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

Abstract

The present disclosure relates to compounds of Formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein: Ring A is or, and to their pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein are useful for inhibiting EphB3 and may be used in the treatment of disorders in which EphB3 activity is implicated, such as neurodegenerative diseases and cancers.

Description

RELATED APPLICATIONS

[001] 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

[002] 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.

[003] 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.

[004] 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

[005] 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; Ri is C6-Cio aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more Ria; each Ria independently is halo, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxyl, or -C(O)N(Rib)(Ric), or two Ria, together with the atoms to which they are attached, form a C3-C6 cycloalkyl or 5- to 6-membered heterocycle; each Rib independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl; each Ric independently is Ce-Cio aryl optionally substituted with one or more halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, or Ci-Ce alkoxyl; R2 is C2-C6 alkenyl or -C(O)R2a, wherein the C2-C6 alkenyl is optionally substituted with one or more R2b; R2a is Ci-Ce 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, Ce-Cio 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, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio aryl, or 5- to 10membered 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, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl; each R2e independently is halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(Ci-Ce 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, Ce-Cio aryl, 5- to 10-membered heteroaryl, -CO(Ci-Ce alkyl), or -CO2(Ci-Ce alkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2; each R2f independently is halo, -CN, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, -CO2(R2g), -CON(R2g)(R2h), C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -C(0)-NH(Ci-C6 alkyl-Ci-Ce alkoxy), -(O(C2 alkyl))i-6, or -(O(C2 alkyl))i-6-NH2; each R2g independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio 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, Ci-Ce alkyl, or Ci-Ce haloalkyl; each R2h independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl; R3 is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce 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-C6 cycloalkyl or 5- to 6-membered heterocycle; and n is 0, 1, 2, 3, or 4.

[006] 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; Ri is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more Ria; each Ria independently is halo, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxyl, or -C(O)N(Rib)(Ric), or two Ria, together with the atoms to which they are attached, form a C3-C6 cycloalkyl or 5- to 6-membered heterocycle; each Rib independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl; each Ric independently is Ce-Cio aryl optionally substituted with one or more halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, or Ci-Ce alkoxyl; R2 is C2-C6 alkenyl or -C(O)R2a, wherein the C2-C6 alkenyl is optionally substituted with one or more R2b; R2a is Ci-Ce 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, Ce-Cio 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, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio 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, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl; each R2e independently is halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, 5-to 10-membered heterocyclyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -CO(Ci-Ce alkyl), or -CO2(Ci-C6 alkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2; each R2f independently is halo, -CN, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, -CO2(R2g), -CON(R2g)(R2h), C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or -C(0)-NH(Ci-C6 alkyl-Ci-Ce alkoxy); each R2g independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio 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, Ci-Ce alkyl, or Ci-Ce haloalkyl; each R2h independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl; R3 is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 5- to 10-membered heterocyclyl; and n is 0, 1, 2, 3, or 4.

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

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

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

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

[012] 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.

[013] 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).

[014] 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).

[015] 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.

[016] 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.

[017] 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.

[018] 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.

[019] 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

[020] 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.

[021] 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 (nonMS), 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, Sjogren'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.

[022] 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-related macular degeneration, glaucoma, diabetic retinopathy, diabetes-related macular edema, or scleritis.

[023] 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.

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

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

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

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

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

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

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

[031] 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 between the chemical structures and names of the compounds disclosed herein, the chemical structures will control. DETAILED DESCRIPTION

[032] 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

[033] 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; Ri is C6-Cio aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more Ria; each Ria independently is halo, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxyl, or -C(O)N(Rib)(Ric), or two Ria, together with the atoms to which they are attached, form a C3-C6 cycloalkyl or 5- to 6-membered heterocycle; each Rib independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl; each Ric independently is Ce-Cio aryl optionally substituted with one or more halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, or Ci-Ce alkoxyl; R2 is C2-C6 alkenyl or -C(O)R2a, wherein the C2-C6 alkenyl is optionally substituted with one or more R2b; R2a is Ci-Ce 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, Ce-Cio 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, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio aryl, or 5- to 10membered 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, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl; each R2e independently is halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(Ci-Ce 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, Ce-Cio aryl, 5- to 10-membered heteroaryl, -CO(Ci-Ce alkyl), or -CO2(Ci-Ce alkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2; each R2f independently is halo, -CN, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, -CO2(R2g), -CON(R2g)(R2h), C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -C(0)-NH(Ci-C6 alkyl-Ci-Ce alkoxy), -(O(C2 alkyl))i-6, or -(O(C2 alkyl))i-6-NH2; each R2g independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio 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, Ci-Ce alkyl, or Ci-Ce haloalkyl; each R2h independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl; R3 is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce 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-C6 cycloalkyl or 5- to 6-membered heterocycle; and n is 0, 1, 2, 3, or 4.

[034] 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; Ri is C6-Cio aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more Ria; each Ria independently is halo, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxyl, or -C(O)N(Rib)(Ric), or two Ria, together with the atoms to which they are attached, form a C3-C6 cycloalkyl or 5- to 6-membered heterocycle; each Rib independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl; each Ric independently is Ce-Cio aryl optionally substituted with one or more halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, or Ci-Ce alkoxyl; R2 is C2-C6 alkenyl or -C(O)R2a, wherein the C2-C6 alkenyl is optionally substituted with one or more R2b; R2a is Ci-Ce 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, Ce-Cio 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, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio 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, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl; each R2e independently is halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, 5-to 10-membered heterocyclyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -CO(Ci-Ce alkyl), or -CO2(Ci-C6 alkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2; each R2f independently is halo, -CN, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, -CO2(R2g), -CON(R2g)(R2h), C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or -C(0)-NH(Ci-C6 alkyl-Ci-Ce alkoxy); each R2g independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio 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, Ci-Ce alkyl, or Ci-Ce haloalkyl; each R2h independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl; R3 is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 5- to 10-membered heterocyclyl; and n is 0, 1, 2, 3, or 4.

[035] It is understood that, for a compound of Formula (I), Ri, Ria, Rib, Ric, 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 Ri, Ria, Rib, Ric, 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 Ri, Ria, Rib, Ric, R2, R2a, R2b, R2c, R2d, R2e, R2f, R2g, R2h, R3, and n. Formula (II)

[036] In some aspects, the present disclosure relates to a compound of Formula (II): R, / UN or a pharmaceutically acceptable salt thereof, wherein: Ri is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more Ria; each Ria independently is halo, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxyl, or -C(O)N(Rib)(Ric), or two Ria, together with the atoms to which they are attached, form a C3-C6 cycloalkyl or 5- or 6-membered heterocycle; each Rib independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl; each Ric independently is Ce-Cio aryl optionally substituted with one or more halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, or Ci-Ce alkoxyl; R2 is C2-C6 alkenyl or -C(O)R2a, wherein the C2-C6 alkenyl is optionally substituted with one or more R2b; R2a is Ci-Ce 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, Ce-Cio 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, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio aryl, or 5- to 10membered 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, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl; each R2e independently is halo, -CN, -OH, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce 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, Ce-Cio aryl, 5- to 10-membered heteroaryl, -CO(Ci-Ce alkyl), or -CO2(Ci-Ce alkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more -CN, -OH, Ci-C6 alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2; each R2f independently is halo, -CN, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, -CO2(R2g), -CON(R2g)(R2h), C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -C(O)-NH(Ci-Ce alkyl-Ci-Ce alkoxy), -(O(C2 alkyl))i-6, or -(O(C2 alkyl))i-6-NH2; each R2g independently is H, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio 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, Ci-Ce alkyl, or Ci-Ce haloalkyl; each R2h independently is H, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, or Ci-Ce haloalkyl; R3 is Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce 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-C6 cycloalkyl or 5- to 6-membered heterocycle; and n is 0, 1, 2, 3, or 4.

[037] In some aspects, the present disclosure relates to a compound of Formula (II): Rf / HN or a pharmaceutically acceptable salt thereof, wherein: Ri is Ce-Cio aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more Ria; each Ria independently is halo, -OH, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxyl, or -C(O)N(Rib)(Ric), or two Ria, together with the atoms to which they are attached, form a C3-C6 cycloalkyl or 5- or 6-membered heterocycle; each Rib independently is H, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, or Ci-Ce haloalkyl; each Ric independently is Ce-Cio aryl optionally substituted with one or more halo, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, or Ci-Ce alkoxyl; R2 is C2-C6 alkenyl or -C(O)R2a, wherein the C2-C6 alkenyl is optionally substituted with one or more R2b; R2a is Ci-Ce 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, Ce-Cio 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, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio aryl, or 5- to 10membered 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, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl; each R2e independently is halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -CO(Ci-Ce alkyl), or -CO2(Ci-Ce alkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more -CN, -OH, Ci-C6 alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2; each R2f independently is halo, -CN, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, -CO2(R2g), -CON(R2g)(R2h), C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or -C(0)-NH(Ci-C6 alkyl-Ci-Ce alkoxy); each R2g independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio 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, Ci-Ce alkyl, or Ci-Ce haloalkyl; each R2h independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl; R3 is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 5- to 10-membered heterocyclyl; and n is 0, 1, 2, 3, or 4.

[038] In some embodiments, Ri is Ce-Cio aryl optionally substituted with one or more Ria.

[039] In some embodiments, Ri is Ce-Cio aryl substituted with one or more Ria.

[040] In some embodiments, Ri is Ce-Cio aryl.

[041] In some embodiments, Ri is 5- to 10-membered heteroaryl optionally substituted with one or more Ria.

[042] In some embodiments, Ri is 5- to 10-membered heteroaryl substituted with one or more Ria.

[043] In some embodiments, Ri is 5- to 10-membered heteroaryl.

[044] In some embodiments, Ri is 5- or 6-membered heteroaryl optionally substituted with one or more Ria.

[045] In some embodiments, Ri is 5- or 6-membered heteroaryl substituted with one or more Ria.

[046] In some embodiments, Ri is 5- or 6-membered heteroaryl.

[047] In some embodiments, Ri is phenyl optionally substituted with one or more Ria.

[048] In some embodiments, Ri is phenyl substituted with one or more Ria.

[049] In some embodiments, Ri is phenyl substituted with one Ria.

[050] In some embodiments, Ri is phenyl substituted with two Ria.

[051] In some embodiments, Ri is phenyl substituted with three Ria.

[052] In some embodiments, Ri is 5-membered heteroaryl optionally substituted with one or more Ria.

[053] In some embodiments, Ri is 5-membered heteroaryl substituted with one or more Ria.

[054] In some embodiments, Ri is 5-membered heteroaryl substituted with one Ria.

[055] In some embodiments, Ri is 5-membered heteroaryl substituted with two Ria.

[056] In some embodiments, Ri is 5-membered heteroaryl substituted with three Ria.

[057] In some embodiments, Ri is 6-membered heteroaryl optionally substituted with one or more Ria.

[058] In some embodiments, Ri is 6-membered heteroaryl substituted with one or more Ria.

[059] In some embodiments, Ri is 6-membered heteroaryl substituted with one Ria.

[060] In some embodiments, Ri is 6-membered heteroaryl substituted with two Ria.

[061] In some embodiments, Ri is 6-membered heteroaryl substituted with three Ria.

[062] In some embodiments, each Ria independently is halo, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxyl, or -C(O)N(Rib)(Ric).

[063] In some embodiments, each Ria independently is halo, Ci-Ce alkyl, Ci-Ce alkoxyl, or -C(O)N(Rib)(Ric).

[064] In some embodiments, each Ria independently is halo.

[065] In some embodiments, each Ria independently is F, Cl, Br, or I.

[066] In some embodiments, each Ria independently is F. In some embodiments, each Ria independently is Cl. In some embodiments, each Ria independently is Br. In some embodiments, each Ria independently is I.

[067] In some embodiments, each Ria independently is -OH.

[068] In some embodiments, each Ria independently is Ci-Ce alkyl.

[069] In some embodiments, each Ria independently is methyl.

[070] In some embodiments, each Ria independently is C2-C6 alkenyl.

[071] In some embodiments, each Ria independently is C2-C6 alkynyl.

[072] In some embodiments, each Ria independently is Ci-Ce haloalkyl.

[073] In some embodiments, each Ria independently is CH2-CF3 or CF3.

[074] In some embodiments, each Ria independently is CF3.

[075] In some embodiments, each Ria independently is Ci-Ce alkoxyl.

[076] In some embodiments, each Ria independently is methoxy.

[077] In some embodiments, each Ria independently is -C(O)N(Rib)(Ric).

[078] In some embodiments, each Ria independently is Cl, F, CH2-CF3, CF3, methyl, or methoxy.

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

[080] In some embodiments, each Ria independently is Cl, F, methyl, or methoxy.

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

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

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

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

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

[086] In some embodiments, two Ria, together with the atoms to which they are attached, form

[087] In some embodiments, each Rib independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl.

[088] In some embodiments, each Rib independently is H.

[089] In some embodiments, each Rib independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl.

[090] In some embodiments, each Rib independently is Ci-Ce alkyl.

[091] In some embodiments, each Rib independently is C2-C6 alkenyl.

[092] In some embodiments, each Rib independently is C2-C6 alkynyl.

[093] In some embodiments, each Rib independently is Ci-Ce haloalkyl.

[094] In some embodiments, each Ric independently is Ce-Cio aryl.

[095] In some embodiments, each Ric independently is Ce-Cio aryl substituted with one or more halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, or Ci-Ce alkoxyl.

[096] In some embodiments, each Ric independently is Ce-Cio aryl optionally substituted with one or more Ci-Ce haloalkyl.

[097] In some embodiments, each Ric independently is Ce-Cio aryl substituted with one or more Ci-Ce haloalkyl.

[098] In some embodiments, each Ric independently is phenyl.

[099] In some embodiments, each Ric independently is phenyl optionally substituted with one or more halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, or Ci-Ce alkoxyl.

[0100] In some embodiments, each Ric independently is phenyl substituted with one or more halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, or Ci-Ce alkoxyl.

[0101] In some embodiments, each Ric independently is phenyl optionally substituted with one or more Ci-Ce haloalkyl.

[0102] In some embodiments, each Ric independently is phenyl substituted with one or more Ci-Ce haloalkyl.

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

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

[0109] In some embodiments, R2 is -C(O)R2a.

[0110] In some embodiments, R2 is C2-C6 alkenyl.

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

[0112] In some embodiments, R2 is C2-C6 alkenyl substituted with one or more R2b.

[0113] In some embodiments, R2a is Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0114] In some embodiments, R2a is Ci-Ce 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 Ci-Ce alkyl.

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

[0117] In some embodiments, R2a is Ci-Ce alkyl 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, R2a is C2-C6 alkenyl substituted with one or more R2b.

[0121] In some embodiments, R2a is C2-C6 alkynyl.

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

[0123] In some embodiments, R2a is C2-C6 alkynyl substituted with one or more R2b.

[0124] 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.

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

[0126] In some embodiments, each R2b independently 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 R2b independently is I.

[0128] In some embodiments, each R2b independently is -N(R2c)(R2d), -OR2c, or -CO2(R2c).

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

[0130] In some embodiments, each R2b independently is -OR2c.

[0131] In some embodiments, each R2b independently is -CO2(R2c).

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

[0133] In some embodiments, each R2b independently is C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, Ce-Cio 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 R2b independently is C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, Ce-Cio 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 R2b independently is C3-C6 cycloalkyl.

[0136] In some embodiments, each R2b independently is C3-C6 cycloalkyl optionally substituted with one or more R2e.

[0137] In some embodiments, each R2b independently is C3-C6 cycloalkyl 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 R2b independently is 4- to 10-membered heterocyclyl substituted with one or more R2e.

[0141] In some embodiments, each R2b independently is Ce-Cio aryl.

[0142] In some embodiments, each R2b independently is Ce-Cio aryl optionally substituted with one or more R2e.

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

[0144] In some embodiments, each R2b independently 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 R2b independently 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, Ce-Cio aryl, 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 R2c independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio aryl, or 5-to 10-membered heteroaryl.

[0150] In some embodiments, each R2c independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio 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.

[0151] In some embodiments, each R2c independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio 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 R2c independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl.

[0153] In some embodiments, each R2c independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl, wherein the alkyl, alkenyl, alkynyl, or haloalkyl is optionally substituted with one or more R2f.

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

[0155] In some embodiments, each R2c independently is Ci-Ce alkyl.

[0156] In some embodiments, eachR2c independently is Ci-Ce alkyl optionally substituted with one or more R2f.

[0157] In some embodiments, each R2c independently is Ci-Ce alkyl substituted with one or more R2f.

[0158] In some embodiments, each R2c independently is C2-C6 alkenyl.

[0159] In some embodiments, each R2c independently is C2-C6 alkenyl 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 R2c independently is C2-C6 alkynyl substituted with one or more R2f.

[0164] In some embodiments, each R2c independently is Ci-Ce haloalkyl.

[0165] In some embodiments, each R2c independently is Ci-Ce haloalkyl optionally substituted with one or more R2f.

[0166] In some embodiments, each R2c independently is Ci-Ce haloalkyl substituted with one or more R2f.

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

[0168] In some embodiments, each R2c independently is C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio 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 R2c independently is C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio aryl, 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 R2c independently is C3-C6 cycloalkyl.

[0171] In some embodiments, each R2c independently is C3-C6 cycloalkyl 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 R2c independently 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 R2c independently is 5- to 10-membered heterocyclyl substituted with one or more R2f.

[0176] In some embodiments, each R2c independently is Ce-Cio aryl.

[0177] In some embodiments, each R2c independently is Ce-Cio aryl optionally substituted with one or more R2f.

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

[0179] In some embodiments, each R2c independently 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 R2c independently is 5- to 10-membered heteroaryl substituted with one or more R2f.

[0182] In some embodiments, each R2c independently is Ci-Ce alkyl, C3-C6 cycloalkyl, or Ce-C10 aryl, wherein the alkyl, cycloalkyl, or aryl is optionally substituted with one or more R2f.

[0183] In some embodiments, each R2d independently is H.

[0184] In some embodiments, each R2d independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl.

[0185] In some embodiments, each R2d independently is Ci-Ce alkyl.

[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 R2d independently is C2-C6 alkynyl.

[0189] In some embodiments, each R2d independently is Ci-Ce haloalkyl.

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

[0191] In some embodiments, each R2e independently is halo.

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

[0193] In some embodiments, each R2e independently is F. In some embodiments, each R2e independently is Cl. In some embodiments, each R2e independently 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 R2e independently is -NH2.

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

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

[0199] In some embodiments, each R2e independently is C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 haloalkyl, C1-C7 alkoxy, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, Ce-C10 aryl, 5- to 10-membered heteroaryl, -CO(Ci-Ce alkyl), or -CO2(Ci-Ce alkyl).

[0200] In some embodiments, each R2e independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-C10 aryl, 5- to 10-membered heteroaryl, -CO(Ci-Ce alkyl), or -CO2(Ci-Ce alkyl).

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

[0202] In some embodiments, each R2e independently is C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 haloalkyl, C1-C7 alkoxy, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, Ce-C10 aryl, 5- to 10-membered heteroaryl, -CO(Ci-Ce alkyl), or -CO2(Ci-Ce alkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

[0203] In some embodiments, each R2e independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-C10 aryl, 5- to 10-membered heteroaryl, -CO(Ci-Ce alkyl), or -CO2(Ci-Ce alkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

[0204] In some embodiments, each R2e independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-C10 aryl, 5- to 10-membered heteroaryl, -CO(Ci-Ce alkyl), or -CO2(Ci-Ce alkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), 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 R2e independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy.

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

[0208] In some embodiments, each R2e independently is C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 haloalkyl, or C1-C7 alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

[0209] In some embodiments, each R2e independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is optionally substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

[0210] In some embodiments, each R2e independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

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

[0212] In some embodiments, eachR2e independently is C1-C7 alkyl optionally substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

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

[0214] In some embodiments, each R2e independently is Ci-Ce alkyl.

[0215] In some embodiments, eachR2e independently is Ci-Ce alkyl optionally substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

[0216] In some embodiments, each R2e independently is Ci-Ce alkyl substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

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

[0218] In some embodiments, each R2e independently is C2-C7 alkenyl optionally substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

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

[0220] In some embodiments, each R2e independently is C2-C6 alkenyl.

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

[0222] In some embodiments, each R2e independently is C2-C6 alkenyl substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

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

[0224] In some embodiments, each R2e independently is C2-C7 alkynyl optionally substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

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

[0226] In some embodiments, each R2e independently is C2-C6 alkynyl.

