Imidazo-pyrazine derivatives and their use in the treatment of neurologic disorders

Abstract

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Description

IMIDAZOPYRIDINE DERIVATIVES AND METHODS OF USE RELATED APPLICATIONS

[0001] This application claims priority to U.S Provisional Application No. 63 / 554,888, filed February 16, 2024, the entire contents of which is incorporated herein by reference. BACKGROUND

[0002] Astrocytes are the most abundant glial cell type in the central nervous system (CNS). They play a role in CNS development and homeostasis associated with the control of synaptic activity, metabolism, and the maintaining the blood-brain barrier. Astrocytes also contribute to the pathology of neurologic disorders through both cell autonomous neurotoxic mechanisms, as well as cell non-autonomous neurotoxic mechanisms such as the recruitment of pro- inflammatory monocytes, the induction of microglial neurotoxic activity, the decreased support of neuron metabolism, the secretion of soluble neurotoxic molecules, and the direct uptake of synaptic and neuronal processes. Astrocytes and microglia are known to mutually regulate their activities through both secreted factors as well as contact-mediated mechanisms.

[0003] Neurodegenerative diseases affect a significant segment of the global population and represent a tremendous healthcare burden with unmet medical need. For example, multiple sclerosis (MS) is one of the most common neurodegenerative disorders that affects approximately 2.3 million people world-wide with an estimated socioeconomic burden of more than $1 billion. Microglia and astrocytes establish cell contacts during CNS inflammation. For example, bi-directional signaling involving membrane-bound Ephrin receptor B3 (EphB3) in astrocytes and its membrane-bound ligand Ephrin-B3 in microglia promotes pathology in neurodegenerative disorders, such as autoimmune encephalomyelitis (AE) and in MS. EphB3 is a receptor in the ephrin receptor tyrosine kinase family. Ephrin receptors (Ephs) and their ligands, the ephrins, mediate numerous developmental processes, particularly in the nervous system and vascular systems. For example, EphB3 has been suggested to be neuroprotective in stroke and neurodegenerative disease. Upregulation of EphB3 expression after injury may also contribute to an environment in the spinal cord that is inhibitory to axonal regeneration. Therefore, compounds that may inhibit EphB3 signaling would be capable of ameliorating acute and chronic progressive AE and MS and other neurodegenerative diseases.

[0004] This disclosure arises from the need to provide further compounds for the modulation of EphB3. In particular, compounds with improved physiochemical, pharmacological, and pharmaceutical properties to existing compounds are desirable. SUMMARY

[0005] In some aspects, the present disclosure relates to a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:attachment and ** indicates amide attachment; R1is C6-C10aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R1a; each R1a independently is halo, -OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, or -C(O)N(R1b)(R1c), or two R1a, together with the atoms to which they are attached, form a C3-C6cycloalkyl or 5- to 6-membered heterocycle; each R1b independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; each R1cindependently is C6-C10aryl optionally substituted with one or more halo, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxyl; R2is C2-C6alkenyl or -C(O)R2a, wherein the C2-C6alkenyl is optionally substituted with one or more R2b; R2a is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more R2b;each R2b independently is halo, -N(R2c)(R2d), -OR2c, -CO2(R2c), C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R2e; each R2c independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R2f; each R2d independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; each R2eindependently is halo, -CN, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 haloalkyl, C1-C7 alkoxy, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -CO(C1-C6 alkyl), or -CO2(C1-C6alkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more -CN, -OH, C1-C6 alkoxy, -NH-CO2(C1-C6 alkyl), or -NH2; each R2findependently is halo, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -CO2(R2g), -CON(R2g)(R2h), C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -C(O)-NH(C1-C6 alkyl-C1-C6 alkoxy), –(O(C2alkyl))1-6, or –(O(C2alkyl))1-6-NH2; each R2gindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, C1-C6alkyl, or C1-C6 haloalkyl; each R2h independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; R3 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, or 5- to 10-membered heterocyclyl, or two R3, together with the atoms to which they are attached, form a C3-C6cycloalkyl or 5- to 6-membered heterocycle; and n is 0, 1, 2, 3, or 4.

[0006] In some aspects, the present disclosure relates to a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:attachment and ** indicates amide attachment; R1 is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R1a; each R1aindependently is halo, -OH, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxyl, or -C(O)N(R1b)(R1c), or two R1a, together with the atoms to which they are attached, form a C3-C6 cycloalkyl or 5- to 6-membered heterocycle; each R1bindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; each R1c independently is C6-C10 aryl optionally substituted with one or more halo, C1- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl; R2 is C2-C6 alkenyl or -C(O)R2a, wherein the C2-C6 alkenyl is optionally substituted with one or more R2b; R2ais C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more R2b; each R2b independently is halo, -N(R2c)(R2d), -OR2c, -CO2(R2c), C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R2e; each R2c independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R2f; each R2dindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; each R2e independently is halo, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, -CO(C1-C6alkyl), or -CO2(C1-C6 alkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or -NH2; each R2f independently is halo, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, -CO2(R2g), -CON(R2g)(R2h), C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, or -C(O)-NH(C1-C6alkyl-C1-C6alkoxy); each R2g independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, C1-C6 alkyl, or C1-C6haloalkyl; each R2hindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R3is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, or 5- to 10-membered heterocyclyl; and n is 0, 1, 2, 3, or 4.

[0007] In some aspects, the present disclosure relates to a compound of Formula (II):or a pharmaceutically acceptable salt thereof.

[0008] In some aspects, the present disclosure relates to a compound of Formula (III):or a pharmaceutically acceptable salt thereof.

[0009] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, a method for preparing a compound as described herein.

[0010] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described herein and one or more pharmaceutically acceptable carriers or excipients.

[0011] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein.

[0012] In some aspects, the present disclosure provides a method of modulation of EphB3 activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure.

[0013] In some aspects, the present disclosure provides a compound of the present disclosure for use in modulation of EphB3 activity (e.g., in vitro or in vivo).

[0014] In some aspects, the present disclosure provides use of a compound of the present disclosure in the manufacture of a medicament for modulation of EphB3 activity (e.g., in vitro or in vivo).

[0015] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutical composition of the present disclosure.

[0016] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.

[0017] In some aspects, the present disclosure provides use of a compound of the present disclosure in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0018] In some aspects, the disease or disorder is a neurodegenerative disease or disorder. In some aspects, the neurodegenerative disease or disorder is neuromyelitis optica (“NMO”),transverse myelitis, myelin oligodendrocyte glycoprotein, acute disseminated encephalomyelitis (“ADEM”), optic neuritis, amyloidosis, Parkinson's disease, Alzheimer's disease, cerebral amyloid angiopathy, Pick's disease, frontotemporal dementia, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, amyotrophic lateral sclerosis (“ALS”), Huntington's disease, traumatic brain injury, stroke, fatty liver disease, endometriosis, paraneoplastic disorders, inflammatory demyelinating polyneuropathy, amyotrophy, fibromyalgia, multiple system atrophy, Friedrich's ataxia, or cerebellar ataxia.

[0019] In some aspects, the disease or disorder is a psychiatric or neurodevelopmental disease or disorder. In some aspects, the psychiatric or neurodevelopmental disease or disorder is schizophrenia, major depressive disorder, generalized anxiety disorder, panic disorder, social anxiety disorder, agoraphobia, post-traumatic stress disorder, autism spectrum disorder, cerebral palsy, Nasu Hakola disease, bipolar disorder, or substance abuse

[0020] In some aspects, the disease or disorder is a viral or infectious disease or disorder. In some aspects, the viral or infectious disease or disorder is neuro-HIV, viral encephalitis, meningitis, neurocysticercosis, neurosyphilis, neuro-Lyme disease, infectious myelopathies, COVID-19 neuroinflammation, enteroviruses, poliovirus, Epstein-Barr virus (EBV), human herpesvirus, cytomegalovirus, rabies virus, herpes simplex virus, measles, progressive multifocal leukoencephalopathy John Cunningham (“PML JC”) virus, bacterial meningitis, prion disease, or Creutzfeldt Jakob disease.

[0021] In some aspects, the disease or disorder is an autoimmune disease or disorder. In some aspects, the autoimmune disease or disorder is antibody-mediated encephalitis, neurological complications of connective tissue damage, neurosarcoidosid, demyelinating diseases (non- MS), idiopathic autoimmune CNS and PNS syndromes, paraneoplastic neurological disease, CNS vasculitis, type 1 diabetes, type 2 diabetes, Crohn's disease, systemic lupus erythematous (“SLE”), irritable bowel disorders, asthma, chronic obstructive pulmonary disease (“COPD”), atopic dermatitis, obesity-associated inflammation, heart disease, ulcerative colitis, psoriasis, psoriatic arthritis, reactive arthritis, rheumatoid arthritis, Sjögren's syndrome, Reiter's disease, multiple sclerosis, autoimmune encephalitis, myasthenia gravis, idiopathic pulmonary fibrosis, ankylosing spondylitis, antiphospholipid antibody syndrome, osteomyelitis, gout, Henoch- Schonlein Purpura, dermatomyositis, idiopathic arthritis, scleroderma, Kawasaki disease, mixed connective tissue damage, myositis, spondyloarthritis, undifferentiated connective tissue disease, systemic sclerosis, or autoimmune hepatitis.

[0022] In some aspects, the disease or disorder is an eye disease or disorder. In some aspects, the eye disease or disorder is uveitis, keratitis, conjunctivitis, thyroid eye disease, age-relatedmacular degeneration, glaucoma, diabetic retinopathy, diabetes-related macular edema, or scleritis.

[0023] In some aspects, the disease or disorder is autoimmune encephalomyelitis, chronic inflammatory demyelinating polyneuropathy, concentric sclerosis, Charcot-Marie-Tooth disease, Guillain-Barre syndrome, HTLV-I associated myelopathy (“HAM”), Schilder’s disease, dementia, frontotemporal lobar dementia, accessory nerve disorder, autonomic dysreflexia, peripheral neuropathy, chemotherapy-induced peripheral neuropathies, mononeuropathy, polyneuropathy, radial neuropathy, ulnar neuropathy, Villaret's syndrome, diabetic neuropathy, nerve paralysis, progressive bulbar palsy, pseudobulbar palsy, spinal bulbar muscular atrophy, myotonic dystrophy, inclusion body myositis, seizure disorders, lysosomal storage disorders, transmissible spongiform encephalopathy, spinocerebellar ataxia, spinal muscular atrophy, Horner’s syndrome, adrenoleukodystrophy, macular degeneration, or Lewy Body syndrome.

[0024] In some aspects, the disease or disorder is an ocular inflammatory disease.

[0025] In some aspects, the disease or disorder is autoimmune encephalomyelitis or multiple sclerosis.

[0026] In some aspects, the disease or disorder is amyotrophic lateral sclerosis, Alzheimer’s disease, multiple sclerosis, or Huntington’s disease.

[0027] In some aspects, the Alzheimer’s disease is Alzheimer’s disease with APOE4.

[0028] In some aspects, the multiple sclerosis is progression independent of relapses.

[0029] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure.

[0030] In some aspects, the present disclosure provides a method of preparing a compound, comprising one or more steps described herein.

[0031] Unless otherwise defined, 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 belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. In the case of conflict betweenthe chemical structures and names of the compounds disclosed herein, the chemical structures will control. DETAILED DESCRIPTION

[0032] The disclosure relates to compounds useful for the modulation of EphB3. In particular, compounds with improved physicochemical, pharmacological and pharmaceutical properties to existing EphB3-modulating compounds are desired. Compounds of the Present Disclosure

[0033] In some aspects, the present disclosure relates to a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: Ring, wherein * indicates R2 attachment and ** indicates amide attachment; R1is C6-C10aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R1a; each R1a independently is halo, -OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6alkoxyl, or -C(O)N(R1b)(R1c), or two R1a, together with the atoms to which they are attached, form a C3-C6cycloalkyl or 5- to 6-membered heterocycle; each R1bindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; each R1c independently is C6-C10 aryl optionally substituted with one or more halo, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxyl;R2 is C2-C6 alkenyl or -C(O)R2a, wherein the C2-C6 alkenyl is optionally substituted with one or more R2b; R2ais C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more R2b; each R2b independently is halo, -N(R2c)(R2d), -OR2c, -CO2(R2c), C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R2e; each R2c independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R2f; each R2d independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; each R2e independently is halo, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 haloalkyl, C1-C7 alkoxy, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, -CO(C1-C6alkyl), or -CO2(C1-C6alkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more -CN, -OH, C1-C6 alkoxy, -NH-CO2(C1-C6alkyl), or -NH2; each R2findependently is halo, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6 alkoxy, -CO2(R2g), -CON(R2g)(R2h), C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, -C(O)-NH(C1-C6alkyl-C1-C6alkoxy), –(O(C2alkyl))1-6, or –(O(C2alkyl))1-6-NH2; each R2g independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, C1-C6 alkyl, or C1-C6 haloalkyl; each R2hindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R3 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, or 5- to 10-membered heterocyclyl, or two R3, together with the atoms to which they are attached, form a C3-C6cycloalkyl or 5- to 6-membered heterocycle; andn is 0, 1, 2, 3, or 4.

[0034] In some aspects, the present disclosure relates to a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: Ring, wherein * indicates R2attachment and ** indicates amide attachment; R1 is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R1a; each R1aindependently is halo, -OH, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6 alkoxyl, or -C(O)N(R1b)(R1c), or two R1a, together with the atoms to which they are attached, form a C3-C6cycloalkyl or 5- to 6-membered heterocycle; each R1b independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; each R1cindependently is C6-C10aryl optionally substituted with one or more halo, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxyl; R2 is C2-C6 alkenyl or -C(O)R2a, wherein the C2-C6 alkenyl is optionally substituted with one or more R2b; R2ais C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more R2b; each R2bindependently is halo, -N(R2c)(R2d), -OR2c, -CO2(R2c), C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R2e; each R2c independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R2f; each R2dindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; each R2e independently is halo, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, -CO(C1-C6alkyl), or -CO2(C1-C6 alkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or -NH2; each R2f independently is halo, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, -CO2(R2g), -CON(R2g)(R2h), C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, or -C(O)-NH(C1-C6alkyl-C1-C6alkoxy); each R2g independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, C1-C6 alkyl, or C1-C6haloalkyl; each R2hindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R3is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, or 5- to 10-membered heterocyclyl; and n is 0, 1, 2, 3, or 4.

[0035] It is understood that, for a compound of Formula (I), R1, R1a, R1b, R1c, R2, R2a, R2b, R2c, R2d, R2e, R2f, R2g, R2h, R3, and n can each be, where applicable, selected from the groups described herein, and any group described herein for any of R1, R1a, R1b, R1c, R2, R2a, R2b, R2c, R2d, R2e, R2f, R2g, R2h, R3, and n can be combined, where applicable, with any group described herein for one or more of the remainder of R1, R1a, R1b, R1c, R2, R2a, R2b, R2c, R2d, R2e, R2f, R2g, R2h, R3, and n. Formula (II)

[0036] In some aspects, the present disclosure relates to a compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: R1is C6-C10aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R1a; each R1aindependently is halo, -OH, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxyl, or -C(O)N(R1b)(R1c), or two R1a, together with the atoms to which they are attached, form a C3-C6 cycloalkyl or 5- or 6-membered heterocycle; each R1bindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; each R1c independently is C6-C10 aryl optionally substituted with one or more halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl; R2is C2-C6alkenyl or -C(O)R2a, wherein the C2-C6alkenyl is optionally substituted with one or more R2b; R2ais C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more R2b; each R2b independently is halo, -N(R2c)(R2d), -OR2c, -CO2(R2c), C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R2e; each R2c independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R2f; each R2d independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; each R2eindependently is halo, -CN, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 haloalkyl, C1-C7 alkoxy, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, -CO(C1-C6alkyl), or -CO2(C1-C6alkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy,cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more -CN, - OH, C1-C6 alkoxy, -NH-CO2(C1-C6 alkyl), or -NH2; each R2findependently is halo, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6 alkoxy, -CO2(R2g), -CON(R2g)(R2h), C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -C(O)-NH(C1-C6 alkyl-C1-C6 alkoxy), –(O(C2alkyl))1-6, or –(O(C2alkyl))1-6-NH2; each R2gindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, C1-C6 alkyl, or C1-C6 haloalkyl; each R2h independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; R3 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, or 5- to 10-membered heterocyclyl, or two R3, together with the atoms to which they are attached, form a C3-C6cycloalkyl or 5- to 6-membered heterocycle; and n is 0, 1, 2, 3, or 4.

[0037] In some aspects, the present disclosure relates to a compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: R1is C6-C10aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R1a; each R1a independently is halo, -OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6alkoxyl, or -C(O)N(R1b)(R1c), or two R1a, together with the atoms to which they are attached, form a C3-C6cycloalkyl or 5- or 6-membered heterocycle; each R1bindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl;each R1c independently is C6-C10 aryl optionally substituted with one or more halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxyl; R2is C2-C6alkenyl or -C(O)R2a, wherein the C2-C6alkenyl is optionally substituted with one or more R2b; R2a is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more R2b; each R2bindependently is halo, -N(R2c)(R2d), -OR2c, -CO2(R2c), C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R2e; each R2cindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R2f; each R2d independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; each R2eindependently is halo, -CN, -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -CO(C1-C6 alkyl), or -CO2(C1-C6alkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more -CN, - OH, C1-C6 alkoxy, -NH-CO2(C1-C6 alkyl), or -NH2; each R2findependently is halo, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, -CO2(R2g), -CON(R2g)(R2h), C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, or -C(O)-NH(C1-C6 alkyl-C1-C6 alkoxy); each R2gindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, C1-C6alkyl, or C1-C6haloalkyl; each R2h independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; R3is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, or 5- to 10-membered heterocyclyl; andn is 0, 1, 2, 3, or 4.

[0038] In some embodiments, R1 is C6-C10 aryl optionally substituted with one or more R1a.

[0039] In some embodiments, R1is C6-C10aryl substituted with one or more R1a.

[0040] In some embodiments, R1 is C6-C10 aryl.

[0041] In some embodiments, R1 is 5- to 10-membered heteroaryl optionally substituted with one or more R1a.

[0042] In some embodiments, R1is 5- to 10-membered heteroaryl substituted with one or more R1a.

[0043] In some embodiments, R1is 5- to 10-membered heteroaryl.

[0044] In some embodiments, R1is 5- or 6-membered heteroaryl optionally substituted with one or more R1a.

[0045] In some embodiments, R1 is 5- or 6-membered heteroaryl substituted with one or more R1a.

[0046] In some embodiments, R1 is 5- or 6-membered heteroaryl.

[0047] In some embodiments, R1 is phenyl optionally substituted with one or more R1a.

[0048] In some embodiments, R1is phenyl substituted with one or more R1a.

[0049] In some embodiments, R1is phenyl substituted with one R1a.

[0050] In some embodiments, R1 is phenyl substituted with two R1a.

[0051] In some embodiments, R1is phenyl substituted with three R1a.

[0052] In some embodiments, R1is 5-membered heteroaryl optionally substituted with one or more R1a.

[0053] In some embodiments, R1is 5-membered heteroaryl substituted with one or more R1a.

[0054] In some embodiments, R1is 5-membered heteroaryl substituted with one R1a.

[0055] In some embodiments, R1 is 5-membered heteroaryl substituted with two R1a.

[0056] In some embodiments, R1 is 5-membered heteroaryl substituted with three R1a.

[0057] In some embodiments, R1is 6-membered heteroaryl optionally substituted with one or more R1a.

[0058] In some embodiments, R1 is 6-membered heteroaryl substituted with one or more R1a.

[0059] In some embodiments, R1is 6-membered heteroaryl substituted with one R1a.

[0060] In some embodiments, R1is 6-membered heteroaryl substituted with two R1a.

[0061] In some embodiments, R1 is 6-membered heteroaryl substituted with three R1a.

[0062] In some embodiments, each R1aindependently is halo, -OH, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxyl, or -C(O)N(R1b)(R1c).

[0063] In some embodiments, each R1a independently is halo, C1-C6 alkyl, C1-C6 alkoxyl, or - C(O)N(R1b)(R1c).

[0064] In some embodiments, each R1aindependently is halo.

[0065] In some embodiments, each R1a independently is F, Cl, Br, or I.

[0066] In some embodiments, each R1a independently is F. In some embodiments, each R1a independently is Cl. In some embodiments, each R1aindependently is Br. In some embodiments, each R1aindependently is I.

[0067] In some embodiments, each R1a independently is -OH.

[0068] In some embodiments, each R1aindependently is C1-C6alkyl.

[0069] In some embodiments, each R1aindependently is methyl.

[0070] In some embodiments, each R1a independently is C2-C6 alkenyl.

[0071] In some embodiments, each R1a independently is C2-C6 alkynyl.

[0072] In some embodiments, each R1aindependently is C1-C6haloalkyl.

[0073] In some embodiments, each R1a independently is CH2-CF3 or CF3.

[0074] In some embodiments, each R1a independently is CF3.

[0075] In some embodiments, each R1aindependently is C1-C6alkoxyl.

[0076] In some embodiments, each R1aindependently is methoxy.

[0077] In some embodiments, each R1a independently is -C(O)N(R1b)(R1c).

[0078] In some embodiments, each R1aindependently is Cl, F, CH2-CF3, CF3, methyl, or methoxy.

[0079] In some embodiments, each R1a independently is Cl, F, CF3, methyl, or methoxy.

[0080] In some embodiments, each R1aindependently is Cl, F, methyl, or methoxy.

[0081] In some embodiments, two R1a, together with the atoms to which they are attached, form a C3-C6 cycloalkyl or 5- or 6-membered heterocycle.

[0082] In some embodiments, two R1a, together with the atoms to which they are attached, form a C3-C6cycloalkyl.

[0083] In some embodiments, two R1a, together with the atoms to which they are attached, form a 5- or 6-membered heterocycle.

[0084] In some embodiments, two R1a, together with the atoms to which they are attached, form a 5-membered heterocycle.

[0085] In some embodiments, two R1a, together with the atoms to which they are attached, form a 6-membered heterocycle.

[0086] In some embodiments, two R1a, together with the atoms to which they are attached, form.

[0087] In some embodiments, each R1b independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6haloalkyl.

[0088] In some embodiments, each R1b independently is H.

[0089] In some embodiments, each R1b independently is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6haloalkyl.

[0090] In some embodiments, each R1bindependently is C1-C6alkyl.

[0091] In some embodiments, each R1b independently is C2-C6 alkenyl.

[0092] In some embodiments, each R1bindependently is C2-C6alkynyl.

[0093] In some embodiments, each R1bindependently is C1-C6haloalkyl.

[0094] In some embodiments, each R1c independently is C6-C10 aryl.

[0095] In some embodiments, each R1c independently is C6-C10 aryl substituted with one or more halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl.

[0096] In some embodiments, each R1c independently is C6-C10 aryl optionally substituted with one or more C1-C6 haloalkyl.

[0097] In some embodiments, each R1cindependently is C6-C10aryl substituted with one or more C1-C6 haloalkyl.

[0098] In some embodiments, each R1c independently is phenyl.

[0099] In some embodiments, each R1cindependently is phenyl optionally substituted with one or more halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl.

[0100] In some embodiments, each R1c independently is phenyl substituted with one or more halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl.

[0101] In some embodiments, each R1cindependently is phenyl optionally substituted with one or more C1-C6 haloalkyl.

[0102] In some embodiments, each R1c independently is phenyl substituted with one or more C1-C6haloalkyl.

[0103] In some embodiments, each R1c independently is phenyl optionally substituted with one or more -CF3.

[0104] In some embodiments, each R1cindependently is phenyl substituted with one or more - CF3.

[0109] In some embodiments, R2is -C(O)R2a.

[0110] In some embodiments, R2is C2-C6alkenyl.

[0111] In some embodiments, R2 is C2-C6 alkenyl optionally substituted with one or more R2b.

[0112] In some embodiments, R2is C2-C6alkenyl substituted with one or more R2b.

[0113] In some embodiments, R2ais C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl.

[0114] In some embodiments, R2a is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkenyl, or alkynyl is substituted with one or more R2b.

[0115] In some embodiments, R2a is C1-C6 alkyl.

[0116] In some embodiments, R2a is C1-C6 alkyl optionally substituted with one or more R2b.

[0117] In some embodiments, R2ais C1-C6alkyl substituted with one or more R2b.

[0118] In some embodiments, R2a is C2-C6 alkenyl.

[0119] In some embodiments, R2a is C2-C6 alkenyl optionally substituted with one or more R2b.

[0120] In some embodiments, R2ais C2-C6alkenyl substituted with one or more R2b.

[0121] In some embodiments, R2ais C2-C6alkynyl.

[0122] In some embodiments, R2a is C2-C6 alkynyl optionally substituted with one or more R2b.

[0123] In some embodiments, R2ais C2-C6alkynyl substituted with one or more R2b.

[0124] In some embodiments, R2ais C2-C6alkenyl or C2-C6alkynyl, wherein the alkenyl or alkynyl is optionally substituted with one or more R2b.

[0125] In some embodiments, each R2b independently is halo.

[0126] In some embodiments, each R2bindependently is F, Cl, Br, or I.

[0127] In some embodiments, each R2b independently is F. In some embodiments, each R2b independently is Cl. In some embodiments, each R2b independently is Br. In some embodiments, each R2bindependently is I.

[0128] In some embodiments, each R2bindependently is -N(R2c)(R2d), -OR2c, or -CO2(R2c).

[0129] In some embodiments, each R2b independently is -N(R2c)(R2d).

[0130] In some embodiments, each R2bindependently is -OR2c.

[0131] In some embodiments, each R2bindependently is -CO2(R2c).

[0132] In some embodiments, each R2b independently is C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl.

[0133] In some embodiments, each R2bindependently is C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R2e.

[0134] In some embodiments, each R2bindependently is C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with one or more R2e.

[0135] In some embodiments, each R2bindependently is C3-C6cycloalkyl.

[0136] In some embodiments, each R2bindependently is C3-C6cycloalkyl optionally substituted with one or more R2e.

[0137] In some embodiments, each R2bindependently is C3-C6cycloalkyl substituted with one or more R2e.

[0138] In some embodiments, each R2b independently is 4- to 10-membered heterocyclyl.

[0139] In some embodiments, each R2b independently is 4- to 10-membered heterocyclyl optionally substituted with one or more R2e.

[0140] In some embodiments, each R2bindependently is 4- to 10-membered heterocyclyl substituted with one or more R2e.

[0141] In some embodiments, each R2b independently is C6-C10 aryl.

[0142] In some embodiments, each R2bindependently is C6-C10aryl optionally substituted with one or more R2e.

[0143] In some embodiments, each R2b independently is C6-C10 aryl substituted with one or more R2e.

[0144] In some embodiments, each R2bindependently is 5- to 10-membered heteroaryl.

[0145] In some embodiments, each R2b independently is 5- to 10-membered heteroaryl optionally substituted with one or more R2e.

[0146] In some embodiments, each R2bindependently is 5- to 10-membered heteroaryl substituted with one or more R2e.

[0147] In some embodiments, each R2b independently is 4- to 10-membered heterocyclyl, - N(R2c)(R2d), -OR2c,C6-C10aryl, or -CO2(R2c), wherein the heterocyclyl or aryl is optionally substituted with one or more R2e.

[0148] In some embodiments, each R2c independently is H.

[0149] In some embodiments, each R2cindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl.

[0150] In some embodiments, each R2cindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R2f.

[0151] In some embodiments, each R2cindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with one or more R2f.

[0152] In some embodiments, each R2cindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6 haloalkyl.

[0153] In some embodiments, each R2cindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl, wherein the alkyl, alkenyl, alkynyl, or haloalkyl is optionally substituted with one or more R2f.

[0154] In some embodiments, each R2c independently is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl, wherein the alkyl, alkenyl, alkynyl, or haloalkyl is substituted with one or more R2f.

[0155] In some embodiments, each R2c independently is C1-C6 alkyl.

[0156] In some embodiments, each R2c independently is C1-C6 alkyl optionally substituted with one or more R2f.

[0157] In some embodiments, each R2cindependently is C1-C6alkyl substituted with one or more R2f.

[0158] In some embodiments, each R2cindependently is C2-C6alkenyl.

[0159] In some embodiments, each R2cindependently is C2-C6alkenyl optionally substituted with one or more R2f.

[0160] In some embodiments, each R2c independently is C2-C6 alkenyl substituted with one or more R2f.

[0161] In some embodiments, each R2c independently is C2-C6 alkynyl.

[0162] In some embodiments, each R2c independently is C2-C6 alkynyl optionally substituted with one or more R2f.

[0163] In some embodiments, each R2cindependently is C2-C6alkynyl substituted with one or more R2f.

[0164] In some embodiments, each R2cindependently is C1-C6haloalkyl.

[0165] In some embodiments, each R2cindependently is C1-C6haloalkyl optionally substituted with one or more R2f.

[0166] In some embodiments, each R2cindependently is C1-C6haloalkyl substituted with one or more R2f.

[0167] In some embodiments, each R2c independently is C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10-membered heteroaryl.

[0168] In some embodiments, each R2cindependently is C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R2f.

[0169] In some embodiments, each R2cindependently is C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with one or more R2f.

[0170] In some embodiments, each R2cindependently is C3-C6cycloalkyl.

[0171] In some embodiments, each R2cindependently is C3-C6cycloalkyl optionally substituted with one or more R2f.

[0172] In some embodiments, each R2c independently is C3-C6 cycloalkyl substituted with one or more R2f.

[0173] In some embodiments, each R2cindependently is 5- to 10-membered heterocyclyl.

[0174] In some embodiments, each R2c independently is 5- to 10-membered heterocyclyl optionally substituted with one or more R2f.

[0175] In some embodiments, each R2cindependently is 5- to 10-membered heterocyclyl substituted with one or more R2f.

[0176] In some embodiments, each R2c independently is C6-C10 aryl.

[0177] In some embodiments, each R2cindependently is C6-C10aryl optionally substituted with one or more R2f.

[0178] In some embodiments, each R2c independently is C6-C10 aryl substituted with one or more R2f.

[0179] In some embodiments, each R2cindependently is 5- to 10-membered heteroaryl.

[0180] In some embodiments, each R2c independently is 5- to 10-membered heteroaryl optionally substituted with one or more R2f.

[0181] In some embodiments, each R2cindependently is 5- to 10-membered heteroaryl substituted with one or more R2f.

[0182] In some embodiments, each R2c independently is C1-C6 alkyl, C3-C6 cycloalkyl, or C6- C10aryl, wherein the alkyl, cycloalkyl, or aryl is optionally substituted with one or more R2f.

[0183] In some embodiments, each R2dindependently is H.

