Heterocyclic compounds and uses thereof

Abstract

The present disclosure provides compounds that can specifically target a PDGFRα, and thereby, reduce and / or inhibit the activation of the receptor ("PDGFRα inhibitor"). The present disclosure also provides methods of treating a demyelinating disease using the disclosed PDGFRα inhibitors.

Description

HETEROCYCLIC COMPOUNDS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATION

[0001] This PCT application claims the priority benefit of U.S. Provisional Application No.63 / 501,005, filed May 9, 2023, which is incorporated herein by reference in its entirety. REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY VIA EFS-WEB

[0002] The content of the electronically submitted sequence listing (Name: 5411_003PC01_Seqlisting_ST26; Size: 29,305 bytes; and Date of Creation: May 8, 2024) submitted in this application is incorporated herein by reference in its entirety. FIELD OF THE DISCLOSURE

[0003] The present disclosure relates to compounds that can promote remyelination. Specifically, the disclosure relates to PDGFRα inhibitors and the use of such inhibitors to treat diseases associated with impaired myelination (e.g., multiple sclerosis). BACKGROUND OF THE DISCLOSURE

[0004] Proper myelination by oligodendrocytes is essential for central nervous system (CNS) development and function. Gacem et al., Life 11(4): 327 (Apr. 2021). Myelin maintains axon potential conduction velocity of neural signals and provides metabolic support to axons, supporting their survival. During normal development, oligodendrocyte progenitor cells (OPCs) undergo morphological and molecular changes as they differentiate into oligodendrocytes that can myelinate axons. Accordingly, any abnormal developmental processes or pathogenic immune activation and failure of oligodendrocytes to myelinate axons or loss of myelin can lead to neurodegenerative diseases such as multiple sclerosis.

[0005] Multiple sclerosis (MS) is generally characterized by inflammation and demyelination of neuronal axons. Patients with early MS often suffer from isolated immune attacks with effective remyelination and recovery between attacks. However, as the disease progresses, MS patients have a reduced ability to effectively remyelinate resulting inpermanent neurological disability. Current treatments for MS and other neurodegenerative diseases largely focus on reducing the immune attack on myelin but do not restore myelin on the damaged neuronal axons.

[0006] Therefore, there remains a need for a new and more effective treatment of such demyelinating diseases, particularly treatments that can induce the remyelination of demyelinated, vulnerable neuronal axons. BRIEF SUMMARY OF THE DISCLOSURE

[0007] The present disclosure describes the discovery that compounds that inhibit PDGFRα can promote remyelination. Compounds and methods of the present disclosure are therefore useful for treating diseases associated with demyelination (e.g., hypomyelination).

[0008] Provided herein is a compound of Formula I:,

[0009] or a pharmaceutically acceptable salt or solvate thereof, wherein: indicates a single bond or a double bond such that all valences are satisfied; X1, X2, X3, and X4are selected from N and CRa, with the proviso that not more than two of X1, X2, X3, and X4are N; one of Y1and Y2is N and the other of Y1and Y2is C; each Rais independently selected from H, halo, C1-C4alkyl, and C1-C4alkoxy; R1is selected from C1-C4alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, heteroaryl, aryl, and C1-C8alkoxy, all of which can be optionally substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, oxo, C1-C4alkyl, aminoC1- C4alkyl, hydroxyC1-C4alkyl, C1-C4alkoxy, C1-C4alkoxyC1-C4alkyl, 3-8 membered heterocyclyl, and 3-8 membered heterocyclylC1-C4alkyl, with the proviso that the number of substituents does not exceed the number of substitutable positions; R2is selected from cycloalkyl, cycloalkenyl, alkyl, oxoalkylamino, aminoalkylamino, amino, heterocyclyl, heteroaryl, aminoheterocyclyl, heterocyclylamino,and aminoalkylamino, all of which can be optionally substituted with one or more substituents selected from D, halo, hydroxy, oxo, and C1-C4alkyl; R2is substituted by one, two, or three R3; R3is selected from aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)NR31R32, -S(O)2NR31R32, -S(O)(NR33)R31, -S(O)2R31, -S(O)(NR33)NR31R32, -C(S)NR31R32, C3-C8cycloalkyl, 3-8 membered heterocyclyl, and C1-C4alkyl, all of which can be optionally substituted with one, two, three, four, or five R30; each R30is independently selected from D, halo, aryl, -OR300, -NR300R303, -S(O)rR300, -C(O)R300, -C(=CR34R35)R300, and; r is selected from 0, 1, and 2; each R300is independently selected from C1-C6alkyl, C3-C7cycloalkyl, aryl, heteroaryl, 3-8 membered heterocyclyl, and 3-8 membered heterocyclylaryl, all of which can be optionally substituted with one, two, three, four, or five substituents selected from D, halo, hydroxy, amino, alkylamino, cyano, C1-C4alkyl, C1-C4haloalkyl, and C1-C4alkoxy; each R301is independently selected from H, halo, and C1-C4alkyl; each R302is independently selected from H, F, hydroxyl, amino, alkylamino, oxo, and C1-C4alkyoxy; each R303is independently selected from H and C1-C4alkyl; n, o, and p are each independently selected from 0, 1, 2, 3, and 4; each R31is independently selected from C1-C8alkyl, arylC1-C4alkyl, heteroarylC1- C4alkyl, heterocyclyl, heterocyclylC1-C4alkyl, cycloalkyl, and cycloalkylC1-C4alkyl, all of which can be optionally substituted with one, two, three, four, or five substituents selected from D, halo, cyano, hydroxy, amino, -OCF3, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, hydroxyC1-C4alkyl, -S(O)2NR304R305, -C(O)OR304R305, -C(O)NR304R305, and -NR304C(O)R305; each R304and R305is independently selected from H and C1-C4alkyl; each R32is independently selected from H and C1-C4alkyl; orR31and R32together with the atom to which they are connected to form a 5-8 membered heterocycyl, optionally substituted with one, two, three, four, or five substituents selected from D, halo, cyano, C1-C4alkyl, C1-C4haloalkyl, and -C(O)NR34R35; and each R34and R35is independently selected from H, C1-C4alkyl, and C1-C4haloalkyl; and each R33is independently selected from H, C1-C4alkyl, C1-C4haloalkyl, and –C(O)R34; or R31and R33together with the atoms to which they are connected form a 4-8 membered heterocycyl.

[0010] In some aspects, Y1is N and Y2is C.

[0011] In some aspects, Y1is C and Y2is N.

[0012] In some aspects, X1is N, X2is CRa, X3is CRa, and X4is CRa.

[0013] In some aspects, X1is CRa, X2is N, X3is CRa, and X4is CRa.

[0014] In some aspects, X1is CRa, X2is CRa, X3is N, and X4is CRa.

[0015] In some aspects, X1is CRa, X2is CRa, X3is CRa, and X4is N.

[0016] In some aspects, X1is CRa, X2is CRa, X3is CRa, and X4is CRa.

[0017] In some aspects, R1is 5- or 6-membered heteroaryl optionally substituted with C1- C4alkyl or oxo.

[0018] In some aspects, R2is substituted with one R3.

[0019] In some aspects, R1is an optionally substituted pyrazolyl.

[0020] In some aspects, R1is selected from:, , nd

[0021] R10is selected from H, C1-C4alkyl, C1-C4alkoxy, aminoC1-C4alkyl, hydroxyC1- C4alkyl, and C1-C4alkylsulfonyl, wherein the C1-C4alkyl, C1-C4alkoxy, aminoC1-C4alkyl, hydroxyC1-C4alkyl, and C1-C4alkylsulfonyl can be optionally substituted by one or more substituents selected from hydroxyl, C1-C4alkoxy, NR10aR10b, halo, and deuterium, wherein R10aand R10bare selected from hydrogen and C1-C4alkyl, or wherein R10aand R10btaken together with the nitrogen atom to which they are attached form a 4- to 8-membered ring.

[0022] In some aspects, R1is.

[0023] In some aspects, R10is CH3.

[0024] In some aspects, R2is heterocyclyl.

[0025] In some aspects, R2is selected from: ,, , , ,, ,, , , ,, and;

[0026] indicates a single bond or a double bond such that all valences are satisfied;

[0027] m is selected from 0, 1, 2, 3, 4, 5, and 6; and

[0028] Z1, Z2, and Z3are selected from N and CRa.

[0029] In some aspects, R2is selected from:,, , , .

[0030] In some aspects, the compound, or a pharmaceutically acceptable salt or solvate thereof, has Formula Ia:

[0031] wherein a and b are each independently selected from 1, 2, and 3; and

[0032] Q is selected from -CH- and -N-, with the proviso that if Q is -N-, a and b are not 1.

[0033] In some aspects, the compound, or a pharmaceutically acceptable salt or solvate thereof, ihas Formula II:.

[0034] In some aspects, the compound, or a pharmaceutically acceptable salt or solvate thereof, has Formula IIa:.

[0035] In some aspects, R3is heteroaryl optionally substituted with one, two, three, four, or five R30.

[0036] In some aspects, R3is selected from: ,, , , , ,, ,,

[0037] wherein A1is selected from O, S, and NR37, R36is selected from hydrogen, optionally substituted C1-C6alkyl, and optionally substituted C1-C6alkylaryl, and R37is selected from hydrogen and C1-C6alkyl.

[0038] In some aspects, R3is selected from:, ,

[0039] In some aspects, R30is:.

[0040] In some aspects, R300is selected from:

[0041] In some aspects, R300is:.

[0042] In some aspects, R301is H and R302is -OH or CH3.

[0043] In some aspects, R3is selected from:nd.

[0044] In some aspects, R3is selected from:, , .

[0045] In some aspects, the compound, or a pharmaceutically acceptable salt or solvate thereof, has Formula IV:wherein L1is NH or O.

[0046] In some aspects, the compound, or a pharmaceutically acceptable salt or solvate thereof, has Formula V:.

[0047] In some aspects, R31is selected from: ,, , ,,, ,,,,

[0048] wherein R31ais selected from H, D, alkylamino, optionally substituted C1-C4alkyl, C1-C4alkoxy, amino, and C1-C4haloalkyl,

[0049] each R31bis independently selected from H, D, halo, hydroxy, amino, cyano, alkylamino, optionally substituted C1-C4alkyl, C1-C4haloalkyl, optionally substituted C1- C4alkoxy, and C3-C6cycloalkyl, and q is 1, 2, or 3.

[0050] In some aspects, the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is selected from any one of the compounds of Table 1.

[0051] In some aspects, the compound of Formula I can exhibit one or more of the following properties: (i) promote the differentiation of an OPC into an oligodendrocyte, (ii) promote the expression of a protein associated with oligodendrocyte differentiation and / or myelination (e.g., G-protein coupled receptor 17 (GPR17), myelin basic protein (MBP), ASPA, GST-pi, CC1, myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte- specific protein / claudin-11, CNPase, proteolipid protein 1 (PLP1), or a combination thereof), (iii) promote the myelination of an axon, (iv) promote the remyelination of a demyelinated axon, (v) inhibit PDGFRα kinase activity, (vi) achieve a brain to plasma ratio of greater than 0.1 when systemically administered to a subject, and (vii) any combination thereof.

[0052] In some aspects, the compound of Formula I can inhibit PDGFRα kinase activity.

[0053] In some aspects, the compound of Formula I can inhibit PDGFRα kinase activity with an IC50of less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 2.5 nM, less than 1 nM, less than 0.5 nM, or less than 0.2 nM.

[0054] In some aspects, the IC50of the PDGFRα inhibitor of Formula I is determined using an enzymatic PDGFRα kinase assay (e.g., Promega kinase assay described in Example 131).

[0055] In some aspects, the enzymatic PDGFRα kinase assay comprises 20 ng of purified PDGFRα protein, 150 µM of ATP and 1 µg of substrate, Poly (Glu4Tyr1) in a volume of 15 µl.

[0056] In some aspects, the compound of Formula I can inhibit PDGFRα kinase activity with an IC50of from about 500 nM to about 0.001 nM, from about 400 nM to about 0.001 nM, from about 300 nM to about 0.001 nM, from about 200 nM to about 0.001 nM, from about 100 nM to about 0.001 nM, from about 75 nM to about 0.001 nM, from about 50 nM to about 0.001 nM, from about 40 nM to about 0.001 nM, from about 30 nM to about 0.001nM, from about 20 nM to about 0.001 nM, from about 10 nM to about 0.001 nM, from about 5 nM to about 0.001 nM, from about 2.5 nM to about 0.001 nM, from about 1 nM to about 0.001 nM, from about 0.5 nM to about 0.001 nM, or from about 0.2 nM to about 0.001 nM.

[0057] In some aspects, the disclosure provides a compound that can inhibit a PDGFRα activity of a cell and can further exhibit one or more of the following properties: (i) promote the differentiation of an OPC into an oligodendrocyte, (ii) promote the expression of a protein associated with oligodendrocyte differentiation and / or myelination (e.g., G-protein coupled receptor 17 (GPR17), myelin basic protein (MBP), ASPA, GST-pi, CC1, myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein / claudin-11, CNPase, proteolipid protein 1 (PLP1), or a combination thereof), (iii) promote the myelination of an axon, (iv) promote the remyelination of a demyelinated axon, (v) inhibit PDGFRα kinase activity, (vii) achieve a brain to plasma ratio of greater than 0.1 when systemically administered to a subject, or (viii) any combination thereof.

[0058] In some aspects, the compound can inhibit PDGFRα kinase activity with an IC50of less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 75 nM, less than less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 2 nM.

[0059] In some aspects, the IC50of the PDGFRα inhibitor is determined using an enzymatic PDGFRα kinase assay (e.g., Promega™ kinase assay described in Example 131).

[0060] In some aspects, the enzymatic PDGFRα kinase assay comprises 20 ng of purified PDGFRα protein, 150 µM of ATP and 1 µg of substrate, Poly (Glu4Tyr1) in a volume of 15 µl.

[0061] The disclosure also provides a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0062] The disclosure also provides a kit comprising a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a composition disclosed herein, and instructions for use.

[0063] The disclosure also provides a method of producing a PDGFRα inhibitor comprising synthesizing a compound disclosed herein.

[0064] The disclosure also provides a compound disclosed herein, or a pharmaceutical composition disclosed herein, for use as a medicament.

[0065] The disclosure also provides a compound disclosed herein, or a pharmaceutical composition disclosed herein, for use in therapy.

[0066] The disclosure also provides a method of treating a demyelinating disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein.

[0067] The disclosure also provides a method of improving a subject’s performance in a test for assessing one or more symptoms associated with a demyelinating disease, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein, wherein after the administration, the subject’s performance in the test is improved as compared to a reference subject (e.g., the subject prior to the administration).

[0068] In some aspects, the test is selected from one or more of a visual evoked potential (VEP) test, a multifocal visual evoked potential (mfVEP) test, a low contrast visual acuity (LC-VA) test, a magnetic resonance imaging (MRI) (e.g., magnetization transfer ratio (MTR), myelin water fraction (MWF), quantitative susceptibility mapping (QSM), and T2 imaging), an electromyography (EMG), a nerve conduction velocity (NCV) test, an Extended Disability Status Scale (EDSS), a timed walk test (e.g., timed 25-foot walk), a Nine-Hole Peg Test (9HPT), an ocular coherence tomograph (OCT), a quality of life measure test (e.g., Multiple Sclerosis Quality of Life-54 and Vision-Related Quality of Life), cognitive assessment (e.g., Symbol-Digit Modalities Test or Montreal Cognitive Assessment), or combinations thereof.

[0069] In some aspects, the demyelinating disease comprises one or more of an acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalitis, acute transverse myelitis, adrenoleukodystrophy, adrenomyeloneuropathy, Alexander disease, Alzheimer’s disease, aminoacidurias, amyotrophic lateral sclerosis, anti-MAG peripheral neuropathy, anti-MOG associated spectrum, Balo concentric sclerosis, brain injury, CAMFAK syndrome, Canavan disease, carbon monoxide toxicity, central pontine myelinolysis, cerebral hypoxia, cerebral ischemia, Charcot–Marie–Tooth disease, chronic inflammatory demyelinating polyneuropathy, chronic traumatic encephalopathy, clinically isolated syndrome (CIS), congenital cataract, copper deficiency associated condition,delayed post-hypoxic leukoencephalopathy, diffuse cerebral sclerosis of Schilder, diffuse myelinoclastic sclerosis, extrapontine myelinolysis Gaucher disease, Guillain–Barré syndrome, hereditary neuropathy, hereditary neuropathy with liability to pressure palsy, HTLV-1–associated myelopathy, Hurler syndrome, hypomyelination, hypoxic brain injury, Krabbe disease, Leber hereditary optic atrophy and related mitochondrial disorders, leukodystrophic disorders, Marchiafava-Bignami disease, metachromatic leukodystrophy, multiple sclerosis (e.g., primary progressive multiple sclerosis (PPMS), relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), progressive relapsing multiple sclerosis, Marburg multiple sclerosis, tumefactive multiple sclerosis, and optic-spinal multiple sclerosis), multiple system atrophy, myelinoclastic disorders, myelopathy, nerve injury, neuromyelitis optica (NMO), Niemann-Pick disease, optic neuropathy, optic neuritis (e.g., acute optic neuritis and chronic relapsing inflammatory optic neuritis (CRION)), osmotic demyelination syndrome, Parkinson’s disease, Pelizaeus‐ Merzbacher disease, peripheral neuropathy, phenylketonuria, progressive inflammatory neuropathy, progressive multifocal leukoencephalopathy, progressive subcortical ischemic demyelination, reperfusion injury, Schilder disease, solitary sclerosis, spinal cord injury, subacute sclerosing panencephalitis, Tabes dorsalis, Tay-Sachs disease, transverse myelitis, traumatic brain injury, tropical spastic paraparesis, vitamin B12 deficiency, and cerebral palsy.

[0070] In some aspects, the demyelinating disease is characterized by demyelination of one or more cells within the CNS of the subject.

[0071] In some aspects, the demyelinating disease is multiple sclerosis.

[0072] In some aspects, the multiple sclerosis comprises a clinically isolated syndrome (“CIS”), relapsing-remitting MS (“RRMS”), secondary progressive MS (“SPMS”), primary progressive MS (“PPMS”), optic neuritis or transverse myelitis.

[0073] In some aspects, the demyelinating disease is an optic neuritis.

[0074] In some aspects, treating the demyelinating disease comprises reducing one or more symptoms associated with the demyelinating disease.

[0075] In some aspects, the one or more symptoms comprise one or more of fatigue, dizziness, malaise, elevated fever and high body temperature, extreme sensitivity to cold in the hands and feet, weakness and stiffness in muscles and joints, weight changes, digestive or gastrointestinal problems, low blood pressure, high blood pressure, irritability, anxiety,depression, impaired vision (e.g., blurred vision, double vision, reduction in low contrast visual acuity (LC-VA)), ataxia, clonus, spasms, dysarthria, weakness, clumsiness, hand paralysis, hemiparesis, genital anesthesia, sexual dysfunction, incoordination, paresthesias, ocular paralysis, impaired muscle coordination, loss of sensation, tingling, numbness, pain, neurological symptoms, impaired cognition, unsteady gait, balance problems, dizziness, spastic paraparesis, incontinence, hearing problems, speech problems, loss of olfaction, and agusia.

[0076] The disclosure also provides a method of promoting the myelination of an axon in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein.

[0077] In some aspects, promoting the myelination of an axon results in an increase in the expression of one or more of the following markers within the subject: myelin basic protein (MBP) Myelin Oligodendrocyte Glycoprotein (MOG), Oligodendrocyte Specific Protein / Claudin-11, CNPase, proteolipid protein 1 (PLP1), or any combination thereof.

[0078] In some aspects, the myelination of an axon can be determined by visualizing and / or quantifying the expression of one or more of the following markers: myelin basic protein (MBP) Myelin Oligodendrocyte Glycoprotein (MOG), Oligodendrocyte Specific Protein / Claudin-11, CNPase, proteolipid protein 1 (PLP1), or any combination thereof.

[0079] The disclosure also provides method of promoting the remyelination of a demyelinated axon in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein.

[0080] In some aspects, promoting the remyelination of a demyelinated axon results in an increase in the expression of one or more of the following markers within the subject: myelin basic protein (MBP) Myelin Oligodendrocyte Glycoprotein (MOG), Oligodendrocyte Specific Protein / Claudin-11, CNPase, proteolipid protein 1 (PLP1), or any combination thereof.

[0081] In some aspects, the remyelination of a demyelinated axon can be determined by visualizing and / or quantifying the expression of one or more of the following markers: myelin basic protein (MBP), Myelin Oligodendrocyte Glycoprotein (MOG), Oligodendrocyte Specific Protein / Claudin-11, CNPase, proteolipid protein 1 (PLP1), or any combination thereof.

[0082] The disclosure also provides a method of reducing the demyelination of a myelinated neuronal axon in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein.

[0083] In some aspects, reducing the demyelination of a myelinated neuronal axon results in an increase in the expression of one or more of the following markers: myelin basic protein (MBP) Myelin Oligodendrocyte Glycoprotein (MOG), Oligodendrocyte Specific Protein / Claudin-11, CNPase, proteolipid protein 1 (PLP1), or any combination thereof.

[0084] In some aspects, the reduction in the demyelination of a myelinated neuronal axon can be determined by visualizing and / or quantifying the expression of one or more of the following markers: myelin basic protein (MBP) Myelin Oligodendrocyte Glycoprotein (MOG), Oligodendrocyte Specific Protein / Claudin-11, CNPase, proteolipid protein 1 (PLP1), or any combination thereof.

[0085] The present disclosure also provides a method of activating an oligodendrocyte progenitor cell (OPC) within the central nervous system (CNS) of a subject in need thereof, the method comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein.

[0086] In some aspects, the subject has, or is at risk of developing a demyelinating disease, for example a disease disclosed herein.

[0087] In some aspects, the method is a method of treating or preventing a demyelinating disease, for example a disease disclosed herein.

[0088] In some aspects, the compound or the pharmaceutical composition is administered to the subject once.

[0089] In some aspects, the compound or the pharmaceutical composition is administered to the subject more than once using intermittent dosing.

[0090] In some aspects, the intermittent dosing comprises administering the compound or pharmaceutical composition to the subject every other day, every three days, every four days, every five days, every six days, once a week, every eight days, every nine days, every 10 days, every 11 days, every 12 days, every 13 days, once every two weeks, once every three weeks, once a month, once every two months, once every three months, once every four months, once every five months, once every six months, or once every twelve months.

[0091] In some aspects, the intermittent dosing comprises administering to the subject a first dose and a second dose of the compound or pharmaceutical composition, wherein the second dose is administered at least one day, at least two days, at least three days, at least four days, at least five days, at least six days, at least seven days, at least eight days, at least nine days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least two weeks, at least three weeks, at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, or at least 12 months after administering the first dose.

[0092] In some aspects, the second dose is administered to the subject one day, two days, three days, four days, five days, six days, seven days, eight days, nine days, 10 days, 11 days, 12 days, 13 days, two weeks, three weeks, one month, two months, three months, four months, five months, six months, or 12 months after administering the first dose.

[0093] In some aspects, after the administration, the compound or the pharmaceutical composition can achieve a brain to plasma ratio of greater than 0.1, greater than 0.2, greater than 0.3, greater than 0.4, greater than 0.5, greater than 0.6, greater than 0.7, greater than 0.8, greater than 0.9, greater than 1.0, greater than 1.1, greater than 1.2, greater than 1.3, greater than 1.4, greater than 1.5, greater than 1.6, greater than 1.7, greater than 1.8, greater than 1.9, or greater than 2.0. In some aspects, the brain to plasma ratio may be assessed in preclinical species using bioanalytical gas or liquid chromatography and mass spectrometry methods.

[0094] In some aspects, the method further comprises administering to the subject an additional therapeutic agent.

[0095] In some aspects, the additional therapeutic agent comprises a standard care of treatment.

[0096] In some aspects, the additional therapeutic agent comprises an immunomodulatory agent.

[0097] In some aspects, the additional therapeutic agent is selected from interferon beta- 1b, interferon beta-1a, peginterferon beta-1a, alemtuzumab, natalizumab, ocrelizumab, ofatumumab, ublituximab-xiiy, glatiramer acetate, teriflunomide, dimethyl fumarate, monomethyl fumarate, diroximel fumarate, fingolimod hydrochloride, siponimod fumaric acid, ozanimod hydrochloride, ponesimod, cladribine, mitoxantrone, a BTK inhibitor (e.g.,masitinib, evobrutinib, or tolebrutinib), a statin (e.g., simvastatin), or a pharmaceutically acceptable salt thereof.

[0098] In some aspects, the additional therapeutic agent is administered to the subject prior to, concurrently, or after the administration of the compound or the pharmaceutical composition.

[0099] The disclosure also provides a method of inducing the differentiation of an oligodendrocyte progenitor cell (OPC) into an oligodendrocyte, the method comprising contacting the OPC with an effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein.

[0100] In some aspects, inducing the differentiation of the OPC into an oligodendrocyte results in an increase in the expression of the following markers in the subject: GPR17, MBP, ASPA, GST-pi, CC1, myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein / claudin-11, CNPase, proteolipid protein 1 (PLP1), or a combination thereof.

[0101] In some aspects, the differentiation of the OPC into an oligodendrocyte is measured by determining the expression of GPR17, MBP, ASPA, GST-pi, CC1, myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein / claudin-11, CNPase, proteolipid protein 1 (PLP1), or a combination thereof.

[0102] The disclosure also provides a method of inhibiting PDGFRα activity in a cell, the method comprising contacting the cell with an effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein.

[0103] In some aspects, the inhibition of the PDGFRα activity is measured by one or more of the following: an in vitro OPC differentiation assay (e.g., as described in Example 132), a cuprizone model for demyelination, an in vivo OPC differentiation assay (e.g., as described in Example 134), an enzymatic PDGFRα kinase assay (e.g., as described in Example 131), or any combination thereof.

[0104] In some aspects, the contacting occurs ex vivo or in vivo.

[0105] In some aspects, the method is a method of treating by a therapy.

[0106] The disclosure also provides a method of treating a PDGF-associated tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein, wherein after the administration, PDGFRα activity is reduced in the subject.

[0107] In some aspects, the PDGF-associated tumor comprises an oligodendroglioma.

[0108] In some aspects, the method is a method of treatment by therapy. DETAILED DESCRIPTION OF THE DISCLOSURE

[0109] The present disclosure describes compounds that can induce the differentiation of OPCs into cells that have features of mature oligodendrocytes, including morphological characteristics and the protein expression patterns associated with myelination, and can also affect remyelination. Accordingly, as described herein, the compounds of the present disclosure can be useful in treating various diseases, such as those associated with demyelination. Additional aspects of the present disclosure are provided throughout the present application.

[0110] Before the present disclosure is described in greater detail, it is to be understood that this disclosure is not limited to the particular compositions or process steps described, which can, of course, vary. As will be apparent to those of skill in the art upon reading this disclosure, each of the individual aspects described and illustrated herein has discrete components and features, which can be readily separated from, or combined with, the features of any of the other several aspects without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or in any other order which is logically possible.

[0111] The headings provided herein are not limitations of the various aspects of the disclosure, which can be defined by reference to the specification as a whole. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims. I. Terms

[0112] In order that the present disclosure can be more readily understood, certain terms are first defined. As used in this application, except as otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout the application.

[0113] The term “a” or “an” entity refers to one or more of that entity; for example, “a nucleotide sequence,” is understood to represent one or more nucleotide sequences. Assuch, the terms “a” (or “an”), “one or more,” and “at least one” can be used interchangeably herein.

[0114] Furthermore, “and / or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and / or” as used in a phrase such as “A and / or B” herein is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0115] It is understood that wherever aspects are described herein with the language “comprising,” otherwise analogous aspects described in terms of “consisting of” and / or “consisting essentially of” are also provided.

[0116] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure is related. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nded., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 5thed., 2013, Academic Press; and the Oxford Dictionary of Biochemistry and Molecular Biology, 2nded., 2008, Oxford University Press, provide one of skill with a general dictionary of many of the terms used in this disclosure.

[0117] Units, prefixes, and symbols are denoted in their Système International de Unites (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range. Where a range of values is recited, it is to be understood that each intervening integer value, and each fraction thereof, between the recited upper and lower limits of that range is also specifically disclosed, along with each subrange between such values. The upper and lower limits of any range can independently be included in or excluded from the range, and each range where either, neither or both limits are included is also encompassed within the disclosure. Thus, ranges recited herein are understood to be shorthand for all of the values within the range, inclusive of the recited endpoints. For example, a range of 1 to 10 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0118] Where a value is explicitly recited (e.g., 10), it is to be understood that values that are about the same quantity or amount as the recited value (e.g., ± 10%) are also within thescope of the disclosure. Where a combination is disclosed, each subcombination of the elements of that combination is also specifically disclosed and is within the scope of the disclosure. Conversely, where different elements or groups of elements are individually disclosed, combinations thereof are also disclosed. Where any element of a disclosure is disclosed as having a plurality of alternatives, examples of that disclosure in which each alternative is excluded singly or in any combination with the other alternatives are also hereby disclosed; more than one element of a disclosure can have such exclusions, and all combinations of elements having such exclusions are hereby disclosed.

[0119] The term “halo” as used herein by itself or as part of another group refers to Cl, F, Br, or I.

[0120] The term “nitro” as used herein by itself or as part of another group refers to NO2.

[0121] The term “cyano” as used herein by itself or as part of another group refers to CN.

[0122] The term “hydroxy” as herein used by itself or as part of another group refers to OH.

[0123] The term “alkyl” as used herein by itself or as part of another group refers to a straight- or branched-chain aliphatic hydrocarbon containing one to twelve carbon atoms, i.e., a C1-C12alkyl, or the number of carbon atoms designated, e.g., a C1alkyl such as methyl, a C2alkyl such as ethyl, etc. In some aspects, the alkyl is a C1-C10alkyl. In some aspects, the alkyl is a C1-C6alkyl. In some aspects, the alkyl is a C1-C4alkyl. In some aspects, the alkyl is a C1-C3alkyl, i.e., methyl, ethyl, propyl, or isopropyl. Non limiting exemplary C1- C12alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso- butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. In some aspects, one or more of the hydrogen atoms of the alkyl group are replaced by deuterium atoms, i.e., the alkyl group is isotopically-labeled with deuterium. A non-limiting exemplary deuterated alkyl group is - CD3.

[0124] The term “haloalkyl” as used herein by itself or as part of another group refers to an alkyl group wherein one or more hydrogen atoms of the alkyl group are replaced by halo atoms. In some aspects, the haloalkyl group is a -CF3group.

[0125] The term “alkoxy” as used herein by itself or as part of another group refers to an alkyl group attached to a terminal oxygen atom. In some aspects, the alkyl is a C1-C8alkyl and resulting alkoxy is thus referred to as a “C1-C8alkoxy.” In some aspects, the alkyl is aC1-C4alkyl group. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and tert-butoxy.

[0126] The term “alkyoxyalkyl” as used herein by itself or as part of another group refers to an alkyl group substituted with an alkoxyl group. In some aspects, the alkyl is a C1-C4alkyl and the alkoxy is a C1-C4alkoxyl and the resulting alkoxyalkyl is thus referred to as a “C1-C4alkoxyC1-C4alkyl”.

[0127] The term “amino” as used herein by itself or as part of another group refers to -NH2, which may be optionally substituted with one or two alkyl, two alkyl linked to form a ring, haloalkyl, (hydroxy)alkyl, (alkoxy)alkyl, (amino)alkyl, heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, or (heteroaryl)alkyl.

[0128] The term “heterocycylamino” as used herein by itself or as part of another group refers to an amino group substituted with a heterocyclyl group.

[0129] The term “aminoalkyl” as used herein by itself or as part of another group refers to an alkyl group substituted with an amino group. In some aspects, the alkyl is a C1-C4alkyl and the resulting aminoalkyl is thus referred to as an “aminoC1-C4alkyl”.

[0130] The term “hydroxyalkyl” as used herein by itself or as part of another group refers to an alkyl group substituted with a hydroxy group. In some aspects, the alkyl is a C1- C4alkyl and the resulting hydroxyalkyl is thus referred to as a “hydroxyC1-C4alkyl”.

[0131] The term “aminoalkylamino” as used herein by itself or as part of another group refers to an amino group substituted with an aminoalkyl group. In some aspects, the aminoalkylamino group is -NHCH2CH2NH2.

[0132] The term “oxo” as used herein refers to an oxygen atom that is connected to a carbon atom by a double bond, i.e. to form a keto group.

[0133] The term “cycloalkyl” as used herein by itself or as part of another group refers to saturated and partially unsaturated, e.g., containing one or two double bonds, monocyclic, bicyclic, or tricyclic aliphatic hydrocarbons containing three to twelve carbon atoms, i.e., a C3-C12cycloalkyl, or the number of carbons designated, e.g., a C3cycloalkyl such a cyclopropyl, a C4cycloalkyl such as cyclobutyl, etc. In some aspects, the cycloalkyl is bicyclic, i.e., it has two rings. In some aspects, the cycloalkyl is monocyclic, i.e., it has one ring. In some aspects, the cycloalkyl is a C3-C8cycloalkyl. In some aspects, the cycloalkylis a C3-6cycloalkyl, i.e., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some aspects, the cycloalkyl is a C5cycloalkyl, i.e., cyclopentyl or cyclopentenyl. In some aspects, the cycloalkyl is a C6cycloalkyl, i.e., cyclohexyl or cyclohexenyl. A cycloalkyl group containing one or two double bonds may also be referred to as a “cycloalkenyl” group.

[0134] The term “heterocyclyl” as used herein by itself or as part of another group refers to saturated and partially unsaturated, e.g., containing one or two double bonds, monocyclic, bicyclic, or tricyclic groups containing three to fourteen ring members, i.e., a 3- to 14-membered heterocyclyl, comprising one, two, three, or four heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen. The term heterocyclyl includes groups wherein one or more -CH2- groups is replaced with one or more -C(=O)- groups, including cyclic ureido groups such as imidazolidinyl-2-one, cyclic amide groups such as piperidin-2-one or piperazin-2-one, and cyclic carbamate groups such as oxazolidinyl-2- one.

[0135] The term “heterocyclylaryl” as used herein by itself or as part of another group refers to an aryl group that is substituted with a heterocyclyl group.

[0136] The term “arylC1-C4alkyl” as used herein by itself or as part of another group refers to a C1-C4alkyl group substituted with an aryl group.

[0137] The term “heteroarylC1-C4alkyl” as used herein by itself or as part of another group refers to a C1-C4alkyl group substituted with a heteroaryl group.

[0138] The term “heterocyclylC1-C4alkyl” as used herein by itself or as part of another group refers to a C1-C4alkyl group substituted with a heterocyclyl group.

[0139] The term “cycloalkylC1-C4alkyl” as used herein by itself or as part of another group refers to a C1-C4alkyl group substituted with a cycloalkyl group.

[0140] The term “alkylsulfonyl” as used herein by itself or as part of another group refers to a sulfonyl group, i.e., -SO2-, substituted by an alkyl group. A non-limiting exemplary alkylsulfonyl group is -SO2CH3.

[0141] The term “aryl” as used herein by itself or as part of another group refers to an aromatic ring system having six to fourteen carbon atoms, i.e., C6-C14aryl. Non-limiting exemplary aryl groups include phenyl (abbreviated as “Ph”), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In some aspects, the aryl group is phenyl.

[0142] The term “heteroaryl” as used herein by itself or as part of another group refers to monocyclic and bicyclic aromatic ring systems having five to fourteen ring members, i.e., a 5- to 14-membered heteroaryl, comprising one, two, three, or four heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen. In some aspects, the heteroaryl has three heteroatoms. In some aspects, the heteroaryl has two heteroatoms. In some aspects, the heteroaryl has one heteroatom. In some aspects, the heteroaryl is a 5- to 10- membered heteroaryl. In some aspects, the heteroaryl has 5 ring atoms, e.g., thienyl, a 5- membered heteroaryl having four carbon atoms and one sulfur atom. In some aspects, the heteroaryl has 6 ring atoms, e.g., pyridyl, a 6-membered heteroaryl having five carbon atoms and one nitrogen atom. Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, and phenoxazinyl. The term heteroaryl also includes N-oxides. A non-limiting exemplary N-oxide is pyridyl N-oxide.

[0143] The term “aminoheterocyclyl” as used herein by itself or as part of another group refers to a heterocyclyl group substituted with an optionally substituted amino group. Non- limiting exemplary aminoheterocyclyl groups include:.

[0144] The chemical terms used herein may be combined to describe larger substituents. For a monovalent substituent, the substituent that is recited last in the combined term is the substituent that contains the attachment point. For example, an “arylC1-C4alkyl” group contains an attachment point on the alkyl group, whereas an “C1-C4alkylaryl” group contains an attachment point on the aryl group.

[0145] The present disclosure encompasses any of the disclosed compounds being isotopically-labelled (i.e., radiolabeled) by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as1H,2H (or deuterium (D)),3H,11C, 12C,13C,14C,14N15N,18O,17O,16O31P,32P,32S,33S,34S,35S,36S,18F,19F,35Cl,37Cl, and 36Cl, respectively, e.g.,3H,11C, and14C. In some aspects, provided is a composition wherein substantially all of the atoms at a position within the disclosed compound are replaced by an atom having a different atomic mass or mass number. In some aspects, provided is a composition wherein a portion of the atoms at a position within the disclosed compound are replaced, i.e., the disclosed compound is enriched at a position with an atom having a different atomic mass or mass number. Isotopically-labelled disclosed compounds can be prepared by methods known in the art. The present disclosure also encompasses any of the disclosed compounds wherein a quaternary carbon atom is replaced with a silicon atom.