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

[0228] In some embodiments, each R2e independently is C2-C6 alkynyl substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

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

[0230] In some embodiments, each R2e independently is C1-C7 haloalkyl optionally substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

[0231] In some embodiments, each R2e independently is C1-C7 haloalkyl substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

[0232] In some embodiments, each R2e independently is Ci-Ce haloalkyl.

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

[0234] In some embodiments, each R2e independently is Ci-Ce haloalkyl substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

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

[0236] In some embodiments, each R2e independently is C1-C7 alkoxy optionally substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

[0237] In some embodiments, each R2e independently is C1-C7 alkoxy substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

[0238] In some embodiments, each R2e independently is Ci-Ce alkoxy.

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

[0240] In some embodiments, each R2e independently is Ci-Ce alkoxy substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

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

[0242] In some embodiments, each R2e independently is C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

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

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

[0245] In some embodiments, each R2e independently is C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

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

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

[0248] In some embodiments, each R2e independently is C3-C6 cycloalkyl optionally substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

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

[0250] In some embodiments, each R2e independently 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, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

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

[0253] In some embodiments, each R2e independently 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, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

[0255] In some embodiments, each R2e independently is 5- to 10-membered heterocyclyl substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

[0256] In some embodiments, each R2e independently is Ce-Cio aryl.

[0257] In some embodiments, each R2e independently is Ce-Cio aryl optionally substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

[0258] In some embodiments, each R2e independently is Ce-Cio aryl substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), 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, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

[0261] In some embodiments, each R2e independently is 5- to 10-membered heteroaryl substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2.

[0262] In some embodiments, each R2e independently is CO(Ci-Ce alkyl) or -CO2(Ci-Ce alkyl).

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

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

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

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

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

[0268] In some embodiments, each R2e independently is -CO2(Ci-Ce alkyl).

[0269] In some embodiments, each R2e independently is -C02(Ci-Ce alkyl), wherein the alkyl is optionally substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-Ce alkyl), or -NH2.

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

[0271] In some embodiments, each R2e independently is halo, -OH, -CN, -CO(Ci-Ce alkyl), -N(Ci-C6 alkyl)2, or -CO2(Ci-C6 alkyl).

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

[0273] In some embodiments, each R2e independently is Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce 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, Ci-Ce alkoxy, or -NH-CO2(Ci-C6 alkyl).

[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 R2f independently is F, Cl, Br, or I.

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

[0278] In some embodiments, each R2f independently is -CN.

[0279] In some embodiments, each R2f independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy.

[0280] In some embodiments, each R2f independently is Ci-Ce alkyl.

[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 R2f independently is Ci-Ce haloalkyl.

[0284] In some embodiments, each R2f independently is Ci-Ce alkoxy.

[0285] In some embodiments, each R2f independently is -CO2(R2g), -CON(R2g)(R2h), or -C(O)-NH(Ci-Ce alkyl-Ci-Ce alkoxy).

[0286] In some embodiments, each R2f independently is -CO2(R2g).

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

[0288] In some embodiments, each R2f independently is -C(O)-NH(Ci-C6 alkyl-Ci-Ce alkoxy).

[0289] In some embodiments, each R2f independently is C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio 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 R2f independently is Ce-Cio aryl.

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

[0294] In some embodiments, each R2f independently is halo, -CN, Ci-Ce alkyl, Ci-Ce alkoxy, -CO2(R2g), C3-C6 cycloalkyl, C6-Cio aryl, Ci-C6 haloalkyl, or -C(O)-NH(Ci-C6 alkyl-Ci-C6 alkoxy).

[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 R2g independently is H.

[0297] In some embodiments, each R2g independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-C10 aryl, or 5- to 10-membered heteroaryl.

[0298] In some embodiments, each R2g independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-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, Ci-Ce alkyl, or Ci-Ce haloalkyl.

[0299] In some embodiments, each R2g independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-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, Ci-Ce alkyl, or Ci-Ce haloalkyl.

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

[0301] In some embodiments, each R2g independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is optionally substituted with one or more halo, Ci-Ce alkyl, or Ci-Ce haloalkyl.

[0302] In some embodiments, each R2g independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy, wherein the alkyl, alkenyl, alkynyl, haloalkyl, or alkoxy is substituted with one or more halo, Ci-Ce alkyl, or Ci-Ce haloalkyl.

[0303] In some embodiments, each R2g independently is Ci-Ce alkyl.

[0304] In some embodiments, each R2g independently is Ci-Ce alkyl optionally substituted with one or more halo, Ci-Ce alkyl, or Ci-Ce haloalkyl.

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

[0306] In some embodiments, each R2g independently is C2-C6 alkenyl.

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

[0308] In some embodiments, each R2g independently is C2-C6 alkenyl substituted with one or more halo, Ci-Ce alkyl, or Ci-Ce haloalkyl.

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

[0310] In some embodiments, each R2g independently is C2-C6 alkynyl optionally substituted with one or more halo, Ci-Ce alkyl, or Ci-Ce haloalkyl.

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

[0312] In some embodiments, each R2g independently is Ci-Ce haloalkyl.

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

[0314] In some embodiments, each R2g independently is Ci-Ce haloalkyl substituted with one or more halo, Ci-Ce alkyl, or Ci-Ce haloalkyl.

[0315] In some embodiments, each R2g independently is Ci-Ce alkoxy.

[0316] In some embodiments, each R2g independently is Ci-Ce alkoxy optionally substituted with one or more halo, Ci-Ce alkyl, or Ci-Ce haloalkyl.

[0317] In some embodiments, each R2g independently is Ci-Ce alkoxy substituted with one or more halo, Ci-Ce alkyl, or Ci-Ce haloalkyl.

[0318] In some embodiments, each R2g independently is C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl.

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

[0320] In some embodiments, each R2g independently is C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with one or more halo, Ci-Ce alkyl, or Ci-Ce haloalkyl.

[0321] In some embodiments, each R2g independently is C3-C6 cycloalkyl.

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

[0323] In some embodiments, each R2g independently is C3-C6 cycloalkyl substituted with one or more halo, Ci-Ce alkyl, or Ci-Ce haloalkyl.

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

[0325] In some embodiments, each R2g independently is 5- to 10-membered heterocyclyl optionally substituted with one or more halo, Ci-Ce alkyl, or Ci-Ce haloalkyl.

[0326] In some embodiments, each R2g independently is 5- to 10-membered heterocyclyl substituted with one or more halo, Ci-Ce alkyl, or Ci-Ce haloalkyl.

[0327] In some embodiments, each R2g independently is Ce-Cio aryl.

[0328] In some embodiments, each R2g independently is Ce-Cio aryl optionally substituted with one or more halo, Ci-Ce alkyl, or Ci-Ce haloalkyl.

[0329] In some embodiments, each R2g independently is Ce-Cio aryl substituted with one or more halo, Ci-Ce alkyl, or Ci-Ce haloalkyl.

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

[0331] In some embodiments, each R2g independently is 5- to 10-membered heteroaryl optionally substituted with one or more halo, Ci-Ce alkyl, or Ci-Ce haloalkyl.

[0332] In some embodiments, each R2g independently is 5- to 10-membered heteroaryl substituted with one or more halo, Ci-Ce alkyl, or Ci-Ce haloalkyl.

[0333] In some embodiments, each R2g independently is H or Ci-Ce alkyl.

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

[0335] In some embodiments, each R2h independently is H.

[0336] In some embodiments, each R2h independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl.

[0337] In some embodiments, each R2h independently is Ci-Ce alkyl.

[0338] In some embodiments, each R2h independently is C2-C6 alkenyl.

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

[0340] In some embodiments, each R2h independently is Ci-Ce haloalkyl.

[0341] In some

[0345] In some embodiments, R3 is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl.

[0346] In some embodiments, R3 is Ci-Ce alkyl.

[0347] In some embodiments, R3 is C2-C6 alkenyl.

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

[0349] In some embodiments, R3 is Ci-Ce haloalkyl.

[0350] In some embodiments, R3 is C3-C10 cycloalkyl 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, R3 is Ci-Ce alkyl or C3-C10 cycloalkyl.

[0354] In some embodiments, R3 is -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, R3 is -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 (Il-a): (R3> (Il-a), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0366] In some embodiments, the compound of Formula (II) is of Formula (II-b): (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 (Il-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): Rt / MN (III), or a pharmaceutically acceptable salt thereof, wherein: Ri is C6-Cio aryl optionally substituted with one or more Ria; each Ria independently is halo, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, or Ci-Ce alkoxyl; R2 is -C(O)R2a; R2a is Ci-Ce 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, Ce-Cio aryl, or 5- to 10-membered heteroaryl; each R2c independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl; each R2d independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl; R3 is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 5- to 10-membered heterocyclyl; and n is 0, 1, 2, 3, or 4.

[0373] In some embodiments, Ri is Ce-Cio aryl substituted with one or more Ria.

[0374] In some embodiments, Ri is Ce-Cio aryl.

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

[0376] In some embodiments, Ri is phenyl substituted with one or more Ria.

[0377] In some embodiments, Ri is phenyl substituted with one Ria.

[0378] In some embodiments, Ri is phenyl substituted with two Ria.

[0379] In some embodiments, Ri is phenyl substituted with three Ria.

[0380] In some embodiments, each Ria independently is halo, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, or Ci-Ce alkoxyl.

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

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

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

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

[0385] In some embodiments, each Ria independently is Ci-Ce alkyl.

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

[0387] In some embodiments, each Ria independently is C2-C6 alkenyl.

[0388] In some embodiments, each Ria independently is C2-C6 alkynyl.

[0389] In some embodiments, each Ria independently is Ci-Ce haloalkyl.

[0390] In some embodiments, each Ria independently is Ci-Ce alkoxyl.

[0391] In some embodiments, each Ria independently is methoxy.

[0392] In some embodiments, Ri is              .

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

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

[0395] In some embodiments, R2a is Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkenyl, or alkynyl is substituted with one or more R2b.

[0396] In some embodiments, R2a is Ci-Ce alkyl.

[0397] In some embodiments, R2a is Ci-Ce alkyl optionally substituted with one or more R2b.

[0398] In some embodiments, R2a is Ci-Ce alkyl substituted with one or more R2b.

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

[0400] In some embodiments, R2a is C2-C6 alkenyl optionally substituted with one or more R2b.

[0401] In some embodiments, R2a is C2-C6 alkenyl 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, R2a is C2-C6 alkynyl 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, R2a is

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

[0410] In some embodiments, each R2b independently 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 R2b independently is -CO2(R2c).

[0414] In some embodiments, each R2b independently is C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, Ce-Cio 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 Ce-Cio aryl.

[0418] In some embodiments, each R2b independently 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 is or

[0421] In some embodiments, each R2c independently is H.

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

[0423] In some embodiments, each R2c independently is Ci-Ce alkyl.

[0424] In some embodiments, each R2c independently 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 R2c independently is Ci-Ce haloalkyl.

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

[0429] In some embodiments, each R2d independently is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl.

[0430] In some embodiments, each R2d independently is Ci-Ce alkyl.

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

[0432] In some embodiments, each R2d independently is C2-C6 alkenyl.

[0433] In some embodiments, each R2d independently is C2-C6 alkynyl.

[0434] In some embodiments, each R2d independently is Ci-Ce haloalkyl. 0

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

[0437] In some embodiments, R3 is Ci-Ce alkyl.

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

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

[0440] In some embodiments, R3 is Ci-Ce haloalkyl.

[0441] In some embodiments, R3 is C3-C10 cycloalkyl or 5- to 10-membered heterocyclyl.

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

[0443] In some embodiments, R3 is 5- to 10-membered heterocyclyl.

[0444] In some embodiments, R3 is Ci-Ce alkyl or C3-C10 cycloalkyl.