[0184] In some embodiments, each R2d independently is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6haloalkyl.

[0185] In some embodiments, each R2dindependently is C1-C6alkyl.

[0186] In some embodiments, each R2d independently is methyl or ethyl.

[0187] In some embodiments, each R2d independently is C2-C6 alkenyl.

[0188] In some embodiments, each R2dindependently is C2-C6alkynyl.

[0189] In some embodiments, each R2d independently is C1-C6 haloalkyl.

[0190] In some embodiments, each R2e independently is halo, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6alkyl)2.

[0191] In some embodiments, each R2eindependently is halo.

[0192] In some embodiments, each R2e independently is F, Cl, Br, or I.

[0193] In some embodiments, each R2eindependently is F. In some embodiments, each R2eindependently is Cl. In some embodiments, each R2eindependently is Br. In some embodiments, each R2e independently is I.

[0194] In some embodiments, each R2e independently is -CN.

[0195] In some embodiments, each R2e independently is -OH.

[0196] In some embodiments, each R2eindependently is -NH2.

[0197] In some embodiments, each R2e independently is -NH(C1-C6 alkyl).

[0198] In some embodiments, each R2e independently is -N(C1-C6 alkyl)2.

[0199] In some embodiments, each R2eindependently is C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1-C7haloalkyl, C1-C7alkoxy, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6- C10 aryl, 5- to 10-membered heteroaryl, -CO(C1-C6 alkyl), or -CO2(C1-C6 alkyl).

[0200] In some embodiments, each R2eindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6- C10 aryl, 5- to 10-membered heteroaryl, -CO(C1-C6 alkyl), or -CO2(C1-C6 alkyl).

[0201] In some embodiments, each R2e independently is C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7haloalkyl, C1-C7alkoxy, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6- C10 aryl, 5- to 10-membered heteroaryl, -CO(C1-C6 alkyl), or -CO2(C1-C6 alkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or - NH2.

[0202] In some embodiments, each R2e independently is C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7haloalkyl, C1-C7alkoxy, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6- C10aryl, 5- to 10-membered heteroaryl, -CO(C1-C6alkyl), or -CO2(C1-C6alkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or -NH2.

[0203] In some embodiments, each R2eindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6- C10 aryl, 5- to 10-membered heteroaryl, -CO(C1-C6 alkyl), or -CO2(C1-C6 alkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more -CN, -OH, C1-C6 alkoxy, -NH-CO2(C1-C6 alkyl), or - NH2.

[0204] In some embodiments, each R2eindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6- C10 aryl, 5- to 10-membered heteroaryl, -CO(C1-C6 alkyl), or -CO2(C1-C6 alkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or -NH2.

[0205] In some embodiments, each R2e independently is C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 haloalkyl, or C1-C7 alkoxy.

[0206] In some embodiments, each R2eindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0207] In some embodiments, each R2e independently is C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7haloalkyl, or C1-C7alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is optionally substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or -NH2.

[0208] In some embodiments, each R2eindependently is C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1-C7haloalkyl, or C1-C7alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is substituted with one or more -CN, -OH, C1-C6 alkoxy, -NH-CO2(C1-C6 alkyl), or - NH2.

[0209] In some embodiments, each R2eindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is optionally substituted with one or more -CN, -OH, C1-C6 alkoxy, -NH-CO2(C1-C6 alkyl), or -NH2.

[0210] In some embodiments, each R2eindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or - NH2.

[0211] In some embodiments, each R2e independently is C1-C7 alkyl.

[0212] In some embodiments, each R2eindependently is C1-C7alkyl optionally substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or -NH2.

[0213] In some embodiments, each R2e independently is C1-C7 alkyl substituted with one or more -CN, -OH, C1-C6 alkoxy, -NH-CO2(C1-C6 alkyl), or -NH2.

[0214] In some embodiments, each R2eindependently is C1-C6alkyl.

[0215] In some embodiments, each R2e independently is C1-C6 alkyl optionally substituted with one or more -CN, -OH, C1-C6 alkoxy, -NH-CO2(C1-C6 alkyl), or -NH2.

[0216] In some embodiments, each R2eindependently is C1-C6alkyl substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or -NH2.

[0217] In some embodiments, each R2e independently is C2-C7 alkenyl.

[0218] In some embodiments, each R2eindependently is C2-C7alkenyl optionally substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or -NH2.

[0219] In some embodiments, each R2e independently is C2-C7 alkenyl substituted with one or more -CN, -OH, C1-C6 alkoxy, -NH-CO2(C1-C6 alkyl), or -NH2.

[0220] In some embodiments, each R2eindependently is C2-C6alkenyl.

[0221] In some embodiments, each R2e independently is C2-C6 alkenyl optionally substituted with one or more -CN, -OH, C1-C6 alkoxy, -NH-CO2(C1-C6 alkyl), or -NH2.

[0222] In some embodiments, each R2eindependently is C2-C6alkenyl substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or -NH2.

[0223] In some embodiments, each R2e independently is C2-C7 alkynyl.

[0224] In some embodiments, each R2eindependently is C2-C7alkynyl optionally substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or -NH2.

[0225] In some embodiments, each R2e independently is C2-C7 alkynyl substituted with one or more -CN, -OH, C1-C6 alkoxy, -NH-CO2(C1-C6 alkyl), or -NH2.

[0226] In some embodiments, each R2eindependently is C2-C6alkynyl.

[0227] In some embodiments, each R2e independently is C2-C6 alkynyl optionally substituted with one or more -CN, -OH, C1-C6 alkoxy, -NH-CO2(C1-C6 alkyl), or -NH2.

[0228] In some embodiments, each R2eindependently is C2-C6alkynyl substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or -NH2.

[0229] In some embodiments, each R2e independently is C1-C7 haloalkyl.

[0230] In some embodiments, each R2eindependently is C1-C7haloalkyl optionally substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or -NH2.

[0231] In some embodiments, each R2e independently is C1-C7 haloalkyl substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or -NH2.

[0232] In some embodiments, each R2eindependently is C1-C6haloalkyl.

[0233] In some embodiments, each R2e independently is C1-C6 haloalkyl optionally substituted with one or more -CN, -OH, C1-C6 alkoxy, -NH-CO2(C1-C6 alkyl), or -NH2.

[0234] In some embodiments, each R2eindependently is C1-C6haloalkyl substituted with one or more -CN, -OH, C1-C6 alkoxy, -NH-CO2(C1-C6 alkyl), or -NH2.

[0235] In some embodiments, each R2e independently is C1-C7 alkoxy.

[0236] In some embodiments, each R2eindependently is C1-C7alkoxy optionally substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or -NH2.

[0237] In some embodiments, each R2e independently is C1-C7 alkoxy substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or -NH2.

[0238] In some embodiments, each R2eindependently is C1-C6alkoxy.

[0239] In some embodiments, each R2e independently is C1-C6 alkoxy optionally substituted with one or more -CN, -OH, C1-C6 alkoxy, -NH-CO2(C1-C6 alkyl), or -NH2.

[0240] In some embodiments, each R2eindependently is C1-C6alkoxy substituted with one or more -CN, -OH, C1-C6 alkoxy, -NH-CO2(C1-C6 alkyl), or -NH2.

[0241] In some embodiments, each R2e independently is C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl.

[0242] In some embodiments, each R2eindependently is C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or -NH2.

[0243] In some embodiments, each R2e independently is C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with one or more -CN, -OH, C1-C6alkoxy, -NH- CO2(C1-C6 alkyl), or -NH2.

[0244] In some embodiments, each R2e independently is C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl.

[0245] In some embodiments, each R2eindependently is C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or -NH2.

[0246] In some embodiments, each R2e independently is C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with one or more -CN, -OH, C1-C6alkoxy, -NH- CO2(C1-C6 alkyl), or -NH2.

[0247] In some embodiments, each R2e independently is C3-C6 cycloalkyl.

[0248] In some embodiments, each R2eindependently is C3-C6cycloalkyl optionally substituted with one or more -CN, -OH, C1-C6 alkoxy, -NH-CO2(C1-C6 alkyl), or -NH2.

[0249] In some embodiments, each R2e independently is C3-C6 cycloalkyl substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or -NH2.

[0250] In some embodiments, each R2eindependently is 4- to 10-membered heterocyclyl.

[0251] In some embodiments, each R2e independently is 4- to 10-membered heterocyclyl optionally substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or - NH2.

[0252] In some embodiments, each R2e independently is 4- to 10-membered heterocyclyl substituted with one or more -CN, -OH, C1-C6 alkoxy, -NH-CO2(C1-C6 alkyl), or -NH2.

[0253] In some embodiments, each R2eindependently is 5- to 10-membered heterocyclyl.

[0254] In some embodiments, each R2e independently is 5- to 10-membered heterocyclyl optionally substituted with one or more -CN, -OH, C1-C6 alkoxy, -NH-CO2(C1-C6 alkyl), or - NH2.

[0255] In some embodiments, each R2eindependently is 5- to 10-membered heterocyclyl substituted with one or more -CN, -OH, C1-C6 alkoxy, -NH-CO2(C1-C6 alkyl), or -NH2.

[0256] In some embodiments, each R2eindependently is C6-C10aryl.

[0257] In some embodiments, each R2eindependently is C6-C10aryl optionally substituted with one or more -CN, -OH, C1-C6 alkoxy, -NH-CO2(C1-C6 alkyl), or -NH2.

[0258] In some embodiments, each R2e independently is C6-C10 aryl substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or -NH2.

[0259] In some embodiments, each R2e independently is 5- to 10-membered heteroaryl.

[0260] In some embodiments, each R2e independently is 5- to 10-membered heteroaryl optionally substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or - NH2.

[0261] In some embodiments, each R2e independently is 5- to 10-membered heteroaryl substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or -NH2.

[0262] In some embodiments, each R2eindependently is CO(C1-C6alkyl) or -CO2(C1-C6alkyl).

[0263] In some embodiments, each R2e independently is -CO(C1-C6 alkyl) or -CO2(C1-C6 alkyl), wherein the alkyl is optionally substituted with one or more -CN, -OH, C1-C6alkoxy, - NH-CO2(C1-C6alkyl), or -NH2.

[0264] In some embodiments, each R2e independently is -CO(C1-C6 alkyl) or -CO2(C1-C6 alkyl), wherein the alkyl is substituted with one or more -CN, -OH, C1-C6 alkoxy, -NH-CO2(C1- C6alkyl), or -NH2.

[0265] In some embodiments, each R2e independently is CO(C1-C6 alkyl).

[0266] In some embodiments, each R2e independently is -CO(C1-C6 alkyl), wherein the alkyl is optionally substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or -NH2.

[0267] In some embodiments, each R2e independently is -CO(C1-C6 alkyl), wherein the alkyl is substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or -NH2.

[0268] In some embodiments, each R2eindependently is -CO2(C1-C6alkyl).

[0269] In some embodiments, each R2e independently is -CO2(C1-C6 alkyl), wherein the alkyl is optionally substituted with one or more -CN, -OH, C1-C6 alkoxy, -NH-CO2(C1-C6 alkyl), or -NH2.

[0270] In some embodiments, each R2e independently is -CO2(C1-C6 alkyl), wherein the alkyl is substituted with one or more -CN, -OH, C1-C6 alkoxy, -NH-CO2(C1-C6 alkyl), or -NH2.

[0271] In some embodiments, each R2eindependently is halo, -OH, -CN, -CO(C1-C6alkyl), - N(C1-C6alkyl)2, or -CO2(C1-C6alkyl).

[0272] In some embodiments, each R2e independently is F, -OH, -CN, -CO(C1-C6 alkyl), - N(C1-C6alkyl)2, or -CO2(C1-C6alkyl).

[0273] In some embodiments, each R2eindependently is C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C6 cycloalkyl, or 5- to 10-membered heterocyclyl, wherein the alkyl, haloalkyl, alkoxy, cycloalkyl, or heterocyclyl, is optionally substituted with one or more -CN, -OH, C1- C6alkoxy, or -NH-CO2(C1-C6alkyl).

[0274] In some embodiments, each R2f independently is halo or -CN.

[0275] In some embodiments, each R2f independently is halo.

[0276] In some embodiments, each R2findependently is F, Cl, Br, or I.

[0277] In some embodiments, each R2findependently is F. In some embodiments, each R2findependently is Cl. In some embodiments, each R2f independently is Br. In some embodiments, each R2findependently is I.

[0278] In some embodiments, each R2findependently is -CN.

[0279] In some embodiments, each R2f independently is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0280] In some embodiments, each R2findependently is C1-C6alkyl.

[0281] In some embodiments, each R2f independently is C2-C6 alkenyl.

[0282] In some embodiments, each R2f independently is C2-C6 alkynyl.

[0283] In some embodiments, each R2findependently is C1-C6haloalkyl.

[0284] In some embodiments, each R2f independently is C1-C6 alkoxy.

[0285] In some embodiments, each R2f independently is -CO2(R2g), -CON(R2g)(R2h), or -C(O)- NH(C1-C6alkyl-C1-C6alkoxy).

[0286] In some embodiments, each R2findependently is -CO2(R2g).

[0287] In some embodiments, each R2f independently is -CON(R2g)(R2h).

[0288] In some embodiments, each R2findependently is -C(O)-NH(C1-C6alkyl-C1-C6alkoxy).

[0289] In some embodiments, each R2findependently is C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10-membered heteroaryl.

[0290] In some embodiments, each R2f independently is C3-C6 cycloalkyl.

[0291] In some embodiments, each R2f independently is 5- to 10-membered heterocyclyl.

[0292] In some embodiments, each R2findependently is C6-C10aryl.

[0293] In some embodiments, each R2f independently is 5- to 10-membered heteroaryl.

[0294] In some embodiments, each R2f independently is halo, -CN, C1-C6 alkyl, C1-C6 alkoxy, -CO2(R2g), C3-C6cycloalkyl, C6-C10aryl, C1-C6haloalkyl, or -C(O)-NH(C1-C6alkyl-C1-C6alkoxy).

[0295] In some embodiments, each R2f independently is F, -CN, methyl, methoxy, phenoxy, - CO2(R2g), cyclopropyl, phenyl, -CF3, or -C(O)-NH(ethyl-methoxy).

[0296] In some embodiments, each R2gindependently is H.

[0297] In some embodiments, each R2g independently is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6- C10aryl, or 5- to 10-membered heteroaryl.

[0298] In some embodiments, each R2g independently is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6- C10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, C1-C6 alkyl, or C1-C6 haloalkyl.

[0299] In some embodiments, each R2gindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6- C10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with one or more halo, C1-C6alkyl, or C1-C6haloalkyl.

[0300] In some embodiments, each R2g independently is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0301] In some embodiments, each R2gindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is optionally substituted with one or more halo, C1-C6 alkyl, or C1-C6 haloalkyl.

[0302] In some embodiments, each R2gindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is substituted with one or more halo, C1-C6 alkyl, or C1-C6 haloalkyl.

[0303] In some embodiments, each R2gindependently is C1-C6alkyl.

[0304] In some embodiments, each R2gindependently is C1-C6alkyl optionally substituted with one or more halo, C1-C6 alkyl, or C1-C6 haloalkyl.

[0305] In some embodiments, each R2g independently is C1-C6 alkyl substituted with one or more halo, C1-C6 alkyl, or C1-C6 haloalkyl.

[0306] In some embodiments, each R2gindependently is C2-C6alkenyl.

[0307] In some embodiments, each R2g independently is C2-C6 alkenyl optionally substituted with one or more halo, C1-C6 alkyl, or C1-C6 haloalkyl.

[0308] In some embodiments, each R2gindependently is C2-C6alkenyl substituted with one or more halo, C1-C6alkyl, or C1-C6haloalkyl.

[0309] In some embodiments, each R2g independently is C2-C6 alkynyl.

[0310] In some embodiments, each R2gindependently is C2-C6alkynyl optionally substituted with one or more halo, C1-C6alkyl, or C1-C6haloalkyl.

[0311] In some embodiments, each R2g independently is C2-C6 alkynyl substituted with one or more halo, C1-C6 alkyl, or C1-C6 haloalkyl.

[0312] In some embodiments, each R2gindependently is C1-C6haloalkyl.

[0313] In some embodiments, each R2g independently is C1-C6 haloalkyl optionally substituted with one or more halo, C1-C6 alkyl, or C1-C6 haloalkyl.

[0314] In some embodiments, each R2gindependently is C1-C6haloalkyl substituted with one or more halo, C1-C6alkyl, or C1-C6haloalkyl.

[0315] In some embodiments, each R2g independently is C1-C6 alkoxy.

[0316] In some embodiments, each R2gindependently is C1-C6alkoxy optionally substituted with one or more halo, C1-C6alkyl, or C1-C6haloalkyl.

[0317] In some embodiments, each R2g independently is C1-C6 alkoxy substituted with one or more halo, C1-C6alkyl, or C1-C6haloalkyl.

[0318] In some embodiments, each R2gindependently is C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10-membered heteroaryl.

[0319] In some embodiments, each R2g independently is C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, C1-C6 alkyl, or C1-C6 haloalkyl.

[0320] In some embodiments, each R2gindependently is C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with one or more halo, C1-C6 alkyl, or C1-C6 haloalkyl.

[0321] In some embodiments, each R2gindependently is C3-C6cycloalkyl.

[0322] In some embodiments, each R2g independently is C3-C6 cycloalkyl optionally substituted with one or more halo, C1-C6 alkyl, or C1-C6 haloalkyl.

[0323] In some embodiments, each R2gindependently is C3-C6cycloalkyl substituted with one or more halo, C1-C6 alkyl, or C1-C6 haloalkyl.

[0324] In some embodiments, each R2g independently is 5- to 10-membered heterocyclyl.

[0325] In some embodiments, each R2gindependently is 5- to 10-membered heterocyclyl optionally substituted with one or more halo, C1-C6alkyl, or C1-C6haloalkyl.

[0326] In some embodiments, each R2g independently is 5- to 10-membered heterocyclyl substituted with one or more halo, C1-C6alkyl, or C1-C6haloalkyl.

[0327] In some embodiments, each R2gindependently is C6-C10aryl.

[0328] In some embodiments, each R2g independently is C6-C10 aryl optionally substituted with one or more halo, C1-C6 alkyl, or C1-C6 haloalkyl.

[0329] In some embodiments, each R2gindependently is C6-C10aryl substituted with one or more halo, C1-C6 alkyl, or C1-C6 haloalkyl.

[0330] In some embodiments, each R2g independently is 5- to 10-membered heteroaryl.

[0331] In some embodiments, each R2gindependently is 5- to 10-membered heteroaryl optionally substituted with one or more halo, C1-C6alkyl, or C1-C6haloalkyl.

[0332] In some embodiments, each R2g independently is 5- to 10-membered heteroaryl substituted with one or more halo, C1-C6alkyl, or C1-C6haloalkyl.

[0333] In some embodiments, each R2gindependently is H or C1-C6alkyl.

[0334] In some embodiments, each R2g independently is H or tert-butyl.

[0335] In some embodiments, each R2hindependently is H.

[0336] In some embodiments, each R2hindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6 haloalkyl.

[0337] In some embodiments, each R2h independently is C1-C6 alkyl.

[0338] In some embodiments, each R2hindependently is C2-C6alkenyl.

[0339] In some embodiments, each R2h independently is C2-C6 alkynyl.

[0340] In some embodiments, each R2h independently is C1-C6 haloalkyl.,N O N O N O N O N O , NO O O , , N N O , orO O.

[0345] In some embodiments, R3is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl.

[0346] In some embodiments, R3is C1-C6alkyl.

[0347] In some embodiments, R3is C2-C6alkenyl.

[0348] In some embodiments, R3 is C2-C6 alkynyl.

[0349] In some embodiments, R3 is C1-C6 haloalkyl.

[0350] In some embodiments, R3is C3-C10cycloalkyl or 5- to 10-membered heterocyclyl.

[0351] In some embodiments, R3 is C3-C10 cycloalkyl.

[0352] In some embodiments, R3 is 5- to 10-membered heterocyclyl.

[0353] In some embodiments, R3is C1-C6alkyl or C3-C10cycloalkyl.

[0354] In some embodiments, R3is -CH2-CF3, methyl, or cyclopropyl.

[0355] In some embodiments, R3 is methyl or cyclopropyl.

[0356] In some embodiments, two R3, together with the atoms to which they are attached, form a C3-C6 cycloalkyl or 5- to 6-membered heterocycle.

[0357] In some embodiments, two R3, together with the atoms to which they are attached, form a C3-C6 cycloalkyl.

[0358] In some embodiments, two R3, together with the atoms to which they are attached, form a cyclopentyl.

[0359] In some embodiments, two R3, together with the atoms to which they are attached, form a C3-C6 cycloalkyl.

[0360] In some embodiments, R3is -CH2-CF3, methyl, or cyclopropyl, or two R3, together with the atoms to which they are attached, form a cyclopentyl.

[0361] In some embodiments, R3 is methyl or cyclopropyl, or two R3, together with the atoms to which they are attached, form a cyclopentyl.

[0362] In some embodiments, n is 0 or 1.

[0363] In some embodiments, n is 0, 1, or 2.

[0364] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0365] In some embodiments, the compound of Formula (II) is of Formula (II-a):or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0366] In some embodiments, the compound of Formula (II) is of Formula (II-b):or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0367] In some embodiments, the compound of Formula (II) is of Formula (II-b’):or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0368] In some embodiments, the compound of Formula (II) is of Formula (II-c):or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0369] In some embodiments, the compound of Formula (II) is of Formula (II-c’):or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0370] In some embodiments, the compound of Formula (II) is of Formula (II-d):or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0371] In some embodiments, the compound of Formula (II) is of Formula (II-d’):or a prodrug, solvate, or pharmaceutically acceptable salt thereof. Formula (III)

[0372] In some aspects, the present disclosure relates to a compound of Formula (III):(III), or a pharmaceutically acceptable salt thereof, wherein: R1 is C6-C10 aryl optionally substituted with one or more R1a; each R1aindependently is halo, -OH, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl; R2 is -C(O)R2a;R2a is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more R2b; each R2bindependently is halo, -N(R2c)(R2d), -OR2c, -CO2(R2c), C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10-membered heteroaryl; each R2c independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; each R2dindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R3is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, or 5- to 10-membered heterocyclyl; and n is 0, 1, 2, 3, or 4.

[0373] In some embodiments, R1 is C6-C10 aryl substituted with one or more R1a.

[0374] In some embodiments, R1is C6-C10aryl.

[0375] In some embodiments, R1 is phenyl optionally substituted with one or more R1a.

[0376] In some embodiments, R1 is phenyl substituted with one or more R1a.

[0377] In some embodiments, R1is phenyl substituted with one R1a.

[0378] In some embodiments, R1is phenyl substituted with two R1a.

[0379] In some embodiments, R1 is phenyl substituted with three R1a.

[0380] In some embodiments, each R1aindependently is halo, -OH, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl.

[0381] In some embodiments, each R1a independently is halo.

[0382] In some embodiments, each R1aindependently is F, Cl, Br, or I.

[0383] In some embodiments, each R1aindependently is F. In some embodiments, each R1aindependently is Cl. In some embodiments, each R1a independently is Br. In some embodiments, each R1a independently is I.

[0384] In some embodiments, each R1aindependently is -OH.

[0385] In some embodiments, each R1a independently is C1-C6 alkyl.

[0386] In some embodiments, each R1a independently is methyl.

[0387] In some embodiments, each R1aindependently is C2-C6alkenyl.

[0388] In some embodiments, each R1aindependently is C2-C6alkynyl.

[0389] In some embodiments, each R1a independently is C1-C6 haloalkyl.

[0390] In some embodiments, each R1aindependently is C1-C6alkoxyl.

[0391] In some embodiments, each R1aindependently is methoxy.

[0392] In some embodiments,

[0393] In some embodiments, R2 is -C(O)R2a.

[0394] In some embodiments, R2a is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0395] In some embodiments, R2ais C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, wherein the alkyl, alkenyl, or alkynyl is substituted with one or more R2b.

[0396] In some embodiments, R2a is C1-C6 alkyl.

[0397] In some embodiments, R2ais C1-C6alkyl optionally substituted with one or more R2b.

[0398] In some embodiments, R2ais C1-C6alkyl substituted with one or more R2b.

[0399] In some embodiments, R2a is C2-C6 alkenyl.

[0400] In some embodiments, R2ais C2-C6alkenyl optionally substituted with one or more R2b.

[0401] In some embodiments, R2ais C2-C6alkenyl substituted with one or more R2b.

[0402] In some embodiments, R2a is C2-C6 alkynyl.

[0403] In some embodiments, R2a is C2-C6 alkynyl optionally substituted with one or more R2b.

[0404] In some embodiments, R2ais C2-C6alkynyl substituted with one or more R2b.

[0405] In some embodiments, R2a is C2-C6 alkenyl or C2-C6 alkynyl, wherein the alkenyl or alkynyl is optionally substituted with one or more R2b.

[0406] In some embodiments,

[0407] In some embodiments, each R2b independently is halo.

[0408] In some embodiments, each R2b independently is F, Cl, Br, or I.

[0409] In some embodiments, each R2bindependently is F. In some embodiments, each R2bindependently is Cl. In some embodiments, each R2b independently is Br. In some embodiments, each R2b independently is I.

[0410] In some embodiments, each R2bindependently is -N(R2c)(R2d), -OR2c, or -CO2(R2c).

[0411] In some embodiments, each R2b independently is -N(R2c)(R2d).

[0412] In some embodiments, each R2b independently is -OR2c.

[0413] In some embodiments, each R2bindependently is -CO2(R2c).

[0414] In some embodiments, each R2bindependently is C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10-membered heteroaryl.

[0415] In some embodiments, each R2b independently is C3-C6 cycloalkyl.

[0416] In some embodiments, each R2b independently is 4- to 10-membered heterocyclyl.

[0417] In some embodiments, each R2b independently is C6-C10 aryl.

[0418] In some embodiments, each R2bindependently is 5- to 10-membered heteroaryl.

[0419] In some embodiments, each R2b independently is -N(R2c)(R2d) or 4- to 10-membered heterocyclyl.

[0420] In some embodiments, each R2b independently.

[0421] In some embodiments, each R2cindependently is H.

[0422] In some embodiments, each R2c independently is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl.

[0423] In some embodiments, each R2cindependently is C1-C6alkyl.

[0424] In some embodiments, each R2cindependently is methyl.

[0425] In some embodiments, each R2c independently is C2-C6 alkenyl.

[0426] In some embodiments, each R2c independently is C2-C6 alkynyl.

[0427] In some embodiments, each R2cindependently is C1-C6haloalkyl.

[0428] In some embodiments, each R2d independently is H.

[0429] In some embodiments, each R2d independently is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6haloalkyl.

[0430] In some embodiments, each R2d independently is C1-C6 alkyl.

[0431] In some embodiments, each R2d independently is methyl.

[0432] In some embodiments, each R2dindependently is C2-C6alkenyl.

[0433] In some embodiments, each R2dindependently is C2-C6alkynyl.

[0434] In some embodiments, each R2d independently is C1-C6 haloalkyl. ,

[0436] In some embodiments, R3 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl.

[0437] In some embodiments, R3is C1-C6alkyl.

[0438] In some embodiments, R3 is C2-C6 alkenyl.

[0439] In some embodiments, R3 is C2-C6 alkynyl.

[0440] In some embodiments, R3is C1-C6haloalkyl.

[0441] In some embodiments, R3is C3-C10cycloalkyl or 5- to 10-membered heterocyclyl.

[0442] In some embodiments, R3 is C3-C10 cycloalkyl.

[0443] In some embodiments, R3is 5- to 10-membered heterocyclyl.

[0444] In some embodiments, R3is C1-C6alkyl or C3-C10cycloalkyl.

[0445] In some embodiments, n is 0 or 1.

[0446] In some embodiments, n is 0, 1, or 2.

[0447] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0448] In some embodiments, the compound of Formula (III) is of Formula (III-a):or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0449] In some embodiments, the compound of Formula (III) is of Formula (III-b):or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0450] In some embodiments, the compound of Formula (III) is of Formula (III-c):or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0451] In some embodiments, the compound is selected from the compounds described in Tables 1, 2, and 3 and prodrugs and pharmaceutically acceptable salts thereof.

[0452] In some embodiments, the compound is selected from the compounds described in Tables 1, 2, and 3 and pharmaceutically acceptable salts thereof.

[0453] In some embodiments, the compound is selected from the compounds described in Tables 1, 2, and 3.

[0454] In some embodiments, the compound is selected from the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0455] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0456] In some embodiments, the compound is selected from the compounds described in Table 1.

[0457] In some embodiments, the compound is selected from the compounds described in Table 2 and prodrugs and pharmaceutically acceptable salts thereof.

[0458] In some embodiments, the compound is selected from the compounds described in Table 2 and pharmaceutically acceptable salts thereof.

[0459] In some embodiments, the compound is selected from the compounds described in Table 2.

[0460] In some embodiments, the compound is selected from the compounds described in Table 3 and prodrugs and pharmaceutically acceptable salts thereof.

[0461] In some embodiments, the compound is selected from the compounds described in Table 3 and pharmaceutically acceptable salts thereof.