[0146] As noted above, the compounds disclosed herein contain one or more asymmetric carbon atoms and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present disclosure encompasses the use of all such possible forms, as well as their racemic and resolved forms and mixtures thereof. The individual enantiomers can be separated according to methods known in the art in view of the present disclosure. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are also encompassed by the present disclosure.

[0147] As used herein, the term “stereoisomers” is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).

[0148] The term “chiral center” or “asymmetric carbon atom” refers to a carbon atom to which four different groups are attached.

[0149] The terms “enantiomer” and “enantiomeric” refer to a molecule that cannot be superimposed on its mirror image and hence is optically active wherein the enantiomerrotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction.

[0150] The term “racemic” refers to a mixture of equal parts of enantiomers and which mixture is optically inactive. In some aspects, the compounds disclosed are racemic.

[0151] The term “absolute configuration” refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.

[0152] The stereochemical terms and conventions used in the specification are meant to be consistent with those described in Pure & Appl. Chem 68:2193 (1996), unless otherwise indicated.

[0153] The term “enantiomeric excess” or “ee” refers to a measure for how much of one enantiomer is present compared to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as │R – S│*100, where R and S are the respective mole or weight fractions of enantiomers in a mixture such that R + S = 1. With knowledge of the optical rotation of a chiral substance, the percent enantiomeric excess is defined as ([α]obs / [α]max)*100, where [α]obs is the optical rotation of the mixture of enantiomers and [α]max is the optical rotation of the pure enantiomer. Determination of enantiomeric excess is possible using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography or optical polarimetry.

[0154] The terms “administration,” “administering,” and grammatical variants thereof, refer to introducing a composition, such as a PDGFRα inhibitor of the present disclosure, into a subject via a pharmaceutically acceptable route. Any suitable route of administration can be used in administering the PDGFRα inhibitors described herein to a subject. Non- limiting examples of such routes of administration are provided elsewhere in the present disclosure.

[0155] The term “central nervous system” or “CNS” refers to a complex of nerve tissues that control the various activities of the body (e.g., voluntary and involuntary movements) and the mind (e.g., thoughts, perceptions, and emotions). The CNS generally consists of the brain and the spinal cord.

[0156] As used herein, the term “demyelinating disease” refers to any disorder of the nervous system in which there is reduced myelination, including disorders in which insufficient or dysfunctional myelin (e.g., hypomyelination) is generated during development or disorders in which the myelin sheath of neurons is damaged. “Myelin” and“Myelin sheath” refer to the specialized membrane formed by oligodendrocytes that insulates the axons of neurons. The insulation provided by the myelin sheath helps to increase the rate of transmission of nerve signals along the axon, thereby promoting timely and energetically efficient neuronal signaling. Myelin also provides metabolic support of the axons, maintaining their health and survival. In some aspects, the neuronal axon of a subject suffering from or at risk of developing a demyelinating disease is completely demyelinated. In some aspects, the neuronal axon of a subject suffering from or at risk of developing a demyelinating disease is partially demyelinated (e.g., at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 95% compared to a reference neuronal axon that is fully myelinated). Accordingly, unless indicated otherwise, the term “demyelination” comprises any of the following: complete hypomyelination, complete demyelination, partial hypomyelination, partial demyelination, and combinations thereof. In some aspects, because of the partial and / or complete demyelination, the demyelinating diseases described herein are associated with impaired conduction of nerve signals or axonal or neuronal survival, which can, in turn, cause deficiencies in sensation, movement, cognition, or other functions depending on which neurons are affected. Non-limiting examples of demyelinating diseases are provided elsewhere in the present disclosure. In general, the term “under myelination” refers to a cell, tissue, or subject that lacks normal levels of myelination (e.g., level of myelination observed in a corresponding cell, tissue, or subject who does not have a demyelinating disease), regardless of etiology.

[0157] As used herein, the term “hypomyelination” refers to a deficiency in myelin for any reason (e.g., body is unable to produce myelin at normal levels). Unless indicated otherwise, hypomyelination includes demyelination (related to myelin destruction) and dysmyelination (related to abnormal myelin deposition). Accordingly, hypomyelination includes diseases in which insufficient myelin is generated during development as well as diseases associated with demyelination and / or dysmyelination. In some aspects, compared to a reference (e.g., corresponding tissue, e.g., brain, of a subject who does not suffer from a demyelinating disease), there is hypomyelination of all (i.e., “complete hypomyelination”) or a portion of the nervous system (i.e., “partial hypomyelination”), for example the brain (e.g., hypomyelination in white matter and / or gray matter), of at least5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 95%.

[0158] As used herein, the term “neuron” includes electrically excitable cells that process and transmit information through electrical and chemical signals. Neurons are major components of the brain and spinal cord of the CNS, and of the ganglia of the peripheral nervous system (PNS) and can connect to each other to form neural networks. A typical neuron is composed of a cell body (soma), dendrites, and an axon. The “soma” (the cell body) of a neuron contains the nucleus. The “dendrites” of a neuron are cellular extensions generally having many branches, where the majority of input to the neuron occurs. The “axon” (also referred to herein as “neuronal axon”) extends from the soma and carries nerve signals away from the soma and certain types of information back to the soma.

[0159] As used herein, the term “oligodendrocyte progenitor cells” or “OPCs” (also known in the art as “oligodendrocyte precursor cells,” “polydendrocytes,” “NG2 cells,” and “O-2A cells”) refer to a subtype of glial cells in the central nervous system. They are precursors to “oligodendrocytes,” (also known as “oligodendroglia”) which are responsible for generating the myelin sheath that wraps around axons, providing insulation, aiding electrical conduction, and providing metabolic support. Nerve impulses can travel up to 200 times faster along a myelinated axon compared to an unmyelinated axon. OPCs and immature oligodendrocytes are generally positive for the following markers: A2B5, neuron-glial antigen 2 (NG2), and PDGFRα. Other suitable markers that can be used are known in the art.

[0160] As used herein, the term “remyelination” (or derivatives thereof) refers to generation of new myelin sheaths around demyelinated (e.g., including hypomyelinated) axons. The remyelination process involves the differentiation of OPCs into oligodendrocytes that generate functional myelin sheaths around demyelinated axons. Remyelination of the axons can restore action potential conduction properties to axons, and thereby, promote and / or improve neurological function. Further, remyelination can provide metabolic support to axons, preventing their damage or loss. In the context of the present application, unless otherwise specified, “remyelination” refers to any aspect of a process that can result in remyelination. For example, in some aspects, “remyelination” comprises the migration or colonization of OPCs to sites of demyelinated axons. In some aspects, “remyelination” comprises the differentiation of OPCs into oligodendrocytes. In someaspects, “remyelination” comprises the generation of myelin sheaths by oligodendrocytes around demyelinated axons. In some aspects, the term “remyelination” comprises any combination of the following: (i) migration or colonization of OPCs to sites of demyelinated axons; (ii) differentiation of OPCs into oligodendrocytes; and (iii) generation of myelin sheaths by oligodendrocytes around demyelinated (e.g., including hypomyelinated) axons.

[0161] As used herein, the term “restore” (and derivatives thereof) comprises both complete restoration and partial restoration. For example, in some aspects, remyelinating a demyelinated axon restores conduction properties to the axon, such that the conduction properties are the same as those of the axon prior to the demyelination (i.e., complete restoration). In some aspects, remyelinating a demyelinated axon restores conduction properties to the axon, where the conduction properties are improved but not the same as those of the axon prior to the demyelination (i.e., partial restoration). In some aspects, remyelination provides metabolic support to axons, preventing their damage or loss. In some aspects, remyelination provides partial metabolic support to axons, delaying their damage or loss.

[0162] As used herein, the term “promoting” refers to the ability of an agent (e.g., PDGFRα inhibitor described herein) to induce or increase a particular result (e.g., remyelination of a demyelinated axon). In some aspects, the term comprises both inducing and increasing a particular result.

[0163] As used herein, the term “subject” refers to any animal subject including a human, a laboratory animal (e.g., a non-human primate, rat, and mouse), livestock (e.g., cow, sheep, goat, pig, turkey, and chicken), and household pets (e.g., dog, cat, and rodent).

[0164] The terms “treat,” “treating,” and “treatment,” as used herein, refer to any type of intervention or process performed on, or administering an active agent (e.g., PDGFRα inhibitor described herein) to, the subject with the objective of reversing, alleviating, ameliorating, inhibiting, or slowing down; or preventing the progression, development, severity or recurrence of a symptom, complication, condition or one or more biochemical indicia associated with a disease, or enhancing overall survival. As described herein, in some aspects, treatment can be of a subject having a disease (e.g., exhibiting one or more symptoms associated with the disease). In some aspects, treatment can be of a subject with some degree of demyelination but not yet exhibiting any symptoms associated with thedisease. In the context of such subjects, administering a PDGFRα inhibitor of the present disclosure can help delay or prevent the onset of symptoms associated with the disease.

[0165] The term “effective dose” or “effective amount” is defined as an amount sufficient to achieve or at least partially achieve a desired effect (e.g., induce remyelination of a demyelinated neuronal axon). A “therapeutically effective amount” or “therapeutically effective dosage” of a therapeutic agent (e.g., PDGFRα inhibitor) is any amount of the therapeutic agent that, when used alone or in combination with another therapeutic agent, promotes disease regression as evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, a prevention of impairment or disability due to the disease affliction, or a reduction in disease progression. A therapeutically effective amount or dosage of a therapeutic agent includes a “prophylactically effective amount” or a “prophylactically effective dosage,” which is any amount of the therapeutic agent that, when administered alone or in combination with another therapeutic agent to a subject at risk of developing a disease or of suffering a recurrence of disease, inhibits the development or recurrence of the disease. The ability of a therapeutic agent to promote disease reversal or inhibit the development, progression or recurrence of the disease can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.

[0166] As used herein, the term “dosing interval” refers to the amount of time that elapses between multiple (e.g., 2 or more) doses of a PDGFRα inhibitor described herein. Not to be bound by any one theory, in some aspects, a PDGFRα inhibitor provided herein exerts its therapeutic effect by inducing the differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes. Accordingly, in some aspects, for a PDGFRα inhibitor to have a therapeutic effect in a subject (e.g., by inducing OPC differentiation), it is necessary that the subject has a pool of OPCs which a PDGFRα inhibitor described herein can act upon. As demonstrated herein, administering a PDGFRα inhibitor too frequently to a subject can be counterproductive in treating a demyelinating disease because the OPC population would not have sufficient time to repopulate the brain. Accordingly, in some aspects, a dosing interval that is suitable for the present disclosure is the amount of time required for a subject’s OPC population to have sufficiently recovered after the administration of an initial dose of a PDGFRα inhibitor provided herein, or a period longerthan that, such that the administration of a second (or additional dose) of the PDGFRα inhibitor would have a therapeutic effect (e.g., such as those described herein, e.g., increases the number of differentiated oligodendrocytes) in the subject. As is apparent from the present disclosure, in some aspects, a PDGFRα inhibitor described herein is administered to a subject at a dosing interval, wherein the dosing interval is the amount of time required, after the administration of an initial dose of the PDGFRα inhibitor, for the subject’s OPC population (e.g., in size) to be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% to that of a reference OPC population (e.g., the subject’s OPC population prior to the initial administration of the PDGFRα inhibitor). In some aspects, an OPC population may be measured by quantifying the density of NG2+ (neuron-glia antigen 2 / chondroitin sulfate proteoglycan-4) or PDGFRa+ cells in mice, rats, pigs, dogs, non-human primates or other species using immunohistochemistry or fluorescence-activated cell sorting. Repopulation may be calculated as the OPC cell density at a given time after dosing relative to the OPC population in an untreated reference animal.

[0167] In some aspects, a suitable dosing interval for the present disclosure comprises the amount of time required, after an initial dose of the PDGFRα inhibitor, for the plasma level of the PDGFRα inhibitor to reach less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%, as compared to a reference (e.g., plasma level of the PDGFRα inhibitor in a corresponding subject immediately after, e.g., about 4 hours after, the administration of the initial dose of the PDGFRα inhibitor), a suitable dosing interval is the time between administering the first dose of the PDGFRα inhibitor and the subject’s plasma level of the PDGFRα inhibitor reaching a reduced level as compared to the reference. In some aspects, the additional dose of the PDGFRα inhibitor is administered to the subject when the subject’s plasma level has decreased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or about 100% as compared to the reference. In some aspects, the brain to plasma ratio may be assessed in preclinical species using bioanalytical gas or liquid chromatography and mass spectrometry methods.

[0168] As used herein, the terms “binds,” “recognizes,” “targets” are analogous terms and refer to molecules (e.g., PDGFRα inhibitors described herein) that can bind and / or target a particular region of a protein (e.g., PDGFRα), as such binding and / or targeting isunderstood by one skilled in the art. For instance, as described herein, in some aspects, a PDGFRα inhibitor is a small molecule that can target and inhibit the kinase portion of PDGFRα (e.g., by binding to the ATP binding site, by allosterically interfering with PDGFRα kinase activity, or both), and thereby, inhibit its activity. Unless indicated otherwise, the above terms (i.e., binds, recognizes, and targets) are used interchangeably and comprises any binding or targeting of PDGFRα, such that its activity is reduced and / or inhibited (e.g., binding of a small molecule to an ATP binding site of PDGFRα, binding of a small molecule to a substrate binding site of PDGFRα, allosterically interfering with PDGFRα kinase activity, or a combination thereof).

[0169] “Potency” is an expression of the activity of a therapeutic agent in terms of the amount or concentration of the therapeutic agent that achieves a desired effect. Accordingly, functional assays, such as those described herein, can be used to identify compounds useful for the present disclosure.

[0170] Molecules (e.g., PDGFRα inhibitors, such as those described herein) that “compete with another protein or compound for binding to a target” refers to molecules that inhibit (partially or completely) the binding of the other protein (e.g., naturally existing PDGFRα ligand) to the target (e.g., PDGFRα). Whether two compounds compete with each other for binding to a target, i.e., whether and to what extent a PDGFRα inhibitor described herein inhibits the binding of the naturally existing ligand to a PDGFRα, can be determined using known competition experiments. In some aspects, a PDGFRα inhibitor described herein competes with, and inhibits the binding of the naturally existing ligand to PDGFRα by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%. Competition assays can be conducted as described herein or, for example, in Ed Harlow and David Lane, Cold Spring Harb. Protoc.; 2006; doi: 10.1101 / pdb.prot4277 or in Chapter 11 of “Using Antibodies” by Ed Harlow and David Lane, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, USA 1999.

[0171] Additional non-limiting examples of other competitive binding assays that can be used with the present disclosure include: solid phase direct or indirect radioimmunoassay (RIA), solid phase direct or indirect enzyme immunoassay (EIA), sandwich competition assay (see Stahli et al., Methods in Enzymology 9:242 (1983)); solid phase direct biotin- avidin EIA (see Kirkland et al., J. Immunol.137:3614 (1986)); solid phase direct labeledassay, solid phase direct labeled sandwich assay (see Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Press, Second Edition (2014)); solid phase direct label RIA using 1-125 label (see Morel et al., Mol. Immunol.25(1):7 (1988)); solid phase direct biotin-avidin EIA (Cheung et al., Virology 176:546 (1990)); and direct labeled RIA. (Moldenhauer et al., Scand. J. Immunol.32:77 (1990)).

[0172] As further described elsewhere in the present disclosure, in some aspects, the antagonistic activity of a PDGFRα inhibitor described herein does not depend on interfering with the binding of another protein or compound to PDGFRα. Another non-limiting example includes small molecules that can bind to PDGFRα and inhibit (partially or completely) binding of ATP or substrate, or otherwise inhibit PDGFRα activity. In some aspects, a PDGFRα inhibitor described herein can inhibit or reduce PDGFRα activity via allosteric inhibition. In some aspects, a PDGFRα inhibitor can reduce protein levels of PDGFRα by reducing synthesis or enhancing degradation. While exemplary mechanisms of actions are provided, it will be apparent from the present disclosure that the PDGFRα inhibitors described herein are not intended to be limited to such mechanisms.

[0173] As used herein, the terms “ug” and “uM” are used interchangeably with “μg” and “μΜ,” respectively.

[0174] Various aspects described herein are described in further detail in the following subsections. The various aspects and embodiments of the present disclosure can optionally be combined. For instance, in some embodiments any of the disclosed compounds can be used in any of the disclosed methods and uses. II. PDGFRα Inhibitors

[0175] Disclosed herein are compounds that can inhibit PDGFRα activity and / or elicit one or more activities associated with inhibition of the receptor. PDGFRα can bind with high affinity to several PDGF isoforms (i.e., PDGF-A, PDGF-B, PDGF-C, and PDGF-D). As used herein, references to inhibition of PDGFRα binding to its ligand refer to inhibition of binding of one or more of the PDGF isoforms that bind to PDGFRα. In some embodiments, the binding of all isoforms of PDGF that bind to PDGFRα is inhibited. The binding of the platelet-derived growth factor (PDGF) isoforms to PDGFRα affects various cell signaling pathways, such as those involved in cell proliferation and differentiation. Accordingly, PDGFRα activity is critical for both the proper development and long-term maintenance ofcertain tissues and organs. For example, animals globally lacking a functional PDGFRA gene die at birth or soon thereafter due to various developmental defects (e.g., cardiac malformations). Bax et al., Dev. Dyn. 239(8): 2307-2317 (Aug. 2010). Conditional PDGFRα knockout in OPCs during animal development results in severe hypomyelination and the animals die soon after birth. Hamashima et al., Neuroscience 436: 11-26 (Jun.2020)

[0176] In humans, the gene encoding PDGFRα (i.e., PDGFRA) is located on chromosome 4 (for example, nucleotides 54,229,127-54,298,245 of GenBank Accession Number NC_000004.12; plus strand orientation). In addition to those provided above, other synonyms of PDGFRα are known and include: “PDGFRa,” “PDGFR2,” “alpha-type platelet-derived growth factor receptor,” “platelet-derived growth factor receptor A,” “platelet-derived growth factor receptor alpha,” “platelet-derived growth factor receptor 2,” “CD140a,” and “CD140 antigen-like family member A.” As used herein, the term “PDGFRα” includes any variants or isoforms of PDGFRα that are naturally expressed by cells.

[0177] Despite its importance in various biological processes, the present disclosure describes the discovery that inhibiting or reducing PDGFRα activity, for example, with one or more of the compounds described herein, can have certain biological effects that can be useful for treating demyelinating diseases, such as those described herein. As demonstrated herein, in some aspects, inhibiting or reducing PDGFRα activity with the PDGFRα inhibitors described herein can promote oligodendrocyte differentiation and induce myelin formation. In some aspects, the PDGFRα inhibitors of the present disclosure are capable of (and in some embodiments used for) promoting remyelination of demyelinated neuronal axons, which can be useful in the treatment of various demyelinating diseases (e.g., multiple sclerosis). As used herein, the terms “PDGFRα inhibitors” and “PDGFRα antagonists” are used interchangeably and refer to any compound that is capable of (and in some embodiments used for) reducing and / or inhibiting PDGFRα activity (e.g., by any of the exemplary mechanisms or methods described herein). In some aspects, a PDGFRα inhibitor provided herein can inhibit a tyrosine kinase activity of a PDGFRα. In some aspects, a PDGFRα inhibitor provided herein can inhibit any other activity of a PDGFRα. Where the term “capable of” is used herein to describe certain features of a PDGFRα inhibitor, the term means that the PDGFRα inhibitor can (i.e., has the ability to) exhibit such features, e.g., under appropriate conditions. Unless indicated otherwise, the term doesnot mean that the PDGFRα inhibitor always exhibits such features, e.g., when administered to a subject with impaired oligodendrocyte progenitor cell population. The term “capable of” and “can” are used interchangeably in the present application.

[0178] In some aspects, a PDGFRα inhibitor inhibits the kinase activity of PDGFRα. As used herein, unless indicated otherwise, the term “inhibit” (and derivatives thereof) comprises both complete inhibition and partial inhibition (e.g., reduced kinase activity). Accordingly, in some aspects, when an OPC (expressing PDGFRα) interacts with a PDGFRα inhibitor described herein, the PDGFRα kinase activity is reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more (for example, at least 50% or more), compared to PDGFRα kinase activity in a corresponding OPC that was not contacted with the PDGFRα inhibitor described herein (e.g., contacted with a vehicle control). In some aspects, the kinase activity is completely inhibited. As is apparent from the present disclosure, the inhibition (partial or complete) of PDGFRα kinase activity in an OPC can promote the differentiation of the OPC into a myelinating oligodendrocyte. Inhibition of PDGFRα kinase activity can be assayed using methods known in the art. In some aspects, the inhibition of PDGFRα kinase activity can be determined using the in vitro differentiation assay described in Example 132 of the present application. In some aspects, the inhibition of PDGFRα kinase activity can be assessed using a cuprizone model for demyelination, such as that described in Torkildsen et al., Acta Neurol Scand Suppl 188:72-6 (2008). In some aspects, the inhibition of PDGFRα kinase activity is determined using an enzymatic PDGFRα kinase assay, such as that described in Example 131 of the present disclosure. In some aspects, the inhibition of PDGFRα kinase activity can be determined using an in vivo OPC differentiation assay, such as that described in Example 134.

[0179] As described herein, in some aspects, a PDGFRα inhibitor useful for the present disclosure comprises one or more of the following properties: (1) capable of (and in some embodiments used for) promoting (e.g., inducing and / or enhancing) the differentiation of an OPC into an oligodendrocyte (in vitro, in vivo, or both); (2) capable of (and in some embodiments used for) promoting (e.g., inducing and / or enhancing) the expression of a protein associated with oligodendrocyte differentiation and / or myelination (e.g., G-protein coupled receptor 17 (GPR17), myelin basic protein (MBP), ASPA, GST-pi, CC1, myelinoligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein / claudin-11, CNPase, proteolipid protein 1 (PLP1), or a combination thereof); (3) capable of (and in some embodiments used for) promoting (e.g., inducing and / or enhancing) the myelination of a neuronal axon; (4) capable of (and in some embodiments used for) promoting (e.g., inducing and / or enhancing) the remyelination of a demyelinated neuronal axon; (5) capable of (and in some embodiments used for) inhibiting a PDGFRα kinase activity (e.g., IC50of less than 10,000 nM, as measured using a Promega kinase assay; (e.g., described in Example 131); (6) capable of (and in some embodiments used for) penetrating the brain (e.g., following systemic administration) at a sufficient level to support activity in the CNS; and (7) any combination thereof. Non-limiting examples of additional properties are provided elsewhere in the present disclosure.

[0180] In addition to the properties described above, a PDGFRα inhibitor described herein can comprise one or more additional features that are not present in other inhibitors known in the art. As is apparent from the present disclosure, such additional features can be useful in various clinical settings, e.g., to treat a demyelinating disease, such as those described herein.

[0181] As described elsewhere in the present disclosure, some exemplary PDGFRα inhibitors of the present disclosure are capable of have greater therapeutic effect than inhibitors known in the art, e.g., when an inhibitor known in the art and an exemplary inhibitor provided herein are assayed against a vehicle control. For example, in some aspects, a PDGFRα inhibitor can have greater potency compared to inhibitors known in the art. In some aspects, a PDGFRα inhibitor can better penetrate the CNS (e.g., can more effectively pass across the blood-brain barrier). Accordingly, in some aspects, PDGFRα inhibitors described herein are more effective at promoting OPC differentiation as compared to inhibitors known in the art. For example, in some aspects, a PDGFRα inhibitor of the present disclosure can achieve greater than 2-fold increase in GPR17 expression compared to a vehicle control at a dose of less than 50 mg / kg, as measured using an in vivo GPR17 assay (such as that described in Example 134). In some aspects, a PDGFRα inhibitor of the present disclosure can achieve greater than 2-fold increase in GPR17 expression compared to the vehicle control at a dose of less than 40 mg / kg, less than 30 mg / kg, less than 20 mg / kg, less than 10 mg / kg, less than 5 mg / kg, less than 4 mg / kg, less than 3 mg / kg, less than 2 mg / kg, or less than 1 mg / kg, as measured using an in vivo GPR17assay (such as that described in Example 134). As described elsewhere in the present disclosure, GPR17 expression is a suitable marker for OPC differentiation. Additionally, in some aspects, any of the other proteins associated with oligodendrocyte differentiation and / or myelination can be used instead of GPR17 or in combination with GPR17. Non- limiting examples of such proteins include: MBP, ASPA, GST-pi, CC1, MOG, oligodendrocyte-specific protein / claudin-11, CNPase, proteolipid protein 1 (PLP1), or a combination thereof.

[0182] In some aspects, the PDGFRα inhibitor is a compound of Formula I:,

[0183] or a pharmaceutically acceptable salt or solvate thereof, wherein: indicates a single bond or a double bond such that all valences are satisfied; X1, X2, X3, and X4are selected from N and CRa, with the proviso that not more than two of X1, X2, X3, and X4are N; one of Y1and Y2is N and the other of Y1and Y2is C; each Rais independently selected from H, halo, C1-C4alkyl, and C1-C4alkoxy; R1is selected from C1-C4alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, heteroaryl, aryl, and C1-C8alkoxy, all of which can be optionally substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, oxo, C1-C4alkyl, aminoC1- C4alkyl, hydroxyC1-C4alkyl, C1-C4alkoxy, C1-C4alkoxyC1-C4alkyl, 3-8 membered heterocyclyl, and 3-8 membered heterocyclylC1-C4alkyl, with the proviso that the number of substituents does not exceed the number of substitutable positions; R2is selected from cycloalkyl, cycloalkenyl, alkyl, aminoalkylamino, amino, heterocyclyl, heteroaryl, aminoheterocyclyl, heterocyclylamino, and aminoalkylamino, all of which can be optionally substituted with one or more substituents selected from D, halo, oxo, and C1-C4alkyl; R2is substituted with one, two, or three R3; R3is selected from aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)NR31R32, -S(O)2NR31R32, -S(O)2R31, -S(O)(NR33)R31, -S(O)(NR33)NR31R32, -C(S)NR31R32, C3-C8cycloalkyl, 3-8 membered heterocyclyl, and C1-C4alkyl, all of which can be optionally substituted with one, two, three, four, or five R30; each R30is independently selected from D, halo, aryl, -OR300, -NR300R301, -S(O)rR300, -C(O)R300, -C(=CR34R35)R300, and ; r is selected from 0, 1, and 2;each R300is independently selected from C1-C6alkyl, C3-C7cycloalkyl, aryl, heteroaryl, 3-8 membered heterocyclyl, and 3-8 membered heterocyclylaryl, all of which can be optionally substituted with one, two, three, four, or five substituents selected from D, halo, hydroxy, amino, alkylamino, cyano, C1-C4alkyl, C1-C4haloalkyl, and C1-C4alkoxy; each R301is independently selected from H, halo, and C1-C4alkyl; each R302is independently selected from H, F, hydroxy, amino, alkylamino, oxo, and C1-C4alkoxy; each R303is independently selected from H and C1-C4alkyl; n, o, and p are each independently selected from 0, 1, 2, 3, and 4; each R31is independently selected from C1-C8alkyl, arylC1-C4alkyl, heteroarylC1- C4alkyl, heterocyclyl, heterocyclylC1-C4alkyl, cycloalkyl, and cycloalkylC1-C4alkyl, all of which can be optionally substituted with one, two, three, four, or five substituents selected from D, halo, cyano, hydroxy, amino, -OCF3, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, hydroxyC1-C4alkyl, -S(O)2NR304R305, -C(O)OR304R305, -C(O)NR304R305, and -NR304C(O)R305; each R304and R305is independently selected from H and C1-C4alkyl; each R32is independently selected from H and C1-C4alkyl; or R31and R32together with the atom to which they are connected form a 5-8 membered heterocycyl, optionally substituted with one, two, three, four, or five substituents selected from D, halo, cyano, C1-C4alkyl, and C1-C4haloalkyl, and -C(O)NR34R35; each R34and R35is independently selected from H, C1-C4alkyl, and C1-C4haloalkyl; andeach R33is independently selected from H, C1-C4alkyl, C1-C4haloalkyl, and –C(O)R34; or R31and R33together with the atoms to which they are connected form a 4-8 membered heterocycyl.

[0184] In some aspects, Y1is N and Y2is C.

[0185] In some aspects, Y1is C and Y2is N.

[0186] In some aspects, X1is N, X2is CRa, X3is CRa, and X4is CRa.

[0187] In some aspects, X1is CRa, X2is N, X3is CRa, and X4is CRa.

[0188] In some aspects, X1is CRa, X2is CRa, X3is N, and X4is CRa.

[0189] In some aspects, X1is CRa, X2is CRa, X3is CRa, and X4is N.

[0190] In some aspects, X1is CRa, X2is CRa, X3is CRa, and X4is CRa.

[0191] In some aspects, R1is 5- or 6-membered heteroaryl.

[0192] In some aspects, R1is an optionally substituted pyrazolyl.

[0193] In some aspects, R1is selected from:, , and ; and R10is selected from H, C1-C4alkyl, C1-C4alkoxy, aminoC1-C4alkyl, hydroxyC1- C4alkyl, and C1-C4alkylsulfonyl, wherein the C1-C4alkyl, C1-C4alkoxy, aminoC1-C4alkyl, hydroxyC1-C4alkyl, and C1-C4alkylsulfonyl can be optionally substituted by one or more substituents selected from hydroxyl, C1-C4alkoxy, NR10aR10b, halo, and deuterium, wherein R10aand R10bare selected from hydrogen and C1-C4alkyl, or wherein R10aand R10btaken together with the nitrogen atom to which they are attached form a 4- to 8-membered ring.

[0194] In some aspects, R1is.

[0195] In some aspects, R10is CH3.

[0196] In some aspects, R2is selected from cycloalkyl, cycloalkenyl, alkyl, oxoalkylamino, aminoalkylamino, amino, heterocyclyl, heteroaryl, aminoheterocyclyl, heterocyclylamino, and aminoalkylamino, all of which can be optionally substituted with six or more substituents selected from D, halo, hydroxy, oxo, and C1-C4alkyl.

[0197] In some aspects, R2is heterocyclyl optionally substituted with C1-C4alkyl or oxo.

[0198] In some aspects, R2is substituted with one R3.

[0199] In some aspects, R2is selected from: ,, , , ,, ,, , , ,ndindicates a single bond or a double bond such that all valences are satisfied; m is selected from 0, 1, 2, 3, 4, 5, and 6; and Z1, Z2, and Z3are selected from N and CRa.

[0200] In some aspects, R2is selected from:, , , , .

[0201] In some aspects, R2is selected from the group consisting of:.

[0202] In some aspects, R2is:.

[0203] In some aspects, R3is selected from aryl, heteroaryl, -C(O)R31, -C(O)OR31, - C(O)NR31R32, -S(O)2NR31R32, cycloalkyl, and alkyl, all of which can be optionally substituted with one, two, three, four, or five R30.

[0204] In some aspects, R3is selected from heteroaryl optionally substituted with one, two three, four, or five R30and -C(O)OR31.

[0205] In some aspects, the PDGFRα inhibitor is a compound of Formula Ia:,

[0206] or a pharmaceutically acceptable salt or solvate thereof, wherein a and b are each independently selected from 1, 2, and 3; and Q is selected from -CH- and -N-, with the proviso that if Q is –N-, a and b are not 1.

[0207] In some aspects, the PDGFRα inhibitor is a compound of Formula II:, or a pharmaceutically acceptable salt or solvate thereof.

[0208] In some aspects, the PDGFRα inhibitor is a compound of Formula IIa:, or a pharmaceutically acceptable salt or solvate thereof.

[0209] In some aspects, R3is selected from: ,, , , , ,, ,, , wherein A1is selected from O, S, and NR37, R36is selected from hydrogen, optionally substituted C1-C6alkyl, and optionally substituted C1-C6alkylaryl, and R37is selected from hydrogen and C1-C6alkyl.

[0210] In some aspects, R3is selected from:,,,

[0211] In some aspects, R3is selected from:.

[0212] In some aspects, R3is heteroaryl.

[0213] In some aspects, R3is:.

[0214] In some aspects, R30is:.

[0215] In some aspects, R300is selected from:, , , , ,

[0216] In some aspects, R300is:.

[0217] In some aspects, R301is selected from H and CH3.

[0218] In some aspects, R301is H.

[0219] In some aspects, R302is H.

[0220] In some aspects, R301and R302are H.

[0221] In some aspects, R30is benzyl.

[0222] In some aspects, R3is selected from: d.

[0223] In some aspects, R3is selected from:, , .

[0224] In some aspects, R32is H.

[0225] In some aspects, the PDGFRα inhibitor is a compound of Formula IV:, or a pharmaceutically acceptable salt or solvate thereof, wherein L1is a NH or O.

[0226] In some aspects, the PDGFRα inhibitor is a compound of Formula V:, or a pharmaceutically acceptable salt or solvate thereof.

[0227] In some aspects, R31is selected from:, , ,,,, wherein R31ais selected from H, D, alkylamino, optionally substituted C1-C4alkyl, C1- C4alkoxy, amino, and C1-C4haloalkyl;each R31bis independently selected from H, D, halo, hydroxy, amino, cyano, alkylamino, optionally substituted C1-C4alkyl, C1-C4haloalkyl, optionally substituted C1-C4alkoxy, and C3- C6cycloalkyl, and q is 1, 2, or 3.

[0228] Table 1 (below) provides the structure of exemplary compounds that are useful for the present disclosure (e.g., can target and inhibit kinase activity associated with PDGFRα expressed on OPCs). Table 1. Exemplary Compounds With PDGFRα Inhibitory Activity

[0229] In some aspects, the exemplary compounds of the present invention do not include compounds 156, 250 and 275. In some aspects, the exemplary compounds of the present invention do not include the compounds described in Table 1 on pp. 117-170 of International Appl. No. PCT / US2022 / 079480, which is herein incorporated by reference in its entirety.

[0230] In some aspects, the PDGFRa inhibitor is a compound described in Table 1 on pp. 117-170 of International Appl. No. PCT / US2022 / 079480.

[0231] In some aspects, the PDGFRa inhibitor is not a compound described in Table 1 on pp.117-170 of International Appl. No. PCT / US2022 / 079480. III. Pharmaceutical Compositions

[0232] Provided herein are compositions comprising a PDGFRα inhibitor of the present disclosure having the desired degree of purity, and a pharmaceutically acceptable carrier or excipient, in a form suitable for administration to a subject. In some aspects, the PDGFRα inhibitor has a purity of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or greater than about 99%. Pharmaceutically acceptable excipients or carriers can be determined in part by the particular composition being administered, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of pharmaceutical compositions (See, e.g., Remington, 23rdEdition, The Science and Practice of Pharmacy, editor: A. Adejare, 2020, Adademic Press.). The pharmaceutical compositions are generally formulated sterile and in full compliance with all Good Manufacturing Practice (GMP) regulations of the U.S. Food and Drug Administration.

[0233] In some aspects, a pharmaceutical composition comprises a PDGFRα inhibitor described herein, and a pharmaceutically acceptable carrier. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serumalbumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as TWEEN®, PLURONICS®, or polyethylene glycol (PEG).

[0234] In some aspects, a pharmaceutical composition disclosed herein comprises one or more additional components selected from: a bulking agent, stabilizing agent, surfactant, buffering agent, or combinations thereof.

[0235] Buffering agents useful for the current disclosure can be a weak acid or base used to maintain the acidity (pH) of a solution near a chosen value after the addition of another acid or base. Suitable buffering agents can maximize the stability of the pharmaceutical compositions by maintaining pH control of the composition. Suitable buffering agents can also ensure physiological compatibility or optimize solubility. Rheology, viscosity and other properties can also be dependent on the pH of the composition. Common buffering agents include, but are not limited to, a Tris buffer, a Tris-Cl buffer, a histidine buffer, a TAE buffer, a HEPES buffer, a TBE buffer, a sodium phosphate buffer, a MES buffer, an ammonium sulfate buffer, a potassium phosphate buffer, a potassium thiocyanate buffer, a succinate buffer, a tartrate buffer, a DIPSO buffer, a HEPPSO buffer, a POPSO buffer, a PIPES buffer, a PBS buffer, a MOPS buffer, an acetate buffer, a phosphate buffer, a cacodylate buffer, a glycine buffer, a sulfate buffer, an imidazole buffer, a guanidine hydrochloride buffer, a phosphate-citrate buffer, a borate buffer, a malonate buffer, a 3- picoline buffer, a 2-picoline buffer, a 4-picoline buffer, a 3,5-lutidine buffer, a 3,4-lutidine buffer, a 2,4-lutidine buffer, a Aces, a diethylmalonate buffer, a N-methylimidazole buffer, a 1,2-dimethylimidazole buffer, a TAPS buffer, a bis- Tris buffer, a L-arginine buffer, a lactate buffer, a glycolate buffer, or combinations thereof.

[0236] In some aspects, a pharmaceutical composition disclosed herein further comprises a bulking agent. Bulking agents can be added to a pharmaceutical product in order to add volume and mass to the product, thereby facilitating precise metering and handling thereof. Bulking agents that can be used with the present disclosure include, but are not limited to, sodium chloride (NaCl), mannitol, glycine, alanine, or combinations thereof.

[0237] In some aspects, a pharmaceutical composition disclosed herein can also comprise a stabilizing agent. Non-limiting examples of stabilizing agents that can be used with the present disclosure include: sucrose, trehalose, raffinose, arginine, or combinations thereof.

