and FTLD-U, where TDP-43 and other stress granule proteins co-localize with tau pathology. Because modulators of TDP-43 inclusions, such as compounds of Formula (I), can act to block the enzymes that signal stress granule formation (e.g. , the three enzymes that phosphorylate eIF2a: PERK, GCN2 and HRI), compounds of Formula (I) may also reverse stress granules that might not include TDP-43. Accordingly, compounds of Formula (I) can be used for treatment of neurodegenerative diseases and disorders in which the pathology incorporates stress granules, such as Huntington' s chorea and Creutzfeld- Jacob disease.

Compounds of Formula (I) may also be used for treatment of neurodegenerative diseases and disorders that involve TDP-43 multisystem proteinopathy.

The term "neurodegenerative disease" as used herein, refers to a neurological disease characterized by loss or degeneration of neurons. The term "neurodegenerative disease" includes diseases caused by the involvement of genetic factors or the cell death (apoptosis) of neurons attributed to abnormal protein accumulation and so on. Additionally, neurodegenerative diseases include neurodegenerative movement disorders and neurodegenerative conditions relating to memory loss and/or dementia. Neurodegenerative diseases include tauopathies and oc- synucleopathies. Exemplary neurodegenerative diseases include, but are not limited to,

Alzheimer's disease, frontotemporal dementia (FTD), FTLD-U, FTD caused by mutations in the progranulin protein or tau protein (e.g., progranulin-deficient FTLD), frontotemporal dementia with inclusion body myopathy (IBMPFD), frontotemporal dementia with motor neuron disease, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with dementia (ALSD),

Huntington's disease (HD), Huntington's chorea, prion diseases (e.g., Creutzfeld- Jacob disease, bovine spongiform encephalopathy, Kuru, or scrapie), Lewy Body disease, diffuse Lewy body disease (DLBD), polyglutamine (polyQ)-repeat diseases, trinucleotide repeat diseases, cerebral degenerative diseases, presenile dementia, senile dementia, Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), progressive bulbar palsy (PBP), psuedobulbar palsy, spinal and bulbar muscular atrophy (SBMA), primary lateral sclerosis, Pick's disease, primary progressive aphasia, corticobasal dementia, HIV-associated dementia, Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies, Down's syndrome, multiple system atrophy, spinal muscular atrophy (SMA, e.g., SMA Type I (e.g., Werdnig-Hoffmann disease) SMA Type II, SMA Type III (e.g., Kugelberg-Welander disease), and congenital SMA with arthrogryposis), progressive spinobulbar muscular atrophy (e.g., Kennedy disease), post-polio syndrome (PPS), spinocerebellar ataxia, pantothenate kinase- associated neurodegeneration (PANK), spinal degenerative disease/motor neuron degenerative diseases, upper motor neuron disorder, lower motor neuron disorder, age-related disorders and dementias, Hallervorden-Spatz syndrome, Lytigo-bodig (amyotrophic lateral sclerosis- parkinsonism dementia), Guam-Parkinsonism dementia, hippocampal sclerosis, corticobasal degeneration, Alexander disease, Apler's disease, Krabbe's disease, neuroborreliosis, neurosyphilis, Sandhoff disease, Schilder's disease, Batten disease, Cockayne syndrome, Kearns-Sayre syndrome, Gerstmann-Straussler-Scheinker syndrome, hereditary spastic paraparesis, Leigh's syndrome, demyelinating diseases, epilepsy, tremors, depression, mania, anxiety and anxiety disorders, sleep disorders (e.g., narcolepsy, fatal familial insomnia), acute brain injuries (e.g., stroke, head injury) and autism. As used herein, the term "a-synucleopathy" refers to a neurodegenerative disorder or disease involving aggregation of oc-synuclein or abnormal oc-synuclein in nerve cells in the brain (Ostrerova, N., et al. (1999) J Neurosci

19:5782:5791; Rideout, H.J., et al. (2004) J Biol Chem 279:46915-46920). cc-Synucleopathies include, but are not limited to, Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies, Pick's disease, Down's syndrome, multiple system atrophy, amylotrophic lateral sclerosis (ALS), Hallervorden-Spatz syndrome, and the like.

As used herein, the term "tauopathy" refers to a neurodegenerative disease associated with the pathological aggregation of tau protein in the brain. Tauopathies include, but are not limited to, Alzheimer's disease, Pick's disease, corticobasal degeneration, Argyrophilic grain disease (AGD), progressive supranuclear palsy, Frontotemporal dementia, Frontotemporal lobar degeneration, or Pick's complex.

Musculoskeletal diseases: Musculoskeletal diseases and disorders as defined herein are conditions that affect the muscles, ligaments, tendons, and joints, as well as the skeletal structures that support them. Without wishing to be bound by a theory, aberrant expression of certain proteins, such as the full-length isoform of DUX4, has been shown to inhibit protein turnover and increase the expression and aggregation of cytotoxic proteins including insoluble TDP-43 in skeletal muscle cells (Homma, S. et al. Ann Clin Transl Neurol (2015) 2: 151-166). As such, compounds of Formula (I), Formula (II), and Formula (III) may be used to prevent or treat a musculoskeletal disease, e.g., a musculoskeletal disease that results in accumulation of TDP-43 and other stress granule proteins, e.g., in the nucleus, cytoplasm, or cell bodies of a muscle cell or motor neuron. Exemplary musculoskeletal diseases include muscular dystrophy, facioscapulohumeral muscular dystrophy (e.g., FSHD1 or FSHD2), Freidrich's ataxia, progressive muscular atrophy (PMA), mitochondrial encephalomyopathy (MELAS), multiple sclerosis, inclusion body myopathy, inclusion body myositis (e.g., sporadic inclusion body myositis), post-polio muscular atrophy (PPMA), motor neuron disease, myotonia, myotonic dystrophy, sacropenia, spasticity, multifocal motor neuropathy, inflammatory myopathies, paralysis, and other diseases or disorders relating to the aberrant expression of TDP-43 and altered proteostasis. In addition, compounds of Formula (I) may be used to prevent or treat symptoms caused by or relating to said musculoskeletal diseases, e.g., kyphosis, hypotonia, foot drop, motor dysfunctions, muscle weakness, muscle atrophy, neuron loss, muscle cramps, altered or aberrant gait, dystonias, astrocytosis (e.g., astrocytosis in the spinal cords), liver disease, inflammation, headache, pain (e.g., back pain, neck pain, leg pain, inflammatory pain), and the like. In some embodiments, a musculoskeletal disease or a symptom of a musculoskeletal disease may overlap with a neurodegenerative disease or a symptom of a neurodegenerative disease.

Cancers: Cancer cells grow quickly and in low oxygen environments by activating different elements of the cellular stress response. Researchers have shown that drugs targeting different elements of the stress response can be anti-neoplastic. For example, rapamycin blocks mTOR, upregulates autophagy and inhibits some types of tumors. Proteasomal inhibitors, such as velcade (Millenium Pharma) are used to treat some cancers. HSP90 inhibitors, such as 17- allylaminogeldanamycin (17AAG), are currently in clinical trials for cancer. Without wishing to be bound by a theory, compounds of Formula (I) may also be used for treatment of cancer, as a greater understanding of the role of TDP-43 in RNA processing and transcription factor signaling has recently begun to emerge (Lagier-Tourenne, C, et al. (2010) Hum Mol Genet 19:R46-R64; Ayala, Y. M., et al. (2008) Proc Natl Acad Sci U.S.A. 105(10):3785-3789).

Additionally, TDP-43 modulators can be combined with one or more cancer therapies, such as chemotherapy and radiation therapy.

A "cancer" in a subject refers to the presence of cells possessing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features. Often, cancer cells will be in the form of a tumor, but such cells may exist alone within an animal, or may be a non-tumorigenic cancer cell, such as a leukemia cell. In some circumstances, cancer cells will be in the form of a tumor; such cells may exist locally within an animal, or circulate in the blood stream as independent cells, for example, leukemic cells. Examples of cancer include but are not limited to breast cancer, a melanoma, adrenal gland cancer, biliary tract cancer, bladder cancer, brain or central nervous system cancer, bronchus cancer, blastoma, carcinoma, a

chondrosarcoma, cancer of the oral cavity or pharynx, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma, hepatic carcinoma, hepatoma, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, non-small cell lung cancer, ophthalmological cancer, osteosarcoma, ovarian cancer, pancreas cancer, peripheral nervous system cancer, prostate cancer, sarcoma, salivary gland cancer, small bowel or appendix cancer, small-cell lung cancer, squamous cell cancer, stomach cancer, testis cancer, thyroid cancer, urinary bladder cancer, uterine or endometrial cancer, vulval cancer, and the like.

Other exemplary cancers include, but are not limited to, ACTH-producing tumors, acute lymphocytic leukemia, acute nonlymphocytic leukemia, cancer of the adrenal cortex, bladder cancer, brain cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, hairy cell leukemia, head & neck cancer, ophthalmological cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer (small and/or non-small cell), malignant peritoneal effusion, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, ovarian cancer, ovary (germ cell) cancer, prostate cancer, pancreatic cancer, penile cancer, retinoblastoma, skin cancer, soft-tissue sarcoma, squamous cell carcinomas, stomach cancer, testicular cancer, thyroid cancer, trophoblastic neoplasms, uterine cancer, vaginal cancer, cancer of the vulva, Wilm's tumor, and the like.

Exemplary lymphomas include Hodgkin's lymphoma and non-Hodgkin's lymphoma. Further exemplification of non-Hodgkin's lymphoma include, but are not limited to, B-cell lymphomas (e.g. , diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, marginal zone B-cell lymphomas, extranodal marginal B-cell lymphomas, mucosa-associated lymphoid tissue (MALT) lymphomas, modal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, Waldenstrom' s macroglobulinemia, hairy cell leukemia, and primary central nervous system (CNS) lymphoma) and T-cell lymphomas (e.g. , precursor T- lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, adult T-cell lymphoma (e.g. , smoldering adult T-cell lymphoma, chronic adult T-cell lymphoma, acute adult T-cell lymphoma, lymphomatous adult T-cell lymphoma), angioimmunoblastic T- cell lymphoma, extranodal natural killer T-cell lymphoma nasal type (ENKL), enteropathy- associated intestinal T-cell lymphoma (EATL) (e.g. , Type I EATL and Type II EATL), and anaplastic large cell lymphoma (ALCL)).

Ophthalmological diseases: Ophthalmological diseases and disorders (e.g., retinal diseases and disorders) as defined herein affect the retina and other parts of the eye and may contribute to impaired vision and blindness. Several ophthalmological diseases (e.g., retinal diseases) are characterized by the accumulation of protein inclusions and stress granules within or between cells of the eye, e.g., retinal cells and nearby tissues. In addition, an ophthalmological disease (e.g., retinal disease) may also be a symptom of or precursor to neurogenerative diseases, such as ALS and FTD (Ward, M.E., et al. (2014) J Exp ed 211(10): 1937). Therefore, use of compounds that may inhibit formation of protein inclusions and stress granules, including compounds of Formula (I), may play an important role in the prevention or treatment of ophthalmological diseases (e.g., retinal diseases).

Exemplary ophthalmological diseases (e.g., retinal diseases) include, but are not limited to, macular degeneration (e.g. , age-related macular degeneration), diabetes retinopathy, histoplasmosis, macular hole, macular pucker, Bietti's crystalline dystrophy, retinal detachment, retinal thinning, retinoblastoma, retinopathy of prematurity, Usher's syndrome, vitreous detachment, Refsum disease, retinitis pigmentosa, onchocerciasis, choroideremia, Leber congenital amaurosis, retinoschisis (e.g. , juvenile retinoschisis), Stargardt disease,

ophthalmoplegia, and the like.

Viral infections: Stress granules often form during viral illnesses, as viral infections often involve hijacking the cellular reproductive machinery toward production of viral proteins. In this case, inhibitors of stress granules can be useful for interfering with viral function. Other viruses appear to inhibit SG formation to prevent the cell from mobilizing a stress response. In such a case, an inducer of stress granules can interfere with viral activity and help combat viral infections (e.g. , Salubrinal, an eIF2a phosphatase inhibitor and stress granule inducer). Two viruses for which SG biology has been investigated include West Nile virus and respiratory syncytial virus (RSV) (Emara, M.E. and Brinton, M. A. (2007) Proc. Natl. Acad. Sci. USA 104(21): 9041-9046). Therefore, use of compounds that may inhibit formation of protein inclusions and stress granules, including compounds of Formula (I) (e.g., Formula (Ta), (Tb), or (I-c)), may be useful for the prevention and/or treatment of a viral infection.

Exemplary viruses include, but are not limited to, West Nile virus, respiratory syncytial virus (RSV), Epstein-Barr virus (EBV), hepatitis A, B, C, and D viruses, herpes viruses, influenza viruses, chicken pox, avian flu viruses, smallpox, polio viruses, HIV, Ebola virus, and the like. Definitions

Unless stated otherwise, or implicit from context, the following terms and phrases include the meanings provided below. Unless explicitly stated otherwise, or apparent from context, the terms and phrases below do not exclude the meaning that the term or phrase has acquired in the art to which it pertains. The definitions are provided to aid in describing particular embodiments, and are not intended to limit the claimed invention, because the scope of the invention is limited only by the claims. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

As used herein, the terms "compounds" and "agent" are used interchangeably to refer to the inhibitors/antagonists/agonists of the invention. In certain embodiments, the compounds are small organic or inorganic molecules, e.g. , with molecular weights less than 7500 amu, preferably less than 5000 amu, and even more preferably less than 2000, 1500, 1000, 750, 600, or 500 amu. In certain embodiments, one class of small organic or inorganic molecules are non- peptidyl, e.g. , containing 2, 1, or no peptide and/or saccharide linkages.

Unless otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term "about." The term "about" when used in connection with percentages may mean ±1%.

The singular terms "a," "an," and "the" refer to one or to more than one, unless context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise.

Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The term "comprises" means "includes." The abbreviation, "e.g." is derived from the Latin exempli gratia, and is used herein to indicate a non-limiting example. Thus, the abbreviation "e.g." is synonymous with the term "for example."

The terms "decrease", "reduced", "reduction" , "decrease" or "inhibit" are all used herein generally to mean a decrease by a statistically significant amount. However, for avoidance of doubt, "reduced", "reduction", "decrease" or "inhibit" means a decrease by at least 1% as compared to a reference level, for example a decrease by at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% decrease (e.g. absent level as compared to a reference sample), or any decrease between 1-100%, e.g., 10-100% as compared to a reference level.

The terms "increased","increase", "enhance" or "activate" are all used herein to generally mean an increase by a statically significant amount; for the avoidance of any doubt, the terms "increased", "increase", "enhance" or "activate" means an increase by at least 1% as compared to a reference level, for example a decrease by at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase (e.g. absent level as compared to a reference sample), or any increase between 1-100%, e.g., 10- 100% as compared to a reference level.

As used herein, the term "administer" refers to the placement of a composition into a subject by a method or route which results in at least partial localization of the composition at a desired site such that desired effect is produced. A compound or composition described herein can be administered by any appropriate route known in the art including, but not limited to, oral or parenteral routes, including intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), pulmonary, nasal, rectal, intrathecal, and topical (including buccal and sublingual) administration.

Exemplary modes of administration include, but are not limited to, injection, infusion, instillation, inhalation, or ingestion. "Injection" includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, sub capsular, subarachnoid, intraspinal, intracerebro spinal, and intrasternal injection and infusion. In some embodiments, the compositions are administered by intravenous infusion or injection.

By "treatment", "prevention" or "amelioration" of a disease or disorder is meant delaying or preventing the onset of such a disease or disorder, reversing, alleviating, ameliorating, inhibiting, slowing down or stopping the progression, aggravation or deterioration the progression or severity of a condition associated with such a disease or disorder. In one embodiment, at least one symptom of a disease or disorder is alleviated by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%.

As used herein, an amount of a compound or combination effective to treat a disorder (e.g., a disorder as described herein), "therapeutically effective amount", "effective amount" or "effective course" refers to an amount of the compound or combination which is effective, upon single or multiple dose administration(s) to a subject, in treating a subject, or in curing, alleviating, relieving or improving a subject with a disorder (e.g., a disorder as described herein) beyond that expected in the absence of such treatment. Determination of a therapeutically effective amount is well within the capability of those skilled in the art. Generally, a therapeutically effective amount can vary with the subject's history, age, condition, sex, as well as the severity and type of the medical condition in the subject, and administration of other pharmaceutically active agents.

As used herein, a "subject" means a human or animal. Usually the animal is a vertebrate such as a primate, rodent, domestic animal or game animal. Primates include chimpanzees, cynomologous monkeys, spider monkeys, and macaques, e.g. , Rhesus. Rodents include mice, rats, woodchucks, ferrets, rabbits and hamsters. Domestic and game animals include cows, horses, pigs, deer, bison, buffalo, feline species, e.g. , domestic cat, canine species, e.g. , dog, fox, wolf, avian species, e.g. , chicken, emu, ostrich, and fish, e.g. , trout, catfish and salmon. Patient or subject includes any subset of the foregoing, e.g. , all of the above, but excluding one or more groups or species such as humans, primates or rodents. In certain embodiments, the subject is a mammal, e.g. , a primate, e.g. , a human. The terms, "patient" and "subject" are used

interchangeably herein. The terms, "patient" and "subject" are used interchangeably herein. The term "nucleic acid" as used herein refers to a polymeric form of nucleotides, either ribonucleotides or deoxynucleotides or a modified form of either type of nucleotide. The terms should also be understood to include, as equivalents, analogs of either RNA or DNA made from nucleotide analogs, and, as applicable to the embodiment being described, single-stranded (such as sense or antisense) and double- stranded polynucleotides.

As used herein, the terms "modulator of stress granule" and "stress granule modulator" refer to compounds and compositions of Formula (I) that modulate the formation and/or disaggregation of stress granules.

The term "TDP-43 inclusion" as used herein refers to protein-mRNA aggregates that comprise a TDP-43 protein. The TDP-43 protein in a stress granule can be wild-type or a mutant form of TDP-43.

As used herein, the terms "modulator of TDP-43 inclusion" and "TDP-43 inclusion modulator" refer to compounds and compositions of Formula (I) and Formula (II) that modulate the formation and/or disaggregation of cytoplasmic TDP-43 inclusions.

Selected Chemical Definitions

At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term "Ci_₆ alkyl" is specifically intended to individually disclose methyl, ethyl, propyl, butyl, and pentyl.

For compounds of the invention in which a variable appears more than once, each variable can be a different moiety selected from the Markush group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound; the two R groups can represent different moieties selected from the Markush group defined for R. It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

If a compound of the present invention is depicted in the form of a chemical name and as a formula, in case of any discrepancy, the formula shall prevail.

The symbol -~>~ , whether utilized as a bond or displayed perpendicular to a bond indicates the point at which the displayed moiety is attached to the remainder of the molecule, solid support, etc.