[0462] In some embodiments, the compound is selected from the compounds described in Table 3.Table 1.O NH (ethyl(methyl)amino)but-2-enoyl)- 5,6,7,8-tetrahydroimidazo[1,2- N a]pyrazine-3-carboxamide NNNO O O (E)-N-(2-chloro-3-methoxyphenyl)-7- NH Cl (4-(ethyl(methyl)amino)but-2-enoyl)- N 5,6,7,8-tetrahydroimidazo[1,2- NNNa]pyrazine-3-carboxamide O O Cl O (E)-N-(2-chloro-5-methoxyphenyl)-7- NH (4-(ethyl(methyl)amino)but-2-enoyl)- N 5,6,7,8-tetrahydroimidazo[1,2- NNNa]pyrazine-3-carboxamide OTable 2.N (R) O Cl (S)-7-((R,E)-4-(azetidin-1-yl)pent- ONH2-enoyl)-N-(2-chlorophenyl)-5- methyl-5,6,7,8- (S) N tetrahydroimidazo[1,2-a]pyrazine- N N (R) N 3-carboxamide O Cl (5S)-7-[(E,4S)-4-(azetidin-1- ONHyl)pent-2-enoyl]-N-(2- chlorophenyl)-5-methyl-6,8- (S) N dihydro-5H-imidazo[1,2- N N (S) N a]pyrazine-3-carboxamide OCl (5S)-7-[(E,4S)-4-(azetidin-1- O NH yl)hex-2-enoyl]-N-(2- 408 chlorophenyl)-5- methyl-6,8- N (S) N (S) dihydro-5H-imidazo[1,2- N N a]pyrazine-3-carboxamide O Cl (5S)-7-[(E,4R)-4- (azetidin-1- O NH yl)hex-2-enoyl]-N-(2- 409 chlorophenyl)-5-methyl-6,8- N (S) N (R) dihydro-5H-imidazo[1,2- N N a]pyrazine-3-carboxamide OTable 3.Compound No. 642 643 644 645NN3-carboxamide O Cl O NH(E)-N-(2-chlorophenyl)-7-(4-(3- (difluoromethyl)azetidin-1-yl)but- 646 N 2-enoyl)-5-methyl-5,6,7,8- N tetrahydroimidazo[1,2-a]pyrazine- NNF 3-carboxamide O FFN O3-carboxamide Cl ONH(E)-N-(2-chlorophenyl)-7-(4-(1- cyclopropylpyrrolidin-2-yl)but-2- N enoyl)-5-methyl-5,6,7,8- NNtetrahydroimidazo[1,2-a]pyrazine- NO3-carboxamideO FF ClN-(2-chlorophenyl)-7-[(E)-3-[4- FONH(3,3,3-trifluoropropyl)morpholin- 3-yl] prop-2-enoyl]-6,8-dihydro- N N 5H-imidazo[1,2-a]pyrazine-3- NNcarboxamide O Cl (E)-N-(2-chlorophenyl)-6-methyl- O NH7-(3-(4-methylmorpholin-3- yl)acryloyl)-5,6,7,8- N N tetrahydroimidazo[1,2-a]pyrazine- NN3-carboxamide Otetrahydroimidazo[1,2-a]pyrazine- NNN3-carboxamide O Cl O (E)-7-(4-(azetidin-1-yl)pent-2- NH enoyl)-N-(2-chlorophenyl)-5- methyl-5,6,7,8- N tetrahydroimidazo[1,2-a]pyrazine- N N N 3-carboxamide ON O Cl (E)-7-(4-(azetidin-1-yl)-4- O NHcyclopropylbut-2-enoyl)-N-(2- chlorophenyl)-5-methyl-5,6,7,8- N N tetrahydroimidazo[1,2-a]pyrazine- NN3-carboxamide OCompoun No. 717 718 719 720y )pent- -enoy )-5,6, ,8- N tetrahydroimidazo[1,2-a]pyrazine- NN3-carboxamide N O Cl Cl (5R)-N-(2,4-dichlorophenyl)-7- O [(E)-4-[ethyl(methyl)amino]but-2- 721 NH enoyl] -5-methyl-6,8-dihydro-5H- N imidazo[1,2-a]pyrazine-3- N carboxamide NNON tetrahydroimidazo[1,2-a]pyrazine- NNN3-carboxamide O Cl (E)-N-(2-chlorophenyl)-7-(4-(3- ONHethoxyazetidin-1-yl)but-2-enoyl)- N 5-methyl-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine- NNN3-carboxamide O OO N tetrahydroimidazo[1,2-a]pyrazine- N 3-carboxamide NNH OCl (E)-N-(2-chloro-4-methylphenyl)- ONH5-methyl-7-(3-(morpholin-3- yl)acryloyl)-5,6,7,8- O N tetrahydroimidazo[1,2-a]pyrazine- NN3-carboxamide N HONH e y e y a ope -- enoyl)-5,6,7,8- N tetrahydroimidazo[1,2-a]pyrazine- N NN3-carboxamide O Cl Cl (E)-N-(2,4-dichlorophenyl)-5- O ethyl-7-(4- NH (ethyl(methyl)amino)but-2-enoyl)- N 5,6,7,8-tetrahydroimidazo[1,2- a]pyrazine-3-carboxamide NN NO

[0463] In some aspects, the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of any one of the compounds of the Formulae disclosed herein.

[0464] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Tables 1, 2, and 3, or a prodrug or pharmaceutically acceptable salt thereof.

[0465] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Tables 1, 2, and 3, or a pharmaceutically acceptable salt thereof.

[0466] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Tables 1, 2, and 3.

[0467] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1, or a prodrug or pharmaceutically acceptable salt thereof.

[0468] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

[0469] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1.

[0470] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2, or a prodrug or pharmaceutically acceptable salt thereof.

[0471] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2, or a pharmaceutically acceptable salt thereof.

[0472] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2.

[0473] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 3, or a prodrug or pharmaceutically acceptable salt thereof.

[0474] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 3, or a pharmaceutically acceptable salt thereof.

[0475] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 3.

[0476] It is understood that the isotopic derivative can be prepared using any of a variety of art-recognized techniques. For example, the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0477] In some embodiments, the isotopic derivative is a deuterium labeled compound.

[0478] In some embodiments, the isotopic derivative is a deuterium labeled compound of any one of the compounds of the Formulae disclosed herein.

[0479] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Tables 1, 2, and 3, or a prodrug or pharmaceutically acceptable salt thereof.

[0480] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Tables 1, 2, and 3, or a pharmaceutically acceptable salt thereof.

[0481] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Tables 1, 2, and 3.

[0482] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1, or a prodrug or pharmaceutically acceptable salt thereof.

[0483] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

[0484] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1.

[0485] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 2, or a prodrug or pharmaceutically acceptable salt thereof.

[0486] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 2, or a pharmaceutically acceptable salt thereof.

[0487] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 2.

[0488] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 3, or a prodrug or pharmaceutically acceptable salt thereof.

[0489] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 3, or a pharmaceutically acceptable salt thereof.

[0490] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 3.

[0491] It is understood that the deuterium labeled compound comprises a deuterium atom having an abundance of deuterium that is substantially greater than the natural abundance of deuterium, which is 0.015%.

[0492] In some embodiments, the deuterium labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation),or at least 6633.3 (99.5% deuterium incorporation). As used herein, the term “deuterium enrichment factor” means the ratio between the deuterium abundance and the natural abundance of a deuterium.

[0493] It is understood that the deuterium labeled compound can be prepared using any of a variety of art-recognized techniques. For example, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting a deuterium labeled reagent for a non-deuterium labeled reagent.

[0494] A compound of the invention or a pharmaceutically acceptable salt or solvate thereof that contains the aforementioned deuterium atom(s) is within the scope of the invention. Further, substitution with deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.

[0495] For the avoidance of doubt, it is to be understood that, where in this specification a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group.

[0496] A suitable pharmaceutically acceptable salt of a compound of the disclosure is, for example, an acid-addition salt of a compound of the disclosure, which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, formic, citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the disclosure which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0497] It will be understood that the compounds of any one of the Formulae disclosed herein and any pharmaceutically acceptable salts thereof, comprise stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of said compounds.

[0498] As used herein, the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of eachother are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”

[0499] As used herein, the term “chiral center” refers to a carbon atom bonded to four nonidentical substituents.

[0500] As used herein, the term “chiral isomer” means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc.1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ.1964, 41, 116).

[0501] As used herein, the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0502] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity.

[0503] It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It is also to be understood that not all atropic isomers may have the same level of activity.

[0504] As used herein, the term “atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.

[0505] As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.

[0506] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others.

[0507] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0508] The compounds of this disclosure may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and theseparation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the disclosure may have geometric isomeric centers (E- and Z- isomers). It is to be understood that the present disclosure encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess EphB3 modulation activity.

[0509] The present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions.

[0510] It is to be understood that the compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate.

[0511] As used herein, the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion or diethylamine ion. The substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.

[0512] It is to be understood that the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0513] As used herein, the term “solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O.

[0514] As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.

[0515] As used herein, the term “derivative” refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0516] As used herein, the term “bioisostere” refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonamides, tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev.96, 3147-3176, 1996.

[0517] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. A suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate. It is to be understood that the disclosure encompasses all such solvated forms that possess EphB3 modulation activity.

[0518] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exhibit polymorphism, and that the disclosure encompasses all such forms, or mixtures thereof, which possess EphB3 modulation activity. It is generally known that crystalline materials may be analysed using conventional techniques such as X-Ray Powder Diffraction analysis, Differential Scanning Calorimetry, Thermal Gravimetric Analysis, Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and / or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials may be determined by Karl Fischer analysis.

[0519] Compounds of any one of the Formulae disclosed herein may exist in a number of different tautomeric forms and references to compounds of Formula (I), Formula (II), or Formula (III) include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula (I), Formula (II), or Formula (III). Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the followingtautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro.keto enol enolate

[0520] Compounds of any one of the Formulae disclosed herein containing an amine function may also form N-oxides. A reference herein to a compound of Formula (I), Formula (II), or Formula (III) that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidized to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm.1977, 7, 509-514) in which the amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[0521] The compounds of any one of the Formulae disclosed herein may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure. A prodrug may be used to alter the physical properties and / or the pharmacokinetic properties of a compound of the disclosure. A prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property- modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents in a compound of the any one of the Formulae disclosed herein.

[0522] Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof. Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of any one of the Formulae disclosed herein may be a synthetically-produced compound or a metabolically-produced compound.

[0523] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity. Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol.42, p.309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard- Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p.113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; H. E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0524] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of any one of the Formulae disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include C1-C10alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1-C10alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-C6alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4- (C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0525] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1-4alkylamine such as methylamine, a (C1-C4 alkyl)2amine such as dimethylamine, N-ethyl-N-methylamineor diethylamine, a C1-C4 alkoxy-C2-C4 alkylamine such as 2-methoxyethylamine, a phenyl-C1- C4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0526] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-C10alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-C4alkyl)piperazin-1- ylmethyl.

[0527] The in vivo effects of a compound of any one of the Formulae disclosed herein may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of any one of the Formulae disclosed herein. As stated hereinbefore, the in vivo effects of a compound of any one of the Formulae disclosed herein may also be exerted by way of metabolism of a precursor compound (a prodrug).

[0528] Suitably, the present disclosure excludes any individual compounds not possessing the biological activity defined herein. In some aspects, compound of the present disclosure can be prepared according to the following general procedure: Methods of Synthesis

[0529] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure.

[0530] In some aspects, the present disclosure provides a method of a compound, comprising one or more steps as described herein.

[0531] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, or directly obtained by a method for preparing a compound as described herein.

[0532] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein.

[0533] The compounds of the present disclosure can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.

[0534] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.

[0535] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilized.

[0536] It will be appreciated that during the synthesis of the compounds of the disclosure in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed. For examples of protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule. Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.

[0537] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with thechoice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0538] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively, an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0539] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0540] Once a compound of Formula (I), Formula (II), or Formula (III) has been synthesized by any one of the processes defined herein, the processes may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound Formula (I), Formula (II), or Formula (III) into another compound of Formula (I), Formula (II), or Formula (III); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or (iv) forming a prodrug thereof.

[0541] The resultant compounds of Formula (I), Formula (II), or Formula (III) can be isolated and purified using techniques well known in the art.

[0542] Conveniently, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitablesolvents comprise but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2- dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentylmethyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone, methylisobutylketone (MIBK) or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidinone (NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate or methyl acetate, or mixtures of the said solvents or mixtures with water.

[0543] The reaction temperature is suitably between about -100 °C and 300 °C, depending on the reaction step and the conditions used.

[0544] Reaction times are generally in the range between a fraction of a minute and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 minutes and 48 hours.

[0545] Moreover, by utilizing the procedures described herein, in conjunction with ordinary skills in the art, additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

[0546] As will be understood by the person skilled in the art of organic synthesis, compounds of the present disclosure are readily accessible by various synthetic routes, some of which are exemplified in the accompanying examples. The skilled person will easily recognize which kind of reagents and reactions conditions are to be used and how they are to be applied and adapted in any particular instance – wherever necessary or useful – in order to obtain the compounds of the present disclosure. Furthermore, some of the compounds of the present disclosure can readily be synthesized by reacting other compounds of the present disclosure under suitable conditions, for instance, by converting one particular functional group being present in a compound of the present disclosure, or a suitable precursor molecule thereof, into another one by applying standard synthetic methods, like reduction, oxidation, addition or substitution reactions; those methods are well known to the skilled person. Likewise, the skilledperson will apply – whenever necessary or useful – synthetic protecting (or protective) groups; suitable protecting groups as well as methods for introducing and removing them are well- known to the person skilled in the art of chemical synthesis and are described, in more detail, in, e.g., P.G.M. Wuts, T.W. Greene, “Greene’s Protective Groups in Organic Synthesis”, 4th edition (2006) (John Wiley & Sons).

[0547] Compounds of Formula (I), Formula (II), or Formula (III) can be prepared as described in the Examples. Biological Assays

[0548] Compounds designed, selected and / or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and / or binding specificity.

[0549] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art. General methodologies for performing high- throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No.5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.

[0550] Various in vitro or in vivo biological assays may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

[0551] In some embodiments, the biological assay is an in vitro kinase assay.

[0552] In some embodiments, the compounds of the present disclosure are prepared in a solvent and added to an enzyme solution containing EphB2 and incubated followed by termination. In some embodiments, the mixture is analyzed (e.g., at a specific excitation and emission) and the data is present as percent inhibition.

[0553] In some embodiments, the compounds of the present disclosure are prepared in a solvent and added to an enzyme solution containing EphB3 and incubated followed by termination. In some embodiments, the in vitro activity is analyzed (e.g., at a specific excitation and emission) and the data is present as percent inhibition.

[0554] In some embodiments, the biological assay is a cellular assay.

[0555] In some embodiments, the cellular assay is a target engagement assay for EphB2 or EphB3 kinase.

[0556] In some embodiments, the cellular assay measures the cellular affinity of a compound of the present disclosure by competitive displacement of a cell-permeable tracer.

[0557] In some embodiments, the compounds of the present disclosure are dosed in cells (e.g., HEK293 cells) mixed with EphB2 of EphB3 plasmid DNA followed by addition of a compound of the present disclosure and incubation. In some embodiments, the cellular activity is measured at a specific acceptor and donor emission value to calculate IC50. Pharmaceutical Compositions

[0558] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient.

[0559] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described herein and one or more pharmaceutically acceptable carrier, diluent, adjuvant, or excipient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1 or 2. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described herein and one or more pharmaceutically acceptable carrier, diluent, adjuvant, or excipient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described herein and one or more pharmaceutically acceptable carrier, diluent, adjuvant, or excipient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 2.

[0560] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0561] The compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of present disclosure on can also be formulated for intravenous (bolus or in- fusion), intraperitoneal, topical, subcutaneous, intra-muscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0562] The compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0563] The compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.

[0564] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent an EphB3 related condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0565] The size of the dose for therapeutic or prophylactic purposes of a compound of Formula (I), Formula (II), or Formula (III) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine. Methods of Use

[0566] In some aspects, the present disclosure provides a method of modulation of EphB3 activity (e.g., in vitro or in vivo), comprising contacting a cell with a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0567] In some aspects, the present disclosure provides a method of inhibiting EphB3 activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0568] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0569] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering tothe subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0570] In some embodiments, the disease or disorder is associated with an implicated EphB3 activity.

[0571] In some embodiments, the disease or disorder is a neurodegenerative disease or disorder.

[0572] In some aspects, the present disclosure provides a method of treating or preventing a neurodegenerative disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0573] In some aspects, the present disclosure provides a method of treating or preventing a neurodegenerative disease or disorder in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0574] In some aspects, the present disclosure provides a method of treating a neurodegenerative disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0575] In some aspects, the present disclosure provides a method of treating a neurodegenerative disease or disorder in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0576] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in modulation of EphB3 activity (e.g., in vitro or in vivo).

[0577] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.

[0578] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein.

[0579] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a neurodegenerative disease or disorder in a subject in need thereof.

[0580] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a neurodegenerative disease or disorder in a subject in need thereof.

[0581] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulation of EphB3 activity (e.g., in vitro or in vivo).

[0582] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0583] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0584] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a neurodegenerative disease or disorder in a subject in need thereof.

[0585] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a neurodegenerative disease or disorder in a subject in need thereof.

[0586] In some embodiments, modulation of EphB3 is inhibition of EphB3.

[0587] Effectiveness of compounds of the disclosure can be determined by industry-accepted assays / disease models according to standard practices of elucidating the same as described in the art and are found in the current general knowledge.

[0588] In some embodiments, the neurodegenerative disease or disorder is neuromyelitis optica (“NMO”), transverse myelitis, myelin oligodendrocyte glycoprotein, acute disseminated encephalomyelitis (“ADEM”), optic neuritis, amyloidosis, Parkinson's disease, Alzheimer's disease, cerebral amyloid angiopathy, Pick's disease, frontotemporal dementia, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, amyotrophic lateral sclerosis (“ALS”), Huntington's disease, traumatic brain injury, stroke, fatty liver disease, endometriosis, paraneoplastic disorders, inflammatory demyelinating polyneuropathy, amyotrophy, fibromyalgia, multiple system atrophy, Friedrich's ataxia, or cerebellar ataxia.

[0589] In some embodiments, the disease or disorder is a psychiatric or neurodevelopmental disease or disorder.

[0590] In some embodiments, the psychiatric or neurodevelopmental disease or disorder is schizophrenia, major depressive disorder, generalized anxiety disorder, panic disorder, social anxiety disorder, agoraphobia, post-traumatic stress disorder, autism spectrum disorder, cerebral palsy, Nasu Hakola disease, bipolar disorder, or substance abuse.

[0591] In some embodiments, the disease or disorder is a viral or infectious disease or disorder.

[0592] In some embodiments, the viral or infectious disease or disorder is neuro-HIV, viral encephalitis, meningitis, neurocysticercosis, neurosyphilis, neuro-Lyme disease, infectious myelopathies, COVID-19 neuroinflammation, enteroviruses, poliovirus, Epstein-Barr virus (EBV), human herpesvirus, cytomegalovirus, rabies virus, herpes simplex virus, measles, progressive multifocal leukoencephalopathy John Cunningham (“PML JC”) virus, bacterial meningitis, prion disease, or Creutzfeldt Jakob disease.

[0593] In some embodiments, the disease or disorder is an autoimmune disease or disorder.

[0594] In some embodiments, the autoimmune disease or disorder is antibody-mediated encephalitis, neurological complications of connective tissue damage, neurosarcoidosid, demyelinating diseases (non-MS), idiopathic autoimmune CNS and PNS syndromes, paraneoplastic neurological disease, CNS vasculitis, type 1 diabetes, type 2 diabetes, Crohn's disease, systemic lupus erythematous (“SLE”), irritable bowel disorders, asthma, chronic obstructive pulmonary disease (“COPD”), atopic dermatitis, obesity-associated inflammation, heart disease, ulcerative colitis, psoriasis, psoriatic arthritis, reactive arthritis, rheumatoid arthritis, Sjögren's syndrome, Reiter's disease, multiple sclerosis, autoimmune encephalitis, myasthenia gravis, idiopathic pulmonary fibrosis, ankylosing spondylitis, antiphospholipid antibody syndrome, osteomyelitis, gout, Henoch-Schonlein Purpura, dermatomyositis, idiopathic arthritis, scleroderma, Kawasaki disease, mixed connective tissue damage, myositis, spondyloarthritis, undifferentiated connective tissue disease, systemic sclerosis, or autoimmune hepatitis.

[0595] In some embodiments, the disease or disorder is an eye disease or disorder.

[0596] In some embodiments, the disease or disorder is an ocular inflammatory disease.

[0597] In some embodiments, the eye disease or disorder is uveitis, keratitis, conjunctivitis, thyroid eye disease, age-related macular degeneration, glaucoma, diabetic retinopathy, diabetes-related macular edema, or scleritis.

[0598] In some embodiments, the disease or disorder is a neuronal system injury.

[0599] In some embodiments, the disease or disorder is cancer.

[0600] In some embodiments, the neurodegenerative diseases or disorder is autoimmune encephalomyelitis (AE) (including EAE), chronic inflammatory demyelinating polyneuropathy, acute disseminated encephalomyelitis (ADEM), multiple sclerosis (MS), amyotrophic lateral sclerosis, schizophrenia, Alzheimer’s disease, or Parkinson’s disease.

[0601] In some embodiments, the AE is acute. In some embodiments, the AE is chronic.

[0602] In some embodiments, the MS is a late-stage MS disease. In some embodiments, the MS is in a relapsing stage.

[0603] In some embodiments, the disease or disorder is amyotrophic lateral sclerosis, Alzheimer’s disease, multiple sclerosis, or Huntington’s disease.

[0604] In some embodiments, the Alzheimer’s disease is Alzheimer’s disease with APOE4.

[0605] In some embodiments, the multiple sclerosis is progression independent of relapses.

[0606] In some embodiments, the neurodegenerative diseases or disorder is dementia, frontotemporal lobar dementia, Huntington’s disease, accessory nerve disorder, autonomic dysreflexia, peripheral neuropathy, chemotherapy-induced peripheral neuropathies, mononeuropathy, polyneuropathy, radial neuropathy, ulnar neuropathy, Villaret's syndrome, Charcot–Marie–Tooth disease, diabetic neuropathy, nerve paralysis, progressive bulbar palsy, pseudobulbar palsy, spinal bulbar muscular atrophy, myotonic dystrophy, inclusion body myositis, prion disease, seizure disorders, lysosomal storage disorders, transmissible spongiform encephalopathy, Creutzfeldt-Jacob disease (CJD), spinocerebellar ataxia, spinal muscular atrophy, and Horner’s syndrome. In some embodiments, the neurodegenerative disease or condition is driven by dysregulated adaptive (T cells and B cells), or innate (monocytes, microglia and astrocytes) immune responses.

[0607] In some embodiments, the disease or disorder is adrenoleukodystrophy, macular degeneration, glaucoma, optic neuritis, Guillain-Barre syndrome, or Lewy Body syndrome.

[0608] In some embodiments, the disease or disorder is autoimmune encephalomyelitis, chronic inflammatory demyelinating polyneuropathy, acute disseminated encephalomyelitis, multiple sclerosis, amyotrophic lateral sclerosis, schizophrenia, Alzheimer’s disease, Parkinson’s disease, acute disseminated encephalomyelitis (“ADEM”), concentric sclerosis, Charcot-Marie-Tooth disease, Guillain-Barre syndrome, HTLV-I associated myelopathy (“HAM”), neuromyelitis optica, Schilder’s disease, or transverse myelitis.

[0609] In some embodiments, the disease or disorder is a chronic autoimmune inflammatory disease.

[0610] In some embodiments, the disease or disorder is a neuronal system injury characterized by EphB3 kinase activity.

[0611] In some embodiments, the neuronal system injury is a central nervous system injury. In some embodiments, the central nervous system injury is selected from cerebral ischemia and traumatic brain injury.

[0612] In some embodiments, the disease or disorder is stroke, spinal cord injury, or traumatic brain injury.

[0613] In some embodiments, the cancer is selected from leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer.

[0614] In some embodiments, modulation of EphB3 is inhibition of EphB3 receptor signaling in an astrocyte cell of a subject.

[0615] In some embodiments, modulation of EphB3 is inhibition of EphB3 tyrosine kinase in an astrocyte cell of a subject.

[0616] In some embodiments, modulation of EphB3 is inhibition of pro-inflammatory response in an astrocyte cell of a subject.

[0617] In some embodiments, modulation of EphB3 is inhibition of production of TNF-α in an astrocyte cell of a subject.

[0618] In some embodiments, modulation of EphB3 is reduction of production of IL6 in an astrocyte cell of a subject.

[0619] In some embodiments, modulation of EphB3 is reduction of production of CCl2 in an astrocyte cell of a subject.

[0620] In some embodiments, modulation of EphB3 is inhibition of phosphorylation of AKT in astrocyte cell of a subject.

[0621] In some embodiments, modulation of EphB3 is inhibition of activation of mTOR pathway in an astrocyte cell of a subject.

[0622] In some embodiments, modulation of EphB3 is inhibition of production of mitochondrial reactive oxygen species (ROS) in an astrocyte cell of a subject.

[0623] In some embodiments, modulation of EphB3 is inhibition of pro-inflammatory response in a microglial cell of a subject.

[0624] In some embodiments, modulation of EphB3 is restoration of a homeostatic state or a normal activation state of glial cell or a neuron cell of a subject.

[0625] In some embodiments, modulation of EphB3 is inhibition of NFkB activation in a microglial cell of a subject.

[0626] In some embodiments, modulation of EphB3 is inhibition of production of TNF-α in a microglial cell of a subject.

[0627] In some embodiments, modulation of EphB3 is inhibition of demyelination of a neuron cell in a subject.

[0628] In some embodiments, modulation of EphB3 is reduction of pro-inflammatory T cells in a central nervous system of a subject.

[0629] In some embodiments, modulation of EphB3 is reduction of pro-inflammatory macrophages in a central nervous system of a subject.

[0630] In some embodiments, modulation of EphB3 is reductio of pro-inflammatory macrophages in a peripheral nervous system of a subject.

[0631] In some embodiments, modulation of EphB3 is inhibition of CNS inflammation in a subject.

[0632] In some embodiments, modulation of EphB3 is inhibition of PNS inflammation in a subject.

[0633] In some embodiments, modulation of EphB3 is inhibition of neurodegeneration in a subject. Definitions

[0634] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0635] Without wishing to be limited by this statement, it is understood that, while various options for variables are described herein, the disclosure intends to encompass operable embodiments having combinations of the options. The disclosure may be interpreted as excluding the non-operable embodiments caused by certain combinations of the options.

[0636] It is to be understood that a compound of the present disclosure may be depicted in a neutral form, a cationic form (e.g., carrying one or more positive charges), or an anionic form (e.g., carrying one or more negative charges), all of which are intended to be included in the scope of the present disclosure. For example, when a compound of the present disclosure is depicted in an anionic form, such depiction also refers to the various neutral forms, cationic forms, and anionic forms of the compound. For another example, when a compound the present disclosure is depicted in an anionic form, such depiction also refers to various salts (e.g., sodium salt) of the anionic form of the compound.

[0637] A “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to affect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

[0638] As used herein, “alkyl”, “C1, C2, C3, C4, C5 or C6 alkyl” or “C1-C 6 alkyl” is intended to include C1, C2, C3, C4, C5 or C6 straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5or C6branched saturated aliphatic hydrocarbon groups. For example, C1-C6alkyl is intends to include C1, C2, C3, C4, C5and C6alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C1-C6 for straight chain, C3-C6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.

[0639] As used herein, the term “alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C6” includes alkenyl groups containing two to six carbon atoms. The term “C3-C6” includes alkenyl groups containing three to six carbon atoms.

[0640] As used herein, the term “optionally substituted alkenyl” refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0641] As used herein, the term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six orfewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C6” includes alkynyl groups containing two to six carbon atoms. The term “C3- C6” includes alkynyl groups containing three to six carbon atoms. As used herein, “C2-C6alkenylene linker” or “C2-C6 alkynylene linker” is intended to include C2, C3, C4, C5 or C6 chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C2- C6alkenylene linker is intended to include C2, C3, C4, C5and C6alkenylene linker groups.

[0642] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents.

[0643] As used herein, the term “aryl” includes groups with aromaticity, including “conjugated,” or multicyclic systems with one or more aromatic rings and do not contain any heteroatom in the ring structure. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like.

[0644] The aryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system.

[0645] As used herein, the term “substituted,” means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =O), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N).

[0646] “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0647] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0648] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0649] As used herein, the term “hydroxy” or “hydroxyl” includes groups with an -OH or -O-.

[0650] As used herein, the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

[0651] The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms.

[0652] As used herein, the term “alkoxy” or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to,fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.

[0653] As used herein, the expressions “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C”, “selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and / or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise.

[0654] It is to be understood that the present disclosure provides methods for the synthesis of the compounds of any of the Formulae described herein. The present disclosure also provides detailed methods for the synthesis of various disclosed compounds of the present disclosure according to the following schemes as well as those shown in the Examples.

[0655] It is to be understood that, throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated those compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0656] It is to be understood that the synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.

[0657] It is to be understood that compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5thedition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups inOrganic Synthesis, 3rdedition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognized reference textbooks of organic synthesis known to those in the art.

[0658] One of ordinary skill in the art will note that, during the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups. One of ordinary skill in the art will recognize that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons: New York, 1999.

[0659] It is to be understood that, unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment or prophylaxis as is described herein, as well as use of the compounds to prepare a medicament to treat or prevent such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models.

[0660] As used herein, the term “subject” includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In some embodiments, the subject is a human.

[0661] As used herein, the term “subject in need thereof” refers to a subject having a disease or having an increased risk of developing the disease. A subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment. In someembodiments, the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, the subject in need thereof received at least one prior therapy.

[0662] As used herein, the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model. It is to be appreciated that references to “treating” or “treatment” include the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0663] It is to be understood that a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes.

[0664] As used herein, the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.

[0665] It is to be understood that one skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rdedition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18thedition (1990). These texts can, of course, also be referred to in making or using an aspect of the disclosure.

[0666] It is to be understood that the present disclosure also provides pharmaceutical compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0667] As used herein, the term “pharmaceutical composition” is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0668] As used herein, the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0669] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.

[0670] It is to be understood that a pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the followingcomponents: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0671] It is to be understood that a compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. For example, a compound of the disclosure may be injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., a disease or disorder disclosed herein) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.

[0672] As used herein, the term “therapeutically effective amount,” refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0673] It is to be understood that, for any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

[0674] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet,time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance / response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

[0675] The pharmaceutical compositions containing active compounds of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and / or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.

[0676] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL^ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0677] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0678] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0679] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0680] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

[0681] The active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtainedcommercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No.4,522,811.

[0682] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure is dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

[0683] It is to be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0684] It is to be understood that, for the compounds of the present disclosure being capable of further forming salts, all of these forms are also contemplated within the scope of the claimed disclosure.

[0685] As used herein, the term “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

[0686] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt.

[0687] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3.

[0688] Techniques for formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19thedition, Mack Publishing Co., Easton, PA (1995). In an embodiment, the compounds described herein, and the pharmaceutically acceptable salts thereof, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier, excipient, adjuvant, or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.

[0689] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure.

[0690] In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it willbe understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer.

[0691] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow.

[0692] As use herein, the phrase “compound of the disclosure” refers to those compounds which are disclosed herein, both generically and specifically. Exemplary Embodiments

[0693] Exemplary Embodiment 1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: Ring, wherein * indicates R2 attachment and ** indicates amide attachment; R1 is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R1a; each R1aindependently is halo, -OH, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6 alkoxyl, or -C(O)N(R1b)(R1c), or two R1a, together with the atoms to which they are attached, form a C3-C6 cycloalkyl or 5- to 6-membered heterocycle;each R1b independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; each R1cindependently is C6-C10aryl optionally substituted with one or more halo, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxyl; R2 is C2-C6 alkenyl or -C(O)R2a, wherein the C2-C6 alkenyl is optionally substituted with one or more R2b; R2ais C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more R2b; each R2bindependently is halo, -N(R2c)(R2d), -OR2c, -CO2(R2c), C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R2e; each R2c independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R2f; each R2dindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; each R2e independently is halo, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, -CO(C1-C6alkyl), or -CO2(C1-C6 alkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or -NH2; each R2f independently is halo, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, -CO2(R2g), -CON(R2g)(R2h), C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, or -C(O)-NH(C1-C6alkyl-C1-C6alkoxy); each R2g independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, C1-C6 alkyl, or C1-C6haloalkyl; each R2hindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl;R3 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, or 5- to 10-membered heterocyclyl; and n is 0, 1, 2, 3, or 4.