[0238] In some aspects, a pharmaceutical composition disclosed herein comprises a surfactant. In some aspects, the surfactant can be selected from the following: alkyl ethoxylate, nonylphenol ethoxylate, amine ethoxylate, polyethylene oxide, polypropylene oxide, fatty alcohols such as cetyl alcohol or oleyl alcohol, cocamide MEA, cocamide DEA, polysorbates, dodecyl dimethylamine oxide, or combinations thereof. In some aspects, the surfactant is polysorbate 20 or polysorbate 80.

[0239] In some aspects, a pharmaceutical composition disclosed herein (e.g., comprising a PDGFRα inhibitor) further comprises an amino acid. In some aspects, the amino acid is selected from arginine, glutamate, glycine, histidine, or combinations thereof. In some aspects, the composition further comprises a sugar alcohol. Non-limiting examples of sugar alcohol includes: sorbitol, xylitol, maltitol, mannitol, or combinations thereof.

[0240] A pharmaceutical composition disclosed herein (e.g., comprising a PDGFRα inhibitor) can be formulated for any route of administration to a subject. Specific examples of routes of administration include intramuscularly, cutaneously, subcutaneously, ophthalmic, intravenously, intraperitoneally, intradermally, intraorbitally, intracerebrally, intracranially, intraspinally, intraventricularly, intrathecally, intracapsularly, orally, pulmonarily, intranasally, intra-arterially, intralymphatically, periocularly, topically, transdermally, rectally, vaginally, or intratumorally, or via intratympanic injection. Parenteral administration, characterized by, e.g., cutaneous, subcutaneous, intramuscular, or intravenous injection, is also contemplated herein.

[0241] Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. The injectables, solutions and emulsions also contain one or more excipients. Suitable excipients are, for example, water, saline, dextrose, glycerol, or ethanol. In addition, if desired, the pharmaceutical compositions to be administered can also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, and cyclodextrins.

[0242] Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents, and other pharmaceutically acceptable substances. Examples of aqueous vehicles include sodium chloride injection, Ringer’s injection, isotonic dextrose injection, sterile water injection, dextrose, and lactated Ringer’s injection. Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations can be added to parenteral preparations packaged in multiple-dose containers which include, for example, phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride, and benzethonium chloride. Isotonic agents include sodium chloride, and dextrose. Buffers include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcelluose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (TWEEN®80). Sequestering or chelating agent of metal ions includes EDTA. Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol, and propylene glycol for water miscible vehicles; and sodium hydroxide, hydrochloric acid, citric acid, or lactic acid for pH adjustment.

[0243] Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as lyophilized powders, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use, and sterile emulsions. The solutions can be either aqueous or nonaqueous.

[0244] If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol, and mixtures thereof.

[0245] Topical mixtures comprising a compound described herein are prepared as described for the local and systemic administration. The resulting mixture can be a solution, suspension, emulsions, or the like and can be formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches, or any other formulations suitable for topical administration.

[0246] A therapeutic agent described herein (e.g., PDGFRα inhibitor) can be formulated as an aerosol for topical application, such as by inhalation (see, e.g., U.S. Patent Nos. 4,044,126; 4,414,209; and 4,364,923, which describe aerosols for delivery of a steroid useful for treatment of inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insufflations, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the formulation can have diameters of less than about 50 microns, e.g., less than about 10 microns. In some aspects, the particle diameters can have diameters of less than about 50 microns, e.g., less than about 10 microns, as measured by dynamic light scattering (DLS) or static image analysis using microscopy.

[0247] A therapeutic agent disclosed herein (e.g., PDGFRα inhibitor) can be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracisternal or intraspinal application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies.

[0248] Transdermal patches, including iontophoretic and electrophoretic devices, are well known to those of skill in the art, and can be used to administer a therapeutic agent (e.g., those disclosed herein). For example, such patches are disclosed in U.S. Patent Nos. 6,267,983; 6,261,595; 6,256,533; 6,167,301; 6,024,975; 6,010,715; 5,985,317; 5,983,134; 5,948,433; and 5,860,957.

[0249] In some aspects, a pharmaceutical composition comprising a therapeutic agent described herein (e.g., PDGFRα inhibitor) is a lyophilized powder, which can be reconstituted for administration as solutions, emulsions, and other mixtures. It can also be reconstituted and formulated as a solid or a gel. The lyophilized powder is prepared by dissolving an compound as described herein, or a pharmaceutically acceptable derivative thereof, in a suitable solvent. In some aspects, the lyophilized powder is sterile. The solvent can contain an excipient, which improves the stability or other pharmacological componentof the powder or reconstituted solution that is prepared from the powder. Excipients that can be used include, but are not limited to, dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, or other suitable agent. The solvent can also contain a buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, in some aspects, about neutral pH. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation. In some aspects, the resulting solution can be apportioned into vials for lyophilization. Each vial can contain a single dosage or multiple dosages of the compound. The lyophilized powder can be stored under appropriate conditions, such as at about 4°C to room temperature.

[0250] Reconstitution of a lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, the lyophilized powder is added to sterile water or other suitable carrier. The precise amount depends upon the selected compound. Such an amount can be empirically determined.

[0251] Pharmaceutical compositions provided herein (e.g., comprising a PDGFRα inhibitor) can also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated. Many such targeting methods are known to those of skill in the art. All such targeting methods are contemplated herein for use in the instant compositions. For non-limiting examples of targeting methods, see, e.g., U.S. Patent Nos. 6,316,652; 6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; 6,060,082; 6,048,736; 6,039,975; 6,004,534; 5,985,307; 5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874.

[0252] The pharmaceutical compositions to be used for in vivo administration can be sterile. This can be accomplished, for example, by filtration through, e.g., a sterile filtration membrane. IV. Kits

[0253] Also provided herein are kits comprising one or more PDGFRα inhibitors described herein. In some aspects, provided herein is a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions described herein, such as one or more PDGFRα inhibitors provided herein, and optionally, an instruction for use. In some aspects, the kits contain a pharmaceuticalcomposition described herein (e.g., a PDGFRα inhibitor) and any prophylactic or therapeutic agent, such as those described herein. V. Methods of the Disclosure

[0254] As demonstrated herein, PDGFRα inhibitors of the present disclosure are useful in reducing or inhibiting PDGFRα activity, which, in some aspects, can promote the myelination of an axon and / or remyelination of a demyelinated neuronal axon.

[0255] In some aspects, the present disclosure relates to methods of inhibiting or reducing PDGFRα activity in a cell or tissue, e.g., of a subject in need thereof, comprising contacting the cell or tissue with a PDGFRα inhibitor described herein. In some aspects, after the contacting, PDGFRα kinase activity in the cell or tissue is inhibited by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% compared to a reference (e.g., PDGFRα activity in the cell prior to the contacting and / or PDGFRα activity in a corresponding cell that was not contacted with the PDGFRα inhibitor). The PDGFRα activity status of a cell can be determined using any suitable method known in the art. In some aspects, PDGFRα activity can be determined by measuring the corresponding gene expression level, e.g., by qRT- PCR. In some aspects, PDGFRα activity can be determined by measuring the PDGFRα protein level, e.g., by immunoblotting. In some aspects, the PDGFRα activity can be determined by measuring receptor phosphorylation, e.g., by western blotting. An exemplary method of assaying such an activity, a purified protein enzyme assay, is provided in Example 131 (also referred to herein as the "Promega Assay"). In some aspects, the enzymatic PDGFRα kinase assay comprises 20 ng of purified PDGFRα protein, 150 µM of ATP and 1 µg of substrate, Poly (Glu4Tyr1) in a volume of 15 µl. The potency of a compound can be determined using such assays. In general, compounds most useful in the methods of the present disclosure have an IC50below 10,000 nM (e.g., less than 9,000 nM, less than 8,000 nM, less than 7,000 nM, less than 6,000 nM, less than 5,000 nM, less than 4,000 nM, less than 3,000 nM, less than 2,000 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 25 nM, less than 10 nM, less than 5 nM, less than 2.5 nM, less than 1 nM, less than 0.5 nM, or lessthan 0.2 nM, for instance, less than 500 nM) in such an assay. As described herein, in some aspects, the cell is an oligodendrocyte progenitor cell (OPC).

[0256] As both described and demonstrated herein, inhibiting or reducing PDGFRα activity can promote the myelination of a neuron (e.g., an axon of a neuron,), e.g., by promoting the differentiation of an OPC into an oligodendrocyte that, in turn, myelinates the axon. Similarly, inhibiting or reducing PDGFRα activity can also promote the remyelination of a demyelinated neuronal axon. And, as will be apparent to those skilled in the art, in some aspects, remyelination can repair damage to demyelinated (e.g., hypomyelinated) axons, and thereby, aid in recovering axonal signalling or reducing axonal injury or loss.

[0257] Accordingly, in some aspects, provided herein is a method of promoting the myelination of an axon, e.g., in a subject in need thereof (e.g., subject suffering from or at risk of developing a demyelinating disease), the method comprising contacting an OPC with an effective amount of a PDGFRα inhibitor described herein, wherein the contacting results in the OPC to differentiate into an oligodendrocyte, and wherein the oligodendrocyte is capable of (and in some embodiments used for) promoting the myelination of the axon. In some aspects, after the contacting, the number of neurons with axons that are myelinated is increased by at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 15-fold, at least 20- fold, at least 25-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, or at least 50-fold compared to a reference (e.g., the number of neurons with myelinated axons in the subject prior to the administration and / or the number of neurons with myelinated axons in a corresponding subject that did not receive the administration of the PDGFRα inhibitor). The increase in the number of neurons with axons that are myelinated can be determined using any suitable methods known in the art or described herein. In some aspects, the increase in the number of neurons with axons that are myelinated can be determined by visualizing and / or quantifying the expression of a marker associated with myelinated neurons. For example, in some aspects, the marker associated with myelinated neurons comprises myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein / claudin-11, CNPase, proteolipid protein 1 (PLP1), or a combination thereof.

[0258] In some aspects, also provided herein is a method of promoting remyelination of an axon of a neuron (e.g., demyelinated neuronal axon in a subject in need thereof), comprising contacting an OPC with an effective amount of any of the PDGFRα inhibitors described herein, wherein the contacting results in the OPC to differentiate into an oligodendrocyte, and wherein the oligodendrocyte is capable of (and in some embodiments used for) promoting the remyelination of the demyelinated neuronal axon. In some aspects, after the contacting, the number of demyelinated axons that are myelinated is increased by at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, or at least 50-fold compared to a reference (e.g., the number of demyelinated neuronal axons in the subject prior to the administration and / or the amount of demyelinated neuronal axons in a corresponding subject that did not receive the administration of the PDGFRα inhibitor). The increase in the number of demyelinated axons that are myelinated can be determined using any suitable methods known in the art or described herein. In some aspects, the increase in the number of demyelinated axons that are myelinated can be determined by visualizing and / or quantifying the expression of a marker associated with myelinated neurons. For example, in some aspects, the marker associated with myelinated neurons comprises myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein / claudin-11, CNPase, proteolipid protein 1 (PLP1), or a combination thereof.

[0259] In some aspects, also provided herein is a method of increasing remyelination in a subject (e.g., increasing remyelination of a demyelinated neuronal axon in a subject in need thereof), comprising contacting an OPC with an effective amount of any of the PDGFRα inhibitors described herein, wherein the contacting results in the OPC to differentiate into an oligodendrocyte, and wherein the oligodendrocyte is capable of (and in some embodiments used for) increasing remyelination in the subject. In some aspects, after the contacting, the remyelination is increased by at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, or at least 50-fold compared to a reference (e.g., the number of demyelinated neuronal axons in the subject prior to the administration and / or the amount of demyelinated neuronal axons in a corresponding subject that did not receive theadministration of the PDGFRα inhibitor). The increase in the number of demyelinated axons that are myelinated can be determined using any suitable methods known in the art or described herein. In some aspects, the increase in the number of demyelinated axons that are myelinated can be determined by visualizing and / or quantifying the expression of a marker associated with myelinated neurons. For example, in some aspects, the marker associated with myelinated neurons comprises myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein / claudin-11, CNPase, proteolipid protein 1 (PLP1), or a combination thereof.

[0260] In some aspects, provided herein is a method of reducing the demyelination of a myelinated axon (e.g., reducing the rate at which the myelinated axons become demyelinated) in a subject in need thereof, comprising contacting an OPC with an effective amount of any of the PDGFRα inhibitors described herein, wherein the contacting results in the OPC to differentiate into an oligodendrocyte, and wherein the oligodendrocyte is capable of (and in some embodiments used for) reducing the demyelination of the myelinated axon. In some aspects, after the contacting, demyelination of a myelinated axon in the subject is reduced by at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, or at least 50-fold compared to a reference (e.g., demyelination of a myelinated axon in a corresponding subject that did not receive an administration of the PDGFRα inhibitor). The decrease in the number of neurons with axons that are demyelinated can be determined using any suitable methods known in the art or described herein. In some aspects, the decrease in the number of neurons with axons that are demyelinated can be determined by visualizing and / or quantifying the expression of a marker associated with myelinated neurons. For example, in some aspects, the marker associated with myelinated neurons comprises myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein / claudin-11, CNPase, proteolipid protein 1 (PLP1), or a combination thereof.

[0261] In some aspects, provided herein is a method of decreasing the rate of demyelination (e.g., decreasing the rate at which myelinated axons in a subject become demyelinated) in a subject in need thereof, comprising contacting an OPC with an effective amount of any of the PDGFRα inhibitors described herein, wherein the contacting results in the OPC todifferentiate into an oligodendrocyte, and wherein the oligodendrocyte is capable of (and in some embodiments used for) reducing the rate of demyelination in the subject. In some aspects, after the contacting, the rate of demyelination in the subject is decreasing by at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 25- fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, or at least 50-fold compared to a reference (e.g., the rate of demyelination in a corresponding subject that did not receive an administration of the PDGFRα inhibitor). The decrease in the number of neurons with axons that are demyelinated can be determined using any suitable methods known in the art or described herein. In some aspects, the decrease in the number of neurons with axons that are demyelinated can be determined by visualizing and / or quantifying the expression of a marker associated with myelinated neurons. For example, in some aspects, the marker associated with myelinated neurons comprises myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein / claudin-11, CNPase, proteolipid protein 1 (PLP1), or a combination thereof.

[0262] In any of the methods provided herein, in some aspects, the contacting can occur ex vivo (e.g., OPCs of a subject can be isolated and contacted with a PDGFRα inhibitor in vitro to assess the therapeutic efficacy of the inhibitor). In some aspects, the contacting occurs in vivo (e.g., in a subject in need thereof). Where the contacting occurs in vivo, the methods can further comprise administering to the subject an effective amount of any of the PDGFRα inhibitors described herein.

[0263] Not to be bound by any one theory, in some aspects, after administration to a subject, a PDGFRα inhibitor described herein is capable of (and in some embodiments used for) migrating into the CNS of the subject (e.g., by crossing the blood-brain barrier) and interacting with the nervous system cells present within the CNS. For instance, as described and demonstrated herein, PDGFRα inhibitors of the present disclosure are capable of (and in some embodiments used for) targeting PDGFRα expressed on an OPC, and thereby inhibit or reduce the PDGFRα activity of the OPC. In some aspects, this results in the activation of the OPC and the subsequent differentiation of the OPC into an oligodendrocyte. Accordingly, in some aspects, provided herein is a method of activating an OPC within the CNS of a subject in need thereof, the method comprising administering to the subject any of the PDGFRα inhibitors described herein.

[0264] As described herein, the myelin sheath which surrounds the neuronal axons can affect various functions of neurons. For example, in some aspects, by increasing the myelination of neuronal axons, PDGFRα inhibitors described herein can increase the rate of transmission of electrical impulses (i.e., nerve signals or action potentials) along the axon of a neuron. Accordingly, in some aspects, the present disclosure provides a method of increasing electrical impulse transmission along the axon of a neuron, comprising contacting an OPC with an effective amount of any of the PDGFRα inhibitors described herein, wherein the contacting results in the OPC to differentiate into an oligodendrocyte, and wherein the oligodendrocyte is capable of (and in some embodiments used for) myelinating the axon of the neuron, and thereby increase the electrical impulse transmission. In some aspects, after contacting the OPC, the electrical impulse transmission along the axon of the neuron is increased by at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, or at least 50-fold compared to a reference (e.g., electrical impulse transmission across the axon prior to or in the absence of contact with the PDGFRα inhibitors). Action potential conduction velocities can be measured as compound action potentials across the corpus callosum in vitro or by auditory or visual evoked potential recording in vivo. In some aspects, remyelination may overcome conduction block, allowing axonal signals that would be prematurely terminated to be transmitted. Remyelination can enhance axonal health and prevent axonal degradation in a diseased state. Non-limiting examples of methods useful for measuring such properties of a neuronal axon are described in, e.g., Li et al., PLoS One 11(11): e0165637 (Nov.2016); Maheras et al., Sci Rep 8(1): 3798 (Feb. 2018); and Alqudah et al., Audiol Neurootol 23(1): 20-31 (2018).

[0265] As is apparent from the present disclosure, the PDGFRα inhibitors described herein can be useful in the treatment of a demyelinating disease, e.g., by inducing the differentiation of an OPC into an oligodendrocyte, thereby promoting the remyelination of neuronal axons. Accordingly, in some aspects, the present disclosure is directed to a method of treating a demyelinating disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a PDGFRα inhibitor described herein. References to a method of treating a demyelinating disease as described herein also referto the agents and compositions as described herein for use in treating a demyelinating disease.

[0266] The PDGFRα inhibitors provided herein can be used to treat a wide range of demyelinating diseases (including those that are associated with demyelination and / or hypomyelination). In some aspects, the demyelinating disease that can be treated with the present disclosure comprise those that are characterized by demyelination of one or more cells within the CNS. Non-limiting examples of demyelinating disease that can be treated with the present disclosure include one or more of: acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalitis, acute optic neuritis, acute transverse myelitis, adrenoleukodystrophy, adrenomyeloneuropathy, Alexander disease, Alzheimer's disease, aminoacidurias, amyotrophic lateral sclerosis, anti-MAG peripheral neuropathy, anti-MOG associated spectrum, Balo concentric sclerosis, brain injury, CAMFAK Syndrome, Canavan disease, carbon monoxide toxicity, central pontine myelinolysis, cerebral hypoxia, cerebral ischemia, Charcot–Marie–Tooth disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing inflammatory optic neuritis (CRION), chronic traumatic encephalopathy, clinically isolated syndrome (CIS), congenital cataract, copper deficiency associated condition, delayed post-hypoxic leukoencephalopathy, diffuse cerebral sclerosis of Schilder, diffuse myelinoclastic sclerosis, extrapontine myelinolysis Gaucher disease, Guillain–Barré syndrome, hereditary neuropathy, hereditary neuropathy with liability to pressure palsy, HTLV-1–associated myelopathy, Hurler syndrome, hypomyelination, hypoxic brain injury, Krabbe disease, Leber hereditary optic atrophy and related mitochondrial disorders, leukodystrophic disorders, Marburg multiple sclerosis, Marchiafava-Bignami disease, metachromatic leukodystrophy, multiple sclerosis, multiple system atrophy, myelinoclastic disorders, myelopathy, nerve injury, neuromyelitis optica (NMO), Niemann-Pick disease, optic neuropathy, optic-spinal multiple sclerosis, osmotic demyelination syndrome, Parkinson's disease, Pelizaeus‐Merzbacher disease, periventricular leukomalacia, peripheral neuropathy, phenylketonuria, primary progressive multiple sclerosis (PPMS), progressive inflammatory neuropathy, progressive multifocal leukoencephalopathy, progressive subcortical ischemic demyelination, progressive-onset multiple sclerosis, relapsing-onset multiple sclerosis, relapsing-remitting multiple sclerosis (RRMS), reperfusion injury, Schilder disease, secondary progressive multiple sclerosis (SPMS), solitary sclerosis,spinal cord injury, subacute sclerosing panencephalitis, Tabes dorsalis, Tay-Sachs disease, transverse myelitis, traumatic brain injury, tropical spastic paraparesis, tumefactive multiple sclerosis, vitamin B12 deficiency, and cerebral palsy. In some aspects, a disease that can be treated with the present disclosure comprises a tumor associated with abnormal (e.g., increased) PDGF or PDGFRα activity. Such a tumor is referred to herein as "PDGF- associated tumor." Accordingly, in some aspects, provided herein is a method of treating a PDGF-associated tumor in a subject in need thereof, comprising administering to the subject any of the PDGFRα inhibitor described herein. A non-limiting example of a PDGF- associated tumor comprises oligodendroglioma.

[0267] In some aspects, the demyelinating disease that can be treated with a PDGFRα inhibitor described herein comprises multiple sclerosis. As used herein, the term "multiple sclerosis" (MS) refers to a chronic and often disabling disease of the central nervous system characterized by the progressive destruction of the myelin sheath. Multiple sclerosis is generally diagnosed as one of four internationally recognized categories or stages of MS: (1) primary progressive multiple sclerosis (PPMS), (2) relapsing-remitting multiple sclerosis (RRMS), (3) secondary progressive multiple sclerosis (SPMS), and (4) progressive relapsing multiple sclerosis. Standards for diagnosis are known to those of skill in the art and exemplary diagnostic criteria are described in, e.g., "Merck Manual, Professional Version" (www.merckmanuals.com / professional / neurologic- disorders / demyelinating-disorders / multiple-sclerosis-ms). Unless indicated otherwise, the term "multiple sclerosis" encompasses all of the different categories of MS. Accordingly, in some aspects, the PDGFRα inhibitors of the present disclosure can be used to treat all types of MS.

[0268] In some aspects, a PDGFRα inhibitor of the present disclosure can be used to treat clinically isolated syndrome (CIS). In some aspects, a PDGFRα inhibitor of the present disclosure can be used to treat radiologically isolated syndrome (RIS).

[0269] In some aspects, provided herein is a method of treating a relapsing form of multiple sclerosis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of any of the PDGFRα inhibitors provided herein.

[0270] In some aspects, the demyelinating disease that can be treated with the present disclosure is an optic neuritis. Accordingly, in some aspects, a PDGFRα inhibitor is used to ameliorate optic neuritis, e.g., optic neuritis that is due to multiple sclerosis.

[0271] As is apparent from the present disclosure, by promoting the myelination of an axon and / or the remyelination of a demyelinated axon, PDGFRα inhibitors of the present disclosure can help restore nervous system cell function and thereby, reduce and / or alleviate one or more symptoms associated with a demyelinating disease. Accordingly, in some aspects, treating a demyelinating disease comprises reducing one or more symptoms associated with the demyelinating disease. Non-limiting examples of such symptoms include one or more of: fatigue, dizziness, malaise, elevated fever and high body temperature, extreme sensitivity to cold in the hands and feet, weakness and stiffness in muscles and joints, weight changes, digestive or gastrointestinal problems, low blood pressure, high blood pressure, irritability, anxiety, depression, blurred vision, double vision, ataxia, clonus, spasms, dysarthria, weakness, clumsiness, hand paralysis, hemiparesis, genital anesthesia, sexual dysfunction, incoordination, paresthesias, ocular paralysis, impaired muscle coordination, loss of sensation, tingling, numbness, pain, impaired vision, neurological symptoms, unsteady gait, balance problems, dizziness, spastic paraparesis, incontinence, hearing problems, speech problems, loss of olfaction, and agusia.

[0272] Moreover, PDGFRα inhibitors described herein can also be used to prevent or delay the onset of one or more symptoms associated with a demyelinating disease. With many demyelinating diseases, particularly during the early stages, a subject may not exhibit any apparent symptoms of the disease. For instance, in some aspects, the damage to the myelin sheaths may not be as severe, such that the oligodendrocytes present within the CNS of the subject can adequately repair any damages. However, as is the case with most demyelinating diseases (e.g., multiple sclerosis), the damage to the myelin sheaths can become more severe, resulting in the manifestation of one or more symptoms of the disease. In some aspects, by administering a PDGFRα inhibitor described herein to the subject when the damage to the myelin sheath is still minor, the manifestation of the one or more symptoms of the disease can be prevented or delayed. In some aspects, compared to a reference subject (e.g., corresponding subject that did not receive an administration of the PDGFRα inhibitor), the manifestation of the one or more symptoms of the disease is delayed by at least 1.1-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, or at least 50-fold. In some aspects, compared to the reference subject, the subjecttreated with a PDGFRα inhibitor described herein exhibits less number of symptoms and / or the symptoms are reduced in severity.

[0273] Whether a subject exhibits one or more symptoms associated with a demyelinating disease can be assessed using any suitable approaches known in the art. In some aspects, whether a subject exhibits the one or more symptoms associated with a demyelinating disease can be determined by assessing the subject's performance in one or more of the following tests: a visual evoked potential (VEP) test, a multifocal visual evoked potential (mfVEP) test, a low contrast visual acuity (LCVA) test, a magnetic resonance imaging (MRI) (e.g., magnetization transfer ratio (MTR), myelin water fraction (MWF), quantitative susceptibility mapping (QSM), and T2 imaging), an electromyography (EMG), a nerve conduction velocity (NCV) test, an Extended Disability Status Scale (EDSS), a timed walk test (e.g., timed 25-foot walk), a Nine-Hole Peg Test (9HPT), an ocular coherence tomograph (OCT), a quality of life measure test (e.g., Multiple Sclerosis Quality of Life-54 and Vision-Related Quality of Life), cognitive assessment (e.g., Symbol-Digit Modalities Test or Montreal Cognitive Assessment), or combinations thereof. In some aspects, whether a subject exhibits one or more symptoms associated with a demyelinating disease is determined by assessing the subject's performance in a LC-VA test. In some aspects, whether a subject exhibits one or more symptoms associated with a demyelinating disease is determined by assessing the subject's performance in a cognitive assessment.

[0274] In some aspects, an improved performance as compared to a reference performance (e.g., a corresponding subject's performance in the test where the reference subject was not treated with a PDGFRα inhibitor described herein and / or the subject's performance prior to the treatment with a PDGFRα inhibitor) indicates that the one or more symptoms associated with a demyelinating disease is reduced or alleviated in the subject. In some aspects, a comparable or reduced performance as compared to a reference performance (e.g., a corresponding subject's performance in the test where the subject was not treated with a PDGFRα inhibitor described herein and / or the subject's performance prior to the treatment with a PDGFRα inhibitor) indicates that the one or more symptoms associated with a demyelinating disease is maintained or has worsened in the subject.

[0275] Accordingly, some aspects of the present disclosure are directed to methods of treating a demyelinating disease in a subject in need thereof, comprising assessing the subject's performance in a test for assessing one or more symptoms associated with ademyelinating disease, wherein the subject received a treatment comprising a PDGFRα inhibitor described herein prior to the assessment. In some aspects, if the subject's performance in the test is improved as compared to a reference performance (e.g., a corresponding subject's performance in the test where the reference subject was not treated with a PDGFRα inhibitor described herein and / or the subject's performance prior to the treatment with a PDGFRα inhibitor), the treatment comprising a PDGFRα inhibitor can be maintained in the subject (e.g., the subject receives one or more additional administration of the PDGFRα inhibitor at the same dose and / or dosing interval). In some aspects, where the subject exhibits improved performance, the treatment comprising a PDGFRα inhibitor is reduced (e.g., the subject receives one or more additional administration of the PDGFRα inhibitor but at a lower dose and / or longer dosing interval) or stopped. In some aspects, if the subject's performance is comparable or reduced as compared to a reference performance, (e.g., a corresponding subject's performance in the test where the subject was not treated with a PDGFRα inhibitor described herein and / or the subject's performance prior to the treatment with a PDGFRα inhibitor), the treatment comprising a PDGFRα inhibitor is adjusted such that the subject receives one or more administrations of the PDGFRα inhibitor at a higher dose and / or shorter dosing interval.

[0276] Some aspects of the present disclosure are directed to methods of improving a subject's performance in a test for assessing one or more symptoms associated with a demyelinating disease, comprising administering to the subject any of the PDGFRα inhibitors described herein. In some aspects, after the administration, the subject's performance in the test is increased as compared to a reference performance (e.g., a corresponding subject's performance in the test where the reference subject was not treated with a PDGFRα inhibitor described herein and / or the subject's performance prior to the treatment with a PDGFRα inhibitor). In some aspects, the test is one or more of a visual evoked potential (VEP) test, a multifocal visual evoked potential (mfVEP) test, a low contrast visual acuity (LC-VA) test, a magnetic resonance imaging (MRI) (e.g., magnetization transfer ratio (MTR), myelin water fraction (MWF), quantitative susceptibility mapping (QSM), and T2 imaging), an electromyography (EMG), a nerve conduction velocity (NCV) test, an Extended Disability Status Scale (EDSS), a timed walk test (e.g., timed 25-foot walk), a Nine-Hole Peg Test (9HPT), an ocular coherence tomograph (OCT), a quality of life measure test (e.g., Multiple Sclerosis Quality of Life-54 and Vision-Related Quality of Life), cognitive assessment (e.g., Symbol-Digit Modalities Test or Montreal Cognitive Assessment), or combinations thereof. In some aspects, the test is a LCVA test. In some aspects, the test is a cognitive assessment.

[0277] As is apparent from the present disclosure, the introduction of a PDGFRα inhibitor into a subject can be done by any suitable route, including, but not limited to, intratumorally, orally, pulmonarily, intranasally, parenterally (intravenously, intra- arterially, intramuscularly, intraperitoneally, or subcutaneously), rectally, vaginally, intralymphatically, intrathecally, periocularly, cutaneously, intradermally, intraorbitally, intracerebrally, intracranially, intraspinally, intraventricuarly, intracapsularly, or topically. Administration includes self-administration and the administration by another. A suitable route of administration allows the PDGFRα inhibitors described herein to perform its intended function (e.g., inhibit PDGFRα activity and induce OPC differentiation). In some aspects, a suitable route of administration includes that which would allow a PDGFRα inhibitor to reach the CNS or any other sites where OPCs are present. Non-limiting examples of such routes include intranasal delivery, intrathecal administration, intracranial administration, and combinations thereof. In some aspects, a PDGFRα inhibitor described herein is administered orally. In some aspects, a PDGFRα inhibitor of the present disclosure is administered intravenously. In some aspects, a PDGFRα inhibitor can be administered both orally and intravenously.

[0278] In any of the methods provided herein where a PDGFRα inhibitor is administered to a subject, the PDGFRα inhibitor can be administered to the subject using any suitable dosing schedule. In some aspects, the PDGFRα inhibitor is administered to the subject once. In some aspects, multiple doses of the PDGFRα inhibitor are administered to the subject. In some aspects, a PDGFRα inhibitor described herein is administered to a subject according to an intermittent dosing schedule. As used herein, the term "intermittent dosing schedule" (and any variants thereof) refers to a dosing schedule in which the therapeutic agent (e.g., PDGFRα inhibitor) is administered non-continuously (i.e., an intervening period exists between doses). An intermittent dosing schedule useful for the present disclosure can encompass any discontinuous administration regimen that provides a therapeutically effective amount of a PDGFRα inhibitor to a subject in need thereof. Intermittent dosing regimens can use equivalent, lower, or higher doses of a PDGFRα inhibitor than would be used in continuous dosing regimens. Advantages of intermittentdose administration include, but are not limited to, improved safety, decreased toxicity (e.g., decreased weight loss), acceptable levels of ADME criteria, acceptable levels of undesirable effects on organ systems such as heart, pulmonary, hepatic, reproductive (for example, ovarian or testicular) or gastrointestinal, increased exposure, increased efficacy, and / or increased subject compliance. These advantages can be realized when the PDGFRα inhibitor is administered as a single agent and / or when administered in combination with one or more additional therapeutic agents, e.g., standard of care. When administered in combination with one or more additional therapeutic agents, in some aspects, the dosing regimen for the PDGFRα inhibitor (e.g., intermittent dosing) and the additional therapeutic agents are independent of each other. For example, in some aspects, the PDGFRα inhibitor is administered using a first dosing regimen and the additional therapeutic agent is administered using a second dosing regimen, wherein the first and second dosing regimens are different.

[0279] In some aspects, the intermittent dosing schedule comprises administering the PDGFRα inhibitor to the subject every other day. In some aspects, the PDGFRα inhibitor is administered to the subject one time per day. In some aspects, the PDGFRα inhibitor is administered to the subject two times per day. In some aspects, the PDGFRα inhibitor is administered to the subject three times per day. In some aspects, the PDGFRα inhibitor is administered to the subject four times per day. In some aspects, the PDGFRα inhibitor is administered to the subject every three days. In some aspects, the PDGFRα inhibitor is administered to the subject every four days. In some aspects, the PDGFRα inhibitor is administered to the subject every five days. In some aspects, the PDGFRα inhibitor is administered to the subject every six days. In some aspects, the PDGFRα inhibitor is administered to the subject once a week. In some aspects, the PDGFRα inhibitor is administered to the subject once every eight days. In some aspects, the PDGFRα inhibitor is administered to the subject once every nine days. In some aspects, the PDGFRα inhibitor is administered to the subject every 10 days. In some aspects, the PDGFRα inhibitor is administered to the subject every 11 days. In some aspects, the PDGFRα inhibitor is administered to the subject every 12 days. In some aspects, the PDGFRα inhibitor is administered to the subject every 13 days. In some aspects, the PDGFRα inhibitor is administered to the subject once every two weeks. In some aspects, the PDGFRα inhibitor is administered to the subject once every three weeks. In some aspects, the PDGFRαinhibitor is administered to the subject once a month. In some aspects, the PDGFRα inhibitor is administered to the subject once every five weeks. In some aspects, the PDGFRα inhibitor is administered to the subject once every six weeks, In some aspects, the PDGFRα inhibitor is administered to the subject once every seven weeks. In some aspects, the PDGFRα inhibitor is administered to the subject once every two months. In some aspects, the PDGFRα inhibitor is administered to the subject once every nine weeks. In some aspects, the PDGFRα inhibitor is administered to the subject once every 10 weeks. In some aspects, the PDGFRα inhibitor is administered to the subject once every 11 weeks. In some aspects, the PDGFRα inhibitor is administered to the subject once every three months. In some aspects, the PDGFRα inhibitor is administered to the subject once every four months. In some aspects, the PDGFRα inhibitor is administered to the subject once every five months. In some aspects, the PDGFRα inhibitor is administered to the subject once every six months. In some aspects, the PDGFRα inhibitor is administered to the subject once every twelve months.

[0280] In some aspects, the intermittent dosing schedule comprises administering to the subject a first dose and a second dose of a PDGFRα inhibitor, wherein the second dose is administered at least one day after administering the first dose. In some aspects, the second dose is administered at least two days after administering the first dose. In some aspects, the second dose is administered at least three days after administering the first dose. In some aspects, the second dose is administered at least four days after administering the first dose. In some aspects, the second dose is administered at least five days after administering the first dose. In some aspects, the second dose is administered at least six days after administering the first dose. In some aspects, the second dose is administered at least seven days after administering the first dose. In some aspects, the second dose is administered at least eight days after administering the first dose. In some aspects, the second dose is administered at least nine days after administering the first dose. In some aspects, the second dose is administered at least 10 days after administering the first dose. In some aspects, the second dose is administered at least 11 days after administering the first dose. In some aspects, the second dose is administered at least 12 days after administering the first dose. In some aspects, the second dose is administered at least 13 days after administering the first dose. In some aspects, the second dose is administered at least two weeks after administering the first dose. In some aspects, the second dose is administeredat least three weeks after administering the first dose. In some aspects, the second dose is administered at least one month after administering the first dose. In some aspects, the second dose is administered at least two months after administering the first dose. In some aspects, the second dose is administered at least three months after administering the first dose. In some aspects, the second dose is administered at least four months after administering the first dose. In some aspects, the second dose is administered at least five months after administering the first dose. In some aspects, the second dose is administered at least six months after administering the first dose. In some aspects, the second dose is administered at least 12 months after administering the first dose.

[0281] In some aspects, the intermittent dosing schedule comprises administering to the subject a first set of doses and a second set of doses of a PDGFRα inhibitor, wherein the second set of doses is administered at least one day after administering the first set of doses. In some aspects, the first set of doses can be, e.g., one, two, three, or four doses per day, administered over a period of, e.g., one, two, three, or four days. In some aspects, the second set of doses can be, e.g., one, two, three, or four doses per day, administered over a period of, e.g., one, two, three, or four days.

[0282] In some aspects, the second set of doses is administered at least two days after administering the first set of doses. In some aspects, the second set of doses is administered at least three days after administering the first set of doses. In some aspects, the second set of doses is administered at least four days after administering the first set of doses. In some aspects, the second set of doses is administered at least five days after administering the first set of doses. In some aspects, the second set of doses is administered at least six days after administering the first set of doses. In some aspects, the second set of doses is administered at least seven days after administering the first set of doses. In some aspects, the second set of doses is administered at least eight days after administering the first set of doses. In some aspects, the second set of doses is administered at least nine days after administering the first set of doses. In some aspects, the second set of doses is administered at least 10 days after administering the first set of doses. In some aspects, the second set of doses is administered at least 11 days after administering the first set of doses. In some aspects, the second set of doses is administered at least 12 days after administering the first set of doses. In some aspects, the second set of doses is administered at least 13 days after administering the first set of doses. In some aspects, the second set of doses is administeredat least two weeks after administering the first set of doses. In some aspects, the second set of doses is administered at least three weeks after administering the first set of doses. In some aspects, the second set of doses is administered at least one month after administering the first set of doses. In some aspects, the second set of doses is administered at least two months after administering the first set of doses. In some aspects, the second set of doses is administered at least three months after administering the first set of doses. In some aspects, the second set of doses is administered at least four months after administering the first set of doses. In some aspects, the second set of doses is administered at least five months after administering the first set of doses. In some aspects, the second set of doses is administered at least six months after administering the first set of doses. In some aspects, the second set of doses is administered at least 12 months after administering the first set of doses.