[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 (Ill-a): (Ill-a), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0449] In some embodiments, the compound of Formula (III) is of Formula (Ill-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. Compound No. Structure Compound Name 1 Cl-O HN 7-acryloyl-N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 2 o t N-(2-chlorophenyl)-7-propioloyl-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 3 cX) HN 7-(but-2-ynoyl)-N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide 4 Q t (E)-N-(2-chlorophenyl)-7-(4-(dimethylamino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 5 a-Q H'Co (E)-N-(2-chlorophenyl)-7-(4-morpholinobut-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 6 ci-Q HCo Ns (E)-N-(2-chlorophenyl)-7-(4-(pyrrolidin-l-yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 7 Q 0 L M) (E)-N-(2-chlorophenyl)-7-(4-(piperidin-l-yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 8 C,X) HCo methyl (E)-4-(3-((2-chlorophenyl)carbamoyl)-5,6-dihydroimidazo[l,2-a]pyrazin-7(8H)-yl)but-2-enoate 9 ci-XT^ HCo Ns (E)-N-(2-chlorophenyl)-7-(4-methoxybut-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 10 ClX) HN \^0 । A (E)-N-(2-chlorophenyl)-7-(4-(cyclopropyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 11 Cl-O HN y^O A h         o (E)-N-(2-chlorophenyl)-7-(4-(phenylamino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 12 Cl-O HN p. N        N xCr^    o (E)-N-(2-chlorophenyl)-7-(4-(3 -methoxyazetidin-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 13 / \ w x I (S,E)-N-(2-chlorophenyl)-7-(4-(3-hydroxypyrrolidin-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 14 p o p ? (E)-N-(2-chlorophenyl)-7-(4-phenoxybut-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 15 HCo F / x                     / n N          N      N h      O (E)-N-(2-chlorophenyl)-7-(4-((4-fluorophenethyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 16 Cl-O HN y^0 nA (E)-7-(4-(azetidin-1 -yl)but-2-enoyl)-N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 17 ciA) HN yO P^N A ^N-^YN^r? । A (E)-N-(2-chlorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8 -tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide Compound No. Structure Compound Name 18 \ o IZ O (E)-N-(2-chlorophenyl)-7-(4-((2-methoxyethyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide 19 I (R,E)-N-(2-chlorophenyl)-7-(4-(3-hydroxypyrrolidin-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 20 ciUQ HN H             (!) (E)-N-(2-chlorophenyl)-7-(4-(cyclopropylamino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide 21 Cl-O HN y^O ^■N-^ HN          A (E)-N-(2-chlorophenyl)-7-(4-(piperazin-l-yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 22 ciA) HrCo a as An / ^ynxJ^n^ 1                 <5 (E)-N-(2-chlorophenyl)-7-(4-(methyl(phenyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide 23 CI^O ^Lo / --1           r^N-<( i A (E)-N-(2-chlorophenyl)-7-(4-(cyclopentyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide Compound No. Structure Compound Name 24 Cl-O HN 1           r^N Ns । A (E)-7-(4-(tert-butyl(methyl)amino)but-2-enoyl)-N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 25 Cl-O HN y^o r^N N\ N         N (E)-N-(2-chlorophenyl)-7-(4-thiomorpholinobut-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 26 r o 8- tert-butyl (E)-N-(4-(3-((2-chlorophenyl)carbamoyl)-5,6-dihydroimidazo[l,2-a]pyrazin-7(8H)-yl)-4-oxobut-2-en-l-yl)-N-methylglycinate 27 o a., o (E)-N-(4-(3-((2-chlorophenyl)carbamoyl)-5,6-dihydroimidazo[l,2-a]pyrazin-7(8H)-yl)-4-oxobut-2-en-l-yl)-N-methylglycine 28 CI^O HN y=° -y N          N      N । A (E)-N-(2-chlorophenyl)-7-(4-((2-methoxyethyl)(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 29 a HrCo v 1 (E)-N-(2-chlorophenyl)-7-(4-((cyclopropylmethyl)(methyl)amino)b ut-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 30 ClX) HN N         N F^7    0 (E)-N-(2-chlorophenyl)-7-(4-(3 -fluoroazetidin-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 31 Cl-O HN y-0 N (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 32 ClX) HN | / ^'N (E)-7-(4-(benzylamino)but-2-enoyl)-N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 33 c.X) HN y^o I^n ^JN     N ^^N (E)-N-(2-chlorophenyl)-7-(4-(isoindolin-2-yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 34 ci-Q H C° I^^N-y F-l^l     0 (E)-N-(2-chlorophenyl)-7-(4-(4,4-difluoropiperidin-1 -yl)but-2-enoyl) -5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 35 r £ IZ o / (E)-N-(2-chlorophenyl)-7-(4-((2-((2-methoxyethyl)amino)-2-oxoethyl)(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide Compound No. Structure Compound Name 36 Cl HN N          N I tert-butyl (E)-4-(4-(3-((2-chlorophenyl)carbamoyl)-5,6-dihydroimidazo[l,2-a]pyrazin-7(8H)-yl)-4-oxobut-2-en-1 -yl)piperazine-1 -carboxylate 37 ci-^CZ^ HCo (E)-7-(4-( IH-imidazol-1 -yl)but-2-enoyl)-N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 38 ci-^2^ HCo / ¾^              N-"^ N         N (E)-7-(4-( IH-benzo [d] imidazol-1 -yl)but-2-enoyl)-N-(2-chlorophenyl)-5,6,7,8 -tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide 39 1           & (E)-N-(2-chlorophenyl)-7-(4-((2-fluoroethyl)(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 40 Cl— HfCo r^N^ F^^    0 (E)-N-(2-chlorophenyl)-7-(4-(3,3-difluoroazetidin-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide Compound No. Structure Compound Name 41 HrCo (E)-N-(2-chlorophenyl)-7-(4-(3 -cyanoazetidin-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 42 Up H,Co H fl (E)-N-(2-chlorophenyl)-7-(3 -(pyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 43 Cl-O - of (E)-N-(2-chlorophenyl)-7-(4-((2,2,2-trifluoroethyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 44 Cl-O HN v^o (E)-N-(2-chlorophenyl)-7-(4-(methyl(2,2,2-trifluoroethyl)amino)but-2-enoyl)-5,6,7,8 -tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide 45 ci4p H\o H A (E)-N-(2-chlorophenyl)-7-(4-(cyclobutylamino)but-2-enoyl)-5,6,7,8 -tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide Compound No. Structure Compound Name 46 a-Q HICo (E)-7-(4-( 1,4-diazepan-1 -yl)but-2-enoyl)-N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 47 o 1 Q r T (E)-N-(2-chlorophenyl)-7-(4-hydroxybut-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 48 ___ o __o (E)-N-(2-chlorophenyl)-7-(4-(3 -isopropoxyazetidin-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 49 cUp HN yo i (E)-N-(2-chlorophenyl)-7-(3 -(1-methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 50 c.4p HN >0 / —.     r^N\ h        n (E)-N-(2-chlorophenyl)-7-(3 -(pyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 51 CI'O HN tert-butyl (7R)-4-[(E)-4-[3-[(2- chlorophenyl)carbamoyl] -6,8-dihydro-5H-imidazo[l,2-a]pyrazin-7-yl]-4-oxo-but-2-enyl]-7-methyl-l,4-diazepane -1 -carboxylate 52 '0 o t (E)-N-(2-chlorophenyl)-7-(4-(4-methyl-1,4-diazepan-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 53 ' r b (E)-7-(4-(benzyloxy)but-2-enoyl)-N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 54 ciUp HICo tert-butyl (E)-4-(4-(3-((2-chlorophenyl)carbamoyl)-5,6-dihydroimidazo[l,2-a]pyrazin-7(8H)-yl)-4-oxobut-2-en-1 -yl)-1,4-diazepane-1 -carboxylate 55 0 i (E)-N-(2-chlorophenyl)-7-(4-(diethylamino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 56 Cl-O HN N ^\^Y N ।           d (E)-N-(2-chlorophenyl)-7-(4- (cyclobutyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 57 ClX) HN y^o H        n (E)-7-(4-(bicyclo[l. 1. l]pentan-1-ylamino)but-2-enoyl)-N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 58 f — z 0 i (E)-N-(2-chlorophenyl)-7-(4-((2-cyanoethyl)(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 59 \ ( / ) / Q ? O (S,E)-N-(2-chlorophenyl)-7-(3-(piperidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 60 ci-^C^ HrCo X / '"' N XX N N<^   |       J (E)-N-(2-chlorophenyl)-7-(4-((cyanomethyl)(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 61 .X) HCo i         r"N y xx N H         D (E)-7-(4-(tert-butylamino)but-2-enoyl)-N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 62 HCo L abu       n jLk / H      0 (R,E)-N-(2-chlorophenyl)-7-(3-(piperidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 63 ClX) HN y^o H s (E)-N-(2-chlorophenyl)-7-(4-(methylamino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 64 Cl-O HN >0 \ / । <!) (E)-N-(2-chlorophenyl)-7-(4-(dimethylamino)-4-methylpent-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 65 ___ o yy o \ / z (E)-N-(2-chlorophenyl)-7-(3 -(1-methylpiperidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 66 Q . 1 o (E)-N-(2-chlorophenyl)-7-(3 -(1-methylpiperidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide Compound No. Structure Compound Name 67 ciZ) HfCo I^n-4 -'abs F (R,E)-N-(2-chlorophenyl)-7-(4-(3-fluoropyrrolidin-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 68 7 W \ / 0 i M) (S,E)-N-(2-chlorophenyl)-7-(4-(3-fluoropyrro lidin-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 69 0 L (E)-7-(4-(4-acetyl-1,4-diazepan-1 -yl)but-2-enoyl)-N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide 70 o .....Q (E)-N-(2-chlorophenyl)-7-(4-(3 -methoxyazetidin-1 -yl)but-2-enoyl)-8-methyl-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 71 ci-X) HCo r^N-A H s (E)-N-(2-chlorophenyl)-7-(4-((2-cyanoethyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide Compound No. Structure Compound Name 72 IZ p « (E)-N-(2-chlorophenyl)-7-(4-((cyanomethyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide 73 Cl-O HN । fl (E)-7-(4-(bicyclo[l. 1. l]pentan-1-yl(methyl)amino)but-2-enoyl)-N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 74 Cl-O HN x^o / 0V\ । fl N-(2-chlorophenyl)-7-((E)-4-(((lr,3r)-3-methoxycyclobutyl)(methyl)amino)bu t-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 75 -0 w ra ? (R,E)-7-(3-(azetidin-2-yl)acryloyl)-N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 76 aX) HfCo r—A        |^^N-<( \ \abs         Ji 1 y HN^S^x- N (S,E)-7-(3-(azetidin-2-yl)acryloyl)-N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 77 a-O HCo F                             / Fx< N     N "^N H        D (E)-N-(2-chlorophenyl)-7-(4-((3,3-difluorocyclobutyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide Compound No. Structure Compound Name 78 C,X) F                              / n         N 1                 <5 (E)-N-(2-chlorophenyl)-7-(4-((3,3 -difluorocyclobutyl)(methyl)amino)but -2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 79 X HN \=° o < >   XH 1 &1X         N JL- / h      0 (E)-N-(2-chlorophenyl)-7-(3 -(morpholin-3-yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 80 ;7n w ra ? (R,E)-N-(2-chlorophenyl)-7-(3 -(1 -methylazetidin-2-yl)acryloyl) -5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 81 ■7 s w w / (S,E)-N-(2-chlorophenyl)-7-(3-(l-methylazetidin-2-yl)acryloyl) -5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 82 HCo l^N N\ H A (E)-N-(2-chlorophenyl)-7-(4-(ethylamino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 83 ClX) HN X^N -< h        n (E)-N-(2-chlorophenyl)-7-(4-((2-fluoroethyl)amino)but-2-enoyl)-5,6,7,8 -tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide Compound No. Structure Compound Name 84 Cl-O HN yO I abk        k / i           8 (R,E)-N-(2-chlorophenyl)-7-(3-(4-methylmorpholin-3 -yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 85 ClX) HICo rk   kN^C I abU         kk7 I           8 (S,E)-N-(2-chlorophenyl)-7-(3-(4-methylmorpholin-3 -yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 86 r \« / ZI (S,E)-N-(2-chlorophenyl)-7-(3-(2-methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 87 / Q)\ J mF, Q t O (S,E)-N-(2-chlorophenyl)-7-(3-(l,2-dimethylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 88 \ ZI Q ? O (E)-N-(2-chlorophenyl)-7-(5 -(methylamino)pent-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 89 ___ o - Q (E)-N-(2-chlorophenyl)-7-(4-((l-methylcyclobutyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide Compound No. Structure Compound Name 90 ci— HfCo / \      ^'N— । A (E)-N-(2-chlorophenyl)-7-(4-(methyl(l-methylcyclobutyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 91 Cl-O HN \=° / 0V\ 1 fl N-(2-chlorophenyl)-7-((E)-4-(((ls,3s)-3-methoxycyclobutyl)(methyl)amino)bu t-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 92 .....\ Q «r- (E)-N-(2-chlorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-8-methyl-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 93 IZ / Q)\__J 0 i (R,E)-N-(2-chlorophenyl)-7-(3-(2-methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 94 ci— HN _ r / --i       ^-N—k /                        (fl. (R,E)-N-(2-chlorophenyl)-7-(3-(l,2-dimethylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide Compound No. Structure Compound Name 95 Cl-Xx) f      <0 H A N-(2-chlorophenyl)-7-((E)-3 -((4R)-4-fluoropyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 96 ___ o N-(2-chlorophenyl)-7-((E)-3 -((4S)-4-fluoropyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 97 C,X) HICo । l?1 N JL / I A (E)-N-(2-chlorophenyl)-7-(4-(dimethylamino)pent-2-enoyl)-5,6,7,8 -tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide 98 Cl-O HN >0 f^N (E)-7-(4-(azetidin-1 -yl)but-2-enoyl)-N-(2-chlorophenyl)-8-methyl-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 99 HCo । > N jO (E)-7-(4-aminopent-2-enoyl)-N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 100 Cl-O HN F              \=O 1               (¾ 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 101 __ o o      \    / X—z 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 102a c.4p HN —O Ns N        N 1 A 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 102b Cl-O -o        H'C N        N /         J N-(2-chlorophenyl)-7-((E)-3 -((4S)-4-methoxy-1 -methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 103 CI^T) HN y-O "\s c- N         N o (E)-N-(2-chlorophenyl)-7-(4-(3 -methoxyazetidin-1 -yl)but-2-enoyl)-6-methyl-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 104 HfCo (E)-N-(2-chlorophenyl)-7-(5 -(dimethylamino)pent-2-enoyl)-5,6,7,8 -tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide 105 ci-Q H,Co । (E)-N-(2-chlorophenyl)-7-(5 -(ethyl(methyl)amino)pent-2-enoyl)-5,6,7,8 -tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide 106 Z\ J IZ / /   \      o V O N-(2-chlorophenyl)-7-((E)-3 -((4R)-4-methoxypyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 107 / ==^,,01 CI-'XJ / HN \=° / —।     ^'N'A \ Jabs      N Jk / /               fl (R,E) -N-(2,5 -dichlorophenyl)-7-(3-(1 -methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 108 Cl-O HN _ r N-(2-chlorophenyl)-7-(pent-2-ynoyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 109 ci- / ^ HN 1—.     ^^nX H           U | N-(2-chlorophenyl)-8-methyl-7-((E)-3-(pyrro lidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 110 Cl-O H,C / —\ / \abs         J.      | y 1                ft 1 N-(2-chlorophenyl)-8-methyl-7-((E)-3 -((R) -1 -methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 111 HN N          N । fl (E)-N-(2,5-dichlorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 112 1 o (E)-N-(2-chlorophenyl)-7-(4-(3 -(difluoromethyl)azetidin-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 113 / (E)-N-(2-chlorophenyl)-7-(4-(3 -methoxy-3 -methylazetidin-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 114 Cl-O HN >0 |^^N -4 $ (S,E)-N-(2-chlorophenyl)-7-(4-(2-methyl-1,4-diazepan-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 115 Cl-O HN N (E)-N-(2-chlorophenyl)-7-(4-(4-ethyl-1,4-diazepan-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide 116 HN \=° । fl (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 117 a^p NH v^O / --.          N^ (E)-N-(2-chlorophenyl)-7-(3 -(1-isopropylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 118 d-Q HICo \\ 1 fl (E)-N-(2-chlorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-6-methyl-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 119a Cl-O HN v-o "ty fl (R,E)-N-(2-chlorophenyl)-7-(4-(5-methyl-1,4-diazepan-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 119b ciX) HN ■XJ 8 (S,E)-N-(2-chlorophenyl)-7-(4-(5-methyl-1,4-diazepan-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 120 X HICo p- N        N 0 1 (E)-N-(2-chlorophenyl)-7-(4-(3 -(dimethylamino)azetidin-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 121 HCo C- N         N L--J abs        q (S,E)-N-(2-chlorophenyl)-7-(4-(2-methylazetidin-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 122 Cl-O HN x^o N N (E)-N-(2-chlorophenyl)-7-(4-(4-isobutyl-1,4-diazepan-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 124 Cl ciUu* HICo l^N Xs 1           d (E)-N-(2,4-dichlorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide Compound No. Structure Compound Name 125 Cl-O HN / —xn / x^xxn^^n^ (S,E)-N-(2-chlorophenyl)-7-(4-(2,4-dimethyl-1,4-diazepan-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 126 Cl-O HN yo / —\      <^n-\ /    \&1         M     I 7 N ^^n' (E)-N-(2-chlorophenyl)-7-(3 -(1-ethylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 127 z — / "Q X N-(2-chlorophenyl)-7-((E)-4-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2( lH)-yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 128 o X — / \ "Q \ N-(2-chlorophenyl)-7-((E)-4-((3aR,6aS)-5-methylhexahydropyrrolo [3,4-c]pyrrol-2( lH)-yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 129 f^4# o 7 ^NH ^N'^MxyNxyr / 1 fl (E)-N-(5-chloro-2-fluorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 130 Cl O / ^NH OA 1 fl (E)-N-(4-chloro-2-fluorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide Compound No. Structure Compound Name 131 ci-c5 o / -y-NH l^N N          N । A (E)-N-(2-chloro-4-methylphenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 132 °y^cl 1            0 (E)-N-(2-chloro-6-methoxyphenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 133 Cl f--^^ o ? y-NH N      N \^l / । A (E)-N-(3-chloro-2-fluorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 134 F ci-c5 o / y_NH l^N Xs N          N ।                       <!J (E)-N-(2-chloro-4-fluorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 135 Cl o / ^nh N          N 1 ¢) (E)-N-(2,3-dichlorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 136 yx 0    / Vi <^NH u y n4 1           d (E)-N-(2-chloro-3 -methoxyphenyl)-7 -(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 137 yyo x O -^NH N      N xAn ' । A (E)-N-(2-chloro-5 -methoxyphenyl)-7 -(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide Compound No. Structure Compound Name 138 o / NH A^a l fl (E)-N-(2-chloro-5-fluorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 139 aX) o / 'ci ^nh Ul 1 fl (E)-N-(2,6-dichlorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 140 O (Ji P _     z 6 z — (E)-N-(4-chloro-2-methoxyphenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 141 Cl o / ^ ^NH A^A N ZX^' N । A (E)-N-(3 -chloro-2-methoxyphenyl)-7 -(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 142 A, cl"A_-y o / -y-NH A'nA 1 fl (E)-N-(6-chlorobenzo [d] [ 1,3]dioxol-5-yl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 143 AN o y_NH A^m a 1 fl (E)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-N-(thiazol-5-yl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 144 AA ci-Aa o / -y-NH A N          N । fl (E)-N-(4-chloropyridin-3-yl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide Compound No. Structure Compound Name 145 / Yo ci—\ o ^nh 1 fl (E)-N-(5 -chlorobenzo [d] [ 1,3]dioxol-4-yl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 146 Cl o ) ^NH p N      N (E)-N-(3-chloro-2-fluorophenyl)-7-(4-(3 -cyanoazetidin-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 147 F ci^0 0     / -\_NH N          N (E)-N-(2-chloro-4-fluorophenyl)-7-(4-(3 -cyanoazetidin-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 148 / ^\^F CI^YY O ( •^-NH (E)-N-(2-chloro-5-fluorophenyl)-7-(4-(3 -cyanoazetidin-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 149 Cl o-D O / ^NH r- N '"'X^Xx N \ / W (E)-7-(4-(3 -cyanoazetidin-1 -yl)but-2-enoyl)-N-(2,3-dichlorophenyl)-5,6,7,8 -tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide 150 c-Q o, / Yl ^NH p- N         N (E)-7-(4-(3 -cyanoazetidin-1 -yl)but-2-enoyl)-N-(2,6-dichlorophenyl)-5,6,7,8 -tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide 151 Cl Cl o / ^NH (E)-7-(4-(3 -cyanoazetidin-1 -yl)but-2-enoyl)-N-(2,4-dichlorophenyl)-5,6,7,8 -tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide Compound No. Structure Compound Name 152 ryo °y^CI 1 i (E)-N-(4-chlorobenzo [d] [ 1,3]dioxol-5-yl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 153 r- N          N (E)-N-(2-chloro-6-fluorophenyl)-7-(4-(3 -cyanoazetidin-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 154 Cl-O o / △     y-NH '"AAA N     N ^AA । (E)-N-(2-chlorophenyl)-6-cyclopropyl-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide 155 o Al H         H >O N                    / < >    A'NA N ^A| / (E)-N-(2-chlorophenyl)-7-(3 -(piperidin-3 -yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 156 Q A A"NH    x^NA 1 &1J _        L / (E)-N-(2-chlorophenyl)-7-(3 -(piperidin-2 -yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 157 Q A^N ^AA (E)-N-(2-chlorophenyl)-7-(3 -(morpholin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 158 o H^CI (S,E)-N-(2-chlorophenyl)-7-(3-(morpholin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 159a H& ^-0 (S,E)-N-(2-chlorophenyl)-7-(3-(4-methylmorpholin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 159b Ko        \\ (R,E)-N-(2-chlorophenyl)-7-(3-(4-methylmorpholin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 160 F ci-^O HN ^r° । A (E)-N-(2-chloro-3-fluorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 161 n-^. __( / y NH / --,           N X 1               ft (E)-N-(2-methylpyridin-3 -yl)-7-(3-(1 -methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 162a Cl-O HICo 9^9? N-(2-chlorophenyl)-8-methyl-7-((E)-3-((S)-pyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide 162b CI-9A HN ( Jabs / . Jw H         A 1 N-(2-chlorophenyl)-8-methyl-7-((E)-3-((R)-pyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 163 Cl ci-c5 HN / —\      <^N-< i fl (E)-N-(2,4-dichlorophenyl)-7-(3-(l-methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 164 Cl-O H,Co N-(2-chlorophenyl)-8-methyl-7-((E)-3-(1 -methylpyrrolidin-2-yl)acryloyl)-5,6,7,8 -tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide 165 Cl-O HN yO A cA l absJ          N         / H        D (S,E)-N-(2-chlorophenyl)-7-(3-(morpholin-3 -yl)acryloyl)-5,6,7,8 -tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 166 o 0     / 'ci y_NH u f i^N A (Z)-N-(2-chlorophenyl)-7-(2-fluorobut-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 167 4 o Co IZ 7-aery loyl-N-(2-chloro-5 -((3 -(trifluoromethyl)phenyl)carbamoyl)p henyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 168 0    __ "Co F F । r'rC ^Yn^n? N-(2-chloro-5-((3-(trifluoromethyl)phenyl)carbamoyl)p henyl)-7-methacryloyl-5,6,7,8 -tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 169 0   __ F "Co F F r'^N'C N-(2-chloro-5-((3-(trifluoromethyl)phenyl)carbamoyl)p henyl)-7 -propioloyl-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 170 O    __ oi-O'C'Qf "Co     F F 7-(but-2-ynoyl)-N-(2-chloro-5 -((3-(trifluoromethyl)phenyl)carbamoyl)p henyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 171 F R / F HN O=V-x o HN^31 v-o (E)-7-(but-2-enoyl)-N-(2-chloro-5-((3-(trifluoromethyl)phenyl)carbamoyl)p henyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide Compound No. Structure Compound Name 172 cX) 0 Hh0o 5-(but-2-ynoyl)-N-(2-chlorophenyl)-4,5,6,7-tetrahydropyrazolo [1,5-a]pyrazine -3 -carboxamide 173 cX) \^N    A     J (E)-N-(2-chlorophenyl)-5-(4-(pyrrolidin-1 -yl)but-2-enoyl)-4,5,6,7-tetrahydropyrazolo [ 1,5 -a] pyrazine-3 -carboxamide 174 ___o 0=^ V N-(2-chlorophenyl)-5-propioloyl-4,5,6,7-tetrahydropyrazolo [1,5-a]pyrazine-3-carboxamide 175 Q^JO” (E)-N-(2-chlorophenyl)-5-(4-(piperidin-l-yl)but-2-enoyl)-4,5,6,7-tetrahydropyrazolo [ 1,5 -a] pyrazine-3 -carboxamide 176 ci o Hyo 5-acryloyl-N-(2-chlorophenyl)-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine -3 -carboxamide 177 ci-^C2^ 1       0     H \A> N ___ X    J (E)-N-(2-chlorophenyl)-5-(4-(dimethylamino)but-2-enoyl)-4,5,6,7-tetrahydropyrazolo [ 1,5 -a] pyrazine-3 -carboxamide Compound No. Structure Compound Name 178 (S,E)-N-(2-chlorophenyl)-7-(3-(l-(3,3,3 -trifluoropropyl)pyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 179 (R,E)-N-(2-chlorophenyl)-7-(3 -(1(3,3,3 -trifluoropropyl)pyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 180a 180b (R,E)-N-(2-chlorophenyl)-7-(3 -(4-(trifluoromethyl)morpholin-3 -yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide (S,E)-N-(2-chlorophenyl)-7-(3-(4-(trifluoromethyl)morpholin-3 -yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide Compound No. 181a 181b 182a Structure Compound Name (R,E)-N-(2-chlorophenyl)-7-(3 -(4(3,3,3 -trifluoropropyl)morpholin-3 -yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide (S,E)-N-(2-chlorophenyl)-7-(3-(4-(3,3,3 -trifluoropropyl)morpholin-3 -yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide (R,E)-N-(2-chlorophenyl)-7-(3 -(4-(2-cyanoethyl)morpholin-3-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide Compound No. Structure Compound Name 182b o Hbl01 Ck N J fH J (S,E)-N-(2-chlorophenyl)-7-(3-(4-(2-cyanoethyl)morpholin-3-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 183a 0 / \       N C<                    \ 1                                                        / 7 L n                 L a~~^\ (R,E)-N-(2-chlorophenyl)-7-(3 -(4-cyclobutylmorpholin-3-yl)acryloyl)-5,6,7,8 -tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide 183b 0 / \       N \ 1        ^H           1              / 7 Ln       L   n_ fl ° V?) (S,E)-N-(2-chlorophenyl)-7-(3-(4-cyclobutylmorpholin-3-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 184a o /       Cl HN ^==^° H ^S. ^x'abs's. N^ 6 (R,E)-N-(2-chlorophenyl)-7-(3 -(4-(2-methoxyethyl)morpholin-3 -yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 184b o /       Cl HN °\ N         / i Y H 1 (S,E)-N-(2-chlorophenyl)-7-(3-(4-(2-methoxyethy l)morpholin-3 -yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 185a 0 N XkT        ।        \ 1                                                       / 7 L n                 L (R,E)-N-(2-chlorophenyl)-7-(3 -(4-(oxetan-3 -yl)morpholin-3 -yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 185b 0 Xx        N       \ 1         ^H            1               / 7 L       n                 L ° v3 (S,E)-N-(2-chlorophenyl)-7-(3-(4-(oxetan-3 -yl)morpholin-3 -yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 186a O /       Cl HN F      H^J \                -Z'abs'S. F^ F (R,E)-N-(2-chlorophenyl)-7-(3 -(4-(2,2,2-trifluoroethyl)morpholin-3-yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide Compound Name (S,E)-N-(2-chlorophenyl)-7-(3-(4-(2,2,2-trifluoroethyl)morpholin-3-yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide (E)-N-(2-chlorophenyl)-7-(4-((2-methoxyethyl)(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide (E)-N-(2-chlorophenyl)-7-(4-(methyl(3,3,3-trifluoropropyl)amino)but-2-enoyl)-5,6,7,8 -tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide Compound No. Structure Compound Name 189 X) Ov NH H. a u (S,E)-7-(4-(azetidin-1 -yl)but-2-enoyl)-N-(2-chlorophenyl)-5-methyl-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide 190 Ov H l L / * N —-hT (R,E)-7-(4-(azetidin-1 -yl)but-2-enoyl)-N-(2-chlorophenyl)-5-methyl-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide 191 Q / n unumA?       / ° / (S,E)-7-(4-(azetidin-1 -yl)but-2-enoyl)-N-(2-chlorophenyl)-8-methyl-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide 192 1     ^Cl HN rr^V (R,E)-7-(4-(azetidin-1 -yl)but-2-enoyl)-N-(2-chlorophenyl)-8-methyl-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide Compound No. Structure Compound Name 193 A Cl ' rb H S' NZ            O z \ (R,E)-N-(2-chlorophenyl)-7-(4-(ethyl(methyl)amino)pent-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide 194 HN ° CP 1 H / S' hr                o z \ (S,E)-N-(2-chlorophenyl)-7-(4-(ethyl(methyl)amino)pent-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 195 Cl—'"'"'n.         / HN --.              f hr         \ H                               1         z ' ' \ / (R,E)-N-(2-chlorophenyl)-7-(3 -(1-methylpyrrolidin-3 -yl)acryloyl) -5,6,7,8-tetrahydroimidazo[l,2-a] pyrazine -3 -carboxamide 196 FX ----A.       / HN ^===° --1 \ / I H                       1       V (S,E)-N-(2-chlorophenyl)-7-(3-(l-methylpyrrolidin-3 -yl)acryloyl) -5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 197 / A ci—-\ / HN (R,E)-N-(2-chlorophenyl)-7-(3 -(1-isopropylpyrrolidin-3-yl)acryloyl)-5,6,7,8 -tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide 198 ci—■—X      / HN \               --1                        \ \ y i h                  1     7 /   \               N          / /                 \z  "N (S,E)-N-(2-chlorophenyl)-7-(3-(l-isopropylpyrrolidin-3-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 199 Cl-— / HN \ ^N"— \< /      1 H                       1       7 \            N        / / I iH (S)-N-(2-chlorophenyl)-8-methyl-7-((E)-3 -((R) -1 -methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 200 A ^Cl °. NH k (S,E)-N-(2-chlorophenyl)-7-(3-(l-cyclopropylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide Compound No. 201 202a 202b Structure Compound Name (R,E)-N-(2-chlorophenyl)-7-(3 -(1-cyclopropylpyrrolidin-2-yl)acryloyl)-5,6,7,8 -tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide (S,E)-N-(2-chlorophenyl)-7-(3-(l-phenylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide (R,E)-N-(2-chlorophenyl)-7-(3 -(1-phenylpyrrolidin-2-yl)acryloyl)-5,6,7,8 -tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide Compound No. Structure Compound Name 203 HN.     o Ns i h        ✓ (S,E)-N-(2-chlorophenyl)-7-(4-(dimethylamino)pent-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine -3 -carboxamide 204 HN.     o 's (R,E)-N-(2-chlorophenyl)-7-(4-(dimethylamino)pent-2-enoyl)-5,6,7,8 -tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide 205 o / I Bob o (R,E)-N-(2-chlorophenyl)-7-(4-(pyrrolidin-1 -yl)pent-2-enoyl)-5,6,7,8 -tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide 206 Cl‘,****,,\ HN \_^-0 1 ‘ co z^*N           Il (S,E)-N-(2-chlorophenyl)-7-(4-(pyrrolidin-1 -yl)pent-2-enoyl)-5,6,7,8 -tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide Compound No. Structure Compound Name 207 ClUQ HN r^N (E)-N-(2-chlorophenyl)-7-(4-(3 -ethoxyazetidin-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine -3 -carboxamide 208 a-O HN / ° / 0 / '                           xs JV-(2-chlorophenyl)-7-((E)-4-(((lr,3r)-3 -methoxy cyclobutyl)(methyl) amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo [ 1,2-a]pyrazine-3 -carboxamide 209 up o    H \=O 1 I^N^ JV-(2-chlorophenyl)-5-methacryloyl-4,5,6,7-tetrahydropyrazolo [1,5-a]pyrazine-3-carboxamide 210 cr-yj "Vo tert-butyl N-[2-[2-[2-[[(E)-4-[3-[(2-chlorophenyl)carbamoyl] -6,8-dihydro-5H-imidazo[l,2-a]pyrazin-7-yl] -4-oxo-but-2-enyl] -methylamino] ethoxy] ethoxy] ethyl] carbamat e 211 / q / < ( > - / ''> / <x ( > Q ) 7-[(E)-4-[2-[2-(2-aminoethoxy)ethoxy]ethyl-methyl-amino]but-2-enoyl]-N-(2-chlorophenyl)-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Table 2. Compound No. Structure Compound Name 212 rVci HN / —.      r^N-A N "^x^\x N x / ^N 1 (E)-N-(2,5-dichlorophenyl)-7-(3-(l-methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 213 Cl HN y^o 1         i (E)-N-(2,4-dichlorophenyl)-7-(3-(l-methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide. 214 F Cl"^^ HN y^O / ^N (E)-N-(2-chl oro-3 -fluorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 215 c'Q HN y^o N HN^^J       O    2HCI N-(2-chlorophenyl)-7-[(E)-4-piperazin-l-ylbut-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide dihydrochloride 215a c.4p °y~NH HN          0 N-(2-chlorophenyl)-7-[(E)-4-piperazin-l-ylbut-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 216 cX) Xo hci 1                    <y> (E)-N-(2-chlorophenyl)-7-(4-(dimethylamino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide hydrochloride 216a ciXX Anh i {J (E)-N-(2-chlorophenyl)-7-(4-(dimethylamino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 217 cy HN y° k 1        N J^kZ N N-(2-chlorophenyl)-7-[(E)-4-phenoxybut-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carb oxamide 218 Cl\_ □X Y^n YNA 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 219 - O o \ / / z Y z N-(2-chloro-4-fluoro-phenyl)-7-[(E)-4- (3-cyanoazetidin-1 -yl)but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 220 a4?rF yX -4 N-(2-chl oro-5 -fluoro-phenyl)-7-[(E)-4-(3 -cyanoazetidin-1 -yl)but-2-enoyl] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 221 Cl CI-O 7-[(E)-4-(3-cyanoazetidin-l-yl)but-2-enoyl]-N-(2,3-dichlorophenyl)-6,8- dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 222 c|-O yrV01 yN^\^y<   N 7-[(E)-4-(3-cyanoazetidin-l-yl)but-2-enoyl]-N-(2,6-dichlorophenyl) -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 223 Cl y^ \s N J-W N 7-[(E)-4-(3-cyanoazetidin-l-yl)but-2-enoyl] -N-(2,4-dichlorophenyl)-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 224 yiTci ___ N yN^^^y   N N-(2-chloro-6-fluoro-phenyl)-7-[(E)-4-(3 -cyanoazetidin-1 -yl)but-2-enoyl] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 225 Cl- / ^ HN >0 H      0 N-(2-chlorophenyl)-7-[(E)-4-(ethylamino)but-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 226 CI-AQ 0    ? cf3cooh        V-NH PA h      0 N-(2-chlorophenyl)-7-[(E)-4-(2-fluoroethy 1 amino)but-2-enoy 1 ] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3-carboxamide trifluoroacetic acid 226a ci- / ^ °y_NH l^N \\ h      0 N-(2-chlorophenyl)-7-[(E)-4-(2-fluoroethy 1 amino)but-2-enoy 1 ] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3-carboxamide 227 HN r PN \\ h       0 N-(2-chlorophenyl)-7-[(E)-4-(methylamino)but-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 228 IZ^ Z— / \ 0 PyP) 0 N-(2-chlorophenyl)-7-[(E)-4-[(l-methylcyclobutyl)amino]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 229 Cl-O HN r I^N-A 7 ft (E)-N-(2-chlorophenyl)-7-(3-(l-methylazetidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 230 c / O V° n (E)-7-(3-(azetidin-2-yl)acryloyl)-N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 231 a / p a af (E)-7-(3-(1-(7- aminoheptyl)pyrrolidin-2-yl)acryloyl)-N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 232 ci-A^ HN A i^NA । i N-(2-chlorophenyl)-7-[(E)-3-(4-methylmorpholin-3 -yl)prop-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 233 Up °p^NH h      0 (R,E)-N-(2-chlorophenyl)-7-(3-(morpholin-3-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 234 cPP h      0 (S,E)-N-(2-chlorophenyl)-7-(3-(morpholin-3-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 235 Cl^p HN >o i PNA 7-[(E)-4-aminopent-2-enoyl]-N-(2-chlorophenyl)-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 236 HN । N-(2-chlorophenyl)-7-[(E)-4-(dimethylamino)pent-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 237 NH F3C^J      J (E)-N-(2-chlorophenyl)-7-(3-(l-(3,3,3 -trifluoropropyl)pyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 238 0 ^nh 1 (E)-N-(2-chlorophenyl)-7-(5-(methylamino)pent-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 239 Q HN^\, N-(2-chlorophenyl)-7-[(E)-3-(4-piperidyl)prop-2-enoyl]-6,8-dihydro-5H- imidazo[l,2-a]pyrazine-3-carboxamide 240 Q hn'31 h          >° rNo 7n N-(2-chlorophenyl)-7-[(E)-3-(3-piperidyl)prop-2-enoyl]-6,8-dihydro -5H-imidazo[l,2-a]pyrazine-3-carboxamide 241 o hZ^01 I^^NH           \s N-(2-chlorophenyl)-7-[(E)-3-(2-piperidyl)prop-2-enoyl]-6,8-dihydro -5H-imidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 242 fN hH \=° 0^0        A (E)-N-(2-chlorophenyl)-7-(3-(morpholin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 243 c.4p °y-NH 1^0    l^N N-(2-chlorophenyl)-7-[(E)-3-[(2R)-morpholin-2-yl]prop-2 -enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 244 eV 0-7 0 X N-(2-chlorophenyl)-7-[(E)-3-[(2S)-morpholin-2-yl]prop-2-enoyl]- 6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 245 o hn’31 r^N a N-(2-chlorophenyl)-7-[(E)-3-[(2S)-4-methylmorpholin-2-yl]prop -2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 246 c|X^ NH _ y° / 0      A U^ / yV 1 {J 1 N-(2-chlorophenyl)-8-methyl-7-[(E)-3-[(2R)-l-methylpyrrolidin-2-yl]prop-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 247 °^p A N0 N Jss. / 1 W N-(2-chlorophenyl)-6-cyclopropyl-7-[(E)-4-[ethyl(methyl)amino] but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 248 Cl O ^NH N Xk / N 1 i N-(2-chlorophenyl)-7-((E)-4-(((ls,3s)-3-methoxycyclobutyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 249 ClUQ °y,NH N          N .     / / H        11 0 (S) N-(2-chlorophenyl)-7-((E)-4-(((ls,3s)-3-methoxycyclobutyl)(methyl) amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 250 Cl-^^ o Y_NH f^N „GYY (S,E)-N-(2-chlorophenyl)-7-(4-(2-methyl-1,4-diazepan-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 251 Cl-- / ^ HN >0 2HCI HN-Y^ (S,E)-N-(2-chlorophenyl)-7-(4-(2-methyl-1,4-diazepan-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide dihydrochloride 252 Cl— HrCo Sr-A                \\ ^N^v^r / I          0 (E)-N-(2-chlorophenyl)-7-(4-((3,3 -difluorocyclobutyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 253 HN N-(2-chlorophenyl)-7-[(E)-4-(4-ethyl-1,4-diazepan-1 -yl)but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 254 ci"C^ HN p^N N-(2-chlorophenyl)-7-[(E)-4-[(5R)-5-methyl-1,4-diazepan-1 -yl]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 255 a HV° cf3cooh । n \\ N-(2-chlorophenyl)-7-((E)-4-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 2,2,2-trifluoroacetate 255a Clyy °y.NH N-(2-chlorophenyl)-7-((E)-4-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 256 Cl-Q HN >0 HO^^^ N N-(2-chlorophenyl)-7-[(E)-4-hydroxybut-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carb oxamide Compound No. Structure Compound Name 257 pO"' o ) ^NH ryy 1 w N-(5-chloro-2-fluoro-phenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 258 Cl °y_NH 1 w N-(4-chloro-2-fluoro-phenyl)-7-[(E)-4-[ethyl(methyl)amino] but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 259 o,y o J 1 i N-(2-chloro-4-methyl-phenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 260 o-O y^0" ^n^^YN^n? ।                      <y> N-(2-chloro-6-methoxy-phenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 261 O / <^NH ryy 1 i N-(3 -chloro-2-fluoro-phenyl)-7-[(E)-4-[ethyl(methyl)amino] but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 262 F 0^5 CyNH 1           O N-(2-chloro-4-fluoro-phenyl)-7-[(E)-4- [ethyl(methyl)amino]but-2-enoyl] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 263 Cl a-O CyNH ।          o N-(2,3-dichlorophenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-6,8- dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 264 qa 1           i N-(2-chloro-3-methoxy-phenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 265 / V° CIO,^ / x o / ^NH 1          o N-(2-chloro-5-methoxy-phenyl)-7-[(E)-4-[ethyl(methyl) amino]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 266 jTVF CIO' / ^NH 1                     i!> N-(2-chloro-5-fluoro-phenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 267 CV-NFICI _________ N JssKZ 1 i (E)-N-(2,6-dichlorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 268 Cl O ^NH / 'N-'^V ।                    <y> N-(4-chloro-2-methoxy-phenyl)-7-[(E)-4-[ethyl(methyl) amino]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 269 Cl Ox 1 N-(3-chloro-2-methoxy-phenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 270 °-! °^NH o-n^y^ / ।                     <y> N-(6-chl oro-1,3-benzodi oxol-5-yl)-7-[(E)-4-[ethyl(methyl)amino] but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 271 J J 9r 7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-N-thiazol-5-yl-6,8-dihydro- 5H-imidazo[l,2-a]pyrazine-3-carboxamide 272 Cl— o -X-NH i                    <*! N-(4-chloro-3-pyridyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3-carboxamide 273 A-° o ^NH 1 A N-(5 -chi oro-1,3 -b enzodi oxol -4-yl)-7-[(E)-4-[ethyl(methyl)amino] but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 274 ci'X^ °y_NH F N-(2-chlorophenyl)-7-[2-fluorobut-2-enoyl]-6,8-dihydro-5H-imidazo [l,2-a]pyrazine-3-carb oxamide 275 c.4p %-nh N-(2-chlorophenyl)-7-[(E)-2-fluorobut-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carb oxamide 276 a-Q %-NH F N-(2-chlorophenyl)-7-[(Z)-2-fluorobut-2-enoyl]-6,8- dihydro-5H-imidazo[l,2-a]pyrazine-3-carb oxamide 277 y)T^ci । N-(4-chl oro-1,3-benzodi oxol-5-yl)-7-[(E)-4-[ethyl (methyl)amino]but -2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 278 o    H v-o 5-(2-chloroacetyl)-N-(2-chlorophenyl)-4,5,6,7-tetrahydropyrazolo[ 1,5-a]pyrazine-3-carboxamide 279 . °y,NH N-(2-chlorophenyl)-5-methyl-7-[rac-(E)-4-(azetidin-l-yl)but-2-enoyl] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 280 «43 = °y^NH r^N \s (5S)-N-(2-chlorophenyl) -5-methyl-7-[rac-(E)-4-(azetidin-l-yl)but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 281 «43 . °y-NH l^N Vs (5R)-N-(2-chlorophenyl)-5-methyl-7-[rac-(E)-4-(azetidin-l-yl)but-2-enoyl] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 282 Cl-X^ o = y-NH l^N Vs i <!J (5S)-N-(2-chlorophenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-5- methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 283 «43 . °^NH |^nA (5R)-N-(2-chlorophenyl)-5-methyl-7-[(E)-4-pyrrolidin-l-ylbut-2-enoyl]- 6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name (5R)-N-(2-chlorophenyl)-5-methyl-7-[(E)-4-[(2S)-2-methylpyrrolidin-l-yl]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide (5R)-N-(2-chlorophenyl)-5-methyl-7-[(E)-4-[(2R)-2-methylpyrrolidin -l-yl]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide (5S)-N-(2-chlorophenyl)-5-methyl-7-[(E)-4-[(2S)-2-methylpyrrolidin-l-yl]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide (5S)-N-(2-chlorophenyl)-5-methyl-7-[(E)-4-pyrrolidin-l-ylbut-2-enoyl] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 288 (5S)-N-(2-chlorophenyl)-5-methyl-7-[(E)-4-[(2R)-2-methylpyrrolidin-l-yl]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 289 (5R)-N-(2,3-dichlorophenyl)-5-methyl-7-[(E,4S)-4-pyrrolidin-l-ylpent-2- enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 290 ■ y-NH (5R)-N-(2,4-dichlorophenyl)-5-methyl-7-[(E,4S)-4-pyrrolidin-l-ylpent-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 291 cr , y^1 (5R)-N-(2-chloro-3-methyl-phenyl)-5-methyl-7-[(E,4S)-4-pyrrolidin-1- ylpent-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 292 F (5S)-N-(2-chlorophenyl)-7-[(E)-4-[3 -(difluoromethyl)azetidin-1 -yl]but- 2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 293 Cl-^^ . °y,NH 1        rwN"y (5R)-N-(2-chlorophenyl)-7-[(E)-5-[ethyl (methyl)amino] pent-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 294 Cly3 . y^ 1          rwN"y. (5R)-N-(2-chlorophenyl)-7-[(E)-5-(dimethylamino)pent-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 295 Cl-Z^ . °y_NH (5R)-N-(2-chlorophenyl)-7-[(E)-4-(dimethylamino)but-2-enoyl]-5-methyl -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 296 ciUQ °y_NH 1 A (6 S)-N-(2-chlorophenyl)-7- [(E)-4-[ethyl(methyl)amino]but-2-enoyl]-6-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 297 (6R)-N-(2-chlorophenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-6-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 298 1       l^N N\ (E)-N-(2-chlorophenyl)-7-(4-(pyrrolidin-1 -yl)pent-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 299 o o |^N \s .¼ N X> / N-(2-chlorophenyl)-7-[(E,4S)-4-pyrrolidin-1 -ylpent-2-enoyl]-6,8-dihydro -5H-imidazo[l,2-a]pyrazine-3-carboxamide 300 o ■A C o ^r° XNX    l^N N / W ^ibs' / / r / N-(2-chlorophenyl)-7-[(E,4R)-4-pyrrolidin-1 -ylpent-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 301 c.4p °^NH 0 (6S)-N-(2-chlorophenyl)-6-methyl-7-[rac-(E)-4-(3-methoxyazetidin- l-yl)but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 302 cy °y-NH i \ o (6R)-N-(2-chlorophenyl)-6-methyl-7-[rac-(E)-4-(3-methoxyazetidin-l-yl)but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 303 o O (”ul y.NH Ul (S,E)-N-(2-chlorophenyl)-7-(4-(ethyl(methyl)amino)pent-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 304 o O / \l y_NH Ul =     I^n-^ (R,E)-N-(2-chlorophenyl)-7-(4-(ethyl(methyl)amino)pent-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 305 / # crV7 Hyo rys M i X N-(2-chlorophenyl)-7-[(E)-4-(2-methylazetidin-1 -yl)but-2-enoyl] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3-carboxamide 306 f) cr\J HN\___0 N-(2-chlorophenyl)-7-[(E)-4-[(2R)-2-methylazetidin-l-yl]but-2-enoyl] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 307 cHy) HCo OD M   o N-(2-chlorophenyl)-7-[(E)-4-[(2S)-2-methylazetidin-1 -yl]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 308 (5S)-N-(2-chlorophenyl)-5-methyl-7-[(E)-4-(2-methylazetidin-1 -yl)but-2- enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3-carboxamide 309 = °-x,NH o (5S)-N-(2-chlorophenyl)-5- methyl-7-[(E)-4-[(2S)-2-methylazetidin-1 -yl] but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3-carboxamide 310 3 °y^NH r^NA ^ / «1     0 (5S)-N-(2-chlorophenyl)-5-methyl-7-[(E)-4-[(2R)-2-methylazetidin-l-yl]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3-carboxamide 311 3 °y-NH .    [^n\ (5S)-N-(2-chlorophenyl)-5-methyl-7-[(E,4S)-4-pyrrolidin-l-ylpent-2- enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 312 O Q (5R)-N-(2-chlorophenyl)-5-methyl-7-[(E)-4-(2-methylazetidin-1 -yl)but-2- enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3-carboxamide (5R)-N-(2-chlorophenyl)-5-methyl-7-[(E)-4-[(2R)-2-methylazetidin-1 -y 1 ] but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3-carboxamide (5R)-N-(2- chlorophenyl)-5-methyl-7-[(E)-4-[(2S)-2-methylazetidin-l-yl]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3-carboxamide (5R)-N-(2-chlorophenyl)-5-methyl-7-[(E,4R)-4-pyrrolidin-l-ylpent- 2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide (5S)-N-(2-chlorophenyl)-7-[(E,4S)-4-[ethyl(methyl)amino]pent-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide (5R)-N-(2-chlorophenyl)-7-[(E)-4-[3 -(difluoromethyl)azetidin-1 -yl] -but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide (5R)-N-(2-chlorophenyl)-7-[(E)-4-[3 -(difluoromethyl)azetidin-1 -yl] but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 318 o / bi y-NH I^N'A (E)-7-(4-(azetidin-1 -yl)but-2-enoyl)-N-(2-chlorophenyl)-8-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 319 o yPci (R,E)-7-(4-(azetidin-l-yl)but-2-enoyl)-N-(2-chlorophenyl)-8-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 320 u ° m- 4 / ..... (S,E)-7-(4-(azetidin-1 -yl)but-2-enoyl)-N-(2-chlorophenyl)-8-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 321 Cl N-(2-chlorophenyl)-7-[(E)-3-[(2S)-1 -phenylpyrrolidin-2-yl]prop-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 322 c^Q O °rr (E)-N-(2-chlorophenyl)-7-(3-(l-phenylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 323 c,43 ^NH \A^y^A4 (E)-N-(2-chlorophenyl)-7-(3-(l-cyclopropylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide N-(2-chlorophenyl)-7-[(E)-3-[(2R)-l-cyclopropylpyrrolidin-2-yl]prop-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide N-(2-chlorophenyl)-7-[(E)-3-[(2S)-l-cyclopropylpyrrolidin-2-yl]prop-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide (5S)-N-(2-chlorophenyl)-7-[(E)-4-(l-cyclopropyl-4,4-difluoro-pyrrolidin -2-yl)but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide (5R)-N-(2-chlorophenyl)-7-[(E)-4-[(2S)-l-cyclopropylpyrrolidin-2-yl]but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide (5R)-N-(2-chlorophenyl)-7-[(E)-4-[(2R)-l-cyclopropylpyrrolidin-2-yl]but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 329 = °y.NH (5S)-N-(2-chlorophenyl)-5-methyl-7-[(E,4S)-4-pyrrolidin-l-ylpent-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 330 = °y,NH N "X^N 0 (S)-N-(2-chlorophenyl)-7-((E)-4-((R)-1 -cyclopropylpyrrolidin-2-yl)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 331 C.-O 3 °y^NH / yzx^x / N O (5S)-N-(2-chlorophenyl)-7-[(E)-4-[(2S)-l-cyclopropylpyrrolidin-2-yl]but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 332 . °y,NH F Y-N      0 (5R)-N-(2-chlorophenyl)-7-[(E)-4-[(2R)-l-cyclopropyl-4,4-difluoro-pyrrolidin-2-yl]but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 333 O HtT^1 >0 y-NH N-(2-chlorophenyl)-7-((E)-3-((2R,4S)-4-fluoropyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 334 o HrT^01 \=° N-(2-chlorophenyl)-7-((E)-3-((2R,4S)-4-fluoro-l-methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 335 O H^01 / —NH N-(2-chlorophenyl)-7-[(E)-3-[(2S,4R)-4-fluoropyrrolidin-2-yl]prop-2- enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 336 O ,             NH*^1 _ /             y-O / y     l^N N-(2-chlorophenyl)-7-[(E)-3-(l-i sopropylpyrrolidin-3 -yl)prop-2-enoyl] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 337 coa h 0 (6S)-N-(2-chlorophenyl)-6-methyl-7-[(E)-3-morpholin-3-ylprop-2-enoyl] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 338 rvcl Cl-^yy °y_NH / — NH N-(2,5 -dichlorophenyl)-7- [(E)-3 -[(2R)-pyrrolidin-2-yl]prop-2-enoyl] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 339 rVcl CI-'A^ / । °y^NH / —,     r^N vw-^ h        n N-(2,5-dichlorophenyl)-5-methyl-7-[(E)-3-[(2R)-pyrrolidin-2-yl]prop-2- enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 340 ci-Q \         l^N AZA N-(2-chlorophenyl)-7-[(E)-3- [ (3 S ) -1 -i sopropylpyrrolidin-3 -yl]prop-2- enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 341 c^Q °y,A N-(2-chlorophenyl)-7- [(E)-3-[(3R)-1 -i sopropylpyrrolidin-3 -yl]prop-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 342 C,4Z / --.       I^N \s N-(2-chlorophenyl)-7-[(E)-3-(l-methylpyrrolidin-3-yl)prop-2-enoyl]-6,8- dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 343 c,4Z V V™ / —NZ    i^nA AzyAZ N-(2-chlorophenyl)-7-[(E)-3-[(2S)-l-(3,3,3-trifluoropropyl)pyrrolidin-2-yl]prop-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 344 f F   c,4p Af Anh N-(2-chlorophenyl)-7-[(E)-3-[4-(3,3,3 -trifluoropropyl)morpholin-3-yl] prop-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carb oxamide 345 A a A / -nz   AnA f A   n A Pv   'AXZ     N N-(2-chlorophenyl)-7-[(E)-3-[(2S,4R)-4-fluoro-l-methyl-pyrrolidin-2-yl] prop-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide (6R)-N-(2-chlorophenyl)-6-methyl-7-[(E)-3-(4-methylmorpholin-3-yl) prop-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide N-(2-chlorophenyl)-7-[(E)-4-[methyl(3,3,3-trifluoropropyl)amino]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide (5R)-N-(2-chlorophenyl)-5-methyl-7-[(E)-4-(4-methyl-l,4-diazepan-l-yl)-but-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide (5S)-N-(2-chlorophenyl)-5-methyl-7-[(E)-4-(4-methyl-l,4-diazepan-l-yl)-but-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide N-(2-chlorophenyl) -7-[(E)-3-[ (3 S ) -1 -methylpyrrolidin-3 -yl]prop-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide N-(2-chlorophenyl) -7-[(E)-3-[(3R)-1 -methylpyrrolidin-3 -yl]prop-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 352 ryci c|-^V==j 1 °^NH N-(2,5-dichlorophenyl)-5-methyl-7-[(E)-3-[(2R)-l-methylpyrrolidin-2-yl] prop-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carb oxamide 353 CV01 . ^NH (5R)-N-(2,5-dichlorophenyl)-5-methyl-7-[(E)-3-[(2R)-l-methylpyrrolidin -2-yl]prop-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 354 / VCI c|-^v=^ = °y^NH ^NZ (5S)-N-(2,5-dichlorophenyl)-5-methyl-7-[(E)-3-[(2R)-l-methylpyrrolidin-2-yl]prop-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 355 ryci CI-'A^ ^NH (6R)-N-(2,5-dichlorophenyl)-6-methyl-7-[(E)-3-[(2R)-l-methylpyrrolidin -2-yl]prop-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 356 ryci CI'-A^ °y^NH (6S)-N-(2,5-dichlorophenyl)-6-methyl-7-[(E)-3-[(2R)-l-methylpyrrolidin-2-yl]prop-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 357 JV1 °^NH (6R)-N-(2,5-dichlorophenyl)-6-methyl-7-[(E)-3-[(2R)-l-methylpyrrolidin-2-yl]prop-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 358 °-^Nh r~n / r^N X N-(2-chlorophenyl)-8-methyl-7-[(E)-3-(l-methylpyrrolidin -2-yl)prop-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 359 °y^NH A~n /   XA N-(2-chlorophenyl)-8-methyl-7-((E)-3 - (( S ) -1 -methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 360 CS\X 0. I V-nh .H        i 1    > L N     T / > \      0 4 H (R)-N-(2-chlorophenyl)-8-methyl-7-((E)-3-((S)-1 -methyl pyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 361 Cl-O O / - ^K-NH (5S)-N-(2-chlorophenyl)-5-methyl-7-((E)-4-(pyrrolidin-2-yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 362 ci-Q . V^Nh X?nX V-NH     0 (5R)-N-(2-chlorophenyl)-5-methyl-7-[(E)-4-pyrrolidin-2-ylbut-2-enoyl]- 6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 363 ci-Q . °y_NH V-NH     0 (5R)-N-(2-chlorophenyl)-5-methyl-7-[(E)-4-[(2S)-pyrrolidin-2-yl]but- 2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carb oxamide Compound No. Structure Compound Name 364 = °y_NH V-NH     0 (5S)-N-(2-chlorophenyl)-5-methyl-7-[(E)-4-pyrrolidin-2-ylbut-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 365 = °y-NH r^N-A \__NH     0 (5S)-N-(2-chlorophenyl)-5-methyl-7-[(E)-4-[(2R)-pyrrolidin-2-yl]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 366 ci-Q . °y,NH V-NH     0 (5R)-N-(2-chlorophenyl)-5-methyl-7-[(E)-4-[(2R)-pyrrolidin-2-yl]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 367 c.^Q = °y-NH |^nA V-NH    0 (5S)-N-(2-chlorophenyl)-5-methyl-7-[(E)-4-[(2S)-pyrrolidin-2-yl]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 368 . °y_NH V-NH     0 (R)-N-(2-chlorophenyl)-5-methyl-7-((E)-4-((S)-pyrrolidin-2-yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 369 ci-Q = ^NH N \ / ^N V-NH     0 (S)-N-(2-chlorophenyl)-5-methyl-7-((E)-4-((R)-pyrrolidin-2-yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 370 . ^nh V-NH    0 (R)-N-(2-chlorophenyl)-5-methyl-7-((E)-4-((R)-pyrrolidin-2-yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 371 = °-^NH r^N-A F \_,NH      0 (5S)-N-(2-chlorophenyl)-7-((E)-4-(4,4-difluoropyrrolidin-2-yl)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 372 = °y-NH ^n-A F \__NH      0 (5S)-N-(2-chlorophenyl)-7-[(E)-4-[(2R)-4,4-difluoropyrrolidin-2-yl] but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 373 ci-Q = °y-NH F \_,NH      0 (5S)-N-(2-chlorophenyl)-7-[(E)-4-[(2S)-4,4-difluoropyrrolidin-2-yl]but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 374 o.^ . °y,NH F V-NH     0 (5R)-N-(2-chlorophenyl)-7-[(E)-4-(4,4-difluoropyrrolidin-2-yl)but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 375 o.