[0694] Exemplary Embodiment 2. A compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: R1 is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R1a; each R1aindependently is halo, -OH, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6 alkoxyl, or -C(O)N(R1b)(R1c), or two R1a, together with the atoms to which they are attached, form a C3-C6 cycloalkyl or 5- or 6-membered heterocycle; each R1bindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; each R1cindependently is C6-C10aryl optionally substituted with one or more halo, C1- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl; R2 is C2-C6 alkenyl or -C(O)R2a, wherein the C2-C6 alkenyl is optionally substituted with one or more R2b; R2ais C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more R2b; each R2b independently is halo, -N(R2c)(R2d), -OR2c, -CO2(R2c), C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R2e;

[0695] each R2c independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R2f; each R2dindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl;each R2e independently is halo, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, -CO(C1-C6alkyl), or -CO2(C1-C6 alkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more -CN, -OH, C1-C6 alkoxy, -NH-CO2(C1-C6alkyl), or -NH2; each R2findependently is halo, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6 alkoxy, -CO2(R2g), -CON(R2g)(R2h), C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, or -C(O)-NH(C1-C6alkyl-C1-C6alkoxy); each R2g independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, C1-C6 alkyl, or C1-C6 haloalkyl; each R2hindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R3 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, or 5- to 10-membered heterocyclyl; and n is 0, 1, 2, 3, or 4.

[0696] Exemplary Embodiment 3. The compound of any one of the preceding Exemplary Embodiments, wherein R1is phenyl optionally substituted with one or more R1a.

[0697] Exemplary Embodiment 4. The compound of Exemplary Embodiment 1 or Exemplary Embodiment 2, wherein R1 is 5- or 6-membered heteroaryl optionally substituted with one or more R1a.

[0698] Exemplary Embodiment 5. The compound of any one of the preceding Exemplary Embodiments, wherein R1a is halo, C1-C6 alkyl, C1-C6 alkoxyl, or -C(O)N(R1b)(R1c).

[0699] Exemplary Embodiment 6. The compound of any one of the preceding Exemplary Embodiments, wherein R1ais Cl, F, methyl, or methoxy.

[0700] Exemplary Embodiment 7. The compound of any one of Exemplary Embodiments 1-4, wherein two R1a, together with the atoms to which they are attached, form a 5- or 6-membered heterocycle.

[0701] Exemplary Embodiment 8. The compound of any one of Exemplary Embodiments 1-4 or 7, wherein two R1a, together with the atoms to which they are attached, form .

[0702] Exemplary Embodiment 9. The compound of any one of the preceding Exemplary Embodiments, wherein R1bis H.

[0703] Exemplary Embodiment 10. The compound of any one of the preceding Exemplary Embodiments, wherein R1c is C6-C10 aryl optionally substituted with one or more C1-C6 haloalkyl.

[0704] Exemplary Embodiment 11. The compound of any one of the preceding Exemplary Embodiments, wherein R1c is phenyl optionally substituted with one or more -CF3.

[0705] Exemplary Embodiment 12. The compound of any one of the preceding Exemplary F Embodiments, wherein R1c is F F .

[0706] Exemplary Embodiment 13. The compound of any one of the preceding Exemplary , ,,

[0707] Exemplary Embodiment 14. The compound of any one of the preceding Exemplary Embodiments, wherein R2is -C(O)R2a.

[0708] Exemplary Embodiment 15. The compound of any one of Exemplary Embodiments 1- 13, wherein R2is C2-C6alkenyl optionally substituted with one or more R2b.

[0709] Exemplary Embodiment 16. The compound of any one of Exemplary Embodiments 1- 14, wherein R2a is C2-C6 alkenyl or C2-C6 alkynyl, wherein the alkenyl or alkynyl is optionally substituted with one or more R2b.

[0710] Exemplary Embodiment 17. The compound of any one of Exemplary Embodiments 1- 13 or 15, wherein R2b is halo.

[0711] Exemplary Embodiment 18. The compound of any one of Exemplary Embodiments 1- 13, 15, or 17, wherein R2bis Cl.

[0712] Exemplary Embodiment 19. The compound of any one of Exemplary Embodiments 1- 13 or 15, wherein R2b is 4- to 10-membered heterocyclyl, -N(R2c)(R2d), -OR2c, C6-C10 aryl, or - CO2(R2c), wherein the heterocyclyl or aryl is optionally substituted with one or more R2e.

[0713] Exemplary Embodiment 20. The compound of any one of the preceding Exemplary Embodiments, wherein R2c is H.

[0714] Exemplary Embodiment 21. The compound of any one of Exemplary Embodiments 1- 19, wherein R2cis C1-C6alkyl, C3-C6cycloalkyl, or C6-C10aryl, wherein the alkyl, cycloalkyl, or aryl is optionally substituted with one or more R2f.

[0715] Exemplary Embodiment 22. The compound of any one of the preceding Exemplary Embodiments, wherein R2dis H, methyl, or ethyl.

[0716] Exemplary Embodiment 23. The compound of any one of the preceding Exemplary Embodiments, wherein R2e is halo, -OH, -CN, -CO(C1-C6 alkyl), -N(C1-C6 alkyl)2, or -CO2(C1- C6alkyl).

[0717] Exemplary Embodiment 24. The compound of any one of the preceding Exemplary Embodiments, wherein R2e is F, -OH, -CN, -CO(C1-C6 alkyl), -N(C1-C6 alkyl)2, or -CO2(C1- C6alkyl).

[0718] Exemplary Embodiment 25. The compound of any one of Exemplary Embodiments 1- 22, wherein R2e is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 5- to 10- membered heterocyclyl, wherein the alkyl, haloalkyl, alkoxy, cycloalkyl, or heterocyclyl, is optionally substituted with one or more -CN, -OH, C1-C6alkoxy, or -NH-CO2(C1-C6alkyl).

[0719] Exemplary Embodiment 26. The compound of any one of the preceding Exemplary Embodiments, wherein R2f is independently halo, -CN, C1-C6 alkyl, C1-C6 alkoxy, -CO2(R2g), C3-C6cycloalkyl, C6-C10aryl, C1-C6haloalkyl, or -C(O)-NH(C1-C6alkyl-C1-C6alkoxy).

[0720] Exemplary Embodiment 27. The compound of any one of the preceding Exemplary Embodiments, wherein R2f is independently F, -CN, methyl, methoxy, phenoxy, -CO2(R2g), cyclopropyl, phenyl, -CF3, or -C(O)-NH(ethyl-methoxy).

[0721] Exemplary Embodiment 28. The compound of any one of the preceding Exemplary Embodiments, wherein R2g is independently H or C1-C6 alkyl.

[0722] Exemplary Embodiment 29. The compound of any one of the preceding Exemplary Embodiments, wherein R2gis independently H or tert-butyl.

[0723] Exemplary Embodiment 30. The compound of any one of the preceding Exemplary

[0724] Exemplary Embodiment 31. The compound of any one of the preceding Exemplary Embodiments, wherein R3 is C1-C6 alkyl or C3-C10 cycloalkyl.

[0725] Exemplary Embodiment 32. The compound of any one of the preceding Exemplary Embodiments, wherein R3 is methyl or cyclopropyl.

[0726] Exemplary Embodiment 33. The compound of any one of the preceding Exemplary Embodiments, wherein the compound is of Formula (II-a)or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0727] Exemplary Embodiment 34. The compound of any one of the preceding Exemplary Embodiments, wherein the compound is of Formula (II-b)or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0728] Exemplary Embodiment 35. The compound of any one of the preceding Exemplary Embodiments, wherein the compound is of Formula (II-c)or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0729] Exemplary Embodiment 36. The compound of any one of the preceding Exemplary Embodiments, wherein the compound is of Formula (II-d)or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0730] Exemplary Embodiment 37. A compound of Formula (III):or a pharmaceutically acceptable salt thereof, wherein: R1is C6-C10aryl optionally substituted with one or more R1a; each R1a independently is halo, -OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxyl; R2is -C(O)R2a;R2a is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more R2b; each R2bindependently is halo, -N(R2c)(R2d), -OR2c, -CO2(R2c), C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10-membered heteroaryl; each R2c independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; each R2dindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R3is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, or 5- to 10-membered heterocyclyl; and n is 0, 1, 2, 3, or 4.

[0731] Exemplary Embodiment 38. The compound of Exemplary Embodiment 1 or Exemplary Embodiment 37, wherein R1is phenyl optionally substituted with one or more R1a.

[0732] Exemplary Embodiment 39. The compound of any one of Exemplary Embodiments 1 or 37-38, wherein R1a is halo.

[0733] Exemplary Embodiment 40. The compound of any one of Exemplary Embodiments 1 or 37-39, wherein R1ais Cl.

[0734] Exemplary Embodiment 41. The compound of any one of Exemplary Embodiments 1 or 37-40, wherein

[0735] Exemplary Embodiment 42. The compound of any one of Exemplary Embodiments 1 or 37-41, wherein R2a is C2-C6 alkenyl or C2-C6 alkynyl, wherein the alkenyl or alkynyl is optionally substituted with one or more R2b.

[0736] Exemplary Embodiment 43. The compound of any one of Exemplary Embodiments 1 or 37-42, wherein R2b is independently -N(R2c)(R2d) or 4- to 10-membered heterocyclyl.

[0737] Exemplary Embodiment 44. The compound of any one of Exemplary Embodiments 1 or 37-43, wherein R2cis C1-C6alkyl.

[0738] Exemplary Embodiment 45. The compound of any one of Exemplary Embodiments 1 or 37-44, wherein R2cis methyl.

[0739] Exemplary Embodiment 46. The compound of any one of Exemplary Embodiments 1 or 37-45, wherein R2d is C1-C6 alkyl

[0740] Exemplary Embodiment 47. The compound of any one of Exemplary Embodiments 1 or 37-46, wherein R2d is methyl.

[0741] Exemplary Embodiment 48. The compound of any one of Exemplary Embodiments 1 or 37-47, wherein

[0742] Exemplary Embodiment 49. The compound of any one of Exemplary Embodiments 1 or 37-48, wherein

[0743] Exemplary Embodiment 50. The compound of any one of Exemplary Embodiments 1 ,

[0744] Exemplary Embodiment 51. The compound of any one of Exemplary Embodiments 1 or 37-50, wherein the compound is of Formula (III-a)or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0745] Exemplary Embodiment 52. The compound of any one of Exemplary Embodiments 1 or 37-51, wherein the compound is of Formula (III-b)or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0746] Exemplary Embodiment 53. The compound of any one of Exemplary Embodiments 1 or 37-52, wherein the compound is of Formula (III-c)or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0747] Exemplary Embodiment 54. The compound of any one of the preceding Exemplary Embodiments, wherein the compound is selected from the compounds described in Table 1, or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0748] Exemplary Embodiment 55. A compound being an isotopic derivative of the compound of any one of the preceding Exemplary Embodiments.

[0749] Exemplary Embodiment 56. A compound of any one of the preceding Exemplary Embodiments obtainable by, or obtained by, a method described herein.

[0750] Exemplary Embodiment 57. An intermediate obtained by a method for preparing the compound of any one of the preceding Exemplary Embodiments.

[0751] Exemplary Embodiment 58. A pharmaceutical composition comprising the compound of any one of the preceding Exemplary Embodiments and a pharmaceutical acceptable diluent or carrier.

[0752] Exemplary Embodiment 59. A method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of any one of the preceding Exemplary Embodiments, or the pharmaceutical composition of any one of the preceding embodiments.

[0753] Exemplary Embodiment 60. The compound or pharmaceutical composition of anyone of the preceding Exemplary Embodiments, for use in treating or preventing a disease or disorder.

[0754] Exemplary Embodiment 61. Use of the compound of any one of the preceding Exemplary Embodiments in the manufacture of a medicament for treating or preventing a disease or disorder.

[0755] Exemplary Embodiment 62. The method, compound, or use of any one of Exemplary Embodiments 59-61, wherein the disease or disorder is a neurodegenerative disease or disorder.

[0756] Exemplary Embodiment 63. The method, compound, or use of Exemplary Embodiment 62, wherein the neurodegenerative disease or disorder is neuromyelitis optica (“NMO”), transverse myelitis, myelin oligodendrocyte glycoprotein, acute disseminated encephalomyelitis (“ADEM”), optic neuritis, amyloidosis, Parkinson's disease, Alzheimer's disease, cerebral amyloid angiopathy, Pick's disease, frontotemporal dementia, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, amyotrophic lateral sclerosis (“ALS”), Huntington's disease, traumatic brain injury, stroke, fatty liver disease, endometriosis, paraneoplastic disorders, inflammatory demyelinating polyneuropathy, amyotrophy, fibromyalgia, multiple system atrophy, Friedrich's ataxia, or cerebellar ataxia.

[0757] Exemplary Embodiment 64. The method, compound, or use of any one of Exemplary Embodiments 59-61, wherein the disease or disorder is a psychiatric or neurodevelopmental disease or disorder.

[0758] Exemplary Embodiment 65. The method, compound, or use of Exemplary Embodiment 64, wherein the psychiatric or neurodevelopmental disease or disorder is schizophrenia, major depressive disorder, generalized anxiety disorder, panic disorder, social anxiety disorder, agoraphobia, post-traumatic stress disorder, autism spectrum disorder, cerebral palsy, Nasu Hakola disease, bipolar disorder, or substance abuse.

[0759] Exemplary Embodiment 66. The method, compound, or use of any one of Exemplary Embodiments 59-61, wherein the disease or disorder is a viral or infectious disease or disorder.

[0760] Exemplary Embodiment 67. The method, compound, or use of Exemplary Embodiment 66, wherein the viral or infectious disease or disorder is neuro-HIV, viral encephalitis, meningitis, neurocysticercosis, neurosyphilis, neuro-Lyme disease, infectious myelopathies, COVID-19 neuroinflammation, enteroviruses, poliovirus, Epstein-Barr virus (EBV), human herpesvirus, cytomegalovirus, rabies virus, herpes simplex virus, measles, progressive multifocal leukoencephalopathy John Cunningham (“PML JC”) virus, bacterial meningitis, prion disease, or Creutzfeldt Jakob disease.

[0761] Exemplary Embodiment 68. The method, compound, or use of any one of Exemplary Embodiments 59-61, wherein the disease or disorder is an autoimmune disease or disorder.

[0762] Exemplary Embodiment 69. The method, compound, or use of Exemplary Embodiment 68, wherein the autoimmune disease or disorder is antibody-mediated encephalitis, neurological complications of connective tissue damage, neurosarcoidosid, demyelinating diseases (non-MS), idiopathic autoimmune CNS and PNS syndromes, paraneoplastic neurological disease, CNS vasculitis, type 1 diabetes, type 2 diabetes, Crohn's disease, systemic lupus erythematous (“SLE”), irritable bowel disorders, asthma, chronic obstructive pulmonary disease (“COPD”), atopic dermatitis, obesity-associated inflammation, heart disease, ulcerative colitis, psoriasis, psoriatic arthritis, reactive arthritis, rheumatoid arthritis, Sjögren's syndrome, Reiter's disease, multiple sclerosis, autoimmune encephalitis, myasthenia gravis, idiopathic pulmonary fibrosis, ankylosing spondylitis, antiphospholipid antibody syndrome, osteomyelitis, gout, Henoch-Schonlein Purpura, dermatomyositis, idiopathic arthritis, scleroderma, Kawasaki disease, mixed connective tissue damage, myositis, spondyloarthritis, undifferentiated connective tissue disease, systemic sclerosis, or autoimmune hepatitis.

[0763] Exemplary Embodiment 70. The method, compound, or use of any one of Exemplary Embodiments 59-61, wherein the disease or disorder is an eye disease or disorder.

[0764] Exemplary Embodiment 71. The method, compound, or use of Exemplary Embodiment 70, wherein the eye disease or disorder is uveitis, keratitis, conjunctivitis, thyroid eye disease, age-related macular degeneration, glaucoma, diabetic retinopathy, diabetes-related macular edema, or scleritis.

[0765] Exemplary Embodiment 72. The method, compound, or use of any one of Exemplary Embodiments 59-62, wherein the disease or disorder is selected from autoimmune encephalomyelitis, chronic inflammatory demyelinating polyneuropathy, concentric sclerosis, Charcot-Marie-Tooth disease, Guillain-Barre syndrome, HTLV-I associated myelopathy (“HAM”), Schilder’s disease, dementia, frontotemporal lobar dementia, accessory nerve disorder, autonomic dysreflexia, peripheral neuropathy, chemotherapy-induced peripheral neuropathies, mononeuropathy, polyneuropathy, radial neuropathy, ulnar neuropathy, Villaret's syndrome, diabetic neuropathy, nerve paralysis, progressive bulbar palsy, pseudobulbar palsy, spinal bulbar muscular atrophy, myotonic dystrophy, inclusion body myositis, seizure disorders, lysosomal storage disorders, transmissible spongiform encephalopathy, spinocerebellar ataxia, spinal muscular atrophy, Horner’s syndrome, adrenoleukodystrophy, macular degeneration, and Lewy Body syndrome.

[0766] Exemplary Embodiment 73. The method, compound, or use of Exemplary Embodiment 69 or 72, wherein the disease or disorder is autoimmune encephalomyelitis or multiple sclerosis.

[0767] Exemplary Embodiment 74. The method, compound, or use of Exemplary Embodiment 63 or 69, wherein the disease or disorder is amyotrophic lateral sclerosis, Alzheimer’s disease, multiple sclerosis, or Huntington’s disease.

[0768] Exemplary Embodiment 75. The method, compound, or use of Exemplary Embodiment 63 or 74, wherein the Alzheimer’s disease is Alzheimer’s disease with APOE4.

[0769] Exemplary Embodiment 76. The method, compound, or use of Exemplary Embodiment 69, 73, or 74, wherein the multiple sclerosis is progression independent of relapses. EXAMPLES

[0770] For exemplary purpose, salts of the compounds of Formula (I), Formula (II), or Formula (III) are synthesized and tested in the examples. Synthesis of Compounds

[0771] Compounds of Formula (I), Formula (II), or Formula (III) can be prepared using the methods detailed herein. Those skilled in the art may be able to envisage alternative synthetic routes, using a variety of starting materials and reagents to prepare the disclosed compounds of Formula (I), Formula (II), or Formula (III) and to make further modifications.

[0772] In some embodiments, the stereocenters of the compounds of the present disclosure are arbitrarily assigned. HPLC conditions Acidic condition

[0773] Mobile phase: A = water (0.1 % TFA), B = acetonitrile; Flow rate: 30mL\min; Gradient: B = 10-55% in 10 min, stop at 20 min; Column: Boston pHlex ODS 21.2*250mm, 10µm; Detection wavelength: 214 / 254 nm. Basic condition

[0774] Mobile phase: A = water (10 mM NH4HCO3), B = acetonitrile; Flow rate: 30mL\min; Gradient: B = 10-50% in 10 min, stop at 18 min; Column: Boston pHlex ODS 21.2*250mm, 10µm; Detection wavelength: 214 / 254 nm. Synthesis of Intermediates Intermediate V14. Synthesis of N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2- a]pyrazine-3-carboxamide hydrochloride (V14).

[0775] A solution of pyrazin-2-amine (30 g, 315.45 mmol) and ethyl 2-chloro-3-oxo- propanoate (56.99 g, 378.54 mmol) in Ethanol (300 mL) was stirred at 80 °C under N2for 16 hr. After concentration, the residue was diluted with ethyl acetate (200 ml) and filtered. The filtration was concentrated and purified by flash chromatography (EtOAc / petroleum ether = 1 / 1) to give ethyl imidazo[1,2-a]pyrazine-3-carboxylate (V14) (25.5 g, 125.38 mmol, 39.74% yield, 94% purity) as a white solid. LCMS: m / z 192.1 [M+H]+.1H NMR (400 MHz, MeOD) δ 9.24 (dd, J = 4.6, 1.5 Hz, 1H), 9.18 (d, J = 1.4 Hz, 1H), 8.39 (s, 1H), 8.18 (d, J = 4.7 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H). Step 2. Synthesis of 7-(tert-butyl) 3-ethyl 5,6-dihydroimidazo[1,2-a]pyrazine-3,7(8H)- dicarboxylate

[0776] To a solution of ethyl imidazo[1,2-a]pyrazine-3-carboxylate (11.7 g, 51.77 mmol) in Ethyl acetate (150 mL) was added 10% Palladium on carbon wet (4.85 g, 45.56 mmol), Et3N (10.46 g, 103.55 mmol) and Di-tert-butyl dicarbonate (16.95 g, 77.66 mmol, 17.82 mL) and the mixture was stirred at r.t. under H2 overnight. The reaction solution was filtered and the filtration was concentrated to give yellow oil. It was purified by flash chromatography (eluting with petrol ether: ethyl acetate=0-20%) to give 7-(tert-butyl) 3-ethyl 5,6-dihydroimidazo[1,2-a]pyrazine-3,7(8H)-dicarboxylate (13.5 g, 36.57 mmol, 70.63% yield, 80% purity) as yellow oil. LCMS: m / z 296.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ7.71 (s, 1H), 4.73 (s, 2H), 4.40 – 4.24 (m, 4H), 3.84 (t, J = 5.3 Hz, 2H), 1.49 (s, 9H), 1.36 (t, J = 7.1 Hz, 3H). Step 3. Synthesis of 7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3- carboxylic acid

[0777] To a solution of 7-(tert-butyl) 3-ethyl 5,6-dihydroimidazo[1,2-a]pyrazine-3,7(8H)- dicarboxylate (20 g, 67.8 mmol) in EtOH (200 ml) was added LiOH·H2O (8.54 g, 203.3 mmol) in H2O (50 ml). The mixture was stirred at rt for 4 hr, and was adjusted pH 5 with 1N HCl. The pricipitate was filtered and dried to give 7-(tert-butoxycarbonyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxylic acid (15.1 g, 56.6 mmol, 83.4% yield, 96% purity) as a yellow solid. LCMS: m / z 268.2 [M+H]+.1H NMR (400 MHz, DMSO) δ 7.46 (s, 1H), 4.56 (s, 2H), 4.24 (t, J = 5.2 Hz, 2H), 3.80 – 3.70 (m, 2H), 1.44 (s, 9H). Step 4. Synthesis of tert-butyl 3-((2-chlorophenyl)carbamoyl)-5,6-dihydroimidazo[1,2- a]pyrazine-7(8H)-carboxylate

[0778] To a solution of 7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3- carboxylic acid (3.53 g, 13.21 mmol) in DMF (30 mL) and MeCN (30 mL) were added N,N,N',N'-Tetramethylchloroformamidinium-hexafluorophosphate (11.12 g, 39.62 mmol) , 1-methyl-1H-imidazole (3.25 g, 39.62 mmol, 3.16 mL) and 2-chloroaniline (3.37 g, 26.41 mmol) . The reaction was stirred at room temperature overnight. The mixture was concentrated, diluted with water (100 mL) and extracted with ethyl acetate (100 mL x2). The extract was washed with saturated LiCl aqueous solution (100 mL x2) and brine (100 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash chromatography (Biotage, 80 g silica gel column @ 80 mL / min, eluting with 80% - 100% ethyl acetate in petroleum ether, then with 0%-3% methanol in DCM) to give tert-butyl 3-[(2-chlorophenyl)carbamoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carboxylate (2.16 g, 5.01 mmol, 37.90% yield, 87.33% purity) as brown gum. LCMS: m / z 377.0[M+H]+.Step 5. Synthesis of N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3- carboxamide hydrochloride

[0779] To a solution of tert-butyl 3-[(2-chlorophenyl)carbamoyl]-6,8-dihydro-5H- imidazo[1,2-a]pyrazine-7-carboxylate (12.4 g, 32.91 mmol) in DCM (50 mL) was added 4M HCl in dioxane (60 mL) and the mixture was stirred at r.t. overnight. The reaction solution was filtered and solid collected to give N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2- a]pyrazine-3-carboxamide (10.3 g, 32.56 mmol, 98.95% yield, 99% purity, HCl salt) as white solid. LCMS: m / z 277.0[M+H]+.1H NMR (400 MHz, MeOD) δ 7.77 (s, 1H), 7.68 (dd, J = 8.0, 1.5 Hz, 1H), 7.50 (dd, J = 8.0, 1.4 Hz, 1H), 7.35 (td, J = 7.8, 1.5 Hz, 1H), 7.27 – 7.22 (m, 1H), 4.60 (s, 1H), 4.34 (t, J = 5.6 Hz, 2H), 4.06 (s, 2H), 3.25 – 3.18 (m, 2H). Example 1. Synthesis of (E)-N-(2,5-dichlorophenyl)-7-(3-(1-methylpyrrolidin-2- yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.Step 1. Synthesis of tert-butyl 3-((2,5-dichlorophenyl)carbamoyl)-5,6-dihydroimidazo[1,2- a]pyrazine-7(8H)-carboxylate

[0780] To a solution of 7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3- carboxylic acid (801.84 mg, 3 mmol) in DMF (15 mL) was added 2,5-dichloroaniline (583.26 mg, 3.60 mmol, 378.74 μL), N,N,N',N'-Tetramethylchloroformamidinium- hexafluorophosphate (2.53 g, 9.00 mmol) and 1-Methylimidazole (738.93 mg, 9.00 mmol, 716.72 μL). The resulting mixture was stirred at room temperature for 16 h. Water (20 mL)was added, extracted with EtOAc (25 mL x 3). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography with a gradient of EtOAc / PE (0 to 100 percent) to give tert-butyl 3-((2,5- dichlorophenyl)carbamoyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (400 mg, 972.57 μmol, 32.42% yield) as a brown solid. LCMS: m / z 411.0[M+H]+. Step 2. Synthesis of N-(2,5-dichlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3- carboxamide hydrochloride

[0781] tert-butyl 3-((2,5-dichlorophenyl)carbamoyl)-5,6-dihydroimidazo[1,2-a]pyrazine- 7(8H)-carboxylate (200 mg, 486.28 μmol) was dissolved in HCl / dioxane (4 M, 2 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to give N-(2,5-dichlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3- carboxamide (150 mg, crude, HCl salt) as a brown solid. LCMS: m / z 311.0[M+H]+. Step 3. Synthesis of (E)-N-(2,5-dichlorophenyl)-7-(3-(1-methylpyrrolidin-2-yl)acryloyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide

[0782] To a solution of N-(2,5-dichlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3- carboxamide hydrochloride (90 mg, 289.23 μmol) in DMF (3 mL) was added (R,E)-3-(1- methylpyrrolidin-2-yl)acrylic acid (49.38 mg, 318.16 μmol), HATU (219.95 mg, 578.47 μmol) and DIPEA (112.14 mg, 867.70 μmol, 151.14 μL). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated and the residue was purified by Prep-HPLC under alkaline condition to give (E)-N-(2,5-dichlorophenyl)-7-(3-(1- methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide (10.2 mg, 22.75 μmol, 7.87% yield) as a white solid. LCMS: m / z 448.1[M+H]+.1H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 2.4 Hz, 1H), 8.09 (s, 1H), 7.64 (s, 1H), 7.34 (d, J = 8.4 Hz,1H), 7.07 (dd, J = 8.4, 2.4 Hz, 1H), 6.89 (dd, J = 15.2, 7.6 Hz, 1H), 6.45 (d, J = 15.2 Hz, 1H), 4.95 (s, 2H), 4.50 (s, 2H), 4.08 (s, 2H), 3.14 (s, 1H), 2.79 (d, J = 8.0 Hz, 1H), 2.34- 2.20 (m, 4H), 2.08-1.98 (m, 1H), 1.90-1.76 (m, 2H), 1.71-1.65 (m, 1H). Example 2. Synthesis of (E)-N-(2,5-dichlorophenyl)-7-(4-(ethyl(methyl)amino)but-2- enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0783] The method as described for the synthesis of (E)-N-(2,5-dichlorophenyl)-7-(3-(1- methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of (E)-4-(ethyl(methyl)amino)but-2-enoic acid for (R,E)-3-(1- methylpyrrolidin-2-yl)acrylic acid to provide the product (E)-N-(2,5-dichlorophenyl)-7-(4- (ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 436.0[M+H]+.1H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 2.0 Hz, 1H), 8.11 (s, 1H), 7.66 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.08 (dd, J = 8.8, 2.4 Hz, 1H), 7.05-6.98 (m, 1H), 6.51 (d, J = 15.6 Hz, 1H), 4.96 (s, 2H), 4.51 (s, 2H), 4.10-4.02 (m, 2H), 3.21 (d, J = 5.6 Hz, 2H), 2.46 (q, J = 6.8 Hz, 2H), 2.27 (s, 3H), 1.09 (t, J = 7.2 Hz, 3H). Example 3. Synthesis of (E)-N-(2,4-dichlorophenyl)-7-(3-(1-methylpyrrolidin-2- yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0784] The method as described for the synthesis of (E)-N-(2,5-dichlorophenyl)-7-(3-(1- methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of 2,4-dichloroaniline for 2,5-dichloroaniline to provide the product (E)-N-(2,4-dichlorophenyl)-7-(3-(1-methylpyrrolidin-2-yl)acryloyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 448.1[M+H]+.1H NMR (400MHz, CDCl3) δ 8.33 (d, J = 8.9 Hz, 1H), 8.04 (s, 1H), 7.61 (d, J = 19.8 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.29 (dd, J = 8.9, 2.4 Hz, 1H), 6.89 (dd, J = 15.0, 7.4 Hz, 1H), 6.45 (d, J = 13.9 Hz, 1H), 4.95 (s, 2H), 4.48 (s, 2H), 4.08 (s, 2H), 3.35-2.57 (m, 3H), 2.33-1.72 (m, 7H). Example 4. Synthesis of (E)-N-(2,4-dichlorophenyl)-7-(4-(ethyl(methyl)amino)but-2- enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0785] The method as described for the synthesis of (E)-N-(2,5-dichlorophenyl)-7-(3-(1- methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of (E)-4-(ethyl(methyl)amino)but-2-enoic acid for (R,E)-3-(1- methylpyrrolidin-2-yl)acrylic acid and 2,4-dichloroaniline for 2,5-dichloroaniline to provide the product (E)-N-(2,4-dichlorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 436.0[M+H]+.1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 8.9 Hz, 1H), 8.06 (s, 1H), 7.64 (s, 1H), 7.43 (d, J = 2.3 Hz, 1H), 7.29 (dd, J = 8.9, 2.4 Hz, 1H), 7.00 (dt, J = 15.1, 5.8 Hz, 1H), 6.48 (d, J = 15.1 Hz, 1H), 4.94 (s, 2H), 4.48 (s, 2H), 4.09 (s, 2H), 3.19 (d, J = 4.8 Hz, 2H), 2.45 (q, J = 7.1 Hz, 2H), 2.25 (s, 3H), 1.08 (t, J = 7.2 Hz, 3H). Example 5. Synthesis of (E)-N-(2-chloro-3-fluorophenyl)-7-(4-(ethyl(methyl)amino)but- 2-enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0786] The method as described for the synthesis of (E)-N-(2,4-dichlorophenyl)-7-(4- (ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of 2-chloro-3-fluoro-aniline for 2,4-dichloroaniline to providethe product (E)-N-(2-chloro-3-fluorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide (32.6 mg, 77.64 μmol, 45.76% yield) as white solid. LCMS: m / z 420.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.4 Hz, 1H), 8.11 (s, 1H), 7.66 (s, 1H), 7.32 – 7.26 (m, 1H), 7.04 – 6.90 (m, 2H), 6.49 (d, J = 15.1 Hz, 1H), 4.95 (s, 2H), 4.49 (s, 2H), 4.09 (s, 2H), 3.19 (d, J = 5.2 Hz, 2H), 2.46 (q, J = 7.1 Hz, 2H), 2.25 (s, 3H), 1.09 (t, J = 7.1 Hz, 3H). Example 6. Synthesis of (E)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-N-(2-methylpyridin- 3-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0787] The method as described for the synthesis of (E)-N-(2,5-dichlorophenyl)-7-(3-(1- methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of (E)-4-(ethyl(methyl)amino)but-2-enoic acid for (,E)-3-(1- methylpyrrolidin-2-yl)acrylic acid and 2-methylpyridin-3-amine for 2,5-dichloroaniline to provide the product (E)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-N-(2-methylpyridin-3-yl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 383.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.35 (dd, J = 4.7, 1.4 Hz, 1H), 8.19 (d, J = 8.2 Hz, 1H), 7.61 (s, 1H), 7.37 (s, 1H), 7.21 (dd, J = 8.3, 4.9 Hz, 1H), 7.04 – 6.96 (m, 1H), 6.51 (d, J = 15.4 Hz, 1H), 4.95 (s, 2H), 4.54 – 4.44 (m, 2H), 4.13 – 3.98 (m, 2H), 3.21 (d, J = 6.4 Hz, 2H), 2.58 (s, 3H), 2.48 (q, J = 14.4, 7.3 Hz, 2H), 2.27 (s, 3H), 1.09 (t, J = 7.1 Hz, 3H). Example 7. Synthesis of (E)-N-(2-methylpyridin-3-yl)-7-(3-(1-methylpyrrolidin-2- yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0788] The method as described for the synthesis of (E)-N-(2,5-dichlorophenyl)-7-(3-(1- methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamidewas applied with substitution of 2-methylpyridin-3-amine for 2,5-dichloroaniline to provide the (E)-N-(2-methylpyridin-3-yl)-7-(3-(1-methylpyrrolidin-2-yl)acryloyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 395.2[M+H]+.1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 3.4 Hz, 1H), 8.18 (d, J = 7.1 Hz, 1H), 7.62 (s, 1H), 7.43 (s, 1H), 7.21 (dd, J = 8.1, 4.8 Hz, 1H), 6.89 (dd, J = 15.1, 7.4 Hz, 1H), 6.45 (d, J = 14.8 Hz, 1H), 4.95 (s, 2H), 4.49 (s, 2H), 4.07 (s, 2H), 3.14 (t, J = 8.5 Hz, 1H), 2.87 – 2.75 (m, 1H), 2.58 (s, 3H), 2.35 – 2.23 (m, 3H), 2.09 – 1.99 (m, 1H), 1.77 (dd, J = 28.4, 12.6 Hz, 4H). Example 8. Synthesis of 7-acryloyl-N-(2-chloro-5-((3- (trifluoromethyl)phenyl)carbamoyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine- 3-carboxamide.