[0283] Not to be bound by any one theory, in some aspects, the use of an intermittent dosing schedule allows the OPC population of the treated subject (i.e., subject who previously received an administration of the PDGFRα inhibitor) to sufficiently recover prior to the next dose of the PDGFRα inhibitor. As described herein, OPCs are capable of self-renewal and therefore, under a steady-state condition (i.e., no inhibition of PDGFRα activity), the OPC population of a subject is continuously replenished and maintained. As described and demonstrated herein, when a PDGFRα inhibitor described herein is administered to a subject, the PDGFRα inhibitor induces the differentiation of the OPCs within the subject into oligodendrocytes. In some aspects, this can result in a decrease of the OPC population within the subject, and therefore, an immediate or rapid subsequent administration of a PDGFRα inhibitor would have diminished therapeutic activity (e.g., reduced further generation of oligodendrocytes). Accordingly, in some aspects, an intermittent dosing schedule useful for the present disclosure comprises administering a first dose of a PDGFRα inhibitor and a second dose of a PDGFRα inhibitor, wherein the second dose of the PDGFRα inhibitor is administered to the subject after the OPC population of the subject has sufficiently recovered from the effects of the first dose of the PDGFRα inhibitor. When referring to an OPC population (e.g., of a subject treated with a PDGFRα inhibitor), the expression "sufficiently recovered" means that the number of OPCs within the subject has increased, such that an additional administration of the PDGFRα inhibitor is capable of resulting in additional generation of oligodendrocytes. In some aspects, an OPC population has sufficiently recovered is comparable to that of a reference subject, wherein the referencesubject comprises (i) the subject prior to the initial administration of the PDGFRα inhibitor, (ii) a corresponding, normal healthy subject (i.e., does not suffer from a demyelinating disease) who has not received an administration of the PDGFRα inhibitor, or (iii) both (i) and (ii). In some aspects, the number of OPCs within an OPC population that has sufficiently recovered is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of the number of OPCs within the OPC population of the reference subject.

[0284] Accordingly, where a method provided herein comprises administering a first dose and a second dose of a PDGFRα inhibitor to a subject (e.g., to treat a demyelinating disease), in some aspects, a first dose of the PDGFRα inhibitor is administered to a subject and then the subject's OPC population is assessed, wherein if the subject's OPC population has sufficiently recovered as compared to a reference subject (e.g., as described above), a second dose of the PDGFRα inhibitor is administered to the subject. In some aspects, a second dose of the PDGFRα inhibitor is administered to the subject if the size of the subject's OPC population (e.g., number of OPCs within the OPC population) is at least at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of the size of the reference subject's OPC population. In some aspects, where an additional dose of the PDGFRα inhibitor is administered to the subject, the additional dose is administered to the subject at the same dosing interval as that used for the first and second doses of the PDGFRα inhibitor. In some aspects, where an additional dose of the PDGFRα inhibitor is administered to the subject, the method comprises assessing the subject's OPC population again after the second administration, wherein if the subject's OPC population has sufficiently recovered as compared to a reference subject (e.g., as described above), the additional dose of the PDGFRα inhibitor is administered to the subject. In some aspects, the additional dose of the PDGFRα inhibitor is administered to the subject if the size of the subject's OPC population (e.g., number of OPCs within the OPC population) is at least at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of the size of the reference subject's OPC population. As further described elsewhere in the present disclosure, in some aspects, the amount of time required for the subject's OPC population to have sufficiently recovered after an initial administration of a PDGFRα inhibitor is the dosing interval of the PDGFRα inhibitor.

[0285] Whether a subject's OPC population has sufficiently recovered (and thus, determine a dosing interval for a PDGFRα inhibitor) can be determined using any suitable method known in the art. For example, in some aspects, a cuprizone animal model can be used. As demonstrated herein, in some aspects, a dosing interval suitable for a PDGFRα inhibitor described herein can be determined by administering a first dose and second dose of the PDGFRα inhibitor to the cuprizone animal model, and then assessing the number of newly generated oligodendrocytes present within the brain of the animals (e.g., by quantifying the number of GPR17+ cells within the brain). If the number of newly generated oligodendrocytes within the brain is the same or increased compared to a reference (e.g., the number of newly generated oligodendrocytes present within the brain of corresponding animal that received a single administration of the PDGFRα inhibitor), then a suitable dosing interval is the time between the administration of the first dose and the second dose of the PDGFRα inhibitor or any time longer than that. If the number of newly generated oligodendrocytes within the brain is reduced compared to a reference (e.g., the number of newly generated oligodendrocytes present within the brain of corresponding animal that received a single administration of the PDGFRα inhibitor), then a suitable dosing interval is longer than the time between the administration of the first dose and the second dose of the PDGFRα inhibitor.

[0286] In some aspects, a suitable dosing interval for a PDGFRα inhibitor is directly related to the plasma level of the PDGFRα inhibitor. Accordingly, in some aspects, a method of determining a suitable dosing interval for a PDGFRα inhibitor comprises administering a first dose of the PDGFRα inhibitor to a subject and determining the plasma level of the PDGFRα inhibitor in the subject. In some aspects, where the plasma level of the PDGFRα inhibitor is comparable to that of a reference (e.g., a subject who has not previously received a dose of the PDGFRα inhibitor and / or a subject who has previously received a dose of the PDGFRα inhibitor but the subject's OPC population has sufficiently recovered as described herein), a suitable dosing interval is the time between administering the first dose of the PDGFRα inhibitor and the subject's plasma level of the PDGFRα inhibitor being comparable to that of the reference. In some aspects, where the plasma level of the PDGFRα inhibitor is reduced as compared to a reference (e.g., plasma level of the PDGFRα inhibitor in the subject immediately after, e.g., about 4 hours after, the administration of the initial dose of the PDGFRα inhibitor), a suitable dosing interval is the time between administeringthe first dose of the PDGFRα inhibitor and the subject's plasma level of the PDGFRα inhibitor reaching a reduced level as compared to the reference. In some aspects, the additional dose of the PDGFRα inhibitor is administered to the subject when the subject's plasma level has decreased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or about 100% as compared to the reference. In some aspects, the brain to plasma ratio may be assessed in preclinical species using bioanalytical gas or liquid chromatography and mass spectrometry methods.

[0287] In some aspects, the plasma level of the PDGFRα inhibitor is related to the half-life of the PDGFRα inhibitor. In some aspects, an intermittent dosing schedule useful for the present disclosure comprises administering two or more doses of a PDGFRα inhibitor at a dosing interval that is longer than the half-life of the PDGFRα inhibitor. In some aspects, the dosing interval is at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% longer than the half-life of the PDGFRα inhibitor. In some aspects, the dosing interval is at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least about 30-fold, at least 40-fold, or at least 50-fold longer than the half-life of the PDGFRα inhibitor. In some aspects, compared to the half-life of the PDGFRα inhibitor, the dosing interval is at least one day, at least two days, at least three days, at least four days, at least five days, at least six days, at least one week, at least two weeks, at least three weeks, at least one month, at least two months, or at least three months longer.

[0288] In some aspects, the methods described herein (e.g., treating a demyelinating disease) can comprise administering an additional therapeutic agent to the subject. For examples, in some aspects, the PDGFRα inhibitors described herein are used in conjunction with an immunomodulatory drug. In some aspects, the PDGFRα inhibitors are used alone in the methods provided herein.

[0289] As described herein, "immunomodulatory drug" refers to a therapeutic agent that works by modulating (e.g., increasing and / or decreasing) one or more aspects of an immune response. In some aspects, an immunomodulatory drug useful for the present disclosure is capable of reducing or alleviating the proinflammatory nature of a demyelinating disease (e.g., multiple sclerosis). For instance, in some aspects, the immunomodulatory drug could block the production of proinflammatory mediators, promote the production of anti-inflammatory cytokines (e.g., IL-10 or TGF-β), promote the production of regulatory T cells (Tregs), influence B cells, prevent the entry of immune cells into the brain, or any combination thereof. Non-limiting examples of immunomodulatory drugs that are useful for the present disclosure include: interferon beta-1b (BETASERON®, EXTAVIA®), interferon beta-1a (AVONEX®, REBIF®), peginterferon beta-1a (PLEGRIDY®), alemtuzumab (LEMTRADA®), natalizumab (TYSABRI®), ocrelizumab (OCREVUS®), ofatumumab (KESIMPTA®), glatiramer acetate (COPAXONE®, GLATOPA®), teriflunomide (AUBAGIO®), dimethyl fumarate (TECFIDERA®), monomethyl fumarate (BAFIERTAM®), diroximel fumarate (Vumerity®), and combinations thereof.

[0290] Where an additional therapeutic agent (e.g., immunomodulatory drug) is administered to a subject, in some aspects, the additional therapeutic agent is administered to the subject prior to the administration of a PDGFRα inhibitor. Accordingly, in some aspects, any of the methods provided herein (e.g., method of treating a demyelinating disease) comprise administering to the subject a PDGFRα inhibitor, wherein the subject had previously received an additional therapeutic agent (e.g., immunomodulatory drug). In some aspects, the additional therapeutic agent is administered after the administration of a PDGFRα inhibitor. In some aspects, the additional therapeutic agent is administered concurrently with the administration of a PDGFRα inhibitor.

[0291] In some aspects, to improve delivery to the CNS, a PDGFRα inhibitor described herein can be administered to a subject in combination with an agent that assists the delivery of the inhibitor to the CNS (e.g., allows the inhibitor to cross the blood-brain barrier). In some aspects, a PDGFRα inhibitor described herein is administered to a subject in combination with a peptide blood-brain barrier (BBB) shuttle, wherein the peptide BBB shuttle enhances the ability of the PDGFRα inhibitor to cross the blood-brain barrier and reach the CNS. Non-limiting examples of such peptide BBB shuttles are provided in Table 2 (below). See, e.g., Oller-Salvia et al., Chem Soc Rev 45: 4690-4707 (2016), and Jafari et al., Expert Opinion on Drug Delivery 16:583-605 (2019). TABLE 2: Peptide BBB ShuttleNomenclature for cyclic peptides (&) is adapted to the 3-letter amino acid code from the one described by Spengler et al. Pept. Res., 2005, 65, 550–555 [Dap] stands for diaminopropionic acid. VI. Enumerated Clauses

[0292] The present disclosure also provides the following enumerated clauses:

[0293] Clause 1. A compound of Formula I:,

[0294] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0295] indicates a single bond or a double bond such that all valences are satisfied;

[0296] X1, X2, X3, and X4are selected from N and CRa, with the proviso that not more than two of X1, X2, X3, and X4are N;

[0297] one of Y1and Y2is N and the other of Y1and Y2is C;

[0298] each Rais independently selected from H, halo, C1-C4alkyl, and C1-C4alkoxy;

[0299] R1is selected from C1-C4alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, heteroaryl, aryl, and C1-C8alkoxy, all of which can be optionally substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, oxo, C1-C4alkyl, aminoC1- C4alkyl, hydroxyC1-C4alkyl, C1-C4alkoxy, C1-C4alkoxyC1-C4alkyl, 3-8 membered heterocyclyl, and 3-8 membered heterocyclylC1-C4alkyl, with the proviso that the number of substituents does not exceed the number of substitutable positions;

[0300] R2is selected from cycloalkyl, cycloalkenyl, alkyl, oxoalkylamino, aminoalkylamino, amino, heterocyclyl, heteroaryl, aminoheterocyclyl, heterocyclylamino, and aminoalkylamino, all of which can be optionally substituted with one or more substituents selected from D, halo, hydroxy, oxo, and C1-C4alkyl;

[0301] R2is substituted with one, two, or three R3;

[0302] R3is selected from aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)NR31R32, - S(O)2NR31R32, -S(O)(NR33)R31, -S(O)2R31, -S(O)(NR33)NR31R32, -C(S)NR31R32, C3- C8cycloalkyl, 3-8 membered heterocyclyl, and C1-C4alkyl, all of which can be optionally substituted with one, two, three, four, or five R30;

[0303] each R30is independently selected from D, halo, aryl, -OR300, -NR300R303, -S(O)rR300, -C(O)R300, -C(=CR34R35)R300, and;

[0304] r is selected from 0, 1, and 2;

[0305] each R300is independently selected from C1-C6alkyl, C3-C7cycloalkyl, aryl, heteroaryl, 3-8 membered heterocyclyl, and 3-8 membered heterocyclylaryl, all of whichcan be optionally substituted with one, two, three, four, or five substituents selected from D, halo, hydroxy, amino, alkylamino, cyano, C1-C4alkyl, C1-C4haloalkyl, and C1-C4alkoxy;

[0306] each R301is independently selected from H, halo, and C1-C4alkyl;

[0307] each R302is independently selected from H, F, hydroxyl, amino, alkylamino, oxo, and C1-C4alkyoxy;

[0308] each R303is independently selected from H and C1-C4alkyl;

[0309] n, o, and p are each independently selected from 0, 1, 2, 3, and 4;

[0310] each R31is independently selected from C1-C8alkyl, arylC1-C4alkyl, heteroarylC1- C4alkyl, heterocyclyl, heterocyclylC1-C4alkyl, cycloalkyl, and cycloalkylC1-C4alkyl, all of which can be optionally substituted with one, two, three, four, or five substituents selected from D, halo, cyano, hydroxy, amino, -OCF3, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, hydroxyC1-C4alkyl, -S(O)2NR304R305, -C(O)OR304R305, -C(O)NR304R305, and - NR304C(O)R305;

[0311] each R304and R305is independently selected from H and C1-C4alkyl;

[0312] each R32is independently selected from H and C1-C4alkyl; or

[0313] R31and R32together with the atom to which they are connected to form a 5-8 membered heterocycyl, optionally substituted with one, two, three, four, or five substituents selected from D, halo, cyano, C1-C4alkyl, C1-C4haloalkyl, and -C(O)NR34R35; and

[0314] each R34and R35is independently selected from H, C1-C4alkyl, and C1-C4haloalkyl; and

[0315] each R33is independently selected from H, C1-C4alkyl, C1-C4haloalkyl, and – C(O)R34; or

[0316] R31and R33together with the atoms to which they are connected form a 4-8 membered heterocycyl.

[0317] Clause 2. The compound of clause 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Y1is N and Y2is C.

[0318] Clause 3. The compound of clause 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Y1is C and Y2is N.

[0319] Clause 4. The compound of any one of clauses 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein X1is N, X2is CRa, X3is CRa, and X4is CRa.

[0320] Clause 5. The compound of any one of clauses 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein X1is CRa, X2is N, X3is CRa, and X4is CRa.

[0321] Clause 6. The compound of any one of clauses 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein X1is CRa, X2is CRa, X3is N, and X4is CRa.

[0322] Clause 7. The compound of any one of clauses 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein X1is CRa, X2is CRa, X3is CRa, and X4is N.

[0323] Clause 8. The compound of any one of clauses 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein X1is CRa, X2is CRa, X3is CRa, and X4is CRa.

[0324] Clause 9. The compound of any one of clauses 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is 5- or 6-membered heteroaryl.

[0325] Clause 10. The compound of any one of clauses 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is an optionally substituted pyrazolyl.

[0326] Clause 11. The compound of any one of clauses 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0327] R1is selected from:, , nd

[0328] R10is selected from H, C1-C4alkyl, C1-C4alkoxy, aminoC1-C4alkyl, hydroxyC1- C4alkyl, and C1-C4alkylsulfonyl, wherein the C1-C4alkyl, C1-C4alkoxy, aminoC1-C4alkyl, hydroxyC1-C4alkyl, and C1-C4alkylsulfonyl can be optionally substituted by one or more substituents selected from hydroxyl, C1-C4alkoxy, NR10aR10b, halo, and deuterium, wherein R10aand R10bare selected from hydrogen and C1-C4alkyl, or wherein R10aand R10btaken together with the nitrogen atom to which they are attached form a 4- to 8-membered ring.

[0329] Clause 12. The compound of clause 11, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is.

[0330] Clause 13. The compound of clause 11 or 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R10is CH3.

[0331] Clause 14. The compound of any one of clauses 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is heterocyclyl optionally substituted with C1- C4alkyl or oxo.

[0332] Clause 15. The compound of any one of clauses 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is substituted with one R3.

[0333] Clause 16. The compound of any one of clauses 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from: ,,, , , ,

[0334] indicates a single bond or a double bond such that all valences are satisfied;

[0335] m is selected from 0, 1, 2, 3, 4, 5, and 6; and

[0336] Z1, Z2, and Z3are selected from N and CRa.

[0337] Clause 17. The compound of clause 16, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from:, , , , .

[0338] Clause 18. The compound of any one of clauses 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, having Formula Ia:

[0339] wherein a and b are each independently selected from 1, 2, and 3; and

[0340] Q is selected from -CH- and -N-, with the proviso that if Q is -N-, a and b are not 1.

[0341] Clause 19. The compound of any one of clauses 1 to 18, or a pharmaceutically acceptable salt or solvate thereof, having Formula II:.

[0342] Clause 20. The compound of any one of clauses 1 to 19, or a pharmaceutically acceptable salt or solvate thereof, having Formula IIa:.

[0343] Clause 21. The compound of any one of clauses 1 to 20, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is heteroaryl optionally substituted with one, two, three, four, or five R30.

[0344] Clause 22. The compound of any one of clauses 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from: ,, , , , ,, ,,

[0345] wherein A1is selected from O, S, and N and R36is selected from hydrogen, optionally substituted C1-C6alkyl, and optionally substituted C1-C6alkylaryl.

[0346] Clause 23. The compound of any one of clauses 1 to 22, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from:,

[0347] Clause 24. The compound of any of clauses 1 to 23, or a pharmaceutically acceptable salt or solvate thereof, wherein R30is:.

[0348] Clause 25. The compound of clause 24, or a pharmaceutically acceptable salt or solvate thereof, wherein R300is selected from: , ,, , , , , .

[0349] Clause 26. The compound of clause 25, or a pharmaceutically acceptable salt or solvate thereof, wherein R300is:.

[0350] Clause 27. The compound of any one of clauses 1 to 26, or a pharmaceutically acceptable salt or solvate thereof, wherein R301is H and R302is H or CH3.

[0351] Clause 28. The compound of any of clauses 1 to 22, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from: nd.

[0352] Clause 29. The compound of clause 28, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from:, , .

[0353] Clause 30. The compound of clause 29, or a pharmaceutically acceptable salt or solvate thereof, wherein R32is H.

[0354] Clause 31. The compound of any one of clauses 28 to 30, or a pharmaceutically acceptable salt or solvate thereof, wherein R31is selected from:, , ,,, , , ,

[0355] wherein R31ais selected from H, D, alkylamino, C1-C4alkyl, and -CF3, and

[0356] R31bis selected from H, D, halo, hydroxy, amino, alkylamino, C1-C4alkyl, -CF3, and -OCF3.

[0357] Clause 32. The compound of clause 1, or a pharmaceutically acceptable salt or solvate thereof, selected from any one of compounds 156, 250, 275 and 326-406 of Table 1.

[0358] Clause 33. The compound of any one of clauses 1 to 32, which can exhibit one or more of the following properties: (i) promote the differentiation of an OPC into an oligodendrocyte, (ii) promote the expression of a protein associated with oligodendrocyte differentiation and / or myelination (e.g., G-protein coupled receptor 17 (GPR17), myelin basic protein (MBP), ASPA, GST-pi, CC1, myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein / claudin-11, CNPase, or a combination thereof), (iii) promote the myelination of an axon, (iv) promote the remyelination of a demyelinatedaxon, (v) inhibit PDGFRα kinase activity, (vi) achieve a brain to plasma ratio of greater than 0.1 when systemically administered to a subject, and (vii) any combination thereof.

[0359] Clause 34. The compound of clause 33, which can inhibit PDGFRα kinase activity.

[0360] Clause 35. The compound of clause 34, which can inhibit PDGFRα kinase activity with an IC50of less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 75 nM, less than less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, or less than 5 nM.

[0361] Clause 36. The compound of clause 35, wherein the IC50of the PDGFRα inhibitor is determined using an enzymatic PDGFRα kinase assay (e.g., Promega kinase assay described in Example 131).

[0362] Clause 37. The compound of clause 36, wherein the enzymatic PDGFRα kinase assay comprises 20 ng of purified PDGFRα protein, 150 µM of ATP and 1 µg of substrate, Poly (Glu4Tyr1) in a volume of 15 µl.

[0363] Clause 38. A pharmaceutical composition comprising the compound of any one of clauses 1 to 37, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0364] Clause 39. A kit comprising the compound of any one of clauses 1 to 37, or a pharmaceutically acceptable salt or solvate thereof, or the composition of clause 38, and instructions for use.

[0365] Clause 40. A compound of any one of clauses 1 to 37, or the pharmaceutical composition of clause 38, for use in therapy.

[0366] Clause 41. A method of treating a demyelinating disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of any one of clauses 1 to 37 or the pharmaceutical composition of clause 38.

[0367] Clause 42. A method of improving a subject's performance in a test for assessing one or more symptoms associated with a demyelinating disease, comprising administering to the subject a therapeutically effective amount of the compound of any one of clauses 1 to 37 or the pharmaceutical composition of clause 38, wherein after the administration, the subject's performance in the test is improved as compared to a reference subject (e.g., the subject prior to the administration).

[0368] Clause 43. The method of clause 42, wherein the test is selected from a visual evoked potential (VEP) test, a multifocal visual evoked potential (mfVEP) test, a low contrast visual acuity (LC-VA) test, a magnetic resonance imaging (MRI) (e.g., magnetic transfer resonance, myelin water fraction (MWF), and quantitative susceptibility mapping (QSM)), an electromyography (EMG), a nerve conduction velocity (NCV) test, an Extended Disability Status Scale (EDSS), a timed walk test (e.g., timed 25-foot walk), a Nine-Hole Peg Test (9HPT), an ocular coherence tomograph (OCT), a quality of life measure test (e.g., Multiple Sclerosis Quality of Life-54 and Vision-Related Quality of Life), cognitive assessment (e.g., Montreal Cognitive Assessment), or combinations thereof.

[0369] Clause 44. The method of any one of clauses 41 to 43, wherein the demyelinating disease comprises an acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalitis, acute transverse myelitis, adrenoleukodystrophy, adrenomyeloneuropathy, Alexander disease, Alzheimer's disease, aminoacidurias, amyotrophic lateral sclerosis, anti-MAG peripheral neuropathy, anti-MOG associated spectrum, Balo concentric sclerosis, brain injury, CAMFAK syndrome, Canavan disease, carbon monoxide toxicity, central pontine myelinolysis, cerebral hypoxia, cerebral ischemia, Charcot–Marie–Tooth disease, chronic inflammatory demyelinating polyneuropathy, chronic traumatic encephalopathy, clinically isolated syndrome (CIS), congenital cataract, copper deficiency associated condition, delayed post-hypoxic leukoencephalopathy, diffuse cerebral sclerosis of Schilder, diffuse myelinoclastic sclerosis, extrapontine myelinolysis Gaucher disease, Guillain–Barré syndrome, hereditary neuropathy, hereditary neuropathy with liability to pressure palsy, HTLV-1–associated myelopathy, Hurler syndrome, hypomyelination, hypoxic brain injury, Krabbe disease, Leber hereditary optic atrophy and related mitochondrial disorders, leukodystrophic disorders, Marchiafava-Bignami disease, metachromatic leukodystrophy, multiple sclerosis (e.g., primary progressive multiple sclerosis (PPMS), relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), progressive relapsing multiple sclerosis, Marburg multiple sclerosis, tumefactive multiple sclerosis, and optic- spinal multiple sclerosis), multiple system atrophy, myelinoclastic disorders, myelopathy, nerve injury, neuromyelitis optica (NMO), Niemann-Pick disease, optic neuropathy, optic neuritis (e.g., acute optic neuritis and chronic relapsing inflammatory optic neuritis(CRION)), osmotic demyelination syndrome, Parkinson's disease, Pelizaeus‐Merzbacher disease, peripheral neuropathy, phenylketonuria, progressive inflammatory neuropathy, progressive multifocal leukoencephalopathy, progressive subcortical ischemic demyelination, reperfusion injury, Schilder disease, solitary sclerosis, spinal cord injury, subacute sclerosing panencephalitis, Tabes dorsalis, Tay-Sachs disease, transverse myelitis, traumatic brain injury, tropical spastic paraparesis, vitamin B12 deficiency, cerebral palsy, or a combination thereof.

[0370] Clause 45. The method of any one of clauses 41 to 44, wherein the demyelinating disease is characterized by demyelination of one or more cells within the CNS of the subject.

[0371] Clause 46. The method of any one of clauses 41 to 45, wherein the demyelinating disease is multiple sclerosis.

[0372] Clause 47. The method of clause 46, wherein the multiple sclerosis comprises a clinically isolated syndrome ("CIS"), relapsing-remitting MS ("RRMS"), secondary progressive MS ("SPMS"), primary progressive MS ("PPMS"), optic neuritis or transverse myelitis.

[0373] Clause 48. The method of any one of clauses 41 to 45, wherein the demyelinating disease is an optic neuritis.

[0374] Clause 49. The method of any one of clauses 41 to 48, wherein treating the demyelinating disease comprises reducing one or more symptoms associated with the demyelinating disease.

[0375] Clause 50. The method of clause 49, wherein the one or more symptoms comprise fatigue, dizziness, malaise, elevated fever and high body temperature, extreme sensitivity to cold in the hands and feet, weakness and stiffness in muscles and joints, weight changes, digestive or gastrointestinal problems, low blood pressure, high blood pressure, irritability, anxiety, depression, impaired vision (e.g., blurred vision, double vision, reduction in low contrast visual acuity (LC-VA)), ataxia, clonus, spasms, dysarthria, weakness, clumsiness, hand paralysis, hemiparesis, genital anesthesia, sexual dysfunction, incoordination, paresthesias, ocular paralysis, impaired muscle coordination, loss of sensation, tingling, numbness, pain, neurological symptoms, impaired cognition, unsteady gait, balance problems, dizziness, spastic paraparesis, incontinence, hearing problems, speech problems, loss of olfaction, agusia, or combinations thereof.

[0376] Clause 51. A method of promoting the myelination of an axon in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of clauses 1 to 37 or the pharmaceutical composition of clause 38.

[0377] Clause 52. The method of clause 51, wherein promoting the myelination of an axon results in an increase in the expression of one or more of the following markers within the subject: myelin basic protein (MBP) Myelin Oligodendrocyte Glycoprotein (MOG), Oligodendrocyte Specific Protein / Claudin-11, CNPase, or any combination thereof.

[0378] Clause 53. The method of clause 51 or 52, wherein the myelination of an axon can be determined by visualizing and / or quantifying the expression of one or more of the following markers: myelin basic protein (MBP) Myelin Oligodendrocyte Glycoprotein (MOG), Oligodendrocyte Specific Protein / Claudin-11, CNPase, or any combination thereof.

[0379] Clause 54. A method of promoting the remyelination of a demyelinated axon in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of clauses 1 to 37 or the pharmaceutical composition of clause 38.

[0380] Clause 55. The method of clause 54, wherein promoting the remyelination of a demyelinated axon results in an increase in the expression of one or more of the following markers within the subject: myelin basic protein (MBP) Myelin Oligodendrocyte Glycoprotein (MOG), Oligodendrocyte Specific Protein / Claudin-11, CNPase, or any combination thereof

[0381] Clause 56. The method of clause 54 or 55, wherein the remyelination of a demyelinated axon can be determined by visualizing and / or quantifying the expression of one or more of the following markers: myelin basic protein (MBP) Myelin Oligodendrocyte Glycoprotein (MOG), Oligodendrocyte Specific Protein / Claudin-11, CNPase, or any combination thereof.

[0382] Clause 57. A method of reducing the demyelination of a myelinated neuronal axon in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of clauses 1 to 37 or the pharmaceutical composition of clause 38.

[0383] Clause 58. The method of clause 57, wherein reducing the demyelination of a myelinated neuronal axon results in an increase in the expression of one or more of the following markers: myelin basic protein (MBP) Myelin Oligodendrocyte Glycoprotein (MOG), Oligodendrocyte Specific Protein / Claudin-11, CNPase, or any combination thereof.

[0384] Clause 59. The method of clause 57 or 58, wherein the reduction in the demyelination of a myelinated neuronal axon can be determined by visualizing and / or quantifying the expression of one or more of the following markers: myelin basic protein (MBP) Myelin Oligodendrocyte Glycoprotein (MOG), Oligodendrocyte Specific Protein / Claudin-11, CNPase, or any combination thereof.

[0385] Clause 60. A method of activating an oligodendrocyte progenitor cell (OPC) within the central nervous system (CNS) of a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of clauses 1 to 37 or the pharmaceutical composition of clause 38.

[0386] Clause 61. A method according to any one of clauses 51 to 60, wherein the subject has, or is at risk of developing a demyelinating disease, for example a disease according to any one of clauses 44 to 50.

[0387] Clause 62. A method according to any one of clauses 51 to 60, wherein the method is a method of treating or preventing a demyelinating disease, for example a disease according to any one of clauses 44 to 50.

[0388] Clause 63. The method of any one of clauses 41 to 62, wherein the compound or the pharmaceutical composition is administered to the subject once.

[0389] Clause 64. The method of any one of clauses 41 to 62, wherein the compound or the pharmaceutical composition is administered to the subject more than once using intermittent dosing.

[0390] Clause 65. The method of clause 64, wherein the intermittent dosing comprises administering the compound or the pharmaceutical composition to the subject every other day, every three days, every four days, every five days, every six days, once a week, every eight days, every nine days, every 10 days, every 11 days, every 12 days, every 13 days, once every two weeks, once every three weeks, once a month, once every two months, once every three months, once every four months, once every five months, once every six months, or once every twelve months.

[0391] Clause 66. The method of clause 64 or 65, wherein the intermittent dosing comprises administering to the subject a first dose and a second dose of the compound or the pharmaceutical composition, wherein the second dose is administered at least one day, at least two days, at least three days, at least four days, at least five days, at least six days, at least seven days, at least eight days, at least nine days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least two weeks, at least three weeks, at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, or at least 12 months after administering the first dose.

[0392] Clause 67. The method of clause 66, wherein the second dose is administered to the subject one day, two days, three days, four days, five days, six days, seven days, eight days, nine days, 10 days, 11 days, 12 days, 13 days, two weeks, three weeks, one month, two months, three months, four months, five months, six months, or 12 months after administering the first dose.

[0393] Clause 68. The method of any one of clauses 41 to 67, wherein after the administration, the compound or the pharmaceutical composition can achieve a brain to plasma ratio of greater than 0.1, greater than 0.2, greater than 0.3, greater than 0.4, greater than 0.5, greater than 0.6, greater than 0.7, greater than 0.8, greater than 0.9, greater than 1.0, greater than 1.1, greater than 1.2, greater than 1.3, greater than 1.4, greater than 1.5, greater than 1.6, greater than 1.7, greater than 1.8, greater than 1.9, or greater than 2.0.

[0394] Clause 69. The method of any one of clauses 41 to 68, further comprising administering to the subject an additional therapeutic agent.

[0395] Clause 70. The method of clause 69, wherein the additional therapeutic agent comprises a standard care of treatment.

[0396] Clause 71. The method of clause 69 or 70, wherein the additional therapeutic agent comprises an immunomodulatory agent.

[0397] Clause 72. The method of clause 71, wherein the additional therapeutic agent is selected from interferon beta-1b, interferon beta-1a, peginterferon beta-1a, alemtuzumab, natalizumab, ocrelizumab, ofatumumab, glatiramer acetate, teriflunomide, dimethyl fumarate, monomethyl fumarate, diroximel fumarate, fingolimod hydrochloride, siponimod fumaric acid, ozanimod hydrochloride, BTK inhibitor, or a pharmaceutically acceptable salt thereof

[0398] Clause 73. The method of any one of clauses 69 to 72, wherein the additional therapeutic agent is administered to the subject prior to, concurrently, or after the administration of the compound or the pharmaceutical composition.

[0399] Clause 74. A method of inducing the differentiation of an oligodendrocyte progenitor cell (OPC) into an oligodendrocyte, the method comprising contacting the OPC with an effective amount of the compound of any one of clauses 1 to 37 or the pharmaceutical composition of clause 38.

[0400] Clause 75. The method of clause 74, wherein inducing the differentiation of the OPC into an oligodendrocyte results in an increase in the expression of the following markers in the subject: GPR17, MBP, ASPA, GST-pi, CC1, myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein / claudin-11, CNPase, or a combination thereof.

[0401] Clause 76. The method of clause 74 or 75, wherein the differentiation of the OPC into an oligodendrocyte is measured by determining the expression of GPR17, MBP, ASPA, GST-pi, CC1, myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte- specific protein / claudin-11, CNPase, or a combination thereof.

[0402] Clause 77. A method of inhibiting PDGFRα activity in a cell, the method comprising contacting the cell with an effective amount of the compound of any one of clauses 1 to 37 or the pharmaceutical composition of clause 38.

[0403] Clause 78. The method of clause 77, wherein the inhibition of the PDGFRα activity is measured by one or more of the following: an in vitro OPC differentiation assay (e.g., as described in Example 132), a cuprizone model for demyelination (e.g., as described in Example 134), an in vivo OPC differentiation assay (e.g., as described in Example 134), an enzymatic PDGFRα kinase assay (e.g., as described in Example 131), or any combination thereof.

[0404] Clause 79. The method of any one of clauses 74 to 78, wherein the contacting occurs ex vivo or in vivo.

[0405] Clause 80. The method of any one of clauses 74 to 79, wherein the method is a method of treating by a therapy.

[0406] Clause 81. A method of treating a relapsing form of multiple sclerosis in a subject in need thereof, the method comprising administering to the subject an effectiveamount of the compound of any one of clauses 1 to 37 or the pharmaceutical composition of clause 38.

[0407] Clause 82. The method of clause 81, wherein inducing the differentiation of the OPC into an oligodendrocyte results in an increase in the expression of the following marker in the subject: GPR17, MBP, ASPA, GST-pi, CC1, myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein / claudin-11, CNPase, or a combination thereof.

[0408] Clause 83. The method of clause 81 or 82, wherein the differentiation of the OPC into an oligodendrocyte is measured by determining the expression of GPR17, MBP, ASPA, GST-pi, CC1, myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte- specific protein / claudin-11, CNPase, or a combination thereof.

[0409] Clause 84. The method of any one of clauses 81 to 83, wherein the relapsing form of multiple sclerosis comprises a clinically isolated syndrome ("CIS"), relapsing- remitting MS ("RRMS"), secondary progressive MS ("SPMS"), primary progressive MS ("PPMS"), or transverse myelitis.

[0410] Clause 85. The compound of any one of clauses 1 to 37 or the pharmaceutical composition of clause 38, for use in a method of one or more of the following: (i) promote the differentiation of an OPC into an oligodendrocyte, (ii) promote the expression of a protein associated with oligodendrocyte differentiation and / or myelination (e.g., G-protein coupled receptor 17, myelin basic protein (MBP), ASPA, GST-pi, CC1, myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein / claudin-11, CNPase, or a combination thereof), (iii) promote the myelination of an axon, (iv) promote the remyelination of a demyelinated axon, (v) inhibit PDGFRα kinase activity, (vi) achieve a brain to plasma ratio of greater than 0.1 when systemically administered to a subject, and (vii) any combination thereof.

[0411] Clause 86. A method of treating a PDGF-associated tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of clauses 1 to 37 or the pharmaceutical composition of clause 38, wherein after the administration, PDGFRα activity is reduced in the subject.

[0412] Clause 87. The method of clause 86, wherein the PDGF-associated tumor comprises an oligodendroglioma.

[0413] Clause 88. The method of clause 86 or 87, wherein the method is a method of treatment by therapy.

[0414] The specification is most thoroughly understood in light of the teachings of the references cited within the specification. The embodiments within the specification provide an illustration of embodiments and should not be construed to limit the scope. The skilled artisan readily recognizes that many other embodiments are encompassed. All publications and patents cited in this disclosure are incorporated by reference in their entirety. To the extent the material incorporated by reference contradicts or is inconsistent with this specification, the specification will supersede any such material. The citation of any references herein is not an admission that such references are prior art.

[0415] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification, including claims, are to be understood as being modified in all instances by the term "about." Accordingly, unless otherwise indicated to the contrary, the numerical parameters are approximations and can vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

[0416] The following examples are offered by way of illustration and not by way of limitation. The contents of all references cited throughout this application are expressly incorporated herein by reference. EXAMPLES

[0417] As further detailed below, the present disclosure demonstrates that compounds that inhibit PDGFRα kinase activity in OPCs can induce oligodendrocyte differentiation (e.g., in vitro and in vivo), and that the effect is likely specific to the inhibition of PDGFRα kinase activity. Furthermore, the present disclosure demonstrates that such compounds can induce remyelination in an animal model of demyelination.