The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.

As used herein, "alkyl" refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 24 carbon atoms ("C1-C24 alkyl"). In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C1-C12 alkyl"). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("Ci-C₈ alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C1-C6 alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C1-C5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("Ci-C4alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-C₃ alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("Ci-C₂ alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("Ci alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C₂- Cealkyl"). Examples of Ci-Cealkyl groups include methyl (Ci), ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl (C₄), tert-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅), 3- pentanyl (C₅), amyl (C₅), neopentyl (C₅), 3-methyl-2-butanyl (C₅), tertiary amyl (C₅), and n- hexyl (C₆). Additional examples of alkyl groups include n-heptyl (C₇), n-octyl (C₈) and the like. Each instance of an alkyl group may be independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted Ci_io alkyl (e.g., -CH₃). In certain embodiments, the alkyl group is substituted Ci_6 alkyl.

As used herein, "alkenyl" refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 24 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C2-C24 alkenyl"). In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C2-C1₀ alkenyl"). In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2-C8 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C₂-C₆ alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C₂-C5 alkenyl"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C₂-C₄ alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C₂-C₃ alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C₂ alkenyl"). The one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C₂-C₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1- butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like. Examples of C₂-C₆ alkenyl groups include the aforementioned C₂-4 alkenyl groups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and the like. Additional examples of alkenyl include heptenyl (C₇), octenyl (C₈), octatrienyl (C₈), and the like. Each instance of an alkenyl group may be independently optionally substituted, i.e. , unsubstituted (an "unsubstituted alkenyl") or substituted (a

"substituted alkenyl") with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C₂-₁₀ alkenyl. In certain embodiments, the alkenyl group is substituted C₂-6 alkenyl.

As used herein, the term "alkynyl" refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 24 carbon atoms, one or more carbon-carbon triple bonds ("C₂-C₂₄ alkenyl"). In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C₂-Cio alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C₂-C8 alkynyl"). In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C₂-C₆ alkynyl"). In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C₂-C5 alkynyl"). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C₂-C₄ alkynyl"). In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C₂-C₃ alkynyl"). In some embodiments, an alkynyl group has 2 carbon atoms ("C₂ alkynyl"). The one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).

Examples of C₂-C4 alkynyl groups include ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1- butynyl (C₄), 2-butynyl (C₄), and the like. Each instance of an alkynyl group may be independently optionally substituted, i. e. , unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C₂-₁₀ alkynyl. In certain embodiments, the alkynyl group is substituted C₂-6 alkynyl.

As used herein, the term "heteroalkyl," refers to a non-cyclic stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, P, S, and Si may be placed at any position of the heteroalkyl group. Exemplary heteroalkyl groups include, but are not limited to: -CH₂-CH₂-O-CH₃, -CH₂-CH₂-NH- CH₃, -CH₂-CH₂-N(CH₃)-CH₃, -CH₂-S-CH₂-CH₃, -CH₂-CH₂, -S(0)-CH₃, -CH₂-CH₂-S(0)₂-CH₃, -CH=CH-0-CH₃, -Si(CH₃)₃, -CH₂-CH=N-OCH₃, -CH=CH-N(CH₃)-CH₃, -0-CH₃, and -0-CH₂- CH₃. Up to two or three heteroatoms may be consecutive, such as, for example, -CH₂-NH- OCH₃ and -CH₂-0-Si(CH₃)₃. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as -CH₂O, -NR^CR^D, or the like, it will be understood that the terms heteroalkyl and -CH₂O or -NR^CR^D are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as -CH₂O, -NR^CR^D, or the like.

The terms "alkylene," "alkenylene," or "alkynylene," alone or as part of another substituent, mean, unless otherwise stated, a divalent radical derived from an alkyl, alkenyl, or alkynyl, respectively. The term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. An alkylene, alkenylene, or alkynylene group may be described as, e.g., a Ci-C₆-membered alkylene, Ci-C₆-membered alkenylene, or Ci-C₆-membered alkynylene, wherein the term "membered" refers to the non- hydrogen atoms within the moiety. Still further, for alkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written.

As used herein, "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C₆-C14 aryl"). In some embodiments, an aryl group has six ring carbon atoms ("C₆ aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C₁₀ aryl"; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms ("Ci₄ aryl"; e.g., anthracyl). An aryl group may be described as, e.g., a C₆-Cio-membered aryl, wherein the term "membered" refers to the non-hydrogen ring atoms within the moiety. Aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each instance of an aryl group may be independently optionally substituted, i.e. , unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, the aryl group is unsubstituted C₆-Ci4 aryl. In certain embodiments, the aryl group is substituted C₆-Ci4 aryl. As used herein, "heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). A heteroaryl group may be described as, e.g., a 6-10-membered heteroaryl, wherein the term "membered" refers to the non-hydrogen ring atoms within the moiety.

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Each instance of a heteroaryl group may be independently optionally substituted, i.e. , unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl. Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.

Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6- membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl,

benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Other exemplary heteroaryl groups include heme and heme derivatives.

As used herein, "cycloalkyl" refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms ("C3-C1₀ cycloalkyl") and zero heteroatoms in the non-aromatic ring system. In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C₃-C₈cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C₃-C₆ cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C₃-C₆ cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C5-C1₀ cycloalkyl"). A cycloalkyl group may be described as, e.g., a C4-C7-membered cycloalkyl, wherein the term "membered" refers to the non-hydrogen ring atoms within the moiety. Exemplary C₃-C₆ cycloalkyl groups include, without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like. Exemplary C₃-C₈ cycloalkyl groups include, without limitation, the aforementioned C₃-C₆ cycloalkyl groups as well as cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), cubanyl (C₈), bicyclo[l.l.l]pentanyl (C₅),

bicyclo[2.2.2]octanyl (C₈), bicyclo[2.1.1]hexanyl (C₆), bicyclo[3.1.1]heptanyl (C₇), and the like. Exemplary C₃-C1₀ cycloalkyl groups include, without limitation, the aforementioned C₃-C8 cycloalkyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C1₀), cyclodecenyl (Cio), octahydro-lH-indenyl (C9), decahydronaphthalenyl (C1₀), spiro[4.5]decanyl (C1₀), and the like. As the foregoing examples illustrate, in certain embodiments, the cycloalkyl group is either monocyclic ("monocyclic cycloalkyl") or contain a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic cycloalkyl") and can be saturated or can be partially unsaturated. "Cycloalkyl" also includes ring systems wherein the cycloalkyl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is on the cycloalkyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the cycloalkyl ring system. Each instance of a cycloalkyl group may be independently optionally substituted, i.e. , unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C₃-C1₀ cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C₃-C1₀ cycloalkyl.

"Heterocyclyl" as used herein refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3-10 membered heterocyclyl"). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl"), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. A heterocyclyl group may be described as, e.g., a 3-7-membered heterocyclyl, wherein the term "membered" refers to the non- hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, within the moiety. Each instance of heterocyclyl may be independently optionally substituted, i.e. , unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3- 10 membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-8 membered non- aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.

Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

"Cyano" refers to the radical -CN.

As used herein, "halo" or "halogen," independently or as part of another substituent, mean, unless otherwise stated, a fluorine (F), chlorine (CI), bromine (Br), or iodine (I) atom.

As used herein, "haloalkyl" can include alkyl structures that are substituted with one or more halo groups or with combinations thereof. For example, the terms "fluoroalkyl" includes haloalkyl groups in which the halo is fluorine (e.g., -Ci-C₆ alkyl-CFs_, -Ci-C₆ alkyl-Cf^F). Non- limiting examples of haloalkyl include trifluoroethyl, trifluoropropyl, trifluoromethyl, fluoromethyl, diflurormethyl, and fluroisopropyl.

As used herein, "nitro" refers to -NO₂.

Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocyclyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring- forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring- forming substituents are attached to non-adjacent members of the base structure.

Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al. ,

Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al. , Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

As used herein, a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an "S" form of the compound is substantially free from the "R" form of the compound and is, thus, in enantiomeric excess of the "R" form. The term "enantiomeric ally pure" or "pure enantiomer" denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 99% by weight, more than 99.5% by weight, or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or

stereoisomers of the compound.

In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the

enantiomerically pure R-compound in such compositions can, for example, comprise, at least about 95% by weight R-compound and at most about 5% by weight S-compound, by total weight of the compound. For example, a pharmaceutical composition comprising

enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S- compound in such compositions can, for example, comprise, at least about 95% by weight S- compound and at most about 5% by weight R-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

Compound described herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including ²H (D or deuterium), and ³H (T or tritium); C may be in any isotopic form, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopic form, including ¹⁶0 and ¹⁸0; and the like.

The term "pharmaceutically acceptable salt" is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,

monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et al, Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. These salts may be prepared by methods known to those skilled in the art. Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present invention.

Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.

As used herein, the term "substituted" or "substituted with" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which may itself be further substituted), as well as halogen, carbonyl (e.g., aldehyde, ketone, ester, carboxyl, or formyl), thiocarbonyl (e.g., thioester, thiocarboxylate, or thioformate), amino, -N(R^b)(R^c), wherein each R^b and R^c is independently H or Ci-C₆ alkyl, cyano, nitro, -S0₂N(R^b)(R^c), -SOR^d, and S(0)₂R^d, wherein each R^b, R^c, and R^d is independently H or Ci-C₆ alkyl. Illustrative substituents include, for example, those described herein above. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

Contemplated equivalents of the compounds described above include compounds which otherwise correspond thereto, and which have the same general properties thereof (e.g., the ability to inhibit the formation of TDP-43 inclusions), wherein one or more simple variations of substituents are made which do not adversely affect the efficacy of the compound. In general, the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here.

For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. Also for purposes of this invention, the term "hydrocarbon" is contemplated to include all permissible compounds having at least one hydrogen and one carbon atom. In a broad aspect, the permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds which can be substituted or unsubstituted.

Pharmaceutical Compositions and Routes of Administration

Pharmaceutical compositions containing compounds described herein such as a compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) or pharmaceutically acceptable salt thereof can be used to treat or ameliorate a disorder described herein, for example, a neurodegenerative disease, a cancer, an ophthalmological disease (e.g., a retinal disease), or a viral infection.

The amount and concentration of compounds of Formula (I) (e.g., a compound of

Formula (I-a), (I-b), or (I-c)) in the pharmaceutical compositions, as well as the quantity of the pharmaceutical composition administered to a subject, can be selected based on clinically relevant factors, such as medically relevant characteristics of the subject (e.g., age, weight, gender, other medical conditions, and the like), the solubility of compounds in the pharmaceutical compositions, the potency and activity of the compounds, and the manner of administration of the pharmaceutical compositions. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition), where the compound is combined with one or more pharmaceutically acceptable diluents, excipients or carriers. The compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine. In certain embodiments, the compound included in the pharmaceutical preparation may be active itself, or may be a prodrug, e.g. , capable of being converted to an active compound in a physiological setting. Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms such as described below or by other conventional methods known to those of skill in the art.

Thus, another aspect of the present invention provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. As described in detail below, the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), lozenges, dragees, capsules, pills, tablets (e.g. , those targeted for buccal, sublingual, and systemic absorption), boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; (8) transmucosally; (9) nasally; or (10) intrathecally. Additionally, compounds can be implanted into a patient or injected using a drug delivery system. See, for example, Urquhart, et al., (1994) Ann Rev Pharmacol Toxicol 24: 199-236; Lewis, ed. "Controlled Release of Pesticides and Pharmaceuticals" (Plenum Press, New York, 1981); U.S. Patent No. 3,773,919; and U.S. Patent No. 35 3,270,960. The phrase "therapeutically effective amount" as used herein means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect, e.g., by inhibiting TDP-43 inclusions, in at least a sub-population of cells in an animal and thereby blocking the biological consequences of that function in the treated cells, at a reasonable benefit/risk ratio applicable to any medical treatment.

The phrases "systemic administration," "administered systemically," "peripheral administration" and "administered peripherally" as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The phrase "pharmaceutically acceptable carrier" as used herein means a

pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject antagonists from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; (21) cyclodextrins such as Captisol®; and (22) other non-toxic compatible substances employed in pharmaceutical formulations. As set out above, certain embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming

pharmaceutically acceptable salts with pharmaceutically acceptable acids. The term

"pharmaceutically acceptable salts" in this respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like (see, for example, Berge et al. (1977) "Pharmaceutical Salts", J Pharm Sci 66: 1-19).

The pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g. , from non-toxic organic or inorganic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,

methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.

In other cases, the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.

Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (see, for example, Berge et al., supra). Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral, nasal, topical

(including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.

Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in- water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste. In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulations of the pharmaceutical compositions of the invention for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

Alternatively or additionally, compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the heart, lung, bladder, urethra, ureter, rectum, or intestine. Furthermore, compositions can be formulated for delivery via a dialysis port.

Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.

The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more

pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue. When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

The addition of the active compound of the invention to animal feed is preferably accomplished by preparing an appropriate feed premix containing the active compound in an effective amount and incorporating the premix into the complete ration. Alternatively, an intermediate concentrate or feed supplement containing the active ingredient can be blended into the feed. The way in which such feed premixes and complete rations can be prepared and administered are described in reference books (such as "Applied Animal Nutrition", W.H.

Freedman and CO., San Francisco, U.S.A., 1969 or "Livestock Feeds and Feeding" O and B books, Corvallis, Ore., U.S.A., 1977).

Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinacious biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non- degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.

Preferably, the subject is a mammal. The mammal can be a human, non-human primate, mouse, rat, dog, cat, horse, or cow, but are not limited to these examples. Mammals other than humans can be advantageously used as subjects that represent animal models of disorders associated with neurodegenerative disease or disorder, cancer, or viral infections.

In addition, the methods described herein can be used to treat domesticated animals and/or pets. A subject can be male or female. A subject can be one who has been previously diagnosed with or identified as suffering from or having a neurodegenerative disease or disorder, a disease or disorder associated with cancer, a disease or disorder associated with viral infection, or one or more complications related to such diseases or disorders but need not have already undergone treatment. Dosages

Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

The compound and the pharmaceutically active agent can be administrated to the subject in the same pharmaceutical composition or in different pharmaceutical compositions (at the same time or at different times). When administrated at different times, the compound and the pharmaceutically active agent can be administered within 5 minutes, 10 minutes, 20 minutes, 60 minutes, 2 hours, 3 hours, 4, hours, 8 hours, 12 hours, 24 hours of administration of the other agent. When the inhibitor and the pharmaceutically active agent are administered in different pharmaceutical compositions, routes of administration can be different.

The amount of compound that can be combined with a carrier material to produce a single dosage form will generally be that amount of the inhibitor that produces a therapeutic effect. Generally out of one hundred percent, this amount will range from about 0.1% to 99% of inhibitor, preferably from about 5% to about 70%, most preferably from 10% to about 30%.

Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g. , for determining the LD₅₀ (the dose lethal to 50% of the population) and the ED5₀ (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD5₀/ED5₀. Compositions that exhibit large therapeutic indices are preferred.

The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED5₀ with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC₅₀ (i.e., the concentration of the therapeutic which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Levels in plasma may be measured, for example, by high performance liquid chromatography. The effects of any particular dosage can be monitored by a suitable bioassay.

The dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment. Generally, the compositions are administered so that the compound of Formula (I) (e.g., a compound of Formula (I-a), (I-b), or (I-c)) is given at a dose from 1 ng/kg to 200 mg/kg, 10 ng/kg to 100 mg/kg, 10 ng/kg to 50 mg/kg, 100 ng/kg to 20 mg/kg, 100 ng/kg to 10 mg/kg, 100 ng/kg to 1 mg/kg, 1 μg/kg to 100 mg/kg, 1 μg/kg to 50 mg/kg, 1 μg/kg to 20 mg/kg, 1 μg/kg to 10 mg/kg, 1 μg/kg to 1 mg/kg, 10 μg/kg to 10 mg/kg, 10 μg/kg to 50 mg/kg, 10 μg/kg to 20 mg/kg, 10 μg/kg to 10 mg/kg, 10 μg/kg to 1 mg/kg, 100 μg/kg to 50 mg/kg, 100 μg/kg to 20 mg/kg, 1 mg/kg to 100 mg/kg, 1 mg/kg to 50 mg/kg, 1 mg/kg to 20 mg/kg, 1 mg/kg to 10 mg/kg, 1 μg/kg to 10 mg/kg, 10 mg/kg to 100 mg/kg, 10 mg/kg to 50 mg/kg, 10 mg/kg to 20 mg/kg, or 50 mg/kg to 100 mg/kg. It is to be understood that ranges given here include all intermediate ranges, e.g. , the range 1 mg/kg to 10 mg/kg includes 1 mg/kg to 2 mg/kg, 1 mg/kg to 3 mg/kg, 1 mg/kg to 4 mg/kg, 1 mg/kg to 5 mg/kg, 1 mg/kg to 6 mg/kg, 1 mg/kg to 7 mg/kg, 1 mg/kg to 8 mg/kg, 1 mg/kg to 9 mg/kg, 2 mg/kg to 10 mg/kg, 3 mg/kg to 10 mg/kg, 4 mg/kg to 10 mg/kg, 5 mg/kg to 10 mg/kg, 6 mg/kg to 10 mg/kg, 7 mg/kg to 10 mg/kg, 8 mg/kg to 10 mg/kg, 9 mg/kg to 10 mg/kg, and the like. It is to be further undertood that the ranges intermediate to the given above are also within the scope of this invention, for example, in the range 1 mg/kg to 10 mg/kg, dose ranges such as 2 mg/kg to 8 mg/kg, 3 mg/kg to 7 mg/kg, 4 mg/kg to 6 mg/kg, and the like.

With respect to duration and frequency of treatment, it is typical for skilled clinicians to monitor subjects in order to determine when the treatment is providing therapeutic benefit, and to determine whether to increase or decrease dosage, increase or decrease administration frequency, discontinue treatment, resume treatment or make other alteration to treatment regimen. The dosing schedule can vary from once a week to daily depending on a number of clinical factors, such as the subject's sensitivity to the drugs. The desired dose can be administered at one time or divided into subdoses, e.g. , 2-4 subdoses and administered over a period of time, e.g. , at appropriate intervals through the day or other appropriate schedule. Such sub-doses can be administered as unit dosage forms. In some embodiments, administration is chronic, e.g. , one or more doses daily over a period of weeks or months. Examples of dosing schedules are administration daily, twice daily, three times daily or four or more times daily over a period of 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months or more.

The present invention contemplates formulation of the subject compounds in any of the aforementioned pharmaceutical compositions and preparations. Furthermore, the present invention contemplates administration via any of the foregoing routes of administration. One of skill in the art can select the appropriate formulation and route of administration based on the condition being treated and the overall health, age, and size of the patient being treated. EXAMPLES

Examples are provided below to facilitate a more complete understanding of the invention. The following examples illustrate exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to specific embodiments disclosed in these Examples, which are for purposes of illustration only, since alternative methods can be utilized to obtain similar results.