[0789] To a solution of N-[2-chloro-5-[[3-(trifluoromethyl)phenyl]carbamoyl]phenyl]- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide (0.125 g, 269.49 μmol) and triethylamine (54.44 mg, 538.98 μmol) in dichloromethane (5 mL) was added dropwise prop- 2-enoyl chloride (32 mg, 350.34 μmol, 21.25 μL) and the mixture was stirred at room temperature for 2 hours and concentrated. The residue was purified by flash chromatography (eluting with 10mmol NH4HCO3: CH3CN=0-55%) to N-[2-chloro-5-[[3- (trifluoromethyl)phenyl]carbamoyl]phenyl]-7-prop-2-enoyl-6,8-dihydro-5H-imidazo[1,2- a]pyrazine-3-carboxamide. LCMS: m / z 518.0[M+H]+.1H NMR (400 MHz, MeOD) δ 8.28 (d, J = 2.1 Hz, 1H), 8.14 (s, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.89 (s, 1H), 7.83 (dd, J = 8.4, 2.2 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.56 (t, J = 8.1 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 6.93 – 6.82 (m, 1H), 6.31 (dd, J = 16.8, 1.8 Hz, 1H), 5.85 (dd, J = 10.7, 1.7 Hz, 1H), 4.96 (d, J = 24.1 Hz, 2H), 4.54 – 4.46 (m, 2H), 4.14 – 4.08 (m, 2H). Example 9. Synthesis of N-(2-chloro-5-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)- 7-methacryloyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0790] The method as described for the synthesis of 7-acetyl-N-[2-chloro-5-[[3- (trifluoromethyl)phenyl]carbamoyl]phenyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3- carboxamide was applied with substitution of methacryloyl chloride for acetyl chloride to provide the product N-(2-chloro-5-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)-7- methacryloyl-5,6,7,8-tetrahydroimidazo [1,2-a]pyrazine-3-carboxamide. LCMS: m / z 532.2[M+H]+.1H NMR (400 MHz, MeOD) δ 8.28 (d, J = 2.1 Hz, 1H), 8.16 – 8.12 (m, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.89 (s, 1H), 7.83 (dd, J = 8.4, 2.1 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 5.31 (d, J = 65.6 Hz, 2H), 4.91 (s, 2H), 4.49 (t, J = 5.3 Hz, 2H), 4.07 (t, J = 5.4 Hz, 2H), 1.99 (s, 3H). Example 10. Synthesis of 7-(but-2-ynoyl)-N-(2-chloro-5-((3- (trifluoromethyl)phenyl)carbamoyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine- 3-carboxamide.

[0791] The method as described for the synthesis of 7-acetyl-N-[2-chloro-5-[[3- (trifluoromethyl)phenyl]carbamoyl]phenyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3- carboxamide was applied with substitution of but-2-ynoyl chloride for acetyl chloride to provide the product 7-(but-2-ynoyl)-N-(2-chloro-5-((3- (trifluoromethyl)phenyl)carbamoyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3- carboxamide. LCMS: m / z 530.0[M+H]+.1H NMR (400 MHz, MeOD) δ 8.30 – 8.27 (m, 1H), 8.17 – 8.13 (m, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 3.2 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 5.09 (s, 1H),4.88 (s, 1H), 4.48 (dt, J = 35.3, 5.4 Hz, 2H), 4.16 (dt, J = 72.0, 5.5 Hz, 2H), 2.09 (d, J = 5.0 Hz, 3H). Example 11. Synthesis of (E)-7-(but-2-enoyl)-N-(2-chloro-5-((3- (trifluoromethyl)phenyl)carbamoyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a] pyrazine-3-carboxamide.

[0792] The method as described for the synthesis of 7-acetyl-N-[2-chloro-5-[[3- (trifluoromethyl)phenyl]carbamoyl]phenyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3- carboxamide was applied with substitution of (E)-but-2-enoyl chloride for acetyl chloride to provide the product (E)-7-(but-2-enoyl)-N-(2-chloro-5-((3- (trifluoromethyl)phenyl)carbamoyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3- carboxamide. LCMS: m / z 532.2[M+H]+.1H NMR (400 MHz, MeOD) δ 8.28 (d, J = 2.1 Hz, 1H), 8.17 – 8.12 (m, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.89 (s, 1H), 7.82 (dd, J = 8.4, 2.2 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 6.93 (dq, J = 13.7, 6.8 Hz, 1H), 6.66 – 6.49 (m, 1H), 4.99 – 4.90 (m, 2H), 4.48 (s, 2H), 4.09 (t, J = 5.0 Hz, 2H), 1.94 (dd, J = 6.8, 1.5 Hz, 3H). Example 12. Synthesis of N-(2-chloro-5-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)- 7-propioloyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0793] The method as described for the synthesis of N-(2-chlorophenyl)-7-propioloyl-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of N-[2- chloro-5-[[3-(trifluoromethyl)phenyl]carbamoyl]phenyl]-5,6,7,8-tetrahydroimidazo[1,2- a]pyrazine-3-carboxamide hydrochloride for N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide hydrochloride to provide the product N-(2- chloro-5-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)-7-propioloyl-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 516.0 [M+H]+.1H NMR (400 MHz, DMSO) δ 9.86 (s, 1H), 7.88 (s, 1H), 7.54 (t, J = 8.5 Hz, 2H), 7.38 (t, J = 7.7 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 4.98 (s, 1H), 4.72 (s, 1H), 4.42 – 4.24 (m, 2H), 4.17 – 3.87 (m, 2H), 2.08 (d, J = 7.1 Hz, 3H). General method B

[0794] To a solution of methyl (E)-4-bromobut-2-enoate (8 g, 44.69 mmol) in THF (80 mL) were added N-methylethylamine (2.64 g, 44.69 mmol, 3.84 mL) and N,N- Diisopropylethylamine (11.55 g, 89.38 mmol, 15.57 mL). The reaction was stirred at room temperature for 2 h. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (150 mL x3). The extract was washed with brine (150 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash chromatography (Biotage, 120 g silica gel column @ 100 mL / min, eluting with 5% methanol in dichloromethane) to give methyl (E)-4-[ethyl(methyl)amino]but-2-enoate (2 ) (4.42 g, 28.13 mmol, 62.94% yield) as yellow oil. LCMS: m / z 158.1[M+H]+.

[0795] To a solution of methyl (E)-4-[ethyl(methyl)amino]but-2-enoate (2.2 g, 13.99 mmol) in THF (20 mL) was added a solution of NaOH (1.12 g, 27.99 mmol, 525.60 μL) in Water (10 mL). The mixture was stirred at 40 °C overnight. THF was removed under reduced pressure, the aqueous solution was acidified with 1M HCl to pH 3. The mixture was lyophilized to give (E)-4-[ethyl(methyl)amino]but-2-enoic acid (3.56 g, 13.43 mmol, 95.94% yield, 54% purity) as yellow solid. The theoretical amount of product was calculated as the weight of the crude product minus theoretical amount of NaCl (1.64 g). LCMS: m / z 144.1[M+H]+. Step 3. Synthesis of (E)-N-(2-chlorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide

[0796] To a solution of N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3- carboxamide (3 g, 9.58 mmol, CL) in DMF (60 mL) were added HATU (5.46 g, 14.37 mmol), N,N-Diisopropylethylamine (6.19 g, 47.90 mmol, 8.34 mL) and (E)-4- [ethyl(methyl)amino]but-2-enoic acid (3.56 g, 13.41 mmol). The reaction was stirred at room temperature for 2 h. The mixture was diluted with water (400 mL), basified with saturated Na2CO3aqueous solution (100 mL) and extracted with ethyl acetate (150 mL x3). The extract was washed with saturated LiCl aqueous solution (200 mL) and brine (200 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by Prep-HPLC basic condition to give N-(2-chlorophenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-6,8- dihydro-5H-imidazo[1,2-a]pyrazine-3-carboxamide (1.1 g, 2.74 mmol, 28.57% yield) as white solid. LCMS: m / z 400.0[M+H]+.1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.3 Hz, 1H), 8.11 (s, 1H), 7.64 (s, 1H), 7.42 (dd, J = 8.0, 1.2 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.09 (td, J = 7.8, 1.4 Hz, 1H), 7.00 (dt, J = 15.1, 5.8 Hz, 1H), 6.49 (d, J = 15.1 Hz, 1H), 4.95 (s, 2H), 4.50 (s, 2H), 4.09 (s, 2H), 3.19 (d, J = 5.1 Hz, 2H), 2.45 (q, J = 7.1 Hz, 2H), 2.25 (s, 3H), 1.08 (t, J = 7.2 Hz, 3H). Example 13. Synthesis of (E)-7-(4-(azetidin-1-yl)but-2-enoyl)-N-(2-chlorophenyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0797] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(4- (ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of azetidine for N-ethylmethylamine to provide the product (E)- 7-(4-(azetidin-1-yl)but-2-enoyl)-N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2- a]pyrazine-3-carboxamide. LCMS: m / z 400.0[M+H]+.1H NMR (400 MHz, MeOD) δ 7.82 (s, 1H), 7.68 (dd, J = 8.0, 1.4 Hz, 1H), 7.50 (dd, J = 8.0, 1.4 Hz, 1H), 7.35 (td, J = 7.8, 1.4 Hz, 1H), 7.25 (td, J = 7.8, 1.6 Hz, 1H), 6.79 – 6.59 (m, 2H), 4.93 (d, J = 30.7 Hz, 2H), 4.52 – 4.40 (m, 2H), 4.08 (t, J = 5.1 Hz, 2H), 3.38 (t, J = 7.3 Hz, 4H), 3.33 (d, J = 5.1 Hz, 2H), 2.21 – 2.13 (m, 2H). Example 14. Synthesis of (E)-N-(2-chlorophenyl)-7-(4-(methyl(phenyl)amino)but-2- enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0798] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(4- (ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of N-methylaniline for N-ethylmethylamine to provide the product (E)-N-(2-chlorophenyl)-7-(4-(methyl(phenyl)amino)but-2-enoyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 450.0[M+H]+.1H NMR (400 MHz, MeOD) δ 7.81 (s, 1H), 7.68 (dd, J = 7.9, 1.3Hz, 1H), 7.50 (dd, J = 8.0, 1.3 Hz, 1H), 7.35 (t, J = 7.1 Hz, 1H), 7.28 – 7.15 (m, 3H), 6.90 – 6.80 (m, 1H), 6.76 (d, J = 8.2 Hz, 2H), 6.68 (t, J = 7.3 Hz, 1H), 6.61 – 6.46 (m, 1H), 4.88 (s, 2H), 4.39 (s, 2H), 4.16 (dd, J = 4.7, 1.6 Hz, 2H), 3.98 (d, J = 48.0 Hz, 2H), 3.00 (s, 3H). Example 15. Synthesis of (E)-N-(2-chlorophenyl)-7-(4-(3-methoxyazetidin-1-yl)but-2- enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0799] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(4- (ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of 3-methoxyazetidine for N-ethylmethylamine to provide the product (E)-N-(2-chlorophenyl)-7-(4-(3-methoxyazetidin-1-yl)but-2-enoyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 430.1[M+H]+.1H NMR (400 MHz, MeOD) δ 7.82 (s, 1H), 7.69 (dd, J = 8.0, 1.4 Hz, 1H), 7.50 (dd, J = 8.0, 1.3 Hz, 1H), 7.35 (td, J = 7.8, 1.4 Hz, 1H), 7.25 (td, J = 7.8, 1.6 Hz, 1H), 6.74 (dd, J = 13.0, 7.5 Hz, 2H), 4.90 (s, 2H), 4.48 (s, 2H), 4.14 – 4.01 (m, 3H), 3.74 – 3.59 (m, 2H), 3.35 (d, J = 4.5 Hz, 2H), 3.26 (s, 3H), 3.16 – 3.02 (m, 2H). Example 16. Synthesis of (E)-N-(2-chlorophenyl)-7-(4-(phenylamino)but-2-enoyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0800] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(4- (ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of aniline for N-ethylmethylamine to provide the product (E)- N-(2-chlorophenyl)-7-(4-(phenylamino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[1,2- a]pyrazine-3-carboxamide. LCMS: m / z 436.1[M+H]+.1H NMR (400 MHz, MeOD) δ 7.81 (s, 1H), 7.68 (dd, J = 8.0, 1.4 Hz, 1H), 7.49 (dd, J = 8.0, 1.3 Hz, 1H), 7.37 – 7.32 (m, 1H), 7.27 – 7.22 (m, 1H), 7.17 – 7.05 (m, 2H), 6.91 (s, 1H), 6.75 – 6.58 (m,4H), 4.88 (s, 2H), 4.39 (s, 2H), 4.09 – 3.89 (m, 4H). Example 17. Synthesis of (S,E)-N-(2-chlorophenyl)-7-(4-(3-hydroxypyrrolidin-1-yl)but- 2-enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0801] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(4- (ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of (S)-pyrrolidin-3-ol for N-ethylmethylamine to provide the product (S,E)-N-(2-chlorophenyl)-7-(4-(3-hydroxypyrrolidin-1-yl)but-2-enoyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 430.1[M+H]+.1H NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 8.0, 1.3 Hz, 1H), 7.35 (td, J = 7.8, 1.4 Hz, 1H), 7.25 (td, J = 7.8, 1.4 Hz, 1H), 6.97 – 6.65 (m, 2H), 4.94 (d, J = 26.9 Hz, 2H), 4.51 – 4.35 (m, 3H), 4.10 (s, 2H), 3.42 (s, 2H), 2.88 (s, 2H), 2.65 (s, 2H), 2.21 – 2.10 (m, 1H), 1.78 (s, 1H). Example 18. Synthesis of (E)-N-(2-chlorophenyl)-7-(4-(cyclopropylamino)but-2-enoyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0802] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(4- (ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of cyclopropanamine for N-ethylmethylamine to provide the product (E)-N-(2-chlorophenyl)-7-(4-(cyclopropylamino)but-2-enoyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 400.0[M+H]+.1HNMR (400 MHz, MeOD) δ 7.82 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 8.0, 1.3 Hz, 1H), 7.34 (dd, J = 12.3, 4.6 Hz, 1H), 7.25 (dd, J = 10.9, 4.6 Hz, 1H), 6.93 (dt, J = 15.3, 5.8 Hz, 1H), 6.68 (s, 1H), 4.92 (d, J = 16.9 Hz, 2H), 4.47 (s, 2H), 4.06 (d, J = 26.8 Hz, 2H), 3.57 – 3.37 (m, 2H), 2.31 – 2.16 (m, 1H), 0.61 – 0.47 (m, 2H), 0.46 – 0.35 (m, 2H). Example 19. Synthesis of (E)-N-(2-chlorophenyl)-7-(4-(cyclopropyl(methyl)amino)but-2- enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0803] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(4- (ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of N-methylcyclopropanamine for N-ethylmethylamine to provide the product (E)-N-(2-chlorophenyl)-7-(4-(cyclopropyl(methyl)amino)but-2-enoyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 414.0[M+H]+.1HNMR (400 MHz, MeOD) δ 7.82 (s, 1H), 7.69 (dd, J = 8.0, 1.3 Hz, 1H), 7.49 (dd, J = 8.0, 1.4 Hz, 1H), 7.38 – 7.30 (m, 1H), 7.25 (dd, J = 7.8, 1.5 Hz, 1H), 6.90 (s, 1H), 6.73 (d, J = 15.0 Hz, 1H), 4.91 (s, 2H), 4.47 (s, 2H), 4.09 (t, J = 5.3 Hz, 2H), 3.40 (dd, J = 6.6, 1.0 Hz, 2H), 2.36 (d, J = 4.9 Hz, 3H), 1.79 (m, 1H), 0.51 (m, 2H), 0.45 (m, 2H). Example 20. Synthesis of (E)-7-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)but-2-enoyl)-N-(2- chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0804] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(4- (ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of 2-oxa-6-azaspiro[3.3]heptane for N-ethylmethylamine to provide the product (E)-7-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)but-2-enoyl)-N-(2- chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 442.1[M+H]+.1HNMR (400 MHz, MeOD) δ 7.83 (s, 1H), 7.69 (dd, J = 8.0, 1.4 Hz, 1H), 7.50 (dd, J = 8.0, 1.3 Hz, 1H), 7.34 (td, 1H), 7.25 (td, J = 7.8, 1.5 Hz, 1H), 6.77 – 6.58 (m, 2H), 4.98 – 4.89 (m, 2H), 4.74 (s, 4H), 4.51 – 4.41 (m, 2H), 4.11 – 4.06 (m, 2H), 3.49 (s, 4H), 3.27 (d, J = 5.3 Hz, 2H). Example 21. Synthesis of (E)-N-(2-chlorophenyl)-7-(4-(pyrrolidin-1-yl)but-2-enoyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0805] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(4- (ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of pyrrolidine for N-ethylmethylamine to provide the product (E)-N-(2-chlorophenyl)-7-(4-(pyrrolidin-1-yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[1,2- a]pyrazine-3-carboxamide. LCMS: m / z 413.7[M+H]+.1HNMR (400 MHz, MeOD) δ 7.83 (s, 1H), 7.68 (dd, J = 8.0, 1.3Hz, 1H), 7.50 (dd, J = 8.0, 1.3Hz, 1H), 7.35 (td, J = 7.8, 1.44 Hz, 1H), 7.25 (td, J = 7.8, 1.6Hz, 1H), 6.97 – 6.85 (m, 1H), 6.80 -6.67(m, 1H), 5.04 – 4.93 (m, 2H), 4.53 – 4.37 (m, 2H), 4.09 (t, J = 5.2Hz, 2H), 3.38 (dd, J = 6.4, 1.0 Hz, 2H), 2.66 – 2.57 (m, 4H), 1.89 (m, 4H). Example 22. Synthesis of (E)-N-(2-chlorophenyl)-7-(4-(piperidin-1-yl)but-2-enoyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0806] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(4- (ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of pyrrolidine for N-ethylmethylamine to provide the product (E)-N-(2-chlorophenyl)-7-(4-(piperidin-1-yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[1,2- a]pyrazine-3-carboxamide. LCMS: m / z 427.7[M+H]+.1HNMR (400 MHz, MeOD) δ7.82 (s, 1H), 7.68 (dd, J =7.9, 0.9 Hz, 1H), 7.49 (dd, J = 8.0, 1.3 Hz, 1H), 7.34 (td, J = 7.8, 1.4 Hz, 1H), 7.25 (td, J = 7.8, 1.5 Hz, 1H), 6.89 (dt, J = 14.8, 6.5 Hz, 1H), 6.80 -6.68 (m, 1H), 5.00 - 4.89 (m, 2H), 4.52-4.38 (m, 2H), 4.08 (t, J = 5.3 Hz, 2H), 3.23 (d, J = 5.9 Hz, 2H), 2.59 -2.41 (m, 4H), 1.67 -1.60 (m, 4H), 1.53 -1.45 (m, 2H). Example 23. Synthesis of (E)-N-(2-chlorophenyl)-7-(4-((4-fluorophenethyl)amino)but-2- enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0807] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(4- (ethylamino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of 2-(4-fluorophenyl)ethan-1-amine for ethylamine to provide the product (E)-N-(2-chlorophenyl)-7-(4-((4-fluorophenethyl)amino)but-2-enoyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide as a white solid. LCMS: m / z 482.0[M+H]+.1H NMR (400 MHz, MeOD) δ 9.49 (d, J = 7.3 Hz, 1H), 8.49 (s, 1H), 7.76 (dd, J = 8.0, 1.5 Hz, 1H), 7.66 (s, 1H), 7.53 (dd, J = 8.0, 1.4 Hz, 1H), 7.39 (ddd, J = 15.3, 7.6, 1.7 Hz, 2H), 7.28 (td, J = 7.8, 1.6 Hz, 1H), 6.21 (s, 1H), 5.65 (s, 1H), 3.78 (s, 4H), 3.58 (d, J = 4.6 Hz, 2H), 3.51 (d, J = 4.5 Hz, 2H). Example 24. Synthesis of tert-butyl 4-[(E)-4-[3-[(2-chlorophenyl)carbamoyl]-6,8- dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-4-oxo-but-2-enyl]piperazine-1-carboxylate.

[0808] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(4- (ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of tert-butyl piperazine-1-carboxylate for N-ethylmethylamine to provide the product tert-butyl 4-[(E)-4-[3-[(2-chlorophenyl)carbamoyl]-6,8-dihydro-5H- imidazo[1,2-a]pyrazin-7-yl]-4-oxo-but-2-enyl]piperazine-1-carboxylate. LCMS: m / z 529.2[M+H]+.1H NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 6.84 (s, 2H), 4.91 (s, 2H), 4.48 (s, 2H), 4.09 (d, J = 5.5 Hz, 2H), 3.46 (s, 4H), 3.27 (d, J = 6.2 Hz, 2H), 2.49 (s, 4H), 1.45 (s, 9H). Example 25. Synthesis of N-(2-chlorophenyl)-7-[(E)-4-piperazin-1-ylbut-2-enoyl]-6,8- dihydro-5H-imidazo[1,2-a]pyrazine-3-carboxamide.

[0809] The method as described for the synthesis of N-(2-chlorophenyl)-7-[(E)-4-(1,4- diazepan-1-yl)but-2-enoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of tert-butyl 4-[(E)-4-[3-[(2-chlorophenyl)carbamoyl]-6,8-dihydro- 5H-imidazo[1,2-a]pyrazin-7-yl]-4-oxo-but-2-enyl]piperazine-1-carboxylate for tert-butyl 4- [(E)-4-[3-[(2-chlorophenyl)carbamoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-4-oxo- but-2-enyl]-1,4-diazepane-1-carboxylate to provide the product N-(2-chlorophenyl)-7-[(E)-4- piperazin-1-ylbut-2-enoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 429.1[M+H]+.1H NMR (400 MHz, MeOD) δ 8.34 (s, 1H), 7.67 (dd, J = 7.9, 1.5 Hz, 1H), 7.53 (dd, J = 8.0, 1.4 Hz, 1H), 7.38 (td, J = 7.7, 1.5 Hz, 1H), 7.31 (td, J = 7.8, 1.6 Hz, 1H), 7.21 (d, J = 14.6 Hz, 1H), 6.95 – 6.83 (m, 1H), 5.27 (d, J = 72.8 Hz, 2H), 4.78 – 4.53 (m, 2H), 4.30 – 4.09 (m, 4H), 3.75 – 3.58 (m, 8H). Example 26. Synthesis of N-(2-chlorophenyl)-7-(pent-2-ynoyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0810] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(4- (ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of pent-2-ynoic acid for (E)-4-[ethyl(methyl)amino]but-2-enoic acid to provide the product N-(2-chlorophenyl)-7-(pent-2-ynoyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 357.0[M+H]+.1H NMR (400 MHz, CDCl3) δ 8.38-8.34 (m, 1H), 8.13 (s, 1H), 7.66 (s, 1H), 7.42 (dt, J = 8.0, 1.6 Hz, 1H), 7.34-7.29 (m, 1H), 7.09 (td, J = 7.8, 1.2 Hz, 1H), 5.11 (s, 1H), 4.95 (s, 1H), 4.60-4.41 (m, 2H), 4.24-4.02 (m, 2H), 2.47-2.40 (m, 2H), 1.29-1.23 (m, 3H).Example 27. Synthesis of N-(2-chlorophenyl)-7-propioloyl-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0811] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(4- (ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of prop-2-ynoic acid for (E)-4-[ethyl(methyl)amino]but-2-enoic acid to provide the product N-(2-chlorophenyl)-7-propioloyl-5,6,7,8-tetrahydroimidazo[1,2- a]pyrazine-3-carboxamide as a white solid. LCMS: m / z 329.0 [M+H]+.1H NMR (400 MHz, DMSO) δ 10.13 – 9.67 (m, 1H), 7.89 (d, J = 2.6 Hz, 1H), 7.60 – 7.46 (m, 2H), 7.38 (t, J = 7.5 Hz, 1H), 7.29 (td, J = 7.6, 1.3 Hz, 1H), 5.03 – 4.67 (m, 3H), 4.44 – 4.25 (m, 2H), 4.19 – 3.92 (m, 2H). Example 28. Synthesis of 7-(but-2-ynoyl)-N-(2-chlorophenyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0812] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(4- (ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of but-2-ynoic acid for (E)-4-[ethyl(methyl)amino]but-2-enoic acid to provide the product 7-(but-2-ynoyl)-N-(2-chlorophenyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 342.9 [M+H]+.1H NMR (400 MHz, DMSO) δ 9.86 (s, 1H), 7.88 (s, 1H), 7.54 (t, J = 8.5 Hz, 2H), 7.38 (t, J = 7.7 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 4.98 (s, 1H), 4.72 (s, 1H), 4.42 – 4.24 (m, 2H), 4.17 – 3.87 (m, 2H), 2.08 (d, J = 7.1 Hz, 3H). Example 29. Synthesis of (E)-N-(2-chlorophenyl)-7-(4-methoxybut-2-enoyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0813] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(4- (ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of (E)-4-methoxybut-2-enoic acid for (E)-4- [ethyl(methyl)amino]but-2-enoic acid to provide the product (E)-N-(2-chlorophenyl)-7-(4- methoxybut-2-enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 375.1 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.82 (s, 1H), 7.69 (dd, J = 8.0, 1.4 Hz, 1H), 7.50 (dd, J = 8.0, 1.4 Hz, 1H), 7.35 (td, J = 7.8, 1.5 Hz, 1H), 7.25 (td, J = 7.8, 1.6 Hz, 1H), 6.94 – 6.84 (m, 1H), 6.79 – 6.66 (m, 1H), 5.02 – 4.90 (m, 2H), 4.47 (s, 2H), 4.17 – 4.05 (m, 4H), 3.41 (s, 3H). Example 30. Synthesis of (E)-N-(2-chlorophenyl)-7-(4-(dimethylamino)but-2-enoyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide hydrochloride.

[0814] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(4- (ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride for (E)-4-[ethyl(methyl)amino]but-2-enoic acid to provide the product (E)-N-(2-chlorophenyl)-7- (4-(dimethylamino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide hydrochloride. LCMS: m / z 388.0[M+H]+.1H NMR (400 MHz, MeOD) δ 8.34 (s, 1H), 7.67 (dd, J = 7.9, 1.5 Hz, 1H), 7.53 (dd, J = 7.9, 1.3 Hz, 1H), 7.38 (td, J = 7.7, 1.4 Hz, 1H), 7.31 (td, J = 7.7, 1.5 Hz, 1H), 7.12 (d, J = 14.8 Hz, 1H), 6.90 – 6.78 (m, 1H), 5.38 – 5.13 (m, 2H), 4.75 – 4.54 (m, 2H), 4.30 – 4.14 (m, 2H), 4.11 – 3.97 (m, 2H), 2.98 (s, 6H). Example 31. Synthesis of 7-acryloyl-N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2- a]pyrazine-3-carboxamide.