^ . °y,NH F \__NH      0 (5R)-N-(2-chlorophenyl)-7-[(E)-4-[(2R)-4,4-difluoropyrrolidin-2-yl] but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide (5R)-N-(2-chlorophenyl)-7-[(E)-4-[(2S)-4,4-difluoropyrrolidin-2-yl]but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide (5R)-N-(2-chlorophenyl)-5-methyl-7-[(E)-4-[l-(3,3,3-trifluoropropyl)pyrrolidin-2-yl]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide (5S)-N-(2-chlorophenyl)-5-methyl-7-[(E)-4-[l-(3,3,3-trifluoropropyl) pyrrolidin-2-yl]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide N-[4-chloro-2-(trifluoromethyl)phenyl]-7-[(E)-4-[ethyl(methyl)amino] but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-N-[2-(trifluoromethyl)phenyl] -6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 381 F = °y-NH (5 S)-N-(2-chloro-4-fluoro-phenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 382 / V1 HN v-o C^NH N-(2,5-dichlorophenyl)-6-methyl-7-[(E)-3-[(2R)-pyrrolidin-2-yl]prop-2- enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 383 O k. o N-(2,5-dichlorophenyl)-6-methyl-7-[(E)-3-[(2R)-l-methylpyrrolidin-2-yl] prop-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carb oxamide 384 o HkRCI >o / —. (E)-N-(2-chlorophenyl)-7-(3-(hexahy dro-1 H-pyrrolizin-3 -yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 385 °y_NH l^N \s qXzvn^ N-(2-chlorophenyl)-7-(3-(hexahy dro-1 H-pyrrolizin-3 -yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 386 Q r Ay / J* N-(2-chlorophenyl)-7-((E)-3-((3 S)-hexahy dro-1 H-pyrrolizin-3 -yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 387 o N-(2-chlorophenyl)-7-((E)-3-((3R)-hexahy dro-1 H-pyrrolizin-3 -yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 388 cZ) o . y-NH 1      N (5R)-7-[(E,4S)-4-(azetidin-1 -yl)pent-2-enoyl]-N-(2-chlorophenyl)-5- methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 389 Cl-O . °yA (5R)-7-[(E,4R)-4-(azetidin-1 -yl)pent-2-enoyl]-N-(2-chlorophenyl)-5- methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 390 C,AA ■ °ylH = (S)-7-((R,E)-4-(azetidin-1 -yl)pent-2-enoyl)-N-(2-chlorophenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 391 CIAA ■ °ylH "—^""N (5S)-7-[(E,4S)-4-(azetidin-l-yl)pent-2-enoyl]-N-(2-chlorophenyl)-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 392 ryci . y^H (5R)-7-[(E)-4-(azetidin-l-yl)but-2-enoyl]-N-(2,5dichlorophenyl)-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 393 ci-O (S,E)-7-(4-(azetidin-1 -yl)but-2-enoyl)-N-(2-chlorophenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 394 c.-O . °y^NH rwN'A (R,E)-7-(4-(azetidin-l-yl)but-2-enoyl)-N-(2-chlorophenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 395 rv01 ci'^\=== / = °y_NH (5 S)-7-[(E)-4-(azetidin-1 -yl)hex-2-enoyl]-N-(2,5-dichlorophenyl) -5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 396 Q" y^1 (5R)-7-[(E,4S)-4-(azetidin-1 -yl)pent-2-enoyl]-N-(2-chloro-3-methyl- phenyl)-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 397 / ===^-F CT . y^1 .      i^wN"^ (5R)-7-[(E,4S)-4-(azetidin-1 -yl)pent-2-enoyl]-N-(2-chloro-3-fluoro- phenyl)-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 398 c-O o r . y_NH (5R)-N-(2-chlorophenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 399 1 C,X} o . y_NH Joabs'N— (5R)-N-(2-chlorophenyl)-7-[(E)-4-[isopropyl(methyl)amino]but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 400 1 C|-^O 0 . y__NH pNA (5R)-N-(2-chlorophenyl)-7-[(E)-4-[cyclopropyl(methyl)amino] but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 401 । %^h OrA 1 o (5R)-N-(2-chlorophenyl)-5-methyl-7-[(E)-4-[methyl(propyl)amino] but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 402 1 Cl-^^ = °y,NH (5S)-N-(2-chlorophenyl)-7-[(E)-4-(dimethylamino)pent-2-enoyl] -5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 403 Cl-O y^ rwN\ (5R)-7-[(E)-4-(azetidin-l-yl)hex-2-enoyl]-N-(2-chlorophenyl) -5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. 404 405 406 407 408 409 (5R)-7-((E)-4-(azetidin-l-yl)hex-2-enoyl)-N-(2-chlorophenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide (5R)-7-[(E,4S)-4-(azetidin-1 -yl)hex-2-enoyl]-N-(2-chlorophenyl) -5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide (5R)-7-[(E,4R)-4-(azetidin-1 -yl)hex-2-enoyl]-N-(2-chlorophenyl)-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide (5 S)-7-[(E)-4-(azetidin-1 -yl)hex-2-enoyl]-N-(2-chlorophenyl)-5-methyl- 6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide (5S)-7-[(E,4S)-4-(azetidin-l-yl)hex-2-enoyl]-N-(2-chlorophenyl)-5- methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide (5S)-7-[(E,4R)-4- (azetidin-1-yl)hex-2-enoyl]-N-(2-chlorophenyl)-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide (5R)-7-[(E)-4-(azetidin-l-yl)hex-2-enoyl]-N-(2,5-dichlorophenyl)-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide (5R)-7-[(E,4R)-4-(azetidin-1 -yl)hex-2-enoyl]-N-(2,5-dichlorophenyl)-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide (5R)-7-[(E,4S)-4-(azetidin-1 -yl)hex-2-enoyl]-N-(2,5-dichlorophenyl)-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide (5R)-N-(2-chlorophenyl)-7-[(E)-4-(ethyl amino)but-2-enoy 1 ] - 5 -methyl -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide (5R)-N-(2-chlorophenyl)-7-[(E)-4-(di ethyl amino)but-2-enoy 1 ] - 5 -methyl -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide (5S)-N-(2-chlorophenyl)-5-methyl-7-[(E,4R)-4-pyrrolidin-l-ylpent-2- enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 416 CI-O o . y-NH (5R)-N-(2-chlorophenyl)-5-methyl-7-[(E,4S)-4-pyrrolidin-l-ylpent-2- enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 417 c,X) O < H y-NH = yN (R)^^         N (5R)-7-[(E,4R)-4-(azetidin-1 -yl)pent-2-enoyl]-N-(2-chlorophenyl)-5- methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 418 Ct / yH y-NH (R)-7-((S,E)-4-(azetidin-1 -yl)pent-2-enoyl)-N-(2-chloro-4-methylphenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 419 c-Q = °y,NH =    ^N-y (S)-7-((R,E)-4-(azetidin-l-yl)pent-2-enoyl)-N-(2-chloro-4-methylphenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 420 U O \ / / z \ ^—-Z. (S)-7-((S,E)-4-(azetidin-l-yl)pent-2-enoyl)-N-(2-chloro-4-methylphenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 421 O -0 (R)-7-((S,E)-4-(azetidin-1 -yl)pent-2-enoyl)-N-(2-chloro-4-methylphenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 422 o 0V-NH C! bl     f'N'A 0 7-[(E,4R)-4-(azetidin-l-yl)pent-2-enoyl]-N-(2-chlorophenyl)-5-ethyl-6,8- dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 423 O °y-NH a fl              Ki            / 0 (5R)-7-[(E,4R)-4-(azetidin-1 -yl)pent-2-enoyl]-N-(2-chlorophenyl)-5- ethyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 424 o / \        %—NH a \r 0 (5 S)-7-[(E,4R)-4-(azetidin-1 -yl)pent-2-enoyl]-N-(2-chlorophenyl)-5- ethyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 425 Z\      %-Nh V (S)-7-((S,E)-4-(azetidin-l-yl)pent-2-enoyl)-N-(2-chlorophenyl)-5-ethyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 426 C,-Q Nz (R)-7-((S,E)-4-(azetidin-1 -yl)pent-2-enoyl)-N-(2-chlorophenyl)-5-ethyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 427 Cl crQ CL / Hy y—NH V     ■N (5R)-7-[(E,4R)-4-(azetidin-1 -yl)pent-2-enoyl]-N-(2,3-dichlorophenyl) -5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 428 —0 q, / H y-NH h ?           f > (5R)-7-[(E,4R)-4-(azetidin-1 -yl)pent-2-enoyl]-N- (2-chloro-3-methoxy-phenyl)-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 429 —0 Hy y-NH h (5R)-7-[(E,4S)-4-(azetidin-1 -yl)pent-2-enoyl]-N- (2-chloro-3-methoxy-phenyl)-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 430 ci^kj o. / H y-NH (5R)-7-[(E,4R)-4-(azetidin-1 -yl)pent-2-enoyl]-N-(2-chloro-3-methyl- phenyl)-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 431 Cl Jl 0.     / c / rSA py^yyx / W CJ     o (5R)-7-[(E,4R)-4-(azetidin-1 -yl)pent-2-enoyl]-N-(2,4-dichlorophenyl) -5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 432 O (Bl . p-NH p?N-p (5R)-N-(2-chlorophenyl)-7-[(E,4R)-4-(dimethylamino)pent-2-enoyl] -5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 433 cuT) o < H y-NH JL     N. J^k / \ / ^N (5R)-N-(2-chlorophenyl)-7-[(E,4S)-4-(diethylamino)pent-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 434 u 1 y *.....z? ^=0 \ o (5S)-N-(2-chlorophenyl)-7-[(E,4S)-4-(diethylamino)pent-2-enoyl]-5- methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 435 ci-^Cj Q. / H V-NH ■ yy zV-^Ax J          0 (5R)-N-(2-chlorophenyl)-7-[(E,4R)-4-[ethyl(methyl)amino]pent-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 436 ci'XTj a / H V-NH J o (5R)-N-(2-chlorophenyl)-7-[(E,4R)-4-(diethylamino)pent-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 437 o / C! J XN' 0 (5R)-N-(2-chlorophenyl)-7-[(E,4S)-4-(dimethylamino)pent-2-enoyl]-5 -methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 438 ox / ci = Y^NH 0 (5S)-N-(2-chlorophenyl)-7-[(E,4S)-4-(dimethylamino)pent-2-enoyl] -5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 439 o : °y^NH ct ^'hTA 4       n       / (5S)-N-(2-chlorophenyl)-7-[(E,4R)-4-(dimethylamino)pent-2-enoyl]-5- methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 440 Cl^v^ o / ^ . 'K-NH N J^k / (5R)-N-(2-chlorophenyl)-7-[(E)-4-(3 -cyanoazetidin-1 -yl)but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 441 o HN01 / —\  >° cz'5-N-(2-chlorophenyl)-7-[(E)-4-pyrrolidin-1 -ylbut-2-enoyl]-1,7,10- triazatricyclo[7.3.0.02,6]dodeca-9,11-diene-12-carboxamide 442 O / —AH Y-0 hA^nA (2S,6R)-N-(2-chlorophenyl)-7-[(E)-4-pyrrolidin-1 -ylbut-2-enoyl]-1,7,10- triazatricyclo[7.3.0.02,6]dodeca-9,11-diene-12-carboxamide 443 o Hrj'01 / -AH hSAnA (2R,6S)-N-(2 -chlorophenyl)-7-[(E)-4-pyrrolidin-l-ylbut-2-enoyl]-1,7,10- triazatricyclo[7.3.0.02,6]dodeca-9,11-diene-12-carboxamide 444 □43 A i V 4rTN-3 (5R)-N-(2-chlorophenyl)-5-methyl-7- [(E)-4-(2-oxa-5 -azabicyclo [2.2.1]heptan-5-yl)pent-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 445 c43 <2>      . °y-NH (5R)-N-(2-chlorophenyl)-5-methyl-7-[(E,4R)-4-(2-oxa-5-azabicyclo[2.2.1] heptan-5-yl)pent-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 446 c,43 A i (5R)-N-(2-chlorophenyl)-5-methyl-7-[(E,4S)-4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pent-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 447 o 0 A ° r 'N "A 0 (5R)-N-(2-chlorophenyl)-5-methyl-7-[(E)-4-morpholinopent-2-enoyl] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 448 o .0.          0. / ci yX     Z V-NH 0 (5S)-N-(2-chlorophenyl)-5-methyl-7-[(E,4S)-4-(2-oxa-5-azabicyclo[2.2.1] heptan-5-yl)pent-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 449 o jx              Q. / Cl = y^NH TX           A 0 (5S)-N-(2-chlorophenyl)-5-methyl-7-[(E,4R)-4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pent-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 450 o A f XT          \ c'-'Z^y^xZ^N 0 (5R)-N-(2-chlorophenyl)-5-methyl-7-[(E,4R)-4-morpholinopent-2-enoyl] -6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 451 o n i vnh~ ci A^yXA / (5R)-N-(2-chlorophenyl) -5-methyl-7-[(E,4S)-4-morpholinopent-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 452 ci-^O = °y,NH D 1 D (5S)-N-(2-chlorophenyl)-7-[(E)-2,3-dideuterio-4-[ethyl(methyl)amino]but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 453 cr-'Ay 0.      / H z y-NH • D 0 (5R)-N-(2-chlorophenyl)-7-[(E)-2,3-dideuterio-4-[ethyl(methyl)amino]but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 454 Clyy = y^ D i A fi (5 S)-7-[(E)-4-(azetidin-1 -yl)-2,3 -di deuteri o-but-2-enoy 1 ] -N-(2-chlorophenyl)-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 455 c|XD । °y^NH D y / y^ "J    D 0 (5R)-7-[(E)-4-(azetidin-l-yl)-2,3-di deuteri o-but-2-enoy 1 ] -N-(2-chlorophenyl)-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 456 ci-^O o = y_NH d 1            i (5S)-N-(2-chlorophenyl)-7-[(E)-2-deuterio-4- [ethyl(methyl)amino]but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 457 C!-O O H ? ^NH [ N HN^__ (S,E)-7-(4-(l ,4-diazepan-1 -yl)but-2-enoyl)-N-(2-chlorophenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 458 . i'WN'A (5R)-N-(2-chlorophenyl)-7-[(E)-4-(4-cyclopropyl-1,4-diazepan-1 -yl)but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 459 crYY y—• CL / : 'V-AIH rM> c>~VJ $ (5S)-N-(2-chlorophenyl)-7-[(E)-4-(4-cyclopropyl-1,4-diazepan-1 -yl)but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 460 c.^Q = °y-NH V (5 S)-7-[(E)-4-(azetidin-1 -yl)-4-cyclopropyl-but-2-enoyl]-N-(2-chlorophenyl)-5-methyl-6,8- dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 461 Cl-O O H Y---Nh gY"'" (5 S)-7-[(E,4R)-4-(azetidin-1 -yl)-4-cyclopropyl-but-2-enoyl]-N-(2-chlorophenyl)-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 462 A O / ., H y-NH (5S)-7-[(E,4S)-4-(azetidin-l-yl)-4-cyclopropyl-but-2-enoyl]-N-(2-chlorophenyl)-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 463 Ok ' H V-NH Y Y'nY <7     o (5R)-7-[(E)-4-(azetidin-l-yl)-4-cyclopropyl-but-2-enoyl]-N-(2-chlorophenyl)-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 464 cYTY Ck / H V-NH Y fiY A   j\l , A / 77 hK L / n            ii 0 (5R)-7-[(E,4R)-4-(azetidin-l-yl)-4-cyclopropyl-but-2-enoyl]-N-(2-chlorophenyl)-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 465 cf'^Z^ H %-NH Y >L jL Aw C?Ap N "        0 (5R)-7-[(E,4S)-4-(azetidin-1 -yl)-4-cyclopropyl-but-2-enoyl]-N-(2-chlorophenyl)-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 466 o o / \l W.NH N-(2-chlorophenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-6,8- dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 467 V-NH 1 0 (5S)-N-(2-chlorophenyl)-7-[(E)-5-[ethyl(methyl)amino]pent-2-enoyl]-5- methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 468 ci-As / o. / H    %-—NH ^X / ^x^^x^n' 0 (5S)-N-(2-chlorophenyl)-7-[(E)-5-(dimethylamino)pent-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 469 «'O'F = °y^NH i A (5S)-N-(2-chloro-5-fluoro-phenyl)-7-[(E)-4-[ethyl(methyl)amino]but- 2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 470 CI^Q = y^F KtsTN'A 1           i (5 S)-N-(2-chloro-6-fluoro-phenyl)-7-[(E)-4-[ethyl(methyl)amino]but- 2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 471 F Cl-^^ = °y_NH (5S)-N-(2-chloro-3-fluoro-phenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 472 o / ■ y~NH 1           i (5R)-N-(2-chloro-5-fluoro-phenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 473 F ■ °y_NH (5R)-N-(2-chloro-3-fluoro-phenyl)-7-[(E)-4-[ethyl(methyl)amino] but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 474 F ci-Jl5 o . y-NH r^N-y (5R)-N-(2-chloro-4-fluoro-phenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 475 ci"Ci . y^F (5R)-N-(2-chloro-6-fluoro-phenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 476 . °yi^ (5R)-N-(2-chloro-4-methyl-phenyl)-5-methyl-7-[(E,4S)-4-pyrrolidin-1- ylpent-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 477 Cl f ci- HN j y° X^-^XX^X^XX^ I            0 (5R)-N-(2,4-dichlorophenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl] -5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 478 FA o, f x\ x'C X X XX xx N i          0 (5R)-N-(2-chloro-4-methyl-phenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 479 ckCTj CL ' H V-NH \ (5R)-7-[(E,4S)-4-(azetidin-1 -yl)pent-2-enoyl]-N-(2-chloro-4-methyl- phenyl)-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 480 Cl CL / V^NH X^ / x^x^N.^ / 0 (5R)-N-(2,3-dichlorophenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 481 C| ov / < H V-NH v. m (5R)-7-[(E,4S)-4-(azetidin-1 -yl)pent-2-enoyl]-N-(2,3-dichlorophenyl)-5- methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 482 cr-C / °y-NH H / y VJ    o (5R)-N-(2-chloro-3-methoxy-phenyl)-5-methyl-7-[(E,4S)-4-pyrrolidin-1- ylpent-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 483 —-o o. H z V-NH ।            0 (5R)-N-(2-chloro-3-methoxy-phenyl)-7-[(E)-4-[ethyl(methyl)amino] but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 484 Ci Cl / < H y^NH \H y?’? (5R)-7-[(E,4S)-4-(azetidin-1 -yl)pent-2-enoyl]-N-(2,4-dichlorophenyl)-5- methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 485 chCj q. / y-NH i           0 N-(2-chloro-3-methyl-phenyl)-7-[(E)-4-[ethyl(methyl)amino] but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 486 Ox / V-NH rSA 1           0 (5R)-N-(2-chloro-3-methyl-phenyl)-7-[(E)-4-[ethyl(methyl)amino] but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 487 e cH-yj q„ / y H V-NH vJ     o (5R)-N-(2-chloro-3-fluoro-phenyl)-5-methyl-7-[(E,4S)-4-pyrrolidin-1- ylpent-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 488 F o . A-NH A ® (5R)-N-(2-chloro-4-fluoro-phenyl)-7-[(E)-4-[cyclopropyl(ethyl)amino]but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 489 F ov / a j y-NH u 0 (5 S)-N-(2-chloro-4-fluoro-phenyl)-7-[(E)-4-[cyclopropyl(ethyl)amino]but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 490 uO rV< . ^V-NH A ^15 J 0 (5R)-N-(2-chloro-6-fluoro-phenyl)-7-[(E)-4-[cyclopropyl(ethyl)amino]but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 491 F Q, / Cl 1 y-nh CD (5R)-N-(2-chloro-5-fluoro-phenyl)-7-[(E)-4-[cyclopropyl(ethyl)amino] but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 492 ry j y *      Ari 0 (5R)-N-(2-chloro-3-fluoro-phenyl)-7-[(E)-4-[cyclopropyl(ethyl)amino] but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 493 #7 cryy CL / D-NH v cd (5R)-7-[(E,4R)-4-(azetidin-1 -yl)pent-2-enoyl]-N-(2-chloro-3-fluoro- phenyl)-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 494 C-C . oy_NH rwND N JD / N (5R)-N-(2-chlorophenyl)-7-[(E)-4-(3 -ethoxy azeti din-1 -yl)but-2-enoyl] -5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide b 495 o \ D.x 7 \ *r\    / '—Z A=O ? Z-y o / (5R)-N-(2-chlorophenyl)-7-[(E)-4-(3 -methoxy azeti din-1 -yl)but-2-enoyl]- 5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 496 (5R)-N-(2-chlorophenyl)-7-[(E)-4-(3 -methoxy-3 -methyl-azetidin-1 -yl) but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide (5R)-N-(2-chlorophenyl)-7-[(E)-4-(3 -isopropoxy azeti din- l-yl)but-2-enoyl]-5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 498 499 500 (5R)-N-(2-chloro-4-fluoro-phenyl)-5-methyl-7-[(E)-3-morpholin-3- ylprop-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide (5R)-N-(2-chloro-4-fluoro-phenyl)-5-methyl-7-[(E)-3-[(3S)-morpholin-3- yl]prop-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3-carboxamide (5R)-N- (2-chloro-4-fluoro-phenyl)-5-methyl-7-[(E)-3-[(3R)-morpholin-3-yl]prop-2-enoyl]-6,8- dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 501 Cl d y H °V-N H ° A AyC H       0 (5R)-N-(2,4-dichlorophenyl)-5-methyl-7-[(E)-3-morpholin-3-ylprop -2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 502 A H Vnh ° A Ari yA^yAA H H     o (5R)-N-(2-chloro-4-methyl-phenyl)-5-methyl-7-[(E)-3-morpholin-3- ylprop-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 503 H \-NH H H     o (5R)-N-(2-chloro-4-methyl-phenyl)-5-methyl-7-[(E)-3-[(3R)-morpholin- 3-yl]prop-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3-carboxamide 504 cAa 0.      / * H y-NH PyC, H H     0 (5R)-N-(2- chloro-4-methyl-phenyl)-5-methyl-7-[(E)-3-[(3S)-morpholin-3-yl]prop-2-enoyl]-6,8- dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 505 R A Ox A < H y-NH A An> H A (5R)-N-(2-chl oro-3 -fluoro-phenyl)-5-methyl-7-[(E)-3-morpholin-3- ylprop-2-enoyl]-6,8- dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 506 R Ya a xA y H A-NH A M H H     0 (5R)-N-(2-chl oro-3 -fluoro-phenyl)-5-methyl-7-[(E)-3-[(3R)-morpholin- 3-yl]prop-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3-carboxamide 507 R h c|\a Ov / . H V-NH A aa Ai HH   J (5R)-N-(2- chioro-3 -fluoro-phenyl)-5-methyl-7-[(E)-3-[(3S)-morpholin-3-yl]prop-2-enoyl]-6,8- dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 508 □“mV-—- / J Z-y zL L^A-q q (5R)-N-(2,4-dichlorophenyl)-5-methyl-7-[(E)-3-[(3R)-morpholin-3-yl] prop-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carb oxamide 509 Cl d o. / Cl 1 H V-NH A Ar$ H               II (5R)-N- (2,4-dichlorophenyl)-5-methyl-7-[(E)-3-[(3S)-morpholin-3-yl]prop-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carb oxamide 510 o . H VaA A Ad aaa^ 0 (5R)-N-(2-chlorophenyl)-5-methyl-7-[(E)-3-morpholin-3-ylprop-2-enoyl] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 511 ci--Cy Q. / . H y-NH A An H H         II (5R)-N-(2-chlorophenyl)-5-methyl-7-[(E)-3-[(3R)-morpholin-3-yl]prop -2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carb oxamide 512 c nCTj Q. / * H V-NH A An (5R)-N-(2- chlorophenyl)-5-methyl-7-[(E)_3-[(3S)-morpholin-3-yl]prop-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carb oxamide 513 ci-O o / < H y-NH (5R)-7-[(E)-4-[(3aR,6aS)-l,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl] but-2-enoyl]-N-(2-chlorophenyl)-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 514 ci-Q . °y,NH i    rANA n-yn^ (5R)-7-[(E)-4-[(3aS,6aR)- l,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol- 5-yl]pent-2-enoyl]-N-(2-chlorophenyl)-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 515 ci-Q . °y,NH rwJ    8 (5R)-7-[(E,4S)-4-[(3aS,6aR)-l,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol- 5-yl]pent-2-enoyl]-N-(2-chlorophenyl)-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 516 ci-Q . °^nh =     I^N-4 (5R)-7-[(E,4R)-4-[(3aS,6aR)-l,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol- 5-yl]pent-2-enoyl]-N-(2-chlorophenyl)-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 517 o ? = ^NH b oa 0 (5S)-N-(2-chlorophenyl)-5-ethyl- 7-[(E)-4-[ethyl(methyl)amino]but- 2- enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 518 Cl'^o o H    y-NH 1 fl (6S)-N-(2-chlorophenyl)-6-cyclopropyl-7-[(E)-4-[ethyl(methyl)amino] but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 519 Cl^ o ? H    y-NH 1 fl (6R)-N-(2-chlorophenyl)-6-cyclopropyl-7-[(E)-4-[ethyl(methyl)amino] but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 520 ci-Xj ,- H 1 fl N-(2-chlorophenyl)-5-cyclopropyl-7-[(E)-4-[ethyl(methyl) amino]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound Name (5R)-N-(2-chlorophenyl)-5-cyclopropyl-7-[(E)-4-[ethyl(methyl) amino]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide (5S)-N-(2- chlorophenyl)-5-cyclopropyl-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3-carboxamide 7-[(E,4S)-4-(azetidin-l-yl)pent-2-enoyl]-N-(2-chlorophenyl)-5-cyclopropyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide (5R)-7-[(E,4S)-4-(azetidin-1 -yl)pent-2-enoyl]-N-(2-chlorophenyl)-5 -cyclopropyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide (5S)-7-[(E,4S)-4-(azetidin-l-yl)pent-2-enoyl]-N-(2-chlorophenyl)-5-cyclopropyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 526 <> xr / XyUX 0 7-[(E,4R)-4-(azetidin-l-yl)pent-2-enoyl]-N-(2-chlorophenyl)-5-cyclopropyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 527 o Y y-NH v 0 (5R)-7-[(E,4R)-4-(azetidin- l-yl)pent-2-enoyl]-N-(2-chlorophenyl)-5- cyclopropyl-6,8- dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 528 o >"'V / \=o (5S)-7-[(E,4R)-4- (azetidin-1-yl)pent-2-enoyl]-N-(2-chlorophenyl)-5-cyclopropyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 529 V °y-NH I fi (S)-N-(2-chlorophenyl)-5-cyclopropyl-7-((S,E)-4-(dimethylamino)pent-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 530 —z O=Y rx-o Q (5S)-N-(2-chlorophenyl)-5-cyclopropyl-7-[(E)-4-(dimethylamino) but-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 531 o h v 1 (5 S)-7-[(E)-4-(azetidin-1 -yl)but-2-enoyl]-N-(2-chlorophenyl)-5-cyclopropyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 532 H v y nH" a eh OD 1            0 (5R)-N-(2-chlorophenyl)-5-cyclopropyl-7-[(E,4S)-4-(dimethylamino) pent-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3-carboxamide 533 o hY Vn«” Cl 1 ? Y 0 (5R)-N-(2-chlorophenyl)-5-cyclopropyl-7-[(E)-4-(dimethylamino) but-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 534 FF Yy$ (5R)-7-[(E)-4-(azetidin-l-yl)but-2-enoyl]-N-(2-chlorophenyl)-5-cyclopropyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 535 Cl Cl- / ^ i r (5R)-5-cyclopropyl-N-(2,4-dichlorophenyl)-7-[(E)-4-(dimethylamino) but-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide b Compound No. Structure Compound Name 536 Cl / o V ox / ci fY A I            0 (5S)-5-cyclopropyl-N-(2,4-dichlorophenyl)-7’[(E)_4-(dimethylamino)but -2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 537 Cl »Y yi> .. y,, 0 (5R)-5-cyclopropyl-N-(2,4-dichlorophenyl)-7- [(E,4 S)-4-(dimethylamino) pent-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3-carboxamide 538 Cl (y hY °3A Lh XYz 1            0 (5S)-5-cyclopropyl-N-(2,4-dichlorophenyl)-7- [(E,4 S)-4-(dimethylamino) pent-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3-carboxamide 539 o o A y*01 7-((S,E)-4-(azetidin-1 -yl)pent-2-enoyl)-N-(2-chlorophenyl)-5-ethyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 540 o o "x K Cl Y (5R)-7-[(E,4S)-4-(azetidin-1 -yl)pent-2-enoyl]-N-(2-chlorophenyl)-5- ethyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 541 o \    0     / ci y-NH (5S)-7-[(E,4S)-4- (azetidin-1-yl)pent-2-enoyl]-N-(2-chlorophenyl)-5-ethyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 542 Cl o \ o / "ci ! H YH (5S)-N-(2,4-dichlorophenyl)-5-ethyl-7-[(E,4S)-4-[ethyl(methyl)amino] pent-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 543 Ci ( / 0V-NH Cl H-4 / (5R)-N-(2,4-dichlorophenyl)-5-ethyl-7-[(E)-4-[ethyl(methyl)amino] but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 544 Cl Q \ CL / Cl H> VNH (5S)-N-(2,4-dichlorophenyl)-5-ethyl-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 545 Cl ., A, •“Ys     / ? „ rYS 1            o (5S)-N-(2,4-dichlorophenyl)-5-ethyl-7-[(E,4R)-4-[ethyl(methyl)amino] pent-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. 