General. All oxygen and/or moisture sensitive reactions were carried out under N2 atmosphere in glassware that was flame-dried under vacuum (0.5 mmHg) and purged with N2 prior to use. All reagents and solvents were purchased from commercial vendors and used as received, or synthesized according to the footnoted references. NMR spectra were recorded on a Bruker 400 (400 MHz ¾ 75 MHz ¹³C) or Varian (400 MHz 1H, 75 MHz ¹³C) spectrometer. Proton and carbon chemical shifts are reported in ppm (δ) referenced to the NMR solvent. Data are reported as follows: chemical shifts, multiplicity (br = broad, s = singlet, t = triplet, q = quartet, m = multiplet; coupling constant (s) in Hz). Unless otherwise indicated NMR data were collected at 25 °C. Flash chromatography was performed using 100-200 mesh Silica Gel. Liquid

Chromatography/Mas s Spectrometry (LCMS) was performed on Agilent 1200HPLC and 6110MS. Analytical thin layer chromatography (TLC) was performed on 0.2 mm silica gel plates. Visualization was accomplished with UV light and aqueous potassium permanganate (KMn0₄) stain followed by heating.

Table 1: Abbreviations

Abbreviation Definition

j CbzCl benzyl chloroformate

j DAST diethylaminosulfur trifluoride j DCM dichloromethane

j DIAD diisopropylazodicarboxylate

j DMAP dimethylamino pyridine

\ DMF N, N-dimethyl formamide

j HATU 0-(7-azabenzotriazol- l-yl)-N,N,N' ,Ν' - tetramethyluronium hexafluorophosphate

j HPLC high performance liquid chromatography

j i-PrOH isopropyl alcohol

j LCMS liquid chromatography mass spectrum

\ MTBE methyl tert-butyl ether

j TFA trifluoroacetic acid

j THF tetrahydrofuran

j TLC thin layer chromatography

j TMSCN trimethylsilyl cyanide

General Protocol A for Synthesis of Exemplary Compounds

General Protocol A to synthesize exemplary compounds of the invention is described in Scheme 1 and the procedures set forth below.

4 compound 100

Scheme 1: Overview of General Protocol A as applied to Compound 100

Example 1. Synthesis of Compound 100

Preparation of compound 2: To a mixture of phenethylamine 1 (15 g, 124 mmol, 1.0 eq) and 4- chlorobutanoyl chloride (19 g, 136 mmol, 1.1 eq) in 300 mL of DMF was added triethylamine (25 g, 248 mmol, 2.0 eq) in one portion at 20°C under N₂. The mixture was stirred at 20°C for 2hrs, then NaH was added (15 g, 371 mmol, 60% purity, 3.0 eq) at 0°C and the reaction was stirred for 16 hours at 20°C. The reaction was monitored by TLC and allowed to run until complete. The reaction mixture was quenched by addition of 200 mL of aqueous NH₄C1 at 0°C, and then and extracted with three 200 mL portions of ethyl acetate. The combined organic layers were washed twice with 300 mL of brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column

chromatography eluting with a gradient of petroleum ether/ethyl acetate = 10: 1 to 0: 1) to afford compound 2 (20 g, 106 mmol, 85% yield) as a yellow oil.

2 3

Preparation of compound 3: To a mixture of pyrrolidinone 2 (10 g, 53 mmol, 1.0 eq) in 200 mL of dichloromethane was added trimethylsilyl chloride (12 g, 106 mmol, 2.0 eq) in one portion at 0°C under N₂. The mixture was stirred at 0 °C for 30 min, then iodine was added (20 g, 79 mmol, 1.5 eq). The mixture was stirred for 20°C for 16 hrs. The reaction mixture was quenched by addition 200 mL of water at 25 °C and then extracted with three 200 mL portions of dichloromethane. The combined organic layers were washed three times with 250 mL of brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography eluting with a gradient of petroleum ether/ethyl acetate = 15: 1 to 0: 1 to afford compound 3 (2.0 g, 6.4 mmol, 12.0% yield) as a yellow oil.

3

Preparation of compound 4: To a mixture of pyrrolidinone 3 (500 mg, 1.6 mmol, 1.0 eq) in 2 mL of THF was added ethanamine (1.4 g, 31 mmol, 19 eq) in one portion at 20°C under N₂. The mixture was stirred at 20 °C for 16 hrs. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude product compound 4 (300.0 mg, crude) was used into the next step without further purification as a yellow oil.

compound 100

Preparation of compound 100: To a mixture of lH-indole-2-carboxylic acid (100 mg, 621 μιηοΐ, 1.0 eq) and amine 4 (130 mg, 558.5 μιηοΐ, 0.9 eq) in 2 mL of DMF was added HATU (283 mg, 745 μιηοΐ, 1.2 eq), triethylamine (94 mg, 931 u_mol, 1.5 eq) in one portion at 20°C under N₂. The mixture was stirred at 20 °C for 16 hrs. The reaction was monitored by TLC and allowed to run until complete. The reaction mixture was quenched by addition 2 mL of water at 20°C, and then extracted with three 2 mL portions of ethyl acetate. The combined organic layers were washed three times with 2 mL of brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (TFA condition) to afford compound 100 (32 mg, 84 μιηοΐ, 13% yield) as a white solid.

^!H NMR (400MHz, DMSO-cfe) δ ppm 11.60 (s, 1H), 7.62 (br d, J=7.9 Hz, 1H), 7.42 (d, J=8.1 Hz, 1H), 7.33 - 7.25 (m, 4H), 7.24 - 7.16 (m, 2H), 7.07 - 7.02 (m, 1H), 6.81 (br s, 1H), 3.52 (br s, 2H), 3.40 (br d, J=9.3 Hz, 2H), 3.37 - 3.33 (m, 2H), 3.31 - 3.24 (m, 1H), 2.82 (t, J=7.3 Hz, 2H), 2.42 - 2.28 (m, 1H), 2.08 (br s, 1H), 1.20 (br s, 3H)

LCMS (ESI+): m/z 376.1 (M+H)

The following compound was made using analogous chemistry:

Compound 101:

^!H NMR (400 MHz, CHLOROFORM-^) δ ppm 9.17 (br s, 1 H) 7.59 (d, 7=8.0 Hz, 1 H) 7.32 (d, 7=8.4 Hz, 1 H) 7.23-7.15 (m, 6 H) 7.07-7.05 (m, 1 H) 6.77 (s, 1 H) 3.84 (br s, 2 H) 3.54-3.43 (m, 2 H) 3.04-3.02 (m, 1 H) 2.88-2.84 (m, 2 H) 2.28 (br s, 1 H) 2.00 (br s, 1H) 1.83 (br s, 3H) 1.70 (br s, 1H) 1.40-1.18 (m, 3 H)

LCMS (ESI+): m/z 390.1 (M+H) Example 2. Synthesis of Compound 102

Preparation of compound 5: To a mixture of amine 4 (300 mg, 1.3 mmol, 1.0 eq) in 5.00 mL of THF was added BH₃.THF (1 M, 3.9 mL, 3.00 eq) in one portion at 20°C under N₂. The mixture was then heated to 70°C and stirred for 16 hrs. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was quenched by addition 5 mL of methanol at 60°C, and then the reaction mixture was concentrated under reduced pressure to remove solvent to afford compound 5 (280 mg) as a yellow oil. This compound was used directly in the next reaction without further purification.

Preparation of compound 102: To a mixture of lH-indole-2-carboxylic acid (150 mg, 930.8 μιηοΐ, 1.0 eq) and compound 5 (261 mg, 837.7 μιηοΐ, 0.9 eq) in 1 mL of DMF was added HATU (425 mg, 1.1 mmol, 1.2 eq), triethylamine (141 mg, 1.4 mmol, 1.5 eq) in one portion at 20°C under N₂. The mixture was stirred at 20 °C for 16 hours. The reaction was monitored by LCMS and allowed to run until completion. The reaction mixture was quenched by addition 2 mL of water at 20°C, and then extracted with three 2 mL portions of ethyl acetate. The combined organic layers were washed with three 2 mL portions of brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (TFA condition) to afford compound 102(26.1 mg, 52.0 μιηοΐ, 5.6% yield, 94.7% purity, TFA salt) as a yellow oil.

H NMR (400MHz, DMSO-cfe) δ ppm 11.63 - 11.51 (m, 1H), 7.63 - 7.59 (m, 1H), 7.46 - 7.40 (m, 1H), 7.37 - 7.31 (m, 2H), 7.31 - 7.23 (m, 3H), 7.21 - 7.16 (m, 1H), 7.07 - 7.01 (m, 1H), 6.85 (br s, 1H), 3.90 - 3.78 (m, 1H), 3.76 - 3.58 (m, 3H), 3.55 - 3.44 (m, 2H), 3.43 - 3.31 (m, 2H), 3.19 - 3.08 (m, 1H), 3.02 - 2.94 (m, 2H), 2.33 - 2.14 (m, 2H), 1.25 (q, J=6.7 Hz, 3H)

LCMS (ESI+): m/z 362.2 (M+H)

The following compound was prepared analogously: Compound 103:

^!H NMR (400 MHz, CHLOROFORM-^) δ ppm 12.57 (br s, 1 H) 9.28 (br s, 1 H) 7.60 (d, 7=8.0 Hz, 1 H) 7.33 (d, 7=8.0 Hz, 1 H) 7.24-7.05 (m, 7 H) 6.76 (s, 1 H) 3.91 (br s, 1 H) 3.72-3.66 (m, 4 H) 3.52 (m, 1H) 3.17-3.14 (m, 2 H) 3.03-3.01 (m, 2 H) 2.66-2.60 (m, 2 H) 2.06-1.88 (m, 3 H) 1.38-1.35 (m, 3 H)

LCMS (ESI+): m/z 376.2 (M+H)

General Protocol B for Synthesis of Exemplary Compounds

General Protocol B to synthesize exemplary compounds of the invention is described in Scheme 2 and the procedures set forth below.

16 compound 104

Scheme 2: Overview of General Protocol B as applied to Compound 104 Example 3. Synthesis of Compound 104

6⁷

Preparation of compound 7: A solution of compound 6 (5.0 g, 33.1 mmol, 1.0 eq) and 2- bromoethylbenzene (6.1 g, 33.1 mmol, 1.0 eq) in 50 mL of i-PrOH was stirred for 3 days at

90°C. The reaction was monitored by TLC. The reaction mixture was concentrated and the residue was dissolved in 100 mL of methyl tert-butyl ether (MTBE). After stirring for 5 mins, the clear solution was poured, and the oil was washed twice with 100 mL of MTBE. The final oil was concentrated to give 10 g of compound 7 as a yellow solid.

Preparation of compound 8: A solution of K3[Fe(CN)₆] (12.2 g, 2.5 eq) in 50 mL of water was mixed with compound 7 (5.0 g, 14.9 mmol, 1.0 eq) at 20°C. The mixture was cooled to 0°C and then KOH (6.7 g, 8.0 eq) was added into portions to control the temperature no higher than 5°C. After that, DCM (80 mL) was added and the reaction was stirred for 1 hour at 0°C. A solution of K₃[Fe(CN)₆] (7.8 g, 1.6 eq) in 30 mL of H₂0 was added followed by KOH (3.3 g, 4.0 eq) at 0°C and the final reaction was stirred for another 16 hours at 20°C. The reaction was monitored by LCMS and allowed to run until complete. The water layer was separated and IN HC1 was added to pH~2. The solution was extracted with three 100 mL portions of ethyl acetate. The combined organic layers were washed with 200 mL of brine, dried over Na₂S0₄, filtered and the filtrate was concentrated to give 2 g of compound 8 as a white solid.

Preparation of compound 9: A mixture of compound 8 (2.0 g, 8.2 mmol, 1.0 eq) and 10% Pd/C (2.0 g,) in 50 mL of methanol was stirred for 12 hours at 20°C under a ¾ balloon (~ 15 psi). The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was filtered and the filtrate was concentrated to give 2.0 g of compound 9 as a colorless oil.

Preparation of compound 10: To a solution of compound 9 (2.0 g, 8.1 mmol, 1.0 eq) and triethylamine (2.5 g, 24.3 mmol, 3.0 eq) in 20 mL of DCM was added methyl carbonochloridate (1.5 g, 16.2 mmol, 2.0 eq) at 0°C and the reaction was stirred for 2 hours at 20°C. The reaction was monitored by TLC and allowed to run until complete. The reaction mixture was quenched by 20 mL of iced water and extracted twice with 20 mL of DCM. The combined organic layers were washed with 20 mL of brine, dried over Na₂S0₄, filtered and the filtrate was concentrated to give 1.9 g of compound 10 as a white solid.

10 11

Preparation of compound 11: To a solution of compound 10 (1.9 g, 6.1 mmol, 1.0 eq) in 20 mL of methanol was added NaBH₄ (500.0 mg, 13.2 mmol, 2.2 eq) at 0°C and the reaction was stirred for 2 days at 20°C. The reaction was monitored by LCMS and allowed to run until completion. The reaction mixture was poured into 30 mL of iced IN HC1 and then extracted with three 30 mL portions of ethyl acetate. The combined organic layers were washed twice with 50 mL with brine, dried over Na₂S0₄, filtered and the filtrate was concentrated to give a residue (1.4 g). The residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate = 1/1 progressing to ethyl acetate/methanol = 10/1) to give 550 mg of compound 11 as a colorless oil.

Preparation of compound 12: PPI1₃ (450 mg, 1.7 mmol, 2.0 eq) and DIAD (347 mg, 1.7 mmol, 2.0 eq) were dissolved into 3 mL of THF and cooled to 0°C. After stirring for 30 mins, a solution of compound 11 (200 mg, 857 μιηοΐ, 1.0 eq) and isoindoline-l,3-dione (252 mg, 1.7 mmol, 2.0 eq) in 2 Ml of THF was added drop-wise to the reaction mixture. The reaction was stirred for 1 hour at 0°C then 11 hours at 20°C. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was diluted with 10 mL of water and extracted with three 10 mL portions of ethyl acetate. The combined organic layers were washed twice with 20 mL of brine, dried over Na₂S0₄, filtered and the filtrate was concentrated to give the residue. The residue was purified by prep-TLC (S1O₂, ethyl acetate) to give 840 mg of compound 12 as a yellow solid (mixed with Pli₃P=0). This material was used directly in the next reaction without further purification.

Preparation of compound 13: A mixture of compound 12 (310 mg, 855 μιηοΐ, 1.0 eq) and Ν₂Η₄Ή₂0 (85.6 mg, 1.7 mmol, 2.0 eq) in 10 mL of ethanol was stirred for 2 hours at 80°C. The reaction was monitored by TLC and allowed to run until complete. The reaction mixture was filtered to remove the solid and the filtrate was concentrated to give 710 mg of crude compound 13 as a yellow solid mixed with Pli₃P=0. The effective content of 13 was calculated to be -180 mg, which was used in the next step with further purification.

13 14

Preparation of compound 14: To a solution of compound 13 (180 mg, 775 μιηοΐ, 1.0 eq) and triethylamine (235 mg, 2.3 mmol, 3.0 eq) in 10 mL of DCM was added Boc₂0 (203mg, 930 μιηοΐ, 1.2 eq) at 20°C and the reaction was stirred for 1 hour at 20°C. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was concentrated to give the residue. The residue was purified by prep-TLC (S1O₂, ethyl acetate) to give 400 mg of crude compound 14 as a yellow solid.

14 15

Preparation of compound 15: To a solution of compound 14 (257 mg, 773 μιηοΐ, 1.0 eq) in 10 mL of DMF was added NaH (37 mg, 928 μιηοΐ, 60% purity, 1.2 eq) at 0°C. After stirring for 30 mins at 0°C, ethyl iodide (181 mg, 1.2 mmol, 1.5 eq) was added carefully. The reaction was stirred for another 11.5 hours at 0°C. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was quenched with 10 mL of iced saturated aqueous NH₄CI and extracted with three 10 mL portions of ethyl acetate. The combined organic layers were washed twice with 20 mL of brine, dried over Na₂S0₄, filtered and the filtrate was concentrated to give 350 mg of crude compound 15 as a yellow solid.

Preparation of compound 16: A solution of compound 15 (350 mg, 971 μιηοΐ, 1.0 eq) in 10 mL of HCl/ethyl acetate was stirred for 2 hours at 20°C. The reaction was monitored by TLC and allowed to run until complete. The reaction mixture was concentrated to give 300 mg of compound 16 as the HC1 salt isolated as a yellow solid.

16 compound 104

Preparation of compound 104: To a solution of indole-2-carboxyllic acid (75 mg, 463 μιηοΐ, 1.1 eq) and triethylamine (213 mg, 2.1 mmol, 5.0 eq) in 3 mL of DMF was added HATU (176 mg, 463 μιηοΐ, 1.1 eq) at 20°C. After stirring for 30 mins, compound 16 (125 mg, 421 μιηοΐ, 1.0 eq, HC1 salt) was added and the reaction was stirred for 12 hours at 20°C. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was diluted with 10 mL of ¾0 and extracted with three 10 mL portions of ethyl acetate. The combined organic layers were washed twice with 20 mL of brine, dried over Na₂S0₄, filtered and the filtrate was concentrated to give a residue. The residue was purified by prep-TLC (S1O₂, ethyl acetate) then prep-HPLC (TFA condition) to give 5.8 mg of compound 104 as a white solid.

Compound 104:

^!H NMR (400 MHz, CHLOROFORM-^) δ ppm 9.59 (br s, 1H) 7.60 (d, 7=8.0 Hz, 1 H) 7.37 (d, 7=8.4 Hz, 1 H) 7.22-7.18 (m, 3 H) 7.13-7.12 (m, 3 H) 7.06 (m, 1 H) 6.74 (br s, 1H) 3.70-3.68 (m, 2 H) 3.57-3.51 (m, 2 H) 3.44-3.21 (m, 2 H) 3.06-3.04 (m, 2 H) 2.79-2.76 (m, 2H) 2.50-2.46 (m, 1H) 2.25 (br s, 1 H) 2.10-2.06 (m, 1H) 1.80-1.76 (m, 1 H) 1.42 - 1.18 (m, 4 H)

LCMS (ESI+): m/z 404.2 (M+H) General Protocol C for Synthesis of Exemplary Compounds

General Protocol C to synthesize exemplary compounds of the invention is described in Scheme 3 and

compound

Scheme 3: Overview of General Protocol A as applied to Compound 105

Example 4. Synthesis of Compound 105

7 18

Preparation of compound 18 To a mixture of compound 17 (1 g, 5.0 mmol, 1.0 eq) and 2,2,2- trifluoroethanamine (497 mg, 5.0 mmol, 1.0 eq) in 5 mL of methanol was added acetic acid (30 mg, 502 μιηοΐ, 0.1 eq) in one portion at 15°C under N₂. The mixture was stirred at 15 °C for 30 min, then NaBl¾CN (315 mg, 5.0 mmol, 1.0 eq) was added and the mixture was stirred at 15°C for 12 hours. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with 10 mL of water and extracted with three 10 ml portions of ethyl acetate. The combined organic layers were washed twice with 5 ml of brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to afford 1.2 g of the crude compound 18 as a colorless oil which was used in the next step without further purification.

