CA2901671A1 - .gamma.-diketones as wnt/.beta. -catenin signaling pathway activators - Google Patents

.gamma.-diketones as wnt/.beta. -catenin signaling pathway activators

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CA2901671A1
CA2901671A1 CA2901671A CA2901671A CA2901671A1 CA 2901671 A1 CA2901671 A1 CA 2901671A1 CA 2901671 A CA2901671 A CA 2901671A CA 2901671 A CA2901671 A CA 2901671A CA 2901671 A1 CA2901671 A1 CA 2901671A1
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formula
unsubstituted
compound
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CA2901671C (en
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Sunil Kumar Kc
David Mark Wallace
John Hood
Charlene F. Barroga
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Biosplice Therapeutics Inc
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Samumed LLC
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    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
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Abstract

The present disclosure provides ?-diketones or analogs thereof, that activate Wnt/ß-catenin signaling and thus treat or prevent diseases related to signal transduction, such as osteoporosis and osteoarthropathy; osteogenesis imperfecta, bone defects, bone fractures, periodontal disease, otosclerosis, wound healing, craniofacial defects, oncolytic bone disease, traumatic brain injuries or spine injuries, brain atrophy/neurological disorders related to the differentiation and development of the central nervous system, including Parkinson's disease, strokes, ischemic cerebral disease, epilepsy, Alzheimer's disease, depression, bipolar disorder, schizophrenia; otic disorders like cochlear hair cell loss; eye diseases such as age related macular degeneration, diabetic macular edema or retinitis pigmentosa and diseases related to differentiation and growth of stem cell, such as hair loss, hematopoiesis related diseases and tissue regeneration related diseases.

Description

y ¨DIKETONES AS WNT/I3 -CATENIN SIGNALING PATHWAY ACTIVATORS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application Serial No. 61/768,033, filed February 22, 2013, which is incorporated by reference in its entirety herein.
BACKGROUND
Technical Field
[0002] This disclosure relates to activators of one or more proteins in the Wnt pathway, including activators of one or more Wnt proteins, and compositions comprising the same. More particularly, it concerns the use of a y-diketones or salts or analogs thereof, in the treatment of osteoporosis and osteoarthropathy; osteogenesis imperfecta;
bone defects; bone fractures; periodontal disease; otosclerosis; wound healing;
craniofacial defects; oncolytic bone disease; traumatic brain or spine injuries; brain atrophy/neurological disorders related to the differentiation and development of the central nervous system, including Parkinson's disease, strokes, ischemic cerebral disease, epilepsy, Alzheimer's disease, depression, bipolar disorder, and schizophrenia; otic disorders like cochlear hair cell loss; eye diseases such as age related macular degeneration, diabetic macular edema or retinitis pigmentosa; and diseases related to differentiation and growth of stem cell, such as hair loss, hematopoiesis related diseases and tissue regeneration related diseases.
Background
[0003] The Wnt/I3-catenin signaling pathway is involved in many biological processes. For example, aberrant activation of the Wnt/13-catenin pathway has led to several phenotypes, including the development of a variety of human cancers, and diseases leading to abnormal development and functioning of stem cells [Oncogene (2009), 28(2/), 2163-2172; Cancer Cell (2008), 14(6), 471-484; American Journal of Pathology (2003), 162(5), 1495-1502]. Chronic activation of the Wnt/13-catenin signaling pathway has been implicated in the development of a variety of human malignancies, including high bone mass syndrome, sclerosteosis, colorectal carcinomas, hepatocellular carcinomas (HCCs), ovarian, uterine, pancreatic carcinomas, and melanomas [RioEssays (1999) 21(12), 1021-1030; Cell (2000), 103(2), 311-320; Genes Dev. (2000), 14(1.5), 1837-1851]. Since the Wnt/13-catenin pathway is involved in a number of growth and development processes, mutation of the proteins involved in the Wnt/13-catenin signal transduction system has also been linked to other human diseases such as abnormalities in development, hair follicle morphogenesis, stem cell differentiation, bone formation, and cell proliferation.
SUMMARY
[0004] The present disclosure relates to methods for increasing cell or tissue regeneration in a vertebrate patient. The disclosure relates to methods for increasing the activity of embryonic and/or adult stem cells, progenitor cells, mesenchymal progenitor/stem cells and/or differentiated cells in vivo in a vertebrate patient. The disclosure further relates to methods for increasing cell or tissue regeneration in a vertebrate patient by administering to a vertebrate patient in need thereof a compound according to Formula I, II, III, Ma, Mb, and/or IV, and increasing a stem cell, progenitor cell, and/or differentiated cell population in the vertebrate patient as compared to the stem cell, progenitor cell, and/or differentiated cell population in the vertebrate patient before treatment. Increasing the stem cell, progenitor cell, or differentiated cell population in the vertebrate patient can be a result of one or more of cell proliferation, cell homing, decreased apoptosis, self-renewal, and increased cell survival.
[0005] In one embodiment, the cell or tissue regeneration can occur in tissues including but not limited to, bone, chondrocytes/cartilage, muscle, skeletal muscle, cardiac muscle, pancreatic cells, endothelial cells, vascular endothelial cells, adipose cells, liver, skin, connective tissue, hematopoietic stem cells, neonatal cells, umbilical cord blood cells, fetal liver cells, adult cells, bone marrow cells, peripheral blood cells, erythroid cells, granulocyte cells, macrophage cells, granulocyte-macrophage cells, B
cells, T cells, multipotent mixed lineage colony types, embryonic stern cells, mesenchymal progenitor/stem cells, mesodermal progenitor/stem cells, neural progenitor/stem cells, or nerve cells. The vertebrate can be mammalian, avian, reptilian, amphibian, osteichthyes, or chondrichthyes.
[0006] In one embodiment, the present disclosure provides a composition for preventing or decreasing the loss of hair and/or for stimulating or increasing hair growth or regrowth in a patient, wherein the composition comprises a compound according to Formula I, II, III, Ina, Mb, and/or IV.
[0007] In one embodiment, the present disclosure provides a composition for preventing cochlear hair cell loss in a patient, wherein the composition comprises a compound according to Formula I, II, III, Ma, Mb, and/or IV.
[0008] One embodiment of the present disclosure provides a pharmaceutical composition for the treatment of a neurodegenerative disease in a patient.
[0009] For example, the neurological disorder can be Alzheimer's disease, schizophrenia or schizo-affective disorder, bipolar disorder or unipolar disorder, depression, substance abuse, neurodegenerative disease, autism or autism spectrum disorder, or a disorder resulting from neural damage such as spinal injuries or brain injuries. The neurodegenerative disease may be, for instance, amyotrophic lateral sclerosis (Lou Gehrig's disease) or Parkinson's disease. In some embodiments, the disclosure provides methods for treating a brain injury resulting from a traumatic injury or stroke.
[0010] In some embodiments, the neurological disorder is an eye disease such as age related macular degeneration, diabetic macular edema or retinitis pigmentosa.
[0011] In one embodiment, the disclosure relates to methods for (i) reducing loss of bone mass or bone density, (ii) increasing bone mass or bone density, (iii) maintaining bone mass or bone density and/or (iv) reducing loss of calcium from bone in a patient, the method comprising: administering to the patient a therapeutically effective amount of a compound according to Foimula I, II, III, Ma, IIIb, and/or IV. As used in this disclosure, the teini "bone mass" and "bone density" are used interchangeably.
[0012] In one embodiment, the disclosure relates to methods for regulating osteoblast activity or osteoclast activity comprising the use of a compound according to Formula I, II, III, Ma, Mb, and/or IV. Osteoblast activity can be regulated by regulating the proliferation or function of osteoblasts. The function of osteoblasts and/or osteoclasts can be regulated directly or indirectly.
[0013] In one embodiment, the method is for the treatment of a bone condition or a bone defect. For example, the bone condition being treated can include frailty, an osteoporotic fracture, a bone defect, childhood idiopathic bone loss, alveolar bone loss, mandibular bone loss, bone fracture, osteotomy, bone loss associated with periodontitis, or prosthetic ingrowth. In some embodiments, the bone condition being treated is Paget's disease. In another embodiment, the bone condition being treated is oncolytic bone disease.
[0014] In another embodiment, the disclosure relates to methods for promoting healing of bone fractures, bone defects, craniofacial defects, otosclerosis or osteogenesis imperfecta comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to Formula I, II, III, Ina, Mb, and/or IV.
[0015] In another embodiment, the disclosure relates to methods for bone tissue engineering comprising the use of a compound according to Formula I, II, III, IIIa, Mb, and/or IV. In one embodiment, the cells used for bone tissue engineering are contacted with an effective amount of a compound according to Formula I, II, III, Ina, Mb, and/or IV.
[0016] In another embodiment, the disclosure relates to the use of a compound according to Formula I, II, III, Ma, Mb, and/or IV as a medicament for healing bone fractures or repairing bone defects in a mammal.
[0017] In one embodiment, the bone condition being treated is osteoporosis.
For example, the osteoporosis being treated can be selected from the group consisting of:
gluco corticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin-induced osteoporosis, and innnunosuppressive-induced osteoporosis.
[0018] In one embodiment, a compound according to Formula I, II, III, Ilia, Illb, and/or IV is administered conjointly with an agent that increases bone mass or prevents the loss of bone mass. In one embodiment, the agent that increases bone mass is a growth factor, a mineral, a vitamin, a hormone, a prostaglandin, an inhibitor of 15-lipoxygenase, a bone morphogenic protein or another member of the TGF-beta superfamily which increases bone fornlation, an ACE inhibitor, a Hedgehog protein, examethasone, calcitonin, or an active fragment thereof In one embodiment, the agent that prevents the loss of bone mass is progestin, estrogen, an estrogen/progestin combinations, estrone, estriol, 17a- or 173-ethynyl estradiol, SB242784, polyphosphonates, bisphosphonates, or an active fragment thereof
[0019] In one embodiment of the disclosure, a compound according to Formula I, II, III, Ma, Mb, and/or IV, is administered to a patient in need thereof to enhance proliferation of intestinal epithelium, for the treatment, or as a therapeutic adjunct in the treatment, of diseases that compromise the intestinal epithelia, including inflammatory bowel diseases, mucositis (oral and gastrointestinal) and Celiac disease.
[0020] In another embodiment, the disclosure relates to methods for organ tissue engineering comprising the use of a compound according to Formula I, II, III, Ma, Mb, and/or IV. In one embodiment the cells used for organ tissue engineering are contacted with an effective amount of a compound according to Fonnula I, II, III, Ma, Mb, and/or IV.
[0021] Some embodiments disclosed herein include a Wnt/13-catenin signaling pathway activator containing a y-diketone core. Other embodiments disclosed herein include pharmaceutical compositions and methods of treatment using one or more of the compounds provided herein.
[0022] One embodiment of a Wnt/13-catenin signaling pathway activator disclosed herein includes compounds of Formula I:
o (R2),, B
(Ri)n 0 , or a pharmaceutically acceptable salt thereof
[0023] In some embodiments of Formula I:
Ring A is a 7-12 membered heteroaryl, with the proviso that a carbon atom on the ring is attached to the carbonyl carbon;

Ring B is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, with the proviso that a carbon atom on the ring is attached to the carbonyl carbon;
RI is a substituent attached to Ring A and is independently selected at each occurrence from the group consisting of H, unsubstituted -Ci_6 alkyl, -C1_3 haloalkyl, halide, -0R3, CF3, and CN;
R2 is a substituent attached to Ring B and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R31)2, -C1.3 haloalkyl, halide, -0R3, CF3, and CN;
each R3 is independently selected from the group consisting of H, unsubstituted -C1_6 alkyl, -C1_3 haloalkyl, and CF3;
each R31' is independently selected from the group consisting of H and unsubstituted ¨Ci_3 alkyl;
each n is an integer of 1 to 10; and each m is an integer of 1 to 5.
[0024] Another embodiment of a Wnt/P-catenin signaling pathway activator disclosed herein includes compounds of Formula II:
(RN

(R4)p or a pharmaceutically acceptable salt thereof.
[0025] In some embodiments of Formula II:
Ring C is a 5-6 membered heteroaryl, with the proviso that a carbon atom on the ring is attached to the carbonyl carbon;
Ring D is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, with the proviso that a carbon atom on the ring is attached to the carbonyl carbon;
R4 is a substituent attached to Ring C and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -C1_3 haloalkyl, halide, -0R6, CF3, and CN;

R5 is a substituent attached to Ring D and is independently selected at each occurrence from the group consisting of H, unsubstituted -Ci_6 alkyl, -CH2OH, -CH2N(R6b)2, -C1_3 haloalkyl, halide, -0R6, CF3, and CN;
each R6 is independently selected from the group consisting of H, unsubstituted -C1_6 alkyl, -C1-3 haloalkyl, and CF3;
each R6b is independently selected from the group consisting of H and unsubstituted ¨C1,3 alkyl;
each q is an integer of 1 to 4; and each p is an integer of 1 to 5.
[0026] Another embodiment of a Wnt/P-catenin signaling pathway activator disclosed herein includes compounds of Formula III:
(R8)q (R)q III
or a phaimaceutically acceptable salt thereof.
[0027] In some embodiments of Foimula III:
R7 is a substituent attached to the phenyl ring and is independently selected at each occurrence from the group consisting of unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R9a)2, -C1_3 haloalkyl, halide, -0R9, CF3, and CN;
R8 is a substituent attached to the phenyl ring and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R9a)2, -C1_3 haloalkyl, halide, -0R9, CF3, and CN;
each R9 is independently selected from the group consisting of H, unsubstituted -C1_6 alkyl, -C1_3 haloalkyl and CF3;
each R9a is independently selected from the group consisting of H and unsubstituted ¨CI _3 alkyl; and each q is an integer of 1 to 5.
[0028] Another embodiment of a Wnt/13-catenin signaling pathway activator disclosed herein includes compounds of Formula Ma:

(R12)q wo OR"
lila or a phan-naceutically acceptable salt thereof.
[0029] In some embodiments of Formula Illa:
RI is selected from the group consisting of H, unsubstituted -C1,6 alkyl, -C1-haloalkyl, halide, -0R13, CF3, and CN;
R" is selected from the group consisting of unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R13)2, haloalkyl, halide, -0R13, CF3, and CN;
R12 is a substituent attached to the phenyl ring and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -CI-120H, -CH2N(R13b)2, -C1_3 haloalkyl, halide, -0R13, CF3, and CN;
each R13 is independently selected from the group consisting of unsubstituted 6 alkyl, -C1_3 haloalkyl, and CF3;
each R131' is independently selected from the group consisting of H and unsubstituted ¨Ci_3 alkyl; and each q is an integer of 1 to 5.
[0030] Another embodiment of a Wnt/13-catenin signaling pathway activator disclosed herein includes compounds of Formula Mb:
(Ris)q Ilib or a pharmaceutically acceptable salt thereof
[0031] In some embodiments of Formula Mb:
R14 is selected from the group consisting of unsubstituted -C1,6 alkyl, -C1-3 haloalkyl, and CF3;

15 i R s selected from the group consisting of unsubstituted -C1_6 alkyl, -Ci_3 haloalkyl, and CF3;
R16 is a substituent attached to the phenyl ring and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, CH2OH, -CH2N(R17b)2, -C1_3 haloalkyl, halide, -0R17, CF3, and CN;
each R17 is independently selected from the group consisting of unsubstituted -Ci-6 alkyl, -C1_3 haloalkyl, and CF3;
each R17b is independently selected from the group consisting of H and unsubstituted ¨C1_3 alkyl; and each q is an integer of 1 to 5.
[0032] Another embodiment of a Wnt/13-catenin signaling pathway activator disclosed herein includes compounds of Formula IV:

II
,R18,p 0 iv or a phaimaceutically acceptable salt thereof.
[0033] In some embodiments of Foimula IV:
Ring F is r( 40 ;
R"b Ring G is selected from the group consisting of R19a $ la I
01 \
Feil9c/ \
Risb , and a 5-6 membered heteroary1R19d , with the proviso that a carbon atom on the ring is attached to the carbonyl carbon;
each R18 is a substituent attached to Ring F and is independently selected at each occurrence from the group consisting of H, -C1_3 haloalkyl, halide, -0R20, CF3, and CN;

R19a is a substituent attached to the para position of phenyl and is selected from the group consisting of H, unsubstituted ¨C2_6 alkyl, -CH2OH, -CH2N(R21)2, -C1-haloalkyl, F, Br, I, -0R20, CF3, and CN;
RI" is a substituent attached to the meta or ortho position of phenyl and is selected from the group consisting of H, unsubstituted ¨C2_6 alkyl, -CH2OH, -CH2N(R21)2, -C1_3 haloalkyl, halide, -0R20, CF3, and CN;
R19e is 2-5 substituents, each attached to the phenyl and are independently selected at each occurrence from the group consisting of H, -CH2OH, -CH2N(R21)2, -C1-3 haloalkyl, halide, -0R20, CF3, and CN;
Ri9d is 1-4 substituents, each attached to the heteroaryl ring and is independently selected at each occurrence from the group consisting of H, -CH2OH, -CH2N(R21)2, -C1-3 haloalkyl, halide, -0R20, CF3, and CN;
each R2 is independently selected from the group consisting of H, unsubstituted ¨
C3_6 alkyl, -Ci_3 haloalkyl, and CF3;
each R21 is independently selected from the group consisting of H and unsubstituted ¨Ci_3 alkyl;
p is an integer of 1 to 13; and r is an integer of 1 to 5.
[0034] Some embodiments include stereoisomers of a compound of Fonnula I, II, III, Ma, and/or IIIb.
[0035] Some embodiments include prodrugs of a compound of Formula I, II, III, Ma, and/or IIIb. For example, prodrugs of a compound of Formula I, II, III, Ma, and/or IIIb can be prodrug polymer conjugates for delayed release or extended release.
[0036] Also provided herein are pharmaceutical compositions comprising a compound of Formula I, II, III, Ma, and/or IIIb and a pharmaceutically acceptable carrier, diluent, or excipient.
[0037] Some embodiments of the present disclosure include methods to prepare compounds of Formula I, II, III, Ma, and/or Mb.
[0038] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION
[0039] Provided herein are y-diketones capable of activating the Wnt43-catenin signaling pathway. The Wnt/13-catenin signaling pathway has been found to play a role in the differentiation and development of nerve cells for the central nervous system, bone formation, hair follicle development and regeneration, and stimulation of stern cell growth, maintenance and differentiation.
[0040] The present disclosure relates to methods for increasing cell or tissue regeneration in a vertebrate patient. The disclosure relates to methods for increasing the activity of embryonic and/or adult stem cells, progenitor cells, mesenchymal progenitor/stem cells, or differentiated cells in vivo in a vertebrate patient. The disclosure further relates to methods for increasing cell or tissue regeneration by administering a compound according to Formula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, Ii, II, Ha, Hb, Hc, lid, He, Hf, III, Ma, Mb, Inc, Hid, and/or IV to a vertebrate patient in need thereof, and increasing a stem cell, progenitor cell population, or differentiated cell in the vertebrate patient compared to the stem cell or progenitor cell, or differentiated cell population in the vertebrate patient before treatment. In some embodiments, a method for increasing stem cell or progenitor cell population can be used to repair or replace damaged tissue in a vertebrate patient, wherein the cell or tissue regeneration occurs in bone, chondrocytes/cartilage, muscle, skeletal muscle, cardiac muscle, pancreatic cells, endothelial cells, vascular endothelial cells, adipose cells, liver, skin, connective tissue, hematopoietic stem cells, neonatal cells, umbilical cord blood cells, fetal liver cells, adult cells, bone marrow cells, peripheral blood cells, erythroid cells, granulocyte cells, macrophage cells, granulocyte-macrophage cells, B cells, T cells, multipotent mixed lineage colony types, embryonic stem cells, mesenchymal progenitor/stem cells, mesodermal progenitor/stem cells, neural progenitor/stem cells, or nerve cells.
Hair Growth
[0041] Compositions comprising one or more compounds according to Formula I, Ia, Ib, Ic, Id, he, If, Ig, Ih, Ii, II, Ha, IIb, Hc, lid, He, hf, III, Ina, Mb, Mc, IIId, and/or IV can be used to promote hair growth.
[0042] "Promoting hair growth" refers to maintaining, inducing, stimulating, accelerating, or revitalizing the growth of hair.
[0043] The methods of the present disclosure can be useful in the treatment of alopecia in mammals, and as such may be used to promote, increase, or assist in the growth of hair. Patients may be male or female. The term alopecia refers to both the complete absence of hair in skin which typically exhibits hair growth, as well as to a loss or diminution in the amount of hair. Multiple types and causes of alopecia are recognized in humans, including male pattern baldness, chemotherapy induced hair loss, congenital alopecia, and alopecia areata. The treatment of alopecia can include the treatment of skin with a total absence of hair growth as well as the treatment of skin having reduced or patchy hair growth. Successful treatment results in an increased number of hairs.
[0044] Patients to be treated according to the disclosure include human patients as well as other mammalian patients, such as dogs, cats, mice, rats, goats, llamas, minks, seals, beavers, ermines, and sheep. Patients can be treated for hair loss or to enhance the growth of hair, for example to increase wool or pelt production.
[0045] "Treating alopecia" refers to (i) preventing alopecia in an animal which may be predisposed to alopecia, (ii) inhibiting, retarding or reducing alopecia, (iii) promoting hair growth, and/or (iv) prolonging the anagen phase of the hair cycle.
[0046] A method for promoting hair growth in accordance with the present disclosure can include applying an effective amount of a compound according to Formula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, hf, III, Ma, IIIb, Mc, Hid, and/or IV, or a pharmacologically acceptable salt thereof, to the skin of mammals. For example, the compound can be applied to a human scalp.
Cochlear hair cell loss
[0047] Compositions comprising one or more compounds according to Formula I, Ia, Ib, Ic, Id, he, If, Ig, Ih, Ii, II, Ha, Hb, Hc, lid, He, Hf, III, Ma, Ha, Mc, IIId, and/or IV can be used to promote regeneration of lost or damaged sensory hair cells.
[0048] "Promoting the regeneration of sensory hair cells" refers to maintaining, inducing, stimulating, accelerating, or revitalizing the growth of sensory hair cells.
[0049] The methods of the present disclosure are useful in the treatment of presbycusis in mammals, and as such may be used to promote, increase, or assist in the growth of cochlea hair cells. Mammalian cochlear hair cells come in two anatomically and functionally distinct types: the outer and inner hair cells. Patients may be male or female. Presbycusis can be caused by the slow loss of hearing that occurs as a result of ageing, after repeated exposure to loud noises, or as a symptom of certain medical conditions or medications. Multiple types and causes of presbycusis are recognized in humans, including, for example, arteriosclerosis (may diminish vascularity of the cochlea, thereby reducing its oxygen supply), diabetes mellitus (may cause vasculitis and endothelial proliferation in the blood vessels of the cochlea, thereby reducing its blood supply), poor diet (increased intake of saturated fat may accelerate atherosclerotic changes), stress, heart disease, diabetes blood vessel complications, high blood pressure, smoking (postulated to accentuate atherosclerotic changes in blood vessels), and viral or bacterial infections. Drugs, medications, substances, or toxins that can cause presbycusis as a symptom include, for example, aminoglycosides (gentamycin, streptomycin, etc.) and other antibiotics (macrolides and vancomycin), antineoplastic agents (platinum-based compounds cisplatin and carboplatin), salicylates (aspirin), quinine, and loop diuretics (ethacrynic acid, furosemide, bumetanide, etc.).
[0050] The term treating presbycusis refers to both the treatment of patients with total hearing loss as well as partial hearing loss. Successful treatment results in an improvement in a patient's hearing.
[0051] A method for promoting the regeneration of sensory hair cells in accordance with the present disclosure can include applying an effective amount of a compound according to Formula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, Ii, II, Ha, lib, Hc, lid, He, Ht., III, Ma, En, Mc, Hid, and/or IV, or a pharmacologically acceptable salt thereof, in the ear of mammals. For example, the compound may be applied to the inner ear, or via intratympanic injection to the round window membrane or vicinity of the round window membrane.
1.'3 Neurological Disorder
[0052] Compounds according to the present disclosure can modulate the cellular fate of neural stem cells and promote the differentiation of these neural precursors to functional neurons and glial cells.
[0053] Compositions comprising one or more compounds according to Formula 1, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, Ii, II, Ha, lab, Hc, lid, He, Hf, III, Ma, Mb, Mc, Hid, and/or IV can be used to treat neurodegenerative diseases.
[0054] Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, schizophrenia or schizo-affective disorder, bipolar disorder or unipolar disorder, depression, substance abuse, neurodegenerative disease, autism or autism spectrum disorder, or a disorder resulting from neural damage such as spinal injuries or brain injuries. The neurodegenerative disease may be, for instance, amyotrophic lateral sclerosis (Lou Gehrig's disease) or Parkinson's disease.
[0055] Other non-limiting examples of neurodegenerative diseases include eye diseases including, but not limited to, wet age-related macular degeneration, dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, diabetic macular edema, retinal detachment, retinal degeneration, retinal vein occlusion, retinopathy of prematurity, retinitis pigmentosa, retinopathies, Leber congenital amaurosis and glaucoma.
[0056] The disclosure also provides methods for treating brain injury resulting from a traumatic injury or stroke.
[0057] Another aspect of the disclosure is a method for enhancing neural progenitor proliferation and differentiation by contacting a neural progenitor cell with a compound according to Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, Ii, II, Ha, Hb, Hc, lid, He, IH, III, HIa, Mb, HIc, Hid, and/or IV in an effective amount to enhance neural progenitor proliferation and differentiation.
[0058] In one aspect the disclosure provides a method for enhancing nerve generation, by contacting a nerve with a compound according to Formula I, Ia, Ib, Ic, Id, he, If, Ig, Ih, Ii, II, Ha, lib, Hc, Hd, He, IH, III, IIIa, IIIb, Hie, Hid, and/or IV in an effective amount to enhance nerve generation.
[0059] In another aspect, the present disclosure provides a method for treating a neurodegenerative disease in a patient requiring such treatment, which comprises administering an effective amount of a compound of Formula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, Ill, III, Ma, IIIb, Hie, Hid, and/or IV, or a pharmaceutically acceptable salt thereof
[0060] The compounds according to the present disclosure may be administered alone or in combination with another active agent. In one embodiment, a compound provided herein can be co-administered with an acetylcholinesterase inhibitor (e.g. Aricept) for Alzheimer's disease or L-DOPA for Parkinson disease.
Bone Formation
[0061] Compositions comprising one or more compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, Ha, IIb, He, lid, He, hf, III, Ma, Mb, Hie, Hid, and/or IV can be used to treat, prevent or alleviate bone conditions. The present disclosure provides methods for (i) reducing loss of bone mass, (ii) increasing bone mass, (iii) maintaining bone mass, and/or (iv) reducing loss of calcium from bone, comprising:
administering to a patient in need thereof a therapeutically effective amount of a compound according to Fotmula I, Ia, Ib, Ic, Id, he, If, Ig, Ih, Ii, II, Ha, lib, He, Hd, He, III, III, Ina, IIIb, Mc, Hid, and/or IV. The method could be used for treating, preventing, or delaying a bone condition. The disclosure further provides a method for promoting the healing of bone fractures or bone defects comprising:
administering to a patient a therapeutically effective amount of a compound according to Formula I, Ia, Ib, Ic, Id, he, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, III', III, IIIa, HIb, he, Hid, and/or IV.
Any of the above mentioned methods can involve the conjoint administration of an agent that increases bone mass or prevents the loss of bone mass.
[0062] The disclosure also provides for the use of a compound according to Formula I, Ia, Ib, Ic, Id, he, If, Ig, Ih, Ii, II, Ha, lab, He, lid, He, hf, III, Ma, BM, Inc, Hid, and/or IV as a medicament for treating, preventing or delaying a bone condition.
[0063] As used herein, the term "bone condition" includes any condition where it is desirable to increase bone mass or bone density and/or prevent the loss of bone mass or bone density. A bone condition includes any condition that increases osteoclast number, increases osteoclast activity, increases bone resorption, increases marrow fibrosis, or alters the calcium content of bone.
[0064] Non-limiting examples of bone conditions include metabolic bone conditions such as renal osteodystrophy, primary forms of osteoporosis (e.g., postmenopausal and senile osteoporosis), and secondary forms of osteoporosis that develop as a result of an underlying disease state. For example, osteoporosis can develop in patients that have endocrine disorders such as hyperparathyroidism, hypo-and hyperthyroidism, hypogonadism, hypercalcemia due to malignancy, pituitary tumors, type I diabetes, or Addison's disease. Neoplasias such as multiple myeloma and carcinomatosis also can lead to development of osteoporosis. In addition, gastrointestinal problems such as malnutrition, malabsorption, hepatic insufficiency, and vitamin C or D
deficiencies, and chronic administration of drugs such as anticoagulants, chemotherapeutics, corticosteroids, anticonvulsants, and alcohol can lead to development of osteoporosis.
[0065] Non-limiting examples of bone conditions also include osteonecrosis, osteoarthritis, rheumatoid arthritis, Paget's disease, osteogenesis imperfecta, chronic hyperparathyroidism, hyperthyroidism, Gorham-Stout disease, McCune-Albright syndrome, and alveolar ridge bone loss.
[0066] Bone conditions can also include, without limitation, conditions resulting in bone loss, for example, cancers and tumors (such as osteosarcoma and multiple myeloma), renal disease (including acute renal failure, chronic renal failure, renal bone dystrophy and renal reperfusion injury), kidney disease, and premature ovarian failure.
[0067] Endocrine disorders, vitamin deficiencies and viral infections also can lead to the development of bone conditions that can be treated as described herein. An example of a bone condition caused by a nutritional disorder is osteomalacia, a nutritional disorder caused by a deficiency of vitamin D and calcium. It is referred to as "rickets" in children, and "osteomalacia" in adults. It is marked by a softening of the bones (due to impaired mineralization, with excess accumulation of osteoid), pain, tenderness, muscle wasting and weakness, anorexia, and overall weight loss. It can result from malnutrition, repeated pregnancies and lactation (exhausting or depleting vitamin D and calcium stores), and vitamin D resistance.
[0068] Bone conditions include conditions resulting from the treatment of a patient with drugs, for example the osteopenia resulting from the treatment with Cyclosporin A or FK506.
[0069] Bone conditions also include bone fractures, bone trauma, conditions associated with post-traumatic bone surgery, post-prosthetic joint surgery, post-plastic bone surgery, post-dental surgery, bone chemotherapy, post-dental surgery, and bone radiotherapy. Fractures include all types of microscopic and macroscopic fractures.
Examples of fractures includes avulsion fracture, comminuted fracture, transverse fracture, oblique fracture, spiral fracture, segmental fracture, displaced fracture, impacted fracture, greenstick fracture, torus fracture, fatigue fracture, intra-articular fracture (epiphyseal fracture), closed fracture (simple fracture), open fracture (compound fracture), and occult fracture.
[0070] Other non-limiting examples of bone conditions include bone deformation, spinal deformation, prosthesis loosening, bone dysplasia, scoliosis, periodontal disease and defects, tooth repair, and fibrous osteitis.
[0071] The disclosure also provides a method for treating a patient with a therapeutically effective amount of a compound according to Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, Ii, II, Ha, lib, Hc, lid, He, III, III, Ma, IIIb, HIc, Hid, and/or IV, wherein the patient is in need of bone repair following surgery, such as cranio-maxillofacial repair following tumor removal, surgical bone reconstruction following traumatic injury, repair of hereditary or other physical abnormalities, and promotion of bone healing in plastic surgery.
[0072] The disclosure also provides a method for treating a patient with a therapeutically effective amount of a compound according to Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, Et, II, Ha, Hb, IIc, lid, He, Hf, III, Ma, HIb, Mc, Hid, and/or IV, wherein the patient is in need of bone repair after receiving an implant (including joint replacements and dental implants), prosthesis or a bone graft.
[0073] The disclosure also provides a method for treating a patient with a therapeutically effective amount of a compound according to Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, hf, III, Ma, IIIb, Me, IIId, and/or IV, wherein the patient: a) is in need of increased bone density or bone healing; b) has undergone or is presently undergoing corticosteroid therapy, dialysis, chemotherapy for post-menopausal bone loss, radiation therapy for cancer, or hormone replacement therapy; c) is immobilized or subjected to extended bed rest due to bone injury; d) suffers from alcoholism, diabetes, hyperprolactinemia, anorexia nervosa, primary and secondary amenorrhea, or oophorectomy; e) suffers from renal failure; f) is 50 years or older; or g) is a female.
[0074] The disclosure also provides a method for treating a patient with a therapeutically effective amount of a compound according to Formula I, Ia, Ib, Ie, Id, Ie, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, Hf, III, Ma, Mb, IHc, Hid, and/or IV, wherein the patient is affected by a disease selected from arterial calcification, ankylosing spondylitis, ossification of the posterior longitudinal ligament, myositis ossificans, diffuse idiopathic skeletal hyperostosis, calcific tendonitis, rotator cuff disease of the shoulders, bone spurs, cartilage or ligament degeneration due to hydroxyapatite crystal deposition, and chondrocalcinosis.
[0075] The disclosure also provides a method for treating a patient with a therapeutically effective amount of a compound according to Formula I, Ia, Ib, Ic, Id, he, If, Ig, Ih, Ii, II, Ha, Hb, He, lid, He, hf, III, Ma, IIIb, Mc, IIId, and/or IV conjointly with an agent that increases bone mass or prevents the loss of bone mass. In one embodiment, the agent that increases bone mass is a growth factor, a mineral, a vitamin, a hormone, a prostaglandin, an inhibitor of 15-lipoxygenase, a bone morphogenic protein or another member of the TGF-beta superfamily which increases bone formation, an ACE inhibitor, a Hedgehog protein, examethasone, calcitonin, or an active fragment thereof In one embodiment, the agent that prevents the loss of bone mass is progestin, estrogen, an estrogen/progestin combinations, estrone, estriol, 17a- or 17J3-ethynyl estradiol, SB242784, polyphosphonates, bisphosphonates, or an active fragment thereof Intestinal Diseases
[0076] Compounds according to Formula I, Ia, Ib, Ie, Id, Ie, If, Ig, Ih, Ii, II, Ha, Hb, He, Hd, He, hf, III, Ma, Mb, Mc, hid, and/or IV can also administered for the treatment of gastrointestinal inflammation. "Gastrointestinal inflammation" as used herein refers to inflammation of a mucosal layer of the gastrointestinal tract, and encompasses acute and chronic inflammatory conditions. Acute inflammation is generally characterized by a short time of onset and infiltration or influx of neutrophils.
[0077] "Chronic gastrointestinal inflammation" refers to inflammation of the mucosal of the gastrointestinal tract that is characterized by a relatively longer period of onset, is long-lasting (e. g., from several days, weeks, months, or years and up to the life of the patient), and is associated with infiltration or influx of mononuclear cells and can be further associated with periods of spontaneous remission and spontaneous occurrence.
Thus, patients with chronic gastrointestinal inflammation may be expected to require a long period of supervision, observation, or care. "Chronic gastrointestinal inflammatory conditions" (also referred to as "chronic gastrointestinal inflammatory diseases") having such chronic inflammation include, but are not necessarily limited to, inflammatory bowel disease (IBD), colitis induced by environmental insults (e. g., gastrointestinal inflammation (e. g., colitis) caused by or associated with (e. g., as a side effect) a therapeutic regimen, such as administration of chemotherapy, radiation therapy, and the like), colitis in conditions such as chronic granulomatous disease, celiac disease, celiac sprue (a heritable disease in which the intestinal lining is inflamed in response to the ingestion of a protein known as gluten), food allergies, gastritis, infectious gastritis or enterocolitis (e. g., Helicobacter pylori-infected chronic active gastritis) and other forms of gastrointestinal inflammation caused by an infectious agent, and other like conditions.
[0078] As used herein, "inflammatory bowel disease" or "IBD" refers to any of a variety of diseases characterized by inflammation of all or part of the intestines.
Examples of inflammatory bowel diseases include, but are not limited to, Crohn's disease and ulcerative colitis. Reference to IBD throughout the specification is used throughout the specification as an example of the gastrointestinal inflammatory conditions provided herein, and is not meant to be limiting.
[0079] Compounds according to Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, Ha, hib, He, lid, He, Hf, III, Ma, Illb, Hie, Ind, and/or IV can be administered to a patient prior to onset of more severe symptoms (e.g., prior to onset of an acute inflammatory attack), or after onset of acute or chronic symptoms (e.g., after onset of an acute inflammatory attack). As such, the agents can be administered at any time, and may be administered at any interval. In one embodiment, a compound according to Foimula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, III, III, Ma, Mb, Mc, IIId, and/or IV can be administered about 8 hours, about 12 hours, about 24 hours, about 2 days, about 4 days, about 8 days, about 16 days, about 30 days or 1 month, about 2 months, about 4 months, about 8 months, or about 1 year after the initial onset of gastrointestinal inflammation-associated symptoms and/or after diagnosis of gastrointestinal inflammation in the patient.
[0080] When multiple doses are administered, subsequent doses can be administered within about 16 weeks, about 12 weeks, about 8 weeks, about 6 weeks, about 4 weeks, about 2 weeks, about 1 week, about 5 days, about 72 hours, about 48 hours, about 24 hours, about 12 hours, about 8 hours, about 4 hours, or about 2 hours or less of the previous dose. In one embodiment, does are administered at intervals ranging from at least every two weeks to every four weeks (e.g., monthly intervals) in order to maintain the maximal desired therapeutic effect (e.g., to provide for maintenance of relief from IBD-associated symptoms).
[0081] Compounds according to Formula I, Ia, Ib, Ic, Id, he, If, Ig, Ih, Ii, II, Ha, hib, He, lid, He, Elf, III, HIa, Mb, Hie, Hid, and/or IV can also be administered for the treatment of mucositis. "Mucositis" as used herein refers to inflammatory and/or ulcerative lesions anywhere along the gastrointestinal (GI) tract. Infectious disease, immune deficiency, and medications can be causative. One of the major causes of mucositis is high-dose cancer therapy. In some embodiments, the mucositis is alimentary tract mucositis or oral mucositis. Alimentary tract mucositis refers to the expression of mucosal injury across the continuum of oral and gastrointestinal mucosa, from the mouth to the anus. Oral mucositis refers to the particular inflammation and ulceration that occurs in the mouth. Oral mucositis is a common and often debilitating complication of cancer treatment.
Regenerative Medicine
[0082] According to the present disclosure, pluripotent stem cells (PS
cells) are capable of differentiating into any cell type of the body and retain the property of self-renewal, thereby providing a potentially unlimited source of new healthy tissue. In this regard, PS cells have attracted a great deal of attention due to their potential use for tissue and cell based therapies. PS cell derivation originally depended on the viral expression of the four transcription factors i.e. Oct4, Sox2, Klf4 and c-Myc. However, recent efforts to avoid genetic manipulation with the ultimate goal of clinical applications have led researchers to further define the signaling pathways involved in cell reprogramming with the aim of replacing ectopic gene expression with proteins or small molecules.
Wnt/f3-catenin signaling in particular has been highlighted as one of the key pathways in this process.
[0083] Somatic cells as referred to in the present disclosure refer to cells that have reached differentiation into cells that compose various organs of the body. In some embodiments, two or more somatic cells may be used in the methods described herein.
For example, a combination of an epithelial cell line and mesenchymal cells, a combination of endothelial cells and mesenchymal cells, or a combination of epithelial cells and mesenchymal cells can be used.
[0084] There are no particular limitations on organs capable of being formed by the somatic cells provided herein. Non-limiting examples include various organs such as hair follicle, lung, kidney, liver, pancreas, spleen, heart, gallbladder, small intestine, colon, large intestine, joint, bone, tooth, blood vessel, lymph duct, cornea, cartilage, olfactory organ, or auditory organ.
[0085] Various mammals can be used without limitation as the origin of the cells provided herein depending on the ultimate intended purpose of the cells.
For example, mammals include chimpanzees, other primates, domestic animals such as dogs or cats, farm animals such as cows, pigs, horses, sheep or goats, laboratory animals such as rabbits, rats, mice or guinea pigs. In some embodiments, the mammals are nude mice, SCID mice, or nude rats. In addition, combinations of cells can include homogeneous combinations or heterogeneous combinations. In some embodiments, the combination is a homogeneous combination. In some embodiments, culturing somatic cells of one or more types of differentiated somatic cells as described above can be combine with one or more Wnt/13-catenin signaling pathway activators according to Formula I, Ia, Ib, Ie, Id, Ie, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, IIf, III, Ina, HE), Hie, Hid, and/or IV.

Definitions
[0086] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.
[0087] As used herein, "alkyl" means a branched, or straight chain chemical group containing only carbon and hydrogen, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl and neo-pentyl.
Alkyl groups can either be unsubstituted or substituted with one or more substituents.
Alkyl groups can be saturated or unsaturated (e.g., containing -C¨C- or -CC-subunits), at one or several positions. Typically, alkyl groups will comprise 1 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).
[0088] As used herein, "carbocycly1" means a cyclic ring system containing only carbon atoms in the ring system backbone, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Carbocyclyls may include multiple fused rings. Carbocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. Carbocyclyl groups can either be unsubstituted or substituted with one or more substituents. Typically, carbocyclyl groups will comprise 3 to 10 carbon atoms, for example, 3 to 6 carbon atoms.
[0089] As used herein, "lower alkyl" means a subset of alkyl having 1 to 3 carbon atoms, which is linear or branched. Examples of lower alkyls include methyl, ethyl, n-propyl and isopropyl. Likewise, radicals using the terminology "lower" refer to radicals having 1 to about 3 carbons in the alkyl portion of the radical.
[0090] As used herein, "aryl" means an aromatic ring system containing a single-ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) with only carbon atoms present in the ring backbone. Aryl groups can either be unsubstituted or substituted with one or more substituents. In some embodiments, the aryl is phenyl.
[0091] As used herein, "arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a Ci4alkyl moiety. Exemplary arylalkyl groups include benzyl and 2-phenethyl.
[0092] As used herein, the term "heteroaryl" means a mono-, bi-, tri- or polycyclic group having 5 to 14 ring atoms, alternatively 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 pi electrons shared in a cyclic array; wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, 0, and S. Heteroaryl groups can either be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido [2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo [3,4-b]pyridinyl, pyrazolo [3 ,4-c]pyridinyl, pyrazolo [4,3 -c] pyridine, pyrazolo [4,3 -b]pyridinyl, tetrazolyl, chromane, 2,3 -dihydrobenzo [b] [1,4] dioxine, benzo [d] [1,3] dioxole, 2,3 -dihydrobenzofuran, 2,3 -dihydrobenzo [b] [1,4]
oxathiine, and others.
[0093] As used herein, "heteroarylalkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a C1-4 alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.
[0094] As used herein, "acyl" means an H-00- or alkyl-CO-, carbocyclyl-CO-, aryl-CO-, heteroaryl-CO-, or heterocyclyl-00- group wherein the alkyl, carbocyclyl, aryl or heterocyclyl group is as herein described. In some embodiments, acyls contain a lower alkyl. Exemplary alkyl acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, t-butylacetyl, butanoyl, and palmitoyl.
[0095] As used herein, "alkoxycarbonyl" means an alkyl-0¨00¨ group in which the alkyl group is as described herein. Exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbonyl.
[0096] As used herein, "alkoxy" means an alkyl-0¨ group in which the alkyl group is as described herein. Exemplary alkoxy groups include difluoromethoxy, methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, pentoxy, hexoxy and heptoxy, and also the linear or branched positional isomers thereof
[0097] As used herein, "halo", "halide" or "halogen" is a chloro, bromo, fluoro, or iodo atom radical. In some embodiments, a halo is a chloro, bromo or fluoro.
For example, a halo can be fluoro.
[0098] As used herein, "haloalkyl" means a hydrocarbon substituent, which is a linear or branched or cyclic alkyl, alkenyl or alkynyl substituted with one or more chloro, bromo, fluoro, or iodo atom(s). In some embodiments, a haloalkyl is a fluoroalkyls, wherein one or more of the hydrogen atoms have been substituted by fluoro.
In some embodiments, haloalkyls are of 1 to about 3 carbons in length (e.g., 1 to about 2 carbons in length or 1 carbon in length). The term "haloalkylene" means a diradical variant of haloalkyl, and such diradicals may act as spacers between radicals, other atoms, or between a ring and another functional group.
[0099] As used herein, "heterocycly1" means a nonaromatic cyclic ring system comprising at least one heteroatom in the ring system backbone.
Heterocyclyls may include multiple fused rings. Heterocyclyls may be substituted or unsubstituted with one or more substituents. In some embodiments, heterocycles have 5-7 members.
In six membered monocyclic heterocycles, the heteroatom(s) are selected from one up to three of 0, N or S, and wherein when the heterocycle is five membered, it can have one or two heteroatoms selected from 0, N, or S. Examples of heterocyclyl include azirinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2-dithiazolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, oxazinyl, thiazinyl, thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, pyrazolidinyl imidazolidinyl, thiomorpholinyl, and others.
[00100] The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more non-hydrogen atoms of the molecule. It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. Substituents can include, for example, an alkyl, a halide, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a folinyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a carbocyclyl, a heterocyclyl, an arylalkyl, a heteroarylalkyl, an aryl, or heteroaryl moiety.
[00101] As used herein, when two groups are indicated to be "linked" or "bonded" to faun a "ring", it is to be understood that a bond is formed between the two groups and may involve replacement of a hydrogen atom on one or both groups with the bond, thereby foiming a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring.
The skilled artisan will recognize that such rings can and are readily formed by routine chemical reactions. In some embodimenets, such rings have from 3-7 members, for example, 5 or 6 members.
[00102] The skilled artisan will recognize that some structures described herein may be resonance forms or tautomers of compounds that may be fairly represented by other chemical structures, even when kinetically, the artisan recognizes that such structures are only a very small portion of a sample of such compound(s). Such compounds are clearly contemplated within the scope of this disclosure, though such resonance forms or tautomers are not represented herein.
[00103] The compounds provided herein may encompass various stereochemical forms. The compounds also encompass diastereomers as well as optical isomers, e.g. mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.
[00104] The term "administration" or "administering" refers to a method of providing a dosage of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian, where the method is, e.g., orally, subcutaneously, intravenously, intralymphatic, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, ontologically, neuro-otologically, intraocularly, subconjuctivally, via anterior eye chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, intrapleurally, via wound irrigation, intrabuccally, intra-abdominally, intra-articularly, intra-aurally, intrabronchially, intracapsularly, intrameningeally, via inhalation, via endotracheal or endobronchial instillation, via direct instillation into pulmonary cavities, intraspinally, intrasynovially, intrathoracically, via thoracostomy irrigation, epidurally, intratympanically, intracistemally, intravascularly, intraventricularly, intraosseously, via irrigation of infected bone, or via application as part of any admixture with a prosthetic device. The method of administration can vary depending on various factors, e.g., the components of the phaimaceutical composition, the site of the disease, the disease involved, and the severity of the disease.
[00105] A "diagnostic" as used herein is a compound, method, system, or device that assists in the identification or characterization of a health or disease state. The diagnostic can be used in standard assays as is known in the art.
[00106] The term "pharmaceutically acceptable carrier", "pharmaceutically acceptable diluent" or "pharmaceutically acceptable excipient" includes any and all solvents, co-solvents, complexing agents, dispersion media, coatings, isotonic and absorption delaying agents and the like which are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.
Supplementary active ingredients can also be incorporated into the compositions. In addition, various adjuvants such as are commonly used in the art may be included. These and other such compounds are described in the literature, e.g., in the Merck Index, Merck & Company, Rahway, NJ. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (2010);
Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 12th Ed., The McGraw-Hill Companies.
[00107] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the compounds provided herein and, which are not biologically or otherwise undesirable. In many cases, the compounds provided herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like;
particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, for example, as described in WO
87/05297.
[00108] "Solvate" refers to the compound formed by the interaction of a solvent and a Wnt pathway activator as provided herein or a salt thereof Suitable solvates are phamiaceutically acceptable solvates including hydrates.
[00109] The term "patient" as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate, or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate. In some embodiments, the patient is a human.
[00110] The term "mammal" is used in its usual biological sense. Thus, it specifically includes humans, cattle, horses, monkeys, dogs, cats, mouse, rat, a cow, sheep, pig, goat, and non-human primate but also includes many other species.
[00111] The term "vertebrate" is used in its usual biological sense. Thus, it specifically includes the classes' agnatha (jawless fishes), chondrichthyes (cartilaginous fishes), osteichthyes (bony fishes), amphibia (amphibians), reptilia (reptiles), ayes (birds) and mammalia (mammals).
[00112] By "therapeutically effective amount" or "pharmaceutically effective amount" of a compound as provided herein is one which is sufficient to achieve the desired physiological effect and may vary according to the nature and severity of the disease condition, and the potency of the compound. "Therapeutically effective amount"
is also intended to include one or more of the compounds of Formula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, III, III, Ma, IIIb, Mc, Hid, and/or IV in combination with one or more other agents that are effective to treat Wnt related diseases and/or conditions. The combination of compounds can be a synergistic combination.
Synergy, as described, for example, by Chou and Talalay, Advances in Enzyme Regulation (1984), 22, 27-55, occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. It will be appreciated that different concentrations may be employed for prophylaxis than for treatment of an active disease. This amount can further depend upon the patient's height, weight, sex, age and medical history.
[00113] A therapeutic effect relieves, to some extent, one or more of the symptoms of the disease, and can include curing a disease. "Curing" means that the symptoms of a disease are eliminated. However, certain long-term or permanent effects of the disease may exist even after a cure is obtained (such as extensive tissue damage).
[00114] "Treat," "treatment," or "treating," as used herein refers to administering a compound or pharmaceutical composition as provided herein for therapeutic purposes. The term "therapeutic treatment" refers to administering treatment to a patient already suffering from a disease thus causing a therapeutically beneficial effect, such as ameliorating existing symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, postponing or preventing the further development of a disorder, and/or reducing the severity of symptoms that will or are expected to develop.
[00115] The expression "compound-eluting" shall be understood to refer to any and all mechanisms, e.g., diffusion, migration, permeation, and/or desorption by which the compound(s) incorporated in the compound-eluting material or coating pass therefrom over time into the surrounding body tissue.
[00116] The expression "controlled release" encompasses many types of controlled release, including, for example, immediate release, pulsatile release, slow release, sustained release, and delayed release, to achieve a desired compound delivery profile.
[00117] The expression "compound-eluting material" and/or "compound-eluting coating" and/or "controlled release material" shall be understood herein to mean any natural, synthetic, or semi-synthetic material into which one or more compounds can be incorporated and from which incorporated compound(s) are capable of eluting over time. Materials for the delivery of a compound include a wide range of polymers and small-molecule matrices. For many compound-polymer systems, the release of the compound is dominated by the diffusion of the compound through a polymer matrix.
Polymer materials for compound delivery coatings may be durable or degradable [see, e.g., Current Pharmaceutical Design (2010), 16(36), 3978-3988]. Durable polymers are used in devices such as Cordis Cypher, Boston Scientific Taxus, Boston Scientific Promus, Abbott Xience, and Medtronic Resolute stents. Durable polymers can allow for longer delivery times and the underlying matrix does not change over time.
Degradable polymer coatings are used in devices such as OrbusNeich Combo stent. These materials enable control over the release of a compound by both diffusion (similar to durable systems) and degradation of the polymer, which can change the polymer Tg, coating thickness, and encapsulation of the compound over time. Some devices utilize both durable and biodegradable coatings, such as a stent coated on the inner and outer lumen for two different compound delivery mechanisms in a single device. In some embodiments, water insoluble/hydrophobic compounds may be coated directly onto the device with or without one or more additives [U.S. Pat. Appl. Publ. (2004), US20040224003 & PCT Int. Appl. (2013), W0/2013/169724].
[00118] The following abbreviations have the indicated meanings:
AD = Alzheimer's disease APC = adenomatous polyposis coli L-DOPA = L-3,4-dihydroxyphenylalanine Lef = lymphoid enhancing factor MMTV = mouse mammary tumor virus SCID = severe combined immunodeficiency TCF = T-cell factor TGF = transfoiming growth factor Wnt = wingless-type MMTV integration site family member Compounds
[00119] The compounds and compositions described herein are capable of activating the Wnt/13-catenin signaling pathway. The Wnt/13-catenin signaling pathway has been found to play a role in the differentiation and development of nerve cells for the central nervous system, bone formation, hair follicle development and regeneration, and stimulation of stem cell growth, maintenance, and differentiation.
[00120] Some embodiments of the present disclosure include compounds of Formula (I):
(R2)m (RiL

or salts, phaimaceutically acceptable salts, or prodrugs thereof.
[00121] In some embodiments of Formula I, Ring A is a 7-12 membered heteroaryl, wherein a carbon atom on the ring is attached to the carbonyl carbon.
[00122] In some embodiments of Formula I, Ring B is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, with the proviso that a carbon atom on the ring is attached to the carbonyl carbon.
[00123] In some embodiments of Formula I, Rl is a substituent attached to Ring A and is independently selected at each occun-ence from the group consisting of H, unsubstituted -C1_6 alkyl, -C1_3 haloalkyl, halide, -0R3, CF3, and CN.
[00124] In some embodiments of Formula I, R2 is a substituent attached to Ring B and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R31')2, -Ci_3 haloalkyl, halide, -OW, CF3, and CN.
[00125] In some embodiments of Fonnula I, each R3 is independently selected from the group consisting of H, unsubstituted -C1_6 alkyl, -Ci_3 haloalkyl, and CF3.
[00126] In some embodiments of Formula I, each R3b is independently selected from the group consisting of H and unsubstituted ¨C1_3 alkyl.
[00127] In some embodiments of Foimula I, each n is an integer of 1 to 10.
[00128] In some embodiments of Fonnula I, each m is an integer of 1 to 5.
[00129] In some embodiments of Fonnula I, there is the proviso that a compound of Fonnula I is not a compound selected from the group consisting of:
o * 0 0 0 , 0 0 N 0 S \
\ -., .,-So 40 0 . .
, , *
/ OH

\ 10 \ 10 0 -, , 0 0 \ 40 0 40 OMe 40 ., 0 o 40 0 1 0 -,0 4110 s , , , . 0 ..õ.
0 , 0 0 411 =
Br, 0 CI
1 i , , 40 o el CI
HN
I i 4i S 0 0 S 0 CI , 401 0 0 Br 0 el = S 0 Br ii 0 0 M N
and \ 0 M. .
, ,
[00130] In some embodiments of Formula I, Ring A is a 9-membered bicyclic heteroaryl ring containing 1-3 heteroatoms selected from the group consisting of N, 0, and S.
[00131] In some embodiments of Formula I, Ring A is a 10-membered bicyclic heteroaryl ring containing 1-3 heteroatoms selected from the group consisting of N, 0, and S.
[00132] In some embodiments of Formula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, and/or Ii, R1 is selected from the group consisting of H, F, Cl, Me, OMe, OH, CF3, and CN.
[00133] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, and/or Ii, R1 is H.
[00134] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, and/or Ii, Rl is a halide.
[00135] In some embodiments of Formula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, and/or Ii, R1 is F.
[00136] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, and/or Ii, RI is Cl.
[00137] In some embodiments of Foimula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, and/or Ii, Rl is Me.
[00138] In some embodiments of Foimula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, and/or Ii, RI is OH.
[00139] In some embodiments of Formula I, Ia, Ib, Ic, Id, le, If, Ig, 1h, and/or Ii, R1 is OMe.
[00140] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, and/or Ii, R1 is CF3.
[00141] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, and/or Ii, RI- is CN.
[00142] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, and/or n is an integer from 1-8.
[00143] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, and/or n is an integer from 1-6.
[00144] In some embodiments of Formula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, and/or n is an integer from 1-4.
[00145] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/or n is an integer from 1-2.
[00146] In some embodiments of Formula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, and/or Ii, RI is F; and n is 1.
[00147] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, and/or Ii, le is F; and n is an integer from 1-2.
[00148] In some embodiments of Foimula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, and/or Ii, R1 is F; and n is an integer from 3-4.
[00149] In some embodiments of Formula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, and/or Ii, le is OH; and n is an integer from 1-2.
[00150] In some embodiments of Formula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, and/or Ii, RI is OMe; and n is an integer from 1-2.
[00151] In some embodiments of Formula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, and/or Ii, le is -Ci_2 alkyl.
[00152] In some embodiments of Formula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, and/or Ti, R1 is -C1_3 alkyl.
[00153] In some embodiments of Foimula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, and/or Ii, RI is -Ci_4 alkyl.
[00154] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, and/or Rl is -Ci_5 alkyl.
[00155] In some embodiments of Fon-nula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, and/or Ii, RI is -C1_6 alkyl.
[00156] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, and/or Ii, Rl is ¨C2_6 alkyl.
[00157] In some embodiments of Formula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, and/or Ii, RI is ¨C3,6 alkyl.
[00158] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, and/or Ii, R1 is ¨C4_6 alkyl.
[00159] In some embodiments, each Rl is the same.
[00160] In some embodiments of Formula I, Ring A is selected from the group consisting of:
o HO 0F 0 S
FS
F
F..,õ IP
, 0 , 0 F-0 0 1 1 S '0 F-0 /
OH OMe OMe S OH''5 / OH, OH OMe '0 10 OMe,/

