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WO2020150545A1 - Pyrazole derivatives as modulators of the wnt/b-catenin signaling pathway - Google Patents

Pyrazole derivatives as modulators of the wnt/b-catenin signaling pathway Download PDF

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WO2020150545A1
WO2020150545A1 PCT/US2020/013983 US2020013983W WO2020150545A1 WO 2020150545 A1 WO2020150545 A1 WO 2020150545A1 US 2020013983 W US2020013983 W US 2020013983W WO 2020150545 A1 WO2020150545 A1 WO 2020150545A1
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disease
optionally substituted
alkylene
unsubstituted
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Sunil Kumar Kc
Chi Ching Mak
Brian Walter Eastman
Joseph Timothy Marakovits
Venkataiah Bollu
Jianguo Cao
Gopi Kumar Mittapalli
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Biosplice Therapeutics Inc
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Samumed LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This disclosure relates to inhibitors of one or more proteins in the Wnt pathway, including inhibitors of one or more Wnt proteins, and compositions comprising the same. More particularly, it concerns the use of a pyrazole compound or salts or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, Alzheimer's disease, lung disease, inflammation, auto-immune diseases fibrotic disorders, cartilage (chondral) defects, and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases and neurological conditions/disorders/diseases due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Also provided are methods for treating Wnt-related disease states, as well as neurological conditions/disorders/diseases linked to overexpression of DYRK1A.
  • Wnt pathway signaling e.g., cancer, abnormal
  • the Wnt growth factor family includes more than 10 genes identified in the mouse and at least 19 genes identified in the human.
  • Members of the Wnt family of signaling molecules mediate many short-and long-range patterning processes during invertebrate and vertebrate development.
  • the Wnt signaling pathway is known for its role in the inductive interactions that regulate growth and differentiation, and it also plays roles in the homeostatic maintenance of post-embryonic tissue integrity.
  • Wnt stabilizes cytoplasmic b-catenin, which stimulates the expression of genes including c-myc, c jun, fra-1, and cyclin Dl.
  • misregulation of Wnt signaling can cause developmental defects and is implicated in the genesis of several human cancers.
  • the Wnt pathway has also been implicated in the maintenance of stem or progenitor cells in a growing list of adult tissues including skin, blood, gut, prostate, muscle, and the nervous system.
  • Dual specificity tyrosine-phosphorylation-regulated kinase 1A is an enzyme that in humans is encoded by the DYRK1A gene.
  • DYRK1A is a member of the dual-specificity tyrosine phosphorylation -regulated kinase (DYRK) family.
  • DYRK1A contains a nuclear targeting signal sequence, a protein kinase domain, a leucine zipper motif, and a highly conservative 13- consecutive-histidine repeat. It catalyzes its autophosphorylation on serine/threonine and tyrosine residues. It may play a significant role in a signaling pathway regulating cell proliferation and may be involved in brain development.
  • DYRK1A is localized in the Down syndrome critical region of chromosome 21 , and is considered to be a candidate gene for learning defects associated with Down syndrome. DYRK1A is also expressed in adult brain neurons, indicating that DYRK1A may play a role in the mature central nervous system. Thus, several lines of evidence point to some synaptic functions of DYRK1A. For instance, it has been found that DYRK1A phosphorylates and modulates the interaction of several components of the endocytic protein complex machinery (Dynamin 1, Amphiphysin, and Synaptojanin), suggesting a role in synaptic vesicle recycling. In addition, a polymorphism (SNP) in DYRK 1 A was found to be associated with HIV-1 replication in monocyte-derived macrophages, as well as with progression to AIDS in two independent cohorts of HIV- 1 -infected individuals.
  • SNP polymorphism
  • the present disclosure provides methods and reagents, involving contacting a cell with an agent, such as a pyrazole compound, in a sufficient amount to antagonize a Wnt activity, e.g., to reverse or control an aberrant growth state or correct a genetic disorder due to mutations in Wnt signaling components.
  • an agent such as a pyrazole compound
  • the present disclosure also provides methods and reagents, involving contacting a cell with an agent, such as a pyrazole compound, in a sufficient amount to antagonize DYRK1A activity, e.g., i) to normalize prenatal and early postnatal brain development; ii) to improve cognitive function in youth and adulthood; and/or iii) to attenuate Alzheimer’s-type neurodegeneration.
  • an agent such as a pyrazole compound
  • Some embodiments disclosed herein include Wnt and/or DYRK1A inhibitors containing a pyrazole core. Other embodiments disclosed herein include pharmaceutical compositions and methods of treatment using these compounds.
  • One embodiment disclosed herein includes a compound having the structure of Formula (I):
  • R 1 is selected from the group consisting of H, halide, and unsubstituted -(C1-3 alkyl);
  • R 3 is selected from the group consisting of -heterocyclyl substituted with 1-10 R 11 , -(C1-4 alkylene) p phenyl substituted with 1-5 R 12 , -heteroaryl optionally substituted with 1-4 R 13 , and - (Ci- 4 alkylene)OR 14 ; wherein heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, 5,6,7,8-tetrahydroimidazo[l,2- a]pyrazinyl, 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridinyl, 1,
  • R 3 is selected from -heteroaryl optionally substituted with 1-4 R 13 ; wherein heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, 5,6,7,8-tetrahydroimidazo[l,2- a]pyrazinyl, 4,5,6,7-tetrahydro-lH-imidazo[
  • each R 4 is halide
  • each R 5 is independently selected from the group consisting of halide, Me, and Et;
  • each R 6 is independently selected from the group consisting of methyl, -CFfiF, -CHF2, - CF 3 , -OR 15a , and -(Ci-4 alkylene) p N(R 16a )(R 16b ); wherein -(C1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein;
  • R 8 is unsubstituted -(C 1-9 alkyl);
  • R 9 is unsubstituted -(C 1-9 alkyl);
  • R 10 is -aryl optionally substituted with 1-5 R 21 ;
  • each R 11 is independently selected from the group consisting of halide, methyl, and ethyl
  • R 14 is selected from the group consisting of unsubstituted -(Cw alkyl) and -aryl optionally substituted with 1-5 R 22 ; each R 15a is independently selected from the group consisting of unsubstituted -(C2-3 alkyl), and -heterocyclyl optionally substituted with 1-10 R 20b ;
  • each R 15b is independently selected from the group consisting of H, unsubstituted -(C2-9 alkyl), and -heterocyclyl optionally substituted with 1-10 R 20b ;
  • each R 16a is independently selected from the group consisting of H and unsubstituted -(Ci-
  • each R 16b is unsubstituted -(C 1-2 alkyl);
  • each R 17 is unsubstituted -(C 1-9 alkyl);
  • each R 18 is independently selected from the group consisting of H and Me;
  • each R 19 is unsubstituted -(C1-9 alkyl);
  • each R 20a is independently selected from the group consisting of halide and unsubstituted -(C 2-9 alkyl);
  • each R 20b is independently selected from the group consisting of halide and unsubstituted -(Ci-9 alkyl);
  • each R 21 is independently selected from the group consisting of halide and unsubstituted - (Ci- 9 alkyl);
  • each R 22 is independently selected from the group consisting of halide and unsubstituted - (Ci- 9 alkyl);
  • each R 23a is independently selected from the group consisting of unsubstituted -(C2-9 alkyl), — (Ci-4 alkylene)OR 25 , and -(C1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 20b ; wherein each -(Cw alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • each R 23b is independently selected from the group consisting of unsubstituted -(C1-9 alkyl), — (Ci-4 alkylene)OR 25 , and -(C1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 20b ; wherein each -(Cw alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • each R 25 is independently selected from the group consisting of H and unsubstituted -(Ci-
  • each p is independently an integer of 0 or 1.
  • Some embodiments include stereoisomers and pharmaceutically acceptable salts of a compound of Formula (I). Some embodiments include pharmaceutically acceptable salts of a compound of Formula (I).
  • Some embodiments include pro-drugs of a compound of Formula (I).
  • compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier, diluent, or excipient.
  • inventions disclosed herein include methods of inhibiting one or more members of the Wnt pathway, including one or more Wnt proteins by administering to a patient affected by a disorder or disease in which aberrant Wnt signaling is implicated, such as cancer and other diseases associated with abnormal angiogenesis, cellular proliferation, cell cycling and mutations in Wnt signaling components, a compound according to Formula (I). Accordingly, the compounds and compositions provided herein can be used to treat cancer, to reduce or inhibit angiogenesis, to reduce or inhibit cellular proliferation and correct a genetic disorder due to mutations in Wnt signaling components.
  • DYRK1A includes methods of inhibiting DYRK1A by administering to a patient affected by a disorder or disease in which DYRK1A overexpression is implicated, such as Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, Down Syndrome, Frontotemporal Dementia with Parkinsonism- 17 (FTDP-17), Lewy body dementia, Parkinson’s Disease, Pick's Disease, and additional diseases with pronounced neurodegeneration such as Autism, Dementia, Epilepsy, Huntington’s Disease, Multiple Sclerosis; diseases and disorders associated with acquired brain injury such as Chronic Traumatic Encephalopathy, Traumatic Brain Injury, Tumor and Stroke.
  • a disorder or disease in which DYRK1A overexpression is implicated such as Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, Down Syndrome, Frontotemporal Dementia with Parkinsonism- 17 (FTDP-17), Lewy body dementia, Parkinson’s Disease, Pick's Disease, and additional diseases with pronounced neurodegeneration such as Autism, Dementia, Epi
  • Non-limiting examples of diseases which can be treated with the compounds and compositions provided herein include a variety of cancers, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, sepsis, ankylosing spondylitis, psoriasis, scleroderma, mycotic and viral infections, osteochondrodysplasia, Alzheimer’s disease, lung disease, bone/osteoporotic (wrist, spine, shoulder and hip) fractures, articular cartilage (chondral) defects, degenerative disc disease (or intervertebral disc degeneration), polyposis coli, osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia syndrome, Miillerian-duct regression and virilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome, Al-Awadi/
  • Some embodiments of the present disclosure include methods to prepare compounds of Formula (I).
  • compositions and methods for inhibiting one or more members of the Wnt pathway including one or more Wnt proteins.
  • compositions and methods for inhibiting DYRK1A are provided herein.
  • Some embodiments provided herein relate to a method for treating a disease including, but not limited to, neurological diseases or disorders, cancers, chronic inflammation, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, sepsis, ankylosing spondylitis, psoriasis, scleroderma, mycotic and viral infections, bone and cartilage diseases, lung disease, osteoarthritis, articular cartilage (chondral) defects, degenerative disc disease (or intervertebral disc degeneration), polyposis coli, bone density and vascular defects in the eye (Osteoporosis - pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Miillerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/
  • bone and cartilage diseases which can be treated with the compounds and compositions provided herein include bone spur (osteophytes), craniosynostosis, fibrodysplasia ossificans progressive, fibrous dysplasia, giant cell tumor of bone, hip labral tear, meniscal tears, osteoarthritis, articular cartilage (chondral) defects, degenerative disc disease (or intervertebral disc degeneration), osteochondritis dissecans, osteochondroma (bone tumor), osteopetrosis, relapsing polychondritis, and Salter-Harris fractures.
  • bone spur osteophytes
  • craniosynostosis osteophytes
  • fibrodysplasia ossificans progressive fibrous dysplasia
  • giant cell tumor of bone hip labral tear
  • meniscal tears osteoarthritis
  • articular cartilage (chondral) defects degenerative disc disease (or intervertebral disc degeneration)
  • non-limiting examples of a neurological disease or disorder associated with tau protein, amyloid or alpha-synuclein pathology which can be treated with the compounds and compositions provided herein include, but are not limited to, Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, Down Syndrome, Frontotemporal Dementia with Parkinsonism- 17 (FTDP-17), Lewy body dementia, Parkinson’s Disease, Pick's Disease, and additional diseases with pronounced neurodegeneration such as Autism, Dementia, Epilepsy, Huntington’s Disease, Multiple Sclerosis; diseases and disorders associated with acquired brain injury such as Chronic Traumatic Encephalopathy, Traumatic Brain Injury, Tumor, and Stroke.
  • non-limiting examples of diseases in which chronic inflammation is involved which can be treated with the compounds and compositions provided herein include eye disorders, joint pain, arthritis (rheumatoid, osteo, psoriatic gout), cancers (colon, breast, lung, pancreas, and others), gastrointestinal disorders (ulcerative colitis and inflammatory bowel diseases), pulmonary disorders (chronic obstructive pulmonary disorder and asthma), allergies, skin disorders (atopic dermatitis and psoriasis), diabetes, pancreatitis, tendonitis, hepatitis, heart disease, myocarditis, stroke, lupus, and neurological disorders such as multiple sclerosis, Parkinson’s and dementia including Alzheimer’s disease.
  • non-limiting examples of cancers which can be treated with the compounds and compositions provided herein include colon, ovarian, pancreatic, breast, liver, prostate, and hematologic cancers.
  • compositions are provided that are effective for treatment of a disease of an animal, e.g., a mammal, caused by either the pathological activation or mutations of the Wnt pathway or DYRK 1 A overexpression.
  • the composition includes a pharmaceutically acceptable carrier and a compound as described 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 include 1 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).
  • alkynyl means a straight or branched chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, and the like.
  • alkynyl groups can either be unsubstituted or substituted with one or more substituents.
  • alkynyl groups will comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).
  • alkylene means a bivalent branched, or straight chain chemical group containing only carbon and hydrogen, such as methylene, ethylene, n-propylene, iso-propylene, n-butylene, iso-butylene, sec-butylene, tert-butylene, n-pentylene, iso-pentylene, sec-pentylene and neo-pentylene.
  • Alkylene groups can either be unsubstituted or substituted with one or more substituents.
  • alkylene groups include 1 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).
  • alkenylene means a bivalent branched, or straight chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond, such as ethenylene, 1-propenylene, 2-propenylene, 2-methyl-l-propenylene, 1- butenylene, 2-butenylene, and the like.
  • alkenylene groups can either be unsubstituted or substituted with one or more substituents.
  • alkenylene groups will comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).
  • alkynylene means a bivalent branched, or straight chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon triple bond, such as ethynyl ene, 1-propynylene, 1-butynylene, 2-butynylene, and the like.
  • alkynylene groups can either be unsubstituted or substituted with one or more substituents.
  • alkynylene groups will comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).
  • alkoxy means an alkyl -O— group in which the alkyl group is as described herein.
  • exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, pentoxy, hexoxy and heptoxy, and also the linear or branched positional isomers thereof.
  • haloalkoxy means a haloalkyl-0— group in which the haloalkyl group is as described herein.
  • exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and also the linear or branched positional isomers thereof.
  • “carbocyclyl” 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 none of the rings in the ring system are aromatic.
  • Carbocyclyl groups can either be unsubstituted or substituted with one or more substituents. In some embodiments, carbocyclyl groups include 3 to 10 carbon atoms, for example, 3 to 6 carbon atoms.
  • aryl means a mono-, bi-, tri- or polycyclic group with only carbon atoms present in the ring backbone having 5 to 14 ring atoms, alternatively 5, 6, 9, or 10 ring atoms; and having 6, 10, or 14 pi electrons shared in a cyclic array; wherein at least one ring in the system is aromatic.
  • Aryl groups can either be unsubstituted or substituted with one or more substituents. Examples of aryl include phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydro-lH- indenyl, and others. In some embodiments, the aryl is phenyl.
  • arylene means a bivalent moiety obtained by removing two hydrogen atoms of an aryl ring, as defined above.
  • arylalkylene means an aryl-alkylene- group in which the aryl and alkylene moieties are as previously described.
  • arylalkylene groups contain a Ci-4alkylene moiety.
  • exemplary arylalkylene groups include benzyl and 2-phenethyl.
  • heteroaryl means a mono-, bi-, tri- or polycyclic group having 5 to 14 ring atoms, alternatively 5, 6, 9, or 10 ring atoms; and 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, O, and S. Heteroaryl groups can either be unsubstituted or substituted with one or more substituents.
  • heteroaryl examples include thienyl, pyridinyl, ftiryl, 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
  • the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.
  • heteroarylene means a bivalent moiety obtained by removing two hydrogen atoms of a heteroaryl ring, as defined above.
  • halo is a chloro, bromo, fluoro, or iodo atom radical.
  • a halo is a chloro, bromo or fluoro.
  • a halide can be fluoro.
  • haloalkyl means a hydrocarbon substituent, which is a linear or branched, alkyl, alkenyl or alkynyl substituted with one or more chloro, bromo, fluoro, and/or iodo atom(s).
  • a haloalkyl is a fluoroalkyls, wherein one or more of the hydrogen atoms have been substituted by fluoro.
  • haloalkyls are of 1 to about 3 carbons in length (e.g., 1 to about 2 carbons in length or 1 carbon in length).
  • 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.
  • heterocyclyl 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 3-11 members. In six membered monocyclic heterocycles, the heteroatom(s) are selected from one to three of O, N or S, and wherein when the heterocycle is five membered, it can have one or two heteroatoms selected from O, N, or S.
  • heterocyclyl examples 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.
  • the heterocyclyl is selected from azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and tetrahydropyridinyl.
  • “monocyclic heterocyclyl” means a single nonaromatic cyclic ring comprising at least one heteroatom in the ring system backbone. Heterocyclyls may be substituted or unsubstituted with one or more substituents. In some embodiments, heterocycles have 3-7 members.
  • heteroatom(s) are selected from one to three of O, N or S, and wherein when the heterocycle is five membered, it can have one or two heteroatoms selected from O, N, or S.
  • heterocyclyls 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, oxazolidiny
  • bicyclic heterocyclyl means a nonaromatic bicyclic ring system comprising at least one heteroatom in the ring system backbone. Bicyclic heterocyclyls may be substituted or unsubstituted with one or more substituents. In some embodiments, bicyclic heterocycles have 4-11 members with the heteroatom(s) being selected from one to five of O, N or S. Examples of bicyclic heterocyclyls include 2 -azabicyclof 1.1.0] butane, 2- azabicyclo[2.1.0]pentane, 2-azabicyclo[l . l .
  • spirocyclic heterocyclyl means a nonaromatic bicyclic ring system comprising at least one heteroatom in the ring system backbone and with the rings connected through just one atom. Spirocyclic heterocyclyls may be substituted or unsubstituted with one or more substituents. In some embodiments, spirocyclic heterocycles have 5-11 members with the heteroatom(s) being selected from one to five of O, N or S.
  • 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, -(C 1-9 alkyl) optionally substituted with one or more of hydroxyl, -NEE, -NH(C I-3 alkyl), and -N(C I -3 alkyl) 2 ; -(C1-9 haloalkyl); a halide; a hydroxyl; a carbonyl [such as -C(0)0R, and -C(0)R]; a thiocarbonyl [such as -C(S)OR, -C(0)SR, and -C(S)R]; -(C1-9 alkoxy) optionally substituted with one or more of halide, hydroxyl, -NH2, -NH(C I -3 alkyl), and -N(C I -3 alkyl)2; - OPO(OH) 2 ; a phosphonate [such as -PO(OH) 2 and -PO(OR’) 2 ]; -OPO(OR’)
  • the substituent is selected from— (Ci- 6 alkyl), -(Ci- 6 haloalkyl), a halide (e.g., F), a hydroxyl, -C(0)0R, -C(0)R, -(Ci- 6 alkoxyl), -NRR’, -C(0)NRR’, and a cyano, in which each occurrence of R and R’ is independently selected from H and -(Ci- 6 alkyl).
  • a halide e.g., F
  • 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.
  • the present disclosure includes all pharmaceutically acceptable isotopically labeled compounds of Formula I, wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the disclosure include, but are not limited to, isotopes of hydrogen, such as 2 H (deuterium) and 3 H (tritium), carbon, such as n C, 13 C and 14 C, chlorine, such as 36 C1, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • isotopes of hydrogen such as 2 H (deuterium) and 3 H (tritium)
  • carbon such as n C, 13 C and 14 C
  • chlorine such as 36 C1
  • fluorine such as 18 F
  • iodine such as 123 I and 125 I
  • nitrogen such as 13 N and 15 N
  • oxygen such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P
  • sulfur such as 35 S.
  • administration 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
  • 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.
  • mammal is used in its usual biological sense. Thus, it specifically includes humans, cattle, horses, monkeys, dogs, cats, mice, rats, cows, sheep, pigs, goats, and non human primates, but also includes many other species.
  • compositions include 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.
  • pharmaceutically acceptable carrier 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.
  • various adjuvants such as are commonly used in the art may be included.
  • salts refers to salts that retain the biological effectiveness and properties of the compounds provided herein and, which are not biologically or otherwise undesirable.
  • 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.
  • “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.
  • the patient is a human.
  • A“therapeutically 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, in combination with one or more other agents that are effective to treat the diseases and/or conditions described herein.
  • 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.
  • a therapeutic effect relieves, to some extent, one or more of the symptoms of the disease.
  • Treatment refers to administering a compound or pharmaceutical composition as provided herein for therapeutic purposes.
  • 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, ameliorating 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.
  • Drug-eluting and/or controlled release refers to any and all mechanisms, e.g., diffusion, migration, permeation, and/or desorption by which the drug(s) incorporated in the drug -eluting material pass therefrom over time into the surrounding body tissue .
  • Drug-eluting material and/or controlled release material as used herein refers to any natural, synthetic or semi -synthetic material capable of acquiring and retaining a desired shape or configuration and into which one or more drugs can be incorporated and from which incorporated drug(s) are capable of eluting over time.
  • “Elutable drug” as used herein refers to any drug or combination of drugs having the ability to pass over time from the drug-eluting material in which it is incorporated into the surrounding areas of the body.
  • the compounds and compositions described herein can be used as antiproliferative agents, e.g., anti-cancer and anti-angiogenesis agents, and/or as inhibitors of the Wnt signaling pathway, e.g., for treating diseases or disorders associated with aberrant Wnt signaling.
  • the compounds can be used as inhibitors of one or more kinases, kinase receptors, or kinase complexes.
  • Such compounds and compositions are also useful for controlling cellular proliferation, differentiation, and/or apoptosis.
  • the compounds and compositions described herein can be used to inhibit DYRK1A for treating a disorder or disease in which DYRK1A overexpression is implicated, such as Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, Down Syndrome, Frontotemporal Dementia with Parkinsonism- 17 (FTDP-17), Lewy body dementia, Parkinson’s Disease, Pick's Disease, and additional diseases with pronounced neurodegeneration such as Autism, Dementia, Epilepsy, Huntington’s Disease, Multiple Sclerosis; diseases and disorders associated with acquired brain injury such as Chronic Traumatic Encephalopathy, Traumatic Brain Injury, Tumor, and Stroke.
  • a disorder or disease in which DYRK1A overexpression is implicated such as Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, Down Syndrome, Frontotemporal Dementia with Parkinsonism- 17 (FTDP-17), Lewy body dementia, Parkinson’s Disease, Pick's Disease, and additional diseases with pronounced neurodegeneration such as Autism, Dementia, Epilepsy, Hunt
  • R 1 is selected from the group consisting of H, halide (e.g., F, Cl, Br, I), and unsubstituted -(C1-3 alkyl) (e.g., C1-2, Ci).
  • R 1 is selected from the group consisting of H, F, and Me.
  • R 1 is H.
  • R 2 is selected from the group consisting of unsubstituted -(C1-3 alkyl) (e.g., C1-2, Ci), unsubstituted -(C2-9 alkenyl) (e.g., C2-8, C2-7, C2-6, C2-5, C2-4, C2-3, C2), unsubstituted— (C1-9 haloalkyl) (e.g., Ci-s, C1-7, Ci- 6 , C1-5, C1-4, C1-3, C1-2, Ci),— (C1-2 alkylene) p (C3-6 carbocyclyl) optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1- 5, 1-4, 1-3, 1-2, 1) R 4 , -monocyclic heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1- 7, 1-6, 1-5, 1-4, 1-3, 1-3, 1) R 4 , -mon
  • R 2 is selected from the group consisting of unsubstituted -(C1-9 alkyl) (e.g., Ci-s, C1-7, Ci- 6 , C1-5, C1-4, C1-3, Ci- 2, Ci), unsubstituted -(C2-9 alkenyl) (e.g., C 2.8 , C2-7, C2-6, C2-5, C 2.4 , C2-3, C 2 ), unsubstituted -(C1-9 haloalkyl) (e.g., Ci-s, C1-7, Ci-
  • Ci-s, Ci-4, Ci-3, Ci- 2 Ci),— (Ci- 2 alkylene) p (C3-6 carbocyclyl) optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 4 , -monocyclic heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 5 , -phenyl substituted with 1- 5 (e.g., 1-4, 1-3, 1-2, 1) R 6 , -heteroaryl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R 7 , - C0 2 R 8 , -OR 9 , and -(C 0)R 10 ; wherein heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazine
  • R 2 is selected from the group consisting of unsubstituted -(C1-3 alkyl) (e.g., Ci- 2, Ci), unsubstituted -(C 2 -9 alkenyl) (e.g., C 2- s, C 2- 7, C 2-6 , C 2- s, C 2-4 , C 2-3 , C 2 ), unsubstituted— (C1-9 haloalkyl) (e.g., Ci-s, C1-7, Ci- 6 , C1-5, C1-4, C1-3, Ci- 2, Ci),— (Ci- 2 alkylene) p (C3-6 carbocyclyl) optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1- 5, 1-4, 1-3, 1-2, 1) R 4 , -monocyclic heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-
  • the heteroaryl of R 2 is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxazolyl, oxadiazolyl, thiazolyl, 2,3- dihydrobenzo[b]dioxinyl, 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazinyl, 4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridinyl, isoquinolinyl, and quinolinyl.
  • R 2 is selected from the group consisting of unsubstituted -(C1-3 alkyl) (e.g., Ci- 2, Ci), -(CH 2 )(cyclopropyl), -(cyclopropyl), -monocyclic heterocyclyl optionally substituted with 1 R 5 , -phenyl substituted with 1-2 R 6 , and -pyridinyl optionally substituted with 1 R 7 .
  • -(C1-3 alkyl) e.g., Ci- 2, Ci
  • -monocyclic heterocyclyl optionally substituted with 1 R 5
  • -phenyl substituted with 1-2 R 6 e.g., -phenyl substituted with 1-2 R 6
  • -pyridinyl optionally substituted with 1 R 7 .
  • R 2 is -pyridinyl optionally substituted with 1 R 7 .
  • R 2 is selected from the group consisting of -phenyl substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R 6 and -heteroaryl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R 7 ; wherein heteroaryl selected from the group consisting of pyridinyl, oxazolyl, oxadiazolyl, thiazolyl, 2,3- dihydrobenzo[b]dioxinyl, 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazinyl, 4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridinyl, isoquinolinyl, and quinolinyl.
  • R 3 is selected from the group consisting of -heterocyclyl substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 11 , -(Cw alkylene) p phenyl substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R 12 , -heteroaryl optionally substituted with l-4 (e.g., 1-3, 1-2, 1) R 13 , and -(Ci-4alkylene)OR 14 ; wherein heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl, imidazo[4,5-b]pyridinyl
  • R 3 is selected from the group consisting of -heterocyclyl substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 11 , -(Cw alkylene) p phenyl substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R 12 , -heteroaryl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R 13 , and -(Ci-4 alkylene)OR 14 ; wherein each -(Ci- 4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • 1-10 e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1
  • R 11 e.g., -(Cw alkylene) p phenyl substituted with 1-5 (e.g., 1-4,
  • the heteroaryl of R 3 is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazinyl, 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridinyl,
  • R 3 is selected from the group consisting of -heterocyclyl substituted with 1 R 11 , -(Ci- 4 alkylene ) p phenyl substituted with 1 R 12 , -heteroaryl optionally substituted with 1 R 13 , and -(C2-3 alkylene)0(Ci-3 alkyl). [081] In some embodiments of Formula (I), R 3 is -pyridinyl optionally substituted with 1 R 13 .
  • R 3 is -benzimidazolyl optionally substituted with 1 R 13 .
  • R 3 is selected from -heteroaryl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R 13 ; wherein heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazinyl, 4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridinyl, 1,2,3,4-tetrahydroisoquinolinyl, isoquinoliny
  • each R 4 is halide (e.g., F, Cl, Br, I).
  • each R 5 is independently selected from the group consisting of halide (e.g., F, Cl, Br, I), Me, and Et.
  • halide e.g., F, Cl, Br, I
  • each R 6 is independently selected from the group consisting of methyl, -CFfiF, -CHF2, -CF3, -OR 15a , and -(C1-4 alkylene) p N(R 16a )(R 16b ); wherein -(C1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein.
  • the optional R 7 is independently selected from the group consisting of F, methyl, -CF3, -Oheterocyclyl optionally substituted with 1 R 20b , - (CFyheterocyclyl optionally substituted with 1-2 R 20b , -NMe2, and -(03 ⁇ 4)NMe 2 .
  • R 8 is unsubstituted -(C1-9 alkyl) (e.g., Cl-8, Cl-7, Cl-6, Cl-5, Cl-4, Cl-3, Cl-2, Cl).
  • R 9 is unsubstituted -(C1-9 alkyl) (e.g.,
  • R 10 is -aryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R 21 .
  • each R 11 is independently selected from the group consisting of halide (e.g., F, Cl, Br, I), methyl, and ethyl.
  • halide e.g., F, Cl, Br, I
  • each R 12 is independently selected from the group consisting of -(Ci- 4 alkylene) p heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1- 8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 20a , -aryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R 22 ,— (Ci-4 alkylene)N(R 16a )(R 16b ), and -OR 23a ; wherein heterocyclyl selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • 1-10 e.g., 1-9, 1- 8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1
  • R 20a e.g.,
  • each R 13 is independently selected from the group consisting of F, methyl, -CFfiF, -CHF2, -CF3, -(C1-4 alkylene) p N(R 16a )2, -OR 23b , -(C1-4 alkylene) p heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 20b , -aryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R 22 , and -heteroaryl substituted with 1-4 (e.g., 1-3, 1-2, 1) R 24 ; wherein -(C1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein.
  • 1-10 e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1
  • R 20b e.g.,
  • the optional R 13 is independently selected from the group consisting of F, methyl, -CF3, -OMe, -Oheterocyclyl optionally substituted with 1 R 20b , -heterocyclyl optionally substituted with 1-2 R 20b , -(CFb)heterocyclyl optionally substituted with 1-2 R 20b , -(CFfiCFyheterocyclyl optionally substituted with 1-2 R 20b , - phenyl optionally substituted with 1 R 22 , and -heteroaryl substituted with 1 R 24 .
  • R 14 is selected from the group consisting of unsubstituted -(C1-4 alkyl) (e.g., C1-3, C1-2, Ci) and -aryl optionally substituted with 1-5 (e.g., 1- 4, 1-3, 1-2, 1) R 22 .
  • C1-4 alkyl e.g., C1-3, C1-2, Ci
  • -aryl optionally substituted with 1-5 (e.g., 1- 4, 1-3, 1-2, 1) R 22 .
  • each R 15a is independently selected from the group consisting of unsubstituted -(C2-3 alkyl) (e.g., ethyl),, and -heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 20b .
  • each R 15b is independently selected from the group consisting of H, unsubstituted -(C2-9 alkyl) (e.g., C2-8, C2-7, C2-6, C2-5, C2-4, C2-3, C2), and -heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 20b .
  • C2-9 alkyl e.g., C2-8, C2-7, C2-6, C2-5, C2-4, C2-3, C2
  • -heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 20b .
  • each R 16a is independently selected from the group consisting of H and unsubstituted -(C1-2 alkyl) (e.g. methyl).
  • each R 16b is unsubstituted -(C1-2 alkyl) (e.g. methyl).
  • each R 17 is unsubstituted -(C1-9 alkyl) (e.g., Cl-8, Cl-7, Cl-6, Cl-5, Cl-4, Cl-3, Cl-2, Cl).
  • each R 18 is independently selected from the group consisting of H and Me.
  • each R 19 is unsubstituted -(C1-9 alkyl) (e.g., Cl-8, Cl-7, Cl-6, Cl-5, Cl-4, Cl-3, Cl-2, Cl).
  • each R 20a is independently selected from the group consisting of halide (e.g., F, Cl, Br, I) and unsubstituted -(C2-9 alkyl) (e.g., C2-8, C2-7, C2-
  • halide e.g., F, Cl, Br, I
  • unsubstituted -(C2-9 alkyl) e.g., C2-8, C2-7, C2-
  • each R 20b is independently selected from the group consisting of halide (e.g., F, Cl, Br, I) and unsubstituted -(C1-9 alkyl) (e.g., Ci-s, C1-7, Ci- 6, Cl-5, Cl-4, Cl-3, Cl-2, Cl).
  • halide e.g., F, Cl, Br, I
  • unsubstituted -(C1-9 alkyl) e.g., Ci-s, C1-7, Ci- 6, Cl-5, Cl-4, Cl-3, Cl-2, Cl.
  • each R 21 is independently selected from the group consisting of halide (e.g., F, Cl, Br, I) and unsubstituted -(C1-9 alkyl) (e.g., Ci-s, C1-7, Ci- 6, Cl-5, Cl-4, Cl-3, Cl-2, Cl).
  • halide e.g., F, Cl, Br, I
  • unsubstituted -(C1-9 alkyl) e.g., Ci-s, C1-7, Ci- 6, Cl-5, Cl-4, Cl-3, Cl-2, Cl.
  • each R 22 is independently selected from the group consisting of halide (e.g., F, Cl, Br, I) and unsubstituted -(C1-9 alkyl) (e.g., Ci-s, C1-7, Ci-
  • each R 23a is independently selected from the group consisting of unsubstituted -(C2-9 alkyl) (e.g., C2-8, C2-7, C2-6, C2-5, C2-4, C2-3, C2), -(C1-4 alky lene) OR 25 , and -(Ci-4 alkylene) p heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-
  • R 20b wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • each R 23b is independently selected from the group consisting of unsubstituted -(C1-9 alkyl) (e.g., Ci-s, C1-7, Ci- 6 , C1-5, C1-4, C1-3, C1-2, Ci), - (Ci-4 alkylene)OR 25 , and -(Ci-4 alkylene) p heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-
  • each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • each R 24 is independently selected from the group consisting of halide (e.g., F, Cl, Br, I) and unsubstituted -(C1-9 alkyl) (e.g., Ci-s, C1-7, Ci- 6, Cl-5, Cl-4, Cl-3, Cl-2. Cl).
  • halide e.g., F, Cl, Br, I
  • unsubstituted -(C1-9 alkyl) e.g., Ci-s, C1-7, Ci- 6, Cl-5, Cl-4, Cl-3, Cl-2. Cl.
  • each R 25 is independently selected from the group consisting of H and unsubstituted -(C 1-9 alkyl) (e.g., Ci-s, C1-7, Ci- 6 , C1-5, Cw, C1-3, C1-2, C l ).
  • L 1 is selected from the group consisting
  • NR 18 (C 0)NR 18 -, -NH(CH 2 ) p- , and -(CH 2 ) P NH-.
  • L 1 is selected from the group consisting of a bond, -
  • L 1 is selected
  • L 1 is selected from the group
  • L 1 is selected from the group consisting of
  • L 1 is selected from the group
  • L 1 is selected from the group
  • L 1 is selected from the group
  • L 1 is selected from the
  • L 1 is selected from the group consisting of -
  • L is selected from the group consisting of a bond
  • L 1 is selected
  • L 1 is selected from the group consisting of a bond, H-; in some embodiments,
  • L 1 is selected
  • L 1 is selected from the group consisting of
  • L 1 is selected from the group consisting of -
  • L 1 is selected from the group consisting of-
  • L is selected from the group consisting of a bond, , -
  • L 1 is
  • L is selected from the group consisting of , -
  • L is selected from the group consisting of
  • L 1 is selected
  • L 1 is selected
  • L 1 is a bond; in some embodiments, L 1
  • each p is independently an integer of 0 or 1.
  • a compound of Formula I is not a compound selected from the group consisting of:
  • each -(Cw alkylene) is -(Ci-2 alkylene).
  • each -(Ci-4 alkylene) is -(Ci alkylene).
  • each -(C 1-4 alkylene) is optionally substituted with F.
  • R 1 is selected from the group consisting of H, halide, and unsubstituted -(C 1-3 alkyl);
  • R 2 is selected from the group consisting of -phenyl substituted with 1-5 R 6 and -heteroaryl optionally substituted with 1-4 R 7 ; wherein heteroaryl selected from the group consisting of pyridinyl, oxazolyl, oxadiazolyl, thiazolyl, 2,3- dihydrobenzo[b]dioxinyl, 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazinyl, 4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridinyl, isoquinolinyl, and quinolinyl;
  • each R 5 is independently selected from the group consisting of halide, Me, and Et;
  • each R 6 is independently selected from the group consisting of -CEfF, -CHF 2 , -CF 3 , - OR 15a , and -(C 1-4 alkylene) p N(R 16a )(R 16b ); wherein -(Cw alkylene) is optionally substituted with one or more substituents as defined anywhere herein;
  • R 8 is unsubstituted -(C 1-9 alkyl);
  • R 10 is -aryl optionally substituted with 1-5 R 21 ;
  • each R 11 is independently selected from the group consisting of halide, methyl, and ethyl
  • R 14 is selected from the group consisting of unsubstituted -(C 1-4 alkyl) and -aryl optionally substituted with 1-5 R 22 ;
  • each R 15a is independently selected from -heterocyclyl optionally substituted with 1-10 j ⁇ 20b.
  • each R 15b is independently selected from the group consisting of H, unsubstituted -(C 2-9 alkyl), and -heterocyclyl optionally substituted with 1-10 R 20b ;
  • each R 16a is independently selected from the group consisting of H and unsubstituted -(Ci-
  • each R 17 is unsubstituted -(C 1-9 alkyl);
  • each R 18 is independently selected from the group consisting of H and Me;
  • each R 19 is unsubstituted -(C 1-9 alkyl);
  • each R 20a is independently selected from the group consisting of halide and unsubstituted -(C 2-9 alkyl);
  • each R 20b is independently selected from the group consisting of halide and unsubstituted -(Ci-9 alkyl); each R 21 is independently selected from the group consisting of halide and unsubstituted - (Ci- 9 alkyl);
  • each R 22 is independently selected from the group consisting of halide and unsubstituted - (Ci- 9 alkyl);
  • each R 23a is independently selected from the group consisting of unsubstituted -(C 2-9 alkyl), — (Ci- 4 alkylene)OR 25 , and -(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 20b ; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • each R 23b is independently selected from the group consisting of unsubstituted -(C 1-9 alkyl), — (Ci- 4 alkylene)OR 25 , and -(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 20b ; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • each R 24 is independently selected from the group consisting of halide and unsubstituted - (Ci- 9 alkyl);
  • each R 25 is independently selected from the group consisting of H and unsubstituted -(Ci-
  • each p is independently an integer of 0 or 1.
  • each R 6 is independently selected from the group consisting of -CFfiF, -CHF2, -CF3, -OR 15a , and -(C 1-4 alkylene) p N(R 16a )(R 16b ); wherein — (Ci- 4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein.
  • each R 6 is independently selected from the group consisting of -CF3, -OR 15a , and -(C 1-4 alkylene) p N(R 16a )(R 16b ); wherein -(C 1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein.
  • each R 15a is independently selected from -heterocyclyl optionally substituted with 1-10 R 20b .
  • compositions comprising: (a) a therapeutically effective amount of a compound provided herein, or its corresponding enantiomer, diastereoisomer or tautomer, or pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable carrier.
  • the compounds provided herein may also be useful in combination (administered together or sequentially) with other known agents.
  • Non-limiting examples of diseases which can be treated with a combination of a compound of Formula (I) and other another active agent are colorectal cancer, ovarian cancer, chronic inflammation, diabetic retinopathy, pulmonary fibrosis, and osteoarthritis.
  • a compound of Formula (I) can be combined with one or more chemotherapeutic compounds.
  • colorectal cancer can be treated with a combination of a compound of Formula (I) and one or more of the following drugs: 5-Fluorouracil (5-FU), which can be administered with the vitamin-like drug leucovorin (also called folinic acid); capecitabine (XELODA ® ), irinotecan (CAMPOSTAR ® ), oxaliplatin (ELOXATIN ® ).
  • 5-FU 5-Fluorouracil
  • leucovorin also called folinic acid
  • capecitabine XELODA ®
  • CAMPOSTAR ® irinotecan
  • ELOXATIN ® oxaliplatin
  • Examples of combinations of these drugs which could be further combined with a compound of Formula (I) are FOLFOX (5- FU, leucovorin, and oxaliplatin), FOLFIRI (5-FU, leucovorin, and irinotecan), FOLFOXIRI (leucovorin, 5-FU, oxaliplatin, and irinotecan) and CapeOx (Capecitabine and oxaliplatin).
  • FOLFOX 5- FU, leucovorin, and oxaliplatin
  • FOLFIRI 5-FU, leucovorin, and irinotecan
  • FOLFOXIRI leucovorin, 5-FU, oxaliplatin, and irinotecan
  • CapeOx CapeOx
  • chemo with 5-FU or capecitabine combined with radiation may be given before surgery (neoadjuvant treatment).
  • ovarian cancer can be treated with a combination of a compound of Formula (I) and one or more of the following drugs: Topotecan, Liposomal doxorubicin (DOXIL ® ), Gemcitabine (GEMZAR ® ), Cyclophosphamide (CYTOXAN ® ), Vinorelbine (NAVELBINE ® ), Ifosfamide (IFEX ® ), Etoposide (VP-16), Altretamine (HEXALEN ® ), Capecitabine (XELODA ® ), Irinotecan (CPT-11, CAMPTOSAR ® ), Melphalan, Pemetrexed (ALIMTA ® ) and Albumin bound paclitaxel (nab-paclitaxel, ABRAXANE ® ).
  • Topotecan Liposomal doxorubicin (DOXIL ® ), Gemcitabine (GEMZAR ® ), Cyclophosphamide (CYTOXAN ®
  • TIP paclitaxel [Taxol], ifosfamide, and cisplatin
  • VelP vinblastine, ifosfamide, and cisplatin
  • VIP etoposide [VP- 16], ifosfamide, and cisplatin
  • Chemotherapy using topoisomerase inhibitors such as irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, and teniposide;
  • Chemotherapy using cytotoxic antibiotics such as actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and mitomycin;
  • Chemotherapy using tyrosine-kinase inhibitors such as Imatinib mesylate (GLEEVEC ® , also known as STI-571), Gefitinib (Iressa, also known as ZD 1839), Erlot
  • obatoclax in clinical trials ABT-263, and Gossypol
  • PARP inhibitors e.g. Iniparib, Olaparib in clinical trials
  • PI3K inhibitors e.g. perifosine in a phase III trial
  • VEGF Receptor 2 inhibitors e.g. Apatinib
  • AN-152 e.g. AN-152, (AEZS-108)
  • Braf inhibitors e.g. vemurafenib, dabrafenib and LGX818)
  • MEK inhibitors e.g. trametinib and MEK162
  • CDK inhibitors e.g.
  • PD-0332991 PD-0332991
  • salinomycin and Sorafenib
  • Chemotherapy using monoclonal antibodies such as Rituximab (marketed as MABTHERA ® or RITUXAN ® ), Trastuzumab (Herceptin also known as ErbB2), Cetuximab (marketed as ERBITUX ® ), and Bevacizumab (marketed as AVASTIN ® ); and
  • radiation therapy e.g., radiation therapy using monoclonal antibodies such as Rituximab (marketed as MABTHERA ® or RITUXAN ® ), Trastuzumab (Herceptin also known as ErbB2), Cetuximab (marketed as ERBITUX ® ), and Bevacizumab (marketed as AVASTIN ® ); and (k) radiation therapy.
  • Rituximab marketed as MABTHERA ® or RITUXAN ®
  • diabetic retinopathy can be treated with a combination of a compound of Formula (I) and one or more of the following natural supplements: Bilberry, Butcher's broom, Ginkgo, Grape seed extract, and Pycnogenol (Pine bark).
  • natural supplements Bilberry, Butcher's broom, Ginkgo, Grape seed extract, and Pycnogenol (Pine bark).
  • idiopathic pulmonary fibrosis/pulmonary fibrosis can be treated with a combination of a compound of Formula (I) and one or more of the following drugs: pirfenidone (pirfenidone was approved for use in 2011 in Europe under the brand name Esbriet ® ), prednisone, azathioprine, N-acetylcysteine, interferon-g lb, bosentan (bosentan is currently being studied in patients with IPF, [The American Journal of Respiratory and Critical Care Medicine (2011), 184(1), 92-9]), Nintedanib (BIBF 1120 and Vargatef), QAX576 [British Journal of Pharmacology (2011), 163(1), 141-172], and anti-inflammatory agents such as corticosteroids.
  • pirfenidone pirfenidone was approved for use in 2011 in Europe under the brand name Esbriet ®
  • prednisone azathioprine
  • a compound of Formula (I) can be used to treat idiopathic pulmonary fibrosis/pulmonary fibrosis in combination with any of the following methods: oxygen therapy, pulmonary rehabilitation and surgery.
  • a compound of Formula (I) can be used to treat osteoarthritis in combination with any of the following methods: (a) Nonsteroidal anti inflammatory drugs (NSAIDs) such as ibuprofen, naproxen, aspirin and acetaminophen; (b) physical therapy; (c) injections of corticosteroid medications; (d) injections of hyaluronic acid derivatives (e.g.
  • NSAIDs Nonsteroidal anti inflammatory drugs
  • Hyalgan, Synvisc Hyalgan, Synvisc
  • narcotics like codeine
  • f in combination with braces and/or shoe inserts or any device that can immobilize or support your joint to help you keep pressure off it (e.g., splints, braces, shoe inserts or other medical devices);
  • splints e.g., splints, braces, shoe inserts or other medical devices
  • realigning bones osteotomy
  • arthroplasty joint replacement
  • i) in combination with a chronic pain class a chronic pain class.
  • macular degeneration can be treated with a combination of a compound of Formula (I) and one or more of the following drugs: Bevacizumab (Avastin ® ), Ranibizumab (Lucentis ® ), Pegaptanib (Macugen), Aflibercept (Eylea ® ), verteporfm (Visudyne ® ) in combination with photodynamic therapy (PDT) or with any of the following methods: (a) in combination with laser to destroy abnormal blood vessels (photocoagulation); and (b) in combination with increased vitamin intake of antioxidant vitamins and zinc.
  • Bevacizumab Avastin ®
  • Ranibizumab Ranibizumab
  • Pegaptanib Macugen
  • Aflibercept Eylea ®
  • verteporfm Visudyne ®
  • PDT photodynamic therapy
  • retinitis pigmentosa can be treated with a combination of a compound of Formula (I) and one or more of the following drugs: UF-021 (OcusevaTM), vitamin A palmitate and pikachurin or with any of the following methods: (a) with the Argus ® II retinal implant; and (b) with stem cell and/or gene therapy.
  • Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration, including, but not limited to, orally, subcutaneously, intravenously, 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, intrac
  • 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.
  • the compounds may be obtained, for example, as solid plugs, powders, or fdms 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 be used for this purpose.
  • 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.
  • the compounds can be administered either alone or in combination with a conventional pharmaceutical carrier, excipient or the like.
  • 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,
  • Cyclodextrins such as a-, b, and g-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3- hydroxypropyl- -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% of a compound provided herein, 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, 22 nd Edition (Pharmaceutical Press, London, UK. 2012).
  • the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a compound provided herein, 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, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like.
  • a diluent such as lactose, sucrose, dicalcium phosphate, or the like
  • a lubricant such as magnesium stearate or the like
  • a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like.
  • 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).
  • a capsule gelatin or cellulose base capsule.
  • Unit dosage forms in which one or more compounds provided herein or additional active agents 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.
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. a compound 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, coacervate or suspension.
  • a carrier e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like
  • the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, co-solvents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).
  • nontoxic auxiliary substances such as wetting agents, emulsifying agents, co-solvents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).
  • the unit dosage of compounds of Formula (I) is about 0.25 mg/Kg to about 50 mg/Kg in humans.
  • the unit dosage of compounds of Formula (I) is about 0.25 mg/Kg to about 20 mg/Kg in humans.
  • the unit dosage of compounds of Formula (I) is about 0.50 mg/Kg to about 19 mg/Kg in humans.
  • the unit dosage of compounds of Formula (I) is about 0.75 mg/Kg to about 18 mg/Kg in humans.
  • the unit dosage of compounds of Formula (I) is about 1.0 mg/Kg to about 17 mg/Kg in humans.
  • the unit dosage of compounds of Formula (I) is about 1.25 mg/Kg to about 16 mg/Kg in humans.
  • the unit dosage of compounds of Formula (I) is about 1.50 mg/Kg to about 15 mg/Kg in humans.
  • the unit dosage of compounds of Formula (I) is about 1.75 mg/Kg to about 14 mg/Kg in humans.
  • the unit dosage of compounds of Formula (I) is about 2.0 mg/Kg to about 13 mg/Kg in humans. [0292] In some embodiments, the unit dosage of compounds of Formula (I) is about 3.0 mg/Kg to about 12 mg/Kg in humans.
  • the unit dosage of compounds of Formula (I) is about 4.0 mg/Kg to about 11 mg/Kg in humans.
  • the unit dosage of compounds of Formula (I) is about 5.0 mg/Kg to about 10 mg/Kg in humans.
  • compositions are provided in unit dosage forms suitable for single administration.
  • compositions are provided in unit dosage forms suitable for twice a day administration.
  • compositions are provided in unit dosage forms suitable for three times a day administration.
  • Injectables can be prepared in conventional forms, either as liquid solutions, colloid, liposomes, 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 highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the patient. However, percentages of active ingredient of 0.01% to 10% in solution are employable, and could be higher if the composition is a solid or suspension, which could be subsequently diluted to the above percentages.
  • the composition will comprise about 0.1-10% of the active agent in solution.
  • the composition will comprise about 0.1-5% of the active agent in solution.
  • the composition will comprise about 0.1-4% of the active agent in solution.
  • the composition will comprise about 0.15-3% of the active agent in solution.
  • the composition will comprise about 0.2-2% of the active agent in solution.
  • compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-96 hours.
  • compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-72 hours.
  • the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-48 hours.
  • compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-24 hours.
  • compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-12 hours.
  • compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-6 hours.
  • compositions can be administered by intravenous infusion to humans at doses of about 5 mg/m 2 to about 300 mg/m 2 .
  • compositions can be administered by intravenous infusion to humans at doses of about 5 mg/m 2 to about 200 mg/m 2 .
  • compositions can be administered by intravenous infusion to humans at doses of about 5 mg/m 2 to about 100 mg/m 2 .
  • compositions can be administered by intravenous infusion to humans at doses of about 10 mg/m 2 to about 50 mg/m 2 .
  • compositions can be administered by intravenous infusion to humans at doses of about 50 mg/m 2 to about 200 mg/m 2 .
  • compositions can be administered by intravenous infusion to humans at doses of about 75 mg/m 2 to about 175 mg/m 2 .
  • compositions can be administered by intravenous infusion to humans at doses of about 100 mg/m 2 to about 150 mg/m 2 .
  • 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 should 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.
  • inhaled particle size For nasal delivery, a larger inhaled particle size may be desired to maximize impaction on the nasal mucosa and to minimize or prevent pulmonary deposition of the administered formulation.
  • aerosols intended for delivery to the lung are provided for inhalation through the nose or the mouth.
  • inhaled aerodynamic particle sizes of about less than 10 pm are useful (e.g., about 1 to about 10 microns).
  • Inhaled particles may be defined as liquid droplets containing dissolved drug, liquid droplets containing suspended drug particles (in cases where the drug is insoluble in the suspending medium), dry particles of pure drug substance, drug substance incorporated with excipients, liposomes, emulsions, colloidal systems, coacervates, aggregates of drug nanoparticles, or dry particles of a diluent which contain embedded drug nanoparticles.
  • compounds of Formula (I) disclosed herein intended for respiratory delivery 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 drug substance effectively. A desired particle size and distribution may be obtained by choosing an appropriate device.
  • compositions of Formula (I) disclosed herein can be administered to the ear by various methods.
  • a round window catheter e.g., U.S. Pat. Nos. 6,440,102 and 6,648,873 can be used.
  • formulations 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).
  • formulations of the disclosure can be incorporated into a gel formulation (e.g., U.S. Pat. Nos. 4,474,752 and 6,911,211).
  • compounds of Formula (I) disclosed herein intended for delivery to the ear can be administered via an implanted pump and delivery system through a needle directly into the middle or inner ear (cochlea) or through a cochlear implant stylet electrode channel or alternative prepared drug delivery channel such as but not limited to a needle through temporal bone into the cochlea.
  • 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).
  • Intratympanic injection of therapeutic agents is the technique of injecting a therapeutic agent behind the tympanic membrane into the middle and/or inner ear.
  • the formulations described herein are administered directly onto the round window membrane via transtympanic injection.
  • 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.
  • the formulation described herein is administered onto the round window membrane via a surgical approach to the round window membrane comprising modification of the crista fenestrae cochleae.
  • the compounds of Formula (I) are formulated in 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.
  • Suppositories for rectal administration of the drug can be prepared by mixing a compound provided herein 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.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter, is first melted.
  • Solid compositions can be provided in various different types of dosage forms, depending on the physicochemical properties of the compound provided herein, the desired dissolution rate, cost considerations, and other criteria.
  • 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.
  • Examples of single units which may be used as dosage forms for the solid composition include tablets, such as compressed tablets, fdm-like units, foil-like units, wafers, lyophilized matrix units, and the like.
  • the solid composition is a highly porous lyophilized form.
  • Such lyophilizates, sometimes also called wafers or lyophilized tablets, are particularly useful for their rapid disintegration, which also enables the rapid dissolution of the compound.
  • the solid composition may also be formed as a multiple unit dosage form as defined above.
  • multiple units are powders, granules, microparticles, pellets, mini-tablets, beads, lyophilized powders, and the like.
  • 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 formation 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.
  • Another type of multiparticulate system which is also capable of achieving rapid drug dissolution is that of powders, granules, or pellets from water-soluble excipients which are coated with a compound provided herein so that the compound is located at the outer surface of the individual particles.
  • the water-soluble low molecular weight excipient may be useful for preparing the cores of such coated particles, which can be subsequently coated with a coating composition comprising the compound and, for example, 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.
  • kits typically include one or more compounds or compositions as described herein.
  • 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).
  • 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 cancer.
  • 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 hepatocellular carcinoma, colon cancer, leukemia, lymphoma, sarcoma, ovarian cancer, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, sepsis, ankylosing spondylitis, psoriasis, scleroderma, mycotic and viral infections, bone and cartilage diseases, Alzheimer’s disease, lung disease, bone/osteoporotic (wrist, spine, shoulder and hip) fractures, articular cartilage (chondral) defects, degenerative disc disease (or intervertebral disc degeneration), polyposis coli, bone density and vascular defects in the eye (Osteoporosis - pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, t
  • the compounds and compositions provided herein can be used as inhibitors and/or modulators of one or more components of the Wnt pathway, which may include 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 cancer and other diseases associated with abnormal angiogenesis, cellular proliferation, and cell cycling. Accordingly, the compounds and compositions provided herein can be used to treat cancer, to reduce or inhibit angiogenesis, to reduce or inhibit cellular proliferation, to correct a genetic disorder, and/or to treat a neurological condition/disorder/disease due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components.
  • Non-limiting examples of diseases which can be treated with the compounds and compositions provided herein include a variety of cancers, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, scleroderma, mycotic and viral infections, bone and cartilage diseases, neurological conditions/diseases such as Alzheimer's disease, amyotrophic lateral sclerosis (AFS), motor neuron disease, multiple sclerosis or autism, lung disease, bone/osteoporotic (wrist, spine, shoulder and hip) fractures, polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Miillerian-duct regression and virilization, SERKAF syndrome, type II diabetes, Fuhrmann syndrome, Al- Awadi/Raas-Rothschild
  • the Wnt pathway is known to be constitutively activated in a variety of cancers including, for example, colon cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, prostate cancer , pancreatic cancer and leukemias such as CML, CLL and T-ALL. Accordingly, the compounds and compositions described herein may be used to treat these cancers in which the Wnt pathway is constitutively activated.
  • the cancer is chosen from hepatocellular carcinoma, colon cancer, leukemia, lymphoma, sarcoma and ovarian cancer.
  • cancers that may be treated by the compounds, compositions and methods described herein include, but are not limited to, the following:
  • Breast cancers including, for example ER + breast cancer, ER breast cancer, her2 breast cancer, her2 + breast cancer, stromal tumors such as fibroadenomas, phyllodes tumors, and sarcomas, and epithelial tumors such as large duct papillomas; carcinomas of the breast including in situ (noninvasive) carcinoma that includes ductal carcinoma in situ (including Paget's disease) and lobular carcinoma in situ, and invasive (infiltrating) carcinoma including, but not limited to, invasive ductal carcinoma, invasive lobular carcinoma, medullary carcinoma, colloid (mucinous) carcinoma, tubular carcinoma, and invasive papillary carcinoma; and miscellaneous malignant neoplasms.
  • in situ (noninvasive) carcinoma that includes ductal carcinoma in situ (including Paget's disease) and lobular carcinoma in situ
  • invasive (infiltrating) carcinoma including, but not limited to, invasive ductal carcinoma, invasive lobular carcinoma, medu
  • breast cancers can include luminal A, luminal B, basal A, basal B, and triple negative breast cancer, which is estrogen receptor negative (ER ), progesterone receptor negative, and her2 negative (her2 ).
  • the breast cancer may have a high risk Oncotype score.
  • Cardiac cancers including, for example sarcoma, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma; fibroma; lipoma and teratoma.
  • sarcoma e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma
  • myxoma rhabdomyoma
  • fibroma fibroma
  • lipoma and teratoma.
  • Lung cancers including, for example, bronchogenic carcinoma, e.g., squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchial adenoma; sarcoma; lymphoma; chondromatous hamartoma; and mesothelioma.
  • bronchogenic carcinoma e.g., squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma
  • alveolar and bronchiolar carcinoma bronchial adenoma
  • sarcoma sarcoma
  • lymphoma chondromatous hamartoma
  • mesothelioma mesothelioma
  • Gastrointestinal cancer including, for example, cancers of the esophagus, e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; cancers of the stomach, e.g., carcinoma, lymphoma, and leiomyosarcoma; cancers of the pancreas, e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, and vipoma; cancers of the small bowel, e.g., adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma; cancers of the large bowel, e.g., adenocarcinoma, tubular adenom
  • Genitourinary tract cancers including, for example, cancers of the kidney, e.g., adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, and leukemia; cancers of the bladder and urethra, e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma; cancers of the prostate, e.g., adenocarcinoma, and sarcoma; cancer of the testis, e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, and lipoma.
  • adenocarcinoma Wilm's tumor (nephroblastoma), lymphoma, and leukemia
  • Liver cancers including, for example, hepatoma, e.g., hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hepatocellular adenoma; and hemangioma.
  • hepatoma e.g., hepatocellular carcinoma
  • cholangiocarcinoma e.g., hepatocellular carcinoma
  • hepatoblastoma hepatoblastoma
  • angiosarcoma hepatocellular adenoma
  • hemangioma hemangioma
  • Bone cancers including, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochrondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors.
  • osteogenic sarcoma osteosarcoma
  • fibrosarcoma malignant fibrous histiocytoma
  • chondrosarcoma chondrosarcoma
  • Ewing's sarcoma malignant lymphoma (reticulum cell sarcoma)
  • multiple myeloma malignant giant cell tumor chordoma
  • Nervous system cancers including, for example, cancers of the skull, e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans; cancers of the meninges, e.g., meningioma, meningiosarcoma, and gliomatosis; cancers of the brain, e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, oligodendrocytoma, schwannoma, retinoblastoma, and congenital tumors; and cancers of the spinal cord, e.g., neurofibroma, meningioma, glioma, and sarcoma.
  • the spinal cord e.g., neurofibrom
  • Gynecological cancers including, for example, cancers of the uterus, e.g., endometrial carcinoma; cancers of the cervix, e.g., cervical carcinoma, and pre tumor cervical dysplasia; cancers of the ovaries, e.g., ovarian carcinoma, including serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa theca cell tumors, Sertoli Leydig cell tumors, dysgerminoma, and malignant teratoma; cancers of the vulva, e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma; cancers of the vagina, e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, and embryonal rhabdomyosarcoma;
  • Hematologic cancers including, for example, cancers of the blood, e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, and myelodysplastic syndrome, Hodgkin's lymphoma, non-Hodgkin’s lymphoma (malignant lymphoma) and Waldenstrom's macroglobulinemia.
  • Skin cancers and skin disorders including, for example, malignant melanoma and metastatic melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, and scleroderma.
  • Adrenal gland cancers including, for example, neuroblastoma.
  • tumors of the central nervous system that may be treated by the compounds, compositions and methods described herein include:
  • Astrocytic tumors e.g., diffuse astrocytoma (fibrillary, protoplasmic, gemistocytic, mixed), anaplastic (malignant) astrocytoma, glioblastoma multiforme (giant cell glioblastoma and gliosarcoma), pilocytic astrocytoma (pilomyxoid astrocytoma), pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, and gliomatosis cerebri.
  • diffuse astrocytoma fibrillary, protoplasmic, gemistocytic, mixed
  • anaplastic (malignant) astrocytoma e.g., glioblastoma multiforme (giant cell glioblastoma and gliosarcoma)
  • pilocytic astrocytoma pilomyxoid astrocytoma
  • Oligodendroglial tumors e.g., oligodendroglioma and anaplastic oligodendroglioma.
  • Oligoastrocytic tumors e.g., oligoastrocytoma and anaplastic oligoastrocytoma.
  • Ependymal tumors e.g., subependymoma, myxopapillary ependymoma, ependymoma, (cellular, papillary, clear cell, tanycytic), and anaplastic (malignant) ependymoma.
  • Choroid plexus tumors e.g., choroid plexus papilloma, atypical choroid plexus papilloma, and choroid plexus carcinoma.
  • Neuronal and mixed neuronal -glial tumors e.g., gangliocytoma, ganglioglioma, dysembryoplastic neuroepithelial tumor (DNET), dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos), desmoplastic infantile astrocytoma/ganglioglioma, central neurocytoma, anaplastic ganglioglioma, extraventricular neurocytoma, cerebellar liponeurocytoma, Papillary glioneuronal tumor, Rosette -forming glioneuronal tumor of the fourth ventricle, and paraganglioma of the fdum terminale.
  • DNET dysembryoplastic neuroepithelial tumor
  • DNET dysplastic gangliocytoma of the cerebellum
  • desmoplastic infantile astrocytoma/ganglioglioma central neurocytoma
  • anaplastic ganglioglioma extra
  • Pineal tumors e.g., pineocytoma, pineoblastoma, papillary tumors ofthe pineal region, and pineal parenchymal tumor of intermediate differentiation.
  • Embryonal tumors e.g., medulloblastoma (medulloblastoma with extensive nodularity, anaplastic medulloblastoma, desmoplastic, large cell, melanotic, medullomyoblastoma), medulloepithelioma, supratentorial primitive neuroectodermal tumors, and primitive neuroectodermal tumors (PNETs) such as neuroblastoma, ganglioneuroblastoma, ependymoblastoma, and atypical teratoid/rhabdoid tumor.
  • medulloblastoma medulloblastoma with extensive nodularity, anaplastic medulloblastoma, desmoplastic, large cell, melanotic, medullomyoblastoma
  • medulloepithelioma supratentorial primitive neuroectodermal tumors
  • PNETs neuroectodermal tumors
  • Neuroblastic tumors e.g., olfactory (esthesioneuroblastoma), olfactory neuroepithelioma, and neuroblastomas of the adrenal gland and sympathetic nervous system.
  • Glial tumors e.g., astroblastoma, chordoid glioma of the third ventricle, and angiocentric glioma.
  • Tumors of cranial and paraspinal nerves e.g., schwannoma, neurofibroma Perineurioma, and malignant peripheral nerve sheath tumor.
  • Tumors of the meninges such as tumors of meningothelial cells, e.g., meningioma (atypical meningioma and anaplastic meningioma); mesenchymal tumors, e.g., lipoma, angiolipoma, hibernoma, liposarcoma, solitary fibrous tumor, fibrosarcoma, malignant fibrous histiocytoma, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, chondroma, chondrosarcoma, osteoma, osteosarcoma, osteochondroma, haemangioma, epithelioid hemangioendothelioma, haemangiopericytoma, anaplastic haemangiopericytoma, angiosarcoma, Kaposi Sarcoma, and Ewing Sarcoma
  • Tumors of the hematopoietic system e.g., malignant Lymphomas, plasmocytoma, and granulocytic sarcoma.
  • Germ cell tumors e.g., germinoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma, and mixed germ cell tumors.
  • Tumors of the sellar region e.g., craniopharyngioma, granular cell tumor, pituicytoma, and spindle cell oncocytoma of the adenohypophysis.
  • Cancers may be solid tumors that may or may not be metastatic. Cancers may also occur, as in leukemia, as a diffuse tissue. Thus, the term“tumor cell,” as provided herein, includes a cell afflicted by any one of the above identified disorders.
  • a method of treating cancer using a compound or composition as described herein may be combined with existing methods of treating cancers, for example by chemotherapy, irradiation, or surgery (e.g., oophorectomy).
  • a compound or composition can be administered before, during, or after another anticancer agent or treatment.
  • the compounds and compositions described herein can be used as anti- angiogenesis agents and as agents for modulating and/or inhibiting the activity of protein kinases, thus providing treatments for cancer and other diseases associated with cellular proliferation mediated by protein kinases.
  • the compounds described herein can inhibit the activity of one or more kinases. Accordingly, provided herein is a method of treating cancer or preventing or reducing angiogenesis through kinase inhibition.
  • the compounds and compositions described herein can function as cell-cycle control agents for treating proliferative disorders in a patient.
  • Disorders associated with excessive proliferation include, for example, cancers, scleroderma, immunological disorders involving undesired proliferation of leukocytes, and restenosis and other smooth muscle disorders.
  • such compounds may be used to prevent de -differentiation of post-mitotic tissue and/or cells.
  • Diseases or disorders associated with uncontrolled or abnormal cellular proliferation include, but are not limited to, the following:
  • cancers including, but not limited to, carcinoma, hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system and other tumors including melanoma, seminoma and Kaposi's sarcoma.
  • a disease process which features abnormal cellular proliferation e.g., benign prostatic hyperplasia, familial adenomatosis polyposis, neurofibromatosis, atherosclerosis, arthritis, glomerulonephritis, restenosis following angioplasty or vascular surgery, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections.
  • Fibrotic disorders such as skin fibrosis; scleroderma; progressive systemic fibrosis; lung fibrosis; muscle fibrosis; kidney fibrosis; glomerulosclerosis; glomerulonephritis; hypertrophic scar formation; uterine fibrosis; renal fibrosis; cirrhosis of the liver, liver fibrosis; fatty liver disease (FLD); adhesions, such as those occurring in the abdomen, pelvis, spine or tendons; chronic obstructive pulmonary disease; fibrosis following myocardial infarction; pulmonary fibrosis; fibrosis and scarring associated with diffuse/interstitial lung disease; central nervous system fibrosis, such as fibrosis following stroke; fibrosis associated with neuro -degenerative disorders such as Alzheimer's Disease or multiple sclerosis; fibrosis associated with proliferative vitreoretinopathy (PVR); restenosis; endometriosis; ischemic disease and radiation fibrosis
  • apoptosis-associated conditions such as cancers (including but not limited to those types mentioned herein), viral infections (including but not limited to herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV -infected individuals, autoimmune diseases (including but not limited to systemic lupus erythematosus, rheumatoid arthritis, sepsis, ankylosing spondylitis, psoriasis, scleroderma, autoimmune mediated glomerulonephritis, inflammatory bowel disease and autoimmune diabetes mellitus), neuro -degenerative disorders (including but not limited to Alzheimer’s disease, lung disease, amyotrophic lateral sclerosis, retinitis pigmentosa, Parkinson's disease, AIDS-related dementia, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial in
  • Wnt signaling components such as polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Miillerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas- Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith
  • ATRX alpha-
  • the compounds and compositions provided herein have been found to possess immunomodulatory activities and are expected to control the innate and adaptive immune system (e.g. macrophages, microglia, dendritic cells, B and T cells) and suppress pro-inflammatory cytokine release (e.g. TNF, IF-6, IF-1, IFND) which is well known to be involved in chronic inflammation in a wide variety of disease areas.
  • innate and adaptive immune system e.g. macrophages, microglia, dendritic cells, B and T cells
  • pro-inflammatory cytokine release e.g. TNF, IF-6, IF-1, IFND
  • compounds and compositions provided herein can used to treat chronic inflammation associated with disorders and diseases including but not limited to eye disorders, joint pain, arthritis (rheumatoid, osteo, psoriatic gout), cancers (colon, breast, lung, pancreas, and others), gastrointestinal disorders (ulcerative colitis and inflammatory bowel diseases), pulmonary disorders (chronic obstructive pulmonary disorder and asthma), allergies, skin disorders (atopic dermatitis and psoriasis), diabetes, pancreatitis, tendonitis, hepatitis, heart disease, myocarditis, stroke, lupus, and neurological disorders such as multiple sclerosis, Parkinson’s and dementia including Alzheimer’s disease.
  • disorders and diseases including but not limited to eye disorders, joint pain, arthritis (rheumatoid, osteo, psoriatic gout), cancers (colon, breast, lung, pancreas, and others), gastrointestinal disorders (ulcerative colitis and inflammatory bowel diseases), pulmonary disorders (chronic
  • the compounds and compositions provided herein can be used as inhibitors and/or modulators of the enzyme DYRK1 A, and thus can be used to treat a variety of disorders and diseases associated with tau protein, amyloid, alpha-synuclein, TDP-43 or FUS pathology including, but not limited to, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), down syndrome, frontotemporal dementia (FTD) including FTD with Parkinsonism-17 (FTDP-17), behavioural variant frontotemporal dementia (bvFTD), FTD in patients with motor neuron disease (MND) (typically amyotrophic lateral sclerosis, also called FTD-ALS), corticobasal degeneration (CBD) (also called corticobasal ganglionic degeneration), progressive supranuclear palsy, primary progressive aphasia (PPA), globular glial tauopathy (GGT), myotonic dystrophy type 1 (DM1) (also called Steinert disease), myo
  • Non-limiting examples of neurological disorders which can be treated with the compounds and compositions provided herein include Alzheimer's disease, aphasia, apraxia, arachnoiditis, ataxia telangiectasia, attention deficit hyperactivity disorder, auditory processing disorder, autism, alcoholism, Bell's palsy, bipolar disorder, brachial plexus injury, Canavan disease, carpal tunnel syndrome, causalgia, central pain syndrome, central pontine myelinolysis, centronuclear myopathy, cephalic disorder, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral gigantism, cerebral palsy, cerebral vasculitis, cervical spinal stenosis, Charcot-Marie-Tooth disease, Chiari malformation, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic pain, Coffm-Lowry syndrome, complex regional pain syndrome, compression neuropathy, congenital facial diplegia
  • CIDP chronic inflammatory demyelinating polyn
  • the compounds and compositions may also be useful in the inhibition of the development of invasive cancer, tumor angiogenesis and metastasis.
  • the disclosure provides a method for treating a disease or disorder associated with aberrant cellular proliferation by administering to a patient in need of such treatment an effective amount of one or more of the compounds of Formula (I), in combination (simultaneously or sequentially) with at least one other agent.
  • the disclosure provides a method of treating or ameliorating in a patient a disorder or disease selected from the group consisting of: cancer, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), degenerative disc disease, bone/osteoporotic fractures, bone or cartilage disease, and osteoarthritis, the method comprising administering to the patient a therapeutically effective amount of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof.
  • a disorder or disease selected from the group consisting of: cancer, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), degenerative disc disease, bone/osteoporotic fractures, bone or cartilage disease, and osteoarthritis
  • the disclosure provides a method of treating or ameliorating in a patient a disorder or disease selected from the group consisting of: chronic inflammation, systemic inflammation, diabetes, cancer, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), degenerative disc disease, bone/osteoporotic fractures, a bone or cartilage disease, a neurological condition/disorder/disease, osteoarthritis, lung disease, a fibrotic disorder.
  • the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the method of treats a disorder or disease in which aberrant Wnt signaling is implicated in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the disorder or disease is the pain and inflammation associated with cancer.
  • the disorder or disease is the pain and inflammation associated with a joint.
  • the disorder or disease is the pain and inflammation associated with the knee.
  • the disorder or disease is the pain and inflammation associated with the hip.
  • the disorder or disease is the pain and inflammation associated with the shoulder.
  • the disorder or disease is the pain and inflammation associated with arthritis.
  • the disorder or disease is the pain and inflammation associated with gastrointestinal disorders.
  • the disorder or disease is the pain and inflammation associated with pulmonary disorders.
  • the disorder or disease is the pain and inflammation associated with allergies.
  • the disorder or disease is the pain and inflammation associated with skin disorders.
  • the disorder or disease is the pain and inflammation associated with diabetes.
  • the disorder or disease is the pain and inflammation associated with pancreatitis.
  • the disorder or disease is the pain and inflammation associated with tendonitis. [0394] In some embodiments, the disorder or disease is the pain and inflammation associated with heart disease.
  • the disorder or disease is the pain and inflammation associated with lupus.
  • the disorder or disease is the pain and inflammation associated with a neurological disorder.
  • the disorder or disease is the pain and inflammation associated with multiple sclerosis.
  • the disorder or disease is the pain and inflammation associated with Parkinson’s.
  • the disorder or disease is cancer.
  • the disorder or disease is systemic inflammation.
  • the disorder or disease is metastatic melanoma.
  • the disorder or disease is fatty liver disease.
  • the disorder or disease is liver fibrosis.
  • the disorder or disease is tendon regeneration.
  • the disorder or disease is diabetes.
  • the disorder or disease is degenerative disc disease.
  • the disorder or disease is osteoarthritis.
  • the disorder or disease is diabetic retinopathy.
  • the disorder or disease is pulmonary fibrosis.
  • the disorder or disease is idiopathic pulmonary fibrosis
  • the disorder or disease is degenerative disc disease.
  • the disorder or disease is rheumatoid arthritis.
  • the disorder or disease is scleroderma.
  • the disorder or disease is a bone or cartilage disease.
  • the disorder or disease is a neurological disorder.
  • the disorder or disease is Alzheimer's disease.
  • the disorder or disease is osteoarthritis.
  • the disorder or disease is lung disease.
  • the disorder or disease is a genetic disease caused by mutations in Wnt signaling components, wherein the genetic disease is selected from: polyposis coli, osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia syndrome, Miillerian-duct regression and virilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome, Al-Awadi/Raas- Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split- hand/foot malformation, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha- thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman
  • the patient is a human.
  • the cancer is chosen from: hepatocellular carcinoma, colon cancer, breast cancer, pancreatic cancer, chronic myeloid leukemia (CMF), chronic myelomonocytic leukemia, chronic lymphocytic leukemia (CFF), acute myeloid leukemia, acute lymphocytic leukemia, Hodgkin lymphoma, lymphoma, sarcoma and ovarian cancer.