18 19 Preparation of compound 19: To a mixture of compound 18 (226 mg, 802 μιηοΐ, 0.8 eq) in 2 mL of pyridine was added lH-indole-2-carbonyl chloride (180 mg, 1.0 mmol, 1.0 eq) in one portion at 15°C under N₂. The mixture was stirred at 15 °C for 2 hours. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-TLC (S1O₂, petroleum ether:ethyl acetate = 1: 1) to afford 220 mg of compound 19 as a yellow oil.

19 20

Preparation of compound 20: A mixture of compound 19 (200 mg, 470 μιηοΐ, 1.0 eq) in 5 mL of HCl/ethyl acetate (4M) was degassed and purged with N₂ three times and then the mixture was stirred at 15°C for 0.5 hour under N₂ atmosphere. The reaction was monitored by TLC and allowed to run until complete. The reaction mixture was concentrated under reduced pressure to afford 110 mg of the crude product compound 20, as a yellow oil of the HCl salt which was used into the next step without further purification.

20 compound 105

Preparation of compound 105 : To a mixture of compound 20 (80 mg, 221 umol, 1.0 eq, HCl) and 2-bromoethylbenzene (41 mg, 221.1 μιηοΐ, 1.0 eq) in 2.00 mL of DMF was added potassium iodide (18 mg, 111 μιηοΐ, 0.5 eq), triethylamine (45 mg, 442 μιηοΐ, 2.0 eq) in one portion at 15°C under N₂. The mixture was stirred at 15 °C for 16 hours. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was diluted with 5 mL of water and extracted with three 10 ml portions of ethyl acetate. The combined organic layers were washed twice with 5 ml of brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to afford 44.5 mg of compound 105 (33.30% yield, TFA salt) as a white solid.

H NMR (400MHz, CHLOROFORM-^) δ ppm 9.52 (br s, 1H), 7.68 (br d, J=7.9 Hz, 1H), 7.39 (br d, J=8.2 Hz, 1H), 7.33 - 7.22 (m, 4H), 7.15 (br d, J=5.3 Hz, 3H), 6.88 (br s, 1H), 4.70 - 4.54 (m, IH), 4.23 (br d, J=7.7 Hz, 2H), 3.81 (br d, J=9.5 Hz, IH), 3.65 - 3.48 (m, 2H), 3.20 - 3.11 (m, 2H), 3.07 - 2.98 (m, 2H), 2.61 (br t, J=l l.l Hz, IH), 2.43 (br s, IH), 2.11 - 1.93 (m, 3H)

LCMS (ESI+): m/z 430.2 (M+H)

The following compound was prepared analogously:

Compound 106:

^!H NMR (400MHz, CHLOROFORM-^) δ ppm 9.34 (br s, IH), 7.68 (br d, J=8.2 Hz, IH), 7.43 (d, J=8.2 Hz, IH), 7.35 - 7.24 (m, 4H), 7.21 - 7.14 (m, 3H), 6.82 (s, IH), 4.42 (br d, J=7.9 Hz, 3H), 4.07 - 3.88 (m, IH), 3.71 (br d, J=7.1 Hz, 2H), 3.53 - 3.29 (m, 3H), 3.06 (br d, J=8.6 Hz, 2H), 2.64 - 2.51 (m, IH), 2.39 (br s, IH)

LCMS (ESI+): m/z 416.2 (M+H)

General Protocol D for Synthesis of Exemplary Compounds

General Protocol D to synthesize exemplary compounds of the invention is described in Scheme 4 and the procedures set forth below.

pound 107

Scheme 4: Overview of General Protocol D as applied to Compound 107 Example 5: Synthesis of Compound 107

21

Preparation of compound 21: A solution of compound 3 (1.0 g, 3.2 mmol, 1.0 eq) in 10 mL of ΝΗ₃Ή₂0 was stirred for 12 hours at 80 °C. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was extracted with twice with 5 mL portions of ethyl acetate. The combined organic layers were dried over Na₂S0₄, filtered and the filtrate was concentrated to give 610 mg of crude compound 21 as a brown oil.

Preparation of compound 22: To a solution of N-4-methoxybenzylindole-2-carboxylic acid (434 mg, 1.5 mmol, 1.1 eq) and triethylamine (446 mg, 4.4 mmol, 3.0 eq) in 5 mL of DMF was added HATU (587 mg, 1.5 mmol, 1.1 eq) at 15°C. After stirring for 30 mins, compound 21 (300 mg, 1.5 mmol, 1.0 eq) was added and the reaction was stirred for 12 hours at 15°C. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was diluted with 10 mL of H₂O and extracted with three 10 mL portions of ethyl acetate. The combined organic layers were washed twice with 20 mL of brine, dried over Na₂S0₄, filtered and the filtrate was concentrated to give a residue. The residue was purified by prep-TLC (S1O₂, ethyl acetate) to give 350 mg of compound 22 as a yellow oil.

Preparation of compound 23: To a solution of compound 22 (320 mg, 684 μιηοΐ, 1.0 eq) in 2 mL of DMF was added NaH (137 mg, 3.4 mmol, 60% purity, 5.0 eq) at 0°C. After stirring for 30 mins at 0°C, 2,2,2-trifluoroethyl trifluoromethanesulfonate (477 mg, 2.1 mmol, 3.0 eq) was added and the reaction was allowed to warm to 15°C and stirred for 1.5 hour at this temperature. The reaction was monitored by TLC and allowed to run until complete. The reaction mixture was quenched with 10 mL of iced saturated aqueous NH₄C1 and extracted with three 10 mL portions of ethyl acetate. The combined organic layers were washed with twice 20 mL of brine, dried over Na₂S0₄, filtered and the filtrate was concentrated to give the residue. The residue was purified by prep-TLC (S1O₂, petroleum ether/ethyl acetate = 1/1) to give 120 mg of compound 23 as a light-yellow gum.

23 compoun

Preparation of compound 107: To a solution of compound 23 (60 mg, 109 μιηοΐ, 1.0 eq) in 1 mL of DCM was added butane- 1 -thiol (840 mg, 9.3 mmol, 85 eq) followed by TFA (1.5 g, 13.5 mmol, 124 eq) at 15°C and the reaction was stirred for 12 hours at this temperature. The reaction was monitored by LCMS and allowed to run until complete. The reaction was concentrated to give a residue. The residue was purified by prep-HPLC (TFA condition) to give 11.9 mg of compound 107 as a white solid.

Compound 107:

H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.19 (br s, 1 H) 7.60 (d, 7=8.0 Hz, 1 H) 7.34 (d, 7=8.4 Hz, 1 H) 7.26-7.17 (m, 4 H) 7.08-7.06 (m, 3 H) 6.79 (s, 1 H) 4.80-4.09 (m, 3 H) 3.57-3.49 (m, 2 H) 3.37-3.33 (m, 1 H) 3.23-3.19 (m, 1 H) 2.86-2.83 (m, 2 H) 2.38-2.36 (m, 1 H) 2.24-2.22 (m, 1 H)

LCMS (ESI+): m z 430.1 (M+H)

General Protocol E for Synthesis of Exemplary Compounds

General Protocol E to synthesize exemplary compounds of the invention is described in Scheme 5 and the procedures set forth below.

Scheme 5: Overview of General Protocol E as applied to Compound 108

Example 6. Synthesis of Compound 108

Preparation of compound 25: To a solution of compound 24 in 10 mL of DCM was added compound 1A (400 mg, 1.9 mmol, 1.0 eq) followed by Ti(Oi-Pr)₄ (532 mg, 1.9 mmol, 1.0 eq) at 15°C and the reaction was stirred for 16 hours at 15°C. After stirring, TMSCN (278 mg, 2.8 mmol, 1.5 eq) was added drop wise at 15°C and the reaction was stirred for 1 hour at this temperature. The reaction was warmed to 40°C and stirred continuously for another 16 hours at 40°C. The reaction was monitored by TLC and allowed to run until complete. The reaction was concentrated under vacuum, then d 20 mL of ethyl acetate and 0.53 mL of brine were added, and the mixture filtered. The filtrate was washed twice with 30 mL of saturated aqueous Na₂C0₃, dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum to give 600 mg of crude compound 25 as a yellow oil.

25 26

Preparation of compound 26: To the mixture of compound 25 (600 mg, 1.7 mmol, 1.0 eq) in 10 mL of THF was added MeMgBr (3M, 2.78 mL, 5.0 eq) dropwise at -78°C, then the reaction was stirred at -78°C for 0.5 hour and 15°C for 16 hours. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was quenched by adding 50 mL of saturated aqueous NH₄C1 and extracted with three 20 mL portions of ethyl acetate. The combined organic layers were dried with anhydrous Na₂S0₄, filtered and concentrated under vacuum. The residue was purified by prep-HPLC (neutral condition) to give 150 mg of compound 26 as a yellow oil.

26 27

General procedure for preparation of compound 27: To a solution of compound 26 (150 mg, 432 μιηοΐ, 1.0 eq) in 2 mL of DMF was added NaH (52 mg, 1.3 mmol, 60% purity, 3.0 eq) at 0°C, and the mixture was stirred at 0°C for 10 mins. Then ethyl iodide (202 mg, 1.3 mmol, 3.0 eq) was added. The mixture was stirred at 15°C for 2 hours. The reaction was monitored by TLC and allowed to run until complete. The reaction mixture was poured into 30 mL of ice- water and extracted with four 5 mL portions of ethyl acetate. The combined organic layers were dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum to give 200 mg of crude compound 27 as an orange oil.

27 28

Preparation of compound 28: To the mixture of compound 27 (30 mg, 80 μιηοΐ, 1.0 eq) in 500 μΐ_^ of DCM was added TFA (154 mg, 1.4 mmol, 16.9 eq) at 15°C. The reaction mixture was stirred at 15°C for 0.5 hour. The reaction was monitored by TLC and allowed to run until complete. The reaction mixture was concentrated under vacuum to give 50 mg of crude compound 28 (isolated as the tris-TFA salt) as a yellow oil.

28 compound 108

Preparation of compound 108: To the mixture of indole-2-carboxylic acid (14.4 mg, 89 μιηοΐ, 1.1 eq) in 1 mL of DMF was added HATU (34mg, 89 μιηοΐ, 1.1 eq) and triethylamine (41 mg, 405 μιηοΐ, 5.0 eq) in one portion at 15°C. The mixture was stirred at 15°C for 0.5 hour. Then compound 28 (50 mg, 81 μιηοΐ, 1.0 eq, 3TFA salt) was added. The reaction mixture was stirred at 15°C for 12 hours. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was filtered. The filtrate was purified by prep-HPLC (TFA condition) to give 18.3 mg of compound 108(42% yield, TFA salt) as a white solid.

Compound 108:

H NMR δ (400 MHz, METHANOL-^) δ ppm 8.81 (br s, 2 H) 8.03 (br d, 7=5.07 Hz, 2 H) 7.63 (br d, 7=8.16 Hz, 1 H) 7.44 (br d, 7=8.38 Hz, 1 H) 7.22 (br t, 7=7.50 Hz, 1 H) 7.03 - 7.12 (m, 1 H) 6.87 (br s, 1 H) 3.82 (br d, 7=10.36 Hz, 4 H) 3.61 (br s, 2 H) 3.40 (br s, 2 H) 3.17 (br t, 7=12.35 Hz, 2 H) 2.22 (br s, 1 H) 2.12 (br d, 7=13.45 Hz, 2 H) 1.68 (br s, 2 H) 1.29 - 1.45 (m, 9 H)

LCMS (ESI+): m/z 419.2 (M+H)

General Protocol F for Synthesis of Exemplary Compounds

General Protocol F to synthesize exemplary compounds of the invention is described in Scheme 6 and the procedures set forth below.

H

29 31 33

34 35

38 compound 109

Scheme 6: Overview of General Protocol F as applied to Compound 109

Example 7. Synthesis of Compound 109

29 31

Preparation of compound 31: To a solution of oxetan-3-one 30 (3.7 g, 52 mmol, 1.0 eq) in 100 mL of DCM was added compound 29 (19.9 g, 57.1 mmol, 1.1 eq) at 0°C. The mixture was stirred at 20°C for 0.5 hour. The reaction was monitored by TLC and allowed to run until complete. The mixture was concentrated to give a residue. The residue was purified by silica gel chromatography to afford 7.1 g of compound 31 as a yellow oil.

31 32

Preparation of compound 32: To compound 31 (4.0 g, 28 mmol, 1.0 eq) in 30 mL of EtOH was added 10% Pd/C (2.0 g). The mixture was stirred at 25°C for 1 hour under H₂ (15 Psi). The reaction was monitored by TLC and allowed to run until complete. The mixture was filtered and concentrated in vacuo to give 4.0 g of compound 32 as a yellow oil.

32 33

Preparation of compound 33: To compound 32 (4.0 g, 28 mmol, 1.0 eq) in 20 mL of THF and 20 mL of H₂0 was added NaOH (3.3 g, 83 mmol, 3.0 eq) at 20°C. The mixture was stirred at 20°C for 12 hours. The reaction was monitored by TLC and allowed to run until complete. The mixture was concentrated (-0.08Mpa) to remove the THF, the aqueous phase was adjusted to pH = 3, and extracted with three 20 mL portions of ethyl acetate. The combined organic layers were separated and concentrated to give 2.0 g of compound 33 as a yellow oil.

1A 34

Preparation of compound 34: To a solution of compound 1A (1.9 g, 8.6 mmol, 1.0 eq) and compound 33 (1.0 g, 8.6 mmol, 1.0 eq) in 15 mL of DMF was added HATU (3.3 g, 8.6 mmol, 1.0 eq) and triethylamine (2.6 g, 25.8 mmol, 3.0 eq). The mixture was stirred at 25°C for 2 hours. The reaction was monitored by TLC and allowed to run until complete. The mixture was poured into 200 mL of ice-water and extracted with five 30 mL portions of ethyl acetate. The combined organic phases were washed twice with 50 mL of brine, dried with anhydrous Na₂S0₄, filtered and concentrated in vacuo. The residue was purified by column chromatography (S1O₂, eluting with petroleum ether/ethyl acetate = 5/1 progressing to 1/2) to give 2.5 g of crude compound 34 as a colorless oil.

34 35

Preparation of compound 35: To a mixture of compound 34 (2.5 g, 8.0 mmol, 1.0 eq) in 50 mL of DMF was added NaH (1.3 g, 32 mmol, 60% purity, 4.0 eq) at 0°C. The mixture was stirred at 0°C for 0.5 hour. Then ethyl iodide (6.2 g, 40 mmol, 3.2 mL, 5.0 eq) was added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction was monitored by TLC and allowed to run until complete. The mixture was poured into 100 mL of ice cold aqueous NH₄C1 to quench the reaction and then extracted with four 30 mL portions of ethyl acetate. The combined organic phases were washed twice with 50 mL of brine, dried with anhydrous Na₂S0₄, filtered and concentrated in vacuo to give 2.5 g of crude compound 35 as a yellow oil.

Preparation of compound 36: To a solution of compound 35 (2.3 g, 6.8 mmol, 1.0 eq) in 20 mL of THF was added ZrCl₄ (1.7 g, 7.4 mmol, 1.1 eq) at -10°C. The mixture was stirred at -10°C for 1 hour. Then MeMgBr (3M, 15.8 mL, 7.0 eq) was added dropwise at -10°C. The reaction mixture was warmed to 25 °C and stirred for 12 hours. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was quenched by 200 mL of aq. NH₄C1 and extracted with three 50 mL portions of ethyl acetate. The combined organic phases were washed with 30 mL of brine, dried with anhydrous Na₂S0₄, filtered and concentrated in vacuo. The residue was purified by prep-TLC (S1O₂, ethyl acetate/methanol = 5/1) to give 100 mg of crude compound 36 as a light-yellow oil.

Preparation of compound 37: To a solution of compound 36 (100 mg, 268 umol, 1.0 eq) in 500 μΐ_^ of THF was added n-BuLi (2.5 M, 120 μί, 1.1 eq) at 0°C, and the mixture was stirred for 30 minutes at 0°C. To the mixture was added a solution of p-toluenesulfonyl chloride (51 mg, 268 μιηοΐ, 1.0 eq) in 500 of THF and the resulting mixture was allowed to warm to 20°C and stirred for 1 hour. To the reaction mixture was added n-BuLi (2.5 M, 120 μΐ,, 1.1 eq) at 0°C, and the resulting mixture was stirred for 12 hours at 60 °C. The reaction was monitored by

LCMS and allowed to run until complete. The reaction mixture was quenched by 10 mL of aq. NH₄C1 and extracted with four 5 mL portions of ethyl acetate. The combined organic phases were dried with anhydrous Na₂S0₄, filtered and concentrated in vacuo to give 80 mg of crude compound 37 as light yellow oil.

37 38

Preparation of compound 38: The reaction mixture of compound 37 (80 mg, 226 μιηοΐ, 1.0 eq) in ImL of DCM was added TFA (308 mg, 2.7 mmol, 200 μί, 12 eq). The reaction mixture was stirred at 25 °C for 0.5 hour. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was concentrated in vacuo to give 60 mg of crude compound 38 isolated as the TFA salt as a light-yellow oil.

38 compound 109

Preparation of compound 109: To the mixture of indole-2-carboxylic acid (24 mg, 149 μιηοΐ, 1.1 eq) in 1 mL of DMF was added HATU (57 mg, 149 μιηοΐ, 1.1 eq) and triethylamine (41 mg, 407 μιηοΐ, 3.0 eq) in one portion at 15°C. The mixture was stirred at 15°C for 0.5 hour. To the reaction was added compound 38 (50 mg, 136 umol, 1.0 eq, TFA salt). The reaction mixture was stirred at 15°C for 12 hours. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was filtered. The filtrate was purified by prep-HPLC (TFA condition) to give 2.4 mg of compound 109TFA salt as a yellow gum.

