Compositions and methods for inhibiting kinases

Abstract

The present disclosure provides methods for the prevention or treatment of multiple system atrophy using Abelson-family tyrosine kinase inhibitors.

Description

Related Applications This application claims the benefit of priority to U.S. Provisional Application No. 63 / 562,837, filed March 8, 2024, the entire contents of which are incorporated herein by reference. Background of the Invention Multiple System Atrophy (MSA) is a rare but rapidly progressing neurodegenerative disorder, with an estimated prevalence ranging from 1.9-4.9 / 100,000. MSA is a synucleinopathy, related to but distinct from Parkinson’s Disease (PD) and Dementia with Lewy Body (DLB). All three diseases share the characteristic of aggregates forming in neural cells and tissues of the non-essential protein a-synuclein However, in contrast to PD and DLB, aggregates of a-synuclein in MSA form in cells known as oligodendroglia and these aggregates so formed are termed Glial Cytoplasmic Inclusions (GCIs). MSA emerges in the fifth to sixth decade of life and usually progresses rapidly, limiting patient mobility, affecting speech, swallowing, heart function and other vital activities with most patients succumbing to the disease 6-9 years after symptomatic onset. Presently, no treatment options exist for MSA and disease modification to alter the course of the disease remains an urgent unmet medical need. Furthermore, treatments effective for Parkinson’s Disease are generally not effective for MSA. Accordingly, improved agents for treating MSA are needed. Summary of the Invention In certain aspects, the invention provides methods of treating or preventing multiple system atrophy (MSA), comprising administering to a subject a compound having a structure of Formula (I) or a pharmaceutically acceptable salt thereof Formula (I) wherein, independently for each occurrence, R1 is selected from hydrogen or lower alkyl; and 5 Cy1 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl. In certain embodiments, R1 is deuterated. In certain embodiments, the compound is pharmaceutically acceptable salt thereof. or a 10          In certain embodiments, the compound is a pharmaceutically acceptable salt thereof. Brief Description of the Drawings FIG. 1 shows post-natal PLP mice being evaluated behaviorally by the ability to traverse a notched beam of 1 meter length. Bar graphs show the percentage of hind limb errors on a notched bar test in WT and PLP mice aged 11 weeks (Baseline) and 31 weeks (after 20 weeks of daily treatment with vehicle or compound 809 oral gavage). Bars represent group mean (+ standard error). Open circles and triangles represent female and male individual values, respectively. Data were analyzed using one-way ANOVA followed by Turkey’s multiple comparisons test. **p<0.01, ***p<0.001 vs Wild Type; # p<0.05 and ## p<0.01 vs PLP-SYN + Vehicle. FIG. 2 shows post-natal PLP mice being evaluated behaviorally by the ability to traverse a caged beam of 1 meter length. Bar graphs show the number of errors and error to step ratio crossing the caged beam test in WT and PLP mice at 31 weeks (after 20 weeks of Ix / day oral gavage with vehicle or compound 809). Bars represent group mean (+ standard error). Open circles and triangles represent female and male individual values, respectively. Data were analyzed using one-way ANOVA followed by Turkey’ s multiple comparisons test. *p<0.05 vs Wild Type; ## p<0.01 vs PLP-SYN + Vehicle. FIG. 3A shows a western blot demonstrating reduction of pathologic a-synuclein identified using an antibody that recognizes the post-translational phosphorylation of Ser129 of a-synuclein (phospho-S129) in a-synuclein that occurs only in the pathological form of the protein. The western blot demonstrates the reduction in pathological a-synuclein following daily oral treatment with compound 809 treatment (standardized by actin) in the soluble fraction of striatal protein extracts of the different groups (G1: wild type mice treated with vehicle; G2: PLP mouse model treated with vehicle; G3: PLP mouse model treated with 150 mg / kg of compound 809). Bars represent the group mean + SEM; open circles and triangles represent the individual animal values (triangles: males; open circles: females). The data were analyzed with a one-way ANOVA followed by Tukey’s post hoc test between all groups. *p<0.05, ****p<0.0001 vs Gl. #p<0.05, ####p<0.0001 vs G2. FIG. 3B shows a western blot demonstrating reduction of phospho-S129 by compound 809 treatment (standardized by actin) in the insoluble fraction of striatal protein extracts of the different groups (Gl: wild type mice treated with vehicle; G2: PLP mouse model treated with vehicle; G3: PLP mouse model treated with 150 mg / kg of compound 809). Bars represent the group mean + SEM; open circles and triangles represent the individual -3 - animal values (triangles: males; open circles: females). The data were analyzed with a oneway ANOVA followed by Tukey’s post hoc test between all groups. *p<0.05, ****p<0.0001 vs Gl. #p<0.05, ####p<0.0001 vs G2. FIG. 4 shows alpha-synuclein expressing C57B1 / 6 mice undergoing monthly behavioral analyses as performed using mixed-model analysis of the time it took for lesioned mice to cross a 1-meter transverse beam. For multiple comparison analysis, each month was analyzed relative to the baseline measures pre-lesion. FIG. 5 shows that glial cytoplasmic inclusions (GCIs) from human MSA patient brain contain Tyr39-phosphorylated and Ser129-phosphorylated alpha-synuclein aggregates. 40 pm coronal sections of human postmortem brain from MSA patients with a diagnosis of “definite MSA” were immunostained using antibodies to detect pathological forms of alpha-synuclein, phosphorylated at Ser129 (pS129 a-Syn) and phosphorylated at Tyr39 (pY39 a-Syn). Putamenal sections (left column) show positive staining of glial cytoplasmic inclusions (GCIs) throughout the entire putamen with both pS129 and pY39. Nigral sections (second column from left) show positive staining of GCIs throughout the substantia nigra, in close vicinity to neuromelanin positive neurons. Scale bars = 25 pm. FIG. 6 shows immunofluorescence results demonstrating tropism of OligOO 1 to oligodendrocytes in rodent brain. OligOO 1 expressing GFP colocalized with oligodendrocytes (Olig2 Abs) in the corpus callosum and striatum, but not with neurons (NeuN Abs) or astrocytes (GFAP Abs) in rodent brain, establishing the tropism of OligOO 1 in the primary cell type affected in MSA. FIG. 7 shows a demonstration of an MSA model in the nigrostriatal region of rat brain. Five months following striatal injection of OligOO 1-a-Syn, widespread expression of pS 129 is seen throughout the striatum (A) in the corpus callosum (B) and striatal patch matrix (B’). Additionally, pS129 staining is seen in the substantia nigra (C) and confocal microscopy indicates these inclusions are found in TH+ DA neurons. Decreased Luxol Fast Blue staining (E top left) indicates demyelination in the striatum in areas associate with pS129 expression (E bottom left), with no loss of myelin seen in GFP injected animals (E right pannels) indicating demyelination is specific to alpha-synuclein expression. FIG. 8A shows GCIs of MSA modeled in rat and NHP and compared to human patient brain stained for pY39 and pS129 alpha-synuclein aggregates. 40 pm coronal sections of human postmortem brain from MSA patients with a diagnosis of “definite MSA” were -4 - immunostained using antibodies to detect pathological forms of alpha synuclein, phosphorylated at serine residue 129 (pS129) and phosphorylated at tyrosine residue 39 (pY39). Punctate staining with antibodies specific for the indicated phosphorylated synuclein residue are seen in rat and NHP models and appear similarly to that seen in MSA patient brain. Putamenal sections show positive staining of glial cytoplasmic inclusions (GCIs) throughout the entire putamen for both pS129 and pY39. Nigral sections (second column from left) show positive staining of GCIs throughout the extent of the substantia nigra (punctate staining), in close vicinity to neuromelanin positive neurons. Similar to the human postmortem cases, following injection of OligOOl-a-Syn vector in the striatum, robust pS129 staining was seen in both rat and nonhuman primate cases. Level matched striatal sections of rat and nonhuman primate injected with OligOOl-a-Syn also show pY39 staining (bottom panel, right columns) indicating that our model recapitulates both pathological species of a-Synuclein that are present in the human postmortem cases. FIG. 8B shows superposition panels demonstrating that GCIs carry pS129 and pY39 simultaneously at high magnification in the putamen. Scale bars = 25 pm. Detailed Description of the Invention Abelson-family tyrosine kinases (ATKs), such as c-Abll, c-Abl2, c-Kit (also known as SCF), PDGFRa, and PGDFRb, collectively referred to as c-Abl hereafter, have been implicated in certain neurological diseases. c-Abl phosphorylation of several key proteins drives the neurodegenerative disease process in Parkinson’s disease and in Multiple System Atrophy (MSA). Following internalization, c-Abl phosphorylation of alpha-synuclein at tyrosine 39 (Tyr39) and serine 129 (Ser129)) promote aggregation of alpha-synuclein and drive the deleterious effects of alpha-synuclein on neurons in the brain. Similarly, c-Abl acts to inactivate the protein parkin, an essential regulator of mitochondrial function and biogenesis. Aberrant activation of c-Abl can down-regulate parkin activity by phosphorylation at Tyr143. Thus, the process of neurodegeneration in Parkinson’s and MSA is driven by alpha-synuclein aggregate internalization, followed by c-Abl activation, which in turn phosphorylates several protein factors driving the degenerative disease process. A c-Abl inhibitor, therefore, could act to block these deleterious processes. Multiple system atrophy (MSA) is a neurodegenerative movement disorder affecting approximately 20,000 people in the US. It occurs sporadically, usually presenting between the age 35 and 65 with a variable combination of parkinsonian, cerebellar, and autonomic features that rapidly progress to dangerous morbidity. Some phenotypes of MSA have little or no clinically pertinent parkinsonism, and instead present with cerebellar ataxia or dysautonomia, most frequently as orthostatic hypotension. Research toward potential treatments for MSA, as with many rare diseases, has been limited, resulting in a paucity of knowledge regarding its underlying causes, and there are no currently effective treatments to halt pathological progression. Initial clues into the origins of MSA came from studying alphasynuclein and its hallmark histopathology in the brains of patients with MSA. These studies established that MSA is characterized by the presence of alpha-synuclein aggregates called glial cytoplasmic inclusions (GCIs) that reside predominantly in oligodendroglial cells. GCIs are comprised of abnormal conformations of alpha-synuclein. Alpha-synuclein inclusions from MSA patient brain are capable of propagating to adjacent cells and inducing neurodegeneration when injected into transgenic mice, suggesting that MSA, like PD, may be a prion disease. Additionally, alpha-synuclein in oligodendrocytes induce deficits in myelination in contrast to what is seen for alpha-synuclein aggregates in PD. Previously, it was unclear whether c-Abl activation plays a role in MSA. This application demonstrates the utility of certain c-Abl inhibitors in treating MSA. The c-Abl inhibitor nilotinib has been studied in preclinical neurodegenerative models, and it has been proposed that nilotinib might interfere with pathogenic mechanisms relevant to dementia with Lewy bodies; this proposal motivated the study of nilotinib in a preclinical study of MSA (Lopez-Cuina et al., Movement Disorders 35(7):1163-1172 (2020)). The study confirmed the presence of pY39 in glial cytoplasmic inclusions (GCIs) that are formed by alpha-synuclein aggregate formation in oligodendrocytes, but the study showed that nilotinib did not reduce alpha-synuclein burden in the striatum and did not protect dopamine neurons in the substantia nigra compacta from cell death. Thus, nilotinib is not a therapeutic option for MSA. The origin of pathological alpha-synuclein in the oligodendrocytes of MSA patients has long been a mystery, but understanding this process is key to the development of interventional therapeutics. One possibility is that toxic alpha-synuclein aggregates form in neurons but are taken up by oligodendroglial cells as neurons degrade. Alternatively, these aggregates may form natively in oligodendroglial cells and drive a process of -6- neurodegeneration through a novel mechanism in neurons. Using new animal models it is demonstrated that exclusive expression of alpha-synuclein in oligodendroglial cells does result in Tyr39 and Ser129 phosphorylation, so formation of what may be the toxic form of synuclein aggregate in MSA can form natively in oligodendrocytes. Thus, the phosphorylated form of alpha-synuclein that is the disease-causing entity in other neurodegenerative diseases is also formed in oligodendroglial cells in MSA patient brain and in MSA models. Thus, MSA is dependent on c-Abl activation for disease initiation / progression, regardless of the site of origin of c-Abl activation during the disease course. While the presence of synuclein aggregates is associated with the cell type undergoing degeneration, GCIs in oligodendroglial cells somehow induce neurodegeneration in cortical and subcortical regions of the brain in MSA. It is known that MSA patient brain contains both pS129 and pY39 alpha-synuclein in putamen and in the substantia nigra as previously discussed (FIG. 5), thus, the hallmarks of toxic alpha-synuclein exist in the MSA patient brain. Suppression of c-Abl activation in MSA could therefore have a therapeutic benefit. To evaluate the role of c-Abl activation in the disease process required the development and validation of progressive disease models of MSA that are initiated by GCI formation in oligodendroglial cells. Such models have been created in both rat and monkey. One such model utilizes a novel AAV capsid, termed OligOO 1, that was engineered by capsid shuffling and directed evolution to transduce oligodendrocytes in the striatum and corpus callosum in the brain. Using Green Fluorescent Protein (GFP) as a marker for the cellular tropism of OligoOOl, it was demonstrated that it is possible to deliver GFP into oligodendroglial cells four weeks following intrastriatal injection of OligOO 1. GFP expression is specific to oligodendroglia in the brains of rats and monkeys transduced with OligoOOl, with little expression of GFP in neurons or astrocytes (FIG. 6). When OligOO 1 was used to express human alpha-synuclein in the striatum and corpus callosum of rats, widespread expression of alpha-synuclein occurs in the white matter of the striatum, almost exclusively in oligodendroglia within 5 months (FIG. 7) and GCI-associated alpha-synuclein contains pS129 (FIG. 7) and pY39 (FIGs. 8A-8B). The formation of pS129 and pY39 was coincident with demyelination in the striatum and corpus callosum and activated microglia in the substantia nigra (FIG. 7). Oligodendroglial expression of alpha-synuclein was also accompanied by neurodegeneration in the striatum. After five months, -20% of NeuN+ neurons degrade in the striatum compared to OligOO 1-GFP injected controls (FIG. 7). NeuN is a cell-surface marker for visualizing neurons. The widespread expression and nigrostriatal neurodegeneration accompanying alpha-synuclein transfer to the substantia nigra in the rat model demonstrates that tropic expression of alpha-synuclein in the striatum is a model of MSA. Targeting to oligodendrocytes was more than 90% efficient, with demyelination observed in the cerebellum and striatum of rats (FIG. 7) as well as significant loss of striatal neurons. After 6 months, there is substantial spread of GCI associated pS129 and pY39 throughout the putamen and other areas of brain. It is clear that the slow progression requires longer wait times to properly reproduce the human pathology, but does not detract from the evidence that this is a representative model of human disease. As the ability to use formation and propagation of GCIs as a target for therapeutic approaches is evaluated, it is noted that in c-Abl knockout in PD models, removal of c-Abl not only suppresses neurodegeneration, it suppresses both pY39 and pS129 formation, suggesting a concerted process of chemical modifications driven by c-Abl activation. In MSA, it is observed in model brain that just as the phenotype emerges that pS129 and pY39 co-localize (FIGs. 8A-8B), but not all pS129 inclusions stain with pY39. This could be due to technical issues of differential sensitivity between antibodies, or it might imply that c-Abl modified GCIs represent a subset of the inclusions that form in the disease. If the latter is true, it suggests only a subset of GCIs represent true disease-causing entities and therefore knowing how and why these forms could be important to the development and evaluation of therapeutic interventions. In summary, c-Abl inhibition by a small molecule therapeutic inhibitor would be predicted to be an accessible, effective therapy to modify the disease course in MSA. In certain aspects, the invention relates to compounds represented by formula (I) or a pharmaceutically acceptable salt thereof: Formula (I) 5 wherein: R1 is selected from hydrogen or lower alkyl; and Cy1 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl, provided that Cy1 is not unsubstituted pyrid-4-yl. These compounds were also described in 10 U.S. Patent No. 9,828,370, which is hereby incorporated herein by reference in its entirety, and particularly for the compounds described therein. In certain embodiments, R1 is enriched for deuterium. In certain embodiments, Cy1 is selected from: wherein, independently for each occurrence, R2 and R3 are selected from hydrogen, alkyl, amino, monoalkylamino, dialkylamino, cycloalkyl, halo, cyano, alkoxy, -C(O)OH, and -C(O)N(R4)(R4); 5 n is 1, 2, 3 or 4; X is C(R4)2, S, O, or NR4; R4 is selected from hydrogen and substituted or unsubstituted alkyl, aralkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, cycloalkylalkyl, or heterocyclylalkyl. 