Methods of treating neurological disorders

Abstract

The present disclosure relates to a compound of formula (I) and pharmaceutically acceptable salts thereof # imgabs0 # wherein the variables are as described herein, and compositions thereof and their use for the treatment of neurological disorders.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the priority of U.S. Provisional Application No. 63 / 429,760, filed on December 2, 2022. The disclosure of the prior application is considered to be part of the disclosure of this application and is incorporated herein by reference. Technical Field

[0003] The present disclosure relates to compounds of formula (I), their pharmaceutically acceptable salts, their compositions, and their use for the treatment of neurological disorders.

[0004] Sequence Listing

[0005] This application contains a sequence listing that has been electronically submitted as an XML file named "52308 - 0020WO1.XML". The XML file, created on November 20, 2023, is 3,556 bytes in size. The material in the XML file is incorporated herein by reference in its entirety. Background Art

[0006] Proteinopathies are a class of disorders in which one or more proteins misfold and / or have abnormal structures, often leading to loss of function and / or toxicity and / or gain of pathological function. Proteinopathies can be caused by, for example, abnormal post - translational modifications such as hyperphosphorylation, truncation, or amplification of a polypeptide sequence due to mutations in the encoding gene sequence, or lead to mislocalization and aggregation of proteins within cells.

[0007] Casein kinase 1δ (CK - 1δ or CK - 1d) is a member of the casein kinase 1 (CK1) family of protein kinases, which are serine / threonine - selective kinases that act as regulators of signal transduction pathways in most eukaryotic cell types. Mammals have seven CK1 family members encoded by different genes: α, β1, γ1, γ2, γ3, δ, and ε. CK1 protein kinases range from 22 to 55 kDa and have been identified in the membranes, nuclei, and cytoplasm of eukaryotes and also in the mitotic spindles of mammalian cells.

[0008] TAR DNA-binding protein (TDP-43) is a nuclear DNA / RNA-binding protein that plays a role in RNA transcription, maturation, and stability. Mis-localization of TDP-43 can trigger various downstream pathological processes, such as hyperphosphorylation, ubiquitination, and sequestration of the cleaved form of the protein in cytoplasmic aggregates. CK-1δ is one of several protein kinases that can phosphorylate TDP-43. CK-1δ is associated with abnormal hyperphosphorylation of TDP-43 in the cytoplasm, including serine 409 and 410, which are considered representative markers of neuropathology. SUMMARY OF THE INVENTION

[0009] Some embodiments provide a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0010]

[0011] wherein:

[0012] R 1 is hydrogen or C1-C6 alkyl;

[0013] R 2 is C1-C8 alkyl, C1-C8 haloalkyl, C3-C8 cycloalkyl or -NR A R B ;

[0014] R A and R B are independently hydrogen or C1-C6 alkyl, or R A and R B together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group;

[0015] Each R 3 is independently halogen, cyano, hydroxy or C1-C6 alkyl;

[0016] X is CH, CR 3 or N;

[0017] R 4 is chlorine, cyano, hydroxy or trifluoromethyl;

[0018] Each R 5 is independently halogen, cyano, hydroxy, C1-C6 alkyl or C1-C6 haloalkyl; and

[0019] m and n are independently 0, 1, 2 or 3.

[0020] Some embodiments provide a compound selected from the group consisting of:

[0021] or a pharmaceutically acceptable salt of any of the foregoing.

[0022] Some embodiments provide a compound or a pharmaceutically acceptable salt thereof, wherein the compound is 5-(4-chlorophenyl)-2-isobutyl-6-(pyridin-4-yl)pyrimidin-4(3H)-one, which has the structure of, or a pharmaceutically acceptable salt thereof.

[0023] Some embodiments provide a compound or a pharmaceutically acceptable salt thereof, wherein the compound is 5-(4-chlorophenyl)-3-methyl-2-(methylamino)-6-(pyridin-4-yl)pyrimidin-4(3H)-one, which has the structure of, or a pharmaceutically acceptable salt thereof.

[0024] Some embodiments provide a compound or a pharmaceutically acceptable salt thereof, wherein the compound is 5-(4-chloro-2-fluorophenyl)-2-isobutyl-6-(2-methylpyridin-4-yl)pyrimidin-4(3H)-one, which has the structure of, or a pharmaceutically acceptable salt thereof.

[0025] Some embodiments provide a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0026] Some embodiments provide a method for treating a CK-1δ-associated neurological disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0027] Some embodiments provide a method for inhibiting TDP-43 phosphorylation in cells comprising TDP-43 and CK-1δ, the method comprising contacting the cells with a compound of formula (I) or a pharmaceutically acceptable salt thereof. Detailed Description

[0028] Casein kinase 1δ

[0029] CK-1δ is encoded by the CSNK1D gene located at chromosome 17q25.3 (chr17: 82,239,019-82,273,750, GRCh38 / hg38). The CSNK1D mRNA polynucleotide sequence encoding CK-1δ is the NCBI reference sequence: NM_001893.6.

[0030] The CSNK1D mRNA polynucleotide sequence encoding CK-1δ can be alternatively spliced. For example, CSNK1D transcript variant 2 (NCBI reference sequence: NM_139062.4) has been reported, and CSNK1D transcript variant 4 (NCBI reference sequence: NM_001363749.2) has been reported.

[0031] The 415-amino acid polypeptide sequence of CK-1δ protein (UniProt P48730) is listed below as SEQ ID NO: 1:

[0032]

[0033] TAR DNA-binding protein

[0034] TDP-43 is encoded by the TARDBP gene located at chromosome 1p36.22 (chr1: 11,012,654-11,030,528, GRCh38 / hg38). The TARDBP mRNA polynucleotide sequence encoding TDP-43 is NCBI reference sequence: NM_007375.4.

[0035] The 414-amino acid polypeptide sequence of TDP-43 protein (UniProt Q13148) is listed below as SEQ ID NO: 2:

[0036]

[0037] Mutations in the TARDBP gene encoding TDP-43 protein have been associated with a variety of neurological disorders including, for example, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Mutations in TARDBP associated with ALS and FTD are described in Table 1 below, for example.

[0038] Table 1

[0039]

[0040] Definition

[0041] To facilitate understanding of the disclosure set forth herein, many additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly employed in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. All patents, applications, published applications, and other publications mentioned throughout this specification and the accompanying appendices are hereby incorporated by reference in their entirety.

[0042] As used herein, the term "about", when referring to a numerical value or a numerical range, means that the numerical value or numerical range being referred to is an approximation, e.g., within experimental variation and / or statistical experimental error, such that the numerical value or numerical range can vary by ±10% of the stated numerical value or numerical range.

[0043] As used herein, the term "acceptable" with respect to a formulation, composition or ingredient means that it has no continuing adverse effect on the general health of the subject being treated.

[0044] The term "pharmaceutically acceptable salt" refers to a preparation of a compound that does not cause significant irritation to the organism to which it is administered and does not eliminate the biological activity and properties of the compound. In some cases, pharmaceutically acceptable salts are obtained by reacting the compounds described herein with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid, etc. In some cases, pharmaceutically acceptable salts are formed by reacting the compounds described herein having acidic groups with bases to form salts such as ammonium salts, alkali metal salts such as sodium salts or potassium salts, alkaline earth metal salts such as calcium salts or magnesium salts, salts of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine and lysine, or are obtained by other previously established methods. There is no particular limitation on pharmaceutically acceptable salts as long as they can be used in drugs. Examples of salts formed by the compounds described herein with bases include the following: its salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum; its salts with organic bases such as methylamine, ethylamine and ethanolamine; its salts with basic amino acids such as lysine and ornithine; and ammonium salts. The salts may be acid addition salts, and specific examples thereof are acid addition salts with the following acids: inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

[0045] As used herein, "subject" refers to any animal, including mammals, such as primates (e.g., humans), mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibits at least one symptom of the disorder to be treated.

[0046] "Treatment" or "therapy" of a subject refers to any type of intervention or process performed on a subject or the administration of an active agent to a subject, with the aim of reversing, alleviating, improving, inhibiting, slowing down or preventing the onset, progression, development, severity or recurrence of symptoms, complications, conditions or biochemical markers associated with a disease. In some embodiments, the disease is a neurological disorder. As used herein, when referring to the treatment of, for example, a neurological disorder, the terms "treatment" and "treating" are not intended to be absolute terms. For example, "treatment of a neurological disorder" and "treating a neurological disorder" as used in a clinical setting are intended to include achieving a beneficial or desired clinical outcome, and may include improving the condition of a subject suffering from a neurological disorder. Beneficial or desired clinical outcomes include, but are not limited to, one or more of the following: reducing the rate of disease progression, reducing the severity and / or frequency of symptoms, reducing biochemical and / or cellular markers of a particular disease or condition, increasing the remission period (partial or complete) of the subject (e.g., compared to one or more metrics in subjects with a similar condition who have not received treatment or a different treatment, or compared to one or more metrics in the same subject prior to treatment), improving the quality of life of those subjects suffering from the disease (e.g., as assessed using a clinical questionnaire) and / or prolonging the survival of subjects suffering from the disease. "Treatment" may also mean prolonging survival compared to the expected survival without treatment.