OMe S
le F ___________ /< 101 < 10 OMe 0 0 I. OH, OH 0 F 0 0 0 I (t4 0 <N
<sS
110 / lel N/ el 0 40 S <N NH 0 S N NH 0 N
\/ I. / la / el / 1401 S=, NH , S , and 0 ; wherein, unless otherwise designated, the carbonyl carbon of Formula I can faint a bond with any unsubstituted carbon on Ring A.
[00161] In some embodiments of Formula I, Ring A is selected from the group consisting of:
le o s s 40/ . 10 /o fi& / io / 40 '-o o 1.1 s o s \o IW , \o , \s N/
/
N N ' /
0 <
< lel NH 40 NH lei 0 40 O NH s 40, and 0 ; wherein the carbonyl carbon of Formula I can form a bond with any unsubstituted carbon on Ring A.
[00162] In some embodiments of Formula I, Ring A is selected from the group consisting of:

o s s 0 io1 o o s o Mlfrill o , s , NH 0 S , and o ; wherein the carbonyl carbon of Formula I can form a bond with any unsubstituted carbon on the Ring A.
[00163] In some embodiments of Formula I, Ring A is selected from the group consisting of:
o o i:) SI , o la <0 10 /NH 411 , and /0 lei ; wherein the carbonyl carbon of Formula I can form a bond with any unsubstituted carbon on the Ring A.
[00164] In some embodiments of Fonnula I, Ring A is selected from the group s S N
H
consisting of < 0 10 \ Oil <s IP o lal /NH 0 <N 411 N(1-I el , i 0 , 0 7o , 0 \c, , s , and 0 ;
wherein the carbonyl carbon of Formula I can form a bond with any unsubstituted carbon on the Ring A.
[00165] In some embodiments of Foimula I, Ring A is selected from the group <o a <s < a consisting of o o I=

rift W s , s a o , s 10 /NHS, /s el , , , 0and 0 ;
wherein the carbonyl carbon of Formula I can form a bond with any unsubstituted carbon on the Ring A.
[00166] In some embodiments of Formula I, Ring A is selected from the group / 40consisting of o MP , NH WI , and 0 ;
wherein the carbonyl carbon of Formula I can form a bond with any unsubstituted carbon on the Ring A.
[00167] In some embodiments of Formula I, Ring A is selected from the group o a s s ., a 1110, and s 10 .
consisting of 0 o a s , , o
[00168] In some embodiments of Formula I, Ia, Ib, Ic, Id, le, If, Ig, 1k, and/or Ii, RI is independently selected at each occurrence from the group consisting of H, F, Cl, Me, OMe, OH, CF3; and CN, and n is 1 or 2.
[00169] In some embodiments, Ring A is selected from the group consisting of o and 0
[00170] In some embodiments of Formula I, Ib, Ic, Ic, If, Ih, and/or Ii, Ring B
is phenyl.
[00171] In some embodiments of Folinula I, Ib, Ic, Ic, If, Ih, and/or Ii, Ring B
is a 5-membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, 0, and S.
[00172] In some embodiments of Folinula I, Ib, Ic, Ic, If, Ih, and/or Ii, Ring B
is a 6-membered heteroaryl containing 1-2 nitrogen atoms.
[00173] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, III, and/or Ii, R2, R2a, R2b, R2c, R2d, R2e, -2f, K and/or R2g is -CH2OH.
[00174] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, and/or Ii, R2, R2a, R2b, R2c, R2d, R2e, R2f, and/or -2g is -CH2N(R3b)2-
[00175] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, and/or Ii, R2, R2a, R21', R2c, R2d, R2e, 1(-2f, and/or R2g is -CH2NI12.
[00176] In some embodiments of Formula I, Ia, Ib, Ic, Id, le, If, Ig, 1k, and/or Ii, R2, R2a, R2b, R2c, R2d, R2e, R2, and/or R2g is -CH2NHMe
[00177] In some embodiments of Formula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, and/or Ii, R2, R2a, R21, R2c, R2a, R2e, -2f, x and/or R2g is -CH2NMe2.
[00178] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, and/or Ii, R2, R2a, R2b, R2c, R2d, R2e, R2, and/or R2g is -CH2NHEt.
[00179] In some embodiments of Foimula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, and/or Ii, R2, R2a, R2b, R2c, R2d, R2e, and/or R2g is -CH2N(Me)(Et)
[00180] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, and/or R2, R2a, R21, R2c, R2d, R2e, R2f, and/or -2g K is -CH2NEt2.
[00181] In some embodiments of Formula I, Ib, Ic, Ic, If, Ih, and/or Ii, R2 is independently selected at each occurrence from the group consisting of H, F, Cl, Me, OMe, OH, CF3, and CN.
[00182] In some embodiments of Formula I, Ib, Ic, le, If, Ih, and/or Ii, R2 is H.
[00183] In some embodiments of Formula I, Ib, Ic, Ic, If, Ih, and/or Ii, R2 is a halide.
[00184] In some embodiments of Formula I, Ib, Ic, le, If, Ih, and/or Ii, R2 is F.
[00185] In some embodiments of Formula I, Ib, Ic, Ic, If, Ih, and/or Ii, R2 is Cl.
[00186] In some embodiments of Fottnula I, Ib, Ic, Ic, If, Ih, and/or Ii, R2 is Me.
[00187] In some embodiments of Formula I, Ib, Ic, le, If, Ih, and/or Ii, R2 is OH.
[00188] In some embodiments of Formula I, Ib, Ic, le, If, Ih, and/or Ii, R2 is OMe.
[00189] In some embodiments of Formula I, Ib, Ic, Ic, If, Ih, and/or Ii, R2 is CF3.
[00190] In some embodiments of Fottnula I, Ib, Ic, le, If, Ih, and/or Ii, R2 is CN.
[00191] In some embodiments of Formula I, Ib, Ic, Ic, If, Ih, and/or Ii, m is an integer from 1-4.
[00192] In some embodiments of Formula I, Ib, Ic, Ic, If, Ih, and/or Ii, m is an integer from 1-2.
[00193] In some embodiments of Formula I, Ib, Ic, Ic, If, Ih, and/or Ii, m is 1.
[00194] In some embodiments of Formula I, Ib, Ic, Ic, If, Ih, and/or Ii, m is 2.
[00195] In some embodiments of Formula I, Ib, Ic, le, If, Ih, and/or Ii, R2 is F;
and m is 1.
[00196] In some embodiments of Formula I, Ib, Ic, Ic, If, Ih, and/or Ii, R2 is F;
and m is 2.
[00197] In some embodiments of Formula I, Ib, Ic, Ic, If, Ih, and/or Ii, R2 is Me; and m is 1.
[00198] In some embodiments of Formula I, Ib, Ic, le, If, Ih, and/or Ii, R2 is Me; and m is 2.
[00199] In some embodiments of Formula I, Ib, Ic, Ic, If, Ih, and/or Ii, R2 is CF3; and m is 1.
[00200] In some embodiments of Formula I, Ib, Ic, le, If, Ih, and/or Ii, R2 is CF3; and m is 2.
[00201] In some embodiments of Foimula I, Ib, Ic, le, If, Ih, and/or Ii, R2 is OMe; and m is 1.
[00202] In some embodiments of Formula I, Ib, Ic, le, If, Ih, and/or Ii, R2 is OMe; and m is 2.
[00203] In some embodiments of Formula I, Ib, Ic, Ic, If, Ih, and/or Ii, R2 is F
and Me' and m is 2.
[00204] In some embodiments of Formula I, Ib, Ic, le, If, Ih, and/or Ii, R2 is F
and CF3; and m is 2.
[00205] In some embodiments of Formula I, Ib, Ic, Ic, If, Ih, and/or Ii, R2 is F
and OMe; and m is 2.
[00206] In some embodiments of Formula I, Ib, Ic, le, If, Ih, and/or Ii, R2 is CN; and m is 1.
[00207] In some embodiments of Formula I, Ib, Ic, le, If, Ih, and/or Ii, R2 is CN; and m is 2.
[00208] In some embodiments of Formula I, Ib, Ic, le, If, Ih, and/or Ii, R2 is F
and CN; and m is 2.
[00209] In some embodiments of Formula I, Ib, Ic, le, If, Ih, and/or Ii, R2 is -CI _2 alkyl.
[00210] In some embodiments of Formula I, Ib, Ic, Ic, If, Ih, and/or Ii, R2 is -C _3 alkyl.
[00211] In some embodiments of Formula I, Ib, Ic, le, If, Ih, and/or Ii, R2 is -C14 alkyl.
[00212] In some embodiments of Formula I, Ib, Ic, Ic, If, Ih, and/or Ii, R2 is -C1_5 alkyl.
[00213] In some embodiments of Formula I, Ib, Ic, le, If, Ih, and/or Ii, R2 is -Ci_6 alkyl.
[00214] In some embodiments of Formula I, Ib, Ic, Ic, If, Ih, and/or Ii, R2 is ¨
C2_6 alkyl.
[00215] In some embodiments of Folinula I, Ib, Ic, Ie, If, Ih, and/or Ii, R2 is ¨
C36 alkyl.
[00216] In some embodiments of Formula I, Ib, Ic, Ic, If, Ih, and/or Ii, R2 is ¨
C4_6 alkyl.
[00217] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, and/or Ii, R3 is -Ci_2 alkyl.
[00218] In some embodiments of Formula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, and/or Ii, R3 is -C1..3 alkyl.
[00219] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, and/or Ii, R3 is -Ci_4 alkyl.
[00220] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, and/or Ii, R3 is -Ci_5 alkyl.
[00221] In some embodiments of Formula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, and/or Ii, R3 is -C1_6 alkyl.
[00222] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, and/or Ii, R3 and/or R3a is ¨C26 alkyl.
[00223] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, and/or Ii, R3 and/or R3a is ¨C3_6 alkyl.
[00224] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, and/or Ii, R3 and/or R3 is ¨C4..6 alkyl.
[00225] In some embodiments of Formula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, and/or Ii, R3 and/or R3a is ¨C2.5 alkyl.
[00226] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, and/or Ii, R3 and/or R3a is ¨C3_4 alkyl.
[00227] In some embodiments of Formula I, Ib, Ic, le, If, Ih, and/or Ii, Ring B
is a phenyl or 6-membered heteroaryl; R2 is selected from the group consisting of F, Cl, Me, OMe, OH, CF3, and CN; in is 1; and R2 is attached to an ortho carbon of the 6-membered ring.
[00228] In some embodiments of Formula I, Ib, Ic, Ic, If, Ih, and/or Ii, Ring B
is a phenyl; R2 is selected from the group consisting of F, Cl, Me, OMe, OH, CF3; and CN; m is 1; and R2 is attached to an ortho position of the phenyl ring.
[00229] In some embodiments of Folinula I, Ib, Ic, Ic, If, Ih, and/or Ii, Ring B
is a pyridine; R2 is selected from the group consisting of F, Cl, Me, OMe, OH, CF3, and CN; m is 1; and R2 is attached to an ortho carbon of the pyridine ring.
[00230] In some embodiments of Formula I, Ib, Ic, le, If, Ih, and/or Ii, 0 ,R2,m F

is selected from the group consisting of:
a F3C a Me0 fla Me 0 NC a HO
-N/
gio N-%\
F I CI-1- F3CH- Me 1 /
ti3A' /
N, Nll 3>2' it, /FAA, N
NN
/
Isl KIN / O NN NS NN NNSrN /N
N
/ /
(N PIN 3 N, N
/ N , and N ; wherein the carbonyl carbon of Formula I, Ib, Ic, le, If, Ih, and/or Ii, can form a bond with any unsubstituted carbon on the Ring B.
[00231] In some embodiments of Formula I, Ib, Ic, Ic, If, Ih, and/or Ii, co,R2,m is selected from the group consisting of:

F CI CF3 OMe Me CN
110 F, * * * * *

_Nõ.,..õd.2, ...,N),, ..õ.õN)4 24.õ,-õ,õ..)-2, ..,..Nõ..,õõ..--\ ..õ...õN)...4 101 OH 110 111,. I , 1N II c)Th, s), ; wherein the carbonyl carbon of , 5 , Formula I, Ib, Ic, Ic, If, Ih, and/or Ii, can form a bond with any unsubstituted carbon on the Ring B.
[00232] In some embodiments of Formula I, Ib, Ic, le, If, Ih, and/or Ii, 0 (R2)m is selected from the group consisting of:
F CI CF3 OMe Me CN
101 . 110 01 , , * ,* , ;wherein the carbonyl carbon of Formula I, Ib, Ic, Ic, If, Ih, and/or Ii, can form a bond with any unsubstituted carbon on the Ring B.
[00233] In some embodiments of Formula I, Ib, Ic, le, If, Ih, and/or Ii, B
(R2)rn \
fr' 140 (F), II
is selected from the group consisting of , , \ \ \ \
rr. r---- 1--- r--'-' ii (NC
(cl)m ii (F,c)m II (Me0)m II (Me)m )m 401 .%- and , 5 and m is 1 or 2.
[00234] In some embodiments of Formula I, Ib, Ic, le, If, Ih, and/or Ill, F
0 (R2)m F
*is selected from the group consisting of 0 , 11 CI CF3 OMe Me CN
0 10 10 1401 , and SI
, , .
[00235] In some embodiments of Formula I, Ib, Ic, Ic, If, Ih, and/or Ii, (R2)m (R2)n /,)A
) is selected from the group consisting of s (R2) N_)õ..\ (R2)m (R2)m (R26 ni 17(2)./¨µõN) NN ) s) ko) ks) H and (R2)ni N¨x-N)\
H ; and m is 1 or 2.
[00236] In some embodiments of Fointula I, Ib, Ic, Ic, If, Ih, and/or Ii, 4:0 (R2)m is selected from the group consisting of 0 and S ; and R2 is H
[00237] In some embodiments of Formula I, Ib, Ic, Ie, If, Ih, and/or Ii, 0 (R2)m Nfl ) ) is selected from the group consisting of (R26 (R)m 5 (R2)mN
N/N
and (R2)m ; and m is 1 or 2.
[00238] In some embodiments of Formula I, Ib, Ic, Ic, If, Ih, and/or Ii, 0 (R2).
, is selected from the group consisting of , , , and ; and R2 is H.
[00239] Some additional embodiments of Formula I include compounds of Formula (Ia):

(R1)n Ia or salts, pharmaceutically acceptable salts, or prodrugs thereof.
[00240] In some embodiments of Formula Ia, Ring A is
[00241] In some embodiments of Formula Ia, Ring B is selected from the R2b \ R-\
2d /\
group consisting of R2a 55-'5 R2b R2C
2e R2\ R2e `11,11, Ilfµf R 2 f R2g __ R2g U¨U
S31 ( \
klW
vvs7 R2g .11 and G7
[00242] In some embodiments of Formula Ia, each R1 is a substituent attached to Ring A and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1.6 alkyl, -C1_3 haloalkyl, halide, -0R3, CF3, and CN.
[00243] In some embodiments of Founula Ia, R2a is a substituent attached to the para position of phenyl and selected from the group consisting of unsubstituted ¨C1-6 alkyl, -CH2OH, -CH2N(R3b)2, -C1_3 haloalkyl, Cl, Br, I, -0R3a, CF3, and CN.
[00244] In some embodiments of Formula Ia, R2b is a substituent attached to the meta or ortho position of phenyl and selected from the group consisting of unsubstituted -Ci_6 alkyl, -CH2OH, -CH2N(R31')2, -Ci_3 haloalkyl, halide, -0R3a, CF3, and CN.
[00245] In some embodiments of Formula Ia, R2e is 2-5 substituents, each attached to the phenyl and are independently selected at each occurrence from the group consisting of unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R3b)2, -C1_3 haloalkyl, halide, -0R3, CF3, and CN.
[00246] In some embodiments of Formula Ia, R2d is 1-4 substituents, each attached to the heteroaryl ring and are independently selected at each occurrence from the group consisting of unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R31')2, -C1_3 haloalkyl, halide, -0R3, CF3, and CN.
4:
[00247] In some embodiments of FoHnula Ia, R2e is 1-4 substituents, each attached to the heteroaryl ring and are independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R3b)2, -Ci_3 haloalkyl, halide, -0R3, CF3, and CN.
[00248] In some embodiments of Formula Ia, R2f is 1-3 substituents, each attached to the heteroaryl ring and are independently selected at each occurrence from the group consisting of unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R31')2, -C1_3 haloalkyl, halide, -0R3, CF3, and CN.
[00249] In some embodiments of Formula Ia, R2g is 1-3 substituents, each attached to the heteroaryl ring and are independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R3b)2, -C1_3 haloalkyl, halide, -OW, CF3, and CN.
[00250] In some embodiments of Formula Ia, each R3 is independently selected from the group consisting of H, unsubstituted -C1_6 alkyl, -C1_3 haloalkyl, and CF3.
[00251] In some embodiments of Formula Ia, each R3a is independently selected from the group consisting of unsubstituted ¨C2_6 alkyl, -C1_3 haloalkyl, and CF3.
[00252] In some embodiments of Formula Ia, each R3b is independently selected from the group consisting of H and unsubstituted ¨C1_3 alkyl.
[00253] In some embodiments of Formula Ia, each W is N or C.
[00254] In some embodiments of Formula Ia, at least two W must be N.
[00255] In some embodiments of Formula Ia, each U is N or C.
[00256] In some embodiments of Formula Ia, at least one U must be N and at least one U must be C.
[00257] In some embodiments of Formula Ia, G is NH or 0.
[00258] In some embodiments of Fonnula Ia, each J is N or C.
[00259] In some embodiments of Formula Ia, at least one J must be C.
[00260] In some embodiments of Formula Ia, n is an integer of 1 to 7.
[00261] In some embodiments of Formula Ia, Ring A is selected from the F
F
group consisting of *, and F 0
[00262] In some embodiments of Formula Ia, Ring B is selected from the F
\
group consisting of I i $ F, * \ I * \
i , *\ is la 101 F3C CF ClCI * , , CI, CN
0 * 1401 *
NC CN OH , and 10 ii , ,=
[00263] In some embodiments of Formula Ia, Ring B is selected from the F F
(11N,,,)-4 ..!s.c 1 , group consist ixing of F F , õN
, --")2, ,NN,)l2, .N,)-z, N/\)2,-N,\' N
CF3 CI ''''CN F '\-/ CF3 ''CI
, , , N.-----=:-..,,,,õ.)-2, 1 1 1 1 _, 1 1 CN INI-F CF3 'N-CI , and i'4".'-"CN .
,
[00264] In some embodiments of Foimula Ia, Ring B is selected from the I\1N\' 1 11 k 1 group consisting of N , N 1 , N , N- , and .
[00265] In some embodiments of Foimula Ia, Ring B is selected from the N F
c Cl group consisting of F S
s , , s , F3c s NC
S ( and , S S S
S ,
[00266] In some embodiments of Formula Ia, Ring B is selected from the F CI
i ;1-1' ;F
F- `=-=,s S S
group consisting of 'S , , F3C7\ NC .?1-L, &
S CI \ i S CN
S , and , , , (s \
[00267] In some embodiments of Formula Ia, Ring B is selected from the ) R29\ R29\ ?1-, R2g\ 1< ;'-'\ // (\
N N N N
group consisting of R2g S s \ SZ , R29--(s/11 R2g R2 NNs R2g g N ______________ R2g b __ R2g R294._ N
17/ ( N) , 3INS
N NNs N
S S , and N¨N
R2g S
[00268] In some embodiments of Formula Ia, Ring B is selected from the R2g\ R2g\
N R2g\
/G NN NN /INI
group consisting of G R2g G , G
, G
, R2g N N

R29 R2g R2gt N
\N R2g t ( G7 R2g G
N NR2g R2g NN
NG , and
[00269] In some embodiments of Foimula Ia and/or Id, R2a is Cl.
[00270] In some embodiments of Formula Ia, Id, and/or Ig, R2a is Me.
[00271] In some embodiments of Foimula Ia, Id, and/or Ig. R2a is CF3.
[00272] In some embodiments of Formula Ia, Id, and/or Ig, R2a is CN.
[00273] In some embodiments of Formula Ia, Id, and/or Ig. R2a is 1 substituent and is Me.
[00274] In some embodiments of Formula Ia, Id, and/or Ig, R2a is 2 substituents and both are Me.
[00275] In some embodiments of Formula Ia, Id, and/or Ig, R2a is 1 substituent and is CF3.
[00276] In some embodiments of Folinula Ia, Id, and/or Ig, R2a is 2 substituents and both are CF3.
[00277] In some embodiments of Formula Ia, Id, and/or Ig, R2a is 1 substituent and is CN.
[00278] In some embodiments of Formula Ia, Id, and/or Ig, R2a is 2 substituents and both are CN.
[00279] In some embodiments of Formula Ia, Id, and/or Ig, R2a is -C1_2 alkyl.
[00280] In some embodiments of Formula Ia, Id, and/or Ig, R2a is -C1_3 alkyl.
[00281] In some embodiments of Formula Ia, Id, and/or Ig. R2a is -C14 alkyl.
[00282] In some embodiments of Formula Ia, Id, and/or Ig, R2a is -C1_5 alkyl.
[00283] In some embodiments of Formula Ia, Id, and/or Ig, R2a is -C1_6 alkyl.
[00284] In some embodiments of Formula Ia, Id, and/or Ig. R2a is ¨C2_6 alkyl.
[00285] In some embodiments of Formula Ia, Id, and/or Ig. R2a is ¨C3_6 alkyl.
[00286] In some embodiments of Formula Ia, Id, and/or Ig, R2a is ¨C4_6 alkyl.
[00287] In some embodiments of Fonnula Ia, Id, and/or Ig, R2a is ¨C2_5 alkyl.
[00288] In some embodiments of Formula Ia, Id, and/or Ig, R2a is ¨C3_4 alkyl.
[00289] In some embodiments of Formula Ia and/or Ig, R2b is a halide.
[00290] In some embodiments of Formula Ia, Id, and/or Ig. R2b is F.
[00291] In some embodiments of Formula Ia and/or Ig. R2b is Cl.
[00292] In some embodiments of Formula Ia, R21 is Me.
[00293] In some embodiments of Formula Id and/or Ig, R2b is OH.
[00294] In some embodiments of Formula Id and/or Ig, R2b is OMe.
[00295] In some embodiments of Fonnula Ia, Id, and/or Ig, R21 is CF3.
[00296] In some embodiments of Formula Ia, Id, and/or Ig, R2b is CN.
[00297] In some embodiments of Formula Ia, Id, and/or Ig, R2b is 1 substituent and is F.
[00298] In some embodiments of Formula Ia, Id, and/or Ig. R2b is 2 substituents and both are F.
[00299] In some embodiments of FoHnula Ia, R2b is 1 substituent and is Me.
[00300] In some embodiments of Formula Ia, R2b is 2 substituents and both are Me.
[00301] In some embodiments of Formula Ia, Id, and/or Ig, R2b is 1 substituent and is CF3.
[00302] In some embodiments of Formula Ia, Id, and/or Ig. R2b is 2 substituents and both are CF3.
[00303] In some embodiments of Formula Id and/or Ig, R2b is 1 substituent and is OMe.
[00304] In some embodiments of Fomiula Id and/or Ig, R21 is 2 substituents and both are OMe.
[00305] In some embodiments of Formula Ia, R2b is 2 substituents and are F
and Me.
[00306] In some embodiments of Formula Ia, Id, and/or 1g. R21 is 2 substituents and are F and CF3.
[00307] In some embodiments of Formula Id and/or Ig, R2b is 2 substituents and are F and OMe.
[00308] In some embodiments of Formula Ia, Id, and/or Ig, R2b is 1 substituent and is CN.
[00309] In some embodiments of Formula Ia, Id, and/or Ig, R2b is 2 substituents and both are CN.
[00310] In some embodiments of Formula Ia, Id, and/or Ig. R21 is 2 substituents and are F and CN.
[00311] In some embodiments of Formula Ia, R2b is -C1_2 alkyl.
[00312] In some embodiments of Formula la, R2b is -Ci_3 alkyl.
[00313] In some embodiments of Formula Ia, R2b is -C1_4 alkyl.
[00314] In some embodiments of Formula Ia, R2b is -C1_5 alkyl.
[00315] In some embodiments of Formula Ia, R21 is -C1_6 alkyl.
[00316] In some embodiments of Formula Ia, Id, and/or Ig. R2b is ¨C2_6 alkyl.
[00317] In some embodiments of Formula Ia, Id, and/or Ig, R21' is ¨C3_6 alkyl.
[00318] In some embodiments of Formula Ia, Id, and/or Ig, R2b is ¨C4_6 alkyl.
[00319] In some embodiments of Formula Ia, Id, and/or Ig, R2b is ¨C2_5 alkyl.
[00320] In some embodiments of Formula Ia, Id, and/or Ig, R2b is ¨C3_4 alkyl.
[00321] In some embodiments of Formula Ia and/or Ig, R2' is a halide.
[00322] In some embodiments of Formula Ia, Id, and/or Ig. R2e is F.
[00323] In some embodiments of Formula Ia and/or Ig, R2e is Cl.
[00324] In some embodiments of Formula Ia, Id, and/or Ig, R2e is Me.
[00325] In some embodiments of Formula Ia, Id, and/or Ig. R2e is OH.
[00326] In some embodiments of Formula Ia, Id, and/or Ig, R2e is OMe.
[00327] In some embodiments of Formula Ia, Id, and/or Ig. R2e is CF3.
[00328] In some embodiments of Formula Ia, Id, and/or Ig, R2e is CN.
[00329] In some embodiments of Formula Ia, Id, and/or Ig. R2' is 1 substituent and is F.
[00330] In some embodiments of Fonnula Ia, Id, and/or Ig. R2c is 2 substituents and both are F.
[00331] In some embodiments of Formula Ia, Id, and/or Ig, R2c is 1 substituent and is Me.
[00332] In some embodiments of Formula Ia, Id, and/or Ig. R2c is 2 substituents and both are Me.
[00333] In some embodiments of Fonnula Ia, Id, and/or Ig, R2c is 1 substituent and is CF3.
[00334] In some embodiments of Formula Ia, Id, and/or Ig. R2e is 2 substituents and both are CF3.
[00335] In some embodiments of Formula Ia, Id, and/or Ig, R2e is 1 substituent and is OMe.
[00336] In some embodiments of Formula Ia, Id, and/or Ig. R2e is 2 substituents and both are OMe.
[00337] In some embodiments of Formula Ia, Id, and/or Ig, R2c is 2 substituents and are F and Me.
[00338] In some embodiments of Formula Ia, Id, and/or Ig, R2c is 2 substituents and are F and CF3.
[00339] In some embodiments of Formula Ia, Id, and/or Ig, R2e is 2 substituents and are F and OMe.
[00340] In some embodiments of Formula Ia, Id, and/or Ig, R2' is 1 substituent and is CN.
[00341] In some embodiments of Formula Ia, Id, and/or Ig. R2e is 2 substituents and both are CN.
[00342] In some embodiments of Fonnula Ia, Id, and/or Ig. R2e is 2 substituents and are F and CN.
[00343] In some embodiments of Formula Ia, Id, and/or Ig. R2e is -C1_2 alkyl.
[00344] In some embodiments of Formula Ia, Id, and/or Ig. R2' is -C1_3 alkyl.
[00345] In some embodiments of Formula Ia, Id, and/or Ig, R2c is -C1_4 alkyl.
[00346] In some embodiments of Fonnula Ia, Id, and/or Ig. R2c is -C1_5 alkyl.
[00347] In some embodiments of Formula Ia, Id, and/or Ig, R2c is -C1_6 alkyl.
[00348] In some embodiments of Formula Ia, Id, and/or Ig, R2' is ¨C2_6 alkyl.
[00349] In some embodiments of Formula Ia, Id, and/or Ig, R2e is ¨C3_6 alkyl.
[00350] In some embodiments of Formula Ia, Id, and/or Ig, R2' is ¨C4_6 alkyl.
[00351] In some embodiments of Formula Ia, Id, and/or 1g. R2' is ¨C2.5 alkyl.
[00352] In some embodiments of Fonnula Ia, Id, and/or Ig, R2e is ¨C3_4 alkyl.
[00353] In some embodiments of Fonnula Ia and/or Ig, R2d is a halide.
[00354] In some embodiments of Formula Ia, hi, and/or Ig, R2d is F.
[00355] In some embodiments of Formula Ia, Id, and/or Ig, R2d is Cl.
[00356] In some embodiments of Formula Ia, Id, and/or Ig, R2d is Me.
[00357] In some embodiments of Formula Ia, Id, and/or Ig. R2d is OH.
[00358] In some embodiments of Formula Ia, Id, and/or Ig, R2d is OMe.
[00359] In some embodiments of Formula Ia, Id, and/or Ig, R2d is CF3.
[00360] In some embodiments of Formula Ia, Id, and/or Ig. R2d is CN.
[00361] In some embodiments of Fonnula Ia, Id, and/or Ig, R2d is 1 substituent and is F.
[00362] In some embodiments of Formula Ia, Id, and/or Ig. R2d is 2 substituents and both are F.
[00363] In some embodiments of Fonnula Ia, Id, and/or Ig, R2d is 1 substituent and is Me.
[00364] In some embodiments of Formula Ia, Id, and/or Ig. R2d is 2 substituents and both are Me.
[00365] In some embodiments of Formula Ia, Id, and/or Ig, R2d is 1 substituent and is CF3.
[00366] In some embodiments of Formula Ia, hi, and/or Ig, R2d is 2 substituents and both are CF3.
[00367] In some embodiments of Formula Ia, Id, and/or Ig, R2d is 1 substituent and is OMe.
[00368] In some embodiments of Formula Ia, Id, and/or Ig. R2d is 2 substituents and both are OMe.
[00369] In some embodiments of Formula Ia, Id, and/or Ig. R2d is 2 substituents and are F and Me.
[00370] In some embodiments of Formula Ia, Id, and/or Ig, R2d is 2 substituents and are F and CF3.
[00371] In some embodiments of Formula Ia, Id, and/or Ig, R2d is 2 substituents and are F and OMe.
[00372] In some embodiments of Formula Ia, Id, and/or Ig. R2d is 1 substituent and is CN.
[00373] In some embodiments of Formula Ia, Id, and/or Ig, R2d is 2 substituents and both are CN.
[00374] In some embodiments of Formula Ia, Id, and/or Ig, R2d is 2 substituents and are F and CN.
[00375] In some embodiments of Formula Ia, hi, and/or Ig, R2d is -C1_2 alkyl.
[00376] In some embodiments of Formula Ia, Id, and/or Ig, R2d is -Ci_3 alkyl.
[00377] In some embodiments of Formula Ia, Id, and/or Ig, R2d is -C14 alkyl.
[00378] In some embodiments of Formula Ia, Id, and/or Ig, R2d is -Ci_5 alkyl.
[00379] In some embodiments of Formula Ia, Id, and/or Ig, R2d is -Ci_6 alkyl.
[00380] In some embodiments of Formula Ia, Id, and/or Ig. R2d is ¨C2_6 alkyl.
[00381] In some embodiments of Formula Ia, Id, and/or Ig. R2d is ¨C3_6 alkyl.
[00382] In some embodiments of Formula Ia, hi, and/or Ig, R2d is ¨C4_6 alkyl.
[00383] In some embodiments of Formula Ia, Id, and/or Ig, R2d is ¨C2_5 alkyl.
[00384] In some embodiments of Formula Ia, Id, and/or Ig. R2d is ¨C3_4 alkyl.
[00385] In some embodiments of Formula Ia and/or Id, R2e is H.
[00386] In some embodiments of Formula Ia and/or Id, R2e is a halide.
[00387] In some embodiments of Formula Ia and/or Id, R2e is F.
[00388] In some embodiments of Formula Ia and/or Id, R2e is Cl.
[00389] In some embodiments of Fonnula Ia and/or Id, R2e is Me.
[00390] In some embodiments of Formula Ia and/or Id, R2e is OH.
[00391] In some embodiments of Foimula Ia and/or Id, R2e is OMe.
[00392] In some embodiments of Formula Ia and/or Id, R2e is CF3.
[00393] In some embodiments of Fonnula Ia and/or Id, R2e is CN.
[00394] In some embodiments of Formula Ia and/or Id, R2e is 1 substituent and is F.
[00395] In some embodiments of Formula Ia and/or Id, R2e is 2 substituents and both are F.
[00396] In some embodiments of Fornmla Ia and/or Id, R2e is 1 substituent and is Me.
[00397] In some embodiments of Formula Ia and/or Id, R2e is 2 substituents and both are Me.
[00398] In some embodiments of Formula Ia and/or Id, R2e is 1 substituent and is CF3.
[00399] In some embodiments of Formula Ia and/or Id, R2e is 2 substituents and both are CF3.
[00400] In some embodiments of Formula Ia and/or Id, R2e is 1 substituent and is OMe.
[00401] In some embodiments of Formula Ia and/or Id, R2e is 2 substituents and both are OMe.
[00402] In some embodiments of Formula Ia and/or Id, R2e is 2 substituents and are F and Me.
[00403] In some embodiments of Formula Ia and/or Id, R2e is 2 substituents and are F and CF3.
[00404] In some embodiments of Formula Ia and/or Id, R2e is 2 substituents and are F and OMe.
[00405] In some embodiments of Formula Ia and/or Id, R2e is 1 substituent and is CN.
[00406] In some embodiments of Formula Ia and/or Id, R2e is 2 substituents and both are CN.
[00407] In some embodiments of Formula Ia and/or Id, R2e is 2 substituents and are F and CN.
[00408] In some embodiments of Formula Ia and/or Id, R2e is -C1_2 alkyl.
[00409] In some embodiments of Formula Ia and/or Id, R2e is -C1_3 alkyl.
[00410] In some embodiments of Formula Ia and/or Id, R2e is -C1_4 alkyl.
[00411] In some embodiments of Formula Ia and/or Id, R2e is -C1_5 alkyl.
[00412] In some embodiments of Formula Ia and/or Id, R2e is -C1_6 alkyl.
[00413] In some embodiments of Formula Ia and/or Id, R2e is ¨C2_6 alkyl.
[00414] In some embodiments of Formula Ia and/or Id, R2e is ¨C3_6 alkyl.
[00415] In some embodiments of Formula Ia and/or Id, R2e is ¨C4_6 alkyl.
[00416] In some embodiments of Formula Ia and/or Id, R2e is ¨C2_5 alkyl.
[00417] In some embodiments of Formula Ia and/or Id, R2e is ¨C3_4 alkyl.
[00418] In some embodiments of Formula Ia, R2f is a halide.
[00419] In some embodiments of Fonnula Ia, R2f is F.
[00420] In some embodiments of Formula Ia, R2f is Cl.
[00421] In some embodiments of Fonnula Ia, R2f is Me.
[00422] In some embodiments of Formula Ia, R2f is OH.
[00423] In some embodiments of Formula Ia, R2f is OMe.
[00424] In some embodiments of Formula Ia, R2f is CF3.
[00425] In some embodiments of Formula Ia, R2f is CN.
[00426] In some embodiments of Fonaula Ia, R2f is 1 substituent and is F.
[00427] In some embodiments of Formula Ia, R2f is 2 substituents and both are F.
[00428] In some embodiments of Formula Ia, R2f is 1 substituent and is Me.
[00429] In some embodiments of Formula Ia, R2f is 2 substituents and both are Me.
[00430] In some embodiments of Fonnula Ia, R2f is 1 substituent and is CF3.
[00431] In some embodiments of Fonnula Ia, R2f is 2 substituents and both are CF3.
[00432] In some embodiments of Formula Ia, R2f is 1 substituent and is OMe.
[00433] In some embodiments of Formula Ia, R2f is 2 substituents and both are OMe.
[00434] In some embodiments of Formula Ia, R2f is 2 substituents and are F
and Me.
[00435] In some embodiments of Formula Ia, R2f is 2 substituents and are F
and CF3.
[00436] In some embodiments of Fonnula Ia, R2f is 2 substituents and are F
and OMe.
[00437] In some embodiments of Formula Ia, R2f is 1 substituent and is CN.
[00438] In some embodiments of Formula Ia, R2f is 2 substituents and both are N.
[00439] In some embodiments of Formula Ia, R2f is 2 substituents and are F
and CN.
[00440] In some embodiments of Formula Ia, R2f is -C1_7 alkyl.
[00441] In some embodiments of Formula Ia, R2f is -C1_3 alkyl.
[00442] In some embodiments of Formula Ia, R2f is -C1_4 alkyl.
[00443] In some embodiments of Formula Ia, R2f is -C1_5 alkyl.
[00444] In some embodiments of Formula Ia, R2f is -Ci_6 alkyl.
[00445] In some embodiments of Foimula Ia, R2f is ¨C2_6 alkyl.
[00446] In some embodiments of Formula Ia, R2f is ¨C3_6 alkyl.
[00447] In some embodiments of Formula Ia, R2f is ¨C4_6 alkyl.
[00448] In some embodiments of Foimula Ia, R2f is ¨C2_5 alkyl.
[00449] In some embodiments of Foimula Ia, R2f is ¨C3_4 alkyl.
[00450] In some embodiments of Formula Ia, R2g is H.
2g
[00451] In some embodiments of Formula Ia, R is a halide.
[00452] In some embodiments of Formula Ia, R2g is F.
[00453] In some embodiments of Formula Ia, R2g is Cl.
[00454] In some embodiments of Formula Ia, R2g is Me.
[00455] In some embodiments of Formula Ia, R2g is OH.
[00456] In some embodiments of Formula Ia, R2g is OMe.
[00457] In some embodiments of Formula Ia, R2g is CF3.
[00458] In some embodiments of Formula Ia, R2g is CN.
[00459] In some embodiments of Formula Ia, R2g is 1 substituent and is F.
[00460] In some embodiments of Formula Ia, R2g is 2 substituents and both are F.
[00461] In some embodiments of Formula Ia, R2g is 1 substituent and is Me.
[00462] In some embodiments of Formula Ia, R2g is 2 substituents and both are Me.
[00463] In some embodiments of Formula Ia, R2g is 1 substituent and is CF3.
[00464] In some embodiments of Formula Ia, R2g is 2 substituents and both are CF3.
[00465] In some embodiments of Fommla Ia, R2g is 1 substituent and is OMe.
[00466] In some embodiments of Foimula Ia, R2g is 2 substituents and both are OMe.
[00467] In some embodiments of Formula Ia, R2g is 2 substituents and are F
and Me.
[00468] In some embodiments of Formula Ia, R2g is 2 substituents and are F
and CF3.
[00469] In some embodiments of Foimula Ia, R2g is 2 substituents and are F
and OMe.
[00470] In some embodiments of Formula Ia, R2g is 1 substituent and is CN.
[00471] In some embodiments of Fotinula Ia, R2g is 2 substituents and both are CN.
[00472] In some embodiments of Formula Ia, R2g is 2 substituents and are F
and CN.
[00473] In some embodiments of Formula Ia, R2g is -C1_2 alkyl.
[00474] In some embodiments of Formula Ia, R2g is -C1_3 alkyl.
[00475] In some embodiments of Formula Ia, R2g is -C1_4 alkyl.
[00476] In some embodiments of Formula Ia, R2g is -C1_5 alkyl.
[00477] In some embodiments of Formula Ia, R2g is -C1_6 alkyl.
[00478] In some embodiments of Formula Ia, R2g is ¨C2_6 alkyl.
[00479] In some embodiments of Formula Ia, R2g is ¨C3_6 alkyl.
[00480] In some embodiments of Formula Ia, R2g is ¨C4_6 alkyl.
[00481] In some embodiments of Formula Ia, R2g is ¨C2_5 alkyl.
[00482] In some embodiments of Formula Ia, R2g is ¨C3.4 alkyl.
[00483] Some additional embodiments of Formula I include compounds of Formula (Ib):
o (R2)m (R1),, Ib or salts, pharmaceutically acceptable salts, or prodrugs thereof.
[00484] In some embodiments of Formula Ib, Ring A is
[00485] In some embodiments of Fommla Ib, Ring B is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, wherein a carbon atom on the ring is attached to the carbonyl carbon.
[00486] In some embodiments of Formula Ib, each 121 is a substituent attached to Ring A and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1,6 alkyl, -Ci_3 haloalkyl, halide, -0R3, CF3, and CN.
[00487] In some embodiments of Formula Ib, each R2 is a substituent attached to Ring B and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R31)2, -C1,3 haloalkyl, halide, -0R3, CF3, and CN.
[00488] In some embodiments of Formula Ib, each R3 is independently selected from the group consisting of H, unsubstituted -Ci_6 alkyl, -Ci_3 haloalkyl, and CF3.
[00489] In some embodiments of Formula Ib, each R3b is independently selected from the group consisting of H and unsubstituted ¨Ci_3 alkyl.
[00490] In some embodiments of Fommla Ib, each M is independently selected from the group consisting of N, C, S and 0.
[00491] In some embodiments of Formula Ib, both M are not 0.
[00492] In some embodiments of Formula Ib, both M are not C.
[00493] In some embodiments of Formula Ib, m is an integer of 1 to 5.
[00494] In some embodiments of Formula Ib, n is an integer of 1 to 10.
[00495] In some embodiments of Fommla Ib, Ring A is selected from the F S

group consisting of o -o F 0
[00496] Some additional embodiments of Formula ns includeI
compounds of Founula (Ic):
(R2),, (R1)n IC

or salts, pharmaceutically acceptable salts, or prodrugs thereof.
[00497] In some embodiments of Formula Ic, Ring A is Ivi"
[00498] In some embodiments of Formula Ic, Ring B is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, wherein a carbon atom on the ring is attached to the carbonyl carbon.
[00499] In some embodiments of Formula Ic, each RI is a substituent attached to Ring A and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -C1_3 haloalkyl, halide, -0R3, CF3, and CN.
[00500] In some embodiments of Formula Ic, each R2 is a substituent attached to Ring B and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R3b)2, -C1_3 haloalkyl, halide, -0R3, CF3, and CN.
[00501] In some embodiments of Formula Ic, each R3 is independently selected from the group consisting of H, unsubstituted -Ci_6 alkyl, -C1_3 haloalkyl, and CF3.
[00502] In some embodiments of Foimula Ic, each R3b is independently selected from the group consisting of H and unsubstituted ¨C1_3 alkyl.
[00503] In some embodiments of Formula Ic, each M is independently selected from the group consisting of N, C, S and 0.
[00504] In some embodiments of Formula Ic, if one M is C, the other M is selected from the group consisting of N, S, and 0.
[00505] In some embodiments of Formula Ic, m is an integer of 1 to 5.
[00506] In some embodiments of Formula Ic, n is an integer of 1 to 10.
[00507] In some embodiments of Formula Ic, Ring A is selected from the <c' F = 401 <: a ,s group consisting of o F 0 \S S. 0 5, and s S.
[00508] Some additional embodiments of Formula I include compounds of Formula (Id):

(R1)n Id or salts, pharmaceutically acceptable salts, or prodrugs thereof.
140 [00509] In some embodiments of Fonnula Id, Ring A is 0.
[00510] In some embodiments of Formula Id, Ring B is selected from the R2b \
I
5SS5 110 R2c group consisting of R2a , and a membered heteroary1R2e, wherein a carbon atom on the ring is attached to the carbonyl carbon.
[00511] In some embodiments of Formula Id, each RI- is a substituent attached to Ring A and is independently selected at each occurrence from the group consisting of H, unsubstituted -Ci_6 alkyl, -Ci_3 haloalkyl, halide, -0R3, CF3, and CN.
[00512] In some embodiments of Fomiula Id, R2a is a substituent attached to the para position of phenyl and selected from the group consisting of H, unsubstituted ¨
C1_6 alkyl, -CH2OH, -CH2N(R3b)2, -C1_3 haloalkyl, Cl, Br, I, -0R3a, CF3, and CN.
[00513] In some embodiments of Formula Id, R2b is a substituent attached to the meta position of phenyl and selected from the group consisting of H, unsubstituted ¨
C2_6 alkyl, -CH2OH, -CH2N(R31')2, -C1_3 haloalkyl, F, I, -0R3, CF3, and CN.
[00514] In some embodiments of Formula Id, R2c is a substituent attached to the ortho position of phenyl and selected from the group consisting of H, unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R31)2, -Ci_3 haloalkyl, F, Br, I, -0R3, CF3, and CN.
[00515] In some embodiments of Formula Id, R2d is 2-5 substituents, each attached to the phenyl and are independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -C1-120H, -CH2N(R3b)2, -C1_3 haloalkyl, halide, -0R3, CF3, and CN.

[00516] In some embodiments of Fonnula Id, R2' is 1-3 substituents, each attached to the heteroaryl ring and are independently selected at each occurrence from the group consisting of H, unsubstituted -Ci_6 alkyl, -CH2OH, -CH2N(R3b)2, -Ci_3 haloalkyl, halide, -0R3, CF3, and CN.
[00517] In some embodiments of Formula Id, each R3 is independently selected from the group consisting of H, unsubstituted -Ci_6 alkyl, -C1_3 haloalkyl, and CF3.
[00518] In some embodiments of Formula Id, each R3a is independently selected from the group consisting of H, unsubstituted ¨C2,6 alkyl, -Ci_3 haloalkyl, and CF3;
[00519] In some embodiments of Formula Id, each R3b is independently selected from the group consisting of H and unsubstituted ¨Ci_3 alkyl.
[00520] In some embodiments of Formula Id, Q is S or NH.
[00521] In some embodiments of Formula Id, n is an integer of 1 to 5.
[00522] In some embodiments of Fonnula Id, Ring A is selected from the \
group consisting of S and H.
[00523] In some embodiments of Formula Id, R2a is H.
[00524] In some embodiments of Formula Id, R21 is H.
[00525] In some embodiments of Formula Id, R2' is H.
[00526] In some embodiments of Formula Id, R2d is H.
[00527] Some additional embodiments of Formula I include compounds of Founula (Ie):
(R2o ),, (R1)õ

Ie or salts, pharmaceutically acceptable salts, or prodrugs thereof.

'Art, W
II
W, [00528] In some embodiments of Formula le, Ring A is W .
[00529] In some embodiments of Formula Ie, Ring B is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, wherein a carbon atom on the ring is attached to the carbonyl carbon.
[00530] In some embodiments of Formula le, each Rl is a substituent attached to Ring A and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -Ci_3haloalkyl, halide, -0R3, CF3, and CN.
[00531] In some embodiments of Formula le, each R2 is a substituent attached to Ring B and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R31)2, -C1_3 haloalkyl, halide, -0R3, CF3, and CN.
[00532] In some embodiments of Formula Ie, each R3 is independently selected from the group consisting of H, unsubstituted -C1_6 alkyl, -C1_3 haloalkyl, and CF3.
[00533] In some embodiments of Formula le, each R3b is independently selected from the group consisting of H and unsubstituted ¨C1_3 alkyl.
[00534] In some embodiments of Foimula Ie, each W is N or C.
[00535] In some embodiments of Foimula Ie, at least one W must be N.
[00536] In some embodiments of Formula le, Q is S or NH.
[00537] In some embodiments of Formula Ie, m is an integer of 1 to 5.
[00538] In some embodiments of Formula le, n is an integer of 1 to 4.
[00539] In some embodiments of Fonnula Ie, Ring A is selected from the \ N
\ N
N/
group consisting of 101S and [00540] Some additional embodiments of Formula I include compounds of Formula (If):

(R2),, B
(R1)n 0 If or salts, pharmaceutically acceptable salts, or prodrugs thereof 1/1(Vil II w vil (31 [00541] In some embodiments of Foimula If, Ring A is ve---- .
[00542] In some embodiments of Formula If, Ring B is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, wherein a carbon atom on the ring is attached to the carbonyl carbon.
[00543] In some embodiments of Formula If, each R1 is a substituent attached to Ring A and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -C1_3 haloalkyl, halide, -0R3, CF3, and CN.
[00544] In some embodiments of Formula If, each R2 is a substituent attached to Ring B and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R3b)2, -C1_3 haloalkyl, halide, -0R3, CF3, and CN.
[00545] In some embodiments of Formula If, each R3 is independently selected from the group consisting of H, unsubstituted -Ci_6 alkyl, -C1_3 haloalkyl, and CF3.
[00546] In some embodiments of Formula If, each R3b is independently selected from the group consisting of H and unsubstituted ¨C1_3 alkyl.
[00547] In some embodiments of Formula If, each W is N or C.
[00548] In some embodiments of Foimula If, m is an integer of 1 to 5.
[00549] In some embodiments of Formula If, n is an integer of 1 to 5.
[00550] In some embodiments of Formula If, Ring A is selected from the 10\ \
group consisting of 0 and 0 07 .
[00551] Some additional embodiments of Formula I include compounds of Formula (Ig):

(R1)n Ig or salts, pharmaceutically acceptable salts, or prodrugs thereof [00552] In some embodiments of Formula Ig, Ring A is Q
[00553] In some embodiments of Formula 1g, Ring B is selected from the R2b \
sssc 1001 R2b group consisting of R2a :1 R2 , and a 5-6 membered heteroary1R2d, wherein a carbon atom on the ring is attached to the carbonyl carbon.
[00554] In some embodiments of Formula 1g, each RI- is a substituent attached to Ring A and is independently selected at each occurrence from the group consisting of H, unsubstituted -C16 alkyl, -Ci_3haloalkyl, halide, -0R3, CF3, and CN.
[00555] In some embodiments of Formula Ig, R2 is a substituent attached to the para position of phenyl and is selected from the group consisting of unsubstituted ¨CI_ 6 alkyl, -CH2OH, -CH2N(R31)2, -C1_3 haloalkyl, F, I, -0R3, CF3, and CN.
[00556] In some embodiments of Formula Ig, R21' is a substituent attached to the meta or ortho position of phenyl and is selected from the group consisting of unsubstituted ¨C2_6 alkyl, -CH2OH, -CH2N(R3b)2, -Ci_3 haloalkyl, halide, -0R3, CF3, and CN.
[00557] In some embodiments of Formula Ig, R2' is 2-5 substituents, each attached to the phenyl and are independently selected at each occurrence from the group consisting of unsubstituted -Ci_6 alkyl, -CH2OH, -CH2N(R3b)2, -Ci_3 haloalkyl, halide, -0R3, CF3, and CN.
[00558] In some embodiments of Formula Ig, R2d is 1-3 substituents, each attached to the heteroaryl ring and are independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R3b)2, -C1_3 haloalkyl, halide, -0R3, CF3, and CN.
[00559] In some embodiments of Formula Ig, each R3 is independently selected from the group consisting of H, unsubstituted -C1_6 alkyl, -Ci_3 haloalkyl, and CF3.
[00560] In some embodiments of Formula Ig, each R31 is independently selected from the group consisting of H and unsubstituted ¨C1_3 alkyl.
[00561] In some embodiments of Formula Ig, Q is independently selected from the group consisting of 0, S, and NH.
[00562] In some embodiments of Formula Ig, n is an integer of 1 to 5.
[00563] In some embodiments of Foimula Ig, Ring A is selected from the N
group consisting of a 0 S , and H
[00564] In some embodiments of Formula Ig, R2a is F.
[00565] In some embodiments of Formula Ig, R2a is OH.
[00566] In some embodiments of Formula Ig, R2a is OMe.
[00567] In some embodiments of Formula Ig, R2a is 1 substituent and is F.
[00568] In some embodiments of Formula Ig, R2a is 2 substituents and both are F.
[00569] In some embodiments of Formula Ig, R2a is 1 substituent and is OMe.
[00570] In some embodiments of Formula Ig, R2a is 2 substituents and both are OMe.
[00571] In some embodiments of Formula Ig, R2a is 2 substituents and are F
and Me.
[00572] In some embodiments of Formula Ig, R2a is 2 substituents and are F
and CF3.
[00573] In some embodiments of Formula Ig, R2a is 2 substituents and are F
and OMe.
[00574] In some embodiments of Formula Ig, R2a is 2 substituents and are F
and CN.

[00575] Some additional embodiments of Formula I include compounds of Fommla (Ih):
(R2)o ,, (R1)õ
Ih or salts, pharmaceutically acceptable salts, or prodrugs thereof.
w w, [00576] In some embodiments of Foimula Ih, Ring A is w Q
[00577] In some embodiments of Formula Ih, Ring B is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, wherein a carbon atom on the ring is attached to the carbonyl carbon.
[00578] In some embodiments of Formula Ih, each RI- is a substituent attached to Ring A and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -C1_3 haloalkyl, halide, -0R3, CF3, and CN.
[00579] In some embodiments of Formula Ih, each R2 is a substituent attached to Ring B and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R31)2, -Ci_3 haloalkyl, halide, -0R3, CF3, and CN.
[00580] In some embodiments of Formula Ih, each R3 is independently selected from the group consisting of H, unsubstituted -C1_6 alkyl, -C1_3 haloalkyl, and CF3.
[00581] In some embodiments of Formula Ih, each R3b is independently selected from the group consisting of H and unsubstituted ¨C1_3 alkyl.
[00582] In some embodiments of Formula Ih, each W is N or C.
[00583] In some embodiments of Formula Ih, at least one W must be N.
[00584] In some embodiments of Formula Ih, Q is independently selected from the group consisting of 0, S, and NH.
[00585] In some embodiments of Foimula Ih, m is an integer of 1 to 5.
[00586] In some embodiments of Formula Ih, n is an integer of 1 to 4.

[00587] In some embodiments of Fonnula Ih, Ring A is selected from the N
$ N> la N, group consisting of 0 , s , and 0 NH).
[00588] Some additional embodiments of Formula I include compounds of Formula (Ii):
0 (R2),õ
B
(R1)õ 0 Ii or salts, pharmaceutically acceptable salts, or prodrugs thereof.
\ilk _w w" ------II W
111L ------...,/
[00589] In some embodiments of Formula Ii, Ring A is w ' , wherein a carbon atom on the ring is attached to the carbonyl carbon.
[00590] In some embodiments of Formula Ii, Ring B is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, wherein a carbon atom on the ring is attached to the carbonyl carbon.
[00591] In some embodiments of Formula Ii, each R1 is a substituent attached to Ring A and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -C1_3 haloalkyl, halide, -0R3, CF3, and CN.
[00592] In some embodiments of Formula Ii, each R2 is a substituent attached to Ring B and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R3b)2, -C1_3 haloalkyl, halide, -0R3, CF3, and CN.
[00593] In some embodiments of Formula Ii, each R3 is independently selected from the group consisting of H, unsubstituted -C1_6 alkyl, -C1_3 haloalkyl, and CF3.
[00594] In some embodiments of Formula Ii, each R3b is independently selected from the group consisting of H and unsubstituted ¨Ci_3 alkyl.
[00595] In some embodiments of Formula Ii, each W is N or C.
[00596] In some embodiments of Formula Ii, at least one W is C

[00597] In some embodiments of Formula Ii, Q is independently selected from the group consisting of 0, S, and N.
[00598] In some embodiments of Folinula Ii, m is an integer of 1 to 5.
[00599] In some embodiments of Formula Ii, n is an integer of 1 to 7.
[00600] In some embodiments of Formula Ii, Ring A is selected from the \ m \ N

group consisting of 401 0 S

\ N N 0 N
s), and 110 N
H
[00601] Some embodiments of the present disclosure include compounds of Formula (II):
(R5 0 )q (R4)p = 0 or salts, pharmaceutically acceptable salts, or prodrugs thereof [00602] In some embodiments of Formula II, Ring C is a 5-6 membered heteroaryl, wherein a carbon atom on the ring is attached to the carbonyl carbon.
[00603] In some embodiments of Folinula II, Ring D is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, wherein a carbon atom on the ring is attached to the carbonyl carbon.
[00604] In some embodiments of Formula II, each R4 is a substituent attached to Ring C and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -C1_3 haloalkyl, halide, -0R6, CF3, and CN.
[00605] In some embodiments of Formula II, each R5 is a substituent attached to Ring D and is independently selected at each occurrence from the group consisting of H, unsubstituted -Ci_6 alkyl, -CH2OH, -CH2N(R6b)2, -Ci_3 haloalkyl, halide, -0R6, CF3, and CN.
[00606] In some embodiments of Formula II, each R6 is independently selected from the group consisting of H, unsubstituted -Ci_6 alkyl, -Ci_3 haloalkyl, and CF3.

[00607] In some embodiments of Foimula II, each R6b is independently selected from the group consisting of H and unsubstituted ¨C1-3 alkyl.
[00608] In some embodiments of Formula II, each q is an integer of 1 to 4.
[00609] In some embodiments of Foimula II, each p is an integer of 1 to 5.
[00610] In some embodiments of Formula II, there is the proviso that a compound of Formula II is not a compound selected from thegroup consisting of:
OMe NH
\ / 0 OMe /
I -.., I N
Me0--- 1 OMe HN 0 \ NH 0 5 Ni 0 s 1 o HO N

HO 0 \ 0 0 7") I \
/ / /N-, fq HN N\ I
0 OH N__N \ NH H

I
\ N"---N 0 N---- H N

O I \ N Cl 0 o 0 H \
\ NH 0 3õ, N

, \ NH 0 0i N OMe ..).,- 33._---O n I 0 I
-..., N N Me0 N \
OMe N
I I
Le, 0 0 N 0 0 , Me0 N---Cl o Cl cl 0 Cl õõ 11 \ N Br CI \ - CI I 140 0 0 I N OMe I
,.i=N 0 N ,-- ci 0 CI , \
rJL
Br CI / 0 OMe OMe OMe OMe 0 0 OMe 0 40 OMe 0 Aab RP
, OMe Me0 Me0 \ OMe 1 N OMe \ OMe Me0 NI õ,..
I A l ___ \ OMe Me0 0 0 /
Me0 N OMe OMe OMe OMe OMe OMe idit OMe .1 OMe 0 0 OMe s OMe . 0 Me0 \ \
I 0 IIIIF OMe I 0 WI Me 1 / N., 0 OMe I 0 5 N , Me0 5 , N 5 I. 0 410 I
N -\
I I
0 0 0 OMe \ S
=I'l N HO N OH 0 0 0 OMe 3...õ N 3., -,õ
\ S 0 \ S 0 \ S 0 OH \ S 0 o 0 o -----, OM
e -..,õ CF3 --__ ---,.
\ S 0 \S 0 , \ S 0 \ S 0 40 Br 40 0 ill 0 Br 0F3 -,. C F3 Br \ S 0 3 7 7 5 CI 0 0 Cl CI

--õ --, \ S 0 -,_ CI , \ S 0 Cl \ S 0 0 OMe 0 411 0 -----, ---, 0 --....,, \ S 0 \ S 0, , CI \ S 0 Br I s\
----,.._ --, -..õ S -,..õõ
\ S 0 \ S 0 \ S 0 Br \
\ S 0 Br I \ Br Br 0 I s\ 0 I \ 0 I \ ---..
\ S 0 Cl \ S 0 \ S 0 NC

Br Br 1 Me \ 0 5 I \

/ \ 0 \ S 0 -,..._, S
\ S 0 , \ S 0 Me 5 Me 5 0 I \ Br 0 I I s\ Br CI \
\ S 0 Br 0 S
\ S Br \__S 0 I \ Br 0 I \ Br ---,. S 0 I \ 0 I \
S
\ S 0 Br \ S 0 \ S 0 CI

I \ 0 -----1 \
CI

S ..,,, S
CI --..õ S

\ S 0 S I

CI

CI
CI CI

1 \ CI 0 ------I \ 1 , S 5 0 \
CI
0 CI /, S 0 CI S 0 \ S 0 ci o o ¨ I \ CI
o 0 s 0 /
S --, S ' \ 0 CI , C I 0 , , 0 0 ' , OMe o o * o *
-, -, '---. OMe \ o o \ 0 0 \ 0 0 OH \ o o 0 0 OMe I \
0 ¨' 0 0 I \

and \ o 0 , 0 =
, [00611] In some embodiments of Foimula IT, Ring C is a 5-membered heteroaryl ring containing 1-3 heteroatoms selected from the group consisting of N, 0, and S.
0 (R4)p [00612] In some embodiments of Formula II, is selected from the (R4),, ...\ (R4)p____vit_ __ (R4)0...41 3.___A
(R4"./_ o) NNO NN, N
o group consisting of , (114)p-41-ip (R4),--4 (R4)p 'ZZ21 ( R4) l/ .3...., R4 N
( )p------/t_ 3_---12, NNO NO NS' , NS
(R4)p....4. ____________________________ \A (R4)p.4_ _ 153A (R4)p_____1 . Isp (R4)p_,I7LN (R4)p----t (R4)p---.4._ N N NN
NS'N
S S S N N

(R4)-._yA, (R4)p.___#_ (R4)p_____AL. 3.___A (R4)0....11-1:,p, (R4)pThN_ NN NN
N N NNN'N N , and N ; and p is 1 or 2.
=(R4 /
[00613] In some embodiments of Formula II, is s .
[00614] In some embodiments of Formula II, Ring C is a 6-membered heteroaryl ring containing 1-2 nitrogens.