546 547 548 549 Structure Compound Name (5R)-N-(2,4-dichlorophenyl)-5-ethyl-7-((R,E)-4-(ethyl(methyl)amino)pent-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide (5R)-N-(2,4-dichlorophenyl)-5-ethyl-7-[(E,4S)-4-[ethyl(methyl)amino] pent-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide (5S)-N-(2,4-dichlorophenyl)-7-[(E)-4-(dimethylamino)but-2-enoyl]-5 -ethyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide (5R)-N-(2,4-dichlorophenyl)-7-[(E)-4-(dimethylamino)but-2-enoyl] -5-ethyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 550 < / \ o. V v* T % (5S)-N-(2-chlorophenyl)-7-[(E)-4-(dimethylamino)but-2-enoyl]-5-ethyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3-carboxamide 551 o \           / Ci h! TH O > Y -- N I           0 (5R)-N-(2-chlorophenyl)-7-[(E)-4-(dimethylamino)but-2-enoyl]-5-ethyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3-carboxamide 552 Q X| °y-NH C! / V<XaA ’           0 (5R)-N-(2-chlorophenyl)-5-ethyl-7-[(E,4R)-4-[ethyl(methyl)amino]pent- 2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 553 \ V x / "'K_ ) —@3 — / (5S)-N-(2,4-dichlorophenyl)-5-ethyl-7-[(E,4S)-4-[ethyl(methyl)amino] pent-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 554 Vy? \r    [^N 7-((S,E)-4-(azetidin-1 -yl)pent-2-enoyl)-N-(2-chlorophenyl)-5-cyclobutyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound Name (5R)-7-[(E,4S)-4-(azetidin-1 -yl)pent-2-enoyl]-N-(2-chlorophenyl) -5-cyclobutyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide (5S)-7-[(E,4S)-4-(azetidin-l-yl)pent-2-enoyl]-N-(2-chlorophenyl)-5-cyclobutyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 7-[(E,4R)-4-(azetidin-l-yl)pent-2-enoyl]-N-(2-chlorophenyl)-5-cyclobutyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide (5R)-7-[(E,4R)-4-(azetidin-1 - yl)pent-2-enoyl]-N-(2-chlorophenyl)-5- cyclobutyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide (5 S)-7-[(E,4R)-4-(azetidin-1 -yl)pent-2-enoyl]-N-(2-chlorophenyl)-5-cyclobutyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 560 o \  0 / "vl ? h N          N (5S)-N-(2-chlorophenyl)-5-ethyl-7-[(E,4R)-4-[ethyl(methyl)amino]pent- 2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 561 CKy / o. r V-NH j r^r> 0 (5R)-N-(2-chlorophenyl)-7-[(E,4S)-4- [ethyl(methyl)amino]pent-2-enoyl] -5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 562 o h> yN(T 1 UH      ! i > zyXiyAA 1           0 (5R)-N-(2-chlorophenyl)-5-ethyl-7-[(E,4S)-4-[ethyl(methyl)amino] pent-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 563 N-(2-chlorophenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-5- (2,2,2-trifluoroethyl)-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Table 3. Compound No. Structure Compound Name 564 J^V01 HN / --. |^N \ N 1 (E)-N-(2,5-dichlorophenyl)-7-(3-(l-methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 565 Cl HN /         J (E)-N-(2,4-dichlorophenyl)-7-(3-(l-methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide. 566 F Cl-^^ HN >o \s (E)-N-(2-chl oro-3 -fluorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 567 C'O HN Vs HN^^I       O    2HCI N-(2-chlorophenyl)-7-[(E)-4-piperazin-l-ylbut-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide dihydrochloride 567a c,yp °y-NH r^N \s HN          0 N-(2-chlorophenyl)-7-[(E)-4-piperazin-l-ylbut-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 568 --Q HCo HCI 1                    <y> (E)-N-(2-chlorophenyl)-7-(4-(dimethylamino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide hydrochloride Compound No. Structure Compound Name 568a °y^NH l^N (E)-N-(2-chlorophenyl)-7-(4-(dimethylamino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 569 p z—n. /   \      o V vy y o N-(2-chlorophenyl)-7-[(E)-4-phenoxybut-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carb oxamide 570 Cl °y_ nh r^N 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 571 F c,y °y,NH \s N-(2-chloro-4-fluoro-phenyl)-7-[(E)-4- (3-cyanoazetidin-1 -yl)but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 572 c.4X N-(2-chl oro-5 -fluoro-phenyl)-7-[(E)-4-(3 -cyanoazetidin-1 -yl)but-2-enoyl] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 573 Cl C|JO °y.NH 7-[(E)-4-(3-cyanoazetidin-l-yl)but-2-enoyl]-N-(2,3-dichlorophenyl)-6,8- dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 574 ci-Q Xs 7-[(E)-4-(3-cyanoazetidin-l-yl)but-2-enoyl]-N-(2,6-dichlorophenyl) -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 575 Cl Cly5 y^ ^~N Xs 7-[(E)-4-(3-cyanoazetidin-l-yl)but-2-enoyl] -N-(2,4-dichlorophenyl)-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 576 F-XTj^ y^cl Xs N-(2-chloro-6-fluoro-phenyl)-7-[(E)-4-(3 -cyanoazetidin-1 -yl)but-2-enoyl] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 577 CI-^O HN y^o r^N \s h      0 N-(2-chlorophenyl)-7-[(E)-4-(ethylamino)but-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 578 0 CF3COOH        V-NH h      0 N-(2-chlorophenyl)-7-[(E)-4-(2-fluoroethy 1 amino)but-2-enoy 1 ] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3-carboxamide trifluoroacetic acid 578a a^Q °y_NH h      0 N-(2-chlorophenyl)-7-[(E)-4-(2-fluoroethy 1 amino)but-2-enoy 1 ] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3-carboxamide 579 HN >0 r^N -n^-y^n^ h       0 N-(2-chlorophenyl)-7-[(E)-4-(methylamino)but-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 580 IZ^ Z— /  \      O 0 N-(2-chlorophenyl)-7-[(E)-4-[(l-methylcyclobutyl)amino]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 581 QY u      \   / (E)-N-(2-chlorophenyl)-7-(3-(l-methylazetidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 582 cijp HN (E)-7-(3-(azetidin-2-yl)acryloyl)-N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 583 a-O a of (E)-7-(3-(1-(7- aminoheptyl)pyrrolidin-2-yl)acryloyl)-N-(2-chlorophenyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 584 Cl^ HN yd A   I^NA N-(2-chlorophenyl)-7-[(E)-3-(4-methylmorpholin-3 -yl)prop-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 585 HN yO । r^N H2N^\^^ 7-[(E)-4-aminopent-2-enoyl]-N-(2-chlorophenyl)-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 586 ClA^ HN yo 1     p^N A N-(2-chlorophenyl)-7-[(E)-4-(dimethylamino)pent-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 587 NH a (E)-N-(2-chlorophenyl)-7-(3-(l-(3,3,3 -trifluoropropyl)pyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 588 ci-O (E)-N-(2-chlorophenyl)-7-(5-(methylamino)pent-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 589 o J^CI \^° N-(2-chlorophenyl)-7-[(E)-3-(4-piperidyl)prop-2-enoyl]-6,8-dihydro-5H- imidazo[l,2-a]pyrazine-3-carboxamide 590 o Hhl^1 H          >° a rn N-(2-chlorophenyl)-7-[(E)-3-(3-piperidyl)prop-2-enoyl]-6,8-dihydro -5H-imidazo[l,2-a]pyrazine-3-carboxamide 591 o hZ^01 / NW        \s N-(2-chlorophenyl)-7-[(E)-3-(2-piperidyl)prop-2-enoyl]-6,8-dihydro -5H-imidazo[l,2-a]pyrazine-3-carboxamide 592 o hZ^ci >0 (E)-N-(2-chlorophenyl)-7-(3-(morpholin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 593 °y-NH 1^0     l^N NX (E)-N-(2-chlorophenyl)-7-(3-(4-methylmorpholin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 594 ci-Q °y,NH / -NZ (E)-N-(2-chlorophenyl)-8-methyl-7-(3-(1 -methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 595 °^p A N Jssk / 1 W N-(2-chlorophenyl)-6-cyclopropyl-7-[(E)-4-[ethyl(methyl)amino] but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 596 CI'O o X-NH V-V        N J^k? 1 i (E)-N-(2-chlorophenyl)-7-(4-((3-methoxycyclobutyl)(methyl)amino )but-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 597 Cl-^^ o ) ^NH f^N A JU H    A O (E)-N-(2-chlorophenyl)-7-(4-(((3-methoxycyclobutyl)methyl)amino) but-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 598 °y__NH r^N a CTA"^ (E)-N-(2-chlorophenyl)-7-(4-(2-methyl-1,4-diazepan-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 599 °    2HCI (E)-N-(2-chlorophenyl)-7-(4-(2-methyl-1,4-diazepan-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide dihydrochloride 600 Cl—^^ HrCo I          0 (E)-N-(2-chlorophenyl)-7-(4-((3,3 -difluorocyclobutyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 601 ci-Xp HN >0 N-(2-chlorophenyl)-7-[(E)-4-(4-ethyl-1,4-diazepan-1 -yl)but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 602 °^NH (E)-N-(2-chlorophenyl)-7-(4-(5-methyl-1,4-diazepan-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 603 l^N \s HN^ / \7 (E)-N-(2-chlorophenyl)-7-(4-(hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 604 XT cf3cooh 'y-Nn l^N (E)-N-(2-chlorophenyl)-7-(4-(hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 2,2,2-trifluoroacetate 605 t z—a W6 N-(2-chlorophenyl)-7-[(E)-4-hydroxybut-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carb oxamide 606 f_Q'ci 0 ^NH 1 w N-(5 -chloro-2-fluoro-phenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 607 Cl °y_NH 1 w N-(4-chloro-2-fluoro-phenyl)-7-[(E)-4-[ethyl(methyl)amino] but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 608 ci^Q 0 J 1 i N-(2-chloro-4-methyl-phenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 609 ^n^^YN^n? 1                      <y> N-(2-chloro-6-methoxy-phenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 610 pp ^NH । i N-(3 -chloro-2-fluoro-phenyl)-7-[(E)-4-[ethyl(methyl)amino] but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 611 F °^NH 1           o N-(2-chloro-4-fluoro-phenyl)-7-[(E)-4- [ethyl(methyl)amino]but-2-enoyl] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 612 Cl 1          O N-(2,3-dichlorophenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-6,8- dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 613 Q-°x °y-NHcl ^n^-yn^n? 1           i N-(2-chloro-3-methoxy-phenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 614 jy°, °^NH 1          o N-(2-chloro-5-methoxy-phenyl)-7-[(E)-4-[ethyl(methyl) amino]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 615 JVF a^\7 °^NH f^A 1                     i!> N-(2-chloro-5-fluoro-phenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 616 CI"A—X cl 1 i (E)-N-(2,6-dichlorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 617 Cl m3 O / ^NH 1 N-(4-chloro-2-methoxy-phenyl)-7-[(E)-4-[ethyl(m ethyl) amino]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 618 Cl O -^NH 1                3) N-(3-chloro-2-methoxy-phenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 619 jv YltH ।                     <y> N-(6-chl oro-1,3-benzodi oxol-5-yl)-7-[(E)-4-[ethyl(methyl)amino] but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 620 J 3 7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-N-thiazol-5-yl-6,8-dihydro- 5H-imidazo[l,2-a]pyrazine-3-carboxamide 621 Ai Cl—Ms / °-x Nh Ya ^n^ynJ"3 i <!!> N-(4-chloro-3-pyridyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3-carboxamide 622 / V° O / \S y-NH 1 A N-(5 -chi oro-1,3 -b enzodi oxol -4-yl)-7-[(E)-4-[ethyl(methyl)amino] but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 623 Cl'^^ °yNH F l^N Vs N-(2-chlorophenyl)-7-[2-fluorobut-2-enoyl]-6,8-dihydro-5H-imidazo [l,2-a]pyrazine-3-carb oxamide Compound No. Structure Compound Name 624 °y,NH N-(2-chlorophenyl)-7-[(E)-2-fluorobut-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carb oxamide 625 °^NH F N-(2-chlorophenyl)-7-[(Z)-2-fluorobut-2-enoyl]-6,8- dihydro-5H-imidazo[l,2-a]pyrazine-3-carb oxamide 626 0_ 1 i N-(4-chl oro-1,3-benzodi oxol-5-yl)-7-[(E)-4-[ethyl (methyl)amino]but -2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 627 ay o    H \-0 CI^N^X 5-(2-chloroacetyl)-N-(2-chlorophenyl)-4,5,6,7-tetrahydropyrazolo[ 1,5-a]pyrazine-3-carboxamide 628 c^Q . °y-NH N-(2-chlorophenyl)-5-methyl-7-[rac-(E)-4-(azetidin-l-yl)but-2-enoyl] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 629 c|-"C^ , °y^NH l'N \\ 1 (E)-N-(2-chlorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 630 ci-Q . °^NH (E)-N-(2-chlorophenyl)-5-methyl-7-(4-(pyrrolidin-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 631 . ^Nh (E)-N-(2-chlorophenyl)-5-methyl-7-(4-(2-methylpyrrolidin-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 632 r==\^CI °x ।        nh ।       i^n \\ (E)-N-(2,3-dichlorophenyl)-5-methyl-7-(4-(pyrrolidin-l-yl)pent-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 633 Oc . y^1 1      l'N (E)-N-(2-chloro-3-methylphenyl)-5-methyl-7-(4-(pyrrolidin-l-yl)pent-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 634 ci'X^ , °y,NH 1        । H (E)-N-(2-chlorophenyl)-7-(5-(ethyl(methyl)amino)pent-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 635 Cl-^^ . °y,NH ।        । H (E)-N-(2-chlorophenyl)-7-(5-(dimethylamino)pent-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 636 Cl-Z^ . °y_NH r^N (E)-N-(2-chlorophenyl)-7-(4-(dimethylamino)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 637 ciUQ °y_NH 1 i (E)-N-(2-chlorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-6-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 638 Cl-O °y^NH 1                              Vs (E)-N-(2-chlorophenyl)-7-(4-(pyrrolidin-1 -yl)pent-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 639 ci-Q °y,NH \s 0 (E)-N-(2-chlorophenyl)-7-(4-(3-methoxyazetidin-l-yl)but-2-enoyl)-6-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 640 ci^Q °y.NH 1       l^N Vs N-(2-chlorophenyl)-7-[(E)-4-pyrrolidin-1 -ylpent-2-enoyl]-6,8-dihydro -5H-imidazo[l,2-a]pyrazine-3-carboxamide 641 o 0   / <21 y,NH Ul i       r^N Vs 1 (Ji (E)-N-(2-chlorophenyl)-7-(4-(ethyl(methyl)amino)pent-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 642 ...          o I Y X & XJ / > N-(2-chlorophenyl)-7-[(E)-4-(2-methylazetidin-1 -yl)but-2-enoyl] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3-carboxamide 643 (E)-N-(2-chlorophenyl)-5-methyl-7-(4-(2-methylazetidin-l-yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 644 . °y.NH 1             "A (E)-N-(2-chlorophenyl)-5-methyl-7-(4-(pyrrolidin-1 -yl)pent-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 645 Cl"^^ . °y_NH 1       ("N Vs 1           i (E)-N-(2-chlorophenyl)-7-(4-(ethyl(methyl)amino)pent-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 646 , °y^ l^N Vs yrn'^ (E)-N-(2-chlorophenyl)-7-(4-(3-(difluoromethyl)azetidin-l-yl)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 647 o l^N Xs (E)-7-(4-(azetidin-1 -yl)but-2-enoyl)-N-(2-chlorophenyl)-8-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 648 ci-Q O / --hF^ i^N-A \A^yN^Q (E)-N-(2-chlorophenyl)-7-(3-(l-phenylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 649 ci-Q °y,NH (E)-N-(2-chlorophenyl)-7-(3-(l-cyclopropylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 650 . ^nh l^N \\ F             0 (E)-N-(2-chlorophenyl)-7-(4-(l-cyclopropyl-4,4-difluoropyrrolidin-2-yl)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 651 c.^Q . °y.NH V-N^^  0 (E)-N-(2-chlorophenyl)-7-(4-(l-cyclopropylpyrrolidin-2-yl)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 652 o / ■—NH (E)-N-(2-chlorophenyl)-7-(3-(4-fluoropyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 653 O HN^01 y^o / ~-N / (E)-N-(2-chlorophenyl)-7-(3-(4-fluoro-l-methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 654 O /       yJ1 Ny      l^N Xs N-(2-chlorophenyl)-7-[(E)-3-(l-i sopropylpyrrolidin-3 -yl)prop-2-enoyl] -6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 655 ci-Q °^NH Cvxd h      0 (E)-N-(2-chlorophenyl)-6-methyl-7-(3 -(morpholin-3 -yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 656 rvci c|,>yV °X^NH / --NH              \s (E)-N-(2,5-dichlorophenyl)-7-(3-(pyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 657 CV01 r^N H fl (E)-N-(2,5-dichlorophenyl)-5-methyl-7-(3-(pyrrolidin-2-yl)acryl oyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 658 \ z^i (E)-N-(2-chlorophenyl)-7-(3-(l-isopropylpyrrolidin-3-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 659 c,^ °yrT N-(2-chlorophenyl)-7-[(E)-3-(l-methylpyrrolidin-3-yl)prop-2-enoyl]-6,8- dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 660 C.42 °rr a~n / ^ ^nA (E)-N-(2-chlorophenyl)-7-(3-(l-(3,3,3 -trifluoropropyl)pyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 661 F F   Cl^ °y,NH ^'"'hr     |^N^, N-(2-chlorophenyl)-7-[(E)-3-[4-(3,3,3 -trifluoropropyl)morpholin-3-yl] prop-2-enoyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carb oxamide 662 c.4p °^NH ~Xxl^X'N (E)-N-(2-chlorophenyl)-6-methyl-7-(3 -(4-methylmorpholin-3 -yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 663 °y^NH n         N 1 {J N-(2-chlorophenyl)-7-[(E)-4-[methyl(3,3,3-trifluoropropyl)amino]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 664 c.4p । °AH (E)-N-(2-chlorophenyl)-5-methyl-7-(4-(4-methyl-1,4-diazepan-1 -yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 665 yr (E)-N-(2-chlorophenyl)-7-(3-(l-methylpyrrolidin-3-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 666 rvci 1 / -NZ     l"N Vs V^-J Y (E)-N-(2,5-dichlorophenyl)-5-methyl-7-(3-(l-methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 667 ryci cl-'-ry °^Nh / -NZ (E)-N-(2,5-dichlorophenyl)-6-methyl-7-(3-(l-methylpyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 668 ci-Q °-^nh / —nz xA^yyW N-(2-chlorophenyl)-8-methyl-7-[(E)-3-(l-methylpyrrolidin -2-yl)prop-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 669 ci-O , °<^nh h    Al? (E)-N-(2-chlorophenyl)-5-methyl-7-(4-(pyrrolidin-2-yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 670 c.^Q . °y,NH F \__NH      0 (5S)-N-(2-chlorophenyl)-7-((E)-4-(4,4-difluoropyrrolidin-2-yl)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 671 । °y-NH r^N \s V-N      0 / t (E)-N-(2-chlorophenyl)-5-methyl-7-(4-(1-(3,3,3-trifluoropropyl)pyrrolidin-2-yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 672 Cl o 0  (\^F l^N Vs 1 i! N-[4-chloro-2-(trifluoromethyl)phenyl]-7-[(E)-4-[ethyl(methyl)amino] but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 673 Q 0 / VF l^N Vs / 'N^Yn-X 1 il 7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-N-[2-(trifluoromethyl)phenyl] -6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 674 F , °y_NH (E)-N-(2-chloro-4-fluorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 675 rVci ci-\ / HN >O <^NH         \s H jT (E)-N-(2,5-dichlorophenyl)-6-methyl-7-(3-(pyrrolidin-2-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 676 Q Hn / --,        r^N \\ QnJ^yn^W (E)-N-(2-chlorophenyl)-7-(3-(hexahy dro-1 H-pyrrolizin-3 -yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 677 °y_NH N-(2-chlorophenyl)-7-(3-(hexahy dro-1 H-pyrrolizin-3 -yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 678 CI-O o । ■y-NH 1                              Vs 1     N JkK? (E)-7-(4-(azetidin-l-yl)pent-2-enoyl)-N-(2-chlorophenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 679 ryci l"N \\ (E)-7-(4-(azetidin-1 -yl)but-2-enoyl)-N-(2,5-dichlorophenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 680 । °y-NH (E)-7-(4-(azetidin-1 -yl)but-2-enoyl)-N-(2-chlorophenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 681 / VCI ci-\ / o .         । V-nh Sr (E)-7-(4-(azetidin-l-yl)hex-2-enoyl)-N-(2,5-dichlorophenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 682 Ca . y^1 (E)-7-(4-(azetidin-l-yl)pent-2-enoyl)-N-(2-chl oro-3 -methylphenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 683 , y^1 (E)-7-(4-(azetidin-l-yl)pent-2-enoyl)-N-(2-chl oro-3 -fluorophenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 684 CIXX , y^ (~'N \\ (E)-N-(2-chlorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 685 C!-O o 7 ।         r^N (E)-N-(2-chlorophenyl)-7-(4-(isopropyl(methyl)amino)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 686 ci^O , °y-NH A             A 1 i (E)-N-(2-chlorophenyl)-7-(4-(cyclopropyl(methyl)amino)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 687 0 । y-NH r^N \s 1 i (E)-N-(2-chlorophenyl)-5-methyl-7-(4-(methyl(propyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 688 . °y-NH 1       [^N Vs 1 iJ (E)-N-(2-chlorophenyl)-7-(4-(dimethylamino)pent-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 689 / z— \-z (E)-7-(4-(azetidin-l-yl)hex-2-enoyl)-N-(2-chlorophenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 690 rVcl o .         | y,NH \r (E)-7-(4-(azetidin-l-yl)hex-2-enoyl)-N-(2,5-dichlorophenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 691 C!-O o / । y-NH h      0 (E)-N-(2-chlorophenyl)-7-(4-(ethylamino)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 692 ci^ , ^NH (E)-N-(2-chlorophenyl)-7-(4-(diethylamino)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 693 a-C3 o / \ H y-NH 1      l^N (E)-7-(4-(azetidin-l-yl)pent-2-enoyl)-N-(2-chloro-4-methylphenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 694 c.^O IT" 1                1 N 7-[(E,4R)-4-(azetidin-l-yl)pent-2-enoyl]-N-(2-chlorophenyl)-5-ethyl-6,8- dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 695 / ^==^, Cl °k x^ci । y-NH 1       l"N Vs (E)-7-(4-(azetidin-l-yl)pent-2-enoyl)-N-(2,3-dichlorophenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 696 / ^==^,0 y x °x । y-NH 1       [^N Vs (5R)-7-[(E,4R)-4-(azetidin-1 - yl)pent-2-enoyl]-N- (2-chloro-3-methoxy-phenyl)-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 697 o 1 y-NH 1         A (5R)-7-[(E,4R)-4-(azetidin-1 -yl)pent-2-enoyl]-N-(2-chloro-3-methyl- phenyl)-5-methyl-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 698 Cl Cl'^^ o ? 1 y-NH i inA (E)-7-(4-(azetidin-l-yl)pent-2-enoyl)-N-(2,4-dichlorophenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 699 ci--C^ , °y_NH 1       l^N Vs 1 iJ (E)-N-(2-chlorophenyl)-7-(4-(dimethylamino)pent-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 700 ci-O o . H y-NH 1      l"N JL      n (E)-N-(2-chlorophenyl)-7-(4-(diethylamino)pent-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 701 c-O o 1T 1      l"N V 1 / . N i                         <!! (E)-N-(2-chlorophenyl)-7-(4-(dimethylamino)pent-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 702 C!-O o / ^ 1         nh N (E)-N-(2-chlorophenyl)-7-(4-(3-cyanoazetidin-l-yl)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazi ne-3-carboxamide 703 o HN^01 ar (E)-N-(2-chlorophenyl)-5-(4-(pyrrolidin-1 -yl)but-2-enoyl)-5,5a,6,7,8,8a-hexahydro-4H-cyclopenta[e]imidazo[l,2-a]pyrazine-1 -carboxamide 704 ci-^3 , °y_.NH l       ["N \\ 1     N J^k / (E)-7-(4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pent-2-enoyl)-N-(2-chlorophenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazi ne-3-carboxamide 705 c.43 । °y-NH i 1 n jay (E)-N-(2-chlorophenyl)-5-methyl-7-(4-morpholinopent-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 706 “Or o / 17 D      N 7 ZK ZK X N JUk? (E)-N-(2-chlorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl-2,3-d2)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazi ne-3-carboxamide Compound No. Structure Compound Name 707 A j D a N (E)-7-(4-(azetidin-1 -yl)but-2-enoyl-2,3-d2)-N-(2-chlorophenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazi ne-3-carboxamide 708 CI—XX o ? । y-NH D i {J (E)-N-(2-chlorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl-2-d)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 709 Cl-O o H z y HN^__} (E)-7-(4-(l ,4-diazepan-1 -yl)but-2-enoyl)-N-(2-chlorophenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 710 c.^Q , yr (E)-N-(2-chlorophenyl)-7-(4-(4-cyclopropyl-1,4-diazepan-1 -yl)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 711 c.^Q 1 \r [ nA (E)-7-(4-(azetidin-1 -yl)-4-cyclopropylbut-2-enoyl)-N-(2-chlorophenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 712 cXj o r . H y-NH y H A (E)-7-(4-(azetidin-1 -yl)-4-cyclopropylbut-2-enoyl)-N-(2-chlorophenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 713 n O / Y| y_NH N-(2-chlorophenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-6,8- dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide 714 aX) o / ^ । y-NH (E)-N-(2-chlorophenyl)-7-(5-(ethyl(methyl)amino)pent-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 715 o / 41" (E)-N-(2-chlorophenyl)-7-(5-(dimethylamino)pent-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 716 c.4>F o r । y-NH [^N"A N J^k / (E)-N-(2-chloro-5-fluorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 717 cluQ (E)-N-(2-chloro-6-fluorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 718 F , °y-NH l^N Vs (E)-N-(2-chl oro-3 -fluorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 719 F 0    ? । y-NH f^N Vs (E)-N-(2-chloro-4-fluorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 720 c.X) । °y^NH 1      |N Vs (E)-N-(2-chloro-4-methylphenyl)-5-methyl-7-(4-(pyrrolidin-l-yl)pent-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 721 Cl ^"'CS . °y_NH [^N Vs (5R)-N-(2,4-dichlorophenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl] -5-methyl-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide Compound No. Structure Compound Name 722 Ci^j , °y,NH (E)-N-(2-chloro-4-methylphenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 723 ^z z— \-z Il \ o o Z       T T vA- (E)-7-(4-(azetidin-l-yl)pent-2-enoyl)-N-(2-chloro-4-methylphenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 724 Cl . %^NH (E)-N-(2,3-dichlorophenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 725 If o X^CI 1 x—nh I (E)-7-(4-(azetidin-l-yl)pent-2-enoyl)-N-(2,3-dichlorophenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 726 / ^\,o vrx i v^1 1     ["NA (E)-N-(2-chloro-3- methoxyphenyl)-5-methyl-7-(4-(pyrrolidin-1 -yl)pent-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 727 oz _ \ o 7 z— (E)-N-(2-chl oro-3-methoxyphenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 728 CL X X—NH 0 N-(2-chloro-3-methyl-phenyl)-7-[(E)-4-[ethyl(methyl)amino] but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 729 Z—a (E)-N-(2-chloro-3-methylphenyl)-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 730 / ^X—F , y^kcl ।     r~N k (E)-N-(2-chl oro-3 -fluorophenyl)-5-methyl-7-(4-(pyrrolidin-l-yl)pent-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 731 F ,  °0-NH l^N \s A ® (E)-N-(2-chloro-4-fluorophenyl)-7-(4- (cyclopropyl(ethyl)amino)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 732 i y^F A ® (E)-N-(2-chloro-6-fluorophenyl)-7-(4-(cyclopropyl(ethyl)amino)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 733 c,yYF O f । y^NH [^N Vs A ® (E)-N-(2-chloro-5-fluorophenyl)-7-(4-(cyclopropyl(ethyl)amino)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 734 F Cl-^^ . °y-NH l'^1 Vs A ® (E)-N-(2-chl oro-3 -fluorophenyl)-7-(4-(cyclopropyl(ethyl)amino)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 735 V\ i v^1 1       l^N Vs (E)-7-(4-(azetidin-l-yl)pent-2-enoyl)-N-(2-chl oro-3 -fluorophenyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 736 o J Z—A \-z (E)-N-(2-chlorophenyl)-7-(4-(3-ethoxyazetidin-1 -yl)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 737 (E)-N-(2-chlorophenyl)-7-(4-(3-methoxy-3 -methylazetidin-1 -yl)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 738 a-Q । °y^NH l^N \s 1 x^cr'-'      O (E)-N-(2-chlorophenyl)-7-(4-(3-isopropoxyazetidin-l-yl)but-2-enoyl)-5-methyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 739 O O \ / / z \ ^-Z (E)-N-(2-chloro-4-fluorophenyl)-5-methyl-7-(3-(morpholin-3-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 740 °X)^ — ^y^v' O O \ / / z \ z (E)-N-(2,4-dichlorophenyl)-5-methyl-7-(3 -(morpholin-3 -yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 741 u O \ / / z \ z (E)-N-(2-chloro-4-methylphenyl)-5-methyl-7-(3-(morpholin-3-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 742 743 744 745 746 (E)-N-(2-chl oro-3 -fluorophenyl)-5-methyl-7-(3-(morpholin-3-yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide (E)-N-(2,4-dichlorophenyl)-5-methyl-7-(3 -(morpholin-3 -yl)acryloyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide (E)-N-(2-chlorophenyl)-5-methyl-7-(3 -(morpholin-3 -yl)acryloyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide (E)-N-(2-chlorophenyl)-5-methyl-7-(4-(tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)-yl)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide (E)-N-(2-chlorophenyl)-5-ethyl-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 747 °y-NH (E)-N-(2-chlorophenyl)-6-cyclopropyl-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 748 ci-O 1 i N-(2-chlorophenyl)-5-cyclopropyl-7-[(E)-4-[ethyl(methyl) amino]but-2-enoyl]-6,8-dihydro-5H-imidazo[ 1,2-a]pyrazine-3 -carboxamide 749 ci-Q J / (E)-7-(4-(azetidin-l-yl)pent-2-enoyl)-N-(2-chlorophenyl)-5-cyclopropyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 750 , X i <!J (E)-N-(2-chlorophenyl)-5-cyclopropyl-7-(4-(dimethylamino)pent-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 751 ci-X3 i {J (E)-N-(2-chlorophenyl)-5-cyclopropyl-7-(4-(dimethylamino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 752 V (E)-7-(4-(azetidin-1 -yl)but-2-enoyl)-N-(2-chlorophenyl)-5-cyclopropyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 753 Cl Ci^5 1 il (E)-5-cyclopropyl-N-(2,4-dichlorophenyl)-7-(4-(dimethylamino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 754 Cl ci'X^ . xy (E)-5-cyclopropyl-N-(2,4-dichlorophenyl)-7-(4-(dimethylamino)pent-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide 755 o N (E)-7-(4-(azetidin-l-yl)pent-2- enoyl)-N-(2-chlorophenyl)-5-ethyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 756 Cl ci--XS S' °y_NH 1       l"N \\ i A (E)-N-(2,4-dichlorophenyl)-5-ethyl-7-(4-(ethyl(methyl)amino)pent-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 757 Cl Cl-A-S / o / S y-NH (E)-N-(2,4-dichlorophenyl)-5-ethyl-7-(4-(ethyl(methyl)amino)but-2-enoyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxamide Compound No. Structure Compound Name 758 Cl Cl-J^ / o / s' y-NH [^N Xs (E)-N-(2,4-dichlorophenyl)-7-(4-(dimethylamino)but-2-enoyl)-5-ethyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 759 Cl— S' °y^NH l^N Vs 1 iJ (E)-N-(2-chlorophenyl)-7-(4-(dimethylamino)but-2-enoyl)-5-ethyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 760 ci— / 0 f y-NH 1             1 N \s 1           i (E)-N-(2-chlorophenyl)-5-ethyl-7-(4-(ethyl(methyl)amino)pent-2-enoyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 761 N      |"N \\ Ay Y (E)-7-(4-(azetidin-l-yl)pent-2-enoyl)-N-(2-chlorophenyl)-5-cyclobutyl-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyrazine-3-carboxamide 762 Cl— 1 it N-(2-chlorophenyl)-7-[(E)-4-[ethyl(methyl)amino]but-2-enoyl]-5- (2,2,2-trifluoroethyl)-6,8-dihydro-5H-imidazo[l,2-a]pyrazine-3-carboxamide