[0047] The phrase "therapeutically effective amount" means an amount of a compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a disease or condition associated with CK-1δ, (ii) attenuate, ameliorate or eliminate one or more symptoms of a particular disease, condition or disorder, or (iii) delay the onset of one or more symptoms of a particular disease, condition or disorder described herein.

[0048] The term "inhibit" or "inhibition of" means to reduce a measurable amount or to prevent completely (e.g., 100% inhibition).

[0049] The term "halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0050] The term "cyano" refers to the -CN radical.

[0051] The term "hydroxy" refers to the -OH group.

[0052] The term "alkyl" refers to a saturated acyclic hydrocarbon group that can be straight-chain or branched-chain and contains a specified number of carbon atoms. For example, C1-C10 represents a group that can have from 1 to 10 (including the end values) carbon atoms. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, and n-hexyl. As used in this context, the term "saturated" means that only single bonds are present between the constituent carbon atoms, and the other available valences are occupied by hydrogen and / or other substituents as defined herein.

[0053] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced by independently selected halogen atoms.

[0054] As used herein, the term "cycloalkyl" refers to a cyclic saturated or partially unsaturated hydrocarbon group having, for example, from 3 to 20 ring carbons, preferably from 3 to 16 ring carbons, more preferably from 3 to 12 ring carbons or from 3 to 10 ring carbons or from 3 to 6 ring carbons, wherein the cycloalkyl group can be optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The cycloalkyl group can include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl groups include: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[3.2.1]octane, and bicyclo[2.2.2]octane, etc. The cycloalkyl group also includes spiro rings (e.g., spiro bicyclic rings in which the two rings are connected by only one atom). Non-limiting examples of spiro cycloalkyl groups include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, and spiro[5.5]undecane, etc. As used in this context, the term "saturated" means that only single bonds are present between the constituent carbon atoms.

[0055] The term "heterocyclic group" refers to a mono-, bi-, tri- or polycyclic saturated or partially unsaturated ring system having 3 to 16 ring atoms (e.g., a 5- to 8-membered monocyclic, 8- to 12-membered bicyclic or 11- to 14-membered tricyclic ring system), which has 1 to 3 heteroatoms if monocyclic, 1 to 6 heteroatoms if bicyclic, and 1 to 9 heteroatoms if tricyclic or polycyclic, said heteroatoms being selected from O, N or S (e.g., carbon atoms and 1 to 3, 1 to 6 or 1 to 9 heteroatoms each being N, O, or S if monocyclic, bicyclic or tricyclic), where one or more ring atoms may be substituted by 1 to 3 oxo groups (forming, for example, lactams), and one or more N or S atoms may be substituted by 1 to 2 oxidato groups (forming, for example, N-oxides, S-oxides or S,S-dioxides) when the valence allows; and where 0, 1, 2 or 3 atoms of each ring may be substituted by substituents. Examples of heterocyclic groups include piperazinyl, pyrrolidinyl, dioxolanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridinyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrrolyl, dihydrofuranyl, and dihydrothienyl, etc. The heterocyclic group may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclic groups include: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, and 3-oxabicyclo[3.2.1]octane, etc. The heterocyclic group also includes spiro rings (e.g., spirobicyclic rings where two rings are connected by only one atom).Non-limiting examples of spiro heterocyclic groups include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, and 3-oxa-9-azaspiro[5.5]undecane, etc.

[0056] As used herein, when a ring is described as "partially unsaturated", it means that the ring has one or more additional degrees of unsaturation (in addition to the unsaturation attributed to the ring itself; for example, one or more double or triple bonds between the ring atoms constituting the ring), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, and cycloheptene, etc.

[0057] For the avoidance of doubt, and unless otherwise stated, for rings and cyclic groups (such as the heterocyclic groups and cycloalkyl groups described herein, etc.) containing a sufficient number of ring atoms to form a bicyclic or higher-order ring system (for example, a tricyclic, polycyclic ring system), it should be understood that such rings and cyclic groups encompass those having fused rings, including those in which the fusion occurs at (i) adjacent ring atoms (for example, an [x.x.0] ring system, where 0 represents a zero-atom bridge (for example )); (ii) a single ring atom (a spiro-fused ring system) (for example ), or (iii) consecutively arranged ring atoms (a bridged ring system with all bridge lengths > 0) (for example ).

[0058] In addition, the compounds generally or specifically disclosed herein are intended to include all tautomeric forms. Thus, for example, a compound containing a moiety covers the tautomeric form containing a moiety . Similarly, a pyridyl or pyrimidinyl moiety described as optionally substituted with a hydroxyl group covers the pyridone or pyrimidinone tautomeric forms. For example, it should be understood that the description of includes 1 when R

[0059] The compounds provided herein can encompass various stereochemical forms. The compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, and mixtures of enantiomers (e.g., R and S isomers), including racemic mixtures and mixtures of diastereomers, as well as individual enantiomers and diastereomers resulting from structural asymmetry in certain compounds. Unless otherwise specified, when the disclosed compounds are named or depicted by a structure without specifying stereochemistry (e.g., a "flat" structure) and have one or more chiral centers, it is to be understood as representing all possible stereoisomers of the compound. Similarly, unless otherwise specified, when the disclosed compounds are named or depicted by a structure specifying stereochemistry (e.g., a structure with "wedged" and / or "dashed" bonds) and have one or more chiral centers, it is to be understood as representing the indicated stereoisomers of the compound.

[0060] In addition, the atoms constituting the compounds of this embodiment are intended to include all isotopic forms of such atoms. As used herein, isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include tritium and deuterium, isotopes of carbon include 11 C, 13 C, and 14 C, and isotopes of fluorine include 18 F.

[0061] Details of one or more embodiments of the present disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the present disclosure will be apparent from the description, the drawings, and the claims.

[0062] Compound

[0063] Some embodiments provide a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0064]

[0065] wherein:

[0066] R 1 is hydrogen or C1-C6 alkyl;

[0067] R 2 is C1-C8 alkyl, C1-C8 haloalkyl, C3-C8 cycloalkyl, or -NR A R B ;

[0068] R A and R B are independently hydrogen or C1-C6 alkyl, or R A and R Bform a 4-6 membered heterocyclic group together with the nitrogen atom to which they are attached;

[0069] each R 3 is independently halogen, cyano, hydroxy or C1-C6 alkyl;

[0070] X is CH, CR 3 or N;

[0071] R 4 is chlorine, cyano, hydroxy or trifluoromethyl;

[0072] each R 5 is independently halogen, cyano, hydroxy, C1-C6 alkyl or C1-C6 haloalkyl; and

[0073] m and n are independently 0, 1, 2 or 3.

[0074] In some embodiments of formula (I) or a pharmaceutically acceptable salt thereof:

[0075] R 1 is hydrogen or C1-C6 alkyl;

[0076] R 2 is C1-C8 alkyl, C1-C8 haloalkyl, C3-C8 cycloalkyl or -NR A R B ;

[0077] R A and R B are independently hydrogen or C1-C6 alkyl, or R A and R B form a 4-6 membered heterocyclic group together with the nitrogen atom to which they are attached, provided that the 4-6 membered heterocyclic group is not N-piperazine;

[0078] each R 3 is independently halogen, cyano, hydroxy or C1-C6 alkyl;

[0079] X is CH, CR 3 or N;

[0080] R 4 is chlorine, cyano, hydroxy or trifluoromethyl;

[0081] each R 5 is independently halogen, cyano, hydroxy, C1-C6 alkyl or C1-C6 haloalkyl; and

[0082] m and n are independently 0, 1, 2 or 3.

[0083] In some embodiments of formula (I) or a pharmaceutically acceptable salt thereof:

[0084] R1 is hydrogen or a C1-C6 alkyl group;

[0085] R 2 is a C1-C8 alkyl group, a C1-C8 haloalkyl group, a C3-C8 cycloalkyl group, or -NR A R B ;

[0086] R A and R B are independently hydrogen or a C1-C6 alkyl group;

[0087] Each R 3 is independently a halogen, a cyano group, a hydroxy group, or a C1-C6 alkyl group;

[0088] X is CH, CR 3 or N;

[0089] R 4 is chlorine, a cyano group, a hydroxy group, or a trifluoromethyl group;

[0090] Each R 5 is independently a halogen, a cyano group, a hydroxy group, a C1-C6 alkyl group, or a C1-C6 haloalkyl group; and

[0091] m and n are independently 0, 1, 2, or 3.

[0092] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is not a compound selected from the group consisting of: or a pharmaceutically acceptable salt of any of the foregoing.

[0093] In some embodiments, R 1 is a C1-C6 alkyl group. In some embodiments, R 1 is a methyl group.

[0094] In some embodiments, R 1 is hydrogen.

[0095] In some embodiments, R 2 is a C1-C8 alkyl group. In some embodiments, R 2 is a C3-C5 alkyl group. In some embodiments, R 2 is isobutyl.

[0096] In some embodiments, R 2 is a C1-C8 haloalkyl group.

[0097] In some embodiments, R 2 is a C3-C8 cycloalkyl group.

[0098] In some embodiments, R 2is a C3-C5 cycloalkyl group.