0 (R4)p [00615] In some embodiments of Formula II, is selected from the ____________________ 5N ____ ) N) N/) group consisting of ("P (R4),N (R4)p _ , and ("P ; and p is 1 or 2.
0 (R4)P
[00616] In some embodiments of Formula II, is 1% .
[00617] In some embodiments of Formula II, each R4 is independently selected from the group consisting of H, F, Cl, Me, OMe, OH, CF3 and CN.
[00618] In some embodiments of Formula II, Ha, He, lid, He, and/or III, each R4 is independently selected from the group consisting of H, F, Cl, Me, OMe, OH, CF3 and CN; and p is 1 or 2.
[00619] In some embodiments of Formula II, Ha, Hb, Hc, lid, He, and/or In R4 is H.
[00620] In some embodiments of Formula II, Ha, In, He, lid, He, and/or R4 is a halide.
[00621] In some embodiments of Formula II, Ha, lib, He, lid, He, and/or R4 is F.
[00622] In some embodiments of Formula II, Ha, hlb, He, lid, He, and/or R4 is Cl.
[00623] In some embodiments of Formula II, Ha, Hb, Hc, Hd, Ile, and/or R4 is Me.
[00624] In some embodiments of Formula II, Ha, He, Hd, He, and/or Hf, R4 is OH.
[00625] In some embodiments of Formula II, Ha, lib, He, lid, He, and/or III, R4 is OMe.
[00626] In some embodiments of Formula II, Iia, hhb, He, Hd, He, and/or llf, R4 is CF3.
[00627] In some embodiments of Formula II, Ha, lib, Hc, Hd, He, and/or R4 is CN.

[00628] In some embodiments of Fonnula II, Ha, lib, He, lid, He, and/or p is an integer from 1-3.
[00629] In some embodiments of Formula II, Ha, lib, Hc, lid, He, and/or p is an integer from 1-2.
[00630] In some embodiments of Formula II, Ha, Hb, He, lid, He, and/or Hf, pis2.
[00631] In some embodiments of Formula II, Ha, lib, Hc, lid, He, and/or p is 1.
[00632] In some embodiments of Formula II, Ha, lib, He, lid, Ile, and/or R4 is F; and p is 1.
[00633] In some embodiments of Formula II, Ha, Hb, He, lid, He, and/or Ill, R4 is F; and p is 2.
[00634] In some embodiments of Formula II, Ha, He, lid, He, and/or 'If, R4 is OH; and p is 1.
[00635] In some embodiments of Formula II, Ha, Hb, Hc, Hd, He, and/or III;
R4 is OMe; and p is an integer from 1-2.
[00636] In some embodiments of Formula II, Ha, lib, He, lid, He, and/or Hf, R4 is -2 alkyl.
[00637] In some embodiments of Formula II, Ha, lib, He, lid, Ile, and/or Hf, R4 is -CI _3 alkyl.
[00638] In some embodiments of Formula II, Ha, Hb, He, lid, He, and/or R4 is -C1_4 alkyl.
[00639] In some embodiments of Foimula II, Ha, lib, He, lid, He, and/or III;
R4 is -C1_5 alkyl.
[00640] In some embodiments of Formula II, Ha, hIb, He, Hd, He, and/or Hf, R4 is -Ci_6 alkyl.
[00641] In some embodiments of Formula II, Ha, Hb, He, Hd, He, and/or Hf, R4 is ¨C2_6 alkyl.
[00642] In some embodiments of Formula II, Ha, Hb, He, Hd, He, and/or R4 is ¨C3_6 alkyl.

[00643] In some embodiments of Foimula II, Ha, Ith, Hc, lid, He, and/or Iff, R4 is ¨C4_6 alkyl.
[00644] In some embodiments of Folmula II, Ha, Hb, Hc, lid, He, and/or Eft R4 is ¨C2_5 alkyl.
[00645] In some embodiments of Formula II, Ha, lib, Hc, lid, He, and/or Hf, R4 is ¨C3_5 alkyl.
[00646] In some embodiments of Formula II, Ring C is selected from the group consisting of:
risp /FAA N¨Ip ______________ I ___ / 11&4 iNi N N N
No Nor N N N N, t N\
S ti3AS NNS NNS S Nsr S N NN N
, 5 5 , , N
// 12, tit /FAA' Nõ Nõ NN ,N

N N .
[00647] In some embodiments of Formula II and/or lib, Ring D is phenyl.
0 (R5)q [00648] In some embodiments of Foimula II and/or lib, is \
(F)q 40 (C1)q __ ii selected from the group consisting of 1001 , , \ \ \ \
(F3c), ,1 (meo),, ii wog ,i (NC)q II
..,,- ,and.--/ ; and q is 1 or 2.
, co (R5)q [00649] In some embodiments of Formula II and/or Ith, is selected from the group consisting of5 F
401 10 10 Si OMe Me CN
,= ,$ , and 1401 .

[00650] In some embodiments of Formula II and/or In, Ring D is a 5-membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, 0, and S.
co(R5)q [00651] In some embodiments of Foimula II and/or lib, is ( (R 5)q4 ; , selected from the group consisting of V , NNO V
(R5),__z_i, ',,,, (R5)41_,¨N \ (R6)q3_ (R5)q___41 (R5),,-\ (R)q934, NNo) NoOrN
(R5)q----- ______ 3___A (R5)q---.4. õ4_; (R5),,,x IA (R5)4_41 ,IA
(R5)q,iNf, _Arrr_rk N N
N.s7 (R5)q_4_ __ _12, (R5)q-----1(4 3,.4, (R5)cr---//, __----µ5T1_,A, (R5)q.--4. 12.3A (R)q NN
and (R5),,,4__ NNN ;; and q is 1 or 2.
0 (R5)q [00652] In some embodiments of Formula II and/or lib, is /
OA
selected from the group consisting of 0 and S .
[00653] In some embodiments of Formula II and/or III), Ring D is a 6-membered heteroaryl containing 1-2 nitrogen atoms.
__________________________________________________________________ (R5)q D
[00654] In some embodiments of Formula II and/or lib,iS
N 5 Is.1 N __ 5 k} I _______________________________________ y ) y, ) 1 N
selected from the group consisting of (RN (R 5 'N
, )q (R6)qN , and ("q ; and , q is 1 or 2.

0 ("ci [00655] In some embodiments of Foimula II and/or Hb, is selected from the group consisting of , , , and ; and R5 is H.
[00656] In some embodiments of Formula II, Ha, lib, He, lid, He, and/or R5, R5a, R5b, R5e, R5d, R'e, R'", R5g, R51, and/or R5' is -CH2OH.
[00657] In some embodiments of Formula II, Ha, lib, He, lid, He, and/or R5, R5a, R5b, R5c, R5d, Rse, 5f 5 I
R R, R5', and/or R5i is -CH2N(R3h)2.
[00658] In some embodiments of Formula II, Ha, lib, He, lid, He, and/or R5, R5a, R51', R5c, R5d, R5e, R5f, R5g, K -5h, and/or R51 is -CH2NH2.
[00659] In some embodiments of Formula II, Ha, Hb, He, lid, He, and/or III, R5, R5a, R5b, R5c, R5d, -5e, R5f, R5g, R51, and/or R5' is -CH2NHMe.
[00660] In some embodiments of Formula II, Ha, lib, He, lid, He, and/or R', R5a, R5b, R5e, R5d, R5e, R, R5g, R5h, and/or R5' is -CH2NMe2.
[00661] In some embodiments of Formula II, Ha, lib, He, lid, He, and/or R5, R5a, R5b, R5c, R5d, R5e, R5f, R5g, R5h, and/or R5' is -CH2NHEt [00662] In some embodiments of Formula II, Ha, Hb, He, lid, He, and/or Hf, R5, R5a, R5b, R5c, R5d, R5e, R5f, R5g, R51, and/or R5' is -CH2N(Me)(Et).
[00663] In some embodiments of Formula II, Ha, Ihb, He, lid, He, and/or III;
R5a, R5h, R5e, R5d, R5e, R1, R5g, R5h, and/or R5' is -CH2NEt2.
[00664] In some embodiments of Formula II and/or lib, each R5 is independently selected from the group consisting of H, F, Cl, Me, OMe, OH, CF3, and CN.
[00665] In some embodiments of Formula II and/or Hb, R5 is H.
[00666] In some embodiments of Formula II and/or lab, R5 is a halide.
[00667] In some embodiments of Foimula II and/or Hb, R5 is F.
[00668] In some embodiments of Formula II and/or lab, R5 is Cl.
[00669] In some embodiments of Formula II and/or lib, R5 is Me.
[00670] In some embodiments of Formula II and/or Hb, R5 is OH.
[00671] In some embodiments of Formula II and/or lib, R5 is OMe.

[00672] In some embodiments of Formula!! and/or lib, R5 is CF3.
[00673] In some embodiments of Fonnula II and/or lib, R5 is CN.
[00674] In some embodiments of Formula II and/or lib, q is an integer from 1-4.
[00675] In some embodiments of Formula II and/or Ith, q is an integer from 1 -2.
[00676] In some embodiments of Formula II and/or lib, q is 1.
[00677] In some embodiments of Formula II and/or lib, q is 2.
[00678] In some embodiments of Fonnula II and/or Hb, R5 is F; and q is 1.
[00679] In some embodiments of Formula II and/or lib, R5 is F; and q is 2.
[00680] In some embodiments of Formula II and/or lib, R5 is Me; and q is 1.
[00681] In some embodiments of Formula II and/or Hb, R5 is Me; and q is 2.
[00682] In some embodiments of Formula II and/or lib, R5 is CF3; and q is 1.
[00683] In some embodiments of Formula II and/or lib, R5 is CF3; and q is 2.
[00684] In some embodiments of Formula H and/or lib, R5 is OMe; and q is 1.
[00685] In some embodiments of Fonnula II and/or lib, R5 is OMe; and q is 2.
[00686] In some embodiments of Fon-nula II and/or Ith, R5 is F and Me; and q is 2.
[00687] In some embodiments of Formula II and/or Fib, R5 is F and CF3; and q is 2.
[00688] In some embodiments of Formula II and/or Ith, R5 is F and OMe; and q is 2.
[00689] In some embodiments of Formula II and/or lib, R5 is CN; and q is 1.
[00690] In some embodiments of Formula H and/or lib, R5 is CN; and q is 2.
[00691] In some embodiments of Formula II and/or lib, R5 is F and CN; and q is 2.
[00692] In some embodiments of Formula II and/or lib, R5 is -C1_2 alkyl.
[00693] In some embodiments of Formula II and/or lib, R5 is -C1_3 alkyl.
[00694] In some embodiments of Formula II and/or lib, R5 is -C1_4 alkyl.
[00695] In some embodiments of Formula II and/or lib, R5 is -C1-5 alkyl.
[00696] In some embodiments of Fonliula II and/or lib, R5 is -C1_6 alkyl.

[00697] In some embodiments of Formula II and/or lib, R5 is ¨C2,6 alkyl.
[00698] In some embodiments of Fotmula II and/or lib, R5 is -C3-6 alkyl.
[00699] In some embodiments of Formula II and/or lib, R5 is ¨C4,6 alkyl.
[00700] In some embodiments of Formula II and/or Hb, R5 is -C2-5 alkyl.
[00701] In some embodiments of Formula II and/or lib, R5 is -C3_5 alkyl.
[00702] In some embodiments of Formula II, Ha, lib, Hc, lid, He, and/or IIf, R6 is -C1-2 alkyl.
[00703] In some embodiments of Formula II, Ha, lib, He, lid, He, and/or 'If, R6 is -C1_3 alkyl.
[00704] In some embodiments of Formula II, Ha, Hb, He, lid, He, and/or R6 is -C14 alkyl.
[00705] In some embodiments of Formula II, Ha, Hb, He, lid, He, and/or Hf, R6 is -C1,5 alkyl.
[00706] In some embodiments of Formula II, Ha, lab, Hc, lid, He, and/or R6 is -C1_6 alkyl.
[00707] In some embodiments of Formula II, Ha, lib, He, lid, He, and/or R6 is ¨C2_6 alkyl.
[00708] In some embodiments of Formula II, Ha, lib, Hc, lid, He, and/or III, R6 is -C3-6 alkyl.
[00709] In some embodiments of Formula II, Ha, Hb, He, lid, He, and/or R6 is ¨C4,6 alkyl.
[00710] In some embodiments of Formula II, Ha, lib, He, lid, He, and/or IIf, R6 is ¨C2,5 alkyl.
[00711] In some embodiments of Formula II, Ha, lib, He, lid, He, and/or Ilf, R6 is ¨C3,5 alkyl.
[00712] In some embodiments of Foimula II, Ring D is a phenyl or 6-membered heteroaryl; R5 is selected from the group consisting of F, Cl, Me, OMe, OH, CF3 and CN; q is 1; and R5 is attached to an ortho carbon of the 6-membered ring.
[00713] In some embodiments of Fotmula II, Ring D is a phenyl, R5 is selected from the group consisting of F, Cl, Me, OMe, OH, CF3 and CN; q is 1; and R5 is attached to an ortho position of the phenyl ring.

[00714] In some embodiments of Foimula II, Ring D is a pyridine, R5 is selected from the group consisting of F, Cl, Me, OMe, OH, CF3 and CN; q is 1;
and R5 is attached to an ortho carbon of the pyridine ring.
0 (R5)q [00715] In some embodiments of Formula II, is selected from the group consisting of:

(F), ______ ii n (cl)q ii h (F3C)q II
(Me0)q 11 II
(Me)q l'''''' .--(NC)q II 1 (F)q I (CI), 1 (F3C), I (WO), I
N
-.----\

(Me)q¨H (NC),H¨ 7 ___ & 1s 11--'\z' N
N, (N
N N N
S))2' N/NO, S , H , H , and H ; wherein the carbonyl carbon of Formula II can form a bond with any unsubstituted carbon on the Ring D.
0 (R5)q [00716] In some embodiments of Formula II, is selected from the group consisting of:
F CI CF3 OMe Me CN

. 0 0 0 0 illia 8 )._...._ ,( S o ;
wherein the carbonyl carbon of Formula II can form a bond with any unsubstituted carbon on the Ring D.
0 (R5)q [00717] In some embodiments of Formula II, is selected from the group consisting of:

CI CF3 OMe Me CN

; wherein the carbonyl carbon of Formula II can form a bond with any unsubstituted carbon on the Ring D.
[00718] Some additional embodiments of Formula II include compounds of Folinula (Ha):

(R4)p Ha or salts, pharmaceutically acceptable salts, or prodrugs thereof.
[00719] In some embodiments of Formula Ha, Ring C is .
[00720] In some embodiments of Formula Ha, Ring D is selected from the R5c R5b A)2' R5d-t A R5e J J
A NV
group consisting of R5a R5e U U
and NQ , wherein a carbon atom on the ring is attached to the carbonyl carbon.
[00721] In some embodiments of Formula Ha, each R4 is a substituent attached to Ring C and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -C1_3 haloalkyl, halide, -0R6, CF3, and CN.
[00722] In some embodiments of Formula Ha, R5a is 1-5 substituents, each attached to Ring D and are independently selected at each occurrence from the group consisting of unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R6b)2, -Ci_3 haloalkyl, halide, -OR6a, CF3, and CN.
[00723] In some embodiments of Formula Ha, R5b is 1-4 substituents, each attached to Ring D and are independently selected at each occurrence from the group _ consisting of unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R6b)2, -C1_3 haloalkyl, F, I, -0R6a, CF3, and CN.
[00724] In some embodiments of Formula Ha, R5c is 1-3 substituents, each attached to Ring D and are independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R6b)2, -Ci_3haloalkyl, halide, -0R6, CF3, and CN.
[00725] In some embodiments of Formula Ha, R5d is 1-2 substituents, each attached to Ring D and are independently selected at each occurrence from the group consisting of unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R61)2, -C1_3 haloalkyl, halide, -0R6, CF3, and CN.
[00726] In some embodiments of Fonnula Ha, R5e is 1-3 substituents, each attached to Ring D and are independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R6b)2, -Ci_3haloalkyl, halide, -0R6, CF3, and CN.
[00727] In some embodiments of Fonnula Ha, each R6 is independently selected from the group consisting of H, unsubstituted -Ci_6 alkyl, -Ci_3 haloalkyl, and CF3.
[00728] In some embodiments of Founula Ha, each R6a is independently selected from the group consisting of H, unsubstituted ¨C2_6 alkyl, -C1_3 haloalkyl, and CF3.
[00729] In some embodiments of Formula Ha, each R6b is independently selected from the group consisting of H and unsubstituted ¨C1_3 alkyl.
[00730] In some embodiments of Formula Ha, each A is N or C.
[00731] In some embodiments of Formula Ha, at least two A must be N.
[00732] In some embodiments of Formula Ha, each J is N or C.
[00733] In some embodiments of Formula Ha, at least one J must be N and at least one J must be C.
[00734] In some embodiments of Formula Ha, each U is N or C.
[00735] In some embodiments of Formula Ha, at least one U must be C.
[00736] In some embodiments of Formula Ha, Q is 0 or N.
[00737] In some embodiments of Formula Ha, p is an integer of 1 to 4.

[00738] In some embodiments of Formula Ha, Ring D is selected from the R5c R5\b Fts\c R5 N \\7)1,N
N-_--=- N
group consisting of R5a N , N
, R5c IRc R5fl R5e--4._3____A R5e¨itN.
R5e I 1+L N
NN
R5e N .13...LA R5e4 3...v...A R5e_,..4. _________ R5e N R5e¨?9, _3,A
N, ---- NN ---( 'S S S NO 0 NNO7N
R5e¨#13õA R5e N r=vp, R5e____INt_ 3.___A R5e-4, R5e1 3_,A R5e¨#
N N N
R5e __ ..ip, R5e N _Isp R5e4 NN ---(Ni NN
N , and N , wherein a carbon atom on the ring is , attached to the carbonyl carbon.
[00739] In some embodiments of Formula Ha, Ring D is selected from the group consisting of:
N/;\ N
F 0 CI 0 ,3c $Me i$ NC 101 / /
N N

N'-` 1 I __ F_ CI 1 F3C.¨ Me0 1 Me¨!--N'' OA NiN Ni N NN
N
and N
(N
H .
[00740] In some embodiments of Formula Ha, Hd, He, and/or III*, R5a is 1 substituent and is F.
[00741] In some embodiments of Formula Ha, lid, He, and/or HI, R5 is 2 substituents and are both F.

[00742] In some embodiments of Formula Ha, He, and/or Hf, R5a is 1 substituent and is Me.
[00743] In some embodiments of Formula Ha, He, and/or Ulf, R5a- is 2 substituents and are both Me.
[00744] In some embodiments of Formula Ha, lid, He, and/or 'If, R5a is 1 substituent and is CF3.
[00745] In some embodiments of Formula Ha, lid, He, and/or III, R5a is 2 substituents and are both CF3.
[00746] In some embodiments of Formula Ha, He, and/or Hf, R5a is 2 substituents and are F and Me.
[00747] In some embodiments of Foimula Ha, lid, He, and/or III, lea is 2 substituents and are F and CF3.
[00748] In some embodiments of Formula Ha, He, lid, He, and/or Hf, R5a is 1 substituent and is CN.
[00749] In some embodiments of Formula Ha, He, Hd, He, and/or hf, R5a is 2 substituents and are both CN.
[00750] In some embodiments of Formula Ha, Hd, He, and/or Hf, R5a is 2 substituents and are F and CN.
[00751] In some embodiments of Formula Ha, He, and/or Hf, lea is -C1.7 alkyl.
[00752] In some embodiments of Formula Ha, He, and/or Ill*, R5a is -C1_3 alkyl.
[00753] In some embodiments of Fonaula Ha, He, and/or Hf, R5a is -C14 alkyl.
[00754] In some embodiments of Formula Ha, He, and/or hf, R5a is -C1_5 alkyl.
[00755] In some embodiments of Fonnula Ha, He, and/or Hf, R5a is -C1_6 alkyl.
[00756] In some embodiments of Formula Ha, Hd, He, and/or hf, R5a. is ¨C2-6 alkyl.
[00757] In some embodiments of Formula Ha, lid, He, and/or Hf, R5a is ¨C3-6 alkyl.
[00758] In some embodiments of Formula Ha, Hd, He, and/or Hf, lea is ¨C4-6 alkyl.
[00759] In some embodiments of Formula Ha, Hd, He, and/or Hf, R5a is ¨C2_5 alkyl.

[00760] In some embodiments of Formula Ha, lid, He, and/or Hf, R5' is ¨C3_5 alkyl.
[00761] In some embodiments of Formula Ha, He, lid, He, and/or Hir, R5b is 1 substituent and is F.
[00762] In some embodiments of Formula Ha, He, lid, He, and/or 'If, R5b is 2 substituents and both are F.
[00763] In some embodiments of Formula Ha, He, lid, He, and/or hf, R5b is 1 substituent and is Me.
[00764] In some embodiments of Formula Ha, He, lid, He, and/or III*, R5b is 2 substituents and both are Me.
[00765] In some embodiments of Formula Ha, lid, He, and/or Hf, R5b is 1 substituent and is CF3.
[00766] In some embodiments of Fonnula Ha, lid, He, and/or Hf, R5b is 2 substituents and both are CF3.
[00767] In some embodiments of Formula Ha, He, lid, He, and/or hf, R5b is 2 substituents and are F and Me.
[00768] In some embodiments of Formula Ha, lid, He, and/or hf, R51' is 2 substituents and are F and CF3.
[00769] In some embodiments of Formula Ha, He, lid, He, and/or hf, leb is 1 substituent and is CN.
[00770] In some embodiments of Foimula Ha, lie, lid, He, and/or hf, R5b is 2 substituents and both are CN.
[00771] In some embodiments of Formula Ha, He, lid, He, and/or Ilf, R5b is 2 substituents and are F and CN.
[00772] In some embodiments of Formula Ha, He, Hd, He, and/or hf, R5b is -C1_2 alkyl.
[00773] In some embodiments of Formula Ha, He, lid, He, and/or Ilf, R5b is -C1_3 alkyl.
[00774] In some embodiments of Formula Ha, He, Hd, He, and/or Ill, R51 is -C14 alkyl.

[00775] In some embodiments of Fonnula Ha, He, lid, He, and/or Hf, R5b is -CI _5 alkyl.
[00776] In some embodiments of Formula Ha, Hc, lid, He, and/or hf, R5b is -CI _6 alkyl.
[00777] In some embodiments of Formula Ha, He, lid, He, and/or hf, R5b is -C2_6 alkyl.
[00778] In some embodiments of Fonnula Ha, He, lid, He, and/or Hf, le is -C3_6 alkyl.
[00779] In some embodiments of Formula Ha, He, lid, He, and/or hf, R5b is -C4_6 alkyl.
[00780] In some embodiments of Formula Ha, He, lid, He, and/or hf, R5b is -C2_5 alkyl.
[00781] In some embodiments of Formula Ha, He, lid, He, and/or hf, R5b is -C3_5 alkyl.
[00782] In some embodiments of Formula Ha and/or lib, R5' is H.
[00783] In some embodiments of Formula Ha, lid, and/or He, R5' is a halide.
[00784] In some embodiments of Formula Ha, He, lid, and/or He, R5' is F.
[00785] In some embodiments of Formula Ha, lid, and/or He, R5' is Cl.
[00786] In some embodiments of Formula Ha and/or IIc, R5' is Me.
[00787] In some embodiments of Formula Ha, lid, and/or He, R5' is OH.
[00788] In some embodiments of Formula Ha, lid, and/or He, R5' is OMe.
[00789] In some embodiments of Formula Ha, He, lid, and/or He, R5' is CF3.
[00790] In some embodiments of Formula Ha, He, lid, and/or He, R5' is CN.
[00791] In some embodiments of Formula Ha, He, lid, and/or He, R5' is I
substituent and is F.
[00792] In some embodiments of FoHnula Ha, Hc, lid, and/or He, R5' is 2 substituents and are both F.
[00793] In some embodiments of Formula Ha and/or He, R5' is 1 substituent and is Me.
[00794] In some embodiments of Formula Ha and/or He, R5' is 2 substituents and are both Me.

[00795] In some embodiments of Fonnula Ha, He, lid, and/or He, R5' is 1 substituent and is CF3.
[00796] In some embodiments of Fotmula Ha, He, lid, and/or He, R5' is 2 substituents and both are CF3.
[00797] In some embodiments of Formula Ha, lid, and/or He, R5' is 1 substituent and is OMe.
[00798] In some embodiments of Formula Ha, lid, and/or He, R5' is 2 substituents and both are OMe.
[00799] In some embodiments of Formula Ha and/or He, R5' is 2 substituents and are F and Me.
[00800] In some embodiments of Formula Ha, He, lid, and/or He, R5' is 2 substituents and are F and CF3.
[00801] In some embodiments of Folinula Ha, lid, and/or He, R5' is 2 substituents and are F and OMe.
[00802] In some embodiments of Formula Ha, He, Hd, and/or He, R5' is 1 substituent and is CN.
[00803] In some embodiments of Formula Ha, He, lid, and/or He, R5' is 2 substituents and both are CN.
[00804] In some embodiments of Formula Ha, Hc, Hd, and/or He, R5' is 2 substituents and are F and CN.
[00805] In some embodiments of Formula Ha and/or He, R5' is -C1_2 alkyl.
[00806] In some embodiments of Formula Ha and/or IIc, R5' is -C1_3 alkyl.
[00807] In some embodiments of Formula Ha and/or IIc, R5' is -C14 alkyl.
[00808] In some embodiments of Formula Ha and/or He, R5' is -C1_5 alkyl.
[00809] In some embodiments of Formula Ha and/or He, R5' is -C1_6 alkyl.
[00810] In some embodiments of Formula Ha, He, lid, and/or He, R5' is ¨C2-6 alkyl.
[00811] In some embodiments of Formula Ha, He, Hd, and/or He, R5' is ¨C3-6 alkyl.
[00812] In some embodiments of Formula Ha, He, lid, and/or He, R5' is ¨C4-6 alkyl.

[00813] In some embodiments of Foimula Ha, He, lid, and/or He, R5c is ¨C2_5 alkyl.
[00814] In some embodiments of Formula Ha, He, Hd, and/or He, R5e is ¨C3_5 alkyl.
[00815] In some embodiments of Formula Ha, He, lid, and/or He, R5d is a halide.
[00816] In some embodiments of Foimula Ha, He, lid, and/or He, R5d is F.
[00817] In some embodiments of Formula Ha, He, lid, and/or He, R5d is Cl.
[00818] In some embodiments of Formula Ha, Hc, and/or lid, R5d is Me.
[00819] In some embodiments of Formula Ha, and/or lid, R5d is OH.
[00820] In some embodiments of Foimula Ha, and/or Hd, R5d is OMe.
[00821] In some embodiments of Formula Ha, He, lid, and/or He, R5d is CF3.
[00822] In some embodiments of Formula Ha, He, lid, and/or He, R5d is CN.
[00823] In some embodiments of Formula Ha, He, Hd, and/or He, R5d is 1 substituent and is F.
[00824] In some embodiments of Folmula Ha, He, lid, and/or He, R5d is 2 substituents and both are F.
[00825] In some embodiments of Formula Ha, He, and/or lid, R5d is 1 substituent and is Me.
[00826] In some embodiments of Formula Ha, He, and/or lid, R5d is 2 substituents and both are Me.
[00827] In some embodiments of Formula Ha, He, Hd, and/or He, R5d is 1 substituent and is CF3.
[00828] In some embodiments of Formula Ha, He, lid, and/or He, R5d is 2 substituents and both are CF3.
[00829] In some embodiments of Formula Ha and/or lid, R5d is 1 substituent and is OMe.
[00830] In some embodiments of Formula Ha and/or Hd, R5d is 2 substituents and are both OMe.
[00831] In some embodiments of Formula Ha, He, and/or lid, R5d is 2 substituents and are F and Me.

[00832] In some embodiments of Formula Ha, He, lid, and/or He, R5d is 2 substituents and are F and CF3.
[00833] In some embodiments of Formula Ha and/or lid, R5d is 2 substituents and are F and OMe.
[00834] In some embodiments of Foimula Ha, He, lid, and/or He, R5d is 1 substituent and is CN.
[00835] In some embodiments of Formula Ha, He, lid, and/or He, R5d is 2 substituents and both are CN.
[00836] In some embodiments of Formula Ha, He, lid, and/or He, R5d is 2 substituents and are F and CN.
[00837] In some embodiments of Formula Ha, Hc, and/or lid, R5d is -C1-2 alkyl.
[00838] In some embodiments of Formula Ha, He, and/or Hd, R5d is -C1-3 alkyl.
[00839] In some embodiments of Fommla Ha, He, and/or hid, R5d is -C1_4 alkyl.
[00840] In some embodiments of Foimula Ha, He, and/or lid, R5d is -C1-5 alkyl.
[00841] In some embodiments of Formula Ha, He, and/or lid, R5d is -C1-6 alkyl.
[00842] In some embodiments of Foimula Ha, He, lid, and/or He, R5d is ¨C2-6 alkyl.
[00843] In some embodiments of Formula Ha, He, lid, and/or He, R5d is ¨C3-6 alkyl.
[00844] In some embodiments of Formula Ha, He, lid, and/or He, R5d is ¨C4-6 alkyl.
[00845] In some embodiments of Formula Ha, He, Hd, and/or He, R5d is ¨C2-5 alkyl.
[00846] In some embodiments of Formula Ha, He, lid, and/or He, R5d is ¨C3_5 alkyl.
[00847] In some embodiments of Formula Ha and/or lid, R5e is H.

[00848] In some embodiments of Formula Ha and/or lid, R5e is a halide.
[00849] In some embodiments of Formula Ha, He, and/or lid, lee is F.
[00850] In some embodiments of Foimula Ha and/or lid, R5e is Cl.
[00851] In some embodiments of FoHnula Ha and/or lid, R5e is Me.
[00852] In some embodiments of Formula Ha, Hc, and/or lid, R5e is OH.
[00853] In some embodiments of Formula Ha, He, and/or lid, R5e is OMe.
[00854] In some embodiments of Formula Ha and/or lid, R5e is CF3.
[00855] In some embodiments of Formula Ha, He, and/or lid, R5e is CN.
[00856] In some embodiments of Formula Ha, He, and/or lid, R5e is 1 substituent and is F.
[00857] In some embodiments of Formula Ha, He, and/or Ed, lee is 2 substituents and are both F.
[00858] In some embodiments of Formula Ha and/or Hd, R'e is 1 substituent and is Me.
[00859] In some embodiments of Formula Ha and/or lid, R5e is 2 substituents and are both Me.
[00860] In some embodiments of Formula Ha and/or lid, R5e is 1 substituent and is CF3.
[00861] In some embodiments of Formula Ha and/or Hd, R5e is 2 substituents and are both CF3.
[00862] In some embodiments of Foimula Ha, lie, and/or lid, R5e is 1 substituent and is OMe. , [00863] In some embodiments of Formula Ha, He, and/or lid, Rse is 2 substituents and are both OMe.
[00864] In some embodiments of Formula Ha and/or lid, R5e is 2 substituents and are F and Me.
[00865] In some embodiments of Formula Ha and/or lid, Rse is 2 substituents and are F and CF3.
[00866] In some embodiments of Formula Ha, He, and/or Hd, R5e is 2 substituents and are F and OMe.

[00867] In some embodiments of Formula Ha, He, and/or Hd, R5e is 1 substituent and is CN.
[00868] In some embodiments of Formula Ha, He, and/or lid, R5e is 2 substituents and are both CN.
[00869] In some embodiments of Formula Ha, He, and/or lid, Rse is 2 substituents and are F and CN.
[00870] In some embodiments of Formula Ha and/or Hd, R5' is -Ci_2 alkyl.
[00871] In some embodiments of Foimula Ha and/or Hd, R5e is -C1_3 alkyl.
[00872] In some embodiments of Formula Ha and/or Hd, R5e is -C14 alkyl.
[00873] In some embodiments of Formula Ha and/or lid, R5e is -C1_5 alkyl.
[00874] In some embodiments of Formula Ha and/or Hd, R5e is -C1_6 alkyl.
[00875] In some embodiments of Formula Ha and/or Hd, R5e is ¨C2_6 alkyl.
[00876] In some embodiments of Formula Ha, He, Hd, and/or He, R5e is ¨C3-6 alkyl.
[00877] In some embodiments of Formula Ha and/or lid, R5e is ¨C4_6 alkyl.
[00878] In some embodiments of Formula Ha, He, and/or lid, R5e is ¨C2-5 alkyl.
[00879] In some embodiments of Formula Ha, He, and/or lid, R5e is ¨C3_5 alkyl.
[00880] Some additional embodiments of Formula II include compounds of Formula (hib):
o (RN
(R4)p Hb or salts, pharmaceutically acceptable salts, or prodrugs thereof.
A11A)2' A A
[00881] In some embodiments of Formula lib, Ring C is [00882] In some embodiments of Formula lib, Ring D is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, wherein a carbon atom on the ring is attached to the carbonyl carbon.
[00883] In some embodiments of Foimula HU, each R4 is a substituent attached to Ring C and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1.6 alkyl, -C1..3 haloalkyl, halide, -0R6a, CF3, and CN.
[00884] hi some embodiments of Formula lib, each R5 is a substituent attached to Ring D and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R61')2, haloalkyl, halide, -0R6, CF3, and CN.
[00885] In some embodiments of Formula lib, each R6 is independently selected from the group consisting of H, unsubstituted -Ci_6 alkyl, -Ci_3 haloalkyl, and CF3.
[00886] In some embodiments of Formula lab, each R6a is independently selected from the group consisting of unsubstituted ¨C1,6 alkyl, -C1.3 haloalkyl, and CF3.
[00887] In some embodiments of Formula lib, each R6b is independently selected from the group consisting of H and unsubstituted ¨C1,3 alkyl.
[00888] In some embodiments of Formula lib, each A is N or C.
[00889] In some embodiments of Formula lib, at least two A must be N.
[00890] In some embodiments of Folinula lib, p is an integer of 1 to 3.
[00891] In some embodiments of Formula lib, q is an integer of 1 to 5.
[00892] In some embodiments of Formula lib, Ring C is selected from the N)2, group consisting of , and [00893] Some additional embodiments of Formula II include compounds of Foimula (Ile):

(R4)p IIe or salts, phannaceutically acceptable salts, or prodrugs thereof.
[00894] In some embodiments of Formula He, Ring C is S
[00895] In some embodiments of Formula He, Ring D is selected from the R5b \
R5e-t group consisting of R5. R5c R
R s R5h4---1A R5L4-Ao, u u u u and , NN., NQ , wherein a carbon atom on the ring is attached to the carbonyl carbon.
[00896] In some embodiments of Formula He, each R4 is a substituent attached to Ring C and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -C1_3 haloalkyl, halide, -0R6, CF3, and CN.
[00897] In some embodiments of Formula lie, R5a is a substituent attached to the para position of phenyl and is selected from the group consisting of unsubstituted ¨C2-6 alkyl, -CH2OH, -CH2N(R61')2, -C2_3 haloalkyl, iodide, -0R6, and CN.
[00898] In some embodiments of Formula tic, R5b is a substituent attached to the meta position of phenyl and is selected from the group consisting of unsubstituted -Ci_6 alkyl, -CH2OH, -CH2N(R6b)2, -C2_3 haloalkyl, halide, -0R6a, and CN.
[00899] In some embodiments of Formula lac, R5c is a substituent attached to the ortho position of phenyl and is selected from the group consisting of unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R6b)7, -C1_3 haloalkyl, F, Br, I, -0R6a, CF3, and CN.
[00900] In some embodiments of Formula He, R5d is 2-5 substituents, each attached to the phenyl and are independently selected at each occurrence from the group consisting of unsubstituted -Ci_6 alkyl, -CH2OH, -CH2N(R6b)2, -C1,3 haloalkyl, halide, -OR6a, CF3, and CN.
[00901] In some embodiments of Formula He, R5e is 1 substituent attached to Ring D and selected from the group consisting of unsubstituted ¨C2_5 alkyl, -CH2OH, -CH2N(R6b)2, -C1_3 haloalkyl, F, I, -0R6, CF3, and CN.
[00902] In some embodiments of Formula He, R5f is 1-2 substituents, each attached to Ring D and are independently selected at each occurrence from the group consisting of H, unsubstituted -Ci_6 alkyl, -CH2OH, -CH2N(R61')2, -C1_3 haloalkyl, F, Br, I, -0R6, CF3, and CN.
[00903] In some embodiments of Formula IIc, R5g is 1-3 substituents, each attached to Ring D and are independently selected at each occurrence from the group consisting of unsubstituted -Ci_6 alkyl, -CH2OH, -CH2N(R6b)2, -Ci_3 haloalkyl, halide, -0R6, CF3, and CN.
[00904] In some embodiments of Formula He, R51 is 1-2 substituents, each attached to Ring D and are independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R61)2, -C1_3 haloalkyl, halide, -0R6, CF3, and CN.
[00905] In some embodiments of Formula He, R5i is 1-4 substituents, each attached to Ring D and are independently selected at each occurrence from the group consisting of H, unsubstituted -Ci_6 alkyl, -CH2OH, -CH2N(R6b)2, -C1_3 haloalkyl, halide, -0R6, CF3, and CN.
[00906] In some embodiments of Formula He, each R6 is independently selected from the group consisting of H, unsubstituted -Ci_6 alkyl, -C1_3 haloalkyl, and CF3.
[00907] In some embodiments of Formula IIc, each R6a is independently selected from the group consisting of unsubstituted ¨C2_6 alkyl, -C1_3 haloalkyl, and CF3.
[00908] In some embodiments of Formula He, each R6b is independently selected from the group consisting of H and unsubstituted ¨C1_3 alkyl.
[00909] In some embodiments of Formula He, each J is N or C.
[00910] In some embodiments of Formula lie, at least one J must be C.
[00911] In some embodiments of Formula lie, Q is S or 0.
[00912] In some embodiments of Formula He, each U is N or C.
[00913] In some embodiments of Formula He, at least one U must be N and at least one U must be C.
[00914] In some embodiments of Formula He, p is an integer of 1 to 3.

[00915] In some embodiments of Formula He, Ring D is selected from the R5b /',"\
401 \ 0 \

---/,,..,..
group consisting of R5a 1 1 I R5c R5d , R5f S , R5114_ R5h1 ________ vyA, R51 R511_4_ __________ N3__A, R5h11¨Isp N N N N

R5---.. 6 N 3_4 R56....4/._ 3_,A, , Rai N 3....A, R56,...4. __ _\\_A R56_4_ _13 , . . . . A R5 N
---- ...-, R5h N _______________________________ ,y.¨µ, R51-.4_ 3,..µ R...4._ 3_,A, R.
Rsiõ,.., _y_AN R5i1-13A
--.....#__ N
NN NN NN zN N

R5L2,1`.11...
NN
and N , wherein a carbon atom on the ring is attached to the carbonyl carbon.
[00916] In some embodiments of Formula He, R5f is H.
[00917] In some embodiments of Formula He, R5f is a halide.
[00918] In some embodiments of Formula lie, R5f is F.
[00919] In some embodiments of Formula Hc, R5f is Cl.
[00920] In some embodiments of Formula He, R5f is Me.
[00921] In some embodiments of Formula He, R5f is OH.
[00922] In some embodiments of Formula He, R5f is OMe.
[00923] In some embodiments of Formula He, R5f is CF3.
[00924] In some embodiments of Formula Hc, R5f is CN.
[00925] In some embodiments of Formula He, R5f is 1 substituent and is F.
[00926] In some embodiments of Formula He, R5f is 2 substituents and are both F.
[00927] In some embodiments of Fonnula He, R5f is 1 substituent and is Me.
[00928] In some embodiments of Formula He, R5f is 2 substituents and are both Me.
[00929] In some embodiments of Formula Hc, R5f is 1 substituent and is CF3.
[00930] In some embodiments of Formula He, R5f is 2 substituents and are both CF3.

[00931] In some embodiments of Fonnula He, R5f is 1 substituent and is OMe.
[00932] In some embodiments of Fonnula Hc, R5f is 2 substituents and are both OMe.
[00933] In some embodiments of Formula IIc, R5f is 2 substituents and are F
and Me.
[00934] In some embodiments of Fonnula He, R5f is 2 substituents and are F
and CF3.
[00935] In some embodiments of Formula IIc, R5f is 2 substituents and are F
and OMe.
[00936] In some embodiments of Formula He, R5f is I substituent and is CN.
[00937] In some embodiments of Formula IIc, R5f is 2 substituents and are both CN.
[00938] In some embodiments of Foimula Ile, R5f is 2 substituents and are F
and CN.
[00939] In some embodiments of Formula He, R5f is -C1_2 alkyl.
[00940] In some embodiments of Formula Ile, R5f is -C1_3 alkyl.
[00941] In some embodiments of Formula lie, R5f is -C1_4 alkyl.
[00942] In some embodiments of Formula lie, R5f is -C1_5 alkyl.
[00943] In some embodiments of Formula He, R5f is -C1_6 alkyl.
[00944] In some embodiments of Formula He, R5f is ¨C7_6 alkyl.
[00945] In some embodiments of Formula He, R5f is ¨C3_6 alkyl.
[00946] In some embodiments of Formula He, R5f is ¨C4_6 alkyl.
[00947] In some embodiments of Formula He, R5f is ¨C2_5 alkyl.
[00948] In some embodiments of Foimula lie, R5f is -C3_5 alkyl.
[00949] In some embodiments of Formula He, R5g is a halide.
[00950] In some embodiments of Formula He, leg is F.
[00951] In some embodiments of Formula He, R5g is Cl.
[00952] In some embodiments of Faimula Ile, R5g is Me.
[00953] In some embodiments of Formula He, R5g is OH.
[00954] In some embodiments of Formula He, R5g is OMe.
[00955] In some embodiments of Formula He, R5g is CF3.

[00956] In some embodiments of Formula He, R5g is CN.
[00957] In some embodiments of Formula He, R5g is 1 substituent and is F.
[00958] In some embodiments of Formula Hc, R5g is 2 substituents and are both F.
[00959] In some embodiments of Formula He, R5g is 1 substituent and is Me.
[00960] In some embodiments of Fonnula Hc, R5g is 2 substituents and are both Me.
[00961] In some embodiments of Formula Hc, R5g is 1 substituent and is CF3.
[00962] In some embodiments of Formula He, R5g is 2 substituents and are both CF3.
[00963] In some embodiments of Formula Hc, R5g is 1 substituent and is OMe.
[00964] In some embodiments of Formula Hc, R5g is 2 substituents and are both OMe.
[00965] In some embodiments of Formula He, R5g is 2 substituents and are F
and Me.
[00966] In some embodiments of Formula Hc, R5g is 2 substituents and are F
and CF3.
[00967] In some embodiments of Formula He, R5g is 2 substituents and are F
and OMe.
[00968] In some embodiments of Formula lie, R5g is 1 substituent and is CN.
[00969] In some embodiments of Formula He, leg is 2 substituents and are both CN.
[00970] In some embodiments of Founula Ile, R5g is 2 substituents and are F
and CN.
[00971] In some embodiments of Formula Mc, R5g is -C1_2 alkyl.
[00972] In some embodiments of Formula He, R5g is -C1_3 alkyl.
[00973] In some embodiments of Formula He, R5g is -C1_4 alkyl.
[00974] In some embodiments of Formula He, R5g is -C1_5 alkyl.
[00975] In some embodiments of Foimula lie, R5g is -C1_6 alkyl.
[00976] In some embodiments of Formula He, R5g is ¨C2_6 alkyl.
[00977] In some embodiments of Formula He, R5g is ¨C3_6 alkyl.

[00978] In some embodiments of Formula Hc, R5g is ¨C4,6 alkyl.
[00979] In some embodiments of Formula He, R5g is ¨C2_5 alkyl.
[00980] In some embodiments of Formula IIc, R5g is ¨C3_5 alkyl.
[00981] In some embodiments of Formula He, R5i is H.
[00982] In some embodiments of Formula IIc, R5' is a halide.
[00983] In some embodiments of Formula He, R5i is F.
[00984] In some embodiments of Formula IIc, R5' is Cl.
[00985] In some embodiments of Formula He, R5' is Me.
[00986] In some embodiments of Formula He, R5' is OH.
[00987] In some embodiments of Formula Ile, R51 is OMe.
[00988] In some embodiments of Formula Hc, R5' is CF3.
[00989] In some embodiments of Formula He, R5' is CN.
[00990] In some embodiments of Formula He, R51 is 1 substituent and is F.
[00991] In some embodiments of Formula He, R5' is 2 substituents and are both F.
[00992] In some embodiments of Formula He, R5i is 1 substituent and is Me.
[00993] In some embodiments of Formula He, R5' is 2 substituents and are both Me.
[00994] In some embodiments of Formula He, R5' is 1 substituent and is CF3.
[00995] In some embodiments of Formula Ile, R5' is 2 substituents and are both CF3.
[00996] In some embodiments of Formula He, R5i is 1 substituent and is OMe.
[00997] In some embodiments of Formula He, R5' is 2 substituents and are both OMe.
[00998] In some embodiments of Formula lie, R51 is 2 substituents and are F
and Me.
[00999] In some embodiments of Formula He, R5' is 2 substituents and are F
and CF3.
[001000] In some embodiments of Formula He, R51 is 2 substituents and are F
and OMe.
[001001] In some embodiments of Formula He, R5' is 1 substituent and is CN.

[001002] In some embodiments of Formula He, R51 is 2 substituents and are both CN.
[001003] In some embodiments of Formula lie, lei is 2 substituents and are F
and CN.
[001004] In some embodiments of Formula IIc, R51 is -C1_2 alkyl.
[001005] In some embodiments of Formula IIc, R5i is -C1_3 alkyl.
[001006] In some embodiments of Formula He, R51 is -C14 alkyl.
[001007] In some embodiments of Formula Ile, R5i is -Ci_5 alkyl.
[001008] In some embodiments of Formula He, R51 is -C1_6 alkyl.
[001009] In some embodiments of Formula He, R51 is ¨C7_6 alkyl.
[001010] In some embodiments of Formula He, R51 is ¨C3_6 alkyl.
[001011] In some embodiments of Formula IIc, R51 is ¨C4_6 alkyl.
[001012] In some embodiments of Formula IIc, R5i is ¨C2_5 alkyl.
[001013] In some embodiments of Formula He, R5i is ¨C3_5 alkyl.
[001014] Some additional embodiments of Formula II include compounds of Formula (lad):

(R4)p lid or salts, pharmaceutically acceptable salts, or prodrugs thereof.
[001015] In some embodiments of Formula lid, Ring C is 0 [001016] In some embodiments of Formula lid, Ring D is selected from the J
R50-t Rsd J¨A_A J R5e U U
."
group consisting of R5a R5b , and N , wherein a carbon atom on the ring is attached to the carbonyl carbon.

[001017] In some embodiments of Foinmla lid, each R4 is a substituent attached to Ring C and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -C1_3 haloalkyl, halide, -0R6, CF3, and CN.
[001018] In some embodiments of Formula lid, R5a is 1 substituent attached to Ring D and selected from the group consisting of unsubstituted ¨C2_6 alkyl, -CH2OH, -CH2N(R6b)2, -C1_3 haloalkyl, halide, -0R6a, and CN.
[001019] In some embodiments of Formula lid, R5b is 1-4 substituents, each attached to Ring D and are independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R61')2, -C1_3 haloalkyl, halide, -0R6a, CF3, and CN.
[001020] In some embodiments of Founula lid, R5e is 1-3 substituents, each attached to Ring D and are independently selected at each occurrence from the group consisting of unsubstituted ¨C2_5 alkyl, -CH2OH, -CH2N(R61)2, -C1_3 haloalkyl, halide, -0R6, CF3, and CN.
[001021] In some embodiments of Formula lid, Rd is 1-2 substituents, each attached to Ring D and are independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R6b)2, -C1_3 haloalkyl, halide, -0R6, CF3, and CN.
[001022] In some embodiments of Formula lid, R5e is 1-4 substituents, each attached to Ring D and are independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R6b)2, -Ci_3 haloalkyl, halide, -0R6, CF3, and CN.
[001023] In some embodiments of Formula lid, each R6 is independently selected from the group consisting of H, unsubstituted -C1_6 alkyl, -C1_3 haloalkyl, and CF3.
[001024] In some embodiments of Foimula lid, each R6a is independently selected from the group consisting of unsubstituted ¨C7_6 alkyl, -C1_3 haloalkyl, and CF3.
[001025] In some embodiments of Formula lid, each R6b is independently selected from the group consisting of H and unsubstituted ¨C1_3 alkyl.
[001026] In some embodiments of Formula lid, each J is N or C.

[001027] In some embodiments of Formula lid, at least one J must be N and at least one J must be C.
[001028] In some embodiments of Formula lid, Q is S or 0.
[001029] In some embodiments of Formula lid, each U is N or C.
[001030] In some embodiments of Formula lid, at least one U must be C.
[001031] In some embodiments of Formula lid, p is an integer of 1 to 3.
[001032] In some embodiments of Formula lid, Ring D is selected from the Rsd--4_ NN R5d N
group consisting of R5a R5b 0 Rsd N R5d N R5e NNo,N NNo NN NN

RGe N Rse--/INIL
NN ,N N2 NN
, and N , wherein a carbon atom on the ring is attached to the carbonyl carbon.
[001033] In some embodiments of Formula lid, R5b is H.
[001034] In some embodiments of Formula lid and/or He, R5d is H.
[001035] Some additional embodiments of Formula II include compounds of Formula (He):

(R4)p He or salts, pharmaceutically acceptable salts, or prodrugs thereof.
A¨A.A
AN ,A
[001036] In some embodiments of Formula He, Ring C is N , wherein a carbon atom on the ring is attached to the carbonyl carbon.

[001037] In some embodiments of Formula He, Ring D is selected from the R5c-t R5 group consisting of d R5a U U
R5b , and NNv , wherein a carbon atom on the ring is attached to the carbonyl carbon.
[001038] In some embodiments of Formula He, each R4 is a substituent attached to Ring C and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -C1_3 haloalkyl, halide, -0R6, CF3, and CN.
[001039] In some embodiments of Fonnula He, R55 is a substituent attached to the para position of phenyl and is selected from the group consisting of H, unsubstituted ¨
C1-6 alkyl, -CH2OH, -CH2N(R6b)2, -C1_3 haloalkyl, F, Br, I, -0R6, CF3, and CN.
[001040] In some embodiments of Foimula He, R5b is 1-4 substituents, each attached to Ring D and are independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -CH20H, -CH2N(R6b)2, -C1,3 haloalkyl, halide, -0R6, CF3, and CN.
[001041] In some embodiments of Fotmula He, fee is 1-4 substituents, each attached to Ring D and are independently selected at each occurrence from the group consisting of unsubstituted ¨C2_5 alkyl, -CH2OH, -CH2N(R6b)2, -C1_3 haloalkyl, halide, -0R6, CF3, and CN.
[001042] In some embodiments of Formula He, R5d is 1-2 substituents, each attached to Ring D and are independently selected at each occurrence from the group consisting of H, unsubstituted ¨C2_6 alkyl, -CH2OH, -CH2N(R61')2, -C1_3 haloalkyl, halide, -0R6', CF3, and CN.
[001043] In some embodiments of Formula He, each R6 is independently selected from the group consisting of H, unsubstituted -C1_6 alkyl, -C1_3 haloalkyl, and CF3.
[001044] In some embodiments of Formula He, each R6a is independently selected from the group consisting of unsubstituted ¨C1_6 alkyl, -C1_3 haloalkyl, and CF3.
[001045] In some embodiments of Formula He, each R6b is independently selected from the group consisting of H and unsubstituted ¨C1_3 alkyl.
[001046] In some embodiments of Formula He, each A is N or C.

[001047] In some embodiments of Formula Ile, at least one A must be C.
[001048] In some embodiments of Formula He, each U is N or C.
[001049] In some embodiments of Formula Ile, at least one U must be N and at least one U must be C.
[001050] In some embodiments of Formula Ile, p is an integer of 1 to 4.
[001051] In some embodiments of Formula Ile, Ring C is selected from the (-3) NIN
NN
//
1/1--13A, NN
NN
group consisting of N N N , and N
[001052] In some embodiments of Formula Ile, Ring D is selected from the 5b R5c,t Rbd R5a NN
group consisting of R
R54_ R64_ R5t34 R5d41 NN NN NN
, and N , wherein a carbon atom on the ring is attached to the carbonyl carbon.
[001053] In some embodiments of Formula Ile, R5 is 1 substituent and is OMe.
[001054] In some embodiments of Foimula Ile, R55 is 2 substituents and both are OMe.
[001055] In some embodiments of Formula Ile, R5a is 2 substituents and are F
and OMe.
[001056] In some embodiments of Formula He and/or llf, R5b is H.
[001057] In some embodiments of Formula He and/or Hf, R5b is 1 substituent and is OMe.
[001058] In some embodiments of Formula He and/or IIf, R5b is 2 substituents and both are OMe.
[001059] In some embodiments of Formula He and/or hf, R5b is 2 substituents and are F and OMe.
[001060] Some additional embodiments of Foimula II include compounds of Formula (If):

(R4)p 'If or salts, pharmaceutically acceptable salts, or prodrugs thereof.
A--20Ak\_A
AN ,A
[001061] In some embodiments of Formula HI, Ring C is Q , wherein a carbon atom on the ring is attached to the carbonyl carbon.
[001062] In some embodiments of Formula Hf, Ring D is selected from the group consisting of R5a and a 5-membered heteroary1R5b, wherein a carbon atom on the ring is attached to the carbonyl carbon.
[001063] In some embodiments of Formula HI, each R4 is a substituent attached to Ring C and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -C1_3 haloalkyl, halide, -OR6, CF3, and CN.
[001064] In some embodiments of Foimula hf, R5a is 1-5 substituents, each attached to phenyl and selected from the group consisting of H, unsubstituted ¨Ci_6 alkyl, -CH2OH, -CH2N(R6b)2, -C1_3 haloalkyl, halide, -0R6a, CF3, and CN.
[001065] In some embodiments of Formula Hf, Rsb is 1-4 substituents, each attached to Ring D and are independently selected at each occurrence from the group consisting of H, unsubstituted -C1,6 alkyl, -CH2OH, -CH2N(R61)2, -C1_3 haloalkyl, halide, -0R6, CF3, and CN.
[001066] In some embodiments of Fonnula Hf, each R6 is independently selected from the group consisting of H, unsubstituted -C1,6 alkyl, -C1_3 haloalkyl, and CF3.
[001067] In some embodiments of Formula Ulf, each R6a is independently selected from the group consisting of unsubstituted ¨C2_6 alkyl, -C1_3 haloalkyl, and CF3.
[001068] In some embodiments of Formula IH, each R6b is independently selected from the group consisting of H and unsubstituted ¨Ci_3 alkyl.

[001069] In some embodiments of Formula Ili, each A is N or C.
[001070] In some embodiments of Fatinula Iff, at least one A must be N and at least one A must be C.
[001071] In some embodiments of Formula Iff, Q is S or 0.
[001072] In some embodiments of Fonnula llf, p is an integer of 1 to 4.
[001073] In some embodiments of Formula IIf, Ring C is selected from the N N

NI Nt Nt N d ( ( ( ( //
Nx group consisting of 0 , S 0 , S , 0 , S , 0 N /T--p N N N N N N N
S
i N N N .--- N ,-, , o , S , 0 ,and S
[001074] In some embodiments of Formula Iff, Ring D is selected from the R5b,t __ A, group consisting of R6a S , 0 , N , R5b NN S R5b- ---N ¨3A sbNN s_'N A 544NN 3A 5b (N V R5b- -7N13....A, S S S NS
R5).22 N ---.

Nor NN
0 ---( 0 --ft-NN

R5b R5b--#_N 3,-µ Rsb.,4... ___\\__A1:3_A R5b N¨Isp, NN N INN ,N NN ----(N
and R5b N
--t/-NN
N , wherein a carbon atom on the ring is attached to the carbonyl carbon.
[001075] Some embodiments of the present disclosure include compounds of Formula (III):
(R8)q (R7),, I

III
or salts, pharmaceutically acceptable salts or prodrugs thereof.

[001076] In some embodiments of Folinula III, each R7 is a substituent attached to the phenyl ring and is independent' selected at each occurrence from the group consisting of unsubstituted -C1,6 alkyl, -CH2OH, -CH2N(R9a)2, -C1,3 haloalkyl, halide, -0R9, CF3, and CN.
[001077] In some embodiments of Formula III, each R8 is a substituent attached to the phenyl ring and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1,6 alkyl, -CH2OH, -CH2N(R9a)2, -C1,3 haloalkyl, halide, -0R9, CF3, and CN.
[001078] In some embodiments of Formula III, each R9 is independently selected from the group consisting of H, unsubstituted -C1,6 alkyl, -C1,3 haloalkyl, and CF3.
[001079] In some embodiments of Formula III, each R9a is independently selected from the group consisting of H and unsubstituted ¨C1,3 alkyl.
[001080] In some embodiments of Formula III, each q is an integer of 1 to 5.
[001081] In some embodiments of Formula III, each R7 is independently selected from the group consisting of F, Cl, Me, OMe, OH, CF3 and CN.
[001082] In some embodiments of Formula III, R7 is a halide.
[001083] In some embodiments of Formula III, R7 is F.
[001084] In some embodiments of Formula III, R7 is Cl.
[001085] In some embodiments of Formula III, R7 is Me.
[001086] In some embodiments of Formula III, R7 is OH.
[001087] In some embodiments of Formula III, R7 is OMe.
[001088] In some embodiments of Fonnula III, R7 is CF3.
[001089] In some embodiments of Formula III, R7 is CN.
[001090] In some embodiments of Formula III, q is an integer from 1-4.
[001091] In some embodiments of Formula III, q is an integer from 1-3.
[001092] In some embodiments of Formula III, q is an integer from 1-2.
[001093] In some embodiments of Formula III, q is 2.
[001094] In some embodiments of Formula III, q is 1.
[001095] In some embodiments of Formula III, R7 is F; and q is 1.
[001096] In some embodiments of Formula III, R7 is F; and q is 2.