[0815] The method as described for the synthesis of 7-(2-chloroacetyl)-N-(2-chlorophenyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of prop-2-enoyl chloride for 2-chloroacetyl chloride to provide the product 7-acryloyl-N-(2- chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 331.1[M+H]+.1H NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 7.68 (d, J = 7.1 Hz, 1H), 7.50 (dd, J = 8.0, 1.4 Hz, 1H), 7.35 (td, J = 7.8, 1.5 Hz, 1H), 7.25 (td, J = 7.8, 1.6 Hz, 1H), 6.97 – 6.78 (m, 1H), 6.31 (dd, J = 16.8, 1.8 Hz, 1H), 5.84 (dd, J = 10.6, 1.6 Hz, 1H), 4.94 (d, J = 23.4 Hz, 2H), 4.52 – 4.41 (m, 2H), 4.10 (t, 2H). Example 32. Synthesis of methyl (E)-4-(3-((2-chlorophenyl)carbamoyl)-5,6- dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)but-2-enoate.

[0816] To a solution of N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3- carboxamide (0.4 g, 1.45 mmol) and triethylamine (321.19 mg, 3.18 mmol) in THF (20 mL) was added methyl (E)-4-bromobut-2-enoate (284.64 mg, 1.59 mmol), the mixture was stirred at room temperature under N2 overnight. Water (20 mL) was added, the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was concentrated, the residue was purified by flash chromatography ( eluting with dichloromethane: methanol=0- 5%) to give methyl (E)-4-[3-[(2-chlorophenyl)carbamoyl]-6,8-dihydro-5H-imidazo[1,2- a]pyrazin-7-yl]but-2-enoate (0.32 g, 828.13 μmol, 57.29% yield, 97% purity) as white solid. LCMS: m / z 375.1 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.78 (s, 1H), 7.69 (dd, J = 8.0, 1.5 Hz, 1H), 7.49 (dd, J = 8.0, 1.4 Hz, 1H), 7.34 (td, J = 7.8, 1.5 Hz, 1H), 7.24 (td, J = 7.8, 1.6 Hz, 1H), 6.98 (dt, J = 15.7, 6.1 Hz, 1H), 6.13 (dt, J = 15.7, 1.5 Hz, 1H), 4.39 (t, J = 5.5 Hz, 2H), 3.78 (s, 2H), 3.74 (s, 3H), 3.43 (dd, J = 6.1, 1.5 Hz, 2H), 2.97 (t, J = 5.6 Hz, 2H).Example 33. Synthesis of N-(2-chlorophenyl)-7-[(E)-4-phenoxybut-2-enoyl]-6,8-dihydro- 5H-imidazo[1,2-a]pyrazine-3-carboxamide.

[0817] To a solution of methyl (E)-4-bromobut-2-enoate (2.85 g, 15.94 mmol) and phenol (1.0 g, 10.63 mmol, 933.71 μL) in acetone (20 mL) was added K2CO3 (2.93 g, 21.25 mmol) . The resulting mixture was stirred at 60°C overnight and concentrated. The residue was added water (20 mL) and EtOAc (20 mL), the organic phase was separated, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by Silica gel chromatography (eluting with EtOAc / petroleum ether = 1 / 5-1 / 3 ) to give methyl (E)-4- phenoxybut-2-enoate (1.2 g, 3.87 mmol, 36.43% yield, 62% purity) as a colorless oil. LCMS: m / z 193.3[M+H]+. Step 2. Synthesis of (E)-4-phenoxybut-2-enoic acid

[0818] To a solution of methyl (E)-4-phenoxybut-2-enoate (1.2 g, 3.87 mmol) in MeOH (8 mL) was added a solution of NaOH (464.49 mg, 11.61 mmol, 218.07 μL) in water (4 mL). The resulting mixture was stirred at room temperature overnight and concentrated, the residue was diluted with water (20 mL). The aqueous phase was adjusted pH to 3-4 with 1M HCl, and extracted with EtOAc (30 mL x 3). The combined organic phase was concentrated to give (E)-4-phenoxybut-2-enoic acid (500 mg, 2.58 mmol, 66.69% yield, 92% purity) as a light yellow solid, which was used directly for the next step. LCMS: m / z 179.1[M+H]+. Step 3. Synthesis of N-(2-chlorophenyl)-7-[(E)-4-phenoxybut-2-enoyl]-6,8-dihydro-5H- imidazo[1,2-a]pyrazine-3-carboxamide

[0819] To a solution of N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3- carboxamide hydrochloride (60 mg, 191.58 μmol, CL) , (E)-4-phenoxybut-2-enoic acid (108.70 mg, 561.22 μmol) and HATU (109.27 mg, 287.37 μmol) in DMF (2.93 mL) was added DIPEA (49.52 mg, 383.16 μmol, 66.74 μL). The resulting mixture was stirred at room temperature overnight and then purified by Prep-HPLC under basic condition to give N-(2- chlorophenyl)-7-[(E)-4-phenoxybut-2-enoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3- carboxamide (30 mg, 68.67 μmol, 35.84% yield, 100% purity) as a white solid. LCMS: m / z 437.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.34 (t, J = 8.3 Hz, 1H), 8.10 (d, J = 5.6 Hz, 1H), 7.63 (d, J = 7.4 Hz, 1H), 7.42 (dd, J = 8.0, 1.3 Hz, 1H), 7.37 – 7.28 (m, 3H), 7.13 – 7.04 (m, 2H), 7.04 – 6.92 (m, 2H), 6.75 – 6.50 (m, 1H), 4.93 (d, J = 4.9 Hz, 2H), 4.56 – 4.40 (m, 2H), 4.13 – 3.92 (m, 2H), 3.50 – 3.35 (m, 2H). General Method CStep 1.1. General procedure for Synthesis of methyl (E)-4-(3-cyanoazetidin-1-yl)but-2-enoate

[0820] To a solution of azetidine-3-carbonitrile (11.92 g, 100.55 mmol, 1.2 eq, HCl) in MeCN (150 mL) was added dropwise TEA (25.44 g, 251.38 mmol, 34.99 mL, 3 eq) at 25℃ and stirred at 25°C for 10 min. Then methyl (E)-4-bromobut-2-enoate (15 g, 83.79 mmol, 9.86 mL, 1 eq) was added dropwise to the reaction mixture at 0°C. The reaction mixture was warmed to 25°C and stirred at 25°C for 12 h. The reaction mixture was cooled to 0°C, quenched by addition ice-water (300 mL) at 0°C. The mixture was extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (150 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 160 g SepaFlash® Silica Flash Column, Eluent of 0~43% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give methyl (E)-4-(3-cyanoazetidin-1-yl)but-2-enoate (10 g, 55.49 mmol, 66.23% yield) as yellow oil.1H NMR (CDCl3400 MHz) δ 6.82-6.75 (m, 1H), 5.98-5.94 (m, 1H), 3.73 (s, 3H), 3.62 (t, J=7.2 Hz, 2H), 3.34-3.31 (m, 2H), 3.24 (s, 1H), 3.23-3.21 (m, 2H).

[0821] To a solution of methyl (E)-4-(3-cyanoazetidin-1-yl)but-2-enoate (6.5 g, 36.07 mmol, 1 eq) in EtOH (28 mL) and H2O (56 mL) was added Ca(OH)2 (10.69 g, 144.28 mmol, 4.77 mL, 4 eq) in one portion at 25°C. The reaction mixture was stirred at 25°C for 2 h. The reaction mixture was cooled to 0°C. The reaction mixture was adjusted pH to 3 with HCl (2 N) at 0°C, then concentrated under reduced pressure to give (E)-4-(3-cyanoazetidin-1-yl)but- 2-enoic acid (8 g, crude) as yellow oil.1H NMR (DMSO-d6, 400 MHz) δ 6.49-6.42 (m, 1H), 5.82-5.78 (m, 1H), 3.45-3.42 (m, 3H), 3.24 (t, J = 4.0 Hz, 2H), 3.12 (dd, J = 3.6 Hz, 2.0 Hz, 2H). Step 2.1 Synthesis of tert-butyl 3-[(3-chloro-2-fluoro-phenyl)carbamoyl] -6,8-dihydro-5H- imidazo[1,2-a]pyrazine-7-carboxylate

[0822] To a solution of 7-tert-butoxycarbonyl-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3- carboxylic acid (215.86 mg, 710.66 μmol, 1 eq, HCl) in MeCN (2 mL) were added NMI (175.03 mg, 2.13 mmol, 169.94 μL, 3 eq), 3-chloro-2-fluoro-aniline (155.17 mg, 1.07 mmol, 1.5 eq) and TCFH (598.19 mg, 2.13 mmol, 3 eq) in one portion at 0°C. The reaction mixture was warmed to 25°C and stirred at 25°C for 18 hrs. LCMS showed 7-tert-butoxycarbonyl- 6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3-carboxylic acid was consumed completely and desired mass was detected. The residue was poured into ice-water (4 mL) and stirred for 2 min at 25°C. The mixture was extracted with ethyl acetate (2 mL x 3). The combined organic phase was washed with brine (2 mL x 1), dried over Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® Silica Flash Column, Eluent of 0~42% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give tert-butyl 3-[(3-chloro-2-fluoro-phenyl)carbamoyl]-6,8- dihydro-5H-imidazo[1,2-a]pyrazine-7-carboxylate (300 mg, crude) as a yellow solid. LCMS: m / z 395.0 [M+H]+. Step 2.2 Synthesis of N-(3-chloro-2-fluoro-phenyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine -3-carboxamide

[0823] To a solution of tert-butyl 3-[(3-chloro-2-fluoro-phenyl)carbamoyl]-6,8-dihydro-5H- imidazo[1,2-a]pyrazine-7-carboxylate (300 mg, 759.83 μmol, 1 eq) in DCM (3 mL) was added dropwise HCl / dioxane (4 M, 189.96 μL, 1 eq) at 25°C. The reaction mixture was stirred at 25°C for 1 hr. LCMS showed tert-butyl 3-[(3-chloro-2-fluoro-phenyl) carbamoyl]- 6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carboxylate was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give N-(3-chloro-2-fluoro-phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine -3-carboxamide (250 mg, crude) as a yellow solid. LCMS: m / z 295.0 [M+H]+. Step 3 Synthesis of N-(3-chloro-2-fluoro-phenyl)-7-[(E)-4-(3- cyanoazetidin-1-yl)but-2-

[0824] To a solution of N-(3-chloro-2-fluoro-phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a] pyrazine-3-carboxamide (220 mg, 664.31 μmol, 1 eq, HCl) in DMF (3 mL) were added dropwise DIEA (257.57 mg, 1.99 mmol, 347.13 μL, 3 eq), HOBt (179.53 mg, 1.33 mmol, 2 eq), EDCI (318.37 mg, 1.66 mmol, 2.5 eq) and (E)-4-(3-cyanoazetidin-1-yl)but-2-enoic acid (220.78 mg, 1.33 mmol, 2 eq) at 25°C. The reaction mixture was stirred at 25°C for 15 hrs. LCMS showed N-(3-chloro-2-fluoro-phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3- carboxamide was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Waters X bridge BEH C18100*30mm*10um; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 15%-45% B over 8.0 min) to give N-(3-chloro-2-fluoro-phenyl)- 7-[(E)-4-(3-cyanoazetidin-1-yl)but-2-enoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3- carboxamide (40.5 mg, 85.96 μmol, 12.94% yield, 93.98% purity) as a pale yellow solid. LCMS: m / z 443.1 [M+H]+.1H NMR (DMSO-d6, 400 MHz) δ 10.09 (s, 1H), 7.85 (s, 1H), 7.52 (t, J = 6.8 Hz, 1H), 7.43 (t, J = 6.8 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 6.63-6.53 (m, 2H), 4.91-4.74 (m, 2H), 4.32-4.28 (m, 2H), 3.99-3.94 (m, 2H), 3.49 (s, 3H), 3.29 (s, 2H), 3.21 (d, J = 4.8 Hz, 2H).

[0825] Compounds in Table A were synthesized following the procedure for N-(3-chloro-2- fluoro-phenyl)-7-[(E)-4-(3- cyanoazetidin-1-yl)but-2-enoyl]-6,8-dihydro-5H-imidazo[1,2- a]pyrazine-3-carboxamide. Table AGeneral method D Example 34. Synthesis of N-(2-chlorophenyl)-7-[(E)-4-(ethylamino)but-2-enoyl]-6,8- dihydro-5H-imidazo[1,2-a]pyrazine-3-carboxamide.

[0826] To a solution of ethylamine (901.67 mg, 20 mmol, 2 N in THF, 10 mL) and Et3N (4.04 g, 40.00 mmol) in THF (20 mL) was added methyl (E)-4-bromobut-2-enoate (1.79 g, 10.00 mmol) . The resulting mixture was stirred at room temperature for 3 hours, and then tert-butoxycarbonyl tert-butyl carbonate (5.46 g, 25.00 mmol, 5.74 mL) was added. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (150 mL x3). The extract was washed with brine (150 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (eluting with EtOAc / petroleum ether = 1 / 5-1 / 1) to give methyl (E)-4-[tert-butoxycarbonyl(ethyl)amino]but-2-enoate (0.98 g, 3.83 mmol, 38.27% yield,) as an off-white solid. LCMS: m / z 144.2[M+H-Boc]+.

[0827] To a solution of (E)-4-[tert-butoxycarbonyl(ethyl)amino]but-2-enoate (980 mg, 4.03 mmol) in THF (8 mL) was added a solution of NaOH (480.00 mg, 12 mmol) in water (4 mL). The resulting mixture was stirred at 50°C overnight and then concentrated, the residue was added water (20 mL). The aqueous phase was acidified with 1M HCl to pH 3-4, extracted with EtOAc (30 mLx3). The combined organic phase was concentrated to give (E)- 4-[tert-butoxycarbonyl(ethyl)amino]but-2-enoic acid (620 mg, crude) as a light yellow solid, which was used directly for the next step. LCMS: m / z 130.2 [M+H-Boc]+.Step 3. Synthesis of tert-butyl N-[(E)-4-[3-[(2-chlorophenyl)carbamoyl]-6,8-dihydro-5H- imidazo[1,2-a]pyrazin-7-yl]-4-oxo-but-2-enyl]-N-ethyl-carbamate

[0828] To a solution of (E)-4-[tert-butoxycarbonyl(ethyl)amino]but-2-enoic acid (160.00 mg, 697.86 μmol), N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide (80 mg, 255.44 μmol, CL) and HATU (126.27 mg, 332.08 μmol) in DMF (3 mL) was added DIPEA (66.03 mg, 510.89 μmol). The resulting mixture was stirred at room temperature overnight and diluted with water (15 mL). The precipitate was filtered and dried to give tert-butyl N-[(E)-4-[3-[(2-chlorophenyl)carbamoyl]-6,8-dihydro-5H- imidazo[1,2-a]pyrazin-7-yl]-4-oxo-but-2-enyl]-N-ethyl-carbamate (120 mg, crude) as a white solid, which was used directly for the next step. LCMS: m / z 488.2 [M+H]+. Step 4. Synthesis of N-(2-chlorophenyl)-7-[(E)-4-(ethylamino)but-2-enoyl]-6,8-dihydro-5H- imidazo[1,2-a]pyrazine-3-carboxamide

[0829] To a solution of tert-butyl N-[(E)-4-[3-[(2-chlorophenyl)carbamoyl]-6,8-dihydro-5H- imidazo[1,2-a]pyrazin-7-yl]-4-oxo-but-2-enyl]-N-ethyl-carbamate (120 mg, 245.91 μmol) in DCM (3 mL) was added HCl (36.46 mg, 1 mmol) at 0°C. The resulting mixture was stirred at room temperature for 3 hours, and then diluted with DCM (20 mL). The organic phase was washed with aq. sat. NaHCO3 (10 mL x 3), brine and concentrated. The residue was purified by Prep-HPLC under acidic condition to give N-(2-chlorophenyl)-7-[(E)-4- (ethylamino)but-2-enoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3-carboxamide (22 mg, 43.83 μmol, 17.83% yield, TFA) as white solid. LCMS: m / z 388.0 [M+H]+.1H NMR (400 MHz, MeOD) δ 8.05 (d, J = 23.3 Hz, 1H), 7.66 (d, J = 7.0 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.37 (t, J = 7.2 Hz, 1H), 7.28 (t, J = 7.4 Hz, 1H), 7.04 – 6.87 (m, 1H), 6.86 – 6.74 (m, 1H),5.18 – 4.97 (m, 2H), 4.53 (d, J = 33.6 Hz, 2H), 4.14 (s, 2H), 3.87 (d, J = 6.4 Hz, 2H), 3.11 (q, J = 7.3 Hz, 2H), 1.33 (t, J = 7.3 Hz, 3H). Example 35. Synthesis of N-(2-chlorophenyl)-7-[(E)-4-(2-fluoroethylamino)but-2-enoyl]- 6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3-carboxamide.

[0831] The method as described for the synthesis of N-(2-chlorophenyl)-7-[(E)-4- (ethylamino)but-2-enoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of methylamine for ethylamine and purified under basic condition to provide the product N-(2-chlorophenyl)-7-[(E)-4-(methylamino)but-2-enoyl]-6,8-dihydro- 5H-imidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 374.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.4 Hz, 1H), 8.11 (s, 1H), 7.64 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.12 – 6.98 (m, 2H), 6.50 (d, J = 14.4 Hz, 1H), 4.95 (s, 2H), 4.50 (s, 2H), 4.16 – 3.94 (m, 2H), 3.43 (d, J = 4.6 Hz, 2H), 2.49 (s, 3H).Example 37. Synthesis of tert-butyl N-[(E)-4-[3-[(2-chlorophenyl)carbamoyl]-6,8- dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-4-oxo-but-2-enyl]-N-(1- methylcyclobutyl)carbamate.

[0832] The method as described for the synthesis of tert-butyl N-[(E)-4-[3-[(2- chlorophenyl)carbamoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-4-oxo-but-2-enyl]-N- ethyl-carbamate was applied with substitution of 1-methylcyclobutan-1-amine for ethylamine, and purified by Prep-HPLC under basic condition to provide the product tert- butyl N-[(E)-4-[3-[(2-chlorophenyl)carbamoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]- 4-oxo-but-2-enyl]-N-(1-methylcyclobutyl)carbamate. LCMS: m / z 528.2[M+H]+.1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.7 Hz, 1H), 8.11 (s, 1H), 7.64 (s, 1H), 7.42 (dd, J = 8.1, 1.3 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.09 (dd, J = 11.0, 4.5 Hz, 1H), 7.00 (s, 1H), 6.38 (d, J = 15.2 Hz, 1H), 4.93 (s, 2H), 4.50 (s, 2H), 4.03 (d, J = 54.1 Hz, 2H), 3.81 (s, 2H), 2.23 (d, J = 10.9 Hz, 2H), 1.94 (s, 2H), 1.70 (s, 2H), 1.46 (s, 9H), 1.39 (s, 3H). Example 38. Synthesis of N-(2-chlorophenyl)-7-[(E)-4-[(1-methylcyclobutyl)amino]but- 2-enoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3-carboxamide.

[0833] The method as described for the synthesis of N-(2-chlorophenyl)-7-[(E)-4- (ethylamino)but-2-enoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of 1-methylcyclobutan-1-amine for ethylamine and purified by Prep-HPLC under basic condition to provide the product N-(2-chlorophenyl)-7-[(E)-4-[(1- methylcyclobutyl)amino]but-2-enoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3- carboxamide. LCMS: m / z 428.1[M+H]+.1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 7.8 Hz, 1H), 8.11 (s, 1H), 7.64 (s, 1H), 7.42 (dd, J = 8.0, 1.3 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.08(ddd, J = 10.1, 5.6, 3.9 Hz, 2H), 6.53 (d, J = 15.1 Hz, 1H), 4.95 (s, 2H), 4.49 (s, 2H), 4.08 (s, 2H), 3.40 (d, J = 3.6 Hz, 2H), 1.91 (dt, J = 10.0, 8.2 Hz, 4H), 1.80 – 1.70 (m, 2H), 1.29 (s, 3H). Example 39. Synthesis of N-(2-chlorophenyl)-7-[(E)-4-[methyl-(1- methylcyclobutyl)amino]but-2-enoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3- carboxamide.

[0834] The method as described for the synthesis of (R,E)-N-(2-chlorophenyl)-7-(3-(1- methylazetidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of 1-methylcyclobutan-1-amine for tert-butyl 2-formylazetidine-1- carboxylate to provide N-(2-chlorophenyl)-7-[(E)-4-[methyl-(1-methylcyclobutyl)amino]but- 2-enoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 442.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 8.0 Hz, 1H), 8.11 (s, 1H), 7.64 (s, 1H), 7.42 (dd, J = 8.0, 1.3 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.09 (td, J = 7.8, 1.5 Hz, 1H), 6.96 (dt, J = 15.0, 5.7 Hz, 1H), 6.53 (d, J = 14.6 Hz, 1H), 4.95 (s, 2H), 4.50 (s, 2H), 4.08 (s, 2H), 3.05 (s, 2H), 2.08 (s, 3H), 1.97 (s, 2H), 1.74 (s, 4H), 1.12 (s, 3H). Example 40. Synthesis of 7-[(E)-4-[2-[2-(2-aminoethoxy)ethoxy]ethyl-methyl-amino]but- 2-enoyl]-N-(2-chlorophenyl)-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3-carboxamideStep 1: Synthesis of methyl (E)-4-[2-[2-[2-(tert- butoxycarbonylamino)ethoxy]ethoxy]ethylamino]but-2-enoate

[0835] To a solution of tert-butyl N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]carbamate (4 g, 16.11 mmol) and DIPEA (6.25 g, 48.33 mmol, 8.42 mL) in THF (60 mL) was added a solution of methyl (E)-4-bromobut-2-enoate (2.31 g, 12.89 mmol) in THF ( 20 mL) at 0°C. The resulting mixture was stirred at room temperature overnight and then concentrated, the residue was purified by silica gel chromatography (eluting with EtOAc / petroleum ether = 1 / 5-1 / 1) to give methyl (E)-4-[2-[2-[2-(tert- butoxycarbonylamino)ethoxy]ethoxy]ethylamino]but-2-enoate (2.9 g, 7.95 mmol, 49.37% yield, 95% purity) as an off-white solid. LCMS: m / z 347.2 [M+H]+. Step 2: Synthesis of methyl (E)-4-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethyl- methyl-amino]but-2-enoate

[0836] To a solution of methyl (E)-4-[2-[2-[2-(tert- butoxycarbonylamino)ethoxy]ethoxy]ethylamino]but-2-enoate (2.3 g, 6.64 mmol) in ACN (50 mL) was added AcOH (2 drops) and HCHO (6.11 g, 66.39 mmol, 37% purity). The resulting mixture was stirred at room temperature for 1 hour, and then NaBH(OAc)3 (4.22 g, 19.92 mmol) was added. The mixture was stirred at room temperature overnight, filtered and purified by silica gel chromatography (eluting with EtOAc / petroleum ether = 1 / 5-1 / 1) to give methyl (E)-4-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethyl-methyl- amino]but-2-enoate (2.1 g, 4.95 mmol, 74.59% yield, 85% purity) as a yellow oil. LCMS: m / z 361.2 [M+H]+. Step 3: Synthesis of (E)-4-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethyl-methyl- amino]but-2-enoic acid

[0837] To a solution of methyl (E)-4-[2-[2-[2-(tert- butoxycarbonylamino)ethoxy]ethoxy]ethyl-methyl-amino]but-2-enoate (720 mg, 2.00 mmol) in THF (10 mL) was added a solution of NaOH (239.70 mg, 5.99 mmol, 112.54 μL) in water (3 mL) The resulting mixture was stirred at 50°C overnight and then concentrated, the residue was added water (20 mL). The aqueous phase was adjusted pH to 5-6 with 1N HCl and lyophilized to give (E)-4-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethyl-methyl- amino]but-2-enoic acid (900 mg, crude) as a light yellow solid, which was used directly for the next step. LCMS: m / z 347.2 [M+H]+.Step 4: Synthesis of tert-butyl N-[2-[2-[2-[[(E)-4-[3-[(2-chlorophenyl)carbamoyl]-6,8- dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-4-oxo-but-2-enyl]-methyl- amino]ethoxy]ethoxy]ethyl]carbamate

[0838] To a solution of N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3- carboxamide (V14) (718.93 mg, 2.30 mmol, CL), (E)-4-[2-[2-[2-(tert- butoxycarbonylamino)ethoxy]ethoxy]ethyl-methyl-amino]but-2-enoic acid (900 mg, 2.60 mmol) and DIPEA (436.50 mg, 3.38 mmol, 588.27 μL) in DMF (10 mL) was added HATU (2.96 g, 7.79 mmol). The resulting mixture was stirred at room temperature overnight and diluted with water (15 mL). The precipitate was filtered, dried and purified by Prep- HPLC under basic condition to give tert-butyl N-[2-[2-[2-[[(E)-4-[3-[(2- chlorophenyl)carbamoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-4-oxo-but-2-enyl]- methyl-amino]ethoxy]ethoxy]ethyl]carbamate (350 mg, 578.39 μmol, 22.26% yield) as a pale solid. LCMS: m / z 605.3 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 8.1 Hz, 1H), 8.14 (s, 1H), 7.65 (s, 1H), 7.42 (dd, J = 8.0, 1.3 Hz, 1H), 7.36 – 7.28 (m, 1H), 7.09 (td, J = 7.9, 1.4 Hz, 1H), 6.98 (dt, J = 15.1, 5.6 Hz, 1H), 6.57 (d, J = 14.8 Hz, 1H), 4.95 (s, 2H), 4.49 (s, 2H), 4.20 – 3.92 (m, 2H), 3.72 – 3.48 (m, 8H), 3.38 – 3.20 (m, 4H), 2.63 (t, J = 5.5 Hz, 2H), 2.33 (s, 3H), 1.43 (s, 9H). Step 5: Synthesis of 7-[(E)-4-[2-[2-(2-aminoethoxy)ethoxy]ethyl-methyl-amino]but-2-enoyl]- N-(2-chlorophenyl)-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3-carboxamide Cl HN

[0839] To a solution of give tert-butyl N-[2-[2-[2-[[(E)-4-[3-[(2-chlorophenyl)carbamoyl]- 6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-4-oxo-but-2-enyl]-methyl- amino]ethoxy]ethoxy]ethyl]carbamate (200 mg, 330.51 μmol) in DCM (3 mL) wasadded TFA (444.00 mg, 3.89 mmol, 0.3 mL) at 0°C. The resulting mixture was stirred at room temperature overnight, and then diluted with DCM (20 mL). The organic phase was washed with aq. sat. NaHCO3 (10 mL x 3), brine and concentrated. The residue was purified by Prep-HPLC under basic condition to give 7-[(E)-4-[2-[2-(2-aminoethoxy)ethoxy]ethyl- methyl-amino]but-2-enoyl]-N-(2-chlorophenyl)-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3- carboxamide (150 mg, 297.02 μmol, 89.87% yield) as white solid. LCMS: m / z 505.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 7.8 Hz, 1H), 8.12 (s, 1H), 7.64 (s, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 7.7 Hz, 1H), 7.03 – 6.93 (m, 1H), 6.55 (d, J = 13.1 Hz, 1H), 4.95 (s, 2H), 4.50 (s, 2H), 4.09 (s, 2H), 3.70 – 3.57 (m, 6H), 3.52 (t, J = 5.1 Hz, 2H), 3.26 (d, J = 4.6 Hz, 2H), 2.87 (t, J = 4.9 Hz, 2H), 2.63 (t, J = 5.6 Hz, 2H), 2.32 (s, 3H). General method E Example 41. Synthesis of (E)-N-(2-chlorophenyl)-7-(3-(1-methylazetidin-2-yl)acryloyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.Step 1. Synthesis of tert-butyl 2-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate

[0840] To a solution of 1-tert-butoxycarbonylazetidine-2-carboxylic acid (2 g, 9.94 mmol) in DMF (15 mL) were added N-methoxymethanamine (1.36 g, 13.92 mmol, CL), HATU (4.54 g, 11.93 mmol) and N-ethyl-N-isopropyl-propan-2-amine (3.08 g, 23.85 mmol, 4.16 mL). The mixture was stirred at room temperature for 4 h. The reaction was quenched with water and extracted with EtOAc (30 mL x 3). The extracts were washed with water (20mL x2 ), brine (20 mL x 1), dried over Na2SO4 and concentrated to give tert-butyl (2R)-2- [methoxy(methyl)carbamoyl]azetidine-1-carboxylate (5.09 g, crude) as white gum. LCMS: m / z 145.2 [M+H-Boc]+. Step 2. Synthesis of tert-butyl 2-formylazetidine-1-carboxylate

[0841] To a solution of tert-butyl 2-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate (5.09 g, 12.50 mmol) in THF (30 mL) was added LiAlH4 (1.14 g, 30.00 mmol) in portions at 0°C. The mixture was stirred at 0°C for 1 h. The reaction was quenched with Sodium sulfate decahydrate (5 g). The mixture was diluted with EtOAc (60 mL) and filtered through Celite. The filtrate was concentrated to give tert-butyl 2-formylazetidine-1-carboxylate (2.6 g, crude) as colorless oil which was used in next step without further purification. LCMS: m / z 130.1 [M-t-Bu+H]+.