[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 each other 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 the separation 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 following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro. H ,O \ OH H+ x o' —c-c(       C=QZ — c=cz |   \       /   \ H+ /   \ 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 di chi or om ethane.

[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 propertymodifying 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., Chern. 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 Ci-Cio alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, Ci-Cio alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(Ci-Ce alkyl)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 a-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 Ci-4alkylamine such as methylamine, a (C1-C4 alkyl)2amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a C1-C4 alkoxy-C2-C4 alkylamine such as 2-methoxyethylamine, a phenyl-Ci-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-C10 alkanoyl 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-(Ci-C4 alkyl)piperazin-l-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 the choice 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 suitable solvents 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 skilled person 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 ICso. 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 infusion), 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 to the 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, Sjogren'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 Homer’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-a 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 CC12 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-a 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”, “Ci, C2, C3, C4, Cs or Ce alkyl” or “Ci-C 6 alkyl” is intended to include Ci, C2, C3, C4, Cs or Ce straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, Cs or Ce branched saturated aliphatic hydrocarbon groups. For example, CrC6 alkyl is intends to include Cb C2, C3, C4, C5 and C6 alkyl 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., Ci-Ce 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 or fewer 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-Ce” includes alkynyl groups containing three to six carbon atoms. As used herein, “C2-C6 alkenylene linker” or “C2-C6 alkynylene linker” is intended to include C2, C3, C4, Cs or Ce chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C2-C6 alkenylene linker is intended to include C2, C3, C4, Cs and Ce alkenylene 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., =0), 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, MB., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, 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, 3rd edition, 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 some embodiments, 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 (3rd edition), 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, 18th edition (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 following components: 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 by incorporating 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 obtained commercially 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-l -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, 19th edition, 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 will be 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: attachment and ** indicates amide attachment; Ri is C6-Cio aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more Ria; each Ria independently is halo, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxyl, or -C(O)N(Rib)(Ric), or two Ria, toget...