[001097] In some embodiments of Formula III, R7 is Me; and q is 1.
[001098] In some embodiments of Formula III, R7 is Me; and q is 2.
[001099] In some embodiments of Fonnula III, R7 is CF3; and q is 1.
[001100] In some embodiments of Formula III, R7 is CF3; and q is 2.
[001101] In some embodiments of Fonnula III, R7 is OMe; and q is 1.
[001102] In some embodiments of Fonnula III, R7 is OMe; and q is 2.
[001103] In some embodiments of Fonnula III, R7 is F and Me; and q is 2.
[001104] In some embodiments of Fonnula III, R7 is F and CF3; and q is 2.
[001105] In some embodiments of Formula III, R7 is F and OMe; and q is 2.
[001106] In some embodiments of Formula III, R7 is CN; and q is 1.
[001107] In some embodiments of Formula III, R7 is CN; and q is 2.
[001108] In some embodiments of Formula III, R7 is F and CN; and q is 2.
[001109] In some embodiments of Formula III, R7 is -Ci_2 alkyl.
[001110] In some embodiments of Formula III, R7 is -Ci_3 alkyl.
[001111] In some embodiments of Fonnula III, R7 is -C14 alkyl.
[001112] In some embodiments of Fonnula III, R7 is -C1_5 alkyl.
[001113] In some embodiments of Formula III, R7 is -C1-6 alkyl.
[001114] In some embodiments of Formula III, R7 is ¨C2_6 alkyl.
[001115] In some embodiments of Formula III, R7 is ¨C3_6 alkyl.
[001116] In some embodiments of Formula III, R7 is ¨C44 alkyl.
[001117] In some embodiments of Formula III, R7 is ¨C2_5 alkyl.
[001118] In some embodiments of Formula III, R7 is ¨C3_5 alkyl.
[001119] In some embodiments of Formula III, each R8 is independently selected from the group consisting of H, F, Cl, Me, OMe, OH, CF3 and CN.
[001120] In some embodiments of Formula III, R8 is H.
[001121] In some embodiments of Fonnula III, R8 is a halide.
[001122] In some embodiments of Formula III, R8 is F.
[001123] In some embodiments of Formula III, R8 is Cl.
[001124] In some embodiments of Formula III, R8 is Me.
[001125] In some embodiments of Fonnula III, R8 is OH.
[001126] In some embodiments of Formula III, R8 is OMe.

[001127] In some embodiments of Formula III, R8 is CF3.
[001128] In some embodiments of Formula III, R8 is CN.
[001129] In some embodiments of Formula III, q is an integer from 1-4.
[001130] In some embodiments of Formula III, q is an integer from 1-3.
[001131] In some embodiments of Formula III, q is an integer from 1-2.
[001132] In some embodiments of Formula III, q is 2.
[001133] In some embodiments of Formula III, q is 1.
[001134] In some embodiments of Formula III, R8 is F; and q is 1.
[001135] In some embodiments of Formula III, R8 is F; and q is 2.
[001136] In some embodiments of Formula III, R8 is Me; and q is 1.
[001137] In some embodiments of Formula III, R8 is Me; and q is 2.
[001138] In some embodiments of Formula III, R8 is CF3; and q is 1.
[001139] In some embodiments of Formula III, R8 is CF3; and q is 2.
[001140] In some embodiments of Formula III, R8 is OMe; and q is 1.
[001141] In some embodiments of Formula III, R8 is OMe; and q is 2.
[001142] In some embodiments of Formula III, R8 is F and Me; and q is 2.
[001143] In some embodiments of Formula III, R8 is F and CF3; and q is 2.
[001144] In some embodiments of Formula III, R8 is F and OMe; and q is 2.
[001145] In some embodiments of Formula III, R8 is CN; and q is 1.
[001146] In some embodiments of Formula III, R8 is CN; and q is 2.
[001147] In some embodiments of Foimula III, R8 is F and CN; and q is 2.
[001148] In some embodiments of Formula III, R8 is -Ci_2 alkyl.
[001149] In some embodiments of Formula III, R8 is -C1_3 alkyl.
[001150] In some embodiments of Formula III, R8 is -C1-4 alkyl.
[001151] In some embodiments of Formula III, R8 is -C1_5 alkyl.
[001152] In some embodiments of Formula III, R8 is -C1_6 alkyl.
[001153] In some embodiments of Formula III, R8 is ¨C2_6 alkyl.
[001154] In some embodiments of Formula III, R8 is ¨C3_6 alkyl.
[001155] In some embodiments of Formula III, R8 is ¨C4_6 alkyl.
[001156] In some embodiments of Formula III, R8 is ¨C2_5 alkyl.
[001157] In some embodiments of Formula III, R8 is ¨C3_5 alkyl.

[001158] In some embodiments of Formula III, R9 is -C1_2 alkyl.
[001159] In some embodiments of Foimula III, R9 is -C1_3 alkyl.
[001160] In some embodiments of Formula III, R9 is -C14 alkyl.
[001161] In some embodiments of Formula III, R9 is -C1_5 alkyl.
[001162] In some embodiments of Formula III, R9 is -C1_6 alkyl.
[001163] In some embodiments of Formula III, R9 is ¨C2_6 alkyl.
[001164] In some embodiments of Formula III, R9 is -C3-6 alkyl.
[001165] In some embodiments of Fonnula III, R9 is ¨C4_6 alkyl.
[001166] In some embodiments of Folinula III, R9 is -C2.5 alkyl.
[001167] In some embodiments of Fonnula III, R9 is -C3_5 alkyl.
[001168] In some embodiments of Formula III, R7 and/or R8 is -CH2OH.
[001169] In some embodiments of Formula III, R7 and/or R8 is -CH2N(R9a)2.
[001170] In some embodiments of Formula III, R7 and/or R8 is -CH2M-12.
[001171] In some embodiments of Formula III, R7 and/or R8 is -CH2NHMe.
[001172] In some embodiments of Formula III, R7 and/or R8 is -CH2NMe2.
[001173] In some embodiments of Formula III, R7 and/or R8 is -CH2NHEt, [001174] In some embodiments of Formula III, R7 and/or R8 is -CH2N(Me)(Et).
[001175] In some embodiments of Formula III, R7 and/or R8 is -CH2NEt2=
[001176] Some additional embodiments of Folinula III include compounds of Formula (Ma):
(R12)q 1101 R" 0 Ilia or salts, pharmaceutically acceptable salts, or prodrugs thereof.
[001177] In some embodiments of Formula Ina, Rl is selected from the group consisting of H, unsubstituted -C1_6 alkyl, -C1_3 haloalkyl, halide, -0R13, CF3, and CN.
[001178] In some embodiments of Formula ilia, R11 is selected from the group consisting of unsubstituted -Ci_6 alkyl, -CH2OH, -CH2N(R13b)2, -C1.3 haloalkyl, halide, -OR13, CF3, and CN.

[001179] In some embodiments of Foimula IIIa, each le2 is a substituent attached to the phenyl ring and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1,6 alkyl, -CH2OH, -CH2N(R13b)2, -C1,3 haloalkyl, halide, -0R13, CF3, and CN.
[001180] In some embodiments of Foimula Ina, each R13 is independently selected from the group consisting of unsubstituted -C1_6 alkyl, -C1,3 haloalkyl, and CF3.
[001181] In some embodiments of Formula Ina, each Ri3b is independently selected from the group consisting of H and unsubstituted ¨C,..3 alkyl.
[001182] In some embodiments of Formula Ma, each q is an integer of 1 to 5.
[001183] In some embodiments of Formula Ma, there is the proviso that a compound Formula Ina is not a compound selected from the group consisting of:
.

o 40 cõ

0 0 c, 0 $ CI 0 1101 CI 0 ' F
CN OMe CI

* o * 0 10 0 0 0 CI
Cl Cl CI OMe 5 3 , 5 Br CI

40 o5 0 10 0 5 0 40 OMe OMe OMe OMe , 5 5 5 Cl Br I. 0 CI I. 0 CI 50 lel 0 OMe CI CI CI

CI

0 .
40 0 0 0, 0 0 0, 10 . 40 . 5 0 1101 0 CI CI CI CI
, ) , is OMe 0 Br el 0 1100 5 0 5 110 0 Br I.1 0 OMe CI CI Br OMe OMe 0 OMe 0 op OMe OMe 40 0 ci c, ,and I. OMe [001184] In some embodiments of Formula Ma and/or Inc, R1 is selected from the group consisting of H, F, Cl, Me, OMe, CF3, and CN.
[001185] In some embodiments of Fonaula Ma and/or Mc, R11 is selected from the group consisting of F, Cl, Me, OMe, CF3, and CN.
[001186] In some embodiments of Formula Ma and/or Me, R1 is H; and R11 is F.
[001187] In some embodiments of Folinula IIIa and/or Inc, R1 is H; and Ri1 is Cl.
[001188] In some embodiments of Formula Ma and/or Mc, R1 is H; and Ril is Me.
[001189] In some embodiments of Formula Ina and/or IIIc, R1 is H; and is OMe.
[001190] In some embodiments of Formula Ma and/or IIIc, R1 is H; and R11 is CF3.
[001191] In some embodiments of Formula Ma and/or Me, R1 is H; and R" is CN.
[001192] In some embodiments of Formula Ma and/or Inc, R1 is F; and R" is F.
[001193] In some embodiments of Formula Ina and/or Inc, R1 is F; and R11 is Cl.
[001194] In some embodiments of Formula Ma and/or Me, R1 is F; and R11 is Me.
[001195] In some embodiments of Formula Ma and/or Mc, R1 is F; and R" is OMe.
[001196] In some embodiments of Formula Ma and/or Tile, R1 is F; and R" is CF3.

[001197] In some embodiments of Formula Ma and/or Mc, R1 is F; and R11 is CN.
[001198] In some embodiments of Formula Ma and/or Mc, R1 is -C1_2 alkyl.
[001199] In some embodiments of Formula IIIa and/or Mc, R1 is -Ci_3 alkyl.
[001200] In some embodiments of Formula Ma and/or Mc, R1 is -C1_4 alkyl.
[001201] In some embodiments of Formula Ma and/or IIIc, R1 is -C1_5 alkyl.
[001202] In some embodiments of Formula Ma and/or Mc, R1 is -C1_6 alkyl.
[001203] In some embodiments of Formula Ma and/or Inc, R1 is ¨C2_6 alkyl.
[001204] In some embodiments of Formula Ma and/or Inc, R1 is ¨C3_6 alkyl.
[001205] In some embodiments of Folinula Ma and/or Mc, R1 is ¨C4_6 alkyl.
[001206] In some embodiments of Formula Ma and/or Inc, R1 is ¨C2_5 alkyl.
[001207] In some embodiments of Formula Ma and/or Inc, R1 is ¨C3_5 alkyl.
[001208] In some embodiments of Formula Ma and/or Mc, RH is -Ci_2 alkyl.
[001209] In some embodiments of Formula Ma and/or Inc, RH is -Ci_3 alkyl.
[001210] In some embodiments of Formula ilia and/or Mc, R11 is -C14 alkyl.
[001211] In some embodiments of Formula Ma and/or IHc, RH is -C1_5 alkyl.
[001212] In some embodiments of Formula HIa and/or Mc, R11 is -C1_6 alkyl.
[001213] In some embodiments of Formula Ma and/or Mc, R11 is ¨C2_6 alkyl.
[001214] In some embodiments of Formula IIIa and/or Mc, R11 is ¨C3_6 alkyl.
[001215] In some embodiments of Formula 'Ha and/or Inc, RH is ¨C4_6 alkyl.
[001216] In some embodiments of Formula Ma and/or Mc, RH is ¨C2_5 alkyl.
[001217] In some embodiments of Formula Ma and/or Mc, RH is ¨C3_5 alkyl.
[001218] In some embodiments of Formula Ma, each R12 is selected from the group consisting of H, F, Cl, Me, OMe, CF3, and CN.
[001219] In some embodiments of Formula Ma, R12 is H.
[001220] In some embodiments of Formula Ma, R12 is a halide.
[001221] In some embodiments of Formula Ma, R12 is F.
[001222] In some embodiments of Formula Ma, R12 is Cl.
[001223] In some embodiments of Foimula IIIa, R12 is Me.
[001224] In some embodiments of Formula Ma, R12 is OH.
[001225] In some embodiments of Fottnula Ma, R12 is OMe.

[001226] In some embodiments of Formula Ma, R12 is CF3.
[001227] In some embodiments of Formula Ma, R12 is CN.
[001228] In some embodiments of Formula Ina and/or Mc, q is an integer from 1-4.
[001229] In some embodiments of Formula Ma and/or Mc, q is an integer from 1-3.
[001230] In some embodiments of Formula Ma, q is an integer from 1-2.
[001231] In some embodiments of Formula Ma and/or Inc, q is 2.
[001232] In some embodiments of Formula Ma and/or Mc, q is 1.
[001233] In some embodiments of Formula Ma, R12 is F; and q is 1.
[001234] In some embodiments of Formula IIIa, R12 is F; and q is 2.
[001235] In some embodiments of Formula IIIa, R12 is Me; and q is 1.
[001236] In some embodiments of Formula Ina, R12 is Me; and q is 2.
[001237] In some embodiments of Formula Ma, R12 is CF3; and q is 1.
[001238] In some embodiments of Formula Ma, R12 is CF3; and q is 2.
[001239] In some embodiments of Formula Ma, R12 is OMe; and q is 1.
[001240] In some embodiments of Formula HIa, R12 is OMe; and q is 2.
[001241] In some embodiments of Fottnula Ma, R12 is F and Me; and q is 2.
[001242] In some embodiments of Fottnula Ma, R12 is F and CF3; and q is 2.
[001243] In some embodiments of Formula Ma, R12 is F and OMe; and q is 2.
[001244] In some embodiments of Formula Ma, R12 is CN; and q is 1.
[001245] In some embodiments of Formula Ma, R12 is CN; and q is 2.
[001246] In some embodiments of Formula Ma, R12 is F and CN; and q is 2.
[001247] In some embodiments of Formula HIa, R12 is F or Cl; q is 1.
[001248] In some embodiments of Formula Ma, R12 is -Ci_2 alkyl.
[001249] In some embodiments of Formula Ma, R12 is -C1_3 alkyl.
[001250] In some embodiments of Formula Ma, R12 is -C1_4 alkyl.
[001251] In some embodiments of Formula Ina, R12 is -C1_5 alkyl.
[001252] In some embodiments of Formula Ma, R12 is -C1_6 alkyl.
[001253] In some embodiments of Formula Ma, R12 is ¨C2_6 alkyl.
[001254] In some embodiments of Formula Ma, R12 is ¨C3_6 alkyl.

[001255] In some embodiments of Folinula Ma, R12 is ¨C4_6 alkyl.
[001256] In some embodiments of Fottnula IIIa, R12 is ¨C2_5 alkyl.
[001257] In some embodiments of Formula Ma, R12 is ¨C3_5 alkyl.
[001258] In some embodiments of Formula Ma and/or Mc, R11 is -CH2OH.
[001259] In some embodiments of Formula Ma and/or Me, R" is -CH2N(R13)2.
[001260] In some embodiments of Fottnula Ma and/or Me, R11 is -CH2N112.
[001261] In some embodiments of Formula Ma and/or Me, R11 is -CH2NHMe.
[001262] In some embodiments of Fointula Ina and/or Me, R11 is -CH2NMe2.
[001263] In some embodiments of Formula IIIa and/or Inc, R" is -CH2NHEt.
[001264] In some embodiments of Formula Ma and/or Me, R" is -CH2N(Me)(Et) [001265] In some embodiments of Formula Ma and/or Me, R11 is -CH2NEt2.
[001266] In some embodiments of Formula Ina and/or Me, R13 is -C1_2 alkyl.
[001267] In some embodiments of FoHnula Ina and/or Mc, R13 is -C1_3 alkyl.
[001268] In some embodiments of Formula Ma and/or Me, R13 is -C1_4 alkyl.
[001269] In some embodiments of Formula Ma and/or Me, R13 is -C1_5 alkyl.
[001270] In some embodiments of Fonnula Ina and/or Me, R13 is -C1_6 alkyl.
[001271] In some embodiments of Formula Ma and/or Me, R13 is ¨C2_6 alkyl.
[001272] In some embodiments of Formula Ma and/or Me, R13 is ¨C3_6 alkyl.
[001273] In some embodiments of Formula Ma and/or Mc, R13 is ¨C4_6 alkyl.
[001274] In some embodiments of Formula Ma and/or Me, R13 is ¨C2_5 alkyl.
[001275] In some embodiments of Formula Ina and/or life, R13 is ¨C3_5 alkyl.
[001276] Some additional embodiments of Formula III include compounds of Formula (IIIb):
(Ri 6)ci /
Ruo IIIb or salts, pharmaceutically acceptable salts, or prodrugs thereof.

[001277] In some embodiments of Formula IIIb, R14 is selected from the group consisting of unsubstituted -C1_6 alkyl, -C1_3 haloalkyl, and CF3.
[001278] In some embodiments of Formula IIIb, R15 is selected from the group consisting of unsubstituted -C1_6 alkyl, -C1_3 haloalkyl, and CF3.
[001279] In some embodiments of Formula Mb, each R16 is a substituent attached to the phenyl ring and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R17b)2, -C1_3 haloalkyl, halide, -0R17, CF3, and CN.
[001280] In some embodiments of Formula Mb, each R17 is independently selected from the group consisting of unsubstituted -C1_6 alkyl, -C1_3 haloalkyl, and CF3.
[001281] In some embodiments of Formula Mb, each R176 is independently selected from the group consisting of H and unsubstituted ¨C1_3 alkyl.
[001282] In some embodiments of Formula Mb, each q is an integer of 1 to 5.
[001283] In some embodiments of Formula Mb, there is the proviso that a compound of Formula Mb is not a compound selected from the group consisting of:
OMe OMe Et0 Me0 0 Et OMe Me0 and Me0 [001284] In some embodiments of Formula IIIb and/or IIId, R14 is Me [001285] In some embodiments of Formula IIIb and/or HId, R14 is Et.
[001286] In some embodiments of Formula IIIb and/or Ind, R14 is -C1_2 alkyl.
[001287] In some embodiments of Formula IIIb and/or IIId, R14 is -C1_3 alkyl.
[001288] In some embodiments of Formula Mb and/or Hid, R14 is -C14 alkyl.
[001289] In some embodiments of Formula Mb and/or Hid, R14 is -C1_5 alkyl.
[001290] In some embodiments of Formula IIIb and/or Hid, R14 is -C1_6 alkyl.
[001291] In some embodiments of Formula Mb and/or IIId, R14 is ¨C2_6 alkyl.
[001292] In some embodiments of Formula II1b and/or Hid, R14 is ¨C3,6 alkyl.
[001293] In some embodiments of Formula Mb and/or Hid, R14 is ¨C4_6 alkyl.
[001294] In some embodiments of Formula Mb and/or Hid, R14 is ¨C2_5 alkyl.
[001295] In some embodiments of Formula nib and/or Hid, R14 is ¨C3_5 alkyl.

[001296] In some embodiments of Formula Mb and/or Ind, R14 is -C1-2 haloalkyl.
[001297] In some embodiments of Formula Illb and/or IIId, R14 is -C1-3 haloalkyl.
[001298] In some embodiments of Formula IIIb and/or IIId, R14 is ¨C2-3 haloalkyl.
[001299] In some embodiments of Formula IIIb and/or IIId, R14 is CF3.
[001300] In some embodiments of Formula Mb and/or IIId, R15 is Me [001301] In some embodiments of Formula Illb and/or IIId, R15 is Et.
[001302] In some embodiments of Formula Mb and/or IIId, R15 is -C1,2 alkyl.
[001303] In some embodiments of Formula IIIb and/or Ind, R15 is -Ci_3 alkyl.
[001304] In some embodiments of Formula Mb and/or Ind, R15 is -C1_4 alkyl.
[001305] In some embodiments of Formula Mb and/or IIId, R15 is -C1,5 alkyl.
[001306] In some embodiments of Formula Mb and/or Ind, R15 is -C1_6 alkyl.
[001307] In some embodiments of Formula Mb and/or Ind, R15 is ¨C2,6 alkyl.
[001308] In some embodiments of Formula Mb and/or IIId, R15 is ¨C3,6 alkyl.
[001309] In some embodiments of Formula IIIb and/or Ind, R15 is ¨C4,6 alkyl.
[001310] In some embodiments of Formula IIIb and/or Ind, R15 is ¨C2,5 alkyl.
[001311] In some embodiments of Formula IIIb and/or IIId, R15 is ¨C3_5 alkyl.
[001312] In some embodiments of Fa( ___________________________________ nula Mb and/or IIId, R1 is -C1-2 haloalkyl.
[001313] In some embodiments of Formula IIIb and/or Ind, R15 is -C1_3 haloalkyl.
[001314] In some embodiments of Formula Illb and/or Hid, R15 is ¨C2-3 haloalkyl.
[001315] In some embodiments of Formula Mb and/or IIId, R15 is CF3.
[001316] In some embodiments of Formula IIIb, each R16 is selected from the group consisting of H, F, Cl, Me, OMe, CF3, and CN.
[001317] In some embodiments of Formula IIIb, R16 is H.
[001318] In some embodiments of Formula Mb and/or IIId, R16 is a halide.
[001319] In some embodiments of Formula IIIb and/or Hid, R16 is F.

[001320] In some embodiments of Formula Mb and/or Hid, R16 is Cl.
[001321] In some embodiments of Formula Mb and/or Md, R16 is Me.
[001322] In some embodiments of Formula Mb, R16 is OH.
[001323] In some embodiments of Formula Mb, R16 is OMe.
[001324] In some embodiments of Formula Mb and/or Md, R16 is CF3.
[001325] In some embodiments of Formula Mb and/or Md, R16 is CN.
[001326] In some embodiments of Formula Mb and/or Md, q is an integer from 1-4.
[001327] In some embodiments of Formula TIM and/or Hid, q is an integer from 1-3.
[001328] In some embodiments of Formula Mb and/or Md, q is an integer from 1-2.
[001329] In some embodiments of Fonnula Mb and/or Hid, q is 2.
[001330] In some embodiments of Formula IIIb and/or Md, q is 1.
[001331] In some embodiments of Formula Mb and/or Hid, R16 is F; and q is 1.
[001332] In some embodiments of Formula Mb and/or Md, R16 is F; and q is 2.
[001333] In some embodiments of Fonnula Illb and/or Hid, R16 is Me; and q is 1.
[001334] In some embodiments of Formula Mb and/or Hid, R16 is Me; and q is 2.
[001335] In some embodiments of Formula HIb and/or Hid, R16 is CF3; and q is 1.
[001336] In some embodiments of Formula Mb and/or Hid, R16 is CF3; and q is 2.
[001337] In some embodiments of Formula Mb, R16 is OMe; and q is 1.
[001338] In some embodiments of Formula Mb, R16 is OMe; and q is 2.
[001339] In some embodiments of Foimula Mb and/or IIId, R16 is F and Me;
and q is 2.

[001340] In some embodiments of Formula Into and/or IIId, R16 is F and CF3;
and q is 2.
[001341] In some embodiments of Formula Mb, R16 is F and OMe; and q is 2.
[001342] In some embodiments of Formula IIIb and/or Hid, R16 is CN; and q is 1.
[001343] In some embodiments of Formula IIIb and/or IIId, R16 is CN; and q is 2.
[001344] In some embodiments of Formula IIIb and/or IIId, R16 is F and CN;
and q is 2.
[001345] In some embodiments of Formula IIIb and/or Hid, R16 is F or Cl; q is 1.
[001346] In some embodiments of Formula Mb and/or Hid, R16 is -C1_2 alkyl.
[001347] In some embodiments of Formula Mb and/or Hid, R16 is -C1_3 alkyl.
[001348] In some embodiments of Formula Mb and/or Hid, R16 is -C1_4 alkyl.
[001349] In some embodiments of Formula Mb and/or IIId, R16 is -Ci_5 alkyl.
[001350] In some embodiments of Formula Mb and/or Hid, R16 is -Ci_6 alkyl.
[001351] In some embodiments of Formula IIIb and/or IIId, R16 is ¨C2_6 alkyl.
[001352] In some embodiments of Formula Mb and/or Hid, R16 is ¨C3_6 alkyl.
[001353] In some embodiments of Formula nib and/or IIId, R16 is ¨C4_6 alkyl.
[001354] In some embodiments of Formula Mb and/or Hid, R16 is ¨C2_5 alkyl.
[001355] In some embodiments of Formula tub and/or Hid, R16 is ¨C3_5 alkyl.
[001356] In some embodiments of Formula Mb, R17 is -Ci_2 alkyl.
[001357] In some embodiments of Formula nib, R17 is -Ci_3 alkyl.
[001358] In some embodiments of Formula tub, R17 is -C1_4 alkyl.
[001359] In some embodiments of Formula IIIb, R17 is -Ci_5 alkyl.
[001360] In some embodiments of Formula tub, R17 is -C1_6 alkyl.
[001361] In some embodiments of Formula IIIb, R17 is ¨C2_6 alkyl.
[001362] In some embodiments of Formula tub, R17 is ¨C3_6 alkyl.
[001363] In some embodiments of Formula Mb, R17 is ¨C4_6 alkyl.
[001364] In some embodiments of Formula En, R17 is ¨C2_5 alkyl.
[001365] In some embodiments of Formula IIIb, R17 is ¨C3_5 alkyl.

[001366] In some embodiments of Foimula Mb, R16 is -CH2OH.
[001367] In some embodiments of Formula Mb, R16 is -CH2N(R17)2.
[001368] In some embodiments of Formula Mb, R16 is -CH2NEI2.
[001369] In some embodiments of Formula Mb, R16 is -CH2NHMe [001370] In some embodiments of Fonnula Mb, R16 is -CH2NMe2.
[001371] In some embodiments of Formula Illb, R16 is -CH2NHEt [001372] In some embodiments of Formula Mb, R16 is -CII,N(Me)(Et).
[001373] In some embodiments of Formula Mb, R16 is -CH2NEt2.
[001374] Some additional embodiments of Formula III include compounds of Formula (Mc):
R"

Inc or salts, pharmaceutically acceptable salts, or prodrugs thereof.
[001375] In some embodiments of Folinula Mc, Ring E is selected from the Rub R
R , and 12a 11101 1101 110 R12e ud group consisting of [001376] In some embodiments of Formula Mc, RI- is selected from the group consisting of H, unsubstituted -C1_6 alkyl, -C1..3 haloalkyl, halide, -0R13, CF3, and CN.
[001377] In some embodiments of Formula Mc, is selected from the group consisting of unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(RI3b)2, -C1_3 haloalkyl, halide, -OR13, CF3, and CN.
[001378] In some embodiments of Formula Inc, R12a is a substituent attached to the para position of the phenyl ring and is independently selected at each occurrence from the group consisting of unsubstituted ¨C2_6 alkyl, -CH2OH, -CH2N(R13b)2, -C2_3 haloalkyl, Cl, I, -0Et, and CN.
[001379] In some embodiments of Foimula Inc, Rub is a substituent attached to the meta position of the phenyl ring and is independently selected at each occurrence from the group consisting of unsubstituted ¨C2_6 alkyl, -CH2OH, -CH2N(R13b)2, -haloalkyl, iodide, -0R13', and CF3.
[001380] In some embodiments of Formula Mc, R12c is a substituent attached to the ortho position of the phenyl ring and is independently selected at each occurrence from the group consisting of unsubstituted ¨C2_6 alkyl, -CH2OH, -CH2N(R13b)2, -haloalkyl, F, I, -0R13a, CF3, and CN.
[001381] In some embodiments of Formula Mc, R12d is 2-5 substituents, each attached to Ring E and are independently selected at each occurrence from the group consisting of unsubstituted -C1_6 alkyl, -CH2OH, -CH2N(R13b)2, -Ci_3 haloalkyl, F, Br, I, -OR13, CF3, and CN.
[001382] In some embodiments of Formula Mc, each R13 is independently selected from the group consisting of unsubstituted -C1_6 alkyl, -C1..3 haloalkyl, and CF3.
[001383] In some embodiments of Formula Mc, each R13a is independently selected from the group consisting of unsubstituted ¨C2_6 alkyl, -C1_3 haloalkyl, and CF3.
[001384] In some embodiments of Formula Inc, each R13b is independently selected from the group consisting of H and unsubstituted ¨C1_3 alkyl.
[001385] In some embodiments of Formula Mc, q is an integer of 1 to 5.
[001386] In some embodiments of Formula Mc, R12a R121), R12c, R12d and/or R13a is ¨C2_6 alkyl.
, [001387] In some embodiments of Formula Inc, R12a R121), R12c Rua and/or R13' is ¨C2_5 alkyl.
a , [001388] In some embodiments of Formula Mc, R12 R121), R12e R12d and/or R13a is ¨C24 alkyl.
[001389] In some embodiments of Formula Hie, R12a R121), R12c, R12d and/or K is ¨C3_6 alkyl.
[001390] In some embodiments of Formula Hie, R12a R121), R12c, R12d and/or R13a is ¨C4-6 alkyl.
[001391] In some embodiments of Formula Inc, R12d and/or R13a is Me.
[001392] In some embodiments of Formula Mc, R121), R12c, R12d and/or R13' is CF3.
[001393] In some embodiments of Formula Mc, R12c and/or R12d is F.

[001394] In some embodiments of Formula Mc, R12' is Cl.
[001395] In some embodiments of Formula Mc, R12a, Ri2e, and/or R12d is CN.
[001396] In some embodiments of Formula Mc, R12a, R121), R12c, and/or R12" is _ CH2OH.
[001397] In some embodiments of Formula Mc, R12a, R1213, R12c, and/or R12d is -CH2N(R131)2.
[001398] In some embodiments of Formula Mc, R12a, R121), R12c, and/or R12d is -CH2NH2.
[001399] In some embodiments of Formula Mc, R12a, R1213, R12c, and/or R12d is -CH2NHMe.
[001400] In some embodiments of Formula Mc, R12a, R1213, R12c, and/or R12d is -CH2NMe2.
[001401] In some embodiments of Formula Inc, R12a, R121), R12c, and/or R12" is _ CH2NHEt [001402] In some embodiments of Formula Mc, R12a, R1213, R12c, and/or Rua is _ CH2N(Me)(Et) [001403] In some embodiments of Formula Ina and/or Mc, R11 is -CH2NE12.
[001404] Some additional embodiments of Formula III include compounds of Formula (IIId):
(R16)q R150 0la Ind or salts, pharmaceutically acceptable salts, or prodrugs thereof.
[001405] In some embodiments of Formula Hid, R14 is selected from the group consisting of unsubstituted -C1_6 alkyl, -C1_3 haloalkyl, and CF3.
[001406] In some embodiments of Formula IIId, R15 is selected from the group consisting of unsubstituted -C1_6 alkyl, -C1_3 haloalkyl, and CF3.
[001407] In some embodiments of Formula HMI, each R16 is a substituent attached to the phenyl ring and is independently selected at each occurrence from the group consisting of unsubstituted -C1,6 alkyl, -CH2OH, -CH2N(R17b)2, -C1_3 haloalkyl, halide, -0R17a, CF3, and CN.
[001408] In some embodiments of Formula Ind, each Ri7a is independently selected from the group consisting of unsubstituted ¨C3_6 alkyl, -Ci_3 haloalkyl, and CF3.
[001409] In some embodiments of Formula IIId, each Rub is independently selected from the group consisting of H and unsubstituted ¨C1_3 alkyl.
[001410] In some embodiments of Formula Ind, q is an integer of 1 to 5.
[001411] In some embodiments of Formula IIId, R17 is ¨C3_6 alkyl.
[001412] In some embodiments of Formula IIId, R17 is ¨C4,6 alkyl.
[001413] In some embodiments of Formula IIId, R17 is ¨C3_5 alkyl.
[001414] In some embodiments of Formula IIId, R16 is -CH2OH.
[001415] In some embodiments of Formula IIId, R16 is -CH2N(R17b)2.
[001416] In some embodiments of Formula Md, R16 is -CH2NH2.
[001417] In some embodiments of Formula IIId, R16 is -CH2NHMe [001418] In some embodiments of Formula Hid, R16 is -CH2NMe2.
[001419] In some embodiments of Formula Hid, R16 is -CH2NHEt [001420] In some embodiments of Formula IlId, R16 is -CH2N(Me)(Et).
[001421] In some embodiments of Formula IIId, R16 is -CH2NEt2.
[001422] Some embodiments of the present disclosure include compounds of Formula (IV):

0,18,p 40 iv or salts, pharmaceutically acceptable salts, or prodrugs thereof.
[001423] In some embodiments of Formula IV, Ring Ring F is [001424] In some embodiments of Formula IV, Ring G is selected from the Risb \ 40/I /
R19a sssS R19b R19c group consisting of , and a membered heteroary1R19d, wherein a carbon atom on the ring is attached to the carbonyl carbon.
[001425] In some embodiments of Formula IV, each R18 is a substituent attached to Ring F and is independently selected at each occurrence from the group consisting of H, -Ci_3haloalkyl, halide, -0R20, CF3, and CN.
[001426] In some embodiments of Formula IV, R19a is a substituent attached to the para position of phenyl and is selected from the group consisting of H, unsubstituted ¨
C2_6 alkyl, -CH2OH, -CH2N(R21)2, -C1_3 haloalkyl, F, Br, I, -0R20, CF3, and CN.
[001427] In some embodiments of Formula IV, R19b is a substituent attached to the meta or ortho position of phenyl and is selected from the group consisting of H, unsubstituted ¨C2.6 alkyl, -CH2OH, -CH2N(R21)2, -C1_3 haloalkyl, halide, -0R20, CF3, and CN.
[001428] In some embodiments of Formula IV, R19c is 2-5 substituents, each attached to the phenyl and are independently selected at each occurrence from the group consisting of H, -CH2OH, -CH2N(R21)2, -C1_3 haloalkyl, halide, -0R20, CF3, and CN.
[001429] In some embodiments of Formula IV, R19d is 1-4 substituents, each attached to the heteroaryl ring and is independently selected at each occurrence from the group consisting of H, -CH2OH, -CH2N(R21)2, -C1_3 haloalkyl, halide, -0R20, CF3, and CN.
[001430] In some embodiments of Formula IV, each R2 is independently selected from the group consisting of H, unsubstituted ¨C3.6 alkyl, -C1_3 haloalkyl, and CF3.
[001431] In some embodiments of Formula IV, each R21 is independently selected from the group consisting of H and unsubstituted ¨C1.3 alkyl.
[001432] In some embodiments of Formula IV, p is an integer of 1 to 13.
[001433] In some embodiments of Formula IV, r is an integer of 1 to 5.

,R18, [001434] In some embodiments of Foimula IV, is selected from the group consisting of:
SO , and Ile =
(R18)p [001435] In some embodiments of Formula IV, is selected from the group consisting of:
410 1110 4110 SO , and 110 [001436] In some embodiments of Formula IV, R1913, R.19 , and/or Ri9d is selected from the group consisting of H, F, Cl, Me, OMe, CF3, and CN.
[001437] In some embodiments of Foimula IV, R19a, R191), R19c, and/or R19d is H.
[001438] In some embodiments of Formula IV, RI9b, R19c, and/or R19d is a halide.
ob, Ri9e, [001439] In some embodiments of Formula IV, R19a, R and/or R19d is F.
[001440] In some embodiments of Formula IV, R191, lee, and/or R19d is Cl.
[001441] In some embodiments of Foimula IV, ea, R191, R19c, and/or Ri9d is Me.
[001442] In some embodiments of Foimula IV, R Ri9b, Roc, i9a, and/or R19d is OH.
[001443] In some embodiments of Formula IV, R19 Rob, Roe, R'9, and/or R19d is OMe.
[001444] In some embodiments of Foimula IV, R19a, R191), R19c, and/or R19d is CF3.
[001445] In some embodiments of Formula IV, R19a, R19b, R19c, and/or R19d is CN.
[001446] In some embodiments of Formula IV, Ri9d is 2 substituents and both are F.

[001447] In some embodiments of Formula IV, R19d is 2 substituents and both are Me.
[001448] In some embodiments of Formula IV, R191 is 2 substituents and both are CF3.
[001449] In some embodiments of Formula IV, R19d is 2 substituents and both are OMe.
[001450] In some embodiments of Formula IV, Ri9d is 2 substituents and are F
and Me.
[001451] In some embodiments of Formula IV, R19d is 2 substituents and are F
and CF3.
[001452] In some embodiments of Formula IV, Ri9d is 2 substituents and are F
and OMe.
[001453] In some embodiments of Formula IV, R19d is 2 substituents and both are CN.
[001454] In some embodiments of Formula IV, R19d is 2 substituents and are F
and CN.
[001455] In some embodiments of Formula IV, R19d is 2 substituents and are F
and Cl.
[001456] In some embodiments of Formula IV, R19a R19b, Ri9c, and/or R19d is -C1_2 alkyl.
, 19 t9b, Rc [001457] In some embodiments of Formula IV, R19a R and/or R19d is -C1_3 alkyl.
[001458] In some embodiments of Formula IV, R19a Ri9b, R19c, and/or Ri9d is -C14 alkyl.
[001459] In some embodiments of Fonnula IV, R19a R191), R19c, and/or R19d is -C1_5 alkyl.
19b, Ri9c, [001460] In some embodiments of Formula IV, RI9a R and/or R19d is -C1_6 alkyl.
c [001461] In some embodiments of Formula IV, R19 Ri9b, Ro, R'9, and/or R19d is ¨
C2_6 alkyl.

[001462] In some embodiments of Formula IV, R19a, R191), R19c, and/or Ri9d is -C3_6 alkyl.
[001463] In some embodiments of Formula IV, R19a, Rl9b, R19 , and/or ed is -C4_6alkyl.
[001464] In some embodiments of Formula IV, R19a, Rl9b, RI9c, and/or Ri9d is C2_5 alkyl.
[001465] In some embodiments of Formula IV, R19a, 9b, Ri and/or R19d is -C3_5 alkyl.
[001466] In some embodiments of Foimula IV, R19a, 91', Ri9c , and/or ed is -CH2OH.
[001467] In some embodiments of Foim R191), R19c, ula IV, R19a, and/or R19d is -CH2N(R13b)2.
[001468] In some embodiments of Foim R191), R19c , ula IV, R19a, and/or R19d is -CH2NH2.
[001469] In some embodiments of Formula IV, R19a, R19b, R19% and/or R19d is -CH2NHMe.
[001470] In some embodiments of Formula IV, R19a, R191), R19c, and/or R19d is -CH2NMe2.
[001471] In some embodiments of Formula IV, R19a, 9b, Ri9c, and/or R19d is -CH2NHEt [001472] In some embodiments of Foimula IV, R19a, R191), R19c, and/or R19d is -CH2N(Me)(Et).
[001473] In some embodiments of Foimula IV, R19a, R19b, R19c, and/or ed is -CH2NEt2.
[001474] In some embodiments of Foimula IV, is selected from the ci group consisting of: F =

HO a -N
Me0 401 Me NC

FH- CI 1 F3C 1 Me-- NCH-N N
/
NI"-'--/
OA' 1/1-3A' P IJI---? /No `o `o No' s ' NI l''''?' NI N OA
N., / 0 S 0 1%1 N's N N = NiiN.Y\ (N N, INI
NS S NS7 N N , , N , and ----X\
Isl N ; wherein the carbonyl carbon of Foimula IV can form a bond with any unsubstituted carbon on the Ring G.

[001475] In some embodiments of Foimula IV, is selected from the group consisting of:
F CI CF3 OMe Me CN

* OH 140 , 1 1 , N\, \% F \%' CF3 I II c) ( )1 , S , III
[001476] In some embodiments of Formula IV, is selected from the group consisting of:
F CI CF3 OMe Me CN
$ * * 140 * 10 ,,..,N..,..,..,õ...)-z, I
/ / / .
[001477] Illustrative compounds of Formulas I, Ia, Ib, Lc, Id, le, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, II!', HI, IIIa, nib, Hie, IIId, and IV are shown in Table 1.

Table 1.
OSA o 1401 o F

*

o 4 116 o OH
OH OH

. / OMe 0 O 5 o 6 OH o OMe 1411111 OMe 0 11101 o 0 OMe 8 0 OMe OMe 9 o 01 o I. o O II6 o F

110 0 12 o 110 0 OMe /
Ili 0 \

OMe . 1 0 / 110 0 \
(:) 0 I
1.1 A
, o o CF3 o o o 0 u3 ' 17 s S18 o 10 o I. o F

19 20 s .--0 \o 0 0 0 o 21 A I. F
.õs 0 o 10 0 OMe OMe O ei OMe 4111 s o A
o o o o / o I

A .,. N

Ol A

I

A

10o o INI
o -õ
o cF3 o 140o ,,,,o 30 1401 0 CF3 \ o 110 S s 0 14.111 31 5 o 32 o o 50 F
S S
F

33 A 14111 34 o S
OMe 0 el0 0 OMe s \s is OMe / 1 o A
o 1,1 o 1 o / N
I

o -,,s s o o 141 42 I.
,,o s 5 $
o 0 CF3 \
S S

0 . CF3 43 S 0 44 s 1.1 s o s o F

1.1ell 40 s -s 0 F

S
F

48 ,,S 1.1 5 0 OMe S
S
OMe 0 OMe 49 s 11101 lei 50 A O
,--o s 0 A
51 \N \ N
52 s \

0 /'. N 0 I.

I
,,õ s 40 \ s o s 40 o s 1.1 55 o o cF3 o 0 o 0 u3 o 58 o o 57 0, o F F

40 60 o 401 o 40 140 o OMe o 40 01 62 o 61 o o OMe o ,OMe / 1 le o 64 o 63 o 10 o o / 1 o 65 o 40 N 66 o NI

el 67 o 40 410 68 o o F3 o c $
cF3 o 0 u3 o $ 4111 70 140 o o o F

0o O F
0 . 0 __ __ . _____ .= _ _ = __ ______ 0 $ 5 o 0 OMe OMe 0 OMe o o o *
o *
o i I o I

N 78 ., N

0 = 0 *

o 0 o . o *
*
S

o F
81 FO 40 82 F...,,0 40 F2\0 0 0 u3 o F F

83 F0 40 84 Fo 10 F2\0 0 F

F

F
F\_ 5 OMe 0 e l ., F
87 , 88 F 0111 ,0 =

F>\0 0 OMe F2\0 0 is OMe / 1 F F I

---,.---- 90 F., õ0 , \
N
F 401 x 0 F> 1101 F F I

0 \ N FO
F 10 F *
F>\0 0 0 _0=
F F
F., ,-0 F, S
93 , 0 94 , F 1101 F *
F>\0 0 F S
96 5 o cF3 FS *

F\0 0 F

97 e O l 98 F S

F
F>\0 1 F \_---0 F FX0 $

F F
99 R..,,___..s iso F

F (40 F>\0 0 OMe OMe 0 OMe 102 Fs 5 o F., ,..S
, F *
F\0 0 F>0 F F
103 F.._.,-S 40 N 104 FS 10 \ N
F
F->0 . 0 F/'\0 0 F I F e l F 106 ,__ S F..õ ,...s , F 10 F (0 F>\0 0 F>\0 0 F 0 ell F,-0 F,, F>. S

F F

109 FO 110 ---...---F>\S 0 F [410 S 0 F
F

F
F=. 0 411 112 FO

F2\S 0 FS

OMe FO F
113 0 114 F.2) 5 0 OMe F S F2\S 0 0 OMe 0 / 1 F
115 F0 * 116 F..A * \
N
F',, S
F>\S 0 I -- N
F F

F ,, N 118 F O
-,0 -., op F *
F>\S 0 OMe 0 /
119 FO la 0 120 \o * 0 CF3 OMe OMe 0 OMe 0 .1 o o la o OMe OMe F
OMe 0 0 6 1.1 OMe 0 /
123 124 ,(:) 5 o F

OMe OMe OMe 0 OMe 0 ---- ----o 5 o --,.o 5 0 OMe OMe OMe OMe ,OMe OMe 0 OMe 0 127 o 1011 128 2) o --,o 111111 0 OMe OMe OMe 0 ...--- 1 I OMe 0 / 1 I
0 ---.. 0 \ N
---- N ----So -,o 110 0 OMe OMe OMe 0 N

0 -..., Oil --....o o 0 OH o CF3 -,....õ
OMe . CF3 OH o 133 o 10 A 40 ...--01 OH -,., 0 \,c) 0 OH
F

el136 OH 0 101 o 135 ( la o F ----0 OH -..õ.0 110 0 OH

137 A 10 lel 138 F
OH 0 o -...,,, OH o 0 OH 0 OMe OMe 0 OMe 139 o ------,o IP OH 0 -,,,O OH 0 0 is0H1 0 ..OH 0 I
141 --- ---, N 142 ,...,,o .., N
-...,. 0 -.., OH 0 -AN OMe 0 I

___, --..,,, 144 __õ,o el ell o o CF3 --...,, o OMe OMe 0 OMe 0 CF3 145 o io lel 146 40 O
OMe ---o ---, o -,..,,,.
O OMe F
OMe 0 0 40 1111148 OMe 0 147 o 101 ,--0 OMe ---..o OMe 0 OMe 0 OMe 0 F
o -.......õ o 0 OMe 0 OMe 0 OMe OMe OMe 0 OMe OMe 0 151 o is 411 152 40 ------...0 o õ, o OMe o OMe OMe 0 ...--" 1 I OMe 0 ----- 1 ,,,,...0 ---. \ N

o III
,-...,, -,...,. o 0 OMe 0 OMe OMe 0 N 0 ____0 -,..õ, III ---,0 II 0 CF3 0 OMe 0 OMe OMe lel 0 157 o 158 0 el ell o ,..,,o OMe o 0 OMe OMe OMe F

lel ------e II 160 ___, o o F l0 OMe --..o OMe OMe OMe 0 e ll F

0 0 ell / le .---- ill o 0 OMe 0 OMe 0 OMe OMe OMe OMe . OMe 163 A el 164 A 40 Oil 0 OMe o -..,,o OMe 0 OMe OMe 0 .---- 1 i 0 1 .-------- e N
165 , 166 , l Si OMe OMe OMe OMe I

/ ----Oil 1 OMe 168 0 o o CF3 OMe OH

169 ,,,õo 0 170 ----o III o --...o SI o ,õ.c.
OH OH

F

el 0 Oil ..----III172 o -- el o O F
OH OH

,F 0 ---- ..---=

Oil 0 OMe 0 ,....o OH OH
OMe O 176 40 OMe 175 o el 411 o --...o 0 o OH
OH
O ---"- 0 ..----O ----.. 0 \ N

N

,..., o 0 OH OH
O ------ O

II
0 --...., 0 il o o --...,.. o o OH OH

e 182 ll 0 .,,,õ,o -.....õ, ill -....,. 0 , 0 F

185 o ell o ---o --,o 101 OH o 0 OH

OMe 187 188 o o la OH 0 OMe le 0 (:) OH
40 OMe /

'OH 190 O0 (:) OH 0 0 / , I
23 40 \ N 0 o o o 0 o OH OH

A 40 o /

OOH o o le 0 CF3 CF3 s 196 CF3 195 o 40 41/ A .
o o o o F

197 198 o o 0 F
o 140 0 OH

199 A 0 40F 200o o 40 o o OMe OMe el OMe 201 o 401 411 A is o o o o \
203 o o o la o o I
el 23 o o o o 40 o I
o o , I
O o N

o 40 o o 40 o O
I
el 0 flo o o % o c F3 CO
ei C F3 o 0 212 <o io o 40 <0 o o F
O
o 40 401 / 0 214 o <0 0 F 0 0 o 215 o <

< o la IS
0 o 0 o OMe OMe 217 OMe o el 218 o 40 I.
<co <o0 o o o \ IN
219 o 5 220 0 o N
<o 5 < 0 0 221 o lo 222 <0< 5 O o co o F \< 0 224 F 0 0 o CF3 0 F\( 5 o F

F \<
o F F\< 1.

F

1401 228 F o 40 0 F
F 0 5 F \<
F\<

OMe 0 e F 0 lp \< l 0 OMe 0 0 F \< 5 0 0 ,OMe /
231 $
F F\<
o 232 F 0 F \< 0 0 / , F \<
\ N 0 F \< 40 o o o o el 235 F 0 5 o F \<

CF3 el CF3 237 0 238 o o le o 140 0 F

=, o 239 o 40 0 F 240 o 5 o '0 0 0 e 0 l 242 o 0 o 0 OMe OMe 40 OMe 0 o o le o o o o 1 o 0 I I
246 o 245 0, o la o N
0 0=1 0 0 el 247 o le o !
248 o o cF3 o el o N

o 0 cF, H o el o 0 F
N
H H
F

, 40 0 N4 o N H
H
OMe el 0 0 OMe H
0 OMe I
257 / 0 258 /$ N
N N

H

\ N

o o N N
H H

N

o < I. 0 CF3 N N
H

o <
0 o < 0 N
N H
H
F

<140 0 F 266 N
N <N 0 0 H
H

<
267 N N 140 0 <lati IW 0 OMe N
H H
OMe O OMe 270 <

<N 5 N

H
H
0 / , I

<N 0 0 272 N
l'i <
N
H H

NI

< 1101 <N 0 N N
H H

le 276 o CF3 /
o o o is u3 O o 277 el / le /le o F
o o o F
o o el 1 / le / 140 o O o o OMe o 281 1.1 282 o 0 OMe 40 OMe 0 _ 0 / , -, IN 0 NI

o o o o 0:
o 5 o <o I.
o cF3 o cF3 290 N .
289 cF3 o o N
<0 < 140 o o o o F
o < 40 291 N el N
292 o 0 F
< 0 93 N el <140 0 <1 0 OMe OMe 40 OMe N (14 10 < 10 0 0 0 N 298 N -, N
<N 0 o < 0 o o o o / N 0 I

<o < o o 10 o le o 40302 o 301 0 0 o /
0 u3 s S
0 u3 o o 303 / la 304 o o F
S S
F F

/5 o o s S
OMe el 308 o 0 OMe S

0 OMe o o s s le o , I

o o s s 4040 , o 313 314 el o o CF3 S HN

411 ip 40 i o CF3 o I o F
. 1 0 317 401 318 '/ o el HN
OMe = 1 0 319 11 320 o # I 401 HN 0 OMe 0 HN
/
321 322 i N
HN 0 OMe # 0 ip 1 0 ¨I\ N = o NI

= 0 HN 0 HN---"N 0 CF3 = o I
I o HN-N o HN¨N
F
. 1 0 329 = 330 # i o HN-N o F i HN-N o # o 332 # 1 HN-N o HN-N 0 OMe OMe OMe = 0 I

40 334 = i o i I

HN-N o HN-N o HN¨N 0 HN¨N 0 I

HN-N o HN-N o I

o I o 1 - o I, 341 o is 342 A II
o o .c) 10 o o 00 o 343 o 0 344 o10 o o o o N 0 I \

345A -. N 346 o o 10 o o la 0 N, 1.1 F
347 A / 348 F \A

\o $ 0 F
F/
0 'C) F\ 0 I
0 . 0 _0 350 F F,\O

F F
N
N\

, õ F0 F

F \/ 5 F \A
F N 352 40 \NI
F ./...õ 0 F /-= 0 F 1 \
F\

i ' 354 F S
F /,õ 1101 0 F /,õ 0 F F
,N
0 i \

F\A F n \

355 F F \-- 10 F /7-.õ 0 0 F F /-,, F u Nõ

F I

357 F \A

F *

Si o o N
N\

361 Si N 362 O N

0 o/\% 0 0 -AN 0 I \
) S

o o I.1 0O0 o 1 \ o ,N

I
365 o 366 o o o 0 o *
NõN

I
SI
367 368 o 40 o <o o o o o 369 o 10 0 370 o 10 0 <0 o <so 0 N
N
0 ) 0 371 o 0 N 372 o 0 <o o <o o N

0 N 0 1 \
373 /o 0 374/o s \c) 10 \) o o o I \ o N
375o o 10 i o o 376 o 10 <o o N,, 377 o 0 378 F\ /A0 10 <so o 379 F\ /0 0 380 F\ /A0 0 40 FA 0 o F
N
N\
0 ) 0 381 Fx0 0 0 \ N 382 F\ /0 0 , o A
,-F Co 0 N
F
00 I \
NI
383 F\ /0 0 1,1 384 F\ /0 s A o FAcs 1401 0 0 I \ 0 N
385 F\ /0 0 F 40 o 386 F\ /0 0 40 A A
o F o N,, I s 387 F\ /0 FACo 0 0 0 388 0 389 s O
o o o N
N\

S
391 s 0 392 N
o 0 \o le 0 1 \
õ, ) S
/ s SI o o,...,, ...,, o o ,-N
0 I \ 0 i lelo 396 o .----.., o -., o o N, N
I F\ _s IP
398 F ' -..õ
110 0 F /, ell400 F 0 \ s F s \ el 399 F \-- le F
F /- 0 F /., 1101 0 F F
N
O ..---- ) F\ F\ 1 s Fs 0 N 1 401 F \`' re N 402 F \--. 40 N

F /-F
F
O -. N 0 Fs I \
) F
\S 40 s 403 F \'' le N 404 F
F/' 0 F 7,, 0 F
F
,... N

F I \ F\ c 1 \S 10 o 406 F \µ' 40 --..õ.

F/ -, 0 F /-N., 0 F F
N., e I
S ll 407 F F\ c \`' --,,, 408 le S
F

ell s 409 s 40 410 0 o o s s N
O --- ) 0 N

/ la ,,-N

S S
O N 0 I \

0 ii /

S S
0 I \ 0 S
415 ./

S
N, I

S
418 Me0 is S Me0 Me0 10 Me0 is 419 I. F 420 Me0 0 0Me0 Me0 el 10 Me0 0 - rr Me0 Me0 Me0 10423 Me 10 424 Me0 Me0 0 0 el Me0 425 Me0 Me0 Me0 ellOMe l Me0 10 Me0 a 0 OMe 0 Me0 Me0 0 OMe N

\ NI
429 me 0 430 Me0 10 Me0 0 Me0 0 0 N\ 0 .- N
)Me0I. -=. õ. Me0 0 Me0 431 N 432 N Me0 N N, I
433 Me0 ip \ 434 Me0 10 \
Me0 0 Me0 0 elI 0 .1 435 o 00 o 436 0 40 o o o I.

il o o II
\ N
437 o 140 o 438 o 0 o o 0 N i I o 0 N
) 39 o o N
o 10 o 1 \ 1 \
441 o le o s 442 0, o o ,N N, I
443 o . o 444 o 0 o "
o 01 o SI

N
o N o H H

\ NI

o o N N
H H

o N o N
o N o H H
o I \ o I \
451 / la s 452 / 10 N N o o o H H
IµL
o N o N
I

o o H H
o o , 0 / /r -o o o o o 1.1 o N

_______ o o o o o N 1 ________ o o 10) o o o I \ o 1 \
461 / 10 s 462 / la o o o o o ,,N NI..
o N-- 1 I o / NI
463 / $ 464 o o o o o el466 o el / le o S o s o S o 467 / INI, ll N

S
o o 10 s N) o o s s o I \ o i \
471 / 0 . s 472 / le o S
o s o .,N N0 N 1 I

/ 401 / le o o s s o N
<N 40 N la o H H

40 0 ,,,, N
N
<N 10 0 478 N

<N 101 0 H H

) <N 101 0 N
N

le H H

I \ 0 I \

s 482 ( 10 < lal o o N N
H H
N N.,, I

(N 0 0 484 N
( 0 0 N
H H

485 N el 486 N
< lel 0 < 0 el 0 _)NI.., < 10 0 <e 0 0 l 0 N o N
) < 10 0 N
(N

0 0 lei I \ 0 I \
N
< 10 s 492 o o o (oN
491 o 10 lµi N., 0 N-' o N
I

( 40 0 < 0 o el o 0 F \ 0 0 N N
H H

N/
0 \N 10 0 CF3 N
H H

= cF3 N/ 10 cF3 500 N/ le o o N N
H H

N/
o \ o N N
H H
o lei 00 N
0 \ 5 0 OMe N N
H H
0 la 0 0 om e 506 0 40 OMe N/

N N
H H

I
\ \ N

O \ 0 N N
H H
N
0 /..- N 0 I / )
509 N 0 / 110 510 N/ N

\ 0 N N
H H
O N''''' 0 N
511 N( 0 N 512 /

N
O \ 0 N N
H H

O 111 0 1 \
l S

N/ el N
O \ 0 N N
H H
,N
0 I \ 0 N' 1 I

\ o N\/ [01 H H
lµl o I o N HN
H
o 519 520 11 ,'-'\

1 i N
II
521 o i ) \ N 522 o \

. o N
\ ) 523 I \
s I I

INI
. i 0 I \ 0 N1 525 o 526 HN
N õ
. 0 / N 0 I

i 1 . 1 0 0 HN¨N o HN¨N o # o 21) o . 1 I
N

N 534 s HN¨N o HN¨N 0 ,,N

. i 0 I \ 0 IsV
535 o 536 I \ I
HN¨N o o HN-N
,PL
. 0 N 0 I I

el 0 F
II

I I

401o el I I

o 0 u3 o I I

=

I I

II
547 1 N 548 1 N OMe I I
/ 0 OMe / 0 N
0 N 0 ) I
549 N 550 N \ N
I I
\% 0 \% 0 O N 0 ..N
) N
I I
\% 0 \% 0 N N
553 s 554 o I I
o o O N' 1 I

I I
\% 0 \% 0 557 40 0 1 558 =
F
\ S 0 F \ S 0 559 560 o el el \ s o cF3 \ s o o 561 0 562 o el \ s o \ s o OMe O , 0 NI
I
563 I .,. N 564 1\1"
\ S 0 \ S 0 ,JA, 0 'N 0 N-) 1 N
\ S 0 \ S 0 \ s o o o O NH V o N

o 10 o F \o 10 0 CF3 o 1401 o OMe \so 10 0 OH

5730 574 =,---o 1101 N/
I \o 401 0 o 10 o F 0 0 CF3 577 ¨ 578 110 o le o OMe 0 --..,_-- 0 o 10 N/ 0 I

581 o 582 o HOO

lel 0 OMe 0 HOO HOO OH

o o F I
la 585 586 F--- lal HOO F r.,0 I F

F>A
F---,/
587 588 le F

F F

589 F_ 590 la F /,õ 40 0 OMe F----N) 0 OH
F F

F, 0 F
---/.0 0 F I 4.

o F 0 C F3 0 I 0 14.1 el o o Me 0 0 la 0 $ OH

I

o N/

O N/

I

S A
o 01 0 F 0 1 0 CF3 O N/

601 ,,-s 602 ,s o 01 o OMe \ci 10 0 OH

N /

/ I
603 604 o o N
I / <0 10 605 o 10 606 o O o F <0 * 0 CF3 O I\V 1 0 607 o 608 o 40 <so 10 o OMe <0 0 OH

<0 o N/ 610 F\ /0 0 F---% 0 I

FF.,,yo 40 Fx 0 F F * 0 CF3 0 r\V 1 0 613 F 0 SI 614 F? 10 F>.< 0 OMe \co 0 FXo 10 615 616 / lel H

I

/NI 10 618 / I.1 H H

I.