[0418] Table 3 below defines the different abbreviations used in the below examples and else wherein the present disclosure.Table 3. Abbreviationse

[0419] In general, for compounds having stereoisomers that were separated, e.g., using chiral chromatography, the absolute stereochemistry of each compound was arbitrarily assigned. Preparation of Compounds for Synthesis of Exemplary PDGFRα Inhibitors

[0420] To synthesize the exemplary compounds disclosed herein, intermediate compounds were first prepared as described below. Synthesis of 3-bromo-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine (Compound S3)Step 1. Preparation of 5-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-ol

[0421] To a solution of 5-chloropyridazin-3-ol (1.00 g, 7.66 mmol) and 1-methylpyrazole- 4-boronic acid pinacol ester (1.59 g, 7.66 mmol) in dioxane (18 mL) was added 2M Na2CO3(15.3 mL, 30.6 mmol). The biphasic mixture was sparged for 10 min with argon then Pd(dppf)Cl2(0.28 g, 0.38 mmol) was added. The reaction was sparged with argon for 10 min, then heated to 75 °C for 6 h under an argon. The reaction was cooled to rt and stirred overnight. The mixture was concentrated under reduced pressure then water (30 mL) was added. The aqueous mixture was extracted with 10% EtOH in EtOAc (4 x 50 mL) and 50% EtOAc in THF (3 x 50 mL). Brine (30 mL) was added to the aqueous layer, then extracted with 10% EtOH in EtOAc (3 x 50 mL). The organic layers were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by silica gel chromatography eluting with 0-10% MeOH in DCM to afford 0.93 g (69%) of 5-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-ol as a pale yellow solid. MS (ESI) m / z [M+H]+calcd. for C8H9N4O, 171.1; found, 171.0.Step 2. Preparation of 3-chloro-5-(1-methyl-1H-pyrazol-4-yl)pyridazine

[0422] 5-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-ol (6.0 g, 30 mmol, as prepared in the previous step) was treated with POCl3(75 mL, 0.80 mol). The suspension was warmed at 80 °C for 1.5 h. The reaction was cooled to rt and the excess POCl3was removed in vacuo. Toluene was added to the residue then the solvent was removed under reduced pressure. This was repeated twice more. The residue was slowly treated with ice water (350 mL) then solid NaHCO3was slowly added to adjust the pH to 8. The reaction was stirred for 30 min, then extracted with 10% MeOH in DCM (2 x 200 mL). The aqueous layer was diluted with water (100 mL) and extracted with 10% MeOH in DCM (2 x 200 mL) and 10% trifluoroethanol in DCM (3 x 200 mL). The organic layers were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-100% of 5% MeOH in DCM solution / DCM to afford 5.14 g (87%) of 3-chloro-5-(1-methyl-1H-pyrazol-4- yl)pyridazine as a white solid. MS (ESI) m / z [M+H]+calcd. for C8H8ClN4, 195.0; found, 195.0. Step 3. Preparation of N-(2,2-dimethoxyethyl)-5-(1-methyl-1H-pyrazol-4-yl)pyridazin-3- amine

[0423] A suspension of 3-chloro-5-(1-methyl-1H-pyrazol-4-yl)pyridazine (5.10 g, 26.2 mmol, as prepared in the previous step) and aminoacetaldehyde dimethyl acetal (29 mL, 0.27 mol) was warmed in an oil bath at 120 °C for 20 h, then additional aminoacetaldehyde dimethyl acetal (15 mL, 0.14 mol) was added. The reaction was stirred at 120 °C for 27 h, then cooled to rt, and concentrated under reduced pressure. The residue was partitioned between sat. aqueous NaHCO3(100 mL) and 10% MeOH in DCM (100 mL). The aqueous layer was washed with 10% MeOH in DCM (4 x 100 mL). The organic layers were combined, dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated underreduced pressure then the residue was purified by silica gel chromatography eluting with 0-100% of 10% MeOH in DCM solution / DCM to afford 6.56 g (95%) of N-(2,2- dimethoxyethyl)-5-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-amine as a tan solid. MS (ESI) m / z [M+H]+calcd. for C12H18N5O2, 264.2; found, 264.0. Step 4.7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine

[0424] Conc. H2SO4(52 mL) was cautiously added to N-(2,2-dimethoxyethyl)-5-(1- methyl-1H-pyrazol-4-yl)pyridazin-3-amine (15.7 g, 59.6 mmol, as prepared in the previous step) while stirring. After 15 minutes, the reaction was cooled in an ice bath and 1M NaOH (100 mL) was carefully added to the reaction. 50% NaOH (approx. 210 mL) was slowly added to the cold reaction until basic (pH 12). The pH was adjusted to pH 8 with slow addition of 1M H2SO4. The reaction was partitioned between DCM (400 mL) and water (1200 mL). The aqueous layer was washed with DCM (2 x 300 mL). The aqueous layer containing an emulsion was filtered through a pad of Celite. The filter pad was washed with DCM which was then used to wash the aqueous layer (2 x 300 mL). The filter pad was then washed with 10% MeOH in DCM that was in turn used to wash the aqueous layer (4 x 300 mL). The aqueous layer was washed again with 10% MeOH in DCM (4 x 100 mL) or until no product was evident in the aqueous layer by HPLC. The organic layers were combined, dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 10.5 g (89%) of 7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine as a tan solid. MS (ESI) m / z [M+H]+calcd. for C10H10N5, 200.1; found, 200.0. Step 5. Preparation of 3-bromo-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine (Compound S3)

[0425] A solution of 7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine (2.98 g, 15.0 mmol, as prepared in the previous step) in DMF (85.0 mL) was cooled in an ice bath thenNBS (2.93 g, 16.4 mmol) was added. The reaction was stirred at 0°C for 2.5 h, then was poured into a solution of sat. aqueous Na2S2O3 (28.6 mL, 112 mmol) and sat. aqueous NaHCO3(66.1 mL, 68.3 mmol). The reaction was diluted with water (120 mL). The ice bath was removed, and the reaction allowed to warm to rt. After stirring 1 h, the reaction was further diluted with water (270 mL). The solids were filtered off, washed with water (2 x 45 mL) and dried under a nitrogen press to afford 3.80 g (91%) of 3-bromo-7-(1- methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine (Compound S3) as a yellow solid. (400 MHz, DMSO-d6) δ (ppm) 9.00 (d, J=1.96 Hz, 1H) 8.45 (s, 1H) 8.33 (d, J=2.08 Hz, 1H) 8.17 (s, 1H) 7.85 (s, 1H) 3.90 (s, 3H); MS (ESI) m / z [M+H]+calcd. for C10H9BrN5, 278.0; found, 277.9; HPLC purity: 210 nm: 97.9%; 254 nm: 97.5%. Synthesis of O-(mesitylsulfonyl)hydroxylamine (Compound S4)

[0426] To a solution of ethyl N-hydroxyacetimidate (40.0 g, 329.2 mmol) and 2,4,6- trimethylbenzenesulfonyl chloride (40.0 g, 182.8 mmol) in DMF (300 mL) was added TEA (27.7 g, 274.3 mmol) dropwise at rt then the mixture was stirred at rt for 2 h. The reaction was poured into ice water (900 mL) then the mixture was filtered, and the filter cake was washed with H2O (3 x 200 mL) and dried under reduced pressure. The solids were dissolved in dioxane (26 mL), then solution was cooled to 0°C, then HClO4 (16 mL) was added dropwise at 0°C. After completion of addition, the mixture was stirred at 0°C for 30 min, then poured into ice water (400 mL). The mixture was filtered, then the filter cake was washed with H2O (3 x 200 mL). The solids were dissolved in DCM (200 mL) to afford a DCM solution of O-(mesitylsulfonyl)hydroxylamine (Compound S4). Synthesis of 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Compound S5)Step 1. Synthesis of 1-amino-3-bromopyrazin-1-ium 2,4,6-trimethylbenzenesulfonate

[0427] To a solution of 2-bromopyrazine (22.0 g, 138.3 mmol) in DCM (154 mL) was added a solution of O-(mesitylsulfonyl)hydroxylamine (Compound S4) (38.6 g, 179.8 mmol) in DCM (308 mL) dropwise at rt, then the mixture was stirred at rt overnight. The reaction was concentrated under reduced pressure then the residue was triturated with MTBE (100 mL) and dried under reduced pressure to afford 34.0 g (66%) of 1-amino-3- bromopyrazin-1-ium 2,4,6-trimethylbenzenesulfonate as a black solid. Step 2. Synthesis of ethyl 6-bromopyrazolo[1,5-a]pyrazine-3-carboxylate

[0428] To a solution of K2CO3(12.4 g, 97.4 mmol) and ethyl propiolate (27.0 g, 108.2 mmol) in DMF (270 mL) was added 1-amino-3-bromopyrazin-1-ium 2,4,6- trimethylbenzenesulfonate (27.0 g, 72.1 mmol, as prepared in the previous step) in portions at rt, then the reaction mixture was stirred at rt overnight. The mixture was diluted with H2O, the mixture was extracted with MTBE (3 x 200 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography to afford 2.0 g (10%) of ethyl 6-bromopyrazolo[1,5-a]pyrazine-3- carboxylate as a yellow solid.1H NMR (400 MHz, CDCl3) δ (ppm) 9.41 (s, 1H), 8.66 (d, J=0.8Hz, 1H), 8.46 (s, 1H), 4.45 (q, J=7.2 Hz, 2H), 1.45 (t, J=7.2Hz, 3H). Step 3. Synthesis of ethyl 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3- carboxylate

[0429] To a mixture of ethyl 6-bromopyrazolo[1,5-a]pyrazine-3-carboxylate (5.0 g, 18.5 mmol, as prepared in the previous step) in dioxane (80 mL) and water (20 mL) was added1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.7g, 27.7 mmol), Na2CO3(5.7 g, 55.4 mmol), and Pd(dppf)Cl2(1.0 g) under nitrogen. The mixture was heated to reflux and stirred under nitrogen for 2.5 h. The mixture was cooled to rt and filtered. The filtrate was poured into cold water, extracted with DCM / MeOH (10 / 1) ten times, the organic phase was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography to afford 3.5 g (70%) of ethyl 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazine-3-carboxylate as a yellow solid.1H NMR (400 MHz, CDCl3) δ (ppm) 9.56 (d, J=1.6 Hz, 1H), 8.59 (d, J=1.2 Hz, 1H), 8.45 (s, 1H), 7.96 (d, J=7.2 Hz, 2H), 4.45 (q, J=7.2Hz, 2H), 4.01 (s, 3H), 1.46 (t, J=7.2 Hz, 3H). Step 4. Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine

[0430] To a mixture of ethyl 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3- carboxylate (3.5 g, 12.9 mmol, as prepared in the previous step) in 40% aqueous H2SO4(35 mL) was stirred at 100°C overnight, then the mixture was poured into water, and the pH was adjusted to 8 with aqueous NaOH. The precipitate was isolated by filtration, the filter cake was washed with water, and dried to afford 1.7 g (66%) of 6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazine as yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.19 (d, J=1.6 Hz, 1H), 9.14 (d, J=0.8 Hz, 1H), 8.26 (s, 1H), 8.12 (d, J=2.4 Hz, 1H), 8.05 (s, 1H), 6.956 (dd, J=0.8, 2.4Hz, 1H), 3.89 (s, 3H). Step 5. Synthesis of 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Compound S5)

[0431] To a mixture of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (1.0 g, 5.0 mmol, as prepared in the previous step) in DMF (30 mL) was added NBS (1.76 g, 5.0 mmol) in portions. The mixture was stirred at rt for 1 h, poured into water, and extracted with EtOAc three times. The combined organic phase was washed with water and brine,dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with DCM / MeOH from 1:0 to 100:1 to afford 600 mg (43%) of 3-bromo-6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Compound S5) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.19 (d, J=1.2 Hz, 1H), 9.09 (d, J=1.2 Hz, 1H), 8.28 (s, 2H), 8.07 (s, 1H), 3.90 (s, 3H). Synthesis of 3-bromo-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine (Compound S7)Step 1. Synthesis of 7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine

[0432] To a mixture of 7-bromoimidazo[1,2-a]pyridine (4.5 g, 22.8 mmol) in dioxane (100 mL) and H2O (20 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazole (7.1 g, 34.3 mmol), Na2CO3(5.3 g, 50.3 mmol), and Pd(dppf)Cl2(0.9 g) under nitrogen. The mixture was heated to reflux and stirred under nitrogen for 6 h. The mixture was cooled to rt and filtered. The filtrate was poured into cold water, extracted with DCM / MeOH (10 / 1) ten times, then the combined organic phase was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by silica gel chromatography to afford 3.4 g (75%) of 7-(1-methyl- 1H-pyrazol-4-yl)imidazo[1,2-a]pyridine as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.50 (d, J=7.2Hz, 1H), 8.29 (s, 1H), 8.03 (s, 1H), 7.86 (s, 1H), 7.76 (s, 1H), 7.52 (s,1H), 7.14 - 7.16 (m, 1H), 3.88 (s, 3H).Step 2. Synthesis of 3-bromo-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine (Compound S7)

[0433] To a mixture of 7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine (4.1 g, 20.7 mmol, as prepared in the previous step) in ACN (120 mL) was added NBS (3.7 g, 20.7 mmol) in portions. The mixture was stirred at rt for 2 h, poured into water and extracted with DCM / MeOH (10 / 1) ten times. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by silica gel chromatography to afford 2.2 g (39%) of 3-bromo-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine (Compound S7) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.36 (s, 1H), 8.29 (d, J=7.2Hz, 1H), 8.08 (s, 1H), 7.85 (s, 1H), 7.67 (s, 1H), 7.32 - 7.35 (m, 1H), 3.88 (s, 3H). Synthesis of 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-b]pyridazine (Compound S8)Step 1. Synthesis of 1-amino-3-bromopyridazin-1-ium 2,4,6-trimethylbenzenesulfonate

[0434] To a solution of 3-bromopyridazine (20.0 g, 125.7 mmol) in DCM (300 mL) was added the solution of O-(mesitylsulfonyl)hydroxylamine (Compound S4) (35.1 g, 125.7 mmol) in DCM (300 mL) dropwise at rt then the reaction mixture was stirred overnight at rt. The mixture was concentrated under reduced pressure then the residue was triturated with MTBE (80 mL) and filtered to afford 24.0 g (51%) of 1-amino-3-bromopyridazin-1- ium 2,4,6-trimethylbenzenesulfonate as black solid.Step 2. Synthesis of ethyl 6-bromopyrazolo[1,5-b]pyridazine-3-carboxylate

[0435] To a solution of K2CO3(12.4 g, 89.8 mmol) and ethyl propiolate (7.5 g, 77.0 mmol) in DMF (230 mL) was added 1-amino-3-bromopyridazin-1-ium 2,4,6- trimethylbenzenesulfonate (24.0 g, 64.1 mmol, as prepared in the previous step) in portions at rt then the reaction mixture was stirred overnight at rt. The mixture was diluted with H2O and extracted with MTBE (3x200 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by chromatography to afford 2.2 g (13%) of ethyl 6-bromopyrazolo[1,5-b]pyridazine-3-carboxylate as a yellow solid.1H NMR (400 MHz, CDCl3) δ (ppm) 8.40-8.44 (m, 2H), 7.40 (d, J=9.6 Hz, 1H), 4.43 (q, J=7.2 Hz, 2H), 1.44 (t, J=7.2 Hz, 3H). Step 3. Synthesis of ethyl 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-b]pyridazine-3- carboxylate

[0436] To a mixture of ethyl 6-bromopyrazolo[1,5-b]pyridazine-3-carboxylate (9.0 g, 33.3 mmol, as prepared in the previous step) in dioxane (144 mL) and water (36 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10.4 g, 49.9 mmol), Na2CO3(10.6g, 99.9 mmol), and Pd(dppf)Cl2(1.0 g) under nitrogen. The mixture was heated to reflux and stirred under nitrogen for 2 h. The mixture was cooled to rt and filtered. The filtrate was poured into cold water and extracted with DCM / MeOH (10 / 1) ten times. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by silica gel chromatography to afford 9 g (99%) of ethyl 6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-b]pyridazine-3-carboxylate as a yellow solid.1H NMR (400 MHz, CDCl3) δ (ppm) 8.48 (d, J=9.2 Hz, 1H), 8.42(s, 1H), 8.06 (d, J=4.4 Hz, 1H), 7.45 (d, J=9.2Hz, 1H), 7.86 (s, 1H), 4.43 (q, J=7.2 Hz, 2H), 4.03 (s, 3H), 1.45 (t, J=7.2 Hz, 3H).Step 4. Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-b]pyridazine

[0437] To a mixture of ethyl 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-b]pyridazine-3- carboxylate (4.5 g, 16.6 mmol, as prepared in the previous step) in 40% aqueous H2SO4(45 mL) was stirred at 100°C overnight, then the mixture was poured into water and extracted with DCM / MeOH (10 / 1) ten times. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was washed with MTBE to afford 2.5 g (76%) of 6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-b]pyridazine as a yellow solid.1H NMR (400 MHz, CDCl3) δ (ppm) 8.04 (d, J=7.2 Hz, 2H), 7.98 (d, J=2.4 Hz, 1H), 7.93 (d, J=9.6 Hz, 1H), 7.21 (d, J=9.2 Hz, 1H), 6.61 (d, J=2.4 Hz, 1H), 4.00 (s, 3H). Step 5. Synthesis of 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-b]pyridazine (Compound S8)

[0438] To a mixture of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-b]pyridazine (2.5 g, 12.5 mmol, as prepared in the previous step) in ACN (50 mL) was added NBS (2.2 g, 12.5 mmol) in portions. The mixture was stirred at rt for 1 h, then poured into water and extracted with DCM / MeOH (10 / 1) ten times. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 2.5 g (71%) of 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- b]pyridazine (Compound S8) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.51 (s, 1H), 8.14-8.19 (m, 3H), 7.65 (d, J=9.6Hz, 1H), 3.93 (s, 3H).Synthesis of 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (Compound S9)Step 1. Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

[0439] To a mixture of 6-bromopyrazolo[1,5-a]pyridine (4.5 g, 22.8 mmol) in dioxane (90 mL) and water (18 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazole (7.1 g, 34.2 mmol), Na2CO3(7.2g, 68.8 mmol), and Pd(dppf)Cl2(0.45 g) under nitrogen. The mixture was heated to reflux and stirred under nitrogen for 3 h. The mixture was cooled to rt and filtered. The filtrate was poured into cold water and extracted with DCM / MeOH (10 / 1) ten times. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by silica gel chromatography to afford 3.5 g (78%) of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine as a yellow solid.1H NMR (400 MHz, CDCl3) δ (ppm) 8.61 (s, 1H), 7.95(d, J=1.6 Hz, 1H), 7.77 (s, 1H), 7.63 (s, 1H), 7.57 (d, J=9.2 Hz, 1H), 7.23-7.26 (m,1H), 6.52 (d, J=1.6 Hz, 1H), 3.99 (s, 3H). Step 2. Synthesis of 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (Compound S9)

[0440] To a mixture of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (4.0 g, 20.2 mmol, as prepared in the previous step) in ACN (80 mL) was added NBS (4.3 g, 24.2 mmol) in portions. The mixture was stirred at rt for 1 h, then poured into water and extracted with DCM / MeOH (10 / 1) ten times. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressurethen the residue was purified by silica gel chromatography to afford 2.5 g (45%) of 3- bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (Compound S9) as a yellow solid.1H NMR (400 MHz, CDCl3) δ (ppm) 8.55 (s, 1H), 7.92 (s, 1H), 7.77 (s, 1H), 7.65 (s, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.53 (dd, J=0.8, 9.2 Hz, 1H), 4.00 (s, 3H). Synthesis of 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine (Compound S10)Step 1. Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine

[0441] To a mixture of 6-bromopyrazolo[1,5-a]pyrimidine (4.5 g, 22.7 mmol) in dioxane (90 mL) and water (18 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (7.0 g, 34.1 mmol), Na2CO3(7.2g, 68.1 mmol), and Pd(dppf)Cl2(0.45 g) under nitrogen. The mixture was heated to reflux and stirred under nitrogen for 3 h. The mixture was cooled to at rt and filtered. The filtrate was poured into cold water and extracted with DCM / MeOH (10 / 1) ten times. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by silica gel chromatography to afford 3.5 g (78%) of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine as a yellow solid.1H NMR (400 MHz, CDCl3) δ (ppm) 8.75-8.76 (m, 1H), 8.64 (d, J=2 Hz, 1H), 8.12 (d, J=2.4 Hz, 1H), 7.80 (s, 1H), 7.70 (s, 1H), 6.72-6.73 (m,1H), 4.02 (s, 3H).Step 2. Synthesis of 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine (Compound S10)

[0442] To a mixture of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine (7.0 g, 35.1 mmol, as prepared in the previous step) in ACN (140 mL) was added NBS (7.5 g, 42.1 mmol) in portions. The mixture was stirred at rt for 1 h, poured into water and extracted with DCM / MeOH (10 / 1) ten times. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by silica gel chromatography to afford 5 g (51%) of 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine (Compound S10) as a yellow solid.1H NMR (400 MHz, CDCl3) δ (ppm) 8.72-8.69 (m, 2H), 8.10 (s, 1H), 7.79 (s, 1H), 7.72 (s, 1H), 4.02 (s, 3H). Synthesis of tert-butyl 4-[6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3- yl]piperazine-1-carboxylate (Compound 11)

[0443] To a round bottom flask containing 3-bromo-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine (Compound S9) (4.00 g, 14.4 mmol) and tert-butyl-1- piperazinecarboxylate (3.23 g, 17.3 mmol) was added tBuOH (202 mL) and dioxane (124 mL). The solution was sparged with nitrogen for 20 min at 25°C. To the solution was added tBuXPhos Pd G1 (248 mg, 5.41 mmol) and NaOtBu (520 mg, 0.54 mmol) and the reaction mixture was sparged with nitrogen for an additional 10 min at 25°C. The flask was heated in a 55°C bath for 1.5 h, cooled to rt and diluted with EtOAc. The mixture was washed with H2O and brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by silica gel chromatography eluting with 10-90% EtOAc / DCM. The solids obtained were dried under reduced pressure to afford 1.62 g (29%) of tert-butyl 4-[6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3- yl]piperazine-1-carboxylate (Compound 11) as a yellow solid.1H NMR (400 MHz, CDCl3)δ (ppm) 8.46 (s, 1H), 7.74 (s, 1H), 7.70 (s, 1H), 7.63 (s, 1H), 7.50 (d, J = 7.3 Hz, 1H), 7.14 (d, J = 1.47 Hz, 1H), 4.03-4.01 (m, 4H), 3.98 (s, 3H), 3.64 (m, 4H), 3.02 (m, 4H), 1.50 (s, 9H); MS (ESI) m / z [M+H]+calcd. for C20H27N6O2, 383.2; found, 383.3; HPLC purity: 210 nm: 99.4%; 254 nm: 99.2%. Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)-3-piperazin-1-ylpyrazolo[1,5-a]pyridine (Compound 12)

[0444] To a round bottom flask containing tert-butyl 4-[6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-3-yl]piperazine-1-carboxylate (Compound 11) (0.340 g, 0.89 mmol) was added DCM (6.80 mL) then the solution was cooled on an ice bath and TFA (1.70 mL, 22.1 mmol) was added slowly. After 1 h the solvent was removed under reduced pressure, then MTBE was added to the residue and concentrated under reduced pressure to remove excess TFA. The residue was dissolved in DCM and swirled with sat. aqueous NaHCO3, diluted with H2O, and diluted with MTBE. The aqueous layer was washed with MTBE then extracted with DCM. The DCM layer was dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure to afford 105 mg (42%) of 6- (1-methyl-1H-pyrazol-4-yl)-3-piperazin-1-ylpyrazolo[1,5-a]pyridine (Compound 12) as a yellow solid.1H NMR (400 MHz, CDCl3) δ (ppm) 8.45 (s, 1H), 7.74 (s, 1H), 7.70 (s, 1H), 7.60 (s, 1H), 7.52 (d, J = 9.17 Hz, 1H), 7.11 (d, J = 9.05 Hz, 1H), 3.97 (s, 3H), 3.08 (bs, 5H), 3.06 (bs, 4H); MS (ESI+, m / z): Calcd. for C15H19N6: 283.2. Found: 283.1; HPLC purity: 210 nm: 100%; 254 nm: 100%. Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)-3-piperazin-1-ylpyrazolo[1,5-a]pyridine dihydrochloride salt (Compound S19)

[0445] To a round bottom flask containing tert-butyl 4-[6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-3-yl]piperazine-1-carboxylate (Compound 11) (0.250 g, 0.65 mmol) was added MeOH (5.00 mL) and 4M HCl in dioxane (2 mL). The reaction wasstirred at 27°C for 24 h, then stirred another 5 h at 24°C. The mixture was filtered through a frit, and the solid was rinsed with MeOH (5 mL). The solid was dried under reduced pressure to afford 227 mg (98%) of 6-(1-methyl-1H-pyrazol-4-yl)-3-piperazin-1- ylpyrazolo[1,5-a]pyridine dihydrochloride salt (Compound S19) as a light gray solid. MS (ESI) m / z [M+H]+calcd. for C15H21Cl2N6, 283.2; found, 283.2. Synthesis of di-tert-butyl 4,4'-(1,2-bis(1H-benzo[d][1,2,3]triazol-1-yl)ethane-1,2- diyl)bis(piperazine-1-carboxylate) (Compound S47)

[0446] A solution of 1H-1,2,3-benzotriazole (19.2 g, 161.1 mmol) and tert-butyl piperazine-1-carboxylate (30.0 g, 161.1 mmol) in EtOH (300 mL) was stirred under nitrogen at 25℃ for 20 min. Then glyoxal (40 wt.% in H2O, 4.7 g, 80.5 mmol) was added to the mixture at 25℃. The reaction mixture was stirred at 30℃ for 16 h. The reaction mixture was concentrated under reduced pressure then PE was added. The mixture was stirred for 30 min and filtered, the filter cake was dried to afford 42.0 g (32%) of di-tert- butyl 4,4'-(1,2-bis(1H-benzo[d][1,2,3]triazol-1-yl)ethane-1,2-diyl)bis(piperazine-1- carboxylate (Compound S47) as a white solid.

[0447] Using the procedures described for Compound S47 and reagents, starting materials, and conditions known to those skilled in the art, the following compounds representative of the present disclosure were prepared:Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-amine (Compound S56)Step 1. Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)-3-nitropyrazolo[1,5-a]pyridine

[0448] To a solution of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (4.0 g, 5.05 mmol, as prepared in Compound S9, Step 1) dissolved in conc. H2SO4(10 mL) was added KNO3 (2.24 g, 5.55 mmol). The reaction mixture was stirred for 1 h at rt under nitrogen. The mixture was cooled to 0°C and diluted with water (300 mL). The mixture was neutralized to pH 8 with sat. aqueous Na2CO3. The precipitated solids were collected by filtration and washed with water (3x300 mL). The filter cake was dried under reduced pressure to afford 3.5 g (71%) of 6-(1-methyl-1H-pyrazol-4-yl)-3-nitropyrazolo[1,5- a]pyridine as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.34 (s, 1H), 8.90 (s, 1H), 8.38 (s, 1H), 8.24 (d, J = 9.1 Hz, 1H), 8.15 (d, J = 9.3 Hz, 1H), 8.11 (s, 1H), 3.90 (s, 3H); MS (ESI) m / z [M+H]+calcd. for C11H9N5O2, 244.1; found, 244.1. Step 2. Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-amine (Compound S56)

[0449] To a solution of 6-(1-methyl-1H-pyrazol-4-yl)-3-nitropyrazolo[1,5-a]pyridine (3.0 g, 12.33 mmol, as prepared in the previous step) dissolved in aqueous HBr (50 mL) was added SnCl2·2H2O (8.42 g, 37.0 mmol). The resulting solution was stirred for 4 h at 90°C under nitrogen. The mixture was cooled to rt, the pH was adjusted to pH 9 with aqueous NaOH, and extracted with EtOAc (3 x 500 mL). The combined organic extracts were washed with brine (3x100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 2.5 g (90%) of 6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-3-amine (Compound S56) as a yellow-brown solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.63 (s, 1H), 8.15 (s, 1H), 7.92 (s, 1H), 7.59 (d, J = 9.2 Hz, 1H), 7.44 (s, 1H), 7.11 (d, J = 9.2 Hz, 1H), 4.33 (s, 2H), 3.86 (s, 3H); MS (ESI) m / z [M+H]+calcd. for C11H11N5, 214.1; found, 214.1.Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazolo[1,5-a]pyridine (Compound S57)Step 1. Preparation of 3-iodo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine

[0450] To a solution of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (7.0 g, 35.3 mmol, as prepared in Compound S9, Step 1) in DMF (70 mL) was added NIS (9.53 g, 42.4 mmol). The resulting mixture was stirred for 1 h at rt. The reaction was poured into a stirred mixture of 2.8M aqueous Na2S2O3 (64 mL) and 1.14M aqueous NaHCO3(144 mL). The mixture was stirred vigorously for 1 h resulting in an off-white precipitate. The solids were collected by filtration, washed with H2O (2 x 10 mL), and dried under high vacuum to afford 10 g (79%) of 3-iodo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine as a white solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.06 (s, 1H), 8.28 (s, 1H), 8.08 (s, 1H), 8.02 (d, J = 0.8 Hz, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.52 (d, J = 9.2 Hz, 1H), 3.88 (s, 3H).; MS (ESI) m / z [M+H]+calcd. for C11H9IN4, 325.0; found, 325.1. Step 2. Preparation of 6-(1-methyl-1H-pyrazol-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (Compound S57)

[0451] To a solution of 3-iodo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (9.0 g, 27.8 mmol, as prepared in the previous step) in THF (180 mL) was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (17.1 g, 91.7 mmol) then cooled to 0°C under nitrogen and 1.3M iPrMgCl·LiCl in THF (31.9 mL, 41.7 mmol) was added dropwise. The reaction was stirred for 3 h at 0°C under nitrogen, diluted with DCM (160 mL), and filtered through a pad of silica gel. The pad was washed with EtOAc (100 mL) and the combined filtrates were concentrated under reduced pressure to afford 5.0 g (42%) of 6-(1-methyl- 1H-pyrazol-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (Compound S57) as a grey white solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.08 (s, 1H), 8.26 (s, 1H), 8.12 (s, 1H), 8.01 (d, J = 0.8 Hz, 1H), 7.82 (d, J = 9.1 Hz, 1H), 7.65 (d, J = 9.1 Hz, 1H), 3.89 (s, 3H), 1.32 (s, 12H).; MS (ESI) m / z [M+H]+calcd. for C17H21BN4O2, 325.2; found, 325.2. Synthesis of 2-chloro-5-(pyridin-2-ylmethyl)pyrimidine (Compound S80, Steps 1-2)Step 1. Preparation of potassium pyridine-2-ylacetate

[0452] In dried glassware, a solution of methyl 2-pyridylacetate (0.500 g, 3.31 mmol), absolute ethanol (6.6 mL), and water (0.63 mL, 3.47 mmol) was heated at 60°C. A solution of potassium tert-butoxide (0.390 g, 3.47 mmol) was prepared in absolute ethanol (3.3 mL) in dried glassware, and then added dropwise to the initial solution at 60°C over 30 min. After complete conversion, the solvent was removed under vacuum and the residue was stirred in anhydrous Et2O (6.6 mL) for 30 min. The solids were filtered through a frit and washed in quick sequence with ethanol / ether (1:1, 0.6 mL x2) and Et2O (3 mL x3). The white solid was transferred to a dried flask and placed under vacuum in a 30°C bath for 2 h to afford 468 mg (81%) of potassium pyridine-2-ylacetate as a white solid.1H NMR (400 MHz, DMSO-d6) d (ppm) 8.33 (d, J = 4.3 Hz, 1H) 7.57 (td, J = 7.6, 1.8, 1H) 7.27 (d, J = 7.8 Hz, 1H) 7.06 (dd, J = 6.6, 5.4 Hz 1H) 3.32 (s, 2H);13C NMR (100 MHz, DMSO-d6) d (ppm) 49.5, 119.9, 123.8, 135.1, 147.8, 160.5, 171.5; MS (ESI) m / z [M+H]+calcd. for C7H8NO2: 138.1; found, 138.0.Step 2.2-Chloro-5-(pyridin-2-ylmethyl)pyrimidine (Compound S80)

[0453] 5-Bromo-2-chloropyrimidine (110 mg, 0.590 mmol), Xantphos (22 mg, 0.04 mmol), Pd2(dba)3 (10 mg, 0.01 mmol), potassium pyridin-2-ylacetate (125 mg, 0.713 mmol, as prepared in the previous step), and mesitylene (1.2 mL) were added to a pressure tube that was pre-flushed with argon. It was sparged with more argon, sealed, and heated at 150°C for 24 h. The mixture was cooled to rt and purified by silica gel flash chromatography (acetone with 0.1% Et3N / DCM) to afford 72 mg (59%) of 2-chloro-5- (pyridin-2-ylmethyl)pyrimidine (Compound S80) as an oil.1H NMR (400 MHz, CDCl3) d (ppm) 8.59 (s, 2H) 8.57 (m, 1H) 7.68 (td, J=7.6, 1.8 Hz 1H) 7.21 (m, 2H) 4.13 (s, 2H); MS (ESI) m / z [M+H]+calcd. for C10H9ClN3: 206.5; found, 206.0; HPLC purity: 210 nm: 93.3%; 254 nm: 100.0%. Synthesis of 7-(1-methyl-1H-pyrazol-4-yl)-3-(piperazin-1-yl)imidazo[1,2-b]pyridazine hydrochloride salt (Compound S83)Step 1. Synthesis of tert-butyl 4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3- yl)piperazine-1-carboxylate

[0454] To a 20 mL vial containing 3-bromo-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2- b]pyridazine (Compound S3) (300.4 mg, 1.080 mmol) and tert-butyl 1- piperazinecarboxylate (1.00 g, 5.40 mmol) was added tBuOH (3.0 mL) and dioxane (1.5 mL) then the solution was sparged with argon for 10 min. KOtBu (182 mg, 1.62 mmol) was added and the mixture was sparged again for 10 min with argon. tBuXPhos Pd G1 (111 mg, 0.162 mmol) was added, and the mixture was sparged for 10 min with argon. The mixture was stirred at 55°C under an argon for 1 h. The reaction was cooled to rt, dilutedwith DCM (40 mL), and washed with 10% citric acid solution (3 x 10 mL), H2O (3 x 10 mL), and sat. aqueous NaHCO3(2 x 10 mL). The organic layer was dried over anhydrous Na2SO4and filtered, then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluted with 0-100% (10% MeOH in DCM) / DCM to afford 280.8 mg (68%) of tert-butyl 4-(7-(1-methyl-1H-pyrazol-4- yl)imidazo[1,2-b]pyridazin-3-yl)piperazine-1-carboxylate as a yellow solid.1H NMR (400 MHz, CDCl3) δ (ppm) 8.51 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.84 (s, 1H), 7.75 (s, 1H), 7.25 (s, 1H), 4.00 (s, 3H), 3.75 - 3.64 (m, 4H), 3.29 - 3.20 (m, 4H), 1.51 (s, 9H); MS (ESI) m / z [M+H]+calcd. for C19H25N7O2: 384.2, Found: 384.2; HPLC purity: 210 nm: 97.8%; 254 nm: 100.0%. Step 2. Synthesis of 7-(1-methyl-1H-pyrazol-4-yl)-3-(piperazin-1-yl)imidazo[1,2- b]pyridazine hydrochloride salt (Compound S83)

[0455] A solution of tert-butyl 4-[7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin- 3-yl]piperazine-1-carboxylate (274.5 mg, 0.7159 mmol, as prepared in the previous step) in DCM (30 mL) was cooled to 0°C then a solution of 4M HCl in dioxane (1.8 mL, 7.3 mmol) was added dropwise. After completion of addition, the mixture was warmed to rt and stirred for 7 h. The reaction was concentrated under reduced pressure, then the residue was triturated with ether and filtered. The solid was dried under reduced pressure to afford 214.6 mg (94%) of 7-(1-methyl-1H-pyrazol-4-yl)-3-(piperazin-1-yl)imidazo[1,2- b]pyridazine hydrochloride salt (Compound S83) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.69 (br s, 2H), 9.34 (d, J = 2.0 Hz, 1H), 8.69 (s, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.34 (s, 1H), 7.98 (s, 1H), 3.94 (s, 3H), 3.54 - 3.49 (m, 4H), 3.37 - 3.25 (m, 4H); MS (ESI) m / z [M+H]+calcd. for C14H17N7: 284.2, Found: 284.2; HPLC purity: 210 nm: 95.9%; 254 nm: 100.0%. Synthesis of 5-benzyl-2-chloropyrimidine (Compound S88)

[0456] To a mixture of (2-chloropyrimidin-5-yl)boronic acid (20 g, 0.126 mol) and Na2CO3(40.43 g, 0.381 mol) in dioxane (200 mL) and H2O (80mL) stirred under nitrogen at 25°C was added (Ph3P2PdCl2(4.43 g, 0.0063 mol);benzyl bromide (23.76 g, 0.138 mol) was added after 20 min The reaction mixture was stirred at 100°C for 1 h. The mixture was diluted with water and extracted with EtOAc (3x50mL). The combined organic layers were concentrated under vacuum to give crude product, which was purified by silica gel column eluting with DCM / MeOH (30:1~15:1) to afford 18.18 g (69%) of 5-benzyl-2- chloropyrimidine (Compound S88) as a white solid.1H NMR (400 MHz, CDCl3) δ (ppm) 8.48 (s, 2H), 7.34~7.37 (m, 2H), 7.27~7.31 (m, 1H), 7.19 (d, J=7.2Hz, 2H), 3.98 (s,2H). Synthesis of (R)-1-(4-chlorophenyl)ethyl (2,5-dioxopyrrolidin-1-yl) carbonate (Compound S95)