[0099] In some embodiments, R 2 is -NR A R B .

[0100] In some embodiments, R A is a C1-C6 alkyl group. In some embodiments, R A is methyl.

[0101] In some embodiments, R A is hydrogen.

[0102] In some embodiments, R B is a C1-C6 alkyl group. In some embodiments, R B is methyl. In some embodiments, R B is hydrogen.

[0103] In some embodiments, R A and R B are the same. In some embodiments, R A and R B are different. In some embodiments, one of R A and R B is hydrogen, and the other of R A and R B is a C1-C6 alkyl group. In some embodiments, one of R A and R B is hydrogen, and the other of R A and R B is methyl.

[0104] In some embodiments, R A and R B together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic group.

[0105] In some embodiments, m is 1. In some embodiments, when m is 1, R 3 is in the ortho position to X. In some embodiments, when m is 1, R 3 is in the meta position to X.

[0106] In some embodiments, R 3 is a halogen. In some embodiments, R 3 is chlorine. In some embodiments, R 3 is fluorine.

[0107] In some embodiments, R 3 is a cyano group.

[0108] In some embodiments, R 3 is a hydroxyl group.

[0109] In some embodiments, R 3 is a C1-C6 alkyl group. In some embodiments, R 3 is a methyl group.

[0110] In some embodiments, X is CR 3 .

[0111] In some embodiments, X is CH.

[0112] In some embodiments, X is N.

[0113] In some embodiments, m is 0. In some embodiments, m is 2. In some embodiments, m is 3.

[0114] In some embodiments, R 4 is chlorine.

[0115] In some embodiments, R 4 is a cyano group.

[0116] In some embodiments, R 4 is a hydroxyl group.

[0117] In some embodiments, R 4 is a trifluoromethyl group.

[0118] In some embodiments, n is 1. In some embodiments, when n is 1, R 5 is the ortho position of R 4 . In some embodiments, when n is 1, R 5 is the meta position of R 4 .

[0119] In some embodiments, R 5 is a halogen. In some embodiments, R 5 is chlorine. In some embodiments, R 5 is fluorine.

[0120] In some embodiments, R 5 is a cyano group.

[0121] In some embodiments, R 5 is a hydroxyl group.

[0122] In some embodiments, R 5 is a C1-C6 alkyl group. In some embodiments, R 5 is a methyl group.

[0123] In some embodiments, R 5is a C1-C6 haloalkyl. In some embodiments, R 5 is trifluoromethyl.

[0124] In some embodiments, both m and n are 0. In some embodiments, m is 1 and n is 0. In some embodiments, m is 0 and n is 1.

[0125] In some embodiments, n is 0 and R 4 is chlorine. In some embodiments, n is 0, R 4 is chlorine, and R 1 is hydrogen. In some embodiments, n is 0, R 4 is chlorine, and R 1 is methyl.

[0126] In some embodiments, m is 0 and X is N. In some embodiments, m is 0, X is N, and R 1 is hydrogen. In some embodiments, m is 0, X is N, and R 1 is methyl.

[0127] In some embodiments, m is 0, n is 1, R 5 is fluorine, and R 4 is chlorine.

[0128] In some embodiments, R 2 is isobutyl, n is 0 or 1, m is 0 or 1, and X is N. In some embodiments, R 2 is isobutyl, n is 0, m is 0, and X is N. In some embodiments, R 2 is isobutyl, n is 1, m is 0, and X is N. In some embodiments, R 2 is isobutyl, n is 0, m is 1, and X is N. In some embodiments, R 2 is isobutyl, n is 1, m is 1, and X is N.

[0129] Some embodiments provide compounds selected from the group consisting of:

[0130] or a pharmaceutically acceptable salt of any of the foregoing.

[0131] Some embodiments provide a compound or a pharmaceutically acceptable salt thereof, the compound being 5-(4-chlorophenyl)-2-isobutyl-6-(pyridin-4-yl)pyrimidin-4(3H)-one, which has the structure of, or a pharmaceutically acceptable salt thereof.

[0132] Some embodiments provide a compound or a pharmaceutically acceptable salt thereof, the compound being 5-(4-chlorophenyl)-3-methyl-2-(methylamino)-6-(pyridin-4-yl)pyrimidin-4(3H)-one, which has the structure of, or a pharmaceutically acceptable salt thereof.

[0133] Some embodiments provide a compound or a pharmaceutically acceptable salt thereof, the compound being 5-(4-chloro-2-fluorophenyl)-2-isobutyl-6-(2-methylpyridin-4-yl)pyrimidin-4(3H)-one, which has the structure of, or a pharmaceutically acceptable salt thereof.

[0134] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is the compound of formula (I-A) or a pharmaceutically acceptable salt thereof,

[0135]

[0136] wherein:

[0137] R 1 is hydrogen or C1-C6 alkyl;

[0138] R 2 is C1-C8 alkyl, C1-C8 haloalkyl, C3-C8 cycloalkyl or -NR A R B ;

[0139] R A and R B are independently hydrogen or C1-C6 alkyl, or R A and R B together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic group;

[0140] X is CH, CR 3 or N;

[0141] R 4 is chlorine, cyano, hydroxy or trifluoromethyl;

[0142] each R 5 is independently halogen, cyano, hydroxy, C1-C6 alkyl or C1-C6 haloalkyl; and

[0143] n is 0 or 1.

[0144] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is the compound of formula (I-B) or a pharmaceutically acceptable salt thereof,

[0145]

[0146] Wherein:

[0147] R 1 is hydrogen or methyl;

[0148] R 2 is a C1-C8 alkyl group;

[0149] Each R 3 is independently halogen, cyano, hydroxy or a C1-C6 alkyl group;

[0150] X is CH, CR 3 or N;

[0151] R 4 is chlorine, cyano, hydroxy or trifluoromethyl;

[0152] Each R 5 is independently halogen, cyano, hydroxy, a C1-C6 alkyl group or a C1-C6 haloalkyl group; and

[0153] m and n are independently 0 or 1.

[0154] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (I-C) or a pharmaceutically acceptable salt thereof,

[0155]

[0156] Wherein:

[0157] R 1 is hydrogen or a C1-C6 alkyl group;

[0158] R 2 is a C1-C8 alkyl group, a C1-C8 haloalkyl group, a C3-C8 cycloalkyl group or -NR A R B ;

[0159] R A and R B are independently hydrogen or a C1-C6 alkyl group, or R A and R B together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group;

[0160] X is CH, CR 3 or N; and

[0161] R 4 is chlorine, cyano, hydroxy or trifluoromethyl.

[0162] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (I-D) or a pharmaceutically acceptable salt thereof,

[0163]

[0164] Wherein:

[0165] R 1 is hydrogen or a C1-C6 alkyl group;

[0166] R 2 is a C1-C8 alkyl group, a C1-C8 haloalkyl group, a C3-C8 cycloalkyl group or -NR A R B ;

[0167] R A and R B are independently hydrogen or a C1-C6 alkyl group, or R A and R B together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic group;

[0168] Each R 3 is independently a halogen, a cyano group, a hydroxyl group or a C1-C6 alkyl group;

[0169] X is CH, CR 3 or N;

[0170] R 4 is chlorine, a cyano group, a hydroxyl group or a trifluoromethyl group; and

[0171] m is 0, 1, 2 or 3.

[0172] Pharmaceutical composition

[0173] Some embodiments provide a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0174] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is 5-(4-chlorophenyl)-2-isobutyl-6-(pyridin-4-yl)pyrimidin-4(3H)-one, 5-(4-chlorophenyl)-2-isobutyl-6-(pyridin-4-yl)pyrimidin-4(3H)-one or 5-(4-chloro-2-fluorophenyl)-2-isobutyl-6-(2-methylpyridin-4-yl)pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt of any of the foregoing.

[0175] Some embodiments provide a pharmaceutical composition comprising 5-(4-chlorophenyl)-2-isobutyl-6-(pyridin-4-yl)pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0176] Some embodiments provide a pharmaceutical composition comprising 5-(4-chlorophenyl)-2-isobutyl-6-(pyridin-4-yl)pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0177] Some embodiments provide a pharmaceutical composition comprising 5-(4-chloro-2-fluorophenyl)-2-isobutyl-6-(2-methylpyridin-4-yl)pyrimidin-4(3H)-one, a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0178] In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is a therapeutically effective amount.

[0179] Method of use

[0180] Methods for inhibiting casein kinase 1δ (CK-1δ) encoded by the CSNK1D gene are provided herein. For example, CK-1δ inhibitors are provided herein that can be used to treat or prevent diseases or disorders associated with dysregulation of the expression or activity or level of the CSNK1D gene, CK-1δ protein, or any one thereof (i.e., CK-1δ-associated diseases or disorders), such as neurological disorders (i.e., CK-1δ-associated neurological disorders).

[0181] As used herein, a "CK-1δ inhibitor" includes any compound that exhibits CK-1δ inactivating activity (e.g., inhibits or reduces).