0 OMe 0 H H

o 14 N 10 H

H

N/
\ 0 F \ 10 H H

=

N
N/

0 OMe \
N N OH
H H

/

o H
I S

S
o F S 0 CF3 I.

0 OMe 0 S S OH

o S
N/

0 N. = 0 N

/ le 636 /

o F 0 CF3 el O OMe 0 o I
o V

. 1 0 N
I . i 0 N
I

. 40 1 0 NH ii i 0 o OMe HN 0 HN OH

io = i 0 1 0 i N
645 646 io N

I
0 0 tsV

I
HN¨N 0 F HN-N 0 CF3 HN¨N 0 OMe HN-N 0 OH
651 1 N 652 \ I
HN¨N 0 N
\ 0 I

\ o o F \ 0 0 CF3 IS

\ o o OMe \ 0 0 OH
o I

\ 0 0 N/
\ S

O N'''''j \ s o F \ S 0 CF3 el \ s o OMe \ S 0 OH

1.1. 0 N
N

\ s 0 1 I

O NJ

I

\--% 0 F \.% 0 CF3 O N'' 0 I.

0 OMe / 0 \..% OH

N I e I

O
N I ' = ,,i I \ 1 0 I
O NJ

I

I,N 0 F ,,1 N 0 CF3 Ilei 1,,,..,1 N 0 1\1 0 OMe OH

"-O

I

le 1101 ,,, o cF3 110 OMe ., o 680 OH

I

$0 I

10=,.., o F 684 o CF3 O OMe o OH

1o 0 OMe a 0 OH

10 o 10 o -..
I

o CF3 el O OMe 698 401 o OH

1.1 CF3 0 N

10o Ni- 700 0 o I
CF3 o N CF3 0 N

o F 702 0 .,.

0 OMe 704 SI o OH

OMe 0 N
I

100o V
0 o I
OMe 0 N
I OMe 0 N
I

o F 708 o cF3 OMe 0 N OMe 0 O

0 Me 710 o OH
OMe 0 1.1o N/ 712 1 N el F

II F

I. 714 N 0 N

715 N lei 716 N F3C

Me0 el N
719 o 720 0 .
0 IµV 0 N

0 I .

0 N-'- 1 0 N' 1 O OMe 0 O I 0 .I

el1 0 0 o o F
o o $
oo 1.1 727 el F 728 o o o o 729 730 o o c F3 o OMe O 1.1 0 .

i \ 0 I \
731 o 732s o o o1.1 Ole o 734 Oa
510 0 OMe 737 040 o SO o o el 740 o *el o o F

el O
S
o o Si:: 411 744 C) cF3 510 o OMe 1 \ 0 I \
745 010o o 746 55 o s O

o o o I
n1 0 $ OH I

ele 750 0 l 749 *10 o 0. o OH I

040 o 752 o ell V-OH I
O IµV 1 0 NH

IMO o 754 al O N. 0 N

O cF3 756 0 OMe IMO

010 o o 0o imO o 760 00 o F
0 S 0 i 761._ el F 762 o 111. o elIMO 0 763 o cF3 41110 0 OMe 0 I \ 0 i \

ella 0 s o I\V I 0 N-O I
767 768 HO 0--.....õ---O 0 CI \o 10 0 CI
-769 o 770 FF------o 10 o ci F /-0 0 CI
HOO F/' o I\I 1 0 N/
I

772 s o ci o 10 0 CI
0 .

773 o0 774 F\ /0 40 <0 o ci F---- 0 CI

O N/

I
775 / la 0 776 N N
H H

le /
o ci o ci s 0 10 # 1 o N/

I

I

I 0 N\

c-o 0 CI \s 0 CI

I

\% 0 CI N 0 CI

o CI

O CI

O CI

1 OMe 0 N

10 1 -,, CI

1110 -, O CI

IMO-.

o .

793 S.o ci Administration and Pharmaceutical Compositions [001478] Some embodiments include pharmaceutical compositions comprising:
(a) a therapeutically effective amount of a compound provided herein, or its corresponding enantiomer, diastereoisomer or tautomer, or pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier.
[001479] The compounds provided herein may also be useful in combination (administered together or sequentially) with other known agents.
[001480] Non-limiting examples of diseases which can be treated with a combination of a compound of Fonnula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, IH, III, Ma, Mb, Hie, IIId, and/or IV and other known agents are alopecia, idiopathic pulmonary fibrosis, sensorineural hearing loss (SNHL), spinal cord injury, osteoporosis, Alzheimer's disease, macular degeneration, and retinitis pigmentosa.
[001481] In some embodiments, alopecia can be treated with a combination of a compound of Formula I, Ia, Ib, Ic, Id, he, If, Ig, Ih, II, II, Ha, lib, Hc, lid, He, IH, III, Ina, Mb, Mc, IIId, and/or IV and one or more of Minoxidil (Rogaine) and Finasteride (Propecia).

[001482] In some embodiments, a composition containing a compound of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, III, III, IIIa, Mb, Hie, Hid, and/or IV could be applied after a dennatologic surgeon transplants micrografts of skin containing hair follicles. In some embodiments, the micrografts are transplanted from from one area of the scalp to another.
[001483] In some embodiments, a composition containing a compound of Formula I, Ia, Ib, Ic, Id, he, If, Ig, Ih, Ii, II, Ha, Hb, Hc, lid, He, llf, III, Ma, Mb, Mc, IIId, and/or IV could be applied after scalp reduction, which is the surgical removal of scalp skin without hair, or after flap surgery, which involves moving the scalp with hair to an adjacent area that is lacking hair.
[001484] In some embodiments, idiopathic pulmonary fibrosis can be treated with a combination of a compound of Formula I, Ia, Ib, Ic, Id, he, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, hf, III, Ma, IHb, ITIc, Hid, and/or IV and one or more of:
pirfenidone (Esbriet), prednisone, azathioprine, N-acetylcysteine, interferon gamma-lb, bosentan, Nintedanib (BIBF 1120), QAX576, and an anti-inflammatory agent such as a corticosteroids.
[001485] In some embodiments, sensorineural hearing loss (SNHL) can be treated with a combination of a compound of Formula I, Ia, Ib, Ic, Id, he, If, Ig, Ih, Ii, II, Ha, Hb, Hc, lid, He, Ill, III, ilia, IIIb, Me, IIId, and/or IV and one or more of the following therapies: (a) hair cell regeneration using stem cell and gene therapy; (b) with hearing aids; (c) with cochlear implants; (d) with idebenone or combined with vitamin E;
(e) with an anti-inflammatory agent such as a corticosteroid; or (f) with high doses of vitamins A, C, and E, and magnesium.
[001486] In some embodiments, spinal cord injury can be treated with a combination of a compound of Formula I, Ia, Ib, Ic, Id, he, If, Ig, Ih, Ii, II, Ha, Hb, He, lid, The, Hf, III, HIa, Mb, Me, Hid, and/or IV and one or more of the following therapies: (a) surgery to remove any bone fragments from the spinal canal and to stabilize the spine; (b) an anti-inflammatory agent such as a corticosteroid, such as methylprednisolone; (c) with physical therapy and/or mechanical devices; (d) with the promotion of axonal sprouting/regeneration by co-administration of hydrogels or self-assembling nanofibers; (e) by co-administration of carbon nanotubes; or (f) by co-administration of poly-lactic acid microfibers.
[001487] In some instances, a compound according to Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, hf, III, Ma, Mb, Ilic, IIId, and/or IV is administered in combination with one or more second therapeutic agents, e.g., therapeutic agents useful in the treatment of bone disorders or conditions described herein. For example, certain second therapeutic agents can promote tissue growth or infiltration, such as growth factors. Exemplary growth factors include, without limitation, epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming growth factors (TGFs), parathyroid hoimone (PTH), leukemia inhibitory factor (LIF), and insulin-like growth factors (IGFs). Other second therapeutic agents can promote bone growth, such as bone morphogenetic proteins (U.S. Pat. No. 4,761,471; PCT Pub. WO 90/11366), osteogenin [Sampath, et al., Proc. Natl. Acad. Sci. USA (1987), 84(20), 7109-7113], NaF
[Tencer, et al., Journal of Biomedical Materials Research (1989), 23(6), 571-589], and peptide sequences such as IKVAV [Tashiro, et al., The Journal of Biological Chemistry (1989), 264 (27), 16174-16182].
[001488] In some embodiments, osteoporosis can be treated with a combination of a compound of Formula I, Ia, Ile, Ic, Id, Ie, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, III, Ina, Mb, HIc, Hid, and/or IV and one or more of: Alendronate (Fosamax), Risedronate (Actonel, Atelvia), Ibandronate (Boniva), Zoledronic acid (Reclast, Zometa), Teriparatide, Raloxifene, Denosumab, and strontium ranelate.
[001489] In some embodiments, osteoporosis can be treated with a combination of a compound of Formula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, Ii, II, Ha, Hb, Hc, lid, He, Hi;
III, IIIa, tub, Me, Hid, and/or IV and one or more of the following therapies:
(a) systemic hormone therapy (e.g., estrogen); (b) estrogen in conjunction with progesterone and/or progestin; and (c) with exercise and/or nutritional changes (e.g., an increase in the intake of sources of calcium and vitamin D, and/or an increase in the intake of sources of vitamin D and/or vitamin K).
[001490] In some embodiments, Alzheimer's disease can be treated with a combination of a compound of Formula I, Ia, Ib, Ic, Id, he, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, 'If, III, Ma, Mb, Hie, Hid, and/or IV and one or more of:
cholinesterase inhibitors such as Donepezil (Aricept), Glutamine (Razadyne), and Rivastigmine (Exelon); memantine; or with production blockers to reduce the amount of beta-amyloid formed in the brain.
[001491] In some embodiments, a composition containing a compound of Formula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, Hf, III, Ma, Illb, Mc, IIId, and/or IV could be combined with immunization strategies to prevent beta-amyloid from clumping into plaques and help the body clear it from the brain.
[001492] In some embodiments, macular degeneration can be treated with a combination of a compound of Formula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, Ii, II, Ha, lib, Hc, lid, He, III, III, Ma, Mb, Mc, IIId, and/or IV and one or more of: Bevacizumab (Avastin), Ranibizumab (Lucentis), Pegaptanib (Macugen), or Aflibercept (Eylea).
[001493] In some embodiments, macular degeneration can be treated with a combination of a compound of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, Ulf, III, Ma, Mb, Mc, IIId, and/or IV and one or more of the following therapies: (a) photodynamic therapy (PDT) (in some cases in combination with a compound like verteporfin (Visudyne)); (b) laser treatment; or (c) increased vitamin intake of antioxidant vitamins and/or zinc. The following vitamins are suggested: vitamin C, vitamin E, 13-carotene (often as vitamin A), zinc (as zinc oxide), and copper.
[001494] In some embodiments, retinitis pigmentosa can be treated with a combination of a compound of Formula I, Ia, Ib, Ic, Id, he, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, III, III, IIIa, Mb, Hie, Hid, and/or IV and one or more of the following active agents or therapies: (a) vitamin A palmitate; (b) the Argus II retinal implant; (c) UF-021 (Ocuseva); (d) stem cell and/or gene therapy; or (e) Pikachurin.
[001495] Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intralymphatic, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, ontologically, neuro-otologically, intraocularly, subconjuctivally, via anterior eye chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, intrapleurally, via wound irrigation, intrabuccally, intra-abdominally, intra-articularly, intra-aurally, intrabronchially, intracapsularly, intrameningeally, via inhalation, via endotracheal or endobronchial instillation, via direct instillation into pulmonary cavities, intraspinally, intrasynovially, intrathoracically, via thoracostomy irrigation, epidurally, intratympanically, intracisternally, intravascularly, intraventricularly, intraosseously, via inigation of infected bone, or via application as part of any admixture with a prosthetic device. In some embodiments, a compound is administered orally or parenterally.
[001496] Compounds provided herein intended for pharmaceutical use may be administered as crystalline or amorphous products. Pharmaceutically acceptable compositions may include solid, semi-solid, liquid, solutions, colloidal, liposomes, emulsions, suspensions, complexes, coacervates and aerosols. Dosage forms, such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols, implants, controlled release or the like, are provided herein. The dosage forms may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, milling, grinding, supercritical fluid processing, coacervation, complex coacervation, encapsulation, emulsification, complexation, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may also be used. The compounds can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills (tablets and/or capsules), transdermal (including electrotransport) patches, implants and the like, for prolonged and/or timed, pulsed administration at a predetermined rate.
[001497] Controlled-release systems can include a component selected from the group consisting of immediate release component(s), pulsatile release component(s), delayed release component(s), sustained release component(s), and combinations thereof.
Systems may be in, for example, the form of a matrix, reservoir/membrane, osmotic pump, or hybrids thereof In some embodiments, a controlled-release system can include compounds entrapped in or otherwise incorporated into or coupled with polymer carriers or polymeric devices, such as micelles, nanoparticles, microspheres, hydrogels, and other types of polymer carriers or devices. In some embodiments, the controlled-release system delivers a compound provided herein at a controlled rate for an extended period of time.
In another embodiment, the controlled-release system localizes the action of a compound by spatial placement near where the compound is needed. In another embodiment, the controlled release system includes targeted delivery of a compound to a particular cell type.
[001498] The compounds can be administered either alone or more typically in combination with a conventional pharmaceutical carrier, excipient, diluent, or the like.
The term "excipient" is used herein to describe any ingredient other than the compound(s) provided herein. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethylene glycol 1000 succinate;
surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices; serum proteins, such as human serum albumin;
buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat.
Cyclodextrins such as a-, 13, and y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-b-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein. Dosage forms or compositions containing a compound as described herein in the range of 0.005% to 100% with the balance made up from non-toxic carrier may be prepared. The contemplated compositions may contain 0.001%-100% active ingredient, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press, London, UK. 2012).
[001499] In one embodiment, the compositions can take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, 1'13 polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like.
In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG's, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule) or as a dry powder. Unit dosage forms in which the two active ingredients are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.
[001500] In another preferred embodiment, compositions described herein are used as compound-eluting compositions (e.g., controlled release) for a medical device including, but not limited to a temporary or permanent implant, sponge, polymer, or gel.
[001501] The implant according to an embodiment of the disclosure is an orthopedic implant including, but not limited to (i) a hip joint, (ii) screws, cannulated screws, nails, meshs, cages, wires, pins, intramedullary nails, rods, posts, anchors, and plates intended to join or attach bone fragments, pieces, or parts with each other, (iii) external skeletal fixators such as monolateral, multiplanar or hybrid fixators, (iv) implants intended for treatment of degenerative instabilities, fractures, tumors, and deft:unities in respect of the spine, (v) cranio-maxillofacial implants intended for treatment of fractures, reconstruction, and correction of deformities, of mandible, mid-face, or skull, (vi) surgical stents, collagen stents, intramedullary bone stents, (vii) anterior cruciate ligament (ACL) and/or posterior cruciate ligament (PCL) Reconstruction Systems, and (viii) dental implants.
[001502] Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. a compound as provided herein and optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution, colloid, liposome, emulsion, complexes (including inclusion complexes), coacervate, or suspension. If desired, the phatmaceutical composition can also contain auxiliary substances such as wetting agents, emulsifying agents, co-solvents, solubilizing agents, pH buffering agents, and the like (e.g., sodium acetate, sodium citrate, cyclodextrins and derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).

[001503] In some embodiments, the unit dosage of compounds of Foimula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, hf, III, Ma, Mb, Mc, Md, and/or IV for oral systemic delivery is about 0.25 mg/Kg to about 50 mg/Kg.
[001504] In some embodiments, the unit dosage of compounds of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, hf, III, Ma, Mb, Mc, hid, and/or IV for systemic delivery is about 0.25 mg/Kg to about 20 mg/Kg.
[001505] In some embodiments, the unit dosage of compounds of Formula I, Ia, Ib, Ic, Id, he, If, Ig, Ih, Ii, II, Ha, Hb, He, lid, He, III, III, Ma, Mb, Me, Md, and/or IV for local delivery is about 0.050 g/Kg to about 50 g/Kg.
[001506] In some embodiments, the unit dosage of compounds of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, Ii, II, Ha, lib, Ile, lid, Ile, III*, III, Ma, Mb, Mc, Hid, and/or IV for topical delivery is about 0.1 g/cm2 to about 20 g/cm2.
[001507] In some embodiments, the unit dosage of compounds of Fommla I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, Ii, II, Ha, Hb, He, lid, He, Hf, III, Ma, Mb, Me, Hid, and/or IV is about 1.0 g/eye to about 1 mg/eye.
[001508] In some embodiments, the unit dosage of compounds of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, Hf, III, Ma, Mb, Mc, Hid, and/or IV loaded into a compound-eluting implant is about 0.1 g/Kg to about 1 mg/Kg.
[001509] In some embodiments, the unit dosage of compounds of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, lb. Ii, II, Ha, Hb, He, lid, He, Hf, III, IIIa, Mb, Ille, Hid, and/or IV for pulmonary delivery is about 1 g/dose to about 15 mg/dose.
[001510] In some embodiments, the unit dosage of compounds of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, hf, III, Ma, Mb, Me, Md, and/or IV for parenteral administration is about 0.05 mg/Kg to about 15 mg/Kg.
[001511] In some embodiments, the unit dosage of compounds of Formula I, Ia, Ib, Ic, Id, he, If, Ig, Ih, Ii, II, Ha, Hb, He, lid, Ile, Hf, III, Ma, Mb, Mc, Hid, and/or IV is about 2.0 mg/Kg to about 13 mg/Kg in humans.
[001512] In some embodiments, the unit dosage of compounds of Foimula I, Ia, Ib, Ic, Id, he, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, hIf, III, Ma, Mb, Me, Md, and/or IV is about 3.0 mg/Kg to about 12 mg/Kg in humans.

[001513] In some embodiments, the unit dosage of compounds of Foiniula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, IH, III, Ma, Mb, Mc, Hid, and/or IV is about 4.0 mg/Kg to about 11 mg/Kg in humans.
[001514] In some embodiments, the unit dosage of compounds of Folinula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, Ii, II, Ha, In, He, lid, He, Hf, III, Ma, IIlb, ilk, Hid, and/or IV is about 5.0 mg/Kg to about 10 mg/Kg in humans.
[001515] In some embodiments, the compositions are provided in unit dosage forms suitable for single administration.
[001516] In some embodiments, the compositions are provided in unit dosage forms suitable for twice a day administration.
[001517] In some embodiments, the compositions are provided in unit dosage forms suitable for three times a day administration.
[001518] Injectables can be prepared in conventional forms, either as liquid solutions, colloids, liposomes, complexes (like inclusion complexes), coacervate, or suspensions, as emulsions, or in solid forms suitable for reconstitution in liquid prior to injection. The percentage of a compound provided herein contained in such parenteral compositions is dependent on the specific disorder being treated, the activity of the compound, and the needs of the patient. However, percentages of ingredient compound of about 0.01% to about 10% in solution may be used, and could be higher if the composition is a concentrated solid or suspension, which could be subsequently diluted.
[001519] In some embodiments, a composition can comprise about 0.01 to about 10% of the compound in solution.
[001520] In some embodiments, the composition will comprise about 0.01 to about 5% of the compound in solution.
[001521] In some embodiments, the composition will comprise about 0.01 to about 4% of the compound in solution.
[001522] In some embodiments, the composition will comprise about 0.05 to about 3% of the compound in solution.
[001523] In some embodiments, the composition will comprise about 0.02 to about 2% of the compound in solution.

[001524] In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1 to about 96 hours.
[001525] In some embodiments, the compositions are provided in dosage foims suitable for continuous dosage by intravenous infusion over a period of about 1 to about 72 hours.
[001526] In some embodiments, the compositions are provided in dosage foims suitable for continuous dosage by intravenous infusion over a period of about 1 to about 48 hours.
[001527] In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1 to about 24 hours.
[001528] In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1 to about 12 hours.
[001529] In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1 to about 6 hours.
[001530] In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 1.5 mg/m2 to about 300 mg/m2.
[001531] In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 1.5 mg/m2 to about 200 mg/m2.
[001532] In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 1.5 mg/m2 to about 100 mg/m2.
[001533] In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 1.0 mg/m2 to about 50 mg/m2.
[001534] In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 50 mg/m2 to about 200 mg/m2.
[001535] In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 75 mg/m2 to about 175 mg/m2.

[001536] In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 100 mg/m2 to about 150 mg/m2.
[001537] It is to be noted that concentrations and dosage values may also vary depending on the specific compound and the severity of the condition to be alleviated. It is to be further understood that for any particular patient, specific dosage regimens can be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.
[001538] In one embodiment, the compositions can be administered to the respiratory tract (including nasal and pulmonary) e.g., through a nebulizer, metered-dose inhalers, atomizer, mister, aerosol, dry powder inhaler, insufflator, liquid instillation, or other suitable device or technique.
[001539] In some embodiments, aerosols intended for delivery to the nasal mucosa are provided for inhalation through the nose. For delivery to the nasal cavities, inhaled particle sizes of about 5 to about 100 microns can be used, for example, particle sizes of about 10 to about 60 microns. For nasal delivery, a larger inhaled particle size is can be used. In some embodiments, the larger particles may maximize impaction on the nasal mucosa or minimize or prevent pulmonary deposition of the administered formulation. In some embodiments, aerosols intended for delivery to the lungs are provided for inhalation through the nose or the mouth. For delivery to the lung, inhaled aerodynamic particle sizes of about less than 10 p.m can be used, for example, an aerodynamic particle size of about 1 to about 10 microns can be used. Inhaled particles may be defined as liquid droplets containing dissolved compound, liquid droplets containing suspended compound particles (in cases where the compound is insoluble in the suspending medium), dry particles of pure compound, compound incorporated with excipients, liposomes, emulsions, colloidal systems, coacervates, aggregates of compound nanoparticles, or dry particles of a diluent which contain embedded compound nanoparticles.
[001540] In some embodiments, compounds of Formula I, Ia, Ib, lc, Id, Ie, If, Ig, Ih, Ii, II, Ha, II13, lic, lid, fie, IIf, III, Ina, Mb, Me, IIId, and/or IV disclosed herein intended for respiratory delivery (either systemic or local) can be administered as aqueous formulations, as non-aqueous solutions or suspensions, as suspensions or solutions in halogenated hydrocarbon propellants with or without alcohol, as a colloidal system, as emulsions, coacervates, or as dry powders. Aqueous formulations may be aerosolized by liquid nebulizers employing either hydraulic or ultrasonic atomization or by modified micropump systems (like the soft mist inhalers, the Aerodose , or the AERX systems). Propellant-based systems may use suitable pressurized metered-dose inhalers (pMDIs). Dry powders may use dry powder inhaler devices (DPIs), which are capable of dispersing the compound substance effectively. A desired particle size and distribution may be obtained by choosing an appropriate device.
[001541] In some embodiments, the compositions of Formula I, Ia, Ib, Ic, Id, Ic, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, hf, III, Ma, IIIb, Hie, IIId, and/or IV
disclosed herein can be administered to the ear by various methods. For example, a round window catheter (e.g., U.S. Pat. Nos. 6,440,102 and 6,648,873) can be used.
[001542] Alternatively, fomiulations can be incorporated into a wick for use between the outer and middle ear (e.g., U.S. Pat. No. 6,120,484) or absorbed to collagen sponge or other solid support (e.g., U.S. Pat. No. 4,164,559).
[001543] If desired, formulations of the disclosure can be incorporated into a gel formulation (e.g., U.S. Pat. Nos. 4,474,752 and 6,911,211).
[001544] In some embodiments, compounds of Formula I, Ia, Ib, Ic, Id, he, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, llf, III, Ma, HIb, Hie, IIId, and/or IV
disclosed herein intended for delivery to the ear can be administered via an implanted pump and delivery system (e.g., through a needle directly into the middle or inner ear (cochlea) or through a cochlear implant stylet electrode channel or alternative prepared compound delivery channel such as but not limited to a needle through temporal bone into the cochlea).
[001545] Other options include delivery via a pump through a thin film coated onto a multichannel electrode or electrode with a specially imbedded compound delivery channel (pathways) carved into the thin film for this purpose. In other embodiments, a compound provided herein can be delivered from the reservoir of an external or internal implanted pumping system.

[001546] Formulations of the disclosure also can be administered to the ear by intratympanic injection into the middle ear, inner ear, or cochlea (e.g., U.S.
Pat. No.
6,377,849 and Ser. No. 11/337,815).
[001547] Intratympanic injection of therapeutic agents is the technique of injecting a therapeutic agent behind the tympanic membrane into the middle and/or inner ear. In one embodiment, the foimulations described herein are administered directly onto the round window membrane via transtympanic injection. In another embodiment, the ion channel modulating agent auris-acceptable formulations described herein are administered onto the round window membrane via a non-transtympanic approach to the inner ear. In additional embodiments, the foimulations described herein are administered onto the round window membrane via a surgical approach to the round window membrane comprising modification of the crista fenestrae cochleae.
[001548] In some embodiments, the compounds of Formula I, Ia, Ib, Ie, Id, le, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, IIf, III, Ma, Mb, Me, IIId, and/or IV are formulated into rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), and the like.
[001549] Suppositories for rectal administration of the compound (either as a solution, colloid, suspension, or a complex) can be prepared by mixing the compound with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt or erode/dissolve in the rectum and release the compound. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
[0015501 Solid compositions can be provided in various different types of dosage foims, depending on the physicochemical properties of the compound, the desired dissolution rate, cost considerations, and other criteria. In one of the embodiments, the solid composition is a single unit. This implies that one unit dose of the compound is comprised in a single, physically shaped solid form or article. In other words, the solid composition is coherent, which is in contrast to a multiple unit dosage form, in which the units are incoherent.
[001551] Examples of single units which may be used as dosage forms for the solid composition include tablets, such as compressed tablets, film-like units, foil-like units, wafers, lyophilized matrix units, and the like. In some embodiments, the solid composition is a highly porous lyophilized form. Such lyophilizates, sometimes also called wafers or lyophilized tablets, can be useful for their rapid disintegration, which can allow for the rapid dissolution of the compound.
[001552] In some embodiments, the solid composition may also be foimed as a multiple unit dosage form as defmed above. Examples of multiple units are powders, granules, microparticles, pellets, mini-tablets, beads, lyophilized powders, and the like. In one embodiment, the solid composition is a lyophilized powder. Such a dispersed lyophilized system comprises a multitude of powder particles, and due to the lyophilization process used in the foimation of the powder, each particle has an irregular, porous microstructure through which the powder is capable of absorbing water very rapidly, resulting in quick dissolution. Effervescent compositions are also contemplated to aid the quick dispersion and absorption of the compound.
[001553] Another type of multiparticulate system which is also capable of achieving rapid compound dissolution is that of powders, granules, or pellets from water-soluble excipients which are coated with the compound, so that the compound is located at the outer surface of the individual particles. In this type of system, a water-soluble low molecular weight excipient can be useful for preparing the cores of such coated particles, which can be subsequently coated with a coating composition comprising the compound and, in some cases, one or more additional excipients, such as a binder, a pore former, a saccharide, a sugar alcohol, a film-forming polymer, a plasticizer, or other excipients used in pharmaceutical coating compositions.
[001554] Also provided herein are kits. Typically, a kit includes one or more compounds or compositions as described herein. In certain embodiments, a kit can include one or more delivery systems, e.g., for delivering or administering a compound as provided herein, and directions for use of the kit (e.g., instructions for treating a patient).
In another embodiment, the kit can include a compound or composition as described herein and a label that indicates that the contents are to be administered to a patient with one or more of osteoporosis and osteoarthropathy; osteogenesis imperfecta, bone defects, bone fractures, periodontal disease, otosclerosis, wound healing, craniofacial defects, oncolytic bone disease, traumatic brain injuries related to the differentiation and development of the central nervous system, comprising Parkinson's disease, strokes, ischemic cerebral disease, epilepsy, Alzheimer's disease, depression, bipolar disorder, schizophrenia; otic disorders like cochlear hair cell loss; eye diseases including, but not limited to, wet age-related macular degeneration, dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, diabetic macular edema, retinal detachment, retinal degeneration, retinal vein occlusion, retinopathy of prematurity, retinitis pigmentosa, retinopathies, Leber congenital amaurosis and glaucoma, and diseases related to differentiation and growth of stem cell, comprising hair loss, hematopoiesis related diseases, tissue regeneration related diseases, and other diseases associated with abnottnalities in development, stem cell differentiation and cell proliferation.
[001555] In some embodiments, a compound-eluting coating or a controlled release system comprising a compound of Follaula I, Ia, Ib, le, Id, le, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, Hf, III, Ma, IIIb, Me, IIId, and/or IV, or a pharmaceutically acceptable salt thereof, is provided herein.
[001556] In some embodiments, a medical device comprising a compound of Formula I, Ia, Ib, Ie, Id, le, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, III, HI, Ma, HUI, Mc, IIId, and/or IV, or a pharmaceutically acceptable salt thereof, is provided herein.
[001557] In some embodiments, an implant, sponge, polymer, ointment, cream or gel composition suitable for in vivo use comprising a compound of Formula I, Ia, Ib, Ic, Id, he, If, 1g, Ih, Ii, II, Ha, Hb, He, lid, He, Ilf, III, Ma, IIIb, Me, IHd, and/or IV, or a pharmaceutically acceptable salt thereof, is provided herein.
Methods of Treatment [001558] The compounds and compositions provided herein can be used as activators of one or more members of the Wnt pathway, including one or more Wnt proteins, and thus can be used to treat a variety of disorders and diseases in which aberrant Wnt signaling is implicated, such as osteoporosis and osteoarthropathy;

osteogenesis imperfecta, bone defects, bone fractures, periodontal disease, otosclerosis, wound healing, craniofacial defects, oncolytic bone disease, traumatic brain injuries related to the differentiation and development of the central nervous system, comprising Parkinson's disease, strokes, ischemic cerebral disease, epilepsy, Alzheimer's disease, depression, bipolar disorder, schizophrenia; eye diseases including, but not limited to, wet age-related macular degeneration, dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, diabetic macular edema, retinal detachment, retinal degeneration, retinal vein occlusion, retinopathy of prematurity, retinitis pigmentosa, retinopathies, Leber congenital amaurosis and glaucoma and diseases related to differentiation and growth of stem cell, comprising hair loss, hematopoiesis related diseases, tissue regeneration related diseases and other diseases associated with abnormalities in development, stem cell differentiation and cell proliferation.
[001559] With respect to hair loss, the canonical Wnt/13-catenin signaling pathway has been linked to hair follicle development and regeneration.
Accordingly, the compounds and compositions described herein may be used topically to treat hair loss by modulation of the Wnt/13-catenin signaling pathway.
[001560] With respect to neurodegenerative diseases, Wnt/I3-catenin signal transduction system plays a role in the differentiation and development of nerve cells for the central nervous system. Consequently, the compounds and compositions described herein may be used to reactivate lost Wnt signaling function involved in neurodegeneration.
[001561] Other neurodegenerative diseases can also be treated with the compounds and compositions described herein.
[001562] More particularly, neurodegenerative diseases that may be treated by the compound, compositions and methods described herein include, but are not limited to, the following:
Parkinson's disease, schizophrenia, Huntington's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), bipolar disorder, depression, strokes, spinal cord injury, ischemic cerebral disease, epilepsy, brain damage, and spinocerebellar ataxia type 1(SCA1).

[001563] With respect to eye diseases, Wnt/f3-catenin signal transduction system is thought to regulate the maintenance of a retinal progenitor population in the ciliary marginal zone (CMZ), and thus can function as a putative stem cell factor in the retina.
[001564] Other eye diseases can also be treated with the compounds and compositions described herein.
[001565] More particularly, eye diseases that may be treated by the compound, compositions and methods described herein include, but are not limited to, the following:
wet age-related macular degeneration, dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, diabetic macular edema, retinal detachment, retinal degeneration, retinal vein occlusion, retinopathy of prematurity, retinitis pigmentosa, retinopathies, Leber congenital amaurosis and glaucoma.
[001566] With respect to diseases associated with differentiation and growth of stem cell, Wnt/I3-catenin signaling participates in the self-renewal of stem cells in many different tissues, including the skin, intestine, brain, and blood. Therefore, the compounds and compositions described herein may be used to treat disorders and diseases related to abnormalities in development.
[001567] In some embodiments, the disclosure provides a method for activating the Wnt signaling in order to treat a disorder or disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, II, Ha, lib, Hc, lid, He, hf, III, Ina, nth, Hie, IIId, and/or IV, or a pharmaceutically acceptable salt thereof.
[001568] In some embodiments, the disorder or disease is neurodegenerative disease.
[001569] In some embodiments, the neurodegenerative disease is Parkinson's disease, stroke, spinal cord injury, ischemic cerebral disease, epilepsy, Alzheimer's disease, dementia, depression, bipolar disorder, or schizophrenia.
[001570] In some embodiments, the disorder or disease is an eye disease.
[001571] In some embodiments, the eye diseases include, but are not limited to, wet age-related macular degeneration, dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, diabetic macular edema, retinal detachment, retinal degeneration, retinal vein occlusion, retinopathy of prematurity, retinitis pigmentosa, retinopathies, Leber congenital amaurosis and glaucoma.
[001572] In some embodiments, the disorder or disease is related to differentiation and growth of stem cells such as hair loss, hematopoiesis related diseases, tissue regeneration related diseases and other diseases associated with abnormalities in development, stem cell differentiation, and cell proliferation.
[001573] In some embodiments, the disorder or disease is osteoporosis, osteoarthropathy, osteogenesis imperfecta, bone defects, bone fractures, periodontal disease, otosclerosis, wound healing, mucositis (oral and gastrointestinal), craniofacial defects, and oncolytic bone disease.
[001574] In some embodiments, the patient is a mammal. In some embodiments, the patient is a human.
[001575] In some embodiments, a compound of Formula I, Ia, Ib, Ie, Id, Ie, If, Ig, Ih, Ii, II, Ha, lib, He, lid, He, hf, III, Ma, Mb, Mc, IIId, and/or IV
activates one or more proteins in the Wnt pathway.
[001576] In some embodiments, a compound of Formula I, Ia, Ib, Ie, Id, 1e, If, Ig, Ih, Ii, II, Ha, Hb, Hc, lid, He, Hf, III, Ma, IIIb, Inc, IIId, and/or IV
activates signaling induced by one or more Wnt proteins.
[001577] In some embodiments, the Wnt proteins are chosen from: WNT1, WNT2, WNT2B, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, and WNT 1 6.
[001578] In some embodiments, a pharmaceutical composition provided herein comprises a therapeutically effective amount of a compound of Formula I, Ia, Ib, Ie, Id, he, If, Ig, 1k, Ii, II, Ha, Hb, He, lid, He, Hf, III, Ma, Mb, Hie, IIId, and/or IV, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
[001579] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula I, Ia, Ib, le, Id, he, If, Ig, Ih, Ii, II, Ha, IIb, He, lid, He, Hf, III, Ma, Mb, IIIc, Hid, and/or IV, wherein the composition is suitable for use as or inclusion in a compound-eluting coating for a medical device.

EXAMPLES
Compound preparation [001580] The starting materials used in preparing the compounds of the disclosure are known, made by known methods, or are commercially available. It will be apparent to the skilled artisan that methods for preparing precursors and those compounds functionality related to the compounds provided herein are generally described in the literature. The skilled artisan given the literature and this disclosure is well equipped to prepare any of the compounds.
[001581] It is recognized that the skilled artisan in the art of organic chemistry can readily carry out manipulations without further direction, that is, it is well within the scope and practice of the skilled artisan to carry out these manipulations.
These include reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherifications, esterification and saponification and the like. These manipulations are discussed in standard texts such as March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 7th Ed., John Wiley & Sons (2013), Carey and Sundberg, Advanced Organic Chemistry 5th Ed., Springer (2007), Comprehensive Organic Transformations: A Guide to Functional Group Transformations, 2'' Ed., John Wiley & Sons (1999) and the like.
[001582] The skilled artisan will readily appreciate that certain reactions are best carried out when other functionality is masked or protected in the molecule, thus avoiding any undesirable side reactions and/or increasing the yield of the reaction.
Often the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many of these manipulations can be found for example in T. Greene and P. Wuts Protective Groups in Organic Synthesis, 4th Ed., John Wiley & Sons (2007).
[001583] Trademarks used herein are examples only and reflect illustrative materials used at the time of the invention. The skilled artisan will recognize that variations in lot, manufacturing processes, and the like, are expected. Hence the examples, and the trademarks used in them are non-limiting, but are merely an illustration of how a skilled artisan may choose to perform one or more of the embodiments of the disclosure.
[001584] (1H) nuclear magnetic resonance spectra (NMR) were measured in the indicated solvents on a Bruker NMR spectrometer (Avance TM DRX300, 300 MHz for 1H or Avance TM DRX500, 500 MHz for 1H) or Varian NMR spectrometer (Mercury 400BB, 400 MHz for 1H). Peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane. The peak multiplicities are denoted as follows, s, singlet; d, doublet; t, triplet; q, quartet; ABq, AB quartet; quin, quintet;
sex, sextet; sep, septet; non, nonet; dd, doublet of doublets; ddd, doublet of doublets of doublets; d/ABq, doublet of AB quartet; dt, doublet of triplets; td, triplet of doublets; dq, doublet of quartets; m, multiplet.
[001585] The following abbreviations have the indicated meanings:
Ac20 = acetic anhydride BBr3 = boron tribromide BF3*Et20 = boron trifluoride ethyl etherate Boc20 = di-t-butyl dicarbonate B(0iPr)3 = boron tri-isopropoxide brine = saturated aqueous sodium chloride CDC13 = deuterated chloroform CH(OMe)3 = trimethyl orthoformate Cs2CO3 = cesium carbonate CuBr2 = copper(II) bromide CuI = copper(I) iodide or cuprous iodide DCM = dichloromethane DMAP = 4-dimethylaminopyridine DMF = dimethylforamide DMSO-d6 = deuterated dimethylsulfoxide ESIMS = electron spray mass spectrometry Et0Ac = ethyl acetate HC1= hydrochloric acid HOAc = acetic acid HPLC = high-performance liquid chromatography K2CO3 = potassium carbonate LAH = lithium aluminium hydride m-CPBA = meta-chloroperoxybenzoic acid MeCN = acetonitrile Me0H = methanol MgSO4 = magnesium sulfate NaH = sodium hydride NBS = N-bromosuccinimide NMR = nuclear magnetic resonance Pd(Ph3)4 = tetrakis(triphenylphosphorus) palladium(0) PE = petroleum ether POC13 = phosphorus oxychloride TEA = triethylamine THF = tetrahydrofuran TLC = thin layer chromatography [001586] The following example schemes are provided for the guidance of the reader, and collectively represent exemplary methods for making the compounds provided herein. Furthermore, other methods for preparing compounds of the disclosure will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. The skilled artisan is thoroughly equipped to prepare these compounds by those methods given the literature and this disclosure. The compound numberings used in the synthetic schemes depicted below are meant for those specific schemes only, and should not be construed as or confused with the same numberings in other sections of the disclosure. Unless otherwise indicated, all variables are as defined above.

General procedures [001587] Compounds of Formula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, Ti, II, Ha, Hb, He, lid, He, Iff, III, Ma, Mb, Mc, Hid, and/or IV of the present disclosure can be prepared as depicted in Scheme 1.
iv 0o o HCHO, HCI Ar2CHO
, 12 Arl ' ArlN

Me2N.HCI F10,--y-I, Br Ar s_stse-\ 0 II III V
Scheme 1 [001588] Scheme 1 describes a method for the preparation of unsubstituted 1,4-diketones derivatives (V) by the modified Stetter reaction of a Mannich base as a vinyl ketone precursor with aldehyde. The Mannich base is faulted by first reacting an aryl methyl ketone (II) with paraformaldehyde and dimethylamine hydrochloride to form the 3-dimethylamino-propan- 1 -one (III). Next, Mannich base (III) was reacted with various aryl aldehydes (IV) under standard Stetter conditions using a thiazolium salt as the catalyst yields unsubstituted 1,4-diketone derivatives (V).
[001589] Compounds of Formula I, ha, Ib, Ic, Id, Ic, If, Ig, Ih, Ii, II, Ha, Hb, Hc, lid, He, Ili*, III, IIIa, Mb, Mc, Hld, and/or IV of the present disclosure can also be prepared from a methyl ketone and a-bromo ketone as depicted in Scheme 2.

1. Et2NMgBr.Et20 Ari Br.,......õ.õ--,,,A 2 ______________ AP
r 2. H2SO4, H
20 7 Arl 3. Et3N 0 iti VI v Scheme 2 [001590] Scheme 2 describes a method for the preparation of 1,4-diketones derivatives (V) by the method of Kenn and Kulinkovich [Synthesis (1996), (3), 330-2]
which is based on the application of magnesium reagents in the cross-aldol condensation of aryl methyl ketones with a-bromo ketones. An aryl methyl ketone (II) is reacted with a substituted a-bromo ketone (VI) in the presence of diethylamidomagnesium bromide and acid followed by treatment with TEA to produce the desired 1,4-diketone derivatives (V).
[001591] Compounds of Fonnula I, Ia, Ib, Ic, Id, le, If, Ig, Ih, Ii, II, Ha, Ith, Hc, lid, He, IH, III, Ma, Mb, Mc, IIId, and/or IV of the present disclosure can also be prepared from an a-bromo ketone and a 1,3-diketone as depicted in Scheme 3.
vil 0Ph 2 Br Ari)-)L Ph Ali NaOH
K2CO3, acetone, rt ' Ar2 ' Ar2 Arl Ar VI VIII V
Scheme 3 [001592] Scheme 3 describes a method for preparation of unsubstituted 1,4-diketones derivatives (V) by first reacting an a-bromo ketone (VI) with a 1,3-diketone in the presence of a mild base to form the triketone (VIII). Next, the triketone (VIII) was debenzoylated with strong base to yield unsubstituted 1,4-diketone derivatives (V).
Illustrative Compound Examples [001593] Preparation of intermediate (XVI) is depicted below in Scheme 4.
OMe 01V1e OMe OMe HO 0 HO . 0 NIBS, MeCN BrBr o nBuLi HO
NH40Ac HO K2CO3, DNIF \o B(01P03, THE \

Br Br IX X XI XII H

NaOH
OMe 0 OMe 0 OMe OMe 0 Br /CuB / c2 Ac20 ' 10 , Mel /
<
AlC13 ',0 K2CO3, Dm"' OMe OMe OMe OH
XVI XV XIV xm Scheme 4 Step 1 [001594] To a solution of 3-methoxybenzene-1,2-diol (IX) (15 g, 0.107 mol), and NH40Ac (0.83 g, 10.7 mmol) in MeCN (500 mL) was added NBS (20 g, 0.112 mol) portion wise at room temperature and stirred for an hour. The reaction mixture was concentrated under vacuum, diluted with Et0Ac (300 mL), washed with an aqueous solution of 50% NaHS03 (200 mL), and brine (200 mL). The Et0Ac layer was dried over anhydrous Na2SO4, concentrated under vacuum and purified on a silica gel column (100% DCM) to give 3-bromo-6-methoxybenzene-1,2-diol (X) (18 g, 82.2 mmol, 76%

yield) as a white solid. 1H NMR (CDC13, 500 MHz) 6 ppm 3.87 (s, 3H), 5.54 (s, 1H), 5.60 (s, 1H), 6.42 (d, J=8.78Hz, 111), 6.98 (d, J=8.78Hz, 111).
Step 2 [001595] To a solution of 3-bromo-6-methoxybenzene-1,2-diol (X) (18 g, 82.2 mmol), K2CO3 (25 g, 0.18 mol) and 1,2-dibromoethane (18.53 g, 0.98.6 mmol) in DMF
(100 mL) was stirred at 100 C for 2 h. The reaction mixture was diluted with water (300 mL) and extracted with Et0Ac (3 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over Na2504, and concentrated under vacuum. The residue was purified by column chromatography on silica gel (100% DCM) to produce 5-bromo-8-methoxy-2,3-dihydrobenzo [b][1,4]dioxine (XI) (16 g, 65.3 mmol, 80%
yield) as a white solid. 1E1 NMR (CDC13, 500 MHz) 6 ppm 3.86 (s, 3H), 4.35 (dd, J-13.05Hz, 4.27Hz, 4H), 6.42 (d, J=8.78Hz, 1H), 7.03 (d, J=8.78Hz, 1H).
Step 3 [001596] To a solution of 5-bromo-8-methoxy-2,3-dihydrobenzo [b][1,4]dioxine (XI) (16 g, 65.3 mmol) in anhydrous THE (150 mL) was slowly added n-butyllithium (31.5 mL, 78.4 mmol) dropwise at -78 C. This mixture was stirred at -78 C for an hour before adding triisopropylborate (14.8 g, 78.4 mmol) dropwise. The reaction was allowed warm to room temperature and stir overnight before quenching with 2N HC1 (100 mL).
The mixture was extracted with Et0Ac (2 x 200 mL). The combined organic layers were washed with brine, dried over anhydrous Na2504 and concentrated under vacuum.
The crude solid was recrystallized with Et0Ac/PE to yield 8-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-5-ylboronic acid (XII) (12 g, 57.1 mmol, 87.5%
yield) as a white solid. 1H NMR (CDC13, 500 MHz) 6 ppm 3.91 (s, 3H), 4.30-4.44 (m, 4H), 5.46 (s, 2H), 6.58 (d, J=8.28Hz, 1H), 7.36 (d, J=8.28Hz, 1H).
Step 4 [001597] To a solution of 8-methoxy-2,3-dihydrobenzo [b][1,4]dioxin-5-ylboronic acid (XII) (12 g, 57.14 mmol) in water (60 mL) and THF (60 mL) was added NaOH (4 g, 0.1 mmol) at 0 C and stirred for 20 min. To this clear solution was added H202 (19.4 mL, 0.17 mol) dropwise at 0 C. The reaction mixture was quenched with 50%
aqueous NaHS03 (100 mL), water (50 mL), and extracted with Et0Ac (2 x 200 mL).
The Et0Ac layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give crude 8-methoxy-2,3-dihydrobenzo [b] [1,4]dioxin-5-ol (XHI) (12 g, 57.1 mmol, quantitative yield). The crude product was used for the next step without any additional purification.
Step 5 [001598] A solution of 8-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-5-ol (XIII), K2CO3 (10 g, 70.9 mmol), and Mel (16g, 0.19mmol) in DMF (50 mL) was stirred at for 5 h. This reaction mixture was cooled, diluted with water (150 mL), and extracted with Et0Ac (2 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated under vacuum, and purified using a silica gel column (20%Et0Ac/PE) to give 5,8-dimethoxy-2,3-dihydrobenzo[b][1,4]dioxine (XIV) (3 g, 15.3 mmol, 50% yield) as a yellow oil. 1H NMR (CDC13, 500 MHz) 6 ppm 3.84 (s, 6H), 4.34 (s, 411), 6.40 (s, 2H).
Step 6 [001599] A solution of 5,8-dimethoxy-2,3-dihydrobenzo [b][1,4]dioxine (XIV) (0.75 g, 3.82 mmol), ZnC12 (3.13 g, 23 mmol) and Ac20 in CH3NO2 (25 mL) was stirred at 50 C for 1 h. The reaction mixture was cooled, diluted with Et0Ac (100 mL), and washed with brine (30 mL). The Et0Ac layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by the silica gel column (20%
Et0Ac/PE) to give 1 -(5,8-dimethoxy-2,3 -dihydrob enzo [b][1,4]dioxin-6-yeethanone (XV) (800 mg, 3.36 mmol, 88% yield) as a white solid. 11-1 NMR (CDC13, 500 MHz) 6 ppm 2.64 (s, 3H), 3.89 (d, J=3.26Hz, 6H), 4.37 (dd, J=14.56Hz, 4.77Hz, 4H), 6.96 (s, 1H).
Step 7 [001600] A solution of 1-(5,8-dimethoxy-2,3-dihydrobenzo [b][1 ,4] dioxin-6-yl)ethanone (XV) (800 mg, 3.36 mmol), CuBr2 (1.13 g, 5.04 mmol) in Et0Ac (20 mL), CHC13 (20 mL) and Me0H (1 mL) was stirred at 50-60 C for 5 h. This reaction mixture was cooled, diluted with sat aqueous NH4C1 solution (30 mL), and extracted with Et0Ac (50 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum to give a crude 2-bromo-1-(5,8-dimethoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yeethanone (XVI) (1.1 g, 3.47 mmol). The crude product was used for the next step without any additional purification.
[001601] Preparation of intermediate (XXIII) is depicted below in Scheme 5.
OH 0 OH 0 0 0")-HO BrBr Mel 40 mCPBA
K2CO3, DINH' o K2CO3, DMF DCM, 60 C

XVII XVIII
XIX XX

BF3.Et20 0 Br 0 0 * CuBr2 Mel Et0Ac, CHCI3, 50 C K2CO3, DIME

XXHI XXII XXI
Scheme 5 Step!
[001602] A solution of 1-(2,3,4-trihydroxyphenyl)ethanone (XVII) (30 g, 0.18 mol), 1,2-dibromoethane (33.52 g, 0.18 mol), and K2CO3 (74 g, 0.53 mol) in DMF
(200 mL) was stirred at 100 C for 2 h under N2. The black reaction mixture was cooled, diluted with water (1000 mL), and extracted with 40% Et0Ac/PE (3 x 300 mL).
The combined organic layers were washed with brine (3 x 50 mL), dried over Na2504 and concentrated under vacuum to give 1-(5-hydroxy-2,3-dihydrobenzo [b]
[1,4]dioxin-6-yl)ethanone (XVIII) (11g, 56.6 mmol, 33% yield) as a yellow solid. 1H NMR
(CDC13, 500 MHz) 6 ppm 2.58 (s, 3H), 4.35 (s, 41-f), 6.45 (d, J=8.78Hz, 1H), 7.28 (d, J=9.03Hz, 111), 12.86 (s, 1H).
Step 2 [001603] A solution of 1-(5-hydroxy-2,3-dihydrobenzo [b][1,4]dioxin-6-y1) ethanone (XVIII) (11 g, 56.65 mmol), K2CO3 (15.6 g, 0.113 mol) and Mel (16 g, 0.113 mol) DMF (80 mL) was stirred at room temperature for 18 h. This reaction mixture was diluted with water (300 mL), and extracted with 20% Et0Ac/PE (2 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL), dried with Na2504, and concentrated under vacuum to give 1-(5-methoxy-2,3-dihydrobenzo [b]
[1,4]dioxin-6-yl)ethanone (XIX) (11 g, 52.8 mmol, 94% yield) as a yellow oil. -1H NMR (CDCb, MHz) 6 ppm 2.60 (s, 3H), 3.93 (s, 3H), 4.32 (s, 4H), 6.67 (d, J=8.78Hz, 1H), 7.31 (d, J=9.03Hz, 1H).
Step 3 [001604] A solution of 1 -(5-methoxy-2,3 -dihydrob enzo [b][1,4] dioxin-6-yl)ethanone (XIX) (11 g, 53 mmol) and m-CPBA (55g, 0.23mo1), in DCM (120 mL), was heated to 50-60 C for 18 h. This reaction mixture was cooled and filtered.
The filtrate was diluted with DCM (250 mL) and washed with a 50% aqueous NaHS03 solution (200 mL), sat NaHCO3 (200 mL) and brine. The DCM layer was dried over anhydrous Na2SO4 and concentrated under vacuum, purified by column chromatography on silica gel (20% Et0Ac/PE) to give 5-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-y1 acetate (XX) (6 g, 26.8 mmol, 55% yield) as a white solid. Ill NMR (CDC13, 500 MHz) 6 ppm 2.31 (s, 3H), 3.85 (s, 3H), 4.19-4.43 (m, 4H), 6.49-6.56 (m, 111), 6.58-6.65 (m, 1H).
Step 4 [001605] A solution of 5-methoxy-2,3-dihydrobenzo [b][1,4]dioxin-6-y1 acetate (300 (6 g, 26.8 mmol) in HOAc (3 mL), and BF3*Et20 (6 mL) was stirred at 100 C
for 2 h. The black reaction solution was cooled down, diluted with Et0Ac (150 mL), washed with water (2 x 50 mL), sat NaHCO3 solution (50 mL), and brine (50 mL). The Et0Ac layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude 1-(7-hydroxy-8-methoxy-2,3-dihydrobenzo [b][1,4]dioxin-6-yl)ethanone (XXI) was used directly for the next step without any additional purification.
Step 5 [001606] A solution of crude 1-(7-hydroxy-8-methoxy-2,3-dihydrobenzo [b][1,4]
dioxin-6-yl)ethanone (XCI), K2CO3 (10 g, 70.9 mmol), and Mel (16g, 0.19mmol) in DMF (50 mL) was stirred at 40 C for 5 h. This reaction mixture was cooled, diluted with water (150 mL), and extracted with Et0Ac (2 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated under vacuum, and purified by column chromatography on silica gel (20% Et0Ac/PE) to produce 1-(7,8-dimethoxy-2,3-dihydrobenzo [b] [1,4]dioxin-6-yeethanone (XXII) (3 g, 12.6 mmol, 47.0% yield for two steps) as a yellow oil. 11-1 NMR (CDC13, 500 MHz) 6 ppm 2.59 (s, 3H), 3.90 (d, J=5.27Hz, 611), 4.17-4.27 (m, 2H), 4.28 - 4.41 (m, 211), 7.09 (s, 1H).
Step 6 [001607] A solution of 1-(7,8-dimethoxy-2,3-dihydrobenzo [b][1,4]dioxin-6-ye ethanone (XXII) (0.5 g, 2.1 mmol), and CuBr2 (0.562 g, 2.5 mmol) in a mixture of Et0Ac (20 mL), CHC13 (20 mL), and Me0H (1 mL) was stirred at 50-60 C for 5 h.
The reaction mixture was cooled, diluted with Et0Ac (60 mL), washed with a sat aqueous NH4C1 solution (30 mL), brine (30 mL), dried over anhydrous Na2SO4 and concentrated under vacuum to give a crude 2-bromo-1 -(7,8- dimethoxy-2,3 -dihydrob enzo [b] [1,41dioxin-6-ypethanone (Xail) as an oil (920 mg) which was used directly for the next step without any further purification.
[001608] Preparation of intermediate (XOCH) is depicted below in Scheme 6.
OMe OH OH OAc Me0 H 10 0 BBr3 O o ip AcCI
DCM K2CO3, DMF
Me0 Br HO Br Br 0 Br XXIV XXV XXVI XXVII
BF3*Et20 OMe 0 OMe 0 OH 0 CH3ONa, DMF Mel CuI, 110 C
0 OMe 11 1 Br O Br XXX XXLX XXVIII
CuBr2 OMe 0 0 Br 11.1 OMe XXXI
Scheme 6 Step 1 [001609] The mixture of 5-bromo-1,2,3-trimethoxybenzene (XXIV) (50 g, 0.2 mol) in anhydrous DCM (500 mL) was added BBr3 (167.3 g, 0.66 mol) at -78 C
dropwise while stirring. The black reaction mixture was allowed warm to room temperture and stir overnight. The reaction mixture was poured into ice water (1000 mL), and extracted with Et0Ac (2 x 1000 mL). The Et0Ac layers were dried over anhydrous Na2SO4, and concentrated to give 5-bromobenzene-1,2,3-triol (XXV) as a pale soild. (40 g, 0.195 mol, 96.4% yield) 1H NMR (DMSO-d6, 400 MHz): 6 ppm 6.40 (s, 1H), 9.28 (brs, 3H);
ESIMS
found C6H5BrO3 m/z 205.0 (M+H).