[0457] To a solution of (1R)-1-(4-chlorophenyl)ethanol (20.00 g, 127.7 mmol) in ACN (240 mL was added di(N-succinimidyl) carbonate (49.07 g, 191.6 mmol) then the mixture was cooled to 0°C. TEA (53 mL, 380 mmol) was added dropwise over 5 min then stirred at 0°C for 30 min. The solution was warmed to rt and stirred overnight, then the mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (250 mL) and washed with sat. aqueous NaHCO3. Additional EtOAc (100 mL) was added, then the organic layer was washed with water and brine, then dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. To the residue was added MTBE (150 mL) and the mixture was heated to 45°C. Hexanes (100 mL) was added hot, then the mixture was allowed to cool with efficient stirring. The solids were isolated by filtration, washed with hexanes (100 mL), and dried under reduced pressure to afford 31.85 g (84%) of (R)-1-(4-chlorophenyl)ethyl (2,5-dioxopyrrolidin-1-yl) carbonate (Compound S95) as a light tan solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.49 (s, 4H), 5.89 (q, J = 6.8 Hz, 1H), 2.80 (s, 4H), 1.62 (d, J = 6.8 Hz, 3H).Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)-3-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine (Compound S98)Step 1. Preparation of tert-butyl 4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidin-3-yl)piperazine-1-carboxylate

[0458] To a vial was added 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine (Compound S10) (0.150 g, 0.539 mmol) and tert-butyl 1- piperazinecarboxylate (0.120 g, 0.647 mmol) followed by tBuOH (1.5 mL) and dioxane (3 mL) then the mixture was sparged with argon for 5 min. NaOtBu (0.0778 g, 0.809 mmol) was added then the mixture was sparged for 5 min with argon. tBuXPhos Pd G1 (37.0 mg, 0.0539 mmol) was added then the mixture was sparged with argon for 5 min. The reaction was heated to 80°C for 2.5 h then additional tBuXPhos Pd G1 (15 mg) was added as a slurry in dioxane (0.5 mL) and the mixture was stirred at 80°C overnight. The reaction was cooled to rt, quenched with sat. aqueous NaHCO3, and extracted with DCM (3x). The combined organic extracts were washed with water, then dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by silica gel chromatography to afford 95 mg (46%) of tert-butyl 4-(6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)piperazine-1-carboxylate as a yellow-orange solid.1H NMR (400 MHz, CDCl3) δ (ppm) 8.58 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 2.4 Hz, 1H), 7.78 (s, 1H), 7.77 (s, 1H), 7.68 (s, 1H), 4.01 (s, 3H), 3.71 – 3.65 (m, 4H), 3.30 – 3.24 (m, 4H), 1.51 (s, 9H). MS (ESI) m / z [M+H]+calcd. for C19H25N7O2, 384.2; found, 384.3.Step 2. Preparation of 6-(1-methyl-1H-pyrazol-4-yl)-3-(piperazin-1-yl)pyrazolo[1,5- a]pyrimidine (Compound S98)

[0459] To a solution of tert-butyl 4-[6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrimidin-3-yl]piperazine-1-carboxylate (0.09 g, 0.2 mmol, as prepared in the previous step) in DCM (2 mL) was added TFA (0.2 mL) and the reaction was stirred at rt overnight. The mixture was diluted with DCM (20 mL) and washed with sat. aqueous NaHCO3(25 mL). The aqueous layer was extracted with DCM (2 x 20 mL) and the combined organic extracts were dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure to afford 65 mg (93%) of 6-(1-methyl-1H-pyrazol-4-yl)-3- (piperazin-1-yl)pyrazolo[1,5-a]pyrimidine (Compound S98) as an orange solid.1H NMR (400 MHz, CDCl3) δ (ppm) 8.58 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 2.4 Hz, 1H), 7.79 (s, 1H), 7.77 (s, 1H), 7.68 (s, 1H), 4.01 (s, 3H), 3.37 – 3.31 (m, 4H), 3.20 – 3.14 (m, 4H). MS (ESI) m / z [M+H]+calcd. for C14H17N7, 284.2; found, 284.1. Synthesis of 5-benzyl-2-pyrrolidin-3-ylpyrimidine (Compound S100)Step 1. Preparation of tert-butyl 3-(5-benzylpyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1- carboxylate

[0460] A mixture of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5- dihydro-1H-pyrrole-1-carboxylate (500.0 mg, 1.69 mmol), 5-benzyl-2-chloropyrimidine (Compound S88) (289 mg, 1.41 mmol) and K3PO4 (599 mg, 2.82 mmol) in dioxane (14.3 mL) and H2O (5.1 mL) was sparged with argon for 20 min. (tBu3P)2Pd (108 mg, 0.21 mmol) was added then the mixture was heated to 80°C for 4 h. The reaction was cooled to rt, diluted with H2O (40 mL), and extracted with EtOAc (2 x 25 mL). The combined organicextracts were washed with H2O (25 mL), dried over anhydrous MgSO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by silica gel chromatography eluting with 20-30% EtOAc / hexanes to afford 420 mg (88%) of tert-butyl 3-(5-benzylpyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate as a white solid.1H NMR (400 MHz, CDCl3) δ (ppm) 8.56 (s, 2H), 7.31 - 7.39 (m, 2H), 7.24 - 7.31 (m, 1H), 7.20 (d, J=6.97 Hz, 2H), 6.83 - 6.95 (m, 1H), 4.53 - 4.69 (m, 2H), 4.33 - 4.49 (m, 2H), 3.89 - 4.03 (m, 2 H), 1.53 (s, 9H); MS (ESI) m / z [M+H]+calcd. for C20H24N3O2: 338.2; found, 338.3; HPLC purity 210 nm: 98.3%; 254 nm: 100.0%. Step 2. Preparation of tert-butyl 3-(5-benzylpyrimidin-2-yl)pyrrolidine-1-carboxylate

[0461] To a solution of tert-butyl 3-(5-benzylpyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1- carboxylate (437 mg, 1.30 mmol, as prepared in the previous step) in EtOAc (20 mL) was added 10% Pd / C (100 mg, 50% H2O). The reaction flask was evacuated and filled with hydrogen gas three times and allowed to stir under an atmosphere of hydrogen. After 19 h, the reaction mixture was filtered through a pad of celite, and the pad was washed with an additional 40 mL of EtOAc. The filtrate was concentrated under reduced pressure then the residue was purified by silica gel chromatography eluting with 25-40% EtOAc / hexanes to afford 377 mg (86%) of tert-butyl 3-(5-benzylpyrimidin-2-yl)pyrrolidine-1-carboxylate as a colorless, viscous oil.1H NMR (400 MHz, CDCl3) δ (ppm) 8.52 (s, 2H), 7.30 - 7.39 (m, 2H), 7.22 - 7.30 (m, 1H), 7.19 (d, J=7.09 Hz, 2H), 3.95 (s, 2H), 3.83 (m, 1H), 3.53 - 3.73 (m, 3H), 3.43 (m, 1H), 2.18 - 2.43 (m, 2H), 1.47 (s, 9H); MS (ESI) m / z [M+H]+calcd. for C20H25N3O2: 340.2; found, 340.3; HPLC purity: 210 nm: 100.0%; 254 nm 100.0%. Step 3. Preparation of 5-benzyl-2-pyrrolidin-3-ylpyrimidine (Compound S100)

[0462] A solution of tert-butyl 3-(5-benzylpyrimidin-2-yl)pyrrolidine-1-carboxylate (377 mg, 1.11 mmol, as prepared in the previous step) in DCM (9.0 mL) was cooled to 0°C, then TFA (1.0 mL) was added dropwise. The mixture was stirred for 30 min at 0°C then warmed to rt for 3 h. The reaction was concentrated under reduced pressure then the residue wasdissolved in DCM (10 mL) and concentrated again. The residue was dissolved in DCM (20 mL) and washed with 20 mL sat. aqueous NaHCO3. The organic phase was dried over anhydrous Na2SO4and filtered, then the filtrate was concentrated under reduced pressure to afford 211 mg (79%) of 5-benzyl-2-pyrrolidin-3-ylpyrimidine (Compound S100) as a light pink viscous oil.1H NMR (400 MHz, CD3OD) δ (ppm) 8.58 (s, 2H), 7.27 - 7.36 (m, 2H), 7.19 - 7.27 (m, 3H), 3.99 (s, 2H), 3.56 - 3.69 (m, 1H), 3.32 - 3.38 (m, 1H), 3.23 - 3.30 (m, 1H), 3.13 - 3.23 (m, 1H), 3.08 (dt, J=11.19, 7.37 Hz, 1H), 2.24 - 2.38 (m, 1H), 2.07 - 2.24 (m, 1H); MS (ESI) m / z [M+H]+calcd. for C15H17N3: 240.2; found, 240.1; HPLC purity: 210 nm: 100.0%; 254 nm: 100.0%. Synthesis of 1-benzyl-3-(pyrrolidin-3-yl)-1H-1,2,4-triazole (Compound S101)Step 1. Preparation of 1-benzyl-3-bromo-1H-1,2,4-triazole

[0463] A mixture of 3-bromo-1H-1,2,4-triazole (5.0 g, 33.8 mmol), benzyl bromide (5.8 g, 33.8 mmol) and NaOMe (1.8 g, 33.8 mmol) in DMF (50 mL) was stirred under nitrogen at 35°C for 6 h, then diluted with water and extracted with EtOAc (5 x 100 mL). The combined organic extracts were concentrated under reduced pressure then the residue was purified by silica gel chromatography eluting with 1:50 EtOAc / PE to 1:20 EtOAc / PE to afford 2.5 g (31%) of 1-benzyl-3-bromo-1H-1,2,4-triazole as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.72 (s, 1H), 7.30~7.40 (m, 5H), 5.40 (s, 2H). Step 2. Preparation of tert-butyl 3-(1-benzyl-1H-1,2,4-triazol-3-yl)-2,5-dihydro-1H- pyrrole-1-carboxylate

[0464] To a solution of 1-benzyl-3-bromo-1H-1,2,4-triazole (3.0 g, 12.6 mmol, as prepared in the previous step) in a mixture of dioxane (10 mL) and H2O (30 mL) was added tert- butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1- carboxylate (4.5 g, 15.1 mmol), K3PO4 (5.4 g, 25.2 mmol), and Pd(PPh3)2Cl2(0.4 g, 0.6mmol) under nitrogen. The reaction was stirred at 80°C for 4 h under nitrogen, then poured into water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by silica gel chromatography eluting with 1:10 EtOAc / PE to 1:1 EtOAc / PE to afford 3.3 g (80%) of tert-butyl 3-(1-benzyl-1H-1,2,4-triazol-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.67 (d, J=4.4Hz, 1H), 7.26~7.35 (m, 5H), 6.42 (d, J=12.8Hz, 1H), 5.41 (s, 1H), 4.32 (s, 2H), 4.18 (s, 2H), 1.41~1.43 (m, 12H). Step 3. Preparation of tert-butyl 3-(1-benzyl-1H-1,2,4-triazol-3-yl)pyrrolidine-1- carboxylate

[0465] A mixture of tert-butyl 3-(1-benzyl-1H-1,2,4-triazol-3-yl)-2,5-dihydro-1H-pyrrole- 1-carboxylate (3.0 g, 9.2 mmol, as prepared in the previous step) and 10% Pd / C (50% water, 1.6 g) in EtOAc (30 mL) was stirred at 25°C for 5 h under an atmosphere of hydrogen (20 psi). The mixture was filtered and the filtrate was concentrated to afford 3.0 g (99%) of tert-butyl 3-(1-benzyl-1H-1,2,4-triazol-3-yl)pyrrolidine-1-carboxylate as a yellow solid. 1HNMR (400 MHz, CDCl3) δ (ppm) 7.94 (s, 1H), 7.37 (d, J=7.2Hz, 3H), 7.25-7.29 (m, 2H), 5.28 (d, J=7.2Hz, 2H), 3.79 (s, 1H), 3.42~3.52 (m, 3H), 3.26~3.28 (m, 1H), 2.20~2.23 (m, 2H), 1.37~1.45 (m, 9H). Step 4. Preparation of 1-benzyl-3-(pyrrolidin-3-yl)-1H-1,2,4-triazole (Compound S101)

[0466] To a solution of tert-butyl 3-(1-benzyl-1H-1,2,4-triazol-3-yl)pyrrolidine-1- carboxylate (2.9 g, 8.8 mmol, as prepared in the previous step) in DCM (30 mL) was added TFA (10 mL) at 0°C. The reaction mixture was stirred at 25°C for 3 h under nitrogen. The pH of the mixture was adjusted to pH 9 with sat. aqueous NaHCO3, then extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 1.1 g (55%) of 1-benzyl-3-(pyrrolidin-3-yl)-1H-1,2,4-triazole (Compound S101) asa yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.53 (s, 1H), 7.31~7.34 (m, 3H), 7.26~7.30 (m, 2H), 5.33 (s, 2H), 3.21~3.38 (m, 2H), 2.86~2.96 (m, 3H), 1.87 ~2.05 (m, 2H). Synthesis of 3-(4-(1H-1,2,4-triazol-3-yl)piperazin-1-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine (Compound S102)Step 1. Preparation of a mixture of 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4- triazole and 3-bromo-4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazole and 5-bromo-1- (tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole

[0467] To a solution of 3-bromo-1H-1,2,4-triazole (500 mg, 3.37 mmol) and 3,4-dihydro- 2H-pyran (426.3 mg, 5.06 mmol) in toluene (20 mL) was added TsOH·H2O (64.2 mg, 0.33 mmol) then the mixture was heated to 105°C and stirred overnight under nitrogen. The reaction was cooled to rt then concentrated under reduced pressure. The residue was dissolved in water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic extracts were dried over anhydrous Na2SO4and filtered, then the filtrate was concentrated under reduced pressure to afford 700 mg (89%) of a mixture of 3-bromo-1-(tetrahydro-2H- pyran-2-yl)-1H-1,2,4-triazole and 3-bromo-4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4- triazole and 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole as a black oil. MS (ESI) m / z [M+H]+calcd. for C7H10BrN3O, 232.0; found, 232.0. LCMS purity: 254 nm:85%. Step 2. Preparation of a mixture of 6-(1-methyl-1H-pyrazol-4-yl)-3-(4-(1-(tetrahydro-2H- pyran-2-yl)-1H-1,2,4-triazol-3-yl)piperazin-1-yl)pyrazolo[1,5-a]pyridine, 6-(1-methyl- 1H-pyrazol-4-yl)-3-(4-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)piperazin-1-yl)pyrazolo[1,5-a]pyridine, and 6-(1-methyl-1H-pyrazol-4-yl)-3-(4-(1-(tetrahydro-2H- pyran-2-yl)-1H-1,2,4-triazol-5-yl)piperazin-1-yl)pyrazolo[1,5-a]pyridine

[0468] To a solution of the mixture of 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4- triazole and 3-bromo-4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazole and 5-bromo-1- (tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole (600 mg, 2.58 mmol, as prepared in the previous step) and 6-(1-methyl-1H-pyrazol-4-yl)-3-piperazin-1-ylpyrazolo[1,5-a]pyridine (Compound 12) (364.9 mg, 1.29 mmol) in dioxane (20 mL) were added Cs2CO3(1.68 g, 5.17 mmol) and Pd-PEPPSI-IPentCl2-methylpyridine (326.1 mg, 0.38 mmol), then the reaction was heated to 100°C and stirred overnight under nitrogen. The mixture was cooled to rt then concentrated under reduced pressure. The residue was dissolved in water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic extracts were dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by reversed-phase flash chromatography with a C18 silica gel column eluting with 10% to 50% ACN / water (10mM NH4HCO3to afford 450 mg (40%) of a mixture of 6-(1-methyl-1H-pyrazol-4-yl)-3-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H- 1,2,4-triazol-3-yl)piperazin-1-yl)pyrazolo[1,5-a]pyridine, 6-(1-methyl-1H-pyrazol-4-yl)- 3-(4-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)piperazin-1-yl)pyrazolo[1,5- a]pyridine, and 6-(1-methyl-1H-pyrazol-4-yl)-3-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H- 1,2,4-triazol-5-yl)piperazin-1-yl)pyrazolo[1,5-a]pyridine as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.83 – 8.76 (m, 1H), 8.36 (s, 1H), 8.22 (s, 1H), 7.97 (s, 1H), 7.78 (s, 1H), 7.67 (dd, J = 9.3, 0.9 Hz, 1H), 7.32 (dd, J = 9.2, 1.5 Hz, 1H), 5.33 (dd, J = 9.9, 2.3 Hz, 1H), 3.97 – 3.90 (m, 1H), 3.87 (s, 3H), 3.67 – 3.57 (m, 1H), 3.49-3.47 (m, 4H), 3.07 (t, J = 5.0 Hz, 4H), 2.05 – 1.90 (m, 3H), 1.67 – 1.52 (m, 3H). MS (ESI) m / z [M+H]+calcd. for C22H27N9O, 434.2; found, 434.2.LCMS purity:254 nm:90%.Step 3. 3-(4-(1H-1,2,4-triazol-3-yl)piperazin-1-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine (Compound S102)

[0469] To a solution of a mixture of 6-(1-methyl-1H-pyrazol-4-yl)-3-(4-(1-(tetrahydro-2H- pyran-2-yl)-1H-1,2,4-triazol-3-yl)piperazin-1-yl)pyrazolo[1,5-a]pyridine, 6-(1-methyl- 1H-pyrazol-4-yl)-3-(4-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)piperazin-1- yl)pyrazolo[1,5-a]pyridine, and 6-(1-methyl-1H-pyrazol-4-yl)-3-(4-(1-(tetrahydro-2H- pyran-2-yl)-1H-1,2,4-triazol-5-yl)piperazin-1-yl)pyrazolo[1,5-a]pyridine (400 mg, 0.92 mmol, as prepared in the previous step) in DCM (20 mL) was added 4M HCl in dioxane (336.4 mg, 9.23 mmol) then the reaction was stirred at rt for 2 h under nitrogen. The mixture was concentrated under reduced pressure then the pH of the residue was adjusted to pH 7 with aqueous NH3. The residue was purified by reversed-phase flash chromatography with a C18 silica gel column eluting with10% to 50% ACN / water (10mM NH4HCO3) to afford 270 mg (84%) of 3-(4-(1H-1,2,4-triazol-3-yl)piperazin-1-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine (Compound S102) as a yellow oil.1H NMR (400 MHz, DMSO- d6) δ (ppm) 13.13-12.70 (m, 1H), 8.82 (s, 1H), 8.57-8.20 (m, 2H), 7.97 (s, 1H), 7.78 (s, 1H), 7.68 (d, J = 9.2 Hz, 1H), 7.34-7.30 (m, 1H), 3.87 (s, 3H), 3.50 (t, J = 4.8 Hz, 4H), 3.08 (t, J = 4.8 Hz, 4H). MS (ESI) m / z [M+H]+calcd. for C17H19N9, 350.2; found, 350.2.LCMS purity:254 nm:95%. Synthesis of 1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-3-yl]piperazine (Compound S103)

[0470] To a solution of 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Compound S5) (900 mg, 3.25 mmol) in dioxane (20 mL) was added piperazine (1.39 g, 16.18 mmol), Pd-PEPPSI-IPentCl2-methylpyridine (272.2 mg, 0.32 mmol), and Cs2CO3(2.11 g, 6.47 mmol) then the mixture was heated to 100°C and stirred for 16 h undernitrogen. The mixture was cooled to rt, diluted with water (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by reversed-phase flash chromatography with a C18 silica gel column eluting with 10% to 100% ACN / water (0.1% FA) to afford 500 mg (42%) of 1-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-3-yl]piperazine as a light yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.17 (s, 1H), 8.89 (s, 1H), 8.28 (d, J = 5.6 Hz, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.81 (s, 1H), 3.88 (s, 3H), 3.21 – 3.11 (m, 4H), 3.08 – 2.94 (m, 4H); MS (ESI) m / z [M+H]+calcd. for C14H17N7, 284.1; found, 284.1; LCMS purity: 254 nm: 98.6%. Synthesis of 1-(2-methylbenzo[d]thiazol-6-yl)ethan-1-one (Compound S104)

[0471] To a solution of 6-bromo-2-methylbenzo[d]thiazole (5 g, 21.92 mmol) and tributyl(1-ethoxyvinyl)stannane (11.87 g, 32.88 mmol) in dioxane (500 mL) was added Pd(PPh3)4 (2.53 g, 2.19 mmol) then the mixture was heated to 90°C and stirred for 16 h under nitrogen. The reaction was cooled to rt and concentrated under reduced pressure. Water (150 mL) was added to the residue then the mixture was extracted with EtOAc (3x300 mL). The organic extracts were combined, washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford 3.5 g (83%) of 1-(2-methylbenzo[d]thiazol-6-yl)ethan-1-one (Compound S104) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.72 (d, J = 1.8 Hz, 1H), 8.06 – 7.95 (m, 2H), 2.85 (s, 3H), 2.65 (s, 3H); MS (ESI) m / z [M+H]+calcd. for C10H9NOS, 192.0; found, 192.1. Synthesis of (2-methylbenzo[d]thiazol-6-yl)methanol (Compound S105)

[0472] To a stirred solution of 2-methylbenzo[d]thiazole-6-carboxylic acid (1 g, 5.17 mmol) in THF (20 mL) cooled to 0°C was added a 2M solution of LiAlH4 in THF (5.2 mL) then the mixture was warmed to rt and stirred for 3 h. The reaction was cooled to 0°C andquenched by the addition of saturated aqueous NaHCO3solution. The mixture was filtered, and the filter cake was washed with DCM (3x30 mL). The filtrate was extracted with DCM / MeOH (10:1) (3x80 mL), then the organic extracts were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:1) to afford 400 mg (43%) of (2-methylbenzo[d]thiazol-6-yl)methanol (Compound S105) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.93 (d, J = 1.5 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.41 (dd, J = 8.3, 1.5 Hz, 1H), 5.31 (t, J = 5.7 Hz, 1H), 4.61 (d, J = 5.7 Hz, 2H), 2.78 (s, 3H); MS (ESI) m / z [M+H]+calcd. for C9H9NOS, 180.0; found, 180.1. Synthesis of 2-(hydroxymethyl)-5-methylbenzonitrile (Compound S106)

[0473] To a stirred solution of methyl 2-cyano-4-methylbenzoate (500 mg, 2.85 mmol) and NaBH4 (323.91 mg, 8.56 mmol) in MeOH (10 mL) cooled to 0°C was added LiCl (241.97 mg, 5.70 mmol) in portions then the mixture was warmed to rt and stirred for 1 h. The reaction was diluted with water (30 mL) and extracted with EtOAc (3x50 mL). The organic extracts were combined, washed with brine (2x2 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 400 mg (38%) of 2- (hydroxymethyl)-5-methylbenzonitrile (Compound S106) as a yellow solid. MS (ESI) m / z [M+H]+calcd. for C9H9NO, 148.2; found, 148.0. Synthesis of 2-(hydroxymethyl)-5-(trifluoromethyl)benzonitrile (Compound S107)Step 1. Preparation of methyl 2-cyano-4-(trifluoromethyl)benzoate

[0474] To a solution of 2-bromo-5-(trifluoromethyl)benzonitrile (5 g, 19.99 mmol) in MeOH (30 mL) was added Pd(dppf)Cl2(1.46 g, 2 mmol) in a pressure vessel then the mixture was pressurized to 15 atm with carbon monoxide at 80°C overnight. The reaction was cooled to rt and filtered, then the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford 3 g (65%) of methyl 2-cyano-4-(trifluoromethyl)benzoate as a brown solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.55 – 8.50 (m, 1H), 8.30 (d, J = 8.2 Hz, 1H), 8.24 (dd, J = 8.3, 1.9 Hz, 1H), 3.96 (s, 3H); MS (ESI) m / z [M+H]+calcd. for C10H6F3NO2, 229.0; found, 229.2. Step 2. Preparation of 2-(hydroxymethyl)-5-(trifluoromethyl)benzonitrile (Compound S107)

[0475] To a stirred solution of methyl 2-cyano-4-(trifluoromethyl)benzoate (2.9 g, 12.65 mmol, as prepared in the previous step) in MeOH (29 mL) cooled to 0°C was added NaBH4 (0.96 g, 25.3 mmol) in portions then the mixture was warmed to rt and stirred for 2 h. The reaction was concentrated under reduced pressure then the residue was dissolved in water (300 mL) and extracted with EtOAc (2x200 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 1.5 g (59%) of 2-(hydroxymethyl)-5-(trifluoromethyl)benzonitrile (Compound S107) as a white solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.05 – 7.94 (m, 2H), 7.82 (d, J = 3.8 Hz, 1H), 5.43 (d, J = 8.7 Hz, 2H), 4.55 – 4.53 (m, 1H); MS (ESI) m / z [M+H]+calcd. for C9H6F3NO, 201.0; found, 201.1. Synthesis of 1-(4-(fluoromethyl)phenyl)ethan-1-ol (Compound S108)Step 1. Preparation of 1-(4-(fluoromethyl)phenyl)ethan-1-one

[0476] To a stirred solution of 1-(p-tolyl)ethan-1-one (3 g, 22.3 mmol) and K2S2O8 (18.13 g, 67 mmol) in ACN (30 mL) and H2O (30 mL) was added F-TEDA (23.7 g, 67 mmol) in portions at rt then the mixture was heated to 80°C and stirred overnight. The reaction was cooled to rt and extracted with EtOAc (3x200 mL). The organic extracts were combined,washed with brine (3x100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford 2 g (59%) of 1-(4- (fluoromethyl)phenyl)ethan-1-one as colorless liquid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.00 (dd, J = 8.3, 1.3 Hz, 2H), 7.62 – 7.49 (m, 2H), 5.53 (d, J = 48 Hz, 2H), 2.60 (d, J = 0.8 Hz, 3H); MS (ESI) m / z [M+H]+calcd. for C9H9FO, 153.0; found, 153.0. Step 2. Preparation of 1-(4-(fluoromethyl)phenyl)ethan-1-ol (Compound S108)

[0477] To a solution of 1-(4-(fluoromethyl)phenyl)ethan-1-one (800 mg, 5.2 mmol, as prepared in the previous step) in MeOH (10 mL) cooled to 0°C was added NaBH4 (238 mg, 6.3 mmol) then the mixture was stirred for 1 h. The reaction was concentrated under reduced pressure then the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford 600 mg (74%) of 1-(4-(fluoromethyl)phenyl)ethan-1-ol (Compound S108) as colorless liquid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.43 – 7.29 (m, 4H), 5.38 (d, J = 48 Hz, 2H), 5.20 (d, J = 4.2 Hz, 1H), 4.87 – 4.68 (m, 1H), 1.33 (d, J = 6.4 Hz, 3H). Synthesis of 1-(4-(difluoromethyl)phenyl)ethan-1-ol (Compound S109)

[0478] To a solution of 1-(4-(difluoromethyl)phenyl)ethan-1-one (600 mg, 3.5 mmol) in MeOH (8 mL) cooled to 0°C was added NaBH4 (267 mg, 7 mmol) then the mixture was stirred for 2 h. The reaction was concentrated under reduced pressure then the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford 550 mg (91%) of 1-(4-(difluoromethyl)phenyl)ethan-1-ol (Compound S109) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.76 – 7.41 (m, 4H), 7.01 (t, J = 56.0 Hz, 1H), 5.29 (d, J = 4.3 Hz, 1H), 4.95 – 4.61 (m, 1H), 1.34 (d, J = 6.5 Hz, 3H).Synthesis of 2-((tert-butyldimethylsilyl)oxy)-1-(p-tolyl)ethan-1-ol (Compound S110) and 2-((tert-butyldimethylsilyl)oxy)-2-(p-tolyl)ethan-1-ol (Compound S111)Step 1. Preparation of 2-hydroxy-1-(p-tolyl)ethan-1-one

[0479] To a solution of 2-bromo-1-(4-methylphenyl)ethanone (3 g, 14.08 mmol) in MeOH (20 mL) was added NaOAc (9.24 g, 112.64 mmol) then the mixture was heated to 80°C and stirred for 12 h under nitrogen. The reaction was cooled to rt and concentrated under reduced pressure then the residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to afford 1.47 g (70%) of 2-hydroxy-1-(4-methylphenyl)ethanone as a white solid.1H NMR (400 MHz, CDCl3) δ (ppm) 7.82 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 4.85 (s, 2H), 3.50 (d, J = 7.4 Hz, 1H), 2.43 (s, 3H). Step 2. Preparation of 2-((tert-butyldimethylsilyl)oxy)-1-(p-tolyl)ethan-1-one

[0480] To a solution of 2-hydroxy-1-(4-methylphenyl)ethanone (1.27 g, 8.45 mmol, as prepared in the previous step) in THF (20 mL) was added TBSCl (1.91 g, 12.68 mmol) and imidazole (0.87 g, 12.68 mmol) then the mixture was stirred at rt for 2 h. The reaction was concentrated under reduced pressure then the residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to afford 2.17 g (97%) of 2-((tert- butyldimethylsilyl)oxy)-1-(p-tolyl)ethan-1-one as a colorless liquid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.83 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 4.99 (s, 2H), 2.37 (s, 3H), 0.90 (s, 9H), 0.07 (s, 6H).Step 3. Preparation of 2-((tert-butyldimethylsilyl)oxy)-1-(p-tolyl)ethan-1-ol (Compound S110) and 2-((tert-butyldimethylsilyl)oxy)-2-(p-tolyl)ethan-1-ol (Compound S111)

[0481] To a stirred solution of 2-((tert-butyldimethylsilyl)oxy)-1-(p-tolyl)ethan-1-one (1 g, 3.78 mmol, as prepared in the previous step) in MeOH (10 mL) cooled to 0°C was added NaBH4 (0.22 g, 5.673 mmol) in portions then the mixture was warmed to rt and stirred at rt for 2 h under nitrogen. The reaction was concentrated under reduced pressure then the residue was purified by reversed-phase flash chromatography using a Prep Phenyl column eluting with 35-65% MeOH / water (10mM NH4HCO3) to afford 250 mg (25%) of 2-((tert- butyldimethylsilyl)oxy)-1-(p-tolyl)ethan-1-ol (Compound S110) as colorless liquid and 200 mg (20%) of 2-((tert-butyldimethylsilyl)oxy)-2-(p-tolyl)ethan-1-ol (Compound S111) as a colorless oil.

[0482] 2-((tert-butyldimethylsilyl)oxy)-1-(p-tolyl)ethan-1-ol (Compound S110).1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.21 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 7.9 Hz, 2H), 5.16 (d, J = 4.3 Hz, 1H), 4.49 (q, J = 5.7 Hz, 1H), 3.65 – 3.58 (m, 1H), 3.55 – 3.48 (m, 1H), 2.27 (s, 3H), 0.81 (s, 9H), -0.04 (s, 3H), -0.07 (s, 3H).

[0483] 2-((tert-butyldimethylsilyl)oxy)-2-(p-tolyl)ethan-1-ol (Compound S111).1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.20 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 7.9 Hz, 2H), 4.70 (t, J = 5.7 Hz, 1H), 4.66 – 4.61 (m, 1H), 3.44 – 3.31 (m, 2H), 2.28 (s, 3H), 0.85 (s, 9H), 0.05 (s, 3H), -0.05 (s, 3H). Synthesis of 1-(1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol (Compound S112)Step 1. Preparation of 1-(1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-one

[0484] To a solution of 1-(5-methyl-1H-pyrazol-3-yl)ethan-1-one (1 g, 8.05 mmol) in DCM (20 mL) was added MeI (1.72 g, 12.08 mmol) then the mixture was stirred at rt for 2h. The reaction was filtered, and the filter cake was washed with DCM (2x20 mL), then the filtrate was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography using a C18 silica gel column eluting with 20-30% ACN / water (10mM NH4HCO3) to afford 240 mg (22%) of 1-(1,5-dimethyl-1H-pyrazol-3-yl)ethan-1- one as a white solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 6.47 (s, 1H), 3.81 (s, 3H), 2.41 (s, 3H), 2.27 (s, 3H); MS (ESI) m / z [M+H]+calcd. for C7H10N2O, 139.1; found, 139.2. Step 2. Preparation of 1-(1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol (Compound S112)

[0485] To a stirred mixture of 1-(1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-one (220 mg, 1.59 mmol, as prepared in the previous step) in MeOH (5 mL) cooled to 0°C was added NaBH4(90.3 mg, 2.38 mmol) in portions then the mixture was warmed to rt and stirred for 2 h. The reaction was cooled to 0°C, quenched with water, and extracted with EtOAc (3x20 mL). The organic extracts were combined, washed with water (3x20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by reversed-phase flash chromatography using a C18 silica gel column eluting with 5-10% ACN / water (10mM NH4HCO3) to afford 140 mg (63%) of 1- (1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol (Compound S112) as yellow liquid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 5.92 (s, 1H), 4.83 (d, J = 4.7 Hz, 1H), 4.63 – 4.52 (m, 1H), 3.63 (s, 3H), 2.19 (s, 3H), 1.29 (d, J = 6.5 Hz, 3H). Synthesis of 3-(4-cyclopropylphenyl)propanoic acid (Compound S113)

[0486] To a stirred mixture of 3-(4-bromophenyl)propanoic acid (1 g, 4.36 mmol) and cyclopropylboronic acid (449.9 mg, 5.23 mmol) in dioxane (10 mL) were added Pd(dppf)Cl2(319.4 mg, 0.43 mmol) and Cs2CO3(2.8 g, 8.73 mmol) in portions at rt under nitrogen then the mixture was heated to 100°C and stirred for 2 h. The reaction was cooled to rt, diluted with water (200 mL), and extracted with DCM (2x150 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by reversed-phase flashchromatography using a C18 silica gel column eluting with 5-100% ACN / water (10mM NH4HCO3) to afford 500 mg (60%) of 3-(4-cyclopropylphenyl)propanoic acid (Compound S113) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.08 (d, J = 7.9 Hz, 2H), 6.97 (d, J = 7.9 Hz, 2H), 2.75 (t, J = 7.7 Hz, 2H), 2.44 (t, J = 7.7 Hz, 2H), 1.92 – 1.78 (m, 1H), 0.96 – 0.82 (m, 2H), 0.67 – 0.55 (m, 2H). Synthesis of 1-(4-(2,2,2-trifluoroethyl)phenyl)ethan-1-ol (Compound S114)Step 1. Preparation of 1-(4-(2,2,2-trifluoroethyl)phenyl)ethan-1-one

[0487] To a stirred mixture of 4-acetylphenylboronic acid (1 g, 6.1 mmol) and 1,1,1- trifluoro-2-iodoethane (5.1 g, 24.3 mmol) in dioxane (20 mL) were added Cs2CO3(5.96 g, 18.3 mmol), Pd2(dba)3 (1.1 g, 1.2 mmol), and XantPhos (705 mg, 1.2 mmol) in portions at rt under nitrogen then the mixture was heated to 100°C and stirred overnight under nitrogen. The reaction was cooled to rt and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to afford 800 mg (65%) of 1-(4-(2,2,2-trifluoroethyl)phenyl)ethan-1-one as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.02 – 7.95 (m, 2H), 7.52 (d, J = 8.0 Hz, 2H), 3.77 (q, J = 11.5 Hz, 2H), 2.59 (s, 3H); MS (ESI) m / z [M+H]+calcd. for C10H9F3O, 203.1; found, 203.1. Step 2. Preparation of 1-(4-(2,2,2-trifluoroethyl)phenyl)ethan-1-ol (Compound S114)

[0488] To a stirred solution of 1-(4-(2,2,2-trifluoroethyl)phenyl)ethan-1-one (400 mg, 2 mmol) in MeOH (10 mL) cooled to 0°C was added NaBH4 (89.8 mg, 2.4 mmol) in portions then the mixture was warmed to rt and stirred for 1 h. The reaction was concentrated under reduced pressure then the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford 150 mg (37%) of 1-(4-(2,2,2-trifluoroethyl)phenyl)ethan-1-ol (Compound S114) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.38 – 7.32 (m, 2H), 7.32 – 7.23 (m, 2H), 5.16 (d, J = 4.2 Hz, 1H), 4.85 – 4.53 (m, 1H), 3.61 (q, J = 11.6 Hz, 2H), 1.32 (d, J = 6.4 Hz, 3H). Synthesis of 1-(4-(1,1-difluoroethyl)phenyl)ethan-1-ol (Compound S115)Step 1. Preparation of 1-bromo-4-(1,1-difluoroethyl)benzene

[0489] To a solution of 1-(4-bromophenyl)ethan-1-one (10 g, 50.23 mmol) in DCM (60 mL) was added DAST (64.7 g, 401.9 mmol) dropwise at rt then the mixture was heated to 50°C and stirred overnight. The reaction was cooled to 0°C, quenched with water, and extracted with DCM (2x100 mL). The organic extracts were combined, washed with water (2x100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by silica gel column chromatography eluting with DCM / PE (50:1) to afford 3.4 g (31%) of 1-bromo-4-(1,1- difluoroethyl)benzene as colorless liquid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.70 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H), 1.97 (t, J = 18.9 Hz, 3H). Step 2. Preparation of 1-(4-(1,1-difluoroethyl)phenyl)ethan-1-ol (Compound S115)