10 In certain embodiments, Cy1 is selected from: wherein, independently for each occurrence, 15   R1, each independently, is selected from hydrogen or lower alkyl; R2 and R3 are selected from hydrogen, alkyl, amino, monoalkylamino, dialkylamino, cycloalkyl, halo, cyano, alkoxy, -C(O)OH, and -C(O)N(R4)(R4); R4 is selected from hydrogen and substituted or unsubstituted alkyl, aralkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, cycloalkylalkyl, or heterocyclylalkyl. 5           In certain embodiments, Cy1 is not substituted or unsubstituted pyrid-4-yl. In certain embodiments, Cy1 is not unsubstituted pyrid-4-yl or unsubstituted phenyl. In certain embodiments, Cy1 is not substituted or unsubstituted pyrid-4-yl or substituted or unsubstituted phenyl. In certain embodiments, Cy1 is 5-membered heteroaryl, aryl or heterocyclyl. In 10 some such embodiments, Cy1 is 5-membered heteroaryl. In certain embodiments, R1 is selected from hydrogen, lower alkyl, -CH3, -CDH2, -CD2H, or -CD3; and Cy1 is substituted or unsubstituted 5-membered heteroaryl. 15 In certain embodiments, Cy1 is selected from: In certain embodiments, Cy1 is selected from: In certain embodiments, Cy1 is selected from: In certain embodiments, Cy1 is selected from: In certain embodiments, R1 is selected from hydrogen or lower alkyl, which may be deuterated. In certain preferred embodiments, R1 is methyl, e.g., -CH3, -CDH2, -CD2H, or -CD3. In certain preferred embodiments, the compound is or a pharmaceutically acceptable salt thereof. In some such embodiments, the compound is a methanesulfonic acid salt. In other such embodiments, the compound is a succinic acid salt. In still other such embodiments, the compound is a free base. In other preferred embodiments, the compound is '                                    or a pharmaceutically acceptable salt thereof. In some such embodiments, the compound is a methanesulfonic acid salt. In other such embodiments, the compound is a succinic acid salt. In still other such embodiments, the compound is a free base. In other aspects, the invention provides a pharmaceutical composition comprising a compound as disclosed herein. In certain embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients. In other aspects, the invention provides a compound or composition, as disclosed herein, for conjoint administration with one or more compounds independently selected from central nervous system drugs, such as CNS / respiratory stimulants, analgesics, narcotic agonists, narcotic antagonists, nonsteroidal anti-inflammatory / analgesic agents, behaviormodifying agents, tranquilizers / sedatives, anesthetic agents, inhalants, narcotics, reversal agents, anticonvulsants, skeletal muscle relaxants, smooth muscle relaxants, cardiovascular agents, inotropic agents, anti arrhythmic drugs, anticholinergics, vasodilating agents, agents used in treatment of shock, alpha-adrenergic blocking agents, beta-adrenergic blocking agents, respiratory drugs, bronchodilators, sympathomimetics, antihistamines, antitussives, agents for urinary incontinence / retention, urinary alkalinizers, urinary acidifiers, cholinergic stimulants, agents for urolithiasis, gastrointestinal agents, antiemetic agents, antacids, histamine H2 antagonists, gastromucosal protectants, proton pump inhibitors, appetite stimulants, GI antispasmodics-anticholinergics, GI stimulants, laxatives, saline, lubricant, surfactant, antidiarrheals, hormones / endocrine / reproductive agents, sex hormones, anabolic steroids, posterior pituitary hormones, adrenal cortical steroids, glucocorticoids, antidiabetic agents, thyroid drugs, thyroid hormones, endocrine / reproductive drugs, prostaglandins, antiinfective drugs, antiparasitics, anticoccidial agents, antibiotics, anti-tuberculosis, aminocyclitols, cephalosporins, macrolides, penicillins, tetracyclines, lincosamides, quinolones, sulfonamides, antibacterials, antifungal agents, antiviral agents, blood modifying agents, clotting agents, anticoagulants, erythropoietic agents, antineoplastics / immunosuppressives, alkylating agents, antidotes, bone / joint agents, dermatologic agents (systemic), vitamins and minerals / nutrients, systemic acidifiers, systemic alkalinizers, anti-cancer agents, and anti-viral agents. Definitions The term “alkyl” refers to the radical of saturated aliphatic groups, including straightchain alkyl groups, and branched-chain alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), and more preferably 20 or fewer. In certain embodiments, alkyl groups are lower alkyl groups, e.g. methyl, ethyl, / / -propyl, z-propyl, n-butyl and / / -pentyl. Moreover, the term “alkyl” (or “lower alkyl”) as used throughout the specification, examples, and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. In certain embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains). In preferred embodiments, the chain has ten or fewer carbon (C1-C10) atoms in its backbone. In other embodiments, the chain has six or fewer carbon (Ci-Ce) atoms in its backbone. The term “alkenyl”, as used herein, refers to an aliphatic group containing at least one double bond and is intended to include both “unsubstituted alkenyls” and “substituted alkenyls”, the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated. In preferred embodiments, a straight chain or branched chain alkenyl has 1-12 carbons in its backbone, preferably 1-8 carbons in its backbone, and more preferably 1-6 carbons in its backbone. Exemplary alkenyl groups include allyl, propenyl, butenyl, 2-methyl-2-butenyl, and the like. The term “alkynyl”, as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both “unsubstituted alkynyls” and “substituted alkynyls”, the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated. In preferred embodiments, an alkynyl has 1-12 carbons in its backbone, preferably 1-8 carbons in its backbone, and more preferably 1-6 carbons in its backbone. Exemplary alkynyl groups include propynyl, butynyl, 3-methylpent-1-ynyl, and the like. The term “aralkyl”, as used herein, refers to an alkyl group substituted with one or more aryl groups. The term “aryl”, as used herein, include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5- to 7membered ring, more preferably a 6-membered ring. Aryl groups include phenyl, phenol, aniline, naphthyl, biphenyl, anthracenyl and the like. The term “cycloalkyl”, as used herein, refers to the radical of a saturated aliphatic ring. In preferred embodiments, cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably from 5-7 carbon atoms in the ring structure. Suitable cycloalkyls include cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl. The terms "cycloalkyl" and "cycloalkenyl" refer to cyclic hydrocarbon groups of 3 to 12 carbon atoms. The terms "halogen", “halide” and "halo", as used herein, mean halogen and include fluoro, chloro, bromo and iodo. The terms “heterocyclyl”, “heterocycle”, “heterocyclo” and “heterocyclic” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system. Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, triazolyl, triazinyl, and the like. Exemplary bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo [2,3-c] pyridinyl, furo [3,2-b] pyridinyl] or furo [2,3-b] pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like. The term "heteroalkyl", as used herein, refers to a saturated or unsaturated chain of carbon atoms including at least one heteroatom (e.g., O, S, or NR4, such as where R4 is H or lower alkyl). The term “heteroaryl” includes substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom (e.g., O, N, or S), preferably one to four or one to 3 heteroatoms, more preferably one or two heteroatoms. When two or more heteroatoms are present in a heteroaryl ring, they may be the same or different. The term “heteroaryl” also includes polycyclic ring systems having two or more cyclic rings in which - 18 - two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Preferred polycyclic ring systems have two cyclic rings in which both of the rings are aromatic. Exemplary heteroaryl groups include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, thienyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, quinolinyl, pyridazinyl, triazolyl, triazinyl, and the like. The term "alkoxy" is intended to mean an alkyl radical, as defined herein, attached directly to an oxygen atom. Some embodiments are 1 to 5 carbons, some embodiments are 1 to 4 carbons, some embodiments are 1 to 3 carbons and some embodiments are 1 or 2 carbons. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, 5-isobutoxy, sec-butoxy, and the like. The term “heteroatom”, as used herein, means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur. The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. 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. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In abroad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of the 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. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, an alkylthio, an acyloxy, a phosphoryl, a phosphate, a phosphonate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. Unless specifically stated as “unsubstituted,” references to chemical moi eties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants. Similarly, references to elements are understood to include any suitable isotope of that element. Thus, for example, a hydrogen substituent could be protium, deuterium, or tritium, or a carbon atom could be 12C, 13C, or 14C. In certain embodiments of the compounds disclosed herein, certain atoms may be isotopically enriched, e.g., for radioisotopic labelling or for a metabolically beneficial isotope effect (e.g., by isotopically enriching for deuterium at a hydrogen substituent). In such embodiments, the compound may be isotopically enriched for the desired isotope such that at least 15%, at least 25%, at least 50%, at least 60%, at least 75%, or even at least 90% more of the molecules of the compound in the composition have the desired isotope at the indicated position. The term "unsaturated ring" includes partially unsaturated and aromatic rings. As used herein, the term “tumoral disease” refers to a hyperproliferative disease, such as cancer. As used herein, the term “conjoint administration” means administration of two or more agents to a subject of interest as part of a single therapeutic regimen. The administration(s) can be either simultaneous or sequential, i.e., administering one agent followed by administering of a second (and / or a third one, etc.) at a later time, as long as the agents administered co-exist in the subject being treated, or at least one agent will have the opportunity to act upon the same target tissues of other agents while said target tissues are still under the influence of said other agents. In a certain embodiment, agents to be administered can be included in a single pharmaceutical composition and administered together. In a certain embodiment, the agents are administered simultaneously, including through separate routes. In a certain embodiment, one or more agents are administered continuously, while other agents are administered only at predetermined intervals (such as a single large dosage, or twice a week at smaller dosages, etc.). The present invention includes within its scope the salts and isomers. Compounds of the present invention may in some cases form salts, which are also within the scope of this invention. The term "salt(s)", as employed herein, denotes acidic and / or basic salts formed -20 - with inorganic and / or organic acids and bases. Zwitterions (internal or inner salts) are included within the term "salt(s)" as used herein (and may be formed, for example, where the R substituents comprise an acid moiety such as a carboxyl group). Also included herein are quaternary ammonium salts such as alkylammonium salts. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are useful, for example, in isolation or purification steps which may be employed during preparation. Salts of the compounds may be formed, for example, by reacting a compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates,     dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxy ethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates, undecanoates, and the like. Exemplary basic salts (formed, for example, wherein the substituent comprise an acidic moiety such as a carboxyl group) include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines, N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. The basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. Solvates of the compounds of the invention are also contemplated herein. Solvates of the compounds of formula I are preferably hydrates or other pharmaceutically acceptable solvates. All stereoisomers of the present compounds, such as those which may exist due to asymmetric carbons on the R substituents of the compound, including enantiomeric and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention may have the S or R configuration. As used herein, the term “treating” or “treatment” includes reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a condition in manner to improve or stabilize a subject's condition. As used herein, and as well understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. As used herein, a therapeutic that “prevents” a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample. The present application also envisages within its scope the effect of selection of suitable counterions. The counterion of the compounds of the present invention may be chosen by selecting the dissociation constant for the drug capable of ionization within the said pH range. By estimating the ionized and un-ionized drug concentration of any compound (using well established equations such a Henderson-Hasselbach equation), the solubility and consequently the absorption of the drug may be altered. The compounds generated may be present as a single stereoisomer (e.g., enriched to at least 95% purity relative to the total amount of all stereoisomers present), a racemate, or a mixture of enantiomers or diastereomers in any ratio. Pharmaceutical Compositions The present invention further provides pharmaceutical compositions comprising a compound of formula (I) or its pharmaceutically acceptable salt thereof as an active ingredient along with pharmaceutically acceptable additives / excipients / adjuvants / vehicles. Compounds of the present invention may be used in a pharmaceutical composition, e.g., combined with a pharmaceutically acceptable carrier, for administration to a patient. Such a composition may also contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The term “pharmaceutically acceptable” means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s). The characteristics of the carrier will depend on the route of administration. Such additional factors and / or agents may be included in the pharmaceutical composition to produce a synergistic effect with compounds of the invention, or to minimize side effects caused by the compound of the invention. The pharmaceutical compositions of the invention may be in the form of a liposome or micelles in which compounds of the present invention are combined, in addition to other pharmaceutically acceptable carriers, with amphipathic agents such as lipids which exist in aggregated form as micelles, insoluble monolayers, liquid crystals, or lamellar layers in aqueous solution. Suitable lipids for liposomal formulation include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bile acids, and the like. Preparation of such liposomal formulations is within the level of skill in the art, as disclosed, for example, in U.S. Pat. Nos. 4,235,871; 4,501,728; 4,837,028; and 4,737,323, all of which are incorporated herein by reference. The composition may be administered in a variety of ways including orally, nasally, buccally, sublingually, intravenously, transmucosally, parenterally, by inhalation, spray, transdermally, subcutaneously, intrathecally, topically or rectally and may be formulated according to methods known in the art. The effective dosage form for a mammal may be about 0.1- 100 mg / kg of body weight of active compound, which may be administered as a single dose or in the form of individual doses, such as from 1 to 4 times a day. The mammal may be an adult human. The compounds of the present invention may optionally be administered with one or more additional agents. Exemplary additional agents include one or more compounds independently selected from central nervous system drugs, such as CNS / respiratory stimulants, analgesics, narcotic agonists, narcotic antagonists, nonsteroidal anti-inflammatory / analgesic agents, behavior-modifying agents, tranquilizers / sedatives, anesthetic agents, inhalants, narcotics, reversal agents, anticonvulsants, skeletal muscle relaxants, smooth muscle relaxants, cardiovascular agents, inotropic agents, anti arrhythmic drugs, anticholinergics, vasodilating agents, agents used in treatment of shock, alpha-adrenergic blocking agents, beta-adrenergic blocking agents, respiratory drugs, bronchodilators, sympathomimetics, antihistamines, antitussives, agents for urinary incontinence / retention, urinary alkalinizers, urinary acidifiers, cholinergic stimulants, agents for urolithiasis, gastrointestinal (GI) agents, antiemetic agents, antacids, histamine H2 antagonists, gastromucosal protectants, proton pump inhibitors, appetite stimulants, GI antispasmodics-anticholinergics, GI stimulants, laxatives, saline, bulk producing, lubricant, surfactant, antidiarrheals, hormones / endocrine / reproductive agents, sex hormones, anabolic steroids, posterior pituitary hormones, adrenal cortical steroids, glucocorticoids, antidiabetic agents, thyroid drugs, thyroid hormones, misc. endocrine / reproductive drugs, prostaglandins, antiinfective drugs, antiparasitics, anticoccidial agents, antibiotics, anti-tuberculosis, aminocyclitols, cephalosporins, macrolides, penicillins, tetracyclines, lincosamides, quinolones, sulfonamides, antibacterials, antifungal agents, antiviral agents, blood modifying agents, clotting agents, anticoagulants, erythropoietic agents, antineoplastics / immunosuppressives, alkylating agents, antidotes, bone / joint agents, dermatologic agents (systemic), vitamins and minerals / nutrients, systemic acidifiers, systemic alkalinizers, anti-cancer agents, and anti-viral agents. Methods of use The present invention further provides a method of prophylaxis and / or treatment of, and / or ameliorating the symptoms of, diseases, comprising administering a compound