Compound 109:

H NMR (400 MHz, METHANOL-^) δ ppm 7.63 (d, 7=7.89 Hz, 1 H) 7.44 (br d, 7=8.33 Hz, 1 H) 7.23 (t, 7=7.67 Hz, 1 H) 7.07 (t, 7=7.45 Hz, 1 H) 6.88 (s, 1 H) 3.79 (br s, 2 H) 3.52 - 3.66 (m, 4 H) 3.17 - 3.26 (m, 3 H) 2.74 (br s, 1 H) 2.05 - 2.23 (m, 4 H) 1.98 (br d, 7=10.96 Hz, 1 H) 1.51 (s, 4 H) 1.26 - 1.38 (m, 9 H)

LCMS (ESI+): m/z 398.3 (M+H)

General Protocol G for Synthesis of Exemplary Compounds

General Protocol G to synthesize exemplary compounds of the invention is described in Scheme 7 and the procedures set forth below.

compoun

Scheme 7: Overview of General Protocol G as applied to Compound 110 Example 8. Synthesis of Compound 110

39 40

Preparation of compound 40: To a solution of compound 39 (1.0 g, 4.4 mmol, 1.0 eq) and compound 1A (1.0 g, 4.8 mmol, 1.1 eq) in 5 mL of DMF was added CS2CO₃ (2.9 g, 8.8 mmol, 2.0 eq) and KI (146 mg, 881 μιηοΐ, 0.2 eq). The mixture was stirred at 100°C for 12 hours. The reaction was monitored by TLC and allowed to run until complete. The reaction mixture was quenched by adding 30 mL of water, and then extracted with three 10 mL portions of ethyl acetate. The combined organic layers were washed with 30 mL of brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate = 10/1 progressing to ethyl acetate) to give 600 mg of compound 40 as a yellow oil.

Preparation of compound 41: To a solution of compound 40 (300 mg, 832 μιηοΐ, 1.0 eq) in 3.5 mL of CHCI₃ was added DAST (1.3 g, 8.3 mmol, 10 eq) at 0°C. The mixture was stirred at 70°C for 14 hours. The reaction was monitored by TLC. The reaction mixture was quenched by adding 5 mL of aq. NaHCC^ at 0°C, and then extracted with three 2 mL portions of DCM. The combined organic layers were washed with 10 mL of brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (S1O₂, petroleum ether/ethyl acetate = 1/1) to give 40 mg of compound 41 as a yellow oil.

Preparation of compound 42: To a solution of compound 41 (135 mg, 353 μιηοΐ, 1.0 eq) in 2 mL of DMF was added NaH (28 mg, 706 μιηοΐ, 60% purity, 2.0 eq) at 0°C. After the addition, the mixture was stirred at this temperature for 10 mins, and then ethyl iodide (110 mg, 706 μιηοΐ, 2.0 eq) was added dropwise at 0°C. The resulting mixture was stirred at 20°C for 1 hour. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was quenched by adding 5 mL of aqueous NH₄C1, and then extracted with three 3 mL portions of ethyl acetate. The combined organic layers were washed with 10 mL of brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give 84 mg of crude compound 42 as a yellow oil, which was used to do next step without purification.

Preparation of compound 43: To a solution of compound 42 (84 mg, 205 μιηοΐ, 1.0 eq) in 2 mL of DCM was added TFA (117 mg, 1.0 mmol, 5.0 eq). The mixture was stirred at 20°C for 1 hour. The reaction was monitored by TLC and allowed to run until complete. The mixture was concentrated to 75 mg of crude compound 43 TFA salt as a yellow oil, which was used in next step without purification.

43 compound 110

Preparation of compound 110: To a solution of indole-2-carboxylic acid (28.5 mg, 177 μιηοΐ, 1.0 eq) in 3 mL of DCM was added HATU (67 mg, 177 μιηοΐ, 1.0 eq) and triethylamine (36 mg,

353 μιηοΐ, 2.0 eq). The mixture was stirred at 25°C for 0.5 hour, then compound 43 (75 mg, 177 μιηοΐ, 1.0 eq, TFA salt) was added. The reaction mixture was stirred at 25°C for 1.5 hour. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was quenched by adding 5 mL of aq. NH₄C1, then extracted with three 3 mL portions of ethyl acetate. The combined organic layers were washed with 10 mL of brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by HPLC (TFA condition) to give 1.9 mg of compound 110 TFA salt as a yellow gum.

Compound 110:

H NMR (400 MHz, METHANOL- d₄) δ ppm 7.61 (br d, 7=7.89 Hz, 1 H) 7.51 (br s, 5 H) 7.43 (d, 7=8.33 Hz, 1 H) 7.21 (t, 7=7.67 Hz, 1 H) 7.06 (t, 7=7.24 Hz, 1 H) 6.83 - 6.89 (m, 1 H) 3.78 (br s, 1 H) 3.58 - 3.72 (m, 4 H) 3.50 (br d, 7=14.03 Hz, 2 H) 3.04 - 3.20 (m, 2 H) 2.83 - 2.99 (m, 2 H) 2.15 (s, 1 H) 2.01 (br d, 7=15.35 Hz, 2 H) 1.63 (br s, 2 H) 1.33 (br t, 7=6.80 Hz, 4 H) 1.05 (br d, 7=7.02 Hz, 4 H)

LCMS (ESI+): m/z 454.3 (M+H)

General Protocol H for Synthesis of Exemplary Compounds

General Protocol H to synthesize exemplary compounds of the invention is described in Scheme

compound 111

Scheme 8: Overview of General Protocol H as applied to Compound 111

Example 9. Synthesis of Compound 111

Preparation of compound 44: To a solution of tert-butyl N-(4-piperidylmethyl)carbamate, 1A

(800 mg, 3.7 mmol, 1.0 eq) and 2-(3-pyridyl)acetic acid (648 mg, 3.7 mmol, 1.0 eq, HCl salt) in

15 mL of DMF was added HATU (1.4 g, 3.7 mmol, 1.0 eq) and triethylamine (756 mg, 7.5 mmol, 1.0 mL, 2.0 eq). The mixture was stirred at 15°C for 12 hours. The reaction was monitored by TLC and allowed to run until complete. The reaction mixture was quenched by the addition of 30 mL of saturated aqueous NH₄C1, and then extracted with two 15 mL portions of ethyl acetate. The combined organic layers were washed with 10 mL of brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give 1.2 g of crude compound 44 as a yellow oil which was used into the next step without further purification

44

Preparation of compound 45: To a suspension of bromo(methyl)magnesium (3M, 2.3 mL, 10.0 eq), TiCl₄ (256 mg, 1.4 mmol, 2.0 eq) in 5 mL of THF was added compound 44 (225 mg, 675 μιηοΐ, 1.0 eq) at -20°C and stirred for 30 min. The mixture was warmed to 20°C and stirred for 12 hrs. The reaction was monitored by TLC and allowed to run until complete. The mixture was quenched by 15 mL of saturated aqueous NH₄C1, then IN HC1 was added until the suspension buffer became clear. It was extracted with three 10 mL portions of ethyl acetate, and the combined organic layers were washed three times with 60 mL of brine, then concentrated to give a residue. The residue was purified by pre-HPLC (TFA condition) to give 50 mg of compound 45 isolated as the TFA salt as a yellow solid.

Preparation of compound 46: A mixture of compound 45 (12 mg, 26 μιηοΐ, 1.0 eq, TFA salt) in 1 mL of DMF was cooled to 0°C, NaH (2.1 mg, 52 μιηοΐ, 60% purity, 2.0 eq) was added and the mixture was stirred for 0.5 hour at 10°C, then ethyl iodide (8.1 mg, 52 μιηοΐ, 2.0 eq) was added. The mixture was stirred at 10°C for another 11.5 hours under N₂ atmosphere. It was monitored by LCMS and allowed to run until complete. The reaction mixture was partitioned between 10 mL of water and 10 mL of ethyl acetate. The organic phase was separated, washed three times with 45 mL of water and 10 mL of brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give 12 mg of crude compound 46 as a yellow gum, which was used into the next step without further purification.

46 47

Preparation of compound 47: A mixture of compound 46 (12 mg, 32 μιηοΐ, 1.0 eq) in 0.4 mL of TFA and 2 mL of DCM was stirred at 11°C for 0.5 hour. The reaction was monitored by TLC and allowed to run until complete. It was evaporated under reduced pressure to give 12 mg of crude product compound 47 TFA salt as a brown gum, which was used directly into the next step without further purification.

Preparation of compound 111: A mixture of indole-2-carboxylic acid (4.9 mg, 30.4 μιηοΐ, 1.0 eq), compound 47 (11.8 mg, 30.4 μιηοΐ, 1.0 eq, TFA salt), triethylamine (9.2 mg, 91 μιηοΐ, 3.0 eq), HATU (11.6 mg, 30.4 μιηοΐ, 1.0 eq) in 1 mL of DMF was stirred at 11°C for 12 hours. The reaction was monitored by LCMS and allowed to run until complete. The mixture was filtered and the filtrate was purified by prep-HPLC (TFA condition) to give 2.5 mg of compound 111TFA salt as a brown gum.

Compound 111:

H NMR (400 MHz, DMSO-d₆) δ ppm 11.53 (br s, 1 H) 8.89 (br s, 1 H) 8.49 (br d, 7=6.84 Hz, 2 H) 7.73 (br d, 7=6.17 Hz, 1 H) 7.60 (br d, 7=8.16 Hz, 1 H) 7.42 (br d, 7=7.50 Hz, 2 H) 7.17 (br t, 7=7.39 Hz, 1 H) 7.13 - 7.20 (m, 1 H) 6.99 - 7.06 (m, 1 H) 6.81 (br s, 1 H) 3.66 - 3.72 (m, 3 H) 2.98 - 3.13 (m, 4 H) 2.55 - 2.73 (m, 2 H) 2.11 (br s, 1 H) 1.92 (br d, 7=12.57 Hz, 2 H) 1.52 (br s, 2 H) 1.04 - 1.29 (m, 10 H)

LCMS (ESI+): m/z 419.3 (M+H) General Protocol I for Synthesis of Exemplary Compounds

General Protocol I to synthesize exemplary compounds of the invention is described in Scheme

53 compound 112

Scheme 9: Overview of General Protocol I as applied to Compound 112 Example 10. Synthesis of Compound 112

48 49

Preparation of compound 49: A mixture of compound 48 (600 mg, 2.8 mmol, 1.0 eq), 2-(3- methoxyphenyl) acetic acid (465 mg, 2.8 mmol, 1.0 eq), HATU (1.1 g, 2.8 mmol, 1.0 eq), triethylamine (425 mg, 4.2 mmol, 1.5 eq) in 8 mL of DMF was stirred at 25 °C for 1 hour. The reaction was monitored by TLC and allowed to run until complete. The reaction mixture was diluted with 10 mL of water and extracted twice with 10 mL of ethyl acetate. The combined organic layers were washed with three 20 mL portions of brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give 1.08 g of compound 49 as a crude yellow oil.

49 50

Preparation of compound 50: A mixture of compound 49 (1.08 g, 3.0 mmol, 1.0 eq) in 10 mL of THF was cooled to -40°C, then ZrCl₄ (764 mg, 3.3 mmol, 1.1 was added at -40°C and the mixture was stirred at -40°C for 0.5 hour, then MeMgBr (3M, 6.0 mL, 6.0 eq) was added slowly keeping the temperature at -20°C. The mixture was stirred at 0°C for 15 min, then stirred at 15°C for 11 hours under N₂ atmosphere. The reaction was monitored by TLC and allowed to run until complete. The reaction mixture was quenched by 40 mL of icy saturated aqueous NH₄CI, then 6 mL of IN HC1 was added until the reaction liquid became clear. The mixture was diluted with 5 mL of saturated aqueous NaHCC^ and extracted with two 20 mL portions of ethyl acetate. The combined organic layers were washed with 30 mL of brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give 0.4 g of compound 50 as a crude yellow oil.

Preparation of compound 51: A mixture of compound 50 (400 mg, 1.1 mmol, 1.0 eq) in 1.5 mL of TFA and 8 mL of dichloromethane was stirred at 15°C for 12 hours. The reaction was monitored by LC-MS and allowed to run until complete. The reaction mixture was concentrated under reduced pressure to give an oil. The residue was purified by prep-HPLC (neutral condition) to give 38 mg of compound 51 as a yellow oil.

Preparation of compound 52: A mixture of compound 51 (38 mg, 138 μιηοΐ, 1.0 eq), methyl 2,2,2-trifluoroacetate (88 mg, 687 μιηοΐ, 5.0 eq) in 2 mL of methanol was stirred at 80°C for 12 hours. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was concentrated under reduced pressure to give 65 mg of the desired compound 52 as a crude yellow oil.

52

Preparation of compound 53: To a solution of compound 52 (65 mg, 175 μιηοΐ, 1.0 eq) in 1 mL of THF was added BH₃.THF (1M, 873 μΐ,, 5.0 eq) at 15°C and the mixture was stirred at 80°C for 12 hours under N₂ atmosphere. The reaction was monitored by LCMS and allowed to run until complete. The mixture was quenched with 2 mL of methanol and 0.5 mL of IN HC1. The mixture was stirred at 80°C for 1 hour, then concentrated to afford an oil. The oil was diluted with 10 mL of water and basified by Na₂CC>3 to pH = 9-10, then extracted twice with 10 mL of ethyl acetate. The combined organic layers were washed with 15 mL of brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give 48 mg of compound 53 as a crude colorless oil.

53 compound 112

Preparation of compound 112: A mixture of compound 53 (38 mg, 106 μιηοΐ, 1.0 eq) in 2 mL of pyridine was added compound indole-2-carboxylic acid chloride (38 mg, 212 μιηοΐ, 2.0 eq) at 15°C, and then the mixture was stirred at 15°C for 1 hour. The reaction was monitored by LCMS and allowed to run until completion. The reaction mixture was concentrated under reduced pressure to give an oil. The oil was diluted with 10 mL of ethyl acetate and extracted with twice with 15 mL of saturated aqueous NH₄C1. The organic layer was washed with 20 mL of brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give an oil. The residue was purified by prep-HPLC (TFA condition) to give 18.5 mg of compound 112 (28% yield) as a white solid.

Compound 112:

H NMR (400MHz, CHLOROFORM-d) δ ppm 10.33 (br s, 1H) 7.66 (d, 7=7.9 Hz, 1H) 7.44 (d, 7=8.2 Hz, 1H) 7.32 - 7.27 (m, 1H) 7.19 (t, 7=7.9 Hz, 1H) 7.16 - 7.11 (m, 1H) 6.88 (s, 1H) 6.79 (dd, 7=2.2, 8.2 Hz, 1H) 6.67 (d, 7=7.5 Hz, 1H) 6.63 (d, 7=1.8 Hz, 1H) 4.61 (br dd, 7=8.5, 16.2 Hz, 1H) 4.27 - 4.16 (m, 1H) 4.10 - 3.97 (m, 1H) 3.94 - 3.83 (m, 1H) 3.76 (s, 3H) 3.68 (br d, 7=11.0 Hz, 1H) 3.27 (br s, 1H) 3.00 - 2.91 (m, 2H) 2.68 (br d, 7=9.5 Hz, 2H) 2.54 (br s, 1H) 2.16 - 2.09 (m, 2H) 2.07 - 2.02 (m, 1H) 1.89 (br d, 7=12.8 Hz, 1H) 1.27 (s, 6H) 1.24 - 1.23 (m, 1H)

LCMS (ESI+): m/z 502.5 (M+H) General Protocol J for Synthesis of Exemplary Compounds

General Protocol J to synthesize exemplary compounds of the invention is described in Scheme 10

61 compound 113

Scheme 10: Overview of General Protocol J as applied to Compound 113

Example 11. Synthesis of Compound 113

54 55

Preparation of compound 55: A mixture of compound 54 (10.0 g, 43.6 mmol, 1.0 eq), 2,2,2- trifluoroethanamine (4.3 g, 43.6 mmol, 1.0 eq), HATU (16.6 g, 43.6 mmol, 1.0 eq), triethylamine (8.8 g, 87.2 mmol, 2.0 eq) in 100 mL of DMF was stirred at 25 °C for 12 hours. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was diluted with 300 mL of ethyl acetate and washed twice with 200 mL of water. The combined organic layers were washed with 300 mL of brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give 18.0 g of crude compound 55 as a white solid.

55 56

Preparation of compound 56: To a mixture of compound 55 (9.0 g, 29.0 mmol, 1.0 eq) in 100 mL of THF was added BH₃.THF (1 M, 87.0 mL, 3.0 eq) at 25°C, and then the mixture was stirred at 70°C for 12 hours under N2 atmosphere. The reaction was monitored by LCMS and allowed to run until complete. The mixture was cooled in an ice bath, and quenched with 300 mL of methanol, then the mixture was stirred at 70°C for 1 hour. It was concentrated to afford 17.2 g of crude compound 56 as a light yellow oil.

Preparation of compound 57: To a solution of compound 56 (2.0 g, 6.8 mmol, 1.0 eq) and

DMAP (825 mg, 6.8 mmol, 1.0 eq) in 20 mL of pyridine was added CbzCl (1.7 g, 10.1 mmol, 1.5 eq) at 0°C. The mixture was stirred at 70°C for 16 hours. The reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure to remove the solvent to afford an orange solid. The residue was partitioned between 20 mL of water and 20 mL of ethyl acetate. The organic phase was separated, washed with 20 mL of brine, dried over anhydrous

Na₂S0₄, filtered and concentrated under reduced pressure to give 1.8 g of crude compound 57 as an orange oil.

Preparation of compound 58: A mixture of compound 57 (1.8 g, 4.2 mmol, 1.0 eq) in 20 mL of HCl/ethyl acetate (4M) was stirred at 20 °C for 1 hour. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was concentrated under reduced pressure to remove the solvent to afford an orange oil. The reaction mixture was partitioned between 20 mL of petroleum ether and 20 mL of water. The aqueous phase was separated, and adjusted to pH >10 with saturated aqueous Na₂CC>3, and extracted with 20 mL of ethyl acetate. The organic phase was separated, washed with 20 mL of brine, dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure to give 200 mg of crude compound 58 as a yellow oil.

Preparation of compound 59: A mixture of compound 58 (380 mg, 1.2 mmol, 1.0 eq), 3- methoxyphenylacetic acid (191 mg, 1.2 mmol, 1.0 eq), HATU (525 mg, 1.4 mmol, 1.2 eq) and triethylamine (349 mg, 3.5 mmol, 3.0 eq) in 4 mL of DMF was stirred at 20°C for 1 hour. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was partitioned between 10 mL of water and 10 mL of ethyl acetate. The organic phase was separated, washed three times with 10 mL of brine, dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure to give an oil. The oil was purified by prep-TLC (S1O₂, petroleum ether/ethyl acetate = 1/1) to give 280 mg of compound 59 as a light yellow oil.

Preparation of compound 60: To a solution of compound 59 (280 mg, 585 μιηοΐ, 1.0 eq) in 3 mL of THF was added triisopropoxy(methyl)titanium (1M, 1.4 mL, 2.4 eq) at 0°C. The mixture was stirred for 15 mins at the same temperature. Then EtMgBr (3M, 780 μί, 4.0 eq) was added, and the result reaction mixture was stirred at 20°C for additional 15 hours 45 mins. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was quenched by adding 5 mL of saturated aqueous NH₄C1 at 0°C, and then diluted with 5 mL of ethyl acetate and extracted with 5 mL of ethyl acetate. The combined organic layers were washed with 5 mL of brine, dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure to give an oil. The oil was purified by prep-TLC (S1O₂, petroleum ether/ethyl acetate = 2/1) to give 90 mg of compound 60 as a light yellow oil.