Claims

attachment and ** indicates amide attachment;Ri is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more Ria;each Ria independently is halo, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxyl, or -C(O)N(Rib)(Ric),or two Ria, together with the atoms to which they are attached, form a C3-C6 cycloalkyl or 5- to 6-membered heterocycle;each Rib independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl;each Ric independently is Ce-Cio aryl optionally substituted with one or more halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, or Ci-Ce alkoxyl;R2 is C2-C6 alkenyl or -C(O)R2a, wherein the C2-C6 alkenyl is optionally substituted with one or more R2b;R2a is Ci-Ce 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, Ce-Cio 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, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio 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, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl;each R2e independently is halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(Ci-Ce 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, Ce-Cio aryl, 5- to 10-membered heteroaryl, -CO(Ci-Ce alkyl), or -CO2(Ci-C6 alkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2;each R2f independently is halo, -CN, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, -CO2(R2g), -CON(R2g)(R2h), C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -C(0)-NH(Ci-C6 alkyl-Ci-Ce alkoxy), -(O(C2 alkyl))i-6, or -(O(C2 alkyl))i-6-NH2;each R2g independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio 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, Ci-Ce alkyl, or Ci-Ce haloalkyl;each R2h independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl;R3 is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 5- to 10-membered heterocyclyl, ortwo R3, together with the atoms to which they are attached, form a C3-C6 cycloalkyl or 5- to 6-membered heterocycle; andn is 0, 1, 2, 3, or 4..

2. A compound of Formula (II):(II),or a pharmaceutically acceptable salt thereof, wherein:Ri is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more Ria;each Ria independently is halo, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxyl, or -C(O)N(Rib)(Ric),or two Ria, together with the atoms to which they are attached, form a C3-C6 cycloalkyl or 5- or 6-membered heterocycle;each Rib independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl;each Ric independently is Ce-Cio aryl optionally substituted with one or more halo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, or Ci-Ce alkoxyl;R2 is C2-C6 alkenyl or -C(O)R2a, wherein the C2-C6 alkenyl is optionally substituted with one or more R2b;R2a is Ci-Ce 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, Ce-Cio 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, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio aryl, or 5- to 10membered 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, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl;each R2e independently is halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(Ci-Ce 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, Ce-Cio aryl, 5- to 10-membered heteroaryl, -CO(Ci-Ce alkyl), or -CO2(Ci-Ce alkyl), wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more -CN, -OH, Ci-Ce alkoxy, -NH-CO2(Ci-C6 alkyl), or -NH2;each R2f independently is halo, -CN, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, -CO2(R2g), -CON(R2g)(R2h), C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -C(0)-NH(Ci-C6 alkyl-Ci-Ce alkoxy), -(O(C2 alkyl))i-6, or -(O(C2 alkyl))i-6-NH2;each R2g independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, Ce-Cio 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, Ci-Ce alkyl, or Ci-Ce haloalkyl;each R2h independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl;R3 is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 5- to 10-membered heterocyclyl, ortwo R3, together with the atoms to which they are attached, form a C3-C6 cycloalkyl or 5- to 6-membered heterocycle; andn is 0, 1, 2, 3, or 4.

3. The compound of any one of the preceding claims, wherein Ri is phenyl or 5- or 6membered heteroaryl, wherein each phenyl or 5- or 6-membered heteroaryl independently is substituted with one or more Ria,wherein each Ria is halo, Ci-Ce alkyl, Ci-Ce alkoxyl, or -C(O)N(Rib)(Ric), or two Ria, 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 Ria is Cl, F, CF3, methyl, or methoxy.

5. The compound of any one of the preceding claims, wherein Rib is H.

6. The compound of any one of the preceding claims, wherein Ric is Ce-Cio aryl optionally substituted with one or more Ci-Ce haloalkyl.

8. The compound of any one of the preceding claims, wherein R2is -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; andR2b is halo, 4- to 10- membered heterocyclyl, -N(R2c)(R2d), -OR2c, Ce-Cio 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 R2b is Cl.

11. The compound of any one of the preceding claims, wherein R2c is H.

12. The compound of any one of claims 1-10, wherein R2c is Ci-Ce alkyl, C3-C6 cycloalkyl, or Ce-Cio 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 R2dis H, methyl, or ethyl.

14. The compound of any one of the preceding claims, wherein R2e is F, Cl, -OH, -CN, -CO(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, or -CO2(Ci-C6 alkyl).

15. The compound of any one of claims 1-13, wherein R2e is Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce 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, Ci-Ce alkoxy, or -NH-CO2(Ci-C6 alkyl).

16. The compound of any one of the preceding claims, wherein each R2f is independently halo, -CN, Ci-Ce alkyl, Ci-Ce alkoxy, -CO2(R2g), C3-C6 cycloalkyl, Ce-Cio aryl, Ci-Ce haloalkyl, or -C(O)-NH(Ci-Ce alkyl-Ci-Ce alkoxy).

17. The compound of any one of the preceding claims, wherein each R2f is 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 R2g is independently H or Ci-Ce alkyl.

19. The compound of any one of the preceding claims, wherein each R2g is independently H or te / 7-butyl.

21. The compound of any one of the preceding claims, wherein R3 is Ci-Ce 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 (Il-a), (Il-b), (n-b’), (n-c) (n-c’), (n-d), or (n-d’):or a prodrug, solvate, or pharmaceutically acceptable salt thereof.(ILc)24. A compound of Formula (III):Ri / HNor a pharmaceutically acceptable salt thereof, wherein:Ri is C6-C10 aryl optionally substituted with one or more Ria;each Ria independently is halo, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, or Ci-Ce alkoxyl;R2 is -C(O)R2a;R2a is Ci-Ce 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, Ce-Cio aryl, or 5- to 10-membered heteroaryl;each R2c independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl;each R2d independently is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Ci-Ce haloalkyl;R3 is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C10 cycloalkyl, or 5- to 10-membered heterocyclyl; andn is 0, 1, 2, 3, or 4.

25. The compound of claim 1 or claim 24, wherein Ri is phenyl optionally substituted with one or more Ria.

26. The compound of any one of claims 1 or 24-25, wherein Ria is halo.

27. The compound of any one of claims 1 or 24-26, wherein Ri isci28. The compound of any one of claims 1 or 24-27, wherein R2a is C2-C6 alkenyl or C2-C6 alkynyl, 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 R2b is independently -N(R2c)(R2d) or 4- to 10-membered heterocyclyl.

30. The compound of anyoneof claims 1 or 24-29, wherein R2c is methyl.

31. The compound of anyoneof claims 1 or 24-30, wherein R2d is methyl.

32. The compound of anyof claims 1 or 24-31, wherein R2 isone33. The compound of any one of claims 1 or 24-32, wherein the compound is of Formula (III-a), (Ill-b), or (ni-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, Sjogren'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.