Step 2 [001610] The mixture of 5-bromobenzene-1,2,3-triol (XN) (20 g, 97.6 mmol), K2CO3 (23.8 g, 0.146 mol) and 1,2-dibromoethane (20.16 g, 107.3 mmol) in DMF
(200 mL) was stirred at 100 C for 2 h. The reaction mixture was cooled and diluted with water (600 mL), extracted with 50% Et0Ac/PE (3 x 400 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4, and concentrated under vacuo. The residue was purified by column chromatography on silica gel (20%
Et0Ac/PE) to give 7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-5-ol (XXVI) as a white solid. (4 g, 17.3 mmol, 17.7% yield) 1H NMR (CDC13, 400 MHz): 6 ppm 4.19-4.38 (m, 4H), 5.37 (brs, 1H), 6.62 (d, J=2.01Hz, 1H), 6.69 (d, J=2.01Hz, 1H); ESIMS
found C8H7BrO3 in/ z 230.9 (M+H).
Step 3 [001611] To the mixture of 7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-5-ol (XXVI) (6 g, 26.0 mmol), and TEA (5.3 g, 52 mmol) in DCM (200 mL), was added acetyl chloride (3 g, 39 mmol) at 0 C dropwise which was then stirred at room temperature for 2 h. The reaction mixture was quenched with sat. aq. NaHCO3 (200 mL), and the water layer was seperated. The DCM was washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography on silica gel (20% Et0Ac/PE) to give 7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-5-y1 acetate (XXVII) as a white solid. (6.5 g, 23.8 mmol, 91.5% yield) 1H NMR (CDC13, 400 MHz): 6 ppm 2.30 (s, 3H), 4.18-4.34 (m, 4H), 6.80 (d, J=2.26Hz, 1H), 6.94 (d, J=2.26Hz, 1H); ESIMS found C10H9BrO4 inlz 272.9 (M+H).
Step 4 [001612] The mixture of 7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-5-y1 acetate (XXVH) (6 g, 22.0 mmol) in HOAc (20 mL), and BF3*Et20 (20 mL) was stirred at 100 C for 3 h. The reaction solution was cooled, diluted with Et0Ac (250 mL), washed with water (2 x 100 mL), sat. aq. NaHCO3 solution (2 x 150 mL), and brine (100 mL).
The Et0Ac layer was dried over anhydrous Na2SO4 and concentrated. Crude 1-(7-bromo-5-hydroxy-2,3-dihydrobenzo [b] [1,4]dioxin-6-ypethan-1-one (XXVIII) was used for the next step directly without any purification. ESIMS found C10H9Bra4 m/z 273.0 (M+H).
Step 5 [001613] A solution of the 1-(7-bromo-5-hydroxy-2,3-dihydrobenzo [b][1 ,4]
dioxin-6-yl)ethan-1 -one (XCVIII), K2CO3 (6.6 g, 47.6 mmol), and Mel (6.76 g, 47.6 mmol) in DMF (50 mL) was stirred at room temperture overnight. The reaction mixture was diluted with water (150 mL) and extracted with Et0Ac (2 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated under vacuum, and purified by column chromatography on silica gel (20% Et0Ac/PE) to give 1 -(7-bromo-5 -methoxy-2,3 -dihydrobenzo [b][1,4] dioxin-6-yl)ethan-1-one (XXIX) as a yellow oil. (3 g, 10.4 mmol, 47.5% yield for 2 steps) 1H N1VIR (CDC13, 400 MHz): 6 ppm 2.50 (s, 3H), 3.83 (s, 3H), 4.20-4.37 (m, 4H), 6.87 (s, 1H); ESIMS found CI
iHi iBrat m/z 287.0 (M+H).
Step 6 [001614] A solution of 1-(7-bromo-5-methoxy-2,3-dihydrobenzo [b][1,4]dioxin-6-yl)ethan-1-one (XXIX) (800 mg, 2.79 mmol) in DMF:H20 (95:5)(16 mL) was heated at 80 C for 30 minutes. To this solution was added a solution of 25% Na0Me (1.44 g of Na in 16 mL Me0H) in four portions. The temperature of the resulting solution was raised to 110 C followed by addition of the catalyst CuBr (112 mg, 0.8 mmol).
The reaction mixture was heated under reflux for 6 h. The reaction was cooled and diluted with sat. aq. NH4C1 (40 mL), extracted with Et0Ac (2x). The combined Et0Ac layers were dried over anhydrous Na2SO4, concentrated, and purified by preparative TLC (10%
Et0Ac/PE) to give 1-(5,7-dimethoxy-2,3-dihydrobenzo [b][1,4] dioxin-6-yl)ethan-1 -one WOO as a yellow oil. (70 mg, 0.294 mmol, 10.5% yield) 111 NMR (CDC13, 400 MHz): 6 ppm 2.47 (s, 3H), 3.72 (s, 3H), 3.85 (s, 3H), 4.20-4.33 (in, 4H), 6.22 (s, 1H); ESIMS
found Ci2H1405 m/z 239.1 (M+H).

Step 7 [001615] A mixture of 1-(5,7-dimethoxy-2,3-dihydrobenzo [b][1,4]dioxin-6-yl)ethan-1-one WOO (130 mg, 0.546 mmol), CuBr2 (183 mg, 0.82 mmol) in Et0Ac (10 mL), CHC13 (10 mL) and Me0H (0.2 mL) was stirred at 50-60 C for 5 h. The reaction mixture was cooled, diluted with sat. aq. NH4C1 (30 mL), and extracted with Et0Ac (50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum to give a crude 2-bromo-1-(5,7-dimethoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-ypethan-1-one (X0(1) which directly used for the next step without further purification (170 mg). ESIMS found C121-113BrO5 mtz 317.0 (M+H).
[001616] Preparation of 1-(2,3-dihydrobenzo [b][1,4]dioxin-6-y1)-3-(dimethylamino)propan- 1 -one (XXXIII) is depicted below in Scheme 7.
HCHO, HCI
Me2N.HCI
XXXII XXXIII
Scheme 7 Step 1 [001617] A solution of 142,3 -dihydrob enzo [b][1,4]dioxin-6-ypethanone (XOCH) (4.68 g, 26.3 mmol), dimethylamine hydrochloride (2.78 g, 34.1 mmol), paraformaldehyde (1.18 g, 39.4 mmol) and 12 N HC1 (50 pt) in ethanol (8.0 mL) was refluxed overnight. The solution was cooled to room temperature and the ethanol was evaporated under vacuum. The residue was treated with Et0Ac, heated slightly and sonicated to disperse into fine particles. The solids were filtered and dried at room temperature to produce 1 -(2,3 -dihydrob enzo [b][1,4]dioxin-6-y1)-3-(dimethylamino) propan-1 -one hydrochloride as a white solid, (7.73 g, quantitative yield).
The solid was cooled in minimium about of water (12 inL) and cooled to 0 C. A 20% aqueous solution of NaOH was added until pH=10. The solution was extracted with DCM, dried and evaporated to produce 1 -(2,3 -dihydrob enzo [b][l ,4] dioxin-6-y1)-3-(dimethylamino) propan-1 -one (XXXHI) a colorless oil (2.485 g, 10.6 mmol, 40.2% yield) 111 NMR

(CDC13, 500 MHz): 6 ppm 2.77 (s, 6H), 3.41 (m, 2H), 3.56 (m, 211), 4.25 (m, 4H), 6.85 (m, 1H), 7.45 (m, 2H); ESIMS found C13H17NO3 mlz 236 (M+H).
[001618] The following intermediates were prepared in accordance with the procedure described in the above Scheme 7.

)(XXIV
[001619] 3-(Dimethylamino)-1-phenylpropan-1-one (XXXIV): Yellow oil, (3.9 g, 22.0 mmol, 52.7% yield). NMR
(DMSO-d6, 400 MHz) 6 ppm 2.81 (s, 611), 3.40 (t, J=7.6Hz, 2H), 3.65 (t, J=7.6Hz, 211), 7.58 (t, J=7.6Hz, 211), 7.70 (t, J=7.6Hz, 1I1), 8.03 (d, J=7.2Hz, 211); ESIMS found CI iHi5NO m/z 178.0 (M+H).

VOCV
[001620] 3 -(Dimethylam ino)-1 - (2-fluorophenyl)propan-1-one (XXXV): Yellow oil, (11.8 g, 60.4 mmol, 84.0% yield). ESIMS found C11ii14FN0 m/z 196.2 (M+H).
XXXII
[001621] 3 -(Dimethylamino)-1-(3 -fluorophenyl)propan-l-one (XXXVI):
Yellow oil, (10.3 g, 52.8 mmol, 72.8% yield). 1-11 NMR (CDC13, 400 MHz) 6 ppm 2.31 (s, 6H), 2.78 (t, J=7.2Hz, 211), 3.15 (t, J=7.211z, 211), 7.29 (t, 1H), 7.47 (dq, J=8.0Hz, J=2.4Hz, 111), 7.66 (d, J=9.6Hz, 1H), 7.76 (d, J-8.0Hz, 1H); ESIMS found C1iH14FNO
m/z 196.1 (M+H).
FO

XXXVII
[0016221 3-(Dimethylamino)-1-(4-fluorophenyl)propan-1-one (XXXVII):
Yellow oil, (12.0 g, 61.5 mmol, 85.0% yield). ESIMS found C iHi4FNO m/z 196.1 (M+H).

cF3 XXXVIII
[001623] 3-(Dimethylamino)-1-(2-(trifluoromethyl)phenyl)propan-1-one (XXXVIII): Yellow oil, (1.6 g, 6.5 mmol, 24.6% yield). 1H NMR (CDC13, 400 MHz) ppm 2.27 (s, 611), 2.72 (t, J=7.2Hz, 2H), 3.04 (t, J=7.2Hz, 2H), 7.47 (d, J=7.2Hz, 1H), 7.52-7.67 (m, 211), 7.72 (d, J=7.2Hz, 1H); ESIMS found C121-114F3N0 m/z 246.0 (M+H).

cF3 XXXIX
[001624] 3-(Dimethylamino)-1-(3-(trifluoromethyl)phenyl)propan-1-one (XXXIX): Yellow oil, (7.9 g, 32.2 mmol, 64.0% yield). ESIMS found C12E114F3N0 m/z 246.1 (M+H).
F3c N
XL
[001625] 3-(Dimethylamino)-1-(4-(trifluoromethyl)phenyl)propan-1-one (XL):
Yellow oil, (9.5 g, 38.7 mmol, 77.0% yield). ESIMS found C12H14F3N0 m/z 246.1 (M+H).

XLI

[001626] 3 -(Dimethylamino)-1 -(o-tolyl)propan-l-one (XLI): Yellow oil, (5.1 g, 26.7 mmol, 71.8% yield). 1H NMR (CDC13, 400 MHz) 6 ppm 2.28 (s, 6H), 2.50 (s, 3H), 2.73 (t, J=7.6Hz, 2H), 3.09 (t, J=7.6Hz, 2H), 7.27 (t, J=8.4Hz, 2H), 7.38 (t, J=7.6Hz, 1H), 7.65 (d, J=7.6Hz, 1H); ESIMS found Ci2H17N0 m/z 192.1 (M+H).

=
XLII
[001627] 3 -(Dimethylamino)-1 -(m-tolyeprop an-l-one (XLII): Yellow oil, (5.2 g, 27.2 mmol, 73.2% yield). 1H NMR (CDC13, 400 MHz) 6 ppm 2.30 (s, 6H), 2.42 (s, 3H), 2.67 (t, J=7.6Hz, 2H), 3.15 (t, J=7.6Hz, 2H), 7.31-7.43 (in, 211), 7.71-7.82 (m, 2H);
ESIMS found C12Hi7N0 m/z 192.1 (M+H).

XLIII
[001628] 3 -(Dimethylamino)-1 - (p-tolyl)propan-l-one (XLIII): Yellow oil, (5.1 g, 25.6 mmol, 71.8% yield). 1H NMR (CDC13, 400 MHz) 6 ppm 2.31 (s, 6H), 2.43 (s, 311), 2.77 (t, J=7.6Hz, 211), 3.15 (t, J=7.6Hz, 211), 7.28 (d, J=8.0Hz, 2H), 7.88 (d, J=8.0Hz, 211); ESIMS found Ci2H17N0 m/z 192.0 (M+H).
011fie XLIV
[001629] 3 -(D imethylamino)-1 - (2-methoxyphenyl)prop an-l-one (XLIV):
Yellow oil, (3.1 g, 15.0 mmol, 45.6% yield). 1H NMR (CDC13, 400 MHz) 6 ppm 2.25 (s, 6H), 2.69 (t, J=7.2Hz, 2H), 3.17 (t, J=7.2Hz, 211), 3.88 (s, 311), 6.88-7.03 (m, 211), 7.43 (t, J=7.8Hz, 1H), 7.67 (d, J=8Hz, 111); ESIMS found C1211i7NO2 m/z 208.1 (M+H).

OMe XLV
[001630] 3 -(Dimethyl amino)-1-(3 -methoxyphenyl)propan-1-one (XLV):
Yellow oil, (5.0 g, 24.1 mmol, 72.4% yield). III NMR (CDC13, 400 MHz) 6 ppm 2.32 (s, 6H), 2.79 (t, J=7.6Hz, 2H), 3.17 (t, J=7.6Hz, 2H), 3.86 (s, 3H), 7.12 (dd, J=8.4Hz, J=2.8Hz, 1H), 7.38 (t, J=8.0Hz, 1H), 7.51 (d, J=2.5Hz, 1H), 7.56 (d, J=8.0Hz, 1H);
ESIMS found C12Hi7NO2 m/z 208.1 (M+H).

Me0 XLVI
[001631] 3 -(Dimethylamino)-1-(4-methoxyphenypprop an-l-one (XLVI):
Yellow oil, (5.0 g, 24.1 mmol, 72.4% yield). 'H NMR (CDC13, 400 MHz) 6 ppm 2.29 (s, 6H), 2.74 (t, J=7.6Hz, 2H), 3.10 (t, J=7.6Hz, 2H), 3.86 (s, 3H), 6.93 (d, J=8.6Hz, 2H), 7.95 (d, J=8.6Hz, 2H); ESIMS found Ci2Hi7NO2 m/z 208.1 (M+H).

S
XINH
[001632] 3-(Dimethylamino)-1-(thiophen-2-yl)propan-1-one (XLVH): Yellow oil, (5.1 g, 27.8 mmol, 69.9% yield). 1-11 NMR (CDC13, 400 MHz) 6 ppm 2.30 (s, 6H), 2.77 (t, J=7.4Hz, 2H), 3.10 (t, J=7.4Hz, 2H), 7.14 (t, J=7.6Hz, 1H), 7.64 (dd, J=5.2Hz, J=0.4Hz, 1H), 7.74 (dd, J=4.0Hz, J=0.8Hz, 1H); ESIMS found C9H13NOS m/z 184 (M+H).

\ 0 XL VIII

[001633] 3-(Dimethylamino)-1-(furan-2-yl)propan-1-one (XLVIII): Yellow oil, (4.3 g, 25.7 mmol, 56.6% yield). 1H NMR (CDC13, 400 MHz) 6 ppm 2.27 (s, 6H), 2.73 (t, J=7.4Hz, 2H), 3.00 (t, J=7.4Hz, 211), 6.53 (td, J=3.6Hz, J=1.6Hz, 1H), 7.19 (d, J=3.6Hz, 1H), 7.58 (d, J=5.2Hz, 1H); ESIMS found C9Hi3NO2 m/z 168 (M+H).

XLIX
[001634] 3 -(Dimethylamino)-1 - (5,6,7,8-tetrahydronaphthalen-2-yl)prop an-1 -one (XLIX): White solid (7.3 g, 31.5 mmol, 93% yield). 1H NMR (DMSO-d6, 500 MHz) 6 ppm 1.75-1.77 (m, 411), 2.79 (s, 6H), 2.78-2.81 (m, 411), 3.36-3.39 (m, 2H), 3.54-3.57 (m, 211), 7.23 (d, J=7.9Hz, 1H), 7.70-7.72 (m, 211), 10.53 (brs, 1H); ESIMS
found CI5H2INO m/z 232.0 (M+H).

N
< 0 [001635] 1-(B enzo [d][1,3] dioxo1-5-y1)-3 -(dimethylamino)prop an-1 -one (L):
White solid (16.9 g, 76.4 mmol, 100% yield). 1H NMR (DMSO-d6, 500 MHz) 6 ppm 2.79 (s, 6H), 3.35-3.38 (m, 211), 3.51-3.54 (m, 211), 6.16 (s, 211), 7.09 (d, J=8.2Hz, 111), 7.49 (d, J=1.7Hz, 111), 7.67 (dd, J=1.7Hz, J=8.2Hz, 1H), 10.51 (brs, 1H);
ESIMS found C12H15NO3 m/z 221.9 (M+H).

N

LI
[001636] 1-(Chroman-6-y1)-3 -(dimethylamino)propan-1 -one (LI): White solid (3.99 g, 17.1 mmol, 99.5% yield). 1H NMR (DMSO-d6, 500 MHz) 6 ppm 1.95 (quin, J=5.80 Hz, 211), 2.77-2.85 (m, 911), 3.37 (t, J=7.14 Hz, 2H), 3.51 (t, J=7.14 Hz, 211), 4.23 (t, J=5.00 Hz, 2H), 6.86 (d, J=8 .7 8 Hz, 1H), 7.74 (dd, J=8.51, 2.47 Hz, 1H), 7.78 (d, J=2.20 Hz, 1H), 10.44 (brs, 111); ESIMS found C14Hi9NO2 m/z 234.1 (M+H).

[001637] Preparation of chromane-6-carbaldehyde (LTV) is depicted below in Scheme 8.
Br Br CHO
CHO
Me2N.HCI, TEA 40 re 1. nBuLi, THF N
Et0H, NaCNBH3 2. DMF
LII LIII LIV
Scheme 8 Step 1 [001638] To a solution of dimethylamine hydrochloride (2.25 g, 27.6 mmol) in Et0H (212 mL) was added TEA (3.84 mL, 27.6 mmol). 2-Bromobenzaldehyde (LII) (5.1 g, 27.6 mmol) was then added and the reaction was stirred overnight. NaCNBH3 (3.47 g, 55.1 mmol) was then added and the reaction stirred at room temperature for 6 h. The solvent was removed under nigh vacuum. The residue was dissolved in DCM, washed with sat. aq. NaHCO3, washed with water and then with brine, dried over MgSO4 and concentrated. The crude product was purified on a silica gel column (100%
Et0Ac--415%hexane/Et0Ac) to give 1-(2-bromopheny1)-N,N-dimethylmethanamine (LIII) as a colorless liquid (3.46 g, 16.2 mmol, 58.6% yield). 1H NMR (DMSO-d6, 500 MHz) 6 ppm 2.19 (s, 6H), 3.45 (s, 2H), 7.18-7.22 (m, 1H), 7.35-7.38 (m, 1H), 7.45 (dd, J= 1.7Hz, J=7.6Hz, 1H), 7.59 (dd, J=1.1Hz, J=8.0Hz, 1H); ESIMS found C9H12BrN
m/z 213.8 (M+H).
Step 2 [001639] To a solution of 1-(2-bromopheny1)-N,N-dimethylmethanamine (LIII) in THF (25 mL) cooled to -78 C under N, was added a 2.5M solution of nBuLi in hexane (3.37 inL, 8.42 mmol). The reaction was stirred at -78 C under N2 for 1.5 h before adding DMF (0.68 mL, 8.79 mmol). The reaction was stirred at -78 C under N2 for 1 h and then warmed to room temperature. The solvent was removed under reduced pressure and purified on a silica column (100% CHC13¨ 10%Me0H/CHC13) to produce 2-((dimethylamino)methyl)benzaldehyde (LIV) as a light yellow oil (305 mg, 1.87 mmol, 25.5% yield). 1H NMR (DMSO-d6, 500 MHz) 6 ppm 2.14 (s, 6H), 3.72 (s, 2H), 7.42 (d, J=7.6Hz, 1H), 7.45-7.48 (m, 1H), 7.57-7.59 (m, 1H), 7.78 (dd, J=1.2Hz, J=7.6Hz, 1H), 10.34 (s, 1H); ESIMS found C91-112BrN m/z 163.9 (M+H).
[001640] Preparation of chromane-6-carbaldehyde (LVII) is depicted below in Scheme 9.
Zn POCI3 H (00 AcOH ______________________ a. el DMF

LV LVI LVII
Scheme 9 Step 1 [001641] To a suspension of zinc dust (100 g, 1.56 mol) in HOAc (300 mL) was added chroman-4-one (LV) (10 g, 67.6 mol). The mixture was stirred at 110 C
for 6 h.
Then the mixture was cooled and filtrated. The filtrate was poured into water (500 mL) and extracted with Et0Ac (3 x 100 mL). The organic layer was concentrated to give chromane (LVI) as colorless oil. (8.05 g, 60.0 mmol, 88.7% yield). 1H NMR
(CDC13, 400 MHz) 6 ppm 2.04 (q, J=4.3Hz, 211), 2.81 (t, J=6.6Hz, 2H), 4.21 (t, J=5.2Hz, 211), 6.72-6.92 (m, 2H), 7.00-7.17 (m, 2H); ESIMS found C9H100 m/z 135.0 (M+H).
Step 2 [001642] To a solution of chromane (LVI) (3 g, 22.4 mmol, 1.0 eq) and DMF
(3.3 g, 45.2 mmol, 2 eq) in DCE (20 inL) was added phosphorus oxychloride (3.4 g, 45.2 mmol, 2 eq) dropwise over 30 min below 50 C. The mixture was stirred at 85 C
for 12 h.
The reaction was quenched by water and extracted with Et0Ac (3 x 300 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (PE:Et0Ac=8:1) to give chromane-6-carbaldehyde (LVII) as yellow oil. (2.0 g, 12.3 mmol, 55.1% yield).

NMR (CDC13, 400 MHz) 6 ppm 2.01 (q, J=45.8Hz, 211), 2.82 (t, J=6.4Hz, 2H), 4.24 (t, J=5.2Hz, 2H), 6.85 (d, J=8.4Hz, 1H), 7.52-7.64 (m, 2H), 9.79 (s, 111); ESIMS
found Ci0H1002 m/z 163.1 (M+H).

[001643] Preparation of benzo[d]oxazole-5-carbaldehyde (LXI) is depicted below in Scheme 10.
Br 1110 OH 0 0 0 CH(OMe)3 I:01 1.0, DCM 0 1 reflux Cs2CO3, Pd(PPh3)4 2. Et3N ). 0 1 >
NH2 Br dioxane, H20 LVM LIX LX LXI
Scheme 10 Step 1 [001644] A solution of 2-amino-4-bromophenol (LVIII) (10 g, 53.5 mmol, 1 eq) in trimethyl orthofoimate (200 mL) was stirred at reflux for 2 h. After cooling, the solution was concentrated under reduced pressure to remove trimethyl orthoformate to give 5-bromobenzo [d] oxazole (LIX) (10.06 g, 50.8 mmol, 95.0%). Used in the next reaction without additional purification.
Step 2 [001645] To a suspension of 5-bromobenzo [d] oxazole (LIX) (10.06 g, 50.8 mmol, 1 eq) in dioxane (200 mL) and water (10 mL) was added potassium (ethenyl)trifluoroborate (8.17 g, 61 mmol, 1.2 eq), cesium carbonate (13.8 g, 101.6 mmol, 2 eq) and tetrakis(triphenylphosphorus) palladium(0) (2.9 g, 2.54 mmol, 0.05 eq).
The mixture was stirred at reflux under nitrogen for 5 h. The mixture was then poured onto ice-water (200 mL) and extracted with Et0Ac (3 x 300 mL). The organic phases were combined, dried over anhydrous Na2SO4, filtered and concentrated in vacuo, the residue was purified by chromatography on silica gel (PE:Et0Ac = 20:1¨>10:1) to afford 5-vinylbenzo[d]oxazole (LX) (6.11 g, 42.1 mmol, 82.9%) as an oil. Used in the next reaction directly without additional purification.
Step 3 [001646] To a solution of 5-vinylbenzo[d]oxazole (LX) (6.1 g, 42.1 mmol, 1.0 eq) in DCM (100 mL) was bubbled ozone at -78 C until the solution turn to blue. The solution was then purged with 02 followed by N2 for 5 minutes. TEA (12.8 g, 126.3 mmol, 3 eq) was added and the mixture was stirred at 25 C for 1 h. The solution was poured into water (200 mL) and extracted with Et0Ac (3 x 300 mL). The combined organic phase was dried, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted (PE:Et0Ac = 10:1¨>1:1) to give benzo[d]oxazole-5-carbaldehyde (LXI) (2.1 g, 14.3 mmol, 33.9%) as a colorless oil. 11-1 NMR
(CDC13, 400 MHz) 8 ppm 7.75 (d, J=8.4Hz, 111), 8.02 (dd, J=8.4Hz, J=1.2Hz, 1H), 8.22 (s, 1H), 8.33 (s, 1H), 10.13 (s, 1H); ESIMS found C8H5NO2 m/z 148.0 (M+H).
[001647] Preparation of 2,3-dihydrobenzo [b][1 ,41 oxathiine-6-carbaldehyde (LXIV) is depicted below in Scheme 11.
SH OHC
BrBr POCI3,DMF
K2CO3, acetone E

LXII LXIII LXIV
Scheme 11 Step 1 [001648] To a solution of 2-mercaptophenol (LXII) (10 g, 79 mmol, 1.0 eq) in acetone (500 mL) was added potassium carbonate (21.8 g, 158 mmol, 2 eq) and 1,2-dibromoethane (14.92 g, 79 mmol, 1 eq) in acetone (100 mL) dropwise over 3 h.
The mixture was stirred at 30 C for 12 h. The solid was filtered off and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (100%
PE) to give 2,3-dihydrobenzo[b][1,4]oxathiine (LXIII) as colorless oil. (4.02 g, 26.4 mmol, 33.3%) as a colorless oil. 111 NMR (CDC13, 400 MHz) 6 ppm 3.14 (t, J=4.6Hz, 2H), 4.43 (t, J=4.6Hz, 2H), 6.71-6.92 (m, 2H), 7.02 (td, J=7.6Hz, J=1.6Hz, 1H), 7.07 (dd, J=7.6Hz, J=1.2Hz, 1H); ESIMS found C8H8OS m/z 153.0 (M+H).
Step 2 [001649] To a solution of 2,3-dihydrobenzo[b][1,4]oxathiine (LXIII) (4 g, 26.3 mmol, 1.0 eq) and DMF (7.2 g, 47.2 mmol, 2 eq) in DCE (20 mL) was added phosphorus oxychloride (3.4 g, 47.2 mmol, 2 eq) dropwise over 30 minutes below 50 C. The mixture was stirred at 85 C for 12 h. The reaction was quenched by water and extracted with Et0Ac (3 x 300 mL). The combined organic phase was dried, filtered and concentrated in vacuo, the residue was purified by chromatography on silica gel (PE:Et0Ac =
10:1--45:1) to give 2,3-dihydrobenzo[b][1,4]oxathiine-6-carbaldehyde (LXIV) as yellow oil.
(300 mg, 1.67 mmol, 6.3%) as a colorless oil. 1H 1\11VIR (CDC13, 400 MHz) 6 ppm 3.15 (t, J=4.6Hz, 2H), 4.50 (t, J=4.6Hz, 2H), 6.92 (d, J=8.411z, 1H), 7.51 (dd, J=8.8Hz, J=2.0Hz, 1H), 7.59 (s, 1H), 9.80 (s, 1H); ESIMS found C9H802S miz 181.1 (M+H).
[001650] Preparation of 2,3 -dihydrob enzo [b] [1 ,4] dioxine-5-carbaldehyde (LXVI) is depicted below in Scheme 12.

Br OH K2CO3, acetone LXV LXVI
Scheme 12 Step 1 [001651] To a solution of 2,3-dihydroxybenzaldehyde (LXV) (5 g, 36.2 mmol, 1.0 eq) in acetone (300 mL) was added potassium carbonate (10 g, 72.5 mmol, 2 eq) and 1,2-dibromoethane (6.8 g, 36.2 mmol, 1 eq) in acetone (50 tut) dropwise over 2 h. The mixture was stirred at 30 C for 12 h. The solid was filtered off, the filtrate was concentrated in vacuo and purified by chromatography on silica gel (PE:Et0Ac=10:1) to give 2,3-dihydrobenzo [b] [1,4]dioxine-5-carbaldehyde (LXVI) as a colorless oil. (4.02 g, 26.4 mmol, 68%) ESIMS found C91i1803 in/z 165.0 (M+H).

[001652] Preparation of benzo[b]thiophene-5-carbaldehyde (DM) is depicted below in Scheme 13.

Br NC
Zn(CN)2, Pd(PPh3)4 \ Li0H, H2O I.. HO
DMF, 120 C 120 C
LXVII LXVIII LXIX
LiAIH4 THF
e- MnO2, DCM HO
S
LXXI LXX
Scheme 13 Step 1 [001653] A solution of 5-bromobenzo[b]thiophene (LXVII) (1.2 g, 6 mmol), zinc cyanide (0.66 g, 6 mmol) and tetrakis(triphenylphosphorus)palladium (0) (0.65 g, 0.6 mmol) in dry DMF (10 mL) was stirred at reflux under nitrogen atmosphere for 1 h.
The mixture was poured into cold water and extracted with Et0Ac (3x). The combined organic layers were concentrated in vacuum to give the crude benzo[b]thiophene-carbonitrile (LXVIII) as a white solid. (0.90 g, 6 mmol, 100%) ESIMS found miz 160.0 (M+H).
Step 2 [001654] A suspension of benzo[b]thiophene-5-carbonitrile (LXVIII) (0.9 g, 5.1 mmol) and LiOH (10 g, 0.24 mol) in water (50 ml) was stirred at reflux for 2 h. The reaction was washed with water, acidified to pH 3 with 1M HC1 and extracted with Et0Ac. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentracted in vacuum to give the crude benzo[b]thiophene-5-carboxylic acid (LXIX) as a white solid. (0.9 g, 5.1 mmol, 88.6%) ESIMS found C9H6025 miz 179.1 (M+H).

Step 3 [001655] To a solution of benzo[b]thiophene-5-carboxylic acid (LXIX) (0.9 g, 5.1 mmol) in THF (20 mL) was added LAH (0.28 g, 7mmol) in portions at 0 C
under nitrogen atmosphere. The reaction was quenched by water, washed with 20% aq.
NaOH
(4 rnL) and extracted with Et0Ac. The Et0Ac phase was concentrated in vacuo to give the crude benzo[b]thiophen-5-ylmethanol (L)(X) as yellow solid. (-1 g, used without further purification) ESIMS found C9H8OS m/z 165.0 (M+H).
Step 4 [001656] To a solution of benzo[b]thiophen-5-ylmethanol (DOC) (-1 g, crude) in DCM (20 mL) was added manganese oxide (6.36 g, 0.07 mol). The mixture was stined at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (PE:
Et0Ac=10:1) to give benzo[b]thiophene-5-carbaldehyde (DM) as an orange solid. (570 mg, 3.51 mmol, 68.9% yield for 2 steps) 1H NMR (DMSO-d6, 400 MHz) 6 ppm 7.68 (d, J=5.2Hz, 1H), 7.85 (d, J=8.4Hz, 1H), 7.95 (d, J=5.2Hz, 11I), 8.23 (d, J=8.4Hz, 1H), 8.48 (s, 1H), 10.11 (s, 1H); ESIMS found C9H6OS m/z 163.0 (M+H).
[001657] Preparation of tert-butyl 5-founy1-1H-benzo[d]imidazole-1-carboxylate (L)(XIII) and tert-butyl 6-formy1-1H-benzo[d]imidazole-1-carboxylate (LXXIV) is depicted below in Scheme 14.
Boc N CHO CHO CHO
(Boc)20, DMAP e DCM
LXXII B() LXXIII LXXIV
Scheme 14 Step 1 [001658] A solution of 1H-benzo [d] imidazole-5-carbaldehyde (LXXII) (787 mg, 4.92 mmol, 1 eq) in DCM (5 mL) was added Boc20 (1.13 g, 5.2 mmol, 1.05 eq) and DMAP (60 mg, 0.492 mmol, 0.1 eq). The mixture was then stirred at 25 C for 30 minutes before being poured into water (100 mL) and extracted with EtOAc (3 x 100 mL), the organic phases were combined, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a mixture of tert-butyl 5-formy1-1H-benzo[d]imidazole-1-carboxylate (LXXIII) and tert-butyl 6-formy1-1H-benzo[d]imidazo1e-1-carboxylate (LXXIV) as a white solid. (850 mg, 63.5%) 1H NMR (CDC13, 400 MHz) 6 ppm 1.73 (s, 9H), 7.93 (s, 1H), 7.98 (dd, J=8.4Hz, J=1.2Hz, 1H), 8.16 (d, J=8.4Hz, 1H), 8.30 (s, 1H), 8.55 (s, 1H), 8.60 (s, 1H), 10.12 (s, 1H); ESIMS found Ci3Hi4N203 m/z 247.1 (M+H).
[001659] The following intermediates were prepared in accordance with the procedure described in the above Scheme 14.
CHiO
/N
Boi LXXV
[001660] tert-Butyl 5-foliny1-1H-indole-1-carboxylate (LXXV): White solid, (8.5 g, 34.7 mmol, 50.3% yield). 1H NMR (CDC13, 400 MHz) 6 ppm 1.70 (s, 9H), 6.70 (d, J=4.0Hz, 1H), 7.70 (d, J=4.0Hz, 1H), 7.87 (dd, J=8.8Hz, J=1.6Hz, 1H), 8.11 (s, 1H), 8.30 (d, J=8.8Hz, 1H), 10.08 (s, 1H); ESIMS found C14H15NO3 m/z 246.1 (M+H).
N/ 1:0 CHO
Bo1 LXXVI
[001661] tert-Butyl 5-formy1-1H-indazole-1-carboxylate (LXXVI): White solid, (1.8 g, 7.3 mmol, 93.3% yield). 1H NMR (CDC13, 400 MHz) 6 ppm 1.76 (s, 9H), 8.10 (d, J=8.8Hz, 1H), 8.30 (s, 1H), 8.34 (s, 1H), 8.35 (d, J=8.8Hz, 1H), 10.13 (s, 1H); ESIMS
found Ci3Hi4N203 m/z 247.1 (M+H).
CHO CHO
1101 \11N N¨Boc 1µ
Boc DOWlla & b [001662] tert-Butyl 3-formy1-1H-indazole-1-carboxylate (LXXVIla) and tert-butyl 3-formy1-2H-indazole-2-carboxylate (LXXVIIb): White solid, (1.6 g, 6.5 mmol, 38.1% yield). 1H NMR (CDC13, 400 MHz) 6 ppm 1.77 (s, 9H), 7.45 (t, J=7.4Hz, 1H), 7.60 (t, J=7.4Hz, 1H), 8.18 (d, J=8.4Hz, 1H), 8.32 (d, J=8.4Hz, 1H), 10.34 (s, 111);
ESIMS found C13H14N203 m/z 247.1 (M+H).
Example 1 [001663] Preparation of 1 -(2,3 -dihydrobenzo [b][1 ,4] dioxin-6-y1)-4 -(3 -(trifluoromethyl)phenyebutane-1,4 -dione (1) is depicted below in Scheme 15.

40 CHO XXVill TEA, 85 LC 0 XXXIII
sji 1 Scheme 15 Step 1 [001664] To a solution of 1-(2,3-dihydrobenzo [b][1,4] dioxin-6-y1)-3 -(dimethylamino)propan- 1 -one (XXXIII) (1.05 g, 4.4 mmol) and 2-(trifluoromethyl) benzaldehyde (LXXVIII) (703 tit, 5.3 mmol) in TEA (2.0 mL, 14.2 mmol) and was added 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (336 mg, 1.3 mmol). The solution was -heated overnight at 85 C. The solution was cooled and excess solvent was evaporated under vacuum. The residue was partitioned between Et0Ac and water.
The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by silica gel flash chromatography using (100% hexane¨>Et0Ac/hexane=1:9) to yield 1-(2,3 -dihydrobenzo [b][1 ,4] dioxin-6-y1)-4-(3-(trifluoromethyephenyebutane-1,4-dione 1 as an opaque oil (127.3 mg, 0.35 mmol, 7.8% yield). 111 NMR (DMSO-d6, 500 MHz) ppm 3.22-3.25 (m, 2H), 3.33-3.35 (m, 2H), 4.29-4.30 (m, 2H), 4.33-4.35 (m, 2H), 6.99 (d, J=8.4Hz, 1H), 7.50 (d, J=2.2Hz, 1H), 7.55 (dd, J=8.4Hz, J=2.0Hz, 1H), 7.72-7.75 (m, 1H), 7.82-7.86 (m, 2H), 7.94 (d, J=7.5Hz, 1H); ESIMS found C19H15F304 m/z 365 (M+H).
[001665] The following compounds were prepared in accordance with the procedure described in the above Example 1.

[001666] 1 -(2,3 -dihydrobenzo [b] [1,4] dioxin-6-y1)-4-(3 -fluorophenyl)butane-1,4-dione 2.
[001667] White solid (308.2 mg, 0.98 mmol, 10.4% yield). 1H NMR (DMSO-d6, 500 MHz) 6 ppm 3.29-3.33 (m, 2H), 4.29-4.30 (m, 214), 4.33-4.34 (m, 2H), 6.99 (d, J=8.5Hz, 1H), 7.34-7.39 (m, 2H), 7.47 (d, J=2.1Hz, 111), 7.54 (dd, J=8.5Hz, J=2.1Hz, 1H), 7.67-7.69 (m, 1H), 7.82-7.86 (m, 1H); ESIMS found C18H15F04 m/z 315.0 (M+H).
cF3 o [001668] 1 -(2,3 -Dihydrob enzo [b][1,4] dioxin-6-y1)-4-(3 -(trifluoromethyl) phenyl)butane-1,4-dione 9.
[001669] White solid (30 mg, 0.08 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.39-3.48 (m, 414), 4.30 (d, J=5.2Hz, 211), 4.34 (d, J=5.211z, 2H), 6.94 (AA'BB'quartet, 111), 7.77-7.61 (in, 211), 7.64 (t, J=8Hz, 111), 7.84 (d, J=8Hz, 1H), 8.23 (d, J=8Hz, 111), 8.29 (s, 1H); ESIMS found CI9H15F304 m/z 365.0 (M+H).
cF3 o [001670] 1-(2,3-Dihydrobenzo[b][1 ,4]dioxin-6-y1)-4-(4-(trifluoromethyl) phenyl)butane-1,4-dione 10.
[001671] White solid (25 mg, 0.07 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.45 (s, 4H), 4.32 (d, J=5.211z, 2H), 4.35 (d, J=5.2Hz, 211), 6.96 (AA'BB' quartet, 111), 7.56-7.64 (m, 2H), 7.77 (d, J=8.4Hz, 2H), 8.16 (d, J=8Hz, 2H); ESIMS found Ci9Hi5F304 m/z 365.1 (M+H).

[001672] 1-(2,3 -Dihydrobenzo [b] [1,4] dioxin-6-y1)-4- (3 -fluorophenyl)butane-1,4-dione 11.
[001673] White solid (35 mg, 0.11 mmol). 1H NMR (CDC13, 400 MHz) 8 ppm 3.42 (s, 4H), 4.31 (t, J=5.6Hz, 2H), 4.35 (t, J=5.611z, 2H), 6.95 (AA'BB'quartet, 1H), 7.27-7.32 (m, 1H), 7.48 (q, J=5.6Hz, 1H), 7.60 (dd, J=4Hz, J=2.4Hz, 2H), 7.73 (d, J=9.2Hz, 1H), 7.85 (d, J=8Hz, 1H); ESIMS found Ci8H15F04 m/z 314.9 (M+H).

o 0 OMe [001674] 1-(2,3-Dihydrobenzo[b] [1,4] dioxin-6-y1)-4-(2-methoxyphenyl)butane-1,4-dione 12.
[001675] White solid (20 mg, 0.06 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.33 (t, J=6.4Hz, 2H), 3.43 (t, J=6.4Hz, 2H), 3.93 (s, 3H), 4.24-4.38 (m, 4H), 6.92 (AA'BB'quartet, 1H), 6.95-7.07 (m, 2H), 7.47 (dt, 1H), 7.53-7.62 (m, 2H), 7.76 (dd, J=1.6Hz, J=7.6Hz, 1H); ESIMS found C19111805 m/z 327.0 (M+H).
OMe qr [001676] 1 -(2,3 -Dihydrob enzo [b] [1,4] dioxin-6-y1)-4-(3 -methoxyphenyl)butane-1,4-dione 13.
[001677] White solid (13 mg, 0.04 mmol). 1H NMR (CDC13, 400 MHz) 8 ppm 3.37-3.43 (m, 2H), 3.43-3.48 (m, 2H), 3.88 (s, 3H), 4.29-4.33 (m, 2H), 4.33-4.37 (in, 2H), 6.95 (AA'BB'quartet, 1H), 7.12 (dd, J=4Hz, J=8.8Hz, 1H), 7.41 (t, J=7.6Hz, 2H), 7.56 (t, J=2.4Hz, 1H), 7.57-7.62 (m, 2H), 7.66 (d, J=8.4Hz, 1H); ESIMS found m/z 327.1 (M+H).

o cF3 o [001678] 1 -(2,3 -Dihydrob enzo [b][1,4] oxathiin-6-y1)-4-(2-(trifluoromethyl) phenyl)butane-1,4-dione 16.
[001679] Yellow oil (16 mg, 0.04mmol). 111 NMR (CDC13, 400 MHz) 6 ppm 3.13-3.19 (m, 2H), 3.22-3.30 (m, 2H), 3.36-3.45 (m, 2H), 4.47-4.55 (m, 2H), 6.89 (d, J=8.58Hz, 1H), 7.57 (t, J=7.76Hz, 1H), 7.62-7.80 (m, 5H); ESIMS found m/z 380.9 (M+H).
0 cF3 s õ3 [001680] 1-(2,3-Dihydrobenzo [b] [1,4]oxathiin-6-y1)-4-(4-(trifluoromethyl) phenyl)butane-1,4-dione 18.
[001681] White solid (52 mg, 0.14 mmol). 1H NMR (DMSO-d6, 400 MHz) 6 ppm 3.24 (dd, J=5.27Hz, J=4.02Hz, 2 H), 3.36-3.39 (m, 2H), 3.39-3.45 (m, 2H), 4.39-4.49 (m, 2H), 6.95 (d, J=8.53Hz, 1H),7.67 (dd, J=8.66Hz, J=2.13Hz, 1H), 7.77 (d, J=2.01Hz, 1H), 7.93 (d, J=8.28Hz, 2H), 8.21 (d, J=8.28Hz, 2H); ESIMS found CI9F115F303S m/z 380.9 (M+H).

=
0 wr 0 F

[001682] 1 -(2,3 -D ihydrob enzo [b] [1,4] oxathiin-6-y1)-4-(2-fluorophenyl)butane-1,4-dione 19.
[001683] Yellow oil (11 mg, 0.03 mmol). 111 NMR (CDC13, 400 MHz) 6 ppm 3.14-3.18 (m, 2H), 3.34-3.40 (in, 2H), 3.41-3.45 (m, 2H), 4.47-4.52 (m, 2H), 6.88 (d, J=8.53Hz, 1H), 7.12-7.20 (m, 1H), 7.24 (td, J=7.76, 1.00Hz, 1H), 7.47-7.58 (m, 2H), 7.69 (dd, J=8.53, 2.26Hz, 1H), 7.78 (d, J=2.01Hz, 1H), 7.91 (td, J=7.65, 2.01Hz, 1H);
ESIMS found C181-115F03S m/z 330.9 (M+H).
F

[001684] 1-(2,3-Dihydrobenzo [b] [1,4]oxathiin-6-y1)-4-(4-fluorophenyl)butane-1,4-dione 21.
[0016851 White solid (15 mg, 0.05 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.15-3.20 (m, 2H), 3.38-3.43 (m, 4H), 4.49-4.58 (m, 2H), 6.90 (d, J=8.53Hz, 1H), 7.12-7.21 (m, 2H), 7.70 (dd, J=8.53Hz, J=2.26Hz, 1H), 7.80 (d, J=2.01Hz, 1H), 8.05-8.11 (m, 2H); ESIMS found Ci7H15N04 m/z 330.9 (M+H).

[001686] 1-(2,3-Dihydrobenzo [b] [1,4] oxathiin-6-y1)-4-phenylbutane-1,4-dione 28.
[001687] White solid (8 mg, 0.03 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.14-3.20 (m, 2H), 3.36-3.43 (m, 2H), 3.43-3.49 (m, 2H), 4.48-4.56 (m, 2H), 6.90 (d, J=8.53Hz, 1H), 7.46-7.53 (m, 2H), 7.57-7.63 (m, 1H), 7.71 (dd, J=8.53Hz, J=2.26Hz, 1H), 7.81 (d, J=2.26Hz, 1H), 8.02-8.10 (m, 2H); ESIMS found Ci8f11603S m/z 312.9 (M+H).
o 0 0 Me [0016881 1-(Chroman-7-y1)-4-(2-methoxyphenyebutane-1,4-dione 61.
[001689] Yellow oil (30 mg, 0.09 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 2.84 (t, J=6.40Hz, 2H), 3.31-3.38 (m, 2H), 3.40-3.48 (m, 2H), 3.93 (s, 3H), 4.21-4.29 (m, 2H), 6.83 (d, J=8.281-1z, 111), 6.95-7.08 (m, 2H), 7.4207.52 (m, 1H), 7.74-7.83 (m, 31-1);
ESIMS found C20112004 miz 325.0 (M+H).
0 .õ
IP

[001690] 1-(Chroman-6-y1)-4-(2-(trifluoromethypphenyl)butane-1,4-dione 68.
[001691] Yellow oil (35 mg, 0.10 rrnnol). 11-1 NMR (CDC13, 400 MHz) 6 ppm L99-2.08 (m, 2H), 2.84 (t, J=6.40Hz, 2H), 3.27 (t, J=6.04Hz, 2H), 3.43 (t, J=7.32Hz, 2H), 4.26 (t, J=5.28Hz, 2H), 6.84 (dõ/-8.15Hz, 1H), 7.57 (tõ/-7.52Hz 1H), 7.66 (t, J-7.52Hz, 1H), 7.69-7.83 (m, 4H); ESIMS found C20HI7F303 mlz 363.0 (M+H).
cF3 o [001692] 1-(Chroman-6-y1)-4-(3-(tritluoromethyl)phenyl)butane-1,4-dione 69.
[001693] White solid (52 mg, 0.14 mmol). II-1 NMR (DMSO-d6, 400 MHz) 6' ppm 1.90-2.03 (m, 2H), 2.82 (t, J=6.40Hz, 2H), 3.37 (d, J=2.76Hz, 2H), 3.41-3.48 (m, 1H), 4.19-4.29 (m, 2H), 6.85 (dõ/-8.53Hz, 1H), 7.75 (dd, J-8.53Hz, J=2.26Hz, 1H), 7.78-7.85 (m, 2H), 8.05 (d, J=7.78Hz, 1H), 8.26 (s, 1H), 8.34 (d, J=7.78Hz, 1H); ESIMS
found C201-117E303 inlz 363.1 (M+1-1).

[001694] 1-(Chroman-6-y1)-4-(2-fluorophenyl)butane-1,4-dione 71.
[001695] White solid (20 mg, 0.06 rnmol). II-1 NMR (CDC13, 400 MHz) 6 ppm 1.98-2.11 (m, 2H), 2.85 (t, J=6.8Hz, 2H), 3.34-3.48 (ni, 4H), 4.26 (t, J=5.6Hz, 2H), 6.84 (d, J-8.4Hz, 1H), 7.16 (ABX quartet, 1H), 7.24 (tõ/-7.6Hz, 1H), 7.47-7.58 (m, 1H), 7.78 (s, 1H), 7.81 (d, J=2Hz, 1H), 7.91 (dt, J=1.6Hz, J=7.6Hz, 111); ESIMS found in/z 313.0 (M+H).
0 OMe [001696] 1 -(Chroman-6-y1)-4-(4-methoxyphenyObutane-1,4-dione 76.
[001697] White solid (20 mg, 0.06 mmol). 11-1 NMR (CDC13, 400 MHz) 6 ppm 2.04 (quin, J=6Hz, 2H), 2.84 (t, J=6.4Hz, 2H), 3.33-3.46 (m, 4H), 3.89 (s, 3H), 4.26 (t, J=5.6Hz, 2H), 6.84 (d, J=8.8Hz, 1H), 6.96 (d, J=8.8Hz, 2H), 7.80 (A2X doublet, 2H), 8.03 (d, J=8.8Hz, 2H); ESIMS found C20H2004 miz 325.0 (M+H).
OS
[001698] 1-(Chroman-6-y1)-4-phenylbutane-1,4-dione 80.
[001699] White solid (16 mg, 0.05 mmol). 11-1 NMR (CDC13, 400 MHz) 6 ppm 2.05 (q, J=6.4Hz, 2H), 2.85 (t, J=6.4Hz, 2H), 3.41 (d, J=5.6Hz, 2H), 3.44 (d, J=5.2Hz, 2H), 4.26 (t, J=5.2Hz, 2H), 6.84 (d, J=8.4Hz, 1H), 7.49 (t, J=7.6Hz, 2H), 7.58 (t, J=7.6Hz, 1H), 7.81 (d, J=9.2Hz, 2H), 8.05 (d, J=7.2Hz, 2H); ESIMS found CI9H1803 in/z 295.0 (M+H).
<0o =
0 cF3 [001700] 1-(Benzo [d][1,3]dioxo1-5-y1)-4-(2-(trifluoromethyl)phenyl)butane-1,4-dione 210.
[001701] White solid (66 mg, 0.19 mmol). NMR (CDC13, 400 MHz) 6 ppm 3.26 (t, J=6.4Hz, 2H), 3.40 (t, J=6.4Hz, 2H), 6.05 (s, 2H), 6.87 (d, J=8Hz, 1H), 7.48 (d, J=1.6Hz, 1H), 7.57 (t, 1H), 7.60-7.68 (m, 2H), 7.68-7.79 (m, 2H); ESIMS found C18H13F304 z 350.9 (M+H).

<:00 [001702] 1-(Benzo [d][1,3]dioxo1-5-y1)-4-(2-fluorophenyl)butane-1,4-dione 213.
[001703] White solid (10 mg, 0.03 mmol). IHNMR (CDC13, 400 MHz) 8 ppm 3.32-3.40 (m, 2H), 3.40-3.50 (m, 2H), 6.06 (s, 2H), 6.88 (d, J=8.03Hz, 1H), 7.17 (dd, J=11.17, 8.41Hz, 1H), 7.24 (t, J=7.65Hz, 1H), 7.49 (d, J=1.51Hz, 1H), 7.50-7.59 (m, 1H), 7.66 (dd, J=8.16, 1.63Hz, 1H), 7.91 (td, J=7.65, 1.76Hz, 1H); ESIMS found C17H13F04 m/z 301.0 (M+H).

=

[001704] 1-(B enzo [d][1 ,3]dioxo1-5-y1)-4-(3-fluorophenyl)butane-1,4-dione 214.
[001705] White solid (30 mg, 0.10 mmol). IHNMR (CDC13, 400 MHz) 8 ppm 3.41 (s, 4H), 6.06 (s, 2H), 6.89 (d, J=8.4Hz, 1H), 7.29 (dt, J=2.4Hz, J=7.2Hz, 1H), 7.43-7.53 (m, 2H), 7.67 (dd, J=1.2Hz, J=8Hz, 1H), 7.70 (d, J=8.4Hz, 1H), 7.83 (d, J=8Hz, 1H); ESIMS found C17H13F04 inlz 323.0 (M+H).
o <o 401 0 OMe [001706] 1-(Benzo [cl][1,3]dioxol-5-y1)-4-(2-methoxyphenyl)butane-1,4-dione 216.
[001707] White solid (30 mg, 0.10 mmol). 1HNMR (CDC13, 400 MHz) 8 ppm 3.34 (t, J=6.4Hz, 2H), 3.45 (t, J=6.4Hz, 2H), 3.93 (s, 3H), 6.05 (s, 2H), 6.87 (d, J=8Hz, 1H), 6.96-7.06 (m, 211), 7.48 (t, 1H), 7.50 (d, J=1.2Hz, 1H), 7.66 (dd, J=1.6Hz, J=811z, 1H), 7.77 (dd, J=1.6Hz, J=8Hz, 1H); ESIMS found C18H1605 m/z 313.0 (M+H).

OMe =
<0 Ol [001708] 1-(Benzo [d][1,3]dioxo1-5-y1)-4-(3-methoxyphenyebutane-1,4-dione 217.
[001709] White solid (30 mg, 0.10 mmol). NMR (CDC13, 400 MHz) 6 ppm 3.35-3.41 (m, 2H), 3.41-3.47 (m, 2H), 3.87 (s, 3H), 6.06 (s, 2H), 6.88 (d, J=8.28Hz, 111), 7.13 (ddd, J=8.16, 2.64, 1.00Hz, 1H), 7.40 (t, J=7.91Hz, 1H), 7.50 (d, J=1.52Hz, 1H), 7.55 (dd, J=2.52, J=1.52Hz, 1H), 7.64 (dt, J=7.84, 1.10Hz, 1H), 7.68 (dd, J=8.03, 1.76Hz, 1H); ESIMS found C18111605 m/z 313.0 (M+H).
<o [001710] 1-(Benzo[d] [1,31 dioxo1-5-y1)-4-phenylbutane-1,4-dione 222.
[001711] White solid (48 mg, 0.17 mmol). NMR
(CDC13, 400 MHz) 6 ppm 3.39 (t, J=5.6Hz, 2H), 3.45 (t, J=5.6Hz, 2H), 6.06 (s, 211), 6.88 (d, J=8.4Hz, 1H), 7.43-7.53 (m, 3H), 7.58 (t, J=7.6Hz, 1H), 7.68 (d, J=8.4Hz, 1H), 8.04 (d, J=7.6Hz, 211);
ESIMS found C17H1404 m/z 283.0 (M+H).
F 0 ip F

[001712] 1-(2,2-Difluorobenzo [d][l ,31 dioxo1-5-y1)-4-(pyridin-2-yl)butane-1,4-dione 232.
[001713] White solid (11 mg, 0.03 mmol). NMR
(CDC13, 400 MHz) 6 ppm 3.44 (t, J=6Hz, 2H), 3.73 (t, J=6Hz, 2H), 7.18 (d, J=8.4Hz, 1H), 7.53 (t, J=4Hz, 114), 7.78 (s, 111), 7.83-7.95 (m, 2H), 8.07 (d, J=8Hz, 111), 8.75 (d, J=4Hz, 1H); ESIMS
found Ci6HilF2N04 m/z 320.1 (M+H).

F\< 0 [001714] 1 -(2,2-Difluorob enzo [d][1,3] dioxo1-5 -y1)-4-phenylbutane-1,4-dione 235.
[001715] White solid (20 mg, 0.06 mmol). 11-1 NMR (CDC13, 400 MHz) 6 ppm 3.43 (t, J=6Hz, 211), 3.50 (t, J=6Hz, 211), 7.19 (d, J=8.4Hz, 111), 7.51 (t, J=7.6Hz, 2H), 7.62 (t, J=7.6Hz, 1H), 7.78 (d, J=2Hz, 1H), 7.91 (dd, J=1.5Hz, J=8.4Hz, 114), 8.06 (d, J=7.2Hz, 2H); ESIMS found C17H12F204 m/z 318.9 (M+H).
0 is 0,3 o [001716] 1 -(2,3 -Dihydrob enzo [b] [1,4] dioxin-5-y1)-4-(4-(trifluoromethyl) phenyl)butane-1,4-dione 238.
[001717] White solid (14 mg, 0.04 mmol). 111 NMR (CDC13, 400 MHz) 6 ppm 3.43 (t, J=6Hz, 211), 3.51 (t, J=6Hz, 2H), 4.34 (t, J=4Hz, 211), 4.42 (t, J=4Hz, 2H), 6.91 (t, J=8Hz, 1H), 7.06 (dd, J=1.2Hz, J=8Hz, 111), 7.38 (dd, J=1.6Hz, J=8Hz, 111), 7.77 (d, J=8Hz, 2H), 8.16 (d, J=8.4Hz, 2H); ESIMS found C19H15F304 m/z 365.0 (M+H).
4,0 o [001718] 1-(2,3-Dihydrobenzo [b][1,4] dioxin-5-y1)-4-(3 -fluorophenyl)butane-1,4-dione 240.
[001719] White solid (79 mg, 0.25 mmol). 11-1 NIVIR (CDC13, 400 MHz) 6 ppm 3.40 (t, J=6Hz, 2H), 3.48 (t, J=6Hz, 2H), 4.34 (dd, J=4Hz, J=6Hz, 211), 4.41 (dd, J=4Hz, J=6Hz, 2H), 6.91 (t, J=7.6Hz, 1H), 7.05 (dd, J=1.6Hz, J=8Hz, 111), 7.26-7.32 (m, 111), 7.38 (dd, J=1.6Hz, J=8Hz, 1H), 7.48 (dd, J=7.6Hz, J=8.8Hz, 1H), 7.73 (d, J=8.8Hz, 1H), 7.85 (d, J=7.6Hz, 1H); ESIMS found C181-115F04 m/z 314.9 (M+H).
o 0 OMe [001720] 1-(2,3-Dihydrobenzo [b][1,4]dioxin-5-y1)-4-(2-methoxyphenyObutane-1,4-dione 242.
[001721] White solid (40 mg, 0.12 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.29-3.46 (m, 4H), 3.93 (s, 3H), 4.25-4.35 (m, 2H), 4.35-4.43 (m, 2H), 6.88 (t, J=8Hz, 111), 6.94-7.07 (m, 3H), 3.34 (dd, J=1.6Hz, J=8Hz, 1H), 7.46 (dt, J=1.6Hz, J=7.6Hz, 1H), 7.76 (dd, J=1.6Hz, J=7.6Hz, 111); ESIMS found C19111805 inlz 327.0 (M+H).
o o [001722] 1-(2,3-Dihydrobenzo[b] [1,4] dioxin-5-y1)-4-phenylbutane-1,4-dione 248.
[001723] White solid (28 mg, 0.10 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.39-3.54 (m, 4H), 4.28-4.35 (m, 2H), 4.35-4.44 (m, 2H), 6.89 (t, J=7.6Hz, 111), 7.03 (dd, J=2.4Hz, J=7.6Hz, 1H), 7.36 (dd, J=1.2Hz, J=7.6Hz, 1H), 7.48 (t, J=7.6Hz, 2H), 7.58 (t, J=7.6Hz, 1H), 8.04 (dd, J=1.2Hz, J=8Hz, 2H); ESIMS found C18E11604 m/z 297.0 (M+H).
/
0 o cF3 [001724] 1 -(B enzofuran-5-y1)-4- (2-(trifluoromethyl)phenyl)butane-1,4-dione 275.
[001725] Oil (27 mg, 0.08 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.34 (t, J=6Hz, 2H), 3.57 (t, J=6Hz, 2H), 6.89 (d, J=1.2Hz, 1H), 7.60 (t, J=8.4Hz, 2H), 7.68 (t, J=7.2Hz, 1H), 7.71-7.74 (m, 2H), 7.78 (t, J=7.2Hz, 1H), 8.05 (dd, J=1.6Hz, J=8.4Hz, 1H), 8.36 (s, 1H); ESIMS found Ci9Hi3F303 m/z 346.9 (M+H).