  • CMF chronic myeloid leukemia
  • CFF chronic lymphocytic leukemia
  • acute myeloid leukemia acute lymphocytic leukemia
  • Hodgkin lymphoma lymphoma
  • lymphoma lymphoma
  • sarcoma sarcoma and ovarian cancer.
  • the cancer is chosen from: lung cancer - non-small cell, lung cancer - small cell, multiple myeloma, nasopharyngeal cancer, neuroblastoma, osteosarcoma, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer - basal and squamous cell, skin cancer - melanoma, small intestine cancer, stomach (gastric) cancers, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, laryngeal or hypopharyngeal cancer, kidney cancer, Kaposi sarcoma, gestational trophoblastic disease, gastrointestinal stromal tumor, gastrointestinal carcinoid tumor, gallbladder cancer, eye cancer (melanoma and lymphoma), Ewing tumor, esophagus cancer, endo
  • the cancer is hepatocellular carcinoma.
  • the cancer is colon cancer.
  • the cancer is colorectal cancer.
  • the cancer is breast cancer.
  • the cancer is pancreatic cancer.
  • the cancer is chronic myeloid leukemia (CMF).
  • CMF chronic myeloid leukemia
  • the cancer is chronic myelomonocytic leukemia.
  • the cancer is chronic lymphocytic leukemia (CFF).
  • CFF chronic lymphocytic leukemia
  • the cancer is acute myeloid leukemia.
  • the cancer is acute lymphocytic leukemia.
  • the cancer is sarcoma.
  • the cancer is ovarian cancer.
  • the cancer is lung cancer - small cell.
  • the cancer is multiple myeloma.
  • the cancer is nasopharyngeal cancer.
  • the cancer is neuroblastoma.
  • the cancer is osteosarcoma.
  • the cancer is penile cancer.
  • the cancer is pituitary tumors.
  • the cancer is prostate cancer.
  • the cancer is retinoblastoma.
  • the cancer is rhabdomyosarcoma.
  • the cancer is salivary gland cancer.
  • the cancer is skin cancer - basal and squamous cell.
  • the cancer is skin cancer - melanoma.
  • the cancer is small intestine cancer.
  • the cancer is stomach (gastric) cancers.
  • the cancer is testicular cancer.
  • the cancer is thymus cancer.
  • the cancer is thyroid cancer.
  • the cancer is uterine sarcoma.
  • the cancer is vaginal cancer.
  • the cancer is vulvar cancer.
  • the cancer is Wilms tumor.
  • the cancer is laryngeal or hypopharyngeal cancer.
  • the cancer is kidney cancer.
  • the cancer is Kaposi sarcoma.
  • the cancer is gestational trophoblastic disease.
  • the cancer is gastrointestinal stromal tumor.
  • the cancer is gastrointestinal carcinoid tumor.
  • the cancer is eye cancer (melanoma and lymphoma). [0469] In some embodiments, the cancer is Ewing tumor.
  • the cancer is esophagus cancer.
  • the cancer is endometrial cancer.
  • the cancer is colorectal cancer.
  • the cancer is cervical cancer.
  • the cancer is brain or spinal cord tumor.
  • the cancer is bone metastasis.
  • the cancer is bone cancer.
  • the cancer is bladder cancer.
  • the cancer is bile duct cancer.
  • the cancer is anal cancer.
  • the cancer is adrenal cortical cancer.
  • the disorder or disease is a neurological condition/disorder/disease
  • the neurological condition/disorder/disease is selected from: Alzheimer's disease, frontotemporal dementias, dementia with Lewy bodies, prion diseases, Parkinson's disease, Huntington's disease, progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, amyotrophic lateral sclerosis (ALS), inclusion body myositis, autism, degenerative myopathies, diabetic neuropathy, other metabolic neuropathies, endocrine neuropathies, orthostatic hypotension, multiple sclerosis and Charcot-Marie-Tooth disease.
  • ALS amyotrophic lateral sclerosis
  • the disorder or disease is a neurological condition/disorder/disease associated with tau protein, amyloid, alpha-synuclein pathology, Tar DNA-binding Protein of 43KDa (TDP-43), Prion protein PrP or fused in sarcoma (FUS).
  • tau protein amyloid, alpha-synuclein pathology, Tar DNA-binding Protein of 43KDa (TDP-43), Prion protein PrP or fused in sarcoma (FUS).
  • TDP-43 Tar DNA-binding Protein of 43KDa
  • Prion protein PrP or fused in sarcoma
  • the disorder or disease is a neurological condition/disorder/disease
  • the neurological condition/disorder/disease is selected from the group consisting of: Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, Down Syndrome, Frontotemporal Dementia with Parkinsonism- 17 (FTDP-17), Lewy body dementia, Parkinson’s Disease, Pick's Disease, and additional diseases with pronounced neurodegeneration such as Autism, Dementia, Epilepsy, Huntington’s Disease, Multiple Sclerosis; diseases and disorders associated with acquired brain injury such as Chronic Traumatic Encephalopathy, Traumatic Brain Injury, Tumor, and Stroke.
  • the disorder or disease is a fibrotic disorder, wherein the fibrotic disorder is selected from the group consisting of: skin fibrosis; scleroderma; progressive systemic fibrosis; lung fibrosis; muscle fibrosis; kidney fibrosis; glomerulosclerosis; glomerulonephritis; hypertrophic scar formation; uterine fibrosis; renal fibrosis; cirrhosis of the liver, liver fibrosis; adhesions; chronic obstructive pulmonary disease; fibrosis following myocardial infarction; pulmonary fibrosis; fibrosis and scarring associated with diff ise/interstitial lung disease; central nervous system fibrosis; fibrosis associated with proliferative vitreoretinopathy (PVR); restenosis; endometriosis; ischemic disease, and radiation fibrosis.
  • the fibrotic disorder is selected from the group consisting of: skin fibrosis; scleroderma; progressive system
  • the disorder or disease is chronic inflammation associated with eye disorders, joint pain, arthritis (rheumatoid, osteo, psoriatic gout), cancers (colon, breast, lung, pancreas, and others), gastrointestinal disorders (ulcerative colitis and inflammatory bowel diseases), pulmonary disorders (chronic obstructive pulmonary disorder and asthma), allergies, skin disorders (atopic dermatitis and psoriasis), diabetes, pancreatitis, tendonitis, hepatitis, heart disease, myocarditis, stroke, lupus, and neurological disorders such as multiple sclerosis, Parkinson’s and dementia including Alzheimer’s disease.
  • eye disorders joint pain, arthritis (rheumatoid, osteo, psoriatic gout), cancers (colon, breast, lung, pancreas, and others), gastrointestinal disorders (ulcerative colitis and inflammatory bowel diseases), pulmonary disorders (chronic obstructive pulmonary disorder and asthma), allergies, skin disorders (atopic dermatitis and
  • a compound of Formula (I) inhibits DYRK1A.
  • a compound of Formula (I) inhibits GSK3.
  • a compound of Formula (I) inhibits GSK3 .
  • a compound of Formula (I) inhibits DYRK1A and
  • the compound of Formula (I) inhibits one or more proteins in the Wnt pathway.
  • the compound of Formula (I) inhibits signaling induced by one or more Wnt proteins.
  • 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 WNT16.
  • the compound of Formula (I) inhibits a kinase activity.
  • the method treats a disease or disorder mediated by the
  • the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) inhibits one or more Wnt proteins.
  • the method treats a disease or disorder mediated by kinase activity in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the disease or disorder comprises tumor growth, cell proliferation, or angiogenesis.
  • the method inhibits the activity of a protein kinase receptor, the method comprises contacting the receptor with an effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the method treats a disease or disorder associated with aberrant cellular proliferation in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the method prevents or reduces angiogenesis in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the method prevents or reduces abnormal cellular proliferation in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the method treats a disease or disorder associated with aberrant cellular proliferation in a patient, the method comprises administering to the patient a pharmaceutical composition comprising one or more of the compounds of claim 1 in combination with a pharmaceutically acceptable carrier and one or more other agents.
  • Compounds and compositions described herein can inhibit the kinase activity of, for example, CDK/cyclin complexes, such as those active in the Go or Gi stage of the cell cycle, e.g., CDK2, CDK4, and/or CDK6 complexes.
  • CDK/cyclin complexes such as those active in the Go or Gi stage of the cell cycle, e.g., CDK2, CDK4, and/or CDK6 complexes.
  • the biological activity of the compounds described herein can be tested using any suitable assay known to those of skill in the art, see, e.g., WO 2001/053268 and WO 2005/009997.
  • the activity of a compound may be tested using one or more of the test methods outlined below.
  • tumor cells may be screened for Wnt independent growth.
  • tumor cells of interest are contacted with a compound (i.e. inhibitor) of interest, and the proliferation of the cells, e.g. by uptake of tritiated thymidine, is monitored.
  • tumor cells may be isolated from a candidate patient who has been screened for the presence of a cancer that is associated with a mutation in the Wnt signaling pathway.
  • Candidate cancers include, without limitation, those listed above.
  • one may utilize in vitro assays for Wnt biological activity e.g. stabilization of b-catenin and promoting growth of stem cells.
  • Assays for biological activity of Wnt include stabilization of b-catenin, which can be measured, for example, by serial dilutions of a candidate inhibitor composition.
  • An exemplary assay for Wnt biological activity contacts a candidate inhibitor with cells containing constitutively active Wnt ⁇ -catenin signaling. The cells are cultured for a period of time sufficient to stabilize b-catenin, usually at least about 1 hour, and lysed. The cell lysate is resolved by SDS PAGE, then transferred to nitrocellulose and probed with antibodies specific for b-catenin.
  • the activity of a candidate compound can be measured in a Xenopus secondary axis bioassay (Leyns, L. et al. Cell (1997), 88(6), 747-756).
  • in vitro assays for DYRK1A biological activity may be used, e.g. regulation of microtubule-associated protein tau (MAPT/Tau) phosphorylation in neuronal cell line such as the human SH-SY5Y neuroblastoma cell line.
  • Assays for DYRK1A- regulated level of phosphorylation can include monitoring levels of basal pSer396 Tau, which can be measured, for example, by serial dilutions of a candidate inhibitor composition using a ten micromolar top concentration and detected by ELISA or Western Blotting.
  • An exemplary assay for DYRK-1 A-regulated phosphorylation uses the SH-SY 5Y cells cultured in a 96 well plate format for a period of time sufficient to stabilize microtubules and Tau phosphorylation, usually at least 2 days, then treated with a 1/3 serial dilution of compounds overnight and lysed. The cell lysate is resolved by SDS PAGE, then transferred to nitrocellulose and probed with an antibody specific for pSer396 Tau. The chemiluminescence signal for HRP -linked antibodies used in western blotting is detected using a Carestream Image Station and blot densitometry for pSer396 and beta-actin are analyzed using Image J (NIH).
  • the activity of a candidate compound can be measured by ELISA by adding the lysate mentioned above onto total Tau-coated plates and detected with a specific pSer396 antibody. Colorimetric detection of ELISA signal is performed by Cytation3 plate reader (Biotek).
  • 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.
  • Boc / -butyloxycarbonyl group
  • DIAD diisopropyl azodicarboxylate
  • DIPEA N,N-diisopropylethylamine
  • HATU l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
  • LAH lithium aluminum hydride
  • LC/MS Liquid chromatography-mass spectrometry
  • Ms mesyl or methanesulfonyl group
  • NaBH(OAc) 3 sodium triacetoxyborohydride
  • NaCNB3 ⁇ 4 sodium cyanoborohydride
  • NaHS03 sodium bisulfite
  • NIS N-iodosuccinimide
  • Pd(dba) 3 tris(dibenzylideneacetone)dipalladium(0)
  • Pd(dppf)Cl2 1.1 '-bis(diphcnylphosphino)fcrroccnc-palladium(//)dichloridc
  • Pd(PPli 3 ) 2 Cl 2 bis(triphenylphosphine)palladium(II) dichloride
  • Pd(PPli3)4 tetrakis(triphenylphosphine)palladium(0)
  • Pd(t-Bu3P)2 Bis(tri-/er/-butylphosphine)palladium(0)
  • PE petroleum ether
  • pTsOH p-toluenesulfonic acid or tosylic acid
  • xanthphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
  • Scheme 1 describes a method for preparation of pyrazole intermediate (V) by first iodination using NIS in the presence of TFA to give pyrazole (II) followed by protection of the pyrazole nitrogen by THP.
  • the methyl ester of pyrazole (III) was then hydrolyzed to acid (IV) followed by coupling with N,O-dimethylhydroxylamine to form the Weinreb amide (V).
  • Scheme 2 describes a method for preparation of pyrazole intermediate (XIX) by first iodination using NIS in the presence of TFA to give pyrazole (VII) followed by protection of the pyrazole nitrogen by THP.
  • the protected iodo pyrazole (VIII) was coupled to TMS protected acetylene in the presence of catalytic palladium and copper to give alkyne substituted pyrazole (IX).
  • the TMS protecting group was removed using Li OH followed by Sonogashira coupling of the terminal alkyne with various R 2 -bromines to produce pyrazole (XIX).
  • Scheme 4 describes methods for the preparation of pyrazole intermediates (XXI), (XXIV), and (XXVII) from pyrazole intermediate (VIII).
  • XXI alkyne substituted pyrazol-3-yl-benzoimidazole
  • Sonogashira cross-coupling reaction was used to couple intermediate (VIII) with various substituted alkynes to form (XIX) followed by cyclization with various phenylenediamines to give the benzimidazole (XX) followed by deprotection to yield the final pyrazol-3-yl-benzoimidazole (XXI) derivatives.
  • alkene substituted pyrazol-3-yl- benzoimidazole (XXIV) various substituted alkenes were coupled to pyrazole intermediate (VIII) using the Heck reaction to form (XXII) followed cyclization with various phenylenediamines to give the benzimidazole (XXIII) followed by deprotection to yield the final pyrazol-3-yl- benzoimidazole (XXIV) derivatives.
  • Scheme 5 describes methods for the preparation of pyrazole intermediates (XXXVI) and (XL) from pyrazole intermediate (XXXII).
  • XXXVI diamide pyrazole
  • XXXVII diamide pyrazole
  • XXXIII The amine pyrazole (XXXII) was coupled with various acids to give XXXIII followed by hydrolysis of the ester to give the acid (XXXIV).
  • Acid (XXXIV) was coupled with various amines followed by deprotection to yield the final diamide pyrazole (XXXVI) derivatives.
  • CXXXIII The solution containing l-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- indazole (CXXXIII) was cooled to room temperature before adding 3,5-dibromo-4-nitro-l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazole (CXXXI) (1.0 g, 2.82 mmol, 1 eq), Pd(PPh3)4 (160 mg, 0.14 mmol, 0.05 eq), K3PO4 (1.2 g, 5.6 mmol, 2 eq), and water (2 mL).

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Abstract

Pyrazole compounds (I) for treating various diseases and pathologies are disclosed. More particularly, the present disclosure concerns the use of a pyrazole compounds, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis Alzheimer's disease, lung disease, inflammation, auto-immune diseases and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as neurological conditions/disorders/diseases linked to overexpression of DYRK1A.

Description

PYRAZOLE DERIVATIVES AS MODULATORS OF THE WNT/BETA- CATENIN SIGNALING PATHWAY
RELATED APPLICATIONS
[001] This application claims the benefit of U.S. Provisional Application Nos. 62/793,428, filed January 17, 2019, and 62/831,478, filed April 9, 2019, which are incorporated herein by reference in their entirety.
BACKGROUND
Technical Field
[002] This disclosure relates to inhibitors of one or more proteins in the Wnt pathway, including inhibitors of one or more Wnt proteins, and compositions comprising the same. More particularly, it concerns the use of a pyrazole compound or salts or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, Alzheimer's disease, lung disease, inflammation, auto-immune diseases fibrotic disorders, cartilage (chondral) defects, and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases and neurological conditions/disorders/diseases due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Also provided are methods for treating Wnt-related disease states, as well as neurological conditions/disorders/diseases linked to overexpression of DYRK1A.
Background
[003] The Wnt growth factor family includes more than 10 genes identified in the mouse and at least 19 genes identified in the human. Members of the Wnt family of signaling molecules mediate many short-and long-range patterning processes during invertebrate and vertebrate development. The Wnt signaling pathway is known for its role in the inductive interactions that regulate growth and differentiation, and it also plays roles in the homeostatic maintenance of post-embryonic tissue integrity. Wnt stabilizes cytoplasmic b-catenin, which stimulates the expression of genes including c-myc, c jun, fra-1, and cyclin Dl. In addition, misregulation of Wnt signaling can cause developmental defects and is implicated in the genesis of several human cancers. The Wnt pathway has also been implicated in the maintenance of stem or progenitor cells in a growing list of adult tissues including skin, blood, gut, prostate, muscle, and the nervous system.
[004] Dual specificity tyrosine-phosphorylation-regulated kinase 1A is an enzyme that in humans is encoded by the DYRK1A gene. DYRK1A is a member of the dual-specificity tyrosine phosphorylation -regulated kinase (DYRK) family. DYRK1A contains a nuclear targeting signal sequence, a protein kinase domain, a leucine zipper motif, and a highly conservative 13- consecutive-histidine repeat. It catalyzes its autophosphorylation on serine/threonine and tyrosine residues. It may play a significant role in a signaling pathway regulating cell proliferation and may be involved in brain development. DYRK1A is localized in the Down syndrome critical region of chromosome 21 , and is considered to be a candidate gene for learning defects associated with Down syndrome. DYRK1A is also expressed in adult brain neurons, indicating that DYRK1A may play a role in the mature central nervous system. Thus, several lines of evidence point to some synaptic functions of DYRK1A. For instance, it has been found that DYRK1A phosphorylates and modulates the interaction of several components of the endocytic protein complex machinery (Dynamin 1, Amphiphysin, and Synaptojanin), suggesting a role in synaptic vesicle recycling. In addition, a polymorphism (SNP) in DYRK 1 A was found to be associated with HIV-1 replication in monocyte-derived macrophages, as well as with progression to AIDS in two independent cohorts of HIV- 1 -infected individuals.
SUMMARY
[005] The present disclosure provides methods and reagents, involving contacting a cell with an agent, such as a pyrazole compound, in a sufficient amount to antagonize a Wnt activity, e.g., to reverse or control an aberrant growth state or correct a genetic disorder due to mutations in Wnt signaling components.
[006] The present disclosure also provides methods and reagents, involving contacting a cell with an agent, such as a pyrazole compound, in a sufficient amount to antagonize DYRK1A activity, e.g., i) to normalize prenatal and early postnatal brain development; ii) to improve cognitive function in youth and adulthood; and/or iii) to attenuate Alzheimer’s-type neurodegeneration.
[007] Some embodiments disclosed herein include Wnt and/or DYRK1A inhibitors containing a pyrazole core. Other embodiments disclosed herein include pharmaceutical compositions and methods of treatment using these compounds.
[008] One embodiment disclosed herein includes a compound having the structure of Formula (I):
Figure imgf000004_0001
as well as prodrugs and pharmaceutically acceptable salts thereof.
[009] In some embodiments of Formula (I):
R1 is selected from the group consisting of H, halide, and unsubstituted -(C1-3 alkyl);
R2 is selected from the group consisting of unsubstituted -(C1-3 alkyl), unsubstituted -(C2- 9 alkenyl), unsubstituted -(Ci-9haloalkyl), -(C1-2 alkylene)p(C3-6 carbocyclyl) optionally substituted with 1-12 R4, -monocyclic heterocyclyl optionally substituted with 1-10 R5, -phenyl substituted with 1-5 R6, -heteroaryl optionally substituted with 1-4 R7, -CO2R8, -OR9, and -(C=0)R10; wherein heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxazolyl, oxadiazolyl, thiazolyl, 2,3-dihydrobenzo[b]dioxinyl, 5,6,7,8-tetrahydroimidazo[l,2- a]pyrazinyl, 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridinyl, isoquinolinyl, and quinolinyl; wherein — (Ci-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein; with the proviso that when L1 is a bond, R2 is selected from the group consisting of -phenyl substituted with 1-5 R6 and -heteroaryl optionally substituted with 1-4 R7; wherein heteroaryl selected from the group consisting of pyridinyl, oxazolyl, oxadiazolyl, thiazolyl, 2,3- dihydrobenzo[b]dioxinyl, 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazinyl, 4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridinyl, isoquinolinyl, and quinolinyl;
R3 is selected from the group consisting of -heterocyclyl substituted with 1-10 R11, -(C1-4 alkylene)pphenyl substituted with 1-5 R12, -heteroaryl optionally substituted with 1-4 R13, and - (Ci-4 alkylene)OR14; wherein heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, 5,6,7,8-tetrahydroimidazo[l,2- a]pyrazinyl, 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridinyl, 1,2,3,4-tetrahydroisoquinolinyl,
Figure imgf000004_0002
isoquinolinyl, and quinolinyl; wherein is only substituted at positions 4 and 7; wherein each— (Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; with the proviso that when L2 is a bond, R3 is selected from -heteroaryl optionally substituted with 1-4 R13; wherein heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, 5,6,7,8-tetrahydroimidazo[l,2- a]pyrazinyl, 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridinyl, 1,2,3,4-tetrahydroisoquinolinyl,
Figure imgf000005_0001
isoquinolinyl, and quinolinyl; wherein is only substituted at positions 4 and 7;
each R4 is halide;
each R5 is independently selected from the group consisting of halide, Me, and Et;
each R6 is independently selected from the group consisting of methyl, -CFfiF, -CHF2, - CF3, -OR15a, and -(Ci-4 alkylene)pN(R16a)(R16b); wherein -(C1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein;
each R7 is independently selected from the group consisting of F, methyl, -CFfiF, -CHF2, -CF3, -CF2CH3, -OR15a, -CO2R17, -NR18(C=0)R19, — (Ci-4 alkylene)pheterocyclyl optionally substituted with 1-10 R20b, and -(C1-4 alkylene)pN(R16a)(R16b); wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
R8 is unsubstituted -(C1-9 alkyl);
R9 is unsubstituted -(C1-9 alkyl);
R10 is -aryl optionally substituted with 1-5 R21;
each R11 is independently selected from the group consisting of halide, methyl, and ethyl; each R12 is independently selected from the group consisting of -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R20a, -aryl optionally substituted with 1-5 R22,— (Ci-4 alkylene )N(R16a)(R16b), and -OR23a; wherein heterocyclyl selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; each R13 is independently selected from the group consisting of F, methyl, -CFfiF, -CHF2, -CF3,— (Ci-4 alkylene)pN(R16a)2, -OR23b, -(Cw alkylene)pheterocyclyl optionally substituted with 1-10 R20b, -aryl optionally substituted with 1-5 R22, and -heteroaryl substituted with 1-4 R24; wherein -(C1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein;
R14 is selected from the group consisting of unsubstituted -(Cw alkyl) and -aryl optionally substituted with 1-5 R22; each R15a is independently selected from the group consisting of unsubstituted -(C2-3 alkyl), and -heterocyclyl optionally substituted with 1-10 R20b;
each R15b is independently selected from the group consisting of H, unsubstituted -(C2-9 alkyl), and -heterocyclyl optionally substituted with 1-10 R20b;
each R16a is independently selected from the group consisting of H and unsubstituted -(Ci-
2 alkyl);
each R16b is unsubstituted -(C1-2 alkyl);
each R17 is unsubstituted -(C1-9 alkyl);
each R18 is independently selected from the group consisting of H and Me;
each R19 is unsubstituted -(C1-9 alkyl);
each R20a is independently selected from the group consisting of halide and unsubstituted -(C2-9 alkyl);
each R20b is independently selected from the group consisting of halide and unsubstituted -(Ci-9 alkyl);
each R21 is independently selected from the group consisting of halide and unsubstituted - (Ci-9 alkyl);
each R22 is independently selected from the group consisting of halide and unsubstituted - (Ci-9 alkyl);
each R23a is independently selected from the group consisting of unsubstituted -(C2-9 alkyl), — (Ci-4 alkylene)OR25, and -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R20b; wherein each -(Cw alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R23b is independently selected from the group consisting of unsubstituted -(C1-9 alkyl), — (Ci-4 alkylene)OR25, and -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R20b; wherein each -(Cw alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R24 is independently selected from the group consisting of halide and unsubstituted - (Ci-9 alkyl);
each R25 is independently selected from the group consisting of H and unsubstituted -(Ci-
9 alkyl);
, — CºC—
L1 is selected from the group consisting of a bond, -CH=CH-, , -
(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)p-, -NR18(C=0)NR18-, -NH(CH2)p-, and -(CH2)PNH-; L2 is selected from the group consisting of a bond, -(C=0)NR18-, -NR18(C=0)-, - NHCH2-, and -CH2NH-; and
each p is independently an integer of 0 or 1.
[010] Some embodiments include stereoisomers and pharmaceutically acceptable salts of a compound of Formula (I). Some embodiments include pharmaceutically acceptable salts of a compound of Formula (I).
[Oil] Some embodiments include pro-drugs of a compound of Formula (I).
[012] Some embodiments of the present disclosure include pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier, diluent, or excipient.
[013] Other embodiments disclosed herein include methods of inhibiting one or more members of the Wnt pathway, including one or more Wnt proteins by administering to a patient affected by a disorder or disease in which aberrant Wnt signaling is implicated, such as cancer and other diseases associated with abnormal angiogenesis, cellular proliferation, cell cycling and mutations in Wnt signaling components, a compound according to Formula (I). Accordingly, the compounds and compositions provided herein can be used to treat cancer, to reduce or inhibit angiogenesis, to reduce or inhibit cellular proliferation and correct a genetic disorder due to mutations in Wnt signaling components.
[014] Other embodiments disclosed herein include methods of inhibiting DYRK1A by administering to a patient affected by a disorder or disease in which DYRK1A overexpression is implicated, such as Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, Down Syndrome, Frontotemporal Dementia with Parkinsonism- 17 (FTDP-17), Lewy body dementia, Parkinson’s Disease, Pick's Disease, and additional diseases with pronounced neurodegeneration such as Autism, Dementia, Epilepsy, Huntington’s Disease, Multiple Sclerosis; diseases and disorders associated with acquired brain injury such as Chronic Traumatic Encephalopathy, Traumatic Brain Injury, Tumor and Stroke.
[015] Non-limiting examples of diseases which can be treated with the compounds and compositions provided herein include a variety of cancers, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, sepsis, ankylosing spondylitis, psoriasis, scleroderma, mycotic and viral infections, osteochondrodysplasia, Alzheimer’s disease, lung disease, bone/osteoporotic (wrist, spine, shoulder and hip) fractures, articular cartilage (chondral) defects, degenerative disc disease (or intervertebral disc degeneration), polyposis coli, osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia syndrome, Miillerian-duct regression and virilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto- onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Nome disease, and Rett syndrome.
[016] Some embodiments of the present disclosure include methods to prepare compounds of Formula (I).
[017] 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 disclosure, as claimed.
DETAILED DESCRIPTION
[018] Provided herein are compositions and methods for inhibiting one or more members of the Wnt pathway, including one or more Wnt proteins.
[019] Provided herein are compositions and methods for inhibiting DYRK1A.
[020] Some embodiments provided herein relate to a method for treating a disease including, but not limited to, neurological diseases or disorders, cancers, chronic inflammation, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, sepsis, ankylosing spondylitis, psoriasis, scleroderma, mycotic and viral infections, bone and cartilage diseases, lung disease, osteoarthritis, articular cartilage (chondral) defects, degenerative disc disease (or intervertebral disc degeneration), polyposis coli, bone density and vascular defects in the eye (Osteoporosis - pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Miillerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman's syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Nome disease, and Rett syndrome.
[021] In some embodiments, non-limiting examples of bone and cartilage diseases which can be treated with the compounds and compositions provided herein include bone spur (osteophytes), craniosynostosis, fibrodysplasia ossificans progressive, fibrous dysplasia, giant cell tumor of bone, hip labral tear, meniscal tears, osteoarthritis, articular cartilage (chondral) defects, degenerative disc disease (or intervertebral disc degeneration), osteochondritis dissecans, osteochondroma (bone tumor), osteopetrosis, relapsing polychondritis, and Salter-Harris fractures.
[022] In some embodiments, non-limiting examples of a neurological disease or disorder associated with tau protein, amyloid or alpha-synuclein pathology which can be treated with the compounds and compositions provided herein include, but are not limited to, Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, Down Syndrome, Frontotemporal Dementia with Parkinsonism- 17 (FTDP-17), Lewy body dementia, Parkinson’s Disease, Pick's Disease, and additional diseases with pronounced neurodegeneration such as Autism, Dementia, Epilepsy, Huntington’s Disease, Multiple Sclerosis; diseases and disorders associated with acquired brain injury such as Chronic Traumatic Encephalopathy, Traumatic Brain Injury, Tumor, and Stroke.
[023] In some embodiments, non-limiting examples of diseases in which chronic inflammation is involved which can be treated with the compounds and compositions provided herein include eye disorders, joint pain, arthritis (rheumatoid, osteo, psoriatic gout), cancers (colon, breast, lung, pancreas, and others), gastrointestinal disorders (ulcerative colitis and inflammatory bowel diseases), pulmonary disorders (chronic obstructive pulmonary disorder and asthma), allergies, skin disorders (atopic dermatitis and psoriasis), diabetes, pancreatitis, tendonitis, hepatitis, heart disease, myocarditis, stroke, lupus, and neurological disorders such as multiple sclerosis, Parkinson’s and dementia including Alzheimer’s disease.
[024] In some embodiments, non-limiting examples of cancers which can be treated with the compounds and compositions provided herein include colon, ovarian, pancreatic, breast, liver, prostate, and hematologic cancers.
[025] In some embodiments, pharmaceutical compositions are provided that are effective for treatment of a disease of an animal, e.g., a mammal, caused by either the pathological activation or mutations of the Wnt pathway or DYRK 1 A overexpression. The composition includes a pharmaceutically acceptable carrier and a compound as described herein.
Definitions
[026] 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.
[027] 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. In some embodiments, alkyl groups include 1 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).
[028] As used herein, "alkenyl" means a straight or branched chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl, and the like. In various embodiments, alkenyl groups can either be unsubstituted or substituted with one or more substituents. Typically, alkenyl groups will comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).
[029] As used herein,“alkynyl” means a straight or branched chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, and the like. In various embodiments, alkynyl groups can either be unsubstituted or substituted with one or more substituents. Typically, alkynyl groups will comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).
[030] As used herein, “alkylene” means a bivalent branched, or straight chain chemical group containing only carbon and hydrogen, such as methylene, ethylene, n-propylene, iso-propylene, n-butylene, iso-butylene, sec-butylene, tert-butylene, n-pentylene, iso-pentylene, sec-pentylene and neo-pentylene. Alkylene groups can either be unsubstituted or substituted with one or more substituents. In some embodiments, alkylene groups include 1 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).
[031] As used herein,“alkenylene” means a bivalent branched, or straight chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond, such as ethenylene, 1-propenylene, 2-propenylene, 2-methyl-l-propenylene, 1- butenylene, 2-butenylene, and the like. In various embodiments, alkenylene groups can either be unsubstituted or substituted with one or more substituents. Typically, alkenylene groups will comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).
[032] As used herein,“alkynylene” means a bivalent branched, or straight chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon triple bond, such as ethynyl ene, 1-propynylene, 1-butynylene, 2-butynylene, and the like. In various embodiments, alkynylene groups can either be unsubstituted or substituted with one or more substituents. Typically, alkynylene groups will comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).
[033] As used herein,“alkoxy” means an alkyl -O— group in which the alkyl group is as described herein. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, pentoxy, hexoxy and heptoxy, and also the linear or branched positional isomers thereof.
[034] As used herein,“haloalkoxy” means a haloalkyl-0— group in which the haloalkyl group is as described herein. Exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and also the linear or branched positional isomers thereof.
[035] As used herein,“carbocyclyl” 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 none of the rings in the ring system are aromatic. Carbocyclyl groups can either be unsubstituted or substituted with one or more substituents. In some embodiments, carbocyclyl groups include 3 to 10 carbon atoms, for example, 3 to 6 carbon atoms.
[036] As used herein,“aryl” means a mono-, bi-, tri- or polycyclic group with only carbon atoms present in the ring backbone having 5 to 14 ring atoms, alternatively 5, 6, 9, or 10 ring atoms; and having 6, 10, or 14 pi electrons shared in a cyclic array; wherein at least one ring in the system is aromatic. Aryl groups can either be unsubstituted or substituted with one or more substituents. Examples of aryl include phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydro-lH- indenyl, and others. In some embodiments, the aryl is phenyl.
[037] As used herein,“arylene” means a bivalent moiety obtained by removing two hydrogen atoms of an aryl ring, as defined above.
[038] As used herein,“arylalkylene” means an aryl-alkylene- group in which the aryl and alkylene moieties are as previously described. In some embodiments, arylalkylene groups contain a Ci-4alkylene moiety. Exemplary arylalkylene groups include benzyl and 2-phenethyl.
[039] 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; and 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, O, and S. Heteroaryl groups can either be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, ftiryl, 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 -ri| pyrimidinyl. pyrrolo| 2.3-/ |pyridinyl. quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo| 3.4- > |pyridinyl. pyrazolo[3,4- c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3- >]pyridinyl, tetrazolyl, chromane, 2,3- dihydrobcnzo| A 11 1.4 |dioxinc. bcnzo| z/| 1 1.3 |dioxolc. 2,3-dihydrobenzofuran, tetrahydroquinoline, 2.3-dihydrobcnzo| A 11 1.4 |oxathiinc. isoindoline, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.
[040] As used herein, “heteroarylene” means a bivalent moiety obtained by removing two hydrogen atoms of a heteroaryl ring, as defined above.
[041] 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 halide can be fluoro.
[042] As used herein,“haloalkyl” means a hydrocarbon substituent, which is a linear or branched, alkyl, alkenyl or alkynyl substituted with one or more chloro, bromo, fluoro, and/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.
[043] As used herein, “heterocyclyl” 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 3-11 members. In six membered monocyclic heterocycles, the heteroatom(s) are selected from one to three of O, N or S, and wherein when the heterocycle is five membered, it can have one or two heteroatoms selected from O, 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. In some embodiments, the heterocyclyl is selected from azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and tetrahydropyridinyl. [044] As used herein,“monocyclic heterocyclyl” means a single nonaromatic cyclic ring comprising at least one heteroatom in the ring system backbone. Heterocyclyls may be substituted or unsubstituted with one or more substituents. In some embodiments, heterocycles have 3-7 members. In six membered monocyclic heterocycles, the heteroatom(s) are selected from one to three of O, N or S, and wherein when the heterocycle is five membered, it can have one or two heteroatoms selected from O, N, or S. Examples of heterocyclyls 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.
[045] As used herein,“bicyclic heterocyclyl” means a nonaromatic bicyclic ring system comprising at least one heteroatom in the ring system backbone. Bicyclic heterocyclyls may be substituted or unsubstituted with one or more substituents. In some embodiments, bicyclic heterocycles have 4-11 members with the heteroatom(s) being selected from one to five of O, N or S. Examples of bicyclic heterocyclyls include 2 -azabicyclof 1.1.0] butane, 2- azabicyclo[2.1.0]pentane, 2-azabicyclo[l . l . l]pentane, 3-azabicyclo[3.1.0]hexane, 5- azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3- azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7- azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, and the like.
[046] As used herein,“spirocyclic heterocyclyl” means a nonaromatic bicyclic ring system comprising at least one heteroatom in the ring system backbone and with the rings connected through just one atom. Spirocyclic heterocyclyls may be substituted or unsubstituted with one or more substituents. In some embodiments, spirocyclic heterocycles have 5-11 members with the heteroatom(s) being selected from one to five of O, N or S. Examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, l-azaspiro[3.5]nonane, 2- azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7- diazaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, and the like.
[047] 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, -(C1-9 alkyl) optionally substituted with one or more of hydroxyl, -NEE, -NH(CI-3 alkyl), and -N(CI-3 alkyl)2; -(C1-9 haloalkyl); a halide; a hydroxyl; a carbonyl [such as -C(0)0R, and -C(0)R]; a thiocarbonyl [such as -C(S)OR, -C(0)SR, and -C(S)R]; -(C1-9 alkoxy) optionally substituted with one or more of halide, hydroxyl, -NH2, -NH(CI-3 alkyl), and -N(CI-3 alkyl)2; - OPO(OH)2; a phosphonate [such as -PO(OH)2 and -PO(OR’)2]; -OPO(OR’)R”; -NRR’; - C(0)NRR’ ; -C(NR)NR’R”; -C(NR’)R”; a cyano; a nitro; an azido; -SH; -S-R; -0S02(0R); a sulfonate [such as -S02(0H) and -S02(0R)]; -S02NR’R”; and -S02R; in which each occurrence of R, R’ and R” are independently selected from H; -(C1-9 alkyl); Ce-io aryl optionally substituted with from 1-3R’”; 5-10 membered heteroaryl having from 1-4 heteroatoms independently selected from N, O, and S and optionally substituted with from 1-3 R’”; C3-7 carbocyclyl optionally substituted with from 1-3 R’”; and 3-8 membered heterocyclyl having from 1-4 heteroatoms independently selected from N, O, and S and optionally substituted with from 1 -3 R’”; wherein each R’” is independently selected from -(Ci-6 alkyl), -(Ci-6 haloalkyl), ahalide (e.g., F), a hydroxyl, -C(0)0R, -C(0)R, — (Ci-6 alkoxyl), -NRR’, -C(0)NRR’, and a cyano, in which each occurrence of R and R’ is independently selected from H and -(Ci-6 alkyl). In some embodiments, the substituent is selected from— (Ci-6 alkyl), -(Ci-6 haloalkyl), a halide (e.g., F), a hydroxyl, -C(0)0R, -C(0)R, -(Ci-6 alkoxyl), -NRR’, -C(0)NRR’, and a cyano, in which each occurrence of R and R’ is independently selected from H and -(Ci-6 alkyl).
[048] As used herein, when two groups are indicated to be“linked” or“bonded” to form 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 forming 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 embodiments, such rings have from 3-7 members, for example, 5 or 6 members.
[049] The skilled artisan will recognize that some chemical structures described herein may be represented on paper by one or more other resonance forms; or may exist in one or more other tautomeric forms, even when kinetically, the artisan recognizes that such tautomeric forms represent 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 explicitly represented herein.
[050] 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.
[051] The present disclosure includes all pharmaceutically acceptable isotopically labeled compounds of Formula I, wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature. Examples of isotopes suitable for inclusion in the compounds of the disclosure include, but are not limited to, isotopes of hydrogen, such as 2H (deuterium) and 3H (tritium), carbon, such as nC, 13C and 14C, chlorine, such as 36C1, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 150, 170 and 180, phosphorus, such as 32P, and sulfur, such as 35 S.
[052] 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 pharmaceutical composition, the site of the disease, the disease involved, and the severity of the disease.
[053] 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.
[054] The term“mammal” is used in its usual biological sense. Thus, it specifically includes humans, cattle, horses, monkeys, dogs, cats, mice, rats, cows, sheep, pigs, goats, and non human primates, but also includes many other species.
[055] 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 Brunton el al. (Eds.) (2017); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics. 13th Ed., The McGraw-Hill Companies.
[056] 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. Many such salts are known in the art, for example, as described in WO 87/05297. 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.
[057] “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.
[058] A“therapeutically 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, in combination with one or more other agents that are effective to treat the diseases and/or conditions described herein. 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.
[059] A therapeutic effect relieves, to some extent, one or more of the symptoms of the disease.
[060] “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, ameliorating 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.
[061] “Drug-eluting” and/or controlled release as used herein refers to any and all mechanisms, e.g., diffusion, migration, permeation, and/or desorption by which the drug(s) incorporated in the drug -eluting material pass therefrom over time into the surrounding body tissue .
[062] “Drug-eluting material” and/or controlled release material as used herein refers to any natural, synthetic or semi -synthetic material capable of acquiring and retaining a desired shape or configuration and into which one or more drugs can be incorporated and from which incorporated drug(s) are capable of eluting over time.
[063] “Elutable drug” as used herein refers to any drug or combination of drugs having the ability to pass over time from the drug-eluting material in which it is incorporated into the surrounding areas of the body.
Compounds
[064] The compounds and compositions described herein can be used as antiproliferative agents, e.g., anti-cancer and anti-angiogenesis agents, and/or as inhibitors of the Wnt signaling pathway, e.g., for treating diseases or disorders associated with aberrant Wnt signaling. In addition, the compounds can be used as inhibitors of one or more kinases, kinase receptors, or kinase complexes. Such compounds and compositions are also useful for controlling cellular proliferation, differentiation, and/or apoptosis.
[065] The compounds and compositions described herein can be used to inhibit DYRK1A for treating a disorder or disease in which DYRK1A overexpression is implicated, such as Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, Down Syndrome, Frontotemporal Dementia with Parkinsonism- 17 (FTDP-17), Lewy body dementia, Parkinson’s Disease, Pick's Disease, and additional diseases with pronounced neurodegeneration such as Autism, Dementia, Epilepsy, Huntington’s Disease, Multiple Sclerosis; diseases and disorders associated with acquired brain injury such as Chronic Traumatic Encephalopathy, Traumatic Brain Injury, Tumor, and Stroke.
[066] Some embodiments of the present disclosure include compounds of Formula
(I):
Figure imgf000018_0001
or salts, pharmaceutically acceptable salts, or prodrugs thereof.
[067] In some embodiments of Formula (I), R1 is selected from the group consisting of H, halide (e.g., F, Cl, Br, I), and unsubstituted -(C1-3 alkyl) (e.g., C1-2, Ci).
[068] In some embodiments of Formula (I), R1 is selected from the group consisting of H, F, and Me.
[069] In some embodiments of Formula (I), R1 is H.
[070] In some embodiments of Formula (I), R2 is selected from the group consisting of unsubstituted -(C1-3 alkyl) (e.g., C1-2, Ci), unsubstituted -(C2-9 alkenyl) (e.g., C2-8, C2-7, C2-6, C2-5, C2-4, C2-3, C2), unsubstituted— (C1-9 haloalkyl) (e.g., Ci-s, C1-7, Ci-6, C1-5, C1-4, C1-3, C1-2, Ci),— (C1-2 alkylene)p(C3-6 carbocyclyl) optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1- 5, 1-4, 1-3, 1-2, 1) R4, -monocyclic heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1- 7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R5, -phenyl substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R6, -heteroaryl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R7, -CO2R8, -OR9, and -(C=0)R10; wherein heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxazolyl, oxadiazolyl, thiazolyl, 2,3-dihydrobenzo[b]dioxinyl, 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazinyl, 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridinyl, isoquinolinyl, and quinolinyl; wherein -(Cw alkylene) is optionally substituted with one or more substituents as defined anywhere herein.
[071] In some embodiments of Formula (I), R2 is selected from the group consisting of unsubstituted -(C1-9 alkyl) (e.g., Ci-s, C1-7, Ci-6, C1-5, C1-4, C1-3, Ci-2, Ci), unsubstituted -(C2-9 alkenyl) (e.g., C2.8, C2-7, C2-6, C2-5, C2.4, C2-3, C2), unsubstituted -(C1-9 haloalkyl) (e.g., Ci-s, C1-7, Ci-
6, Ci-s, Ci-4, Ci-3, Ci-2 Ci),— (Ci-2 alkylene)p(C3-6 carbocyclyl) optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R4, -monocyclic heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R5, -phenyl substituted with 1- 5 (e.g., 1-4, 1-3, 1-2, 1) R6, -heteroaryl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R7, - C02R8, -OR9, and -(C=0)R10; wherein heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxazolyl, oxadiazolyl, thiazolyl, 2,3-dihydrobenzo[b]dioxinyl, 5, 6,7,8- tetrahydroimidazo[l,2-a]pyrazinyl, 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridinyl, isoquinolinyl, and quinolinyl; wherein -(Cw alkylene) is optionally substituted with one or more substituents as defined anywhere herein.
[072] In some embodiments of Formula (I), R2 is selected from the group consisting of unsubstituted -(C1-3 alkyl) (e.g., Ci-2, Ci), unsubstituted -(C2-9 alkenyl) (e.g., C2-s, C2-7, C2-6, C2-s, C2-4, C2-3, C2), unsubstituted— (C1-9 haloalkyl) (e.g., Ci-s, C1-7, Ci-6, C1-5, C1-4, C1-3, Ci-2, Ci),— (Ci-2 alkylene)p(C3-6 carbocyclyl) optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1- 5, 1-4, 1-3, 1-2, 1) R4, -monocyclic heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-
7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R5, -phenyl substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R6, -heteroaryl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R7, -C02R8, -OR9, and -(C=0)R10; wherein -(Ci- 4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein.
[073] In some embodiments of Formula (I), the heteroaryl of R2 is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxazolyl, oxadiazolyl, thiazolyl, 2,3- dihydrobenzo[b]dioxinyl, 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazinyl, 4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridinyl, isoquinolinyl, and quinolinyl.
[074] In some embodiments of Formula (I), R2 is selected from the group consisting of unsubstituted -(C1-3 alkyl) (e.g., Ci-2, Ci), -(CH2)(cyclopropyl), -(cyclopropyl), -monocyclic heterocyclyl optionally substituted with 1 R5, -phenyl substituted with 1-2 R6, and -pyridinyl optionally substituted with 1 R7.
[075] In some embodiments of Formula (I), R2 is -pyridinyl optionally substituted with 1 R7.
[076] In some embodiments of Formula (I), there is the proviso that when L1 is a bond, R2 is selected from the group consisting of -phenyl substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R6 and -heteroaryl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R7; wherein heteroaryl selected from the group consisting of pyridinyl, oxazolyl, oxadiazolyl, thiazolyl, 2,3- dihydrobenzo[b]dioxinyl, 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazinyl, 4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridinyl, isoquinolinyl, and quinolinyl.
[077] In some embodiments of Formula (I), R3 is selected from the group consisting of -heterocyclyl substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R11, -(Cw alkylene)pphenyl substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R12, -heteroaryl optionally substituted with l-4 (e.g., 1-3, 1-2, 1) R13, and -(Ci-4alkylene)OR14; wherein heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, 5, 6,7,8- tetrahydroimidazo[l,2-a]pyrazinyl, 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridinyl, 1, 2,3,4-
Figure imgf000020_0001
tetrahydroisoquinolinyl, isoquinolinyl, and quinolinyl; wherein is only substituted at positions 4 and 7; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[078] In some embodiments of Formula (I), R3 is selected from the group consisting of -heterocyclyl substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R11, -(Cw alkylene)pphenyl substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R12, -heteroaryl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R13, and -(Ci-4 alkylene)OR14; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[079] In some embodiments of Formula (I), the heteroaryl of R3 is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazinyl, 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridinyl,
Figure imgf000020_0002
1,2,3,4-tetrahydroisoquinolinyl, isoquinolinyl, and quinolinyl; wherein is only substituted at positions 4 and 7.
[080] In some embodiments of Formula (I), R3 is selected from the group consisting of -heterocyclyl substituted with 1 R11, -(Ci-4 alkylene )pphenyl substituted with 1 R12, -heteroaryl optionally substituted with 1 R13, and -(C2-3 alkylene)0(Ci-3 alkyl). [081] In some embodiments of Formula (I), R3 is -pyridinyl optionally substituted with 1 R13.
[082] In some embodiments of Formula (I), R3 is -benzimidazolyl optionally substituted with 1 R13.
[083] In some embodiments of Formula (I), there is the proviso that when L2 is a bond, R3 is selected from -heteroaryl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R13; wherein heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazinyl, 4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridinyl, 1,2,3,4-tetrahydroisoquinolinyl, isoquinolinyl, and quinolinyl; wherein
Figure imgf000021_0001
is only substituted at positions 4 and 7.
[084] In some embodiments of Formula (I), each R4 is halide (e.g., F, Cl, Br, I).
[085] In some embodiments of Formula (I), each R5 is independently selected from the group consisting of halide (e.g., F, Cl, Br, I), Me, and Et.
[086] In some embodiments of Formula (I), each R6 is independently selected from the group consisting of methyl, -CFfiF, -CHF2, -CF3, -OR15a, and -(C1-4 alkylene)pN(R16a)(R16b); wherein -(C1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein.
[087] In some embodiments of Formula (I), each R7 is independently selected from the group consisting of F, methyl, -CFfiF, -CHF2, -CF3, -CF2CH3, -OR15a, -CO2R17, - NR18(C=0)R19,— (Ci-4 alkylene)pheterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R20b, and -(C1-4 alkylene)pN(R16a)(R16b); wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[088] In some embodiments of Formula (I), the optional R7 is independently selected from the group consisting of F, methyl, -CF3, -Oheterocyclyl optionally substituted with 1 R20b, - (CFyheterocyclyl optionally substituted with 1-2 R20b, -NMe2, and -(0¾)NMe2.
[089] In some embodiments of Formula (I), R8 is unsubstituted -(C1-9 alkyl) (e.g., Cl-8, Cl-7, Cl-6, Cl-5, Cl-4, Cl-3, Cl-2, Cl).
[090] In some embodiments of Formula (I), R9 is unsubstituted -(C1-9 alkyl) (e.g.,
Cl-8, Cl-7, Cl-6, Cl-5, Cl-4, Cl-3, Cl-2, Cl). [091] In some embodiments of Formula (I), R10 is -aryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R21.
[092] In some embodiments of Formula (I), each R11 is independently selected from the group consisting of halide (e.g., F, Cl, Br, I), methyl, and ethyl.
[093] In some embodiments of Formula (I), each R12 is independently selected from the group consisting of -(Ci-4 alkylene)pheterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1- 8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R20a, -aryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R22,— (Ci-4 alkylene)N(R16a)(R16b), and -OR23a; wherein heterocyclyl selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[094] In some embodiments of Formula (I), each R13 is independently selected from the group consisting of F, methyl, -CFfiF, -CHF2, -CF3, -(C1-4 alkylene)pN(R16a)2, -OR23b, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R20b, -aryl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R22, and -heteroaryl substituted with 1-4 (e.g., 1-3, 1-2, 1) R24; wherein -(C1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein.
[095] In some embodiments of Formula (I), the optional R13 is independently selected from the group consisting of F, methyl, -CF3, -OMe, -Oheterocyclyl optionally substituted with 1 R20b, -heterocyclyl optionally substituted with 1-2 R20b, -(CFb)heterocyclyl optionally substituted with 1-2 R20b, -(CFfiCFyheterocyclyl optionally substituted with 1-2 R20b, - phenyl optionally substituted with 1 R22, and -heteroaryl substituted with 1 R24.
[096] In some embodiments of Formula (I), R14 is selected from the group consisting of unsubstituted -(C1-4 alkyl) (e.g., C1-3, C1-2, Ci) and -aryl optionally substituted with 1-5 (e.g., 1- 4, 1-3, 1-2, 1) R22.
[097] In some embodiments of Formula (I), each R15a is independently selected from the group consisting of unsubstituted -(C2-3 alkyl) (e.g., ethyl),, and -heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R20b.
[098] In some embodiments of Formula (I), each R15b is independently selected from the group consisting of H, unsubstituted -(C2-9 alkyl) (e.g., C2-8, C2-7, C2-6, C2-5, C2-4, C2-3, C2), and -heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R20b.
[099] In some embodiments of Formula (I), each R16a is independently selected from the group consisting of H and unsubstituted -(C1-2 alkyl) (e.g. methyl).
[0100] In some embodiments of Formula (I), each R16b is unsubstituted -(C1-2 alkyl) (e.g. methyl). [0101] In some embodiments of Formula (I), each R17 is unsubstituted -(C1-9 alkyl) (e.g., Cl-8, Cl-7, Cl-6, Cl-5, Cl-4, Cl-3, Cl-2, Cl).
[0102] In some embodiments of Formula (I), each R18 is independently selected from the group consisting of H and Me.
[0103] In some embodiments of Formula (I), each R19 is unsubstituted -(C1-9 alkyl) (e.g., Cl-8, Cl-7, Cl-6, Cl-5, Cl-4, Cl-3, Cl-2, Cl).
[0104] In some embodiments of Formula (I), each R20a is independently selected from the group consisting of halide (e.g., F, Cl, Br, I) and unsubstituted -(C2-9 alkyl) (e.g., C2-8, C2-7, C2-
6, C2-5, C2-4, C2-3, C2).
[0105] In some embodiments of Formula (I), each R20b is independently selected from the group consisting of halide (e.g., F, Cl, Br, I) and unsubstituted -(C1-9 alkyl) (e.g., Ci-s, C1-7, Ci- 6, Cl-5, Cl-4, Cl-3, Cl-2, Cl).
[0106] In some embodiments of Formula (I), each R21 is independently selected from the group consisting of halide (e.g., F, Cl, Br, I) and unsubstituted -(C1-9 alkyl) (e.g., Ci-s, C1-7, Ci- 6, Cl-5, Cl-4, Cl-3, Cl-2, Cl).
[0107] In some embodiments of Formula (I), each R22 is independently selected from the group consisting of halide (e.g., F, Cl, Br, I) and unsubstituted -(C1-9 alkyl) (e.g., Ci-s, C1-7, Ci-
6, Cl-5, Cl-4, Cl-3, Cl-2, Cl).
[0108] In some embodiments of Formula (I), each R23a is independently selected from the group consisting of unsubstituted -(C2-9 alkyl) (e.g., C2-8, C2-7, C2-6, C2-5, C2-4, C2-3, C2), -(C1-4 alky lene) OR25, and -(Ci-4 alkylene)pheterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-
7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R20b; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0109] In some embodiments of Formula (I), each R23b is independently selected from the group consisting of unsubstituted -(C1-9 alkyl) (e.g., Ci-s, C1-7, Ci-6, C1-5, C1-4, C1-3, C1-2, Ci), - (Ci-4 alkylene)OR25, and -(Ci-4 alkylene)pheterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-
8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R20b; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0110] In some embodiments of Formula (I), each R24 is independently selected from the group consisting of halide (e.g., F, Cl, Br, I) and unsubstituted -(C1-9 alkyl) (e.g., Ci-s, C1-7, Ci- 6, Cl-5, Cl-4, Cl-3, Cl-2. Cl).
[0111] In some embodiments of Formula (I), each R25 is independently selected from the group consisting of H and unsubstituted -(C 1-9 alkyl) (e.g., Ci-s, C1-7, Ci-6, C1-5, Cw, C1-3, C1-2, Cl). [0112] In some embodiments of Formula (I), L1 is selected from the group consisting
Figure imgf000024_0001
of a bond, -CH=CH- , -(CH2)pNR18(C=0)-, -(C=0)NR18(CH2)P-, -
NR18(C=0)NR18-, -NH(CH2)p-, and -(CH2)PNH-.
[0113] In some embodiments of Formula (I), L1 is selected from the group consisting of a bond, -CH=CH-, — C=C_ -(CH2)pNH(C=0)-, -(C=0)NH(CH2)p-, -NH(C=0)NH-, - NH(CH2)p-, and -(CH2)PNH-.
[0114] In some embodiments of Formula (I), L1 is selected from the group consisting of a bond, -CH=CH-, — C=C_ -(CH2)NH(C=0)-, -(C=0)NH(CH2)-, -NH(C=0)NH-, - NH(CH2)-, and -(CH2)NH-.
[0115] In some embodiments of Formula (I), L1 is selected from the group consisting of a bond, -CH=CH-, — C=C_ _NH(C=0)-, -(C=0)NH-, -NH(C=0)NH-, -NH(CH2)-, and -(CH2)NH-.
[0116] In some embodiments of Formula (I), L1 is selected from the group consisting of a bond, -CH=CH-, — C=C_ _NH(C=0)-, -(C=0)NH-, -NH(C=0)NH-, -NH-, and - (CH2)NH-.
[0117] In some embodiments of Formula (I), L1 is selected from the group consisting of a bond, -CH=CH-, — C=C_ _NH(C=0)-, -(C=0)NH(CH2)-, -NH(C=0)NH-, -NH-, and -(CH2)NH-.
[0118] In some embodiments of Formula (I), L1 is selected from the group consisting of a bond, -CH=CH-, — C=C_ -(CH2)NH(C=0)-, -(C=0)NH-, -NH(C=0)NH-, -NH-, and -(CH2)NH-.
[0119] In some embodiments of Formula (I), L1 is selected from the group consisting of a bond, -CH=CH-, — C=C_ -(CH2)pNR18(C=0)-, -(C=0)NR18(CH2)p-, -
NR18(C=0)NR18-, and -NH(CH2)P-; in some embodiments, L1 is selected from the group consisting of a bond, -CH=CH-, — C=C_ -(CH2)pNR18(C=0)-, -(C=0)NR18(CH2)p-, -
NR18(C=0)NR18-, and -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of a bond, -CH=CH-, — C=C_ -(CH2)pNR18(C=0)-, -(C=0)NR18(CH2)p-, - NH(CH2)p-, and -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of a
Figure imgf000025_0001
bond, -CH=CH-, , -(CH2)pNR18(C=0)-, -NR18(C=0)NR18-, -NH(CH2)P-, and - (CH2)PNH-; in some embodiments, L1 is selected from the group consisting of a bond, -CH=CH-
— CºC—
-(C=0)NR18(CH2)p- -NR18(C=0)NR18-, -NH(CH2)P- and -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of a bond, -CH=CH-, -(CH2)pNR18(C=0)
, -(C=0)NR18(CH2)p-, -NR18(C=0)NR18-, -NH(CH2)P-, and -(CH2)PNH-; in some embodiments,
Figure imgf000025_0002
L1 is selected from the group consisting of a bond, , -(CH2)pNR18(C=0)-, -
(C=0)NR18(CH2)P-, -NR18(C=0)NR18-, -NH(CH2)p-, and -(CH2)PNH-; and in some embodiments, L is selected from the group consisting of -CH=CH-, — c=c— , -
(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)p-, -NR18(C=0)NR18-, -NH(CH2)p- and -(CH2)PNH-.
[0120] In some embodiments of Formula (I), L1 is selected from the group consisting of a bond, -CH=CH-, — cºc— , -(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)p-, and
NR18(C=0)NR18-; in some embodiments, L1 is selected from the group consisting of a bond, -
CH=CH-, — C=C— -(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)p-, and -NH(CH2)P-; in some
, — CºC— embodiments, L1 is selected from the group consisting of a bond, -CH=CH-,
(CH2)PNR18(C=0)-, -NR18(C=0)NR18-, and -NH(CH2)P-; in some embodiments, L1 is selected
Figure imgf000025_0003
from the group consisting of a bond, -CH=CH-, , -(C=0)NR18(CH2)p-, -
NR18(C=0)NR18-, and -NH(CH2)P-; in some embodiments, L1 is selected from the group consisting of a bond, -CH=CH-, -(CH2)pNR18(C=0)-, -(C=0)NR18(CH2)p- -NR18(C=0)NR18-, and -NH(CH2)p-; in some embodiments, L1 is selected from the group consisting of a bond,
_ C=C_ , -(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)P-, -NR18(C=0)NR18-, and -NH(CH2)P-; in some embodiments, L1 is selected from the group consisting of -CH=CH-,— cºc— (CH2)PNR18(C=0)-, -(C=0)NR18(CH2)p-, -NR18(C=0)NR18-, and -NH(CH2)P-; in some embodiments, L1 , is selected from the group consisting of a bond, -CH=CH-,— cºc— (CH2)PNR18(C=0)-, -(C=0)NR18(CH2)p-, and -(CH2)PNH-; in some embodiments, L1 is selected
Figure imgf000025_0004
from the group consisting of a bond, -CH=CH-, , -(CH2)pNR18(C=0)-, -
NR18(C=0)NR18-, and -(CH2)PNH-; in some embodiments, L1 is selected from the group
Figure imgf000026_0001
consisting of a bond, -CH=CH-, , -(C=0)NR18(CH2)p-, -NR18(C=0)NR18-, and -
(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of a bond, -CH=CH- , -(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)p-, -NR18(C=0)NR18-, and -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of a bond, — cºc—
(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)P-, -NR18(C=0)NR18-, and -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of -CH=CH-, — cºc—
(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)p-, -NR18(C=0)NR18-, and -(CH2)PNH-; in some embodiments, L is selected from the group consisting of a bond, -CH=CH-,— cºc— (CH2)PNR18(C=0)-, -NH(CH2)p-, and -(CH2)PNH-; in some embodiments, L1 is selected from the
Figure imgf000026_0002
group consisting of a bond, -CH=CH-, , -NR18(C=0)NR18-, -NH(CH2)P-, and -
(CH2)PNH-. in some embodiments, L1 is selected from the group consisting of a bond, -CH=CH- , -(C=0)NR18(CH2)p-, -NR18(C=0)NR18-, -NH(CH2)P-, and -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of a bond, -(CH2)pNR18(C=0)-, -(C=0)NR18(CH2)p-, - NR18(C=0)NR18-, -NH(CH2)p-, and -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting
Figure imgf000026_0003
-NH(CH2)p-, and -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of a bond, -CH=CH-, — C=C_ -(C=0)NR18(CH2)p- -NH(CH2)P- and -(CH2)PNH-. in some embodiments, L1 is selected from the group consisting of a bond, -CH=CH-, -(CH2)pNR18(C=0)- , -(C=0)NR18(CH2)p-, -NH(CH2)p-, and -(CH2)PNH-; in some embodiments, L1 is selected from
Figure imgf000026_0004
the group consisting of a bond, , -(CH2)pNR18(C=0)-, -(C=0)NR18(CH2)p-, -
NH(CH2)p-, and -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of
Figure imgf000026_0005
L1 is selected from the group consisting of a bond, , -(CH2)PNR18(C=0)-, -
NR18(C=0)NR18-, -NH(CH2)p-, and -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of -CH=CH-, — cºc— , -(CH2)PNR18(C=0)-, -NR18(C=0)NR18-, NH(CH2)P-, and -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of a bond, — C=C— -(C=0)NR18(CH2)P-, -NR18(C=0)NR18-, -NH(CH2)p-, and -(CH2)PNH-; in some embodiments, L1 , is selected from the group consisting of -CH=CH-, — cºc— , -
(C=0)NR18(CH2)P-, -NR18(C=0)NR18-, -NH(CH2)p-, and -(CH2)PNH-.
[0121] In some embodiments of Formula (I), L1 is selected from the group consisting of a bond, -CH=CH-, — cºc— -(CH2)PNR18(C=0)-, and -(C=0)NR18(CH2)p-; in some
— CºC— embodiments, L1 is selected from the group consisting of a bond, -CH=CH-,
(CH2)PNR18(C=0)-, and -(CH2)PNH-; in some embodiments, L1 is selected from the group
Figure imgf000027_0001
consisting of a bond, -CH=CH-, , -NH(CH2)P-, and -(CH2)PNH-; in some
, — CºC— embodiments, L is selected from the group consisting of a bond, -CH=CH-,
(CH2)PNR18(C=0)-, and -NH(CH2)P-; in some embodiments, L1 is selected from the group
Figure imgf000027_0002
consisting of a bond, -CH=CH-, , -NR18(C=0)NR18-, -NH(CH2)P-; in some
, — CºC— embodiments, L is selected from the group consisting of a bond, -CH=CH-,
(CH2)PNR18(C=0)-, and -NR18(C=0)NR18-; in some embodiments, L1 is selected from the group consisting of a bond, -CH=CH-, — cºc— -(C=0)NR18(CH2)P-, and -NR18(C=0)NR18-; in some embodiments, L1 is selected from the group consisting of a bond, -CH=CH-, — cºc—
-(C=0)NR18(CH2)p-, and -(CH2)PNH-; in some embodiments, L1 is selected from the group
Figure imgf000027_0003
consisting of a bond, -CH=CH-, , -(C=0)NR18(CH2)P-, and -NH(CH2)P-; in some
Figure imgf000027_0004
embodiments, L1 is selected from the group consisting of a bond, -CH=CH-, , -
NR18(C=0)NR18-, and -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of a bond, -CH=CH-, -NR18(C=0)NR18-, -NH(CH2)P-, and -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of a bond, -(C=0)NR18(CH2)p-, - NR18(C=0)NR18-, -NH(CH2)p-, and -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of -(CH2)pNR18(C=0)-, -(C=0)NR18(CH2)p- -NR18(C=0)NR18-, -NH(CH2)P- and -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of a bond, - CH=CH-, -(C=0)NR18(CH2)p-, -NR18(C=0)NR18-, -NH(CH2)P-; in some embodiments, L1 is selected from the group consisting of a bond, -(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)P-, - NR18(C=0)NR18-, -NH(CH2)p-; in some embodiments, L1 is selected from the group consisting of
_ C=C— , -(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)p-, -NR18(C=0)NR18-, -NH(CH2)P-; in some embodiments, L1 is selected from the group consisting of a bond, -CH=CH-, - (CH2)PNR18(C=0)-, -(C=0)NR18(CH2)p-, and -NR18(C=0)NR18-; in some embodiments, L1 is
— CºC—
selected from the group consisting of a bond, , -(CH2)PNR (C=0)-, -
(C=0)NR18(CH2)p-, and -NR18(C=0)NR18-; in some embodiments, L1 is selected from the group consisting of -CH=CH-, — C=C_ _(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)P-, and - NR18(C=0)NR18-; in some embodiments, L1 is selected from the group consisting of a bond, - CH=CH-, -(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)p-, and -(CH2)PNH-; in some embodiments, L1
— C— C—
is selected from the group consisting of a bond, , -(CH2)PNR18(C=0)-, -
(C=0)NR18(CH2)p-, and -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of -CH=CH-, — C=C_ -(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)P-, and - (0¾)rNH-; in some embodiments, L1 is selected from the group consisting of a bond, -CH=CH- , -(CH2)PNR18(C=0)-, -NH(0¾)r-, and -(CH2)PNH-; in some embodiments, L1 is selected from
Figure imgf000028_0001
the group consisting of a bond, , -(CH2)PNR18(C=0)-, -NH(0¾)r-, and -(0¾)rNH-
, — CºC—
; in some embodiments, L is selected from the group consisting of -CH=CH-,
(CH2)PNR18(C=0)-, -NH(CH2)p-, and -(CH2)PNH-; in some embodiments, L1 is selected from the
Figure imgf000028_0002
group consisting of a bond, , -NR18(C=0)NR18-, -NH(CH2)P-, and -(0¾)rNH-; in
, — CºC— some embodiments, L1 is selected from the group consisting of -CH=CH-, , -
NR18(C=0)NR18-, -NH(CH2)p-, and -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of -CH=CH-, -(C=0)NR18(CH2)P-, -NR18(C=0)NR18-, -NH(CH2)P-, and - (0¾)rNH-; in some embodiments, L1 is selected from the group consisting of a bond, -CH=CH- , -(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)p-, and -NH(CH2)P-; in some embodiments, L1 is
— CºC—
selected from the group consisting of a bond, , -(CH2)PNR (C=0)-, - (C=0)NR18(CH2)p-, and -NH(CH2)P-; in some embodiments, L1 is selected from the group consisting of -CH=CH- — C=C_ -(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)P- and - NH(CH2)p-; in some embodiments, L1 is selected from the group consisting of a bond, -CH=CH- , -(CH2)PNR18(C=0)-, -NR18(C=0)NR18-, and -(CH2)PNH-; in some embodiments, L1 is selected
Figure imgf000029_0001
from the group consisting of a bond, , -(CH2)PNR18(C=0)-, -NR18(C=0)NR18-, and
-(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of -CH=CH-, , -(CH2)PNR18(C=0)-, -NR18(C=0)NR18-, and -(CH2)PNH-; in some embodiments,
— C=C—
L is selected from the group consisting of a bond, , -(C=0)NR (0¾)r-, -
NH(0¾)r-, and -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of -
CH=CH-, — C=C— -(C=0)NR18(CH2)p-, -NH(CH2)p-, and -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of -CH=CH-, -(CH2)PNR18(C=0)-, - NR18(C=0)NR18-, -NH(CH2)p-, and -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of a bond, -CH=CH-, -(CH2)PNR18(C=0)-, -NR18(C=0)NR18-, and -
, — CºC—
NH(CH2)p-; in some embodiments, L is selected from the group consisting of a bond,
, -(CH2)PNR18(C=0)-, -NR18(C=0)NR18-, and -NH(CH2)P-; in some embodiments, L1 is selected
Figure imgf000029_0002
from the group consisting of -CH=CH-, , -(CH2)PNR18(C=0)-, -NR18(C=0)NR18-, and -NH(CH2)p-; in some embodiments, L1 is selected from the group consisting of a bond, H-; in some embodiments,
Figure imgf000029_0003
L1 is selected from the group consisting of -CH=CH-, , -(C=0)NR18(CH2)P-, -
NR18(C=0)NR18-, and -(0¾)rNH-; in some embodiments, L1 is selected from the group consisting of -CH=CH-, -(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)P-, -NH(CH2)P-, and -
, — CºC—
(CH2)PNH-; in some embodiments, L is selected from the group consisting of a bond,
, -(C=0)NR18(CH2)p-, -NR18(C=0)NR18-, and -NH(CH2)P-; in some embodiments, L1 is selected
— CºC—
from the group consisting of -CH=CH-, , -(C=0)NR18(CH2)p-, -NR18(C=0)NR18-, and -NH(CH2)p-; in some embodiments, L1 is selected from the group consisting of -CH=CH-, - (CH2)PNR18(C=0)-, -(C=0)NR18(CH2)p-, -NR18(C=0)NR18-, and -(CH2)PNH-.
[0122] In some embodiments of Formula (I), L1 is selected from the group consisting of a bond, -CH=CH-, — C=C_ _NH(C=0)-, and -NH(C=0)NH-.