[0842] To a solution of tert-butyl 2-formylazetidine-1-carboxylate (2.6 g, 7.02 mmol) in EtOAc (40 mL) was added ethyl 2-(triphenyl-phosphanylidene)acetate (3.67 g, 10.53 mmol). The mixture was stirred at 25°C for 20 h. The precipitate was filtered and the filtrate was concentrated. The residue was purified on silica flash chromatography with a gradient of EtOAc / PE (0 to 25 percent, Biotage, 40 g) to give tert-butyl (2R)-2-[(E)-3- ethoxy-3-oxo-prop-1-enyl]azetidine-1-carboxylate (359 mg, 1.41 mmol, 20.03% yield) of colorless oil. LCMS: m / z 200.3 [M-t-Bu+H]+. Step 4. Synthesis of (E)-3-(1-(tert-butoxycarbonyl)azetidin-2-yl)acrylic acid

[0843] To a solution of tert-butyl 2-[(E)-3-ethoxy-3-oxo-prop-1-enyl]azetidine-1-carboxylate (359 mg, 1.41 mmol) in Ethanol (10 mL) and Water (3 mL) was added lithium hydroxide hydrate (236.01 mg, 5.62 mmol, 156.30 μL). The mixture was stirred at room temperature for 16 h. The mixture concentrated to obtain (E)-3-[(2R)-1-tert-butoxycarbonylazetidin-2- yl]prop-2-enoic acid (175 mg, 770.06 μmol, 54.76% yield) of colorless oil. LCMS: m / z 172.1 [M-t-Bu+H]+. Step 5. Synthesis of tert-butyl (E)-2-(3-(3-((2-chlorophenyl)carbamoyl)-5,6- dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-3-oxoprop-1-en-1-yl)azetidine-1-carboxylate

[0844] To a solution of N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3- carboxamide (V14) (213.09 mg, 770.06 μmol), (E)-3-[(2R)-1-tert-butoxycarbonylazetidin-2- yl]prop-2-enoic acid (175 mg, 770.06 μmol), DIPEA (298.57 mg, 2.31 mmol, 402.38 μL), HATU (439.20 mg, 1.16 mmol) in DMF (6 mL). The mixture was stirred at room temperature for 16 h. The mixture was quenchded with water and extracted with DCM (20mL × 2). The organic phase washed with saturated LiCl (20 mL), concentrated and the residue was purified on silica flash chromatography with a gradient of MeOH / DCM (0 to 4 percent, Biotage, 40 g) to give tert-butyl (E)-2-(3-(3-((2-chlorophenyl)carbamoyl)-5,6- dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-3-oxoprop-1-en-1-yl)azetidine-1-carboxylate (249 mg, 512.39 μmol, 66.54% yield) of colorless oil. LCMS: m / z 486.1 [M+H]+. Step 6. Synthesis of (E)-7-(3-(azetidin-2-yl)acryloyl)-N-(2-chlorophenyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide

[0845] To a solution of tert-butyl (E)-2-(3-(3-((2-chlorophenyl)carbamoyl)-5,6- dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-3-oxoprop-1-en-1-yl)azetidine-1-carboxylate (36 mg, 74.08 μmol) in DCM (3.05 mL) was added TFA (16.89 mg, 148.16 μmol, 11.41 μL). The mixture was stirred at room temperature for 16 h. The mixture was concentrated to obtain (E)-7-(3-(azetidin-2-yl)acryloyl)-N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2- a]pyrazine-3-carboxamide (21.7 mg, 43.41 μmol, 58.60% yield, TFA) of white solid. LCMS: m / z 386.1 [M+H]+.1H NMR (400 MHz, MeOD) δ 8.01 (d, J = 29.6 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.52 (dd, J = 7.9, 1.0 Hz, 1H), 7.36 (td, J = 7.8, 1.4 Hz, 1H), 7.28 (t, J = 7.4 Hz, 1H), 7.03 (dd, J = 15.1, 6.8 Hz, 1H), 6.91 (d, J = 16.0 Hz, 1H), 5.23 (dd, J = 15.6, 7.9 Hz, 1H), 5.03 (s, 2H), 4.52 (d, J = 33.4 Hz, 2H), 4.20 – 4.07 (m, 3H), 3.93 (td, J = 10.0, 5.4 Hz, 1H), 3.25 (s, 1H), 2.79 – 2.61 (m, 2H). Step 7. Synthesis of (E)-N-(2-chlorophenyl)-7-(3-(1-methylazetidin-2-yl)acryloyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide

[0846] To a solution of formaldehyde (42.02 mg, 1.40 mmol, 38.80 μL), (E)-7-(3-(azetidin-2- yl)acryloyl)-N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide (270 mg, 699.76 μmol) in MeCN (2 mL) was added NaBH(OAc)3(296.70 mg, 1.40 mmol) and acetic acid (52.45 mg, 873.41 μmol, 0.05 mL).The mixture was stirred at room temperature for 2 h. The mixture was purified by Prep-HPLC under basic condition to obtain (E)-N-(2-chlorophenyl)-7-(3-(1-methylazetidin-2-yl)acryloyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide (32.7 mg, 81.78 μmol, 11.69% yield) of white solid. LCMS: m / z 400.1 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 7.68 (dd, J = 7.9, 1.3 Hz, 1H), 7.50 (dd, J = 8.0, 1.3 Hz, 1H), 7.35 (td, J = 7.8, 1.5 Hz, 1H), 7.25 (td, J= 7.8, 1.6 Hz, 1H), 6.88 (dd, J = 15.2, 6.3 Hz, 1H), 6.69 (d, J = 14.0 Hz, 1H), 4.95 (d, J = 32.2 Hz, 2H), 4.47 (d, J = 19.3 Hz, 2H), 4.10 (s, 2H), 3.86 (s, 1H), 3.44 (t, J = 6.2 Hz, 1H), 3.09 – 2.98 (m, 1H), 2.38 (s, 3H), 2.33 – 2.23 (m, 1H), 2.12 (dd, J = 17.8, 9.2 Hz, 1H). Example 42. Synthesis of (E)-N-(2-chlorophenyl)-7-(3-(piperidin-2-yl)acryloyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0847] The method as described for the synthesis of (E)-7-(3-(azetidin-2-yl)acryloyl)-N-(2- chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of tert-butyl 2-formylpiperidine-1-carboxylate for tert-butyl 2-formylazetidine-1- carboxylate to provide the product (E)-N-(2-chlorophenyl)-7-(3-(piperidin-2-yl)acryloyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 414.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 8.0 Hz, 1H), 8.13 (s, 1H), 7.65 (s, 1H), 7.43 (dd, J = 8.0, 1.6 Hz, 1H), 7.35- 7.28 (m, 1H), 7.10 (td, J = 7.6, 1.2 Hz, 1H), 7.00 (dd, J = 15.6, 5.2 Hz, 1H), 6.46 (d, J = 14.8 Hz, 1H), 4.95 (s, 2H), 4.50 (s, 2H), 4.10-4.02 (m, 2H), 3.33 (d, J = 8.0 Hz, 1H), 3.17(d, J = 12.0 Hz, 1H), 2.72 (td, J = 11.6, 2.4 Hz, 1H), 1.88-1.80 (m, 2H), 1.67- 1.64 (m, 1H), 1.51-1.39 (m, 2H), 1.29-1.19 (m, 1H). Example 43. Synthesis of (E)-N-(2-chlorophenyl)-7-(3-(1-methylpiperidin-2-yl)acryloyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0848] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(3-(1- methylazetidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of tert-butyl 2-formylpiperidine-1-carboxylate for tert-butyl 2- formylazetidine-1-carboxylate to provide the product (E)-N-(2-chlorophenyl)-7-(3-(1- methylpiperidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.LCMS: m / z 428.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 8.0 Hz, 1H), 8.13 (s, 1H), 7.65 (s, 1H), 7.43 (dd, J = 8.0, 1.2 Hz, 1H), 7.34-7.30 (m, 1H), 7.10 (td, J = 7.6, 1.2 Hz, 1H), 6.98-6.91 (m, 1H), 6.44 (d, J = 12.8 Hz, 1H), 4.95 (s, 2H), 4.51 (s, 2H), 4.09-4.00 (m, 2H), 2.94-2.90 (m, 1H), 2.59 (t, J = 9.6 Hz, 1H), 2.22 (s, 3H), 2.05 (td, J = 11.6, 2.8 Hz, 1H), 1.79-1.63 (m, 4H), 1.53-1.42 (m, 1H), 1.37-1.25 (m, 1H). Example 44. Synthesis of (R,E)-N-(2-chlorophenyl)-7-(3-(2-methylpyrrolidin-2- yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0849] The method as described for the synthesis of (E)-7-(3-(azetidin-2-yl)acryloyl)-N-(2- chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of 1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid for 1tert- butoxycarbonylazetidine-2-carboxylic acid to provide the product (R,E)-N-(2-chlorophenyl)- 7-(3-(2-methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3- carboxamide. LCMS: m / z 414.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 7.88 (s, 1H), 7.54 (td, J = 8.0, 1.2 Hz, 2H), 7.37 (td, J = 7.6, 1.2 Hz, 1H), 7.28 (td, J = 7.6, 1.6 Hz, 1H), 6.75 (d, J = 14.8 Hz, 1H), 6.59 (d, J = 14.8 Hz, 1H), 4.83 (d, J = 72.4 Hz, 2H), 4.30 (d, J = 14.8 Hz, 2H), 3.97 (d, J = 20.0 Hz, 2H), 2.95-2.78 (m, 2H), 1.77-1.49 (m, 4H), 1.21 (s, 3H). Example 45. Synthesis of N-(2-chlorophenyl)-7-((E)-3-((4R)-4-fluoropyrrolidin-2- yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0850] The method as described for the synthesis of (E)-7-(3-(azetidin-2-yl)acryloyl)-N-(2- chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of (E)-3-((4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)acrylic acid for 1-tert-butoxycarbonylazetidine-2-carboxylic acid to provide the product N-(2-chlorophenyl)-7- ((E)-3-((4R)-4-fluoropyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3- carboxamide. LCMS: m / z 418.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 7.87 (s, 1H), 7.53 (td, J = 8.0, 1.6 Hz, 2H), 7.37 (td, J = 8.0, 1.6 Hz, 1H), 7.28 (td, J = 8.0, 1.6 Hz, 1H), 6.78-6.66 (m, 2H), 5.31-5.14 (m, 1H), 4.84 (d, J = 70.4 Hz, 2H), 4.29 (d, J = 15.6 Hz, 2H), 3.97 (d, J = 27.2 Hz, 2H), 3.74-3.69 (m, 1H), 3.15-3.05 (m, 1H), 2.97-2.84 (m, 1H), 2.33-2.22 (m, 1H), 1.75-1.62 (m, 1H). Example 46. Synthesis of N-(2-chlorophenyl)-7-((E)-3-((4R)-4-fluoro-1-methylpyrrolidin- 2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0851] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(3-(1- methylazetidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of (E)-3-((4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2- yl)acrylic acid 1-tert-butoxycarbonylazetidine-2-carboxylic acid to provide the product N-(2- chlorophenyl)-7-((E)-3-((4R)-4-fluoro-1-methylpyrrolidin-2-yl)acryloyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 432.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.87 (s, 1H), 7.53 (td, J = 7.6, 1.2 Hz, 2H), 7.37 (td, J = 7.6, 1.6 Hz, 1H), 7.28 (td, J = 8.0, 1.6 Hz, 1H), 6.75 (d, J = 15.2 Hz, 1H), 6.60-6.54 (m, 1H), 5.17 (d, J = 55.6 Hz, 1H), 4.84 (d, J = 70.8 Hz, 2H), 4.30 (d, J = 18.8 Hz, 2H), 3.98 (d, J = 24.4 Hz, 2H), 3.23-3.14 (m, 1H), 2.85-2.78 (m, 1H), 2.44-2.33 (m, 2H), 2.18(s, 3H), 1.80-1.64 (m, 1H). Example 47. Synthesis of (E)-N-(2-chlorophenyl)-7-(3-(piperidin-2-yl)acryloyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0852] The method as described for the synthesis of (E)-7-(3-(azetidin-2-yl)acryloyl)-N-(2- chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of tert-butyl 2-formylpiperidine-1-carboxylate for tert-butyl 2-formylazetidine-1- carboxylate to provide the product (E)-N-(2-chlorophenyl)-7-(3-(piperidin-2-yl)acryloyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 414.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.2 Hz, 1H), 8.11 (s, 1H), 7.63 (s, 1H), 7.42 (dd, J = 8.0, 1.3 Hz, 1H), 7.34-7.28 (m, 1H), 7.09 (td, J = 7.9, 1.5 Hz, 1H), 6.99 (dd, J = 14.9, 5.6 Hz, 1H), 6.53-6.42 (m, 1H), 4.95 (s, 2H), 4.49 (s, 2H), 4.16-3.94 (m, 2H), 3.40-3.28 (m, 1H), 3.23-3.12 (m, 1H), 2.73 (td, J = 11.7, 2.7 Hz, 1H), 1.90-1.77 (m, 3H), 1.45 (td, J = 9.1, 2.9 Hz, 2H), 1.34-1.20 (m, 1H). Example 48. Synthesis of (E)-N-(2-chlorophenyl)-7-(3-(1-methylpiperidin-2-yl)acryloyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0853] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(3-(1- methylazetidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of tert-butyl -2-formylpiperidine-1-carboxylate for tert-butyl -2- formylazetidine-1-carboxylate to provide the product (E)-N-(2-chlorophenyl)-7-(3-(1- methylpiperidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 428.5 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 7.9 Hz, 1H), 8.11 (s, 1H), 7.64 (s, 1H), 7.42 (dd, J = 8.0, 1.3 Hz, 1H), 7.35-7.28 (m, 1H), 7.09 (td, J = 7.9, 1.5 Hz, 1H), 6.94 (dd, J = 15.0, 8.5 Hz, 1H), 6.56-6.35 (m, 1H), 4.94 (s, 2H), 4.50 (s, 2H), 4.19-3.90 (m, 2H), 3.01-2.85 (m, 1H), 2.69-2.51 (m, 1H), 2.22 (s, 3H), 2.15-1.98 (m, 1H), 1.84-1.68 (m, 2H), 1.53-1.40 (m, 2H), 1.39-1.19 (m, 2H). Example 49. Synthesis of N-(2-chlorophenyl)-7-((E)-3-((4S)-4-fluoropyrrolidin-2- yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0854] The method as described for the synthesis of (E)-7-(3-(azetidin-2-yl)acryloyl)-N-(2- chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of (E)-3-((4S)-4-fluoropyrrolidin-2-yl)acrylic acid for 1-tert- butoxycarbonylazetidine-2-carboxylic acid to provide the product N-(2-chlorophenyl)-7-((E)- 3-((,4S)-4-fluoropyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3- carboxamide. LCMS: m / z 418.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.87 (s, 1H), 7.58 – 7.48 (m, 2H), 7.38 (td, J = 7.7, 1.4 Hz, 1H), 7.29 (td, J = 7.7, 1.6 Hz, 1H), 6.82 – 6.63 (m, 2H), 5.35 – 5.10 (m, 1H), 4.98 – 4.66 (m, 2H), 4.38 – 4.21 (m, 2H), 4.06 – 3.87 (m, 2H), 3.80 – 3.67 (m, 1H), 3.19 – 3.04 (m, 1H), 3.01 – 2.84 (m, 1H), 2.41 – 2.19 (m, 1H), 1.79 – 1.61 (m, 1H), 1.47 (s, 1H). Example 50. Synthesis of N-(2-chlorophenyl)-7-((E)-3-((4S)-4-fluoro-1-methylpyrrolidin- 2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0855] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(3-(1- methylazetidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of (2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid for (2R)-1-tert-butoxycarbonylazetidine-2-carboxylic acid to provide the product N-(2- chlorophenyl)-7-((E)-3-((4S)-4-fluoro-1-methylpyrrolidin-2-yl)acryloyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 432.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 7.88 (s, 1H), 7.54 (t, J = 9.3 Hz, 2H), 7.38 (t, J = 7.6 Hz, 1H), 7.29 (t, J = 7.7 Hz, 1H), 6.85 – 6.48 (m, 2H), 5.28 – 4.70 (m, 3H), 4.43 – 4.19 (m, 2H), 4.13 – 3.82 (m, 2H), 3.24 – 3.11 (m, 1H), 2.84 – 2.73 (m, 1H), 2.42 – 2.24 (m, 1H), 2.16 (s, 3H), 1.84 – 1.40 (m, 2H).Example 51. Synthesis of N-(2-chlorophenyl)-7-((E)-3-((4R)-4-methoxypyrrolidin-2- yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0856] The method as described for the synthesis of (E)-7-(3-(azetidin-2-yl)acryloyl)-N-(2- chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of (4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid for 1- tert-butoxycarbonylazetidine-2-carboxylic acid to provide the product N-(2-chlorophenyl)-7- ((E)-3-((,4R)-4-methoxypyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine- 3-carboxamide. LCMS: m / z 430.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 7.88 (s, 1H), 7.62 – 7.47 (m, 2H), 7.42 – 7.21 (m, 2H), 6.81 – 6.52 (m, 2H), 4.99 – 4.67 (m, 2H), 4.48 – 4.25 (m, 2H), 4.08 – 3.69 (m, 4H), 3.24 – 3.06 (m, 4H), 2.96 – 2.83 (m, 1H), 2.30 – 2.12 (m, 1H), 2.10 – 1.80 (m, 1H), 1.60 – 1.38 (m, 1H). Example 52. Synthesis of N-(2-chlorophenyl)-7-((E)-3-((4R)-4-methoxy-1- methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3- carboxamide.

[0857] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(3-(1- methylazetidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of (4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid for 1-tert-butoxycarbonylazetidine-2-carboxylic acid to provide the product N-(2- chlorophenyl)-7-((E)-3-((,4R)-4-methoxy-1-methylpyrrolidin-2-yl)acryloyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 444.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.88 (s, 1H), 7.59 – 7.50 (m, 2H), 7.33 (dtd, J = 35.5, 7.7, 1.5 Hz, 2H), 6.75 (t, J = 14.9 Hz, 1H), 6.60 – 6.46 (m, 1H), 4.99 – 4.67 (m, 2H), 4.41 – 4.21(m, 2H), 4.06 – 3.82 (m, 3H), 3.17 (d, J = 8.6 Hz, 3H), 3.11 – 2.92 (m, 1H), 2.42 – 1.48 (m, 7H). Example 53. Synthesis of (E)-N-(2-chlorophenyl)-7-(3-(pyrrolidin-2-yl)acryloyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0858] The method as described for the synthesis of (E)-7-(3-(azetidin-2-yl)acryloyl)-N-(2- chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of tert-butyl 2-formylpyrrolidine-1-carboxylate for tert-butyl 2-formylazetidine- 1-carboxylate to provide the product (E)-N-(2-chlorophenyl)-7-(3-(pyrrolidin-2-yl)acryloyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 400.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 9.74 – 9.33 (m, 1H), 7.90 (s, 1H), 7.57 – 7.49 (m, 2H), 7.38 (t, J = 7.5 Hz, 1H), 7.29 (t, J = 7.4 Hz, 1H), 7.00 (t, J = 14.8 Hz, 1H), 6.84 – 6.73 (m, 1H), 5.02 – 4.70 (m, 2H), 4.43 – 3.84 (m, 5H), 3.29 – 3.15 (m, 2H), 2.23 – 2.11 (m, 1H), 2.04 – 1.72 (m, 3H). Example 54. Synthesis of (E)-N-(2-chlorophenyl)-7-(3-(1-methylpyrrolidin-2- yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0859] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(3-(1- methylazetidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of tert-butyl -2-formylpyrrolidine-1-carboxylate for tert-butyl -2- formylazetidine-1-carboxylate to provide the product (E)-N-(2-chlorophenyl)-7-(3-(1- methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 414.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.87 (s, 1H), 7.54 (t, J = 8.6 Hz, 2H), 7.38 (t, J = 7.6 Hz, 1H), 7.29 (t, J = 7.7 Hz, 1H), 6.73 – 6.70 (m, 1H),6.55 (dd, J = 15.0, 8.0 Hz, 1H), 4.92 (s, 1H), 4.75 (s, 1H), 4.38 – 4.23 (m, 2H), 4.06 – 3.88 (m, 2H), 3.05 – 2.94 (m, 1H), 2.86 – 2.70 (m, 1H), 2.20 – 2.13 (m, 4H), 2.02 – 1.88 (m, 1H), 1.76 – 1.67 (m, 2H), 1.61 – 1.47 (m, 1H). Example 55. Synthesis of (E)-N-(2-chlorophenyl)-7-(3-(pyrrolidin-2-yl)acryloyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0860] The method as described for the synthesis of (E)-7-(3-(azetidin-2-yl)acryloyl)-N-(2- chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of tert-butyl 2-formylpyrrolidine-1-carboxylate for tert-butyl 2-formylazetidine- 1-carboxylate to provide the product (R,E)-N-(2-chlorophenyl)-7-(3-(pyrrolidin-2- yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 400.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 9.09 – 8.96 (m, 1H), 8.82 – 8.61 (m, 1H), 7.89 (s, 1H), 7.57 – 7.48 (m, 2H), 7.38 (td, J = 7.7, 1.3 Hz, 1H), 7.29 (td, J = 7.8, 1.6 Hz, 1H), 6.96 – 6.92 (m, 1H), 6.79 – 6.73 (m, 1H), 4.96 (s, 1H), 4.78 (s, 1H), 4.37 – 4.19 (m, 3H), 4.08 – 3.92 (m, 2H), 2.22 – 2.14 (m, 1H), 2.04 – 1.75 (m, 4H). Example 56. Synthesis of (E)-N-(2-chlorophenyl)-7-(3-(1-methylpyrrolidin-2- yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0861] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(3-(1- methylazetidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of tert-butyl 2-formylpyrrolidine-1-carboxylate for tert-butyl 2- formylazetidine-1-carboxylate to provide the product (E)-N-(2-chlorophenyl)-7-(3-(1- methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 414.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.87 (s, 1H), 7.54(td, J = 8.2, 2.7 Hz, 2H), 7.38 (td, J = 7.7, 1.4 Hz, 1H), 7.29 (td, J = 7.7, 1.6 Hz, 1H), 6.74 – 6.70 (m, 1H), 6.55 (dd, J = 15.0, 8.0 Hz, 1H), 4.92 – 4.89 (m, 1H), 4.81 – 4.66 (m, 1H), 4.40 – 4.18 (m, 2H), 4.10 – 3.89 (m, 2H), 3.08 – 2.96 (m, 1H), 2.86 – 2.71 (m, 1H), 2.17 – 2.14 (m, 4H), 2.03 – 1.90 (m, 1H), 1.77 – 1.67 (m, 2H), 1.62 – 1.45 (m, 1H). Example 57. Synthesis of (E)-7-(3-(azetidin-2-yl)acryloyl)-N-(2-chlorophenyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0862] The method as described for the synthesis of (E)-7-(3-(azetidin-2-yl)acryloyl)-N-(2- chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of 1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid for 1-(tert- butoxycarbonyl)azetidine-2-carboxylic acid to provide the product (E)-7-(3-(azetidin-2- yl)acryloyl)-N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide as a white solid. LCMS: m / z 386.1 [M+H]+.1H NMR (400 MHz, MeOD) δ 8.12 (d, J = 12.4 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.52 (dd, J = 7.9, 0.9 Hz, 1H), 7.37 (td, J = 7.8, 1.1 Hz, 1H), 7.28 (t, J = 7.4 Hz, 1H), 7.04 (dd, J = 14.9, 6.5 Hz, 1H), 6.91 (d, J = 15.6 Hz, 1H), 5.24 (dd, J = 15.6, 8.1 Hz, 1H), 5.07 (s, 2H), 4.60 (dd, J = 35.5, 19.0 Hz, 2H), 4.13 (dd, J = 19.2, 9.0 Hz, 3H), 3.93 (td, J = 10.0, 5.4 Hz, 1H), 2.81 – 2.62 (m, 2H). Example 58. Synthesis of (E)-N-(2-chlorophenyl)-7-(3-(1-methylazetidin-2-yl)acryloyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0863] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(3-(1- methylazetidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of 1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid for 1-(tert- butoxycarbonyl)azetidine-2-carboxylic acid to provide the product (E)-3-(1-methylazetidin-2-yl)acrylaldehyde for (E)-3-(1-methylazetidin-2-yl)acrylaldehyde to provide the product (E)- N-(2-chlorophenyl)-7-(3-(1-methylazetidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2- a]pyrazine-3-carboxamide as a white solid. LCMS: m / z 400.1 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 7.68 (dd, J = 8.0, 1.2 Hz, 1H), 7.50 (dd, J = 8.0, 1.3 Hz, 1H), 7.35 (td, J = 7.8, 1.4 Hz, 1H), 7.25 (td, J = 7.8, 1.5 Hz, 1H), 6.88 (dd, J = 15.2, 6.3 Hz, 1H), 6.70 (d, J = 15.4 Hz, 1H), 4.95 (d, J = 31.2 Hz, 2H), 4.46 (d, J = 21.5 Hz, 2H), 4.10 (s, 2H), 3.89 (d, J = 7.2 Hz, 1H), 3.46 (t, J = 7.9 Hz, 1H), 3.07 (d, J = 7.9 Hz, 1H), 2.40 (s, 3H), 2.29 (dd, J = 16.1, 8.2 Hz, 1H), 2.14 (dd, J = 18.7, 9.2 Hz, 1H). Example 59. Synthesis of (S,E)-N-(2-chlorophenyl)-7-(3-(2-methylpyrrolidin-2- yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0864] The method as described for the synthesis of (R,E)-7-(3-(azetidin-2-yl)acryloyl)-N-(2- chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of tert-butyl 2-formylpyrrolidine-1-carboxylate for tert-butyl 2-formylazetidine- 1-carboxylate to provide the product (S,E)-N-(2-chlorophenyl)-7-(3-(2-methylpyrrolidin-2- yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide as a white solid. LCMS: m / z 414.1 [M+H]+.1H NMR (400 MHz, MeOD) δ 8.03 – 7.92 (m, 1H), 7.72 – 7.66 (m, 1H), 7.53 (dd, J = 7.8, 1.0 Hz, 1H), 7.38 (td, J = 7.8, 1.2 Hz, 1H), 7.30 (dd, J = 11.7, 4.7 Hz, 1H), 7.02 – 6.82 (m, 2H), 5.03 (d, J = 19.8 Hz, 2H), 4.60 – 4.44 (m, 2H), 4.16 (s, 2H), 3.51 – 3.41 (m, 2H), 2.30 – 2.07 (m, 4H), 1.64 (s, 3H). Example 60. Synthesis of (E)-7-(3-(1-(7-aminoheptyl)pyrrolidin-2-yl)acryloyl)-N-(2- chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.Step 1. Synthesis of tert-butyl (E)-(7-(2-(3-(3-((2-chlorophenyl)carbamoyl)-5,6- dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-3-oxoprop-1-en-1-yl)pyrrolidin-1- yl)heptyl)carbamate

[0865] To a solution of (E)-N-(2-chlorophenyl)-7-(3-(pyrrolidin-2-yl)acryloyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide (430 mg, 1.08 mmol) in MeCN (5 mL) was added tert-butyl-N-(7-oxoheptyl)carbamate (493.18 mg, 2.15 mmol) and NaBH(OAc)3 (683.72 mg, 3.23 mmol) and two drops of acetic acid. Then the mixture was stirred at 25°C for 1 h. The mixture was purified by Prep-HPLC under basic condition to give tert-butyl (E)- (7-(2-(3-(3-((2-chlorophenyl)carbamoyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-3- oxoprop-1-en-1-yl)pyrrolidin-1-yl)heptyl)carbamate (200 mg, 326.16 μmol, 30.33% yield) as white solid. LCMS: m / z 613.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.88 (s, 1H), 7.57 – 7.50 (m, 2H), 7.33 (dtd, J = 17.0, 7.6, 1.5 Hz, 2H), 6.93 – 6.40 (m, 3H), 4.99 – 4.67 (m, 2H), 4.37 – 4.22 (m, 2H), 4.08 – 3.88 (m, 2H), 3.13 – 2.83 (m, 3H), 2.16 – 2.00 (m, 2H), 1.98 – 1.86 (m, 1H), 1.81 – 1.67 (m, 2H), 1.56 – 1.12 (m, 22H). Step 2. Synthesis of (E)-7-(3-(1-(7-aminoheptyl)pyrrolidin-2-yl)acryloyl)-N-(2-chlorophenyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide

[0866] To a solution of tert-butyl (E)-(7-(2-(3-(3-((2-chlorophenyl)carbamoyl)-5,6- dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-3-oxoprop-1-en-1-yl)pyrrolidin-1- yl)heptyl)carbamate (180 mg, 293.55 μmol) in DCM (4 mL) was added TFA (100.41 mg, 880.64 μmol). Then the mixture was stirred at 25°C for 4 h. The mixture was neutralized with aqueous sodium bicarbonate. The resulting solution was concentrated and the residue was purified by Prep-HPLC under basic condition to give (E)-7-(3-(1-(7-aminoheptyl)pyrrolidin- 2-yl)acryloyl)-N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide (100 mg, 194.90 μmol, 66.40% yield) as white solid. LCMS: m / z 513.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.60 – 7.43 (m, 2H), 7.33 (dtd, J = 35.5, 7.6, 1.5 Hz,2H), 6.80 – 6.43 (m, 2H), 5.03 – 4.65 (m, 2H), 4.45 – 4.15 (m, 2H), 4.09 – 3.87 (m, 2H), 3.14 – 2.80 (m, 3H), 2.18 – 1.01 (m, 19H). Example 61. Synthesis of (E)-N-(2-chlorophenyl)-7-(4-(dimethylamino)-4-methylpent-2- enoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamideO N Step 1. Synthesis of 2-(dimethylamino)-2-methylpropanal

[0867] To a solution of DMSO (3.12 g, 39.94 mmol, 2.83 mL) in DCM (10 mL) was added a solution of (COCl)2 (3.77 g, 29.95 mmol) in DCM (10 mL) at -78° C. The mixture was stirred at the same temperature for 30 minutes, and then a solution of 2-(dimethylamino)-2- methyl-propan-1-ol (1.17 g, 9.98 mmol) in DCM (10 mL) was added. The resulting mixture was stirred at the same temperature for 20 minutes, Et3N (6.55 g, 64.90 mmol) was added, and the mixture was stirred at the same temperature for 40 minutes. The reaction mixture was warmed to room temperature, and then diluted with DCM (20 mL) The organic layer was washed with sat. aq. sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate and concentrated to give 2-(dimethylamino)-2-methyl-propanal (1.2 g, crude) as a yellow oil. LCMS: m / z 116.1 [M+H]+.

[0868] To a solution of 2-(dimethylamino)-2-methyl-propanal (1.15 g, 10 mmol) in DCM (20 mL) was added ethyl 2-(triphenyl-phosphanylidene)acetate (5.23 g, 15.00 mmol). The resulting mixture was stirred at 40°C overnight and concentrated, the residue was purified by SGC (eluting with Petroleum ether / EtOAc = 3 / 1-1 / 2) to give ethyl (E)-4-(dimethylamino)-4-methyl-pent-2-enoate (400 mg, 1.30 mmol, 12.95% yield, 60% purity) as a yellow oil. LCMS: m / z 186.1 [M+H]+.