[0182] The ability of a test compound to act as a CK-1δ inhibitor can be demonstrated by assays known in the art. The activity of the compounds and compositions provided herein as CK-1δ inhibitors can be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays that measure kinase inhibition. Alternative in vitro assays quantify the ability of an inhibitor to bind to a protein kinase and can be measured by radiolabeling the compound prior to binding, separating the compound / kinase complex, and determining the amount of radiolabel bound, or by running a competition experiment where the new compound is incubated with a kinase bound to a known radioligand.

[0183] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof can selectively target CK-1δ. For example, the compound of formula (I) or a pharmaceutically acceptable salt thereof can selectively target CK-1δ relative to another kinase or non-kinase target.

[0184] The compound of formula (I) or a pharmaceutically acceptable salt thereof (and pharmaceutical compositions comprising the same) can be used to treat diseases and disorders treatable with a CK-1δ inhibitor, such as CK-1δ-associated diseases and disorders.

[0185] As used herein, the term "CK-1δ associated disease or disorder" refers to a disease or disorder associated with or having an abnormality in the regulation of the CSNK1D gene, CK-1δ protein, or any (e.g., one or more) of their expression or activity or levels (e.g., any type of abnormality in the regulation of the CSNK1D gene or CK-1δ protein as described herein, or any of their expression or activity or levels). Non-limiting examples of CK-1δ associated diseases or disorders include, for example, the CK-1δ associated neurological disorders described herein.

[0186] As used herein, the term "CK-1δ associated neurological disorder" refers to a neurological disorder associated with or having an abnormality in the regulation of the CSNK1D gene, CK-1δ protein, or any of their expression or activity or levels. Non-limiting examples of CK-1δ associated neurological disorders include, for example, CK-1δ associated neurological disorders such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease, frontotemporal dementia (FTD), frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), and limbic-predominant age-related TDP-43 encephalopathy (LATE).

[0187] The phrase "abnormal regulation of the CSNK1D gene, CK-1δ protein, or any of their expression or activity or levels" refers to gene mutations (e.g., mutations in the CSNK1D gene that result in CK-1δ expression including at least one amino acid deletion compared to wild-type CK-1δ, mutations in the CSNK1D gene that result in CK-1δ expression with one or more point mutations compared to wild-type CK-1δ, mutations in the CSNK1D gene that result in CK-1δ expression with at least one inserted amino acid compared to wild-type CK-1δ, gene duplications that result in increased levels of CK-1δ in cells, or mutations in regulatory sequences (e.g., promoters and / or enhancers) that result in increased levels of CK-1δ in cells, alternative spliced versions of CK-1δ mRNA that result in CK-1δ with at least one amino acid deletion in CK-1δ compared to wild-type CK-1δ), or increased expression (e.g., increased levels) of wild-type CK-1δ in mammalian cells (e.g., compared to control cells) due to abnormal cell signaling. As another example, abnormal regulation of the CSNK1D gene, CK-1δ protein, or any of their expression or activity or levels can be a mutation in the CSNK1D gene encoding CK-1δ, where CK-1δ is constitutively active or has increased activity compared to the protein encoded by the CSNK1D gene that does not include the mutation.

[0188] Some embodiments provide methods of treating a CK-1δ associated neurological disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0189] Some embodiments provide methods of treating a CK-1δ associated neurological disorder in a subject identified or diagnosed as having a CK-1δ associated neurological disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0190] Some embodiments provide methods of treating a CK-1δ associated neurological disorder in a subject determined to have a CK-1δ associated neurological disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0191] Some embodiments provide methods of treating a CK-1δ associated neurological disorder in a subject having a CK-1δ associated neurological disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0192] Some embodiments provide methods of treating a CK-1δ associated neurological disorder in a subject suspected of having a CK-1δ associated neurological disorder, which comprise administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0193] Some embodiments provide methods of treating a CK-1δ associated neurological disorder in a subject at risk of developing a CK-1δ associated neurological disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0194] Some embodiments provide methods of treating a CK-1δ associated neurological disorder in a subject exhibiting one or more symptoms of a CK-1δ associated neurological disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0195] In some embodiments, the subject has been identified or diagnosed as having an abnormality in the regulation of the CSNK1D gene, CK-1δ protein, or any of their expression or activity or levels (CK-1δ associated neurological disorder) (e.g., as determined using a diagnostically approved (e.g., FDA approved) method, assay, or kit).

[0196] In some embodiments, the subject has been identified or diagnosed as having abnormal phosphorylation of TDP-43. In some embodiments, the subject has been identified or diagnosed as having aggregates and / or inclusion bodies containing TDP-43.

[0197] In some embodiments, the subject is suspected of having a CK-1δ associated neurological disorder. In some embodiments, the subject has a clinical record indicating that the subject has a CK-1δ associated neurological disorder (and optionally, the clinical record indicates that the subject should be treated with the compounds or pharmaceutically acceptable salts thereof provided herein).

[0198] In some embodiments, the subject is suspected of having abnormal phosphorylation of TDP-43. In some embodiments, the subject has a clinical record indicating that the subject has abnormal phosphorylation of TDP-43 (and optionally, the clinical record indicates that the subject should be treated with the compounds or pharmaceutically acceptable salts thereof provided herein).

[0199] In some embodiments, the subject is suspected of having aggregates and / or inclusions that contain TDP-43. In some embodiments, the subject has a clinical record indicating that the subject has aggregates and / or inclusions that contain TDP-43 (and optionally, the clinical record indicates that the subject should be treated with a compound or a pharmaceutically acceptable salt thereof provided herein).

[0200] Some embodiments provide a method of treating a CK-1δ associated neurological disorder in a subject in need thereof, the method comprising (a) determining that the subject has an abnormality in the regulation of the CSNK1D gene, CK-1δ protein, or any of their expression or activity or levels; and (b) administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0201] Some embodiments provide a method of treating a CK-1δ associated neurological disorder in a subject, the method comprising (a) determining that the subject has an abnormality in the regulation of the CSNK1D gene, CK-1δ protein, or any of their expression or activity or levels; and (b) administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0202] Some embodiments provide a method of treating a CK-1δ associated neurological disorder in a subject, the method comprising (a) determining that the subject exhibits one or more symptoms of a CK-1δ associated neurological disorder; and (b) administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0203] Some embodiments provide a method of treating a CK-1δ associated neurological disorder in a subject, the method comprising (a) determining that the subject is at risk of developing a CK-1δ associated neurological disorder; (b) determining that the subject exhibits one or more symptoms of a CK-1δ associated neurological disorder; and (c) administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0204] In some embodiments, the CK-1δ associated neurological disorder is ALS, Alzheimer's disease, FTD, FTLD-U, or LATE. In some embodiments, the CK-1δ associated neurological disorder is ALS, Alzheimer's disease, FTD, or LATE.

[0205] In some embodiments, the CK-1δ-associated neurological disorder is ALS. ALS can be classified as familial or sporadic, depending on whether there is a family history of the disease. Familial ALS may account for 5% to 20%. More than 20 genes have been associated with familial ALS, and four genes account for the majority of familial cases: C9orf72 (40%), SOD1 (20%), FUS (1-5%), and TARDBP (1-5%). The genetics of familial ALS are better understood than those of sporadic ALS. Known ALS genes account for approximately 70% of familial ALS and approximately 15% of sporadic ALS. Overall, the risk of ALS in first-degree relatives of individuals with ALS is 1%. ALS has an oligogenic inheritance pattern, meaning that mutations in two or more genes may contribute to causing the disease.

[0206] In sporadic ALS, there is no family history of the disease. Sporadic ALS and familial ALS present the same clinically and pathologically and are genetically similar. Approximately 10% of people with sporadic ALS have gene mutations known to cause familial ALS.

[0207] In some embodiments, the CK-1δ-associated neurological disorder is Alzheimer's disease.

[0208] In some embodiments, the CK-1δ-associated neurological disorder is FTD.

[0209] In some embodiments, the CK-1δ-associated neurological disorder is FTD-U.

[0210] In some embodiments, the CK-1δ-associated neurological disorder is LATE.

[0211] Some embodiments provide methods of treating ALS in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is suspected of having ALS.

[0212] Some embodiments provide a method of alleviating one or more symptoms of ALS in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more symptoms include generalized muscle weakness, atrophy, muscle spasims due to upper and lower motor neuron degeneration, loss of the ability to initiate and control all voluntary movements, cognitive or behavioral dysfunction, frontotemporal dementia (FTD), language dysfunction, executive dysfunction, problems with social cognition and verbal memory, neuropathic pain, spasticity, muscle cramps, contracture (permanent shortening of a muscle or joint), neck pain, back pain, shoulder pain, pressure ulcers, or any combination thereof. In some embodiments, the one or more symptoms are selected from the group consisting of muscle weakness, atrophy, generalized muscle spasm due to degeneration of upper and lower motor neurons, loss of the ability to initiate and control all voluntary movements, cognitive or behavioral dysfunction, frontotemporal dementia (FTD), language dysfunction, executive dysfunction, problems with social cognition and verbal memory, neuropathic pain, spasticity, muscle cramps, contracture (permanent shortening of a muscle or joint), neck pain, back pain, shoulder pain, pressure ulcers, or any combination thereof. In some embodiments, the one or more symptoms are one, two, or three symptoms.

[0213] Some embodiments provide a method of treating FTD in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is suspected of having FTD.