Preparation of compound 61: To a solution of compound 60 (90 mg, 184 μιηοΐ, 1.0 eq) in 5 mL of methanol was added Pd/C (10 mg, 10% purity) under N₂. The suspension was degassed under vacuum and purged with ¾ several times. The mixture was stirred under ¾ (15 psi) at 20 °C for 15 mins. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was concentrated under reduced pressure to remove the solvent to afford 60 mg of compound 61 as a colorless oil.

Preparation of indole-2-carboxylic acid chloride: To a solution of indole-2-carboxylic acid (200 mg, 1.2 mmol, 1.0 eq) in 2 mL of DCM was added oxalyl chloride (236 mg, 1.9 mmol, 1.5 eq) and DMF (9.1 mg, 124.0 μιηοΐ, 0.1 eq) at 0°C. The mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent to afford 223 mg of crude indole-2-carboxylic acid chloride as a yellow solid, which was used into the next step without further purification.

Preparation of compound 113: To a solution of compound 61 (40 mg, 112 μιηοΐ, 1.0 eq) and triethylamine (34 mg, 337 μιηοΐ, 3.0 eq) in 1 mL of DCM was added indole-2-carboxylic acid chloride (20 mg, 112 μιηοΐ, 1.0 eq) at 0°C. The mixture was stirred at 20°C for 0.5 hour. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was quenched by adding 5 mL of water at 0°C, and then diluted with 5 mL of ethyl acetate and extracted with 5 mL of ethyl acetate. The combined organic layers were washed with 5 mL of brine, dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure to give an oil. The residue was purified by prep-HPLC (TFA condition) to give 31 mg of compound

113(45% yield, TFA salt) as a purple solid.

Compound 113:

H NMR (400 MHz, METHANOL-^) δ ppm 9.60 (s, 1 H) 7.67-7.65 (d, 1 H) 7.42 - 7.40 (d, 1 H) 7.25-7.14 (m, 3 H) 6.83-6.79 (m, 2 H) 6.69-6.64 (m, 2H) 4.33-4.27 (q, 2H) 3.77 (s, 1H) 3.61 (br s, 2 H) 3.51-3.48 (d, 2H) 2.99-2.93 (m, 4H) 2.04 (brs, 1 H) 1.94-1.85 (m, 4 H) 1.46 (brs, 2H) 0.70 (br s, 2H)

LCMS (ESI+): m/z 500.0 (M+H)

General Protocol K for Synthesis of Exemplary Compounds

General Protocol K to synthesize exemplary compounds of the invention is described in Scheme 11 and the procedures set forth below.

compoun

Scheme 11: Overview of General Protocol K as applied to Compound 114 Example 12. Synthesis of Compound 114

Preparation of compound 62: A mixture of compound 58 (300 mg, 908 μιηοΐ, 1.0 eq), 4- fluorophenylacetic acid (140 mg, 908 μιηοΐ, 1.0 eq), HATU (414 mg, 1.1 mmol, 1.2 eq) and triethylamine (184 mg, 1.8 mmol, 2.0 eq) in 5 mL of DMF was stirred at 20°C for 16 hours. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was partitioned between 10 mL of water and 10 mL of ethyl acetate. The organic phase was separated, washed four times with 10 mL of brine, dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure to give an oil. The oil was purified by prep-TLC (S1O₂, petroleum ether:ethyl acetate = 1:2) to give 360 mg of compound 62 as a colorless oil.

Preparation of compound 63: To a solution of compound 62 (200 mg, 429 μιηοΐ, 1.0 eq) in 2 mL of THF was added TiCl₄ (122 mg, 643 μιηοΐ, 1.5 eq) at -40°C. The mixture was stirred for 0.5 hour at the same temperature. Then MeMgBr (3M, 860 μΐ,, 6.0 eq) was added at -40 °C, and the result reaction mixture was stirred at 20°C for additional 15.5 hours. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was quenched by adding 5 mL of saturated aqueous NH₄C1 at 0°C, and then diluted with 5 mL of ethyl acetate and extracted with another 5 mL portion of ethyl acetate. The combined organic layers were washed with 5 mL of brine, dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure to give 130 mg of crude compound 63 as yellow oil, which was used into the next step without further purification.

Preparation of compound 64: To a solution of compound 63 (130 mg, 271 μιηοΐ, 1.0 eq) in 5 mL of methanol was added Pd/C (10 mg, 10% purity) under N₂. The suspension was degassed under vacuum and purged with ¾ several times. The mixture was stirred under ¾ (15 psi) at 20 °C for 0.5 hour. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to remove the solvent to afford a yellow oil. The residue was purified by prep-HPLC (TFA condition) to give 50 mg of compound 64 (TFA salt) as a white solid.

Preparation of compound 114: To a solution of compound 64 (40 mg, 87 μιηοΐ, 1.0 eq, TFA salt) and triethylamine (44 mg, 434 μιηοΐ, 5.0 eq) in 1 mL of DCM was added indole-2-carboxylic acid chloride (15.6 mg, 87 μιηοΐ, 1.0 eq) at 0 °C. The mixture was stirred at 20°C for 15 mins. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was partitioned between 5 mL of water and 5 mL of dichloromethane. The organic phase was separated, washed with 5 mL of brine, dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure to give an oil. The residue was purified by prep-HPLC (TFA condition) to give 15.5 mg of compound 114(30% yield, TFA salt) as a purple solid.

Compound 114:

H NMR (400 MHz, METHANOL-^) δ ppm 11.37 (br s, 1 H) 9.72 (brs, 1 H) 7.61-7.59 (d, 1H) 7.37-7.35 (d, 1 H) 7.25 - 7.20 (m, 1 H) 7.09-7.01 (m, 3 H) 6.94-6.90 (t,2 H) 4.25-4.23 (m, 2H) 3.75-3.4 (m, 4H) 2.94 (s, 2 H) 2.61 (br s, 2 H) 2.1-1.75 (m, 5H) 1.78 (s, 6H)

LCMS (ESI+): m z 490.3 (M+H) General Protocol L for Synthesis of Exemplary Compounds

General Protocol L to synthesize exemplary compounds of the invention is described in Scheme 12 and the procedures set forth below.

Scheme 12: Overview of General Protocol L as applied to Compound 115

Example 13. Synthesis of Compound 115

Preparation of compound 65: A mixture of compound 58 (1.0 g, 3.0 mmol, 1.0 eq), 3- fluorophenylacetic acid (467 mg, 3.0 mmol, 1.0 eq), HATU (1.4 g, 3.6 mmol, 1.2 eq) and triethylamine (919 mg, 9.1 mmol, 3.0 eq) in 10 mL of DMF was stirred at 15°C for 16 hours. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was partitioned between 10 mL of water and 10 mL of ethyl acetate. The organic phase was separated, washed four times with 10 mL of brine, dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure to give an oil. The residue was purified by prep-HPLC (TFA condition) to give 130 mg of compound 65 as a colorless oil.

Preparation of compound 66: To a solution of compound 65 (130 mg, 279 μιηοΐ, 1.0 eq) in 1.5 mL of THF was added triisopropoxy(methyl)titanium (1M, 840 μί, 3.0 eq) at 0°C. The mixture was stirred for 15 mins at the same temperature, then EtMgBr (3M, 650 μί, 7.0 eq) was added, and the resulting reaction mixture was allowed to stirred at 15°C for additional 15 hours 45 mins. The reaction was monitored by LCMS. The reaction mixture was quenched by adding 5 mL of saturated aqueous NH₄CI at 0°C, and then diluted with 5 mL of ethyl acetate and extracted with 5 mL of ethyl acetate. The combined organic layers were washed with 5 mL of brine, dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure to give an oil. The residue was purified by prep-TLC (S1O₂, petroleum ether: ethyl acetate = 2: 1) to give 50 mg of compound 66 as a yellow oil.

Preparation of compound 67: To a solution of compound 66 (50 mg, 105 μιηοΐ, 1.0 eq) in 1 mL of methanol was added Pd/C (10 mg, 10% purity) under N₂. The suspension was degassed under vacuum and purged with ¾ several times. The mixture was stirred under ¾ (15 psi) at 15°C for 1 hour. The reaction was monitored by TLC and allowed to run until complete. The reaction mixture was filtered and concentrated under reduced pressure to remove the solvent to afford 40 mg of crude compound 67 as a colorless oil which was used into the next step without further purification.

Preparation of compound 115: To a solution of compound 67 (30 mg, 87 μιηοΐ, 1.0 eq) in 1 mL of pyridine was added indole-2-carboxylic acid chloride (31 mg, 174 μιηοΐ, 2.0 eq) at 0°C. The mixture was stirred at 15°C for 0.5 hour. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was concentrated under reduced pressure to remove the solvent to afford a yellow oil. The residue was purified by prep-HPLC (TFA condition) to give 11.6 mg of compound 115(22% yield, TFA salt) as a yellow solid.

Compound 115:

H NMR (400 MHz, CHLOROFORM-^) δ ppm 9.62 (s, 1 H) 8.58 (d, 7=8.38 Hz, 1 H) 7.67-7.65 (d, 1 H) 7.42 - 7.40 (d, 1 H) 7.30-7.27 (m, 3 H) 7.18 - 7.15 (s, 1 H) 6.90-6.88 (d, 1H) 6.83-6.82 (m, 2H) 4.34-4.28 (m, 2 H) 3.6 (br s, 2 H) 3.53-3.50 (d, 2H) 3.03 (s, 2H) 2.99 - 2.92 (m, 2 H) 2.07 (brs, 1 H) 1.86 (br s, 4 H) 1.46 (br s, 2H) 0.67 (br s, 2H)

LCMS (ESI+): m/z 488.2(M+H)

General Protocol M for Synthesis of Exemplary Compounds

General Protocol M to synthesize exemplary compounds of the invention is described in Scheme 13 and the procedures set forth below.

Compound 116

Scheme 13: Overview of General Protocol L as applied to Compound 116 Example 14. Synthesis of Compound 116

68 69

Preparation of compound 69: To a solution of 4-methoxyacetophenone 68 (5 g, 33 mmol, 1.0 eq) in 60 mL of tetrahydrofuran was added MeMgBr (3M, 33 mL, 3.0 eq) at 0°C and the reaction was stirred for 12 hours at 20°C. The reaction was monitored by TLC and allowed to run until complete. The reaction mixture was quenched by 15 mL of aqueous NH₄C1 and extracted with three 10 ml portions of ethyl acetate. The combined organic layers were washed twice with 20 ml of brine, dried over Na₂S0₄, filtered and concentrated to give the residue. The residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate = 100: 1 progressing through a gradient to 10: 1) to afford 2.4 g of alcohol 69 as a colorless oil.

69 70

Preparation of compound 70: To a solution of alcohol 69 (600 mg, 3.6 mmol, 1.0 eq) in 3 mL of CCI₄ was added HC1 (12M, 1.5 mL, 5.0 eq) at 0°C and the reaction was stirred for 15 mins at this temperature. The reaction was monitored by TLC and allowed to run until complete. The reaction mixture was separated to isolate the CC1₄ layer. Compound C was obtained as a pink solution in CC1₄.

71 72

Preparation of compound 72: To a mixture of compound 71 (15 g, 65 mmol, 1.1 eq) in 150 mL of DMF was added HATU (25 g, 65 mmol, 1.1 eq) and triethylamine (18 g, 179 mmol, 3.0 eq) in one portion at 25°C. The mixture was stirred at 25°C for 0.5 hour, then 2,2,2- trifluoroethanamine (6 g, 60 mmol, 1.0 eq) was added. The reaction mixture was stirred at 25 °C for 4 hours. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was quenched with 300 ml of ice- water and extracted with three 150 ml portions of dichloromethane. The combined organic layers were washed twice with 200 ml of brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to afford 12 g of compound 72 as a colorless oil.

72 73

Preparation of compound 73: To a mixture of compound 72 (12 g, 38 mmol, 1.0 eq) in 150 mL of THF was added BH₃.THF (1 M, 116 mL, 3.0 eq) at 25 °C, and then the mixture was stirred at 70 °C for 16 hours under N₂ atmosphere. The reaction was monitored by LCMS and allowed to run until complete. The mixture was cooled in a water bath, and quenched with 200 mL of methanol, then the mixture was stirred at 70°C for 1 hour and concentrated to afford 10.6 g of crude compound 73 as a colorless oil.

73 74

Preparation of compound 74: The mixture of compound 73 (200 mg, 675 μιηοΐ, 1.0 eq) and 1H- indole-2-carboxylic acid (109 mg, 675 μιηοΐ, 1.0 eq) in 2 mL of pyridine was added POCI₃ (310 mg, 2 mmol, 3.0 eq) dropwise at 0°C. The mixture was stirred at 25°C for 0.5 hour. The reaction was monitored by LCMS and allowed to run until complete. The reaction was quenched by saturated aqueous NaHCC^ to pH = 7. The mixture was concentrated in vacuo. The residue was dissolved in 10 mL of water, and extracted with three 10 ml portions of ethyl acetate. The combined organic layers were washed twice with 20 ml of brine, dried over Na₂S0₄, filtered and concentrated in vacuo. The residue was purified by prep-TLC (S1O₂, petroleum ether:ethyl acetate = 3: 1) to afford 30 mg of compound 74 as a yellow oil.

74 75

Preparation of compound 75: The mixture of compound 74 (30 mg, 68 μιηοΐ, 1.0 eq) in 1 mL of dichloromethane and TFA (308 mg, 3 mmol, 40.0 eq) was stirred at 25°C for 2 hours. The reaction was monitored by TLC and allowed to run until completion. The reaction mixture was adjusted to pH = 8 by saturated aqueous NaHCC^ and extracted with three 3 ml portions of dichloromethane. The combined organic layers were dried with anhydrous Na₂S0₄, filtered and concentrated in vacuo to afford 30 mg of crude compound 75 as a yellow oil.

compoun

Preparation of compound 116: To a solution of compound 75 (15 mg, 44 μιηοΐ, 1.0 eq) and triethylamine (1.5 g, 14.43 mmol, 326 eq) in 1 mL of acetonitrile was added a solution of compound 70 (8 mg, 44 μιηοΐ, 1.0 eq) in 3 mL of CC1₄ at 0°C. The reaction was stirred for 12 hours at 20°C. The reaction was monitored by TLC and allowed to run until complete. The reaction mixture was concentrated to give a residue. The residue was purified by prep-TLC (S1O₂, petroleum ether/ethyl acetate = 1 : 1), then prep-HPLC (TFA condition) to afford 3.9 mg of compound 116(13% yield, TFA salt) as a white solid.

Compound 116:

^!H NMR (400 MHz, DMSO-d₆) δ ppm 11.72 (br s, 1 H) 7.60 - 7.69 (m, 1 H) 7.36 - 7.52 (m, H) 7.24 (t, 7=7.61 Hz, 1 H) 7.09 (t, 7=7.50 Hz, 1 H) 6.94 (br d, 7=8.38 Hz, 2 H) 4.49 (br d, 7=7.50 Hz, 2 H) 3.73 (s, 3 H) 3.64 (br s, 2 H) 3.14 - 3.28 (m, 1 H) 2.23 - 2.35 (m, 1 H) 1.55 - 1.85 (m, 9 H) 1.00 - 1.20 (m, 1 H)

LCMS (ESI+): m/z 488.3 (M+H) General Protocol N for Synthesis of Exemplary Compounds

General Protocol N to synthesize exemplary compounds of the invention is described in Scheme 14 and the procedures set forth below.

compound 117

Scheme 14: Overview of General Protocol N as applied to Compound 117

Example 15. Synthesis of Compound 117

76 77

Preparation of compound 77: A mixture of lH-pyrrolo[3,2-b]pyridine-2-carboxylic acid, compound 76 (5.0 g, 30.8 mmol, 1.0 eq) in 50 mL of ethyl alcohol was added H₂SO₄ (15.4 g, 154.1 mmol, 98% purity, 5.0 eq) at 15°C, and then the mixture was stirred at 80°C for 12 hours. The reaction was monitored by LCMS and allowed to run until complete. To the reaction mixture was added NaOH (15% in water) to neutralized H₂SO₄ until the pH -7-8. Some brown solids formed which were filtered and washed with 50 mL of water to isolate the crude product (part 1). The filtrate was concentrated under reduced pressure to remove ethyl alcohol and then the aqueous phase was extracted with three 20 mL portions of ethyl acetate. The combined organic layers and part 1 were concentrated under reduced pressure to give 7.9 g of compound 77 as a crude white solid.

Preparation of compound 78: To a mixture of compound 77 (3.95 g, 20.8 mmol, 1.0 eq) in 40 mL of DMF was added NaH (1.25 g, 31.2 mmol, 60% purity, 1.5 eq) at 0°C and then the mixture was stirred at 15°C for 0.5 hour. SEM-Cl (5.2 g, 31.2 mmol, 1.5 eq) was added and the mixture was stirred at 15°C for 0.5 hour under N₂ atmosphere. The reaction was monitored by TLC and allowed to run until complete. The reaction mixture was added dropwise to 150 mL of icy saturated aqueous NH₄CI to quench any remaining NaH, then the mixture was extracted twice with 100 mL of ethyl acetate. The combined organic layers were washed with 100 mL of brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give 12.9 g of compound 78as a brown oil.

Preparation of compound 79: A mixture of ester 78 (6.0 g, 18.7 mmol, 1.0 eq), NaOH (2.3 g, 56.2 mmol, 3.0 eq) in 30 mL of ethyl alcohol and 30 mL of water was stirred at 15°C for 12 hours. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was concentrated under reduced pressure to remove the solvent. The resulting oil was diluted with 30 mL of water and extracted twice with 20 mL of dichloromethane. The mixture was separated to get organic layers which were concentrated under reduced pressure to give an oil. The oil was diluted with 30 mL of water and the acidity adjusted to pH ~6 by HC1 (1 N).

The mixture was extracted with three 20 mL portions of ethyl acetate and the combined organic layers were dried over Na₂S0₄, filtered and concentrated under reduced pressure to give 4.3 g of compound 79as a brown solid. The acidified aqueous layers were extracted with three 10 mL portions of ethyl acetate and the combined organic layers were dried over Na₂S0₄, filtered and concentrated under reduced pressure to give another 130 mg of compound 79 as a yellow solid.

79 80

Preparation of compound 80: To a mixture of compound 79 (0.3 g, 1.0 mmol, 1.0 eq) in 3 mL of dichloromethane was added DMF (37.5 mg, 513.0 μιηοΐ, 0.5 eq) and oxalyl chloride (261 mg, 2.1 mmol, 2.0 eq), and the mixture was stirred at 15°C for 1 hr. The reaction was monitored by TLC and allowed to run until complete. The reaction mixture was concentrated under reduced pressure to give 350 mg of compound 80as a brown solid.