[0869] To a solution of ethyl (E)-4-(dimethylamino)-4-methyl-pent-2-enoate (400 mg, 2.16 mmol) in THF (6 mL) was added a solution of NaOH (240.00 mg, 6 mmol, 112.68 μL) in water (2.00 mL). The resulting mixture was stirred at 50°C overnight and then concentrated, the residue was added water (20 mL). The aqueous phase was acidified with 1M HCl to pH 3-4 and lyophilized to give (E)-4-(dimethylamino)-4-methyl-pent-2-enoic acid (800 mg, crude) as a light yellow solid, which was used directly for the next step. LCMS: m / z 158.1 [M+H]+. Step 4. Synthesis of (E)-N-(2-chlorophenyl)-7-(4-(dimethylamino)-4-methylpent-2-enoyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide

[0870] To a solution of N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3- carboxamide (60 mg, 216.82 μmol CL), (E)-4-(dimethylamino)-4-methyl-pent-2-enoic acid (200 mg, 1.27 mmol) and HATU (82.44 mg, 216.82 μmol) in DMF (3 mL) was added DIPEA. (27.97 mg, 216.82 μmol). The resulting mixture was stirred at room temperature overnight and then purified by Prep-HPLC under basic condition to give (E)-N- (2-chlorophenyl)-7-(4-(dimethylamino)-4-methylpent-2-enoyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide (40 mg, 92.33 μmol, 42.58% yield, 96% purity) as a white solid. LCMS: m / z 416.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 7.7 Hz, 1H), 8.12 (s, 1H), 7.64 (s, 1H), 7.42 (dd, J = 8.0, 1.4 Hz, 1H), 7.35 – 7.28 (m, 1H), 7.09 (td, J = 7.8, 1.5 Hz, 1H), 7.02 (d, J = 15.4 Hz, 1H), 6.46 – 6.25 (m, 1H), 4.96 (s, 2H), 4.50 (s, 2H), 4.10 (brs, 2H), 2.28 (s, 6H), 1.23 (s, 6H). Example 62. Synthesis of N-(2-chlorophenyl)-7-[(E)-3-(4-methylmorpholin-3-yl)prop-2- enoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3-carboxamide.

[0871] To a solution of ethyl 2-(triphenyl-phosphanylidene)acetate (2.43 g, 6.97 mmol) in DCM (30 mL) was added tert-butyl -3-formylmorpholine-4-carboxylate (1.0 g, 4.65 mmol) . The mixture was stirred at 40 °C overnight, and the precipitate was filtered and the filtrate was concentrated. The residue was purified on silica flash chromatography (eluting with EtOAc / petroleum ether 0 to 1 / 1) to give tert-butyl -3-[(E)-3-ethoxy-3-oxo-prop- 1-enyl]morpholine-4-carboxylate (1.2 g, 3.90 mmol, 84.01% yield, 92.8% purity) as colorless oil. LCMS: m / z 186.2 [M+H-Boc]+.

[0872] To a solution of tert-butyl 3-[(E)-3-ethoxy-3-oxo-prop-1-enyl]morpholine-4- carboxylate (1.3 g, 4.21 mmol) in THF (30 mL) was added a solution of NaOH (504.63 mg, 12.62 mmol, 236.91 μL) in water (10 mL) The resulting mixture was stirred at 50°C overnight and then concentrated, the residue was added water (20 mL). The aqueous phase was adjusted pH to 5-6 with 1N HCl, and extracted with EtOAc (30 mL * 3). The combined organic phase was concentrated to give (E)-3-(4-(tert-butoxycarbonyl)morpholin-3-yl)acrylic acid (0.75 g, 2.92 mmol, 69.32% yield) as a light yellow solid, which was used directly for the next step. LCMS: m / z 158.2 [M+H-Boc]+.Step 3: Synthesis of tert-butyl (E)-3-(3-(3-((2-chlorophenyl)carbamoyl)-5,6- dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-3-oxoprop-1-en-1-yl)morpholine-4-carboxylate

[0873] To a solution of (E)-3-[(3S)-4-tert-butoxycarbonylmorpholin-3-yl]prop-2-enoic acid (260 mg, 1.01 mmol) , N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3- carboxamide (210.99 mg, 673.71 μmol, CL) and HATU (307.40 mg, 808.45 μmol) in DMF (5 mL) was added DIPEA (113.19 mg, 875.82 μmol, 152.55 μL) . The resulting mixture was stirred at room temperature overnight and diluted with water (15 mL). The precipitate was filtered, dried and then purified by Prep-HPLC under basic condition to give tert-butyl -3- [(E)-3-[3-[(2-chlorophenyl)carbamoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-3-oxo- prop-1-enyl]morpholine-4-carboxylate (200 mg, 387.61 μmol, 57.53% yield, 100% purity) as a white solid. LCMS: m / z 516.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.39 – 8.30 (m, 1H), 8.11 (s, 1H), 7.64 (s, 1H), 7.42 (dd, J = 8.0, 1.3 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.16 – 6.97 (m, 2H), 6.45 (d, J = 15.0 Hz, 1H), 5.00 – 4.76 (m, 2H), 4.68 – 4.42 (m, 3H), 4.12 – 3.52 (m, 7H), 3.23 – 3.08 (m, 1H), 1.46 (s, 9H). Step 4: Synthesis of (E)-N-(2-chlorophenyl)-7-(3-(morpholin-3-yl)acryloyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide

[0874] To a solution of tert-butyl -3-[(E)-3-[3-[(2-chlorophenyl)carbamoyl]-6,8-dihydro-5H- imidazo[1,2-a]pyrazin-7-yl]-3-oxo-prop-1-enyl]morpholine-4-carboxylate (200 mg, 387.61 μmol) in DCM (5 mL) was added HCl (145.84 mg, 4 mmol, 1 mL) at 0°C. The resulting mixture was stirred at room temperature for 3 hours, and then diluted with DCM (20 mL). The organic phase was washed with aq. sat. NaHCO3 (10 mL x 3), brine and concentrated. The residue was purified by Prep-HPLC under basic condition to give (E)-N-(2-chlorophenyl)-7-(3-(morpholin-3-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3- carboxamide (95 mg, 228.44 μmol, 58.93% yield, 100% purity) as white solid. LCMS: m / z 416.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.1 Hz, 1H), 8.11 (s, 1H), 7.64 (s, 1H), 7.42 (dd, J = 8.0, 1.2 Hz, 1H), 7.35 – 7.28 (m, 1H), 7.13 – 7.05 (m, 1H), 6.89 (dd, J = 15.1, 5.2 Hz, 1H), 6.57 (d, J = 15.0 Hz, 1H), 4.94 (s, 2H), 4.50 (s, 2H), 4.10 (s, 2H), 3.94 – 3.80 (m, 2H), 3.69 – 3.48 (m, 2H), 3.30 – 3.19 (m, 1H), 3.10 – 2.92 (m, 2H). Step 5: Synthesis of (E)-N-(2-chlorophenyl)-7-(3-(4-methylmorpholin-3-yl)acryloyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide

[0875] To a solution of N-(2-chlorophenyl)-7-[(E)-3-morpholin-3-ylprop-2-enoyl]-6,8- dihydro-5H-imidazo[1,2-a]pyrazine-3-carboxamide (65 mg, 156.30 μmol) in ACN (5 mL) was added AcOH (2 drops) and HCHO (143.88 mg, 1.56 mmol, 37% purity). The resulting mixture was stirred at room temperature for 1 hour, and then NaBH(OAc)3 (99.41 mg, 468.89 μmol) was added. The mixture was stirred at room temperature overnight, filtered and purified by Prep-HPLC under basic condition to give N-(2-chlorophenyl)-7-[(E)-3-[(3S)- 4-methylmorpholin-3-yl]prop-2-enoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3- carboxamide (16 mg, 37.22 μmol, 23.81% yield, 100% purity) as a white solid. LCMS: m / z 430.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 7.7 Hz, 1H), 8.11 (s, 1H), 7.64 (s, 1H), 7.46 – 7.39 (m, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.09 (td, J = 7.9, 1.5 Hz, 1H), 6.80 (dd, J = 15.3, 8.4 Hz, 1H), 6.55 (d, J = 14.6 Hz, 1H), 4.93 (s, 2H), 4.50 (s, 2H), 4.20 – 3.90 (m, 2H), 3.85 (d, J = 11.4 Hz, 1H), 3.68 (t, J = 12.4 Hz, 2H), 3.43 – 3.25 (m, 1H), 2.91 – 2.68 (m, 2H), 2.36 – 2.29 (m, 1H), 2.24 (s, 3H). Example 63. Synthesis of tert-butyl (3R)-3-[(E)-3-[3-[(2-chlorophenyl)carbamoyl]-6,8- dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-3-oxo-prop-1-enyl]morpholine-4-carboxylate.

[0876] The method as described for the synthesis of tert-butyl (3S)-3-[(E)-3-[3-[(2- chlorophenyl)carbamoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-3-oxo-prop-1- enyl]morpholine-4-carboxylate was applied with substitution of tert-butyl (3R)-3- formylmorpholine-4-carboxylate for tert-butyl (3S)-3-formylmorpholine-4-carboxylate to provide the product tert-butyl (3R)-3-[(E)-3-[3-[(2-chlorophenyl)carbamoyl]-6,8-dihydro-5H- imidazo[1,2-a]pyrazin-7-yl]-3-oxo-prop-1-enyl]morpholine-4-carboxylate. LCMS: m / z 516.1[M+H]+.1H NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.52 – 7.48 (m, 1H), 7.35 (t, J = 7.1 Hz, 1H), 7.25 (t, J = 7.7 Hz, 1H), 6.93 (dd, J = 15.4, 5.8 Hz, 1H), 6.63 (d, J = 16.8 Hz, 1H), 4.99 – 4.91 (m, 1H), 4.86 – 4.83 (m, 1H), 4.69 – 4.36 (m, 3H), 4.12 – 3.81 (m, 4H), 3.75 – 3.66 (m, 2H), 3.49 (t, J = 10.4 Hz, 1H), 3.25 – 3.16 (m, 1H), 1.50 – 1.42 (m, 9H). Example 64. Synthesis of N-(2-chlorophenyl)-7-[(E)-3-[(3R)-morpholin-3-yl]prop-2- enoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3-carboxamide.

[0877] The method as described for the synthesis of N-(2-chlorophenyl)-7-[(E)-3-[(3S)- morpholin-3-yl]prop-2-enoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of tert-butyl (3R)-3-formylmorpholine-4-carboxylate for tert-butyl (3S)-3-formylmorpholine-4-carboxylate to provide, after chiral SFC, the product N-(2- chlorophenyl)-7-[(E)-3-[(3R)-morpholin-3-yl]prop-2-enoyl]-6,8-dihydro-5H-imidazo[1,2- a]pyrazine-3-carboxamide. LCMS: m / z 416.1[M+H]+.1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.3 Hz, 1H), 8.11 (s, 1H), 7.64 (s, 1H), 7.42 (dd, J = 8.0, 1.3 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.13 – 7.06 (m, 1H), 6.89 (dd, J = 15.0, 5.0 Hz, 1H), 6.57 (d, J = 14.8 Hz, 1H), 4.94 (s,2H), 4.50 (s, 2H), 4.21 – 3.77 (m, 4H), 3.67 – 3.49 (m, 2H), 3.30 – 3.18 (m, 1H), 3.12 – 2.87 (m, 2H). Example 65. Synthesis of (E)-N-(2-chlorophenyl)-7-(3-(4-methylmorpholin-3- yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0878] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(3-(4- methylmorpholin-3-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of tert-butyl -3-formylmorpholine-4-carboxylate for tert-butyl - 3-formylmorpholine-4-carboxylate to provide the product,(E)-N-(2-chlorophenyl)-7-(3-(4- methylmorpholin-3-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 430.0[M+H]+.1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 7.8 Hz, 1H), 8.11 (s, 1H), 7.64 (s, 1H), 7.42 (dd, J = 8.0, 1.3 Hz, 1H), 7.36 – 7.28 (m, 1H), 7.09 (td, J = 7.9, 1.5 Hz, 1H), 6.80 (dd, J = 15.2, 8.3 Hz, 1H), 6.55 (d, J = 15.0 Hz, 1H), 4.93 (s, 2H), 4.47 (d, J = 26.1 Hz, 2H), 4.19 – 3.79 (m, 3H), 3.68 (dt, J = 13.5, 6.9 Hz, 2H), 3.42 – 3.28 (m, 1H), 2.89 – 2.70 (m, 2H), 2.32 (td, J = 11.5, 3.4 Hz, 1H), 2.24 (s, 3H). Example 66. Synthesis of tert-butyl N-[(E)-4-[3-[(2-chlorophenyl)carbamoyl]-6,8- dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-1-methyl-4-oxo-but-2-enyl]carbamate.

[0879] The method as described for the synthesis of tert-butyl (3S)-3-[(E)-3-[3-[(2- chlorophenyl)carbamoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-3-oxo-prop-1- enyl]morpholine-4-carboxylate was applied with substitution of tert-butyl (1-oxopropan-2- yl)carbamate for tert-butyl (3S)-3-formylmorpholine-4-carboxylate to provide the product tert-butyl N-[(E)-4-[3-[(2-chlorophenyl)carbamoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazin- 7-yl]-1-methyl-4-oxo-but-2-enyl]carbamate. LCMS: m / z 474.1[M+H]+.1H NMR (400 MHz,CDCl3) δ 8.35 (d, J = 8.0 Hz, 1H), 8.11 (s, 1H), 7.64 (s, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.31 (t, J = 7.2 Hz, 1H), 7.09 (dd, J = 12.3, 4.7 Hz, 1H), 6.86 (s, 1H), 6.38 (d, J = 15.2 Hz, 1H), 4.93 (s, 2H), 4.45 (d, J = 32.5 Hz, 4H), 4.03 (d, J = 44.9 Hz, 2H), 1.46 (s, 9H), 1.30 (d, J = 6.9 Hz, 3H). Example 67. Synthesis of 7-[(E)-4-aminopent-2-enoyl]-N-(2-chlorophenyl)-6,8-dihydro- 5H-imidazo[1,2-a]pyrazine-3-carboxamide.

[0880] The method as described for the synthesis of N-(2-chlorophenyl)-7-[(E)-3-[(3S)- morpholin-3-yl]prop-2-enoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of tert-butyl (1-oxopropan-2-yl)carbamate for tert-butyl (3S)-3- formylmorpholine-4-carboxylate to provide the product 7-[(E)-4-aminopent-2-enoyl]-N-(2- chlorophenyl)-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 374.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 9.1 Hz, 1H), 8.11 (s, 1H), 7.64 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 6.98 (d, J = 15.3 Hz, 1H), 6.45 (s, 1H), 4.95 (s, 2H), 4.50 (s, 2H), 4.19 – 3.91 (m, 2H), 3.71 (s, 1H), 1.25 (d, J = 6.3 Hz, 3H). Example 68. Synthesis of N-(2-chlorophenyl)-7-[(E)-4-(dimethylamino)pent-2-enoyl]- 6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3-carboxamide.

[0881] The method as described for the synthesis of N-(2-chlorophenyl)-7-[(E)-3-[(3S)-4- methylmorpholin-3-yl]prop-2-enoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of tert-butyl (1-oxopropan-2-yl)carbamate for tert-butyl (3S)-3- formylmorpholine-4-carboxylate to provide the product N-(2-chlorophenyl)-7-[(E)-4- (dimethylamino)pent-2-enoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3-carboxamide.LCMS: m / z 402.1[M+H]+.1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.2 Hz, 1H), 8.11 (s, 1H), 7.64 (s, 1H), 7.42 (dd, J = 8.0, 1.2 Hz, 1H), 7.31 (t, J = 7.3 Hz, 1H), 7.15 – 7.05 (m, 1H), 6.96 (dd, J = 15.1, 7.5 Hz, 1H), 6.39 (d, J = 15.3 Hz, 1H), 4.95 (s, 2H), 4.50 (s, 2H), 4.28 – 3.96 (m, 2H), 3.24 – 3.03 (m, 1H), 2.35 – 2.21 (m, 6H), 1.21 (d, J = 6.7 Hz, 3H). Example 69. Synthesis of (E)-N-(2-chlorophenyl)-7-(3-(1-ethylpyrrolidin-2-yl)acryloyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide.

[0882] The method as described for the synthesis of (E)-N-(2-chlorophenyl)-7-(3-(1- methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxamide was applied with substitution of acetaldehyde for formaldehyde to provide the product N-(2- chlorophenyl)-7-[(E)-3-[(2R)-1-ethylpyrrolidin-2-yl]prop-2-enoyl]-6,8-dihydro-5H- imidazo[1,2-a]pyrazine-3-carboxamide. LCMS: m / z 428.2[M+H]+.1H NMR (400 MHz, MeOD) δ 8.03 (s, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.51 (dd, J = 8.0, 1.1 Hz, 1H), 7.41 – 7.32 (m, 1H), 7.27 (t, J = 7.7 Hz, 1H), 7.04 (t, J = 20.8 Hz, 1H), 6.87 – 6.74 (m, 1H), 5.06 (d, J = 26.8 Hz, 2H), 4.54 (d, J = 29.7 Hz, 2H), 4.24 – 4.04 (m, 3H), 3.89 – 3.64 (m, 1H), 3.39 (dd, J = 12.7, 7.0 Hz, 1H), 3.22 (dd, J = 19.6, 8.8 Hz, 1H), 3.09 (dd, J = 12.9, 7.2 Hz, 1H), 2.41 (dd, J = 12.7, 7.5 Hz, 1H), 2.31 – 2.10 (m, 2H), 2.03 (d, J = 5.3 Hz, 1H), 1.3...

Claims

CLAIMS:

1. A compound of Formula (I):, wherein * indicates R2attachment and ** indicates amide attachment; R1 is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R1a; each R1aindependently is halo, -OH, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6 alkoxyl, or -C(O)N(R1b)(R1c), or two R1a, together with the atoms to which they are attached, form a C3-C6cycloalkyl or 5- to 6-membered heterocycle; each R1b independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; each R1cindependently is C6-C10aryl optionally substituted with one or more halo, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxyl; R2 is C2-C6 alkenyl or -C(O)R2a, wherein the C2-C6 alkenyl is optionally substituted with one or more R2b; R2ais C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more R2b; each R2bindependently is halo, -N(R2c)(R2d), -OR2c, -CO2(R2c), C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R2e; each R2c independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R2f; each R2dindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; each R2e independently is halo, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1-C7haloalkyl, C1-C7alkoxy, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, -CO(C1-C6alkyl), or -CO2(C1-C6 alkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more -CN, -OH, C1-C6alkoxy, -NH-CO2(C1-C6alkyl), or -NH2; each R2f independently is halo, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, -CO2(R2g), -CON(R2g)(R2h), C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, -C(O)-NH(C1-C6alkyl-C1-C6alkoxy), –(O(C2 alkyl))1-6, or –(O(C2 alkyl))1-6-NH2; each R2g independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, C1-C6 alkyl, or C1-C6haloalkyl; each R2hindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R3is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, or 5- to 10-membered heterocyclyl, or two R3, together with the atoms to which they are attached, form a C3-C6 cycloalkyl or 5- to 6-membered heterocycle; and n is 0, 1, 2, 3, or 4..

2. A compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein:R1 is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R1a; each R1aindependently is halo, -OH, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6 alkoxyl, or -C(O)N(R1b)(R1c), or two R1a, together with the atoms to which they are attached, form a C3-C6 cycloalkyl or 5- or 6-membered heterocycle; each R1bindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; each R1cindependently is C6-C10aryl optionally substituted with one or more halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl; R2 is C2-C6 alkenyl or -C(O)R2a, wherein the C2-C6 alkenyl is optionally substituted with one or more R2b; R2ais C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more R2b; each R2b independently is halo, -N(R2c)(R2d), -OR2c, -CO2(R2c), C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R2e; each R2c independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R2f; each R2dindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; each R2e independently is halo, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 haloalkyl, C1-C7 alkoxy, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, -CO(C1-C6alkyl), or -CO2(C1-C6 alkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more -CN, -OH, C1-C6 alkoxy, -NH-CO2(C1-C6alkyl), or -NH2; each R2findependently is halo, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6 alkoxy, -CO2(R2g), -CON(R2g)(R2h), C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, -C(O)-NH(C1-C6alkyl-C1-C6alkoxy), –(O(C2alkyl))1-6, or –(O(C2alkyl))1-6-NH2;each R2g independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halo, C1-C6 alkyl, or C1-C6 haloalkyl; each R2hindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R3 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, or 5- to 10-membered heterocyclyl, or two R3, together with the atoms to which they are attached, form a C3-C6cycloalkyl or 5- to 6-membered heterocycle; and n is 0, 1, 2, 3, or 4.

3. The compound of any one of the preceding claims, wherein R1 is phenyl or 5- or 6- membered heteroaryl, wherein each phenyl or 5- or 6-membered heteroaryl independently is substituted with one or more R1a, wherein each R1ais halo, C1-C6alkyl, C1-C6alkoxyl, or -C(O)N(R1b)(R1c), or two R1a, together with the atoms to which they are attached, form a 5- or 6- membered heterocycle, as valency permits.

4. The compound of any one of the preceding claims, wherein R1a is Cl, F, CF3, methyl, or methoxy.

5. The compound of any one of the preceding claims, wherein R1b is H.

6. The compound of any one of the preceding claims, wherein R1cis C6-C10aryl optionally substituted with one or more C1-C6 haloalkyl.

8. The compound of any one of the preceding claims, wherein R2 is -C(O)R2a.

9. The compound of any one of claims 1-7, wherein: R2 is C2-C6 alkenyl or C2-C6 alkynyl, wherein the alkenyl or alkynyl is optionally substituted with one or more R2b; and R2b is halo, 4- to 10- membered heterocyclyl, -N(R2c)(R2d), -OR2c, C6-C10 aryl, or - CO2(R2c), wherein the heterocyclyl or aryl is optionally substituted with one or more R2e.

10. The compound of any one of claims 1-7 or 9, wherein R2bis Cl.

11. The compound of any one of the preceding claims, wherein R2cis H.

12. The compound of any one of claims 1-10, wherein R2c is C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C10 aryl, wherein the alkyl, cycloalkyl, or aryl is optionally substituted with one or more R2f.

13. The compound of any one of the preceding claims, wherein R2d is H, methyl, or ethyl.

14. The compound of any one of the preceding claims, wherein R2eis F, Cl, -OH, -CN, - CO(C1-C6 alkyl), -N(C1-C6 alkyl)2, or -CO2(C1-C6 alkyl).

15. The compound of any one of claims 1-13, wherein R2eis C1-C6alkyl, C1-C6alkoxy, C1- C6 haloalkyl, C3-C6 cycloalkyl, or 5- to 10-membered heterocyclyl, wherein the alkyl, haloalkyl, alkoxy, cycloalkyl, or heterocyclyl, is optionally substituted with one or more -CN, -OH, C1-C6alkoxy, or -NH-CO2(C1-C6alkyl).

16. The compound of any one of the preceding claims, wherein each R2f is independently halo, -CN, C1-C6alkyl, C1-C6alkoxy, -CO2(R2g), C3-C6cycloalkyl, C6-C10aryl, C1-C6haloalkyl, or -C(O)-NH(C1-C6 alkyl-C1-C6 alkoxy).

17. The compound of any one of the preceding claims, wherein each R2fis independently F, - CN, methyl, methoxy, phenoxy, -CO2(R2g), cyclopropyl, phenyl, -CF3, or -C(O)-NH(ethyl- methoxy).

18. The compound of any one of the preceding claims, wherein each R2gis independently H or C1-C6 alkyl.

19. The compound of any one of the preceding claims, wherein each R2g is independently H or tert-butyl.F FN N N O O , ,O, N O N N N O ,O, , N N O O O , ,21. The compound of any one of the preceding claims, wherein R3 is C1-C6 alkyl or C3-C10 cycloalkyl.

22. The compound of any one of the preceding claims, wherein R3 is methyl or cyclopropyl.

23. The compound of any one of the preceding claims, wherein the compound is of Formula (II-a), (II-b), (II-b’), (II-c) (II-c’), (II-d), or (II-d’):or a prodrug, solvate, or pharmaceutically acceptable salt thereof. (II-c)24. A compound of Formula (III):or a pharmaceutically acceptable salt thereof, wherein: R1 is C6-C10 aryl optionally substituted with one or more R1a; each R1aindependently is halo, -OH, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxyl; R2 is -C(O)R2a; R2a is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more R2b; each R2b independently is halo, -N(R2c)(R2d), -OR2c, -CO2(R2c), C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10-membered heteroaryl; each R2cindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; each R2d independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; R3is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C10cycloalkyl, or 5- to 10-membered heterocyclyl; and n is 0, 1, 2, 3, or 4.

25. The compound of claim 1 or claim 24, wherein R1 is phenyl optionally substituted with one or more R1a.

26. The compound of any one of claims 1 or 24-25, wherein R1ais halo.

27. The compound of any one of claims 1 or 24-26, wherein28. The compound of any one of claims 1 or 24-27, wherein R2ais C2-C6alkenyl or C2-C6alkynyl, wherein the alkenyl or alkynyl is optionally substituted with one or more R2b.

29. The compound of any one of claims 1 or 24-28, wherein R2bis independently - N(R2c)(R2d) or 4- to 10-membered heterocyclyl.

30. The compound of any one of claims 1 or 24-29, wherein R2cis methyl.

31. The compound of any one of claims 1 or 24-30, wherein R2d is methyl. O 32. The compound of any one of claims 1 or 24-31, wherein R2is,33. The compound of any one of claims 1 or 24-32, wherein the compound is of Formula (III- a), (III-b), or (III-c).or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

34. The compound of any one of the preceding claims, wherein the compound is selected from Table 1 or Table 2, or a prodrug, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof.

35. A compound of any one of the preceding claims obtainable by, or obtained by, a method described herein.

36. An intermediate obtained by a method for preparing the compound of any one of the preceding claims.

37. A pharmaceutical composition comprising the compound of any one of the preceding claims and a pharmaceutical acceptable diluent or carrier.

38. A method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of any one of the preceding claims, or the pharmaceutical composition of claim 37.

39. The compound or pharmaceutical composition of any one of claims 1-37, for use in treating or preventing a disease or disorder.

40. Use of the compound of any one of claims 1-35 in the manufacture of a medicament for treating or preventing a disease or disorder.

41. Use of the compound of any one of claims 1-35 for treating or preventing a disease or disorder.

42. The method, compound, or use of any one of claims 38-41, wherein the disease or disorder is a neurodegenerative disease or disorder, a psychiatric or neurodevelopmental disease or disorder, a viral or infectious disease or disorder, an autoimmune disease or disorder, or an eye disease or disorder.

43. The method, compound, or use of claim 42, wherein the neurodegenerative disease or disorder is neuromyelitis optica (“NMO”), transverse myelitis, myelin oligodendrocyte glycoprotein, acute disseminated encephalomyelitis (“ADEM”), optic neuritis, amyloidosis, Parkinson's disease, Alzheimer's disease, cerebral amyloid angiopathy, Pick's disease, frontotemporal dementia, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, amyotrophic lateral sclerosis (“ALS”), Huntington's disease, traumatic brain injury, stroke, fatty liver disease, endometriosis, paraneoplastic disorders, inflammatory demyelinating polyneuropathy, amyotrophy, fibromyalgia, multiple system atrophy, Friedrich's ataxia, or cerebellar ataxia. wherein the psychiatric or neurodevelopmental disease or disorder is schizophrenia, major depressive disorder, generalized anxiety disorder, panic disorder, social anxiety disorder, agoraphobia, post-traumatic stress disorder, autism spectrum disorder, cerebral palsy, Nasu Hakola disease, bipolar disorder, or substance abuse. wherein the viral or infectious disease or disorder is neuro-HIV, viral encephalitis, meningitis, neurocysticercosis, neurosyphilis, neuro-Lyme disease, infectious myelopathies, COVID-19 neuroinflammation, enteroviruses, poliovirus, Epstein-Barr virus (EBV), human herpesvirus, cytomegalovirus, rabies virus, herpes simplex virus, measles, progressive multifocal leukoencephalopathy John Cunningham (“PML JC”) virus, bacterial meningitis, prion disease, or Creutzfeldt Jakob disease. wherein the autoimmune disease or disorder is antibody-mediated encephalitis, neurological complications of connective tissue damage, neurosarcoidosid, demyelinating diseases (non-MS), idiopathic autoimmune CNS and PNS syndromes, paraneoplastic neurological disease, CNS vasculitis, type 1 diabetes, type 2 diabetes, Crohn's disease, systemic lupus erythematous (“SLE”), irritable bowel disorders, asthma, chronic obstructive pulmonary disease (“COPD”), atopic dermatitis, obesity-associated inflammation, heart disease, ulcerative colitis, psoriasis, psoriatic arthritis, reactive arthritis, rheumatoid arthritis, Sjögren's syndrome, Reiter's disease, multiple sclerosis, autoimmune encephalitis, myasthenia gravis, idiopathic pulmonary fibrosis, ankylosing spondylitis, antiphospholipidantibody syndrome, osteomyelitis, gout, Henoch-Schonlein Purpura, dermatomyositis, idiopathic arthritis, scleroderma, Kawasaki disease, mixed connective tissue damage, myositis, spondyloarthritis, undifferentiated connective tissue disease, systemic sclerosis, or autoimmune hepatitis. wherein the eye disease or disorder is uveitis, keratitis, conjunctivitis, thyroid eye disease, age-related macular degeneration, glaucoma, diabetic retinopathy, diabetes-related macular edema, or scleritis.

44. The method, compound, or use of any one of claims 38-42, wherein the disease or disorder is selected from autoimmune encephalomyelitis, chronic inflammatory demyelinating polyneuropathy, concentric sclerosis, Charcot-Marie-Tooth disease, Guillain- Barre syndrome, HTLV-I associated myelopathy (“HAM”), Schilder’s disease, dementia, frontotemporal lobar dementia, accessory nerve disorder, autonomic dysreflexia, peripheral neuropathy, chemotherapy-induced peripheral neuropathies, mononeuropathy, polyneuropathy, radial neuropathy, ulnar neuropathy, Villaret's syndrome, diabetic neuropathy, nerve paralysis, progressive bulbar palsy, pseudobulbar palsy, spinal bulbar muscular atrophy, myotonic dystrophy, inclusion body myositis, seizure disorders, lysosomal storage disorders, transmissible spongiform encephalopathy, spinocerebellar ataxia, spinal muscular atrophy, Horner’s syndrome, adrenoleukodystrophy, macular degeneration, and Lewy Body syndrome.

45. The method, compound, or use of claim 43 or 44, wherein the disease or disorder is autoimmune encephalomyelitis or multiple sclerosis.

46. The method, compound, or use of claim 43, wherein the disease or disorder is amyotrophic lateral sclerosis, Alzheimer’s disease, multiple sclerosis, or Huntington’s disease.

47. The method, compound, or use of claim 43 or 46, wherein the Alzheimer’s disease is Alzheimer’s disease with APOE4.

48. The method, compound, or use of claim 43 or 46-47, wherein the multiple sclerosis is progression independent of relapses.