[0214] Some embodiments provide a method for alleviating one or more symptoms of FTD in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more symptoms include inappropriate social behavior, loss of empathy and other communication skills such as being sensitive to the feelings of others, lack of judgment, loss of inhibition, lack of interest (apathy), repetitive compulsive behaviors such as tapping, clapping or lip-smacking, decreased personal hygiene, changes in eating habits, typically overeating or developing a preference for sweets and carbohydrates, eating inedible objects, a compulsion to put things in the mouth, increased difficulty in using and understanding written and oral language such as difficulty in finding the correct words for speech or naming objects, difficulty naming things, possibly substituting more general words such as "it" for specific words, no longer knowing the meaning of words, having hesitant speech that may sound telegraphic, tremors, stiffness, muscle spasms or twitching, poor coordination, difficulty swallowing, muscle weakness, inappropriate laughing or crying, falling or walking problems, or any combination thereof. In some embodiments, the one or more symptoms are selected from the group consisting of inappropriate social behavior, loss of empathy and other communication skills such as being sensitive to the feelings of others, lack of judgment, loss of inhibition, lack of interest (apathy), repetitive compulsive behaviors such as tapping, clapping or lip-smacking, decreased personal hygiene, changes in eating habits, typically overeating or developing a preference for sweets and carbohydrates, eating inedible objects, a compulsion to put things in the mouth, increased difficulty in using and understanding written and oral language such as difficulty in finding the correct words for speech or naming objects, difficulty naming things, possibly substituting more general words such as "it" for specific words, no longer knowing the meaning of words, having hesitant speech that may sound telegraphic, tremors, stiffness, muscle spasms or twitching, poor coordination, difficulty swallowing, muscle weakness, inappropriate laughing or crying, falling or walking problems, or any combination thereof. In some embodiments, the one or more symptoms are one, two or three symptoms.

[0215] Some embodiments provide a method for treating FTD-U in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is suspected of having FTD-U.

[0216] Some embodiments provide a method of alleviating one or more symptoms of FTD-U in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more symptoms include inappropriate social behavior, loss of empathy and other communication skills, such as being sensitive to the feelings of others, lack of judgment, loss of inhibition, lack of interest (apathy), repetitive compulsive behaviors, such as tapping, clapping or lip-smacking, decline in personal hygiene, change in eating habits, often overeating or developing a preference for sweets and carbohydrates, eating inedible objects, compulsive desire to put things in the mouth, increased difficulty in using and understanding written and oral language, such as difficulty finding the right words for speech or naming objects, difficulty naming things, possibly substituting more general words like "it" for specific words, no longer knowing the meaning of words, having hesitant speech that may sound telegraphic, tremors, stiffness, muscle spasms or twitches, poor coordination, difficulty swallowing, muscle weakness, inappropriate laughing or crying, falling or walking problems, or any combination thereof. In some embodiments, the one or more symptoms are selected from the group consisting of inappropriate social behavior, loss of empathy and other communication skills, such as being sensitive to the feelings of others, lack of judgment, loss of inhibition, lack of interest (apathy), repetitive compulsive behaviors, such as tapping, clapping or lip-smacking, decline in personal hygiene, change in eating habits, often overeating or developing a preference for sweets and carbohydrates, eating inedible objects, compulsive desire to put things in the mouth, increased difficulty in using and understanding written and oral language, such as difficulty finding the right words for speech or naming objects, difficulty naming things, possibly substituting more general words like "it" for specific words, no longer knowing the meaning of words, having hesitant speech that may sound telegraphic, tremors, stiffness, muscle spasms or twitches, poor coordination, difficulty swallowing, muscle weakness, inappropriate laughing or crying, falling or walking problems, or any combination thereof. In some embodiments, the one or more symptoms are one, two or three symptoms.

[0217] Some embodiments provide a method of treating LATE in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is suspected of having LATE.

[0218] Some embodiments provide methods of alleviating one or more symptoms of LATE in a subject in need thereof, which comprise administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, one or more symptoms include wandering or getting lost, making poor decisions, misplacing things, having difficulty driving, having difficulty maintaining personal hygiene, having difficulty dressing, having difficulty cooking, having difficulty paying bills, mental decline, or any combination thereof. In some embodiments, one or more symptoms are selected from the group consisting of: wandering or getting lost, making poor decisions, misplacing things, having difficulty driving, having difficulty maintaining personal hygiene, having difficulty dressing, having difficulty cooking, having difficulty paying bills, mental decline, or any combination thereof. In some embodiments, one or more symptoms are one, two, or three symptoms.

[0219] Some embodiments provide methods of treating Alzheimer's disease in a subject in need thereof, which comprise administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is suspected of having Alzheimer's disease.

[0220] Some embodiments provide methods of alleviating one or more symptoms of Alzheimer's disease in a subject in need thereof, which comprise administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, one or more symptoms include memory loss, misplacing items, forgetting the names of places and objects, becoming less flexible and more hesitant to try new things, confusion and disorientation, compulsive, repetitive or impulsive behavior, delusions, aphasia, mood swings, depression, anxiety, agnosia, akinesia, weight loss, progressive aphasia, significant problems with short-term and long-term memory, or any combination thereof. In some embodiments, one or more symptoms are selected from the group consisting of: memory loss, misplacing items, forgetting the names of places and objects, becoming less flexible and more hesitant to try new things, confusion and disorientation, compulsive, repetitive or impulsive behavior, delusions, aphasia, mood swings, depression, anxiety, agnosia, akinesia, weight loss, progressive aphasia, significant problems with short-term and long-term memory, or any combination thereof. In some embodiments, one or more symptoms are one, two, or three symptoms.

[0221] Some embodiments provide methods of treating ALS in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of: or a pharmaceutically acceptable salt of any of the foregoing.

[0222] Some embodiments provide methods of treating ALS in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, the compound being 5-(4-chlorophenyl)-2-isobutyl-6-(pyridin-4-yl)pyrimidin-4(3H)-one, which has the structure of the compound, or a pharmaceutically acceptable salt thereof.

[0223] Some embodiments provide methods of treating ALS in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, the compound being 5-(4-chlorophenyl)-3-methyl-2-(methylamino)-6-(pyridin-4-yl)pyrimidin-4(3H)-one, which has the structure, or a pharmaceutically acceptable salt thereof.

[0224] Some embodiments provide methods of treating ALS in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, the compound being 5-(4-chloro-2-fluorophenyl)-2-isobutyl-6-(2-methylpyridin-4-yl)pyrimidin-4(3H)-one, which has the structure, or a pharmaceutically acceptable salt thereof.

[0225] Some embodiments provide methods of treating Alzheimer's disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of: or a pharmaceutically acceptable salt of any of the foregoing.

[0226] Some embodiments provide methods of treating Alzheimer's disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, the compound being 5-(4-chlorophenyl)-2-isobutyl-6-(pyridin-4-yl)pyrimidin-4(3H)-one, which has the structure, or a pharmaceutically acceptable salt thereof.

[0227] Some embodiments provide methods of treating Alzheimer's disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, the compound being 5-(4-chlorophenyl)-3-methyl-2-(methylamino)-6-(pyridin-4-yl)pyrimidin-4(3H)-one, which has the structure, or a pharmaceutically acceptable salt thereof.

[0228] Some embodiments provide methods of treating Alzheimer's disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, the compound being 5-(4-chloro-2-fluorophenyl)-2-isobutyl-6-(2-methylpyridin-4-yl)pyrimidin-4(3H)-one, which has the structure of, or a pharmaceutically acceptable salt thereof.

[0229] Some embodiments provide methods of treating FTD in a subject in need thereof, which comprise administering to the subject a therapeutically effective amount of a compound selected from the group consisting of:

[0230] or a pharmaceutically acceptable salt of any of the foregoing.

[0231] Some embodiments provide methods of treating FTD in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, the compound being 5-(4-chlorophenyl)-2-isobutyl-6-(pyridin-4-yl)pyrimidin-4(3H)-one, which has the structure of, or a pharmaceutically acceptable salt thereof.

[0232] Some embodiments provide methods of treating FTD in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, the compound being 5-(4-chlorophenyl)-3-methyl-2-(methylamino)-6-(pyridin-4-yl)pyrimidin-4(3H)-one, which has the structure of, or a pharmaceutically acceptable salt thereof.

[0233] Some embodiments provide methods of treating FTD in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, the compound being 5-(4-chloro-2-fluorophenyl)-2-isobutyl-6-(2-methylpyridin-4-yl)pyrimidin-4(3H)-one, which has the structure of, or a pharmaceutically acceptable salt thereof.

[0234] Some embodiments provide methods of treating FTLD-U in a subject in need thereof, which comprise administering to the subject a therapeutically effective amount of a compound selected from the group consisting of: or a pharmaceutically acceptable salt of any of the foregoing.

[0235] Some embodiments provide methods of treating FTLD-U in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, the compound being 5-(4-chlorophenyl)-2-isobutyl-6-(pyridin-4-yl)pyrimidin-4(3H)-one, which has the structure of, or a pharmaceutically acceptable salt thereof.