/

[001726] 1-(Benzofuran-5-y1)-4-(2-fluorophenyl)butane-1,4-dione 278.
[001727] White solid (34 mg, 0.11 mmol). 1H NMR (DMSO-d6, 400 MHz) 6 ppm 3.34-3.46-3.52 (m, 2H), 7.12 (t, J=1.50Hz, 1H), 7.32-7.44 (m, 2H), 7.65-7.71 (m, 1H), 7.73 (d, J=8.78Hz, 111), 7.86 (td, J=7.65, 1.76Hz, 1H), 7.99 (dd, J=8.78, 1.76Hz, 1H), 8.13 (d, J=2.26Hz, 1H), 7.12 (d, J=1.50Hz, 1H); ESIMS found C18H13F03 m/z 297.0 (M+H).

/
0 0 OMe [001728] 1-(Benzofuran-5-y1)-4-(2-methoxyphenyl)butane-1,4-dione 281.
[001729] White solid (50 mg, 0.16 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.45-3.53 (m, 4H), 3.94 (s, 3H), 6.88 (dd, J=2.26, 0.75Hz, 1H), 6.95-7.08 (m, 2H), 7.49 (ddd, J=8.34, 7.34, 1.88Hz, 1H), 7.57 (d, J=8.53Hz, 1H), 7.70 (d, J=2.26Hz, 1H), 7.79 (dd, J=7.65, 1.88Hz, 1H), 8.05 (dd, J=8.78, 1.76Hz, 111), 8.36 (d, J=1.76Hz, 1H); ESIMS
found C19E11604 m/z 309.1 (M+H).
/ 140o [001730] 1-(Benzofuran-5-y1)-4-phenylbutane-1,4-dione 287.
[001731] White solid (16 mg, 0.06 mmol). 1H NMR (DMSO-d6, 400 MHz) 6 ppm 3.41-3.47 (m, 2H) 3.47-3.52 (m, 211) 7.13 (dd, J=2.13Hz, J=0.88Hz, 1H) 7.57 (t, J=7.56Hz, 2H) 7.67 (t, J=6.99Hz, 1H) 7.74 (d, J=8.78Hz, 1H) 8.00 (dd, J=8.53Hz, J=1.76Hz, 1H) 8.02 - 8.06 (m, 2H) 8.14 (d, J=2.26Hz, 1H) 8.44 (d, J=1.76Hz, 1H);
ESIMS found C18E11403 m/z 279.1 (M+H).
<No 10 0 cF3 [001732] 1-(B enzo oxazol-5-y1)-4-(2-(trifluoromethyl)phenyebutane-1,4-dione 288.
[001733] White solid (15 mg, 0.04 mmol). 11-1 NMR (CDC13, 400 MHz) 6 ppm 3.31-3.38 (m, 2H), 3.54-3.60 (m, 211), 7.59 (t, J=7.66Hz, 1H), 7.66-7.71 (m, 211), 7.74 (d, J=7.7811z, 1H), 7.79 (d, J=7.53Hz, 1H), 8.15 (dd, J=1.6Hz, J=8.31Hz, 1H), 8.21 (s, 1H), 8.50 (d, J=1.51Hz, 1H); ESIMS found CI8H12F3NO3 m/z 348.1 (M+H).

<oN

[001734] 1-(Benzo [d] oxazol-5-y1)-4-(2-fluorophenyl)butane-1,4-dione 291.
[001735] White solid (12 mg, 0.04 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.45-3.59 (m, 4H), 7.18 (ddd, J=11.23, 8.34, 1.00Hz, 1H), 7.22-7.27 (m, 1H), 7.49-7.60 (m, 111), 7.68 (d, J=8.78Hz, 111), 7.92 (td, J=7.65, 1.76Hz, 111), 8.17 (dd, J=8.56, 1.76Hz, 1H), 8.20 (s, 1H), 8.51 (d, J=1.25Hz, 1H); ESIMS found C17H12FN03 m/z 298.1 (M+H).

=
<o.

[001736] 1-(Benzo[d]oxazol-5-y1)-4-(3-fluorophenyl)butane-1,4-dione292.
[001737] White solid (28 mg, 0.09 mmol). 111 NMR (CDC13, 400 MHz) 6 ppm 3.45-3.52 (m, 211), 3.54-3.61 (m, 2H), 7.31 (dt, J=1.00Hz, J=8.28Hz, 1H), 7.50 (td, J=8.03Hz, J=5.52Hz, 111), 7.70 (d, J=8.53Hz, 111), 7.72-7.78 (m, 1H), 7.87 (dt, J=7.78Hz, J=1.13Hz, 1H), 8.18 (d, J=8.73Hz, 1H), 8.21 (s, 1H), 8.53 (d, J=1.51Hz, 1H);
ESIMS found C17H12FN03 mlz 298.0 (M+H).

</0 10 0 OMe [001738] 1-(B enzo [d] oxazol-5-y1)-4-(2-methoxyphenyebutane-1,4-dione 294.
[001739] White solid (10 mg, 0.03 mmol). 11-1 NMR (CDC13, 400 MHz) 6 ppm 3.44-3.56 (m, 4H), 3.95 (s, 3H), 6.95-7.08 (m, 2H), 7.49 (td, J=7.80, 1.50Hz, 1H), 7.67 (d, J=8.53Hz, 1H), 7.79 (dd, J=7.65, 1.63Hz, 1H), 8.16 (dd, J=8.80, 1.50Hz, 1H), 8.19 (s, 111), 8.51 (d, J=1.00Hz, 1H); ESIMS found C181115N04m/z 310.1 (M+H).

<N

[001740] 1-(Benzo[d]oxazol-5-y1)-4-pheny1butane-1,4-dione 300.
[001741] White solid (50 mg, 0.18 mmol). 111 NMR (CDC13, 400 MHz) 6 ppm 3.48-3.59 (m, 4H), 7.46-7.55 (m, 2H), 7.60 (tt, J=1.24Hz, J=7.52Hz, 1H), 7.68 (d, J=8.53Hz, 1H), 8.03-8.09 (m, 2H), 8.17 (dd, J=8.78Hz, J=1.76Hz, 1H), 8.20 (s, 1H), 8.53 (d, J=1.51Hz, 1H); ESIMS found Ci7Hi3NO3 m/z 280.0 (M+H).
c3 [001742] 1-(Benzo[b]thiophen-5-y1)-4-(2-(trifluoromethyl)phenyl)butane-1,4-dione 301.
[001743] White solid (83 mg, 0.23 mmol). 11-1 NMR (DMSO-d6, 400 MHz) 6 ppm 3.30-3.37 (m, 2H), 3.48-3.57 (m, 2H), 7.65 (d, J=5.27Hz, 1H), 7.75 (t, J=7.61Hz, 1H), 7.85 (t, J=7.76 2H), 7.91 (d, J=5.27Hz, 1H), 7.95-8.01 (m, 2H), 8.17 (d, J=8.53Hz, 1H), 8.65 (d, J=1.25Hz, 1H); ESIMS found C191-113F302S m/z 362.9 (M+H).

/
0 OMe [001744] 1-(Benzo[b]thiophen-5-y1)-4-(2-methoxyphenyl)butane-1,4-dione 307.
[001745] Brown solid (20 mg, 0.06 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.52 (s, 2H), 3.95 (s, 2H), 6.97-7.09 (m, 211), 7.43-7.52 (m, 2H), 7.54 (d, J=5.52Hz, 111), 7.79 (dd, j=7.78, 1.76Hz, 1H), 7.96 (d, J= 8.52Hz, 1H), 8.02 (dd, J=8.52, 1.24Hz, 1H), 8.54 (d, J=1.00Hz, 1H); ESIMS found C19E11603S m/z 324.9 (M+H).
o o [001746] 1-(Benzo[b]thiophen-5-y1)-4-(pyridin-2-yl)butane-1,4-dione 310.
[001747] White solid (20 mg, 0.07 mmol). 1H NMR (DMSO-d6, 400 MHz) 6 ppm 3.50-3.55 (m, 211), 3.55-3.61 (m, 2H), 7.63 (d, J=5.52Hz, 111), 7.69 (ddd, J=1.52Hz, J=5.52Hz, J=7.52Hz, 1H), 7.89 (d, J=5.52Hz, 111), 7.92-7.98 (m, 211), 8.02 (dt, J=1.76, J=7.67Hz, 1H), 8.15 (d, J=8.53Hz, 1H), 8.62 (d, J=1.51Hz, 1H), 8.77 (d, J=4.79Hz, 111);
ESIMS found C17H13NO2S m/z 296.1 (M+H).

[001748] 1-(Benzo[b]thiophen-5-y1)-4-phenylbutane-1,4-dione 313.
[001749] White solid (105 mg, 0.36 mmol). 1H NMR (DMSO-d6, 400 MHz) 6 ppm 3.41-3.48 (m, 211), 3.48-3.55 (m, 2H), 7.51-7.61 (m, 2H), 7.62-7.71 (m, 211), 7.91 (d, J=5.52Hz, 1H), 7.96 (dd, J=8.53Hz, J=1.51Hz, 1H), 8.03 (d, J=7.36Hz, 211), 8.16 (d, J=8.53Hz, 111), 8.64 (d, J=1.51Hz, 1H); ESIMS found C18I-11402S m/z 295.1 (M+H).

[0017501 1 -(2,3 -Dihydrob enzo [b][1,4] dioxin-6-y1)-4-(o-tolyl)butane-1,4-dione 342.
[001751] White solid (15 mg, 0.05 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 2.52 (s, 3H), 3.35 (t, J=5.2Hz, 2H), 3.39 (t, J=5.2Hz, 2H), 4.31 (d, J=5.2Hz, 211), 4.35 (d, J=5.2Hz, 2H), 6.95 (AA'BB'quartet, 111), 7.26-7.35 (m, 2H), 7.40 (t, J=7.6Hz, 1H), 7.56-7.61 (m, 2H), 7.83 (d, J=7.2Hz, 1H); ESIMS found C19111804 m/z 311.1 (M+H).

o [0017521 1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-y1)-4-(m-tolyl)butane-1,4-dione 343.
[001753] White solid (13 mg, 0.04 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 2.43 (s, 3H), 3.39 (t, J=4.8Hz, 2H), 3.43 (t, J=4.8Hz, 2H), 4.30 (d, J=5.2Hz, 211), 4.33 (d, J=5.2Hz, 211), 6.93 (AA'BB'quartet, 1H), 7.34-7.42 (m, 2H), 7.56-7.62 (m, 2H), 7.84 (d, J=7.6Hz, 211); ESIMS found C19111804 m/z 311.1 (M+H).
o [001754] 1 -(2,3 -D ihydrob enzo [b] [1,41dioxin-6-y1)-4-(p-toly0butane-1,4-dione 344.
[001755] White solid (26 mg, 0.08 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 2.43 (s, 3H), 3.35-3.45 (m, 4H), 4.30 (d, J=5.6Hz, 211), 4.33 (d, J=5.6Hz, 2H), 6.93 (AA'BB'quartet, 111), 7.26-7.33 (m, 211), 7.57-7.63 (m, 2H), 7.94 (d, J=8Hz, 2H);
ESIMS found C19111804 m/z 311.1 (M+H).
o [001756] 1-(2,3 -Dihydrobenzo [b] [1,4] dioxin-6-y1)-4-(pyrimidin-5-yl)butane-1,4-dione 345.
[001757] White solid (9 mg, 0.03 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.40 (t, J=6Hz, 2H), 3.48 (t, J=6Hz, 2H), 4.28-4.39 (m, 4H), 6.96 (AA'BB'quartet, 1H), 7.55-7.62 (m, 211), 9.34 (s, 2H), 9.41 (s, 1H); ESIMS found C16Hi4N204 m/z 299.0 (M+H).
o I \
,---o 0 [001758] 1 -(2,3 -Dihydrob enzo [b][1,4] dioxin-6-y1)-4-(furan-2-yl)butane-1,4-dione 346.
[001759] White solid (42mg, 0.15 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.29 (t, J=6Hz, 2H), 3.38 (t, J=6Hz, 2H), 4.26-4.31 (m, 2H), 4.31-4.36 (m, 2H), 6.56 (dd, J=2Hz, J=5.2Hz, 1H), 6.92 (AA'BB'quartet, 1H), 7.25-7.29 (m, 111), 7.55-7.64 (m, 214), 7.61 (s, 1H); ESIMS found C161-11405 m/z 287.1 (M+H).
o 111 [001760] 1-(Chroman-6-y1)-4-(o-tolyl)butane-1,4-dione 358.
[001761] Yellow solid (28 mg, 0.09 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 1.99-2.08 (m, 2H), 2.51 (s, 3H), 2.84 (t, J=6.53Hz, 2H), 3.31-3.36 (m, 2H), 3.36-3.42 (m, 211), 4.26 (t, J=5.28Hz, 2H), 6.84 (d, J=8.28Hz, 1E1), 7.24-7.32 (m, 2H), 7.39 (td, J=7.50, 1.52Hz, 1H), 7.77-7.84 (m, 3H); ESIMS found C20112003 m/z 309.2 (M+H).
I \

[001762] 1 -(Chroman-6-y1)-4-(thiophen-2-yl)butane-1,4-dione 364.

[001763] Yellow solid (18 mg, 0.06 mmol). 1H NMR (DMSO-d6, 400 MHz) 6 ppm 1.94 (quin, J=5.02Hz, 2H), 2.80 (t, J=6.15Hz, 2H), 3.31 (s, 4H), 3.36 (s, 4H), 4.21 (t, J=4.76Hz, 2H), 6.83 (d, J=8.53Hz, 111), 7.26 (t, J=4.27Hz, 111), 7.73 (d, J=8.53Hz, 1H), 7.77 (s, 111), 8.00 (d, J=4.77Hz, 1H), 8.04 (d, J=3.76Hz, 111); ESIMS
found Ci7H1603S m/z 301.1 (M+H).
o I X
o =

[001764] 1-(Chroman-6-y1)-4-(furan-2-yl)butane-1,4-dione 365.
[001765] White solid (11 mg, 0.04 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 2.04 (quin, J=5.00Hz, 211), 2.84 (t, J=6.40Hz, 2H), 3.26-3.32 (m, 2H), 3.35-3.42 (m, 211), 4.25 (t, J=5.04Hz, 2H), 6.56 (dd, J=3.51, 1.76Hz, 1H), 6.83 (d, J=8.28Hz, 1H), 7.25-7.28 (m, 111), 7.61 (d, J=0.75Hz, 111), 7.74-7.81 (m, 2H); ESIMS found Ci7H1604 m/z 285.2 (M+H).

[001766] 1-(Benzo [d][1,3]dioxo1-5-y1)-4-(o-tolyl)butane-1,4-dione 368.
[001767] White solid (66 mg, 0.22 mmol). 1H NMR (DMSO-d6, 400 MHz) 6 ppm 2.37 (s, 311), 3.24 (t, J=6Hz, 211), 3.27-3.35 (m, 211), 6.14 (s, 211), 7.06 (d, J=8Hz, 1H), 7.30 (t, J=7.2Hz, 111), 7.35 (d, 111), 7.43 (t, 1H), 7.48 (s, 111), 7.68 (dd, J=1.611z, J=8.4Hz, 1H), 7.84 (d, J=7.211z, 111); ESIMS found C18111604 m/z 297.0 (M+H).
I \
<01 [001768] 1-(Benzo [d][l ,3] dioxo1-5-y1)-4-(thiophen-2-yl)butane-1,4-dione 374.
[001769] White solid (23 mg, 0.08 mmol). 1H NMR (DMSO-d6, 400 MHz) 6 ppm 3.30-3.36 (m, 411), 6.14 (s, 2H), 7.06 (d, J=8.0311z, 111), 7.27 (dd, J=5.02, 3.76Hz, 1H), 7.46 (d, J=1.51Hz, 1H), 7.66 (dd, J=8.28, 1.76Hz, 1H), 8.00 (dd, J=5.02, 1.00Hz, 1H), 8.04 (dd, J=3.76, 1.25Hz, 1H); ESIMS found C15111204S m/z 288.9 (M+H).
I \

<c, o [001770] 1-(Benzo [d][1,3]dioxo1-5-y1)-4-(furan-2-yl)butane-1,4-dione 375.
[001771] White solid (10 mg, 0.04 mmol). 1H NMR (DMSO-dc, 400 MHz) 6 ppm 3.13-3.20 (m, 2H), 3.28-3.35 (m, 2H), 6.14 (s, 2H), 6.73 (dd, J=3.51, 1.76Hz, 1H), 7.05 (d, J=8.03Hz, 1H), 7.46 (d, J=1.76Hz, 1H), 7.49 (d, J=3.86Hz, 1H), 7.66 (dd, J=8.16, 1.63Hz, 1H), 8.00 (d, J=1.00Hz, 1H); ESIMS found C15E11205 inlz 273.0 (M+H).
FX o [001772] 1-(2,2-Difluorobenzo [d][1,3]dioxo1-5-y1)-4-(in-tolyebutane-1,4-dione 379.
[001773] White solid (308.2 mg, 0.98 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 2.43 (s, 3H), 3.41 (t, J=5.6Hz, 2H), 3.47 (t, J=5.6Hz, 2H), 7.17 (d, J=8.4Hz, 1H), 7.39 (q, J=8.8Hz, 2H), 7.77 (d, J=1.6Hz, 111), 7.84 (d, J=6.8Hz, 2H), 7.90 (dd, J=1.6Hz, J=8.4Hz, 1H); ESIMS found Ci8Hi4F204 m/z 333.1 (M+H).
FX

[001774] 1-(2,2-Difluorobenzo [d][1,3]dioxo1-5-y1)-4-(furan-2-yl)butane-1,4-dione 385.
[001775] White solid (11 mg, 0.04 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.33 (t, J=6Hz, 211), 3.39 (t, J=6Hz, 214), 6.57 (dd, J=2.5Hz, J=3.5Hz, 1H), 7.15 (d, J=7.6Hz, 1H), 7.23-7.31 (m, 1H), 7.62 (s, 1H), 7.74 (d, J=1.6Hz, 111), 7.86 (dd, J=1.6Hz, J=7.6Hz, 1H); ESIMS found C151-110F205 m/z 309.1 (M+H).

WO

Me0 [001776] 1-(3,4-Dimethoxypheny1)-4-(in-tolyl)butane-1,4-dione 425.
[001777] White solid (27 mg, 0.09 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 2.43 (s, 3H), 3.45 (s, 4H), 3.95 (s, 3H), 3.97 (s, 3H), 6.93 (d, J=8.53Hz, 1H), 7.35-7.44 (m, 2H), 7.58 (d, J=2.01Hz, 1H), 7.72 (dd, J=8.53, 2.01Hz, 1H), 7.83-7.89 (m, 2H);
ESIMS found C19H2004m/z 313.1 (M+H).

Me0 Me0 [001778] 1-(3,4-Dimethoxypheny1)-4-(p-tolyl)butane-1,4-dione 426.
[001779] White solid (34 mg, 0.11 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 2.43 (s, 3H), 3.44 (s, 4H), 3.94 (s, 3H), 3.97 (s, 3H), 6.93 (d, J=8.53Hz, 1H), 7.29 (d, J=8.03Hz, 2H), 7.57 (d, J=2.01Hz, 1H), 7.72 (dd, J=8.41, 2.13Hz, 1H), 7.95 (d, J=7.71Hz, 2H); ESIMS found C19H2004 m/z 313.0 (M+H).
o [001780] 1-(2,3-Dihydrobenzo [b] [1,41dioxin-5-y1)-4-(furan-2-yl)butane-1,4-dione 442.
[001781] White solid (23 mg, 0.08 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.26 (t, J=6.4Hz, 2H), 3.44 (t, J=6.4Hz, 2H), 4.27-4.35 (m, 2H), 4.35-4.42 (m, 2H), 6.56 (dd, J=1.6Hz, J=3.6Hz, 1H), 6.88 (t, J=8Hz, 1H), 7.03 (dd, J=1.6Hz, J=811z, 1H), 7.24-7.29 (m, 1H), 7.35 (dd, J=1.6Hz, J=7.6Hz, 1H), 7.61 (s, 1H); ESIMS found CI6H1405 m/z 286.9 (M+H).

/

[001782] 1-(Benzofuran-5-y1)-4-(o-tolyl)butane-1,4-dione 455.
[001783] White solid (12 mg, 0.04 mmol). IHNMR (CDC13, 400 MHz) 6 ppm 2.52 (s, 3H), 3.35-3.43 (m, 2H), 3.51-3.57 (m, 2H), 6.88 (dd, J=2.26, 0.75Hz, 1H), 7.24-7.34 (m, 211), 7.40 (td, J=7.52, 1.24Hz, 1H), 7.57 (d, J=8.53Hz, 1H), 7.71 (d, J=2.26Hz, 1H), 7.84 (dd, J=7.65, 1.13Hz, 1H), 8.05 (dd, J=8.78, 1.76Hz, 111), 8.36 (d, J=1.76Hz, 1H); ESIMS found C39111603 nilz 293.0 (M+H).

/

[001784] 1-(Benzofuran-5-y1)-4-(m-tolypbutane-1,4-dione 456.
[001785] White solid (19 mg, 0.07 mmol). 1HNMR (CDC13, 400 MHz) 6 ppm 2.44 (s, 311), 3.50 (d, J=5.2Hz, 2H), 3.53 (d, J=5.2Hz, 2H), 6.88 (s, 111), 7.39 (d, J=7.2Hz, 2H), 7.58 (d, J=8.4Hz, 1H), 7.71 (d, J=2Hz, 1H), 7.86 (d, J=6.8Hz, 2H), 8.06 (d, J=8.4Hz, 1H), 8.37 (s, 111); ESIMS found C19111603 m/z 293.1 (M+H).
/

[001786] 1-(Benzofuran-5-y1)-4-(p-tolyl)butane-1,4-dione 457.
[001787] White solid (73 mg, 0.25 mmol). 1-11NMR (CDC13, 400 MHz) 6 ppm 2.43 (s, 3H), 3.45-3.51 (m, 2H), 3.51-3.57 (m, 211), 6.89 (dd, J=2.13, 0.88Hz, 1H), 7.29 (d, J=8.03Hz, 211), 7.57 (d, J=8.53Hz, 111), 7.71 (d, J=2.26Hz, 1H), 7.96 (d, J=7.72Hz, 211), 8.06 (dd, J=8.66, 1.88Hz, 111), 8.37 (d, J=1.76Hz, 111); ESIMS found C19111603 m/z 293.0 (M+H).

0 I \
/

[001788] 1-(B enzofuran-5 -y1)-4-(furan-2-yl)butane-1,4-dione 462.
[001789] White solid (25 mg, 0.09 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.35 (t, J=6.4Hz, 2H), 3.53 (t, J=6.4Hz, 2H), 6.57 (dd, J=2Hz, J=3.6Hz, 1H), 6.88 (d, J=1.6Hz, 1H), 7.24-7.31 (m, 1H), 7.57 (d, J=8.8Hz, 1H), 7.62 (s, 1H), 7.71 (d, J=2Hz, 1H), 8.03 (dd, J=1.2Hz, J=8.8Hz, 1H), 8.34 (d, J=1.2Hz, 1H); ESIMS found Ci6F11204 m/z 269.2 (M+H).
0=
<N

[001790] 1-(B enzo [d] oxazol-5-y1)-4-(o-tolyl)butane-1,4-dione 485.
[001791] White solid (15 mg, 0.05 mmol). 111 NMR (CDC13, 400 MHz) 6 ppm 2.52 (s, 3H), 3.38-3.44 (m, 2H), 3.51-3.57 (m, 2H), 7.2 -7.35 (m, 2H), 7.40 (dt, J=1.48Hz, J=7.52Hz, 1H), 7.68 (d, J=8.33Hz, 1H), 7.85 (dd, J=7.53Hz, J=1.25Hz, 1H), 8.17 (dd, J=1.76Hz, J=8.63Hz, 1H), 8.20 (s, 1H), 8.52 (d, J=1.51Hz, 1H); ESIMS
found Ci8H15NO3 m/z 294.2 (M+H).

[001792] 1-(2-Fluoropheny1)-4-(pyridin-2-yl)butane-1,4-dione 538.
[001793] White solid (30 mg, 0.12 mmol). 11-1NMR (CDC13, 400 MHz) 6 ppm 3.50 (t, J=6Hz, 2H), 3.70 (t, J=6Hz, 2H), 7.18 (t, J=8.8Hz, 111), 7.27 (t, J=7.2Hz, 1H), 7.45-7.62 (m, 2H), 7.86 (dt, J=1.6Hz, J=7.6Hz, 1H), 7.93 (dt, J=2Hz, 1H), 8.07 (d, J=8Hz, 1H), 8.74 (d, J=4Hz, 1H); ESIMS found C151-112FN02 m/z 258.0 (M+H).

[001794] 1-(Pyridin-2-y1)-4-(2-(trifluoromethyl)phenyl)butane-1,4-dione 541.
[001795] Oil (41 mg, 0.13 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.31 (t, J=6.4Hz, 2H), 3.73 (t, J=6.4Hz, 2H), 7.50 (t, J=4.8Hz, 1H), 7.58 (t, J=7.6Hz, 1H), 7.66 (t, J=7.6Hz, 1H), 7.70-7.77 (m, 2H), 7.85 (dt, J=1.2Hz, J=7.6Hz, 1H), 8.05 (d, J=8Hz, 1H), 8.72 (d, J=4.4Hz, 111); ESIMS found Ci6Hi2F3NO2 m/z 307.9 (M+H).

[001796] 1-(Pyridin-2-y1)-4-(o-tolyl)butane-1,4-dione 544.
[001797] Oil (39 mg, 0.15 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 2.51 (s, 3H), 3.37 (t, J=6.4Hz, 2H), 3.69 (t, J=6.4Hz, 2H), 7.21-7.34 (m, 2H), 7.38 (dt, J=1Hz, J=7.2Hz, 1H), 7.49 (dd, 1H), 7.76-7.90 (m, 2H), 8.05 (d, J=7.6Hz, 1H), 8.72 (d, J=4.4Hz, 1H); ESIMS found C161-115NO2 m/z 254.0 (M+H).

=
0 OMe [001798] 1-(2-Methoxypheny1)-4-(pyridin-2-yl)butane-1,4-dione 547.
[001799] White solid (40 mg, 0.15 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.47 (t, J=6.8Hz, 2H), 3.64 (t, J=6.8Hz, 2H), 3.93 (s, 3H), 6.94-7.07 (m, 2H), 7.41-7.53 (m, 2H), 7.77 (dd, 1H), 7.84 (dt, J=1.2Hz, J=8Hz, 1H), 8.05 (d, J=8Hz, 1H), 8.71 (d, J=4.4Hz, 1H); ESIMS found C16Hi5NO3 inlz 270.1 (M+H).
I \

r [001800] 1-(Furan-2-y1)-4-(pyridin-2-yebutane-1,4-dione 554.

[001801] White solid (11 mg, 0.05 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.32 (t, J=6.8Hz, 214), 3.69 (t, J=6.8Hz, 2H), 6.56 (dd, J=1.6Hz, J=3.2Hz, 1H), 7.23-7.30 (m, 111), 7.50 (t, J=6.4Hz, 1H), 7.61 (s, 1H), 7.85 (dt, J=1.6Hz, J=7.6Hz, 1H), 8.05 (d, J=8.4Hz, 1H), 8.71 (d, J=4.4Hz, 1H); ESIMS found Ci3H11NO3 nitz 230.1 (M+H).

[001802] 1-(2-Fluoropheny1)-4-(thiophen-2-yebutane-1,4-dione 557.
[001803] White solid (15 mg, 0.06 mmol). 111 NMR (CDC13, 400 MHz) 6 ppm 3.35-3.42 (m, 2H), 3.42-3.50 (m, 2H), 7.12-7.20 (m, 2H), 7.24 (td, J=7.80Hz, J=1.00Hz, 1H), 7.49-7.57 (m, 1H), 7.65 (dd, J=4.89Hz, J=1.13Hz, 1H), 7.83 (dd, J=3.89Hz, J=1.13Hz, 111), 7.90 (td, J=7.59Hz, J=1.88Hz, 1H); ESIMS found Ci4H11F02S m/z 262.9 (M+H).
0=

[001804] 1-(Thiophen-2-y1)-4-(2-(trifluoromethyl)phenyl)butane-1,4-dione 559.
[001805] White solid (69 mg, 0.22 mmol). 1H NMR (DMSO-d6, 400 MHz) 6 ppm 3.25-3.31 (m, 211), 3.35-3.40 (m, 2E1), 7.27 (dd, J=4.89, 3.89Hz, 1H), 7.73 (t, J=7.80Hz, 111), 7.80-7.88 (m, 211), 7.92 (d, J=7.56Hz, 1H), 8.03 (dd, J=5.04, 1.00Hz, 1H), 8.06 (dd, J=3.76, 1.00Hz, 1H); ESIMS found C15HilF302S inlz 312.9 (M+H).

s 0 [001806] 1-(Thiophen-2-y1)-4-(o-tolyl)butane-1,4-dione 560.
[001807] White solid (38 mg, 0.15 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 2.53 (s, 3H), 3.34-3.47 (m, 4H), 7.18 (t, J=4.4Hz, 1H), 7.24-7.35 (m, 2H), 7.41 (t, J=7.6Hz, 111), 7.67 (d, J=4.8Hz, 1H), 7.82 (d, J=7.6Hz, 111), 7.85 (d, J=2.8Hz, 111);
ESIMS found Ci5H1402S m/z 259.0 (M+H).

s 0 OMe [001808] 1-(2-Methoxypheny1)-4-(thiophen-2-yl)butane-1,4-dione 562.
[001809] White solid (60 mg, 0.22 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.36 (t, J=6.8Hz, 2H), 3.47 (t, J=6.8Hz, 2H), 3.94 (s, 3H), 6.95-7.07 (m, 2H), 7.16 (dt, J=5.2Hz, 1H), 7.48 (dt, 1H), 7.64 (d, J=4Hz, 1H), 7.78 (dd, J=5.6, J=7.6Hz, 1H), 7.83 (dd, 1H); ESIMS found C151-11403S m/z 275.0 (M+H).
Example 2 [001810] Preparation of 1-(1H-indo1-5-y1)-4-phenylbutane-1,4-dione (261) is depicted below in Scheme 16.
Boc CHO
TEA
XXXIV BolLXXV LXXIX
Na2CO3, Me0H
60 C, 3h 0 Nz Scheme 16 Step 1-2 [001811] To a well stirred solution of 3-(dimethylamino)-1-phenylpropan-1-one (300CIV) (120 mg, 0.678 mmol, 1.0 eq) in 1,4-dioxane (3mL) was added tert-butyl 5-formy1-1H-indole-1-carboxylate (LXXV)(166 mg, 0.678 mmol, 1.0 eq), 3-ethy1-5-(2-hydroxyeth-y1)-4-methylthiazolium brominde (51 mg, 0.203 mmol, 0.3 eq) and TEA
(0.5 mL). The reaction mixture was refluxed for 16 h. TLC analysis (PE:Et0Ac, 3:1) showed the reaction was complete. The solution was cooled to room tempreture and diluted with water (20 mL). The product was extracted with Et0Ac (3 x 30 mL). The combined organic layers was dried over anhydrous Na2SO4, fluted and concentrated under reduced pressure to give crude tert-butyl 5-(4-oxo-4-phenylbutanoy1)-1H-indole-1-carboxylate (LXXIX) (52 mg) as a white solid. The crude product was dissolved in methanol (2 mL).
Anhydrous sodium carbonate (144 mg, 1.36 mmol, 2.0 eq) was added. Then the mixture was stirred at 60 C for 3 h. The solid was filtered off and the residue was concentrated in vacuum to give 1-(1H-indo1-5-y1)-4-phenylbutane-1,4-dione (261) as a white solid. (42 mg, 0.15 mmol, 22.3%) 1H NMR (DMSO-d6, 400 MHz) 6 ppm 3.41 (t, J=6.4Hz, 2H), 3.47 (t, J=6.4Hz, 214), 6.62 (s, 1H), 7.41-7.52 (m, 2H), 7.56 (t, J=7.6Hz, 211), 7.66 (t, 1H), 7.77 (d, J=8.4Hz, 111), 8.03 (d, J=7.2Hz, 214), 8.37 (s, 114), 11.46 (s, 1H); ESIMS
found C181115NO2 m/z 278.0 (M+H).
[001812] The following compounds were prepared in accordance with the procedure described in the above Example 2.

/N o CF3 [001813] 1-(1H-Indo1-5 -y1)-4-(2-(trifluoromethyephenyl)butane-1,4-dione 249.
[001814] White solid (10 mg, 0.03 mmol). 1H NWIR (DMSO-d6, 400 MHz) 6 ppm 3.25-3.32 (m, 2H), 3.45-3.54 (m, 214), 6.62-6.66 (m, 114), 7.47-7.53 (m, 2H), 7.72-7.77 (m, 111), 7.79 (dd, J=8.66Hz, J=1.63Hz, 1H), 7.83-7.89 (m, 2H), 7.99 (d, J=7.53Hz, 1H), 8.38 (s, 1H), 11.49 (brs, 1H); ESIMS found C191414F3NO2 m/z 346.0 (M+H).

/

[001815] 1-(2-Fluoropheny1)-4-(1H-indo1-5-yl)butane-1,4-dione 252.
[001816] White solid (10 mg, 0.03 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.41-3.51 (in, 2H), 3.51-3.60 (m, 2H), 6.66 (s, 1H), 7.10-7.19 (m, 1H), 7.19-7.30 (in, 2H), 7.41 (d, J=8.8Hz, 1H), 7.47-7.58 (m, 1H), 7.83-7.96 (in, 214), 8.40 (s, 1H), 8.59 (brs, 114); ESIMS found C181114FN02 m/z 296.0 (M+H).

0 OMe [001817] 1-(1H-Indo1-5-y1)-4-(2-methoxyphenyl)butane-1,4-dione 255.
[001818] White solid (36 mg, 0.12 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.44-3.57 (m, 4H), 3.94 (s, 3H), 6.69 (ddd, J=3.14, 2.01, 0.88Hz, 1H), 6.97-7.01 (m, 1H), 7.01-7.06 (m, 1H), 7.29 (dd, J=3.26, 2.51Hz, 111), 7.43 (d, J=8.30Hz, 111), 7.45-7.51 (m, 111), 7.79 (dd, J=7.78, 1.76Hz, 1H), 7.94 (dd, J=8.66, 1.63Hz, 1H), 8.38-8.46 (m, 211);
ESIMS found CI9H17NO3 in/z 308.2 (M+H).
o [001819] 1-(1H-Indo1-5-y1)-4-(pyridin-2-yl)butane-1,4-dione 258.
[001820] White solid (10 mg, 0.04 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.56-3.65 (m, 2H), 3.69-3.78 (m, 211), 6.70 (ddd, J=3.2011z, J=2.07Hz, J=1.00Hz, 1H), 7.31 (dd, J=3.14Hz, J=2.38Hz, 1H), 7.45 (d, J=8.53Hz, 1H), 7.51 (ddd, J=7.53Hz, J=4.77Hz, J=1.25Hz, 1H), 7.87 (td, J=7.78Hz, J=1.76Hz, 1H), 7.95 (dd, J=8.66Hz, J=1.63Hz, 1H), 8.09 (dt, J=7.84Hz, J=1.10Hz, 1H), 8.42-8.45 (m, 1H), 8.42-8.50 (brs, 1H), 8.71-8.78 (m, 1H); ESIMS found C17H14N202 nilz 279.1 (M+H).
cF3 <N

[001821] 1 -(1H-B enzo [d]imidazol-5-y1)-4-(3-(trifluoromethyl)phenyl)butane-1,4-dione 263.
[001822] White solid (27 mg, 0.08 mmol). 1H NMR (DMSO-d6, 400 MHz) 6 ppm 3.46-3.62 (m, 4H), 7.78 (d, J=8.53Hz, 1H), 7.83 (t, J=7 .78Hz, 1H), 7.99 (dd, J=8.53Hz, J=1.51Hz, 1H), 8.05 (d, J=7.7811z, 1H), 8.27 (s, 114), 8.35 (d, J=7.78Hz, 111), 8.38 (d, J=1.00Hz, 1H), 8.79 (s, 1H); ESIMS found C181-113F3N202 m/z 346.9 (M+H).

(N

[001823] 1-(1H-Benzo [d]imi dazol- 5 -y1)-4 - (2-fluor ophenyl)butane-1,4-dione 265.
[001824] White solid (15 mg, 0.05 mmol). 111 NMR (DMSO-d6, 400 MHz) 6 ppm 3.33-3.43 (m, 2H), 3.47-3.52 (m, 2H), 7.30-7.39 (m, 2E1), 7.62-7.73 (m, 2H), 7.85 (td, J=7.72Hz, J=1.88Hz, 1H), 7.89 (dd, J=8.53Hz, J=1.51Hz, 1H), 8.30 (brd, J=1.51Hz, 1H), 8.33 (s, 1H), 12.50 (brs, 1H); ESIMS found C17H13FN202 m/z 297.1 (M+H).
OMe <N 110 [001825] 1-(1H-Benzo [d]imidaz ol-5 -y1)- 4 - (3 -methoxy pheny but ane -1,4-dione 269.
[001826] White solid (15 mg, 0.05 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.47 (s, 411), 3.84 (s, 311), 7.12 (dd, J=2.4Hz, J=8.4Hz, 111), 7.38 (t, J=8Hz, 111), 7.49 (s, 1H), 7.60 (d, J=7.6Hz, 1H), 7.81 (d, J=8.4Hz, 1H), 8.14 (d, J=8.8Hz, 111), 8.45 (s, 1H), 9.28 (brs, 111); ESIMS found C18H16N203 m/z 309.0 (M+H).

(N 0 [001827] 1-(1H-Benzo [d] imidazol-5-y1)-4-phenylbutane-1,4-dione 274.
[001828] White solid (20 mg, 0.07 mmol). 1H NMR (DMSO-d6, 400 MHz) 6 ppm 3.40-3.46 (m, 214), 3.47-3.55 (m, 2H), 7.53-7.60 (m, 2H), 7.62-7.71 (m, 2H), 7.90 (d, J=8.78Hz, 111), 8.01-8.09 (m, 211), 8.35-8.49 (m, 2H), 12.80 (brs, 111);
ESIMS found C17H14N202 m/z 279.1 (M+H).
o [001829] 1 -(1H-Indo1-3 -y1)-4-(2-(trifluoromethyl)phenyl)butane-1,4-dione 314.
[001830] White solid (27 mg, 0.08 mmol). 1H NMR (DMSO-d6, 400 MHz) 6 ppm 3.23-3.29 (m, 2H), 3.30-3.36 (m, 2H), 7.13-7.25 (m, 2H), 7.48 (dd, J=7.42, 0.76Hz, 1H), 7.73 (t, J=7.52Hz, 111), 7.84 (t, J=7.02Hz, 2H), 7.98 (dd, J=7.53, 1.24Hz, 1H), 8.17 (d, J=7.26 Hz, 111), 8.43 (s, 111), 11.97 (br. s., 111); ESIMS found C19H14F3NO2 m/z 346.0 (M+H).
HN

[001831] 1-(1H-Indo1-3-y1)-4-(4-(trifluoromethypphenyl)butane-1,4-dione 316.
[001832] White solid (11 mg, 0.03 mmol). 1H NMR (DMSO-d6, 400 MHz) 6 ppm 3.18 (t, J=6.4Hz, 211), 3.44 (t, J=6.4Hz, 211), 7.11-7.27 (m, 2H), 7.49 (d, J=8Hz, 1H), 7.94 (d, J=8Hz, 211), 8.14 (d, J=7.6Hz, 1H), 8.23 (d, J=8Hz, 2H), 8.43 (s, 111), 11.97 (brs, 111); ESIMS found C19H14F3NO2 inlz 345.9 (M+H).
o [001833] I -(2-Fluoropheny1)-4-(1H-indo1-3 -yl)butane-1,4-dione 317.
[001834] White solid (10 mg, 0.03 mmol). 1H NWIR (CDC13, 400 MHz) 6 ppm 3.33-3.42 (m, 211), 3.46-3.56 (m, 2H), 7.17 (dd, J=11.17Hz, J=8.41Hz, 1H), 7.214 (dt, J=0.76Hz, J=7.52Hz, 1H), 7.26 (s, 111), 7.26-7.34 (m, 3H), 7.38-7.46 (m, 1H), 7.48-7.59 (m, H), 7.92 (td, J=7.53Hz, J=1.76 H, 1 H), 7.98 (d, J=3.0Hz, 111), 8.34-8.42 (m, 1H), 8.74 (brs, IH); ESIMS found C18H14FN02 m/z 296.0 (M+H).

HN 0 OMe [001835] 1-(1H-Indo1-3-y1)-4-(2-methoxyphenyl)butane-1,4-dione 319.
[001836] White solid (60 mg, 0.20 mmol). 'H NMR (CDC13, 400 MHz) 6 ppm 3.33 (t, J=6.78Hz, 211), 3.52 (t, J=6.50Hz, 2H), 3.93 (s, 3H), 6.94-7.06 (m, 2H), 7.25-7.32 (m, 1H), 7.38-7.45 (m, 111), 7.48 (ddd, J=8.34, 7.34, 1.88Hz, 1H), 7.79 (dd, J=7.65, 1.88Hz, 1H), 7.96 (d, J=3.01Hz, 1H), 8.36-8.44 (m, 1H), 8.84 (brs, 1H); ESIMS
found CoH17NO3 m/z 308.0 (M+H).
OMe HN

[001837] 1-(1H-Indo1-3-y1)-4-(3-methoxyphenyl)butane-1,4-dione 320.
[001838] White solid (30 mg, 0.10 mmol). NMR
(CDC13, 400 MHz) 6 ppm 3.38 (t, J=6.8Hz, 2H), 3.51 (t, J=6.8Hz, 2H), 3.87 (s, 3H), 7.13 (dd, J=2.4Hz, J=8Hz, 111), 7.24-7.35 (m, 211), 7.36-7.47 (m, 214), 7.56 (s, 111), 7.67 (d, J=8Hz, 111), 7.99 (s, 111), 8.39 (dd, J=3.6 Hz, J=5.2Hz, 111), 8.74 (brs, 111); ESIMS found C19HuNO3 m/z 308.0 (M+H).

HN

[001839] 1-(1H-Indo1-3-y1)-4-phenylbutane-1,4-dione 325.
[001840] White solid (16 mg, 0.06 mmol). 111 NMR (DMSO-d6, 400 MHz) 6 ppm 3.23-3.50 (m, 411), 7.08-7.26 (m, 2H), 7.47 (d, J=8Hz, 111), 7.55 (t, J=7.6Hz, 2H), 7.66 (t, J=7.6Hz, 1H), 8.03 (d, J=7.2Hz, 211), 8.14 (d, J=7.6Hz, 1H), 8.42 (s, 1H), 11.94 (brs, 1H); ESIMS found Ci8Hi5NO2m/z 278.0 (M+H).

HN¨N 0 CF3 [001841] 1-(1H-Indazol-3-y1)-4-(2-(trifluoromethyl)phenyl)butane-1,4-dione 326.
[001842] White solid (20 mg, 0.06 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.36 (t, J=6.27Hz, 2H) 3.71 (dd, j=6.90, 5.65Hz, 2H) 7.33 (ddd, J=8.09, 6.96, 0.75Hz, 1H) 7.45 (ddd, J=8.52Hz, J=7 .78Hz, J=1.00Hz, 1H) 7.53-7.62 (m, 2H) 7.67 (t, J=7.64Hz, 114) 7.76 (dd, J=17.82, 7.53Hz, 2H) 8.35 (td, J=1.00Hz, J=8.14Hz, 1H), 10.57 (brs, 1H);
ESIMS found C18Hi3F3N202 nilz 346.9 (M+H).
o HN¨N 0 F

[001843] 1-(2-Fluoropheny1)-4-(1H-indazol-3-y1)butane-1,4-dione 329.
[001844] White solid (11 mg, 0.04 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.38-3.45 (m, 2H), 3.47-3.63 (m, 2H), 7.28-7.50 (m, 4H), 7.65-7.73 (m, 2H), 7.86 (td, J=7.65, 1.76Hz, 1H), 8.15 (d, J=8.28Hz, 1H); ES1MS found Ci7H13FN202 nilz 297.0 (M+H).
o HN¨N 0 OMe [001845] 1-(1H-Indazol-3-y1)-4-(2-methoxyphenyl)butane-1,4-dione 332.
[001846] Yellow solid (30 mg, 0.10 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.51-3.59 (m, 2H), 3.60-3.70 (m, 2H), 3.94 (s, 3H), 6.95-7.07 (m, 2H), 7.30 (ddd, J=8.09, 7.09, 0.88Hz, 1H), 7.39-7.45 (m, 1H), 7.45-7.51 (m, 1H), 7.53 (d, J=8.53Hz, 1H), 7.82 (dd, J=7.65, 1.88Hz, 1H), 8.34 (d, J=8.05Hz, 1H); ESIMS found C181116N203 miz 309.0 (M+H).

ip 0 \
HN-N

[001847] 1-(1H-Indazol-3-y1)-4-(4-methoxyphenyl)butane-1,4-dione 334.
[001848] White solid (50 mg, 0.16 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.50 (t, J=6.4Hz, 2H), 3.69 (t, J=6.4Hz, 2H), 3.89 (s, 3H), 6.97 (d, J=8.811z, 2H), 7.30 (t, J=7.6Hz, 1H), 7.43 (t, J=7.6Hz, 111), 7.53 (d, J=8.4Hz, 1H), 8.06 (d, J=8.8Hz, 2H), 8.32 (d, J=8Hz, 1H); ESIMS found C18H16N203 nitz 309.2 (M+H).
o HN-N

[001849] 1-(1H-Indazol-3-y1)-4-phenylbutane-1,4-dione 338.
[001850] White solid (25 mg, 0.09 mmol). 1H NMR (DMSO-d6, 400 MHz) 6 ppm 3.44-3.50 (m, 2H), 3.50-3.58 (m, 2H), 7.31 (ddd, J=8.04Hz, J=7.50Hz, J=1.00Hz, 1H), 7.46 (ddd, J=8.28Hz, J=7.64Hz, J=1.28Hz, 1H), 7.53-7.60 (m, 2H), 7.67 (tt, J=7.28Hz, J=1.24Hz, 1H), 7.69 (td, J=8.28Hz, J=1.00Hz, 1H), 8.01-807 (m, 2H), 8.15 (td, J=9.00, 1.00Hz, 1H), 13.87 (s, 1H); ESIMS found C17Hi4N202 ni/z 279.1 (M+H).

[001851] 1-(1H-indo1-5-y1)-4-(o-tolyl)butane-1,4-dione 445.
[001852] White solid (14 mg, 0.05 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 2.53 (s, 3H), 3.32-3.45 (m, 2H), 3.52-3.61 (m, 2H), 6.68 (ddd, J=3.07, 2.07, 0.88Hz, 1H), 7.24-7.34 (m, 3H), 7.38 (dd, J=7.40, 1.38 Hz, 1H), 7.42 (d, J=8.53 Hz, 1H), 7.85 (dd, J=7.45, 0.60Hz, 1H), 7.92 (dd, J=8.69, 1.52Hz, 1H), 8.42 (s, 1H), 8.53 (brs, 1H); ESIMS
found Ci9H17NO2 m/z 292.2 (M+H).

[001853] 1-(1H-Indo1-5-y1)-4-(p-tolyl)butane-1,4-dione 447.
[001854] White solid (11 mg, 0.04 mmol). 111 NMR (CDC13, 400 MHz) 6 ppm 2.43 (s, 3H), 3.48 (t, J=6Hz, 2H), 3.56 (t, J=6Hz, 2H), 6.69 (s, 1H), 7.27 (s, 1H), 7.29 (d, J=8.4Hz, 2H), 7.44 (d, J=8.4Hz, 1H), 7.96 (dt, J=1.6Hz, J=8.4Hz, 1H), 7.97 (d, J=8.4Hz, 2H), 8.44 (s, 1H); ESIMS found Ci9H17NO2 m/z 292.0 (M+H).
0 I \
/

[001855] 1-(1H-Indo1-5-y1)-4-(thiophen-2-yl)butane-1,4-dione 451.
[001856] Yellow solid (17 mg, 0.06 mmol). 111 NMR (DMSO-d6, 400 MHz) 6 ppm 3.29-3.40 (m, 2H), 3.40-3.54 (m, 2H), 6.62 (d, J=2.76Hz, 1H), 7.28 (dd, J=4.89, 3.89 Hz, 1H), 7.45-7.50 (m, 2H), 7.75 (dd, J=8.53, 1.51Hz, 1H), 8.01 (d, J=5.27Hz, 1H), 8.06 (d, J=4.47Hz, 1H), 8.35 (s, 114), 11.49 (brs, 1H); ESIMS found Ci6Hi3NO2S
m/z 284.0 (M+H).
N/

[001857] 1-(2-Fluoropheny1)-4-(1H-indazol-5-yDbutane-1,4-dione 495.
[001858] Yellow solid (7 mg, 0.02 mmol). 114 NMR (CD30D, 400 MHz) 6 ppm 3.41-3.49 (m, 2H), 3.52-3.60 (m, 2H), 7.22-7.35 (m, 2H), 7.61 (d, J=8.78Hz, 2H), 7.89 (td, J=7.65, 1.76Hz, 1H), 8.07 (dd, J=8.78, 1.51Hz, 114), 8.24 (s, 1H), 8.65 (s, 1H);
ESIMS found C171413FN202 m/z 297.0 (M+H).

N/

[001859] 1-(4-Fluoropheny1)-4-(1H-indazol-5-yl)butane-1,4-dione 497.
[001860] White solid (10 mg, 0.03 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.44-3.51 (m, 211), 3.52-3.59 (m, 2H), 7.12-7.22 (m, 2H), 7.56 (d, J=9.03Hz, 1H), 8.04-8.15 (m, 3H), 8.23 (d, J1.00Hz, 1H), 8.53-8.59 (m, 1H), 10.28 (brs, 1H); ESIMS
found C171113FN202 m/z 297.0 (M+H).
N/

[001861] 1-(1H-Indazol-5-y1)-4-(2-(trifluoromethyl)phenyl)butane-1,4-dione 498.
[001862] White solid (21 mg, 0.06 mmol). 1H NMR (DMSO-d6, 400 MHz) 6 ppm 3.26-3.37 (m, 2H), 3.45-3.57 (m, 211), 7.63 (d, J=9.03Hz, 111), 7.74 (t, J=7.39 Hz, 111), 7.85 (t, J=7.76Hz, 211), 7.98 (d, J=8.53Hz, 211), 8.29 (s, 111), 8.64 (s, 1H), 13.42 (brs, 1H); ESIMS found C18H13F3N202 m/z 347.0 (M+H).

N/

[001863] 1-(1H-Indazol-5-y1)-4-(p-tolyl)butane-1,4-dione 503.
[001864] White solid (15 mg, 0.05 mmol). 1H NMR (DMSO-d6, 400 MHz) 6 ppm 2.40 (s, 311), 3.40 (t, J=4Hz, 211), 3.46 (t, J=3.6Hz, 211), 7.36 (d, J=8Hz, 2H), 7.63 (d, J=8.8Hz, 1H), 7.93 (d, J=8Hz, 2H), 7.95 (d, J=8.8Hz, 111), 8.29 (s, 1H), 8.62 (s, 1H);
ESIMS found C181-116N202 miz 293.0 (M+H).

[001865] 1-(1H-Indazol-5-y1)-4-(pyridin-2-yObutane-1,4-dione 507.
[001866] White solid (20 mg, 0.07 mmol). 1H NMR (DMSO-d6, 400 MHz) 6 ppm 3.49-3.54 (m, 2H), 3.54-3.59 (m, 2H), 7.62 (d, J=8.78Hz, 1H), 7.69 (ddd, J=7.40Hz, J=4.77Hz, J=1.38Hz, 1H), 7.93-7.99 (m, 2H), 8.03 (dt, J=1.76Hz, J=7.52Hz, 1H), 8.29 (s, 1H), 8.62 (s, 1H), 8.78 (td, J=1.00Hz, J=4.85Hz, 1H), 13.40 (brs, 1H);
ES1MS found C161-113N302 172/Z 280.1 (M+H).
N/

[001867] 1-(1H-Indazol-5-y1)-4-phenylbutane-1,4-dione 513.
[001868] White solid (18 mg, 0.06 mmol). 1H NMR (DMSO-d6, 400 MHz) 6 ppm 3.40-3.46 (m, 2H), 3.46-3.53 (m, 2H), 7.56 (t, J=7.28, 2H), 7.60-7.70 (m, 2H), 7.96 (dd, J=8.78Hz, J=1.51Hz, 1H), 8.01-8.07 (m, 2H), 8.29 (s, 1H), 8.62 (s, 1H), 13.39 (brs, 1H); ESIMS found C17Hi4N202 m/z 279.0 (M+H).

[001869] 1-(Furan-2-y1)-4-(1H-indazol-5-yl)butane-1,4-dione 515.
[001870] White solid (12 mg, 0.05 mmol). 1H NMR (DMSO-d6, 400 MHz) 6 ppm 3.23 (dd, J=6.78Hz, J=5.27Hz, 2H), 3.47 (dd, J=6.90Hz, J=5.14Hz, 2H), 6.74 (dd, J=3.51Hz, J=1.76Hz, 1H), 7.51 (dd, J=3.51Hz, J=0.75Hz, 1H), 7.62 (d, J=8.78Hz, 1H), 7.95 (dd, J=1.76Hz, J=8.74Hz, 1H), 8.01 (dd, J=0.7611z, J=1.52Hz, 1H), 8.28 (s, 1H), 8.60 (s, 1H), 13.40 (brs, 1H); ESIMS found Ci5Hi2N203 inlz 269.1 (M+H).

-õ- , Os0 HN

[001871] 1-(1H-Indo1-3-y1)-4-(o-tolyl)butane-1,4-dione 518.
[001872] Yellow solid (14 mg, 0.05 mmol). 1H NMR (DMSO-d6, 400 MHz) 6 ppm 2.39 (s, 3H), 3.22-3.33 (m, 411), 7.14-7.25 (m, 2H), 7.26-7.39 (m, 2H), 7.40-7.55 (m, 211), 7.87 (d, J=7.53Hz, 1H),8.15 (d, J=7.03Hz, 111), 8.41 (s, 111), 11.97 (brs, 1H);
ESIMS found Ci9Hi7NO2 m/z 292.2 (M+H).

HN

[001873] 1-(1H-Indo1-3-y1)-4-(thiophen-2-yl)butane-1,4-dione 524.
[001874] White solid (28 mg, 0.10 mmol). 1H NMR (DMSO-d6, 400 MHz) 6 ppm 3.26-3.37 (m, 4H), 7.13-7.23 (m, 2H), 7.27 (dd, J=4.77Hz, J=3.76Hz, 114), 7.47 (d, J=7.4311z, 1H), 8.00 (d, J=5.02Hz, 1H), 8.04 (dd, J=3.76Hz, J=1.00Hz, 1H), 8.13 (d, J=7.5411z, 1H), 8.40 (s, 111), 11.96 (brs, 1H); ESIMS found CI6H13NO2S inlz 283.9 (M+H).
o HN¨N

[001875] 1-(1H-Indazol-3-y1)-4-(o-tolyl)butane-1,4-clione 528.
[001876] Yellow solid (30 mg, 0.10 mmol). 1H NMR (DMSO-d6, 400 MHz) 6 ppm 2.38 (s, 3H), 3.33-3.43 (m, 211), 3.48-3.60 (m, 2H), 7.25-7.40 (m, 311), 7.40-7.53 (m, 2H), 7.69 (d. J=8.04Hz, 111), 7.88 (d, J=7.52Hz, 111), 8.15 (d, J=7.80Hz, 1H);
ESIMS
found Ci8H16N202m/z 293 (M+H).
o [001877] 1-(1H-Indazol-3-y1)-4-(m-tolypbutane-1,4-dione 529.
[001878] White solid (85 mg, 0.29 mmol). NMR (DMSO-d6, 400 MHz) 6 ppm 2.40 (s, 3H), 3.42-3.49 (m, 2H), 3.50-3.56 (m, 2H), 7.31 (ddd, J=8.03Hz, J=7.03Hz, J=1.00Hz, 1H), 7.41-7.51 (m, 3H), 7.69 (d, J=8.53Hz, 1H), 7.80-7.86 (m, 2H), 8.15 (dt, J=8.09Hz, J=0.97Hz, 1H), 13.87 (brs, 1H); ESIMS found Ci8H16N202 nitz 293.1 (M+H).
Example 3 [001879] Preparation of 1-(5,8-dihydroxy-2,3 -dihydrobenzo [b][1,4] dioxin-6-y1)-3 -phenylpropane-1,3 -dione (3) and 1-(5,8-dimethoxy-2,3 -dihydrobenzo [b][1,4] dioxin-6-y1)-3-phenylpropane-1,3-dione (6) is depicted below in Scheme 17.
NN Br 0 /o -CHO N 1,1 HO S A i&
+
TEA, dioxaneo 0 xxxm LXXX 14 Scheme 17 Step 1 [001880] To a well stirred solution of 1-(2,3-dihydrobenzo[b] [1,4]dioxin-6-y1)-3-(dimethylamino)propan-l-one (VOCIII) (100 mg, 0.425 mmol, 1.0 eq) in 1,4-dioxane (3mL) was added nicotinaldehyde (L300) (55 mg, 0.511 mmol, 1.2 eq), 3-ethy1-5-(2-hydroxyethyl)-4-methylthiazolium bromide (32 mg, 0.128 mmol, 0.3 eq) and TEA
(0.5 mL). The reaction mixture was refluxed for 16 h. TLC analysis (PE:Et0Ac 3:1) showed the reaction was complete. The solution was cooled to room temperature and diluted with water (20 mL). The product was extracted with Et0Ac (3 x 30 mL). The combined organic layers was dried over anhydrous Na2504, filtered and concentrated under reduced pressure. The residue was purified by HPLC to give 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-y1)-4-(pyridin-3-yebutane-1,4-dione (14) as a white solid. (13 mg, 0.04 mmol, 10.3%
yield). 1H NMR (CDC13, 400 MHz) 6 ppm 3.43 (s, 4H), 4.27-4.31 (m, 2H), 4.31-4.38 (m, 2H), 6.94 (AA'BB'quartet, 1H), 7.42-7.49 (m, 1H), 7.55-7.61 (m, 2H), 8.31 (d, J=8.4Hz, 114), 8.81 (brs, 1H), 9.28 (brs, 111); ESIMS found Ci7Hi5N04 m/z 298.0 (M+H).