[0123] In some embodiments of Formula (I), L1 is selected from the group consisting
— 0 0—
of a bond, -CH=CH-, , -(CH2)PNR18(C=0)-; in some embodiments, L1 is selected from the group consisting of -(C=0)NR18(CH2)P-, -NR18(C=0)NR18-, -NH(ϋ¼)r-, and - (0¾)rNH-; in some embodiments, L1 is selected from the group consisting of a bond, -CH=CH-
— CºC—
, , -(C=0)NR (ϋ¼)r-; in some embodiments, L is selected from the group consisting of -(CH2)PNR18(C=0)-, -NR18(C=0)NR18-, -NH(CH2)P-, and -(CH2)PNH-; in some
, — CºC— embodiments, L1 is selected from the group consisting of a bond, -CH=CH-, , -
NR18(C=0)NR18-; in some embodiments, L1 is selected from the group consisting of -
(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)p-, -NH(0¾)r-, and -(0¾)rNH-; in some embodiments,
Figure imgf000030_0001
L1 is selected from the group consisting of a bond, -CH=CH-, , -NH(CH2)P-; in some embodiments, L1 is selected from the group consisting of -(CH2)PNR18(C=0)-, - (C=0)NR18(CH2)p-, -NR18(C=0)NR18-, -(0¾)RNH-; in some embodiments, L1 is selected from
Figure imgf000030_0002
the group consisting of a bond, -CH=CH-, , -(0¾)rNH-; in some embodiments, L1 is selected from the group consisting of -(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)P-, - NR18(C=0)NR18-, -NH(CH2)p-; in some embodiments, L1 is selected from the group consisting of -(C=0)NR18(CH2)p-, -NR18(C=0)NR18-, -(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)P-; in some
Figure imgf000030_0003
embodiments, L1 is selected from the group consisting of , -NR18(C=0)NR18-, -
NH(0¾)r-, and -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of- (C=0)NR18(CH2)p-, -NR18(C=0)NR18-, -(CH2)PNR18(C=0)-, -NR18(C=0)NR18-; in some
Figure imgf000030_0004
embodiments, L1 is selected from the group consisting of , -(C=0)NR18(CH2)P-, -
NH(0¾)r-, and -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of-
(C=0)NR18(CH2)p-, -NR18(C=0)NR18-, -(CH2)PNR18(C=0)-, -NH(CH2)p-; in some embodiments, L1 is selected from the group consisting of , -(C=0)NR18(CH2)P-, -
NR18(C=0)NR18-, -(0¾)rNH-; in some embodiments, L1 is selected from the group consisting of -(C=0)NR18(CH2)p-, -NR18(C=0)NR18-, -(CH2)PNR18(C=0)-, -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of — c=c— , -(C=0)NR18(CH2)P-, -
NR18(C=0)NR18-, -NH(CH2)p-; in some embodiments, L1 is selected from the group consisting of a bond, , -(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)P-; in some embodiments, L1 is selected from the group consisting of -CH=CH-, -NR18(C=0)NR18-, -NH(CH2)P-, and -
, — CºC—
(CH2)PNH-; in some embodiments, L is selected from the group consisting of a bond,
, -(CH2)PNR18(C=0)-, -NR18(C=0)NR18-; in some embodiments, L1 is selected from the group consisting of -CH=CH-, -(C=0)NR18(CH2)P-, -NH(CH2)P-, and -(CH2)PNH-; in some
, — CºC— embodiments, L is selected from the group consisting of a bond, , -
(CH2)PNR18(C=0)-, -NH(CH2)p-; in some embodiments, L1 is selected from the group consisting of -CH=CH-, -(C=0)NR18(CH2)p-, -NR18(C=0)NR18-, -(CH2)PNH-; in some embodiments, L1
Figure imgf000031_0001
is selected from the group consisting of a bond, , -(CH2)PNR18(C=0)-, -(0¾)rNH-; in some embodiments, L1 is selected from the group consisting of-CH=CH-, -(C=0)NR18(CH2)P- , -NR18(C=0)NR18-, -NH(CH2)p-; in some embodiments, L1 is selected from the group consisting of-CH=CH-, , -(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)p-; in some embodiments, L1 is selected from the group consisting of a bond, -NR18(C=0)NR18-, -NH(CH2)P-, and -(0¾)rNH-
, — CºC—
; in some embodiments, L1 is selected from the group consisting of -CH=CH-,
(CH2)PNR18(C=0)-, -NR18(C=0)NR18-; in some embodiments, L1 is selected from the group consisting of a bond, -(C=0)NR18(CH2)P-, -NH(0¾)r-, -(0¾)rNH-; in some embodiments, L1
Figure imgf000031_0002
is selected from the group consisting of -CH=CH-, , -(CH2)PNR18(C=0)-, -
NH(CH2)p-; in some embodiments, L1 is selected from the group consisting of a bond, - (C=0)NR18(CH2)p-, -NR18(C=0)NR18-, -(CH2)PNH-; in some embodiments, L1 is selected from
Figure imgf000031_0003
the group consisting of -CH=CH-, , -(CH2)PNR18(C=0)-, -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of a bond, -(C=0)NR18(CH2)P-, - NR18(C=0)NR18-, -NH(CH2)p-; in some embodiments, L1 is selected from the group consisting of a bond, -CH=CH-, -(C=0)NR18(CH2)P-, -NR18(C=0)NR18-; in some embodiments, L1 is selected
Figure imgf000032_0001
from the group consisting of , -(CH2)PNR18(C=0)-, -NH(0¾)r-, -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of a bond, -(CH2)PNR18(C=0)-, - (C=0)NR18(CH2)p-, -NR18(C=0)NR18-; in some embodiments, L1 is selected from the group
— 0 0—
consisting of -CH=CH-, , -NH(CH2)P-, -(CH2)PNH-; in some embodiments, L1 is
Figure imgf000032_0002
selected from the group consisting of -(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)P-, - NR18(C=0)NR18-; in some embodiments, L1 is selected from the group consisting of a bond, - CH=CH-, -NH(CH2)p-, -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of a bond, -CH=CH-, -NR18(C=0)NR18-, -NH(CH2)P-; in some embodiments, L1 is
Figure imgf000032_0003
selected from the group consisting of -(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)P-, - (CH2)PNH-; in some embodiments, L1 is selected from the group consisting of a bond, - (CH2)PNR18(C=0)-, -NR18(C=0)NR18-, -NH(CH2)P-; in some embodiments, L1 is selected from the group consisting of -CH=CH-, — cºc—
-(C=0)NR18(CH2)p (0¾)rNH-; in some
Figure imgf000032_0004
embodiments, L1 is selected from the group consisting of , -(CH2)PNR18(C=0)-, -
NR18(C=0)NR18-, -NH(CH2)p-; in some embodiments, L1 is selected from the group consisting of a bond, -CH=CH-, -(C=0)NR18(CH2)P-, -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of a bond, -CH=CH-, -NH(0¾)r-, -(CH2)PNH-; in some embodiments, L1
Figure imgf000032_0005
is selected from the group consisting of , -(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)P-,
-NR18(C=0)NR18-; in some embodiments, L1 is selected from the group consisting of a bond, - (CH2)PNR18(C=0)-, -NH(CH2)p-, -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of -CH=CH-, — cºc— , -(C=0)NR18(CH2)p-, -NR18(C=0)NR18-; in some
Figure imgf000032_0006
embodiments, L1 is selected from the group consisting of , -(CH2)PNR18(C=0)-, -
NH(CH2)p-, -(0¾)rNH-; in some embodiments, L1 is selected from the group consisting of a bond, -CH=CH-, -(C=0)NR18(CH2)P-, -NR18(C=0)NR18-; in some embodiments, L1 is selected from the group consisting of a bond, -CH=CH-, -(C=0)NR18(CH2)P-, -NH(CH2)P-; in some embodiments, L1 is selected from the group consisting of , -(CH2)PNR18(C=0)-, -
NR18(C=0)NR18-, -(0¾)rNH-; in some embodiments, L1 is selected from the group consisting of a bond, -(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)P-, -NH(CH2)P-; in some embodiments, L1 is
Figure imgf000033_0001
selected from the group consisting of-CH=CH-, , -NR18(C=0)NR18-, -(0¾)rNH-;
, — C=C— in some embodiments, L is selected from the group consisting of , -
(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)p-, -NH(CH2)P-; in some embodiments, L1 is selected from the group consisting of a bond, -CH=CH-, -NR18(C=0)NR18-, -(CH2)PNH-; in some embodiments, L1 is selected from the group consisting of a bond, -CH=CH-, -(C=0)NR18(CH2)P-
, — CºC—
, -(CH2)PNH-; in some embodiments, L is selected from the group consisting of
(CH2)PNR18(C=0)-, -NR18(C=0)NR18-, -NH(CH2)P-; in some embodiments, L1 is selected from the group consisting of a bond, -(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)P-, -(CH2)PNH-; in some
Figure imgf000033_0002
embodiments, L1 is selected from the group consisting of -CH=CH-, , -
NR18(C=0)NR18-, -NH(CH2)p-; in some embodiments, L1 is selected from the group consisting of a bond, -(CH2)PNR18(C=0)-, -NR18(C=0)NR18-, -(0¾)rNH-; and in some embodiments, L1 is
Figure imgf000033_0003
selected from the group consisting of-CH=CH-, , -(C=0)NR18(CH2)P-, -NH(0¾)r-
[0124] In some embodiments of Formula (I), L1 is selected from the group consisting of a bond and -CH=CH-; in some embodiments, L1 is selected from the group consisting of a bond and ; in some embodiments, L1 is selected from the group consisting of a bond and -
(CH2)PNR18(C=0)-; in some embodiments, L1 is selected from the group consisting of a bond and -(C=0)NR18(CH2)p-; in some embodiments, L1 is selected from the group consisting of a bond and -NR18(C=0)NR18-; in some embodiments, L1 is selected from the group consisting of a bond and -NH(0¾)r-; in some embodiments, L1 is selected from the group consisting of a bond and - (0¾)rNH-; in some embodiments, L1 is selected from the group consisting of -CH=CH- and
— CºC—
; in some embodiments, L is selected from the group consisting of-CH=CH- and - (CH2)PNR18(C=0)-; in some embodiments, L1 is selected from the group consisting of -CH=CH- and -(C=0)NR18(CH2)p-; in some embodiments, L1 is selected from the group consisting of - CH=CH- and -NR18(C=0)NR18-; in some embodiments, L1 is selected from the group consisting of-CH=CH- and -NH(0¾)r-; in some embodiments, L1 is selected from the group consisting of -CH=CH- and -(0¾)rNH-; in some embodiments, L1 is selected from the group consisting of
— cºc— and -(CH2)PNR18(C=0)-; in some embodiments, L1 is selected from the group consisting of — c=c— and -(C=0)NR18(CH2)P-; in some embodiments, L1 is selected from
— CºC—
the group consisting of and -NR18(C=0)NR18-; in some embodiments, L1 is selected
— CºC—
from the group consisting of and -NH(CH2)P-; in some embodiments, L1 is selected
— CºC—
from the group consisting of and -(0¾)rNH-; in some embodiments, L is selected from the group consisting of -(CH2)PNR18(C=0)- and -(C=0)NR18(CH2)P-; in some embodiments, L1 is selected from the group consisting of -(CH2)PNR18(C=0)- and - NR18(C=0)NR18-; in some embodiments, L1 is selected from the group consisting of - (CH2)PNR18(C=0)- and NH(0¾)r-; in some embodiments, L1 is selected from the group consisting of -(CH2)PNR18(C=0)- and -(0¾)rNH-; in some embodiments, L1 is selected from the group consisting of -(C=0)NR18(CH2)P- and -NR18(C=0)NR18-; in some embodiments, L1 is selected from the group consisting of-(C=0)NR18(CH2)p- and NH(0¾)r-; in some embodiments, L1 is selected from the group consisting of -(C=0)NR18(CH2)P- and -(0¾)rNH-; in some embodiments, L1 is selected from the group consisting of -NR18(C=0)NR18- and NH(0¾)r-; in some embodiments, L1 is selected from the group consisting of -NR18(C=0)NR18- and - (0¾)rNH-; and in some embodiments, L1 is selected from the group consisting of -NH(0¾)r- and -(CH2)PNH-.
[0125] In some embodiments of Formula (I), L1 is a bond; in some embodiments, L1
Figure imgf000034_0001
is -CH=CH-; in some embodiments, L1 is ; in some embodiments, L1 is -
(CH2)PNR18(C=0)-; in some embodiments, L1 is -(C=0)NR18(CH2)P-; in some embodiments, L1 is -NR18(C=0)NR18-; in some embodiments, L1 is -NH(CH2)P-; and in some embodiments, L1 is -(CH2)PNH-.
[0126] In some embodiments of Formula (I), L2 is selected from the group consisting of a bond, -(C=0)NR18-, -NR18(C=0)-, -NHCH2-, and -CH2NH-; [0127] In some embodiments of Formula (I), L2 is selected from the group consisting of a bond, -(C=0)NH- -NH(C=0)-, -NHCH2- and -CH2NH-;
[0128] In some embodiments of Formula (I), L2 is selected from the group consisting of a bond, -(C=0)NMe-, -NMe(C=0)-, -NHCH2-, and -CH2NH-;
[0129] In some embodiments of Formula (I), L2 is selected from the group consisting of a bond, -(C=0)NR18-, -NR18(C=0)-, and -NHCH2-; in some embodiments, L2 is selected from the group consisting of a bond, -(C=0)NR18-, -NR18(C=0)-, and -CH2NH-; in some embodiments, L2 is selected from the group consisting of a bond, -(C=0)NR18-, -NHCH2-, and - CH2NH-; in some embodiments, L2 is selected from the group consisting of a bond, -NR18(C=0)- , -NHCH2-, and -CH2NH-; and in some embodiments, L2 is selected from the group consisting of -(C=0)NR18-, -NR18(C=0)-, -NHCH2-, and -CH2NH-
[0130] In some embodiments of Formula (I), L2 is selected from the group consisting of a bond, -(C=0)NR18-, and -NR18(C=0)-; in some embodiments, L2 is selected from the group consisting of a bond, -(C=0)NR18-, and -NHCH2-; in some embodiments, L2 is selected from the group consisting of a bond, -NR18(C=0)-, and -NHCH2-; in some embodiments, L2 is selected from the group consisting of-(C=0)NR18-, -NR18(C=0)-, and -NHCH2-; in some embodiments, L2 is selected from the group consisting of a bond, -(C=0)NR18-, and -CH2NH-; in some embodiments, L2 is selected from the group consisting of a bond, -NR18(C=0)-, and -CH2NH-; and in some embodiments, L2 is selected from the group consisting of-(C=0)NR18-, -NR18(C=0)- , and -CH2NH-.
[0131] In some embodiments of Formula (I), L2 is selected from the group consisting of a bond and -(C=0)NR18-; in some embodiments, L2 is selected from the group consisting of a bond and -NR18(C=0)-; in some embodiments, L2 is selected from the group consisting of - (C=0)NR18- and -NR18(C=0)-; in some embodiments, L2 is selected from the group consisting of a bond and -NHCH2-; in some embodiments, L2 is selected from the group consisting of - (C=0)NR18- and -NHCH2-; in some embodiments, L2 is selected from the group consisting of - NR18(C=0)- and -NHCH2-; in some embodiments, L2 is selected from the group consisting of a bond and -CH2NH-; in some embodiments, L2 is selected from the group consisting of - (C=0)NR18- and -CH2NH-; in some embodiments, L2 is selected from the group consisting of - NR18(C=0)- and -CH2NH-; and in some embodiments, L2 is selected from the group consisting of-NHCH2- and -CH2NH-
[0132] In some embodiments of Formula (I), L2 is a bond; in some embodiments, L2 is -(C=0)NR18-; in some embodiments, L2 is -NR18(C=0)-; in some embodiments, L2 is - NHCH2-; and in some embodiments, L2 is -CH2NH-. [0133] In some embodiments of Formula (I), each p is independently an integer of 0 or 1.
[0134] In some embodiments of Formula (I), there is the proviso that a compound of Formula I is not a compound selected from the group consisting of:
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
[0136] In some embodiments of Formula (I), each -(Cw alkylene) is -(Ci-2 alkylene).
[0137] In some embodiments of Formula (I), each -(Ci-4 alkylene) is -(Ci alkylene).
[0138] In some embodiments of Formula (I), each -(Ci-4 alkylene) is -CH2-.
[0139] In some embodiments of Formula (I), each -(C1-4 alkylene) is optionally substituted with halide (e.g., F, Cl, Br, I).
[0140] In some embodiments of Formula (I), each -(C1-4 alkylene) is optionally substituted with F.
[0141] A compound, or a pharmaceutically acceptable salt thereof, of Formula (I):
Figure imgf000038_0002
wherein:
R1 is selected from the group consisting of H, halide, and unsubstituted -(C1-3 alkyl);
R2 is selected from the group consisting of unsubstituted -(C2-9 alkenyl), -phenyl substituted with 1-5 R6, -heteroaryl optionally substituted with 1-4 R7, -CO2R8, -OR9, and - (C=0)R10; wherein heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxazolyl, oxadiazolyl, 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazinyl, 4,5,6,7-tetrahydro- lH-imidazo[4,5-c]pyridinyl, and isoquinolinyl; wherein -(Cw alkylene) is optionally substituted with one or more substituents as defined anywhere herein;
with the proviso that when L1 is a bond, R2 is selected from the group consisting of -phenyl substituted with 1-5 R6 and -heteroaryl optionally substituted with 1-4 R7; wherein heteroaryl selected from the group consisting of pyridinyl, oxazolyl, oxadiazolyl, thiazolyl, 2,3- dihydrobenzo[b]dioxinyl, 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazinyl, 4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridinyl, isoquinolinyl, and quinolinyl;
R3 is selected from the group consisting of -heterocyclyl substituted with 1-10 R11, -(C1-4 alkylene)pphenyl substituted with 1-5 R12, -heteroaryl optionally substituted with 1-4 R13, and - (Ci-4 alkylene)OR14; wherein heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, 5,6,7,8-tetrahydroimidazo[l,2- a]pyrazinyl, 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridinyl, 1,2,3,4-tetrahydroisoquinolinyl,
Figure imgf000039_0001
isoquinolinyl, and quinolinyl; wherein is only substituted at positions 4 and 7 ; wherein each— (Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
with the proviso that when L2 is a bond, R3 is selected from -heteroaryl optionally substituted with 1-4 R13; wherein heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, 5,6,7,8-tetrahydroimidazo[l,2- a]pyrazinyl, 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridinyl, 1,2,3,4-tetrahydroisoquinolinyl,
Figure imgf000039_0002
isoquinolinyl, and quinolinyl; wherein is only substituted at positions 4 and 7;
each R4 is halide;
each R5 is independently selected from the group consisting of halide, Me, and Et;
each R6 is independently selected from the group consisting of -CEfF, -CHF2, -CF3, - OR15a, and -(C1-4 alkylene)pN(R16a)(R16b); wherein -(Cw alkylene) is optionally substituted with one or more substituents as defined anywhere herein; each R7 is independently selected from the group consisting of F, -CFfiF, -CHF2, -CF3, - CF2CH3, -OR15a, -CO2R17, -NR18(C=0)R19,— (Ci-4 alkylene)pheterocyclyl optionally substituted with 1-10 R20b, and -(C1-4 alkylene)N(R16a)(R16b); wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
R8 is unsubstituted -(C1-9 alkyl);
R9 is unsubstituted -(C1-9 alkyl);
R10 is -aryl optionally substituted with 1-5 R21;
each R11 is independently selected from the group consisting of halide, methyl, and ethyl; each R12 is independently selected from the group consisting of -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R20a, -aryl optionally substituted with 1-5 R22,— (Ci-4 alkylene)N(R16a)(R16b), and -OR23a; wherein heterocyclyl selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; each R13 is independently selected from the group consisting of F, methyl, -CFfiF, -CHF2, -CF3,— (Ci-4 alkylene)pN(R16a)2, -OR23b, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R20b, -aryl optionally substituted with 1-5 R22, and -heteroaryl substituted with 1-4 R24; wherein -(C1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein;
R14 is selected from the group consisting of unsubstituted -(C1-4 alkyl) and -aryl optionally substituted with 1-5 R22;
each R15a is independently selected from -heterocyclyl optionally substituted with 1-10 j^ 20b.
each R15b is independently selected from the group consisting of H, unsubstituted -(C2-9 alkyl), and -heterocyclyl optionally substituted with 1-10 R20b;
each R16a is independently selected from the group consisting of H and unsubstituted -(Ci-
2 alkyl);
each R16b is unsubstituted -(C1-2 alkyl);
each R17 is unsubstituted -(C1-9 alkyl);
each R18 is independently selected from the group consisting of H and Me;
each R19 is unsubstituted -(C1-9 alkyl);
each R20a is independently selected from the group consisting of halide and unsubstituted -(C2-9 alkyl);
each R20b is independently selected from the group consisting of halide and unsubstituted -(Ci-9 alkyl); each R21 is independently selected from the group consisting of halide and unsubstituted - (Ci-9 alkyl);
each R22 is independently selected from the group consisting of halide and unsubstituted - (Ci-9 alkyl);
each R23a is independently selected from the group consisting of unsubstituted -(C2-9 alkyl), — (Ci-4 alkylene)OR25, and -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R20b; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R23b is independently selected from the group consisting of unsubstituted -(C1-9 alkyl), — (Ci-4 alkylene)OR25, and -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R20b; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R24 is independently selected from the group consisting of halide and unsubstituted - (Ci-9 alkyl);
each R25 is independently selected from the group consisting of H and unsubstituted -(Ci-
9 alkyl);
Figure imgf000041_0001
L1 is selected from the group consisting of-CH=CH-, , -(CH2)PNR18(C=0)-
, -(C=0)NR18(CH2)p-, -NR18(C=0)NR18-, -NH(CH2)p-, and -(CH2)PNH-;
L2 is selected from the group consisting of a bond, -(C=0)NR18-, -NR18(C=0)-, - NHCH2-, and -CH2NH-;
each p is independently an integer of 0 or 1.
[0142] In some embodiments of Formula (I), R2 is selected from the group consisting of unsubstituted -(C2-9 alkenyl), -phenyl substituted with 1-5 R6, -heteroaryl optionally substituted with 1-4 R7, -CO2R8, -OR9, and -(C=0)R10; wherein heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxazolyl, oxadiazolyl, 5,6,7,8-tetrahydroimidazo[l,2- a]pyrazinyl, 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridinyl, and isoquinolinyl; wherein -(C1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein.
[0143] In some embodiments of Formula (I), each R6 is independently selected from the group consisting of -CFfiF, -CHF2, -CF3, -OR15a, and -(C1-4 alkylene)pN(R16a)(R16b); wherein — (Ci-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein.
[0144] In some embodiments of Formula (I), each R6 is independently selected from the group consisting of -CF3, -OR15a, and -(C1-4 alkylene)pN(R16a)(R16b); wherein -(C1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein. [0145] In some embodiments of Formula (I), each R7 is independently selected from the group consisting of F, -CH2F, -CHF2, -CF3, -CF2CH3, -OR15a, -C02R17, -NR18(C=0)R19, - (Ci-4 alkylene)pheterocyclyl optionally substituted with 1-10 R20b, and -(Ci-4 alkylene)N(R16a)(R16b); wherein each -(Ci-4alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0146] In some embodiments of Formula (I), In some embodiments of Formula (I), each R7 is independently selected from the group consisting of F, -CF3, -CF2CH3, -OR15a, - C02R17, -NR18(C=0)R19, -(CI-4 alkylene)pheterocyclyl optionally substituted with 1-10 R20b, and - (Ci-4alkylene)N(R16a)(R16b); wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0147] In some embodiments of Formula (I), each R15a is independently selected from -heterocyclyl optionally substituted with 1-10 R20b.
[0148] In some embodiments of Formula (I), L1 is selected from the group consisting of -CH=CH-, — C=C— -(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)p- -NR18(C=0)NR18-, - NH(CH2)p-, and -(CH2)PNH-.
[0149] Illustrative compounds of Formula (I) are shown in Table 1.
Table 1.
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Administration and Pharmaceutical Compositions
[0266] 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; and (b) a pharmaceutically acceptable carrier.
[0267] The compounds provided herein may also be useful in combination (administered together or sequentially) with other known agents.
[0268] Non-limiting examples of diseases which can be treated with a combination of a compound of Formula (I) and other another active agent are colorectal cancer, ovarian cancer, chronic inflammation, diabetic retinopathy, pulmonary fibrosis, and osteoarthritis. For example, a compound of Formula (I) can be combined with one or more chemotherapeutic compounds.
[0269] In some embodiments, colorectal cancer can be treated with a combination of a compound of Formula (I) and one or more of the following drugs: 5-Fluorouracil (5-FU), which can be administered with the vitamin-like drug leucovorin (also called folinic acid); capecitabine (XELODA®), irinotecan (CAMPOSTAR®), oxaliplatin (ELOXATIN®). Examples of combinations of these drugs which could be further combined with a compound of Formula (I) are FOLFOX (5- FU, leucovorin, and oxaliplatin), FOLFIRI (5-FU, leucovorin, and irinotecan), FOLFOXIRI (leucovorin, 5-FU, oxaliplatin, and irinotecan) and CapeOx (Capecitabine and oxaliplatin). For rectal cancer, chemo with 5-FU or capecitabine combined with radiation may be given before surgery (neoadjuvant treatment).
[0270] In some embodiments, ovarian cancer can be treated with a combination of a compound of Formula (I) and one or more of the following drugs: Topotecan, Liposomal doxorubicin (DOXIL®), Gemcitabine (GEMZAR®), Cyclophosphamide (CYTOXAN®), Vinorelbine (NAVELBINE®), Ifosfamide (IFEX®), Etoposide (VP-16), Altretamine (HEXALEN®), Capecitabine (XELODA®), Irinotecan (CPT-11, CAMPTOSAR®), Melphalan, Pemetrexed (ALIMTA®) and Albumin bound paclitaxel (nab-paclitaxel, ABRAXANE®). Examples of combinations of these drugs which could be further combined with a compound of Formula (I) are TIP (paclitaxel [Taxol], ifosfamide, and cisplatin), VelP (vinblastine, ifosfamide, and cisplatin) and VIP (etoposide [VP- 16], ifosfamide, and cisplatin).
[0271] In some embodiments, a compound of Formula (I) can be used to treat cancer in combination with any of the following methods: (a) Hormone therapy such as aromatase inhibitors, LHRH [luteinizing hormone-releasing hormone] analogs and inhibitors, and others; (b) Ablation or embolization procedures such as radiofrequency ablation (RFA), ethanol (alcohol) ablation, microwave thermotherapy and cryosurgery (cryotherapy); (c) Chemotherapy using alkylating agents such as cisplatin and carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil and ifosfamide; (d) Chemotherapy using anti-metabolites such as azathioprine and mercaptopurine; (e) Chemotherapy using plant alkaloids and terpenoids such as vinca alkaloids (i.e. Vincristine, Vinblastine, Vinorelbine and Vindesine) and taxanes; (f) Chemotherapy using podophyllotoxin, etoposide, teniposide and docetaxel; (g) Chemotherapy using topoisomerase inhibitors such as irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, and teniposide; (h) Chemotherapy using cytotoxic antibiotics such as actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and mitomycin; (i) Chemotherapy using tyrosine-kinase inhibitors such as Imatinib mesylate (GLEEVEC®, also known as STI-571), Gefitinib (Iressa, also known as ZD 1839), Erlotinib (marketed as TARCEVA®), Bortezomib (VELCADE®) , tamoxifen , tofacitinib, crizotinib, Bcl-2 inhibitors (e.g. obatoclax in clinical trials, ABT-263, and Gossypol), PARP inhibitors (e.g. Iniparib, Olaparib in clinical trials), PI3K inhibitors (e.g. perifosine in a phase III trial), VEGF Receptor 2 inhibitors (e.g. Apatinib), AN-152, (AEZS-108), Braf inhibitors (e.g. vemurafenib, dabrafenib and LGX818), MEK inhibitors (e.g. trametinib and MEK162), CDK inhibitors, (e.g. PD-0332991), salinomycin and Sorafenib; (j) Chemotherapy using monoclonal antibodies such as Rituximab (marketed as MABTHERA® or RITUXAN®), Trastuzumab (Herceptin also known as ErbB2), Cetuximab (marketed as ERBITUX®), and Bevacizumab (marketed as AVASTIN®); and (k) radiation therapy.
[0272] In some embodiments, diabetic retinopathy can be treated with a combination of a compound of Formula (I) and one or more of the following natural supplements: Bilberry, Butcher's broom, Ginkgo, Grape seed extract, and Pycnogenol (Pine bark).
[0273] In some embodiments, idiopathic pulmonary fibrosis/pulmonary fibrosis can be treated with a combination of a compound of Formula (I) and one or more of the following drugs: pirfenidone (pirfenidone was approved for use in 2011 in Europe under the brand name Esbriet®), prednisone, azathioprine, N-acetylcysteine, interferon-g lb, bosentan (bosentan is currently being studied in patients with IPF, [The American Journal of Respiratory and Critical Care Medicine (2011), 184(1), 92-9]), Nintedanib (BIBF 1120 and Vargatef), QAX576 [British Journal of Pharmacology (2011), 163(1), 141-172], and anti-inflammatory agents such as corticosteroids.
[0274] In some embodiments, a compound of Formula (I) can be used to treat idiopathic pulmonary fibrosis/pulmonary fibrosis in combination with any of the following methods: oxygen therapy, pulmonary rehabilitation and surgery. [0275] In some embodiments, a compound of Formula (I) can be used to treat osteoarthritis in combination with any of the following methods: (a) Nonsteroidal anti inflammatory drugs (NSAIDs) such as ibuprofen, naproxen, aspirin and acetaminophen; (b) physical therapy; (c) injections of corticosteroid medications; (d) injections of hyaluronic acid derivatives (e.g. Hyalgan, Synvisc); (e) narcotics, like codeine; (f) in combination with braces and/or shoe inserts or any device that can immobilize or support your joint to help you keep pressure off it (e.g., splints, braces, shoe inserts or other medical devices); (g) realigning bones (osteotomy); (h) joint replacement (arthroplasty); and (i) in combination with a chronic pain class.
[0276] In some embodiments, macular degeneration can be treated with a combination of a compound of Formula (I) and one or more of the following drugs: Bevacizumab (Avastin®), Ranibizumab (Lucentis®), Pegaptanib (Macugen), Aflibercept (Eylea®), verteporfm (Visudyne®) in combination with photodynamic therapy (PDT) or with any of the following methods: (a) in combination with laser to destroy abnormal blood vessels (photocoagulation); and (b) in combination with increased vitamin intake of antioxidant vitamins and zinc.
[0277] In some embodiments, retinitis pigmentosa can be treated with a combination of a compound of Formula (I) and one or more of the following drugs: UF-021 (Ocuseva™), vitamin A palmitate and pikachurin or with any of the following methods: (a) with the Argus® II retinal implant; and (b) with stem cell and/or gene therapy.
[0278] Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration, including, but not limited to, orally, subcutaneously, intravenously, 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 devices. In some embodiments, the administration method includes oral or parenteral administration.
[0279] 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. They may be obtained, for example, as solid plugs, powders, or fdms 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 be used for this purpose. 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.
[0280] The compounds can be administered either alone or in combination with a conventional pharmaceutical carrier, excipient or the like. 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- poly oxypropylene -block polymers, and wool fat. Cyclodextrins such as a-, b, and g-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3- hydroxypropyl- -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% of a compound provided herein, 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).
[0281] In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a compound provided herein, 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, 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). Unit dosage forms in which one or more compounds provided herein or additional active agents 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.
[0282] Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. a compound 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, coacervate or suspension. If desired, the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, co-solvents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).
[0283] In some embodiments, the unit dosage of compounds of Formula (I) is about 0.25 mg/Kg to about 50 mg/Kg in humans.
[0284] In some embodiments, the unit dosage of compounds of Formula (I) is about 0.25 mg/Kg to about 20 mg/Kg in humans.
[0285] In some embodiments, the unit dosage of compounds of Formula (I) is about 0.50 mg/Kg to about 19 mg/Kg in humans.
[0286] In some embodiments, the unit dosage of compounds of Formula (I) is about 0.75 mg/Kg to about 18 mg/Kg in humans.
[0287] In some embodiments, the unit dosage of compounds of Formula (I) is about 1.0 mg/Kg to about 17 mg/Kg in humans.
[0288] In some embodiments, the unit dosage of compounds of Formula (I) is about 1.25 mg/Kg to about 16 mg/Kg in humans.
[0289] In some embodiments, the unit dosage of compounds of Formula (I) is about 1.50 mg/Kg to about 15 mg/Kg in humans.
[0290] In some embodiments, the unit dosage of compounds of Formula (I) is about 1.75 mg/Kg to about 14 mg/Kg in humans.
[0291] In some embodiments, the unit dosage of compounds of Formula (I) is about 2.0 mg/Kg to about 13 mg/Kg in humans. [0292] In some embodiments, the unit dosage of compounds of Formula (I) is about 3.0 mg/Kg to about 12 mg/Kg in humans.
[0293] In some embodiments, the unit dosage of compounds of Formula (I) is about 4.0 mg/Kg to about 11 mg/Kg in humans.
[0294] In some embodiments, the unit dosage of compounds of Formula (I) is about 5.0 mg/Kg to about 10 mg/Kg in humans.
[0295] In some embodiments, the compositions are provided in unit dosage forms suitable for single administration.
[0296] In some embodiments, the compositions are provided in unit dosage forms suitable for twice a day administration.
[0297] In some embodiments, the compositions are provided in unit dosage forms suitable for three times a day administration.
[0298] Injectables can be prepared in conventional forms, either as liquid solutions, colloid, liposomes, 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 highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the patient. However, percentages of active ingredient of 0.01% to 10% in solution are employable, and could be higher if the composition is a solid or suspension, which could be subsequently diluted to the above percentages.
[0299] In some embodiments, the composition will comprise about 0.1-10% of the active agent in solution.
[0300] In some embodiments, the composition will comprise about 0.1-5% of the active agent in solution.
[0301] In some embodiments, the composition will comprise about 0.1-4% of the active agent in solution.
[0302] In some embodiments, the composition will comprise about 0.15-3% of the active agent in solution.
[0303] In some embodiments, the composition will comprise about 0.2-2% of the active agent in solution.
[0304] In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-96 hours.
[0305] In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-72 hours. [0306] In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-48 hours.
[0307] In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-24 hours.
[0308] In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-12 hours.
[0309] In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-6 hours.
[0310] In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 5 mg/m2 to about 300 mg/m2.
[0311] In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 5 mg/m2 to about 200 mg/m2.
[0312] In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 5 mg/m2 to about 100 mg/m2.
[0313] In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 10 mg/m2 to about 50 mg/m2.
[0314] 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.
[0315] 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.
[0316] 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.
[0317] 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 should 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.
[0318] 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. [0319] In some embodiments, aerosols intended for delivery to the nasal mucosa are provided for inhalation through the nose. For optimal delivery to the nasal cavities, inhaled particle sizes of about 5 to about 100 microns are useful, with particle sizes of about 10 to about 60 microns being preferred. For nasal delivery, a larger inhaled particle size may be desired to maximize impaction on the nasal mucosa and to minimize or prevent pulmonary deposition of the administered formulation. In some embodiments, aerosols intended for delivery to the lung are provided for inhalation through the nose or the mouth. For delivery to the lung, inhaled aerodynamic particle sizes of about less than 10 pm are useful (e.g., about 1 to about 10 microns). Inhaled particles may be defined as liquid droplets containing dissolved drug, liquid droplets containing suspended drug particles (in cases where the drug is insoluble in the suspending medium), dry particles of pure drug substance, drug substance incorporated with excipients, liposomes, emulsions, colloidal systems, coacervates, aggregates of drug nanoparticles, or dry particles of a diluent which contain embedded drug nanoparticles.
[0320] In some embodiments, compounds of Formula (I) 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 drug substance effectively. A desired particle size and distribution may be obtained by choosing an appropriate device.
[0321] In some embodiments, the compositions of Formula (I) 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.
[0322] Alternatively, formulations 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).
[0323] 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).
[0324] In some embodiments, compounds of Formula (I) disclosed herein intended for delivery to the ear can be administered via an implanted pump and delivery system through a needle directly into the middle or inner ear (cochlea) or through a cochlear implant stylet electrode channel or alternative prepared drug delivery channel such as but not limited to a needle through temporal bone into the cochlea.
[0325] Other options include delivery via a pump through a thin fdm coated onto a multichannel electrode or electrode with a specially imbedded drug delivery channel (pathways) carved into the thin film for this purpose. In other embodiments the acidic or basic solid compound of Formula (I) can be delivered from the reservoir of an external or internal implanted pumping system.
[0326] 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).
[0327] 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 formulations 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 formulation described herein is administered onto the round window membrane via a surgical approach to the round window membrane comprising modification of the crista fenestrae cochleae.
[0328] In some embodiments, the compounds of Formula (I) are formulated in 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.
[0329] Suppositories for rectal administration of the drug (either as a solution, colloid, suspension or a complex) can be prepared by mixing a compound provided herein 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. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter, is first melted.
[0330] Solid compositions can be provided in various different types of dosage forms, depending on the physicochemical properties of the compound provided herein, 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.
[0331] Examples of single units which may be used as dosage forms for the solid composition include tablets, such as compressed tablets, fdm-like units, foil-like units, wafers, lyophilized matrix units, and the like. In one embodiment, the solid composition is a highly porous lyophilized form. Such lyophilizates, sometimes also called wafers or lyophilized tablets, are particularly useful for their rapid disintegration, which also enables the rapid dissolution of the compound.
[0332] On the other hand, for some applications the solid composition may also be formed as a multiple unit dosage form as defined 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 formation 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.
[0333] Another type of multiparticulate system which is also capable of achieving rapid drug dissolution is that of powders, granules, or pellets from water-soluble excipients which are coated with a compound provided herein so that the compound is located at the outer surface of the individual particles. In this type of system, the water-soluble low molecular weight excipient may be useful for preparing the cores of such coated particles, which can be subsequently coated with a coating composition comprising the compound and, for example, 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.
[0334] 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 cancer. 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 hepatocellular carcinoma, colon cancer, leukemia, lymphoma, sarcoma, ovarian cancer, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, sepsis, ankylosing spondylitis, psoriasis, scleroderma, mycotic and viral infections, bone and cartilage diseases, Alzheimer’s disease, lung disease, bone/osteoporotic (wrist, spine, shoulder and hip) fractures, articular cartilage (chondral) defects, degenerative disc disease (or intervertebral disc degeneration), polyposis coli, bone density and vascular defects in the eye (Osteoporosis - pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Miillerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Nome disease, and Rett syndrome.
Methods of Treatment
[0335] The compounds and compositions provided herein can be used as inhibitors and/or modulators of one or more components of the Wnt pathway, which may include 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 cancer and other diseases associated with abnormal angiogenesis, cellular proliferation, and cell cycling. Accordingly, the compounds and compositions provided herein can be used to treat cancer, to reduce or inhibit angiogenesis, to reduce or inhibit cellular proliferation, to correct a genetic disorder, and/or to treat a neurological condition/disorder/disease due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Non-limiting examples of diseases which can be treated with the compounds and compositions provided herein include a variety of cancers, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, scleroderma, mycotic and viral infections, bone and cartilage diseases, neurological conditions/diseases such as Alzheimer's disease, amyotrophic lateral sclerosis (AFS), motor neuron disease, multiple sclerosis or autism, lung disease, bone/osteoporotic (wrist, spine, shoulder and hip) fractures, polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Miillerian-duct regression and virilization, SERKAF syndrome, type II diabetes, Fuhrmann syndrome, Al- Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha- thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader- Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.
[0336] With respect to cancer, the Wnt pathway is known to be constitutively activated in a variety of cancers including, for example, colon cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, prostate cancer , pancreatic cancer and leukemias such as CML, CLL and T-ALL. Accordingly, the compounds and compositions described herein may be used to treat these cancers in which the Wnt pathway is constitutively activated. In certain embodiments, the cancer is chosen from hepatocellular carcinoma, colon cancer, leukemia, lymphoma, sarcoma and ovarian cancer.
[0337] Other cancers can also be treated with the compounds and compositions described herein.
[0338] More particularly, cancers that may be treated by the compounds, compositions and methods described herein include, but are not limited to, the following:
[0339] 1) Breast cancers, including, for example ER+ breast cancer, ER breast cancer, her2 breast cancer, her2+ breast cancer, stromal tumors such as fibroadenomas, phyllodes tumors, and sarcomas, and epithelial tumors such as large duct papillomas; carcinomas of the breast including in situ (noninvasive) carcinoma that includes ductal carcinoma in situ (including Paget's disease) and lobular carcinoma in situ, and invasive (infiltrating) carcinoma including, but not limited to, invasive ductal carcinoma, invasive lobular carcinoma, medullary carcinoma, colloid (mucinous) carcinoma, tubular carcinoma, and invasive papillary carcinoma; and miscellaneous malignant neoplasms. Further examples of breast cancers can include luminal A, luminal B, basal A, basal B, and triple negative breast cancer, which is estrogen receptor negative (ER ), progesterone receptor negative, and her2 negative (her2 ). In some embodiments, the breast cancer may have a high risk Oncotype score.
[0340] 2) Cardiac cancers, including, for example sarcoma, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma; fibroma; lipoma and teratoma.
[0341] 3) Lung cancers, including, for example, bronchogenic carcinoma, e.g., squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchial adenoma; sarcoma; lymphoma; chondromatous hamartoma; and mesothelioma.
[0342] 4) Gastrointestinal cancer, including, for example, cancers of the esophagus, e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; cancers of the stomach, e.g., carcinoma, lymphoma, and leiomyosarcoma; cancers of the pancreas, e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, and vipoma; cancers of the small bowel, e.g., adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma; cancers of the large bowel, e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyoma.
[0343] 5) Genitourinary tract cancers, including, for example, cancers of the kidney, e.g., adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, and leukemia; cancers of the bladder and urethra, e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma; cancers of the prostate, e.g., adenocarcinoma, and sarcoma; cancer of the testis, e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, and lipoma.
[0344] 6) Liver cancers, including, for example, hepatoma, e.g., hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hepatocellular adenoma; and hemangioma.
[0345] 7) Bone cancers, including, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochrondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors.
[0346] 8) Nervous system cancers, including, for example, cancers of the skull, e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans; cancers of the meninges, e.g., meningioma, meningiosarcoma, and gliomatosis; cancers of the brain, e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, oligodendrocytoma, schwannoma, retinoblastoma, and congenital tumors; and cancers of the spinal cord, e.g., neurofibroma, meningioma, glioma, and sarcoma.
[0347] 9) Gynecological cancers, including, for example, cancers of the uterus, e.g., endometrial carcinoma; cancers of the cervix, e.g., cervical carcinoma, and pre tumor cervical dysplasia; cancers of the ovaries, e.g., ovarian carcinoma, including serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa theca cell tumors, Sertoli Leydig cell tumors, dysgerminoma, and malignant teratoma; cancers of the vulva, e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma; cancers of the vagina, e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, and embryonal rhabdomyosarcoma; and cancers of the fallopian tubes, e.g., carcinoma.
[0348] 10) Hematologic cancers, including, for example, cancers of the blood, e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, and myelodysplastic syndrome, Hodgkin's lymphoma, non-Hodgkin’s lymphoma (malignant lymphoma) and Waldenstrom's macroglobulinemia.
[0349] 11) Skin cancers and skin disorders, including, for example, malignant melanoma and metastatic melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, and scleroderma.
[0350] 12) Adrenal gland cancers, including, for example, neuroblastoma.
[0351] More particularly, tumors of the central nervous system that may be treated by the compounds, compositions and methods described herein include:
[0352] 1) Astrocytic tumors, e.g., diffuse astrocytoma (fibrillary, protoplasmic, gemistocytic, mixed), anaplastic (malignant) astrocytoma, glioblastoma multiforme (giant cell glioblastoma and gliosarcoma), pilocytic astrocytoma (pilomyxoid astrocytoma), pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, and gliomatosis cerebri.
[0353] 2) Oligodendroglial tumors, e.g., oligodendroglioma and anaplastic oligodendroglioma.
[0354] 3) Oligoastrocytic tumors, e.g., oligoastrocytoma and anaplastic oligoastrocytoma.
[0355] 4) Ependymal tumors, e.g., subependymoma, myxopapillary ependymoma, ependymoma, (cellular, papillary, clear cell, tanycytic), and anaplastic (malignant) ependymoma.
[0356] 5) Choroid plexus tumors, e.g., choroid plexus papilloma, atypical choroid plexus papilloma, and choroid plexus carcinoma.
[0357] 6) Neuronal and mixed neuronal -glial tumors, e.g., gangliocytoma, ganglioglioma, dysembryoplastic neuroepithelial tumor (DNET), dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos), desmoplastic infantile astrocytoma/ganglioglioma, central neurocytoma, anaplastic ganglioglioma, extraventricular neurocytoma, cerebellar liponeurocytoma, Papillary glioneuronal tumor, Rosette -forming glioneuronal tumor of the fourth ventricle, and paraganglioma of the fdum terminale.
[0358] 7) Pineal tumors, e.g., pineocytoma, pineoblastoma, papillary tumors ofthe pineal region, and pineal parenchymal tumor of intermediate differentiation.
[0359] 8) Embryonal tumors, e.g., medulloblastoma (medulloblastoma with extensive nodularity, anaplastic medulloblastoma, desmoplastic, large cell, melanotic, medullomyoblastoma), medulloepithelioma, supratentorial primitive neuroectodermal tumors, and primitive neuroectodermal tumors (PNETs) such as neuroblastoma, ganglioneuroblastoma, ependymoblastoma, and atypical teratoid/rhabdoid tumor.
[0360] 9) Neuroblastic tumors, e.g., olfactory (esthesioneuroblastoma), olfactory neuroepithelioma, and neuroblastomas of the adrenal gland and sympathetic nervous system.
[0361] 10) Glial tumors, e.g., astroblastoma, chordoid glioma of the third ventricle, and angiocentric glioma.
[0362] 11) Tumors of cranial and paraspinal nerves, e.g., schwannoma, neurofibroma Perineurioma, and malignant peripheral nerve sheath tumor.
[0363] 12) Tumors of the meninges such as tumors of meningothelial cells, e.g., meningioma (atypical meningioma and anaplastic meningioma); mesenchymal tumors, e.g., lipoma, angiolipoma, hibernoma, liposarcoma, solitary fibrous tumor, fibrosarcoma, malignant fibrous histiocytoma, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, chondroma, chondrosarcoma, osteoma, osteosarcoma, osteochondroma, haemangioma, epithelioid hemangioendothelioma, haemangiopericytoma, anaplastic haemangiopericytoma, angiosarcoma, Kaposi Sarcoma, and Ewing Sarcoma; primary melanocytic lesions, e.g., diffuse melanocytosis, melanocytoma, malignant melanoma, meningeal melanomatosis; and hemangioblastomas.
[0364] 13) Tumors of the hematopoietic system, e.g., malignant Lymphomas, plasmocytoma, and granulocytic sarcoma.
[0365] 14) Germ cell tumors, e.g., germinoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma, and mixed germ cell tumors.
[0366] 15) Tumors of the sellar region, e.g., craniopharyngioma, granular cell tumor, pituicytoma, and spindle cell oncocytoma of the adenohypophysis.
[0367] Cancers may be solid tumors that may or may not be metastatic. Cancers may also occur, as in leukemia, as a diffuse tissue. Thus, the term“tumor cell,” as provided herein, includes a cell afflicted by any one of the above identified disorders.
[0368] A method of treating cancer using a compound or composition as described herein may be combined with existing methods of treating cancers, for example by chemotherapy, irradiation, or surgery (e.g., oophorectomy). In some embodiments, a compound or composition can be administered before, during, or after another anticancer agent or treatment.
[0369] The compounds and compositions described herein can be used as anti- angiogenesis agents and as agents for modulating and/or inhibiting the activity of protein kinases, thus providing treatments for cancer and other diseases associated with cellular proliferation mediated by protein kinases. For example, the compounds described herein can inhibit the activity of one or more kinases. Accordingly, provided herein is a method of treating cancer or preventing or reducing angiogenesis through kinase inhibition.
[0370] In addition, and including treatment of cancer, the compounds and compositions described herein can function as cell-cycle control agents for treating proliferative disorders in a patient. Disorders associated with excessive proliferation include, for example, cancers, scleroderma, immunological disorders involving undesired proliferation of leukocytes, and restenosis and other smooth muscle disorders. Furthermore, such compounds may be used to prevent de -differentiation of post-mitotic tissue and/or cells.
[0371] Diseases or disorders associated with uncontrolled or abnormal cellular proliferation include, but are not limited to, the following:
• a variety of cancers, including, but not limited to, carcinoma, hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system and other tumors including melanoma, seminoma and Kaposi's sarcoma.
• a disease process which features abnormal cellular proliferation, e.g., benign prostatic hyperplasia, familial adenomatosis polyposis, neurofibromatosis, atherosclerosis, arthritis, glomerulonephritis, restenosis following angioplasty or vascular surgery, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections. Fibrotic disorders such as skin fibrosis; scleroderma; progressive systemic fibrosis; lung fibrosis; muscle fibrosis; kidney fibrosis; glomerulosclerosis; glomerulonephritis; hypertrophic scar formation; uterine fibrosis; renal fibrosis; cirrhosis of the liver, liver fibrosis; fatty liver disease (FLD); adhesions, such as those occurring in the abdomen, pelvis, spine or tendons; chronic obstructive pulmonary disease; fibrosis following myocardial infarction; pulmonary fibrosis; fibrosis and scarring associated with diffuse/interstitial lung disease; central nervous system fibrosis, such as fibrosis following stroke; fibrosis associated with neuro -degenerative disorders such as Alzheimer's Disease or multiple sclerosis; fibrosis associated with proliferative vitreoretinopathy (PVR); restenosis; endometriosis; ischemic disease and radiation fibrosis.
• defective apoptosis-associated conditions, such as cancers (including but not limited to those types mentioned herein), viral infections (including but not limited to herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV -infected individuals, autoimmune diseases (including but not limited to systemic lupus erythematosus, rheumatoid arthritis, sepsis, ankylosing spondylitis, psoriasis, scleroderma, autoimmune mediated glomerulonephritis, inflammatory bowel disease and autoimmune diabetes mellitus), neuro -degenerative disorders (including but not limited to Alzheimer’s disease, lung disease, amyotrophic lateral sclerosis, retinitis pigmentosa, Parkinson's disease, AIDS-related dementia, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis), tendinopathies such as tendinitis and tendinosis, aspirin- sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain.
• genetic diseases due to mutations in Wnt signaling components, such as polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Miillerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas- Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Nome disease and Rett syndrome.
[0372] The compounds and compositions provided herein have been found to possess immunomodulatory activities and are expected to control the innate and adaptive immune system (e.g. macrophages, microglia, dendritic cells, B and T cells) and suppress pro-inflammatory cytokine release (e.g. TNF, IF-6, IF-1, IFND) which is well known to be involved in chronic inflammation in a wide variety of disease areas. Therefore compounds and compositions provided herein can used to treat chronic inflammation associated with disorders and diseases including but not limited to eye disorders, joint pain, arthritis (rheumatoid, osteo, psoriatic gout), cancers (colon, breast, lung, pancreas, and others), gastrointestinal disorders (ulcerative colitis and inflammatory bowel diseases), pulmonary disorders (chronic obstructive pulmonary disorder and asthma), allergies, skin disorders (atopic dermatitis and psoriasis), diabetes, pancreatitis, tendonitis, hepatitis, heart disease, myocarditis, stroke, lupus, and neurological disorders such as multiple sclerosis, Parkinson’s and dementia including Alzheimer’s disease.
[0373] The compounds and compositions provided herein can be used as inhibitors and/or modulators of the enzyme DYRK1 A, and thus can be used to treat a variety of disorders and diseases associated with tau protein, amyloid, alpha-synuclein, TDP-43 or FUS pathology including, but not limited to, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), down syndrome, frontotemporal dementia (FTD) including FTD with Parkinsonism-17 (FTDP-17), behavioural variant frontotemporal dementia (bvFTD), FTD in patients with motor neuron disease (MND) (typically amyotrophic lateral sclerosis, also called FTD-ALS), corticobasal degeneration (CBD) (also called corticobasal ganglionic degeneration), progressive supranuclear palsy, primary progressive aphasia (PPA), globular glial tauopathy (GGT), myotonic dystrophy type 1 (DM1) (also called Steinert disease), myotonic dystrophy type 2 (DM2) (also called proximal myotonic myopathy), Guam complex, argyrophilic grain disease, dementia pugilistica, post-encephalitic parkinsonism, Lewy body dementia, Parkinson’s disease, Pick's disease, and additional diseases with pronounced neurodegeneration such as autism, dementia, epilepsy, Huntington’s disease, multiple sclerosis; diseases and disorders associated with acquired brain injury such as chronic traumatic encephalopathy, traumatic brain injury, tumor, and stroke.
[0374] Non-limiting examples of neurological disorders (e.g., neurological conditions and neurological diseases) which can be treated with the compounds and compositions provided herein include Alzheimer's disease, aphasia, apraxia, arachnoiditis, ataxia telangiectasia, attention deficit hyperactivity disorder, auditory processing disorder, autism, alcoholism, Bell's palsy, bipolar disorder, brachial plexus injury, Canavan disease, carpal tunnel syndrome, causalgia, central pain syndrome, central pontine myelinolysis, centronuclear myopathy, cephalic disorder, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral gigantism, cerebral palsy, cerebral vasculitis, cervical spinal stenosis, Charcot-Marie-Tooth disease, Chiari malformation, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic pain, Coffm-Lowry syndrome, complex regional pain syndrome, compression neuropathy, congenital facial diplegia, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, cytomegalic inclusion body disease (CIBD), Dandy-Walker syndrome, Dawson disease, De Morsier's syndrome, Dejerine-Klumpke palsy, Dejerine-Sottas disease, delayed sleep phase syndrome, dementia, dermatomyositis, developmental dyspraxia, diabetic neuropathy, diffuse sclerosis, Dravet syndrome, dysautonomia, dyscalculia, dysgraphia, dyslexia, dystonia, empty sella syndrome, encephalitis, encephalocele, encephalotrigeminal angiomatosis, encopresis, epilepsy, Erb's palsy, erythromelalgia, essential tremor, Fabry's disease, Fahr's syndrome, familial spastic paralysis, febrile seizure, Fisher syndrome, Friedreich's ataxia, fibromyalgia, Foville's syndrome, Gaucher's disease, Gerstmann's syndrome, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, gray matter heterotopia, Guillain-Barre syndrome, HTLV-1 associated myelopathy, Hallervorden-Spatz disease, hemifacial spasm, hereditary spastic paraplegia, heredopathia atactica polyneuritiformis, herpes zoster oticus, herpes zoster, Hirayama syndrome, holoprosencephaly, Huntington's disease, hydranencephaly, hydrocephalus, hypercortisolism, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, infantile phytanic acid storage disease, infantile Refsum disease, infantile spasms, inflammatory myopathy, intracranial cyst, intracranial hypertension, Joubert syndrome, Karak syndrome, Keams- Sayre syndrome, Kennedy disease, Kinsboume syndrome, Klippel Fed syndrome, Krabbe disease, Kugelberg-Welander disease, kuru, Lafora disease, Lambert-Eaton myasthenic syndrome, Landau- Kleffher syndrome, lateral medullary (Wallenberg) syndrome, Leigh's disease, Lennox -Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, Lewy body dementia, lissencephaly, locked- in syndrome, Lou Gehrig's disease, lumbar disc disease, lumbar spinal stenosis, Lyme disease, Machado-Joseph disease (Spinocerebellar ataxia type 3), macrencephaly, macropsia, megalencephaly, Melkersson-Rosenthal syndrome, Meniere’s disease, meningitis, Menkes disease, metachromatic leukodystrophy, microcephaly, micropsia, Miller Fisher syndrome, misophonia, mitochondrial myopathy, Mobius syndrome, monomelic amyotrophy, motor neuron disease, motor skills disorder, Moyamoya disease, mucopolysaccharidoses, multi-infarct dementia, multifocal motor neuropathy, multiple sclerosis, multiple system atrophy, muscular dystrophy, myalgic encephalomyelitis, myasthenia gravis, myelinoclastic diffuse sclerosis, myoclonic Encephalopathy of infants, myoclonus, myopathy, myotubular myopathy, myotonia congenital, narcolepsy, neurofibromatosis, neuroleptic malignant syndrome, lupus erythematosus, neuromyotonia, neuronal ceroid lipofuscinosis, Niemann-Pick disease, O'Sullivan-McLeod syndrome, occipital Neuralgia, occult Spinal Dysraphism Sequence, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus myoclonus syndrome, optic neuritis, orthostatic hypotension, palinopsia, paresthesia, Parkinson's disease, paramyotonia Congenita, paraneoplastic diseases, paroxysmal attacks, Parry- Romberg syndrome, Pelizaeus-Merzbacher disease, periodic paralyses, peripheral neuropathy, photic sneeze reflex, phytanic acid storage disease, Pick's disease, polymicrogyria (PMG), polymyositis, porencephaly, post-polio syndrome, postherpetic neuralgia (PHN), postural hypotension, Prader-Willi syndrome, primary lateral sclerosis, prion diseases, progressive hemifacial atrophy, progressive multifocal leukoencephalopathy, progressive supranuclear palsy, pseudotumor cerebri, Ramsay Hunt syndrome type I, Ramsay Hunt syndrome type II, Ramsay Hunt syndrome type III, Rasmussen's encephalitis, reflex neurovascular dystrophy, Refsum disease, restless legs syndrome, retrovirus-associated myelopathy, Rett syndrome, Reye's syndrome, rhythmic movement disorder, Romberg syndrome, Saint Vitus dance, Sandhoff disease, schizophrenia, Schilder's disease, schizencephaly, sensory integration dysfunction, septo -optic dysplasia, Shy-Drager syndrome, Sjogren's syndrome, snatiation, Sotos syndrome, spasticity, spina bifida, spinal cord tumors, spinal muscular atrophy, spinocerebellar ataxia, Steele-Richardson- Olszewski syndrome, Stiff-person syndrome, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, superficial siderosis, Sydenham's chorea, syncope, synesthesia, syringomyelia, tarsal tunnel syndrome, tardive dyskinesia, tardive dysphrenia, Tarlov cyst, Tay-Sachs disease, temporal arteritis, tetanus, tethered spinal cord syndrome, Thomsen disease, thoracic outlet syndrome, tic douloureux, Todd's paralysis, Tourette syndrome, toxic encephalopathy, transient ischemic attack, transmissible spongiform encephalopathies, transverse myelitis, tremor, trigeminal neuralgia, tropical spastic paraparesis, trypanosomiasis, tuberous sclerosis, ubisiosis, Von Hippel-Lindau disease (VHL), Viliuisk Encephalomyelitis (VE), Wallenberg's syndrome, Werdnig, Hoffman disease, west syndrome, Williams syndrome, Wilson's disease, and Zellweger syndrome.
[0375] The compounds and compositions may also be useful in the inhibition of the development of invasive cancer, tumor angiogenesis and metastasis.
[0376] In some embodiments, the disclosure provides a method for treating a disease or disorder associated with aberrant cellular proliferation by administering to a patient in need of such treatment an effective amount of one or more of the compounds of Formula (I), in combination (simultaneously or sequentially) with at least one other agent.
[0377] In some embodiments, the disclosure provides a method of treating or ameliorating in a patient a disorder or disease selected from the group consisting of: cancer, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), degenerative disc disease, bone/osteoporotic fractures, bone or cartilage disease, and osteoarthritis, the method comprising administering to the patient a therapeutically effective amount of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof.
[0378] In some embodiments, the disclosure provides a method of treating or ameliorating in a patient a disorder or disease selected from the group consisting of: chronic inflammation, systemic inflammation, diabetes, cancer, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), degenerative disc disease, bone/osteoporotic fractures, a bone or cartilage disease, a neurological condition/disorder/disease, osteoarthritis, lung disease, a fibrotic disorder. [0379] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
[0380] In some embodiments, the method of treats a disorder or disease in which aberrant Wnt signaling is implicated in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
[0381] In some embodiments, the disorder or disease is the pain and inflammation associated with cancer.
[0382] In some embodiments, the disorder or disease is the pain and inflammation associated with a joint.
[0383] In some embodiments, the disorder or disease is the pain and inflammation associated with the knee.
[0384] In some embodiments, the disorder or disease is the pain and inflammation associated with the hip.
[0385] In some embodiments, the disorder or disease is the pain and inflammation associated with the shoulder.
[0386] In some embodiments, the disorder or disease is the pain and inflammation associated with arthritis.
[0387] In some embodiments, the disorder or disease is the pain and inflammation associated with gastrointestinal disorders.
[0388] In some embodiments, the disorder or disease is the pain and inflammation associated with pulmonary disorders.
[0389] In some embodiments, the disorder or disease is the pain and inflammation associated with allergies.
[0390] In some embodiments, the disorder or disease is the pain and inflammation associated with skin disorders.
[0391] In some embodiments, the disorder or disease is the pain and inflammation associated with diabetes.
[0392] In some embodiments, the disorder or disease is the pain and inflammation associated with pancreatitis.
[0393] In some embodiments, the disorder or disease is the pain and inflammation associated with tendonitis. [0394] In some embodiments, the disorder or disease is the pain and inflammation associated with heart disease.
[0395] In some embodiments, the disorder or disease is the pain and inflammation associated with lupus.
[0396] In some embodiments, the disorder or disease is the pain and inflammation associated with a neurological disorder.
[0397] In some embodiments, the disorder or disease is the pain and inflammation associated with multiple sclerosis.
[0398] In some embodiments, the disorder or disease is the pain and inflammation associated with Parkinson’s.
[0399] In some embodiments, the disorder or disease is cancer.
[0400] In some embodiments, the disorder or disease is systemic inflammation.
[0401] In some embodiments, the disorder or disease is metastatic melanoma.
[0402] In some embodiments, the disorder or disease is fatty liver disease.
[0403] In some embodiments, the disorder or disease is liver fibrosis.
[0404] In some embodiments, the disorder or disease is tendon regeneration.
[0405] In some embodiments, the disorder or disease is diabetes.
[0406] In some embodiments, the disorder or disease is degenerative disc disease.
[0407] In some embodiments, the disorder or disease is osteoarthritis.
[0408] In some embodiments, the disorder or disease is diabetic retinopathy.
[0409] In some embodiments, the disorder or disease is pulmonary fibrosis.
[0410] In some embodiments, the disorder or disease is idiopathic pulmonary fibrosis
(IPF).
[0411] In some embodiments, the disorder or disease is degenerative disc disease.
[0412] In some embodiments, the disorder or disease is rheumatoid arthritis.
[0413] In some embodiments, the disorder or disease is scleroderma.
[0414] In some embodiments, the disorder or disease is a mycotic or viral infection.
[0415] In some embodiments, the disorder or disease is a bone or cartilage disease.
[0416] In some embodiments, the disorder or disease is a neurological disorder.
[0417] In some embodiments, the disorder or disease is Alzheimer's disease.
[0418] In some embodiments, the disorder or disease is osteoarthritis.
[0419] In some embodiments, the disorder or disease is lung disease.
[0420] In some embodiments, the disorder or disease is a genetic disease caused by mutations in Wnt signaling components, wherein the genetic disease is selected from: polyposis coli, osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia syndrome, Miillerian-duct regression and virilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome, Al-Awadi/Raas- Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split- hand/foot malformation, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha- thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader- Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.
[0421] In some embodiments, the patient is a human.
[0422] In some embodiments, the cancer is chosen from: hepatocellular carcinoma, colon cancer, breast cancer, pancreatic cancer, chronic myeloid leukemia (CMF), chronic myelomonocytic leukemia, chronic lymphocytic leukemia (CFF), acute myeloid leukemia, acute lymphocytic leukemia, Hodgkin lymphoma, lymphoma, sarcoma and ovarian cancer.
[0423] In some embodiments, the cancer is chosen from: lung cancer - non-small cell, lung cancer - small cell, multiple myeloma, nasopharyngeal cancer, neuroblastoma, osteosarcoma, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer - basal and squamous cell, skin cancer - melanoma, small intestine cancer, stomach (gastric) cancers, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, laryngeal or hypopharyngeal cancer, kidney cancer, Kaposi sarcoma, gestational trophoblastic disease, gastrointestinal stromal tumor, gastrointestinal carcinoid tumor, gallbladder cancer, eye cancer (melanoma and lymphoma), Ewing tumor, esophagus cancer, endometrial cancer, colorectal cancer, cervical cancer, brain or spinal cord tumor, bone metastasis, bone cancer, bladder cancer, bile duct cancer, anal cancer and adrenal cortical cancer.
[0424] In some embodiments, the cancer is hepatocellular carcinoma.
[0425] In some embodiments, the cancer is colon cancer.
[0426] In some embodiments, the cancer is colorectal cancer.
[0427] In some embodiments, the cancer is breast cancer.
[0428] In some embodiments, the cancer is pancreatic cancer.
[0429] In some embodiments, the cancer is chronic myeloid leukemia (CMF).
[0430] In some embodiments, the cancer is chronic myelomonocytic leukemia.
[0431] In some embodiments, the cancer is chronic lymphocytic leukemia (CFF).
[0432] In some embodiments, the cancer is acute myeloid leukemia.
[0433] In some embodiments, the cancer is acute lymphocytic leukemia.
[0434] In some embodiments, the cancer is Hodgkin lymphoma. [0435] In some embodiments, the cancer is lymphoma.
[0436] In some embodiments, the cancer is sarcoma.
[0437] In some embodiments, the cancer is ovarian cancer.
[0438] In some embodiments, the cancer is lung cancer - non-small cell.
[0439] In some embodiments, the cancer is lung cancer - small cell.
[0440] In some embodiments, the cancer is multiple myeloma.
[0441] In some embodiments, the cancer is nasopharyngeal cancer.
[0442] In some embodiments, the cancer is neuroblastoma.
[0443] In some embodiments, the cancer is osteosarcoma.
[0444] In some embodiments, the cancer is penile cancer.
[0445] In some embodiments, the cancer is pituitary tumors.
[0446] In some embodiments, the cancer is prostate cancer.
[0447] In some embodiments, the cancer is retinoblastoma.
[0448] In some embodiments, the cancer is rhabdomyosarcoma.
[0449] In some embodiments, the cancer is salivary gland cancer.
[0450] In some embodiments, the cancer is skin cancer - basal and squamous cell.
[0451] In some embodiments, the cancer is skin cancer - melanoma.
[0452] In some embodiments, the cancer is small intestine cancer.
[0453] In some embodiments, the cancer is stomach (gastric) cancers.
[0454] In some embodiments, the cancer is testicular cancer.
[0455] In some embodiments, the cancer is thymus cancer.
[0456] In some embodiments, the cancer is thyroid cancer.
[0457] In some embodiments, the cancer is uterine sarcoma.
[0458] In some embodiments, the cancer is vaginal cancer.
[0459] In some embodiments, the cancer is vulvar cancer.
[0460] In some embodiments, the cancer is Wilms tumor.
[0461] In some embodiments, the cancer is laryngeal or hypopharyngeal cancer.
[0462] In some embodiments, the cancer is kidney cancer.
[0463] In some embodiments, the cancer is Kaposi sarcoma.
[0464] In some embodiments, the cancer is gestational trophoblastic disease.
[0465] In some embodiments, the cancer is gastrointestinal stromal tumor.
[0466] In some embodiments, the cancer is gastrointestinal carcinoid tumor.
[0467] In some embodiments, the cancer is gallbladder cancer.
[0468] In some embodiments, the cancer is eye cancer (melanoma and lymphoma). [0469] In some embodiments, the cancer is Ewing tumor.
[0470] In some embodiments, the cancer is esophagus cancer.
[0471] In some embodiments, the cancer is endometrial cancer.
[0472] In some embodiments, the cancer is colorectal cancer.
[0473] In some embodiments, the cancer is cervical cancer.
[0474] In some embodiments, the cancer is brain or spinal cord tumor.
[0475] In some embodiments, the cancer is bone metastasis.
[0476] In some embodiments, the cancer is bone cancer.
[0477] In some embodiments, the cancer is bladder cancer.
[0478] In some embodiments, the cancer is bile duct cancer.
[0479] In some embodiments, the cancer is anal cancer.
[0480] In some embodiments, the cancer is adrenal cortical cancer.
[0481] In some embodiments, the disorder or disease is a neurological condition/disorder/disease, wherein the neurological condition/disorder/disease is selected from: Alzheimer's disease, frontotemporal dementias, dementia with Lewy bodies, prion diseases, Parkinson's disease, Huntington's disease, progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, amyotrophic lateral sclerosis (ALS), inclusion body myositis, autism, degenerative myopathies, diabetic neuropathy, other metabolic neuropathies, endocrine neuropathies, orthostatic hypotension, multiple sclerosis and Charcot-Marie-Tooth disease.
[0482] In some embodiments, the disorder or disease is a neurological condition/disorder/disease associated with tau protein, amyloid, alpha-synuclein pathology, Tar DNA-binding Protein of 43KDa (TDP-43), Prion protein PrP or fused in sarcoma (FUS).
[0483] In some embodiments, the disorder or disease is a neurological condition/disorder/disease, wherein the neurological condition/disorder/disease is selected from the group consisting of: Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, Down Syndrome, Frontotemporal Dementia with Parkinsonism- 17 (FTDP-17), Lewy body dementia, Parkinson’s Disease, Pick's Disease, and additional diseases with pronounced neurodegeneration such as Autism, Dementia, Epilepsy, Huntington’s Disease, Multiple Sclerosis; diseases and disorders associated with acquired brain injury such as Chronic Traumatic Encephalopathy, Traumatic Brain Injury, Tumor, and Stroke.
[0484] In some embodiments, the disorder or disease is a fibrotic disorder, wherein the fibrotic disorder is selected from the group consisting of: skin fibrosis; scleroderma; progressive systemic fibrosis; lung fibrosis; muscle fibrosis; kidney fibrosis; glomerulosclerosis; glomerulonephritis; hypertrophic scar formation; uterine fibrosis; renal fibrosis; cirrhosis of the liver, liver fibrosis; adhesions; chronic obstructive pulmonary disease; fibrosis following myocardial infarction; pulmonary fibrosis; fibrosis and scarring associated with diff ise/interstitial lung disease; central nervous system fibrosis; fibrosis associated with proliferative vitreoretinopathy (PVR); restenosis; endometriosis; ischemic disease, and radiation fibrosis.
[0485] In some embodiments, the disorder or disease is chronic inflammation associated with eye disorders, joint pain, arthritis (rheumatoid, osteo, psoriatic gout), cancers (colon, breast, lung, pancreas, and others), gastrointestinal disorders (ulcerative colitis and inflammatory bowel diseases), pulmonary disorders (chronic obstructive pulmonary disorder and asthma), allergies, skin disorders (atopic dermatitis and psoriasis), diabetes, pancreatitis, tendonitis, hepatitis, heart disease, myocarditis, stroke, lupus, and neurological disorders such as multiple sclerosis, Parkinson’s and dementia including Alzheimer’s disease.
[0486] In some embodiments, a compound of Formula (I) inhibits DYRK1A.
[0487] In some embodiments, a compound of Formula (I) inhibits GSK3.
[0488] In some embodiments, a compound of Formula (I) inhibits GSK3 .
[0489] In some embodiments, a compound of Formula (I) inhibits DYRK1A and
GSK3 .
[0490] In some embodiments, the compound of Formula (I) inhibits one or more proteins in the Wnt pathway.
[0491] In some embodiments, the compound of Formula (I) inhibits signaling induced by one or more Wnt proteins.
[0492] 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 WNT16.
[0493] In some embodiments, the compound of Formula (I) inhibits a kinase activity.
[0494] In some embodiments, the method treats a disease or disorder mediated by the
Wnt pathway in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.
[0495] In some embodiments, the compound of Formula (I) inhibits one or more Wnt proteins.
[0496] In some embodiments, the method treats a disease or disorder mediated by kinase activity in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.
[0497] In some embodiments, the disease or disorder comprises tumor growth, cell proliferation, or angiogenesis.
[0498] In some embodiments, the method inhibits the activity of a protein kinase receptor, the method comprises contacting the receptor with an effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.
[0499] In some embodiments, the method treats a disease or disorder associated with aberrant cellular proliferation in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.
[0500] In some embodiments, the method prevents or reduces angiogenesis in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.
[0501] In some embodiments, the method prevents or reduces abnormal cellular proliferation in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.
[0502] In some embodiments, the method treats a disease or disorder associated with aberrant cellular proliferation in a patient, the method comprises administering to the patient a pharmaceutical composition comprising one or more of the compounds of claim 1 in combination with a pharmaceutically acceptable carrier and one or more other agents.
[0503] Moreover, the compounds and compositions, for example, as inhibitors of the cyclin-dependent kinases (CDKs), can modulate the level of cellular RNA and DNA synthesis and therefore are expected to be useful in the treatment of viral infections such as HIV, human papilloma virus, herpes virus, Epstein -Barr virus, adenovirus, Sindbis virus, pox virus and the like.
[0504] Compounds and compositions described herein can inhibit the kinase activity of, for example, CDK/cyclin complexes, such as those active in the Go or Gi stage of the cell cycle, e.g., CDK2, CDK4, and/or CDK6 complexes.
Evaluation of Biological Activity
[0505] The biological activity of the compounds described herein can be tested using any suitable assay known to those of skill in the art, see, e.g., WO 2001/053268 and WO 2005/009997. For example, the activity of a compound may be tested using one or more of the test methods outlined below.
[0506] In one example, tumor cells may be screened for Wnt independent growth. In such a method, tumor cells of interest are contacted with a compound (i.e. inhibitor) of interest, and the proliferation of the cells, e.g. by uptake of tritiated thymidine, is monitored. In some embodiments, tumor cells may be isolated from a candidate patient who has been screened for the presence of a cancer that is associated with a mutation in the Wnt signaling pathway. Candidate cancers include, without limitation, those listed above.
[0507] In another example, one may utilize in vitro assays for Wnt biological activity, e.g. stabilization of b-catenin and promoting growth of stem cells. Assays for biological activity of Wnt include stabilization of b-catenin, which can be measured, for example, by serial dilutions of a candidate inhibitor composition. An exemplary assay for Wnt biological activity contacts a candidate inhibitor with cells containing constitutively active Wnt^-catenin signaling. The cells are cultured for a period of time sufficient to stabilize b-catenin, usually at least about 1 hour, and lysed. The cell lysate is resolved by SDS PAGE, then transferred to nitrocellulose and probed with antibodies specific for b-catenin.
[0508] In a further example, the activity of a candidate compound can be measured in a Xenopus secondary axis bioassay (Leyns, L. et al. Cell (1997), 88(6), 747-756).
[0509] In another example, in vitro assays for DYRK1A biological activity may be used, e.g. regulation of microtubule-associated protein tau (MAPT/Tau) phosphorylation in neuronal cell line such as the human SH-SY5Y neuroblastoma cell line. Assays for DYRK1A- regulated level of phosphorylation can include monitoring levels of basal pSer396 Tau, which can be measured, for example, by serial dilutions of a candidate inhibitor composition using a ten micromolar top concentration and detected by ELISA or Western Blotting. An exemplary assay for DYRK-1 A-regulated phosphorylation uses the SH-SY 5Y cells cultured in a 96 well plate format for a period of time sufficient to stabilize microtubules and Tau phosphorylation, usually at least 2 days, then treated with a 1/3 serial dilution of compounds overnight and lysed. The cell lysate is resolved by SDS PAGE, then transferred to nitrocellulose and probed with an antibody specific for pSer396 Tau. The chemiluminescence signal for HRP -linked antibodies used in western blotting is detected using a Carestream Image Station and blot densitometry for pSer396 and beta-actin are analyzed using Image J (NIH).
[0510] In a further example, the activity of a candidate compound can be measured by ELISA by adding the lysate mentioned above onto total Tau-coated plates and detected with a specific pSer396 antibody. Colorimetric detection of ELISA signal is performed by Cytation3 plate reader (Biotek).
[0511] To further illustrate this disclosure, the following examples are included. The examples should not, of course, be construed as specifically limiting the disclosure. Variations of these examples within the scope of the claims are within the purview of one skilled in the art and are considered to fall within the scope of the disclosure as described, and claimed herein. The reader will recognize that the skilled artisan, armed with the present disclosure, and skill in the art is able to prepare and use the disclosure without exhaustive examples.
EXAMPLES
Compound preparation
[0512] 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 functionality related to the compounds claimed 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.
[0513] 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 , 2nd Ed., John Wiley & Sons (1999) (incorporated herein by reference in its entirety) and the like.
[0514] 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 P. Wuts Greene 's Protective Groups in Organic Synthesis, 5th Ed., John Wiley & Sons (2014), incorporated herein by reference in its entirety. [0515] Trademarks used herein are examples only and reflect illustrative materials used at the time of the disclosure. 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, and they are not intended to be limiting, but are merely an illustration of how a skilled artisan may choose to perform one or more of the embodiments of the disclosure.
[0516] (Ή) nuclear magnetic resonance spectra (NMR) were measured in the indicated solvents on a Bruker NMR spectrometer (A vance TM DRX300, 300 MHz for Ή or Avance TM DRX500, 500 MHz for Ή) or Varian NMR spectrometer (Mercury 400BB, 400 MHz for Ή). 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.
[0517] The following abbreviations have the indicated meanings:
Boc = / -butyloxycarbonyl group
brine = saturated aqueous sodium chloride
CDCh = deuterated chloroform
DCE = dichloroethane
DCM = dichloromethane
DHP = dihydropyran
DIAD = diisopropyl azodicarboxylate
DIPEA = N,N-diisopropylethylamine
DMA = dimethylacetamide
DMF = N,N-dimethylformamide
DMSO-r/e = deuterated dimethylsulfoxide
ESIMS = electron spray mass spectrometry
EtOAc = ethyl acetate
HATU = l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
ISCO = Teledyne ISCO, Inc brand CombiFlash® Rf 200
KOAc = potassium acetate
LAH = lithium aluminum hydride
LC/MS = Liquid chromatography-mass spectrometry
MeCN = acetonitrile Me OH = methanol
Ms = mesyl or methanesulfonyl group
MW = microwave irradiation
NaBH(OAc)3 = sodium triacetoxyborohydride
NaCNB¾ = sodium cyanoborohydride
NaHS03 = sodium bisulfite
NIS = N-iodosuccinimide
NMR = nuclear magnetic resonance
ON = overnight
Pd/C = palladium on carbon
Pd(dba)3 = tris(dibenzylideneacetone)dipalladium(0)
Pd(dppf)Cl2 = 1.1 '-bis(diphcnylphosphino)fcrroccnc-palladium(//)dichloridc
Pd(PPli3)2Cl2 = bis(triphenylphosphine)palladium(II) dichloride
Pd(PPli3)4 = tetrakis(triphenylphosphine)palladium(0)
Pd(t-Bu3P)2 = Bis(tri-/er/-butylphosphine)palladium(0)
PE = petroleum ether
r.t. = room temperature
TEA = triethylamine
TFA = trifluoroacetic acid
THF = tetrahydrofuran
THP = tetrahydropyranyl
TLC = thin layer chromatography
TMS = trimethylsilyl group
TsCl = p-toluenesulfonyl chloride
pTsOH = p-toluenesulfonic acid or tosylic acid
xanthphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
[0150] The following example schemes are provided for the guidance of the reader, and collectively represent an example method 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 same numberings in other sections of the application. Unless otherwise indicated, all variables are as defined above.
General procedures
[0151] Compounds of Formula (I) of the present disclosure can be prepared as depicted in Scheme 1.
Figure imgf000086_0001
Scheme 1
[0152] Scheme 1 describes a method for preparation of pyrazole intermediate (V) by first iodination using NIS in the presence of TFA to give pyrazole (II) followed by protection of the pyrazole nitrogen by THP. The methyl ester of pyrazole (III) was then hydrolyzed to acid (IV) followed by coupling with N,O-dimethylhydroxylamine to form the Weinreb amide (V).
[0153] In other embodiments, compounds of Formula (I) of the present disclosure can be prepared as depicted in Scheme 2.
Figure imgf000087_0001
[0154] Scheme 2 describes a method for preparation of pyrazole intermediate (XIX) by first iodination using NIS in the presence of TFA to give pyrazole (VII) followed by protection of the pyrazole nitrogen by THP. The protected iodo pyrazole (VIII) was coupled to TMS protected acetylene in the presence of catalytic palladium and copper to give alkyne substituted pyrazole (IX). The TMS protecting group was removed using Li OH followed by Sonogashira coupling of the terminal alkyne with various R2-bromines to produce pyrazole (XIX).
[0155] In other embodiments, compounds of Formula (I) of the present disclosure can be prepared as depicted in Scheme 3.