1A 81

Preparation of compound 81: A mixture of compound 1A (2.0 g, 9.3 mmol, 1.0 eq), 2-(3- methoxyphenyl) acetic acid (1.6 g, 9.3 mmol, 1.0 eq), HATU (3.6 g, 9.3 mmol, 1.0 eq), triethylamine (1.4 g, 14.0 mmol, 1.5 eq) in 25 mL of DMF was stirred at 15°C for 1 hour. The reaction was monitored by TLC and allowed to run until complete. The reaction mixture was diluted with 50 mL of water and extracted with three 40 mL portions of ethyl acetate. The combined organic layers were washed with three 30 mL portions of brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give 4.2 g of compound 81 as a crude yellow oil.

Preparation of compound 82: A mixture of compound 81 (4.2 g, 11.6 mmol, 1.0 eq) in 40 mL of THF was cooled to -40°C, then ZrCl₄ (3.0 g, 12.8 mmol, 1.1 eq) was added at -40°C and the mixture stirred at -40°C for 0.5 hour. To the mixture was added slowly MeMgBr (3M, 23.2 mL, 6.0 eq) keeping the temperature at -20°C and then the mixture was stirred at 15°C for 12 hours under N₂ atmosphere. The reaction was monitored by TLC and allowed to run until complete. The reaction mixture was quenched by 40 mL of icy saturated aqueous NH₄C1, then HC1 (1M, -lOmL) added until the reaction liquid turned clear. The mixture was diluted with 40 mL of ethyl acetate and 5 mL aqueous NaHCC^ was added. The organic layer was washed with 30 mL of brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give an oil. The residue was purified by prep-HPLC (neutral condition) to give 500 mg of compound 82 as a yellow gum.

82 83

Preparation of compound 83: A mixture of compound 82 (500 mg, 1.3 mmol, 1.0 eq) in

HCl/ethyl acetate (10 mL, 4M) was stirred at 15°C for 1 hour. The reaction was monitored by TLC and allowed to run until complete. It was evaporated under reduced pressure to give a residue. The residue was diluted with 3 mL of water and basified by 15% NaOH until pH -10, extracted with four 2 mL portions of ethyl acetate, and the combined organic layers were dried over Na₂S0₄, filtered and evaporated under reduced pressure to give 370 mg of compound 83 as a crude yellow oil.

Preparation of compound 84: A mixture of compound 83 (370 mg, 1.3 mmol, 1.0 eq), methyl 2,2,2-trifluoroacetate (857 mg, 6.7 mmol, 5.0 eq) in 4 mL of methanol was stirred at 80°C for 12 hours. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was concentrated under reduced pressure to give 570 mg of the desired compound 84 as a crude yellow oil.

Preparation of compound 85: To a mixture of compound 84 (570 mg, 1.5 mmol, 1.0 eq) in 5 mL of THF was added BH₃.THF (1M, 7.7 mL, 5.0 eq) at 15°C, and then the mixture was stirred at 70 °C for 12 hours under N₂ atmosphere. The reaction was monitored by LCMS and allowed to run until complete. The mixture was quenched with 7 mL of methanol and 3 mL of HC1 (1M), then the mixture was stirred at 70 °C for 1 hour. The mixture was concentrated to afford an oil. The oil was diluted with 3 mL of water and basified by NaOH to pH -9-10, then extracted with four 5 mL portions of ethyl acetate. The combined organic layers were washed with 15 mL of brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give 480 mg of compound 85 as a crude light yellow oil.

Preparation of compound 86: A mixture of compound 85 (80 mg, 223.2 μιηοΐ, 1.0 eq) in 1.2 mL of pyridine was added compound 80 (104 mg, 335 μιηοΐ, 1.5 eq) in 1 mL of dichloromethane at 0°C and then the mixture was stirred at 50°C for 4 hr. The reaction was monitored by TLC and allowed to run until complete. The reaction mixture was concentrated under reduced pressure to give a solid. The residue was purified by prep-TLC (S1O₂, ethyl acetate/methanol = 10: 1) to give 90 mg of the desired compound 86 as a crude yellow solid.

86 compound 117

Preparation of compound 117: A mixture of compound 86 (90 mg, 142.2 μιηοΐ, 1.0 eq) in HCl (1.5 mL, 6M) was stirred at 30°C for 12 hours. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was basified by NaOH (solid) to pH -8-9, then the mixture was concentrated under reduced pressure to give a solid. The residue was purified by prep-HPLC (TFA condition) to give 15.4 mg of compound 117(17% yield) as a white solid.

Compound 117:

ln NMR (400MHz, METHANOL-^) δ ppm 8.73 (d, 7=5.6 Hz, IH) 8.65 (d, 7=8.3 Hz, IH) 7.83 (dd, 7=5.7, 8.3 Hz, IH) 7.31 - 7.22 (m, 2H) 6.93 - 6.78 (m, 3H) 4.52 (q, 7=8.5 Hz, 2H) 3.89 - 3.72 (m, 7H) 3.20 - 3.07 (m, 2H) 3.03 (br s, 2H) 2.32 - 1.94 (m, 3H) 1.84 - 1.41 (m, IH) 1.70 (br s, IH) 1.34 (br s, 6H)

LCMS (ESI+): m/z 503.3 (M+H)

General Protocol O for Synthesis of Exemplary Compounds

General Protocol O to synthesize exemplary compounds of the invention is described in Scheme 15 and the procedures set forth below.

compound 118

Scheme 15: Overview of General Protocol O as applied to Compound 118 Example 16. Synthesis of Compound 118

1^{A 87}

Preparation of compound 87: To a mixture of compound 1A (3.0 g, 14.0 mmol, 1.0 eq), 3- fluorophenylacetic acid (2.2 g, 14.0 mmol, 1.0 eq) and HATU (5.3 g, 14.0 mmol, 1.0 eq) in 30 mL of DMF was added triethylamine (2.8 g, 28.0 mmol, 2.0 eq) at 15°C, and then the mixture was stirred at 15°C for 2 hours under N₂ atmosphere. The reaction was monitored by TLC and allowed to run until complete. The mixture was poured into 50 mL of ice-water and extracted with three 30 mL portions of ethyl acetate. The combined organic layers were washed twice with 50 mL of brine, dried with anhydrous Na₂S0₄, filtered and concentrated in vacuo. The residue was purified by column chromatography (S1O₂, petroleum ether/ethyl acetate = 5/1 progressing to 1/1) to give 5.0 g of crude compound 87 as a light-yellow oil.

87 88

Preparation of compound 88: A mixture of compound 87 (5.0 g, 14.3 mmol, 1.0 eq) in 40 mL of THF was cooled to -40°C, then ZrCl₄ (3.7 g, 15.7 mmol, 1.1 eq) was added at -40°C and the mixture stirred at -40°C for 0.5 hour. MeMgBr (3M, 28.5 mL, 6.0 eq) was added slowly keeping the temperature at -40°C and then the mixture was stirred at 15°C for 12 hours under N₂ atmosphere. The reaction was monitored by TLC and allowed to run until complete. The mixture was poured into 200 mL of ice- water and 20 mL of HC1 (IN) was added. The resulting mixture was extracted with four 50 mL portions of ethyl acetate. The combined organic layers were washed with 100 mL of brine, dried with anhydrous Na₂S0₄, filtered and concentrated in vacuo to give 1.8 g of crude compound 88 as an orange oil.

Preparation of compound 89: To a solution of compound 88 (1.7 g, 3.6 mmol, 1.0 eq) in 20 mL of DCM was added TFA (4.6 g, 40.5 mmol, 3.0 mL, 11 eq) dropwise at 15°C. The reaction mixture was stirred at 15°C for 12 hours. The reaction was monitored by TLC and allowed to run until complete. The reaction mixture was concentrated in vacuo and then 20 mL of H₂O were added. The mixture was extracted with 5 mL of ethyl acetate. The aqueous phase was adjusted by NaOH (15%) to pH = 10, and then extracted with four 10 mL portions of ethyl acetate. The combined organic layers were dried with anhydrous Na₂S0₄, filtered and concentrated in vacuo to give 400 mg of crude compound 89 as a yellow oil.

89 90

Preparation of compound 90: To a mixture of compound 89 (400 mg, 1.5 mmol, 1.0 eq) in 5 mL of methanol was added methyl 2,2,2-trifluoroacetate (581 mg, 4.5 mmol, 3.0 eq) in one portion, and then the reaction mixture was stirred at 70°C for 12 hours. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was concentrated in vacuo. The residue was purified by prep-TLC (S1O₂, ethyl acetate: methanol = 10: 1) to give 350 mg of compound 90 as an orange oil.

Preparation of compound 91: To a mixture of compound 90 (350 mg, 971 μιηοΐ, 1.0 eq) in 2 mL of THF was added BH₃.THF (1M, 4.9 mL, 5.0 eq) dropwise at 15°C. The reaction mixture was stirred at 70°C for 12 hours. The reaction was monitored by LCMS and allowed to run until complete. The reaction was quenched by adding 10 mL of methanol and the mixture was stirred at 70°C for 2 hours. The reaction mixture was concentrated in vacuo to give 200 mg of compound 91 as a colorless oil.

Preparation of compound 92: To a solution of compound 91 (100 mg, 289 μιηοΐ, 1.0 eq) in 2 mL of pyridine was added compound 80 (108 mg, 346 μιηοΐ, 1.2 eq) at 0°C. The mixture was stirred at 40°C for 16 hours. The reaction was monitored by LCMS. The reaction mixture was concentrated in vacuo. The residue was purified by prep-TLC (S1O₂, ethyl acetate: methanol = 10: 1) to give 80 mg of crude compound 92 as a yellow solid.

92 compound 118 Preparation of compound 118: A mixture of compound 92 (80 mg, 129 μιηοΐ, 1.0 eq) in 2 mL of HCl (6 N) was stirred at 40 °C for 12 hours. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was adjusted by NaOH (20%) to pH = 9, and the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (TFA condition) to give 14.4 mg of compound 118(18% yield, TFA salt) as a white solid.

Compound

^!H NMR (400 MHz, METHANOL- d₄) δ ppm 8.70 (d, 7=5.51 Hz, 1 H) 8.58 (d, 7=8.38 Hz, 1 H) 7.78 (dd, 7=8.38, 5.73 Hz, 1 H) 7.32 - 7.41 (m, 1 H) 7.23 (s, 1 H) 7.00 - 7.13 (m, 3 H) 4.51 (br d, 7=8.60 Hz, 2 H) 3.77 (br s, 4 H) 2.99 - 3.19 (m, 4 H) 1.88 - 2.35 (m, 3 H) 1.64 (br s, 1 H) 1.32 (br s, 6 H)

LCMS (ESI+): m/z 491.2 (M+H)

General Protocol P for Synthesis of Exemplary Compounds

General Protocol P to synthesize exemplary compounds of the invention is described in Scheme

97 comound 119

Scheme 16: Overview of General Protocol P as applied to Compound 119 Example 17. Synthesis of Compound 119

81

Preparation of compound 93: To a solution of compound 81 (700 mg, 1.9 mmol, 1.0 eq) in 7 mL of THF was added triisopropoxy(methyl)titanium (1M, 9.7 mL, 5.0 eq) at 0°C. The mixture was stirred for 15 mins at the same temperature, then EtMgBr (3M, 7.7 mL, 12.0 eq) was added, and the resulting reaction mixture was stirred at 25°C for additional 15 hours 45 mins. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was partitioned between 10 mL of saturated aqueous NH₄C1 and 10 mL of ethyl acetate. The organic phase was separated, washed with 10 mL of brine, dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure to give 630 mg of crude compound 93 as a yellow oil, which was used into the next step without further purification.

Preparation of compound 94: A mixture of compound 93 (630 mg, 1.7 mmol, 1.0 eq) in 10 mL of HCl/ethyl acetate (4M) was stirred at 15°C for 0.5 hour. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was partitioned between 5 mL of ethyl acetate and 5 mL of water. The aqueous phase was separated, adjusted to pH >7 with NaOH, and extracted with 5 mL of ethyl acetate, then the organic phase was washed with 5 mL of brine, dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure to give 220 mg of crude compound 94 as a yellow oil, which was used into the next step without further purification.

Preparation of compound 5: A mixture of compound 94 (220 mg, 802 μιηοΐ, 1.0 eq) and methyl 2,2,2-trifluoroacetate (103 mg, 802 μιηοΐ, 1.0 eq) in 3 mL of methanol was stirred at 80°C for 16 hours. The reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure to remove the solvent to afford 240 mg of crude compound 95 as a brown oil, which was used into the next step without further purification.

Preparation of compound 96: To a solution of compound 95 (240 mg, 648 μιηοΐ, 1.0 eq) in 3 mL of THF was added BH₃.THF (1M, 3.2 mL, 5.0 eq) at 0°C. The mixture was stirred at 70°C for 16 hours. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was quenched by adding 5 mL of methanol at 0°C, and then filtered and concentrated under reduced pressure to give an oil. The residue was purified by prep-TLC (S1O₂, petroleum ether:ethyl acetate = 2: 1) to give 130 mg of compound 96 as a light-yellow oil.

Preparation of compound 97: To a solution of compound 96 (46 mg, 129 μιηοΐ, 1.0 eq) in 500 μΐ_^ of pyridine was added compound 80 (80 mg, 257 μιηοΐ, 2.0 eq) at 0°C. The mixture was stirred at 40°C for 16 hours. The reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure to remove the solvent to afford 120 mg of crude compound 97 as a brown oil, which was used into the next step without further purification.

Preparation of compound 119: A mixture of compound 97 (90 mg, 143 μιηοΐ, 1.0 eq) in 1 mL of HC1 (6M) was stirred at 30°C for 16 hours. The reaction was monitored by LCMS and allowed to run until complete. The reaction mixture was adjusted to pH~7 and concentrated to afford a yellow solid. The residue was purified by prep-HPLC (TFA condition) to give 7.3 mg of compound 119(8% yield, TFA salt) as a light yellow solid.

Compound 119:

^!H NMR (400 MHz, METHANOL- d₄) δ ppm 8.71-8.70 (d, IH) 8.64-8.61 (d, IH) 7.82-7.79 (dd, IH) 7.26-7.25 (m, 2H) 6.86-8.84 (d, IH) 6.81-6.79 (m, 2H) 4.49-4.44 (m, 2H) 3.78 (s, 3H) 3.71 (brs, 2H) 3.59 (brs, 2H) 3.54 (brs, 2H) 3.21 (brs, 2H) 2.15-1.99 (m, 3H) 1.62-1.29 (m, 2H) 1.10 (brs, 2H) 0.76 (brs, 2H)

LCMS (ESI+): m/z 501.2 (M+H)

General Protocol Q for Synthesis of Exemplary Compounds

General Protocol Q to synthesize exemplary compounds of the invention is described in Scheme 17 and the procedures set forth below.

compound 120

Scheme 17: Overview of General Protocol A as applied to Compound 120 Example 18. Synthesis of Compound 120

Preparation of compound 200: A mixture of compound 1A (2.0 g, 9.3 mmol, 1.0 eq) in 30 mL of acetic acid was cooled to 0°C, oxetan-3-one (1.0 g, 14 mmol, 1.5 eq), TMSCN (2.3 g, 23 mmol, 2.5 eq) were added at the temperature. The mixture was stirred at 25°C for 12 hours under N₂ atmosphere. The reaction was monitored by TLC and allowed to run until complete. It was basified by 4M NaOH until pH ~8, filtered to give 1.8 g of crude compound 200 as a white solid.

Preparation of compound 201: To a solution of compound 200 (1.8 g, 6.1 mmol, 1.0 eq) in 20 mL of DMF cooled to 0°C was added NaH (536 mg, 13.4 mmol, 60% purity, 2.2 eq) and the mixture was stirred at 25°C for 1 hour. Iodoethane (3.8 g, 24 mmol, 4.0 eq) was added, then the mixture was stirred at 25 °C for another 1 hour under N₂ atmosphere. The reaction was monitored by TLC and allowed to run until complete. The reaction mixture was partitioned between 50 mL of water and 50 mL of ethyl acetate. The organic phase was separated, washed three times with 30 mL of water and 30 mL of brine, dried over Na₂S0₄, filtered and

concentrated under reduced pressure to give 2.2 g of compound 201 as a yellow oil.

Preparation of compound 202: To a mixture of compound 201 (500 mg, 1.6 mmol, 1.0 eq) in 15 mL of THF was cooled to -5°C was added phenyllithium (1.8 M, 2.0 mL, 2.3 eq) dropwise. The mixture was stirred at 10°C for 2 hours under N₂ atmosphere. The reaction was monitored by

TLC and allowed to run until complete. The reaction mixture was partitioned between 20 mL of water and 20 mL of ethyl acetate. The organic phase was separated, washed with 20 mL of brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give 650 mg of compound 202 as a yellow oil which was used into the next step without further purification.

202 203

Preparation of compound 203: A mixture of compound 202 (650 mg, 1.6 mmol, 1.0 eq), Pd/C (1.2 g, 50% purity) in 20 mL of methanol was degassed and purged with ¾ 3 times. The mixture was stirred at 50°C for 2 hours under ¾ atmosphere (50 psi). Then Pd(OH)2/C (2.0 g, 50% purity) was added and the mixture stirred for another 2 hours at 50°C under ¾ (50 psi) atmosphere. The reaction was monitored by LCMS and allowed to run until complete. The mixture was filtered, the filtrate was evaporated under reduced pressure to give 190 mg of compound 203 as a light- yellow gum and which was used into the next step without further purification.

203 204

Preparation of compound 204: A mixture of compound 203 (130 mg, 335 μιηοΐ, 1.0 eq) in 1 mL of TFA and 5 mL of DCM was stirred at 12°C for 0.5 hour. The reaction was monitored by TLC and allowed to run until complete. It was evaporated under reduced pressure to give 130 mg of crude compound 204 TFA salt as a brown gum which was used into the next step without further purification.

204 compound 120

Preparation of compound 120: A mixture of indole-2-carboxylic acid (25 mg, 155 μιηοΐ, 1.0 eq), compound 204 (130 mg, 323 μιηοΐ, 2.1 eq, TFA salt), HATU (65 mg, 171 μιηοΐ, 1.1 eq), triethylamine (47 mg, 465 μιηοΐ, 3.0 eq) in 3 mL of DMF was degassed and purged with N2 3 times. The mixture was stirred at 10°C for 1 hour under N2 atmosphere. The reaction was monitored by LCMS and allowed to run until complete. The mixture was filtered and the filtrate was concentrated in vacuo and purified by prep-HPLC (TFA condition) to give compound 120(13.6 mg, 23.5 μιηοΐ, 15% yield, 94% purity, TFA salt) as a white solid.