of formula (I) or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the compound of formula (I) as the active ingredient. Methods of treating other neurodegenerative diseases using Abelson tyrosine kinase (ATK) inhibitors, such as compounds of formula (I), are described in U.S. Patent Application Publication No. 2020 / 0046699, which is incorporated by reference herein in its entirety, and in particular for the compounds disclosed therein. Methods of treating multiple system atrophy (MSA) In certain aspects, the present invention provides methods of treating, inhibiting, or preventing multiple system atrophy (MSA) or its symptoms comprising administering to a subject in need thereof an Abelson-family tyrosine kinase (ATK) inhibitor. In some embodiments, the methods comprise administering a pharmaceutical composition comprising an ATK inhibitor as described herein. In some embodiments, the ATK inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In certain preferred embodiments, the ATK inhibitor is selected from Compound 207, 832, 8270, or 809 or a pharmaceutically acceptable salt thereof. In other preferred embodiments, the ATK inhibitor is selected from Compound 207 or 809, or a pharmaceutically acceptable salt thereof. The ATK inhibitor may be administered by any route known to those of skill in the art. In certain preferred embodiments, the ATK inhibitor or pharmaceutical composition is administered orally, nasally, buccally, sublingually, intravenously, transmucosally, parenterally, by inhalation, spray, transdermally, subcutaneously, topically or rectally. In certain preferred embodiments, the ATK inhibitor or pharmaceutical composition is administered orally or parenterally. Exemplification The invention now being generally described, it will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention. Example 1: Synthetic Protocols The preparation of compounds relevant to the present disclosure is generally described in U.S. Patent No. 9,828,370, which is incorporated by reference as if fully set forth herein. Exemplary synthetic procedures are also set forth below. Scheme 1: Synthesis of Intermediates 5 and 6 Synthesis of (E)-l-(5-bromopyridin-3-yl)-3-(dimethylamino)prop-2-en-l-one (2) A solution of 1 (40.0 g, 200 mmol) and R-l (119.0 g, 1000 mmol) in 500 mL of THF was stirred at 70 °C overnight. TLC indicated the reaction was completed. The mixture was cooled to room temperature and removed the solvent at reduced pressure. The resulting solid was washed with hexane to afford 2 as a yellow solid (47.2 g, 93%). Synthesis of 4-(5-bromopyridin-3-yl)-N-(2-methyl-5-nitrophenyl)pyrimidin-2-amine (3) A mixture of 2 (45 g, 176.5 mmol), 7 (40.6 g, 159.2 mmol), K2CO3 (44.0 g, 318.8 mmol) in 500 mL of n-BuOH was heated at 120°C for 16 hours. The reaction mixture was filtered, and the solvent was removed at reduced pressure. The residue was purified by chromatography column (silica gel, eluted with petroleum ether (PE) / ethyl acetate (EA), PEZEA = 2:1) to afford 3 (47.0 g, 70%) was a light yellow solid. Synthesis of N'-('4-('5-br()m()pyridin-3-yl)pyrimidin-2-yl)-6-melhylbenzene-l,3-diamine (4) A solution of 3 (45.0 g, 116.9 mmol) and SnCh (132.0 g, 585 mmol) in 300 mL of EtOAc was heated to reflux overnight, then the reaction was cooled to room temperature, filtered and the solution was concentrated at reduced pressure to afford 4 (44.0 g, 100%). It was directly used for the next step without any further purification. Synthesis of N-(3-(4-(5-bromopyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenyl)-4-((4-methylpiperazin-l-yl)methyl) benzamide (5) 5          The above crude 4 (30.0 g, 84.5 mmol) and 8 (40.0 g, 123.0 mmol) were dissolved in 300 mL of z-BuOH, then the resulting solution was warmed to 80°C for about 5 hours, after completion of the reaction, the mixture was cooled to room temperature, and removed the solvent under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (Hexane / EA = 2:1) to afford 5 (45.0 g, 93%) as a yellow solid. 10 Synthesis                 of                 5-(2-(2-methyl-5-(4-((4-methylpiperazin-l- yl)methyl) benzamido)phenylamino)pyrimidin-4-yl)pyridin-3-ylboronic acid (6) A mixture of 5 (10.0 g, 17.5 mmol), KOAc (2.8 g ,28.1 mmol), PCys (0.3 g ,1.1 mmol), Pd2(dba)s (0.4 g ,0.5 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (7.1 g, 28.0 mmol) in dioxane (150 mL), was stirred at 80°C overnight, after 15 completion of the reaction. The reaction solution was removed at reduced pressure to afford crude 6 (11.0 g, yield 100%) as yellow solid. It was directly used for next step without further purification. Synthesis of library compounds N' 101 102 103 104 105   106 H            H 107 108 113 114 115 116' 117 118 119 200 201 202 203 207 303 304 305 306 308 309 401 402 403 404 405 Synthesis of Compound 207 Br softiwirtrafl; 100°Cd Bti PdfPFhgJU, TEA, ®<»aneh 10« C4 om 7 £ NHzOH.HGE, KjCQ, EK3H, reflux, 4» 0,. N .W. A solution of 7 (200mg, 0.37 mmol) in DMA-DMA (4 mL) was heated to 100°C and stirred for 2 hours. The excess DMA-DMA was evaporated in vacuo, and the residue was dissolved in ethanol (10 mL), to this solution was added K2CO3 (255 mg, 1.85 mmol) and hydroxylamine hydrochloride (77 mg, 1.11 mmol). The resulting mixture was refluxed -28 - overnight. After cooling, the mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by p / cp-HPLC to afford compound 207 (18 mg, 8%) as a solid. Synthesis of 806, 809, 8120, 8130, 8180, 8230, 8140 15 H H 8180, 8230, 8240 7a R-Bo-c R=M® HATU Fe, NH4C! 4-Methoxy-7V-(2-methyl-5-nitrophenyl)pyrimidin-2-amine (12) To a mixture of 2-chloro-4-methoxypyrimidine (9.54 g, 66 mmol), 2-methyl-5-nitrobenzenamine (10.0 g, 66 mmol), Pd2(dba)s (1.0 g), S-Phos (1.0 g, 24.4 mmol), and 5 CS2CO3 (31.8 g, 99 mmol) in 1,4-dioxane / water (140 mL / 60 mL) was heated at 110°C overnight. The mixture was cooled to room temperature and then filtered through a pad of celite. The filtrate was diluted with ethyl acetate and washed with water. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel to afford compound 12 (12 g.70.6% yield) as a light 10 yellow solid. 2-(2-Methyl-5-nitrophenylamino)pyrimidin-4-ol (13) A mixture of compound 12 (20 g, 77 mol), TMSC1 (15 g, 136 mmol) and Nai (23.4 g, 156 mmol) in acetonitrile (400 mL) was heated at 120°C overnight. The mixture was cooled to room temperature and IN aqueous Na2COs (400 mL) and DCM (400 mL) were added. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (DCM / MeOH = 200:1) to afford compound 13 (12.1 g, 64% yield) as a light yellow solid. 4-Chloro-A-(2-methyl-5-nitrophenyl)pyrimidin-2-amine (14) A mixture of compound 13 (2 g, 8.13 mmol) and DMF (5 drops) in POCI3 (40 mL) was heated under reflux for 2 h. The mixture was cooled to room temperature and most of POCI3 was removed. The residue was poured into aqueous NaOH (100 mL) carefully and the resulting mixture was extracted with DCM (100 mL^2). The combined organic layers were washed with brine and water (100 mL), dried over anhydrous sodium sulfate and concentrated to afford compound 14 (2.0 g, 93% yield) as a yellow solid. General procedure for compound 15 A mixture of compound 14 (1.0 eq), X-Int (1.0 eq), Pd(dppf)C12 (cat.) and K2CO3 (3.0 eq) in 1-4-dioxane (20 mL) and water (20 mL) was heated under reflux for 12 h under N2. The mixture was cooled to room temperature and diluted with ethyl acetate and water. The resulting mixture was filtered and the filtrate was separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by flash column chromatography on silica gel (DCM / MeOH = 200:1) to afford compound 15 as a yellow solid. General procedure for compound 16 To a mixture of iron (1.0 eq), NH4CI (2.0 eq) and SiCE (cat) in ethanol / water (1:1) was heated at 55°C for 10 min. Then a suspension of compound 15 (2.0 eq) in THF was added. The reaction mixture was stirred under reflux for 1 h and cooled to room temperature. The mixture was poured into water and then extracted with ethyl acetate. The combined organic layers were washed with brine and water, dried over anhydrous sodium sulfate and concentrated to afford compound 16. General procedure for preparation of 806, 809, 8120, 8130, 8180, 8230 and 8240 A mixture of compound 16 (1.0 eq), compound 7b (1.0 eq) and HATU (1.0 eq) in DMF (2 mL) was cooled to 0°C and DIPEA (4.0 eq) was added. The reaction mixture was allowed to warm to room temperature and stirred for 15 min. Saturated aqueous sodium bicarbonate was added and the resulting mixture was extracted with ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (DCM / MeOH = 20:1) to afford final compound as a yellow solid. Additional compounds of Formula (I) may be synthesized using the methods described in U.S. Patent No. 9,828,370, which is incorporated by reference herein in its entirety. Example 2: Inhibition of Abelson protein kinases c-Abll, c-Ab!2 and c-Kit and comparison to imatinib, the active ingredient in Gleevec® Cpd c-Abl 1 (nM) c-Abl2 (nM) c-Kit (nM) 101 232.35 224.57 6.80 102 95.33 169.62 6.70 103 200.41 212.18 7.70 107 45.17 66.95 7.20 108 40.53 85.88 7.40 113 35.00 50.11 7.50 114 101.53 142.60 32.40 115 107.81 202.79 8.90 116 91.06 160.89 11.60 117 29.13 34.99 5.70 118 37.16 51.00 8.40 119 117.66 44.68 4.00 201 193.18 514.16 19.30 202 403.88 701.00 31.10 203 250.56 711.96 47.10 207 30.19 73.73 12.20 303 162.15 349.36 18.90 305 397.83 631.35 9.20 309 174.37 149.18 14.00 401 167.28 178.63 12.40 402 183.14 207.42 11.10 404 100.32 116.17 5.80 405 107.09 150.43 5.90 806 84 152 13 809 47 77 7.8 820 84 173 10 830 34 51 6.0 832 53 77 4.0 880 203 341 12 8120 476 783 27 8130 323 423 44 8170 128 182 11 8180 369 303 13 8190 97 91 9.7 8200 96 131 4.3 8230 >1000 >1000 37 8240 >1000 >1000 39 8250 71 216 15 8260 41 236 16 8270 53 100 4.9 8280 57 104 6.2 8290 51 137 5.7 8300 40 39 5.2 imatinib 828.3 1000 30.7 Kinase base buffer (50 mM HEPES, pH 7.5 0.0015% Brij-35; 10 mM MgCh 2 mM DTT) and Stop buffer (100 mM HEPES, pH 7.5 0.015% Brij-35; 0.2% Coating Reagent (50 mM EDTA) are prepared. Test compound is diluted in 100% DMSO to 50-times the desired 5 final inhibitor concentration (the Stock Solution) and serially diluted in half-log increments resulting in final concentrations 250 pM to 75 pM, 25 pM, 7.5 pM, 2.5 pM, 0.75 pM, 0.25 pM, 75 nM, 25 nM, 7.5 nM in DMSO. 10 pl of each compound is placed in a 96-well plate as the intermediate plate. 