Figure imgf000088_0001
Scheme 3
[0156] Scheme 3 describes methods for the preparation of pyrazole intermediates
(XIV), (XVIII), and (XXXI) from pyrazole intermediate (III). To prepare alkyne substituted pyrazole amides (XIV), Sonogashira cross-coupling reaction was used to couple intermediate (III) with various substituted alkynes to form (XI) followed by hydrolysis of the ester to give the acid (XII). Acid (XII) was coupled with various amines followed by deprotection to yield the final pyrazole (XIV) derivatives. To prepare alkene substituted pyrazole amides (XVIII), various substituted alkenes were coupled to pyrazole intermediate (III) using the Heck reaction to form
(XV) followed by hydrolysis of the ester to give the acid (XVI). Acid (XVI) was coupled with various amines followed by deprotection to yield the final pyrazole (XVIII) derivatives. To prepare substituted pyrazole amides (XXXI), various aromatic pinacol esters/boronic acids were coupled to pyrazole intermediate (III) using Suzuki coupling to form (XXVIII) followed by hydrolysis of the ester to give the acid (XXIX). Acid (XXIX) was coupled with various amines followed by deprotection to yield the final pyrazole (XXXI) derivatives.
[0157] In other embodiments, compounds of Formula (I) of the present disclosure can be prepared as depicted in Scheme 4.
Figure imgf000089_0001
[0158] Scheme 4 describes methods for the preparation of pyrazole intermediates (XXI), (XXIV), and (XXVII) from pyrazole intermediate (VIII). To prepare alkyne substituted pyrazol-3-yl-benzoimidazole (XXI), Sonogashira cross-coupling reaction was used to couple intermediate (VIII) with various substituted alkynes to form (XIX) followed by cyclization with various phenylenediamines to give the benzimidazole (XX) followed by deprotection to yield the final pyrazol-3-yl-benzoimidazole (XXI) derivatives. To prepare alkene substituted pyrazol-3-yl- benzoimidazole (XXIV), various substituted alkenes were coupled to pyrazole intermediate (VIII) using the Heck reaction to form (XXII) followed cyclization with various phenylenediamines to give the benzimidazole (XXIII) followed by deprotection to yield the final pyrazol-3-yl- benzoimidazole (XXIV) derivatives. To prepare substituted pyrazol-3-yl-benzoimidazole (XXVII), various aromatic pinacol esters/boronic acids were coupled to pyrazole intermediate (VIII) using Suzuki coupling to form (XXV) followed by cyclization with various phenylenediamines to give the benzimidazole (XXVI) followed by deprotection to yield the final pyrazol-3-yl-benzoimidazole (XXVII) derivatives. [0159] In other embodiments, compounds of Formula (I) of the present disclosure can be prepared as depicted in Scheme 5.
Figure imgf000090_0001
[0160] Scheme 5 describes methods for the preparation of pyrazole intermediates (XXXVI) and (XL) from pyrazole intermediate (XXXII). To prepare diamide pyrazole (XXXVI), The amine pyrazole (XXXII) was coupled with various acids to give XXXIII followed by hydrolysis of the ester to give the acid (XXXIV). Acid (XXXIV) was coupled with various amines followed by deprotection to yield the final diamide pyrazole (XXXVI) derivatives. To prepare amide substituted pyrazol-3-yl-benzoimidazole (XL), acid (XXXIV) was coupling with N,O- dimethylhydroxylamine to form the Weinreb amide (XXXVII) followed by reduction to the aldehyde (XXXVIII). Aldehyde (XXXVIII) was cyclized with various phenylenediamines to give the benzimidazole (XXXIX) followed by deprotection to yield the final pyrazol-3-yl- benzoimidazole (XL) derivatives.
[0161] Preparation of intermediate 3'-fluorobiphenyl-2,3-diamine (XLIV) is depicted below in Scheme 6.
Figure imgf000091_0001
Scheme 6
Step 1
[0162] A solution of 3-bromo-2-nitroaniline (XLI) (3.01 g, 13.89 mmol, 1 eq), 3- fluorophenylboronic acid (XLII) (2.33 g, 16.67 mmol, 1.2 eq), Pd(PPli3)4 (0.80 g, 0.69 mmol, 0.05 eq), and K3PO4 (4.43 g, 20.84 mmol, 1.5 eq) in a mixed solvent of dioxane (70 mL) and water (14 mL) was stirred at 95 °C for 3 h under nitrogen atmosphere. The reaction mixture was partitioned between EtOAc/water. The organic layer was separated, washed with water, brine, dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The resultant residue was purified by chromatography on silica gel (0 30% EtOAc/PE) to afford 3'-fluoro-2-nitro-[l, r-biphenyl]-3- amine (XLIII) as a red orange oil (2.96 g, 12.75 mmol, 91.8% yield). ESIMS found for Ci2HgFN202 m!z 233.1 (M+H).
Step 2
[0163] To a solution of 3'-fluoro-2-nitro-[l,T-biphenyl]-3-amine (XLIII) (2.92 g, 12.57 mmol, 1 eq) in EtOH (85 mL) was added 10% Pd/C (0.43 g) under argon atmosphere, before replacing Ar with Eh. The mixture was stirred for 4 h at room temperature. Then the mixture was filtered through Celite®, and concentrated in vacuo, the resultant residue was purified by chromatography on silica gel (0 50% EtOAc/PE) to afford 3'-fluoro-[l,r-biphenyl]-2,3-diamine (XLIV) as a white solid (1.453 g, 7.18 mmol, 57.2% yield).‘HNMR (DMSO-de, 400 MHz) 5 ppm 4.16 (s, 2H), 4.64 (s, 2H), 6.38 (dd, J=7.6Hz, J=1.6Hz, 1H), 6.51 (t, J=7.6Hz, 1H), 6.60 (d, J=6Hz, 1H), 7.11-7.26 (m, 3H), 7.48 (q, J=6.4Hz, 1H); ESIMS found for Ci2HnFN2 m!z 203.0 (M+H). [0164] The following intermediates were prepared in accordance with the procedure described in the above Scheme 6.
Figure imgf000092_0001
XLV
[0165] 3-(Thiophen-2-yl)benzene-l, 2-diamine (XLV): Brown oil (925.5 mg, 4.86 mmol, 60.9% yield). ESIMS found C10H10N2S m!z 191.1 (M+H).
Figure imgf000092_0002
XL VI
[0166] 3'-Fluoro-[l,l'-biphenyl]-3, 4-diamine (XL VI): Yellow solid (2.14 g, 10.59 mmol, quantitative yield). ESIMS found C12H11FN2 m!z 203.1 (M+H).
[0167] Preparation of intermediate 2-(l-methylpiperidin-4-yl)pyridine-3, 4-diamine (L) is depicted below in Scheme 7.
Figure imgf000092_0003
Step 1
[0168] A solution of 2-chloro-3-nitropyridin -4-amine (XL VII) (2.68 g, 15.46 mmol, 1 eq), l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6-tetrahydropyridine (XL VIII) (4.14 g, 18.55 mmol, 1.2 eq), Pd(PPh3)4 (893 mg, 0.77 mmol, 0.05 eq), and K3P04 (4.92 g, 23.19 mmol, 1.5 eq) in a mixed solvent of dioxane (141 mL) and water (14.1 mL) was stirred at 95°C for overnight under nitrogen atmosphere. The reaction mixture was partitioned between EtO Ac/water. The organic layer was separated, washed with water, brine, dried over anhydrous Na2S04, fdtered and concentrated in vacuo. The resultant residue was purified by chromatography on silica gel (100% CHC13 4% 7N NH3 in MeOH/CHCl3) to afford r-methyl-3-nitro-r,2',3',6'- tetrahydro-[2,4'-bipyridin]-4-amine (XLIX) as a yellow solid (1.2721 g, 5.70 mmol, 36.9% yield). ESIMS found for CnHi4N402 m!z 235.1 (M+H).
Step 2
[0169] To a solution of r-methyl-3-nitro-l',2',3',6'-tetrahydro-[2,4'-bipyridin]-4- amine (XLIX) (1.355 g, 5.79 mmol, 1 eq) in EtOH (38.6 mL) was added 10% Pd/C (170 mg) under argon atmosphere, before replacing Ar with Eh. The mixture was stirred for 72 h at room temperature. Then the mixture was fdtered through Celite®, and concentrated in vacuo, the resultant residue was purified by chromatography on silica gel (0 10% 7N NEE in MeOH/CHCh) to afford 2-(l-methylpiperidin-4-yl)pyridine-3, 4-diamine (L) as an off-white solid (184.1 mg, 0.89 mmol, 15.4% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 1.58 (br d, .7=12.35 Hz, 2 H), 1.74 (qd, •7=12.35, 3.57 Hz, 2 H), 1.93 - 2.02 (m, 2 H), 2.16 (s, 3 H), 2.67 (tt, 7=11.53, 3.57 Hz, 1 H), 2.81 (br d, 7=11.25 Hz, 2 H), 4.19 (s, 2 H), 5.22 (s, 2 H), 6.30 (d, 7=5.21 Hz, 1 H), 7.46 (d, 7=4.94 Hz, 1 H); ESIMS found for CnHi8N4 m!z 207.2 (M+H).
[0170] Preparation of intermediate 3-(5-fluorothiophen-2-yl)benzene-l, 2-diamine (LIV) is depicted below in Scheme 8.
Figure imgf000093_0001
Scheme 8
Step 1
[0171] A solution of 2-bromo-6-nitroaniline (LI) (800 mg, 3.67 mmol, 1.0 eq), 2-(5- fluorothiophen-2-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (LII) (1.0 g, 4.4 mmol, 1.2 eq), Pd(PPh3)4 (268 mg, 0.37 mmol, 0.10 eq) and CS2CO3 (2.39 g, 7.34 mmol, 2.0 eq) in dioxane (20 mL) and water (4 mL) was de-gassed and then heated to 100°C under N2 for 3 h. TLC (PE:EtOAc=l : l) showed the starting material was consumed completely. The mixture was concentrated in vacuum to give a residue, which was purified by column chromatography (10% EtOAc/PE) to afford the 2-(5-fluorothiophen-2-yl)-6-nitroaniline (LIII) (540 mg, 2.27 mmol, 61.7% yield). ESIMS found for C10H7FN2O2S m!z 239.1 (M+H). Step 2
[0172] To a mixture of 2-(5-fluorothiophen-2-yl)-6-nitroaniline (LIII) (500 mg, 2.09 mmol) in EtOAc (20 mL) was added Zn power (410 mg, 6.27 mmol) and cooled to 0~5°C. HO Ac (3 mL) was then added dropwise and the mixture was stirred at room temperature for 1 h. LC/MS showed the starting material was consumed completely. The mixture was fdtered through Celite®, washed with EtOAc (5 x 50 mL), the organic phase was washed with NaHC03 (50 mL x 2), brine (50 mL), water, then concentrated to dryness to afford 3-(5-fluorothiophen-2-yl)benzene-l,2- diamine (LIV) (400 mg, 1.92 mmol, 91.9% yield). ¾ NMR (DMSO-rfe, 400 MHz) d ppm 4.42 (brs, 2H), 4.70 (brs, 2H), 6.45 (s, 1H), 6.46 (s, 1H), 6.56 (t, J=4.4Hz, 1H), 6.71 (dd, J=2.8Hz, =4Hz, 1H), 6.83 (t, .7=4 Hz. 1H); ESIMS found for C10H9PN2S mlz 209.0 (M+H).
[0173] Preparation of intermediate 2-(4-methylpiperazin-l-yl)pyridine-3, 4-diamine (LVII) is depicted below in Scheme 9.
Figure imgf000094_0001
Scheme 9
Step 1
[0174] A mixture of 1-methylpiperazine (LV) (20 mL) and 2-chloro-3-nitropyridin- 4-amine (XL VII) (4.0 g, 23.1 mmol, 1.0 eq) was stirred at 150°C for 1 h under microwave irradiation. The reaction mixture was diluted with water (100 mL) and fdtered, the cake was washed with water (30 mL x 3), dried in vacuo to give 2-(4-methylpiperazin-l-yl)-3-nitropyridin-4-amine (LVI) as a yellow solid (4.0 g, 16.9 mmol, 73.2% yield). ESIMS found for C10H15N5O2 mlz 238.1 (M+H).
Step 2
[0175] A mixture of 2-(4-methylpiperazin-l-yl)-3-nitropyridin-4-amine (LVI) (4.0 g, 16.9 mmol, 1.0 eq) and 10% Pd/C (0.5 g) in MeOH (200 mL) was stirred under 50 psi of ¾ at room temperature overnight. The reaction was monitored by TLC. The mixture was fdtered through Celite®, and the fdtrate was concentrated in vacuo to give 2-(4-methylpiperazin-l-yl)pyridine-3,4- diamine (LVII) as a black solid (3.13 g, 89.6% yield). ¾ NMR (DMSO-ri6, 400 MHz) d ppm 2.74 (s, 4H), 3.12 (s, 3H), 3.44 (brs, 4H), 5.19 (brs, 4H), 6.60 (d, J=6.4Hz, 2H); ESIMS found C10H17N5 mlz 208.1 (M+H).
[0176] Preparation of intermediate [3, 3'-bipyridine]-4, 5-diamine (LXII) is depicted below in Scheme 10.
Figure imgf000095_0001
Scheme 10
Step 1
[0177] A mixture of 3-nitropyridin-4-amine (LVIII) (10 g, 71.94 mmol) and HOAc (120 mL) was added to a sealed tube followed by addition of NaOAc (29.5 g, 93.52 mmol) and dropwise addition of bromine (4.7 mL, 359.7 mmol) under stirring. The sealed tube was heated at 100°C for 28 h until TLC showed consumption of starting material. The reaction mixture was concentrated to obtain a solid which was dissolved in water, basified with NaHCCL and extracted with EtOAc. The combined organic extracts were dried and concentrated to produce 3-bromo-5- nitropyridin-4-amine (LIX) as a yellow solid (12.0 g, 55 mmol, 76.5% yield). Ή NMR (DMSO- de) d ppm 9.19 (s, 1H), 8.58 (s, 1H); ESIMS found for CsILBrNsCE mlz 217, 219 (M+, M+2).
Step 2
[0178] A solution of 3-bromo-5-nitropyridin-4-amine (LIX) (6 g, 26 mmol, 1 eq), pyridin-3-ylboronic acid (LX) (3.54 g, 29 mmol, 1.1 eq), aqueous 1 N Na2CC>3 solution (78 mL) and 1,4-dioxane (150 mL) was degassed with argon thrice. Pd(PPli3)2Cl2 (927 mg, 5 mmol%) was added to the reaction and the solution was refluxed for 15 h until TLC showed the reaction was complete. The reaction was passed through a pad of Celite® and then concentrated under reduced pressure. The reaction mixture was concentrated, and the residue was taken up in EtOAc. The organic extract was washed with water, dried and concentrated under vacuum. The crude product was purified on a silica gel column (100% EtOAc 2% MeOH:DCM) to give 5-nitro-3,3'- bipyridin-4-amine (LXI) as a yellow solid (5 g, 23.1 mmol, 88.8% yield). ¾ NMR (CDC13, 500 MHz,) d ppm 9.31 (s, 1H), 8.80-8.79 (m, 1H), 8.70 (s, 1H), 8.23 (s, 1H), 7.80-7.73 (m, 1H),7.52- 7.48 (m, 1H). ESIMS found CIOH8N402 mlz 216.95 (M+H).
Step 3
[0179] To a solution of 5-nitro-3,3'-bipyridin-4-amine (LXI) (5 g, 23 mmol) in MeOH
(20 mL) was added 10% Pd/C. The solution was purged with hydrogen and stirred at room temperature under hydrogen for 15 h. The suspension was fdtered through Celite® and the concentrated under vacuum to produce 3, 3'-bipyridine-4, 5-diamine (LXII) as off-white solid (3.3 g, 17.7 mmol, 77.0% yield). ¾ NMR (DMSO-d6, 500 MHz,): 5 ppm 8.63-8.53 (m, 1H), 7.90-7.83 (m, 1H), 7.75 (s, 1H), 7.58 (s, 1H), 7.48-7.43 (m, 2H), 6.13 (br s, 2H), 5.31 (br s, 2H). ESIMS found C10H10N4 mlz 187.10 (M+H).
[0180] The following compound was prepared in accordance with the procedure described in the above Scheme 10.
Figure imgf000096_0001
LXII
[0181] 5-(3-Fluorophenyl)pyridine-3, 4-diamine (LXII): Off-white solid, (76% yield), ¾ NMR (CDC13, 500 MHz) d ppm 4.72 (s, 2H), 5.07 (s, 2H), 7.17-7.23 (m, 3H), 7.44 (s, 1H), 7.48-7.52 (m, 1H), 7.68 (s, 1H); ESIMS found CnHi0FN3 mlz 204.1 (M+H).
[0182] Preparation of intermediate 5-(4-methylpiperazin-l-yl)pyridine-3, 4-diamine (LXIV) is depicted below in Scheme 11.
Figure imgf000096_0002
TJX I.XIII LXIV
Scheme 11 Step 1
[0183] A solution of 3-bromo-5-nitropyridin-4-amine (LIX) (618 mg, 2.83 mmol) in 1-methylpiperazine (LV) (1 mL, 8.51 mmol) was heated at 140°C overnight. The reaction was poured into an EtOAc/water mixture; the organic layer was separated, dried over MgSCL and concentrated under vacuum. The crude product was purified on a silica gel column (0 3% 7N N¾ in MeOH/CHCL) to give 3-(4-methylpiperazin-l-yl)-5-nitropyridin-4-amine (LXIII) as a yellow solid (382 mg, 1.61 mmol, 56.7% yield). ¾ NMR (CDCL, 500 MHz,) d ppm 2.20 (s, 3H), 2.35-2.37 (m, 4H), 4.52-3.54 (m, 4H), 5.96 (s, 1H), 7.42 (s, 2H), 8.78 (s, 1H); ESIMS found C10H15N5O2 m!z 238.0 (M+H).
Step 2
[0184] To a solution of 3-(4-methylpiperazin-l-yl)-5-nitropyridin-4-amine (LXIII) (382 mg, 1.61 mmol) in MeOH (11 mL) was added 10% Pd/C. The solution was purged with hydrogen and stirred at room temperature under hydrogen for 4 h. The suspension was filtered through Celite® and then concentrated under vacuum to produce 5-(4-methylpiperazin-l- yl)pyridine-3,4-diamine (LXIV) as purple solid (330 mg, 1.59 mmol, 99% yield). ¾ NMR (DMSO-d6, 500 MHz,): d ppm 2.18 (s, 3H), 2.34-2.36 (m, 4H), 3.13-3.16 (m, 4H), 3.89 (s, 2H), 5.20 (s, 2H), 5.94 (s, 1H), 7.31 (s, 1H); ESIMS found C10H17N5 m!z 208.1 (M+H).
[0185] Preparation of intermediate 4-((l-methylpiperidin-4-yl)oxy)benzene-l,2- diamine (LXVIII) is depicted below in Scheme 12.
Figure imgf000097_0001
Scheme 12
Step 1
[0186] To a solution of 4-amino-3-nitrophenol (LXV) (1.0 g, 6.49 mmol), 1- methylpiperidin-4-ol (LXVI) (0.971 g, 8.43 mmol) and triphenylphosphine (2.212 g, 8.43 mmol) in THF (10 mL) at 0°C was added DIAD (1.892 mL, 9.73 mmol). The mixture was stirred from 0°C to room temperature over 16 h and then poured into water and extracted with CHCh (2 X). The combined organic layers were dried, filtered and concentrated. The crude product was purified on a silica gel column (0 20% MeOH/DCM) to give 4-((l-methylpiperidin-4-yl)oxy)-2-nitroaniline (LXVII) as a brown oil (300 mg, 1.19 mmol, 18.4% yield). ESIMS found C12H17N3O3 mlz 252.1 (M+H).
Step 2
[0187] To a solution of 4-((l-methylpiperidin-4-yl)oxy)-2-nitroaniline (LXVII) (266 mg, 1.06 mmol) in MeOH (10 mL) was added 10% Pd/C (5.63 mg) under nitrogen. The solution was purged with hydrogen and stirred at room temperature under hydrogen for 3 h. The suspension was filtered through Celite® and the concentrated under vacuum to produce 4-((l-methylpiperidin- 4-yl)oxy)benzene-l, 2-diamine (LXVIII) as a deep brown foam (214 mg, 0.967 mmol, 91.3% yield). ESIMS found C12H19N3O mlz 222.1 (M+H).
[0188] Preparation of intermediate 5-((l-(/ert-butoxycarbonyl)piperidin-4- yl)oxy)nicotinic acid (LXXII) is depicted below in Scheme 13.
Figure imgf000098_0001
LXIX LXX LXXI LXXII
Scheme 13
Step 1
[0189] A solution of methyl 5-hydroxynicotinate (LXIX) (3.4 g, 22.2 mmol), tert- butyl 4-((methylsulfonyl)oxy)piperidine-l-carboxylate (LXX) (7.2 g, 25.8 mmol) and CS2CO3 (2.212 g, 8.43 mmol) in DMF (30 mL) was stirred at 90°C for 24 h. The reaction was then partitioned between DMF and EtOAc. The solution was washed with water, brine, dried, filtered and concentrated under vacuum. The crude product was purified on a silica gel column (0 50% EtOAc/hexane) to give methyl 5-((l-(/ert-butoxycarbonyl)piperidin-4-yl)oxy)nicotinate (LXXI) as a colorless oil (3.9 g, 11.6 mmol, 52.2% yield). ESIMS found C17H24N2O5 mlz 337.1 (M+H). Step 2
[0190] To a solution of methyl 5-((l-(/ert-butoxycarbonyl)piperidin-4- yl)oxy)nicotinate (LXXI) (3.5 g, 10.4 mmol) in THF (8 mL) and MeOH (8 mL) was added 4 N LiOH in water (7.5 mL, 30.0 mmol). The solution was stirred at room temperature for 1.5 h. The pH was adjusted 1 -2 with 10% HC1 and concentrated under vacuum. The resulting solid was fdtered and dried to produce 5-((l-(/ert-butoxycarbonyl)piperidin-4-yl)oxy)nicotinic acid (LXXII) as a white solid (2.94 g, 9.12 mmol, 87.7% yield).‘H NMR (499 MHz, DMSO-tT,) d ppm 1.41 (s, 9 H), 1.50 - 1.59 (m, 2 H), 1.88 - 1.96 (m, 2 H), 3.20 (br t, 7=9.47 Hz, 2 H), 3.63 - 3.71 (m, 2 H), 4.76 (tt, 7=7.96, 3.84 Hz, 1 H), 7.79 (dd, .7=2.74, 1.65 Hz, 1 H), 8.52 (d, .7=3.02 Hz, 1 H), 8.67 (d, .7=1.65 Hz, 1 H), 13.44 (br s, 1 H); ESIMS found C16H22N2O5 mlz 323.1 (M+H).
[0191] The following compound was prepared in accordance with the procedure described in the above Scheme 13.
Figure imgf000099_0001
LXXIII
[0192] 3-(( 1 -(/ert-Butoxycarbonyl)piperidin-4-yl)oxy)-5 -fluorobenzoic acid
(LXXIII): White solid, (1.7 g, 5.01 mmol, 98.3% yield), ¾ NMR (499 MHz, DMSO-7,) d ppm 1.40 (s, 9 H), 1.53 (dtd, 7=12.73, 8.52, 8.52, 3.98 Hz, 2 H), 1.90 (ddd, 7=9.54, 6.11, 3.02 Hz, 2 H), 3.21 (br t, .7=9.06 Hz, 2 H), 3.60 - 3.68 (m, 2 H), 4.69 (tt, 7=7.82, 3.70 Hz, 1 H), 7.20 - 7.28 (m, 2 H), 7.32 (s, 1 H), 10.37 (br s, 1 H); ESIMS found C17H22FNO5 mlz 340.1 (M+H).
[0193] Preparation of intermediate 6-(2-(pyrrolidin-l-yl)ethoxy)pyridin-3 -amine (LXXVII) is depicted below in Scheme 14.
Figure imgf000099_0002
Step 1
[0194] A solution of 2-chloro-5-nitropyridine (LXXIV) (5.0 g, 31.5 mmol, 1 eq), 2- (pyrrolidin-l-yl)ethan-l-ol (LXXV) (4.0 g, 34.7 mmol, 1.1 eq), and K2CO3 (6.5 g, 47.1 mmol, 1.5 eq) in DMF (30 mL) was stirred at 100°C for 15 h. The reaction was then partitioned between water and CHCI3. The organic layer was washed with water, brine, dried, fdtered and concentrated under vacuum. The crude product was purified on a silica gel column (0 10% MeOH/CHCT) to give 5- nitro-2-(2-(pyrrolidin-l-yl)ethoxy)pyridine (LXXVI) as a reddish brown solid (5.2 g, 21.9 mmol, 69.5% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 1.63 - 1.70 (m, 4 H), 2.49 - 2.52 (m, 4 H), 2.80 (t, .7=5.90 Hz, 2 H), 4.49 (t, 7=5.76 Hz, 2 H), 7.03 (d, 7=9.06 Hz, 1 H), 8.46 (dd, 7=9.19, 2.88 Hz, 1 H), 9.07 (d, 7=2.74 Hz, 1 H); ESIMS found C11H15N3O3 mlz 238.0 (M+H).
Step 2
[0195] To a solution of 5-nitro-2-(2-(pyrrolidin-l-yl)ethoxy)pyridine (LXXVI) (2.6 g, 11.0 mmol) in MeOH (30 mL) was added 10% Pd/C (1.0 g) under nitrogen. The solution was purged with hydrogen and stirred at room temperature under hydrogen for 19 h. The suspension was filtered through Celite® and the concentrated under vacuum to produce 6-(2-(pyrrolidin-l- yl)ethoxy)pyridin-3 -amine (LXXVII) as a reddish brown solid (2.1 g, 10.1 mmol, 92.5% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 1.62 - 1.70 (m, 4 H), 2.45 - 2.49 (m, 3 H), 2.70 (t, 7=6.04 Hz, 2 H), 4.18 (t, 7=6.17 Hz, 2 H), 4.70 (s, 2 H), 6.52 (d, 7=8.51 Hz, 1 H), 6.99 (dd, 7=8.65, 2.88 Hz, 1 H), 7.48 (d, 7=2.47 Hz, 1 H); ESIMS found C11H17N3O mlz 208.1 (M+H).
[0196] The following compounds were prepared in accordance with the procedure described in the above Scheme 14.
Figure imgf000100_0001
LXXVIII
[0197] 6-(Pyrrolidin-l-yl)pyridin-3 -amine (LXXVIII): Yellow solid, (1.3 g). ESIMS found C9H13N3 mlz 164.0 (M+H).
Figure imgf000100_0002
LXXIX
[0198] 6-(3,3-Difluoropyrrolidin-l-yl)pyridin-3-amine (LXXIX): Red solid, (1.05 g, 84% yield for 2 steps). ESIMS found C9H11F2N3 mlz 200.1 (M+H).
Figure imgf000101_0001
LXXX
[0199] 6-(Piperidin-l-yl)pyridin-3 -amine (LXXX): Purple oil, (840 mg, 4.74 mmol,
98% yield). ESIMS found C10H15N3 mlz 178.0 (M+H).
Figure imgf000101_0002
LXXXI
[0200] 4-(2-(Pyrrolidin-l-yl)ethoxy)aniline (LXXXI): Prepared starting from 4- nitrophenol and l-(2-chloroethyl)pyrrolidine. Yellow oil, (500 mg, 2.42 mmol, 88% yield). ESIMS found C12H18N2O mlz 207.0 (M+H).
Figure imgf000101_0003
LXXXII
[0201] 6-(2-((Tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-3-amine (LXXXII): Yellow oil, (164 mg, 0.69 mmol, 17.2% yield for 2 steps). ESIMS found C12H18N2O3 mlz 239.1 (M+H).
[0202] Preparation of intermediate tert- butyl 4-((5-aminopyridin-2- yl)oxy)piperidine-l-carboxylate (LXXXV) is depicted below in Scheme 15.
Boc
Figure imgf000101_0004
Scheme 15
Step 1
[0203] To a solution NaH (600 mg, 24.8 mmol, 1.1 eq) in THF (30 mL) was added tert- butyl 4-hydroxypiperidine-l-carboxylate (LXXXIII) (5.0 g, 24.8 mmol, 1.1 eq) in THF (20 mL) dropwise at 0°C. 2-Chloro-5-nitropyridine (LXXIV) (3.58 g, 22.6 mmol, 1 eq) was then added and stirred at room temperature for 10 h. The reaction was then partitioned between water and EtOAc. The organic layer separated and washed with water, brine, dried, fdtered and concentrated under vacuum. The crude product was purified on a silica gel column (0 20% EtO Ac/hexane) to give tert- butyl 4-((5-nitropyridin-2-yl)oxy)piperidine-l-carboxylate (LXXXIV) as a pale yellow solid (4.61 g, 14.3 mmol, 63.1% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 1.41 (s, 9 H), 1.55 - 1.67 (m, 2 H), 1.92 - 2.03 (m, 2 H), 3.20 (br s, 2 H), 3.64 - 3.74 (m, 2 H), 5.32 (tt, 7= 8.37, 3.98 Hz, 1 H), 7.02 (d, .7=9.33 Hz, 1 H), 8.47 (dd, 7=9.19, 2.88 Hz, 1 H), 9.07 (d, 7=3.02 Hz, 1 H); ESIMS found C15H21N3O5 mlz 324.1 (M+H).
Step 2
[0204] To a solution of tert- butyl 4-((5-nitropyridin-2-yl)oxy)piperidine-l- carboxylate (LXXXIV) (2.6 g, 8.0 mmol) in MeOH (20 mL) was added 10% Pd/C (500 mg) under nitrogen. The solution was purged with hydrogen and stirred at room temperature under hydrogen for 3 days. The suspension was filtered through Celite® and the concentrated under vacuum to produce /ert-butyl 4-((5-aminopyridin-2-yl)oxy)piperidine-l-carboxylate (LXXXV) as a gray solid (2.31 g, 7.87 mmol, 97.9% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 1.40 (s, 9 H), 1.42 - 1.51 (m, 2 H), 1.83 - 1.91 (m, 2 H), 3.07 - 3.19 (m, 2 H), 3.62 - 3.71 (m, 2 H), 4.72 (s, 2 H), 4.90 - 4.98 (m, 1 H), 6.51 (d, 7=8.51 Hz, 1 H), 6.98 (dd, 7=8.78, 3.02 Hz, 1 H), 7.48 (d, 7=2.47 Hz, 1 H); ESIMS found C15H23N3O3 mlz 294.1 (M+H).
[0205] The following compound was prepared in accordance with the procedure described in the above Scheme 15.
Figure imgf000102_0001
LXXXVI
[0206] 6-((l-Methylpiperidin-4-yl)oxy)pyridin-3 -amine (LXXXVI): Light grey solid, (2.09 g, 10.1 mmol, 95.3% yield), ¾ NMR (499 MHz, DMSO-7,) d ppm 1.58 (dtd, 7=12.62, 9.19, 9.19, 3.84 Hz, 2 H), 1.85 - 1.92 (m, 2 H), 2.11 (br t, 7=9.61 Hz, 2 H), 2.16 (s, 3 H), 2.57 - 2.66 (m, 2 H), 4.69 (s, 2 H), 4.74 (tt, 7=8.75, 4.15 Hz, 1 H), 6.49 (d, 7=9.06 Hz, 1 H), 6.97 (dd, 7=8.78, 3.02 Hz, 1 H), 7.47 (d, 7=2.20 Hz, 1 H); ESIMS found C11H17N3O mlz 208.0 (M+H).
[0207] Preparation of intermediate 5-(piperidin-l-ylmethyl)pyridin-3-amine (XC) is depicted below in Scheme 16.
Figure imgf000103_0001
Step 1
[0208] A solution of 5-nitronicotinaldehyde (LXXXVII) (360 mg, 2.37 mmol, 1 eq) and piperidine (LXXXVIII) (0.3 mL, 3.04 mmol, 1.3 eq) in DCE (6 mL) was stirred at room temperature for 25 min. NaBH(OAc)3 was added and the reaction was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous NaHCCE and then extracted with 3 X DCM. The aqueous layer was washed with water, brine, dried, fdtered and concentrated under vacuum. The crude product was purified on a silica gel column (0 40% EtO Ac/hexane) to give 3-nitro-5-(piperidin-l-ylmethyl)pyridine (LXXXIX) as a colorless oil (280 mg, 1.27 mmol, 53.4% yield). ¾ NMR (499 MHz, DMSO-ri6) d ppm 1.37 - 1.43 (m, 2 H), 1.51 (quin, J= 5.56 Hz, 4 H), 2.36 (br s, 4 H), 3.62 (s, 2 H), 8.45 (t, .7=1.92 Hz, 1 H), 8.87 (d, .7=1.65 Hz, 1 H), 9.25 (d, 7=2.47 Hz, 1 H); ESIMS found C11H15N3O2 mlz 222.1 (M+H).
Step 2
[0209] To a solution of 3-nitro-5-(piperidin-l-ylmethyl)pyridine (LXXXIX) (270 mg, 1.22 mmol) in MeOH (10 mL) was added 10% Pd/C (100 mg) under nitrogen. The solution was purged with hydrogen and stirred at room temperature under hydrogen for 16 h. The suspension was filtered through Celite® and the concentrated under vacuum to produce 5-(piperidin-l- ylmethyl)pyridin-3 -amine (XC) as a white solid (204 mg, 1.07 mmol, 87.4% yield). ESIMS found C11H17N3 mlz 192.0 (M+H).
[0210] The following compound was prepared in accordance with the procedure described in the above Scheme 16.
Figure imgf000103_0002
[0211] 6-(Pyrrolidin-l-ylmethyl)pyridin-3 -amine (XCI): White solid, (133 mg, 0.75 mmol, 90.1% yield). ESIMS found C10H15N3 mlz 178.0 (M+H). [0212] Preparation of intermediate 4,4-diethoxy-l-methylpiperidin-3-amine (XCIV) is depicted below in Scheme 17.
Figure imgf000104_0001
Scheme 17
Step 1
[0213] To a solution of 1 -methylpiperidin-4-one (XCII) (5.066 g, 44.77 mmol, 1 eq) in EtOH (45 mL) was added NH2OH (3.422 g, 49.25 mmol, 1.1 eq). The reaction was stirred at reflux overnight. The solvent was evaporated under vacuum and the residue was dissolved in 7N N¾ in MeOH (20 mL). The solvent was again evaporated under vacuum and the residue was washed with CHCE. The solid was filtered and dried to produce 1 -methylpiperidin-4-one oxime (XCIII) as a white solid (5.17 g, 40.33 mmol, 90.1%). ESIMS found C6Hi2N20 m!z 129.0 (M+H).
Steps 2-3
[0214] To a solution of l-methylpiperidin-4-one oxime (XCIII) (2.02 g, 15.76 (mmol, 1 eq) in THF (78 mL) was added TsCl (3.30 g, 17.33 mmol, 1.1 eq) followed by K2CC>3 (5.27 g, 38.12 mmol, 2.2 eq). The reaction was stirred at room temperature overnight. The solution was first filtered to remove any solids and then evaporated under vacuum. The residue was dissolved in EtOH (50 mL) and added dropwise to a solution of KOEt in EtOH [formed by dissolving K metal (1.23 g, 31.51 mmol, 2 eq) in EtOH (50 mL)] followed by Na2S04 (8.95 g, 63.02 mmol, 4 eq)]. The reaction was stirred at room temperature for 1 h and then 60°C for 1 h. The reaction was filtered, and the solution concentrated under vacuum. The residue was purified on a silica gel column (0 2.5% 7N N¾ in MeOH/CHCT) to produce 4,4-diethoxy- 1- methylpiperidin-3-amine (XCIV) as a golden liquid (1.75 g, 8.63 mmol, 54.8% yield for 2 steps). ESIMS found CI0H22N2O2 m!z 203.0 (M+H). [0215] Preparation of intermediate 3-bromo-5-((3,3-difluoropyrrolidin-l- yl)methyl)pyridine (XCVII) is depicted below in Scheme 18.
Figure imgf000105_0002
xcv XCVII
Scheme 18
Steps 1
[0216] To a mixture of 5-bromopyridine-3-carbaldehyde (XCV) (6.00 g, 32.26 mmol, 1.0 eq), 3,3-difluoropyrrolidine (XCVI) (5.56 g, 38.71 mmol, 1.20 eq) and TEA (5.39 mL, 38.71 mmol, 1.2 eq) in DCE (200 mL) was stirred at room temperature for 30 min, then added sodium triacetoxyborohydride (10.25 g, 48.38 mmol, 1.50 eq) in one portion at room temperature under N2. The mixture was stirred at room temperature for 6 h. TLC showed the reaction was complete. The reaction was quenched with INNaOH (100 mL), extracted with DCE (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried and concentrated. The residue was purified by silica gel chromatography (column height: 50 mm, diameter: 50 mm, 300-400 mesh silica gel (0 5% MeOH/DCM) to give 3-bromo-5-((3,3-difluoropyrrolidin-l-yl)methyl) pyridine (XCVII) as a yellow oil (8.00 g, 28.9 mmol, 89.5% yield). 1H NMR (CDCh, 400 MHz) d ppm 2.30 (spt, =7.2Hz. 2H), 2.75 (t, =6.8Hz, 2H), 2.91 (t, =13.2Hz, 2H), 7.85 (s, 1H), 8.45 (s, 1H), 8.59 (d, J= 2Hz, 1H); ESIMS found for CioHiiBrF2N2 /z 277.0 (M+H).
[0217] The following intermediates were prepared in accordance with the procedure described in the above Scheme 18.
Figure imgf000105_0001
[0218] 3-Bromo-5-(pyrrolidin-l-ylmethyl)pyridine (XCVIII): Golden liquid (1.35 g, 97% yield). ¾ NMR (399 MHz, DMSO-^e) d ppm 1.68-1.71 (m, 4H), 2.42-2.44 (m, 4H), 3.60 (s, 2H), 7.96 (s, 1H), 8.48 (d, =2Hz, 1H), 8.58 (d, =3Hz, 1H); ESIMS found for CioHi BrN2 m/z 242.2 (M+H).
Figure imgf000106_0001
XCIX
[0219] 3-Bromo-5-(piperidin-l-ylmethyl)pyridine (XCIX): Brown liquid (13.1 g, 94% yield). ‘H NMR (399 MHz, DMSO-d6) d ppm 1.36-1.39 (m, 2H), 1.46-1.51 (m, 4H), 2.31- 2.32 (m, 4H), 3.46 (s, 2H), 7.94 (s, 1H), 8.47 (d, =2Hz, 1H), 8.58 (d, J=3Hz, 1H); ESIMS found for CiiHi5BrN2 m!z 257.0 (M+H).
Figure imgf000106_0002
C
[0220] 4-((5-Bromopyridin-3-yl)methyl)morpholine (C): Brown oil (1.53 g, 5.95 mmol, 73.8 % yield). ESIMS found for CioHi3BrN20 m!z 256.8 (M+H).
Figure imgf000106_0003
Cl
[0221] / -Butyl 4-((5-bromopyridin-3-yl)methyl)piperazine-l-carboxylate (Cl): Light brown solid (1.11 g, 3.12 mmol, 38.6% yield). ESIMS found for Ci5H22BrN302 mlz 356.1 (M+H).
[0222] Preparation of intermediate 3-bromo-5-(cyclohexyloxy)pyridine (CIII) is depicted below in Scheme 19.
Figure imgf000106_0004
Scheme 19
Step 1
[0223] A mixture of 5-bromopyridin-3-ol (CII) (2.0 g, 11.49 mmol, 1 eq), tert- butyl 4-((methylsulfonyl)oxy)piperidine-l-carboxylate (LXX) (3.53 g, 12.64 mmol, 1.1 eq) and CS2CO3 (4.87 g, 14.94 mmol, 1.3 eq) in DMF (20 mL) was stirred at 80°C for 16 h. The mixture was diluted with water and then extracted with EtOAc. The organic layer was washed with water, brine, and dried over anhydrous sodium sulfate, fdtered and concentrated under vacuum. The crude product was added to a silica gel column (0 35% EtOAc/hexane) to give tert- butyl 4-((5-bromopyridin- 3-yl)oxy)piperidine-l-carboxylate (CIII) as a white solid (2.88 g, 8.06 mmol, 70.1% yield). ESIMS found for CislEiBrNzCE mlz 357.0 (M+H).
[0224] Preparation of intermediate 4-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazole -3 -carboxylic acid (CVI) is depicted below in Scheme 20.
Figure imgf000107_0001
Scheme 20
Step 1
[0225] A solution of l,2-difluoro-3-iodobenzene (CIV) (3.1 g, 12.92 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (CV) (2.63 mL, 15.50 mmol) in toluene (10 mL) was added TEA (3.60 mL, 25.8 mmol) followed by Pd(t-Bu3P)2 (132 mg, 0.258 mmol) and resulting mixture was purged with argon, then capped and heated at 80°C for overnight. The solvent was evaporated under high vacuum and the residue purified on a silica gel column (0 60% EtOAc/hexane) to produce (E)-2-(2,3-difluorostyryl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (CVI) as a light brown liquid (1.92 g, 7.22 mmol, 55.8% yield). ESIMS found C14H17BF2O2 mlz 267.1 (M+H).
[0226] Preparation of intermediate 4-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazole -3 -carboxylic acid (CIX) is depicted below in Scheme 21.
Figure imgf000107_0002
Scheme 21 Step 1
[0227] A solution of 4-nitro-lH-pyrazole-3-carboxylic acid (CVII) (commercially available from Sigma-Aldrich) (14.1 g, 89.69 mmol, 1 eq), pTsOH (1.71 g, 8.97 mmol, 0.1 eq), and DHP (CVIII) (16.26 mL, 179.4 mmol, 2 eq) in dry THF (150 mL) was refluxed overnight under Ar. The reaction was diluted with EtOAc and the organic layer was washed with IN NaOH. The aqueous phase was washed 2 X EtOAc. The aqueous phase was acidified to pH = 1 with 10% HC1 and washed 3 X EtOAc. The combined organic phases were washed with brine, dried, filtered and concentrated under vacuum give 4-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3 -carboxylic acid (CIX) as a dark brown oil (20.16 g, 83.58 mmol, 93.2% yield). ¾ NMR (499 MHz, DMSO- de) d ppm 1.54 - 1.57 (m, 2H), 1.65 - 1.68 (m, 1H), 1.95 - 1.99 (m, 2H), 2.07 - 2.10 (m, 1H), 3.63 - 3.69 (m, 1H), 3.93 - 3.96 (m, 1H), 5.53 (dd, J=2.6,9.6Hz, 1H), 9.08 (s, 1H), 13.93 (br s, 1H); ESIMS found C9H11N3O5 m/z 242.0 (M+H).
[0228] The following intermediate was prepared in accordance with the procedure described in the above Scheme 21.
Figure imgf000108_0001
[0229] Methyl 4-bromo - 1 -(tetrahydro -2H-pyran-2 -yl) - 1 H-pyrazole-3 -carboxylate (CX): Amber oil (6.01 g, 20.79 mmol, 81.8% yield). ESIMS found for CioH^Br^CE m/z 290.8 (Br81M+H).
[0230] Preparation of intermediate 4-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazole-3-carbaldehyde (CXIV) is depicted below in Scheme 22.
Figure imgf000108_0002
Step 1
[0231] A solution of methyl 4-nitro-lH-pyrazole-3-carboxylate (CXI) (commercially available from Sigma-Aldrich) (4.5 g, 26.29 mmol, 1 eq), pTsOH (500 mg, 2.62 mmol, 0.1 eq), and DHP (5.96 mL, 65.74 mmol, 2.5 eq) in dry THF (40 mL) was refluxed for 4 h under Ar. The reaction was diluted with EtOAc and the organic layer was washed with saturated aqueous NaHCCE, water, brine, dried, fdtered and concentrated under vacuum. The crude product was purified on a silica gel column (100% CHCh) to give methyl 4-nitro-l-(tetrahydro-2H-pyran-2-yl)- lH-pyrazole-3-carboxylate (CXII) as a yellow viscous oil (5.68 g, 22.25 mmol, 84.6% yield). ESIMS found C10H13N3O5 mlz 256.1 (M+H).
Step 2
[0232] To a solution of methyl 4-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3- carboxylate (CXII) (5.65 g, 22.13 mmol, 1 eq) and LiCl in EtOH (79 mL) and THF (158 mL) was added NaBHt (1.67 g, 44.27 mmol, 2 eq). The reaction was stirred at room temperature overnight. The solvent was evaporated under vacuum and the residue was partitioned between EtOAc and water. The organic layer was washed with water, brine, dried, filtered and concentrated under vacuum. The crude product was purified on a silica gel column (0 60% EtO Ac/hexane) to produce (4-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)methanol (CXIII) as a yellow oil (1.66 g, 7.31 mmol, 33.0% yield). ¾ NMR (499 MHz, DMSO-d6) d ppm 1.52 - 1.56 (m, 2H), 1.64 - 1.68 (m, 1H), 1.92 - 1.94 (m, 2H), 2.07 - 2.13 (m, 1H), 3.62 - 3.67 (m, 1H), 3.94 - 3.96 (m, 1H), 4.68 (d, J=5.9Hz, 2H), 5.25 (t, J=5.9Hz, 1H), 5.45 (dd, J=2.1Hz, J=10.0Hz, 1H), 8.97 (s, 1H); ESIMS found C9H13N3O4 mlz 228.1 (M+H).
Step 3
[0233] To a solution of oxalyl chloride (0.74 mL, 8.66 mmol, 1.2 eq) in DCM (20 mL) at -78°C was added dropwise DMSO (0.62 mL, 8.66 mmol, 1.2 eq). The solution was stirred at -78°C for 30 min. To the mixture was added dropwise a solution of (4-nitro-l-(tetrahydro-2H- pyran-2-yl)-lH-pyrazol-3-yl)methanol (CXIII) (1.64 g, 7.21 mmol, 1 eq) in DCM (16 mL). The reaction was at -78°C for 1 h. TEA was added, and the reaction was warmed to room temperature. The reaction was poured into a DCM/water mixture. The organic layer was washed with water, brine, dried, filtered and concentrated under vacuum to give 4-nitro-l-(tetrahydro-2H-pyran-2-yl)- lH-pyrazole-3-carbaldehyde (CXIV) as a light brown waxy solid (1.66 g, 7.37 mmol, 100% yield). ESIMS found C9H11N3O4 mlz 226.1 (M+H). [0234] Preparation of intermediate 3-(ethoxycarbonyl)-l-(tetrahydro-2H-pyran-2- yl)-lH-pyrazole-4-carboxylic acid (CXVII) is depicted below in Scheme 23.
Figure imgf000110_0001
Scheme 23
Step 1
[0235] A solution of ethyl 4-formyl- lH-pyrazole-3-carboxylate (CXV) (2.0 g, 11.89 mmol, 1 eq), pTsOH (230 mg, 1.19 mmol, 0.1 eq), and DHP (1.51 mL, 16.65 mmol, 1.4 eq) in dry THF (36 mL) was room temperature for 16 h under Ar. The reaction was diluted with EtOAc and the organic layer was washed with saturated aqueous NaHCCL, water, brine, dried, filtered and concentrated under vacuum. The crude product was purified on a silica gel column (0 50% EtO Ac/hexane) to give ethyl 4-formyl-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3-carboxylate (CXVI) as an amber oil (1.34 g, 5.31 mmol, 44.7% yield). *H NMR (499 MHz, DMSO-r/e) d ppm 1.33 (t, 7=7.14 Hz, 3 H), 1.50 - 1.59 (m, 2 H), 1.61 - 1.74 (m, 1 H), 1.87 - 1.98 (m, 2 H), 2.04 - 2.15 (m, 1 H), 3.62 - 3.71 (m, 1 H), 3.91 - 3.98 (m, 1 H), 4.37 (q, .7=7.14 Hz, 2 H), 5.57 (dd, 7=9.88, 2.47 Hz, 1 H), 8.62 (s, 1 H), 10.22 (s, 1 H); ESIMS found CI2HI6N204 m!z 253.1 (M+H).
Step 2
[0236] To a solution of ethyl 4-formyl-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3- carboxylate (CXVI) (796.5 mg, 3.16 mmol, 1 eq) in dioxane (13 mL) and water (3 mL) was added KMnCL (748 mg, 4.7 mmol, 1.5 eq). The reaction was stirred at room temperature for 16 h. The solution was fdtered through Celite® and the concentrated under vacuum to produce 3-
(ethoxycarbonyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-4-carboxylic acid (CXVII) as a clear glass (846.5 mg, 3.25 mmol, 99.9% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 1.24 (t, 7=7.14 Hz, 3 H), 1.47 - 1.56 (m, 2 H), 1.59 - 1.70 (m, 1 H), 1.82 - 1.95 (m, 2 H), 1.98 - 2.09 (m, 1 H), 3.55 - 3.63 (m, 1 H), 3.91 (br d, 7=10.98 Hz, 1 H), 4.18 (q, 7=6.95 Hz, 2 H), 5.28 - 5.36 (m, 1 H), 7.69 (s, 1 H).
[0237] Preparation of intermediate methyl 4-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazole-3-carboxylate (CXX) is depicted below in Scheme 24.
Figure imgf000111_0002
CXX
Scheme 24
Step 1
[0238] To a stirring suspension of methyl lH-pyrazole-3-carboxylate (CXVIII) (2.54 g, 20.14 mmol, 1 eq) and N-iodosuccinimide (4.98 g, 22.15 mmol, 1.1 eq) in MeCN (100 mL) under N2 was added TFA (0.465 mL, 6.04 mmol) and the mixture was stirred at room temperature overnight. The solvents were concentrated in vacuo, the residue partitioned between EtOAc and brine. The organic layer was separated, washed with brine solution and was dried over anhydrous Na2SC>4. The solvents were concentrated to obtain methyl 4-iodo-lH-pyrazole-3-carboxylate (CXIX) (4.35 g, 15.54 mmol, 77.2% yield). ESIMS found C5H5IN2O2 m!z 252.9 (M+H).
Step 2
[0239] A solution of methyl 4-iodo-lH-pyrazole-3-carboxylate (CXIX) (4.35 g, 17.26 mmol, 1 eq), pTsOH (328 mg, 1.73 mmol, 0.1 eq), and DHP (3.95 mL, 43.2 mmol, 2.5 eq) in dry THF (40 mL) was refluxed for 15 h under Ar. The reaction was diluted with EtOAc and the organic layer was washed with saturated aqueous NaHC03, water, brine, dried, filtered and concentrated under vacuum. The crude product was purified on a silica gel column (0 30% EtOAc/hexane) to give methyl 4-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3-carboxylate (CXX) as an amber oil (5.9 g, 17.55 mmol, 102% yield). ESIMS found C10H13IN2O3 mlz 336.7 (M+H).
[0240] The following intermediate was prepared in accordance with the procedure described in the above Scheme 24.
Figure imgf000111_0001
VIII [0241] 4-Iodo-l -(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3-carbaldehyde (VIII):
Brown oil (12.0 g, 39.2 mmol, 91.6% yield). ESIMS found for C9H11IN2O2 mlz 307.1 (M+H).
[0242] Preparation of intermediate 4-(aminomethyl)-l-(tetrahydro-2H-pyran-2-yl)- lH-pyrazole -3 -carboxylic acid (CXXIII) is depicted below in Scheme 25.
Figure imgf000112_0001
Step 1
[0243] To a solution of ethyl 4-formyl-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3- carboxylate (CXVI) (380 mg, 1.51 mmol, 1 eq)) and O-methylhydroxylamine (140 mg, 1.68, 1.1 eq) in THF (4 mL) and water (4 mL) was added NaHCCE (140 mg, 1.67 mmol, 1.1 eq). The reaction was stirred at 70°C for 4.5 h. The solution was cooled and extracted with EtOAc. The organic layer was washed with water, brine, dried, fdtered and concentrated under vacuum. The crude product was purified on a silica gel column (0 30% EtOAc/hexane) to give ethyl (E)-4- (((methoxymethylene)amino)methyl) - 1 -(tetrahydro -2H-pyran-2-yl) - 1 H-pyrazole -3 -carboxylate (CXXI) as a colorless oil (248 mg, 0.84 mmol, 55.8% yield). ¾ NMR (499 MHz, DMSO-r 6) d ppm 1.28 - 1.32 (m, 3 H), 1.52 - 1.59 (m, 2 H), 1.61 - 1.71 (m, 1 H), 1.92 (br d, .7=10.15 Hz, 2 H), 2.01 - 2.15 (m, 1 H), 3.61 - 3.70 (m, 1 H), 3.85 (s, 3 H), 3.91 - 3.96 (m, 1 H), 4.28 - 4.32 (m, 2 H), 5.52 (dd, .7=9.88, 2.20 Hz, 1 H), 8.32 (s, 1 H), 8.41 (s, 1 H); ESIMS found C14H21N3O4 mlz 296.1 (M+H).
Step 2
[0244] To a solution of ethyl (E)-4-(((methoxymethylene)amino)methyl)-l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3 -carboxylate (CXXI) (240 mg, 0.81 mmol, 1 eq) in MeOH (50 mL) was added 10% Pd/C (80 mg) under nitrogen. The solution was purged with hydrogen and stirred at room temperature under hydrogen for 60 h. The suspension was filtered through Celite® and the concentrated under vacuum. The residue was purified on a silica gel column (0— >10% 7N N¾ in MeOH/CHCE) to produce a brown solid. NMR showed that the acid, 4- (aminomethyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3-carboxylic acid (CXXIII) (197.1 mg) was isolated and not the ethyl ester (CXXII). Ή NMR (499 MHz, DMSO-r/e) d ppm 1.50 - 1.58 (m, 2 H), 1.61 - 1.73 (m, 1 H), 1.87 - 1.96 (m, 2 H), 1.98 - 2.08 (m, 1 H), 3.59 - 3.67 (m, 1 H), 3.79 (s, 2 H), 3.88 - 3.95 (m, 1 H), 5.43 (dd, .7=9.61, 2.47 Hz, 1 H), 7.87 (s, 1 H); ESIMS found for C10H15N3O3 m!z 226.0 (M+H). The acid was used in following steps.
Example 1.
[0245] Preparation of l-methyl-N-(3-(5-methyl-4,5,6,7-tetrahydro-lH-imidazo[4,5- c]pyridin-2-yl)-lH-pyrazol-4-yl)piperidine-4-carboxamide (12) is depicted below in Scheme 26.
Figure imgf000113_0001
Scheme 26
Step 1
[0246] To a solution of 4-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3- carbaldehyde (CXIV) (517.5 mg, 2.30 mmol, 1 eq) in MeCN (23 mL) was added NH3OH (175 mg, 2.53 mmol, 1.1 eq) and TEA (384 pL, 2.76 mmol, 1.2 eq). The reaction was stirred at 60°C for 1.5 h. The reaction was cooled to 0°C before adding TEA (1.06 mL, 7.58 mmol, 3.3 eq) followed by trichloroacetyl chloride (590 pL, 5.29 mmol, 2.3 eq). The reaction was stirred at room temperature for 30 min and then heated to 60°C overnight. The solvent was evaporated under high vacuum and the residue purified on a silica gel column (0 40% EtO Ac/hexane) to produce 4-nitro-l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3-carbonitrile (CXXIV) as a clear oil (271.5 mg, 1.22 mmol, 53.1% yield). ¾ NMR (499 MHz, DMSO-r 6) d ppm 1.66 - 1.69 (m, 2H), 1.89 - 1.92 (m, 1H), 1.97 - 2.00 (m, 2H), 2.08 - 2.11 (m, 1H), 3.66 - 3.71 (m, 1H), 3.92 - 3.95 (m, 1H), 5.64 (dd, J= 2.9, 9.1Hz, 1H), 9.32 (3, 1H); ESIMS found for C9H10N4O3 mlz 240.0 (M+H20).
Step 2
[0247] To a solution of 4-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3- carbonitrile (CXXIV) (261.1 mg, 1.18 mmol, 1 eq) in MeOH (11 mL) was added NaOMe (190 mg, 3.53 mmol, 3 eq). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with EtOAc. The organic layer was washed with water, brine, dried, fdtered and concentrated under vacuum to produce crude methyl 4-nitro-l-(tetrahydro-2H- pyran-2-yl)-lH-pyrazole-3-carbimidate (CXXV) (228.5 g) as a brown oil. The product was used for the next step without further purification. ESIMS found C10H14N4O4 mlz 254.9 (M+H).
Step 3
[0248] To a solution of 4,4-diethoxy- 1-methylpiperidin -3 -amine (XCIV) (180 mg, 0.90 mmol, 1 eq) in EtOH (5.0 mL) was added methyl 4-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazole-3-carbimidate (CXXV) (228.5 mg, 0.90 mmol, 1 eq) followed by HOAc (102 pL, 1.80 mmol, 2 eq). The reaction was stirred at 50°C overnight. The solvent was removed under high vacuum and the residue partitioned between EtOAc and saturated aqueous NaHC03. The organic layer was washed with water, brine, dried, filtered and concentrated under vacuum. The crude product was purified on a silica gel column (0 3% 7N N¾ in McOH/CHCE) to produce N-(4,4- diethoxy-l-methylpiperidin-3-yl)-4-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3- carboximidamide (CXXVI) as a brown oil (193.8 mg, 0.46 mmol, 38.7% yield for 2 steps). ESIMS found for C19H32N6O5 mlz 425.0 (M+H).
Step 4
[0249] To a solution of N-(4,4-diethoxy-l-methylpiperidin-3-yl)-4-nitro-l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3-carboximidamide (CXXVI) (193.8 mg, 0.46 mmol, 1 eq) in EtOH (2 mL) was added concentrated HC1 (0.57 mL, 6.84 mmol, 15 eq). The reaction was stirred at 80°C overnight. The solution was removed under high vacuum and the residue treated with 7N NH3 in MeOH. The solvent was again evaporated, and the residue purified on a silica gel column (0 10% 7N N¾ in McOH/CHCE) to produce 5-methyl-2-(4-nitro-lH-pyrazol-3-yl)- 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine (CXXVII) as a yellow solid (31.7 mg, 0.13 mmol, 27.8% yield).‘H NMR (499 MHz, DMSO-de) d ppm 2.40 (s, 3H), 2.67- 2.68 (m, 4H), 3.42 - 3.43 (m, 2H), 8.42 (s, 1H), 12.22 (br s, 1H); ESIMS found CIOHI2N602 mlz 248.8 (M+H).
Step 5
[0250] To a solution of 5-methyl-2-(4-nitro-lH-pyrazol-3-yl)-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine (CXXVII) (68.9 mg, 0.28 mmol) in EtOH (2 mL) was added 10% Pd/C (10 mg) under nitrogen. The solution was purged with hydrogen and stirred at room temperature under hydrogen for 4 h. The suspension was filtered through Celite® and the concentrated under vacuum to produce 3-(5-methyl-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazol-4- amine (CXXVIII) as a tan solid (59.0 mg, 0.27 mmol, 97.4% yield). ESIMS found for C10H14N6 mlz 218.8 (M+H).
Step 6
[0251] A solution of 1-methylpiperidine -4 -carboxylic acid (CXXIX) (25.0 mg, 0.14 mmol, 1 eq), HATU (53.0 mg, 0.14 mmol, 1 eq), and DIPEA (72 pL, 0.42 mmol, 3 eq) in DMF (0.5 mL) was stirred at room temperature for 10 minutes before adding 3-(5-methyl-4, 5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazol-4-amine (CXXVIII) (30.2 mg, 0.14 mmol, 1 eq). The resulting mixture was stirred at room temperature for 4 h. The reaction was poured into water and extracted with EtOAc. The organic layer was washed with water, brine, dried, filtered and concentrated under vacuum. The crude product was purified on a silica gel column (0 10% 7N NH3 in MeOH/CHCT) to produce l-methyl-N-(3-(5-methyl-4,5,6,7-tetrahydro-lH-imidazo [4,5-c]pyridin-2-yl)-lH-pyrazol-4-yl)piperidine-4-carboxamide (12) as an off-white solid (23.2 mg, 0.07 mmol, 48.8% yield). ¾ NMR (499 MHz, DMSO-r/6) d ppm 1.61 - 1.68 (m, 2H), 1.85 - 1.87 (m, 2H), 1.91 - 1.96 (m, 2H), 2.16 (s, 3H), 2.22 - 2.26 (m, 1H), 2.39 (s, 3H), 2.60 - 2.66 (m, 4H), 2.77 - 2.79 (m, 2H), 3.36 - 3.40 (m, 2H), 8.11 (s, 1H), 10.39 (s, 1H), 12.32 (s, 1H), 12.75 (s, 1H); ESIMS found for Ci7H25N70 mlz 344.1 (M+l).
Example 2.
[0252] Preparation of N-(3-(lH-indazol-3-yl)-lH-pyrazol-4-yl)nicotinamide (33) is depicted below in Scheme 27.
Figure imgf000116_0001
Scheme 27
Step 1
[0253] A solution of 3,5-dibromo-4-nitro-lH-pyrazole (CXXX) Commercially available from Aldrich/Matrix Scientific) (2.36 g, 8.71 mmol, 1 eq), pTsOH (190 mg, 1.0 mmol, 0.11 eq), and DHP (1.8 mL, 19.73 mmol, 2.25 eq) in dry THF (30 mL) was 80°C in a sealed tube for 2 h under Ar. The reaction concentrated under vacuum. The crude product was triturated with Et20/hexane to give 3,5-dibromo-4-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole (CXXXI) as an off-white solid (2.88 g, 8.11 mmol, 93.1% yield). ¾ NMR (499 MHz, CDCb) d ppm 1.68 - 1.77 (m, 2H), 1.91 - 1.99 (m, 1H), 2.11 - 2.22 (m, 2H), 2.37 - 2.48 (m, 1H), 3.65 - 3.73 (m, 1H), 4.09 - 4.02 (m, 1H), 5.58 (dd, J= 3.0, 9.5Hz, 1H); ESIMS found CsHgBrzNsCE mlz 355.8 (M+H).
Step 2
[0254] A solution of 3-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (CXXXII) (790 mg, 2.81 mmol, 1 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (790 mg, 3.11 mmol, 1.1 eq), Pd(dppf)Cl2 (100 mg, 0.12 mmol, 0.04 eq), and KOAc (820 mg, 8.35 mmol, 3 eq) in dioxane (8 mL) was purged with N2 and stirred at 100°C for 3 h under Ar. The solution containing l-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- indazole (CXXXIII) was cooled to room temperature before adding 3,5-dibromo-4-nitro-l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazole (CXXXI) (1.0 g, 2.82 mmol, 1 eq), Pd(PPh3)4 (160 mg, 0.14 mmol, 0.05 eq), K3PO4 (1.2 g, 5.6 mmol, 2 eq), and water (2 mL). The solution was purged with N2 and stirred at 100°C for 3 h under Ar. The reaction was cooled and extracted with EtOAc. The combined organic layers were washed with brine, dried, and concentrated under vacuum. The residue was purified by silica column (0 30% EtO Ac/hexane) to produce 3-(5-bromo-4-nitro-l- (tetrahydro-2H-pyran-2-yl)- 1 H-pyrazol -3 -yl) - 1 -(tetrahydro -2H-pyran-2 -yl) - 1 H-indazole
(CXXXIV) as a colorless oil (267 mg, 0.56 mmol, 19.9% yield for 2 steps). ¾ NMR (499 MHz, DMSO-7,) 5 ppm 1.56 - 1.67 (m, 2 H), 1.71 - 1.83 (m, 2 H), 1.86 - 1.96 (m, 2 H), 2.02 - 2.14 (m, 4 H), 2.33 - 2.46 (m, 2 H), 3.76 - 3.82 (m, 1 H), 3.83 - 3.93 (m, 3 H), 5.41 (ddd, .7=13.79, 9.95, 2.33 Hz, 1 H), 6.07 (dt, 7=8.78, 2.88 Hz, 1 H), 7.27 - 7.31 (m, 1 H), 7.52 - 7.56 (m, 1 H), 7.60 (dd, 7=8.23, 3.02 Hz, 1 H), 7.90 (d, 7=8.51 Hz, 1 H); ESIMS found C2oH22BrN504 mlz 476.1 (M+H).
Step 3
[0255] To a solution of 3-(5-bromo-4-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazol-3-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (CXXXIV) (260 mg, 0.55 mmol), and HO Ac (5 mL) in MeOH (10 mL) was added 10% Pd/C (100 mg) under nitrogen. The solution was purged with hydrogen and stirred at room temperature under hydrogen for 18 h. The suspension was fdtered through Celite® and the concentrated under vacuum to produce 1 -(tetrahydro-2H- pyran-2-yl)-3-( 1 -(tetrahydro -2H-pyran-2-yl)- lH-indazol-3 -yl)- lH-pyrazol-4-amine (CXXXV) which was used for the next step without further purification.
Step 4
[0256] A solution of crude l-(tetrahydro-2H-pyran-2-yl)-3-(l-(tetrahydro-2H-pyran- 2-yl)-lH-indazol-3-yl)-lH-pyrazol-4-amine (CXXXV) (~0.5 mmol, 1 eq), HATU (200 mg, 0.53 mmol, 1.1 eq), and DIPEA (150 pL, 0.86 mmol, 1.7 eq) in DMF (3 mL) was stirred at room temperature for 10 minutes before adding nicotinic acid (CXXXVI) (65 mg, 0.53 mmol, 1.1 eq). The resulting mixture was stirred at room temperature for 5 h and 65°C for 15 h. The reaction was poured into water and filtered to give a brown solid. The crude product was purified on a silica gel column (0 80% EtO Ac/hexane) to produce N-(l-(tetrahydro-2H-pyran-2-yl)-3-(l-(tetrahydro- 2H-pyran-2-yl)-lH-indazol-3-yl)-lH-pyrazol-4-yl)nicotinamide (CXXXVII) as a brown oil (43 mg, 0.09 mmol, 16.5% yield for 2 steps). ESIMS found C26H28N6O3 mlz 473.1 (M+H). Step 5
[0257] To a solution of N-( 1 -(tetrahydro-2H-pyran-2-yl)-3 -( 1 -(tetrahydro-2H-pyran- 2-yl)-lH-indazol-3-yl)-lH-pyrazol-4-yl)nicotinamide (CXXXVII) (43 mg, 0.09 mmol, 1 eq) in DCE (2 mL) was added TFA (1 mL). The reaction was stirred at 65 °C for 4 h. The reaction was concentrated under vacuum and the crude product was triturated with 7N NIT in MeOH. The crude product was purified by preparative TLC (0 10% MeOH/CHCT) to yield N-(3-(lH-indazol-3- yl)-lH-pyrazol-4-yl)nicotinamide (33) as a white solid (8.0 mg, 0.03 mmol, 28.9% yield). 1 H N M R (499 MHz, DMSO-7,) 5 ppm 7.24 (1 H, t, 7=7.41 Hz), 7.46 (1 H, t, 7=7.41 Hz), 7.61 (1 H, d, 7=8.23 Hz), 7.64 (1 H, dd, 7=7.68, 4.94 Hz), 8.29 - 8.41 (3 H, m), 8.82 (1 H, br d, 7=3.84 Hz), 9.19 (1 H, s), 10.80 (1 H, br s), 13.05 (1 H, br s), 13.45 (1 H, br s); ESIMS found for CI6HI2N60 mlz 304.6 (M+l).
Example 3.
[0258] Preparation of N-(3-(((lH-benzo[d]imidazol-2-yl)amino)methyl)-lH-pyrazol- 4-yl) nicotinamide (34) is depicted below in Scheme 28.
Figure imgf000119_0001
Scheme 28
Step 1
[0259] To a solution of methyl 4-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3- carboxylate (CXII) (14.2 g, 55.6 mmol) in MeOH (50 mL) was added 10% Pd/C (1.5 g) under nitrogen. The solution was purged with hydrogen and stirred at room temperature under hydrogen for 16 h. The suspension was fdtered through Celite® and the concentrated under vacuum to produce methyl 4-amino-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3-carboxylate (CXXXIX) as a dark brown oil (12.66 g, 56.2 mmol, 101% yield). ESIMS found C10H15N3O3 m!z 226.0 (M+H).
Step 2
[0260] A solution of methyl 4-amino-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3- carboxylate (CXXXIX) (1.0 g, 4.44 mmol, 1 eq), HATU (1.7 g, 4.47 mmol, 1 eq), and DIPEA (1.2 mL, 6.89 mmol, 1.6 eq) in DMF (8 mL) was stirred at room temperature for 10 minutes before adding nicotinic acid (CXXXVI) (550 mg, 4.47 mmol, 1 eq). The resulting mixture was stirred at room temperature for 16 h. The reaction was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried, fdtered and concentrated under vacuum. The crude product was purified on a silica gel column (0 80% EtO Ac/hexane) to produce methyl 4-(nicotinamido)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3-carboxylate (CXL) as a white solid (840 mg, 2.54 mmol, 57.3% yield). ¾ NMR (499 MHz, DMSO-r 6) d ppm 1.53 - 1.60 (m, 2H), 1.63 - 1.74 (m, 1H), 1.89 - 1.98 (m, 2H), 2.04 - 2.14 (m, 1H), 3.64 - 3.71 (m, 1H), 3.88 (s, 3H), 3.91 - 3.97 (m, 1H), 5.55 (dd, J= 2.5, 10.0Hz, 1H), 8.26 (dt, .7=1.5, 8.0Hz, 1H), 8.44 (s, 1H), 8.80 (dd, J= 2.0, 5.0Hz, 1H), 9.08 (d, J=2.0Hz, 1H), 9.99 (br s, 1H); ESIMS found CI6HI8N404 mlz 331.1 (M+H).
Step 3
[0261] To a solution of methyl 4-(nicotinamido)-l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazole-3-carboxylate (CXL) (1.70 g, 5.15 mmol, 1 eq) in THF (7.5 mL) and MeOH (7.5 mL) was added 4 N LiOH in water (4.0 mL, 16.0 mmol, 3.1 eq). The solution was stirred at room temperature for 1 h. The reaction was poured into water and the pH was adjusted 3-4 and concentrated under vacuum. The resulting solid was filtered and dried to yield 4-(nicotinamido)-l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3 -carboxylic acid (CXLI) as a white solid (1.15 g, 3.64 mmol, 70.6% yield). ESIMS found CI5HI6N404 mlz 317.1 (M+H).
Step 4
[0262] A solution of 4-(nicotinamido)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3- carboxylic acid (CXLI) (1.149 g, 3.63 mmol, 1 eq), HATU (1.6 g, 4.2 mmol, 1.17 eq), and DIPEA (1.3 mL, 7.5 mmol, 2.1 eq) in DMF (20 mL) was stirred at room temperature for 5 minutes before adding N,O-dimethylhydroxylamine (400 mg, 4.1 mmol, 1.1 eq). The resulting mixture was stirred at room temperature for 4.5 h. The reaction was poured into water and extracted with 2 X EtOAc. The combined organic layers was washed with water, brine, dried, filtered and concentrated under vacuum. The crude product was purified on a silica gel column (0 90% EtO Ac/hexane) to produce N-(3-(methoxy(methyl)carbamoyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)nicotinamide (CXLII) as a colorless oil (1.5 g). ¾ NMR (499 MHz, DMSO-r 6) d ppm 1.51 - 1.61 (m, 2H), 1.62 - 1.75 (m, 1H), 1.90 - 2.02 (m, 2H), 2.06 - 2.18 (m, 1H), 3.47 (br s, 3H), 3.63 - 3.72 (m, 1H), 3.77 (s, 3H), 3.89 - 3.96 (m, 1H), 5.56 (dd, J= 2.5, 9.5Hz, 1H), 7.60 (dd, .7=4.5, 7.5Hz, 1H), 8.22 (dt, .7=1.5, 8.5Hz, 1H), 8.43 (s, 1H), 8.79 (dd, .7=1.5, 4.5Hz, 1H), 9.05 (d, J=2.0Hz, 1H), 10.62 (s, 1H); ESIMS found for CI7H2IN504 IM/Z 360.0 (M+H). Step 5
[0263] To a solution of N-(3-(methoxy(methyl)carbamoyl)-l-(tetrahydro-2H-pyran- 2-yl)-lH-pyrazol-4-yl)nicotinamide (CXLII) (1.2 g, 3.34 mmol, 1 eq) in THF (12 mL) was added L1AIH4 (190 mg, 5.0 mmol, 1.5 eq) at 0°C under Ar. The solution was stirred at 0°C under Ar for 30 min. The reaction was quenched with EtOAc and poured into water before adding IN HC1. The organic layer was washed with water, brine, dried, filtered and concentrated under vacuum. The crude product was purified on a silica gel column (0 100% EtO Ac/hexane) produce N -(3 -formyl - l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)nicotinamide (CXLIII) as a white foam (420 mg, 1.40 mmol, 41.8% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 1.52 - 1.59 (m, 2H), 1.63 - 1.73 (m, 1H), 1.90 - 2.00 (m, 2H), 2.05 - 2.15 (m, 1H), 3.65 - 3.71 (m, 1H), 3.90 - 3.96 (m, 1H), 5.60 (dd, 7=3.0, 10.0Hz, 1H), 7.59 (ddd, 7=1.0, 5.0, 8.0Hz, 1H), 8.25 (dt, 7=1.5, 8.0Hz, 1H), 8.43 (s, 1H), 8.78 (dd, 7=1.5, 5.0Hz, 1H), 9.07 (d, 7=2.0Hz, 1H), 10.02 (s, 1H), 10.19 (s, 1H); ESIMS found CI5HI6N403 mlz 301.1 (M+H).
Step 6
[0264] To a solution of N-(3-formyl-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl) nicotinamide (CXLIII) (100 mg, 0.33 mmol, 1.1 eq) and lH-benzo[d]imidazol-2 -amine (CXLIV) (40 mg, 0.30 mmol, 1 eq) in THF (4 mL) was added HO Ac (8 pL, 0.14 mmol, 0.5 eq). The solution was heated at 65°C for 1.5 h. The solution was cooled and Na(OAc)3BH (100 mg, 0.47 mmol, 1.6 eq) was added and the reaction was heated at 65°C for 15 h. The reaction was quenched with brine and extracted with EtOAc. The combined organic layers were washed with brine, dried, filtered and concentrated under vacuum. The residue was purified by silica gel column (0 8% MeOH/EtOAc) to yield N-(3-(((lH-benzo[d]imidazol-2-yl)amino)methyl)-l-(tetrahydro-2H- pyran-2-yl)-lH-pyrazol-4-yl)nicotinamide (CXLV) as a white solid (33 mg, 0.08 mmol, 26.3% yield). ESIMS found C22H23N7O2 mlz 418.1 (M+H).
Step 7
[0265] To a solution of N-(3-(((lH-benzo[d]imidazol-2-yl)amino)methyl)-l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)nicotinamide (CXLV) (41 mg, 0.10 mmol, 1 eq) in DCM (3 mL) was added TFA (1.5 mL). The reaction was stirred at room temperature for 2 h. The reaction was concentrated under vacuum and the crude product was triturated with MeOH to give N-(3-(((lH-benzo[d]imidazol-2-yl)amino)methyl)-lH-pyrazol-4-yl)nicotinamide (34) as an off- white solid (16.0 mg, 0.05 mmol, 48.8% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 4.51 (2 H, d, .7=6.04 Hz), 6.46 (1 H, br s), 6.68 - 6.86 (2 H, m), 7.07 (1 H, br s), 7.47 (1 H, br s), 7.63 (1 H, dd, J= 7.68, 4.94 Hz), 8.10 (1 H, br s), 8.39 (1 H, dt, J= 7.68, 1.92 Hz), 8.85 (1 H, dd, =4.94, 1.10 Hz), 9.34 (1 H, s), 10.88 (1 H, br s), 12.07 (1 H, br s), 12.64 (1 H, br s); ESIMS found for C17H15N7O m/z 334.0 (M+l).