[0236] Some embodiments provide methods of treating FTLD-U in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, the compound being 5-(4-chlorophenyl)-3-methyl-2-(methylamino)-6-(pyridin-4-yl)pyrimidin-4(3H)-one, which has the structure of, or a pharmaceutically acceptable salt thereof.

[0237] Some embodiments provide methods of treating FTLD-U in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, the compound being 5-(4-chloro-2-fluorophenyl)-2-isobutyl-6-(2-methylpyridin-4-yl)pyrimidin-4(3H)-one, which has the structure of, or a pharmaceutically acceptable salt thereof.

[0238] Some embodiments provide methods of treating LATE in a subject in need thereof, which comprise administering to the subject a therapeutically effective amount of a compound selected from the group consisting of: or a pharmaceutically acceptable salt of any of the foregoing.

[0239] Some embodiments provide methods of treating LATE in a subject in need thereof, which comprise administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, the compound being 5-(4-chlorophenyl)-2-isobutyl-6-(pyridin-4-yl)pyrimidin-4(3H)-one, which has the structure of, or a pharmaceutically acceptable salt thereof.

[0240] Some embodiments provide methods of treating LATE in a subject in need thereof, which comprise administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, the compound being 5-(4-chlorophenyl)-3-methyl-2-(methylamino)-6-(pyridin-4-yl)pyrimidin-4(3H)-one, which has the structure of, or a pharmaceutically acceptable salt thereof.

[0241] Some embodiments provide methods of treating LATE in a subject in need thereof, which comprise administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is 5-(4-chloro-2-fluorophenyl)-2-isobutyl-6-(2-methylpyridin-4-yl)pyrimidin-4(3H)-one, which has the structure of, or a pharmaceutically acceptable salt thereof.

[0242] The term "regulatory agency" refers to an agency that approves the medical use of a pharmaceutical agent in a country. Non-limiting examples of regulatory agencies are the US Food and Drug Administration (FDA).

[0243] Also provided are methods of inhibiting CK-1δ activity in a cell, which comprise contacting the cell with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0244] Also provided are methods of inhibiting TDP-43 phosphorylation in a cell comprising TDP-43 and CK-1δ, the method comprising contacting the cell with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0245] Also provided are methods of inhibiting TDP-43 aggregation in a cell comprising TDP-43 and CK-1δ, the method comprising contacting the cell with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0246] In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo. In some embodiments, the cell is in a sample from a subject, such as a subject at risk of developing a CK-1δ-associated neurological disorder.

[0247] In some embodiments, when the contacting is in vivo, the method comprises administering to a subject having cells with abnormal CK-1δ activity an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0248] In some embodiments, when the contacting is in vivo, the method comprises administering to a subject having cells with abnormal TDP-43 phosphorylation an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0249] In some embodiments, when the contacting is in vivo, the method comprises administering to a subject having cells with TDP-43 aggregation an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0250] In some embodiments, the cell is a nerve cell. In some embodiments, the cell is a mammalian nerve cell.

[0251] As used herein, the term "contact" means bringing the designated moieties together in an in vitro or in vivo system. For example, "contacting" a CK-1δ protein with a compound provided herein includes administering the compound provided herein to an individual or subject, such as a human, having the CK-1δ protein, and also includes, for example, introducing the compound provided herein into a sample containing cells or a purified preparation containing the CK-1δ protein.

[0252] In some embodiments, the Kpuu of the compound of formula (I) is from about 0.21 to about 0.46. In some embodiments, the Kpuu of the compound of formula (I) is from about 0.21 to about 0.33. In some embodiments, the Kpuu of the compound of formula (I) is from about 0.33 to about 0.46. In some embodiments, the Kpuu of the compound of formula (I) is from 0.21 to 0.46. In some embodiments, the Kpuu of the compound of formula (I) is from 0.21 to 0.33. In some embodiments, the Kpuu of the compound of formula (I) is from 0.33 to 0.46. In some embodiments, the Kpuu of the compound of formula (I) is about 0.21, about 0.23, about 0.25, about 0.27, about 0.29, about 0.31, about 0.33, about 0.35, about 0.37, about 0.39, about 0.41, about 0.43, or about 0.46. In some embodiments, the Kpuu of the compound of formula (I) is 0.21, 0.23, 0.25, 0.27, 0.29, 0.31, 0.33, 0.35, 0.37, 0.39, 0.41, 0.43, or 0.46.

[0253] When used as a medicament, the compound of formula (I), including its pharmaceutically acceptable salts, may be administered in the form of a pharmaceutical composition as described herein.

[0254] Examples

[0255] The general methods for preparing the compounds of formula (I) have been described in an illustrative manner and are intended to be descriptive, not limiting. Thus, it will be understood that conditions such as the choice of solvent, reaction temperature, volume, reaction time, etc. may vary while still producing the desired compound. In addition, it will be understood that many of the reagents provided in the following examples may be replaced by other suitable reagents. See, for example, Smith & March, Advanced Organic Chemistry, 7th Edition (2013). Such changes and modifications can be made without departing from its spirit and scope, including but not limited to those related to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations, and / or methods of use provided herein.

[0256] Example 1: 5-(4-chlorophenyl)-3-methyl-2-(methylamino)-6-(pyridin-4-yl)pyrimidin-4(3H)-one (Compound 1)

[0257]

[0258] Step 1: 5-(4-chlorophenyl)-3-methyl-2-(methylthio)-6-(pyridin-4-yl)pyrimidin-4(3H)-one. To a stirred solution of ethyl 2-(4-chlorophenyl)acetate (10 g, 50.3 mmol) in DMF (130 mL) was added isonicotinonitrile (5.35 g, 51.3 mmol) and potassium tert-butoxide (51.3 mL, 51.3 mmol), and the reaction mixture was stirred at 25 °C. After 1.5 h, a solution of methyl isothiocyanate (4.45 g, 60.9 mmol) in DMF (2.6 mL) was added slowly to keep the internal temperature below 25 °C, and the reaction was stirred for 1 h. Then the reaction mixture was cooled to below 5 °C, and methyl iodide (3.21 mL, 51.3 mmol) was added. The reaction mixture was stirred at 25 °C for 1 h. Water (170 mL) was added slowly to the reaction to keep the internal temperature below 10 °C, and the reaction mixture was stirred at 25 °C overnight. The white precipitate was collected by vacuum filtration, washed with water (100 mL), and dried in vacuo to afford 5-(4-chlorophenyl)-3-methyl-2-(methylthio)-6-(pyridin-4-yl)pyrimidin-4(3H)-one as a brown solid (8.2 g, 23.85 mmol, 47.4% yield). MS (m / z) 343.9 [M+H].

[0259] Step 2: 5-(4-chlorophenyl)-2-hydroxy-3-methyl-6-(pyridin-4-yl)pyrimidin-4(3H)-one. To a stirred solution of 5-(4-chlorophenyl)-3-methyl-2-(methylthio)-6-(pyridin-4-yl)pyrimidin-4(3H)-one (240 g, 698 mmol) in 1,4-dioxane (205 mL) was added aqueous sodium hydroxide solution (582 mL, 3.50 mol), and the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to 25 °C and diluted with water (70 mL). The aqueous layer was washed with ethyl acetate, and the pH of the aqueous layer was adjusted to 4 with 1.5 N HCl aqueous solution (~20 mL). The precipitate was collected by vacuum filtration, washed with petroleum ether, and dried in vacuo to afford 5-(4-chlorophenyl)-2-hydroxy-3-methyl-6-(pyridin-4-yl)pyrimidin-4(3H)-one as an off-white solid. MS (m / z) 313.9 [M+H].

[0260] Step 3: 2-Chloro-5-(4-chlorophenyl)-3-methyl-6-(pyridin-4-yl)pyrimidin-4(3H)-one. To a stirred solution of 5-(4-chlorophenyl)-2-hydroxy-3-methyl-6-(pyridin-4-yl)pyrimidin-4(3H)-one (50 g, 159 mmol) in POCl3 (500 mL, 5.36 mol) at 0 °C was added dropwise DIPEA (84 mL, 478 mmol). The reaction mixture was then stirred at 110 °C for 16 h and concentrated. The residue was redissolved in dichloromethane (2.5 L) and quenched back in ice water (2.0 L). The reaction mixture was basified with saturated NaHCO3 (1.0 L), the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 143 g of the crude product. The crude material was triturated with DCM, collected by vacuum filtration and dried in vacuo to afford 2-chloro-5-(4-chlorophenyl)-3-methyl-6-(pyridin-4-yl)pyrimidin-4(3H)-one (34 g, 102 mmol, 64.2% yield). MS (m / z) 332.0 [M+H].