90 pl of Kinase Buffer is added to to each well to prepare the intermediate plate. Mix the compounds in intermediate plate for 10 min on shaker. For the 10 assay of enzyme inhibitions, 5 pl of each well from the intermediate plate is transferred to a 384-well plate in duplicates. Then 10 pl of 2.5x enzyme solution is added to each well of the 384-well assay plate and incubated for 10 min. Then enzyme substrate is added as 10 pl of -34- 2.5x FAM-labeled peptide + ATP solution to each well of the 384-well assay plate The reaction is allowed to proceed at 28 °C and quenched with the addition of 25 pl of stop buffer. The release of fluorescent FAM is quantitated as Percent inhibition = (max-conversion) / (max-min)* 100. “max” stands for DMSO control; “min” stands for low control. Data are fit in XLFit excel add-in version 4.3.1 to obtain IC50 values. Equation used is: Y=Bottom + (Top-Bottom) / (l+(IC50 / X)AHillSlope). Example 3: Inhibition profile of a 500 nM solution of test compounds against 14 protein kinases Kinase base buffer (50 mM HEPES, pH 7.5 0.0015% Brij-35; 10 mM MgCh 2 mM DTT) and Stop buffer (100 mM HEPES, pH 7.5 0.015% Brij-35;0.2% Coating Reagent (50 mM EDTA) are prepared. Test compound is diluted in 100% DMSO to 50-times the desired final inhibitor concentration (the Stock Solution) in DMSO. 10 pl of each compound is placed in a 96-well plate as the intermediate plate. 90 pl of Kinase Buffer is added to each well to prepare the intermediate plate. Mix the compounds in intermediate plate for 10 min on shaker. For the assay of enzyme inhibitions, 5 pl of each well from the intermediate plate is transferred to a 384-well plate in duplicates, 10. Then 10 pl of 2.5x enzyme solution is added to each well of the 384-well assay plate and incubated for 10 min. Then enzyme substrate is added as 10 pl of 2.5x FAM-labeled peptide + ATP solution to each well of the 384-well assay plate. The reaction is allowed to proceed at 28 °C and quenched with the addition of 25 pl of stop buffer. The release of fluorescent FAM is quantitated as Percent inhibition = (max-conversion) / (max-min)*100. “max” stands for DMSO control; “min” stands for low control. Convert conversion values to inhibition values. Percent inhibition = (max-conversion) / (max-min)*100. “max” stands for DMSO control; “min” stands for low control. -36- Table 1 Cpd YES PDG FRa LCK SRC ABL FLT3 KIT PDG FRb FGR LYN A ARG / Abl2 FES FYN JNK2 101 100 42 88 18 73 36 87 99 55 89 74 43 52 25 102 99 39 91 19 83 32 99 99 67 88 75 42 55 26 103 101 42 91 25 71 28 92 98 60 91 71 38 54 17 107 101 59 95 28 91 51 99 101 82 93 87 28 69 1.7 108 100 56 94 34 91 73 100 101 80 93 88 67 66 36 113 100 61 94 37 92 25 98 101 85 95 91 26 75 18 114 100 34 77 18 84 20 99 99 81 91 78 17 72 18 115 100 53 90 29 83 22 96 99 78 93 76 20 67 17 116 100 48 94 29 87 8.4 93 101 83 93 76 19 67 5.9 117 99 74 97 55 94 13 95 99 90 97 91 24 86 14 118 99 66 95 35 92 61 93 101 84 96 88 38 77 14 119 99 67 98 53 83 90 95 100 86 97 90 47 82 42 WO 2025 / 189072                                   PCT / US2025 / 018865 201 99 45 91 18 72 30 91 98 67 87 55 49 53 6.1 202 100 46 87 16 64 19 85 98 64 87 50 27 47 19 203 100 29 88 17 72 31 77 95 59 82 54 21 43 17 207 100 54 95 30 94 19 88 99 79 92 85 31 72 19 303 100 33 87 13 79 25 87 100 58 86 62 31 45 4.7 305 100 16 80 10 62 20 98 100 47 80 50 47 25 4.4 309 101 25 84 13 77 13 96 99 59 87 79 31 44 24 401 100 40 88 18 76 24 98 99 67 90 81 19 50 23 402 100 29 86 19 72 31 96 100 65 89 75 23 48 21 404 100 47 91 21 82 24 97 100 75 90 83 32 56 34 405 101 33 90 16 80 29 95 100 68 90 80 33 52 28 WO 2025 / 189072                                   PCT / US2025 / 018865 - 38 - Table 2 Cpd Abl2 Abll PDG FRa PDG FRb JNK1 JNK2 SRC LCK CKIT FES YES FYN LYNA FLT3 FGR 810 59 65 99 98 25 48 20 83 85 23 44 71 93 26 57 820 76 85 99 98 12 29 23 88 87 32 56 73 91 61 64 830 87 92 100 99 23 52 38 93 92 22 63 81 97 44 77 831 60 48 100 97 15 17 12 82 82 23 25 57 87 38 34 832 81 88 100 100 24 16 28 93 91 24 66 79 106 58 80 840 30 38 99 92 24 56 15 50 73 35 25 64 77 69 24 870 60 60 100 97 17 37 17 70 82 39 23 58 83 73 38 880 61 71 100 100 28 48 15 70 87 35 33 64 80 62 46 8150 54 42 99 97 31 42 14 77 83 26 26 62 90 68 34 8170 73 78 100 98 32 40 25 88 86 67 49 70 93 79 68 8190 81 82 100 99 41 58 28 92 86 51 52 74 96 72 71 8200 75 78 98 97 41 54 22 92 85 52 50 65 100 68 63 8220 54 44 99 97 56 50 22 90 83 57 40 75 93 75 47 8250 68 87 100 98 15 8 20 87 80 37 45 74 85 68 63 8260 67 85 100 101 21 15 22 83 79 16 41 71 88 62 60 8270 80 91 99 98 41 36 33 91 88 60 60 83 104 78 81 WO 2025 / 189072                                   PCT / US2025 / 018865 -39- 8280 80 90 100 99 23 14 28 82 89 32 53 76 98 54 78 8290 75 86 100 100 33 23 26 87 88 36 55 76 98 63 75 8300 89 92 99 98 35 30 45 97 88 19 63 90 108 61 81 WO 2025 / 189072                                   PCT / US2025 / 018865 Example 4: Pharmacokinetic Parameters of Certain Compounds of the Invention Various pharmacokinetic parameters of the compounds described herein were measured in Sprague-Dawley rats. The results of are presented in Table 3. Table 3 Compound: 207 832 809 8270 830 imatinib C (ng / mL) 225.3±83.8 415.8±84.5 170.5 210±31 465±115 241 Lax (h) 5.3±1.2 4.0±0 4 5.3 4 4 *1 / 2 (h) 3.1±ND 2.6±0 2.2 3.3 3.6 -3 AUClast (h*ng / mL) 1647±1084 3178.3±930 1065 1760±268 3715±1090 2726 CL (L / h / kg) 2±0.34 1.3±0.74 2.7 2.6±0.41 1.3±0.33 0.57 Vd(L / kg) 6.5±0.96 3.6±1.8 7.2 7.8±0.70 6.3±1.1 1.1 Bioavailability 32%±21% 33%±10% 24% 46%±7% 47%±14% -53% Caco-2 permeability ratio influx:efflux 0.44 0,63 0.58 2.2 0.52 0.67 Human liver microsome t1 / 2 (min) 17.51 24.46 21.86 20.87 19.56 34.82 Serum protein binding 85.9% ND 85.7% ND ND >98% F old-improvement in brain penetration 2.7 5.3 4.5 2.5 ND 1 5 Example 5: Synucleinopathy Study in Proteolipid Promoter (PLP-SYN) Model MSA is characterized by accumulation of a-synuclein aggregates in oligodendrocytes, the aggregates forming glial cytoplasmic inclusions (GCIs). Lopez-Cuina, et al., Movement Disorders 35(7):1163-1172 (2020). Wild-type mice and mice that express human a-synuclein in oligodendrocytes under the control of PLP-SYN (see Lopez-Cuina, et al.) were treated with 10 a compound of the present disclosure (for example, compound 809). PLP-SYN mice were -40- allocated to receive either a compound of the present disclosure (such as compound 809) or vehicle. Dosing was performed daily for 20 weeks beginning at 11 weeks post-natal. Compounds were dissolved in a vehicle comprising 1% Tween 80,  10% hydroxymethylcellulose and 1% PEG 400 at pH 3.5. The mice were subsequently assessed for pY39 a-synuclein in GCIs and for behavioral changes associated with a-synuclein aggregation (such as changes in gait). Lopez-Cuina, et al. have found pY39 a-synuclein to be present in GCIs, indicating that this particular posttranslational modification of a-synuclein occurs in MSA. Reduction in a-synuclein burden in the striatum or rescue of dopaminergic neurons is considered to be indicative of efficacy against MSA. The results obtained from the PLP-SYN model are depicted in FIGs. 1-4. Briefly, as shown in FIG. 1, post-natal PLP mice were evaluated behaviorally by the ability to traverse a notched beam of 1 meter length. Bar graphs show the percentage of hind limb errors on a notched bar test in WT and PLP mice aged 11 weeks (Baseline) and 31 weeks (after 20 weeks of daily treatment with vehicle or compound 809 oral gavage). PLP-SYN mice receiving compound 809 show a reduction in the percentage of hind limb errors comparable to wild-type error percentages. FIG. 2 shows that post-natal PLP mice were evaluated behaviorally by the ability to traverse a caged beam of 1 meter length. Bar graphs show the number of errors and error to step ratio crossing the caged beam test in WT and PLP mice at 31 weeks (after 20 weeks of Ix / day oral gavage with vehicle or compound 809). PLP-SYN mice which received compound 809 showed a reduction in the percentage of hind limb errors comparable to wild-type error percentages. FIG. 3A demonstrates a reduction of pathologic a-synuclein identified using an antibody that recognizes the post-translational phosphorylation of Ser129 of