Example 4.
[0266] Preparation of 5-(piperidin-l-ylmethyl)-N-(3-((6-(trifluoromethyl)pyridin-3- yl)carbamoyl)-lH-pyrazol-4-yl)nicotinamide (88) is depicted below in Scheme 29.
Figure imgf000122_0001
Scheme 29 Step 1
[0267] A solution of 4-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3-carboxylic acid (CIX) (2.0 g, 8.3 mmol, 1 eq), HATU (3.6 g, 9.46 mmol, 1.15 eq), and DIPEA (2.2 mL, 12.64 mmol, 1.5 eq) in DMF (20 mL) was stirred at room temperature for 10 minutes before adding 6- (trifhioromethyl)pyridin-3-amine (CXLVI) (1.5 g, 9.25 mmol, 1.1 eq). The resulting mixture was stirred at room temperature for 15 h. The reaction was poured into water and extracted with EtOAc. The organic layer was washed with water, brine, dried, fdtered and concentrated under vacuum. The crude product was purified on a silica gel column (0 50% EtO Ac/hexane) to produce 4-nitro- l-(tetrahydro-2H-pyran-2-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-lH-pyrazole-3-carboxamide (CXLVII) as an off-white foam (2.5 g, 6.49 mmol, 78.2% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 1.54 - 1.61 (m, 2 H), 1.64 - 1.75 (m, 1 H), 1.91 - 2.03 (m, 2 H), 2.10 - 2.21 (m, 1 H), 3.64 - 3.74 (m, 1 H), 3.95 - 4.00 (m, 1 H), 5.59 (dd, 7=9.74, 2.61 Hz, 1 H), 7.95 (d, 7=8.51 Hz, 1 H), 8.44 (dd, 7=8.78, 2.20 Hz, 1 H), 8.97 (d, 7=2.47 Hz, 1 H), 9.19 (s, 1 H), 11.37 (s, 1 H); ESIMS found for C15H14F3N5O4 wi!z 386.2 (M+H).
Step 2
[0268] To a solution of 4-nitro-l-(tetrahydro-2H-pyran-2-yl)-N-(6-(trifluoromethyl) pyridin-3-yl)-lH-pyrazole-3-carboxamide (CXLVII) (2.5 g, 6.49 mmol) in MeOH (30 mL) was added 10% Pd/C ( 1.0 g) under nitrogen. The solution was purged with hydrogen and stirred at room temperature under hydrogen for 18 h. The suspension was fdtered through Celite® and the concentrated under vacuum to produce 4-amino- l-(tetrahydro-2H-pyran-2-yl)-N -(6- (trifluoromethyl)pyridin-3-yl)-lH-pyrazole-3-carboxamide (CXLVIII) as a light purple solid (1.7 g, 4.78 mmol, 73.7% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 1.48 - 1.59 (m, 2 H), 1.61 - 1.74 (m, 1 H), 1.87 - 1.99 (m, 2 H), 2.05 - 2.16 (m, 1 H), 3.58 - 3.67 (m, 1 H), 3.96 (br d, .7=10.98 Hz, 1 H), 4.83 (br s, 2 H), 5.35 (dd, .7=10.15, 2.20 Hz, 1 H), 7.33 (s, 1 H), 7.86 (d, .7=8.51 Hz, 1 H), 8.51 (dd, .7=8.65, 2.33 Hz, 1 H), 9.15 (d, 7=2.20 Hz, 1 H), 10.41 (br s, 1 H) ; ESIMS found CISHKTYNSCE m!z 356.1 (M+H).
Step 3
[0269] To a solution of 4-amino-l -(tetrahydro-2H-pyran-2-yl)-N-(6-(trifluoromethyl) pyridin-3-yl)-lH-pyrazole-3-carboxamide (CXLVIII) (670 mg, 1.89 mmol, 1 eq), 5- (methoxycarbonyl)nicotinic acid (CXLIX) (376 mg, 2.08 mmol, 1.1 eq), HATU (790 mg, 2.08 mmol, 1.1 eq) in DMF (5 mL) was added DIPEA (0.5 mL, 2.87 mmol, 1.5 eq). The reaction was stirred at 80°C for 3 h. The reaction was poured into water and extracted with EtOAc. The organic layer was washed with water, brine, dried, filtered and concentrated under vacuum. The crude product was triturated with Et20. The solid was filtered to produce methyl 5-((l-(tetrahydro-2H- pyran-2-yl)-3-((6-(trifluoromethyl)pyridin-3-yl)carbamoyl)-lH-pyrazol-4-yl)carbamoyl) nicotinate (CL) as a brown solid (668 mg, 1.29 mmol, 68.2% yield). ¾ NMR (499 MHz, DMSO- d ) 5 ppm 1.54 - 1.65 (m, 2 H), 1.67 - 1.79 (m, 1 H), 1.95 - 2.07 (m, 2 H), 2.18 - 2.29 (m, 1 H), 3.67 - 3.76 (m, 1 H), 3.95 (s, 3 H), 4.02 (br d, .7=11.25 Hz, 1 H), 5.57 - 5.63 (m, 1 H), 7.93 (d, J= 8.78 Hz, 1 H), 8.53 (s, 1 H), 8.54 - 8.60 (m, 1 H), 8.67 - 8.72 (m, 1 H), 9.18 (s, 1 H), 9.27 (d, 7=1.92 Hz, 1 H), 9.29 (d, 7=1.92 Hz, 1 H), 10.51 (s, 1 H), 10.94 (s, 1 H); ESIMS found for CzsHziFsNeOs mlz 519.2 (M+H).
Step 4
[0270] To a solution of methyl 5-((l-(tetrahydro-2H-pyran-2-yl)-3-((6- (trifluoromethyl)pyridin-3-yl)carbamoyl)-lH-pyrazol-4-yl)carbamoyl) nicotinate (CL) (660 mg, 1.27 mmol, 1 eq) in THF (2 mL) and MeOH (2 mL) was added 4 N LiOH in water (1.0 mL, 4.0 mmol, 3.2 eq). The solution was stirred at room temperature for 1 h. The reaction was poured into water and the pH was adjusted 1-2 with 10% HC1 and concentrated under vacuum. The resulting solid was fdtered and dried to produce 5-((l-(tetrahydro-2H-pyran-2-yl)-3-((6-(trifluoromethyl) pyridin-3-yl)carbamoyl)-lH-pyrazol-4-yl)carbamoyl)nicotinic acid (CLI) as a light brown solid (489 mg, 0.97 mmol, 76.3% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 1.54 - 1.65 (m, 2 H), 1.68 - 1.79 (m, 1 H), 1.94 - 2.07 (m, 2 H), 2.17 - 2.30 (m, 1 H), 3.67 - 3.75 (m, 1 H), 4.02 (br d, 7=10.98 Hz, 1 H), 5.59 (dd, 7=10.02, 2.06 Hz, 1 H), 7.93 (d, 7=8.78 Hz, 1 H), 8.54 (s, 1 H), 8.57 (dd, 7=8.51, 2.20 Hz, 1 H), 8.69 (t, 7=2.06 Hz, 1 H), 9.18 (d, 7=2.20 Hz, 1 H), 9.25 (d, 7=1.92 Hz, 1 H), 9.27 (d, 7=2.20 Hz, 1 H), 10.50 (s, 1 H), 10.95 (s, 1 H), 13.77 (br s, 1 H); ESIMS found C22Hi9F3N605 m!z 505.1 (M+H).
Step 5
[0271] A solution of 5-((l-(tetrahydro-2H-pyran-2-yl)-3-((6-(trifluoromethyl) pyridin-3-yl)carbamoyl)-lH-pyrazol-4-yl)carbamoyl)nicotinic acid (CLI) (480 mg, 0.95 mmol, 1 eq), HATU (430 mg, 1.13 mmol, 1.2 eq), and DIPEA (0.35 mL, 2.0 mmol, 2.1 eq) in DMF (3 mL) was stirred at room temperature for 5 minutes before adding N,O-dimethylhydroxylamine (110 mg, 1.13 mmol, 1.2 eq). The resulting mixture was stirred at room temperature for 2 h. The reaction was poured into water and extracted with CHCE. The organic layer was washed with water, brine, dried, fdtered and concentrated under vacuum. The crude product was purified on a silica gel column (0 70% EtO Ac/hexane). The resulting product was further triturated with MeOH/ETO (1 :3) to produce N3-methoxy-N3 -methyl -N5-(l-(tetrahydro-2H-pyran -2 -yl)-3-((6-(trifluoromethyl) pyridin-3-yl)carbamoyl)-lH-pyrazol-4-yl)pyridine-3, 5 -dicarboxamide (CLII) as a white solid (467 mg, 0.85 mmol, 89.8% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 1.54 - 1.66 (m, 2 H), 1.68 - 1.79 (m, 1 H), 1.96 - 2.06 (m, 2 H), 2.17 - 2.29 (m, 1 H), 3.34 (s, 3 H), 3.62 (s, 3 H), 3.67 - 3.75 (m, 1 H), 4.02 (br d, 7=11.53 Hz, 1 H), 5.59 (dd, 7=10.15, 2.20 Hz, 1 H), 7.93 (d, 7=8.78 Hz, 1 H), 8.45 (t, 7=2.06 Hz, 1 H), 8.55 (s, 1 H), 8.55 - 8.59 (m, 1 H), 9.00 (d, 7=1.92 Hz, 1 H), 9.17 (d, 7=2.20 Hz, 1 H), 9.18 (d, 7=2.20 Hz, 1 H), 10.46 (s, 1 H), 10.96 (s, 1 H); ESIMS found for CMH^NVOS mlz 548.1 (M+H).
Step 6
[0272] To a solution of N3-methoxy-N3-methyl-N5-(l-(tetrahydro-2H-pyran-2-yl)-3- ((6-(trifluoromethyl)pyridin-3-yl)carbamoyl)-lH-pyrazol-4-yl)pyridine-3, 5 -dicarboxamide (CLII) (370 mg, 0.68 mmol, 1 eq) in THF (8 mL) was added LiAITU (35 mg, 0.92 mmol, 1.4 eq) at -78°C under Ar. The solution was stirred at -78°C under Ar for 1.5 h. The reaction was quenched with EtOAc and poured into water. The organic layer was washed with water, brine, dried, filtered and concentrated under vacuum. The crude product was purified on a silica gel column (0 70% EtOAc/hexane) to produce 5-formyl-N-(l-(tetrahydro-2H-pyran-2-yl)-3-((6-(trifluoromethyl) pyridin-3-yl)carbamoyl)-lH-pyrazol-4-yl)nicotinamide (CLIII) as a white solid (241 mg, 0.49 mmol, 72.6% yield). ¾ NMR (499 MHz, DMSO-7,) d rrih 1.55 - 1.67 (m, 2 H), 1.68 - 1.81 (m, 1 H), 1.95 - 2.07 (m, 2 H), 2.17 - 2.29 (m, 1 H), 3.65 - 3.76 (m, 1 H), 4.02 (br d, .7=11.53 Hz, 1 H), 5.60 (dd, .7=9.88, 2.20 Hz, 1 H), 7.93 (d, .7=8.78 Hz, 1 H), 8.55 (s, 1 H), 8.57 (dd, .7=8.51, 2.20 Hz, 1 H), 8.67 (t, .7=2.06 Hz, 1 H), 9.18 (d, 7=2.20 Hz, 1 H), 9.28 (d, 7=1.92 Hz, 1 H), 9.31 (d, 7=2.20 Hz, 1 H), 10.23 (s, 1 H), 10.51 (s, 1 H), 10.95 (s, 1 H); ESIMS found C22Hi9F3N604 mlz 489.1 (M+H).
Step 7
[0273] A solution of 5-formyl-N-(l-(tetrahydro-2H-pyran-2-yl)-3-((6- (trifluoromethyl) pyridin-3-yl)carbamoyl)-lH-pyrazol-4-yl)nicotinamide (CLIII) (135 mg, 0.28 mmol, 1 eq) and piperidine (33 pL, 0.33 mmol, 1.2 eq) in DCE (3 mL) was stirred at room temperature for 5 min. NaBH(OAcf (89 mg, 0.42 mmol, 1.5 eq) was added and the reaction was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous NaHCCE and then extracted with 3 X DCM. The combined organic layers were washed with water, brine, dried, fdtered and concentrated under vacuum. The crude product was triturated with Et20. The solid was fdtered to produce 5-(piperidin-l-ylmethyl)-N-(l-(tetrahydro-2H-pyran-2-yl)-3-((6- (trifluoromethyl)pyridin-3-yl)carbamoyl)-lH-pyrazol-4-yl)nicotinamide (CLIV) as a white solid (133 mg, 0.24 mmol, 85.2% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 1.41 (br d, .7=4.67 Hz, 2 H), 1.53 (quin, 7=5.49 Hz, 4 H), 1.57 - 1.67 (m, 2 H), 1.67 - 1.79 (m, 1 H), 1.95 - 2.06 (m, 2 H), 2.17 - 2.28 (m, 1 H), 2.37 (br s, 4 H), 3.57 (s, 2 H), 3.70 (td, 7=10.77, 3.70 Hz, 1 H), 4.01 (br d, 7=10.98 Hz, 1 H), 5.59 (dd, 7=10.02, 1.78 Hz, 1 H), 7.91 (d, 7=8.51 Hz, 1 H), 8.18 (s, 1 H), 8.52 (s, 1 H), 8.56 (dd, 7=8.64, 2.06 Hz, 1 H), 8.69 (d, 7=1.65 Hz, 1 H), 8.96 (d, 7=2.20 Hz, 1 H), 9.19 (br s, 1 H), 10.44 (br s, 1 H), 10.96 (br s, 1 H); ESIMS found C27H30F3N7O3 mlz 558.2 (M+H).
Step 8
[0274] To a solution of 5-(piperidin-l-ylmethyl)-N-(l-(tetrahydro-2H-pyran-2-yl)-3-
((6-(trifluoromethyl)pyridin-3-yl)carbamoyl)-lH-pyrazol-4-yl)nicotinamide (CLIV) (130 mg, 0.23 mmol, 1 eq) in DCE (2 mL) was added TFA (1 mL). The reaction was stirred at 65°C for 1 h. The reaction was concentrated under vacuum and the crude product was triturated with 7N N¾ in MeOH. The crude product was purified on a silica gel column (0 10% MeOH/CHCE) to yield 5- (piperidin-l-ylmethyl)-N-(3-((6-(trifluoromethyl) pyridin-3-yl)carbamoyl)-lH-pyrazol-4- yl)nicotinamide (88) as a white solid (68.0 mg, 0.14 mmol, 61.6% yield). ¾ NMR (499 MHz, DMSO-7 d ppm 1.41 (2 H, br d, 7=4.12 Hz), 1.53 (4 H, quin, 7=5.42 Hz), 2.37 (4 H, br s), 3.58 (2 H, s), 7.90 (1 H, d, 7=8.78 Hz), 8.18 (1 H, s), 8.42 (1 H, s), 8.57 (1 H, dd, 7=8.64, 2.06 Hz), 8.69 (1 H, d, 7=1.65 Hz), 8.97 (1 H, d, 7=2.20 Hz), 9.21 (1 H, d, 7=1.65 Hz), 10.43 (1 H, br s), 11.01 (1 H, br s), 13.68 (1 H, br s); ESIMS found for C22H22F3N7O2 mlz 474.1 (M+l).
Example 5.
[0275] Preparation of 3-cyclopropyl-l-(3-(4-(3-fluorophenyl)-lH-benzo[d]imidazol-
2-yl)-lH-pyrazol-4-yl)-l-methylurea (108) is depicted below in Scheme 30.
Figure imgf000127_0001
108 CLIX
Scheme 30
Step 1
[0276] To a solution of 4-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3- carbaldehyde (CXIV) (479 mg, 2.37 mmol, 1 eq) and 3'-fluoro-[l, r-biphenyl]-2, 3-diamine (XLIV) (533 mg, 2.37 mmol, 1 eq) in DMA (15 mL) was added NaHSCE (370 mg, 3.55 mmol, 1.5 eq). The reaction was stirred at 100°C for 3 h. The solvent was evaporated under vacuum and the residue partitioned between EtO Ac/water. The organic layer was washed with water, brine, dried, filtered and concentrated under vacuum. The crude product was purified on a silica gel column (0 40% EtOAc/hexane) to produce 4-(3-fluorophenyl)-2-(4-nitro-l-(tetrahydro-2H-pyran-2-yl)- lH-pyrazol -3 -yl)-lH-benzo[d] imidazole (CLV) as a golden amorphous solid (508.1 mg, 1.25 mmol, 52.6% yield).‘H NMR (499 MHz, DMSO-d6) d ppm 1.54 - 1.62 (m, 2H), 1.65 - 1.75 (m, 1H), 1.92 - 2.01 (m, 1H), 2.01 - 2.08 (m, 1H), 2.14 - 2.24 (m, 1H), 3.67 - 3.74 (m, 1H), 3.96 - 4.05 (m, 1H), 5.63 (dd, J= 2.5, 10.0Hz, 1H), 7.20 (td, J= 3.0, 8.0Hz, 1H), 7.40 (t, J=7.75Hz, 1H), 7.50 - 7.55 (m, 2H), 7.57 (d, J=7.0Hz, 1H), 7.62 (d, J=8.0Hz, 1H), 7.98 (d, J=8.0Hz, 1H), 8.08 (d, =10.5Hz, 1H), 9.24 (s, 1H); ESIMS found for C21H18FN5O3 m!z 408.1 (M+l). Step 2
[0277] To a solution of 4-(3-fluorophenyl)-2-(4-nitro-l-(tetrahydro-2H-pyran-2-yl)- lH-pyrazol -3 -yl)-lH-benzo[d] imidazole (CLV) (504.2 mg, 1.24 mmol) in EtOH (30 mL) was added 10% Pd/C (75.0 mg) under nitrogen. The solution was purged with hydrogen and stirred at room temperature under hydrogen for overnight. The suspension was fdtered through Celite® and the concentrated under vacuum to produce 3-(4-(3-fluorophenyl)-lH-benzo[d]imidazol-2-yl)-l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-amine (CL VI) as a reddish brown solid (473.7 mg, 1.26 mmol, 101% yield). ¾ NMR (499 MHz, DMSO-r/6) d ppm 1.50 - 1.60 (m, 2H), 1.64 - 1.75 (m, 1H), 1.91 - 2.02 (m, 1H), 2.08 - 2.20 (m, 1H), 3.59 - 3.68 (m, 1H), 3.92 - 4.00 (m, 1H), 5.06 (br s, 2H), 5.35 (dd, J=2.0, 10.0Hz, 1H), 7.19 (td, 7=2.0, 8.5Hz, 1H), 7.28 (t, J=7.75Hz, 1H), 7.37 (s, 1H), 7.42 - 7.50 (m, 2H), 7.53 (q, J=8.0Hz, 1H), 7.90 - 7.97 (m, 1H), 7.97 - 8.07 (m, 1H), 12.87 (br s, 1H); ESIMS found C21H20FN5O mlz 378.1 (M+H).
Step 3
[0278] To a solution of 3-(4-(3-fluorophenyl)-lH-benzo[d]imidazol-2-yl)-l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-amine (CL VI) (50 mg, 0.13 mmol, 1 eq) and paraformaldehyde (9.8 mg, 0.17 mmol, 1.3 eq) in MeOH (1 mL) was added NaCNBH3 (11.7 mg, 0.19 mmol, 1.4 eq). The reaction was stirred at room temperature for 16 h. The reaction was quenched with saturated aqueous NaHCCE and then extracted with 3 X DCM. The combined organic layers were washed with water, brine, dried, fdtered and concentrated under vacuum. The crude product was purified by silica gel column (0 10% MeOH CHCE) to produce crude 3-(4- (3 -fluorophenyl) - 1 H-benzo [d] imidazol -2 -yl) -N -methyl- 1 -(tetrahydro-2H-pyran-2 -yl)- 1 H- pyrazol-4-amine (CL VII) (29.7 mg, contaminated with demethylated product) which was used without further purification.
Step 4
[0279] To a solution of produce crude 3-(4-(3-fluorophenyl)-lH-benzo[d]imidazol-2- yl)-N-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-amine (CL VII) (29.7 mg, 0.08 mmol, 1 eq) and TEA (32 pL, 0.23 mmol, 3 eq) in DCM (0.5 mL) was added cyclopropyl isocyanate (CL VIII) (6.5 mg, 0.08 mmol, 1.0 eq). The reaction was stirred at 65°C for 16 h. The reaction was quenched with saturated aqueous NaHCCE and then extracted with 3 X DCM. The combined organic layers were washed with water, brine, dried, filtered and concentrated under vacuum. The crude 3 -cyclopropyl- 1 -(3 -(4-(3 -fluorophenyl)- lH-benzo[d]imidazol-2-yl)- 1 -(tetrahydro-2H- pyran-2-yl)-lH-pyrazol-4-yl)-l-methylurea (CLIX) was used without further purification.
Step 5
[0280] To a solution of crude 3-cyclopropyl-l-(3-(4-(3-fluorophenyl)-lH- benzo[d]imidazol-2-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)-l-methylurea (CLIX) (0.08 mmol, 1 eq) in DCM (2 mL) was added TFA (2 mL). The reaction was stirred at room temperature for 16 h. The reaction was concentrated under vacuum and the crude product was triturated with 7N N¾ in MeOH. The crude product was purified on a silica gel column (0 10% 7N N¾ in McOH/CHCT) to produce 3 -cyclopropyl- 1 -(3 -(4-(3 -fluorophenyl)- 1H- benzo[d]imidazol-2-yl)-lH-pyrazol-4-yl)-l-methylurea (108) as a brown solid (9.1 mg, 0.02 mmol, 17.6% yield for 3 steps). ¾ NMR (499 MHz, DMSO-d6) d ppm 0.13 - 0.20 (m, 2H), 0.31 - 0.41 (m, 2H), 2.31 - 2.42 (m, 1H), 3.20 (s, 3H), 5.92 (s, 1H), 7.17 (t, J=7.3Hz, 1H), 7.29 (t, J=5.2Hz, 1H), 7.47 - 7.56 (m, 3H), 7.92 (s, 1H), 8.14 (d, J=l lHz, 1H), 8.24 (d, J=8.5Hz, 1H), 12.84 (br s, 1H), 13.30 (br s, 1H); ESIMS found for C2IHI9FN60 mlz 391.3 (M+l).
Example 6.
[0281] Preparation of 4-((2,3-difluorophenyl)amino)-N-(6-(piperidin-l-yl)pyridin-3- yl)-lH-pyrazole-3 -carboxamide (120) is depicted below in Scheme 31.
Figure imgf000130_0001
Scheme 31
Step 1
[0282] To a solution of 4-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3- carboxylic acid (CIX) (545 mg, 2.26 mmol, 1 eq) in DMF (10 mL) was added 6-(piperidin-l- yl)pyridin-3 -amine (LXXX) (400 mg, 2.26 mmol, 1 eq) and DIPEA (0.79 mL, 24.52 mmol, 2 eq). The reaction was cooled to 0°C under Ar before adding HATU (850 mg, 2.26 mmol, 1 eq). The reaction was warmed to room temperature and stirred for 4 h. The reaction was poured into water and extracted with EtOAc. The organic layer was washed with water, brine, dried, filtered and concentrated under vacuum. The crude product was purified on a silica gel column (0 40% EtOAc/hexane) to produce 4-nitro-N-(6-(piperidin-l-yl)pyridin-3-yl)-l-(tetrahydro-2H-pyran-2- yl)-lH-pyrazole-3 -carboxamide (CLX) (900 mg, 2.25 mmol, 99.4% yield). ESIMS found for Ci9H24N604 m!z 401.0 (M+H).
Step 2
[0283] To a solution of 4-nitro-N-(6-(piperidin-l-yl)pyridin-3-yl)-l-(tetrahydro-2H- pyran-2-yl)-lH-pyrazole-3-carboxamide (CLX) (900 mg, 2.25 mmol) in MeOH (20 mL) was added 10% Pd/C (181 mg) under nitrogen. The solution was purged with hydrogen and stirred at room temperature under hydrogen overnight. The suspension was filtered through Celite® and the concentrated under vacuum to produce 4-amino-N-(6-(piperidin-l-yl)pyridin-3-yl)-l-(tetrahydro- 2H-pyran-2-yl)-lH-pyrazole-3-carboxamide (CLXI) as a dark red brown solid (740 mg, 2.00 mmol, 88.8% yield). ESIMS found CuHzeNeOz mlz 371.1 (M+H).
Step 3
[0284] In a sealed vial was added 4-amino-N-(6-(piperidin-l-yl)pyridin-3-yl)-l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3 -carboxamide (CLXI) (200 mg, 0.54 mmol, 1 eq), 1- bromo-2,3-difluorobenzene (CLXII) (125 mg, 0.65 mmol, 1.2 eq), CS2CO3 (246 mg, 0.76 mmol, 1.4 eq), Pd(dba)3 (15 mg, 0.016 mmol, 0.03 eq), xanthphos (9.0 mg, 0.016 mmol, 0.03 eq) in dioxane (5 mL). The reaction was purged with Ar and heated at 110°C for 72 h. The reaction was then partitioned between DMF and EtOAc. The solution was washed with water, brine, dried, filtered and concentrated under vacuum. The crude product was purified on a silica gel column (0 35% EtOAc/hexane) to give 4-((2,3-difhiorophenyl)amino)-N-(6-(piperidin-l-yl)pyridin-3- yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3-carboxamide (CLXIII) as an amber solid (93 mg, 0.19 mmol, 35.7% yield). ESIMS found CzslEsFzNeCE mlz 483.2 (M+H).
Step 4
[0285] To a solution of 4-((2,3-difhiorophenyl)amino)-N-(6-(piperidin-l-yl)pyridin-
3-yl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3-carboxamide (CLXIII) (93 mg, 0.19 mmol, 1 eq) in DCM (2 mL) was added TFA (4 mL). The reaction was stirred at room temperature for 72 h. The reaction was concentrated under vacuum and the crude product was triturated with 7N N¾ in MeOH. The crude product was purified on a silica gel column (0 6% McOH/CHCE) to yield
4-((2,3-difhiorophenyl)amino)-N-(6-(piperidin-l-yl)pyridin-3-yl)-lH-pyrazole-3-carboxamide (120) as a beige solid (11.1 mg, 0.03 mmol, 14.4% yield). ¾ NMR (499 MHz, DMSO-r/e) d ppm 1.52 - 1.61 (6 H, m), 3.44 - 3.50 (4 H, m), 6.75 - 6.85 (2 H, m), 7.05 - 7.16 (2 H, m), 7.89 (1 H, br dd, .7=8.64, 1.78 Hz), 8.16 (1 H, br s), 8.42 (1 H, br s), 8.64 (1 H, br s), 10.07 (1 H, br s), 13.39 (1 H, br s); ESIMS found for C2oH2oF2N60 mlz 398.9 (M+l).
Example 7.
[0286] Preparation of 4-(benzylamino)-N-(6-(2-hydroxyethoxy)pyridin-3-yl)-lH- pyrazole -3 -carboxamide (133) is depicted below in Scheme 32.
Figure imgf000132_0001
Scheme 32
Step 1
[0287] To a solution of 4-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3- carboxylic acid (CIX) (166 mg, 0.69 mmol, 1 eq) in DMF (2 mL) was added 6-(2-((tetrahydro-2H- pyran-2-yl)oxy)ethoxy)pyridine-3-amine (LXXXII) (164 mg, 0.69 mmol, 1 eq) and DIPEA (240 pL, 1.38 mmol, 2 eq). The reaction mixture was stirred at room temperature overnight. The reaction was diluted with EtOAc and saturated NaHCCE. The organic layer was separated and aqueous was extracted with EtOAc (10 mL x 3). The organic layers were combined and dried (Na2S04). The solvent was removed under vacuum. The crude product was purified on a silica gel column (0— >100% EtO Ac/hexane) to give 4-nitro- 1 -(tctrahydro-2//-pyran-2-yl)-A'-(6-(2-((tctrahydro-2//- pyran-2-yl)oxy)ethoxy)pyridin-3-yl)- l//-pyrazole-3-carboxamide (CLXIV) as a yellow oil (277 mg, 0.60 mmol, 87.2% yield). ESIMS found C21H27N5O7 mlz 462.2 (M+H).
Step 2
[0288] The 4-nitro- 1 -(tctrahydro-2//-pyran-2-yl)-A'-(6-(2-((tctrahydro-2//-pyran-2- yl)oxy) ethoxy)pyridin-3-yl)- l//-pyrazole-3 -carboxamide (CLXIV) (277 mg, 0.60 mmol) was dissolved in MeOH (10 mL) and bubbled argon before adding 10% Pd-C (50 mg). The suspension was bubbled hydrogen for 1 minute. The hydrogenation was taken 2 hours using hydrogen balloon. The suspension was filtered through Celite® and the concentrated under vacuum to afford 4-amino- 1 -(tetrahydro-2//-pyran-2-yl)-'V-(6-(2-((tetrahydro-2//-pyran-2-yl)oxy)ethoxy)pyridin-3-yl)- 1//- pyrazole -3 -carboxamide (CLXV) as a yellow oil (255 mg, 0.59 mmol, 98.3% yield). ESIMS found C21H29N5O5 mlz 432.1 (M+H).
Step 3
[0289] A solution of 4-amino- 1 -(tetrahydro-2//-pyran -2 -yl)-A-(6-(2-((tetrahydro-2/7- pyran-2-yl)oxy)cthoxy)pyridin-3-yl)- l//-pyrazolc-3-carboxamidc (CLXV) (87 mg, 0.20 mmol, 1 eq) in dichloroethane (2 mL) was added benzaldehyde (CLXVI) (21 mg, 0.20 mmol, 1 eq) and sodium triacetoxyborohydride (43 mg, 0.20 mmol, 1 eq). The reaction mixture was stirred at room temperature overnight. The reaction was diluted with EtOAc and brine. The organic layer was separated and aqueous was extracted with EtOAc (10 mL x 3). The organic layers were combined and dried (Na2S04). The solvent was removed under vacuum. The crude product was purified on a silica gel column (0 10% 7N NEE in MeOH/CHCE) to give 4-(benzylamino)- 1 -(tctrahydro-2/7- pyran-2-yl)-A'-(6-(2-((tctrahydro-2//-pyran-2-yl)oxy)cthoxy)pyridin-3-yl)- l//-pyrazolc-3- carboxamide (CLXVII) as a white solid (25 mg, 0.048 mmol, 24.0% yield). ESIMS found C28H35N5O5 mlz 522.2 (M+H).
Step 4
[0290] To a solution of 4-(benzylamino)- 1 -(tetrahydro-2//-pyran-2-yl)-A'-(6-(2- ((tetrahydro-2//-pyran-2-yl)oxy)ethoxy)pyridin-3-yl)- l//-pyrazole-3-carboxamide (CLXVII) (25 mg, 0.048 mmol, 1 eq) in DCE (2 mL) was added TFA (37 pL, 0.48 mmol, 10 eq). The reaction mixture was stirred at room temperature overnight. The reaction was diluted with EtOAc and IN NaOH. The organic layer was separated and aqueous was extracted with EtOAc (10 mL x 3). The organic layers were combined and dried (Na2S04). The solvent was removed under vacuum. The crude product was purified on a silica gel column (0 10% 7N N¾ in MeOH/CHCE) to give 4- (benzylamino)-N-(6-(2-hydroxyethoxy)pyridin-3-yl)-lH-pyrazole-3-carboxamide (133) as a white solid (8.2 mg, 0.023 mmol, 48.3% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 3.69 (2 H, q, .7=5.49 Hz), 4.20 (2 H, br d, .7=6.31 Hz), 4.23 (2 H, t, 7=5.21 Hz), 4.78 (1 H, t, 7=5.49 Hz), 5.61 (1 H, br t, 7=6.31 Hz), 6.78 (1 H, d, 7=8.78 Hz), 7.19 (1 H, s), 7.22 - 7.27 (1 H, m), 7.29 - 7.34 (2 H, m), 7.34 - 7.40 (2 H, m), 8.06 (1 H, br dd, 7=8.78, 1.92 Hz), 8.51 (1 H, br s), 9.90 (1 H, s), 12.82 (1 H, br s); ESIMS found for C18H19N5O3 mlz 354.2 (M+l). Example 8.
[0291] Preparation of 4-((4-methylpiperazin-l-yl)methyl)-N-(pyridin-3-yl)-lH- pyrazole -3 -carboxamide (139) is depicted below in Scheme 33.
Figure imgf000134_0001
Step 1
[0292] A solution of ethyl 4-formyl-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3- carboxylate (CXVI) (475 mg, 1.88 mmol, 1 eq), 1 -methylpiperazine (CLXVIII) (313 pL, 2.82 mmol, 1.5 eq) and TEA (525 pL, 3.77 mmol, 2 eq) in DCE (8 mL) was stirred at room temperature for 1 h. NaBH(OAc)3 (600 mg, 2.82 mmol, 1.5 eq) was added and the reaction was stirred at room temperature overnight. The reaction was quenched with saturated aqueous NaHCCE and then extracted with 3 X CHCE. The combined organic layers were washed with water, brine, dried, filtered and concentrated under vacuum. The crude product was purified on a silica gel column (0 4% 7N NEE in MeOH/CHCE) to give ethyl 4-((4-methylpiperazin-l-yl)methyl)-l-(tetrahydro- 2H-pyran-2-yl)-lH-pyrazole-3-carboxylate (CLXIX) as a white solid (429.8 mg, 1.28 mmol, 68.0% yield). ESIMS found C17H28N4O3 mlz 337.1 (M+H).
Step 2
[0293] To a solution of ethyl 4-((4-methylpiperazin-l-yl)methyl)-l-(tetrahydro-2H- pyran-2-yl)-lH-pyrazole-3-carboxylate (CLXIX) (432.3 mg, 1.28 mmol, 1 eq) in THF (4 mL) and water (2 mL) was added LiOH (123 mg, 5.14 mmol, 4 eq). The solution was stirred at room temperature over the weekend. The reaction was poured into water and the pH was adjusted 6 and concentrated under vacuum. The resulting solid was fdtered and dried to produce 4-((4- methylpiperazin-l-yl)methyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3-carboxylic acid (CLXX) (394 mg, 1.28 mmol, 99.8% yield). ¾ NMR (499 MHz, DMSO-r 6) d ppm 1.49 - 1.58 (m, 2H), 1.60 - 1.72 (m, 1H), 1.86 - 1.96 (m, 2H), 1.98 - 2.08 (m, 1H), 2.26 (br s, 4H), 2.74 (br s, 4H), 3.16 (s, 3H), 3.59 - 3.66 (m, 1H), 3.81 (s, 2H), 3.89 - 3.95 (m, 1H), 5.41 (dd, .7=2.5, 10.0Hz, 1H), 7.92 (s, 1H); ESIMS found C15H24N4O3 mlz 309.0 (M+H).
Step 3
[0294] To a solution of 4-((4-methylpiperazin-l-yl)methyl)-l-(tetrahydro-2H-pyran- 2-yl)-lH-pyrazole-3-carboxylic acid (CLXX) (97.1 mg, 0.31 mmol, 1 eq) in DMF (1 mL) was added pyridin-3-amine (CLXXI) (29 mg, 0.31 mmol, 1 eq) and DIPEA (110 pL, 0.63 mmol, 2 eq). The reaction was cooled to 0°C under Ar before adding HATU (120 mg, 0.31 mmol, 1 eq). The reaction was warmed to room temperature and stirred for 2 h. The reaction was poured into water and extracted with EtOAc. The organic layer was washed with water, brine, dried, fdtered and concentrated under vacuum. The crude product was purified on a silica gel column (0 3% 7N NH3 in MeOH/CHCE) to produce 4-((4-methylpiperazin-l-yl)methyl)-N-(pyridin-3-yl)-l- (tetrahydro-2H-pyran-2-yl)- lH-pyrazole-3 -carboxamide (CLXXII) as an off-white solid (41.1 mg, 0.11 mmol, 34.0% yield). ESIMS found for CztTTsNeOz mlz 385.2 (M+H).
Step 4
[0295] To a solution of 4-((4-methylpiperazin-l-yl)methyl)-N-(pyridin-3-yl)-l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3 -carboxamide (CLXXII) (41.1 mg, 0.11 mmol, 1 eq) in DCM (1 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 72 h. The reaction was concentrated under vacuum and the crude product was triturated with 7N N¾ in MeOH. The crude product was purified on a silica gel column (0 6% MeOH/CHCE) to afford 4- ((4-methylpiperazin-l-yl)methyl)-N-(pyridin-3-yl)-lH-pyrazole-3-carboxamide (139) as a light yellow solid (24.1 mg, 0.08 mmol, 75.1% yield). ESIMS found for C15H20N6O mlz 301.2 (M+l).
Example 9.
[0296] Preparation of (E)-4-((2-(4-(2,3-difluorostyryl)-lH-pyrazol-3-yl)-lH- benzofd] imidazol-5-yl)methyl)morpholine (143) is depicted below in Scheme 34.
Figure imgf000136_0001
Scheme 34
Step 1
[0297] A solution of 4-iodo-lH-pyrazole-3-carbaldehyde (VII) (8.9 g, 40.1 mmol, 1 eq), pTsOH (763 mg, 4.01 mmol, 0.1 eq), and DHP (5.5 mL, 60.1 mmol, 1.5 eq) in dry THF (100 mL) was heated at 70°C for 2 h under Ar. The reaction concentrated under vacuum. The crude product was purified on a silica gel column (0 40% EtO Ac/hexane) to give 4-iodo-l-(tetrahydro- 2H-pyran-2-yl)-lH-pyrazole-3-carbaldehyde (VIII) as an off-white solid (9.5 g, 31.0 mmol, 77.4% yield). ESIMS found C9H11IN2O2 mlz 306.95 (M+H).
Step 2
[0298] To a solution of (E)-2-(2,3-difluorostyryl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (CVI) (1.45 g, 5.45 mmol, 1 eq) and 4-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazole-3-carbaldehyde (VIII) (1.67 g, 5.45 mmol, 1 eq) in dioxane (8 mL) and water (2 mL) was added Pd(PPli3)4 (315 mg, 0.27 mmol, 0.05 eq), K3PO4 (1.90 g, 10.9 mmol, 2 eq). The solution was purged with N2 and stirred at 100°C for 2 h under Ar. The reaction was cooled and extracted with EtOAc. The combined organic layers were washed with brine, dried, and concentrated under vacuum. The residue was purified by silica column (0 40% EtOAc/hexane) to produce (E)-4- (2,3-difluorostyryl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3-carbaldehyde (CLXXIII) (930 mg, 2.92 mmol, 53.6% yield for 2 steps). ESIMS found C17H16F2N2O2 mlz 319.1 (M+H).
Step 3
[0299] To a solution of (E)-4-(2,3-difluorostyryl)-l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazole-3-carbaldehyde (CLXXIII) (123 mg, 0.39 mmol, 1 eq) and 3'-fluoro-[l,l'-biphenyl]-2,3- diamine (CLXXIV) (commercially available from Astatech) (80 mg, 0.39 mmol, 1 eq) in DMA (2 mL) was added sulfur (12.4 mg, 0.39 mmol, 1 eq). The reaction was stirred at 100°C overnight. The solvent was evaporated under vacuum and the residue partitioned between EtO Ac/water. The organic layer was washed with water, brine, dried, filtered and concentrated under vacuum. The crude product was purified on a silica gel column (0 20% MeOH/CHCE) to produce (E)-4-((2- (4-(2,3-difluorostyryl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)-lH-benzo[d]imidazol-5- yl)methyl)morpholine (CLXXV) (65 mg, 0.13 mmol, 33.3% yield). Ή NMR (499 MHz, DMSO- de) d ppm ; ESIMS found for C28H29F2N5O2 mlz 506.2 (M+l).
Step 4
[0300] To a solution of (E)-4-((2-(4-(2,3-difluorostyryl)-l-(tetrahydro-2H-pyran-2- yl)-lH-pyrazol-3-yl)-lH-benzo[d]imidazol-5-yl)methyl)morpholine (CLXXV) (65 mg, 0.13 mmol, 1 eq) in DCE (1 mL) was added TFA (1 mL). The reaction was stirred at room temperature overnight. The reaction was concentrated under vacuum and the crude product was triturated with 7N NH3 in MeOH. The crude product was purified on a silica gel column (0 10% MeOH/CHCE) to give (E)-4-((2-(4-(2,3-difluorostyryl)-lH-pyrazol-3-yl)-lH-benzo[d]imidazol-5-yl) methyl)morpholine (143) as a white solid (39.0 mg, 0.09 mmol, 71.7% yield). 1 H N R (499 MHz, DMSO-7,) d ppm 3.09 - 3.21 (2 H, m), 3.30 (2 H, br d, .7=12.62 Hz), 3.63 (2 H, br t, J=\ 1.80 Hz), 3.97 (2 H, br d, .7=12.35 Hz), 4.47 (2 H, br s), 7.23 - 7.36 (4 H, m), 7.47 (1 H, br t, 7=7.14 Hz), 7.66 (1 H, br s), 7.80 (1 H, br s), 8.23 (1 H, br d, 7=15.37 Hz), 8.51 (1 H, br s), 13.02 (1 H, br s), 13.66 (1 H, br s); ESIMS found for C23H21F2N5O mlz 422.2 (M+l).
Example 10.
[0301] Preparation of (E)-5-methyl-4-(2-(pyridin-3-yl)vinyl)-N-(4-(pyrrolidin-l- ylmethyl) phenyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3-carboxamide (153) is depicted below in Scheme 35.
Figure imgf000138_0001
Scheme 35
Step 1
[0302] A solution of methyl 4-bromo-5-methyl-lH-pyrazole-3-carboxylate (CLXXVI) (commercially available from Aldrich) (1.0 g, 4.57 mmol, 1 eq), pTsOH (87 mg, 0.46 mmol, 0.1 eq), and DHP (1.04 mL, 11.41 mmol, 2.5 eq) in dry THF (10 mL) was heated at reflux for 4 h under Ar. The reaction concentrated under vacuum. The crude product was purified on a silica gel column (0 40% EtO Ac/hexane) to give methyl 4-bromo-5-methyl-l-(tetrahydro-2H- pyran-2-yl)-lH-pyrazole-3-carboxylate (CLXXVII) as an off-white solid (1.36 g, 4.49 mmol, 98.2% yield). ¾ NMR (499 MHz, DMSO-76) d ppm 1.52 - 1.57 (m, 2 H), 1.63 - 1.72 (m, 1 H), 1.88 (dq, 7=13.14, 3.49 Hz, 1 H), 1.96 - 2.03 (m, 1 H), 2.16 - 2.25 (m, 1 H), 2.33 (s, 3 H), 3.63 - 3.70 (m, 1 H), 3.81 (s, 3 H), 3.84 - 3.89 (m, 1 H), 5.56 (dd, 7=9.47, 2.61 Hz, 1 H); ESIMS found CiiHisBrNzCE m!z 303.1 (M+H). Step 2
[0303] To a mixture of methyl 4-bromo-5-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazole-3-carboxylate (CLXXVII) (650 mg, 2.14 mmol, 1 eq) and 4, 4,5, 5-tetramethyl-2 -vinyl- 1, 3, 2-dioxaborolane (CV) (0.436 ml, 2.57 mmol, 1.2 eq) in toluene (7 mL) was added triethylamine (0.598 mL, 4.29 mmol, 2 eq) followed by Pd(t-Bu3P)2 (11 mg, 0.021 mmol 0.01 eq) and resulting mixture was purged with argon, then capped and heated at 50°C for 22 h. The solvent was removed under vacuum, diluted with DCM, added about 100 mg of pinacol and purified on column (0 40% EtO Ac/hexanes) to afford (E)-methyl 3-methyl-l-(tetrahydro-2H-pyran-2-yl)-4-(2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)vinyl)-lH-pyrazole-5-carboxylate (CLXXVIII) as a light brown oil (600 mg, 1.595 mmol, 74.4% yield). ¾ NMR (499 MHz, DMSO-r e) d ppm 1.24 (s, 12 H), 1.51 - 1.58 (m, 2 H), 1.64 - 1.73 (m, 1 H), 1.85 - 1.91 (m, 1 H), 1.96 - 2.03 (m, 1 H), 1.99 (s, 3 H), 2.19 - 2.28 (m, 1 H), 2.42 (s, 3 H), 3.63 - 3.71 (m, 1 H), 3.80 (s, 3 H), 3.84 - 3.90 (m, 1 H), 5.55 (dd, .7=9.61, 2.47 Hz, 1 H), 5.73 (d, .7=18.94 Hz, 1 H), 7.62 (d, 7=18.94 Hz, 1 H); ESIMS found C19H29BN2O5 mlz 377.4 (M+H).
Step 3
[0304] To a microwave vial was added (E)-methyl 5-methyl-l -(tetrahydro-2H-pyran- 2-yl)-4-(2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)vinyl)-lH-pyrazole-3-carboxylate (CLXXVIII) (200 mg, 0.532 mmol, 1 eq), dioxane (8 mL) followed by 3-iodopyridine (CLXXIX) (120 mg, 0.585 mmol, 1.1 eq), K3PO4 (0.399 mL, 0.797 mmol, 1.5 eq) and Pd(PPh3)r (30.7 mg, 0.027 mmol, 0.05 eq). The reaction mixture was purged with nitrogen, sealed and heated at 80°C for 3 h. The solvent was removed in vacuo and the residue purified by silica gel column chromatography (0 100% EtO Ac/hexanes) to produce (E)-methyl 5-methyl-4-(2-(pyridin-3- yl)vinyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3-carboxylate (CLXXX) as a white solid (89 mg, 0.272 mmol, 51.1% yield). ESIMS found C18H21N3O3 mlz 328.2 (M+H).
Step 4
[0305] To a solution of (E)-methyl 5-methyl-4-(2-(pyridin-3-yl)vinyl)-l-(tetrahydro-
2H-pyran-2-yl)-lH-pyrazole-3-carboxylate (CLXXX) (89 mg, 0.272 mmol) in a mixture of MeOH (2.5 mL) and THF (2.5 mL) was added with LiOH (0.102 mL, 0.408 mmol). The mixture was stirred at room temperature for 3 h. The reaction was diluted with water (30 mL) and the pH was adjusted to 3-4 and concentrated under vacuum to produce crude (E)-5-methyl-4-(2-(pyridin-3- yl)vinyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3-carboxylic acid (CLXXXI). Used in the next step w/o purification. ESIMS found C17H19N3O3 mlz 314.2 (M+H). Step 5
[0306] To a solution of (E)-5-methyl-4-(2-(pyridin-3-yl)vinyl)-l-(tetrahydro-2H- pyran-2-yl)-lH-pyrazole-3-carboxylic acid (CLXXXI) (60 mg, 0.191 mmol, 1 eq), 4-(pyrrolidin- l-ylmethyl)aniline, HC1 (CLXXXII) (commercially available from Aldrich) (40.7 mg, 0.191 mmol, 1 eq) and HATU (80 mg, 0.211 mmol, 1.1 eq) in DMF (4 mL) was added DIPEA (100 pL, 0.574 mmol, 3 eq). The mixture was stirred at 60°C for 3 h. Water was added to the reaction mixture followed by extraction with EtOAc (2 X). The combined organic layers were washed with brine; dried with Na2SC>4, fdtered and concentrated. The crude product was added to a silica gel column (0 20% MeOH/CHCE) to give (E)-5-methyl-4-(2-(pyridin-3-yl)vinyl)-N-(4-(pyrrolidin-l- ylmethyl)phenyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole -3 -carboxamide (CLXXXIII) as a colorless oil (72 mg, 0.153 mmol, 80.1% yield). ESIMS found C28H33N5O2 mlz 472.2 (M+H)
Step 6
[0307] To a solution of (E)-5-methyl-4-(2-(pyridin-3-yl)vinyl)-N-(4-(pyrrolidin-l- ylmethyl) phenyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3-carboxamide (CLXXXIII) (70 mg, 0.148 mmol) in MeOH (2 mL) was added with 4N HC1 in dioxane (0.371 mL, 1.48 mmol). The mixture was heated at 60°C for 2 h and concentrated under vacuum. The residue was triturated with 7N NEE in MeOH and then concentrated. The crude product was added to a silica gel column (0— >10% 7N NH3 in MeOH/CHCE) to give (E)-5-methyl-4-(2-(pyridin-3-yl)vinyl)-N-(6- (pyrrolidin-l-ylmethyl)pyridin-3-yl)-lH-pyrazole-3-carboxamide (153) as a white solid (32.0 mg, 0.08 mmol, 55.6% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 1.68 (4 H, dt, 7= 6.66, 3.12 Hz), 2.37 - 2.44 (4 H, m), 3.52 (2 H, s), 6.94 (1 H, d, .7=17.02 Hz), 7.24 (2 H, d, 7=8.51 Hz), 7.38 (1 H, dd, 7=7.96, 4.67 Hz), 7.69 - 7.78 (3 H, m), 7.94 (1 H, dt, 7=8.10, 1.85 Hz), 8.42 (1 H, dd, 7=4.67, 1.65 Hz), 8.67 (1 H, d, 7=1.92 Hz), 10.01 (1 H, s), 13.29 (1 H, br s); ESIMS found for C23H25N5O mlz 388.1 (M+l).
Example 11.
[0308] Preparation of (E)-5-(4-fluorophenyl)-2-(4-(2-(pyridin-3-yl)vinyl)-lH- pyrazol-3-yl)oxazole (157) is depicted below in Scheme 36.
Figure imgf000141_0001
CLXXXIV CLXXXVI 157
Scheme 36
Step 1
[0309] A solution of (E)-4-(2-(pyridin-3-yl)vinyl)-l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazole -3 -carboxylic acid (CLXXXIV) (100 mg, 0.334 mmol, 1 eq), 2-amino-l-(4- fluorophenyl)ethanone hydrochloride (CLXXXV) (commercially available from Enamine) (76 mg, 0.401 mmol, 1.2 eq) in DMA (2 ml) was added HATU (127 mg, 0.334 mmol, 1 eq) followed by DIEA (0.146 ml, 0.835 mmol, 2.5 eq). The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with EtOAc. EtOAc layer was dried, filtered, concentrated to get crude material which was purified on a silica gel column (0 100% EtOAc/DCM) to yield (E)-N-(2-(4-fluorophenyl)-2-oxoethyl)-4-(2-(pyridin-3-yl)vinyl)-l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3 -carboxamide (CLXXXVI) (86 mg, 0.198 mmol, 59.3% yield). ESIMS found for C24H23FN4O3 mlz 435.1 (M+l).
Step 2
[0310] (E)-N -(2 -(4-fluorophenyl) -2-oxoethyl) -4 -(2-(pyridin-3 -yl)vinyl) - 1 -
(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3 -carboxamide (CLXXXVI) (86 mg, 0.198 mmol) was added to a vial followed by concentrated H2SO4 (1 mL, 18.76 mmol). The mixture was stirred at room temperature for about 30 min. The reaction was diluted with water and neutralized slowly with an aqueous NaOH solution. A white solid was collected through filtration and purified on a silica gel column (0 5% MeOH/DCM) to produce (E)-5-(4-fluorophenyl)-2-(4-(2-(pyridin-3- yl)vinyl)-lH-pyrazol-3-yl)oxazole (157) as a white solid (14.0 mg, 0.04 mmol, 21.3% yield). Ή NMR (499 MHz, DMSO-76) d ppm 7.20 (1 H, br d, .7=14.82 Hz), 7.38 (2 H, br t, 7=8.51 Hz), 7.42 (1 H, dd, 7=7.68, 4.94 Hz), 7.74 - 7.92 (4 H, m), 7.95 (1 H, br d, 7=7.68 Hz), 8.38 (1 H, br s), 8.45 (1 H, dd, 7=4.67, 1.37 Hz), 8.67 (1 H, br s), 13.58 (1 H, br s); ESIMS found for C19H13FN4O mlz 333.2 (M+l). Example 12.
[0311] Preparation of N-(6-methoxypyridin-3-yl)-4-(piperidin-4-ylethynyl)-lH- pyrazole -3 -carboxamide (175) is depicted below in Scheme 37.
Figure imgf000142_0001
Step 1
[0312] To a mixture of methyl 4-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3- carboxylate (III) (1.5 g, 4.46 mmol, 1 eq), tert- butyl 4-ethynylpiperidine-l-carboxylate (CLXXXVII) (commercially available from Advanced ChemBlocks) (1.027 g, 4.91 mmol, 1.1 eq), Pd(PPli3)4 (0.258 g, 0.223 mmol, 0.05) and copper (I) iodide (0.085 g, 0.446 mmol, 0.1 eq) in MeCN (10 mL) was purged with N2. TEA (1.24 mL, 8.93 mmol, 2 eq) was added to the above mixture and the reaction stirred at room temperature under an argon balloon for 15 h. The mixture was filtered through a pad of Celite® and concentrated under vacuum. The crude product was added to a silica gel chromatography (0 40% EtO Ac/hexanes) to give tert- butyl 4-((3- (methoxycarbonyl)- 1 -(tetrahydro-2H-pyran-2-yl)- lH-pyrazol-4-yl)ethynyl)piperidine- 1 - carboxylate (CLXXXVIII) as a colorless oil (1.7 g, 4.07 mmol, 91.3% yield). ESIMS found for C22H31N3O5 m!z 418.2 (M+l). Step 2
[0313] To a solution of tert- butyl 4-((3-(methoxycarbonyl)-l-(tetrahydro-2H-pyran- 2-yl)-lH-pyrazol-4-yl)ethynyl)piperidine-l-carboxylate (CLXXXVIII) (1.7 g, 4.07 mmol, 1 eq) in a mixture of MeOH (4 mL) and THF (4 mL) was added with LiOH (2.04 mL, 8.14 mmol, 2 eq). The mixture was stirred at room temperature for 1.5 h and then diluted with water (30 mL). The pH was adjusted to 1-2 with 10% HC1 and concentrated under vacuum. The residue was extracted with CHC1 , (30 mL x 2) and the combined organic layers were dried with anhydrous Na2SC>4, filtered and concentrated to afford 4-((l-(/ert-butoxycarbonyl)piperidin-4-yl)ethynyl)-l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3 -carboxylic acid (CLXXXIX) as a reddish brown foam (1.6 g, 3.97 mmol, 97.5% yield). It was used in the next step without purification. Ή NMR (499 MHz, DMS0- 6) d ppm 1.40 (s, 9 H), 1.45 - 1.57 (m, 4 H), 1.60 - 1.69 (m, 1 H), 1.70 - 1.77 (m, 2 H), 1.90 (br dd, .7=7.68, 2.20 Hz, 2 H), 2.01 - 2.10 (m, 1 H), 2.86 (tt, .7=7.51, 3.88 Hz, 1 H), 3.22 - 3.29 (m, 2 H), 3.52 - 3.59 (m, 2 H), 3.60 - 3.69 (m, 1 H), 3.91 (br d, .7=11.25 Hz, 1 H), 5.43 (dd, .7=9.74, 2.06 Hz, 1 H), 8.19 (s, 1 H), 12.79 (br s, 1 H); ESIMS found for C21H29N3O5 mlz 404.1 (M+l).
Step 3
[0314] In a 20 mL vial, 4-((l-(/ert-butoxycarbonyl)piperidin-4-yl)ethynyl)-l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3 -carboxylic acid (CLXXXIX) (200 mg, 0.496 mmol, 1 eq), 6-methoxypyridin-3 -amine (CXC) (67.7 mg, 0.545 mmol, 1.1 eq) and HATU (226 mg, 0.595 mmol, 1.2 eq) were dissolved in DMF (3 mL) and left open to the air. DIPEA (0.173 mL, 0.991 mmol, 2 eq) was added to the reaction mixture and stirred at room temperature for 3 h. Water (15 mL) was added to the reaction mixture followed by extraction with EtOAc. The organic layer was washed with brine, dried with Na2SC>4, filtered and concentrated. The crude product was added to a silica gel column chromatography (0 50% EtO Ac/hexanes) to give tert- butyl 4-((3- (methoxy(methyl)carbamoyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)ethynyl) piperidine- 1-carboxylate (CXCI) as a white foam (0.9 g, 2.015 mmol, 67.8% yield). ESIMS found for C27H35N5O5 mlz 510.2 (M+l).
Step 4
[0315] To a solution of +' / -butyl 4-((3-((6-methoxypyridin-3-yl)carbamoyl)-l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)ethynyl)piperidine-l-carboxylate (CXCI) (184 mg, 0.361 mmol) in DCE (3 mL) was added TFA (1 mL, 12.98 mmol). The mixture was heated at 60°C for 1 h and concentrated under vacuum. The residue was triturated with 7N N¾ in MeOH and then concentrated. The crude product was added to a silica gel column (0 10% 7N NEL in MeOH/CHCL). The fractions were concentrated and triturated in a mixture of EtO Ac/hexanes (1/1). The resulting solid was fdtered to afford N-(6-methoxypyridin-3-yl)-4-(piperidin-4- ylethynyl)-lH-pyrazole -3 -carboxamide (175) as a beige solid (68.0 mg, 0.21 mmol, 57.9% yield). ¾ NMR (499 MHz, DMSO-r/6) d ppm 1.47 (2 H, dtd, 7=12.80, 9.31, 9.31, 3.70 Hz), 1.71 - 1.78 (2 H, m), 2.51 - 2.56 (2 H, m), 2.62 - 2.72 (1 H, m), 2.86 - 2.95 (2 H, m), 3.83 (3 H, s), 6.82 (1 H, d, .7=8.78 Hz), 8.00 - 8.10 (2 H, m), 8.50 (1 H, d, 7=2.74 Hz), 10.02 (1 H, br s); ESIMS found for C17H19N5O2 m!z 326.3 (M+l).
Example 13.
[0316] Preparation of 2-(4-((5-((3,3-difluoropyrrolidin-l-yl)methyl)pyridin-3- yl)ethynyl)-lH-pyrazol-3-yl)-7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridine (203) is depicted below in Scheme 38.
Figure imgf000144_0001
Scheme 38
Step 1
[0317] To a mixture of 4-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3- carbaldehyde (VIII) (4 g, 13.07 mmol), Pd(PPli3)4 (0.755 g, 0.653 mmol, 0.05 eq) and copper (I) iodide (0.249 g, 1.307 mmol, 0.1 eq) in MeCN (40 mL) was purged with N2. Trimethylsilylacetylene (2.384 mL, 16.99 mmol, 1.3 eq) and TEA (3.64 mL, 26.1 mmol, 2 eq) were added to the above mixture and the reaction stirred at room temperature under a nitrogen atmosphere for 24 h. The mixture was concentrated, and the crude product was added to a silica gel column chromatography (0 20% EtO Ac/hexanes) to give l-(tetrahydro-2H-pyran-2-yl)-4- ((trimethylsilyl)ethynyl)-lH-pyrazole-3-carbaldehyde (CXCII) as a reddish brown oil (3.5 g, 12.66 mmol, 96.9% yield). ESIMS found for C14H20N2O2S1 mlz 277.1 (M+l).
Step 2
[0318] To a solution of l-(tetrahydro-2H-pyran-2-yl)-4-((trimethylsilyl)ethynyl)-lH- pyrazole-3-carbaldehyde (CXCII) (3.5 g, 12.66 mmol, 1 eq) in MeOH (20 mL) was added with lithium hydroxide (3.48 mL, 13.93 mmol, 1.1 eq). The mixture was stirred at room temperature for 1 h and then diluted with water. The pH was adjusted to 1 -2 with 10% HC1 and concentrated under vacuum. The residue was extracted with EtO Ac (30 mL x 2) and the combined organic layers were dried with anhydrous Na2S04, fdtered and concentrated. The crude product was added to a silica gel column chromatography (0 30% EtO Ac/hexanes) to give 4-ethynyl-l-(tetrahydro-2H-pyran-
2-yl)-lH-pyrazole-3-carbaldehyde (CXCIII) as a red oil (2.0 g, 9.79 mmol, 77.3% yield). ESIMS found for C11H12N2O2 mlz 205.0 (M+l).
Step 3
[0319] To a mixture of 4-ethynyl-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3- carbaldehyde (CXCIII) (280 mg, 1.371 mmol, 1 eq), 3-bromo-5-((3,3-difluoropyrrolidin-l- yl)methyl)pyridine (XCVII) (418 mg, 1.508 mmol, 1.1 eq), Pd(PPh3)4 (79 mg, 0.069 mmol, 0.05 eq) and copper (I) iodide (26.1 mg, 0.137 mmol, 0.1 eq) in MeCN (5 mL) was purged with N2. TEA (0.382 mL, 2.74 mmol, 2 eq) was added to the above mixture and the reaction stirred at 60°C under nitrogen atmosphere for 2 h. The mixture was concentrated, and the crude product added to a silica gel column chromatography (0 70% EtOAc/hexanes) to give 4-((5-((3,3- difluoropyrrolidin-l-yl)methyl)pyridin-3-yl)ethynyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-
3-carbaldehyde (CXCIV) as a brown oil (349 mg, 0.872 mmol, 63.6% yield). Ή NMR (499 MHz, DMSO-7,) d ppm 1.54 - 1.61 (m, 2 H), 1.65 - 1.75 (m, 1 H), 1.90 - 1.97 (m, 1 H), 1.99 - 2.04 (m, 1 H), 2.07 - 2.17 (m, 1 H), 2.20 - 2.32 (m, 2 H), 2.72 (t, .7=7.00 Hz, 2 H), 2.90 (t, 7=13.31 Hz, 2 H), 3.64 - 3.74 (m, 3 H), 3.89 - 3.99 (m, 1 H), 5.60 (dd, 7=9.61, 2.74 Hz, 1 H), 7.45 (br d, 7=5.76 Hz, 1 H), 7.86 (s, 1 H), 8.53 (s, 1 H), 8.57 - 8.85 (m, 1 H), 9.99 (s, 1 H); ESIMS found for C21H22F2N4O2 mlz 401.3 (M+l). Step 4
[0320] A solution of 4-((5-((3,3-difluoropyrrolidin-l-yl)methyl)pyridin-3- yl)ethynyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3-carbaldehyde (CXCIV) (160 mg, 0.400 mmol, 1 eq), 5-(3-fluorophenyl)pyridine-3 ,4-diamine (LXII) (89 mg, 0.440 mmol, 1.1 eq) and sulfur (14.09 mg, 0.440 mmol, 1.1 eq) in DMA (5 mL) was heated at 110°C for 4 h. The reaction mixture was diluted with water and stirred at room temperature for 15 min. The resulting solid was filtered, and the crude product added to a silica gel chromatography (0 100% EtO Ac/hexanes 5% MeOH/EtOAc) to give 2-(4-((5-((3,3-difluoropyrrolidin-l-yl)methyl)pyridin-3-yl)ethynyl)-l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)-7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridine (CXCV) as a brown oil (65 mg, 0.111 mmol, 27.9% yield). ESIMS found for C32H28F3N7O mtz 584.1 (M+l).
Step 5
[0321] To a solution of 2-(4-((5-((3,3-difluoropyrrolidin-l-yl)methyl)pyridin-3- yl)ethynyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3-yl)-7-(3-fluorophenyl)-3H-imidazo[4,5- c]pyridine (CXCV) (60 mg, 0.103 mmol) in DCE (3 mL) was added with TFA (1 mL, 12.98 mmol). The mixture was heated at 60°C for 2 h and concentrated under vacuum. The residue was triturated with 7N NEE in MeOH and then concentrated. The crude product was added to a silica gel column (0— >10% 7N NEE in MeOH/CHCE) to produce 2-(4-((5-((3,3-difluoropyrrolidin-l- yl)methyl)pyridin-3-yl)ethynyl)-lH-pyrazol-3-yl)-7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridine (203) as a light brown solid (22.0 mg, 0.04 mmol, 42.8% yield). ¾ NMR (499 MHz, DMSO-r/e) d ppm 2.17 - 2.31 (2 H, m), 2.70 (2 H, br t, J= 6.86 Hz), 2.88 (2 H, br t, .7=13.31 Hz), 3.66 (2 H, s), 7.11 - 7.19 (1 H, m), 7.26 (1 H, br s), 7.79 (1 H, br s), 8.20 (2 H, br s), 8.46 (1 H, s), 8.52 (1 H, d, .7=1.92 Hz), 8.61 (1 H, s), 8.73 (1 H, br s), 8.89 (1 H, br s), 13.64 (1 H, br s), 13.96 (1 H, br s); ESIMS found for C27H20F3N7 mlz 500.2 (M+l).
Example 14.
[0322] Preparation of N-(l-methylpiperidin-4-yl)-4-(4-(trifluoromethyl)phenyl)-lH- pyrazole -3 -carboxamide (213) is depicted below in Scheme 39.
Figure imgf000147_0001
213
Scheme 39
Step 1
[0323] To a solution of 4-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3- carboxylic acid (CXCVI) (600 mg, 2.18 mmol, 1 eq) in DMF (30 mL) was added 1- methylpiperidin-4-amine (CXCVII) (249 mg, 2.18 mmol, 1 eq) and DIPEA (0.76 mL, 4.36 mmol, 2 eq). The reaction was cooled to 0°C under Ar before adding HATU (829 mg, 2.18 mmol, 1 eq). The reaction was warmed to room temperature and stirred for 4 h. The reaction was poured into water and the solid was fdtered and dried to produce 4-bromo-N-(l-methylpiperidin-4-yl)-l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazole-3 -carboxamide (CXCVIII) light yellow solid (748 mg, 2.01 mmol, 92.4% yield). ESIMS found for Ci5H23BrN 402 IM/Z 370.9 (M+H).
Step 2
[0324] To a solution of 4-bromo-N-(l-methylpiperidin-4-yl)-l-(tetrahydro-2H- pyran-2-yl)-lH-pyrazole-3-carboxamide (CXCVIII) (249 mg, 0.671 mmol, 1 eq), (4- (trifluoromethyl)phenyl)boronic acid (CXCIX) (127 mg, 0.671 mmol, 1 eq) in a mixed solvent of dioxane (5 mL) and water (1 mL) at 0°C under Ar was added Pd(PPh ,)4 (23 mg, 0.02 mmol, 0.03 eq) and K3PC>4 (214 mg, 1.01 mmol, 1.5 eq). The reaction was stirred at 90°C for 4 h under Ar. The reaction mixture was partitioned between EtO Ac/water. The organic layer was separated, washed with water, brine, dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The resultant residue was purified by chromatography on a silica gel column (0 4% 7N NH3 in MeOH/CHCl3) to afford N-(l-methylpiperidin-4-yl)-l-(tetrahydro-2H-pyran-2-yl)-4-(4-(trifluoromethyl) phenyl)- lH-pyrazole -3 -carboxamide (CC) as a light purple solid (95 mg, 0.218 mmol, 32.4% yield). ESIMS found for C22H27F3N4O2 mlz 437.1 (M+H).
Step 3
[0325] To a solution of N-(l-methylpiperidin-4-yl)-l-(tetrahydro-2H-pyran-2-yl)-4- (4-(trifluoromethyl) phenyl) -lH-pyrazole -3 -carboxamide (CC) (95 mg, 0.218 mmol) in DCM (3 mL) was added TFA (6 mF). The mixture was stirred at room temperature for 72 h and concentrated under vacuum. The residue was triturated with 7N NFF in MeOH and then concentrated. The crude product was added to a silica gel column (0 10% 7N NFF in MeOH/CHCF) to produce N-(l- methylpiperidin-4-yl)-4-(4-(trifluoromethyl)phenyl)-lH-pyrazole-3 -carboxamide (213) as a beige solid (9.4 mg, 0.03 mmol, 12.2% yield).‘H NMR (499 MHz, DMSO-76) d ppm 1.56 (qd, J= 12 Hz, J= 3.5 Hz, 2H), 1.72 (d, J=9.5Hz, 2H), 1.93 (t, J=10.8Hz, 2H), 2.14 (s, 3H), 2.72 (d, J= 12 Hz, 2H), 3.63 - 3.74 (m, 1H), 7.68 (d, J=8Hz, 2H), 7.80 (d, J=8Hz, 2H), 8.06 (d, J=8Hz, 1H), 8.16 (s, 1H), 13.43 (br s, 1H); ESIMS found for C17H19F3N4O mlz 353.0 (M+l).
[0326] The following compounds were prepared in accordance with the procedures described in the above Schemes 1-39.
Figure imgf000148_0001
1
[0327] N-(3-(4-(3-Fluorophenyl)-lH-benzo[d]imidazol-2-yl)-lH-pyrazol-4- yl)propionamide 1.
[0328] White solid (53.9 mg, 0.15 mmol, 93.8% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.13 (t, J= 7.6 Hz, 3H), 2.43 (q, 7=7.6 Hz, 2H), 7.23 - 7.27 (m, 1H), 7.35 (t, 7=7.7 Hz, 1H), 7.49 (d, .7=7.4 Hz, 1H), 7.52 - 7.58 (m, 2H), 7.92 (d, 7=7.7 Hz, 1H), 7.99 (d, 7=10.6 Hz, 1H), 8.26 (s, 1H), 10.37 (s, 1H), 13.25 (s, 2H); ESIMS found for Ci9Hi6FN50 mlz 350.0 (M+l).
Figure imgf000149_0001
2
[0329] N-(3 -(4 -(3 -Fluorophenyl) - 1 H-benzo [d] imidazol-2-yl) - 1 H-pyrazol -4 - yl)isobutyramide 2.
[0330] White solid (44.5 mg, 0.12 mmol, 83.8% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.23 (d, =7.0Hz, 6H), 2.60 (spt, =7.0Hz, 1H), 7.23 - 7.27 (m, 1H), 7.33 - 7.36 (m, 1H), 7.47 (d, =7.4Hz, 1H), 7.52 - 7.57 (m, 2H), 7.88 (d, =7.8Hz, 1H), 7.93 - 7.95 (m, 1H), 8.26 (s, 1H), 10.36 (s, 1H), 13.25 (s, 1H); ESIMS found for C2oHi8FN50 mlz 364.1 (M+l).
Figure imgf000149_0002
3
[0331] 2,2,2-Trifluoro-N-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)- lH-pyrazol-4-yl)acetamide 3.
[0332] Brown solid (20.7 mg, 0.05 mmol). ¾ NMR (499 MHz, DMSO-d6) d ppm 7.21 (td, =8.5Hz, =2Hz, 1H), 7.50 - 7.58 (m, 1H), 7.93 (br s, 2H), 8.41 (s, 1H), 8.61 (s, 1H), 8.87 (s, 1H), 11.40 (br s, 1H), 13.77 (br s, 1H), 13.88 (br s, 1H); ESIMS found for CI7HIOF4N60 mlz 391.1 (M+l).
Figure imgf000149_0003
4
[0333] N-(3 -(4 -(3 -Fluorophenyl) - 1 H-benzo [d] imidazol-2-yl) - 1 H-pyrazol -4 - yl)acrylamide 4.
[0334] White solid (26.5 mg, 0.08 mmol, 78.7% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 5.78 - 5.86 (1 H, m), 6.21 - 6.29 (1 H, m), 6.33 - 6.42 (1 H, m), 7.27 (1 H, td, 7=8.58, 2.06 Hz), 7.32 - 7.41 (1 H, m), 7.50 (1 H, br d, .7=7.14 Hz), 7.52 - 7.57 (1 H, m), 7.57 - 7.64 (1 H, m), 7.91 (1 H, br d, .7=7.41 Hz), 8.01 (1 H, br d, 7=10.98 Hz), 8.33 (1 H, s), 10.62 (1 H, br s), 13.30 (2 H, br s); ESIMS found for CI9HI4FN50 m/z 348.1 (M+l).
Figure imgf000150_0001
5
[0335] 2-Cyclopropyl -N-(3-(4-(3-fluorophenyl)-lH-benzo[d]imidazol-2-yl)-lH- pyrazol-4-yl)acetamide 5.
[0336] White solid (54.2 mg, 0.14 mmol, 90.9% yield). ¾ NMR (399 MHz, DMSO- d6) d ppm 0.04 - 0.05 (m, 2H), 0.25 - 0.27 (m, 2H), 0.94 - 0.99 (m, 1H), 2.28 (d, 7=7.2Hz, 2H), 7.21 - 7.24 (m, 1H), 7.34 (t, 7=7.7Hz, 1H), 7.43 (d, 7=7.3Hz, 1H), 7.49 - 7.54 (m, 2H), 7.82 (d, 7=7.7Hz, 1H), 7.87 (d, j=10.3Hz, 1H), 8.29 (s, 1H), 10.41 (s, 1H), 13.25 (s, 1H); ESIMS found for C21H18FN5O m/z 375.9 (M+l).
Figure imgf000150_0002
6
[0337] N-(3-((3'-Fluoro-[l,l'-biphenyl]-3-yl)carbamoyl)-lH-pyrazol-4- yl)piperidine-4-carboxamide 6.
[0338] White solid (25.0 mg, 0.06 mmol, 52.1% yield). ¾ NMR (499 MHz, DMSO- d ) d ppm 1.47 (2 H, qd, 7=12.12, 3.98 Hz), 1.75 (2 H, br dd, 7=11.66, 1.23 Hz), 2.45 - 2.55 (2 H, m), 2.93 - 2.99 (2 H, m), 7.18 - 7.26 (1 H, m), 7.42 - 7.46 (2 H, m), 7.46 - 7.50 (1 H, m), 7.50 - 7.56 (2 H, m), 7.87 - 7.93 (1 H, m), 8.17 (1 H, s), 8.27 (1 H, s), 9.61 (1 H, br s), 10.31 (1 H, br s); ESIMS found for C22H22FN5O2 m/z 408.3 (M+l).
Figure imgf000151_0001
7
[0339] N -(3 -((5 -(3 -Fluorophenyl)pyridin-3 -yl)carbamoyl)- lH-pyrazol-4- yl)piperidine-4-carboxamide 7.
[0340] Beige solid (17.0 mg, 0.04 mmol, 70.5% yield).‘H NMR (499 MHz, DMSO- de) d ppm 1.41 - 1.54 (2 H, m), 1.69 - 1.78 (2 H, m), 2.45 - 2.55 (3 H, m), 2.91 - 3.00 (2 H, m), 7.24 - 7.34 (1 H, m), 7.54 - 7.62 (3 H, m), 8.29 (1 H, s), 8.54 (1 H, t, J= 2.20 Hz), 8.66 (1 H, d, .7=1.92 Hz), 9.05 (1 H, d, J= 2.20 Hz), 9.56 (1 H, br s); ESIMS found for C2iH2iFN602 m/z 408.8 (M+l).
Figure imgf000151_0002
8
[0341] N-(3-(4-(3-Fluorophenyl)-lH-benzo[d]imidazol-2-yl)-lH-pyrazol-4- yl)piperidine-4-carboxamide 8.