[0261] Step 4: 5-(4-Chlorophenyl)-3-methyl-2-(methylamino)pyrimidin-4(3H)-one. To a stirred solution of 2-chloro-5-(4-chlorophenyl)-3-methyl-6-(pyridin-4-yl)pyrimidin-4(3H)-one (20 g, 60.2 mmol) in dichloromethane (200 mL) at 0 °C was added methylamine hydrochloride (16.26 g, 241 mmol), then TEA (33.6 mL, 241 mmol) was added dropwise. The reaction was stirred at 40 °C overnight. After 16 h, the reaction mixture was washed with water (200 mL) and brine (2 × 200 mL), dried over sodium sulfate and concentrated in vacuo to give 18 g of the crude product. The crude material was triturated with DCM (100 mL) to afford 5-(4-chlorophenyl)-3-methyl-2-(methylamino)pyrimidin-4(3H)-one as a pale yellow solid (12 g, 36.7 mmol, 61.0% yield). MS (m / z) 327.1 [M+H]. 1 1H NMR (600 MHz, DMSO-d 6 ) δ 8.40 - 8.48 (m, 2H), 7.40 (br d, J = 4.20 Hz, 1H), 7.24 - 7.30 (m, 2H), 7.15 - 7.21 (m, 2H), 7.02 - 7.10 (m, 2H), 3.35 (s, 3H), 2.91 (d, J = 4.20 Hz, 3H).

[0262] Example 2: 5-(4-chlorophenyl)-2-isobutyl-6-(pyridin-4-yl)pyrimidin-4(3H)-one (Compound 2)

[0263]

[0264] Step 1: Ethyl (E)-2-(4-chlorophenyl)-3-(pyridin-4-yl)acrylate. To a stirred solution of ethyl 2-(4-chlorophenyl)acetate (10 g, 50.3 mmol) and isonicotinaldehyde (5.39 g, 50.3 mmol) in 1,4-dioxane (160 mL) at 0 °C was added lithium bis(trimethylsilyl)amide (76 mL, 76 mmol), and the reaction was stirred at ambient temperature. After 1 h, DIEA (88 mL, 503 mmol) and acetic anhydride (85 mL, 906 mmol) were added. The reaction was stirred at ambient temperature for 1 h, then heated to 100 °C and stirred for 16 h. After 16 h, the reaction was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude was purified by column chromatography using 8% ethyl acetate in hexanes as eluent to afford ethyl (E)-2-(4-chlorophenyl)-3-(pyridin-4-yl)acrylate as a colorless liquid (7 g, 24.33 mmol, 48.3% yield). MS (m / z) 288.1 [M+H].

[0265] Step 2: 5-(4-Chlorophenyl)-2-isobutyl-6-(pyridin-4-yl)pyrimidin-4(3H)-one. To a solution of ethyl (E)-2-(4-chlorophenyl)-3-(pyridin-4-yl)acrylate (20.00 g, 69.5 mmol) in DMF (348 mL) was added 3-methylbutanamidine hydrochloride (14.24 g, 104 mmol, enamine) and potassium phosphate (32.5 g, 153 mmol, Aldrich), and the reaction was stirred at 110 °C. After 6 h, the flask was purged with air and stirred overnight. After 16 h, the reaction mixture was cooled to ambient temperature and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with water (10 × 100 mL), dried over anhydrous MgSO4, filtered and concentrated. The crude product was purified by column chromatography eluting with 0-75% ethyl acetate in heptane to afford 5-(4-chlorophenyl)-2-isobutyl-6-(pyridin-4-yl)pyrimidin-4(3H)-one as an off-white solid (16.2 g, 47.8 mmol, 68.7% yield). MS (m / z) 340.0 [M+H]. 1 H NMR (500 MHz, DMSO-d 6) δ ppm 12.83 (broad singlet, 1H), 8.47 (doublet, J = 5.0 Hz, 2H), 7.33 (doublet, J = 7.6 Hz, 2H), 7.13 - 7.21 (multiplet, 4H), 2.18 (doublet of quintets, J = 13.6, 6.8, 6.8, 6.8, 6.8 Hz, 1H), 0.97 (doublet, J = 6.7 Hz, 6H).

[0266] Example 3: 5-(4-chloro-2-fluorophenyl)-2-isobutyl-6-(2-methylpyridin-4-yl)pyrimidin-4(3H)-one (Compound 3)

[0267]

[0268] Similar to Compound 2, Compound 3 was synthesized using ethyl 2-(4-chloro-2-fluorophenyl)acetate in Step 1. LCMS (ESI) [M+H] + m / z: calculated value 371.12, measured value 372.0.

[0269] Detection

[0270] Cell target binding (NanoBRET)

[0271] The cell-based CK-1δ target binding assay is a NanoBRET competition assay that directly quantifies the binding of a compound to the full-length kinase in live cells (Robers M et al., Nat. Comm. No. 6 (2015)). This assay utilizes a cell-permeable fluorescent tracer that reversibly binds to the NanoLuc-tagged kinase expressed in 293T-HEK cells. Intracellular target binding of the unmodified test compound is measured by competitive displacement of the tracer, resulting in a loss of bioluminescence energy transfer (BRET) that is quantified on a microplate luminometer.

[0272] Biochemical kinase assay

[0273] Biochemical inhibition and kinome selectivity of CK-1δ were evaluated using the HotSpot radioisotope filter binding assay (Reaction Biology). In the HotSpot assay, a compound is incubated with the kinase, substrate, cofactor, and radioisotope-labeled ATP. The reaction mixture is then spotted onto a filter paper that binds the quantifiable radioisotope-labeled catalytic product.

[0274] The biological activities of some of the compounds using the above assays are shown in Table 2. IC 50 Range is as follows: For NanoBRET IC 50 (nM), A represents <400 nM; B represents 400 nM ≤ K D<800 nM; C represents K D ≥800 nM. For the detection of biochemical kinases IC 50 (nM), A represents <50 nM; B represents 50 nM ≤ IC 50 <100 nM; C represents ≥100 nm.

[0275] Table 2

[0276]

[0277] Plasma and brain binding assay

[0278] The plasma and brain tissue binding of representative compounds of formula (I) ("Compound A" and "Compound B") was determined using a equilibrium dialysis device. The compound and plasma or brain tissue mixture was loaded onto the donor side of the device, and the dialysis buffer was loaded onto the receptor side of the device. The device was incubated at 37 °C and 5% CO2 for 4 hours. After incubation, the samples were aliquoted, analyzed by LC-MS / MS, and the unbound percentage shown in Tables 3 and 4 was calculated using the concentration.

[0279] Table 3: Compound A

[0280]

[0281]

[0282] Table 4: Compound B

[0283] Detection Species Approximate recovery % Average binding % Average unbound % Plasma protein binding Dog 95 95 5 Plasma protein binding Dog 95 97 3 Plasma protein binding Human 88 97 3 Plasma protein binding Mouse 92 98 2 Plasma protein binding Miniature pig 88 97 3 Brain tissue binding Rat 93 98 2 Plasma protein binding Rat 93 92 8

[0284] These data were used to calculate the brain-to-plasma free ratio (Kpuu), which illustrates the degree of penetration of the compound into the brain. The Kpuu of Compound A in rats was approximately 0.22, and the Kpuu of Compound B in rats was approximately 0.46.

[0285] Numbered embodiments

[0286] 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0287]

[0288] Wherein:

[0289] R 1 is hydrogen or C1-C6 alkyl;

[0290] R 2 is C1-C8 alkyl, C1-C8 haloalkyl, C3-C8 cycloalkyl or -NR A R B;

[0291] R A and R B are independently hydrogen or C1-C6 alkyl, or R A and R B together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic group;

[0292] Each R 3 is independently halogen, cyano, hydroxy or C1-C6 alkyl;

[0293] X is CH, CR 3 or N;

[0294] R 4 is chlorine, cyano, hydroxy or trifluoromethyl;

[0295] Each R 5 is independently halogen, cyano, hydroxy, C1-C6 alkyl or C1-C6 haloalkyl; and

[0296] m and n are independently 0, 1, 2 or 3.

[0297] 2. The compound of embodiment 1, wherein R 1 is C1-C6 alkyl.

[0298] 3. The compound of embodiment 1 or 2, wherein R 1 is methyl.

[0299] 4. The compound of embodiment 1, wherein R 1 is hydrogen.

[0300] 5. The compound of any one of embodiments 1-4, wherein R 2 is C1-C8 alkyl.

[0301] 6. The compound of any one of embodiments 1-5, wherein R 2 is C3-C5 alkyl.

[0302] 7. The compound of any one of embodiments 1-6, wherein R 2 is isobutyl.

[0303] 8. The compound of any one of embodiments 1-4, wherein R 2 is C1-C8 haloalkyl.

[0304] 9. The compound of any one of embodiments 1-4, wherein R 2 is C3-C8 cycloalkyl.

[0305] 10. The compound of any one of embodiments 1-4 or 9, wherein R 2is a C3-C5 cycloalkyl group.

[0306] 11. The compound according to any one of embodiments 1-4, wherein R 2 is -NR A R B .

[0307] 12. The compound according to any one of embodiments 1-4 or 11, wherein R A is a C1-C6 alkyl group.

[0308] 13. The compound according to any one of embodiments 1-4 or 11-12, wherein R A is methyl.

[0309] 14. The compound according to any one of embodiments 1-4 or 11, wherein R A is hydrogen.

[0310] 15. The compound according to any one of embodiments 1-4 or 11, wherein R B is a C1-C6 alkyl group.

[0311] 16. The compound according to any one of embodiments 1-4, 11 or 15, wherein R B is methyl.

[0312] 17. The compound according to any one of embodiments 1-4 or 11, wherein R B is hydrogen.