a-synuclein (phospho-S129) in a-synuclein that occurs only in the pathological form of the protein. Pathological a-synuclein was reduced following daily oral treatment with compound 809 treatment (standardized by actin) in the soluble fraction of striatal protein extracts of the different groups. FIG. 3B demonstrates a reduction of phospho-S129 by compound 809 treatment (standardized by actin) in the insoluble fraction of striatal protein extracts of the different groups. FIG. 4 shows alpha-synuclein expressing C57B1 / 6 mice undergoing monthly behavioral analyses as performed using mixed-model analysis of the time it took for lesioned mice to cross a 1-meter transverse beam. Lesioned mice showed a statistically significant increase in crossing time at 6 and 7 months as compared to control mice. Example 6: Rodent Model of MSA - General Methods and Sample Collection Sprague-Dawley rats undergo baseline activity motor testing and are randomized into six groups receiving recombinant OligOO 1 virus overexpressing either human full-length alphasynuclein (OligOO 1-a-Syn, MSA model) or GFP (OligOO 1-GFP, control animals) with, or without, specific mutation Y39F and / or S129A (Table 4). When these mutations are introduced, kinase phosphorylation is blocked for c-Abl. Use of this mutation strategy in progressive disease models of PD completely block disease formation, suggesting a valid strategy for understanding early events in the MSA model. A separate cohort initiates oral dosing of a novel c-Abl inhibitor compound 809 one month after OligOO 1-a-syn injection to compare to the synuclein mutation approach to blocking kinase phosphorylation of specific sites in alpha-synuclein. Rats receive bilateral stereotactic microinjections of OligOO 1 in the striatum. One month following OligOO 1-a-syn, early MSA pathology is observed (formation of GCIs, demyelination, and inflammation, preceding neurodegeneration observed at later time points. Following sacrifice, all animals undergo a battery of histological and molecular biology techniques listed below to assess alpha-synuclein pathology, neuronal cell loss, and other pathologies relevant to each MSA variant. Stereotactic Surgery Animals are anesthetized with xylazine and ketamine and are placed in a Kopf stereotaxic. Animals receive 2 pL stereotactic injections of either OligOOl-a-Syn (3.75 x io12 vg / ml) or OligOOl-GFP (3.75 x 1012 vg / ml) bilaterally into the striatum and infused at a rate of 0.2 pl / min as defined in Table 1. The needle is left in situ for an additional 5 minutes to allow the injectate to diffuse from the needle tip. Sacrifice All rats are sacrificed 9 or 10 months post-injection after performance of behavioral studies. The brain is removed from the calvarium, cut into 4 mm slabs with a calibrated brain slice apparatus and then the slabs are hemisected. Slabs from one hemisphere have punches taken from the striatum, substantia nigra, cortex and selected downstream regions for HPLC neurotransmitter analysis and total and phosphorylated alpha-synuclein and total synuclein levels using AlphaLISA® and slabs from the other hemisphere are immersion fixed using 4% paraformaldehyde solution for histological analysis. CSF and Blood Collection For rat, CSF (-100 pl) is collected at sacrifice via intraci sternal draws. CSF neurofilament and anti-alpha-synuclein levels are measured using enzyme-linked immunosorbent assays (ELISAs). CSF alpha-synuclein levels are analyzed using AlphaLISA® and compared to tissue levels of alpha-synuclein. The AlphaLISA® platform is a bead-based immunoassay developed as a no-wash assay for highly sensitive, high throughput, widely dynamic and robust detection of analytes in biological samples. It offers several advantages over conventional ELISAs. It is performed with a simple “mix-and-measure” protocol. The generation of the signal is based on the luminescent proximity principle using oxygenchanneling chemistry. In the most commonly used format, the Donor-bead is coupled via streptavidin-biotin link to the first antibody while the second antibody is directly coupled to the Acceptor-bead. Binding of both antibodies to the same analyte brings the two beads into desired proximity. Excitation of Donor-beads at 680nm creates singlet oxygens triggering a cascade of chemical events in Acceptor-beads less than 200nm away leading to a chemiluminescent emission. The assay is optimized for 384 well-plates and may be designed to be carried out at 15-50 pL total volumes, containing 5-40 pL of the sample. A duplex assay for simultaneous quantification of total and pS129 and / or pY39 alpha-synuclein using the AlphaLISA platform has been developed. The assay has a LoD of 4-8 pg / mL and LLoQ of 1215 pg / mL for both analytes. Furthermore, its feasibility has been documented in not only samples experimental animal studies but also in human tissue specimens and most recently also in CSF samples from small (rats) and large (pigs and non-human primates) animals as well as humans. Table 4. Group Designations in the Rat Model of MSA Group # Vector Injection site Follow-up (months) N 1. Healthy Control-WT AAV-OligOOl-GFP Striatum, Bilateral 9 6M + 6F 2. Healthy Control +Y39F AAV-OligOO 1-Y39F-GFP Striatum, Bilateral 9 6M + 6F 2. Healthy Control +S129A AAV-OligOO 1-SI 29 A-GFP Striatum, Bilateral 9 6M + 6F 2. Healthy Control +Y39F+S129A AAV-OligOO 1-Y39F-S129A-GFP Striatum, Bilateral 9 6M + 6F 3. Lesion Control-WT AAV-OligOO 1 -a-Syn Striatum, Bilateral 9 6M + 6F 4. Lesion + Y39F AAV-OligOO 1 -a-Syn Striatum, Bilateral 9 6M + 6F 5. Lesion + S129A AAV-OligOO 1 -a-Syn Striatum, Bilateral 9 6M + 6F 6. Lesion + Y39F+S129A AAV-OligOO 1 -a-Syn Striatum, Bilateral 9 6M + 6F 7. Lesion + compound 809 (100 mg / kg) AAV-OligOO 1 -a-Syn Striatum, Bilateral 9 6M+6F Example 7: Rodent Model of MS A-Behavioral Characterization The Traverse Beam Test is used to evaluate motor and balance skills of each rat as they 5 walk across an elevated beam. The apparatus comprises a narrow wooden beam 2cm wide x 35cm long, elevated 35cm, with an enclosed platform at one end to serve as safe finish point. Performance on the beam is quantified by measuring the time it takes for the rodent to initiate movement, time to traverse the beam and the number of paw slips that occur in the process. Example 8: Rodent Model of MS A-Biochemical Characterization 10          Several antibodies are employed to visualize expression of dopaminergic, non- dopaminergic, and pathological markers across the neuraxis and to perform the following analyses, to include: 1) assessment of formation of mutation-associated reductions of GCIs is performed by stereological analysis of the number of pS129 and pY39 positive-GCIs across regions of the neuraxis and comparison of those estimates across groups; 2) alpha-synuclein 15 expression, spreading and pathology is performed using antibodies against pY39 and pS129, and analysis of the GCIs may be performed with ‘conformation-specific’ alpha-synuclein antibodies (Syn-01, Syn-02, Syn-Fl, Syn-F2); 3) determination of whether pS129 and pY39 immunoreactivity is associated with cellular degeneration is performed by stereological counts of the number NeuN-stained neurons in the striatum and other pY39 and pS129 positive-nuclei, and comparison of those estimates may be performed across mutation groups; 4) proteinase K digestion is performed to determine whether the alpha-synuclein pathology results from soluble (non-aggregated) or insoluble forms across groups; 5) stereological estimates of the number of HLA-DR positive activated microglia and GFAP positive astrocytes is performed across regions of the neuraxis, and comparison those estimates across groups is performed to assess microgliosis and astrocytosis; 6) Luxol Fast Blue and volumetric analyses are performed to assess the degree of demyelination as a result of GCI accumulation, and the volume of demyelination is compared across groups; and 7) tissue neurotransmitter levels in the striatum (dopamine and metabolites) are measured using HPLC, and are compared across groups. Example 9: Statistics and Power Analysis Significant ANOVA pairwise comparisons employ the Mann-Whitney test. With a significant group by time interaction, pairwise comparisons that control for multiple comparisons are employed. For all stereological and histological quantification, a factorial ANOVA is employed and with significance pair-wise comparisons employ a post-hoc test that controls for multiple comparisons. For power analysis, a sample size of 6 rats per group is sufficient to detect a 25% difference between groups of NeuN+ neurons in the striatum measured by stereological estimation, assuming a power of 80% with a two-tailed alpha of .05 and a SD of 18% based on preliminary estimations of NeuN cell populations in rat striatum (1,740,168 ±326,050). This n value has been increased to 12 per group to account for potential experimental issues, as well as to increase the experimental power. INCORPORATION BY REFERENCE Each of the patents, published patent applications, and non-patent references cited herein are hereby incorporated by reference in their entirety. EQUIVALENTS 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 encompassed by the following claims.