[0342] White solid (37.9 mg, 0.09 mmol, 74.4% yield). ¾ NMR (499 MHz, DMSO- de) d ppm 1.42 - 1.50 (m, 2H), 1.69 - 1.71 (m, 2H), 2.35 - 2.40 (m, 1H), 2.43 - 2.47 (m, 2H), 2.88 - 2.91 (m, 2H), 7.24 - 7.28 (m, 1H), 7.32 - 7.25 (m, 1H), 7.44 (d, =7.0Hz, 1H), 7.53 (d, =7.6Hz, 1H), 7.56 - 7.60 (m, 1H), 7.88 - 7.92 (m, 2H), 8.28 (s, 1H), 10.28 (m, 1H), 13.0 (br s, 1H); ESIMS found for C H FN O m/z 405.3 (M+l).
Figure imgf000152_0001
[0343] N-(3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazol-4- yl)piperidine-4-carboxamide 9.
[0344] White solid (70.0 mg, 0.17 mmol, 53.6% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.50 - 1.64 (2 H, m), 1.82 (2 H, br d, 7=11.25 Hz), 2.43 - 2.49 (1 H, m), 2.53 - 2.62 (2 H, m), 3.01 (2 H, br d, .7=12.08 Hz), 7.26 (1 H, td, 7=8.58, 2.33 Hz), 7.55 - 7.64 (1 H, m), 7.97 (1 H, d, 7=7.68 Hz), 8.04 (1 H, br d, 7=10.98 Hz), 8.24 (1 H, s), 8.50 (1 H, s), 8.79 (1 H, s), 10.52 (1 H, br s); ESIMS found for C21H20FN7O m!z 405.9 (M+l).
Figure imgf000152_0002
10
[0345] N-(3 -(4 -(3 -Fluorophenyl) - 1 H-benzo [d] imidazol-2-yl) - 1 H-pyrazol -4 -yl) - 1 - methylpiperidine -4 -carboxamide 10.
[0346] White solid (38.3 mg, 0.09 mmol, 64.4% yield). ¾ NMR (499 MHz, DMSO- d ) d ppm 1.57 - 1.60 (m, 2H), 1.73 - 1.75 (m, 2H), 1.82 - 1.86 (m, 2H), 2.16 (s, 3H), 2.23 - 2.26 (m, 1H), 2.70 - 2.72 (m, 2H), 7.25 - 7.28 (m, 1H), 7.34 (t, 7=7.7 Hz, 1H), 7.45 (d, 7=7.4 Hz, 1H), 7.53 (d, 7=7.8 Hz, 1H), 7.56 - 7.60 (m, 1H), 7.88 - 7.91 (m, 2H), 8.28 (s, 1H), 10.31 (s, 1H), 13.26 (s, 2H); ESIMS found for C23H23FN60 m!z 419.0 (M+l).
Figure imgf000153_0001
11
[0347] N-(3-(4-(5-Fluorothiophen-2-yl)-lH-benzo[d]imidazol-2-yl)-lH-pyrazol-4- yl)- 1 -methylpiperidine-4-carboxamide 11.
[0348] White solid (26.1 mg, 0.06 mmol, 59.2% yield). ¾ NMR (399 MHz, DMSO- de) d ppm 1.70 - 1.78 (m, 2H), 1.84 - 1.86 (m, 2H), 1.90 - 1.94 (m, 2H), 2.17 (s, 3H), 2.50 - 2.53 (m, 1H), 2.83 - 2.85 (m, 2H), 6.86 (dd, =4.2Hz, =2.2Hz, 1H), 7.29 (t, =7.8Hz, 1H), 7.43 (d, =8.4Hz, 1H), 7.57 (d, =4.0Hz, 1H), 7.67 (d, =7.5Hz, 1H), 8.31 (s, 1H), 10.24 (s, 1H), 13.29 (s, 1H); ESIMS found for C2IH2IFN6OS m/z 424.9 (M+l).
Figure imgf000153_0002
13
[0349] N-(3 -(4 -(3 -Fluorophenyl) - 1 H-benzo [d] imidazol-2-yl) - 1 H-pyrazol -4 - yl)benzamide 13.
[0350] White solid (23.1 mg, 0.06 mmol, 64.2% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 7.29 - 7.37 (m, 4H), 7.41 - 7.42 (m, 1H), 7.48 - 7.52 (m, 1H), 7.55 - 7.56 (m, 1H), 7.58 - 7.61 (m, 1H), 7.79 - 7.82 (m, 1H), 7.88 (d, J= 7.8 Hz, 1H), 8.46 (s, 1H), 10.96 (s, 1H), 13.32 (s, 1H), 13.39 (s, 1H); ESIMS found for C23HI6FN50 m!z 398.0 (M+l).
Figure imgf000153_0003
14 [0351] 4-(3,4-Difluorobenzamido)-N-(6-(2-(pyrrolidin-l-yl)ethoxy)pyridin-3-yl)- lH-pyrazole -3 -carboxamide 14.
[0352] Beige solid (13.0 mg, 0.03 mmol, 39.2% yield).‘H NMR (499 MHz, DMSO- d6) d ppm 1.67 (4 H, dt, J= 6.93, 3.26 Hz), 2.50 - 2.52 (4 H, m), 2.76 (2 H, t, .7=6.04 Hz), 4.32 (2 H, t, .7=6.04 Hz), 6.79 (1 H, d, 7=8.78 Hz), 7.40 (1 H, dt, 7=10.70, 8.51 Hz), 7.45 - 7.50 (1 H, m), 7.75 (1 H, ddd, 7=12.62, 7.96, 2.20 Hz), 8.05 (1 H, dd, 7=8.78, 2.74 Hz), 8.21 (1 H, s), 8.48 (1 H, d, 7=2.47 Hz), 10.26 (1 H, br s), 13.60 (1 H, br s); ESIMS found for C21H21F2N5O2 m/z 414.2 (M+l).
Figure imgf000154_0001
15
[0353] 4-(2,3-Difluorobenzamido)-N-(6-(piperidin-l-yl)pyridin-3-yl)-lH-pyrazole- 3 -carboxamide 15.
[0354] White solid (43.2 mg, 0.10 mmol, 47.1% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.48 - 1.64 (6 H, m), 3.43 - 3.52 (4 H, m), 6.82 (1 H, d, 7=9.06 Hz), 7.36 - 7.45 (1 H, m), 7.65 - 7.75 (1 H, m), 7.76 - 7.84 (1 H, m), 7.89 (1 H, dd, 7=9.06, 2.74 Hz), 8.39 - 8.47 (2 H, m), 10.22 (1 H, br s), 10.76 (1 H, br d, 7=7.68 Hz), 13.50 (1 H, br s); ESIMS found for C2IH2OF2N602 m/z 427.2 (M+l).
Figure imgf000154_0002
[0355] 4-(2, 6-Dichlorobenzamido) -N -(pyridin-3 -yl) - 1 H-pyrazole-3 -carboxamide 17.
[0356] White solid (20.0 mg, 0.05 mmol, 12.1% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 7.35 (dd, 7=8Hz, 7=4.5Hz, 1H), 7.48 - 7.55 (m, 1H), 7.55 - 7.59 (m, 2H), 8.18 (dd, 7=8.5Hz, 7=2Hz, 1H), 8.29 (dd, 7=5Hz, 7=1.5Hz, 1H), 8.46 (s, 1H), 8.96 (d, 7=2Hz, 1H), 10.12 (s, 1H), 10.57 (s, 1H), 13.63 (br s, 1H); ESIMS found for CieHnChNsCE m/z 376.1 (M+l).
Figure imgf000155_0001
18
[0357] 4-(3-Fluoro-5-(piperidin-4-yloxy)benzamido)-N-(6-(pyrrc>lidin-l-yl)pyridin- 3 -yl)-lH-pyrazole -3 -carboxamide 18.
[0358] Beige solid (75.0 mg, 0.15 mmol, 93.5% yield).‘H NMR (499 MHz, DMSO- d6) d ppm 1.79 - 1.90 (2 H, m), 1.92 - 1.98 (4 H, m), 2.13 (2 H, ddd, .7=10.09, 6.79, 3.16 Hz), 3.08 (2 H, ddd, .7=12.56, 8.85, 3.29 Hz), 3.26 (2 H, br dd, 7=7.41, 4.12 Hz), 3.37 (4 H, br t, 7=6.59 Hz), 4.73 - 4.81 (1 H, m), 6.45 (1 H, d, 7=8.78 Hz), 7.20 - 7.27 (2 H, m), 7.28 (1 H, d, 7=1.65 Hz), 7.85 (1 H, dd, 7=8.92, 2.61 Hz), 8.37 (1 H, br s), 8.34 (1 H, s), 8.40 (1 H, d, 7=2.47 Hz), 10.19 (1 H, s), 10.52 (1 H, s), 13.50 (1 H, br s); ESIMS found for C25H28FN7O3 m/z 494.5 (M+l).
Figure imgf000155_0002
19
[0359] N-(3-((l-Methylpiperidin-4-yl)carbamoyl)-lH-pyrazol-4-yl)nicotinamide 19.
[0360] White solid (35.0 mg, 0.11 mmol, 39.5% yield). ¾ NMR (499 MHz, DMSO- d ) d ppm 1.60 - 1.76 (m, 4H), 1.87 - 1.97 (m, 2H), 2.15 (s, 3H), 2.69 - 2.84 (m, 2H), 3.69 - 3.89 (m, 1H), 7.62 (dd, 7=8Hz, 7=5.5Hz, 1H), 8.22 (dt, 7=8Hz, 7=2Hz, 1H), 2.29 - 8.35 (m, 2H), 8.80 (dd, 7=5Hz, 7=1.5Hz, 1H), 9.05 (d, 7=2Hz, 1H), 10.81 (s, 1H), 13.34 (br s, 1H); ESIMS found for CI6H2ON602 m!z 329.1 (M+l).
Figure imgf000155_0003
20
[0361] N-(3-((3'-Fluoro-[l,r-biphenyl]-3-yl)carbamoyl)-lH-pyrazol-4- yl)nicotinamide 20.
[0362] White solid (43.0 mg, 0.11 mmol, 35.9% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 7.18 - 7.26 (1 H, m), 7.44 - 7.57 (5 H, m), 7.62 (1 H, dd, J= 7.96, 4.94 Hz), 7.95 (1 H, br d, .7=4.12 Hz), 8.16 (1 H, s), 8.26 (1 H, dt, J= 8.23, 1.78 Hz), 8.42 (1 H, s), 8.80 (1 H, dd, .7=4.80, 1.51 Hz), 9.09 (1 H, d, .7=1.65 Hz), 10.43 (1 H, br s), 10.54 (1 H, br s), 13.58 (1 H, br s); ESIMS found for C22H16FN5O2 m/z 402.3 (M+l).
Figure imgf000156_0001
21
[0363] N-(3-(Pyridin-3-ylcarbamoyl)-lH-pyrazol-4-yl)nicotinamide 21.
[0364] White solid (51.0 mg, 0.17 mmol, 42.4% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 7.39 (dd, =8.5Hz, =4.5Hz, 1H), 7.62 (ddd, =8Hz, =4.5Hz, =1.0Hz, 1H), 8.26 (dt, =8Hz, =1.5Hz, 2H), 8.32 (dd, =5Hz, =1.5Hz, 1H), 8.42 (s, 1H), 8.80 (dd, =5Hz, =1.5Hz, 1H), 9.01 (d, =2.5Hz, 1H), 9.09 (dd, =2Hz, =0.5Hz, 1H), 10.50 (s, 1H), 10.64 (s, 1H), 13.61 (s, 1H); ESIMS found for Ci5Hi2N602 m/z 309.0 (M+l).
Figure imgf000156_0002
22
[0365] N -(3 -((5 -Fluoropyridin-3 -yl)carbamoyl) - 1 H-pyrazol -4 -yl)nicotinamide 22.
[0366] White solid (15.0 mg, 0.05 mmol, 46.0% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 7.63 (dd, =8Hz, =5.5Hz, 1H), 8.23 - 8.28 (m, 2H), 8.34 (d, =3Hz, 1H), 8.43 (s, 1H), 8.81 (dd, =5Hz, =1.5Hz, 1H), 8.93 (s, 1H), 9.10 (d, =1.5Hz, 1H), 10.41 (s, 1H), 10.89 (br s, 1H), 13.66 (br s, 1H); ESIMS found for CI5HIIFN602 m/z 326.8 (M+l).
Figure imgf000157_0001
23
[0367] N-(3-((6-(Trifluoromethyl)pyridin-3-yl)carbamoyl)-lH-pyrazol-4- yl)nicotinamide 23.
[0368] White solid (8.0 mg, 0.02 mmol, 23.6% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 7.63 (ddd, =8Hz, =5Hz, =0.5Hz, 1H), 7.92 (d, =8.5Hz, 1H), 8.27 (dt, =7.5Hz, =1.5Hz, 1H), 8.44 (s, 1H), 8.59 (dd, =8.5Hz, =2Hz, 1H), 8.81 (dd, =4.5Hz, =1.5Hz, 1H), 9.10 (d, =2Hz, 1H), 9.19 (d, =2Hz, 1H), 10.41 (s, 1H), 11.03 (br s, 1H), 13.69 (br s, 1H); ESIMS found for CI6HIIF3N602 m/z 376.9 (M+l).
Figure imgf000157_0002
24
[0369] N -(3 -((6-Methoxypyridin-3 -yl)carbamoyl)- lH-pyrazol-4-yl)nicotinamide 24.
[0370] White solid (68.0 mg, 0.20 mmol, 60.9% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 3.84 (s, 3H), 6.84 (d, =9Hz, 1H), 7.62 (dd, =7.5Hz, =4.5Hz, 1H), 8.12 (dd, =8.5Hz, =2.5Hz, 1H), 8.25 (dt, =8Hz, =2Hz, 1H), 8.40 (s, 1H), 8.55 (d, =2.5Hz, 1H), 8.80 (dd, =5Hz, =1.5Hz, 1H), 9.08 (d, =2Hz, 1H), 10.48 (s, 1H), 10.56 (s, 1H), 13.50 (br s, 1H); ESIMS found for CI6HI4N603 m/z 338.9 (M+l).
Figure imgf000157_0003
25
[0371] N-(3-((6-(Pyrrolidin-l-yl)pyridin-3-yl)carbamoyl)-lH-pyrazol-4- yl)nicotinamide 25. [0372] White solid (45.0 mg, 0.12 mmol, 56.8% yield). ¾ NMR (499 MHz, DMSO- d6) 5 ppm 1.90 - 1.98 (4 H, m), 3.34 - 3.43 (4 H, m), 6.45 (1 H, d, .7=9.06 Hz), 7.62 (1 H, dd, 7=7.96, 4.67 Hz), 7.88 (1 H, dd, J= 9.06, 2.74 Hz), 8.24 (1 H, dt, 7=7.96, 2.06 Hz), 8.35 - 8.43 (2 H, m), 8.80 (1 H, dd, .7=4.80, 1.51 Hz), 9.07 (1 H, d, .7=1.92 Hz), 10.20 (1 H, br s), 10.65 (1 H, br s), 13.48 (1 H, br s); ESIMS found for C19H19N7O2 m!z 378.0 (M+l).
Figure imgf000158_0001
26
[0373] N-(3 -((6-(3 ,3 -Difluoropyrrolidin- 1 -yl)pyridin-3 -yl)carbamoyl)- lH-pyrazol-
4-yl)nicotinamide 26.
[0374] Off-white solid (39.0 mg, 0.09 mmol, 23.5% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 2.51 - 2.61 (2 H, m), 3.61 (2 H, t, 7=7.27 Hz), 3.82 (2 H, t, 7=13.31 Hz), 6.58 (1 H, d, 7=8.78 Hz), 7.62 (1 H, dd, 7=7.82, 4.80 Hz), 7.98 (1 H, dd, 7=8.78, 2.47 Hz), 8.24 (1 H, dt, 7=8.03, 1.89 Hz), 8.39 (1 H, s), 8.49 (1 H, d, 7=2.20 Hz), 8.80 (1 H, dd, 7=4.67, 1.37 Hz), 9.07 (1 H, d, 7=1.65 Hz), 10.31 (1 H, br s), 10.62 (1 H, br s), 13.51 (1 H, br s); ESIMS found for C19H17F2N7O2 m!z 413.9 (M+l).
Figure imgf000158_0002
27
[0375] N -(3 -((6-(Piperidin- 1 -yl)pyridin-3 -yl)carbamoyl)- lH-pyrazol-4- yl)nicotinamide 27.
[0376] Off-white solid (23.0 mg, 0.06 mmol, 49.0% yield). Ή NMR (499 MHz, DMSO-7e) d ppm 1.50 - 1.57 (m, 4H), 1.57 - 1.63 (m, 2H), 3.43 - 3.51 (m, 4H), 6.82 (d, 7=9Hz, 1H), 7.62 (dd, 7=7.5Hz, 7=3Hz, 1H), 7.92 (dd, 7=9Hz, 7=2.5Hz, 1H), 8.24 (dt, 7=8Hz, 7=2Hz, 1H), 8.39 (d, 7=1.0Hz, 1H), 8.46 (d, 7=2Hz, 1H), 9.07 (d, J=2Hz, 1H), 10.27 (s, 1H), 10.63 (s, 1H), 13.51 (s, 1H); ESIMS found for C20H21N7O2 m/z 392.0 (M+l).
Figure imgf000159_0001
28
[0377] N-(3-((5-(3-Fluorophenyl)pyridin-3-yl)carbamoyl)-lH-pyrazol-4- yl)nicotinamide 28.
[0378] Beige solid (49.0 mg, 0.12 mmol, 62.4% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 7.25 - 7.33 (1 H, m), 7.54 - 7.60 (3 H, m), 7.60 - 7.64 (1 H, m), 8.27 (1 H, dt, J= 8.23, 1.78 Hz), 8.43 (1 H, s), 8.54 (1 H, t, J= 2.20 Hz), 8.68 (1 H, d, .7=1.92 Hz), 8.80 (1 H, dd, .7=4.94, 1.65 Hz), 9.09 (2 H, dd, 7=6.04, 1.92 Hz), 10.46 (1 H, br s), 10.71 (1 H, br s), 13.64 (1 H, br s); ESIMS found for C2iHi5FN602 m/z 403.3 (M+l).
Figure imgf000159_0002
29
[0379] N-(3-(lH-Indol-2-yl)-lH-pyrazol-4-yl)nicotinamide 29.
[0380] Beige solid (15.8 mg, 0.05 mmol, 53.1% yield). ¾ NMR (499 MHz, DMSO- ά6) d ppm 6.69 (s, 1H), 6.96 (br s, 1H), 7.07 (t, 7=7.5Hz, 1H), 7.41 (d, 7=8Hz, 1H), 7.51 (d, 7=7.5Hz, 1H), 7.60 (dd, 7=8Hz, 7=5Hz, 1H), 8.02 Br s, 1H), 8.36 (d, 7=8Hz, 1H), 8.78 (d, 7=4Hz, 1H), 9.19 (s, 1H), 10.07 (s, 1H), 11.31 (br s, 1H), 13.09 (br s, 1H); ESIMS found for C17H13N5O m/z 304.0 (M+l).
Figure imgf000159_0003
30
[0381] N-(3-((lH-Benzo[d]imidazol-2-yl)carbamoyl)-lH-pyrazol-4-yl)nicotinamide 30.
[0382] Tan solid (135.8 mg, 0.39 mmol, 68.0% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 7.21 (2 H, dd, 7=5.90, 3.16 Hz), 7.45 - 7.53 (2 H, m), 7.59 - 7.69 (1 H, m), 8.28 - 8.35 (2 H, m), 8.82 (1 H, dd, 7=4.94, 1.65 Hz), 9.15 (1 H, d, .7=1.65 Hz), 10.85 (1 H, br s), 12.61 (2 H, br s); ESIMS found for C17H13N7O2 m/z 348.2 (M+l).
Figure imgf000160_0001
31
[0383] N-(3 -(4 -(3 -Fluorophenyl) - 1 H-benzo [d] imidazol-2-yl) - 1 H-pyrazol -4 - yl)nicotinamide 31.
[0384] Off-white solid (227.8 mg, 0.57 mmol, 76.4% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 7.24 (1 H, td, 7=8.51, 2.20 Hz), 7.35 (2 H, t, 7=7.55 Hz), 7.43 (1 H, br d, 7=7.68 Hz), 7.46 - 7.52 (1 H, m), 7.55 (1 H, br d, 7=7.41 Hz), 7.76 (1 H, br d, 7=9.88 Hz), 7.94 (1 H, br d, 7=7.41 Hz), 8.04 - 8.10 (1 H, m), 8.46 (1 H, s), 8.80 (1 H, br d, 7=4.67 Hz), 9.07 (1 H, s), 10.98 (1 H, br s), 13.36 (2 H, br s); ESIMS found for C22HI5FN60 m/z 398.9 (M+l).
Figure imgf000160_0002
32
[0385] N-(3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazol-4- yl)nicotinamide 32.
[0386] Brown solid (10.0 mg, 0.30 mmol, 10.5% yield). *H NMR (499 MHz, DMSO- d6) d ppm 7.31 (1 H, td, 7=8.58, 2.33 Hz), 7.38 - 7.47 (1 H, m), 7.53 - 7.62 (1 H, m), 7.85 (1 H, br d, 7=9.06 Hz), 8.03 (1 H, br d, 7=6.59 Hz), 8.15 (1 H, br d, 7=5.49 Hz), 8.49 (1 H, br s), 8.59 (1 H, br s), 8.81 (1 H, br d, .7=4.67 Hz), 8.85 (1 H, br s), 9.11 (1 H, br s), 10.84 (1 H, br s), 13.60 (1 H, br s), 13.76 (1 H, br s); ESIMS found for C2IHI4FN70 m/z 400.4 (M+l).
Figure imgf000161_0001
35
[0387] 5-Fluoro-N-(3-((6-(trifluoromethyl)pyridin-3-yl)carbamoyl)-lH-pyrazol-4- yl)nicotinamide 35.
[0388] White solid (34.0 mg, 0.09 mmol, 66.5% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 7.91 (1 H, d, .7=8.51 Hz), 8.16 (1 H, dt, .7=8.78, 2.33 Hz), 8.42 (1 H, s), 8.58 (1 H, dd, .7=8.51, 1.65 Hz), 8.84 (1 H, d, 7=2.74 Hz), 8.96 (1 H, s), 9.18 (1 H, d, 7=1.10 Hz), 10.41 (1 H, br s), 11.01 (1 H, br s), 13.69 (1 H, br s); ESIMS found for CI6HIOF4N602 m/z 394.7 (M+l).
Figure imgf000161_0002
36
[0389] 5-fluoro-N-(3-((6-(pyrrolidin-l-yl)pyridin-3-yl)carbamoyl)-lH-pyrazol-4- yl)nicotinamide 36.
[0390] White solid (28.6 mg, 0.07 mmol). *HNMR (499 MHz, DMSO-T,) d ppm 1.94 (4 H, dt, 7=6.31, 3.43 Hz), 3.37 (4 H, br t, 7=6.59 Hz), 6.44 (1 H, d, 7=9.06 Hz), 7.88 (1 H, dd, 7=8.92, 2.61 Hz), 8.12 (1 H, dt, 7=9.13, 2.30 Hz), 8.37 (1 H, s), 8.40 (1 H, d, 7=2.47 Hz), 8.83 (1 H, d, 7=2.74 Hz), 8.93 (1 H, s), 10.19 (1 H, br s), 10.64 (1 H, br s), 13.50 (1 H, br s); ESIMS found for C19H18FN7O2 m/z 395.8 (M+l).
Figure imgf000162_0001
37
[0391] N-(3-((6-(3,3-Difluoropyrrolidin-l-yl)pyridin-3-yl)carbamoyl)-lH-pyrazol- 4-yl)-5-fluoronicotinamide 37.
[0392] Off-white solid (16.1 mg, 0.04 mmol, 22.2% yield). Ή NMR (499 MHz, DMSO-7,) d ppm 2.52 - 2.60 (2 H, m), 3.61 (2 H, t, .7=7.27 Hz), 3.82 (2 H, t, .7=13.45 Hz), 6.58 (1 H, d, .7=9.06 Hz), 7.98 (1 H, dd, 7=8.92, 2.33 Hz), 8.13 (1 H, dt, 7=9.06, 2.20 Hz), 8.38 (1 H, s), 8.49 (1 H, d, 7=2.20 Hz), 8.83 (1 H, d, 7=2.74 Hz), 8.93 (1 H, s), 10.29 (1 H, br d, 7=1.10 Hz), 10.60 (1 H, br s), 13.52 (1 H, br s); ESIMS found for Ci9Hi6F3N702 m!z 431.9 (M+l).
Figure imgf000162_0002
38
[0393] 5 -Fluoro-N-(3 -((6-(piperazin- 1 -yl)pyridin-3 -yl)carbamoyl)- lH-pyrazol-4- yl)nicotinamide 38.
[0394] White solid (28.0 mg, 0.07 mmol, 45.0% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 2.74 - 2.83 (4 H, m), 3.34 - 3.38 (4 H, m), 6.80 (1 H, d, 7=9.06 Hz), 7.94 (1 H, dd, 7=9.06, 2.74 Hz), 8.10 - 8.17 (1 H, m), 8.37 (1 H, s), 8.48 (1 H, d, 7=2.74 Hz), 8.83 (1 H, d, 7=2.74 Hz), 8.93 (1 H, t, 7=1.51 Hz), 10.29 (1 H, br s), 10.60 (1 H, br s), 13.50 (1 H, br s); ESIMS found for CigHisFNgCF m/z 410.6 (M+l).
Figure imgf000163_0001
39
[0395] 5-Fluoro-N-(3 -((6-(4-methylpiperazin- 1 -yl)pyridin-3-yl)carbamoyl)- 1H- pyrazol-4-yl)nicotinamide 39.
[0396] White solid (7.9 mg, 0.02 mmol, 31.0% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 2.21 (3 H, s), 2.36 - 2.42 (4 H, m), 3.40 - 3.47 (4 H, m), 6.84 (1 H, d, .7=9.06 Hz), 7.95 (1 H, dd, 7=9.06, 2.47 Hz), 8.08 - 8.16 (1 H, m), 8.37 (1 H, s), 8.49 (1 H, d, 7=2.47 Hz), 8.83 (1 H, d, 7=2.74 Hz), 8.93 (1 H, s), 10.29 (1 H, br s), 10.59 (1 H, s), 13.52 (1 H, br s); ESIMS found for C20H21FN8O2 m/z 424.8 (M+l).
Figure imgf000163_0002
[0397] 5-Fluoro-N-(3-((6-(piperidin-4-yloxy)pyridin-3-yl)carbamoyl)-lH-pyrazol-4- yl)nicotinamide 40.
[0398] Off-white solid (60.1 mg, 0.14 mmol, 74.4% yield). Ή NMR (499 MHz, DMSO-7 d ppm 1.47 - 1.59 (2 H, m), 1.92 - 2.01 (2 H, m), 2.62 - 2.71 (2 H, m), 3.00 (2 H, dt, 7=12.49, 4.19 Hz), 4.98 - 5.06 (1 H, m), 6.79 (1 H, d, 7=9.06 Hz), 8.10 (1 H, dd, 7=8.92, 2.61 Hz),
8.13 (1 H, dt, 7=9.13, 2.30 Hz), 8.38 (1 H, s), 8.51 (1 H, d, 7=2.74 Hz), 8.83 (1 H, d, 7=2.74 Hz), 8.93 (1 H, s), 10.48 (2 H, br s); ESIMS found for C20H20FN7O3 m/z 426.0 (M+l).
Figure imgf000163_0003
[0399] 5-Fluoro-N-(3-((6-((l-methylpiperidin-4-yl)oxy)pyridin-3-yl)carbamoyl)- lH-pyrazol-4-yl)nicotinamide 41.
[0400] White solid (25.0 mg, 0.06 mmol, 34.2% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.59 - 1.71 (2 H, m), 1.90 - 1.99 (2 H, m), 2.08 - 2.22 (2 H, m), 2.18 (3 H, s), 2.58 - 2.68 (2 H, m), 4.93 (1 H, tt, 7=8.64, 4.25 Hz), 6.79 (1 H, d, .7=8.78 Hz), 8.09 (1 H, dd, 7=8.92, 2.61 Hz), 8.11 - 8.16 (1 H, m), 8.38 (1 H, s), 8.51 (1 H, d, 7=2.47 Hz), 8.83 (1 H, d, 7=2.74 Hz), 8.91 - 8.96 (1 H, m), 10.45 (1 H, br s), 10.55 (1 H, br s), 13.56 ( 1 H, br s); ESIMS found for C21H22FN7O3 m/z 439.8 (M+l).
Figure imgf000164_0001
42
[0401] 5-Fluoro-N-(3-((6-(2-(pyrrobdin-l-yl)ethoxy)pyridin-3-yl)carbamoyl)-lH- pyrazol-4-yl)nicotinamide 42.
[0402] White solid (14.0 mg, 0.03 mmol, 20.9% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.92 (4 H, br s), 2.50 - 2.53 (4 H, m), 3.50 (2 H, br s), 4.53 (2 H, br t, 7=5.08 Hz), 6.91 (1 H, d, 7=8.78 Hz), 8.07 - 8.16 (1 H, m), 8.18 (1 H, dd, 7=8.78, 2.74 Hz), 8.39 (1 H, s), 8.59 (1 H, d, 7=2.47 Hz), 8.84 (1 H, d, 7=2.74 Hz), 8.93 (1 H, s), 10.53 (2 H, s), 13.61 (1 H, s); ESIMS found for C21H22FN7O3 m/z 440.1 (M+l).
Figure imgf000164_0002
43
[0403] 5-Fluoro-N-(3-((6-phenylpyridin-3-yl)carbamoyl)-lH-pyrazol-4- yl)nicotinamide 43.
[0404] White solid (10.0 mg, 0.03 mmol, 76.0% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 7.37 - 7.44 (1 H, m), 7.46 - 7.52 (2 H, m), 7.98 (1 H, d, 7=8.23 Hz), 8.06 (1 H, s), 8.07 - 8.10 (1 H, m), 8.15 - 8.20 (1 H, m), 8.37 (1 H, dd, 7=8.64, 2.61 Hz), 8.42 (1 H, s), 8.84 (1 H, d, .7=2.74 Hz), 8.96 (1 H, s), 9.10 (l H, d, .7=2.20 Hz), 10.51 (1 H, br s), 10.74 (1 H, br s), 13.64 (1 H, br s); ESIMS found for C2iHi5FN602 m/z 403.3 (M+l).
Figure imgf000165_0001
44
[0405] 5 -Fluoro-N-(3 -((5 -(3 -fluorophenyl)pyridin-3 -yl)carbamoyl)- lH-pyrazol-4- yl)nicotinamide 44.
[0406] White solid (20.0 mg, 0.05 mmol, 60.0% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 7.25 - 7.34 (1 H, m), 7.53 - 7.63 (3 H, m), 8.13 - 8.21 (1 H, m), 8.42 (1 H, s), 8.54 (1 H, t, 7=1.92 Hz), 8.68 (1 H, d, 7=2.20 Hz), 8.83 (1 H, d, 7=2.74 Hz), 8.96 (1 H, s), 9.08 (1 H, d, 7=1.92 Hz), 10.45 (1 H, br s), 10.70 (1 H, br s), 13.67 (1 H, br s); ESIMS found for C2IHI4F2N602 m/z 421.1 (M+l).
Figure imgf000165_0002
45
[0407] 5 -Fluoro-N -(3 -(quinolin-3 -ylcarbamoyl) - 1 H-pyrazol -4 -yl)nicotinamide 45.
[0408] Brown solid (12.0 mg, 0.03 mmol, 73.4% yield). *H NMR (499 MHz, DMSO- de) d ppm 7.56 - 7.62 (1 H, m), 7.68 (1 H, ddd, 7=8.44, 6.93, 1.37 Hz), 7.95 - 7.98 (1 H, m), 7.99 (1 H, s), 8.15 - 8.22 (1 H, m), 8.43 (1 H, s), 8.85 (1 H, d, 7=2.74 Hz), 8.90 (1 H, d, 7=2.20 Hz), 8.95 - 9.01 (1 H, m), 9.24 (1 H, d, 7=1.92 Hz), 10.51 (1 H, br s), 10.88 (1 H, br s), 13.66 (1 H, br s); ESIMS found for Ci9Hi3FN602 m/z 377.3 (M+l).
Figure imgf000165_0003
46
[0409] 5 -Chloro-N -(3 -((6 -(trifluoromethyl)pyridin-3 -yl)carbamoyl) - 1 H-pyrazol-4 - yl)nicotinamide 46.
[0410] Off-white solid (24.0 mg, 0.06 mmol, 41.3% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 7.91 (1 H, d, .7=8.51 Hz), 8.35 (1 H, t, .7=2.06 Hz), 8.41 (1 H, s), 8.53 - 8.62 (1 H, m), 8.87 (1 H, d, 7= 2.20 Hz), 9.02 (1 H, d, .7=1.92 Hz), 9.18 (1 H, d, .7=1.10 Hz), 10.40 (1 H, br s), 10.35 - 10.46 (1 H, m), 11.00 (1 H, br s), 13.69 (1 H, br s); ESIMS found for CieHioC^NeOz m!z 411.0 (M+l).
Figure imgf000166_0001
47
[0411] 5-Chloro-N-(3-((6-(pyrrolidin-l-yl)pyridin-3-yl)carbamoyl)-lH-pyrazol-4- yl)nicotinamide 47.
[0412] White solid (33.0 mg, 0.08 mmol). *HNMR (499 MHz, DMSO-7,) d ppm 1.94 (4 H, dt, 7=6.31, 3.43 Hz), 3.37 (4 H, br t, 7=6.59 Hz), 6.45 (1 H, d, 7=9.06 Hz), 7.88 (1 H, dd, 7=8.92, 2.61 Hz), 8.28 - 8.34 (1 H, m), 8.37 (1 H, s), 8.40 (1 H, d, 7=2.47 Hz), 8.87 (1 H, d, 7=2.47 Hz), 8.99 (1 H, d, 7=1.65 Hz), 10.18 (1 H, br s), 10.62 (1 H, br s), 13.49 (1 H, br s); ESIMS found for C19H18CIN7O2 m!z 411.9 (M+l).
Figure imgf000166_0002
48
[0413] 5 -Chloro-N -(3 -((6 -(3 ,3 -difluoropyrrolidin- 1 -yl)pyridin-3 -yl)carbamoyl) - 1 H- pyrazol-4-yl)nicotinamide 48.
[0414] Off-white solid (22.5 mg, 0.05 mmol, 28.9% yield). ¾ NMR (499 MHz, DMSO-7 d ppm 2.51 - 2.60 (2 H, m), 3.61 (2 H, t, 7=7.27 Hz), 3.82 (2 H, t, 7=13.45 Hz), 6.58 (1 H, d, .7=9.06 Hz), 7.98 (1 H, dd, 7=9.06, 2.47 Hz), 8.31 (1 H, t, 7=2.06 Hz), 8.37 (1 H, s), 8.49 (1 H, d, 7=2.20 Hz), 8.86 (1 H, d, 7=2.20 Hz), 8.99 (1 H, d, 7=1.65 Hz), 10.29 (1 H, br s), 10.58 (1 H, br s), 13.52 (1 H, br s); ESIMS found for CigHieClFzNvCE m/z 448.0 (M+l).
Figure imgf000167_0001
49
[0415] 5-Chloro-N-(3-((6-(piperidin-l-yl)pyridin-3-yl)carbamoyl)-lH-pyrazol-4- yl)nicotinamide 49.
[0416] White solid (20.0 mg, 0.05 mmol, 35.7% yield). ¾ NMR (499 MHz, DMSO- de) d ppm 1.49 - 1.57 (4 H, m), 1.57 - 1.64 (2 H, m), 3.43 - 3.51 (4 H, m), 6.82 (1 H, d, 7=9.06 Hz), 7.91 (1 H, dd, 7=9.06, 2.47 Hz), 8.31 (1 H, t, 7=2.06 Hz), 8.37 (1 H, s), 8.45 (1 H, d, 7=2.20 Hz), 8.86 (1 H, d, 7=2.20 Hz), 8.99 (1 H, d, 7=1.92 Hz), 10.24 (1 H, br s), 10.59 (1 H, br s), 13.51 (1 H, br s); ESIMS found for C20H20CIN7O2 m/z 425.6 (M+l).
Figure imgf000167_0002
50
[0417] 5-Chloro-N-(3 -((5 -(piperidin- 1 -ylmethyl)pyridin-3 -yl)carbamoyl)- 1H- pyrazol-4-yl)nicotinamide 50.
[0418] Beige solid (40.0 mg, 0.09 mmol, 47.6% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.35 - 1.43 (2 H, m), 1.50 (4 H, quin, 7=5.49 Hz), 2.34 (4 H, br s), 3.46 (2 H, s), 8.21 (2 H, s), 8.34 (1 H, t, 7=2.20 Hz), 8.38 (1 H, s), 8.86 (2 H, t, 7=1.92 Hz), 9.01 (1 H, d, 7=1.65 Hz), 10.46 (1 H, br s), 10.58 (1 H, br s), 13.59 (1 H, br s); ESIMS found for C21H22CIN7O2 m/z 439.7 (M+l).
Figure imgf000168_0001
51
[0419] 5-Chloro-N-(3-((6-(piperazin-l-yl)pyridin-3-yl)carbamoyl)-lH-pyrazol-4- yl)nicotinamide 51.
[0420] White solid (37.0 mg, 0.09 mmol, 60.8% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 2.74 - 2.83 (4 H, m), 3.34 - 3.39 (4 H, m), 6.81 (1 H, d, .7=9.33 Hz), 7.93 (1 H, dd, 7=9.06, 2.74 Hz), 8.31 (1 H, t, 7=2.06 Hz), 8.37 (1 H, s), 8.48 (1 H, d, 7=2.47 Hz), 8.86 (1 H, d, 7=2.47 Hz), 8.99 (1 H, d, 7=1.92 Hz), 10.28 (1 H, br s), 10.58 (1 H, br s), 13.48 (1 H, br s); ESIMS found for CigHisClNgCE m/z 427.0 (M+l).
Figure imgf000168_0002
52
[0421] 5-Chloro-N-(3-((6-(4-methylpiperazin-l-yl)pyridin-3-yl)carbamoyl)-lH- pyrazol-4-yl)nicotinamide 52.
[0422] Off-white solid (17.1 mg, 0.04 mmol, 60.0% yield). Ή NMR (499 MHz, DMSO-7 d ppm 2.22 (3 H, s), 2.41 (4 H, br t, 7=4.53 Hz), 3.41 - 3.49 (4 H, m), 6.84 (1 H, d, 7=9.33 Hz), 7.95 (1 H, dd, 7=9.19, 2.61 Hz), 8.32 (1 H, t, 7=2.06 Hz), 8.37 (1 H, s), 8.49 (1 H, d, 7=2.47 Hz), 8.87 (1 H, d, 7=2.20 Hz), 8.99 (1 H, d, 7=1.92 Hz), 10.28 (1 H, s), 10.58 (1 H, s), 13.52 (1 H, br s); ESIMS found for CzoHziCINgOz m/z 441.2 (M+l).
Figure imgf000168_0003
53
[0423] 5 -Chloro-N -(3 -((6 -(piperidin-4-yloxy)pyridin-3 -yl)carbamoyl) - 1 H-pyrazol -
4-yl)nicotinamide 53.
[0424] Off-white solid (56.1 mg, 0.13 mmol, 63.6% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 1.41 - 1.54 (2 H, m), 1.90 - 1.99 (2 H, m), 2.55 - 2.63 (2 H, m), 2.96 (2 H, dt, •7=12.76, 4.05 Hz), 4.94 - 5.05 (1 H, m), 6.78 (1 H, d, .7=8.78 Hz), 8.09 (1 H, dd, 7=8.92, 2.61 Hz), 8.32 (1 H, t, 7=2.06 Hz), 8.37 (1 H, s), 8.50 (1 H, d, 7=2.74 Hz), 8.86 (1 H, d, 7=2.20 Hz), 9.00 (1 H, d, 7=1.92 Hz), 10.50 (2 H, br s); ESIMS found for C20H20CIN7O3 m!z 442.0 (M+l).
Figure imgf000169_0001
54
[0425] 5-Chloro-N-(3 -((6-(( 1 -methylpiperidin-4-yl)oxy)pyridin-3 -yl)carbamoyl)- lH-pyrazol-4-yl)nicotinamide 54.
[0426] White solid (35.0 mg, 0.08 mmol, 41.4% yield). ¾ NMR (499 MHz, DMSO- de) d ppm 1.79 (1 H, ddd, 7=7.27, 5.08, 2.20 Hz), 1.94 - 2.19 (2 H, m), 2.22 - 2.35 (1 H, m), 2.51 - 2.53 (1 H, m), 2.81 (3 H, br s), 3.07 - 3.26 (2 H, m), 3.41 - 3.58 (1 H, m), 5.03 - 5.31 (1 H, m), 6.86 (1 H, br d, 7=8.51 Hz), 8.15 (1 H, br d, 7=7.96 Hz), 8.32 (1 H, t, 7=2.06 Hz), 8.39 (1 H, s), 8.56 (1 H, d, 7=2.20 Hz), 8.87 (1 H, d, 7=2.47 Hz), 8.99 (1 H, d, 7=1.92 Hz), 9.52 (1 H, br s), 10.50 (1 H, s), 10.51 (1 H, s), 13.60 (1 H, s); ESIMS found for C21H22CIN7O3 m/z 456.3 (M+l).
Figure imgf000169_0002
[0427] 5-Chloro-N-(3-((6-(2-(pyrrolidin-l-yl)ethoxy)pyridin-3-yl)carbamoyl)-lH- pyrazol-4-yl)nicotinamide 55.
[0428] Beige solid (46.0 mg, 0.10 mmol, 60.4% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.74 (4 H, br s), 2.69 (4 H, br s), 2.95 (2 H, br s), 4.38 (2 H, br t, 7=5.63 Hz), 6.84 (1 H, d, 7=8.78 Hz), 8.12 (1 H, dd, 7=8.92, 2.61 Hz), 8.32 (1 H, t, 7=2.06 Hz), 8.38 (1 H, s), 8.55 (1 H, d, .7=2.47 Hz), 8.87 (1 H, d, 7=2.20 Hz), 8.99 (1 H, d, 7=1.65 Hz), 10.47 (1 H, s), 10.52 (1 H, s), 13.57 (1 H, br s); ESIMS found for C21H22CIN7O3 m/z 456.3 (M+l).
Figure imgf000170_0001
56
[0429] N-(3-((3-Isopropoxypropyl)carbamoyl)-lH-pyrazol-4-yl)-6- methylnicotinamide 56.
[0430] White solid (50.0 mg, 0.15 mmol, 25.3% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.09 (6 H, d, 7=6.04 Hz), 1.74 (2 H, quin, 7=6.59 Hz), 2.56 (3 H, s), 3.35 (2 H, q, 7=6.77 Hz), 3.42 (2 H, t, 7=6.04 Hz), 3.52 (1 H, spt, 7=6.08 Hz), 7.46 (1 H, d, 7=7.96 Hz), 8.09 (1 H, dd, 7=8.23, 2.47 Hz), 8.29 (1 H, s), 8.47 (1 H, br s), 8.93 (1 H, d, 7=1.92 Hz), 10.74 (1 H, br s), 13.29 (1 H, br s); ESIMS found for C17H23N5O3 m/z 345.8 (M+l).
Figure imgf000170_0002
[0431] 6-Methyl -N-(3-((6-(2-(pyrrolidin-l-yl)ethoxy )pyridin-3-yl)carbamoyl)-lH- pyrazol-4-yl)nicotinamide 57.
[0432] White solid (40.0 mg, 0.09 mmol, 43.4% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.68 (4 H, dt, 7=6.86, 3.16 Hz), 2.50 - 2.53 (4 H, m), 2.57 (3 H, s), 2.77 (2 H, t, 7=6.04 Hz), 4.33 (2 H, t, 7=5.90 Hz), 6.83 (1 H, d, 7=9.33 Hz), 7.46 (1 H, d, 7=7.96 Hz), 8.11 (2 H, td, 7=8.30, 2.61 Hz), 8.38 (1 H, s), 8.53 (1 H, d, 7=2.47 Hz), 8.95 (1 H, d, 7=1.92 Hz), 10.46 (1 H, br s), 10.51 (1 H, br s), 13.53 (1 H, br s); ESIMS found for C22H25N7O3 m/z 436.4 (M+l).
Figure imgf000170_0003
58
[0433] 6-(Trifluoromethyl)-N-(3-((6-(trifluoromethyl)pyridin-3-yl)carbamoyl)-lH- pyrazol-4-yl)nicotinamide 58.
[0434] Off-white solid (21.0 mg, 0.05 mmol, 53.1% yield). ¾ NMR (499 MHz, DMSO- e) d ppm 7.92 (1 H, d, .7=8.51 Hz), 8.14 (1 H, d, .7=8.23 Hz), 8.45 (1 H, s), 8.53 (1 H, dd, 7= 7.82, 2.06 Hz), 8.57 (1 H, dd, 7= 8.23, 1.65 Hz), 9.20 (1 H, d, .7=1.65 Hz), 9.24 (1 H, d, .7=1.37 Hz), 10.51 (1 H, br s), 11.02 (1 H, br s), 13.72 (1 H, br s); ESIMS found for CI7HIOF6N602 mlz 444.6 (M+l).
Figure imgf000171_0001
59
[0435] N-(3-((6-(Pyrrolidin-l-yl)pyridin-3-yl)carbamoyl)-lH-pyrazol-4-yl)-6- (trifluoromethyl)nicotinamide 59.
[0436] White solid (32.4 mg, 0.07 mmol). *HNMR (499 MHz, DMSO-7,) d ppm 1.89 - 1.97 (4 H, m), 3.37 (4 H, br t, 7=6.59 Hz), 6.44 (1 H, d, 7=9.06 Hz), 7.88 (1 H, dd, 7=8.92, 2.61 Hz), 8.13 (1 H, d, 7=8.23 Hz), 8.36 - 8.44 (2 H, m), 8.50 (1 H, dd, 7=8.23, 1.65 Hz), 9.21 (1 H, d, 7=1.37 Hz), 10.20 (1 H, s), 10.73 (1 H, s), 13.52 (1 H, s); ESIMS found for C20H18F3N7O2 mlz 445.9 (M+l).
Figure imgf000171_0002
[0437] N-(3 -((6-(3 ,3 -Difluoropyrrolidin- 1 -yl)pyridin-3 -yl)carbamoyl)- lH-pyrazol-
4-yl) -6 -(trifluoromethyl)nicotinamide 60.
[0438] Off-white solid (35.2 mg, 0.07 mmol, 46.5% yield). ¾ NMR (499 MHz, DMSO-7 d ppm 2.51 - 2.60 (2 H, m), 3.61 (2 H, t, 7=7.27 Hz), 3.82 (2 H, t, 7=13.31 Hz), 6.58 (1 H, d, .7=9.06 Hz), 7.99 (1 H, dd, .7=8.92, 2.61 Hz), 8.13 (1 H, d, 7=8.23 Hz), 8.41 (1 H, s), 8.47 - 8.54 (2 H, m), 9.22 (1 H, d, 7=1.65 Hz), 10.31 (1 H, s), 10.69 (1 H, s), 13.54 (1 H, s); ESIMS found for C20H16F5N7O2 m/z 482.0 (M+l).
Figure imgf000172_0001
61
[0439] N -(3 -((6-(Piperidin- 1 -yl)pyridin-3 -yl)carbamoyl)- lH-pyrazol-4-yl)-6-
(trifluoromethyl)nicotinamide 61.
[0440] Yellow solid (13.0 mg, 0.03 mmol, 41.6% yield). *HNMR (499 MHz, DMSO- de) d ppm 1.49 - 1.57 (4 H, m), 1.57 - 1.65 (2 H, m), 3.43 - 3.51 (4 H, m), 6.82 (1 H, d, 7=9.06 Hz), 7.91 (1 H, dd, 7=9.06, 2.74 Hz), 8.13 (1 H, d, 7=8.23 Hz), 8.41 (1 H, s), 8.46 (1 H, d, 7=2.47 Hz), 8.50 (1 H, dd, 7=8.23, 1.92 Hz), 9.22 (1 H, d, 7=1.65 Hz), 10.27 (1 H, s), 10.71 (1 H, s), 13.54 (1 H, s); ESIMS found for C21H20F3N7O2 m/z 459.9 (M+l).
Figure imgf000172_0002
62
[0441] 5-(Trifluoromethyl)-N-(3-((6-(trifluoromethyl)pyridin-3-yl)carbamoyl)-lH- pyrazol-4-yl)nicotinamide 62.
[0442] Off-white solid (37.0 mg, 0.08 mmol, 50.5% yield). Ή NMR (499 MHz, DMSO-7 d ppm 7.91 (1 H, d, 7=8.78 Hz), 8.42 (1 H, s), 8.57 (1 H, dd, 7=8.51, 1.92 Hz), 8.61 (1 H, s), 9.19 (1 H, br d, 7=1.37 Hz), 9.22 (1 H, d, 7=1.10 Hz), 9.35 (1 H, d, 7=1.65 Hz), 10.50 (1 H, br s), 10.99 (1 H, br s), 13.70 (1 H, br s); ESIMS found for CI7HIOF6N602 m/z 444.8 (M+l).
Figure imgf000173_0001
63
[0443] N-(3-((6-(Pyrrc>lidin-l-yl)pyridin-3-yl)carbamoyl)-lH-pyrazol-4-yl)-5- (trifluoromethyl)nicotinamide 63.
[0444] White solid (14.5 mg, 0.03 mmol). *HNMR (499 MHz, DMSO-7,) d ppm 1.92 - 1.98 (4 H, m), 3.37 (4 H, br t, .7=6.45 Hz), 6.45 (1 H, d, 7= 9.06 Hz), 7.87 (1 H, dd, 7=8.92, 2.33 Hz), 8.38 (1 H, s), 8.41 (1 H, br d, 7=2.20 Hz), 8.56 (1 H, br s), 9.21 (1 H, s), 9.32 (1 H, s), 10.17 (1 H, br s), 10.69 (1 H, br s), 13.50 (1 H, br s); ESIMS found for C20H18F3N7O2 m!z 446.1 (M+l).
Figure imgf000173_0002
64
[0445] N-(3 -((6-(3 ,3 -Difluoropyrrolidin- 1 -yl)pyridin-3 -yl)carbamoyl)- lH-pyrazol-
4-yl) -5 -(trifluoromethyl)nicotinamide 64.
[0446] Off-white solid (16.4 mg, 0.03 mmol, 21.2% yield). Ή NMR (499 MHz, DMSO-7 d ppm 2.52 - 2.60 (2 H, m), 3.61 (2 H, t, 7=7.27 Hz), 3.82 (2 H, t, 7=13.45 Hz), 6.58 (1 H, d, 7=9.06 Hz), 7.98 (1 H, dd, 7=8.92, 2.33 Hz), 8.39 (1 H, s), 8.50 (1 H, d, 7=2.20 Hz), 8.57 (1 H, s), 9.21 (1 H, s), 9.32 (1 H, s), 10.28 (1 H, br s), 10.66 (1 H, s), 13.53 (1 H, br s); ESIMS found for C2OHI6F5N702 m!z 481.8 (M+l).
Figure imgf000173_0003
65
[0447] N -(3 -((6-(Piperidin- 1 -yl)pyridin-3 -yl)carbamoyl)- lH-pyrazol-4-yl)-5 -
(trifluoromethyl)nicotinamide 65.
[0448] Light brown solid (45.0 mg, 0.10 mmol, 69.2% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 1.55 (4 H, br d, .7=4.94 Hz), 1.57 - 1.63 (2 H, m), 3.43 - 3.51 (4 H, m), 6.82 (1 H, d, 7= 9.06 Hz), 7.91 (1 H, dd, 7=9.19, 2.61 Hz), 8.39 (1 H, s), 8.46 (1 H, d, 7=2.47 Hz), 8.56 (1 H, s), 9.21 (1 H, d, 7=1.10 Hz), 9.32 (1 H, d, 7=1.37 Hz), 10.24 (1 H, s), 10.67 (1 H, s), 13.52 (1 H, br s); ESIMS found for C21H20F3N7O2 m!z 460.1 (M+l).
Figure imgf000174_0001
66
[0449] N -(3 -((6-(Piperazin- 1 -yl)pyridin-3 -yl)carbamoyl)- lH-pyrazol-4-yl)-5 -
(trifluoromethyl)nicotinamide 66.
[0450] Light brown solid (40.0 mg, 0.09 mmol, 63.6% yield). ¾ NMR (499 MHz, DMSO-7e) d ppm 2.76 - 2.81 (4 H, m), 3.34 - 3.39 (4 H, m), 6.81 (1 H, d, 7=9.33 Hz), 7.93 (1 H, dd, 7=9.19, 2.61 Hz), 8.38 (1 H, s), 8.48 (1 H, d, 7=2.47 Hz), 8.57 (1 H, s), 9.20 (1 H, s), 9.32 (1 H, d, 7=1.65 Hz), 10.29 (1 H, br s), 10.66 (1 H, br s), 13.49 (1 H, br s); ESIMS found for C20H19F3N8O2 nt!z 460.9 (M+l).
Figure imgf000174_0002
67
[0451] N-(3-((6-(4-Methylpiperazin-l-yl)pyridin-3-yl)carbamoyl)-lH-pyrazol-4-yl)- 5-(trifluoromethyl)nicotinamide 67.
[0452] Beige solid (18.5 mg, 0.04 mmol, 54.9% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 2.22 (3 H, s), 2.40 (4 H, br t, 7=5.08 Hz), 3.41 - 3.48 (4 H, m), 6.84 (1 H, d, 7=9.06 Hz), 7.94 (1 H, dd, .7=9.06, 2.74 Hz), 8.38 (1 H, s), 8.50 (1 H, d, .7=2.47 Hz), 8.57 (1 H, s), 9.21 (1 H, d, .7=1.10 Hz), 9.32 (1 H, d, 7=1.65 Hz), 10.27 (1 H, s), 10.66 (1 H, s), 13.53 (1 H, br s); ESIMS found for C21H21F3N8O2 m!z 474.9 (M+l).
Figure imgf000175_0001
[0453] N-(3-((6-(Piperidin-4-yloxy)pyridin-3-yl)carbamoyl)-lH-pyrazol-4-yl)-5- (trifluoromethyl)nicotinamide 68.
[0454] Off-white solid (70.3 mg, 0.15 mmol, 68.1% yield). ¾ NMR (499 MHz, DMSO-r/e) d ppm 1.42 - 1.54 (2 H, m), 1.90 - 1.98 (2 H, m), 2.54 - 2.64 (2 H, m), 2.97 (2 H, dt, 7=12.56, 4.01 Hz), 4.95 - 5.05 (1 H, m), 6.78 (1 H, d, 7=8.78 Hz), 8.08 (1 H, dd, 7=8.78, 2.74 Hz), 8.39 (1 H, s), 8.51 (1 H, d, 7=2.47 Hz), 8.57 (1 H, s), 9.20 (1 H, s), 9.33 (1 H, d, 7=1.37 Hz), 10.51 (2 H, br s); ESIMS found for C21H20F3N7O3 m!z 475.7. (M+l).
Figure imgf000175_0002
69
[0455] N-(3-((6-((l-Methylpiperidin-4-yl)oxy)pyridin-3-yl)carbamoyl)-lH-pyrazol- 4-yl) -5 -(trifluoromethyl)nicotinamide 69.
[0456] White solid (31.0 mg, 0.06 mmol, 40.3% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.58 - 1.72 (2 H, m), 1.90 - 1.98 (2 H, m), 2.08 - 2.23 (2 H, m), 2.18 (3 H, s), 2.58 - 2.70 (2 H, m), 4.89 - 5.00 (1 H, m), 6.79 (1 H, d, 7=8.78 Hz), 8.08 (1 H, dd, 7=8.78, 2.74 Hz), 8.39 (1 H, s), 8.52 (1 H, d, 7=2.47 Hz), 8.57 (1 H, s), 9.21 (1 H, s), 9.32 (1 H, s), 10.43 (1 H, br s), 10.61 (1 H, br s), 13.57 (1 H, br s); ESIMS found for C22H22F3N7O3 m/z 490.1 (M+l).
Figure imgf000176_0001
[0457] N-(3-((6-(2-(Pyrrolidin-l-yl)ethoxy)pyridin-3-yl)carbamoyl)-lH-pyrazol-4- yl)-5-(trifluoromethyl)nicotinamide 70.
[0458] Beige solid (25.0 mg, 0.05 mmol, 43.1% yield).‘H NMR (499 MHz, DMSO- d6) d ppm 1.70 (4 H, br s), 2.57 (4 H, br s), 2.83 (2 H, br s), 4.35 (2 H, t, .7=6.04 Hz), 6.83 (1 H, d, .7=8.78 Hz), 8.10 (1 H, dd, 7=9.06, 2.74 Hz), 8.39 (1 H, s), 8.54 (1 H, d, 7=2.47 Hz), 8.57 (1 H, s), 9.21 (1 H, d, 7=1.10 Hz), 9.32 (1 H, d, 7=1.65 Hz), 10.44 (1 H, s), 10.61 (1 H, s), 13.57 (1 H, br s); ESIMS found for C22H22F3N7O3 m/z 489.9 (M+l).
Figure imgf000176_0002
[0459] N -(3 -((5 -(3 -Fluorophenyl)pyridin-3 -yl)carbamoyl) - 1 H-pyrazol-4 -yl) -5 -
(trifluoromethyl)nicotinamide 71.
[0460] White solid (38.0 mg, 0.08 mmol, 83.0% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 7.23 - 7.33 (1 H, m), 7.53 - 7.63 (3 H, m), 8.43 (1 H, s), 8.55 (1 H, s), 8.60 (1 H, s), 8.68 (1 H, d, 7=1.92 Hz), 9.09 (1 H, d, 7=1.92 Hz), 9.21 (1 H, d, 7=0.82 Hz), 9.35 (1 H, d, 7=1.65 Hz), 10.56 (1 H, s), 10.69 (1 H, br s), 13.66 (1 H, br s); ESIMS found for C22Hi4F4N602 m/z 471.3 (M+l).
Figure imgf000176_0003
[0461] N-(3-(isoquinolin-4-ylcarbamoyl)-lH-pyrazol-4-yl)-5-(trifluoromethyl) nicotinamide 72.
[0462] White solid (55.0 mg, 0.13 mmol, 88.0% yield). ¾ NMR (499 MHz, DMSO- d6) 5 ppm 7.69 - 7.76 (1 H, m), 7.82 (1 H, br t, 7=7.55 Hz), 7.97 (1 H, d, .7=8.51 Hz), 8.20 (1 H, d, .7=8.23 Hz), 8.44 (1 H, s), 8.53 (1 H, s), 8.62 (1 H, s), 9.17 (1 H, s), 9.24 - 9.31 (2 H, m), 10.57 (1 H, s), 10.64 (1 H, br s), 13.64 (1 H, br s); ESIMS found for CzoH^NeCE m/z 427.3 (M+l).
Figure imgf000177_0001
73
[0463] N -(3 -((4-((Dimethylamino)methyl)phenyl)carbamoyl) - 1 H-pyrazol -4 -yl) -5 - methoxynicotinamide 73.
[0464] White solid (33.0 mg, 0.08 mmol, 61.7% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 2.13 (6 H, s), 3.35 (2 H, s), 3.93 (3 H, s), 7.25 (2 H, d, .7=8.51 Hz), 7.74 - 7.80 (3 H, m), 8.37 (1 H, s), 8.53 (1 H, d, .7=2.74 Hz), 8.67 (1 H, d, .7=1.65 Hz), 10.31 (1 H, br s), 10.56 (1 H, br s), 13.52 (1 H, br s); ESIMS found for C20H22N6O3 m/z 395.4 (M+l).
Figure imgf000177_0002
74
[0465] 5 -Methoxy-N -(3 -((4 -(pyrrolidin- 1 -ylmethyl)phenyl)carbamoyl) - 1 H-pyrazol -
4-yl)nicotinamide 74.
[0466] Beige solid (13.0 mg, 0.03 mmol, 39.0% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.69 (4 H, dt, 7=6.66, 3.12 Hz), 2.41 (4 H, br s), 3.53 (2 H, s), 3.93 (3 H, s), 7.26 (2 H, d, 7=8.51 Hz), 7.72 - 7.79 (3 H, m), 8.37 (1 H, s), 8.53 (1 H, d, 7=2.74 Hz), 8.66 (1 H, d, 7=1.65 Hz), 10.30 (1 H, br s), 10.56 (1 H, s), 13.52 (1 H, br s); ESIMS found for C22H24N603 m/z 421.3 (M+l).
Figure imgf000178_0001
75
[0467] 5 -Methoxy-N -(3 -((6 -(piperazin- 1 -yl)pyridin-3 -yl)carbamoyl) - 1 H-pyrazol -4 - yl)nicotinamide 75.
[0468] Off-white solid (58.3 mg, 0.14 mmol, 61.2% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 2.81 - 2.86 (4 H, m), 3.37 - 3.42 (4 H, m), 3.93 (3 H, s), 6.82 (1 H, d, .7=9.33 Hz), 7.76 (1 H, br d, 7=1.65 Hz), 7.95 (1 H, dd, 7=9.06, 2.74 Hz), 8.36 (1 H, s), 8.49 (1 H, d, 7=2.47 Hz), 8.52 (1 H, d, 7=2.74 Hz), 8.65 (1 H, d, 7=1.37 Hz), 10.29 (1 H, s), 10.58 (1 H, br s), 13.53 (1 H, br s); ESIMS found for C20H22N8O3 m!z 423.1 (M+l).
Figure imgf000178_0002
76
[0469] 5-Methoxy-N-(3-((6-(4-methylpiperazin-l-yl)pyridin-3-yl)carbamoyl)-lH- pyrazol-4-yl)nicotinamide 76.
[0470] Grey solid (12.2 mg, 0.03 mmol, 18.1% yield). ¾ NMR (499 MHz, DMSO- de) d ppm 2.21 (3 H, s), 2.37 - 2.42 (4 H, m), 3.41 - 3.47 (4 H, m), 3.93 (3 H, s), 6.84 (1 H, d, 7=9.33 Hz), 7.74 - 7.78 (1 H, m), 7.95 (1 H, dd, 7=9.06, 2.74 Hz), 8.36 (1 H, s), 8.49 (1 H, d, 7=2.74 Hz), 8.52 (1 H, d, 7=2.74 Hz), 8.65 (1 H, d, 7=1.65 Hz), 10.29 (1 H, s), 10.58 (1 H, s), 13.51 (1 H, br s); ESIMS found for C21H24N8O3 m/z 437.4 (M+l).
Figure imgf000178_0003
77
[0471] 5-Methoxy-N-(3-((4-(2-(pyrrolidin-l-yl)ethoxy)phenyl)carbamoyl)-lH- pyrazol-4-yl)nicotinamide 77.
[0472] White solid (36.5 mg, 0.08 mmol). *HNMR (499 MHz, DMSO-T,) d ppm 1.69 (4 H, dt, 7= 6.52, 3.19 Hz), 2.52 (4 H, br s), 2.78 (2 H, br t, 7= 5.76 Hz), 3.93 (3 H, s), 4.05 (2 H, t, 7=5.90 Hz), 6.89 - 6.94 (2 H, m), 7.72 (2 H, d, 7= 9.06 Hz), 7.75 - 7.78 (1 H, m), 8.36 (1 H, s), 8.53 (1 H, d, 7= 2.74 Hz), 8.66 (1 H, d, .7=1.65 Hz), 10.24 (1 H, s), 10.60 (1 H, s), 13.50 (1 H, s); ESIMS found for C23H26N6O4 m/z 451.1 (M+l).
Figure imgf000179_0001
78
[0473] 5-Methoxy-N-(3 -((6-(2-(pyrrolidin- 1 -yl)ethoxy)pyridin-3 -yl)carbamoyl)- 1H- pyrazol-4-yl)nicotinamide 78.
[0474] Beige solid (45.0 mg, 0.10 mmol, 53.4% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.68 (4 H, dt, 7=6.86, 3.16 Hz), 2.50 - 2.55 (4 H, m), 2.77 (2 H, t, 7=5.90 Hz), 3.93 (3 H, s), 4.33 (2 H, t, 7=6.04 Hz), 6.82 (1 H, d, 7=8.78 Hz), 7.76 (1 H, dd, 7=2.74, 1.92 Hz), 8.10 (1 H, dd, 7=8.78, 2.74 Hz), 8.38 (1 H, s), 8.53 (2 H, dd, 7=4.94, 2.74 Hz), 8.66 (1 H, d, 7=1.92 Hz), 10.45 (1 H, br s), 10.52 (1 H, br s), 13.54 (1 H, br s); ESIMS found for C22H25N7O4 m/z 452.4 (M+l).
Figure imgf000179_0002
79
[0475] N-(3 -((6-(3 ,3 -Difluoropyrrolidin- 1 -yl)pyridin-3 -yl)carbamoyl)- lH-pyrazol-
4-yl)-5-methoxynicotinamide 79.
[0476] White solid (20.3 mg, 0.05 mmol). *HNMR (499 MHz, DMSO-7,) d ppm 2.52 - 2.61 (2 H, m), 3.61 (2 H, t, 7=7.27 Hz), 3.82 (2 H, t, 7=13.45 Hz), 3.93 (3 H, s), 6.58 (1 H, d, 7=9.06 Hz), 7.76 (1 H, dd, 7=2.74, 1.92 Hz), 7.98 (1 H, dd, 7=8.92, 2.61 Hz), 8.37 (1 H, d, 7=0.82 Hz), 8.49 (1 H, d, .7=2.47 Hz), 8.52 (1 H, d, .7=3.02 Hz), 8.65 (1 H, d, 7=1.65 Hz), 10.30 (1 H, s), 10.58 (1 H, s), 13.51 (1 H, s); ESIMS found for C20H19F2N7O3 m!z 444.3 (M+l).
Figure imgf000180_0001
[0477] 5 -Methoxy-N -(3 -((6 -(piperidin-4 -yloxy)pyridin-3 -yl)carbamoyl) - 1 H- pyrazol-4-yl)nicotinamide 80.
[0478] Off-white solid (45.4 mg, 0.10 mmol, 42.4% yield). ¾ NMR (499 MHz, DMSO-r/e) d ppm 1.42 - 1.53 (2 H, m), 1.90 - 1.98 (2 H, m), 2.53 - 2.62 (2 H, m), 2.95 (2 H, dt, 7=12.49, 3.91 Hz), 3.93 (3 H, s), 4.95 - 5.03 (1 H, m), 6.78 (1 H, d, 7=9.06 Hz), 7.76 (1 H, dd, 7=2.74, 1.92 Hz), 8.09 (1 H, dd, 7=8.78, 2.74 Hz), 8.37 (1 H, s), 8.51 (2 H, dd, 7=7.41, 2.74 Hz), 8.66 (1 H, d, 7=1.65 Hz), 10.50 (2 H, br s); ESIMS found for C21H23N7O4 m!z 437.9 (M+l).
Figure imgf000180_0002
[0479] 5-Methoxy-N-(3 -((6-(( 1 -methylpiperidin-4-yl)oxy)pyridin-3 -yl)carbamoyl)- lH-pyrazol-4-yl)nicotinamide 81.
[0480] Off-white solid. ¾ NMR (499 MHz, DMSO-7,) d ppm 1.60 - 1.71 (2 H, m), 1.92 - 2.01 (2 H, m), 2.11 - 2.17 (2 H, m), 2.18 (3 H, s), 2.59 - 2.68 (2 H, m), 3.93 (3 H, s), 4.94 (1 H, tt, 7=8.61, 4.15 Hz), 6.79 (1 H, d, 7=8.78 Hz), 7.76 (1 H, dd, 7=2.74, 1.92 Hz), 8.09 (1 H, dd, 7=8.92, 2.61 Hz), 8.38 (1 H, s), 8.52 (2 H, t, 7=3.02 Hz), 8.65 (1 H, d, 7=1.65 Hz), 10.45 (1 H, s), 10.53 (1 H, s), 13.55 (1 H, br d, 7=0.82 Hz); ESIMS found for C22H25N7O4 m!z 452.0 (M+l).
Figure imgf000180_0003
82
[0481] 5-Methoxy-N-(3-((l,2,3,4-tetrahydroisoquinolin-6-yl)carbamoyl)-lH- pyrazol-4-yl)nicotinamide 82.
[0482] Beige solid (60.0 mg, 0.15 mmol, 51.5% yield).‘H NMR (499 MHz, DMSO- d6) d ppm 2.71 (2 H, br t, J= 5.63 Hz), 2.98 (2 H, t, 7= 5.90 Hz), 3.85 (2 H, s), 3.93 (3 H, s), 6.99 (1 H, d, 7= 8.23 Hz), 7.54 (1 H, dd, 7= 8.23, 1.92 Hz), 7.60 (1 H, s), 7.77 (1 H, dd, J= 2.74, 1.92 Hz), 8.37 (1 H, s), 8.53 (1 H, d, .7=2.74 Hz), 8.66 (1 H, d, .7=1.65 Hz), 10.18 (1 H, br s), 10.53 (1 H, br s); ESIMS found for C2oH2oN603 m!z 393.2 (M+l).
Figure imgf000181_0001
83
[0483] 5-Methoxy-N-(3-((2-methyl-l,2,3,4-tetrahydroisoquinolin-6-yl)carbamoyl)- lH-pyrazol-4-yl)nicotinamide 83.
[0484] White solid (8.0 mg, 0.02 mmol, 25.6% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 2.33 (3 H, s), 2.58 (2 H, br t, .7=5.90 Hz), 2.81 (2 H, br t, 7=5.63 Hz), 3.44 (2 H, s), 3.93 (3 H, s), 7.01 (1 H, d, 7=8.51 Hz), 7.53 (1 H, br dd, 7=8.37, 1.78 Hz), 7.63 (1 H, s), 7.74 - 7.81 (1
H, m), 8.36 (1 H, s), 8.53 (1 H, d, 7=2.74 Hz), 8.66 (1 H, d, 7=1.65 Hz), 10.19 (1 H, br s), 10.54 (1 H, br s), 13.02 (1 H, br s); ESIMS found for C2IH22N603 m/z 407.2 (M+l).
Figure imgf000181_0002
[0485] 5-Isopropoxy-N-(3-((6-((l-methylpiperidin-4-yl)oxy)pyridin-3- yl)carbamoyl) - 1 H-pyrazol -4-yl)nicotinamide 84.
[0486] White solid (40.0 mg, 0.08 mmol, 42.0% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.33 (6 H, d, 7=6.04 Hz), 1.65 (2 H, dtd, 7=12.66, 9.18, 9.18, 3.57 Hz), 1.92 - 2.00 (2 H, m), 2.09 - 2.22 (2 H, m), 2.18 (3 H, s), 2.60 - 2.69 (2 H, m), 4.82 (1 H, spt, 7=5.99 Hz), 4.93 (1 H, tt, .7=8.58, 4.19 Hz), 6.79 (1 H, d, .7=8.78 Hz), 7.69 - 7.75 (1 H, m), 8.09 (1 H, dd, .7=9.06, 2.74 Hz), 8.37 (1 H, s), 8.48 (1 H, d, .7=2.74 Hz), 8.52 (1 H, d, 7=2.74 Hz), 8.62 (1 H, d, 7=1.65 Hz), 10.45 (1 H, br s), 10.50 (1 H, s), 13.54 (1 H, br s); ESIMS found for C24H29N7O4 m/z 480.3 (M+l).
Figure imgf000182_0001
85
[0487] 5-((3-((6-(Trifluoromethyl)pyridin-3-yl)carbamoyl)-lH-pyrazol-4- yl)carbamoyl)nicotinic acid 85.
[0488] White solid (15.0 mg, 0.04 mmol, 45.1% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 7.92 (1 H, d, 7=8.51 Hz), 8.43 (1 H, s), 8.57 (1 H, dd, 7=8.37, 1.78 Hz), 8.69 (1 H, t, 7=1.92 Hz), 9.19 (1 H, d, 7=1.92 Hz), 9.25 (1 H, d, 7=1.92 Hz), 9.27 (1 H, d, 7=2.20 Hz), 10.49 (1 H, s), 11.00 (1 H, s), 13.71 (1 H, br s); ESIMS found for CI7HIIF3N604 m/z 421.2 (M+l).
Figure imgf000182_0002
86
[0489] Methyl 5-((3-((6-(trifluoromethyl)pyridin-3-yl)carbamoyl)-lH-pyrazol-4- yl)carbamoyl)nicotinate 86.
[0490] White solid (23.0 mg, 0.05 mmol, 62.5% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 3.95 (3 H, s), 7.92 (1 H, d, 7=8.78 Hz), 8.43 (1 H, s), 8.58 (1 H, dd, 7=8.65, 1.78 Hz), 8.71 (1 H, t, 7=2.06 Hz), 9.19 (1 H, s), 9.27 (1 H, d, 7=2.20 Hz), 9.30 (1 H, d, 7=2.20 Hz), 10.51 (1 H, br d, 7=0.82 Hz), P .00 (1 H, br s), 13.69 (1 H, br s); ESIMS found for CISH FSNSCE m/z 434.9 (M+l).
Figure imgf000183_0001
[0491] N4-(5-(Piperidin-l-ylmethyl)pyridin-3-yl)-N3-(pyridin-3-yl)-lH-pyrazole- 3,4-dicarboxamide 87.
[0492] Tan solid (5.8 mg, 0.014 mmol). ¾ NMR (499 MHz, DMSO-7,) d ppm 1.40 (2 H, br d, .7=3.29 Hz), 1.51 (4 H, br s), 2.30 - 2.44 (4 H, m), 3.49 (2 H, br s), 7.44 (1 H, dd, 7=7.96, 4.67 Hz), 8.07 (1 H, br s), 8.20 - 8.26 (2 H, m), 8.38 (1 H, dd, 7=4.67, 1.10 Hz), 8.57 (1 H, s), 8.76 (1 H, br s), 8.98 (1 H, br s), 11.00 (1 H, br s), 12.18 (1 H, br s), 14.16 (1 H, br s); ESIMS found for C21H23N7O2 m!z 406.4 (M+l).
Figure imgf000183_0002
89
[0493] 5-(Piperidin-4-yloxy)-N-(3 -(pyridin-3 -ylcarbamoyl)- lH-pyrazol-4- yl)nicotinamide 89.
[0494] Beige solid (9.0 mg, 0.02 mmol, 29.0% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.45 - 1.58 (2 H, m), 1.94 - 2.03 (2 H, m), 2.57 - 2.67 (2 H, m), 2.98 (2 H, dt, 7=8.23, 4.12 Hz), 4.58 - 4.68 (1 H, m), 7.39 (1 H, dd, 7=8.23, 4.67 Hz), 7.74 - 7.80 (1 H, m), 8.22 - 8.28 (1 H, m), 8.32 (1 H, dd, 7=4.53, 1.23 Hz), 8.38 (1 H, s), 8.51 (1 H, d, 7=2.74 Hz), 8.64 (1 H, d, 7=1.37 Hz), 9.00 (1 H, d, 7=2.47 Hz), 10.46 (1 H, br s), 10.60 (1 H, br s); ESIMS found for C20H21N7O3 m/z 408.0 (M+l).