[0490] To a stirred solution of 1-bromo-4-(1,1-difluoroethyl)benzene (500 mg, 2.26 mmol, as prepared in the previous step) in THF (10 mL) cooled to -78°C was added 2.5M nBuLi in hexane (1.4 mL, 3.39 mmol) dropwise under nitrogen then the mixture was stirred at - 78°C for 30 minutes under nitrogen. A solution of 5M acetaldehyde in THF (0.6 mL, 2.71 mmol) was added dropwise over 5 minutes at -78°C then the reaction was warmed to rt and stirred for 1 h. The reaction was cooled to 0°C, quenched with saturated aqueous NH4Clsolution, and extracted with EtOAc (2x30 mL). The organic extracts were combined, washed with water (2x30 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by reversed-phase flash chromatography using a C18 silica gel column eluting with 30-40% ACN / water (10mM NH4HCO3) to afford 180 mg (43%) of 1-(4-(1,1-difluoroethyl)phenyl)ethan-1-ol (Compound S115) as yellow liquid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.50 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 5.25 (d, J = 4.3 Hz, 1H), 4.81 – 4.71 (m, 1H), 1.95 (t, J = 18.8 Hz, 3H), 1.32 (d, J = 6.5 Hz, 3H). Synthesis of 2-(4-(trifluoromethyl)phenyl)propanoic acid (Compound S116)Step 1. Preparation of methyl 2-(4-(trifluoromethyl)phenyl)acetate

[0491] To a stirred solution of 2-(4-(trifluoromethyl)phenyl)acetic acid (1.2 g, 5.878 mmol) in MeOH (20 mL) was added conc. H2SO4(1.15 g, 11.756 mmol) dropwise at rt then the mixture was heated to 80°C and stirred overnight. The reaction was cooled to rt, diluted with water (50 mL), and the pH was adjusted to pH 7 with saturated aqueous NaHCO3solution. The resulting mixture was extracted with Et2O (3x100mL) then the organic extracts were combined, washed with brine (3x10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford 800 mg (62%) of methyl 2-(4-(trifluoromethyl)phenyl)acetate as a yellow oil. The product was used without further purification. Step 2. Preparation of methyl 2-(4-(trifluoromethyl)phenyl)propanoate

[0492] To a stirred solution of methyl 2-(4-(trifluoromethyl)phenyl)acetate (500 mg, 2.292 mmol, as prepared in the previous step) in THF (20 mL) cooled to -78°C was added NaH(60% wt., 183.2 mg, 4.584 mmol) in portions under nitrogen then the mixture was stirred at -78°C for 30 minutes under nitrogen. To the stirred reaction at -78°C was added MeI (650.5 mg, 4.584 mmol) in portions then the mixture was warmed to rt and stirred overnight. The reaction was poured into a water / ice mixture, then extracted with EtOAc (3x100 mL). The organic extracts were combined, washed with brine (3x50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford 130 mg (24%) of methyl 2-(4-(trifluoromethyl)phenyl)propanoate as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.70 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 3.97 (q, J = 7.2 Hz, 1H), 3.61 (s, 3H), 1.43 (d, J = 7.2 Hz, 3H); MS (ESI) m / z [M+H]+calcd. for C11H11F3O, 231.0; found, 231.2. Step 3. Preparation of 2-(4-(trifluoromethyl)phenyl)propanoic acid (Compound S116)

[0493] To a stirred solution of methyl 2-(4-(trifluoromethyl)phenyl)propanoate (110 mg, 0.474 mmol, as prepared in the previous step) in MeOH (10 mL) was added LiOH (22.6 mg, 0.948 mmol) in portions at rt then the mixture was heated to 50°C and stirred overnight. The reaction was cooled to rt, diluted with water (20 mL), and the pH was adjusted to pH 4 with 1M HCl solution. The mixture was extracted with EtOAc (3x50 mL) then the organic extracts were combined, washed with brine (3x10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford 150 mg (145%) of 2-(4-(trifluoromethyl)phenyl)propanoic acid (Compound S116) as a yellow green solid. The solid was used without further purification. MS (ESI) m / z [M-H]- calcd. for C10H9F3O2, 217.2; found, 217.0. Synthesis of 1-(2-methylquinolin-6-yl)ethan-1-ol (Compound S117)Step 1. Preparation of N-methoxy-N,2-dimethylquinoline-6-carboxamide

[0494] To a stirred mixture of 2-methylquinoline-6-carboxylic acid (2 g, 10.7 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.5 g, 16.11 mmol) in DCM (30 mL) were added HATU (6.1 g, 16 mmol) and DIEA (5.5 g, 42.71 mmol) then the mixture was stirred at rt for 3 h. The reaction was concentrated under reduced pressure then the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford 1.6 g (65%) of N-methoxy-N,2-dimethylquinoline-6-carboxamide as a white solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.35 (d, J = 8.4 Hz, 1H), 8.22 (d, J = 1.8 Hz, 1H), 8.00 – 7.93 (m, 1H), 7.88 (dd, J = 8.7, 1.9 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 3.57 (s, 3H), 3.32 (s, 3H), 2.68 (s, 3H); MS (ESI) m / z [M+H]+calcd. for C13H14N2O2, 231.1; found, 231.1. Step 2.1-(2-methylquinolin-6-yl)ethan-1-one

[0495] To a stirred solution of N-methoxy-N,2-dimethylquinoline-6-carboxamide (1.5 g, 6.5 mmol, as prepared in the previous step) in THF (20 mL) cooled to -78°C was added 3M MeMgBr in THF (5 mL, 19.5 mmol) dropwise under nitrogen then the mixture was stirred at -78°C for 1 h under nitrogen. The reaction was warmed to 0°C, quenched with saturated aqueous NH4Cl solution, and extracted with DCM (3x300 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford 800 mg (66%) of 1-(2- methylquinolin-6-yl)ethan-1-one as a white solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.67 (d, J = 2.1 Hz, 1H), 8.49 – 8.39 (m, 1H), 8.17 (dd, J = 8.8, 2.0 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 2.71 (s, 3H), 2.70 (s, 3H); MS (ESI) m / z [M+H]+calcd. for C12H11NO, 186.1; found, 186.1.Step 3.1-(2-methylquinolin-6-yl)ethan-1-ol (Compound S117)

[0496] To a mixture of 1-(2-methylquinolin-6-yl)ethan-1-one (500 mg, 2.7 mmol, as prepared in the previous step) in MeOH (10 mL) cooled to 0°C was added NaBH4 (204 mg, 5.4 mmol) then the mixture was stirred for 1 h. The reaction was concentrated under reduced pressure then the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford 320 mg (63%) of 1-(2-methylquinolin-6-yl)ethan-1-ol (Compound S117) as colorless oil.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.21 (dd, J = 8.5, 0.8 Hz, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.71 (dd, J = 8.7, 2.0 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 5.37 (d, J = 4.2 Hz, 1H), 5.07 – 4.86 (m, 1H), 2.64 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H); MS (ESI) m / z [M+H]+calcd. for C12H13NO, 188.1; found, 188.1. Synthesis of 1-(2-methylquinolin-7-yl)ethan-1-ol (Compound S118)

[0497] To a solution of 7-bromo-2-methylquinoline (500 mg, 2.25 mmol) in THF (10 mL) cooled to -78°C was added 2.5M nBuLi in hexane (1.4 mL, 3.37 mmol) dropwise over 5 minutes under nitrogen, followed by the dropwise addition of 5M acetaldehyde in THF solution (0.54 mL, 2.70 mmol) at -78°C then the mixture was warmed to rt and stirred for 1 h. The reaction was cooled to 0°C, quenched with saturated aqueous NH4Cl solution, and extracted with DCM (3x20 mL). The organic extracts were combined, washed with water (3x20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by reversed-phase flash chromatography using a C18 silica gel column eluting with 40-50% ACN / water (10mM NH4HCO3) to afford 210 mg (50%) of 1-(2-methylquinolin-7-yl)ethanol (Compound S118) as a yellow solid. MS (ESI) m / z [M+H]+calcd. for C12H13NO, 188.1; found, 188.1.Synthesis of 1-(4-(oxetan-3-yl)phenyl)ethan-1-ol (Compound S119)

[0498] To a stirred solution of 3-(4-bromophenyl)oxetane (500 mg, 2.34 mmol) in THF (6 mL) cooled to -78°C was added 2.5M nBuLi in hexane (1.4 mL, 3.52 mmol) dropwise under nitrogen then the mixture was stirred for 30 minutes. To the stirred reaction was added 5M acetaldehyde in THF solution (0.56 mL, 2.81 mmol) dropwise at -78°C then the mixture was warmed to rt and stirred for 2 h. The reaction was quenched with water (100 mL) and extracted with EtOAc (2x150 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by reversed-phase flash chromatography using a C18 silica gel column eluting with 5-100% ACN / water (10mM NH4HCO3) to afford 200 mg (48%) of 1-(4-(oxetan-3-yl)phenyl)ethan-1-ol (Compound S119) as a yellow solid. MS (ESI) m / z [M+H]+calcd. for C11H14O2, 178.1; found, 178.2. Synthesis of 1-(4-isopropylphenyl)ethan-1-ol (Compound S120)

[0499] To a stirred solution of 1-(4-isopropylphenyl)ethan-1-one (500 mg, 3.1 mmol) in MeOH (10 mL) cooled to 0°C was added NaBH4 (140 mg, 3.7 mmol) in portions then the mixture was warmed to rt and stirred for 2 h. The reaction was concentrated under reduced pressure then the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford 500 mg (99%) of 1-(4-isopropylphenyl)ethan-1-ol (Compound S120) as colorless oil.1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.28 – 7.22 (m, 2H), 7.18 – 7.16 (m, 2H), 5.04 (d, J = 4.2 Hz, 1H), 4.73 – 4.62 (m, 1H), 2.92 – 2.79 (m, 1H), 1.30 (d, J = 6.5 Hz, 3H), 1.19 (d, J = 6.9 Hz, 6H). Synthesis of 1-(quinolin-7-yl)ethan-1-ol (Compound S121)

[0500] To a stirred solution of 1-(quinolin-7-yl)ethan-1-one (400 mg, 2.33 mmol) in MeOH (10 mL) cooled to 0°C was added NaBH4 (132.5 mg, 3.50 mmol) in portions then the mixture was warmed to rt and stirred for 2 h. The reaction was quenched with water (50 mL) and extracted with DCM (2x150 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 350 mg (86%) of 1-(quinolin-7-yl)ethan-1-ol (Compound S121) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.89 (dd, J = 4.2, 1.8 Hz, 1H), 8.33 (dd, J = 8.6, 2.2 Hz, 1H), 8.00 – 7.90 (m, 2H), 7.62 (dd, J = 8.5, 1.7 Hz, 1H), 7.49 (dd, J = 8.3, 4.2 Hz, 1H), 5.45 – 5.38 (m, 1H), 5.01 – 4.91 (m, 1H), 1.44 (d, J = 6.4 Hz, 3H). Synthesis of 1-(4-(oxetan-2-yl)phenyl)ethan-1-ol (Compound S122)

[0501] To a stirred solution of 2-(4-bromophenyl)oxetane (500 mg, 2.34 mmol) in THF (10 mL) cooled to -78°C was added 2.5M nBuLi in hexane (1.4 mL, 3.52 mmol) dropwise under nitrogen followed by the addition of 5M acetaldehyde in THF solution (0.56 mL, 2.81 mmol) dropwise at -78°C then the mixture was warmed to rt and stirred for 1 h. The reaction was cooled to 0°C, quenched with saturated aqueous NH4Cl solution, and extracted with DCM (3x20 mL). The organic extracts were combined, washed with water (3x20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by reversed-phase flash chromatography using a C18 silica gel column eluting with 15-20% ACN / water (10mM NH4HCO3) to afford 170 mg (41%) of 1-(4-(oxetan-2-yl)phenyl)ethan-1-ol (Compound S122) as a yellow liquid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.40 – 7.33 (m, 4H), 5.69 (t, J = 7.5 Hz, 1H), 5.13 (d, J = 4.2 Hz, 1H), 4.77 – 4.62 (m, 2H), 4.56 – 4.48 (m, 1H), 3.00 – 2.90 (m, 1H), 2.60 – 2.52 (m, 1H), 1.31 (d, J = 6.4 Hz, 3H). Synthesis of 1-(quinolin-6-yl)ethan-1-ol (Compound S123)

[0502] To a stirred solution of 1-(quinolin-7-yl)ethan-1-one (300 mg, 1.75 mmol) in MeOH (5 mL) cooled to 0°C was added NaBH4 (132.5 mg, 3.50 mmol) in portions then the mixture was warmed to rt and stirred for 2 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (3x20 mL). The organic extracts were combined, washed with brine (2x3 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 300 mg (99%) of 1-(quinolin-7-yl)ethan-1-ol (Compound S123) as a colorless oil.1H NMR (400 MHz, CDCl3) δ (ppm) 8.89 (dd, J = 4.2, 1.6 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 8.11 (d, J = 8.7 Hz, 1H), 7.82 (d, J = 1.5 Hz, 1H), 7.74 (dd, J = 8.7, 1.9 Hz, 1H), 7.41 (dd, J = 8.3, 4.3 Hz, 1H), 5.12 (q, J = 6.5 Hz, 1H), 3.49 (s, 1H), 1.60 (d, J = 6.5 Hz, 3H). Synthesis of 1-(2-chloroquinolin-6-yl)ethan-1-ol (Compound S124)Step 1. Preparation of 1-(2-chloroquinolin-6-yl)ethan-1-one

[0503] To a stirred solution of 6-bromo-2-chloroquinoline (1 g, 4.1 mmol) and tributyl(1- ethoxyethenyl)stannane (1.8 g, 4.9 mmol) in dioxane (15 mL) was added Pd(dppf)Cl2(0.6 g, 0.8 mmol) in portions under nitrogen then the mixture was heated to 100°C and stirred overnight. The reaction was cooled to rt and 0.1M HCl solution (15 mL, 2 mmol) was added dropwise over 5 minutes. The reaction was stirred at rt for 1 h then extracted with DCM (3x300 mL). The organic extracts were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by silica gel column chromatography eluting with DCM / MeOH (10:1) to afford 200 mg (24%) of 1-(2-chloroquinolin-6-yl)ethan-1-one as a white solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.80 (d, J = 2.0 Hz, 1H), 8.65 (d, J = 8.6 Hz, 1H), 8.28 (dd, J = 8.8, 2.0 Hz, 1H), 8.05 (d, J = 8.9 Hz, 1H), 7.73 (d, J = 8.6 Hz, 1H), 2.73 (s, 3H).Step 2.1-(2-chloroquinolin-6-yl)ethan-1-ol (Compound S124)

[0504] To a solution of 1-(2-chloroquinolin-6-yl)ethan-1-one (190 mg, 0.9 mmol, as prepared in the previous step) in MeOH (10 mL) cooled to 0°C was added NaBH4 (41.9 mg, 1.1 mmol) in portions then the mixture was stirred at 0°C for 1 h. The reaction concentrated under reduced pressure then the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford 170 mg (89%) of 1-(2- chloroquinolin-6-yl)ethan-1-ol (Compound S124) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.45 (dd, J = 8.7, 0.8 Hz, 1H), 7.98 (d, J = 1.9 Hz, 1H), 7.92 (d, J = 8.7 Hz, 1H), 7.83 (dd, J = 8.8, 2.0 Hz, 1H), 7.57 (d, J = 8.6 Hz, 1H), 5.43 (d, J = 4.2 Hz, 1H), 4.98 – 4.88 (m, 1H), 1.42 (d, J = 6.5 Hz, 3H). Synthesis of 2-((tert-butyldimethylsilyl)oxy)-1-(4-fluorophenyl)ethan-1-ol (Compound S125) and 2-((tert-butyldimethylsilyl)oxy)-2-(4-fluorophenyl)ethan-1-ol (Compound S126)Step 1. Preparation of 2-((tert-butyldimethylsilyl)oxy)-1-(4-fluorophenyl)ethan-1-one

[0505] To a stirred mixture of 1-(4-fluorophenyl)-2-hydroxyethan-1-one (1 g, 6.49 mmol) and imidazole (0.88 g, 12.9 mmol) in THF (20 mL) cooled to 0°C was added TBSCl (1.6 g, 9.73 mmol) in portions then the mixture was warmed to rt and stirred overnight. The reaction was concentrated under reduced pressure then the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford 600 mg (34%) of 2- ((tert-butyldimethylsilyl)oxy)-1-(4-fluorophenyl)ethan-1-one as colorless oil.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.06 – 7.98 (m, 2H), 7.40 – 7.32 (m, 2H), 5.03 (s, 2H), 0.90 (s, 9H), 0.08 (s, 6H).Step 2. Preparation of 2-((tert-butyldimethylsilyl)oxy)-1-(4-fluorophenyl)ethan-1-ol (Compound S125) and 2-((tert-butyldimethylsilyl)oxy)-2-(4-fluorophenyl)ethan-1-ol (Compound S126)

[0506] To a stirred solution of 2-((tert-butyldimethylsilyl)oxy)-1-(4-fluorophenyl)ethan-1- one (1 g, 3.72 mmol, as prepared in the previous step) in MeOH (20 mL) cooled to 0°C was added NaBH4 (84.5 mg, 2.23 mmol) in portions then the mixture was warmed to rt and stirred overnight. The reaction was concentrated under reduced pressure then the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford 700 mg (69%) of 2-((tert-butyldimethylsilyl)oxy)-1-(4-fluorophenyl)ethan-1-ol (Compound S125) as a yellow solid and 350 mg (35%) of 2-((tert-butyldimethylsilyl)oxy)- 2-(4-fluorophenyl)ethan-1-ol (Compound S126) as a yellow solid.

[0507] 2-((tert-butyldimethylsilyl)oxy)-1-(4-fluorophenyl)ethan-1-ol (Compound S125). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.42 – 7.32 (m, 2H), 7.18 – 7.08 (m, 2H), 5.33 (d, J = 4.4 Hz, 1H), 4.60 – 4.51 (m, 1H), 3.66 (dd, J = 10.1, 6.0 Hz, 1H), 3.53 (dd, J = 10.1, 5.9 Hz, 1H), 0.81 (s, 9H), -0.05 (s, 3H), -0.08 (s, 3H).

[0508] 2-((tert-butyldimethylsilyl)oxy)-2-(4-fluorophenyl)ethan-1-ol (Compound S126). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.40 – 7.30 (m, 2H), 7.18 – 7.09 (m, 2H), 4.77 (t, J = 5.7 Hz, 1H), 4.68 (dd, J = 6.8, 5.2 Hz, 1H), 3.47 – 3.38 (m, 2H), 0.84 (s, 9H), 0.05 (s, 6H). Synthesis of 2-(4-(1-hydroxyethyl)phenyl)propan-2-ol (Compound S127)Step 1. Preparation of 1-(4-(2-hydroxypropan-2-yl)phenyl)ethan-1-one

[0509] To a stirred mixture of N,O-dimethylhydroxylamine hydrochloride (5.47 g, 56.12 mmol) in THF (30 mL) cooled to 0°C was added 1.5M DIBAL-H in toluene (38 mL, 56.12 mmol) dropwise under nitrogen then the mixture was warmed to rt and stirred for 2 h. The reaction was cooled to 0°C, methyl 4-acetylbenzoate (5 g, 28.06 mmol) was added, and the mixture was stirred at 0 °C for 1 h. To the stirred mixture at 0°C was added 1M MeMgBr in THF (33.7 mL, 33.672 mmol) dropwise over 30 minutes then the reaction was stirred at 0°C for 2 h. The reaction was cooled to -78°C and 3M MeLi in Et2O (11.2 mL, 33.672 mmol) was added dropwise over 30 minutes then the mixture was stirred at -78°C for 1 h. The reaction was poured into a water / ice mixture and extracted with EtOAc (3x100 mL). The organic extracts were combined, washed with brine (3x10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford 1 g (20%) of 1-(4-(2-hydroxypropan-2-yl)phenyl)ethan-1-one as yellow oil.1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.92 – 7.90 (m, 2H), 7.59 – 7.57 (m, 2H), 2.58 (s, 3H), 1.59 (s, 6H). Step 2. Preparation of 2-(4-(1-hydroxyethyl)phenyl)propan-2-ol (Compound S127)

[0510] To a stirred solution of 1-(4-(2-hydroxypropan-2-yl)phenyl)ethan-1-one (1.8 g, 10.09 mmol, as prepared in the previous step) in MeOH (10 mL) cooled to 0°C was added NaBH4 (460 mg, 12.11 mmol) in portions under nitrogen then the mixture was warmed to rt and stirred overnight. The reaction was concentrated under reduced pressure to afford 300 mg of 2-(4-(1-hydroxyethyl)phenyl)propan-2-ol (Compound S127) was used directly without further purification.Example 1: Synthesis of Exemplary Compound 156 3-(4-(1-benzyl-1H-1,2,4-triazol-3-yl)piperazin-1-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine (Compound 156)Step 1. Preparation of 1-benzyl-3-chloro-1H-1,2,4-triazole

[0511] To a solution of 3-chloro-1H-1,2,4-triazole (5 g, 48.3 mmol) and benzyl bromide (9.09 g, 53.14 mmol) in DMF (200 mL) was added K2CO3(13.35 g, 96.61 mmol) then the reaction was stirred at 80°C under nitrogen for 16 h. The mixture was cooled to rt, then concentrated under reduced pressure. The residue was filtered, then the filter cake was washed with DCM (3 x 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with a C18 silica gel column eluting with 10% to 100% ACN / water (10mM NH4HCO3) to afford 3.9 g (42%) of 1-benzyl-3-chloro-1H-1,2,4-triazole as a white solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.76 (s, 1H), 7.46 – 7.26 (m, 5H), 5.40 (s, 2H).; MS (ESI) m / z [M+H]+calcd. for C9H8ClN3, 194.1; found, 194.2. Step 2. 3-(4-(1-benzyl-1H-1,2,4-triazol-3-yl)piperazin-1-yl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine (Compound 156)

[0512] To a solution of 1-benzyl-3-chloro-1H-1,2,4-triazole (5 g, 25.82 mmol, as prepared in the previous step) and 6-(1-methyl-1H-pyrazol-4-yl)-3-piperazin-1-ylpyrazolo[1,5- a]pyridine (Compound 12) (7.29 g, 25.82 mmol) in dioxane (200 mL) were added Cs2CO3(16.83 g, 51.64 mmol) and Pd-PEPPSI-IPentCl2-methylpyridine (2.17 g, 2.58 mmol). Thereaction was stirred at 90°C under nitrogen for 16 h then the resulting mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with DCM (6 x 100 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by silica gel chromatography eluting with MeOH / DCM (1:15) then recrystallized from ACN / THF (5:1) to afford 5.14 g (45%) of 3-(4-(1-benzyl-1H- 1,2,4-triazol-3-yl)piperazin-1-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (Compound 156) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.82 (s, 1H), 8.32 (s, 1H), 8.23 (s, 1H), 7.97 (s, 1H), 7.77 (s, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.43 – 7.25 (m, 6H), 5.24 (s, 2H), 3.87 (s, 3H), 3.46 (t, J = 4.8 Hz, 4H), 3.06 (t, J = 4.8 Hz, 4H); MS (ESI) m / z [M+H]+calcd. for C24H25N9, 440.2; found, 440.05; LCMS purity: 254 nm: 99.7%. Example 2: Synthesis of Exemplary Compound 275 1-(5-benzylpyrimidin-2-yl)-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-1,4- diazepan-2-one (Compound 275).

[0513] 6-(1-Methyl-1H-pyrazol-4-yl)-3-piperazin-1-ylpyrazolo[1,5-a]pyridine hydrochloride salt (Compound S19) (5.25 g, 16.5 mmol) was added to a solution of 1- chloro-4-(isocyanatomethyl)benzene (2.76 g, 16.5 mmol) in ACN (110 mL) and DIEA (14.0 mL, 80.4 mmol). The reaction was stirred at rt for 1 h, then the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with acetone (0.1% TEA additive) / EtOAc to afford 5.90 g (80%) of N-(4-chlorobenzyl)-4-[6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3- yl]piperazine-1-carboxamide (Compound 275) as a solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.81 (s, 1H), 8.22 (s, 1H) 7.96 (s, 1H) 7.77 (s, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.37 (m, 2H), 7.31 (m, 3H) 7.21 (t, J = 5.9 Hz, 1H), 4.25 (d, J = 5.7 Hz, 2H), 3.87 (s, 3H), 3.52 (m, 4H), 2.95 (m, 4H); MS (ESI) m / z [M+Na]+calcd. for C23H24ClN7NaO: 472.2. Found: 472.2; HPLC purity: 210 nm: 98.7%; 254 nm: 98.3%.Example 3: Synthesis of Exemplary Compound 326 1-(5-benzylpyrimidin-2-yl)-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-1,4- diazepan-2-one (Compound 326)Step 1. Preparation of tert-butyl (3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin- 3-yl)amino)propyl)carbamate

[0514] To a solution of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-amine (Compound S56) (1.0 g, 4.69 mmol) in DMF (30 mL) was added tert-butyl (3- bromopropyl)carbamate (1.34 g, 5.63 mmol) and K2CO3(1.94 g, 14.07 mmol). The reaction was stirred at 90°C under nitrogen for 16 h, cooled to rt, and diluted with water (50 mL). The mixture was extracted with EtOAc (3 x 200 mL), then the combined organic extracts were washed with brine (3x100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by Prep- TLC (MeOH / DCM 1:20) to afford 500 mg (19%) of tert-butyl (3-((6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)amino)propyl)carbamate as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.67 (s, 1H), 8.17 (s, 1H), 7.93 (s, 1H), 7.60 (dd, J = 9.2, 1.2 Hz, 1H), 7.49 (s, 1H), 7.14 (dd, J = 9.2, 1.6 Hz, 1H), 6.88 (t, J = 5.6 Hz, 1H), 4.70 (t, J = 6.4 Hz, 1H), 3.86 (s, 3H), 3.09 – 2.98 (m, 4H), 1.73 – 1.62 (m, 2H), 1.38 (s, 9H); MS (ESI) m / z [M+H]+calcd. for C19H26N6O2, 371.2; found, 371.2. Step 2. Preparation of ethyl N-(3-((tert-butoxycarbonyl)amino)propyl)-N-(6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)glycinate

[0515] To a solution of tert-butyl (3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridin-3-yl)amino)propyl)carbamate (500 mg, 1.35 mmol, as prepared in the previous step) and ethyl 2-iodoacetate (346.6 mg, 1.62 mmol) in DMF (10 mL) was added K2CO3(373.1 mg, 2.70 mmol) then the reaction was stirred at rt under nitrogen for 16 h. The mixture was concentrated under reduced pressure then the residue was dissolved in water (30 mL). The mixture was extracted with EtOAc (3 x 50 mL), then the combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by reversed- phase flash chromatography with a C18 silica gel column eluting with 10% to 100% ACN / water (0.1% FA) to afford 300 mg (49%) of ethyl N-(3-((tert- butoxycarbonyl)amino)propyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin- 3-yl)glycinate as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.77 (s, 1H), 8.20 (s, 1H), 7.95 (s, 1H), 7.76 (s, 1H), 7.57 (d, J = 9.3 Hz, 1H), 7.29 (dd, J = 9.3 ,1.2 Hz, 1H), 6.79 (t, J = 5.3 Hz, 1H), 4.04 (q, J = 7.1 Hz, 2H), 3.93 - 3.82 (m, 5H), 3.22 - 3.13 (m, 2H), 2.96 (q, J = 6.3 Hz, 2H), 1.52 (q, J = 6.3 Hz, 2H), 1.35 (s, 9H), 1.14 (t, J = 7.1 Hz, 3H) ;MS (ESI) m / z [M+H]+calcd. for C23H32N6O4, 457.2; found, 457.3. Step 3. Preparation of ethyl N-(3-aminopropyl)-N-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-3-yl)glycinate hydrochloride salt

[0516] To a solution of ethyl N-(3-((tert-butoxycarbonyl)amino)propyl)-N-(6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)glycinate (300 mg, 0.68 mmol, as prepared in the previous step) in DCM (10 mL) was added 4M HCl in dioxane (3 mL) then the mixture was stirred at rt under nitrogen for 2 h. The reaction was concentrated under reduced pressure to afford 200 mg (77%) of ethyl N-(3-aminopropyl)-N-(6-(1-methyl-1H-pyrazol- 4-yl)pyrazolo[1,5-a]pyridin-3-yl)glycinate hydrochloride salt as a white solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.77 (s, 1H), 8.19 (s, 1H), 7.95 (s, 1H), 7.77 (s, 1H), 7.63 - 7.54 (m, 1H), 7.29 (d, J = 9.3 Hz, 1H), 4.04 (q, J = 7.1 Hz, 2H), 3.94 - 3.88 (m, 2H), 3.86 (s, 3H), 3.26 - 3.18 (m, 2H), 2.98 (q, J = 5.8 Hz, 1H), 2.58 (t, J = 6.7 Hz, 1H), 1.58 - 1.43 (m, 2H), 1.14 (t, J = 7.1 Hz, 3H); MS (ESI) m / z [M+H]+calcd. for C19H25N2O2, 356.2 found, 356.2.Step 4. Preparation of 4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-1,4- diazepan-2-one

[0517] To a solution of ethyl N-(3-aminopropyl)-N-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-3-yl)glycinate hydrochloride (200 mg, 0.55 mmol, as prepared in the previous step) in MeOH (5 mL ) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (152.6 mg, 1.10 mmol) then the mixture was stirred at 90°C under nitrogen for 16 h. The reaction was concentrated under reduced pressure then the residue was dissolved in water (30 mL). The mixture was extracted with EtOAc (3 x 50 mL), then the combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by Prep-TLC (MeOH / DCM 1:3) to afford 160 mg (84%) of 4-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-3-yl)-1,4-diazepan-2-one as a white solid.1H NMR (400 MHz, CD3OD) δ (ppm) 8.56 (s, 1H), 8.03 (s, 1H), 7.87 (s, 1H), 7.80 (s, 1H), 7.66 (d, J = 9.3 Hz, 1H), 7.34 (dd, J = 9.3, 1.4 Hz, 1H), 3.95 (d, J = 5.5 Hz, 1H), 3.59 - 3.52 (m, 2H), 3.45 - 3.39 (m, 2H), 1.94 - 1.85 (m, 2H); MS (ESI) m / z [M+H]+calcd. for C16H18N6O, 311.2; found, 311.3. Step 5. 1-(5-benzylpyrimidin-2-yl)-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridin-3-yl)-1,4-diazepan-2-one (Compound 326)

[0518] To a solution of 4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-1,4- diazepan-2-one (150.0 mg, 0.48 mmol, as prepared in the previous step) and 5-benzyl-2- chloropyrimidine (Compound S88) (118.7 mg, 0.58 mmol) in dioxane (10 mL) were added Pd2(dba)3 (88.5 mg, 0.01 mmol), XantPhos (55.9 mg, 0.01 mmol), and K3PO4 (205.2 mg, 0.97 mmol), then the mixture was stirred at 90°C under nitrogen for 16 h. The reaction was concentrated under reduced pressure then the residue was purified by Prep-TLC (MeOH / DCM 1:10) and by Prep-HPLC to afford 42.3 mg (18%) of 1-(5-benzylpyrimidin-2-yl)-4- (6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-1,4-diazepan-2-one (Compound 326) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.87(s, 1H), 8.70 (m, 3H), 8.21 (s, 1H), 7.90 (s, 1H), 7.65 (dd, J = 9.2, 1.0 Hz, 1H), 7.35 - 7.27 (m, 5H), 7.26 - 7.18 (m, 1H), 4.15 (d, J = 7.2 Hz, 4H), 4.00-3.80 (m, 5H), 3.52 (t, J = 5.4 Hz, 2H), 1.94 - 1.81 (m, 2H); MS (ESI) m / z [M+H]+calcd. for C27H26N8O,479.2; found,479.1; LCMS purity: 254 nm: 99.0% Example 4: Synthesis of Exemplary Compound 327 (R)-1-phenylethyl (R)-2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3- yl)piperazine-1-carboxylate (Compound 327)Step 1. Preparation of tert-butyl (R)-2-methyl-4-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-3-yl)piperazine-1-carboxylate

[0519] To a solution of 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (Compound S9) (2.0 g, 7.22 mmol) dissolved in dioxane (30 mL) and tBuOH (30 mL) was added tert-butyl (R)-2-methylpiperazine-1-carboxylate (7.21 g, 36.08 mmol), tBuXPhos Pd G1 (0.99 g, 1.44 mmol), and KOtBu (1.62 g, 14.43 mmol), then the reaction was stirred at 90°C under nitrogen for 16 h. The reaction was cooled rt then diluted with water (200 mL). The mixture was extracted with EtOAc (3 x 200 mL) then the combined organic extracts were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by silica gel chromatography eluting with EtOAc / PE (3:2) to afford 1.2 g (42%) of tert-butyl (R)-2- methyl-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]piperazine-1-carboxylate as a light blue solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.82 (s, 1H), 8.22 (s, 1H),7.96 (s, 1H), 7.75 (s, 1H), 7.57 (d, J = 9.2 Hz, 1H), 7.33 (dd, J = 9.2, 1.6 Hz, 1H), 4.22 (dd, J = 7.6, 4.0 Hz, 1H), 3.87 (s, 3H), 3.84 – 3.76 (m, 1H), 3.22 – 3.19 (m, 1H), 3.14 – 3.07 (m, 1H), 2.77 (dd, J = 11.6, 3.6 Hz, 1H), 2.68 – 2.58 (m, 1H), 2.08 – 1.93 (m, 1H), 1.43 (s, 9H), 1.34 (d, J = 6.8 Hz, 3H); MS (ESI) m / z [M+H]+calcd. for C21H28N6O2, 397.2; found, 397.2. Step 2. Preparation of (R)-6-(1-methyl-1H-pyrazol-4-yl)-3-(3-methylpiperazin-1- yl)pyrazolo[1,5-a]pyridine

[0520] To a solution of tert-butyl (R)-2-methyl-4-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-3-yl)piperazine-1-carboxylate (800 mg, 2.02 mmol, as prepared in the previous step) in DCM (10 mL) cooled to 0°C was added 4M HCl in dioxane (3 mL) then the reaction was stirred at 0°C under nitrogen for 1 h. The mixture was neutralized to pH 8 with sat. aqueous Na2CO3then extracted with MeOH / DCM (1:10) (3 x 100 mL). The combined organic extracts were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 500 mg (83%) of (R)-6-(1-methyl-1H-pyrazol-4-yl)-3-(3-methylpiperazin-1-yl)pyrazolo[1,5- a]pyridine as a light yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.79 (s, 1H), 8.21 (s, 1H), 7.96 (d, J = 0.8 Hz, 1H), 7.70 (s, 1H), 7.60 (dd, J = 9.2, 1.0 Hz, 1H), 7.27 (dd, J = 9.2, 1.2 Hz, 1H), 3.86 (s, 3H), 3.21 – 3.11 (m, 2H), 2.91 (dd, J = 8.4, 2.8 Hz, 3H), 2.67 – 2.54 (m, 1H), 2.28 (d, J = 10.4 Hz, 1H), 1.23 (s, 1H), 1.00 (d, J = 6.4 Hz, 3H); MS (ESI) m / z [M+H]+calcd. for C16H20N6, 297.2; found, 297.2. Step 3. Preparation of (R)-1-phenylethyl (R)-2-methyl-4-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-3-yl)piperazine-1-carboxylate (Compound 327)

[0521] To a solution of (R)-6-(1-methyl-1H-pyrazol-4-yl)-3-(3-methylpiperazin-1- yl)pyrazolo[1,5-a]pyridine (400 mg, 1.35 mmol, as prepared in the previous step) and (R)-1-phenylethan-1-ol (494.6 mg, 4.05 mmol) in pyridine (15 mL) cooled to 0°C was added triphosgene (400.5 mg, 1.35 mmol) in portions over 1 min. The reaction was warmed to rt and stirred for 1 h, then diluted with water (100 mL) and extracted with EtOAc (6 x 100 mL). The combined organic extracts were washed with brine (6 x 100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by Prep-HPLC to afford 158 mg (26%) of (R)-1-phenylethyl (R)- 2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)piperazine-1- carboxylate (Compound 327) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.84 (s, 1H), 8.23 (s, 1H), 7.98 (d, J = 0.8 Hz, 1H), 7.76 (s, 1H), 7.59 (dd, J = 9.2, 1.0 Hz, 1H), 7.43 – 7.31 (m, 5H), 7.31 – 7.26 (m, 1H), 5.76 (q, J = 6.4 Hz, 1H), 4.33 (s, 1H), 3.92 (d, J = 13.2 Hz, 1H), 3.88 (s, 3H), 3.38 – 3.28 (m, 1H), 3.26 (d, J = 12.4 Hz, 1H), 3.18 – 3.09 (m, 1H), 2.81 (dd, J = 11.4, 4.0 Hz, 1H), 2.73 – 2.63 (m, 1H), 1.49 (d, J = 6.8 Hz, 3H), 1.38 (d, J = 6.0 Hz, 3H); MS (ESI) m / z [M+H]+calcd. for C25H28N6O2, 445.2; found, 445.1; LCMS purity: 254 nm: 98.5%; chiral purity: 100%. Example 5: Synthesis of Exemplary Compound 329 (R)-1-phenylethyl (S)-2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3- yl)piperazine-1-carboxylate (Compound 329)Step 1. Preparation of tert-butyl (S)-2-methyl-4-(6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridin-3-yl)piperazine-1-carboxylate