Compound 120:

H NMR (400 MHz, CHLOROFORM-^) δ ppm 9.46 (br s, 1 H) 7.67 (d, J=7.94 Hz, 1 H) 7.34 - 7.44 (m, 4 H) 7.26 - 7.33 (m, 3 H) 7.15 (t, J=7.61 Hz, 1 H) 6.83 (br s, 1 H) 5.11 (br d, J=7.50 Hz, 2 H) 4.55 (br d, J=7.72 Hz, 2 H) 3.77 (br s, 2 H) 3.39 (br s, 4 H) 3.15 (br s, 2 H) 2.80 (br s, 2 H) 2.24 (br s, 1 H) 1.97 (br s, 4 H) 1.35 (br s, 3 H)

LCMS (ESI+): m/z 432.3 (M+H)

The following compound was prepared analogously from intermediate 204 and acid 76:

204 compound 121

Preparation of compound 121: A mixture of compound 204 (20 mg, 123 μιηοΐ, 1.0 eq), 1H- pyrrolo[3,2-b]pyridine-2-carboxylic acid 76 (55 mg, 136 μιηοΐ, 1.1 eq, TFA salt), HATU (52 mg, 136 μιηοΐ, 1.1 eq), triethylamine (37 mg, 370 μιηοΐ, 3.0 eq) in 1.5 mL of DMF was degassed and purged with N2 3 times and then the mixture was stirred at 15°C for 12 hours under N2 atmosphere. The reaction was monitored by LCMS and allowed to run until complete. The mixture was filtered and the filtrate was concentrated in vacuo and purified by prep-HPLC (TFA condition) to give 15 mg of compound 121TFA salt as a yellow gum.

Compound 121:

^!H NMR (400 MHz, METHANOL-^) δ ppm 8.68 (d, 7=5.73 Hz, 1 H) 8.63 (d, 7=8.38 Hz, 1 H) 7.79 (dd, 7=8.38, 5.95 Hz, 1 H) 7.34 - 7.49 (m, 5 H) 7.17 (s, 1 H) 4.83 (br d, 7=7.94 Hz, 2 H) 4.54 - 4.72 (m, 1 H) 4.54 - 4.72 (m, 1 H) 3.57 - 3.75 (m, 4 H) 3.35 - 3.56 (m, 2 H) 3.09 - 3.29 (m, 4 H) 1.93 - 2.35 (m, 3 H) 1.70 - 1.88 (m, 1 H) 1.79 (br d, 7=12.35 Hz, 1 H) 1.47 (br s, 1 H) 1.31 (br t, 7=6.84 Hz, 3 H)

LCMS (ESI+): m/z 433.3 (M+H) Example 19. Dose Response Assay for TDP-43 Inhibition

Exemplary compounds of the invention were evaluated for efficacy in inhibiting TDP-43 inclusions using a concentration-response assay. Briefly, PC 12 cells stably expressing a GFP- tagged mutant form of TDP-43 (TDP-43^Q331K::eGFP) were pre-treated for 1 hour with exemplary compounds and stressed with 15 μΜ sodium arsenite for 23 hours to induce TDP-43

aggregation. The inhibitory effect on TDP-43 aggregation was measured using fluorescence microscopy. The ratio of cells with TDP-43 aggregates was calculated based on the total number of cells with detectable GFP expression. A 10-point dose response curve was generated, and the IC₅₀ for each compound tested was determined and is summarized in Table 2 below, wherein A represents an IC₅₀ value of < 250 nM; B represents an IC₅₀ value of 250 nm to 5 μΜ; C represents an IC₅₀ value of 5 μΜ to 10 μΜ; and D represents an IC₅₀ value of > 10 μΜ.

Table 2: Efficacy of Exemplary Compounds of the Invention

( (impound No. Κ .^,ο ^{( η}Μ ⁾

100 C

101 B

102 B

103 D

104 B

105 B

106 C

107 D

108 D

109 D

110 B

111 B

112 B

113 A

114 A 115 A

116 A

117 A

118 A

119 A

120 A

121 A

EQUIVALENTS

It will be recognized that one or more features of any embodiments disclosed herein may be combined and/or rearranged within the scope of the invention to produce further

embodiments that are also within the scope of the invention.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be within the scope of the present invention.

Although the invention has been described and illustrated in the foregoing illustrative embodiments, it is understood that the present disclosure has been made only by way of example, and that numerous changes in the details of implementation of the invention can be made without departing from the spirit and scope of the invention, which is limited only by the claims that follow. Features of the disclosed embodiments can be combined and/or rearranged in various ways within the scope and spirit of the invention to produce further embodiments that are also within the scope of the invention. Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically in this disclosure. Such equivalents are intended to be encompassed in the scope of the following claims.

All patents, patent applications and publications cited herein are hereby incorporated by reference in their entirety. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.

Claims

A compound of Fo

Formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is heterocyclyl, aryl, or heteroaryl;

X is CCR¹) or N;

L¹ is a bond or Ci-C₆ alkylene;

L² is Ci-C₆ alkylene optionally substituted with 1-5 R⁵;

R¹ is hydrogen, halo, or -OR^A;

R² is Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ heteroalkyl, or Ci-C₆ haloalkyl; each R³ is independently Ci-C₆ alkyl, halo, cyano, or oxo, wherein each alkyl is optionally substituted with 1-8 R⁶;

each R⁴ is independently Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ heteroalkyl, Ci-C₆ haloalkyl, halo, or -OR^A, wherein each alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with 1-5 R⁷;

each R⁵ is independently Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ heteroalkyl, Ci-C₆ haloalkyl, halo, cyano, cycloalkyl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with 1-8 R⁸;

or two R⁵ are taken together with the atoms to which they are attached to form a ring optionally substituted with 1-8 R⁸;

each R^A is independently hydrogen or Ci-C₆ alkyl;

each R⁶ , R⁷, and R⁸ is independently Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ heteroalkyl, Ci-C₆ haloalkyl, halo, cyano, oxo, cycloalkyl, or heterocyclyl;

each of n and o is indepedendently 0 or 1, wherein the sum of n + o is not greater than 1; q is independently 0, 1, 2, 3, 4, 5, or 6; and

p is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

2. The compound of claim 1, wherein Ring A is aryl (e.g., phenyl).

3. The com ound of any one of the preceding claims, wherein Ring A is phenyl, (e.g.,

4. The compound of claim 1, wherein Ring A is heteroaryl. 5. The com ound of claim 4, wherein Ring A is a 6-membered heteroaryl (e.g., pyridyl,

6. The compound of claim 1, wherein Ring A is heterocyclyl (e.g., 4-membered heterocyclyl or oxygen-containing heterocyclyl).

7. The compound of claim 6, wherein Ring A is oxetanyl (e.g.,

).

8. The compound of any one of the preceding claims, wherein q is 0 or 1.

9. The compound of any one of the preceding claims, wherein q is 1 and R⁴ is halo (e.g., fluoro) or -OR^A (e.g., -OCH₃).

10. The compound of any one of the preceding claims, wherein X is CR¹ (e.g., CH).

11. The compound of any one of claims 1-9, wherein X is N.

12. The compound of any one of the preceding claims, wherein L¹ is a bond.

13. The compound of any one of claims 1-12, wherein L¹ is Ci-C₆ alkylene (e.g., Ci alkylene).

14. The compound of any one of the preceding claims, wherein L² is Ci-C₂ alkylene (e.g., ethylene or methylene), optionally substituted with 1-5 R⁵.

15. The compound of claim 14, wherein R⁵ is Ci-C₆ alkyl (e.g., methyl) or halo (e.g., fluoro).

16. The compound of claim 14, wherein two R⁵ are taken together with the atoms to which they are attached to form a ring (e.g., cycloalkyl or heterocyclyl, e.g., cyclopropyl or oxetanyl).

17. The compound of any one of the preceding claims, wherein R² is Ci-C₆ alkyl or Ci-C₆ haloalkyl (e.g., ethyl or -CH₂CF₃).

18. The compound of any one of the preceding claims, wherein n is 0 and o is 0.

19. The compound of any one of claims 1-17, wherein n is 1 and o is 0.

20. The compound of any one of claims 1-17, wherein n is 0 and o is 1.

21. The compound of any one of the preceding claims, p is 0.

22. The compound of any one of claims 1-20, wherein p is 1 and R³ is oxo.

23. The compound of any one of the preceding claims, wherein the compound of Formula (I) is selected from:

The compound of claim 1, wherein the compound of Formula (I) is a compound of

Formula (I- a)

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is phenyl, pyridyl, or oxetanyl;

X is CH or N;

L¹ is a bond or methylene;

L² is C₁-C₂ alkylene optionally substituted with 1-5 R⁵;

R² is ethyl or -CH₂CF₃;

R³ is oxo;

each R⁴ is independently fluoro or -OCH₃;

each R⁵ is independently methyl or fluoro;

or two R⁵ are taken together with the atoms to which they are attached to form cyclopropyl or oxetanyl);

each of n and o is indepedendently 0 or 1, wherein the sum of n + o is not greater than 1; q is independently 0 or 1 ; and

p is 0 or 1.

The compound of cl nd of Formula (I-b):

Formula (I-b)

pharmaceutically acceptable salt thereof, wherein:

L¹ is Ci-C₆ alkylene;

L² is Ci-C₆ alkylene substituted with 1-5 R⁵;

R² is Ci-C₆ alkyl or Ci-C₆ haloalkyl; each R³ is independently Ci-C₆ alkyl, halo, cyano, or oxo, wherein each alkyl is optionally substituted with 1-8 R⁶;

each R⁵ is independently Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ heteroalkyl, Ci-C₆ haloalkyl, halo, cyano, cycloalkyl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with 1-8 R⁸; or two R⁵ are taken together with the atoms to which they are attached to form a ring optionally substituted with 1-8 R⁸;

each R^A is independently hydrogen or Ci-C₆ alkyl;

each of n and o is indepedendently 0 or 1, wherein the sum of n + o is equal to 1; q is independently 0, 1, 2, 3, 4, 5, or 6; and

p is 0, 1, 2, 3, 4, 5, 6, 7, or 8. :

pharmaceutically acceptable salt thereof.

The compound of claim 1, wherein the compound is a compound of Formula (I-c):

Formula (I-c)

or a pharmaceutically acceptable salt thereof, wherein:

X is CCR¹) or N;

L¹ is a bond or Ci-C₆ alkylene;

L² is Ci-C₆ alkylene optionally substituted with 1-5 R⁵;

R¹ is hydrogen, halo, or -OR^A;

each R³ is independently Ci-C₆ alkyl, halo, cyano, or oxo, wherein each alkyl is optionally substituted with 1-8 R⁶;

each R^A is independently hydrogen or Ci-C₆ alkyl;

p is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

28. The compound of claim 27, wherein the compound of Formula (I-c) is selected from:

29. A pharmaceutical composition comprising at least one compound according to any one of claims 1-28 or a pharmaceutically acceptable salt thereof in a mixture with a pharmaceutically acceptable excipient, diluent or carrier.

30. A pharmaceutical composition for use in modulating stress granules, wherein the composition comprises a compound according to any one of claims 1-28 or a pharmaceutically acceptable salt thereof.

31. The composition of claim 30, wherein stress granule formation is inhibited.

32. The composition of claim 30, wherein the stress granule is disaggregated.

33. The composition of claim 30, wherein stress granule formation is stimulated.

34. The composition of any of claims 31-33, wherein the stress granule comprises tar DNA binding protein-43 (TDP-43), T-cell intracellular antigen 1 (TIA-1), TIA1 cytotoxic granule- associated RNA binding protein-like 1 (TIAR), GTPase activating protein binding protein 1 (G3BP-1), GTPase activating protein binding protein 2 (G3BP-2), tris tetraprolin (TTP), fused in sarcoma (FUS), or fragile X mental retardation protein (FMRP).

35. A pharmaceutical composition for use in modulating TDP-43 inclusion formation, wherein the composition comprises a compound of Formula (I) (e.g., a compound of Formula (I- a), (I-b), or (I-c)) or a pharmaceutically acceptable salt thereof according to claims 1-28.

36. The composition of claim 35, wherein TDP-43 inclusion formation is inhibited.

37. The composition of claim 35, wherein the TDP-43 inclusion is disaggregated.

38. The composition of claim 35, wherein TDP-43 inclusion formation is stimulated.

39. The composition of any one of claims 35-38, wherein the composition is administered to a subject suffering from a neurodegenerative disease or disorder, a musculoskeletal disease or disorder, a cancer, an ophthalmological disease or disorder, and/or a viral infection.

40. The composition of claim 39, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, frontotemporal dementia (FTD), FTLD-U, FTD caused by mutations in the progranulin protein or tau protein (e.g., progranulin-deficient FTLD), frontotemporal dementia with inclusion body myopathy (IBMPFD), frontotemporal dementia with motor neuron disease, amyotrophic lateral sclerosis (ALS), Huntington' s disease (HD), Huntington's chorea, prion diseases (e.g., Creutzfeld-Jacob disease, bovine spongiform encephalopathy, Kuru, or scrapie), Lewy Body disease, diffuse Lewy body disease (DLBD), polyglutamine (poly Q) -repeat diseases, trinucleotide repeat diseases, cerebral degenerative diseases, presenile dementia, senile dementia, Parkinsonism linked to chromosome 17 (FTDP- 17), progressive supranuclear palsy (PSP), progressive bulbar palsy (PBP), psuedobulbar palsy, spinal and bulbar muscular atrophy (SBMA), primary lateral sclerosis, Pick's disease, primary progressive aphasia, corticobasal dementia, HIV-associated dementia, Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies, Down's syndrome, multiple system atrophy, spinal muscular atrophy (SMA, e.g., SMA Type I (e.g., Werdnig-Hoffmann disease) SMA Type II, SMA Type III (e.g., Kugelberg-Welander disease), or congenital SMA with arthrogryposis), progressive spinobulbar muscular atrophy (e.g., Kennedy disease), post- polio syndrome (PPS), spinocerebellar ataxia, pantothenate kinase-associated neurodegeneration (PANK), spinal degenerative disease/motor neuron degenerative diseases, upper motor neuron disorder, lower motor neuron disorder, age-related disorders and dementias, Hallervorden-Spatz syndrome, cerebral infarction, cerebral trauma, chronic traumatic encephalopathy, transient ischemic attack, Lytigo-bodig (amyotrophic lateral sclerosis-parkinsonism dementia), Guam- Parkinsonism dementia, hippocampal sclerosis, corticobasal degeneration, Alexander disease, Apler' s disease, Krabbe's disease, neuroborreliosis, neurosyphilis, Sandhoff disease, Tay-Sachs disease, Schilder' s disease, Batten disease, Cockayne syndrome, Kearns-Sayre syndrome, Gerstmann-Straussler-Scheinker syndrome and other transmissible spongiform

encephalopathies, hereditary spastic paraparesis, Leigh' s syndrome, demyelinating diseases, neuronal ceroid lipofuscinoses, epilepsy, tremors, depression, mania, anxiety and anxiety disorders, sleep disorders (e.g., narcolepsy, fatal familial insomnia), acute brain injuries (e.g., stroke, head injury), autism, and any combination thereof.

41. The composition of claim 39, wherein the musculoskeletal disease is selected from the group consisting of muscular dystrophy, facioscapulohumeral muscular dystrophy (e.g., FSHDl or FSHD2), Freidrich's ataxia, progressive muscular atrophy (PMA), mitochondrial encephalomyopathy (MELAS), multiple sclerosis, inclusion body myopathy, inclusion body myositis (e.g., sporadic inclusion body myositis), post-polio muscular atrophy (PPMA), motor neuron disease, myotonia, myotonic dystrophy, sacropenia, multifocal motor neuropathy, inflammatory myopathies, and paralysis.

42. The composition of claim 39, wherein the cancer is selected from the group consisting of breast cancer, a melanoma, adrenal gland cancer, biliary tract cancer, bladder cancer, brain or central nervous system cancer, bronchus cancer, blastoma, carcinoma, a chondrosarcoma, cancer of the oral cavity or pharynx, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma, hepatic carcinoma, hepatoma, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, non-small cell lung cancer, ophthalmological cancer, osteosarcoma, ovarian cancer, pancreas cancer, peripheral nervous system cancer, prostate cancer, sarcoma, salivary gland cancer, small bowel or appendix cancer, small-cell lung cancer, squamous cell cancer, stomach cancer, testis cancer, thyroid cancer, urinary bladder cancer, uterine or endometrial cancer, vulval cancer, and any combination thereof.

43. The composition of claim 42, wherein the non-Hodgkin' s lymphoma is selected from a B-cell lymphoma and a T-cell lymphoma.

44. The composition of claim 43, wherein the B-cell or T-cell lymphoma is selected from the group consisting of diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, marginal zone B-cell lymphomas, extranodal marginal B-cell lymphomas, mucosa-associated lymphoid tissue (MALT) lymphomas, modal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, Waldenstrom' s macroglobulinemia, hairy cell leukemia, primary central nervous system (CNS) lymphoma, precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, smoldering adult T-cell lymphoma, chronic adult T-cell lymphoma, acute adult T-cell lymphoma, lymphomatous adult T-cell lymphoma, angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma nasal type (ENKL), enteropathy-associated intestinal T-cell lymphoma (EATL), and anaplastic large cell lymphoma (ALCL).

45. The composition of claim 39, wherein the ophthalmological disease is selected from the group consisting of macular degeneration, age-related macular degeneration, diabetes retinopathy, histoplasmosis, macular hole, macular pucker, Bietti' s crystalline dystrophy, retinal detachment, retinal thinning, retinoblastoma, retinopathy of prematurity, Usher's syndrome, vitreous detachment, Refsum disease, retinitis pigmentosa, onchocerciasis, choroideremia, Leber congenital amaurosis, retinoschisis, juvenile retinoschisis, Stargardt disease, ophthalmoplegia, and any combination thereof.

46. The composition of claim 39, wherein the viral infection is caused by a virus selected from the group consisting of West Nile virus, respiratory syncytial virus (RSV), herpes simplex virus 1, herpes simplex virus 2, Epstein-Barr virus (EBV), hepatitis virus A, hepatitis virus B, hepatitis virus C, influenza viruses, chicken pox, avian flu viruses, smallpox, polio viruses, HIV- 1, HIV-2, Ebola virus, and any combination thereof.

47. The composition of any one of claims 39-46, wherein the subject is a mammal.

48. The composition of claim 47, wherein the subject is human.

49. The composition of any one of claims 39-48, further comprising the step of diagnosing the subject with the neurodegenerative disease or disorder, musculoskeletal disease or disorder, cancer, ophthalmological disease or disorder, or viral infection prior to onset of said

administration.

50. The composition of any of claims 39-49, wherein pathology of said neurodegenerative disease or disorder, said musculoskeletal disease or disorder, said cancer, said ophthalmological disease or disorder, and said viral infection comprises stress granules.

51. The composition of any of claims 39-50, wherein pathology of said neurodegenerative disease, said musculoskeletal disease or disorder, said cancer, said ophthalmological disease or disorder, and said viral infection comprises TDP-43 inclusions.