[0313] 18. The compound according to any one of embodiments 1-4 or 11-17, wherein R A and R B are the same.

[0314] 19. The compound according to any one of embodiments 1-4 or 11-17, wherein R A and R B are different.

[0315] 20. The compound according to any one of embodiments 1-4, 11-17 or 19, wherein one of R A and R B is hydrogen and the other of R A and R B is a C1-C6 alkyl group.

[0316] 21. The compound according to any one of embodiments 1-4, 11-17 or 19-20, wherein one of R A and R B is hydrogen and the other of R A and R B is methyl.

[0317] 22. A compound according to any one of embodiments 1-4 or 11, wherein R A and R B together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic group.

[0318] 23. A compound according to any one of embodiments 1-22, wherein m is 1.

[0319] 24. A compound according to any one of embodiments 1-23, wherein R 3 is a halogen.

[0320] 25. A compound according to any one of embodiments 1-24, wherein R 3 is chlorine.

[0321] 26. A compound according to any one of embodiments 1-24, wherein R 3 is fluorine.

[0322] 27. A compound according to any one of embodiments 1-23, wherein R 3 is a cyano group.

[0323] 28. A compound according to any one of embodiments 1-23, wherein R 3 is a hydroxyl group.

[0324] 29. A compound according to any one of embodiments 1-23, wherein R 3 is a C1-C6 alkyl group.

[0325] 30. A compound according to any one of embodiments 1-23 or 29, wherein R 3 is methyl.

[0326] 31. A compound according to any one of embodiments 1-30, wherein X is CR 3 .

[0327] 32. A compound according to any one of embodiments 1-22, wherein X is CH.

[0328] 33. A compound according to any one of embodiments 1-22, wherein X is N.

[0329] 34. A compound according to any one of embodiments 1-22 or 31-33, wherein m is 0.

[0330] 35. A compound according to any one of embodiments 1-22 or 31-33, wherein m is 2.

[0331] 36. A compound according to any one of embodiments 1-22 or 31-33, wherein m is 3.

[0332] 37. A compound according to any one of embodiments 1-36, wherein R 4is chlorine.

[0333] 38. The compound of any one of embodiments 1-36, wherein R 4 is cyano.

[0334] 39. The compound of any one of embodiments 1-36, wherein R 4 is hydroxy.

[0335] 40. The compound of any one of embodiments 1-36, wherein R 4 is trifluoromethyl.

[0336] 41. The compound of any one of embodiments 1-40, wherein n is 1.

[0337] 42. The compound of any one of embodiments 1-41, wherein R 5 is halogen.

[0338] 43. The compound of any one of embodiments 1-42, wherein R 5 is chlorine.

[0339] 44. The compound of any one of embodiments 1-42, wherein R 5 is fluorine.

[0340] 45. The compound of any one of embodiments 1-41, wherein R 5 is cyano.

[0341] 46. The compound of any one of embodiments 1-41, wherein R 5 is hydroxy.

[0342] 47. The compound of any one of embodiments 1-41, wherein R 5 is C1-C6 alkyl.

[0343] 48. The compound of any one of embodiments 1-41 or 47, wherein R 5 is methyl.

[0344] 49. The compound of any one of embodiments 1-41, wherein R 5 is C1-C6 haloalkyl.

[0345] 50. The compound of any one of embodiments 1-41 or 49, wherein R 5 is trifluoromethyl.

[0346] 51. A compound selected from the group consisting of:

[0347] or a pharmaceutically acceptable salt of any of the foregoing.

[0348] 52. A compound or a pharmaceutically acceptable salt thereof, the compound being 5-(4-chlorophenyl)-2-isobutyl-6-(pyridin-4-yl)pyrimidin-4(3H)-one, which has the structure as shown, or a pharmaceutically acceptable salt thereof.

[0349] 53. A compound or a pharmaceutically acceptable salt thereof, the compound being 5-(4-chlorophenyl)-3-methyl-2-(methylamino)-6-(pyridin-4-yl)pyrimidin-4(3H)-one, which has the structure as shown, or a pharmaceutically acceptable salt thereof.

[0350] 54. A compound or a pharmaceutically acceptable salt thereof, the compound being 5-(4-chloro-2-fluorophenyl)-2-isobutyl-6-(2-methylpyridin-4-yl)pyrimidin-4(3H)-one, which has the structure as shown, or a pharmaceutically acceptable salt thereof.

[0351] 55. A pharmaceutical composition comprising the compound according to any one of embodiments 1-54 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0352] 56. A method for treating a CK-1δ-associated neurological disorder in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of the compound according to any one of embodiments 1-54 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 55.

[0353] 57. The method of embodiment 56, wherein the CK-1δ-associated neurological disorder is amyotrophic lateral sclerosis (ALS), Alzheimer's disease, frontotemporal dementia (FTD), frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), or limbic-predominant age-related TDP-43 encephalopathy (LATE).

[0354] 58. The method of embodiment 56 or 57, wherein the CK-1δ-associated neurological disorder is ALS.

[0355] 59. The method of embodiment 56 or 57, wherein the CK-1δ-associated neurological disorder is Alzheimer's disease.

[0356] 60. The method of embodiment 56 or 57, wherein the CK-1δ-associated neurological disorder is FTD.

[0357] 61. The method of embodiment 56 or 57, wherein the CK-1δ-associated neurological disorder is FTLD-U.

[0358] The method of embodiment 56 or 57, wherein the CK-1δ associated neurological disorder is LATE.

[0359] A method of inhibiting TDP-43 phosphorylation in a cell comprising TDP-43 and CK-1δ, the method comprising contacting the cell with a compound of any one of embodiments 1-54 or a pharmaceutically acceptable salt thereof.

[0360] Other embodiments

[0361] It should be understood that although the present disclosure has been described in connection with its detailed description, the foregoing description is intended to be illustrative and not limiting of the scope of the present disclosure as defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the appended claims.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 1 is hydrogen or a C1-C6 alkyl group; R 2 is a C1-C8 alkyl group, a C1-C8 haloalkyl group, a C3-C8 cycloalkyl group or -NR A R B ; R A and R B are independently hydrogen or C1-C6 alkyl, or R A and R B together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic group; Each R 3 is independently halogen, cyano, hydroxyl or C1-C6 alkyl; X is CH, CR 3 or N; R 4 is chlorine, cyano, hydroxyl or trifluoromethyl; Each R 5 is independently a halogen, cyano, hydroxyl, C1-C6 alkyl or C1-C6 haloalkyl; and m and n are independently 0, 1, 2 or 3.

2. The compound or salt according to claim 1, wherein R 1 is a C1-C6 alkyl group.

3. The compound or salt according to claim 1, wherein R 1 is hydrogen.

4. The compound or salt according to any one of claims 1-3, wherein R 2 is a C1-C8 alkyl group.

5. The compound or salt according to any one of claims 1-4, wherein R 2 is isobutyl.

6. The compound or salt according to any one of claims 1-3, wherein R 2 is -NR A R B .

7. The compound or salt according to any one of claims 1 - 3 and 6, wherein R A is C1 - C6 alkyl.

8. The compound or salt according to any one of claims 1-3 and 6-7, wherein R A is methyl.

9. The compound or salt according to any one of claims 1 - 3 and 6, wherein R A is hydrogen.

10. The compound or salt according to any one of claims 1-3 and 6-9, wherein R B is C1-C6 alkyl.

11. The compound or salt according to any one of claims 1-3 and 6-10, wherein R B is methyl.

12. The compound or salt according to any one of claims 1-3 and 6-9, wherein R B is hydrogen.

13. The compound or salt according to any one of claims 1-12, wherein m is 1.

14. The compound or salt according to any one of claims 1-13, wherein R 3 is a halogen.

15. The compound or salt according to any one of claims 1-14, wherein R 3 is chlorine.

16. The compound or salt according to any one of claims 1-14, wherein R 3 is fluorine.

17. The compound or salt according to any one of claims 1-13, wherein R 3 is C1-C6 alkyl.

18. The compound or salt according to any one of claims 1-13 and 17, wherein R 3 is methyl.

19. The compound or salt according to any one of claims 1-12, wherein m is 0.

20. The compound or salt according to any one of claims 1-19, wherein X is N.

21. The compound or salt according to any one of claims 1-20, wherein R 4 is chlorine.

22. The compound or salt according to any one of claims 1-21, wherein n is 1.

23. The compound or salt according to any one of claims 1-22, wherein R 5 is halogen.

24. The compound or salt according to any one of claims 1-23, wherein R 5 is chlorine.

25. The compound or salt according to any one of claims 1-23, wherein R 5 is fluorine.

26. The compound or salt according to any one of claims 1-21, wherein n is 0.

27. A compound selected from the group consisting of: or a pharmaceutically acceptable salt of any of the foregoing.

28. A pharmaceutical composition comprising the compound according to any one of claims 1-27 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

29. A method of treating a CK-1δ associated neurological disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1-27 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 28.

30. The method according to claim 29, wherein the CK-1δ associated neurological disorder is amyotrophic lateral sclerosis (ALS), Alzheimer's disease, frontotemporal dementia (FTD), frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), or limbic-predominant age-related TDP-43 encephalopathy (LATE).

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