Figure imgf000184_0001
[0495] 5-(Piperidin-4-yloxy)-N-(3-((6-(trifluoromethyl)pyridin-3-yl)carbamoyl)-lH- pyrazol-4-yl)nicotinamide 90.
[0496] Beige solid (122.0 mg, 0.26 mmol, 62.7% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.82 - 1.94 (2 H, m), 2.16 (2 H, ddd, .7=10.15, 7.00, 3.43 Hz), 3.12 (2 H, ddd, .7=12.69, 8.85, 3.70 Hz), 3.24 - 3.30 (2 H, m), 4.88 (1 H, tt, .7=7.41, 3.57 Hz), 7.83 - 7.87 (1 H, m), 7.91 (1 H, d, .7=8.51 Hz), 8.40 (1 H, s), 8.56 (1 H, dd, 7=8.64, 2.33 Hz), 8.59 (1 H, d, 7=2.74 Hz), 8.70 (1 H, d, 7=1.65 Hz), 9.20 (1 H, d, 7=2.20 Hz), 10.35 (1 H, s), 11.00 (1 H, br s); ESIMS found for C21H20F3N7O3 m/z 476.0 (M+l).
Figure imgf000184_0002
91
[0497] N-(3-((6-Methoxypyridin-3-yl)carbamoyl)-lH-pyrazol-4-yl)-5-(piperidin-4- yloxy)nicotinamide 91.
[0498] White solid (31.0 mg, 0.07 mmol, 73.5% yield).‘H NMR (499 MHz, DMSO- d6) d ppm 1.44 - 1.57 (2 H, m), 1.94 - 2.02 (2 H, m), 2.56 - 2.64 (2 H, m), 2.97 (2 H, dt, 7=12.69, 3.95 Hz), 3.84 (3 H, s), 4.57 - 4.66 (1 H, m), 6.83 (1 H, d, 7=8.78 Hz), 7.74 - 7.78 (1 H, m), 8.12 (1 H, dd, 7=8.92, 2.61 Hz), 8.36 (1 H, s), 8.51 (1 H, d, 7=2.74 Hz), 8.55 (1 H, d, 7=2.47 Hz), 8.62 (1 H, d, 7=1.65 Hz), 10.50 (2 H, br s); ESIMS found for C21H23N7O4 m/z 438.4 (M+l).
Figure imgf000185_0001
92
[0499] 5-(Piperidin-4-yloxy)-N-(3-((6-(pyrrolidin-l-yl)pyridin-3-yl)carbamoyl)-lH- pyrazol-4-yl)nicotinamide 92.
[0500] White solid (20.0 mg, 0.04 mmol, 60.9% yield). ¾ NMR (499 MHz, DMSO- d6) 5 ppm 1.46 - 1.57 (2 H, m), 1.91 - 2.04 (6 H, m), 2.58 - 2.67 (2 H, m), 2.98 (2 H, dt, .7=12.69, 4.08 Hz), 3.37 (4 H, br t, J= 6.59 Hz), 4.58 - 4.68 (1 H, m), 6.44 (1 H, d, J= 9.06 Hz), 7.72 - 7.78 (1 H, m), 7.88 (1 H, dd, .7=8.92, 2.61 Hz), 8.35 (1 H, s), 8.40 (1 H, d, .7=2.74 Hz), 8.51 (1 H, d, .7=2.74 Hz), 8.62 (1 H, d, .7=1.65 Hz), 10.18 (1 H, br s), 10.61 (1 H, br s); ESIMS found for CzJtsNgOs ra/z 477.2 (M+l).
Figure imgf000185_0002
93
[0501] N-(3 -((6-(3 ,3 -Difluoropyrrolidin- 1 -yl)pyridin-3 -yl)carbamoyl)- lH-pyrazol-
4-yl)-5-(piperidin-4-yloxy)nicotinamide 93.
[0502] Beige solid (46.0 mg, 0.09 mmol, 55.9% yield). ¾ NMR (499 MHz, DMSO- de) d ppm 1.83 - 1.96 (2 H, m), 2.15 (2 H, ddd, .7=13.72, 7.14, 3.29 Hz), 2.51 - 2.60 (2 H, m), 3.12 (2 H, ddd, .7=12.62, 8.92, 3.43 Hz), 3.24 - 3.30 (2 H, m), 3.61 (2 H, t, .7=7.27 Hz), 3.82 (2 H, t, .7=13.45 Hz), 4.84 - 4.93 (1 H, m), 6.58 (1 H, d, .7=9.06 Hz), 7.80 - 7.87 (1 H, m), 7.97 (1 H, dd, .7=8.92, 2.33 Hz), 8.36 (1 H, s), 8.49 (1 H, d, .7=2.47 Hz), 8.58 (1 H, d, .7=2.74 Hz), 8.67 (1 H, d, .7=1.65 Hz), 10.30 (1 H, s), 10.55 (1 H, s), 13.57 (1 H, br s); ESIMS found for Cz^FzNgCE m/z 513.5 (M+l).
Figure imgf000186_0001
94
[0503] N -(3 -((6-(Piperidin- 1 -yl)pyridin-3 -yl)carbamoyl)- lH-pyrazol-4-yl)-5 -
(piperidin-4-yloxy)nicotinamide 94.
[0504] Beige solid (30.0 mg, 0.06 mmol, 58.9% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.44 - 1.64 (8 H, m), 1.92 - 2.02 (2 H, m), 2.56 - 2.66 (2 H, m), 2.97 (2 H, dt, .7=12.49, 3.91 Hz), 3.44 - 3.51 (4 H, m), 4.55 - 4.67 (1 H, m), 6.81 (1 H, d, 7=9.33 Hz), 7.75 (1 H, d, 7=2.20 Hz), 7.92 (1 H, dd, 7=9.06, 2.74 Hz), 8.35 (1 H, s), 8.45 (1 H, d, 7=2.47 Hz), 8.51 (1 H, d, 7=2.74 Hz), 8.62 (1 H, d, 7=1.37 Hz), 10.25 (1 H, br s), 10.58 (1 H, br s); ESIMS found for CzsftoNgCE m/z 491.3 (M+l).
Figure imgf000186_0002
[0505] N -(3 -((5 -(3 -Fluorophenyl)pyridin-3 -yl)carbamoyl) - 1 H-pyrazol-4 -yl) -5 -
(piperidin-4-yloxy)nicotinamide 95.
[0506] White solid (20.0 mg, 0.04 mmol, 54.7% yield). ¾ NMR (499 MHz, DMSO- de) d ppm 1.43 - 1.57 (2 H, m), 1.92 - 2.01 (2 H, m), 2.54 - 2.64 (2 H, m), 2.95 (2 H, dt, 7=12.69, 4.08 Hz), 4.57 - 4.67 (1 H, m), 7.24 - 7.33 (1 H, m), 7.54 - 7.63 (3 H, m), 7.76 - 7.80 (1 H, m), 8.39 (1 H, s), 8.50 (1 H, d, 7=2.74 Hz), 8.54 (1 H, t, 7=2.20 Hz), 8.65 (1 H, d, 7=1.65 Hz), 8.68 (1 H, d, 7=1.92 Hz), 9.08 (1 H, d, 7=2.20 Hz), 10.44 (1 H, br s), 10.75 (1 H, br s); ESIMS found for C26H24FN7O3 m/z 502.3 (M+l).
Figure imgf000187_0001
96
[0507] N-(3-((6-(2-(Pyrrolidin-l-yl)ethoxy)pyridin-3-yl)carbamoyl)-lH-pyrazol-4- yl)isonicotinamide 96.
[0508] Beige solid (25.0 mg, 0.07 mmol, 61.2% yield).‘H NMR (499 MHz, DMSO- d6) d ppm 1.72 (4 H, br s), 2.63 (4 H, br d, .7=1.92 Hz), 2.89 (2 H, br s), 4.36 (2 H, t, 7=5.90 Hz), 6.82 (1 H, d, 7=8.78 Hz), 7.61 - 7.67 (2 H, m), 8.07 (1 H, dd, 7=8.78, 2.74 Hz), 8.37 (1 H, s), 8.48 - 8.56 (3 H, m), 10.36 (1 H, s), 13.72 (1 H, br s); ESIMS found for C2oH22N602 m/z 379.1 (M+l).
Figure imgf000187_0002
[0509] N-(4-(Pyridin-3-ylcarbamoyl)-lH-pyrazol-3-yl)nicotinamide 97.
[0510] Off-white solid (44.4 mg, 0.14 mmol, 1.8% yield). ¾ NMR (499 MHz, METHANOL-74) d ppm 7.45 (1 H, dd, 7=8.37, 4.80 Hz), 7.61 - 7.68 (1 H, m), 8.18 (1 H, br s), 8.26 (1 H, br d, 7=6.04 Hz), 8.30 (1 H, br d, 7=4.94 Hz), 8.43 (1 H, br d, 7=8.23 Hz), 8.75 - 8.83 (1 H, m), 8.91 (1 H, br s), 9.19 (1 H, br s); ESIMS found for Ci5Hi2N602 m/z 309.0 (M+l).
Figure imgf000187_0003
[0511] N3,N4-Di(pyridin-3-yl)-lH-pyrazole-3, 4-dicarboxamide 98.
[0512] Off-white solid (42.9 mg, 0.14 mmol, 43.5% yield). ¾ NMR (499 MHz, DMSO-7 d ppm 7.37 - 7.48 (2 H, m), 8.13 (1 H, br d, 7=8.23 Hz), 8.24 (1 H, br d, 7=6.86 Hz), 8.32 (1 H, br d, 7=4.39 Hz), 8.38 (1 H, dd, 7=4.67, 1.37 Hz), 8.59 (1 H, br d, 7=7.68 Hz), 8.86 (1 H, d, .7=2.20 Hz), 8.98 (1 H, br s), 10.98 (1 H, br s), 12.28 (1 H, br s), 14.14 (1 H, br d, 7=1.10 Hz); ESIMS found for Ci5Hi2N602 m/z 309.1 (M+l).
Figure imgf000188_0001
99
[0513] Ethyl 2-((3-(4-(3-fluorophenyl)-lH-benzo[d]imidazol-2-yl)-lH-pyrazol-4- yl)amino)-2-oxoacetate 99.
[0514] White solid (26.2 mg, 0.05 mmol, 39.3% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.26 (3 H, t, 7=7.14 Hz), 4.31 (2 H, q, 7=7.14 Hz), 7.18 - 7.25 (1 H, m), 7.32 - 7.38 (1 H, m), 7.50 - 7.56 (2 H, m), 7.58 - 7.66 (1 H, m), 7.80 - 7.87 (1 H, m), 8.17 - 8.24 (1 H, m), 8.37 - 8.42 (1 H, m), 11.37 (1 H, br s), 13.31 (1 H, br s), 13.49 (1 H, br s); ESIMS found for C2oHi6FN503 m/z 394.1 (M+l).
Figure imgf000188_0002
100
[0515] Ethyl (3-(4-(3-fluorophenyl)-lH-benzo[d]imidazol-2-yl)-lH-pyrazol-4- yl)carbamate 100.
[0516] White solid (39.0 mg, 0.11 mmol, 73.5% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.28 (3 H, br t, 7=7.00 Hz), 4.12 - 4.23 (2 H, m), 7.21 - 7.28 (1 H, m), 7.34 (1 H, br t, 7=7.55 Hz), 7.46 - 7.58 (3 H, m), 7.88 - 7.94 (1 H, m), 7.94 - 7.99 (1 H, m), 8.02 (1 H, br s), 9.77 (1 H, br s), 13.23 (2 H, br s); ESIMS found for CI9HI6FN502 m/z 366.15 (M+l).
Figure imgf000189_0001
[0517] l-(3-(4-(3 -Fluorophenyl) - 1 H-benzo [d] imidazol-2-yl) - 1 H-pyrazol -4 -yl) -3 - isopropylurea 101.
[0518] White solid (22.8 mg, 0.06 mmol, 62.6% yield). ¾ NMR (499 MHz, DMSO- d6) 5 ppm 1.03 - 1.06 (m, 6H), 3.68 (br s, 1H), 6.34 (s, 1H), 7.21 - 7.24 (m, 1H), 7.31 (t, =7.7Hz, 1H), 7.47 - 7.56 (m, 3H), 7.95 (br s, 1H), 8.02 (s, 1H), 8.09 (s, 1H), 8.88 (s, 1H), 13.05 (s, 2H); ESIMS found for C20HI9FN6O m/z 379.1 (M+l).
Figure imgf000189_0002
102
[0519] 4-(3 -Cyclopropylureido) -N -(piperidin-4-yl)- 1 H-pyrazole -3 -carboxamide
102
[0520] Off-white solid (36.2 mg, 0.11 mmol, 51.6% yield). Ή NMR (499 MHz, DMS0- 6) d ppm 0.39 - 0.41 (m, 2H), 0.64 - 0.65 (m, 2H), 1.81 - 1.84 (m, 2H), 1.89 - 1.91 (m, 2H), 2.48 - 2.49 (m, 1H), 2.94 - 3.01 (m, 2H), 3.27 - 3.30 (m, 2H), 4.02 - 4.05 (m, 1H), 7.20 (s, 1H), 7.96 (s, 1H), 8.37 (d, =7.3Hz, 1H), 8.54 - 8.56 (m, 1H), 8.85 - 8.93 (m, 1H); ESIMS found for CI3H2ON602 m!z 293.1 (M+l).
Figure imgf000189_0003
[0521] tert- Butyl 4-(4-(3-cyclopropylureido)- lH-pyrazole-3 -carboxamido) piperidine -1-carboxylate 103.
[0522] White solid (104.1 mg, 0.27 mmol, 27.1% yield). ¾ NMR (399 MHz, DMSO- d6) 5 ppm 0.39 - 0.41 (m, 2H), 0.64 - 0.65 (m, 2H), 1.40 (s, 9H), 1.48 - 1.50 (m, 2H), 1.70 - 1.72 (m, 2H), 2.46 - 2.48 (m, 1H), 2.76 - 2.82 (m, 2H), 3.93 - 3.95 (m, 3H), 7.18 (s, 1H), 7.95 (s, 1H), 8.07 (d, =8.4Hz, 1H), 8.87 (s, 1H), 12.95 (s, 1H); ESIMS found for CI8H28N604 m/z 393.0 (M+l).
Figure imgf000190_0001
104
[0523] 4-(3-Cyclopropylureido)-N-(pyridin-3-yl)-lH-pyrazole-3-carboxamide 104.
[0524] Yellow solid (137.0 mg, 0.478 mmol, 36.3% yield). ¾ NMR (499 MHz, DMS0- 6) d ppm 0.41 (br s, 2H), 0.65 (d, =6Hz, 2H), 2.51 - 2.54 (m, 1H), 7.32 (br s, 1H), 7.36 (dd, =8Hz, =4.5Hz, 1H), 8.07 (s, 1H), 8.19 (d, =8.5Hz, 1H), 8.29 (dd, =5Hz, =1.5Hz, 1H), 8.71 (br s, 1H), 9.01 (d, =2Hz, 1H), 10.38 (s, 1H), 13.25 (br s, 1H); ESIMS found for CI3HI4N602 m/z 287.1 (M+l).
Figure imgf000190_0002
[0525] 1 -(3 -( 1 H-Benzo [d] imidazol-2-yl) - 1 H-pyrazol -4 -yl) -3 -cyclopropylurea 105.
[0526] White solid (68.0 mg, 0.24 mmol, 9.8% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 0.54 (br s, 2H), 0.84 (br s, 2H), 2.57 - 2.65 (m, 1H), 7.14 - 7.25 (m, 3H), 7.47 (d, =7Hz, 1H), 7.63 (d, =7.5Hz, 1H), 8.06 (s, 1H), 9.66 (br s, 1H), 12.87 (s, 1H), 13.02 (s, 1H); ESIMS found for CI4HI4N60 m/z 283.0 (M+l).
Figure imgf000191_0001
[0527] 1 -Cyclopropyl -3-(3-(4-(3-fluorophenyl)-lH-benzo[d]imidazol-2-yl)-lH- pyrazol-4-yl)urea 107.
[0528] White solid (45.6 mg, 0.12 mmol, 83.4% yield). ¾ NMR (399 MHz, DMSO- d6) d ppm -0.02 - -0.01 (m, 2H), 0.22 - 0.24 (m, 2H), 2.31 - 2.32 (m, 1H), 6.93 (s, lh), 7.14 - 7.17 (m, 1H), 7.31 - 7.32 (m, 2H), 7.45 - 7.47 (m, 1H), 7.51 - 7.52 (m, 1H), 7.73 (s, 2H), 8.08 (s, 1H), 9.48 (s, 1H), 13.08 (s, 1H), 13.11 (s, 1H); ESIMS found for C2oHi7FN60 m/z 377.1 (M+l).
Figure imgf000191_0002
[0529] l-Cyclopropyl-3-(3-(5-(3-fluorophenyl)-lH-benzo[d]imidazol-2-yl)-lH- pyrazol-4-yl)urea 109.
[0530] Tan solid (12.0 mg, 0.03 mmol). ¾ NMR (499 MHz, DMSO-d6) d ppm 0.55 (s, 2H), 0.58 (s, 2H), 2.55 (s, 1H), 7.12 - 7.26 (m, 2H), 7.45 - 7.58 (m, 5H), 7.70 (s, 1H), 8.07 (s, 1H), 9.61 (s, 1H), 13.03 (br s, 1H), 13.06 (br s, 1H); ESIMS found for C2oHi7FN60 m/z 377.2 (M+l).
Figure imgf000191_0003
[0531] l-Cyclopropyl-3-(3-(4-(thiophen-2-yl)-lH-benzo[d]imidazol-2-yl)-lH- pyrazol-4-yl)urea 110.
[0532] White solid (6.8 mg, 0.019 mmol, 50.2% yield). ¾ NMR (399 MHz, DMSO- d6) d ppm 0.36 - 0.38 (m, 4H), 2.58 - 2.59 (m, 1H), 6.96 - 6.99 (m, 1H), 7.08 - 7.10 (m, 1H), 7.24 - 7.28 (m, 1H), 7.41 - 7.44 (m, 2H), 7.60 (d, =4.5Hz, 1H), 7.91 (d, =2.9Hz, 1H), 8.10 (s, 1H), 9.28 (s, 1H), 13.08 (s, 1H), 13.10 (s, 1H); ESIMS found for CI8HI6N6OS m/z 365.2 (M+l).
Figure imgf000192_0001
[0533] l-Cyclopropyl-3-(3-(4-(5-fluorothiophen-2-yl)-lH-benzo[d]imidazol-2-yl)- lH-pyrazol-4-yl)urea 111.
[0534] White solid (30.7 mg, 0.08 mmol, 64.3% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 0.41 - 0.42 (m, 2H), 0.51 - 0.52 (m, 2H), 2.60 - 2.64 (m, 1H), 6.73 - 6.74 (m, 1H), 7.02 (s, 1H), 7.25 (t, =7.7Hz, 1H), 7.42 - 7.43 (m, 2H), 7.54 - 7.55 (m, 1H), 8.09 (s, 1H), 9.09 (s, 1H), 13.11 (s, 1H); ESIMS found for CI8HI5FN6OS m/z 383.0 (M+l).
Figure imgf000192_0002
112
[0535] 1 -Cyclopentyl -3-(3-(4-(3-fluorophenyl)-lH-benzo[d]imidazol-2-yl)-lH- pyrazol-4-yl)urea 112.
[0536] White solid (27.5 mg, 0.07 mmol, 57.8% yield). ¾ NMR (499 MHz, DMSO- df,) d ppm 1.37 - 1.43 (m, 4H), 1.57 - 1.62 (m, 2H), 1.65 - 1.73 (m, 2H), 3.86 (br s, 1H), 6.56 (s, 1H), 7.20 - 7.23 (m, 1H), 7.31 (t, =7.7Hz, 1H), 7.46 - 7.55 (m, 3H), 7.95 (br s, 1H), 8.03 (s, 1H), 8.07 (s, 1H), 8.87 (s, 1H), 13.04 (br s, 2H); ESIMS found for C22H2IFN60 m/z 405.4 (M+l).
Figure imgf000193_0001
113
[0537] N-(3-(4-(3-Fluorophenyl)-lH-benzo[d]imidazol-2-yl)-lH-pyrazol-4-yl)-4- methylpiperazine - 1 -carboxamide 113.
[0538] White solid (40.8 mg, 0.10 mmol, 79.4% yield). ¾ NMR (499 MHz, DMSO- d6) 5 ppm 2.11 - 2.13 (m, 4H), 2.15 (s, 3H), 3.26 - 3.28 (m, 4H), 7.25 - 7.29 (m, 1H), 7.32 - 7.34 (m, 2H), 7.51 - 7.55 (m, 2H), 7.70 - 7.72 (m, 1H), 7.76 (d, =7.7Hz, 1H), 8.07 (s, 1H), 9.46 (s, 1H), 13.17 (br s, 2H); ESIMS found for C22H22FN7O m/z 420.0 (M+l).
Figure imgf000193_0002
[0539] 4-(3-(Pyridin-3-yl)ureido)-N-(6-(trifluoromethyl)pyridin-3-yl)-lH-pyrazole- 3 -carboxamide 114.
[0540] White solid (27.0 mg, 0.07 mmol, 50.4% yield). ¾ NMR (499 MHz, DMSO- d6) 5 ppm 7.31 (1 H, dd, .7=8.10, 4.53 Hz), 7.92 (1 H, d, .7=8.51 Hz), 7.94 - 7.99 (1 H, m), 8.18 (1 H, dd, 7=4.67, 1.37 Hz), 8.21 (1 H, s), 8.51 (1 H, dd, 7=8.64, 2.06 Hz), 8.62 (1 H, d, .7=2.47 Hz), 9.07 (1 H, br s), 9.26 (1 H, d, 7=2.20 Hz), 9.97 (1 H, br s), 10.85 (1 H, br s), 13.46 (1 H, br s); ESIMS found for C16H12F3N7O2 m/z 392.0 (M+l).
Figure imgf000193_0003
115
[0541] N-(3-(4-(3-Fluorophenyl)-lH-benzo[d]imidazol-2-yl)-lH-pyrazol-4- yl)ethene sulfonamide 115.
[0542] White solid (31.3 mg, 0.06 mmol, 69.9% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 5.97 (1 H, d, .7=9.88 Hz), 6.14 (1 H, d, 7=16.47 Hz), 6.82 (1 H, dd, 7=16.33, 10.02 Hz), 7.22 (1 H, td, 7=8.44, 2.33 Hz), 7.31 - 7.38 (1 H, m), 7.47 - 7.56 (3 H, m), 7.82 (1 H, s), 7.88 (1 H, br d, 7=10.98 Hz), 7.98 (1 H, br d, 7=7.68 Hz), 9.58 (1 H, br s), 13.23 (1 H, br s), 13.38 (1 H, br s); ESIMS found for CigHwFNsCES m/z 384.1 (M+l).
Figure imgf000194_0001
[0543] N-(3 -(4 -(3 -Fluorophenyl) - 1 H-benzo [d] imidazol-2-yl) - 1 H-pyrazol -4 - yl)cyclopropanesulfonamide 116.
[0544] Off-white solid (41.8 mg, 0.11 mmol, 73.2% yield). ¾ NMR (499 MHz, DMSO-7 d ppm 0.80 - 0.83 (m, 2H), 0.89 - 0.92 (m, 2H), 2.67 - 2.70 (m, 1H), 7.20 - 7.24 (m, 1H), 7.33 - 7.36 (m, 1H), 7.49 - 7.54 (m, 3H), 7.86 - 7.89 (m, 1H), 7.96 (d, 7=7.8 Hz, 1H), 9.45 (s, 1H), 13.26 (s, 1H), 13.93 (s, 1H); ESIMS found for Ci9Hi6FN502S m/z 398.0 (M+l).
Figure imgf000194_0002
117
[0545] N-((3 -(4 -(3 -Fluorophenyl) - 1 H-benzo [d] imidazol -2 -yl) - 1 H-pyrazol-4- yl)methyl)acrylamide 117.
[0546] White solid (62.3 mg, 0.17 mmol, 72.6% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 4.72 (2 H, br d, 7=5.49 Hz), 5.48 - 5.56 (1 H, m), 6.00 - 6.07 (1 H, m), 6.09 - 6.19 (1 H, m), 7.18 (1 H, td, 7=8.30, 2.06 Hz), 7.31 (1 H, t, 7=7.68 Hz), 7.46 - 7.55 (3 H, m), 7.81 (1 H, s), 8.04 (1 H, br d, .7=7.96 Hz), 8.07 (1 H, br d, 7=11.25 Hz), 8.64 (1 H, br t, .7=4.94 Hz), 13.00 (1 H, br s), 13.27 (1 H, br s); ESIMS found for C2oHi6FN50 m/z 362.1 (M+l).
Figure imgf000195_0001
118
[0547] N-((3 -(Pyridin-3 -ylcarbamoyl) - 1 H-pyrazol -4 -yl)methyl)nicotinamide 118.
[0548] Beige solid (18.5 mg, 0.06 mmol, 25.0% yield).‘H NMR (499 MHz, DMSO- d6) d ppm 4.68 (2 H, br d, .7=5.49 Hz), 7.36 (1 H, dd, 7=8.10, 4.80 Hz), 7.50 (1 H, dd, 7=7.82, 4.80 Hz), 7.83 (1 H, s), 8.20 - 8.23 (1 H, m), 8.24 (1 H, dd, 7=8.37, 2.33 Hz), 8.28 (1 H, br d, 7=4.39 Hz), 8.70 (1 H, dd, 7=4.80, 1.51 Hz), 9.00 (1 H, d, 7=2.20 Hz), 9.02 (1 H, br s), 9.04 (1 H, d, 7=1.92 Hz), 10.34 (1 H, br s), 13.37 (1 H, br s); ESIMS found for CI6HI4N602 m/z 323.1 (M+l).
Figure imgf000195_0002
[0549] N-((3-(4-(3-Fluorophenyl)-lH-benzo[d]imidazol-2-yl)-lH-pyrazol-4- yl)methyl)nicotinamide 119.
[0550] White solid (12.9 mg, 0.03 mmol, 55.5% yield). ¾ NMR (500 MHz, DMSO- d6) d ppm 4.86 (2 H, d, 7=5.49 Hz), 7.00 (1 H, td, 7=8.51, 2.20 Hz), 7.26 (1 H, dd, 7=7.96, 4.94 Hz), 7.30 - 7.36 (1 H, m), 7.36 - 7.43 (1 H, m), 7.45 - 7.51 (1 H, m), 7.53 (1 H, dd, 7=7.96, 0.82 Hz), 7.86 (1 H, dt, 7=7.96, 1.92 Hz), 7.92 (1 H, s), 7.96 (1 H, d, 7=7.96 Hz), 8.00 (1 H, dt, 7=11.05, 2.02 Hz), 8.59 (1 H, dd, 7=4.80, 1.51 Hz), 8.81 (1 H, d, 7=1.65 Hz), 9.61 (1 H, t, 7=5.90 Hz), 13.09 (1 H, s), 13.31 (1 H, s); ESIMS found for C23Hi7FN60 m/z 413.1 (M+l).
Figure imgf000195_0003
121
[0551] 4-(Benzylamino)-N-phenyl-lH-pyrazole-3-carboxamide 121.
[0552] White solid (11.5 mg, 0.04 mmol, 16.6% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 4.21 (2 H, br d, .7=6.04 Hz), 5.64 (1 H, br s), 7.04 (1 H, t, .7=7.41 Hz), 7.20 (1 H, s), 7.21 - 7.26 (1 H, m), 7.27 - 7.35 (4 H, m), 7.35 - 7.39 (2 H, m), 7.79 (2 H, br d, .7=7.41 Hz), 9.75 (1 H, s), 12.81 (1 H, br s); ESIMS found for CI7HI6N40 m/z 292.8 (M+l).
Figure imgf000196_0001
122
[0553] 4-(Benzylamino) -N -(3 -hydroxyphenyl) - 1 H-pyrazole -3 -carboxamide 122.
[0554] White solid (220.0 mg, 0.71 mmol, 22.6% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 4.20 (2 H, br d, 7=5.49 Hz), 5.62 (1 H, br t, 7=5.76 Hz), 6.45 (1 H, dd, 7=8.23, 1.65 Hz), 7.02 - 7.08 (1 H, m), 7.15 (1 H, br d, 7=8.23 Hz), 7.20 (1 H, s), 7.22 - 7.27 (1 H, m), 7.29 - 7.35 (2 H, m), 7.35 - 7.39 (3 H, m), 9.29 (1 H, s), 9.58 (1 H, s), 12.79 (1 H, s); ESIMS found for CI7HI6N402 m/z 309.0 (M+l).
Figure imgf000196_0002
[0555] 4-(Benzylamino)-N-(3-methoxyphenyl)-lH-pyrazole-3-carboxamide 123.
[0556] Yellow wax solid (10.5 mg, 0.03 mmol, 9.4% yield). ¾ NMR (499 MHz, DMSO-7e) d ppm 3.73 (3 H, s), 4.20 (2 H, br d, 7=6.31 Hz), 5.63 (1 H, br t, 7=6.17 Hz), 6.62 (1 H, dd, 7=8.23, 1.92 Hz), 7.16 - 7.21 (2 H, m), 7.21 - 7.26 (1 H, m), 7.30 - 7.35 (2 H, m), 7.35 - 7.41 (3 H, m), 7.52 (1 H, s), 9.72 (1 H, s), 12.81 (1 H, s); ESIMS found for CI8HI8N402 m/z 323.2 (M+l).
Figure imgf000197_0001
124
[0557] 4-(Benzylamino)-N-(3-((dimethylamino)methyl)phenyl)-lH-pyrazole-3- carboxamide 124.
[0558] White solid (14.7 mg, 0.04 mmol, 8.5% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 2.14 (6 H, s), 3.34 (2 H, s), 4.20 (2 H, br d, .7=6.04 Hz), 5.65 (1 H, br s), 6.96 (1 H, br d, .7=7.41 Hz), 7.20 (1 H, s), 7.21 - 7.26 (2 H, m), 7.29 - 7.35 (2 H, m), 7.35 - 7.40 (2 H, m), 7.59 (1 H, br d, .7=7.96 Hz), 7.83 (1 H, br s), 9.71 (1 H, s), 12.80 (1 H, br s); ESIMS found for C20H23N5O m/z 350.4 (M+l).
Figure imgf000197_0002
125
[0559] 4-(Benzylamino)-N-(4-(4-methylpiperazin- 1 -yl)phenyl)- lH-pyrazole-3 - carboxamide 125.
[0560] White solid (23.2 mg, 0.06 mmol, 14.8% yield). ¾ NMR (499 MHz, DMSO- de) d ppm 2.21 (3 H, s), 2.41 - 2.47 (4 H, m), 3.05 - 3.10 (4 H, m), 4.20 (2 H, br d, .7=6.04 Hz), 5.60 - 5.66 (1 H, m), 6.87 (2 H, br d, 7=8.78 Hz), 7.18 (1 H, s), 7.21 - 7.27 (1 H, m), 7.29 - 7.35 (2 H, m), 7.35 - 7.39 (2 H, m), 7.58 - 7.64 (2 H, m), 9.54 (1 H, s), 12.74 (1 H, br s); ESIMS found for C22H26N60 m/z 391.0 (M+l).
Figure imgf000198_0001
126
[0561] 4-(Benzylamino)-N-(3-(pyrrolidin-l-ylmethyl)phenyl)-lH-pyrazole-3- carboxamide 126.
[0562] White solid (24.4 mg, 0.06 mmol, 20.9% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.69 (4 H, dt, 7=6.45, 3.09 Hz), 2.43 (4 H, br s), 3.53 (2 H, s), 4.21 (2 H, br d, .7=6.04 Hz), 5.64 (1 H, br s), 6.98 (1 H, d, 7=7.41 Hz), 7.19 (1 H, s), 7.23 (2 H, q, 7=7.50 Hz), 7.29 - 7.35 (2 H, m), 7.35 - 7.40 (2 H, m), 7.60 (1 H, br d, 7=8.23 Hz), 7.81 (1 H, br s), 9.69 (1 H, s), 12.79 (1 H, br s); ESIMS found for C22H25N5O m/z 376.4 (M+l).
Figure imgf000198_0002
[0563] 4-(Benzylamino) -N -(pyridin-3 -yl) - 1 H-pyrazole -3 -carboxamide 127.
[0564] White solid (37.8 mg, 0.13 mmol, 41.2% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 4.21 (d, 7=6.3 Hz, 2H), 5.31 (t, 7=6.3 Hz, 1H), 7.21 (s, 1H), 7.22 - 7.25 (m, 1H), 7.31 - 7.38 (m, 5H), 8.19 - 8.21 (m, 1H), 8.25 (d, 7=4.6 Hz, 1H), 8.97 (d, 7=2.3 Hz, 1H), 10.09 (s, 1H), 12.89 (s, 1H); ESIMS found for CI6HI5N50 m/z 294.0 (M+l).
Figure imgf000198_0003
[0565] 4-(Benzylamino)-N-(5-hydroxypyridin-3-yl)-lH-pyrazole-3-carboxamide
128. [0566] White solid (3.5 mg, 0.011 mmol, 2%% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 4.22 (2 H, br d, 7= 5.76 Hz), 5.63 (1 H, br s), 7.19 - 7.21 (1 H, m), 7.21 - 7.26 (1 H, m), 7.30 - 7.35 (2 H, m), 7.35 - 7.38 (2 H, m), 7.76 (1 H, d, .7=2.20 Hz), 7.82 (1 H, d, 7=2.47 Hz), 8.42 (1 H, s), 9.95 (1 H, s), 12.89 (1 H, br s); ESIMS found for CieHisNsCE m/z 310.3 (M+l).
Figure imgf000199_0001
[0567] 4-(Benzylamino)-N-(5-methoxypyridin-3-yl)-lH-pyrazole-3-carboxamide
129.
[0568] Yellow solid (233.0 mg, 0.72 mmol, 30% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 3.81 (3 H, s), 4.21 (2 H, d, 7=6.31 Hz), 5.60 - 5.69 (1 H, m), 7.20 (1 H, s), 7.22 - 7.26 (1 H, m), 7.30 - 7.35 (2 H, m), 7.35 - 7.39 (2 H, m), 7.93 (1 H, d, 7=2.20 Hz), 7.99 (1 H, d, 7=2.47 Hz), 8.62 (1 H, s), 10.06 (1 H, s), 12.89 (1 H, br s); ESIMS found for C17H17N5O2 m/z 323.7 (M+l).
Figure imgf000199_0002
130
[0569] 4-(Benzylamino)-N-(6-(pyrrolidin- 1 -yl)pyridin-3-yl)- lH-pyrazole-3 - carboxamide 130.
[0570] Brown solid (3.7 mg, 0.01 mmol, 3.6% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.89 - 1.97 (m, 4H), 3.32 - 3.39 (m, 4H), 4.19 (d, 7=6Hz, 2H), 5.61 (t, 7=6.3Hz, 1H), 6.77 (d, 7=9.5Hz, 1H), 7.18 (s, 1H), 7.23 (t, 7=7.3Hz, 1H), 7.28 - 7.38 (m, 4H), 7.88 (dd, 7=9Hz, 7=2.5Hz, lH), 8.44 (d, 7=2.5Hz, 1H), 9.68 (s, 1H), 12.76 (s, 1H); ESIMS found for C2oH22N60 m/z 363.2 (M+l).
Figure imgf000200_0001
131
[0571] 4-(Benzylamino)-N-(6-(piperidin-l-yl)pyridin-3-yl)-lH-pyrazole-3- carboxamide 131.
[0572] Yellow wax (5.6 mg, 0.015 mmol, 6.8% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.50 - 1.61 (m, 6H), 3.44 (t, =5.3Hz, 4H), 4.19 (d, =6.5Hz, 2H), 5.61 (br s, 1H), 6.41 (d, =9Hz, 1H), 7.17 (s, 1H), 7.23 (t, =7.3Hz, 1H), 7.29 - 7.38 (m, 4H), 7.84 (br d, =8Hz, 1H), 8.38 (br s, 1H), 9.60 (br s, 1H), 12.74 (br s, 1H); ESIMS found for C2iH24N60 m/z 377.0 (M+l).
Figure imgf000200_0002
132
[0573] 4-(Benzylamino)-N-(6-(pyrrolidin-l-ylmethyl)pyridin-3-yl)-lH-pyrazole-3- carboxamide 132.
[0574] Yellow wax (10.0 mg, 0.04 mmol, 20.3% yield). ¾ NMR (499 MHz, DMSO- d ) d ppm 1.67 - 1.72 (4 H, m), 2.42 - 2.47 (4 H, m), 3.57 (2 H, s), 4.21 (2 H, d, .7=6.31 Hz), 5.61 - 5.69 (1 H, m), 7.20 (1 H, s), 7.21 - 7.27 (1 H, m), 7.30 - 7.35 (2 H, m), 7.35 - 7.40 (2 H, m), 8.17 (1 H, d, .7=1.65 Hz), 8.22 (1 H, br s), 8.81 (1 H, d, 7=2.20 Hz), 10.07 (1 H, br s), 12.90 (1 H, br s); ESIMS found for C2iH24N60 mlz 377.3 (M+l).
Figure imgf000200_0003
134 [0575] 4-((4-(Dimethylamino)benzyl)amino)-N-(pyridin-3-yl)-lH-pyrazole-3- carboxamide 134.
[0576] Off-white solid (14.3 mg, 0.04 mmol, 28.3% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 2.86 (s, 6H), 4.06 (d, J= 5.9 Hz, 2H), 5.41 (t, J= 5.6 Hz, 1H), 6.67 (d, J= 8.6 Hz, 2H), 7.18 (d, J= 8.6 Hz, 2H), 7.24 (s, 1H), 7.32 (dd, J= 8.2 Hz, 4.7 Hz, 1H), 8.18 - 8.20 (m, 1H), 8.24 - 8.25 (m, 1H), 8.96 (s, 1H), 10.06 (s, 1H), 12.88 (s, 1H); ESIMS found for Ci8H2oN60 mlz 337.0 (M+l).
Figure imgf000201_0001
135
[0577] 4-((3 -((Dimethylamino)methyl)benzyl)amino) -N -(pyridin-3 -yl)- 1H- pyrazole -3 -carboxamide 135.
[0578] Yellow solid (57.8 mg, 0.16 mmol, 49.6% yield). *HNMR (499 MHz, DMSO- d6) 5 ppm 2.11 (s, 6H), 3.35 (s, 2H), 4.20 (d, J=6.2 Hz, 2H), 5.59 - 5.65 (m, 1H), 7.13 - 7.15 (m, 1H), 7.20 (s, 1H), 7.23 - 7.27 (m, 2H), 7.28 - 7.30 (m, 1H), 7.33 (dd, 7=8.3 Hz, 4.7 Hz, 1H), 8.18 - 8.20 (m, 1H), 8.25 (dd, 7= 4.6 Hz, 1.3 Hz, 1H), 8.96 - 8.97 (m, 1H), 10.07 (s, 1H), 12.88 (s, 1H); ESIMS found for Ci9H22N60 mlz 351.1 (M+l).
Figure imgf000201_0002
136
[0579] 4-((2-((Dimethylamino)methyl)benzyl)amino) -N -(pyridin-3 -yl)- 1H- pyrazole -3 -carboxamide 136.
[0580] White solid (64.6 mg, 0.18 mmol, 41.2% yield). ¾ NMR (499 MHz, DMSO- de) d ppm 2.16 (s, 6H), 3.45 (s, 2H), 4.28 (s, 2H), 5.82 (br s, 1H), 7.18 - 7.25 (m, 3H), 7.29 (s, 1H), 7.32 (dd, .7=8.3 Hz, 4.7 Hz, 1H), 7.36 - 7.38 (m, 1H), 8.18 - 8.20 (m, 1H), 8.24 (d, .7=4.1 Hz, 1H), 8.97 (d, J=1.7 Hz, 1H), 10.03 (s, 1H), 12.87 (s, 1H); ESIMS found for Ci9H22N60 mlz 351.0 (M+l).
Figure imgf000202_0001
137
[0581] N-(Pyridin-3-yl)-4-((pyridin-3-ylmethyl)amino)-lH-pyrazole-3-carboxamide
137.
[0582] Light yellow solid (32.5 mg, 0.11 mmol, 62.3% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 4.25 (d, 7=6.5 Hz, 2H), 5.75 - 5.76 (m, 1H), 7.27 (s, 1H), 7.27 - 7.35 (m, 2H), 7.77 (dt, 7=7.7 Hz, 1.9 Hz, 1H), 8.19 - 8.21 (m, 1H), 8.25 - 8.26 (m, 1H), 8.44 (dd, 7=4.7 Hz, 1.5 Hz, 1H), 8.58 (d, .7=1.7 Hz, 1H), 8.98 (s, 1H), 10.09 (s, 1H); ESIMS found for CI5HI4N60 mlz 295.0 (M+l).
Figure imgf000202_0002
138
[0583] 4-(((2,3 -Dihydrobenzo [b] [ 1 ,4]dioxin-6-yl)methyl)amino)-N -(pyridin-3 -yl)- lH-pyrazole -3 -carboxamide 138.
[0584] Tan solid (51.7 mg, 0.15 mmol, 61.5% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 4.07 (d, 7=6.2 Hz, 2H), 4.19 - 4.20 (m, 4H), 5.54 (t, .7=6.2 Hz, 1H), 6.78 (d, J= 8.2 Hz, 1H), 6.82 (dd, 7=8.2 Hz, 1.9 Hz, 1H), 6.85 (d, 7=1.8 Hz, 1H), 7.22 (s, 1H), 7.33 (dd, 7=8.2 Hz, 4.7 Hz, 1H), 8.19 (d, 7=8.2 Hz, 1H), 8.25 (d, 7=3.7 Hz, 1H), 8.97 (s, 1H), 10.07 (s, 1H), 12.88 (s, 1H); ESIMS found for CisHivNsCL mlz 352.0 (M+l).
Figure imgf000202_0003
140 [0585] Ethyl (£)-3-(3 -(4-(3 -fluorophenyl)- lH-benzo[d]imidazol-2-yl)- lH-pyrazol-4- yl)acrylate 140.
[0586] White solid (15.3 mg, 0.04 mmol, 56.7% yield). ¾ NMR (499 MHz, DMSO- d6) 5 ppm 1.23 (3 H, t, .7=7.14 Hz), 4.19 (2 H, q, 7=7.14 Hz), 6.68 (1 H, d, .7=16.19 Hz), 7.22 (1 H, td, .7=8.51, 2.20 Hz), 7.33 (1 H, t, 7= 7.68 Hz), 7.48 - 7.61 (3 H, m), 7.96 - 8.09 (1 H, m), 8.20 (1 H, br s), 8.52 - 8.66 (2 H, m), 13.03 (1 H, br s), 13.72 (1 H, br s); ESIMS found for C21H17FN4O2 m/z 377.15 (M+l).
Figure imgf000203_0001
[0587] (E)-4-(3-Fluorophenyl)-2-(4-(3-fluorostyryl)-lH-pyrazol-3-yl)-lH- benzofd] imidazole 141.
[0588] Light purple solid (15.0 mg, 0.04 mmol, 26.0% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 7.09 (1 H, td, .7=8.44, 1.78 Hz), 7.18 (1 H, d, .7=16.74 Hz), 7.23 - 7.28 (2 H, m), 7.32 (1 H, t, .7=7.82 Hz), 7.35 - 7.39 (1 H, m), 7.39 - 7.45 (1 H, m), 7.52 (2 H, d, 7= 7.68 Hz), 7.54 - 7.60 (1 H, m), 8.11 (1 H, d, 7=7.96 Hz), 8.18 (1 H, dt, 7=10.77, 2.16 Hz), 8.32 (1 H, d, 7=16.74 Hz), 8.40 (1 H, s), 12.98 (1 H, s), 13.54 (1 H, br s); ESIMS found for C2 HI6F2N m/z 399.3 (M+l).
Figure imgf000203_0002
142
[0589] (E)-2-(4-(2,3-Difluorostyryl)-lH-pyrazol-3-yl)-4-(4-methylpiperazin-l-yl)- lH-imidazo[4,5-c]pyridine 142.
[0590] White solid (49.0 mg, 0.12 mmol, 60.2% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 2.25 (3 H, s), 2.47 - 2.50 (4 H, m), 4.12 (4 H, br s), 6.83 (1 H, d, 7=5.76 Hz), 7.19 (1 H, d, 7=16.74 Hz), 7.20 - 7.25 (1 H, m), 7.27 - 7.36 (1 H, m), 7.39 (1 H, br t, 7=7.14 Hz), 7.80 (1 H, d, .7=5.49 Hz), 8.29 (1 H, br d, 7=16.74 Hz), 8.49 (1 H, s), 12.96 (1 H, br s), 13.54 (1 H, br s); ESIMS found for C22H21F2N7 m/z 422.2 (M+l).
Figure imgf000204_0001
144
[0591] (E)-2-(4-(2,3-Difluorostyryl)-lH-pyrazol-3-yl)-5-((l-methylpiperidin-4- yl)oxy) - 1 H-benzo [d] imidazole 144.
[0592] White solid (26.0 mg, 0.06 mmol, 26.4% yield). ¾ NMR (499 MHz, DMSO- de) d ppm 1.61 - 1.71 (2 H, m), 1.90 - 1.98 (2 H, m), 2.10 - 2.20 (2 H, m), 2.17 (3 H, s), 2.59 - 2.66 (2 H, m), 4.32 (1 H, dt, 7=7.68, 4.12 Hz), 6.82 (1 H, dd, 7=8.64, 2.33 Hz), 7.08 (1 H, s), 7.20 - 7.35 (3 H, m), 7.46 (1 H, d, 7=8.78 Hz), 7.50 (1 H, br t, 7=7.00 Hz), 8.18 (1 H, d, 7=16.74 Hz), 8.41 (1 H, s); ESIMS found for C24H23F2N5O m/z 436.15 (M+l).
Figure imgf000204_0002
145
[0593] (E)-3-(3-(4-(3-Fluorophenyl)-lH-benzo[d]imidazol-2-yl)-lH-pyrazol-4-yl)- l-phenylprop-2-en-l-one 145.
[0594] White solid (64.7 mg, 0.16 mmol, 73.3% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 7.20 (1 H, td, 7=8.58, 2.33 Hz), 7.34 (1 H, t, 7=7.82 Hz), 7.48 - 7.61 (5 H, m), 7.61 - 7.67 (1 H, m), 7.94 (1 H, d, 7=15.92 Hz), 8.00 (1 H, br s), 8.08 (2 H, d, 7=7.41 Hz), 8.32 (1 H, br s), 8.72 - 8.84 (2 H, m), 13.24 (2 H, br s); ESIMS found for C25H17FN4O m/z 409.1 (M+l).
Figure imgf000205_0001
[0595] (E)-N-(3-Phenylpropyl)-4-(2-(pyridin-3-yl)vinyl)-lH-pyrazole-3- carboxamide 146.
[0596] Beige solid (45.0 mg, 0.14 mmol, 75.0% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.83 (2 H, quin, .7=7.41 Hz), 2.62 (2 H, br t, 7= 7.68 Hz), 3.27 (2 H, q, 7=6.59 Hz), 7.06 (1 H, d, 7=16.74 Hz), 7.15 - 7.20 (1 H, m), 7.20 - 7.24 (2 H, m), 7.26 - 7.30 (2 H, m), 7.38 (1 H, dd, 7=7.68, 4.67 Hz), 7.72 - 7.80 (1 H, m), 7.85 - 7.92 (1 H, m), 8.23 (1 H, br t, 7=5.90 Hz), 8.26 (1 H, br s), 8.42 (1 H, dd, 7=4.67, 1.65 Hz), 8.60 (1 H, d, 7=1.37 Hz), 13.35 (1 H, br s); ESIMS found for C20H20N4O m/z 332.9 (M+l).
Figure imgf000205_0002
147
[0597] (E)-N-(3 -Isopropoxypropyl)-4-(2-(pyridin-3 -yl)vinyl)- lH-pyrazole-3 - carboxamide 147.
[0598] Beige solid (16.0 mg, 0.05 mmol, 33.8% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.09 (6 H, d, 7=6.04 Hz), 1.72 (2 H, quin, 7=6.52 Hz), 3.26 - 3.31 (2 H, m), 3.41 (2 H, t, 7=6.17 Hz), 3.52 (1 H, spt, 7=6.13 Hz), 7.05 (1 H, d, 7=17.02 Hz), 7.38 (1 H, dd, 7=7.96, 4.94 Hz), 7.77 (1 H, d, 7=16.74 Hz), 7.87 (1 H, br d, 7=7.96 Hz), 8.15 (1 H, br t, 7=5.76 Hz), 8.27 (1 H, s), 8.42 (1 H, br d, 7=3.57 Hz), 8.60 (1 H, s), 13.35 (1 H, s); ESIMS found for C17H22N4O2 m/z 315.0 (M+l).
Figure imgf000205_0003
[0599] (E)-N-(3 -Phenoxypropyl)-4-(2 -(pyridin-3 -yl) vinyl) - 1 H-pyrazole -3 - carboxamide 148.
[0600] Beige solid (24.0 mg, 0.07 mmol, 45.8% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.98 (2 H, quin, 7=6.45 Hz), 3.42 (2 H, q, .7=6.31 Hz), 4.02 (2 H, br t, .7=6.17 Hz), 6.88 - 6.97 (3 H, m), 7.06 (1 H, br d, 7=16.74 Hz), 7.23 - 7.30 (2 H, m), 7.38 (1 H, dd, 7=7.82, 4.80 Hz), 7.77 (1 H, br d, 7=16.74 Hz), 7.87 (1 H, br d, 7=7.96 Hz), 8.26 - 8.32 (2 H, m), 8.42 (1 H, dd, 7=4.67, 1.65 Hz), 8.60 (1 H, s), 13.37 (1 H, br s); ESIMS found for C20H20N4O2 m/z 349.1 (M+l).
Figure imgf000206_0001
[0601] (E)-4-(2-(Pyridin-3-yl)vinyl)-N-(4-(pyrrolidin-l-ylmethyl)phenyl)-lH- pyrazole -3 -carboxamide 149.
[0602] Beige solid (27.0 mg, 0.07 mmol, 38.9% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.69 (4 H, br t, 7=3.16 Hz), 2.41 (4 H, br s), 3.52 (2 H, s), 7.11 (1 H, d, 7=16.74 Hz), 7.25 (2 H, d, 7=8.23 Hz), 7.39 (1 H, dd, 7=7.82, 4.80 Hz), 7.69 - 7.80 (3 H, m), 7.92 (1 H, br d, 7=7.96 Hz), 8.35 (1 H, s), 8.43 (1 H, dd, 7=4.67, 1.37 Hz), 8.63 (1 H, d, 7=1.92 Hz), 10.05 (1 H, br s), 13.56 (1 H, br s); ESIMS found for C22H23N5O m/z 373.9 (M+l).
Figure imgf000206_0002
[0603] (E)-4-(2-(Pyridin-3-yl)vinyl)-N-(4-(2-(pyrrolidin-l-yl)ethoxy)phenyl)-lH- pyrazole -3 -carboxamide 150.
[0604] Beige solid (65.0 mg, 0.16 mmol, 78.5% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.68 (4 H, dt, 7=6.86, 3.16 Hz), 2.51 - 2.55 (4 H, m), 2.77 (2 H, t, 7=5.90 Hz), 4.04 (2 H, t, 7=6.04 Hz), 6.91 (2 H, d, 7=9.33 Hz), 7.10 (1 H, d, 7=16.74 Hz), 7.39 (1 H, dd, 7=7.96, 4.67 Hz), 7.71 (2 H, d, 7=9.06 Hz), 7.76 (1 H, d, 7=17.02 Hz), 7.91 (1 H, dt, 7=8.03, 1.75 Hz), 8.34 (1 H, s), 8.43 (1 H, dd, .7=4.80, 1.51 Hz), 8.62 (1 H, d, 7=1.92 Hz), 9.97 (1 H, s), 13.52 (1 H, br s); ESIMS found for C23H25N5O2 m/z 404.1 (M+l).
Figure imgf000207_0001
151
[0605] (E)-N-(5-(3-Fluorophenyl)pyridin-3-yl)-4-(2-(pyridin-3-yl)vinyl)-lH- pyrazole -3 -carboxamide 151.
[0606] White solid (28.0 mg, 0.07 mmol, 45.5% yield). ¾ NMR (499 MHz, DMSO- de) d ppm 7.14 (1 H, d, 7=16.74 Hz), 7.25 - 7.32 (1 H, m), 7.39 (1 H, dd, 7=7.96, 4.67 Hz), 7.53 - 7.62 (3 H, m), 7.78 (1 H, d, 7=16.74 Hz), 7.94 (1 H, dt, 7=7.96, 1.78 Hz), 8.41 (1 H, s), 8.44 (1 H, dd, 7=4.67, 1.65 Hz), 8.58 (1 H, t, 7=2.20 Hz), 8.64 (1 H, d, 7=1.92 Hz), 8.65 (1 H, d, 7=2.20 Hz), 9.05 (1 H, d, 7=2.20 Hz), 10.48 (1 H, br s), 13.68 (1 H, br s); ESIMS found for C22HI6FN50 m/z 386.2 (M+l).
Figure imgf000207_0002
152
[0607] (E)-N-(6-(Piperazin-l-yl)pyridin-3-yl)-4-(2-(pyridin-3-yl)vinyl)-lH- pyrazole -3 -carboxamide 152.
[0608] White solid (57.0 mg, 0.15 mmol, 65.4% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 2.74 - 2.80 (4 H, m), 3.34 (4 H, br dd, 7=5.90, 4.25 Hz), 6.79 (1 H, d, 7=9.06 Hz), 7.10 (1 H, d, 7=16.74 Hz), 7.39 (1 H, dd, 7=7.96, 4.67 Hz), 7.76 (1 H, d, 7=17.02 Hz), 7.91 (1 H, dt, 7=7.96, 1.65 Hz), 7.94 (1 H, dd, 7=9.06, 2.74 Hz), 8.34 (1 H, s), 8.43 (1 H, dd, 7=4.67, 1.37 Hz), 8.48 (1 H, d, 7=2.47 Hz), 8.62 (1 H, d, 7=2.20 Hz), 10.01 (1 H, br s), 13.51 (1 H, br s); ESIMS found for C20H21N7O m/z 376.4 (M+l).
Figure imgf000208_0001
[0609] (E)-N-(6 -(Piperidin-4 -yloxy)pyridin-3 -yl)-4-(2 -(pyridin-3 -yl) vinyl) - 1 H- pyrazole -3 -carboxamide 154.
[0610] Beige solid (40.0 mg, 0.10 mmol, 48.3% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.41 - 1.52 (2 H, m), 1.93 (2 H, dt, 7=8.44, 3.74 Hz), 2.53 - 2.61 (2 H, m), 2.95 (2 H, dt, 7=12.56, 4.01 Hz), 4.94 - 5.03 (1 H, m), 6.76 (1 H, d, 7=9.06 Hz), 7.11 (1 H, d, 7=16.74 Hz), 7.39 (1 H, dd, 7=7.96, 4.67 Hz), 7.75 (1 H, d, 7=16.74 Hz), 7.91 (1 H, dt, 7=8.03, 1.75 Hz), 8.08 (1 H, dd, 7=9.06, 2.74 Hz), 8.35 (1 H, s), 8.43 (1 H, dd, 7=4.80, 1.51 Hz), 8.50 (1 H, d, 7=2.47 Hz), 8.62 (1 H, d, 7=2.20 Hz), 10.19 (1 H, br s); ESIMS found for C2IH22N602 m/z 391.3 (M+l).
Figure imgf000208_0002
[0611] (E)-N-(6-((l-Methylpiperidin-4-yl)oxy)pyridin-3-yl)-4-(2-(pyridin-3- yl)vinyl) - 1 H-pyrazole -3 -carboxamide 155.
[0612] Beige solid (54.0 mg, 0.13 mmol, 65.2% yield).‘H NMR (499 MHz, DMSO- de) d ppm 1.65 (2 H, dtd, 7=12.66, 9.18, 9.18, 3.57 Hz), 1.91 - 1.99 (2 H, m), 2.10 - 2.21 (2 H, m), 2.18 (3 H, s), 2.59 - 2.67 (2 H, m), 4.89 - 4.97 (1 H, m), 6.77 (1 H, d, 7=8.78 Hz), 7.11 (1 H, d, 7=16.74 Hz), 7.39 (1 H, dd, 7=7.96, 4.67 Hz), 7.75 (1 H, d, 7=16.74 Hz), 7.91 (1 H, dt, 7=7.96, 1.78 Hz), 8.08 (1 H, dd, 7=8.78, 2.74 Hz), 8.36 (1 H, s), 8.43 (1 H, dd, 7=4.80, 1.51 Hz), 8.51 (1 H, d, 7=2.47 Hz), 8.62 (1 H, d, 7=2.20 Hz), 10.19 (1 H, br s), 13.59 (1 H, br s); ESIMS found for C22H24N602 m/z 405.4 (M+l).
Figure imgf000209_0001
156
[0613] (E)-5 -Methyl -N-(6 -(( 1 -methylpiperidin-4 -yl)oxy)pyridin-3 -yl) -4 -(2-(pyridin-
3 -yl)vinyl) - 1 H-pyrazole -3 -carboxamide 156.
[0614] White solid (13.0 mg, 0.03 mmol, 68.4% yield). ¾ NMR (499 MHz, DMSO- de) d ppm 1.64 (2 H, dtd, 7=12.59, 9.28, 9.28, 3.70 Hz), 1.91 - 1.98 (2 H, m), 2.09 - 2.22 (2 H, m), 2.17 (3 H, s), 2.58 - 2.67 (2 H, m), 4.88 - 4.98 (1 H, m), 6.76 (1 H, d, .7=8.78 Hz), 6.94 (1 H, d, .7=17.02 Hz), 7.38 (1 H, dd, 7=7.96, 4.67 Hz), 7.73 (1 H, d, 7=17.02 Hz), 7.93 (1 H, dt, 7=8.10, 1.72 Hz), 8.08 (1 H, dd, 7=8.78, 2.74 Hz), 8.42 (1 H, dd, 7=4.67, 1.37 Hz), 8.50 (1 H, d, 7=2.74 Hz), 8.67 (1 H, d, 7=2.20 Hz), 10.14 (1 H, br s), 13.31 (1 H, br s); ESIMS found for CzsHzeNeCE m/z 419.0 (M+l).
Figure imgf000209_0002
158
[0615] (E)-2-(4-Fluorophenyl)-5-(4-(2-(pyridin-3-yl)vinyl)-lH-pyrazol-3-yl)-l,3,4- oxadiazole 158.
[0616] White solid (51.0 mg, 0.15 mmol, 74.3% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 7.19 - 7.32 (1 H, m), 7.43 (1 H, br dd, 7=7.55, 4.80 Hz), 7.50 (2 H, br t, 7=8.23 Hz), 7.74 (1 H, br d, 7=16.47 Hz), 7.97 (1 H, br d, 7=7.14 Hz), 8.09 - 8.20 (2 H, m), 8.42 - 8.54 (2 H, m), 8.69 (1 H, br s), 13.84 (1 H, br s); ESIMS found for CI8HI2FN50 m/z 334.2 (M+l).
Figure imgf000209_0003
159
[0617] (E)-4-(3-Fluorophenyl)-2-(4-(2-(pyridin-3-yl)vinyl)-lH-pyrazol-3-yl)-lH- benzo[d] imidazole 159.
[0618] Brown solid (37.7 mg, 0.10 mmol, 57.5% yield). *H NMR (499 MHz, DMSO- d6) d ppm 7.20 (1 H, d, .7=16.74 Hz), 7.28 (1 H, td, .7=8.44, 2.33 Hz), 7.33 (1 H, br t, 7=7.68 Hz), 7.41 (1 H, dd, 7=7.82, 4.80 Hz), 7.53 (2 H, br d, 7=7.41 Hz), 7.56 - 7.63 (1 H, m), 7.95 (1 H, br d, 7=7.96 Hz), 8.13 (1 H, br d, 7=7.96 Hz), 8.19 (1 H, br d, 7=11.25 Hz), 8.35 - 8.45 (2 H, m), 8.47 (1 H, dd, 7=4.67, 1.37 Hz), 8.69 (1 H, s), 13.00 (1 H, br s), 13.55 (1 H, br s); ESIMS found for C23HI6FN5 m/z 381.8 (M+l).
Figure imgf000210_0001
160
[0619] (E)-7-(3-Fluorophenyl)-2-(4-(2-(pyridin-3-yl)vinyl)-lH-pyrazol-3-yl)-3H- imidazo[4,5-c]pyridine 160.
[0620] Tan solid (25.0 mg, 0.07 mmol, 34.5% yield).‘H NMR (499 MHz, DMSO-7,) d ppm 7.23 (1 H, d, 7=16.74 Hz), 7.33 (1 H, td, 7=8.58, 2.33 Hz), 7.42 (1 H, dd, 7=7.82, 4.80 Hz), 7.59 - 7.68 (1 H, m), 7.97 (1 H, br d, 7=7.96 Hz), 8.14 - 8.30 (2 H, m), 8.37 (1 H, br d, 7=17.84 Hz), 8.46 (1 H, br s), 8.48 (1 H, dd, 7=4.67, 1.37 Hz), 8.69 (1 H, br s), 8.71 (1 H, d, 7=1.92 Hz), 8.84 (1 H, br s), 13.58 (2 H, br s); ESIMS found for C22HI5FN6 m/z 382.6 (M+l).
Figure imgf000210_0002
[0621] (E)-4-((2-(4-(2-(5-Fluoropyridin-3-yl)vinyl)-lH-pyrazol-3-yl)-lH- benzo [d] imidazol -5 -yl)methyl)morpholine 161. [0622] White solid (34.0 mg, 0.08 mmol, 47.8% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 2.40 (4 H, br s), 3.58 (6 H, br s), 7.10 - 7.21 (1 H, m), 7.25 (1 H, d, .7=16.74 Hz), 7.40 - 7.45 (1 H, m), 7.62 - 7.69 (1 H, m), 7.78 - 7.87 (1 H, m), 8.14 - 8.24 (1 H, m), 8.39 (1 H, s), 8.45 (1 H, d, 7=2.20 Hz), 8.57 (1 H, br s), 12.70 (1 H, br d, 7=8.78 Hz), 13.53 (1 H, br s); ESIMS found for C22H2IFN60 m/z 405.1 (M+l).
Figure imgf000211_0001
[0623] (E)-2-(4-(2-(5-Fluoropyridin-3-yl)vinyl)-lH-pyrazol-3-yl)-4-(l- methylpiperidin-4-yl) - 1 H-imidazo [4,5 -c] pyridine 162.
[0624] White solid (11.4 mg, 0.03 mmol, 14.6% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.92 - 2.01 (2 H, m), 2.04 - 2.12 (2 H, m), 2.17 (2 H, dt, 7=10.84, 1.17 Hz), 2.24 (3 H, s), 2.51 - 2.53 (1 H, m), 2.97 (2 H, br d, 7=10.15 Hz), 7.27 - 7.41 (2 H, m), 7.79 (1 H, br d, 7=10.43 Hz), 8.19 (1 H, br d, 7=5.49 Hz), 8.30 - 8.39 (1 H, m), 8.42 (1 H, br s), 8.47 (1 H, d, 7=2.47 Hz), 8.58 (1 H, s), 13.12 (1 H, br s), 13.59 (1 H, br s); ESIMS found for C22H22FN7 m/z 404.2 (M+l).
Figure imgf000211_0002
[0625] (E)-2-(4-(2-(5-Fluoropyridin-3-yl)vinyl)-lH-pyrazol-3-yl)-4-(4- methylpiperazin- 1 -yl) - 1 H-imidazo [4,5 -c] pyridine 163.
[0626] White solid (36.0 mg, 0.09 mmol, 46.1% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 2.24 (3 H, s), 2.51 - 2.54 (4 H, m), 4.12 (4 H, br s), 6.84 (1 H, d, 7=5.49 Hz), 7.19 (1 H, d, 7=16.74 Hz), 7.70 - 7.76 (1 H, m), 7.79 (1 H, d, 7=5.49 Hz), 8.24 (1 H, br d, 7=16.47 Hz), 8.39 (1 H, s), 8.46 (1 H, d, 7=2.74 Hz), 8.53 (1 H, s), 13.24 (2 H, br s); ESIMS found for C2IH2IFN8 m/z 405.2 (M+l).
Figure imgf000212_0001
164
[0627] (E)-2-(4-(2-(5-Fluoropyridin-3-yl)vinyl)-lH-pyrazol-3-yl)-7-(4- methylpiperazin-l-yl)-3H-imidazo[4,5-c]pyridine 164.
[0628] White solid (30.0 mg, 0.07 mmol, 38.2% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 2.23 (3 H, s), 2.45 (4 H, br t, .7=4.80 Hz), 3.41 - 3.46 (4 H, m), 6.66 (1 H, br s), 7.25 (1 H, d, 7=16.74 Hz), 7.84 (1 H, br d, 7=9.88 Hz), 8.09 (1 H, br d, 7=16.74 Hz), 8.38 (1 H, br s), 8.45 (1 H, d, 7=2.74 Hz), 8.55 - 8.63 (2 H, m), 12.66 (1 H, br s), 13.57 (1 H, br s); ESIMS found for C2IH2IFN8 m/z 405.1 (M+l).
Figure imgf000212_0002
165
[0629] (E)-N-(3 -Isopropoxypropyl) -4 -(2-(6 -methylpyridin-3 -yl)vinyl) - 1 H-pyrazole -
3-carboxamide 165.
[0630] White solid (12.0 mg, 0.04 mmol, 43.1% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.09 (6 H, d, 7=6.31 Hz), 1.72 (2 H, quin, 7=6.45 Hz), 2.46 (3 H, s), 3.27 - 3.30 (2 H, m), 3.42 (2 H, t, 7=6.31 Hz), 3.52 (1 H, spt, 7=6.08 Hz), 7.02 (1 H, d, 7=16.74 Hz), 7.24 (1 H, d, 7=8.23 Hz), 7.65 - 7.73 (1 H, m), 7.77 (1 H, dd, 7=8.23, 2.20 Hz), 8.13 (1 H, t, 7=5.63 Hz), 8.23 (1 H, br s), 8.46 (1 H, d, 7=1.92 Hz), 13.32 (1 H, br s); ESIMS found for C18H24N4O2 m/z 329.1 (M+l).
Figure imgf000212_0003
166
[0631] (E)-N-(5-(3-Fluorophenyl)pyridin-3-yl)-4-(2-(6-methylpyridin-3-yl)vinyl)- lH-pyrazole -3 -carboxamide 166.
[0632] White solid (18.0 mg, 0.05 mmol, 72.6% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 2.46 (3 H, s), 7.10 (1 H, d, .7=16.74 Hz), 7.25 (1 H, d, 7= 8.23 Hz), 7.27 - 7.31 (1 H, m), 7.56 - 7.58 (2 H, m), 7.59 (1 H, dt, 7=2.61, 1.44 Hz), 7.71 (1 H, br d, 7=16.74 Hz), 7.84 (1 H, dd, 7=8.23, 2.20 Hz), 8.38 (1 H, s), 8.49 (1 H, d, 7=2.20 Hz), 8.57 (1 H, t, 7=2.06 Hz), 8.65 (1 H, d, 7=1.92 Hz), 9.05 (1 H, d, 7=1.92 Hz), 10.45 (1 H, br s), 13.65 (1 H, br s); ESIMS found for C H FN O m/z 400.1 (M+l).
Figure imgf000213_0001
167
[0633] (E)-4-(5-(2-(3-(4-(3-Fluorophenyl)-lH-benzo[d]imidazol-2-yl)-lH-pyrazol- 4-yl)vinyl)pyridin-3 -yl)morpholine 167.
[0634] White solid (35.0 mg, 0.08 mmol, 74.4% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 3.11 - 3.18 (4 H, m), 3.72 - 3.77 (4 H, m), 7.15 - 7.25 (2 H, m), 7.29 (1 H, br s), 7.32 (1 H, t, 7=7.68 Hz), 7.50 - 7.59 (3 H, m), 8.13 (1 H, br d, 7=11.53 Hz), 8.18 - 8.26 (3 H, m), 8.28 (1 H, s), 8.38 (1 H, br s), 13.00 (1 H, br s), 13.52 (1 H, br s); ESIMS found for C27H23FN60 m/z 467.1 (M+l).
Figure imgf000213_0002
[0635] (E)-N-(5-(3-Fluorophenyl)pyridin-3-yl)-4-(2-(5-(pyrrolidin-l- ylmethyl)pyridin-3 -yl)vinyl) - 1 H-pyrazole -3 -carboxamide 168. [0636] White solid (11.0 mg, 0.02 mmol, 39.3% yield). ¾ NMR (499 MHz, DMSO- d6) 5 ppm 1.70 (4 H, dt, 7=6.45, 3.09 Hz), 2.45 (4 H, br s), 3.62 (2 H, s), 7.15 (1 H, d, .7=16.47 Hz), 7.25 - 7.33 (1 H, m), 7.54 - 7.63 (3 H, m), 7.77 (1 H, d, 7=16.47 Hz), 7.84 (1 H, s), 8.35 (1 H, d, 7=1.92 Hz), 8.41 (1 H, s), 8.51 (1 H, d, 7=2.20 Hz), 8.56 (1 H, t, 7=2.20 Hz), 8.66 (1 H, d, 7=2.20 Hz), 9.05 (1 H, d, 7=2.20 Hz), 10.47 (1 H, br s), 13.68 (1 H, br s); ESIMS found for C27H25FN60 m/z 469.0 (M+l).
Figure imgf000214_0001
[0637] (E)-4-(3-Fluorophenyl)-2-(4-(2-(5-(pyrrolidin-l-ylmethyl)pyridin-3- yl)vinyl) - 1 H-pyrazol -3 -yl) - 1 H-benzo [d] imidazole 169.
[0638] Brown solid (69.0 mg, 0.15 mmol, 65.2% yield). *H NMR (499 MHz, DMSO- d6) d ppm 1.67 (4 H, br s), 2.42 (4 H, br s), 3.61 (2 H, s), 7.17 - 7.27 (2 H, m), 7.33 (1 H, t, 7=7.96 Hz), 7.54 (2 H, br d, 7=7.68 Hz), 7.57 - 7.65 (1 H, m), 7.73 (1 H, br s), 8.16 (1 H, br d, 7=11.53 Hz), 8.20 (1 H, br d, 7=7.14 Hz), 8.26 (1 H, br d, 7=15.92 Hz), 8.38 (1 H, d, 7=1.65 Hz), 8.41 (1 H, s), 8.62 (1 H, d, 7=1.65 Hz); ESIMS found for C28H25FN6 m/z 465.0 (M+l).
Figure imgf000214_0002
[0639] (E)-N-(6-Methoxypyridin-3-yl)-4-(2-(5-(piperidin-l-ylmethyl)pyridin-3- yl)vinyl) - 1 H-pyrazole -3 -carboxamide 170.
[0640] Light brown solid (14.0 mg, 0.03 mmol, 28.1% yield). nH NMR (499 MHz, DMSO-7 d ppm 1.39 (2 H, br d, 7=4.67 Hz), 1.50 (4 H, quin, 7=5.49 Hz), 2.34 (4 H, br s), 3.47 (2 H, s), 3.84 (3 H, s), 6.82 (1 H, d, 7=9.06 Hz), 7.12 (1 H, d, 7=17.02 Hz), 7.75 (1 H, br d, 7=16.74 Hz), 7.79 (1 H, s), 8.10 (1 H, dd, 7=8.92, 2.61 Hz), 8.33 (1 H, d, 7=1.65 Hz), 8.37 (1 H, s), 8.50 (1 H, d, .7=1.92 Hz), 8.55 (1 H, d, 7=2.47 Hz), 10.21 (1 H, br s), 13.58 (1 H, br s); ESIMS found for C23H26N6O2 m/z 419.1 (M+l).
Figure imgf000215_0001
171
[0641] (E)-4-(3-Fluorophenyl)-2-(4-(2-(6-(piperidin-l-ylmethyl)pyrazin-2-yl)vinyl)- 1 H-pyrazol -3 -yl) - 1 H-benzo [d] imidazole 171.
[0642] White solid (28.0 mg, 0.06 mmol, 66.4% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.40 (2 H, br s), 1.53 (4 H, br s), 2.40 (4 H, br s), 3.58 (2 H, br s), 7.22 (1 H, td, 7=8.37, 2.47 Hz), 7.30 - 7.40 (2 H, m), 7.53 (2 H, br d, 7=9.06 Hz), 7.55 - 7.61 (1 H, m), 8.10 - 8.18 (2 H, m), 8.49 (1 H, br s), 8.54 (1 H, s), 8.61 (1 H, br d, 7=16.47 Hz), 13.02 (1 H, s), 13.64 (1 H, br s); ESIMS found for CzsHzeFNv m/z 480.2 (M+l).
Figure imgf000215_0002
[0643] (E)-4-(3 -Fluorophenyl)-2-(4-(2-(5 -((4-methylpiperazin- 1 -yl)methyl)pyridin-
3 -yl)vinyl) - 1 H-pyrazol -3 -yl)- 1 H-benzo [d] imidazole 172.
[0644] White solid (25.0 mg, 0.05 mmol, 63.2% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 2.15 (3 H, s), 2.19 - 2.48 (8 H, m), 3.50 (2 H, s), 7.19 - 7.28 (2 H, m), 7.33 (1 H, t, 7=7.68 Hz), 7.54 (2 H, t, 7=7.14 Hz), 7.56 - 7.64 (1 H, m), 7.71 (1 H, s), 8.17 (1 H, dd, 7=11.11, 2.06 Hz), 8.20 (1 H, br d, 7=7.96 Hz), 8.27 (1 H, br d, 7=16.74 Hz), 8.37 (1 H, d, 7=1.37 Hz), 8.42 (1 H, br s), 8.64 (1 H, d, 7=1.65 Hz), 12.99 (1 H, br s), 13.56 (1 H, br s); ESIMS found for C29H28FN7 m/z 494.2 (M+l).
Figure imgf000216_0001
173
[0645] (E)-4-((5-(2-(3-(4-(3-Fluorophenyl)-lH-benzo[d]imidazol-2-yl)-lH-pyrazol- 4-yl)vinyl)pyridin-3 -yl)methyl)morpholine 173.
[0646] White solid (17.0 mg, 0.04 mmol, 54.6% yield). ¾ NMR (500 MHz, DMSO- d6) d ppm 2.36 (4 H, br s), 3.55 (6 H, br s), 7.20 - 7.29 (2 H, m), 7.33 (1 H, t, J= 7.68 Hz), 7.54 (2 H, br t, .7=8.37 Hz), 7.57 - 7.63 (1 H, m), 7.74 (1 H, br s), 8.14 - 8.22 (2 H, m), 8.29 (1 H, br d, .7=16.47 Hz), 8.41 (1 H, br s), 8.44 (1 H, s), 8.67 (1 H, br s), 13.01 (1 H, s), 13.57 (1 H, br s); ESIMS found for C H FN O m!z 481.2 (M+l).