Claims

WE CLAIM1. A method of treating multiple system atrophy (MSA), comprising administering to a subject a compound having a structure of Formula (I) or a pharmaceutically acceptable salt thereof:Formula (I)wherein:R1 is selected from hydrogen or lower alkyl, which is optionally enriched for deuterium; andCy1 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, 10           and substituted or unsubstituted heterocyclyl.

2. The method of claim 1, wherein Cy1 is selected from:wherein, independently for each occurrence,R2 and R3 are selected from hydrogen, alkyl, amino, monoalkylamino, dialkylamino, cycloalkyl, halo, cyano, alkoxy, -C(O)OH, and -C(O)N(R4)(R4);n is 1, 2, 3 or 4;5 X is C(R4)2, S, O, or NR4;R4 is selected from hydrogen and substituted or unsubstituted alkyl, aralkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, cycloalkylalkyl, or heterocyclylalkyl.

3. The method of claim 1, wherein Cy1 is selected from:wherein, independently for each occurrence,R1 is selected from hydrogen or lower alkyl;R2 and R3 are selected from hydrogen, alkyl, amino, monoalkylamino, dialkylamino, 15          cycloalkyl, halo, cyano, alkoxy, -C(O)OH, and -C(O)N(R4)(R4);R4 is selected from hydrogen and substituted or unsubstituted alkyl, aralkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, cycloalkylalkyl, or heterocyclylalkyl.

4. The method of claim 1, wherein Cy1 is not unsubstituted pyrid-4-yl or unsubstituted phenyl.

5. The method of claim 1, wherein Cy1 is not substituted or unsubstituted pyrid-4-yl or substituted or unsubstituted phenyl.5   6.     The method of claim 1, wherein Cy1 is 5-membered heteroaryl, aryl or heterocyclyl.

7. The method of claim 1, wherein R1 is selected from hydrogen, lower alkyl, -CH3, -CDH2, -CD2H, or -CD3; and Cy1 is substituted or unsubstituted 5-membered heteroaryl.

8. The method of claim 6, wherein Cy1 is selected from:

10. The method of claim 6, wherein Cy1 is selected from:

12. The method of any one of claims 1-11, wherein R1 is -CH3, -CDH2, -CD2H, or -CD3.

13. The method of claim 1, wherein the compound isH Hor a pharmaceutically acceptable salt thereof.

14. The method of claim 13, wherein the compound is a methanesulfonic acid salt.

15. The method of claim 13, wherein the compound is a succinic acid salt.

16. The method of claim 13, wherein the compound is a free base.5   17. The method of claim 1, wherein the compound is,O-. Nn' J '1                                   or a pharmaceutically acceptable salt thereof.

18. The method of claim 17, wherein the compound is a methanesulfonic acid salt.

19. The method of claim 17, wherein the compound is a succinic acid salt.

20. The method of claim 17, wherein the compound is a free base.10   21.    The method of any one of claims 1-20, wherein the ATK inhibitor is administeredorally or parenterally.

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