[001881] The following compound was prepared in accordance with the procedure described in the above Example 3.
o [001882] 1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-y1)-4-(pyridin-4-yl)butane-1,4-dione 15.
[001883] White solid (30 mg, 0.10 mmol). 1H NWIR (CDC13, 400 MHz) 6 ppm 3.32-3.50 (m, 4H), 4.24-4.45 (m, 4H), 6.94 (AA'BB'quartet, 1H), 7.52-7.64 (m, 2H), 7.82 (d, J=6Hz, 2H), 8.84 (d, J=5.6Hz, 211); ESIMS found Ci711i5N04 m/z 298.0 (M+H).

[001884] 1-(3,4-Dimethoxypheny1)-4-(pyridin-2-yl)butane-1,4-dione 207.
[001885] White solid (12 mg, 0.04 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.46 (t, J=6.4Hz, 211), 3.69 (t, J=6.4Hz, 2H), 3.93 (s, 3H), 3.97 (s, 3H), 6.93 (d, J=8.4Hz, 1H), 7.51 (dd, J=4.8Hz, J=7.6Hz, 1H), 7.58 (s, 1H), 7.71 (dd, J=2Hz, J=8.4Hz, 1H), 7.87 (t, 1E1), 8.07 (d, J=7.6Hz, 1H), 8.74 (d, J=4.4Hz, 1H); ESIMS found C17Hi7N04 mlz 300.0 (M+H).
NI
0 I. o [001886] 1-(3,4-Dimethoxypheny1)-4-(pyridin-3-yl)butane-1,4-dione 208.
[001887] White solid (10 mg, 0.03 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.41-3.53 (m, 411), 3.94 (s, 3H), 3.97 (s, 3H), 6.94 (d, J=8.4Hz, 1H), 7.48 (dd, J=4.8Hz, J=7.6Hz, 111), 7.56 (d, J=1.6Hz, 1H), 7.71 (dd, J=1.6Hz, J=8Hz, 111), 8.34 (d, J=8Hz, 1H), 8.82 (d, J=3.2Hz, 111), 9.29 (s, IH); ESIMS found Ci7H17N04 m/z 300.0 (M+H).

o 0 14.1 [001888] 1 -(3,4-Dimethoxypheny1)-4-(pyridin-4-yl)butane-1,4-dione 209.
[001889] White solid (40 mg, 0.13 mmol). 111 NMR (CDC13, 400 MHz) 6 ppm 3.42 (t, J=6Hz, 2H), 3.48 (t, J=6.4Hz, 211), 3.94 (s, 3H), 3.97 (s, 3H), 6.93 (d, J=8Hz, 1H), 7.56 (d, J=2Hz, 1H), 7.70 (dd, J=2Hz, J=8.4Hz, 1H), 7.83 (dd, J=1.2Hz, J=8.4Hz, 2H), 8.85 (dd, J=1.6Hz, J=6Hz, 211); ESIMS found C171117N04 m/z 300.0 (M+H).
0 Nj [001890] 1 -(2,3 -Dihydrobenzo [b] [1,4] dioxin-6-y1)-4-(pyrimidin-2-yl)butane-1,4-dione 339.
[001891] White solid (20 mg, 0.07 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.46 (t, J=6.40Hz, 2H), 3.65 (t, J=6.30Hz, 211), 4.24-4.36 (m, 4H), 6.86-6.95 (m, 1H), 7.46 (t, J=4.77Hz, 1H), 7.51-7.61 (m, 2H), 8.95 (d, J=4.90Hz, 2H); ESINIS
found Ci6H14N204 m/z 299.0 (M+H).

[001892] 1 -(2,3 -Dihydrob enzo [b][1,4]dioxin-6-y1)-4-(pyrimidin-4-yl)butane-1,4-dione 340.
[001893] White solid (30 mg, 0.10 mmol). 111 NMR (CDC13, 400 MHz) 6 ppm 3.39-3.46 (m, 211), 3.57-3.64 (m, 2H), 4.26-4.37 (m, 411), 6.89-6.96 (m, 1H), 7.52-7.60 (m, 211), 7.91 (dd, J=5.02Hz, J=1.51Hz, 1H), 8.99 (d, J=5.02Hz, 111), 9.40 (d, J=1.26Hz, 1H); ESEVIS found C16H14N204 m/z 299.1 (M+H).

,N

o 0 [001894] 1-(2,3-Dihydrobenzo [b] [1,4]dioxin-6-y1)-4-(pyridazin-3-yl)butane-1,4-dione 341.
[001895] White solid (30 mg, 0.10 mmol). 1H NMR (CDC13, 400 MHz) 6 ppm 3.41-3.48 (m, 2H), 3.75-3.84 (m, 2H), 4.24-4.34 (m, 4H), 6.87-6.94 (m, 1H), 7.50-7.58 (m, 2H), 7.64 (dd, J=8.53Hz, J=5.02Hz, 1H), 8.11 (dd, J=8.53Hz, J=1.76Hz, 1H), 9.33 (dd, J=5.02Hz, J=1.76Hz, 1H); ESIMS found C16H14N204 m/z 299.0 (M+H).

I

[001896] 1-(Chroman-6-y1)-4-(pyrimidin-2-yl)butane-1,4-dione 362.
[001897] Brown oil (175.7 mg, 0.59 mmol). 1H NMR (DMSO-d6, 500 MHz) 6 ppm 1.95 (quin, J=5.50 Hz, 2H), 2.81 (t, J=6.31 Hz, 2H), 3.36 (t, J=5.50 Hz, 2H), 3.50 (t, J=6.00 Hz, 2H), 4.22 (t, J=5.20 Hz, 2H), 6.84 (d, J=8.78 Hz, 1H), 7.72-7.76 (m, 2H), 7.77 (s, 1H), 9.04 (d, J=4.94 Hz, 2H); ESIMS found Ci7H16N203 m/z 296.9 (M+H).

[001898] 1-(Benzo [d][1,3]dioxo1-5-y1)-4-(pyrimidin-2-yl)butane-1,4-dione 372.
[001899] Light brown solid (55.2 mg, 0.19 mmol). 1H NMR (DMSO-d6, 500 MHz) 6 ppm 3.38 (t, J=6.10 Hz, 2H), 3.51 (t, J=6.10 Hz, 2H), 6.15 (s, 2H), 7.06 (d, J=8.23 Hz, 1H), 7.47 (d, J=1.65 Hz, 1H), 7.68 (dd, J=8.23, 1.65 Hz, 1H), 7.74 (t, J=4.81 Hz, 1H), 9.04 (d, J=4.39 Hz, 2H); ESIMS found C15H12N204 m/z 385.1 (M+H).

Me0 õ N

Me0 [001900] 1-(3,4-Dimethoxypheny1)-4-(pyrimidin-5-y1)butane-1,4-dione 430.
[001901] White solid (10 mg, 0.03 mmol). 11-1 NMR (CDC13, 400 MHz) 6 ppm 3.40 (t, J=5.6Hz, 2H), 3.51 (t, J=6Hz, 2H), 3.93 (s, 3H), 3.97 (s, 3H), 6.93 (d, J=8.4Hz, 1H), 7.53 (d, J=2Hz, 1H), 7.69 (dd, J=2Hz, J=8.4Hz, 1H), 9.33 (s, 2H), 9.39 (s, 1H);
ESIMS found C16H16N204 in/z 301.0 (M+H).

Me0 MeO

[001902] 1-(3,4-Dimethoxypheny1)-4-(pyrimidin-2-yl)butane-1,4-dione 431.
[001903] White solid (70 mg, 0.23 mmol). NMR (CDC13, 400 MHz) 6 ppm 3.51 (t, J=6.4Hz, 2H), 3.68 (t, J=6.4Hz, 2H), 3.93 (s, 3H), 3.96 (s, 3H), 6.92 (d, J=8.4Hz, 1H), 7.48 (t, J=4.8Hz, 1H), 7.55 (d, J=1.6Hz, 1H), 7.70 (dd, J=2Hz, J=8.4Hz, 1H), 8.96 (d, J=4.4Hz, 2H); ESIMS found C16H16N204 inlz 301.1 (M+H).
o N
Me0 N) MeO

[001904] 1-(3,4-Dimethoxypheny1)-4-(pyrimidin-4-yl)butane-1,4-dione 432.
[001905] White solid (40 mg, 0.13 mmol). NMR (CDC13, 400 MHz) 6 ppm 3.48 (t, J=6Hz, 2H), 3.62 (t, J=6Hz, 2H), 3.93 (s, 3H), 3.96 (s, 3H), 6.92 (d, J=8Hz, 1H), 7.54 (d, J=1.2Hz, 1H), 7.68 (d, J=8Hz, 1H), 7.92 (d, J=4.8Hz, 1H), 9.00 (d, J=5.4Hz, 1H), 9.41 (s, 1H); ESIMS found C16H16N204 in/z 301.0 (M+H).
,N
0 N' Me0 Me0 [001906] 1 -(3 ,4-Dimethoxypheny1)-4-(pyridazin-3 -yebutane-1,4-dione 433.
[001907] White solid (70 mg, 0.23 mmol). IHNMR (CDC13, 400 MHz) 6 ppm 3.52 (t, J=6Hz, 211), 3.84 (t, J=6Hz, 2H), 3.93 (s, 311), 3.97 (s, 3H), 6.94 (d, J=8.4Hz, 111), 7.56 (d, J=1.6Hz, 111), 7.62-7.74 (m, 211), 8.15 (dd, J=2Hz, J=8.4Hz, 1H), 9.36 (dd, J=2Hz, J=4.8Hz, 111); ESIMS found C16Hi6N204 m/z 301.1 (M+H).
O N

[001908] 1-(2,3-Dihydrobenzo [b] [1,4]dioxin-6-y1)-4-(3-methylpyridin-2-y1) butane-1,4-dione 568.
[001909] White solid (207.8 mg, 0.30 mmol, 7.9% yield). 111 NMR (DMSO-d6, 500 MHz) 6 ppm 2.45 (s, 3H), 3.29-3.32 (m, 2H), 3.42-3.45 (m, 211), 4.28-4.30 (m, 2H), 4.32-4.34 (m, 2H), 6.98 (d, J=8.4Hz, 1H), 7.47 (d, J=2.1Hz, 111), 7.51-7.55 (in, 2H), 7.78 (dd, J=0.7Hz, 7.7Hz, 1H), 8.59 (dd, J=1.0Hz, J=4.6Hz, 1H); ESIMS found CislliiNat m/z 312.0 (M+H).
O N

[001910] 1 -(2,3 -Dihydrobenzo [b][1,4] dioxin-6-y1)-4-(3 -fluoropyridin-2-y1) butane-1,4-dione 569.
[001911] White solid (94.8 mg, 0.30 mmol, 3.8% yield). 1H NMR (DMSO-d6, 500 MHz) 6 ppm 3.32-3.34 (m, 211), 3.43-3.46 (m, 2H), 4.29-4.30 (m, 2H), 4.33-4.34 (m, 2H), 6.99 (d, J=8.4Hz, 111), 7.48 (d, J=2.1Hz, 1H), 7.54 (dd, J=2.1Hz, J=8.4Hz, 111), 7.76-7.78 (m, 1H), 7.88-7.92 (m, 111), 8.59 (dt, J1.4Hz, J=4.5Hz, 1H); ESIMS
found C17H14FNO4 m/z 315.9 (M+H).
O N

[001912] 1-(2,3-Dihydrobenzo[b] [1,4] dioxin-6-y1)-4-(3 -(trifluoromethyl) pyridin-2-yl)butane-1,4-dione 570.
[001913] Tan solid (449 mg, 1.23 mmol, 22.0% yield). 1H NMR (DMSO-d6, 500 MHz) 6 ppm 3.32-3.35 (m, 211), 3.45-3.48 (m, 2H), 4.29-4.30 (m, 214), 4.33-4.34 (m, 2H), 6.99 (d, J=8.4Hz, 1H), 7.48 (d, J=2.1Hz, 1H), 7.55 (dd, J=2.1Hz, J=8.5Hz, 1H), 7.84 (dd, J=4.9Hz, J=7.9Hz, 1H), 8.37 (d, J=8.0Hz, 1H), 8.96 (d, J=4.6Hz, 111); ESIMS
found Ci3H14F3N04 m/z 366.3 (M+H).

[001914] 1-(2-Fluoropheny1)-4-(pyrimidin-2-yObutane-1,4-dione 712.
[001915] Off-white solid (167.2 mg, 0.65 mmol). 1H NMR (DMSO-d6, 500 MHz) 6 ppm 3.39 (m, 2H), 3.56 (t, J=6.10 Hz, 2H), 7.34-7.41 (m, 214), 7.66-7.71 (m, 1H), 7.74 (t, J=4.94 Hz, 1H), 7.85 (td, J=7.68, 1.65 Hz, 1H), 9.04 (d, J=4.94 Hz, 214);
ESIMS found C14H1iFN202 m/z 259.0 (M+H).

[001916] 1-(Pyrimidin-2-y1)-4-(o-tolyl)butane-1,4-dione 715.
[001917] Brown solid (17.9 mg, 0.07 mmol). 1H NMR (DMSO-d6, 500 MHz) 6 ppm 2.38 (s, 3H), 3.33 (t, J=6.10 Hz, 2H), 3.54 (t, J=6.10 Hz, 2H), 7.30 (d, J=7.43 Hz, 1H), 7.35 (t, J=7.67 Hz, 111), 7.44 (td, J=7.60, 1.10 Hz, 1H), 7.74 (t, J=4.90 Hz, 1H), 7.86 (d, J=7.68 Hz, 1H), 9.04 (d, J=4.94 Hz, 211); ESIMS found C15Hi4N202 inlz 255.0 (M+H).
0 F3c [001918] 1 -(Pyrimidin-2-y1)-4-(2 -(trifluoromethyl)phenyl)butane-1,4-dione 716.
[001919] Light brown solid (85.8 mg, 0.28 mmol). 1H NMR (DMSO-d6, 500 MHz) 6 ppm 3.34 (t, J=6.30 Hz, 2H), 3.56 (t, J=6.10 Hz, 2H), 7.72-7.77 (m, 2H), 7.81-7.88 (m, 2H), 7.92 (d, J=7.14 Hz, 1H), 9.05 (d, J=4.94 Hz, 2H); ESIMS found Ci5tl11F3N202 m/z 309.0 (M+H).

[001920] 1-Pheny1-4-(pyrimidin-2-yl)butane-1,4-dione 718.
[001921] Off-white solid (186.5 mg, 0.78 mmol). NMR
(DMSO-d6, 500 MHz) 6 ppm 3.46 (t, J=6.10 Hz, 2H), 3.56 (t, J=6.10 Hz, 2H), 7.56 (t, J=7.70 Hz, 2H), 7.67 (t, J=7.40 Hz, 1H), 7.75 (t, J=4.94 Hz, 1H), 8.02 (d, J=7.36 Hz, 2H), 9.05 (d, J=4.94 Hz, 2H); ESIMS found Ci4H12N202 m/z 241.1 (M+H).

[001922] 1-(Pyrimidin-2-y1)-4-(5,6,7,8-tetrahydronaphthalen-2-yl)butane-1,4-dione 737.
[001923] Off-white solid (480 mg, 1.63 mmol, 24.2% yield). 'H NMR (DMSO-d6, 500 MHz) 6 ppm 1.75-1.77 (m, 4H), 2.78-2.80 (m, 4H), 3.38-3.41 (m, 2H), 3.51-3.53 (m, 2H), 7.21 (d, J=7.8Hz, 1H), 7.61-7.71 (m, 2H), 7.74 (t, J=4.9Hz, 1H), 9.04 (d, J=4.9Hz, 1H); ESIMS found C18Hi8N202 m/z 295.0 (M+H).

[001924] 1 -(3 -Chloropyridin-2-y1)-4-(2,3 -dihydrob enzo [b][1 ,4]dioxin-6-y1) butane-1,4-dione 767.

[001925] White solid (311 mg, 0.94 mmol, 12.6% yield). Ili NMR (DMSO-d6, 500 MHz) 6 ppm 3.30-3.34 (m, 2H), 3.40-3.43 (m, 2H), 4.28-4.30 (m, 2H), 4.33-4.34 (m, 2H), 6.99 (d, J=8.4Hz, 1H), 7.48 (d, J=2.1Hz, 1H), 7.54 (dd, J=2.1Hz, J=8.4Hz, 1H), 7.65 (dd, J=4.6Hz, J=8.2Hz, 1H), 8.08 (dd, J=1.3Hz, J=8.211z, 1H), 8.67 (dd, J=1.3Hz, J=4.5Hz, 1H); ESIMS found Ci7H14C1N04 m/z 331.9 (M+H).
Example 4 [001926] Preparation of 1-(5,8-dihydroxy-2,3-dihydrobenzo [b][1,4]dioxin-6-y1)-3 -phenylpropane-1,3 -dione (3) and 1-(5,8-dimethoxy-2,3 -dihydrobenzo [b][1,4] dioxin-6-y1)-3-phenylpropane-1,3-dione (6) is depicted below in Scheme 18.
0 Ph OMe 0 LXXXI OMe 0 o Br On PePh Ph K2CO3, acetone, reflux \

OMe OMe XVI LXXXH
NaOH
OH 0 0 OMe 0 0 Ph BBr3 Ph DCM

OH OMe Scheme 18 Step 1 [001927] A solution of crude 2-bromo-1-(5,8-dimethoxy-2,3-dihydrobenzo [b] [1,4]dioxin-6-yl)ethanone (XVI) (1.1 g, 3.36 mmol), 1,3-diphenylpropane-1,3-dione ("XXXI) (778 mg, 3.47 mmol), K2CO3 (480 mg, 3.47 mmol), and KI (10 mg) in acetone was heated to reflux for 2 h. The reaction mixture was cooled, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel (20%
Et0Ac/PE) to give 2-benzoy1-4-(5,8-dimethoxy-2,3-dihydrobenzo [b][1,4]dioxin-6-y1)-1-phenylbutane-1,4-dione (L)00(H) (1.1 g, 2.39 mmol, 70% yield for two steps) as a yellow solid. 1H NMR (CDC13, 500 MHz) 6 ppm 3.79-3.88 (m, 5H), 3.90 (s, 3H), 4.36 (dd, J-19.32Hz, 4.52Hz, 4H), 6.08 (t, J=6.40Hz, 1H), 6.98 (s, 1H) 7.43-7.52 (m, 4H), 7.54-7.63 (m, 2H), 8.02 (d, J=7.53Hz, 4H).
Step 2 [001928] A solution of 2-benzoy1-4-(5,8-dimethoxy-2,3-dihydrobenzo [b][1,4]dioxin-6-y1)-1-phenylbutane-1,4-dione (LXXXII) (1.1 g, 2.4 mmol) in Et0H (20 mL) was added 2% aqueous NaOH (20 mL, 10 mmol) dropwise at 10 C and then stirred at room temperature for 18 h. The reaction mixture was filtered, and the solid was washed with water (20 mL), 10% Et0Ac/PE (50 mL) and dissolved in DCM (60 mL). The DCM
layer was washed with 0.5 N HC1 (20 mL), brine (20 mL), dried over anhydrous Na2SO4 and concentrated under vacuum to produce 1-(5,8-dimethoxy-2,3-dihydrobenzo [b]
[1,4]
dioxin-6-y1)-3-phenylpropane-1,3-dione (6) (750 mg, 2.19 mmol, 88% yield) as a yellow solid. 11-1 NMR (CDC13, 500 MHz) 6 ppm 3.42 (d, J=6.02Hz, 2H), 3.49 (d, J=6.02Hz, 2H), 3.87 (s, 3H), 3.96 (s, 3H) ,4.37 (dd, J=14.18Hz, 4.89Hz, 4H), 6.97 (s, 1H), 7.42-7.52 (m, 2H), 7.56 (d, J=7.28Hz, 1H), 8.04 (d, J=7.28Hz, 2H).
Step 3 [001929] To a solution of 1-(5,8-dimethoxy-2,3-dihydrobenzo [b][1,4]dioxin-6-y1)-3-phenylpropane-1,3-dione (6) (750 mg, 2.1 mmol) in anhydrous DCM (100 mL) was added a solution of BBr3 (0.56 mL, 6.3 mmol) in anhydrous DCM (1 mL) at -10 C
dropwise. This reaction solution was stirred at -10 C for 3 h and then quenched with ice water (40 mL). The DCM layer was dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by the silica gel column (10%
Me0H/DCM), and recrystallized with (MeOH:DCM:Et0Ac= 1:2:2) (20 mL) to yield 1-(5,8-dihydroxy-2,3-dihydrobenzo [b][1,4]dioxin-6-y1)-3-phenylpropane-1,3-dione (3) as a light yellow solid (200 mg, 0.64 mmol, 29.0% yield). 114 NMR (DMSO-d6, 500 MHz) 6 ppm 3.23-3.49 (m, 4H), 4.26 (d, J=4Hz, 2H), 4.33 (d, J=2.4Hz, 2H), 6.96 (s, 1H), 7.55 (t, J=7.2Hz, 2H), 7.66 (t, J=7.2Hz, 1H), 8.01 (d, J=7.6Hz, 2H), 9.06 (s, 1H), 11.81 (s, 1H); ESIMS
found C17E11406 in/z 315.1 (M+H).

[001930] The following compound was prepared in accordance with the procedure described in the above Example 4.

o OH 0 OH

[001931] 1-(7,8-dihydroxy-2,3 -dihydrobenzo [b][1,4]dioxin-6-y1)-4-phenylbutane-1,4-dione 4.
[001932] Light yellow solid (160 mg, 0.51 mmol, 69.7% yield). 1H NMR (CDC13, MHz): 6 ppm 3.37-3.45 (m, 4H), 4.27 (t, J=4Hz, 214), 4.41 (t, J=4Hz, 2H), 5.49 (s, 1H), 7.03 (s, 1H), 7.49 (t, J=7.6Hz, 2H), 7.59 (t, J=7.6Hz, 1H), 8.03 (d, J=7.6Hz, 1H), 12.08 (s, 1H); ESIMS found C18H1606 ni/z 329.1 (M+H).
Evaluation of Biological Activity [001933] The biological activity of the compounds described herein can be tested using any suitable assay known to those of skill in the art, e.g., those assays described in WO
2001/053268 or WO 2005/009997, both of which are incorporated by reference in their entireties. For example, the activity of a compound may be tested using one or more of the test methods described below.
Example 5 [001934] Compounds that enhance the Wnt activity, or Activators, were assayed as follows. Reporter cell lines were generated by stably transducing cells of colon cancer cell lines (with a lentiviral construct that included a Wnt-responsive promoter driving expression of the firefly luciferase gene).
[001935] Lentiviral constructs were made in which the SP5 promoter, a promoter having eight TCF/LEF binding sites derived from the SP5 promoter, was linked upstream of the firefly luciferase gene. The lentiviral constructs also included a hygromycin resistance gene as a selectable marker. The SP5 promoter construct was used to transduce SW480 cells, a colon cancer cell line having a mutated APC gene that generates a truncated APC protein, leading to de-regulated accumulation off3-catenin.
[001936] Cultured SW480 cells bearing a reporter construct were distributed at approximately 10,000 cells per well into 384- or 96-well multiwell plates.
Compounds from a small molecule compound library were then added to the wells in half-log dilutions using a maximum concentration of three or ten micromolar. A series of control wells for each cell type received only buffer and compound solvent DMSO.
Twenty-four hours after the addition of compound, reporter activity for luciferase was assayed, for example, by addition of the BrightGlo luminescence reagent (Promega) and the Victor3 plate reader (Perkin Elmer). Readings were normalized to DMSO only treated cells, and any activities above DMSO were considered activation. Compounds were considered activators if reporter activities were 2x fold or greater than DMSO. EC50 is the concentration at half maximal activation. Table 2 shows the activity of selected activators.
Table 2.
Wnt Wnt Wnt Compound activation, Compound activation, Compound activation, EC50 (uM) EC50 (1M) EC50 (1M) 1 0.005 265 0.201 379 >10 2 0.001-0.003 269 >10 385 0.165 3 >10 274 6.8 425 5.95 4 >10 275 0.009 426 8.80 9 0.1 278 0.018 430 >10 >10 281 0.061 431 >10 11 0.013 287 0.087 432 4.8 12 0.005 288 >10 433 >10 13 0.192 291 0.125 442 2.15 14 0.306 292 0.595 445 0.010 0.09 294 1.721 447 >10 16 0.007 300 0.018 451 0.037 18 >10 301 0.039 455 0.032 19 0.003 307 0.055 456 0.673 21 0.031 310 0.068 457 2.89 28 0.009 313 0.044 462 0.424 61 0.025 314 0.016 485 >10 68 0.006 316 >10 495 0.008 69 >10 317 >10 497 0.048 71 0.0025 319 0.279 498 0.012 76 >10 320 >10 503 0.487 80 0.01 325 0.063 507 0.036 207 >10 326 0.117 513 0.039 208 >10 329 0.089 515 0.127 209 >10 332 0.680 518 0.646 210 0.002 334 >10 524 0.088 213 0.018 338 0.064 528 0.148 214 0.01 339 0.009 529 0.695 216 0.011 340 0.209 538 0.063 217 0.343 341 0.095 541 2.81 222 0.003 342 0.009 544 0.9 232 0.134 343 0.351 547 >10 235 0.494 344 0.307 554 >10 238 >10 345 >10 557 0.026 240 0.669 346 0.024 559 0.340 242 0.789 358 0.014 560 0.055 248 >10 362 0.188 562 0.106 249 0.004 364 0.013 569 0.00196 252 0.001 365 0.033 570 0.026 255 0.017 368 0.016 718 0.681 258 0.016 372 0.097 737 0.022 261 0.042 374 0.013 767 0.002164 263 >10 375 0.071 [001937] The term "comprising" as used herein is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.

Claims (120)

WHAT IS CLAIMED IS:
1. A compound of Formula or a pharmaceutically acceptable salt thereof, wherein:
Ring A is a 7-12 membered heteroaryl, wherein a carbon atom on the ring is attached to the carbonyl carbon;
Ring B is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, wherein a carbon atom on the ring is attached to the carbonyl carbon;
R1 is a substituent attached to Ring A and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, halide, -OR3, CF3, and CN;
R2 is a substituent attached to Ring B and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R3b)2, -C1-3 haloalkyl, halide, -OR3, CF3, and CN;
each R3 is independently selected from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, and CF3;
each R3b is independently selected from the group consisting of H and unsubstituted -C1-3 alkyl;
each n is an integer of 1 to 10; and each m is an integer of 1 to 5;
with the proviso that the compound of Formula I is not a compound selected from the group consisting of:

2. The compound of claim 1, wherein Ring A is a 9-membered bicyclic heteroaryl ring containing 1-3 heteroatoms selected from the group consisting of N, O, and S.
3. The compound of any one of claims 1-2, wherein Ring A is selected from the group consisting of
4. The compound of any one of claims 1-3, wherein Ring A is selected from the group consisting of and
5. The compound of any one of claims 1-4, wherein Ring A is selected from the group consisting of
6. The compound of any one of claims 1-5, wherein Ring A is a 10-membered bicyclic heteroaryl ring containing 1-3 heteroatoms selected from the group consisting of N, O, and S.
7. The compound of any one of claims 1-6, wherein Ring A is selected from the group consisting of.
8. The compound of any one of claims 1-7, wherein Ring A is selected from the group consisting of
9. The compound of any one of claims 1-8, wherein R1 is selected from the group consisting of H, F, Cl, Me, OMe, OH, CF3 and CN; and n is 1 or 2.
10. The compound of any one of claims 1-9, wherein R1 is H.
11. The compound of any one of claims 1-10, wherein R1 is F; and n is 1.
12. The compound of any one of claims 1-11, wherein Ring B is phenyl.
13. The compound of any one of claims 1-12, wherein is selected from the group consisting of (MeO)m ; and m is 1 or 2.
14. The compound of any one of claims 1-13, wherein is selected from the group consisting of
15. The compound of any one of claims 1-14, wherein Ring B is a 5-membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, O, and S.
16. The compound of any one of claims 1-15, wherein is selected from the group consisting of ; and m is 1 or 2.
17. The compound of any one of claims 1-16, wherein R2 is H.
18. The compound of any one of claims 1-17, wherein R2 is F; and m is 1.
19. The compound of any one of claims 1-18, wherein is selected from the group consisting of and ; and R2 is H.
20. The compound of any one of claims 1-19, wherein Ring B is a 6-membered heteroaryl containing 1-2 nitrogen atoms.
21. The compound of any one of claims 1-20, wherein is selected from the group consisting of and m is 1 or 2.
22. The compound of any one of claims 1-21, wherein R2 is H.
23. The compound of any one of claims 1-22, wherein R2 is F; and m is 1.
24. The compound of any one of claims 1-23, wherein is selected from the group consisting of ; and R2 is H.
25. The compound of any one of claims 1-24, wherein the compound of Formula I is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
26. A compound of Formula Ia:
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is Ring B is selected from the group consisting of each R1 is a substituent attached to Ring A and is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, halide, -OR3, CF3, and CN;
R2a is selected from the group consisting of unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R3b)2, -C1-3 haloalkyl, Cl, Br, I, -OR3a, CF3, and CN;

R2b is selected from the group consisting of unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R3b)2, -C1-3 haloalkyl, halide, -OR3a, CF3, and CN;
R2c is 2-5 substituents, each independently selected at each occurrence from the group consisting of unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R3b)2, -C1-3 haloalkyl, halide, -OR3, CF3, and CN;
R2d is 1-4 substituents, each independently selected at each occurrence from the group consisting of unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R3b)2, -C1-3 haloalkyl, halide, -OR3, CF3, and CN;
R2e is 1-4 substituents, each independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R3b)2, -C1-3 haloalkyl, halide, -OR3, CF3, and CN;
R2f is 1-3 substituents, each independently selected at each occurrence from the group consisting of unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R3b)2, -C1-3 haloalkyl, halide, -OR3, CF3, and CN;
R2g is 1-3 substituents, each independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R3b)2, -C1-3 haloalkyl, halide, -OR3, CF3, and CN;
each R3 is independently selected from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, and CF3;
each R3a is independently selected from the group consisting of unsubstituted ¨C2-6 alkyl, -C1-3 haloalkyl, and CF3;
each R3b is independently selected from the group consisting of H and unsubstituted ¨C1-3 alkyl;
each W is N or C, wherein at least two W are N;
each U is N or C, wherein at least one U is N and at least one U is C;
G is NH or O;
each J is N or C, wherein at least one J is C; and n is an integer of 1 to 7.
27. The compound of claim 26, wherein the compound of Formula Ia is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
28. A compound of Formula Ib:

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is Ring B is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, wherein a carbon atom on the ring is attached to the carbonyl carbon;
each R1 is independently selected at each occurrence from the group consisting of H, unsubstituted -C1,6 alkyl, -C1-3 haloalkyl, halide, -OR3, CF3, and CN;
each R2 is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R3b)2, -C1-3 haloalkyl, halide, -OR3, CF3, and CN;
each R3 is independently selected from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, and CF3;
each R3b is independently selected from the group consisting of H and unsubstituted ¨C1-3 alkyl;
each M is independently selected from the group consisting of N, C, S and O, wherein both M are not O and both M are not C;
m is an integer of 1 to 5; and n is an integer of 1 to 10.
29. The compound of claim 28, wherein the compound of Formula Ib is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
30. A compound of Formula Ic:
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is Ring B is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, wherein a carbon atom on the ring is attached to the carbonyl carbon;
each R1 is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, halide, -OR3, CF3, and CN;
each R2 is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R3b)2, -C1-3 haloalkyl, halide, -OR3, CF3, and CN;
each R3 is independently selected from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, and CF3;
each R3b is independently selected from the group consisting of H and unsubstituted ¨C1-3 alkyl;
each M is independently selected from the group consisting of N, C, S and O, wherein if one M is C, the other M is selected from the group consisting of N, S, and O;
m is an integer of 1 to 5; and n is an integer of 1 to 10.
31. The compound of claim 30, wherein the compound of Formula Ic is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
32. A compound of Formula Id:
or a pharmaceutically acceptable salt thereof, wherein:

Ring A is ;
Ring B is selected from the group consisting of and a 5-6 membered heteroarylR2e, wherein a carbon atom on the ring is attached to the carbonyl carbon;
each R1 is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, halide, -OR3, CF3, and CN;
R2a is selected from the group consisting of H, unsubstituted ¨C1-6 alkyl, -CH2OH, -CH2N(R3b)2, -C1-3 haloalkyl, CI, Br, I, -OR3a, CF3, and CN;
R2b is selected from the group consisting of H, unsubstituted ¨C2-6 alkyl, -CH2OH, -CH2N(R3b)2, -C1-3 haloalkyl, F, I, -OR3, CF3, and CN;
R2c is selected from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R3b)2, -C1-3 haloalkyl, F, Br, I, -OR3, CF3, and CN;
R2d is 2-5 substituents, each independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R3b)2, -C1-3 haloalkyl, halide, -OR3, CF3, and CN;
R2e is 1-3 substituents, each independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R3b)2, -C1-3 haloalkyl, halide, -OR3, CF3, and CN;
each R3 is independently selected from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, and CF3;
each R3a is independently selected from the group consisting of H, unsubstituted ¨
C2-6 alkyl, -C1-3 haloalkyl, and CF3;
each R3b is independently selected from the group consisting of H and unsubstituted ¨C1-3 alkyl;
Q is S or NH; and n is an integer of 1 to 5.
33. The compound of claim 32, wherein the compound of Formula Id is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof
34. A compound of Formula Ie:
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is Ring B is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, wherein a carbon atom on the ring is attached to the carbonyl carbon;
each R1 is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, halide, -OR3, CF3, and CN;
each R2 is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R3b)2, -C1-3 haloalkyl, halide, -OR3, CF3, and CN;
each R3 is independently selected from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3haloalkyl, and CF3;
each R3b is independently selected from the group consisting of H and unsubstituted ¨C1-3 alkyl;
each W is N or C, wherein at least one W is N;
Q is S or NH;
m is an integer of 1 to 5; and n is an integer of 1 to 4.
35. The compound of claim 34, wherein the compound of Formula Ie is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
36. A compound of Formula If:
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is Ring B is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, wherein a carbon atom on the ring is attached to the carbonyl carbon;
each R1 is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, halide, -OR3, CF3, and CN;
each R2 is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R3b)2, -C1-3 haloalkyl, halide, -OR3, CF3, and CN;
each R3 is independently selected from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, and CF3;
each R3b is independently selected from the group consisting of H and unsubstituted -C1-3 alkyl;
each W is N or C;
m is an integer of 1 to 5; and n is an integer of 1 to 5.
37. A compound of Formula Ig:
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is Ring B is selected from the group consisting of and a 5-6 membered heteroarylR2d, wherein a carbon atom on the ring is attached to the carbonyl carbon;
each R1 is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, halide, -0R3, CF3, and CN;
R2a is selected from the group consisting of unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R3b)2, -C1-3 haloalkyl, F, I, -OR3, CF3, and CN;
R2b is selected from the group consisting of unsubstituted -C2-6 alkyl, -CH2OH, -CH2N(R3b)2, -C1-3 haloalkyl, halide, -OR3, CF3, and CN;
R2c is 2-5 substituents, each independently selected at each occurrence from the group consisting of unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R3b)2, -C1-3 haloalkyl, halide, -OR3, CF3, and CN;
R2d is 1-3 substituents, each independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R3b)2, -C1-3 haloalkyl, halide, -OR3, CF3, and CN;
each R3 is independently selected from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, and CF3;
each R3b is independently selected from the group consisting of H and unsubstituted -C1-3 alkyl;
Q is selected from the group consisting of O, S, and NH; and n is an integer of 1 to 5.
38. A compound of Formula Ih:

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is Ring B is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, wherein at a carbon atorn on the ring is attached to the carbonyl carbon;
each R1 is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, halide, -OR3, CF3, and CN;
each R2 is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R3b)2, -C1-3 haloalkyl, halide, -OR3, CF3, and CN;
each R3 is independently selected from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, and CF3;
each R3b is independently selected from the group consisting of H and unsubstituted -C1-3 alkyl;
each W is N or C, wherein at least one W is N;
Q is selected from the group consisting of O, S, and NH;
m is an integer of 1 to 5; and n is an integer of 1 to 4.
39. A compound of Formula Ii:
or a pharmaceutically acceptable salt thereof, wherein:

Ring A is wherein a carbon atom on the ring is attached to the carbonyl carbon;
Ring B is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, wherein a carbon atom on the ring is attached to the carbonyl carbon;
each R1 is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, halide, -OR3, CF3, and CN;
each R2 is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R3b)2, -C1-3 haloalkyl, halide, -OR3, CF3, and CN;
each R3 is independently selected from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, and CF3;
each R3b is independently selected from the group consisting of H and unsubstituted -C1-3 alkyl;
each W is N or C, wherein at least one W is C;
Q is selected from the group consisting of O, S, and N;
in is an integer of 1 to 5; and n is an integer of 1 to 7.
40. The compound of claim 39, wherein the compound of Formula Ii is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
41. A compound of Formula II:
or a pharmaceutically acceptable salt thereof, wherein:
Ring C is a 5-6 membered heteroaryl, wherein a carbon atom on the ring is attached to the carbonyl carbon;
Ring D is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, wherein a carbon atom on the ring is attached to the carbonyl carbon;
each R4 is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, halide, -OR6, CF3, and CN;
each R5 is independently selected at each occurrence from the group consisting of H, unsubstituted -C1,6 alkyl, -CH2OH, -CH2N(R6b)2, -C1-3 haloalkyl, halide, -OR6, CF3, and CN;
each R6 is independently selected from the group consisting of H, unsubstituted -C1,6 alkyl, -C1-3 haloalkyl, and CF3;
each R6b is independently selected from the group consisting of H and unsubstituted -C1-3 alkyl;
p is an integer of 1 to 4; and q is an integer of 1 to 5.
with the proviso that the compound of Formula II is not a compound selected from the group consisting of:
42. The compound of claim 41, wherein Ring C is a 5-membered heteroaryl ring containing 1-3 heteroatoms selected from the group consisting of N, O, and S.
43. The compound of any one of claims 41-42, wherein is selected from the group consisting of and p is 1 or 2.
44. The compound of any one of claims 41-43, wherein
45. The compound of any one of claims 41-44, wherein Ring C is a 6-membered heteroaryl ring containing 1-2 nitrogens.
46. The compound of any one of claims 41-45, where is selected from the group consisting of and p is 1 or 2.
47. The compound of any one of claims 41-46, wherein is
48. The compound of any one of claims 41-47, wherein R4 is selected from the group consisting of H, F, Cl, Me, OMe, OH, CF3, and CN; and p is 1 or 2.
49. The compound of any one of claims 41-48, wherein R4 is H.
50. The compound of any one of claims 41-49, wherein R4 is F; and p is 1.
51. The compound of any one of claims 41-50, wherein Ring D is phenyl.
52. The compound of any one of claims 41-51, wherein is selected from the group consisting of and 1 is 1 or 2.
53. The compound of any one of claims 41-52, wherein is selected from the group consisting of
54. The compound of any one of claims 41-53, wherein Ring D is a 5-membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, O, and S.
55. The compound of any one of claims 41-54, wherein is selected from the group consisting of and q is 1 or 2.
56. The compound of any one of claims 41-55, wherein R5 is H.
57. The compound of any one of claims 41-56, wherein R5 is F; and q is 1.
58. The compound of any one of claims 41-57, wherein is selected from the group consisting of
59. The compound of any one of claims 41-58, wherein Ring B is a 6-membered heteroaryl containing 1-2 nitrogen atoms.
60. The compound of any one of claims 41-59, wherein is selected from the group consisting of and q is 1 or 2.
61. The compound of any one of claims 41-60, wherein R5 is H.
62. The compound of any one of claims 41-61, wherein R5 is F; and q is 1.
63. The compound of any one of claims 41-62, wherein is selected from the group consisting of and R5 is H.
64. The compound of any one of claims 41-63, wherein the compound of Formula II is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
65. A compound of Formula IIa:
IIa or a pharmaceutically acceptable salt thereof, wherein:
Ring C is Ring D is selected from the group consisting of , wherein a carbon atom on the ring is attached to the carbonyl carbon;
each R4 is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, halide, -OR6, CF3, and CN;
R5a is 1-5 substituents, each independently selected at each occurrence from the group consisting of unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R6b)2, -C1-3 haloalkyl, halide, -OR6a, CF3, and CN;
R5b is 1-4 substituents, each independently selected at each occurrence from the group consisting of unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R6b))2, -C1-3 haloalkyl, F, I, -OR6a, CF3, and CN;
R5c is 1-3 substituents, each independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R6)2, -C1-3 haloalkyl, halide, -OR6, CF3, and CN;
R5d is 1-2 substituents, each independently selected at each occurrence from the group consisting of unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R6)2, -C1-3 haloalkyl, halide, -OR6, CF3, and CN;
R5e is 1-3 substituents, each independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -CH7OH, -CH2N(R6b)2, -C1-3 haloalkyl, halide, -OR6, CF3, and CN;
each R6 is independently selected from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, and CF3;

each R6a is independently selected from the group consisting of H, unsubstituted -C2-6 alkyl, -C1-3 haloalkyl, and CF3;
each R6b is independently selected from the group consisting of H and unsubstituted ¨C1-3 alkyl;
each A is N or C, wherein at least two A are N;
each J is N or C, wherein at least one J is N and at least one J is C;
each U is N or C, wherein at least one U is C;
Q is O or N; and p is an integer of 1 to 4.
66. The compound of claim 65, wherein the compound of Formula IIa is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
67. A compound of Formula IIb:
or a pharmaceutically acceptable salt thereof, wherein:
Ring C is Ring D is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, wherein a carbon atom on the ring is attached to the carbonyl carbon;
each R4 is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, halide, -OR6a, CF3, and CN;
each R5 is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R6b)2, -C1-3 haloalkyl, halide, -OR6, CF3, and CN;
each R6 is independently selected from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, and CF3;
each R6a is independently selected from the group consisting of unsubstituted ¨C1-6 alkyl, -C1-3 haloalkyl, and CF3;
each R6b is independently selected from the group consisting of H and unsubstituted ¨C1-3 alkyl;

each A is N or C, wherein at least two A are N;
p is an integer of 1 to 3; and q is an integer of 1 to 5.
68. The compound of claim 67, wherein the compound of Formula IIb is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
69. A compound of Formula IIc:
or a pharmaceutically acceptable salt thereof, wherein:
Ring D is selected from the group consisting of wherein a carbon atom on the ring is attached to the carbonyl carbon;
each R4 is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, halide, -OR6, CF3, and CN;
R5a is selected from the group consisting of unsubstituted ¨C2-6 alkyl, -CH2OH, -CH2N(R6b)2, -C2-3 haloalkyl, iodide, -OR6a, and CN;
R5b is selected from the group consisting of unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R6b)2, -C2-3 haloalkyl, halide, -OR6a, and CN;

R5c is selected from the group consisting of unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R6b)2, -C1-3haloalkyl, F, Br, I, -OR6a, CF3, and CN;
R5d is is 2-5 substituents, each independently selected at each occurrence from the group consisting of unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R6b)2, -C1-3 haloalkyl, halide, -OR6a, CF3, and CN;
R5e is 1 substituent and selected from the group consisting of unsubstituted ¨C2-5 alkyl, -CH2OH, -CH2N(R6b)2, -C1-3 haloalkyl, F, I, -OR6, CF3, and CN;
R5f is 1-2 substituents, each independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R6b)2, -C1-3 haloalkyl, F, Br, I, -OR6, CF3, and CN;
R5g is 1-3 substituents, each independently selected at each occurrence from the group consisting of unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R6b)2, -C1-3 haloalkyl, halide, -OR6, CF3, and CN;
R51 is 1-2 substituents, each independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R6b)2, -C1-3 haloalkyl, halide, -OR6, CF3, and CN;
R5i is 1-4 substituents, each independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R6b)2, -C1-3 haloalkyl, halide, -OR6, CF3, and CN;
each R6 is independently selected from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, and CF3;
each R6a is independently selected from the group consisting of unsubstituted ¨C2-6 alkyl, -C1-3 haloalkyl, and CF3;
each R6b is independently selected from the group consisting of H and unsubstituted ¨C1-3 alkyl;
each J is N or C, wherein at least one J is C;
Q is S or O;
each U is N or C, wherein at least one U is N and at least one U is C; and p is an integer of 1 to 3.
70. The compound of claim 69, wherein the compound of Formula IIc is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
71. A compound of Formula IId:
or a pharmaceutically acceptable salt thereof, wherein:
Ring C is Ring D is selected from the group consisting of wherein a carbon atom on the ring is attached to the carbonyl carbon;
each R4 is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, halide, -OR6, CF3, and CN;
R5a is 1 substituent and selected from the group consisting of unsubstituted ¨C2-6 alkyl, -CH2OH, -CH2N(R6)9, -C1-3 haloalkyl, halide, -OR6a, and CN;

R5b is 1-4 substituents, each independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R6b)2, -C1-3 haloalkyl, halide, -OR6a, CF3, and CN;
R5c is 1-3 substituents, each independently selected at each occurrence from the group consisting of unsubstituted -C2-5 alkyl, -CH2OH, -CH2N(R6b)2, -C1-3 haloalkyl, halide, -OR6, CF3, and CN;
R5d is 1-2 substituents, each independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R6b)2, -C1-3 haloalkyl, halide, -OR6, CF3, and CN;
R5e is 1-4 substituents, each independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R6b)2, -C1-3 haloalkyl, halide, -OR6, CF3, and CN;
each R6 is independently selected from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, and CF3;
each R6a is independently selected from the group consisting of unsubstituted -6 alkyl, -C1-3 haloalkyl, and CF3;
each R6b is independently selected from the group consisting of H and unsubstituted -C1-3 alkyl;
each J is N or C, wherein at least one J is N and at least one J isC;
Q is S or O;
each U is N or C, wherein at least one U is C; and p is an integer of 1 to 3.
72. The compound of claim 7 1, wherein the compound of Formula IId is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
73. A compound of Formula IIe:

or a pharmaceutically acceptable salt thereof, wherein:
Ring C is wherein a carbon atom on the ring is attached to the carbonyl carbon;
Ring D is selected from the group consisting of and wherein a carbon atom on the ring is attached to the carbonyl carbon;
each R4 is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, halide, -OR6, CF3, and CN;
R5a is selected from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R6b)2, -C1-3 haloalkyl, F, Br, I, -OR6, CF3, and CN;
R5b is 1-4 substituents, each independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R6b)2, -C1-3 haloalkyl, halide, -OR6, CF3, and CN;
R5c is 1-4 substituents, each independently selected at each occurrence from the group consisting of unsubstituted -C2-5 alkyl, -CH2OH, -CH2N(R6b)2, -C1-3 haloalkyl, halide, -OR6, CF3, and CN;
R5d is 1-2 substituents, each independently selected at each occurrence from the group consisting of H, unsubstituted -C2-6 alkyl, -CH2OH, -CH2N(R6b)7, -C1-3 haloalkyl, halide, -OR6a, CF3, and CN;
each R6 is independently selected from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, and CF3;

each R6a is independently selected from the group consisting of unsubstituted -6 alkyl, -C1-3 haloalkyl, and CF3;
each R6b is independently selected from the group consisting of H and unsubstituted -C1-3 alkyl;
each A is N or C, wherein at least one A is C;
each U is N or C, wherein at least one U is N and at least one U is C;
p is an integer of 1 to 4.
74. A compound of Formula IIf:
or a pharmaceutically acceptable salt thereof, wherein:
Ring C is wherein a carbon atom on the ring is attached to the carbonyl carbon;
Ring D is selected from the group consisting of and a 5-membered heteroarylR5b, wherein a carbon atom on the ring is attached to the carbonyl carbon;
each R4 is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, halide, -OR6, CF3, and CN;
R5a is 1-5 substituents, each independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R6b)2, -C1-3 haloalkyl, halide, -OR6a, CF3, and CN;
R5b is 1-4 substituents, each independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R6b)2, -C1-3 haloalkyl, halide, -OR6, CF3, and CN;

each R6 is independently selected from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, and CF3;
each R6a is independently selected from the group consisting of unsubstituted -6 alkyl, -C1-3 haloalkyl, and CF3;
each R6b is independently selected from the group consisting of H and unsubstituted -C1-3 alkyl;
each A is N or C, wherein at least one A is N and at least one A is C;
Q is S or O; and p is an integer of 1 to 4.
75. A compound of Formula IIIa:
or a pharmaceutically acceptable salt thereof, wherein:
R10 is selected from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-haloalkyl, halide, -OR13, CF3, and CN;
R11 is selected from the group consisting of unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R13b)2, -C1-3 haloalkyl, halide, -OR13, CF3, and CN;
each R12 is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R13b)2, -C1-3 haloalkyl, halide, -OR13, CF3, and CN;
each R13 is independently selected from the group consisting of unsubstituted -6 alkyl, -C1-3 haloalkyl, and CF3;
each R13b is independently selected from the group consisting of H and unsubstituted -C1-3 alkyl; and q is an integer of 1 to 5;
with the proviso that the compound of Formula IIIa is not a compound selected from the group consisting of:

76. The compound of claim 75, wherein R10 is selected from the group consisting of H, F, CI, Me, OMe, CF3, and CN.
77. The compound of any one of claims 75-76, wherein R11 is selected from the group consisting of H, F, Cl, Me, OMe, CF3, and CN.
78. The compound of any one of claims 75-77, wherein R10 is H; and R11 is F.
79. The compound of any one of claims 75-78, wherein R10 is H;, and R11 is CF3.
80. The compound of any one of claims 75-79, wherein R10 is F; and R11 is F.
81. The compound of any one of claims 75-80, wherein R10 is F; and R11 is CF3.
82. The compound of any one of claims 75-81, wherein R12 is selected from the group consisting of H, F, Cl, Me, OMe, CF3, and CN.
83. The compound of any one of claims 75-82, wherein R12 is H.
84. The compound of any one of claims 75-83, wherein R12 is F or Cl; and q is 1.
85. The compound of any one of claims 75-84, wherein R12 is CF3; and q is 1.
86. The compound of any one of claims 75-85, wherein the compound of Formula IIIa is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
87. A compound , of Formula IIIb:

or a pharmaceutically acceptable salt thereof, wherein:
R14 is selected from the group consisting of unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, and CF3;
R15 is selected from the group consisting of unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, and CF3;
each R16 is independently selected at each occurrence from the group consisting of H, unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R17b)2, -C1-3 haloalkyl, halide, -OR17, CF3, and CN;
each R17 is independently selected from the group consisting of unsubstituted -6 alkyl, -C1-3 haloalkyl, and CF3;
each R17b is independently selected from the group consisting of H and unsubstituted -C1-3 alkyl; and q is an integer of 1 to 5;
with the proviso that the compound of Formula IIIb is not a compound selected from the group consisting of:
88. The compound of claim 87, wherein R14 is -C1-6 alkyl.
89. The compound of any one of claims 87-88, wherein R14 is Me.
90. The compound of any one of claims 87-89, wherein R15 is -C1-6 alkyl.
91. The compound of any one of claims 87-90, wherein R15 is Me.
92. The compound of any one of claims 87-91, wherein R16 is selected from the group consisting of H, F, Cl, Me, OMe, CF3, and CN.
93. The compound of any one of claims 87-92, wherein R16 is H.
94. The compound of any one of claims 87-93, wherein R16 is F or Cl; and q is 1.
95. The compound of any one of claims 87-94, wherein R16 is CF3; and q is 1.
96. The compound of any one of claims 87-95, wherein the compound of Formula IIIb is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
97. A compound of Formula IIIc:

or a pharmaceutically acceptable salt thereof, wherein:
Ring E is selected from the group consisting of R10 is selected from the group consisting of H, unsubstituted -C1-6 alkyl, -C1-haloalkyl, halide, -OR13, CF3, and CN;
R11 is selected from the group consisting of unsubstituted -C1-6 alkyl, -CH2OH, -CH2N(R13b)2, -C1-3 haloalkyl, halide, -OR13, CF3, and CN;
R12a is selected from the group consisting of unsubstituted -C2-6 alkyl, -CH2OH, -CH2N(R13b)2, -C2-3 haloalkyl, Cl, I, -OEt, and CN;
R12b is selected from the group consisting of unsubstituted -C2-6 alkyl, -CH2OH, -CH2N(R13)2, -C1-3 haloalkyl, iodide, -OR13a, and CF3;
R12c is selected from the group consisting of unsubstituted -C2-6 alkyl, -CH2OH, -CH2N(R13b)2, -C1-3 haloalkyl, F, I, -OR13a, CF3, and CN;
R12d is 2-5 substituents, each independently selected at each occurrence from the group consisting of unsubstituted -C1-6 alkyl, -CH,OH, -CH2N(R13b)2, -C1-3 haloalkyl, F, Br, I, -OR13, CF3, and CN;
each R13 is independently selected from the group consisting of unsubstituted -6 alkyl, -C1-3 haloalkyl, and CF3;
each R13a is independently selected from the group consisting of unsubstituted -C2-6 alkyl, -C1-3 haloalkyl, and CF3;

each R13b is independently selected from the group consisting of H and unsubstituted ¨C1-3 alkyl; and q is an integer of 1 to 5.
98. The compound of claim 97, wherein the compound of Formula IIIc is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
99. A compound , of Formula IIId:
or a pharmaceutically acceptable salt thereof, wherein:
R14 is selected from the group consisting of unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, and CF3;

R15 is selected from the group consisting of unsubstituted -C1-6 alkyl, -C1-3 haloalkyl, and CF3;
each R16 is independently selected at each occurrence from the group consisting of unsubstituted -C1,6 alkyl, -CH2OH, -CH2N(R17b)2, -C1-3 haloalkyl, halide, -OR17a, CF3, and CN;
each R17a is independently selected from the group consisting of unsubstituted -C3-6 alkyl, -C1-3 haloalkyl, and CF3;
each R17b is independently selected from the group consisting of H and unsubstituted ¨C1-3 alkyl; and q is an integer of 1 to 5.
100. The compound of claim 99, wherein the compound of Formula IIId is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
101. A compound , of Formula IV:
or a pharmaceutically acceptable salt thereof, wherein:
Ring F is Ring G is selected from the group consisting of , and a 5-6 membered heteroaryl R19d, wherein a carbon atom on the ring is attached to the carbonyl carbon;
each R18 is independently selected at each occurrence from the group consisting of H, -C1-3 haloalkyl, halide, -OR20, CF3, and CN;
R19a is selected from the group consisting of H, unsubstituted -C2-6 alkyl, -CH2OH, -CH2N(R21)2, -C1-3 haloalkyl, F, Br, I, -OR20, CF3, and CN;
each R19b is independently selected at each occurrence from the group consisting of H, unsubstituted -C2-6 alkyl, -CH2OH, -CH2N(R21)2, -C1-3 haloalkyl, halide, -OR20, CF3, and CN;
R19c is 2-5 substituents, each independently selected at each occurrence from the group consisting of H, -CH2OH, -CH2N(R21)2, -C1-3 haloalkyl, halide, -OR20, CF3, and CN;
R19d is 1-4 substituents, each independently selected at each occurrence from the group consisting of H, -CH2OH, -CH2N(R21)2, -C1-3 haloalkyl, halide, -OR20, CF3, and CN;
each R20 is independently selected from the group consisting of H, unsubstituted ¨
C3-6 alkyl, -C1-3 haloalkyl, and CF3;
each R21 is independently selected from the group consisting of H and unsubstituted ¨C1-3 alkyl;
p is an integer of 1 to 13; and r is an integer of 1 to 5.
102. The compound of claim 101, wherein the compound of Formula IV is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
103. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
104. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1-103, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
105. The pharmaceutical composition according to claim 104, wherein the composition is a component in a compound-eluting coating for a medical device.
106. A method of treating a disorder or disease selected from the group consisting of a neurodegenerative disease, eye disease, osteoporosis, osteoarthropathy, osteogenesis imperfecta, bone defects, bone fractures, periodontal disease, otosclerosis, wound healing, oral mucositis, gastrointestinal mucositis, craniofacial defects, and oncolytic bone disease, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1-103, or a pharmaceutically acceptable salt thereof.
107. The method of claim 106, wherein the disorder or disease is a neurodegenerative disease.
108. The method according to any one of claims 106-107, wherein the neurodegenerative disease is Parkinson's disease, stroke, spinal cord injury, ischemic cerebral disease, epilepsy, Alzheimer's disease, dementia, depression, bipolar disorder, or schizophrenia.
109. The method of claim 106, wherein the disorder or disease is an eye disease.
110. The method according to any one of claims 106 and 109, wherein the eye disease is wet age-related macular degeneration, dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, diabetic macular edema, retinal detachment, retinal degeneration, retinal vein occlusion, retinopathy of prematurity, retinitis pigmentosa, retinopathies, Leber congenital amaurosis and glaucoma.
111. The method of claim 106, wherein the disorder or disease is osteoporosis, osteoarthropathy, osteogenesis imperfecta, bone defects, bone fractures, periodontal disease, otosclerosis, wound healing, oral mucositis, gastrointestinal mucositis, craniofacial defects, or oncolytic bone disease.
112. A method of treating a disorder or disorder or disease related to differentiation and growth of stem cells and is selected from the group consisting of hair loss, hematopoiesis related diseases, tissue regeneration related diseases, and other diseases associated with abnormalities in development, stem cell differentiation, and cell proliferation, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1-103, or a pharmaceutically acceptable salt thereof.
113. The method of claim 106 or 112, wherein the patient is a mammal.
114. The method of claim 113, wherein the mammal is a human.
115. The method of claim 106, wherein the compound activates one or more proteins in the Wnt pathway.
116. The method of claim 115, wherein the compound activates signaling induced by one or more Wnt proteins.
117. The method according to any one of claims 106 and 115-116, wherein the one or more Wnt proteins are selected from the group consisting of: WNT1, WNT2, WNT2B, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, and WNT16.
118. A compound-eluting coating or a controlled release system comprising a compound according to any one of claims 1-103, or a pharmaceutically acceptable salt thereof.
119. A medical device comprising a compound according to any one of claims 1-103, or a pharmaceutically acceptable salt thereof.
120. An implant, sponge, polymer, ointment, cream or gel composition suitable for in vivo use comprising a compound according to any one of claims 1-103, or a pharmaceutically acceptable salt thereof.
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