[0522] To a solution of 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (Compound S9) (2 g, 7.21 mmol) and tert-butyl (S)-2-methylpiperazine-1-carboxylate (7.23 g, 36.08 mmol) in dioxane (50 mL) and tBuOH (50 mL) were added KOtBu (1.62 g, 14.43 mmol) and tBuXPhos Pd G1 (0.99 g, 1.44 mmol) then the mixture was stirred at90°C under nitrogen overnight. The reaction was cooled to rt and concentrated under reduced pressure. The mixture was diluted with water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic extracts were dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by reversed-phase flash chromatography with a C18 silica gel column eluting with 10% to 50% ACN / water (0.1% FA) to afford 370 mg (13%) of tert-butyl (S)-2-methyl-4-(6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)piperazine-1-carboxylate as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.84 (t, J = 1.3 Hz, 1H), 8.23 (s, 1H), 7.97 (d, J = 0.8 Hz, 1H), 7.76 (s, 1H), 7.59 – 7.57 (m, 1H), 7.35 – 7.33 (m, 1H), 4.22 (s, 1H), 3.87 (s, 3H), 3.85 – 3.77 (m, 1H), 3.25 – 3.20 (m, 2H),3.13 – 3.09 (m, 1H), 2.79 – 2.75 (m, 1H), 2.69 – 2.58 (m, 1H), 1.43 (s, 9H), 1.34 (d, J = 6.7 Hz, 3H); MS (ESI) m / z [M+H]+calcd. for C21H28N6O2, 397.2; found, 397.2. Step 2. Preparation of (S)-6-(1-methyl-1H-pyrazol-4-yl)-3-(3-methylpiperazin-1- yl)pyrazolo[1,5-a]pyridine hydrochloride salt

[0523] To a solution of (S)-2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridin-3-yl)piperazine-1-carboxylate (360 mg, 0.90 mmol, as prepared in the previous step) in dioxane (10 mL) was added 4M HCl in dioxane (2.3 mL, 9.0 mmol) then the mixture was stirred at rt for 30 minutes. The reaction was concentrated under reduced pressure to afford 300 mg (78%) of (S)-6-(1-methyl-1H-pyrazol-4-yl)-3-(3- methylpiperazin-1-yl)pyrazolo[1,5-a]pyridine hydrochloride salt as a white solid. MS (ESI) m / z [M+H]+calcd. for C16H20N6, 297.1; found, 297.1. Step 3. (R)-1-phenylethyl (S)-2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridin-3-yl)piperazine-1-carboxylate (Compound 329)

[0524] To a solution of (S)-6-(1-methyl-1H-pyrazol-4-yl)-3-(3-methylpiperazin-1- yl)pyrazolo[1,5-a]pyridine hydrochloride salt (200 mg, 0.67 mmol, as prepared in the previous step) and (R)-1-phenylethan-1-ol (247.3 mg, 2.02 mmol) in pyridine (15 mL) was added triphosgene (200.2 mg, 0.67 mmol), then the mixture was stirred at rt under nitrogen overnight. The reaction was concentrated under reduced pressure then the residue was dissolved in water (50 mL) and the mixture was extracted with DCM (3 x 50 mL). The combined organic extracts were dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure then the residue was purified by Prep-HPLC to afford 57.2 mg (19%) of (R)-1-phenylethyl (S)-2-methyl-4-[6-(1-methylpyrazol-4- yl)pyrazolo[1,5-a]pyridin-3-yl]piperazine-1-carboxylate (Compound 329) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.84 (s,1H), 8.23 (s, 1H), 7.97 (s,1H), 7.76 (s, 1H), 7.59 (d, J = 9.2 Hz, 1H), 7.43 – 7.26 (m, 6H), 5.75 (q, J = 6.6 Hz, 1H), 4.34 (s, 1H), 3.92 (d, J = 12.9 Hz, 1H), 3.87 (s, 3H), 3.28 – 3.11 (m, 3H), 2.80 (d, J = 11.3 Hz, 1H), 2.72 – 2.62 (m, 1H), 1.49 (d, J = 6.6 Hz, 3H), 1.37 (d, J = 6.7 Hz, 3H); MS (ESI) m / z [M+H]+calcd. for C25H28N6O2, 445.1; found, 445.1.LCMS purity:254 nm: 99.9%; chiral purity: 99.6%. Example 6: Synthesis of Exemplary Compound 330 (R)-1-phenylethyl 4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-3-yl)-1,4- diazepane-1-carboxylate (Compound 330)Step 1. Preparation of tert-butyl 4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin- 3-yl)-1,4-diazepane-1-carboxylate

[0525] To a solution of 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Compound S5) (500 mg, 1.80 mmol) and tert-butyl 1,4-diazepane-1-carboxylate (1.80 g, 9.00 mmol) in tBuOH (6 mL) and dioxane (3 mL) was added KOtBu (302 mg, 2.70 mmol) and tBuXPhos Pd G1 (185 mg, 0.27 mmol) under nitrogen then the reaction was stirred at 60°C under nitrogen for 16 h. The mixture was concentrated under reduced pressure then the residue was purified by silica gel chromatography eluting with EtOAc / PE (2:1) and reversed-phase flash chromatography with a C18 silica gel column eluting with 10% to 70% ACN / water (10mM NH4HCO3) to afford 150 mg (19%) of tert-butyl 4-(6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-3-yl)-1,4-diazepane-1-carboxylate as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.06 (d, J = 4.4 Hz, 1H), 8.74 (d, J = 5.6 Hz, 1H), 8.16 (s, 1H), 7.97 (s, 1H), 7.65 (d, J = 9.2 Hz, 1H), 3.87 (s, 3H), 3.71 – 3.63 (m, 1H), 3.60 – 3.48 (m, 5H), 3.35 – 3.24 (m, 2H), 1.90 – 1.81 (m, 2H), 1.37 – 1.01 (m, 9H); MS (ESI) m / z [M+H]+calcd. for C20H27N7O2, 398.2; found, 398.3. Step 2. Preparation of 3-(1,4-diazepan-1-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazine hydrochloride salt

[0526] To a solution of tert-butyl 4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin- 3-yl)-1,4-diazepane-1-carboxylate (150 mg, 0.38 mmol, as prepared in the previous step) in dioxane (5 mL) was added 4M HCl in dioxane (5 mL) then the reaction was stirred at rt for 1 h. The mixture was concentrated under reduced pressure to afford 170 mg (135%) of 3-(1,4-diazepan-1-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine hydrochloride salt as a red solid. MS (ESI) m / z [M+H]+calcd. for C15H19N7, 298.2; found, 298.3.Step 3. Preparation of (R)-1-phenylethyl 4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-3-yl)-1,4-diazepane-1-carboxylate (Compound 330).

[0527] To a solution of 3-(1,4-diazepan-1-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazine hydrochloride salt (75 mg, 0.25 mmol, as prepared in the previous step), (R)-1- phenylethan-1-ol (37.0 mg, 0.30 mmol), and pyridine (79.8 mg, 1.01 mmol) in DCM (2 mL) cooled to 0°C was added triphosgene (22.5 mg, 0.08 mmol) in small portions then the reaction was stirred at 0°C for 1h. MeOH (2 mL) was added then the mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC to afford 16.3 mg (14%) of (R)-1-phenylethyl 4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazin-3-yl)-1,4-diazepane-1-carboxylate (Compound 330) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.11 – 9.02 (m, 1H), 8.79 – 8.71 (m, 1H), 8.17 (s, 1H), 7.97 (s, 1H), 7.66 (d, J = 3.0 Hz, 1H), 7.34 – 7.15 (m, 4H), 7.15 – 7.06 (m, 1H), 5.66 – 5.47 (m, 1H), 3.88 (s, 3H), 3.83 – 3.69 (m, 1H), 3.69 – 3.34 (m, 7H), 2.03 – 1.70 (m, 2H), 1.41 – 1.15 (m, 3H); MS (ESI) m / z [M+H]+calcd. for C24H27N7O2, 446.2; found, 446.1; LCMS purity: 254 nm: 99.0%. Example 7: Synthesis of Exemplary Compound 328 (R)-1-phenylethyl 4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-1,4- diazepane-1-carboxylate (Compound 328)Step 1. Preparation of tert-butyl 4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3- yl)-1,4-diazepane-1-carboxylate

[0528] To a solution of 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (Compound S9) (500 mg, 1.80 mmol) and tert-butyl 1,4-diazepane-1-carboxylate (1.81 g, 9.02 mmol) in tBuOH (6 mL) and dioxane (3 mL) were added KOtBu (304 mg, 2.71 mmol) and tBuXPhos Pd G1 (186 mg, 0.27 mmol) under nitrogen, then the reaction was stirred at 60℃ under nitrogen for 16 h. The mixture was concentrated under reduced pressure then the residue was purified by silica gel chromatography eluting with EtOAc / PE (1:1) and reversed-phase flash chromatography with a C18 silica gel column eluting with 10% to 70% ACN / water (10mM NH4HCO3) to afford 255 mg (32%) of tert-butyl 4-(6-(1-methyl- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-1,4-diazepane-1-carboxylate as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.73 (s, 1H), 8.19 (s, 1H), 7.94 (s, 1H), 7.65 (d, J = 9.2 Hz, 1H), 7.57 (d, J = 9.4 Hz, 1H), 7.24 – 7.14 (m, 1H), 3.86 (s, 3H), 3.55 – 3.49 (m, 2H), 3.46 – 3.39 (m, 1H), 3.39 – 3.32 (m, 4H), 3.30 (s, 1H), 1.91 – 1.79 (m, 2H), 1.46 – 1.13 (m, 9H); MS (ESI) m / z [M+H]+calcd. for C21H28N6O2, 397.2; found, 397.3. Step 2. Preparation of 3-(1,4-diazepan-1-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridine hydrochloride salt

[0529] To a solution of tert-butyl 4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin- 3-yl)-1,4-diazepane-1-carboxylate (245 mg, 0.62 mmol, as prepared in the previous step) in dioxane (6 mL) was added 4M HCl in dioxane (12 mL) then the reaction was stirred at rt for 1 h. The mixture was concentrated under reduced pressure to afford 290 mg (87%) of 3-(1,4-diazepan-1-yl)-6-(1-methyl-1H-pyrazol-4-yl) pyrazolo[1,5-a]pyridine hydrochloride salt as a light yellow solid. MS (ESI) m / z [M+H]+calcd. for C16H20N6, 297.2; found, 297.3.Step 3. Preparation of (R)-1-phenylethyl 4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridin-3-yl)-1,4-diazepane-1-carboxylate (Compound 328)

[0530] To a solution of 3-(1,4-diazepan-1-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridine hydrochloride salt (50 mg, 0.17 mmol, as prepared in the previous step), (R)-1- phenylethan-1-ol (25 mg, 0.20 mmol) and pyridine (20 mg, 0.25 mmol) in DCM (2 mL) cooled to 0°C was added triphosgene (15 mg, 0.05 mmol) in small portions then the reaction was stirred at 0°C for 1 h. The mixture was concentrated under reduced pressure then the residue was purified by Prep-HPLC to afford 54 mg (72%) of (R)-1-phenylethyl 4-(6-(1- methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-1,4-diazepane-1-carboxylate (Compound 328) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.76 – 8.71 (m, 1H), 8.20 (s, 1H), 7.95 (s, 1H), 7.66 (d, J = 1.2 Hz, 1H), 7.60 – 7.53 (m, 1H), 7.34 (d, J = 4.3 Hz, 2H), 7.31 – 7.18 (m, 4H), 5.75 – 5.59 (m, 1H), 3.87 (s, 3H), 3.75 – 3.49 (m, 3H), 3.49 – 3.41 (m, 2H), 3.41 – 3.33 (m, 2H), 3.31 – 3.22 (m, 1H), 2.01 – 1.73 (m, 2H), 1.50 – 1.27 (m, 3H); MS (ESI) m / z [M+H]+calcd. for C25H28N6O2, 445.2; found, 445.1; LCMS purity: 254 nm: 99.4% Example 8: Synthesis of Exemplary Compound 331 3-(4-(5-benzylpyrimidin-2-yl)-1,4-diazepan-1-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazine (Compound 331)

[0531] To a solution of 3-(1,4-diazepan-1-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyrazine hydrochloride salt (50.0 mg, 0.15 mmol, as prepared in Example 6, Step 2) and DIEA (58.1 mg, 0.45 mmol) in IPA (2 mL) was added 5-benzyl-2-chloropyrimidine (Compound S88) (30.7 mg, 0.15 mmol) then the reaction was stirred at 100°C for 16 h. The mixture was cooled to rt and concentrated under reduced pressure then the residue was purified by Prep-HPLC to afford 26.1 mg (37%) of 3-(4-(5-benzylpyrimidin-2-yl)-1,4-diazepan-1-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Compound 331) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.04 (d, J = 1.5 Hz, 1H), 8.70 (d, J = 1.4 Hz, 1H), 8.19 (s, 2H), 8.16 (s, 1H), 7.96 (d, J = 0.8 Hz, 1H), 7.63 (s, 1H), 7.32 – 7.23 (m, 2H), 7.22 – 7.14 (m, 3H), 3.96 (t, J = 5.4 Hz, 2H), 3.87 (s, 3H), 3.73 (s, 2H), 3.67 (t, J = 6.0 Hz, 2H), 3.65 – 3.60 (m, 2H), 3.51 – 3.46 (m, 2H), 2.01 – 1.91 (m, 2H); MS (ESI) m / z [M+H]+calcd. for C26H27N9, 466.2; found, 466.1; LCMS purity: 254 nm: 99.1% Example 9: Synthesis of Exemplary Compound 332 tert-butyl 8-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (Compound 332)

[0532] To a round bottom flask containing 3-bromo-6-(1-methyl-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine (Compound S9) (200 mg, 0.72 mmol) and tert-butyl-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (613 mg, 2.89 mmol) was added tBuOH (2 mL) and dioxane (1 mL). The solution was sparged with nitrogen for 20 min at rt then tBuXPhos Pd G1 (50 mg, 0.07 mmol) and KOtBu (121 mg, 1.08 mmol) were added and the reaction mixture was sparged with nitrogen for 5 min at rt. The reaction was heated to 60°C for 4 h, cooled to rt, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 10-60% acetone / DCM to afford 166 mg (56%) of tert- butyl 8-[6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]piperazine-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (Compound 332).1H NMR (400 MHz, CDCl3) δ (ppm) 8.42 (s, 1H), 7.74 (s, 1H) 7.61 (s, 1H) 7.57 (s, 1H) 7.51 (d, J = 9.3 Hz, 1H) 7.27 (s, 1H) 7.10 (dd, J = 9.2, 1.5 Hz, 1H) 3.98 (s, 3H) 3.75-3.91 (m, 4H) 3.25-3.36 (m, 2H) 2.04 (d, J = 4 Hz, 2H) 1.81 (dd, J = 13, 7.4 Hz, 2H) 1.49 (s, 9H); MS (ESI) m / z [M+H]+calcd. for C22H29N6O2, 409.2; found, 409.2; HPLC purity: 210 nm: 100%; 254 nm: 100%. Example 10: Synthesis of Exemplary Compound 333 3-(4-(isobutylsulfonyl)cyclohexyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (Compound 333)Step 1. Preparation of 4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]p...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I:, or a pharmaceutically acceptable salt or solvate thereof, wherein: indicates a single bond or a double bond such that all valences are satisfied; X1, X2, X3, and X4are selected from N and CRa, with the proviso that not more than two of X1, X2, X3, and X4are N; one of Y1and Y2is N and the other of Y1and Y2is C; each Rais independently selected from H, halo, C1-C4alkyl, and C1-C4alkoxy; R1is selected from C1-C4alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, heteroaryl, aryl, and C1-C8alkoxy, all of which can be optionally substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, oxo, C1-C4alkyl, aminoC1-C4alkyl, hydroxyC1- C4alkyl, C1-C4alkoxy, C1-C4alkoxyC1-C4alkyl, 3-8 membered heterocyclyl, and 3-8 membered heterocyclylC1-C4alkyl, with the proviso that the number of substituents does not exceed the number of substitutable positions; R2is selected from cycloalkyl, cycloalkenyl, alkyl, oxoalkylamino, aminoalkylamino, amino, heterocyclyl, heteroaryl, aminoheterocyclyl, heterocyclylamino, and aminoalkylamino, all of which can be optionally substituted with one or more substituents selected from D, halo, hydroxy, oxo, and C1-C4alkyl; R2is substituted with one, two, or three R3; R3is selected from aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)NR31R32, -S(O)2NR31R32, -S(O)(NR33)R31, -S(O)2R31, -S(O)(NR33)NR31R32, -C(S)NR31R32, C3-C8cycloalkyl, 3-8 membered heterocyclyl, and C1-C4alkyl, all of which can be optionally substituted with one, two, three, four, or five R30;each R30is independently selected from D, halo, aryl, -OR300, -NR300R303, -S(O)rR300, -C(O)R300, -C(=CR34R35)R300, and; r is selected from 0, 1, and 2; each R300is independently selected from C1-C6alkyl, C3-C7cycloalkyl, aryl, heteroaryl, 3-8 membered heterocyclyl, and 3-8 membered heterocyclylaryl, all of which can be optionally substituted with one, two, three, four, or five substituents selected from D, halo, hydroxy, amino, alkylamino, cyano, C1-C4alkyl, C1-C4haloalkyl, and C1-C4alkoxy; each R301is independently selected from H, halo, and C1-C4alkyl; each R302is independently selected from H, F, hydroxyl, amino, alkylamino, oxo, and C1-C4alkyoxy; each R303is independently selected from H and C1-C4alkyl; n, o, and p are each independently selected from 0, 1, 2, 3, and 4; each R31is independently selected from C1-C8alkyl, arylC1-C4alkyl, heteroarylC1- C4alkyl, heterocyclyl, heterocyclylC1-C4alkyl, cycloalkyl, and cycloalkylC1-C4alkyl, all of which can be optionally substituted with one, two, three, four, or five substituents selected from D, halo, cyano, hydroxy, amino, -OCF3, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, hydroxyC1-C4alkyl, -S(O)2NR304R305, -C(O)OR304R305, -C(O)NR304R305, and - NR304C(O)R305; each R304and R305is independently selected from H and C1-C4alkyl; each R32is independently selected from H and C1-C4alkyl; or R31and R32together with the atom to which they are connected to form a 5-8 membered heterocycyl, optionally substituted with one, two, three, four, or five substituents selected from D, halo, cyano, C1-C4alkyl, C1-C4haloalkyl, and -C(O)NR34R35; and each R34and R35is independently selected from H, C1-C4alkyl, and C1-C4haloalkyl; and each R33is independently selected from H, C1-C4alkyl, C1-C4haloalkyl, and – C(O)R34; orR31and R33together with the atoms to which they are connected form a 4-8 membered heterocycyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Y1is N and Y2is C.

3. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Y1is C and Y2is N.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein X1is N, X2is CRa, X3is CRa, and X4is CRa.

5. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein X1is CRa, X2is N, X3is CRa, and X4is CRa.

6. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein X1is CRa, X2is CRa, X3is N, and X4is CRa.

7. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein X1is CRa, X2is CRa, X3is CRa, and X4is N.

8. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein X1is CRa, X2is CRa, X3is CRa, and X4is CRa.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is 5- or 6-membered heteroaryl.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is an optionally substituted pyrazolyl.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein: R1is selected from:, , d R10is selected from H, C1-C4alkyl, C1-C4alkoxy, aminoC1-C4alkyl, hydroxyC1- C4alkyl, and C1-C4alkylsulfonyl, wherein the C1-C4alkyl, C1-C4alkoxy, aminoC1-C4alkyl, hydroxyC1-C4alkyl, and C1-C4alkylsulfonyl can be optionally substituted by one or more substituents selected from hydroxyl, C1-C4alkoxy, NR10aR10b, halo, and deuterium, wherein R10aand R10bare selected from hydrogen and C1-C4alkyl, or wherein R10aand R10btaken together with the nitrogen atom to which they are attached form a 4- to 8- membered ring.

12. The compound of claim 11, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is.

13. The compound of claim 11 or 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R10is CH3.

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is heterocyclyl optionally substituted with C1-C4alkyl or oxo.

15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is substituted with one R3.

16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from:,,,, , , ,indicates a single bond or a double bond such that all valences are satisfied; m is selected from 0, 1, 2, 3, 4, 5, and 6; and Z1, Z2, and Z3are selected from N and CRa.

17. The compound of claim 16, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from:, , , , .

18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, having Formula Ia:wherein a and b are each independently selected from 1, 2, and 3; and Q is selected from -CH- and -N-, with the proviso that if Q is -N-, a and b are not 1.

19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt or solvate thereof, having Formula II:.

20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt or solvate thereof, having Formula IIa:.

21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is heteroaryl optionally substituted with one, two, three, four, or five R30.

22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from: ,, , , , ,, ,, wherein A1is selected from O, S, and NR37, R36is selected from hydrogen, optionally substituted C1-C6alkyl, and optionally substituted C1-C6alkylaryl, and R37is selected from hydrogen and C1-C6alkyl.

23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from:, ,,, , .

24. The compound of any of claims 1 to 23, or a pharmaceutically acceptable salt or solvate thereof, wherein R30is:.

25. The compound of claim 24, or a pharmaceutically acceptable salt or solvate thereof, wherein R300is selected from:, , , , , ,,, , , , , .

26. The compound of claim 25, or a pharmaceutically acceptable salt or solvate thereof, wherein R300is:.

27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt or solvate thereof, wherein R301is H and R302is H or CH3.

28. The compound of any of claims 1 to 22, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from:

29. The compound of claim 28, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from:, , .

30. The compound of claim 29, or a pharmaceutically acceptable salt or solvate thereof, wherein R32is H.

31. The compound of any one of claims 28 to 30, or a pharmaceutically acceptable salt or solvate thereof, wherein R31is selected from:, , ,, , , ,, wherein R31ais selected from H, D, alkylamino, optionally substituted C1-C4alkyl, C1-C4alkoxy, amino, and C1-C4haloalkyl, each R31bis independently selected from H, D, halo, hydroxy, amino, cyano, alkylamino, optionally substituted C1-C4alkyl, C1-C4haloalkyl, optionally substituted C1- C4alkoxy, and C3-C6cycloalkyl, , and q is 1, 2, or 3.

32. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, selected from any one of the compounds of Table 1.

33. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt or solvate thereof, which can exhibit one or more of the following properties: (i) promote the differentiation of an OPC into an oligodendrocyte, (ii) promote the expression of a protein associated with oligodendrocyte differentiation and / or myelination (e.g., G-protein coupled receptor 17 (GPR17), myelin basic protein (MBP), ASPA, GST-pi, CC1, myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein / claudin-11, CNPase, proteolipid protein 1 (PLP1), or a combination thereof), (iii) promote the myelination of an axon, (iv) promote the remyelination of a demyelinated axon, (v) inhibit PDGFRα kinase activity, (vi) achieve a brain to plasma ratio of greater than 0.1 when systemically administered to a subject, and (vii) any combination thereof.

34. The compound of claim 33, or a pharmaceutically acceptable salt or solvate thereof, which can inhibit PDGFRα kinase activity.

35. The compound of claim 34, or a pharmaceutically acceptable salt or solvate thereof, which can inhibit PDGFRα kinase activity with an IC50of less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 75 nM, less than less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 2.5 nM, less than 1 nM, less than 0.5 nM, or less than 0.2 nM.

36. The compound of claim 35, or a pharmaceutically acceptable salt or solvate thereof, wherein the IC50of the PDGFRα inhibitor is determined using an enzymatic PDGFRα kinase assay (e.g., Promega kinase assay described in Example 131).

37. The compound of claim 36, or a pharmaceutically acceptable salt or solvate thereof, wherein the enzymatic PDGFRα kinase assay comprises 20 ng of purified PDGFRα protein, 150 µM of ATP and 1 µg of substrate, Poly (Glu4Tyr1) in a volume of 15 µl.

38. A pharmaceutical composition comprising the compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

39. A kit comprising the compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt or solvate thereof, or the composition of claim 38, and instructions for use.

40. A compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 38, for use in therapy.

41. A method of treating a demyelinating disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 38.

42. A method of improving a subject's performance in a test for assessing one or more symptoms associated with a demyelinating disease, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition ofclaim 38, wherein after the administration, the subject's performance in the test is improved as compared to a reference subject (e.g., the subject prior to the administration).

43. The method of claim 42, wherein the test is one or more of a visual evoked potential (VEP) test, a multifocal visual evoked potential (mfVEP) test, a low contrast visual acuity (LCVA) test, a magnetic resonance imaging (MRI) (e.g., magnetization transfer ratio (MTR), myelin water fraction (MWF), quantitative susceptibility mapping (QSM), and T2 imaging), an electromyography (EMG), a nerve conduction velocity (NCV) test, an Extended Disability Status Scale (EDSS), a timed walk test (e.g., timed 25-foot walk), a Nine-Hole Peg Test (9HPT), an ocular coherence tomograph (OCT), a quality of life measure test (e.g., Multiple Sclerosis Quality of Life-54 and Vision-Related Quality of Life), cognitive assessment (e.g., Symbol Digit Modalities Test or Montreal Cognitive Assessment), or combinations thereof.

44. The method of any one of claims 41 to 43, wherein the demyelinating disease comprises one or more of an acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalitis, acute transverse myelitis, adrenoleukodystrophy, adrenomyeloneuropathy, Alexander disease, Alzheimer's disease, aminoacidurias, amyotrophic lateral sclerosis, anti-MAG peripheral neuropathy, anti-MOG associated spectrum, Balo concentric sclerosis, brain injury, CAMFAK syndrome, Canavan disease, carbon monoxide toxicity, central pontine myelinolysis, cerebral hypoxia, cerebral ischemia, Charcot–Marie–Tooth disease, chronic inflammatory demyelinating polyneuropathy, chronic traumatic encephalopathy, clinically isolated syndrome (CIS), congenital cataract, copper deficiency associated condition, delayed post-hypoxic leukoencephalopathy, diffuse cerebral sclerosis of Schilder, diffuse myelinoclastic sclerosis, extrapontine myelinolysis Gaucher disease, Guillain–Barré syndrome, hereditary neuropathy, hereditary neuropathy with liability to pressure palsy, HTLV-1–associated myelopathy, Hurler syndrome, hypomyelination, hypoxic brain injury, Krabbe disease, Leber hereditary optic atrophy and related mitochondrial disorders, leukodystrophic disorders, Marchiafava-Bignami disease, metachromatic leukodystrophy, multiple sclerosis (e.g., primary progressive multiple sclerosis (PPMS), relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), progressive relapsing multiple sclerosis, Marburg multiple sclerosis, tumefactive multiple sclerosis, and optic-spinal multiple sclerosis), multiple system atrophy, myelinoclastic disorders, myelopathy, nerve injury, neuromyelitis optica (NMO), Niemann-Pick disease, optic neuropathy, optic neuritis (e.g., acute optic neuritis and chronic relapsing inflammatory optic neuritis (CRION)), osmotic demyelination syndrome, Parkinson's disease, Pelizaeus‐Merzbacher disease, peripheral neuropathy, phenylketonuria, progressive inflammatory neuropathy, progressive multifocal leukoencephalopathy, progressive subcortical ischemic demyelination, reperfusion injury, Schilder disease, solitary sclerosis, spinal cord injury, subacute sclerosing panencephalitis, Tabes dorsalis, Tay-Sachs disease, transverse myelitis, traumatic brain injury, tropical spastic paraparesis, vitamin B12 deficiency, and cerebral palsy.

45. The method of any one of claims 41 to 44, wherein the demyelinating disease is characterized by demyelination of one or more cells within the CNS of the subject.

46. The method of any one of claims 41 to 45, wherein the demyelinating disease is multiple sclerosis.

47. The method of claim 46, wherein the multiple sclerosis comprises a clinically isolated syndrome ("CIS"), relapsing-remitting MS ("RRMS"), secondary progressive MS ("SPMS"), primary progressive MS ("PPMS"), optic neuritis or transverse myelitis.

48. The method of any one of claims 41 to 45, wherein the demyelinating disease is an optic neuritis.

49. The method of any one of claims 41 to 48, wherein treating the demyelinating disease comprises reducing one or more symptoms associated with the demyelinating disease.

50. The method of claim 49, wherein the one or more symptoms comprise one or more of fatigue, dizziness, malaise, elevated fever and high body temperature, extreme sensitivity to cold in the hands and feet, weakness and stiffness in muscles and joints, weight changes, digestive or gastrointestinal problems, low blood pressure, high blood pressure, irritability, anxiety, depression, impaired vision (e.g., blurred vision, double vision, reduction in low contrast visual acuity (LCVA)), ataxia, clonus, spasms, dysarthria, weakness, clumsiness, hand paralysis, hemiparesis, genital anesthesia, sexual dysfunction, incoordination, paresthesias, ocular paralysis, impaired muscle coordination, loss of sensation, tingling,numbness, pain, neurological symptoms, impaired cognition, unsteady gait, balance problems, dizziness, spastic paraparesis, incontinence, hearing problems, speech problems, loss of olfaction, and agusia.

51. A method of promoting the myelination of an axon in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 38.

52. The method of claim 51, wherein promoting the myelination of an axon results in an increase in the expression of one or more of the following markers within the subject: myelin basic protein (MBP) Myelin Oligodendrocyte Glycoprotein (MOG), Oligodendrocyte Specific Protein / Claudin-11, CNPase, proteolipid protein 1 (PLP1), or any combination thereof.

53. The method of claim 51 or 52, wherein the myelination of an axon can be determined by visualizing and / or quantifying the expression of one or more of the following markers: myelin basic protein (MBP) Myelin Oligodendrocyte Glycoprotein (MOG), Oligodendrocyte Specific Protein / Claudin-11, CNPase, proteolipid protein 1 (PLP1), or any combination thereof.

54. A method of promoting the remyelination of a demyelinated axon in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 38.

55. The method of claim 54, wherein promoting the remyelination of a demyelinated axon results in an increase in the expression of one or more of the following markers within the subject: myelin basic protein (MBP) Myelin Oligodendrocyte Glycoprotein (MOG), Oligodendrocyte Specific Protein / Claudin-11, CNPase, proteolipid protein 1 (PLP1), or any combination thereof 56. The method of claim 54 or 55, wherein the remyelination of a demyelinated axon can be determined by visualizing and / or quantifying the expression of one or more of the following markers: myelin basic protein (MBP) Myelin Oligodendrocyte Glycoprotein (MOG),Oligodendrocyte Specific Protein / Claudin-11, CNPase, proteolipid protein 1 (PLP1), or any combination thereof.

57. A method of reducing the demyelination of a myelinated neuronal axon in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 38.

58. The method of claim 57, wherein reducing the demyelination of a myelinated neuronal axon results in an increase in the expression of one or more of the following markers: myelin basic protein (MBP) Myelin Oligodendrocyte Glycoprotein (MOG), Oligodendrocyte Specific Protein / Claudin-11, CNPase, proteolipid protein 1 (PLP1), or any combination thereof.

59. The method of claim 57 or 58, wherein the reduction in the demyelination of a myelinated neuronal axon can be determined by visualizing and / or quantifying the expression of one or more of the following markers: myelin basic protein (MBP) Myelin Oligodendrocyte Glycoprotein (MOG), Oligodendrocyte Specific Protein / Claudin-11, CNPase, proteolipid protein 1 (PLP1), or any combination thereof.

60. A method of activating an oligodendrocyte progenitor cell (OPC) within the central nervous system (CNS) of a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 38.

61. A method according to any one of claims 51 to 60, wherein the subject has, or is at risk of developing a demyelinating disease, for example a disease according to any one of claims 44 to 50.

62. A method according to any one of claims 51 to 60, wherein the method is a method of treating or preventing a demyelinating disease, for example a disease according to any one of claims 44 to 50.

63. The method of any one of claims 41 to 62, wherein the compound or the pharmaceutical composition is administered to the subject once.

64. The method of any one of claims 41 to 62, wherein the compound or the pharmaceutical composition is administered to the subject more than once using intermittent dosing.

65. The method of claim 64, wherein the intermittent dosing comprises administering the compound or the pharmaceutical composition to the subject every other day, every three days, every four days, every five days, every six days, once a week, every eight days, every nine days, every 10 days, every 11 days, every 12 days, every 13 days, once every two weeks, once every three weeks, once a month, once every two months, once every three months, once every four months, once every five months, once every six months, or once every twelve months.

66. The method of claim 64 or 65, wherein the intermittent dosing comprises administering to the subject a first dose and a second dose of the compound or the pharmaceutical composition, wherein the second dose is administered at least one day, at least two days, at least three days, at least four days, at least five days, at least six days, at least seven days, at least eight days, at least nine days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least two weeks, at least three weeks, at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, or at least 12 months after administering the first dose.

67. The method of claim 66, wherein the second dose is administered to the subject one day, two days, three days, four days, five days, six days, seven days, eight days, nine days, 10 days, 11 days, 12 days, 13 days, two weeks, three weeks, one month, two months, three months, four months, five months, six months, or 12 months after administering the first dose.

68. The method of any one of claims 41 to 67, wherein after the administration, the compound or the pharmaceutical composition can achieve a brain to plasma ratio of greater than 0.1, greater than 0.2, greater than 0.3, greater than 0.4, greater than 0.5, greater than 0.6, greater than 0.7, greater than 0.8, greater than 0.9, greater than 1.0, greater than 1.1, greater than 1.2, greater than 1.3, greater than 1.4, greater than 1.5, greater than 1.6, greater than 1.7, greater than 1.8, greater than 1.9, or greater than 2.0.

69. The method of any one of claims 41 to 68, further comprising administering to the subject an additional therapeutic agent.

70. The method of claim 69, wherein the additional therapeutic agent comprises a standard care of treatment.

71. The method of claim 69 or 70, wherein the additional therapeutic agent comprises an immunomodulatory agent.

72. The method of claim 71, wherein the additional therapeutic agent is selected from interferon beta-1b, interferon beta-1a, peginterferon beta-1a, alemtuzumab, natalizumab, ocrelizumab, ofatumumab, ublituximab-xiiy, glatiramer acetate, teriflunomide, dimethyl fumarate, monomethyl fumarate, diroximel fumarate, fingolimod hydrochloride, siponimod fumaric acid, ozanimod hydrochloride, ponesimod, cladribine, mitoxantrone, a BTK inhibitor, a statin, or a pharmaceutically acceptable salt thereof.

73. The method of any one of claims 69 to 72, wherein the additional therapeutic agent is administered to the subject prior to, concurrently, or after the administration of the compound or the pharmaceutical composition.

74. A method of inducing the differentiation of an oligodendrocyte progenitor cell (OPC) into an oligodendrocyte, the method comprising contacting the OPC with an effective amount of the compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 38.

75. The method of claim 74, wherein inducing the differentiation of the OPC into an oligodendrocyte results in an increase in the expression of the following markers in the subject: GPR17, MBP, ASPA, GST-pi, CC1, myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein / claudin-11, CNPase, proteolipid protein 1 (PLP1), or a combination thereof.

76. The method of claim 74 or 75, wherein the differentiation of the OPC into an oligodendrocyte is measured by determining the expression of GPR17, MBP, ASPA, GST- pi, CC1, myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein / claudin-11, CNPase, proteolipid protein 1 (PLP1), or a combination thereof.

77. A method of inhibiting PDGFRα activity in a cell, the method comprising contacting the cell with an effective amount of the compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 38.

78. The method of claim 77, wherein the inhibition of the PDGFRα activity is measured by one or more of the following: an in vitro OPC differentiation assay (e.g., as described in Example 132), a cuprizone model for demyelination, an in vivo OPC differentiation assay (e.g., as described in Example 134), an enzymatic PDGFRα kinase assay (e.g., as described in Example 131), or any combination thereof.

79. The method of any one of claims 74 to 78, wherein the contacting occurs ex vivo or in vivo.

80. The method of any one of claims 74 to 79, wherein the method is a method of treating by a therapy.

81. A method of treating a relapsing form of multiple sclerosis in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 38.

82. The method of claim 81, wherein inducing the differentiation of the OPC into an oligodendrocyte results in an increase in the expression of the following marker in the subject: GPR17, MBP, ASPA, GST-pi, CC1, myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein / claudin-11, CNPase, proteolipid protein 1 (PLP1), or a combination thereof.

83. The method of claim 81 or 82, wherein the differentiation of the OPC into an oligodendrocyte is measured by determining the expression of GPR17, MBP, ASPA, GST- pi, CC1, myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein / claudin-11, CNPase, proteolipid protein 1 (PLP1), or a combination thereof.

84. The method of any one of claims 81 to 83, wherein the relapsing form of multiple sclerosis comprises a clinically isolated syndrome ("CIS"), relapsing-remitting MS ("RRMS"),secondary progressive MS ("SPMS"), primary progressive MS ("PPMS"), or transverse myelitis.

85. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 38, for use in a method of one or more of the following: (i) promote the differentiation of an OPC into an oligodendrocyte, (ii) promote the expression of a protein associated with oligodendrocyte differentiation and / or myelination (e.g., G-protein coupled receptor 17, myelin basic protein (MBP), ASPA, GST-pi, CC1, myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein / claudin-11, CNPase, proteolipid protein 1 (PLP1), or a combination thereof), (iii) promote the myelination of an axon, (iv) promote the remyelination of a demyelinated axon, (v) inhibit PDGFRα kinase activity, (vi) achieve a brain to plasma ratio of greater than 0.1 when systemically administered to a subject, and (vii) any combination thereof.

86. A method of treating a PDGF-associated tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 38, wherein after the administration, PDGFRα activity is reduced in the subject.

87. The method of claim 86, wherein the PDGF-associated tumor comprises an oligodendroglioma.

88. The method of claim 86 or 87, wherein the method is a method of treatment by therapy.

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