Figure imgf000216_0002
[0647] (E)-3-(2-(3-(4-(3-Fluorophenyl)-lH-benzo[d]imidazol-2-yl)-lH-pyrazol-4- yl)vinyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine 174.
[0648] White solid (9.0 mg, 0.02 mmol, 37.6% yield). ¾ NMR (500 MHz, DMSO- d6) d ppm 3.22 (2 H, br t, 7=5.63 Hz), 3.96 (2 H, br t, 7=5.49 Hz), 4.04 (2 H, s), 7.02 (1 H, br d, 7=16.74 Hz), 7.19 (1 H, s), 7.24 (1 H, td, 7=8.51, 2.47 Hz), 7.31 (1 H, br t, 7=7.82 Hz), 7.49 - 7.59 (3 H, m), 7.98 (1 H, br d, 7=17.02 Hz), 8.09 (1 H, d, 7=7.68 Hz), 8.17 (1 H, br d, 7=10.70 Hz), 8.38 (1 H, br s), 12.96 (1 H, br s), 13.50 (1 H, br s); ESIMS found for C24H20FN7 m/z 426.2 (M+l).
Figure imgf000217_0001
[0649] N-(6-(3 , 3 -Difluoropyrrolidin- 1 -yl)pyridin-3 -yl) -4 -(piperidin-4 -ylethynyl)- lH-pyrazole -3 -carboxamide 176.
[0650] Beige solid (20.0 mg, 0.05 mmol, 15.1% yield).‘H NMR (499 MHz, DMSO- de) d ppm 1.47 (2 H, dtd, 7=12.76, 9.26, 9.26, 3.57 Hz), 1.70 - 1.80 (2 H, m), 2.51 - 2.59 (4 H, m), 2.61 - 2.71 (1 H, m), 2.87 - 2.95 (2 H, m), 3.60 (2 H, t, .7=7.27 Hz), 3.81 (2 H, t, 7=13.45 Hz), 6.57 (1 H, d, 7=8.78 Hz), 7.93 (1 H, dd, 7=8.92, 2.61 Hz), 8.02 (1 H, s), 8.44 (1 H, d, 7=2.47 Hz), 9.81 (1 H, br s); ESIMS found for C2oH22F2N60 m/z 401.1 (M+l).
Figure imgf000217_0002
[0651] 2-(4-(Piperidin-4-ylethynyl)-lH-pyrazol-3-yl)-lH-benzo[d]imidazole 177.
[0652] Beige solid (39.0 mg, 0.13 mmol, 79.8% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.50 - 1.61 (2 H, m), 1.79 (2 H, ddt, 7=12.69, 6.11, 3.22, 3.22 Hz), 2.56 (2 H, ddd, 7=12.08, 8.92, 2.88 Hz), 2.75 (1 H, tt, 7=8.37, 3.98 Hz), 3.02 (2 H, ddd, 7=12.01, 5.83, 3.57 Hz), 7.15 - 7.22 (2 H, m), 7.52 - 7.60 (2 H, m), 8.03 (1 H, s); ESIMS found for C17H17N5 m/z 292.2 (M+l).
Figure imgf000217_0003
178
[0653] 4-(3-Fluorophenyl)-2-(4-(piperidin-4-ylethynyl)-lH-pyrazol-3-yl)-lH- benzo[d] imidazole 178.
[0654] Reddish brown solid (14.0 mg, 0.04 mmol, 51.9% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 1.41 - 1.52 (2 H, m), 1.71 - 1.80 (2 H, m), 2.43 - 2.49 (2 H, m), 2.67 - 2.76 (1 H, m), 2.83 - 2.92 (2 H, m), 7.19 (1 H, td, 7=8.37, 2.20 Hz), 7.31 (1 H, t, .7=7.68 Hz), 7.47 - 7.56 (3 H, m), 8.06 (1 H, br d, 7=4.39 Hz), 8.10 (1 H, s), 8.17 - 8.27 (1 H, m); ESIMS found for C23H20FN5 m!z 386.1 (M+l).
Figure imgf000218_0001
[0655] 7-(3 -Fluorophenyl) -2 -(4-(piperidin-4-ylethynyl) - 1 H-pyrazol-3 -yl) -3 H- imidazo[4,5-c]pyridine 179.
[0656] Beige solid (29.0 mg, 0.08 mmol, 61.2% yield). ¾ NMR (499 MHz, DMSO- de) d ppm 1.57 - 1.69 (2 H, m), 1.83 - 1.93 (2 H, m), 2.74 (2 H, br t, 7=9.33 Hz), 2.89 (1 H, ddd, 7=12.62, 8.51, 3.57 Hz), 3.05 - 3.11 (2 H, m), 7.26 (1 H, td, 7=8.51, 1.92 Hz), 7.57 (1 H, td, 7=8.03, 6.45 Hz), 8.06 (1 H, br d, 7=7.41 Hz), 8.15 (1 H, s), 8.18 (1 H, br s), 8.63 (1 H, s), 8.84 (1 H, s); ESIMS found for C22HI9FN6 m/z 387.2 (M+l).
Figure imgf000218_0002
[0657] 4-((3-Fluorophenyl)ethynyl)-N-(6-(2-(pyrrolidin-l-yl)ethoxy)pyridin-3-yl)- lH-pyrazole -3 -carboxamide 180.
[0658] Beige solid (27.0 mg, 0.06 mmol, 49.9% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.67 (4 H, dt, 7=6.72, 3.22 Hz), 2.50 - 2.53 (4 H, m), 2.76 (2 H, t, 7=6.04 Hz), 4.32 (2 H, t, 7=5.90 Hz), 6.81 (1 H, d, 7=9.06 Hz), 7.25 (1 H, td, 7=8.64, 2.20 Hz), 7.29 (1 H, dd, 7=9.61, 2.47 Hz), 7.33 (1 H, d, 7= 7.68 Hz), 7.42 - 7.50 (1 H, m), 8.07 (1 H, dd, .7=8.78, 2.74 Hz), 8.29 (1 H, s), 8.51 (1 H, d, 7=2.74 Hz), 10.20 (1 H, s), 13.79 (1 H, br s); ESIMS found for C23H22FN5O2 ra/z 420.0 (M+l).
Figure imgf000219_0001
181
[0659] 4-(3 -Fluorophenyl) -2 -(4-((3 -fluorophenyl)ethynyl) - 1 H-pyrazol -3 -yl) - 1 H- benzo[d] imidazole 181.
[0660] Light purple solid (36.0 mg, 0.09 mmol, 47.4% yield). ¾ NMR (499 MHz, DMSO-r/e) d ppm 7.07 - 7.14 (1 H, m), 7.17 - 7.29 (4 H, m), 7.33 (1 H, brt, 7=7.68 Hz), 7.36 - 7.43 (1 H, m), 7.49 - 7.57 (2 H, m), 8.05 - 8.16 (2 H, m), 8.37 (1 H, br s), 12.99 (1 H, br s), 13.74 (1 H, br s); ESIMS found for C H F N m/z 397.3 (M+l).
Figure imgf000219_0002
182
[0661] N-( 1 -Ethylpiperidin-4-yl)-4-(pyridin-3 -ylethynyl)- lH-pyrazole-3 - carboxamide 182.
[0662] White solid (52.0 mg, 0.16 mmol). *HNMR (499 MHz, DMSO-7,) d ppm 0.98 (3 H, t, 7=7.14 Hz), 1.58 (2 H, qd, 7=11.71, 3.57 Hz), 1.75 (2 H, br d, 7=9.61 Hz), 1.94 (2 H, br t, 7=10.57 Hz), 2.28 (2 H, q, 7=7.14 Hz), 2.81 (2 H, br d, 7=11.53 Hz), 3.68 - 3.81 (1 H, m), 7.41 - 7.47 (1 H, m), 7.83 - 7.92 (2 H, m), 8.16 (1 H, s), 8.56 (1 H, dd, 7=4.80, 1.51 Hz), 8.67 (1 H, d, 7=1.65 Hz), 13.63 (1 H, br s); ESIMS found for CI H IN50 m/z 324.2 (M+l).
Figure imgf000220_0001
[0663] N -(3 '-Fluoro-[ 1 , 1 '-biphenyl] -3 -yl)-4-(pyridin-3 -ylethynyl)- lH-pyrazole-3 - carboxamide 183.
[0664] White solid (60.0 mg, 0.16 mmol, 52.3% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 7.17 - 7.25 (1 H, m), 7.43 (2 H, s), 7.44 - 7.47 (2 H, m), 7.47 - 7.55 (2 H, m), 7.88 - 7.93 (2 H, m), 8.13 (1 H, br s), 8.35 (1 H, br s), 8.56 (1 H, dd, 7=4.80, 1.51 Hz), 8.69 (1 H, d, .7=1.37 Hz), 10.22 (1 H, s), 13.84 (1 H, br s); ESIMS found for C23H15FN4O m/z 383.0 (M+l).
Figure imgf000220_0002
[0665] N-(Pyridin-3-yl)-4-(pyridin-3-ylethynyl)-lH-pyrazole-3-carboxamide 184.
[0666] White solid (28.0 mg, 0.10 mmol, 51.5% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 7.37 (1 H, dd, .7=8.23, 4.67 Hz), 7.45 (1 H, dd, 7=7.96, 4.94 Hz), 7.90 (1 H, dt, 7=7.89, 1.82 Hz), 8.18 - 8.26 (1 H, m), 8.30 (1 H, dd, 7=4.67, 1.10 Hz), 8.35 (1 H, br s), 8.57 (1 H, dd, 7=4.80, 1.51 Hz), 8.68 (1 H, d, 7=1.37 Hz), 8.96 (1 H, d, 7=2.20 Hz), 10.40 (1 H, s), 13.85 (1 H, br s); ESIMS found for Ci6HnN50 m/z 290.1 (M+l).
Figure imgf000220_0003
[0667] N-(6-(3 , 3 -Difluoropyrrolidin- 1 -yl)pyridin-3 -yl) -4 -(pyridin-3 -ylethynyl)- 1 H- pyrazole -3 -carboxamide 185.
[0668] Off-white solid (49.0 mg, 0.12 mmol, 66.1% yield). ¾ NMR (499 MHz, DMSO-70 d ppm 2.51 - 2.60 (2 H, m), 3.60 (2 H, t, .7=7.27 Hz), 3.81 (2 H, t, .7=13.31 Hz), 6.57 (1 H, d, 7=9.06 Hz), 7.41 - 7.48 (1 H, m), 7.89 (1 H, dt, 7=7.96, 1.92 Hz), 7.97 (1 H, dd, 7=8.78, 2.47 Hz), 8.32 (1 H, br s), 8.47 (1 H, d, 7=2.47 Hz), 8.56 (1 H, dd, 7=4.67, 1.65 Hz), 8.67 (1 H, d, 7=1.37 Hz), 10.03 (1 H, s), 13.76 (1 H, br s); ESIMS found for C2oHi6F2N60 m!z 395.2 (M+l).
Figure imgf000221_0001
[0669] N-(6-(4 -Methylpiperazin- 1 -yl)pyridin-3 -yl) -4 -(pyridin-3 -ylethynyl) - 1 H- pyrazole -3 -carboxamide 186.
[0670] White solid (12.0 mg, 0.03 mmol, 48.6% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 2.21 (3 H, s), 2.37 - 2.43 (4 H, m), 3.39 - 3.46 (4 H, m), 6.83 (1 H, d, 7=9.06 Hz), 7.44 (1 H, ddd, 7=7.96, 4.94, 0.82 Hz), 7.89 (1 H, dt, 7=7.96, 1.92 Hz), 7.94 (1 H, dd, 7=9.06, 2.47 Hz), 8.29 (1 H, s), 8.47 (1 H, d, 7=2.47 Hz), 8.56 (1 H, dd, 7=4.67, 1.65 Hz), 8.64 - 8.70 (1 H, m), 10.02 (1 H, s), 13.76 (1 H, br s); ESIMS found for C2IH2IN70 m/z 388.4 (M+l).
Figure imgf000221_0002
187
[0671] N-(6-((l-Methylpiperidin-4-yl)oxy)pyridin-3-yl)-4-(pyridin-3-ylethynyl)-lH- pyrazole -3 -carboxamide 187.
[0672] White solid (40.0 mg, 0.10 mmol, 48.3% yield). ¾ NMR (499 MHz, DMSO- 76) d ppm 1.65 (2 H, dtd, 7=12.69, 9.16, 9.16, 3.57 Hz), 1.91 - 2.00 (2 H, m), 2.11 - 2.22 (2 H, m), 2.18 (3 H, s), 2.59 - 2.68 (2 H, m), 4.87 - 4.97 (1 H, m), 6.77 (1 H, d, 7=8.78 Hz), 7.44 (1 H, ddd, 7=7.82, 4.80, 0.82 Hz), 7.89 (1 H, dt, 7=7.96, 1.92 Hz), 8.07 (1 H, dd, 7=8.78, 2.74 Hz), 8.31 (1 H, s), 8.49 (1 H, d, .7=2.74 Hz), 8.56 (1 H, dd, .7=4.94, 1.65 Hz), 8.65 - 8.69 (1 H, m), 10.20 (1 H, br s), 13.80 (1 H, br s); ESIMS found for C22H22N602 m/z 403.4 (M+l).
Figure imgf000222_0001
[0673] 4-(Pyridin-3-ylethynyl)-N-(6-(2-(pyrrolidin-l-yl)ethoxy)pyridin-3-yl)-lH- pyrazole -3 -carboxamide 188.
[0674] Beige solid (32.0 mg, 0.08 mmol, 51.6% yield).‘H NMR (499 MHz, DMSO- d6) d ppm 1.67 (4 H, dt, 7=6.86, 3.16 Hz), 2.50 - 2.53 (4 H, m), 2.76 (2 H, t, 7=6.04 Hz), 4.32 (2 H, t, 7=6.04 Hz), 6.81 (1 H, d, 7=8.78 Hz), 7.41 - 7.48 (1 H, m), 7.89 (1 H, dt, 7=7.96, 1.92 Hz), 8.08 (1 H, dd, 7=8.92, 2.61 Hz), 8.32 (1 H, s), 8.51 (1 H, d, 7=2.47 Hz), 8.56 (1 H, dd, 7=4.94, 1.65 Hz), 8.63 - 8.72 (1 H, m), 10.21 (1 H, br s), 13.80 (1 H, br s); ESIMS found for C22H22N602 m/z 403.2 (M+l).
Figure imgf000222_0002
189
[0675] N-(5 -(3 -Fluorophenyl)pyridin-3 -yl) -4 -(pyridin-3 -ylethynyl) - 1 H-pyrazole -3 - carboxamide 189.
[0676] Beige solid (44.0 mg, 0.12 mmol, 53.7% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 7.28 (1 H, dtd, 7=8.88, 4.55, 4.55, 2.61 Hz), 7.45 (1 H, ddd, 7=7.96, 4.94, 0.82 Hz), 7.53 - 7.62 (3 H, m), 7.91 (1 H, dt, 7=7.96, 1.92 Hz), 8.37 (1 H, s), 8.53 (1 H, t, 7=2.20 Hz), 8.57 (1 H, dd, 7=4.67, 1.65 Hz), 8.65 (1 H, d, 7=1.92 Hz), 8.69 (1 H, dd, 7=2.20, 0.82 Hz), 9.04 (1 H, d, 7=2.20 Hz), 10.50 (1 H, br s), 13.91 (1 H, br s); ESIMS found for C22H14FN5O m/z 383.8 (M+l).
Figure imgf000223_0001
190
[0677] 2-(Pyridin-3-yl)-5-(4-(pyridin-3-ylethynyl)-lH-pyrazol-3-yl)-l,3,4- oxadiazole 190.
[0678] Light brown solid (108.0 mg, 0.34 mmol, 76.0% yield). Ή NMR (499 MHz, DMS0- 6) d ppm 7.44 - 7.53 (1 H, m), 7.62 - 7.69 (1 H, m), 7.97 (1 H, dt, =7.82, 1.99 Hz), 8.41 (1 H, dt, .7=8.03, 2.02 Hz), 8.47 (1 H, s), 8.60 (1 H, dd, =4.94, 1.65 Hz), 8.75 (1 H, d, .7=1.37 Hz), 8.82 (1 H, dd, =4.80, 1.51 Hz), 9.18 - 9.23 (1 H, m), 14.17 (1 H, br s); ESIMS found for CI7HI0N6O m!z 315.2 (M+l).
Figure imgf000223_0002
191
[0679] N-(lH-Benzo[d]imidazol-2-yl)-4-(pyridin-3-ylethynyl)-lH-pyrazole-3- carboxamide 191.
[0680] Beige solid (18.0 mg, 0.06 mmol, 50.2% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 7.14 (2 H, dd, =5.90, 3.16 Hz), 7.42 - 7.50 (3 H, m), 7.94 (1 H, dt, J= 7.82, 1.85 Hz), 8.23 (1 H, br s), 8.58 (1 H, dd, =4.80, 1.51 Hz), 8.71 - 8.76 (1 H, m), 12.37 (2 H, br s); ESIMS found for C isH^NhO m!z 329.2 (M+l).
Figure imgf000223_0003
192 [0681] 4-(3 -Fluorophenyl) -2 -(4-(pyridin-3 -ylethynyl) - 1 H-pyrazol-3 -yl) - 1 H- benzo[d] imidazole 192.
[0682] Purple solid (25.0 mg, 0.07 mmol, 30.9% yield).‘H NMR (499 MHz, DMSO- d6) d ppm 7.04 - 7.13 (1 H, m), 7.16 - 7.24 (1 H, m), 7.33 (1 H, t, J= 7.68 Hz), 7.39 (1 H, dd, 7=7.82, 4.80 Hz), 7.53 (2 H, d, .7=7.96 Hz), 7.78 - 7.84 (1 H, m), 8.12 (2 H, d, 7=8.23 Hz), 8.40 (1 H, s), 8.56 (1 H, dd, 7=4.94, 1.65 Hz), 8.62 - 8.69 (1 H, m), 13.01 (1 H, s), 13.76 (1 H, s); ESIMS found for C23H14FN5 m/z 380.2 (M+l).
Figure imgf000224_0001
193
[0683] N-(4-((Dimethylamino)methyl)phenyl)-4-((5-methoxypyridin-3-yl)ethynyl)- lH-pyrazole -3 -carboxamide 193.
[0684] Beige solid (55.0 mg, 0.15 mmol, 61.2% yield).‘H NMR (499 MHz, DMSO- d6) d ppm 2.13 (6 H, s), 3.34 (2 H, s), 3.85 (3 H, s), 7.23 (2 H, d, 7=8.51 Hz), 7.45 (1 H, dd, 7=3.02, 1.65 Hz), 7.74 (2 H, d, 7=8.51 Hz), 8.28 (2 H, dd, 7=9.33, 2.20 Hz), 8.30 (1 H, s), 10.09 (1 H, s), 13.80 (1 H, br s); ESIMS found for C21H21N5O2 m/z 376.0 (M+l).
Figure imgf000224_0002
[0685] 4-((5-Methoxypyridin-3-yl)ethynyl)-N-(4-(pyrrolidin-l-ylmethyl)phenyl)- lH-pyrazole -3 -carboxamide 194.
[0686] Beige solid (40.0 mg, 0.10 mmol, 56.9% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.68 (4 H, dt, 7=6.66, 3.12 Hz), 2.38 - 2.44 (4 H, m), 3.52 (2 H, s), 3.85 (3 H, s), 7.25 (2 H, d, 7=8.51 Hz), 7.45 (1 H, dd, 7=2.74, 1.65 Hz), 7.72 (2 H, d, 7=8.51 Hz), 8.28 (2 H, dd, 7=9.19, 2.33 Hz), 8.30 (1 H, s), 10.08 (1 H, s), 13.78 (1 H, br s); ESIMS found for C23H23N5O2 m/z 402.2 (M+l).
Figure imgf000225_0001
195
[0687] 4-((5-Methoxypyridin-3 -yl)ethynyl)-N-(4-(2-(pyrrolidin- 1 -yl)ethoxy) phenyl) - 1 H-pyrazole -3 -carboxamide 195.
[0688] Beige solid (33.0 mg, 0.08 mmol, 35.8% yield).‘H NMR (499 MHz, DMSO- d6) d ppm 1.68 (4 H, dt, J= 6.72, 3.22 Hz), 2.51 (4 H, br s), 2.77 (2 H, t, 7=5.90 Hz), 3.85 (3 H, s), 4.04 (2 H, t, J= 5.90 Hz), 6.91 (2 H, d, 7= 9.06 Hz), 7.44 (1 H, dd, 7=2.74, 1.65 Hz), 7.68 (2 H, d, 7= 8.78 Hz), 8.23 - 8.30 (3 H, m), 9.99 (1 H, s), 13.76 (1 H, br s); ESIMS found for C24H25N5O3 m/z 432.3 (M+l).
Figure imgf000225_0002
[0689] N-(6-(3 , 3 -Difluoropyrrobdin- 1 -yl)pyridin-3 -yl) -4 -((5 -methoxypyridin-3 - yl)ethynyl) - 1 H-pyrazole -3 -carboxamide 196.
[0690] Tan solid (68.9 mg, 0.16 mmol, 46.4% yield).‘H NMR (499 MHz, DMSO-7,) d ppm 2.51 - 2.60 (2 H, m), 3.60 (2 H, t, J= 7.27 Hz), 3.81 (2 H, t, .7=13.31 Hz), 3.86 (3 H, s), 6.57 (1 H, d, 7=9.06 Hz), 7.45 (1 H, dd, 7=2.47, 1.65 Hz), 7.97 (1 H, dd, 7=9.06, 2.47 Hz), 8.26 (1 H, d, 7=1.37 Hz), 8.28 (1 H, d, 7=2.74 Hz), 8.32 (1 H, br s), 8.47 (1 H, d, 7=2.47 Hz), 10.04 (1 H, s), 13.77 (1 H, br s); ESIMS found for C2iHi8F2N602 m!z 425.3 (M+l).
Figure imgf000225_0003
197
[0691] 4-((5-Methoxypyridin-3-yl)ethynyl)-N-(6-(piperazin-l-yl)pyridin-3-yl)-lH- pyrazole -3 -carboxamide 197.
[0692] Tan solid (51.1 mg, 0.13 mmol, 64.7% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 2.75 - 2.80 (4 H, m), 3.33 - 3.37 (4 H, m), 3.85 (3 H, s), 6.79 (1 H, d, 7= 9.06 Hz), 7.44 (1 H, dd, 7=2.74, 1.65 Hz), 7.92 (1 H, dd, 7= 9.06, 2.74 Hz), 8.26 (1 H, d, .7=1.65 Hz), 8.28 - 8.29 (2 H, m), 8.46 (1 H, d, 7=2.47 Hz), 10.01 (1 H, s); ESIMS found for C21H21N7O2 m!z 404.3 (M+l).
Figure imgf000226_0001
[0693] 4-((5-Methoxypyridin-3-yl)ethynyl)-N-(6-(4-methylpiperazin-l-yl)pyridin-3- yl)- lH-pyrazole-3 -carboxamide 198.
[0694] Tan solid (27.2 mg, 0.07 mmol, 52.7% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 2.21 (3 H, s), 2.37 - 2.42 (4 H, m), 3.39 - 3.45 (4 H, m), 3.85 (3 H, s), 6.83 (1 H, d, 7=9.06 Hz), 7.45 (1 H, dd, 7=2.74, 1.65 Hz), 7.93 (1 H, dd, 7=9.06, 2.74 Hz), 8.26 (1 H, d, 7=1.65 Hz), 8.28 (1 H, d, 7=2.74 Hz), 8.30 (1 H, br s), 8.47 (1 H, d, 7=2.47 Hz), 10.03 (1 H, s), 13.77 (1 H, br s); ESIMS found for C22H23N7O2 m!z 418.2 (M+l).
Figure imgf000226_0002
[0695] 4-((5-Methoxypyridin-3-yl)ethynyl)-N-(6-(piperidin-4-yloxy)pyridin-3-yl)- lH-pyrazole -3 -carboxamide 199.
[0696] Tan solid (66.6 mg, 0.16 mmol, 57.8% yield). ¾ NMR (499 MHz, DMSO-7,) d ppm 1.43 - 1.54 (2 H, m), 1.91 - 1.99 (2 H, m), 2.56 - 2.65 (2 H, m), 2.97 (2 H, dt, 7=12.69, 4.08 Hz), 3.86 (3 H, s), 4.95 - 5.05 (1 H, m), 6.77 (1 H, d, 7=9.06 Hz), 7.44 (1 H, dd, 7=2.74, 1.65 Hz), 8.06 (1 H, dd, 7=9.06, 2.74 Hz), 8.26 (1 H, d, 7=1.65 Hz), 8.28 (1 H, d, 7=2.74 Hz), 8.31 (1 H, s), 8.49 (1 H, d, 7=2.74 Hz), 10.20 (1 H, br s); ESIMS found for C22H22N603 m!z 419.2 (M+l).
Figure imgf000227_0001
200
[0697] 4-((5-Methoxypyridin-3-yl)ethynyl)-N-(6-((l-methylpiperidin-4-yl)oxy) pyridin-3 -yl)-l H-pyrazole -3 -carboxamide 200.
[0698] Tan solid (46.0 mg, 0.11 mmol, 48.2% yield). ¾ NMR (499 MHz, DMSO-7,) 5 ppm 1.65 (2 H, dtd, .7=12.62, 9.26, 9.26, 3.70 Hz), 1.91 - 1.99 (2 H, m), 2.08 - 2.20 (2 H, m), 2.18 (3 H, s), 2.59 - 2.68 (2 H, m), 3.86 (3 H, s), 4.93 (1 H, tt, 7=8.54, 4.22 Hz), 6.77 (1 H, d, 7= 9.06 Hz), 7.44 (1 H, dd, 7= 3.02, 1.65 Hz), 8.06 (1 H, dd, 7= 9.06, 2.74 Hz), 8.26 (1 H, d, .7=1.65 Hz), 8.29 (1 H, d, .7=2.74 Hz), 8.32 (1 H, s), 8.50 (1 H, d, .7=2.47 Hz), 10.21 (1 H, s), 13.81 (l H, br s); ESIMS found for C23H24N603 m!z 433.4 (M+l).
Figure imgf000227_0002
[0699] 4-((5-Methoxypyridin-3-yl)ethynyl)-N-(6-(2-(pyrrolidin-l-yl)ethoxy)pyridin- 3 -yl)-l H-pyrazole -3 -carboxamide 201.
[0700] Beige solid (30.0 mg, 0.07 mmol, 39.8% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.67 (4 H, dt, 7=6.66, 3.12 Hz), 2.50 - 2.53 (4 H, m), 2.76 (2 H, t, 7=6.04 Hz), 3.86 (3 H, s), 4.32 (2 H, t, 7=5.90 Hz), 6.81 (1 H, d, 7=8.78 Hz), 7.42 - 7.47 (1 H, m), 8.07 (1 H, dd, 7=8.92, 2.61 Hz), 8.26 (1 H, d, 7=1.37 Hz), 8.29 (1 H, d, 7=3.02 Hz), 8.32 (1 H, s), 8.52 (1 H, d, 7=2.74 Hz), 10.22 (1 H, s), 13.77 (1 H, br s); ESIMS found for C23H24N603 m/z 433.4 (M+l).
Figure imgf000227_0003
[0701] 4-((5-Methoxypyridin-3-yl)ethynyl)-N-(l,2,3,4-tetrahydroisoquinolin-6-yl)- lH-pyrazole -3 -carboxamide 202.
[0702] Beige solid (45.0 mg, 0.12 mmol, 51.7% yield).‘H NMR (499 MHz, DMSO- d6) d ppm 2.66 (2 H, br t, J= 5.76 Hz), 2.93 (2 H, t, 7= 5.90 Hz), 3.80 (2 H, s), 3.86 (3 H, s), 6.95 (1 H, d, J= 8.23 Hz), 7.43 - 7.49 (2 H, m), 7.55 (1 H, s), 8.27 (1 H, d, .7=1.65 Hz), 8.28 (1 H, s), 8.29 (1 H, d, 7=2.74 Hz), 9.93 (1 H, s); ESIMS found for C21H19N5O2 m/z 374.2 (M+l).
Figure imgf000228_0001
204
[0703] 4-((5-(Piperidin-l-ylmethyl)pyridin-3-yl)ethynyl)-N-(pyridin-3-yl)-lH- pyrazole -3 -carboxamide 204.
[0704] Beige solid (18.0 mg, 0.05 mmol, 31.3% yield).‘H NMR (499 MHz, DMSO- d6) d ppm 1.39 (2 H, br d, 7=4.67 Hz), 1.50 (4 H, quin, 7=5.56 Hz), 2.33 (4 H, br s), 3.48 (2 H, s), 7.37 (1 H, dd, 7=8.51, 4.67 Hz), 7.78 (1 H, t, 7=2.06 Hz), 8.20 - 8.27 (1 H, m), 8.30 (1 H, dd, 7=4.67, 1.37 Hz), 8.35 (1 H, s), 8.46 (1 H, d, 7=1.92 Hz), 8.56 (1 H, d, 7=1.92 Hz), 8.96 (1 H, d, 7=2.47 Hz), 10.41 (1 H, s), 13.86 (1 H, br s); ESIMS found for C22H22N60 m/z 387.1 (M+l).
Figure imgf000228_0002
[0705] 7-(3-Fluorophenyl)-2-(4-((5-(piperidin-l-ylmethyl)pyridin-3-yl)ethynyl)-lH- pyrazol-3-yl)-3H-imidazo[4,5-c]pyridine 205.
[0706] Beige solid (23.0 mg, 0.05 mmol, 45.1% yield).‘H NMR (499 MHz, DMSO- d6) d ppm 1.37 (2 H, br d, 7=1.10 Hz), 1.47 (4 H, br s), 2.35 (4 H, ddd, 7=11.94, 4.39, 1.78 Hz), 3.40 - 3.63 (2 H, m), 7.12 (1 H, br t, 7=7.41 Hz), 7.20 - 7.28 (1 H, m), 7.76 (1 H, br s), 8.18 - 8.27 (2 H, m), 8.44 (1 H, br s), 8.50 (1 H, br s), 8.60 (1 H, br s), 8.73 (1 H, br s), 8.85 (1 H, s), 13.49 (1 H, br s), 13.94 (1 H, br s); ESIMS found for C28H24FN7 m/z 478.4 (M+l).
Figure imgf000229_0001
206
[0707] 7-(3-Fluorophenyl)-2-(4-((5-(piperazin-l-ylmethyl)pyridin-3-yl)ethynyl)-lH- pyrazol-3-yl)-3H-imidazo[4,5-c]pyridine 206.
[0708] Brown solid (15.0 mg, 0.03 mmol, 26.0% yield). *H NMR (499 MHz, DMSO- d6) d ppm 2.34 (4 H, br s), 2.74 (4 H, br s), 3.47 (2 H, s), 7.10 - 7.18 (1 H, m), 7.24 - 7.32 (1 H, m), 7.77 (1 H, s), 8.18 (1 H, br s), 8.20 (1 H, br s), 8.36 (1 H, s), 8.49 (1 H, d, .7=1.92 Hz), 8.59 (1 H, d, .7=1.92 Hz), 8.67 (1 H, s), 8.85 (1 H, s); ESIMS found for C27H23FN8 m/z 479.2 (M+l).
Figure imgf000229_0002
207
[0709] 4-((5-((3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazol-4- yl)ethynyl)pyridin-3 -yl)methyl)morpholine 207.
[0710] Beige solid (10.0 mg, 0.02 mmol, 12.6% yield).‘H NMR (499 MHz, DMSO- d6) d ppm 2.35 (4 H, br d, 7=4.12 Hz), 3.49 (2 H, s), 3.52 - 3.57 (4 H, m), 7.09 - 7.18 (1 H, m), 7.27 (1 H, br s), 7.78 (1 H, br s), 8.20 (2 H, br s), 8.40 (1 H, br s), 8.50 (1 H, d, 7=1.92 Hz), 8.60 (1 H, d, 7=1.92 Hz), 8.69 (1 H, br s), 8.86 (1 H, br s), 13.68 (2 H, br s); ESIMS found for C27H22FN7O m/z 480.1 (M+l).
Figure imgf000229_0003
208
[0711] 4-((5-(Piperidin-4-yloxy)pyridin-3-yl)ethynyl)-N-(pyridin-3-yl)-lH- pyrazole -3 -carboxamide 208.
[0712] Beige solid (24.0 mg, 0.06 mmol, 64.4% yield). ¾ NMR (499 MHz, DMSO- de) d ppm 1.41 - 1.54 (2 H, m), 1.92 (2 H, br dd, 7=8.37, 4.25 Hz), 2.56 - 2.65 (2 H, m), 2.92 - 2.99 (2 H, m), 4.51 - 4.61 (1 H, m), 7.37 (1 H, dd, .7=8.51, 4.67 Hz), 7.49 (1 H, dd, .7=2.74, 1.65 Hz), 8.21 - 8.24 (1 H, m), 8.24 (1 H, d, .7=1.65 Hz), 8.27 (1 H, d, .7=2.74 Hz), 8.29 (1 H, dd, .7=4.67, 1.37 Hz), 8.31 (1 H, s), 8.96 (1 H, d, .7=2.47 Hz), 10.39 (1 H, br s); ESIMS found for C2iH2oN602 m/z 389.1 (M+l).
Figure imgf000230_0001
209
[0713] 4-(3-Fluorophenyl)-2-(4-((5-(piperidin-4-yloxy)pyridin-3-yl)ethynyl)-lH- pyrazol-3 -yl) - 1 H-benzo [d] imidazole 209.
[0714] Purple solid (80.0 mg, 0.17 mmol, 47.0% yield). ¾ NMR (499 MHz, DMSO- d ) d ppm 1.39 - 1.50 (2 H, m), 1.83 - 1.94 (2 H, m), 2.51 - 2.56 (2 H, m), 2.91 (2 H, dt, 7=12.83, 4.15 Hz), 4.41 - 4.50 (1 H, m), 7.04 (1 H, td, 7=8.30, 2.06 Hz), 7.13 - 7.21 (1 H, m), 7.33 (1 H, t, 7=7.68 Hz), 7.44 (1 H, dd, 7=2.74, 1.65 Hz), 7.52 - 7.59 (2 H, m), 8.12 - 8.20 (2 H, m), 8.25 (1 H, d, 7=1.37 Hz), 8.28 (1 H, d, 7=2.74 Hz), 8.35 (1 H, s); ESIMS found for C28H23FN60 mlz 479.4 (M+l).
Figure imgf000230_0002
[0715] 7-(3 -Fluorophenyl) -2 -(4-((5 -(piperidin-4-yloxy)pyridin-3 -yl)ethynyl) - 1 H- pyrazol-3-yl)-3H-imidazo[4,5-c]pyridine 210. [0716] Beige solid (60.0 mg, 0.13 mmol, 63.9% yield).‘H NMR (499 MHz, DMSO- d6) d ppm 1.77 - 1.87 (2 H, m), 2.05 - 2.14 (2 H, m), 3.06 (2 H, br s), 3.26 (5 H, br s), 4.74 (1 H, br s), 7.08 - 7.18 (1 H, m), 7.18 - 7.29 (1 H, m), 7.56 (1 H, br s), 8.17 - 8.26 (1 H, m), 8.32 (1 H, s), 8.37 (1 H, d, .7=2.74 Hz), 8.44 (1 H, s), 8.52 (1 H, br d, 7= 2.20 Hz), 8.75 (1 H, br d, .7=1.37 Hz), 8.88 (1 H, br s), 13.63 (1 H, br s), 14.00 (1 H, br s); ESIMS found for C27H22FN7O m/z 480.1 (M+l).
Figure imgf000231_0001
211
[0717] 4-(3 -Fluorophenyl) -N -( 1 -methylpiperidin-4-yl) - 1 H-pyrazole -3 -carboxamide
211.
[0718] White solid (132.1 mg, 0.44 mmol, 55.2% yield). ¾NMR (499 MHz, DMSO- d6) d ppm 1.56 (qd, J= 12 Hz, .7=3.5 Hz, 2H), 1.72 (d, 7=9.5Hz, 2H), 1.93 (t, 7=10.8Hz, 2H), 2.14 (s, 3H), 2.72 (d, J= 12 Hz, 2H), 3.63 - 3.75 (m, 1H), 7.05 (td, 7=3Hz, 7=1.0Hz, 1H), 7.32 - 7.38 (m, 1H), 7.40 - 7.45 (m, 1H), 7.50 (dd, 7=11.5Hz, 7=2.5Hz, 1H), 8.03 (d, 7=8Hz, lH), 8.13 (s, 1H), 13.36 (br s, 1H); ESIMS found for CI6HI9FN40 m/z 302.9 (M+l).
Figure imgf000231_0002
212
[0719] N-(l-Methylpiperidin-4-yl)-4-(2-(trifluoromethyl)phenyl)-lH-pyrazole-3- carboxamide 212.
[0720] Beige solid (11.2 mg, 0.03 mmol, 11.9% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.58 (qd, 7=12 Hz, 7=3.5 Hz, 2H), 1.72 (d, 7=9.5Hz, 2H), 1.93 (t, 7=10.8Hz, 2H), 2.14 (s, 3H), 2.71 (d, 7=12 Hz, 2H), 3.63 - 3.73 (m, 1H), 7.53 - 7.62 (m, 2H), 7.87 (d, 7=7Hz, 1H), 8.00 (s, 1H), 8.06 (br d, 7=7.5Hz, 1H), 8.20 (br s, 1H), 13.42 (br s, 1H); ESIMS found for C17H19F3N4O m/z 353.2 (M+l).
Figure imgf000232_0001
214
[0721] N-(l-Methylpiperidin-4-yl)-4-(3-(trifluoromethyl)phenyl)-lH-pyrazole-3- carboxamide 214.
[0722] Beige solid (5.4 mg, 0.02 mmol, 5.8% yield). ¾ NMR (499 MHz, DMSO-d6) 5ppm 1.48- 1.58 (m, 2H), 1.62 (d, =9.5Hz, 2H), 1.87 (t, =10.8Hz, 2H),2.12(s, 3H), 2.61 - 2.71 (m, 2H), 3.48 - 3.58 (m, 1H), 7.34 (d, =7.5Hz, 1H), 7.52 (t, =7.3Hz, 1H), 7.60 (t, =7.5Hz, 1H), 7.73 (d, =7.5Hz, 2H), 7.80 (br s, 1H), 13.34 (br s, 1H); ESIMS found for C17H19F3N4O mlz 353.0 (M+l).
Figure imgf000232_0002
215
[0723] N-( 1 -Methylpiperidin-4-yl)-4-(pyridin-3 -yl)-l H-pyrazole-3 -carboxamide
215.
[0724] White solid (88.4 mg, 0.31 mmol, 88.0% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.58 (qd, J= 12 Hz, J= 3.5 Hz, 2H), 1.71 (d, =9.5Hz, 2H), 1.92 (t, =10.8Hz, 2H), 2.14 (s, 3H), 2.72 (d, J= 12 Hz, 2H), 3.63 - 3.74 (m, 1H), 7.35 (ddd, =8Hz, =4.5Hz, =0.5Hz, 1H), 7.98 (dt, =7.5Hz, =1.5Hz, 1H), 8.02 (d, =8Hz, 1H), 8.15 (s, 1H), 8.43 (dd, =5Hz, =2Hz, 1H), 8.74 (d, =1.5Hz, 1H), 13.43 (brs, 1H); ESIMS found for C15H19N5O mlz 286.1 (M+l).
Figure imgf000232_0003
216
[0725] 4-(Pyridin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-lH-pyrazole-3-carboxamide
216. [0726] White solid (19.5 mg, 0.07 mmol, 56.8% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.53 - 1.65 (m, 2H), 1.71 (d, J=l lHz, 2H), 3.35 (td, J=12Hz, J=2Hz, 2H), 3.85 (dd, =8.5Hz, =3Hz, 2H), 3.89 - 4.00 (m, 1H), 7.36 (ddd, J=8Hz, J=4.5Hz, J=0.5Hz, 1H), 7.99 (dt, =7.5Hz, J=1.5Hz, 1H), 8.14 (br s, 1H), 8.18 (br s, 1H), 8.43 (dd, J=5Hz, J=2Hz, 1H), 8.75 (d, =1.5Hz, 1H), 13.44 (br s, 1H); ESIMS found for CI4HI6N402 m/z 273.0 (M+l).
Figure imgf000233_0001
[0727] 4-((2-(4-(Pyridin-3-yl)-lH-pyrazol-3-yl)-lH-benzo[d]imidazol-5- yl)methyl)morpholine 217.
[0728] Off-white solid (100.0 mg, 0.28 mmol, 68.5% yield). ¾ NMR (499 MHz, DMS0- 6) d ppm 2.36 (4 H, br s), 3.47 - 3.62 (6 H, m), 7.05 - 7.21 (1 H, m), 7.37 - 7.45 (2 H, m), 7.45 - 7.54 (1 H, m), 8.22 - 8.33 (2 H, m), 8.44 - 8.51 (1 H, m), 8.97 (1 H, s), 12.65 (1 H, br d, J= 7.96 Hz), 13.62 (1 H, br s); ESIMS found for C2oH2oN60 m/z 361.2 (M+l).
Figure imgf000233_0002
218
[0729] 7-(3-Fluorophenyl)-2-(4-(pyridin-3-yl)-lH-pyrazol-3-yl)-3H-imidazo[4,5- c]pyridine 218.
[0730] Tan solid (31.5 mg, 0.09 mmol, 20.4% yield). ¾ NMR (499 MHz, DMSO-d6) d ppm 7.22 (t, J=7.3Hz, 1H), 7.42 - 7.48 (m, 1H), 7.48 - 7.54 (m, 1H), 8.00 (d, J=7.5Hz, 2H), 8.35 (s, 1H), 8.41 (d, J=7Hz, 1H), 8.54 (d, J=3.5Hz, 1H), 8.68 (s, 1H), 8.82 (s, 1H), 8.88 (s, 1H), 13.44 (br s, 1H), 13.84 (br s, 1H); ESIMS found for C20HI3FN6 m/z 356.9 (M+l).
Figure imgf000234_0001
219
[0731] 4-(5-((Dimethylamino)methyl)pyridin-3-yl)-N-(pyridin-3-yl)-lH-pyrazole-3- carboxamide 219.
[0732] Light brown solid (45.6 mg, 0.14 mmol, 27.1% yield). Ή NMR (499 MHz, DMS0- 6) d ppm 2.16 (s, 6H), 3.43 (s, 2H), 7.36 (dd, =8.5Hz, =5Hz, 1H), 7.88 (t, =2Hz, 1H), 8.18 (d, =8Hz, 1H), 8.26 (s, 1H), 8.28 (dd, =4.5Hz, =1.5Hz, 1H), 8.36 (d, 2Hz, 1H), 8.66 (d, =2Hz, 1H), 8.93 (d, =2Hz, 1H), 10.46 (s, 1H), 13.70 (br s, 1H); ESIMS found for CI7HI8N60 mlz 322.9 (M+l).
Figure imgf000234_0002
220
[0733] N-(5-(3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazol-4- yl)pyridin-3-yl)propionamide 220.
[0734] Beige solid (80.6 mg, 0.19 mmol, 51.0% yield). ¾ NMR (399 MHz, DMSO- d6) 5 ppm 1.00 (t, =7.8Hz, 3H), 2.28 (q, =7.5Hz, 2H), 7.16 (t, =7.5Hz, 1H), 7.33 - 7.43 (m, 1H), 7.90 (d, =10Hz, 1H), 7.97 (d, =7.5Hz, 1H), 8.28 (s, 1H), 8.38 (s, 1H), 8.51 (s, 1H), 8.65 (s, 1H), 8.82 (d, =8Hz, 2H), 10.08 (br s, 1H), 13.41 (br s, 1H), 13.81 (br s, 1H); ESIMS found for C23H18FN7O mlz 428.2 (M+l).
Figure imgf000235_0001
221
[0735] 4-(3 -Fluorophenyl)-2-(4-(6-(4-methylpiperazin- 1 -yl)pyridin-3-yl)- 1H- pyrazol-3 -yl) - 1 H-benzo [d] imidazole 221.
[0736] Off-white solid (72.0 mg, 0.16 mmol, 39.7% yield). Ή NMR (499 MHz, DMSO-7,) d ppm 2.24 (3 H, s), 2.43 (4 H, br t, .7=4.80 Hz), 3.50 - 3.56 (4 H, m), 6.87 (1 H, d, .7=8.78 Hz), 7.17 (1 H, td, 7=8.37, 2.20 Hz), 7.29 (1 H, t, 7=7.68 Hz), 7.42 - 7.54 (3 H, m), 7.97 (1 H, d, 7=7.96 Hz), 8.03 (1 H, br d, 7=10.98 Hz), 8.13 (1 H, br s), 8.23 (1 H, br d, 7=8.78 Hz), 8.46 (1 H, br s), 12.84 (1 H, br s), 13.50 (1 H, br s); ESIMS found for C26H24FN7 m!z 454.3 (M+l).
Figure imgf000235_0002
222
[0737] N -(Pyridin-3 -yl)-4-(5 -(pyrrolidin- 1 -ylmethyl)pyridin-3 -yl) - 1 H-pyrazole -3 - carboxamide 222.
[0738] White solid (21.2 mg, 0.06 mmol, 21.7% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.68 (br s, 4H), 2.47 (br s, 4H), 3.62 (br s, 2H), 7.36 (dd, 7=8Hz, 7=4.5Hz, 1H), 7.90 (s, 1H), 8.18 (d, 7=8Hz, 1H), 8.24 - 8.30 (m, 2H), 8.39 (s, 1H), 8.65 (s, 1H), 8.94 (s, 1H), 10.47 (s, 1H), 13.70 (br s, 1H); ESIMS found for Ci9H2oN60 m/z 349.1 (M+l).
Figure imgf000235_0003
223
[0739] 4-(5-(Piperidin-l-ylmethyl)pyridin-3-yl)-N-(pyridin-3-yl)-lH-pyrazole-3- carboxamide 223.
[0740] White solid (11.3 mg, 0.03 mmol, 3.9% yield). ¾ NMR (499 MHz, DMSO- d6) 5 ppm 1.31 - 1.40 (m, 2H), 1.40 - 1.51 (m, 4H), 2.33 (br s, 4H), 3.46 (s, 2H), 7.35 (dd, =8.5Hz, =4.5Hz, 1H), 7.88 (s, 1H), 8.18 (d, =8.5Hz, 1H), 8.26 (s, 1H), 8.28 (dd, =5Hz, =1.5Hz, 1H), 8.36 (d, =2Hz, 1H), 8.64 (d, =2Hz, 1H), 8.94 (d, =2Hz, 1H), 10.47 (s, 1H), 13.70 (br s, 1H); ESIMS found for C2oH22N60 m/z 363.4 (M+l).
Figure imgf000236_0001
224
[0741] 7-(3-Fluorophenyl)-2-(4-(5-(piperidin-l-ylmethyl)pyridin-3-yl)-lH-pyrazol- 3 -yl) -3H-imidazo [4,5 -c] pyridine 224.
[0742] Tan solid (23.2 mg, 0.05 mmol, 17.7% yield). ¾ NMR (499 MHz, DMSO-d6) d ppm 1.30 (br s, 2H), 1.36 (br s, 4H), 2.23 (br s, 4H), 3.41 (br s, 2H), 7.21 (t, J=7.5Hz, 1H), 7.40 - 7.48 (m, 1H), 7.88 - 7.99 (m, 2H), 8.05 (s, 1H), 8.34 (s, 1H), 8.43 (s, 1H), 8.66 (s, 1H), 8.79 (s, 1H), 8.81 (s, 1H), 13.42 (br s, 1H), 13.82 (br s, 1H); ESIMS found for C26H24FN7 m/z 453.8 (M+l).
Figure imgf000236_0002
[0743] 2-(4-(5-(Piperidin- 1 -ylmethyl)pyridin-3-yl)- lH-pyrazol-3 -yl)-7-(pyridin-3 - yl)-3H-imidazo[4,5-c]pyridine 225.
[0744] Tan solid (21.4 mg, 0.05 mmol, 16.9% yield). ¾ NMR (399 MHz, DMSO-d6) d ppm 1.31 (br s, 2H), 1.37 (br s, 4H), 2.25 (br s, 4H), 3.49 (br s, 2H), 7.44 (t, J=5Hz, 1H), 8.14 (s, 1H), 8.35 (s, 1H), 8.44 (s, 2H), 8.58 (d, J=4Hz, 1H), 8.66 (s, 1H), 8.78 (s, 1H), 8.84 (s, 1H), 9.27 (s, 1H), 13.44 (br s, 1H), 13.83 (br s, 1H); ESIMS found for C25H24N8 m!z 437.1 (M+l).
Figure imgf000237_0001
226
[0745] 4-(Isoquinolin-7-yl)-N-(l-methylpiperidin-4-yl)-lH-pyrazole-3-carboxamide
226.
[0746] White solid (47.0 mg, 0.14 mmol, 56.0% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.53 - 1.63 (2 H, m), 1.71 - 1.78 (2 H, m), 1.89 - 1.98 (2 H, m), 2.12 - 2.17 (3 H, m), 2.71 (2 H, br d, 7=11.80 Hz), 3.66 - 3.78 (1 H, m), 7.79 (1 H, d, .7=5.49 Hz), 7.89 - 7.95 (1 H, m), 8.00 (1 H, dd, 7=8.64, 1.78 Hz), 8.04 (1 H, br d, 7=7.96 Hz), 8.21 (1 H, s), 8.30 (1 H, s), 8.46 (1 H, d, 7=5.76 Hz), 9.24 (1 H, s), 13.42 (1 H, br s); ESIMS found for C19H21N5O m!z 336.3 (M+l).
Figure imgf000237_0002
Ill
[0747] N-(l-Methylpiperidin-4-yl)-4-(quinolin-6-yl)-lH-pyrazole-3-carboxamide
111.
[0748] White solid (16.7 mg, 0.05 mmol, 35.4% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.52 - 1.64 (3 H, m), 1.75 (2 H, br d, 7=9.61 Hz), 1.90 - 1.98 (2 H, m), 2.14 (3 H, s), 2.71 (2 H, br d, 7=11.25 Hz), 3.66 - 3.78 (1 H, m), 7.51 (1 H, dd, 7=8.23, 4.12 Hz), 7.92 - 8.00 (2 H, m), 8.03 (1 H, br d, 7=7.68 Hz), 8.16 (1 H, s), 8.18 (1 H, s), 8.29 (1 H, dd, 7=8.37, 1.51 Hz), 8.85 (1 H, dd, 7=4.12, 1.65 Hz), 13.40 (1 H, br s); ESIMS found for C19H21N5O m/z 335.7 (M+l).
Figure imgf000238_0001
228
[0749] 3 -(4 -(3 -Fluorophenyl)- 1 H-benzo [d] imidazol-2 -yl) -N -(pyridin-3 -yl) - 1 H- pyrazole-4-carboxamide 228.
[0750] White solid (82.2 mg, 0.21 mmol, 84.9% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 7.06 (1 H, br d, 7=0.82 Hz), 7.08 - 7.16 (1 H, m), 7.24 - 7.31 (1 H, m), 7.32 - 7.38 (1 H, m), 7.39 - 7.46 (2 H, m), 7.57 - 7.66 (2 H, m), 7.66 - 7.72 (1 H, m), 8.21 (1 H, br s), 8.47 (1 H, br s), 8.61 (1 H, s), 13.31 (1 H, br s), 13.49 (1 H, br s), 14.04 (1 H, br s); ESIMS found for C22HI5FN60 m/z 399.15 (M+l).
Figure imgf000238_0002
[0751] 2-( 1 , 1 -Difluoroethyl)-N -(3 -((6-(2-(pyrrolidin- 1 -yl)ethoxy)pyridin-3 - yl)carbamoyl)-lH-pyrazol-4-yl)isonicotinamide 229.
[0752] White solid (47.0 mg, 0.10 mmol, 52.6% yield). ¾ NMR (499 MHz, DMSO- d6) d ppm 1.68 (4 H, dt, 7=6.86, 3.16 Hz), 2.06 (3 H, t, .7=19.21 Hz), 2.51 (4 H, br s), 2.77 (2 H, t, .7=5.90 Hz), 4.33 (2 H, t, 7=6.04 Hz), 6.83 (1 H, d, 7=8.78 Hz), 7.95 (1 H, dd, 7=4.94, 1.37 Hz), 8.07 (1 H, s), 8.10 (1 H, dd, 7=8.92, 2.61 Hz), 8.41 (1 H, s), 8.53 (1 H, d, 7=2.47 Hz), 8.92 (1 H, d, 7=4.94 Hz), 10.48 (1 H, br s), 10.69 (1 H, br s), 13.59 (1 H, br s); ESIMS found for C23H25F2N7O3 m/z 486.3 (M+l).
Figure imgf000239_0001
230
[0753] N-(3-((6-(2-(Pyrrolidin-l-yl)ethoxy)pyridin-3-yl)carbamoyl)-lH-pyrazol-4- yl)nicotinamide 230.
[0754] Beige solid (18.0 mg, 0.05 mmol, 31.5% yield).‘H NMR (499 MHz, DMSO- d6) d ppm 1.71 (4 H, br s), 2.62 (4 H, br s), 2.88 (2 H, br s), 4.35 (2 H, t, 7= 5.76 Hz), 6.80 (1 H, d, .7=8.78 Hz), 7.38 (1 H, dd, 7=7.82, 4.80 Hz), 8.01 (1 H, dt, 7=7.89, 1.82 Hz), 8.06 (1 H, dd, 7=8.92, 2.61 Hz), 8.24 (1 H, s), 8.46 (1 H, dd, 7=4.67, 1.37 Hz), 8.50 (1 H, d, 7=2.47 Hz), 8.77 (1 H, d, 7=1.65 Hz), 10.28 (1 H, s), 13.66 (1 H, br s); ESIMS found for C2oH22N602 m/z 378.9 (M+l).
Example 15.
[0518] The screening assay for Wnt activity is described as follows. Reporter cell lines can be generated by stably transducing cancer cell lines (e.g., colon cancer) or primary cells (e.g., IEC-6 intestinal cells) with a lentiviral construct that includes a Wnt-responsive promoter driving expression of the firefly luciferase gene.
[0519] SW480 colon carcinoma cells were transduced with a lentiviral vector expressing luciferase with a human Sp5 promoter consisting of a sequence of eight TCF/LEF binding sites. SW480 cells stably expressing the Sp5-Luc reporter gene and a hygromycin resistance gene were selected by treatment with 150 pg/mL of hygromycin for 7 days. These stably transduced SW480 cells were expanded in cell culture and used for all further screening activities. Each compound was dissolved in DMSO as a 10 mM stock and used to prepare compound source plates. Serial dilution (1 :3, 10-point dose-response curves starting from 10 pM) and compound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale, CA) into 384-well white solid bottom assay plates (Greiner Bio-One) with appropriate DMSO backfdl for a final DMSO concentration of 0.1%. For Sp5-Luc reporter gene assays, the cells were plated at 4,000 cells/well in 384-well plates with a DMEM medium containing 1% fetal bovine serum, and 1% Penicillin- Streptomycin and incubated for 36 to 48 hours at 37°C and 5% C02. Following incubation, 15 pi of BriteLite Plus luminescence reagent (Perkin Elmer) was added to each well of the 384-well assay plates. The plates were placed on an orbital shaker for 2 min and then luminescence was quantified using the Envision (Perkin Elmer) plate reader. Readings were normalized to DMSO only treated cells, and normalized activities were utilized for EC50 calculations using the dose- response log (inhibitor) vs. response -variable slope (four parameters) nonlinear regression feature available in GraphPad Prism 5.0 (or Dotmatics).
[0520] Table 2 shows the measured activity for representative compounds of Formula (I) as described herein.
Table 2.
Figure imgf000240_0001
Figure imgf000241_0001
Example 16. DYRK1A Kinase Activity Assay
[0521] Representative compounds were screened using the assay procedure for DYRK1A kinase activity as described below.
[0522] Each compound was dissolved in DMSO as a 10 mM stock and used to prepare compound source plates. Serial dilution (1 :3, 11 -point dose-response curves from 10 pM to 0.00016 mM) and compound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale, CA) into 1536-well black-walled round bottom plates (Coming).
[0523] The DYRK1A kinase assay was run using the Ser/Thr 18 peptide Z-lyte assay kit according to manufacturer’s instructions (Life Technologies- a Division of Thermo-Fisher). This is a non-radioactive assay using fluorescence resonance energy transfer (FRET) between coumarin and fluorescein to detect kinase activity which is represented as a ratio of coumarin emission/fluorescein emission.
[0524] Briefly, recombinant DYRK1A kinase, ATP and Ser/Thr peptide 18 were prepared in IX Kinase buffer to final concentrations of 0.19 pg/mL, 30 pM, and 4 pM respectively. The mixture was allowed to incubate with the representative compounds for one hour at room temperature. All reactions were performed in duplicate. Unphosphorylated (“0% Control”) and phosphorylated (“100% control”) forms of Ser/Thr 18 served as control reactions. Additionally, an 11-point dose-response curve of Staurosporine (luM top) was run to serve as a positive compound control.
[0525] After incubation, Development Reagent A was diluted in Development Buffer then added to the reaction and allowed to further incubate for one hour at room temperature. The plate was read at Ex 400 Em 455 to detect the coumarin signal and Ex 400 Em 520 to measure the signal (EnVision Multilabel Plate Reader, PerkinElmer).
[0526] The Emission ratio (Em) was calculated as a ratio of the coumarin (C) emission signal (at 445 nm)/Fluorescein (F) emission signal (at 520 nm). The percent phosphorylation was then calculated using the following formula: [1 - ((Em ratio X F100%)-C100%)/ ((C0%-C100%) + (Em ratio X (FI 00% - F0%)))]. Dose-response curves were generated and inhibitory concentration (IC50) values were calculated using non-linear regression curve fit in the Dotmatics’ Studies Software (Bishops Stortford, UK).
[0527] Table 3 shows the measured activity for representative compounds of Formula (I) as described herein.
Table 3.
Figure imgf000242_0001
Figure imgf000243_0001
Example 17. GSK3B Kinase Activity Assay
[0528] Representative compounds were screened using the assay procedure for GSK3 kinase activity as described below.
[0529] Each compound is dissolved in DMSO as a 10 mM stock and used to prepare compound source plates. Serial dilution (1 :3, 11-point dose-response curves from 10 mM to 0.0003 mM) and compound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale, CA) into 1536-well black-walled round bottom plates (Coming).
[0530] The GSK3 kinase assay is run using the Ser/Thr 09 peptide Z-lyte assay kit according to manufacturer’s instructions (Life Technologies- a Division of Thermo-Fisher). This is a non-radioactive assay using fluorescence resonance energy transfer (FRET) between coumarin and fluorescein to detect kinase activity which is represented as ratio of coumarin emission/fluorescein emission.
[0531] Briefly, recombinant GSK3 kinase, ATP and Ser/Thr peptide 09 are prepared in IX Kinase buffer to final concentrations of 0.04 pg/mL, 46 pM, and 4 pM respectively. The mixture is allowed to incubate with the representative compounds for one hour at room temperature . All reactions were performed in duplicate. Unphosphorylated (“0% Control”) and phosphorylated (“100% control”) forms of Ser/Thr 18 serve as control reactions. [0532] After incubation, diluted Development Buffer is added to the reaction and allowed to further incubate for one hour at room temperature. The plate is read at Ex 400 Em 455 to detect the coumarin signal and Ex 400 Em 520 to measure the signal (EnVision Multilabel Plate Reader, PerkinElmer).
[0533] The Emission ratio (Em) is calculated as a ratio of the coumarin (C) emission signal (at 445 nm)/Fluorescein (F) emission signal (at 520 nm). The percent phosphorylation is then calculated using the following formula: [1 - ((Em ratio X F100%)-C100%)/ ((C0%-C100%) + (Em ratio X (FI 00% - F0%)))].
[0534] Dose-response curves are generated and inhibitory concentration (IC50) values are calculated using non-linear regression curve fit in the Dotmatics’ Studies Software (Bishops Stortford, UK).
[0535] Table 4 shows the activity of representative compounds of Formula (I) as provided herein.
Table 4.
Figure imgf000244_0001
Figure imgf000245_0001
Example 18. CLK2 Kinase Activity Assay
[0755] Representative compounds were screened using the assay procedure for CLK2 kinase activity as described below.
[0756] Each compound was dissolved in DMSO as a 10 mM stock and used to prepare compound source plates. Serial dilution (1:3, 11-point dose-response curves from 10 mM to 0.00016 pM) and compound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale, CA) into 1536-well black-walled round bottom plates (Coming).
[0757] The CLK2 kinase assay was run using the Ser/Thr 6 peptide Z-lyte assay kit according to manufacturer’s instructions (Life Technologies- a Division of Thermo-Fisher). This is a non-radioactive assay using fluorescence resonance energy transfer (FRET) between coumarin and fluorescein to detect kinase activity which is represented as a ratio of coumarin emission/fluorescein emission.
[0758] Briefly, recombinant CLK2 kinase, ATP and Ser/Thr peptide 6 were prepared in IX Kinase buffer to final concentrations of 0.43 pg/mL, 60 pM, and 4 pM respectively. The mixture was allowed to incubate with the representative compounds for one hour at room temperature. All reactions were performed in duplicate. Unphosphorylated (“0% Control”) and phosphorylated (“100% control”) forms of Ser/Thr 6 served as control reactions. Additionally, an 11 -point dose-response curve of Staurosporine (luM top) was run to serve as a positive compound control.
[0759] After incubation, Development Reagent A was diluted in Development Buffer then added to the reaction and allowed to further incubate for one hour at room temperature. The plate was read at Ex 400 Em 455 to detect the coumarin signal and Ex 400 Em 520 to measure the signal (EnVision Multilabel Plate Reader, PerkinElmer).
[0760] The Emission ratio (Em) was calculated as a ratio of the coumarin (C) emission signal (at 445 nm)/Fluorescein (F) emission signal (at 520 nm). The percent phosphorylation was then calculated using the following formula: [1 - ((Em ratio X F100%)- C100%)/ ((C0%-C100%) + (Em ratio X (FI 00% - F0%)))]. Dose-response curves were generated and inhibitory concentration (IC50) values were calculated using non-linear regression curve fit in the Dotmatics’ Studies Software (Bishops Stortford, UK).
[0761] Table 5 shows the activity of representative compounds of Formula (I) as provided herein.
Table 5.
Figure imgf000246_0001
Figure imgf000247_0001
Example 19. Tau Ser396 Phosphorylation Activity Assay
[0536] Representative compounds were screened using the assay procedure for tau phosphorylation activity described below.
[0537] SH-SY5Y cells (human neuroblastoma) were cultured in DMEM/F-12 medium supplemented with 15% FBS, Non-essential Amino Acid and Penicillin/Streptomycin. Two days before treatment, cells were seeded onto 96 well plates at 5 x 104 cells/well.
[0538] The above synthesized compounds were screened using the cell assay procedure to assess decrease Tau phosphorylation at Ser396 (pSer396) described below.
[0539] DMSO-resuspended compounds were dispensed to 8 wells as a serial titration from 10 mM to 4.6 nM final in medium and cells were exposed overnight (16-18 h) in a humidified incubator at 36.6c before harvest. Wells were visually checked for cell death or change in morphology and supernatants were tested for cytotoxicity by measurement of lactate dehydrogenase release (FDH, CytoToxOne kit, Promega) if necessary. As controls, commercially available DYRK1A inhibitors, Harmine and Indy which were shown to have good DYRK1A inhibition in the kinase assay with no CDK1 activity (EC50 18 and 53 nM respectively, 6 mM for CDK1) but weak EC50 in the Tau assay >10 pM.
[0540] Cells were lysed with RIPA buffer complemented with phosphatase and protease inhibitors then lysates were spun down at 12,000g for 10 min to remove any cellular debris. Lysates are then either directly tested for pSer396 by ELISA (Life Technology, Kit KHB7031) or loaded on NuPage Bis-Tris gels for western blot analysis. Colorimetric detection of ELISA signal is performed by Cytation3 plate reader (Biotek) and the chemiluminescence signal for HRP -linked antibodies used in western blotting is detected using a Carestream Image Station. The same pSer396 antibody is used for detection of pTau in both assays.
[0541] Blot densitometry for pSer396 and b-actin were analyzed using ImageJ (NIH) and pSer396 Tau ELISA signal was used to plot, draw the curve fitting, and determine each compounds EC50 in Prism (GraphPad).
[0542] Table 6 shows the activity of representative compounds Formula (I) as provided herein.
Table 6.
Figure imgf000248_0001
Example 20. Cell Viability Activity Assay
[0543] Representative compounds were screened using the assay procedure to assess the effect on cell viability as described below.
[0544] SW480 colon carcinoma cells were transduced with a lentiviral vector expressing luciferase with a human Sp5 promoter consisting of a sequence of eight TCF/LEF binding sites. SW480 cells stably expressing the Sp5-Luc reporter gene and a hygromycin resistance gene were selected by treatment with 150 pg/mL of hygromycin for 7 days. These stably transduced SW480 cells were expanded in cell culture and used for all further screening activities. Each compound was dissolved in DMSO as a 10 mM stock and used to prepare compound source plates. Serial dilution (1 :3, 8-point dose-response curves from 10 pM to 0.0045 pM) and compound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale, CA) into 384-well white solid bottom assay plates (Greiner Bio-One) with appropriate DMSO backfdl for a final DMSO concentration of 0.1%.
[0545] For the Cell Viability Assays, the cells were plated at 2,000 cells/well in 384- well plates with a DMEM medium containing 1% fetal bovine serum, and 1% Penicillin- Streptomycin and incubated for four days hours at 37°C and 5% CO2. Eight replicates of DMSO- treated cells served as controls and cells treated with compound were performed in duplicate.
[0546] After incubation, 10 pL of CellTiter-Glo (Promega) was added to each well allowed to incubate for approximately 12 minutes. This reagent“results in cell lysis and generation of a luminescent signal proportional to the amount of ATP present. The amount of ATP is directly proportional to the number of cells present in culture, in agreement with previous reports. The CellTiter-Glo® Assay generates a "glow-type" luminescent signal, produced by the luciferase reaction (Promega.com)”.
[0547] After incubation, the plates were read at Ex 560 nm Em 590 nm (Cytation 3, BioTek). Dose-response curves were generated and EC50 concentration values were calculated using non-linear regression curve fit in the GraphPad Prism (San Diego, CA) or Dotmatics’ Studies Software (Bishops Stortford, UK).
[0548] Table 7 shows the activity of representative compounds of Formula (I) as provided herein. Table 7.
Figure imgf000250_0001
Figure imgf000251_0001
Example 21. Fibrosis Activity Assay
[0549] Representative compounds were screened using primary human fibroblasts (derived from IPF patients) treated with TGF-bI to determine their ability to inhibit the fibrotic process.
[0550] Human Fibroblast Cell Culture : Primary human fibroblasts derived from IPF patients (LL29 cells) [1Xiaoqiu Liu, et.al.,“Fibrotic Lung Fibroblasts Show Blunted Inhibition by cAMP Due to Deficient cAMP Response Element-Binding Protein Phosphorylation”, Journal of Pharmacology and Experimental Therapeutics (2005), 315(2), 678-687; 2Watts. K. L., et.al., “RhoA signaling modulates cyclin D1 expression in human lung fibroblasts; implications for idiopathic pulmonary fibrosis”, Respiratory Research (2006), 7(1), 88] were obtained from American Type Culture Collection (ATCC) and expanded in F12 medium supplemented with 15% Fetal Bovine Serum and 1% Penicillin/Streptomycin.
[0551] Compound Screening: Each compound was dissolved in DMSO as a 10 mM stock and used to prepare compound source plates. Serial dilution (1:2, 11-point dose-response curves from 10 mM to 0.94 nM) and compound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale, CA) into 384-well clear bottom assay plates (Greiner Bio-One) with appropriate DMSO backfill for a final DMSO concentration of 0.1%. LL29 cells were plated at 1,500 cells/well in 70 pL/well F12 medium supplemented with 1% Fetal Bovine Serum. TGF-bI (Peprotech; 20 ng/mL) was added to the plates to induce fibrosis (ref. 1 and 2 above). Wells treated with TGF-bI and containing DMSO were used as positive control, and cells with only DMSO were negative control. Cells were incubated at 37°C and 5% CO2 for 4 days. Following incubation for 4 days, SYTOX green nucleic acid stain (Life Technologies [Thermo Fisher Scientific]) was added to the wells at a final concentration of 1 mM and incubated at room temperature for 30 min. Cells were then fixed using 4% formaldehyde (Electron Microscopy Sciences), washed 3 times with PBS followed by blocking and permeabilization using 3% Bovine Serum Albumin (BSA; Sigma) and 0.3% Triton X-100 (Sigma) in PBS. Cells were then stained with antibody specific to a-smooth muscle actin (aSMA; Abeam) (ref. 1 and 2 above) in 3% Bovine Serum Albumin (BSA; Sigma) and 0.3% Triton X-100 (Sigma) in PBS, and incubated overnight at 4°C. Cells were then washed 3 times with PBS, followed by incubation with Alexa Flor-647 conjugated secondary antibody (Life Technologies [Thermo Fisher Scientific]) and DAPI in 3% Bovine Serum Albumin (BSA; Sigma) and 0.3% Triton X-100 (Sigma) in PBS at room temperature for 1 hour. Cells were then washed 3 times with PBS and plates were sealed for imaging. aSMA staining was imaged by excitation at 630 nm and emission at 665 nm and quantified using the Compartmental Analysis program on the Celllnsight CX5 (Thermo Scientific). Dead or apoptotic cells were excluded from analysis based on positive SYTOX green staining. % of total cells positive for aSMA were counted in each well and normalized to the average of 11 wells treated with TGF-bI on the same plate using Dotmatics’ Studies Software. The normalized averages (fold change over untreated) of 3 replicate wells for each compound concentration were used to create dose -responses curves and EC50 values were calculated using non-linear regression curve fit in the Dotmatics’ Studies Software. For EC50 of >10 mM, the percent inhibition at 10 pM is provided.
[0552] Table 8 shows the activity of representative compounds of Formula (I) as provided herein.
Table 8.
Figure imgf000252_0001
Figure imgf000253_0001
Example 22. IL-6 Activity Assay
[0553] Representative compounds were screened using the following assay procedure to determine their ability to inhibit IL-6 and therefore demonstrate their anti-inflammatory properties.
[0554] Human Peripheral Blood Mononuclear Cells: Fresh Normal PB MNC (Catalog # PB001, AllCells, Alameda, CA) were shipped overnight at 4°C and resuspended in Roswell Park Memorial Institute (RPMI) 1640 Medium, with GlutaMAX Supplement (Catalog #61870127, ThermoFisher Scientific, Waltham, MA) supplemented with 1% Penicillin- Streptomycin (Catalog# 15140163, ThermoFisher Scientific, Waltham, MA) and 1% fetal bovine serum (FBS) ( Catalog # 16140089, ThermoFisher Scientific, Waltham, MA) assay media.
[0555] Compound Screening: Fresh normal human peripheral blood mononuclear cells (huPBMCs) were resuspended in 1% FBS-RPMI assay media with 1% Penicillin- Streptomycin 1% to a cell concentration of 1 x 10e6 cells/mL. Each compound was dissolved in DMSO (Catalog # D8418- 100ml, Sigma- Aldrich, St. Louis, MO) as a 10 mM stock and used to prepare compound source plates. Serial dilution (1:3, 10-point dose-response curves starting from 10 mM) and compound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale, CA) into 384-well white Proxiplate-Plus assay plates (Catalog #6008289, PerkinElmer, Shelton, CT) with appropriate DMSO backfill for a final DMSO concentration of 0.25%. huPBMCs were plated at 5000 cells/well in the 384-well Proxiplate-Plus assay plates and incubated at 37°C-5% CO2 for 2 hours. 50 ng/mL of Lipopolysaccharides from Escherichia coli 0111 :B4 (Catalog #L5293-2ML, Sigma-Aldrich, St. Louis, MO) was added after 2 hours and cells were incubated for another 22 hours at 37°C-5% CO2 . After 22 hour incubation, a mixture of anti-IL6 XL665 and anti-IL-6 Cryptate diluted in reconstitution buffer (Catalog #62IL6PEC, Cisbio Inc., Bedford, MA) was added to each well. Following incubation for 3 hours at room temperature, Homogeneous Time- Resolved Fluorescence (HTRF) was measured using the Envision (Perkin Elmer, Shelton, CT) at 665 nm and 620 nM. The ratio of fluorescence at 665 nm to 620 nm was used as a readout for IL- 6 quantification. All samples were processed in duplicate. Readings were normalized to DMSO treated cells and normalized activities were utilized for EC50 calculations. EC50 was determined using software generated by Dotmatics Limited (Windhill Bishops Stortford Herts, UK) using the Levenberg-Marquardt 4 parameter fitting procedure with finite different gradients. For EC50 of >10 mM, the percent inhibition at 10 mM is provided.
[0556] Table 9 shows the activity of representative compounds of Formula (I) as provided herein.
Table 9.
Figure imgf000254_0001
Figure imgf000255_0001

Claims

WHAT IS CLAIMED IS:
1. A compound, or a pharmaceutically acceptable salt thereof, of Formula (I):
Figure imgf000256_0001
wherein:
R1 is selected from the group consisting of H, halide, and unsubstituted -(C1-3 alkyl);
R2 is selected from the group consisting of unsubstituted -(C1-3 alkyl), unsubstituted -(C2- 9 alkenyl), unsubstituted -(Ci-9haloalkyl), -(C1-2 alkylene)p(C3-6 carbocyclyl) optionally substituted with 1-12 R4, -monocyclic heterocyclyl optionally substituted with 1-10 R5, -phenyl substituted with 1-5 R6, -heteroaryl optionally substituted with 1-4 R7, -CO2R8, -OR9, and -(C=0)R10; wherein heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxazolyl, oxadiazolyl, thiazolyl, 2,3-dihydrobenzo[b]dioxinyl, 5,6,7,8-tetrahydroimidazo[l,2- a]pyrazinyl, 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridinyl, isoquinolinyl, and quinolinyl; wherein — (Ci-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein; with the proviso that when L1 is a bond, R2 is selected from the group consisting of -phenyl substituted with 1-5 R6 and -heteroaryl optionally substituted with 1-4 R7; wherein heteroaryl selected from the group consisting of pyridinyl, oxazolyl, oxadiazolyl, thiazolyl, 2,3- dihydrobenzo[b]dioxinyl, 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazinyl, 4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridinyl, isoquinolinyl, and quinolinyl;
R3 is selected from the group consisting of -heterocyclyl substituted with 1-10 R11, -(C1-4 alkylene)pphenyl substituted with 1-5 R12, -heteroaryl optionally substituted with 1-4 R13, and - (Ci-4 alkylene)OR14; wherein heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, 5,6,7,8-tetrahydroimidazo[l,2- a]pyrazinyl, 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridinyl, 1,2,3,4-tetrahydroisoquinolinyl,
Figure imgf000256_0002
isoquinolinyl, and quinolinyl; wherein is only substituted at positions 4 and 7 ; wherein each— (Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; with the proviso that when L2 is a bond, R3 is selected from -heteroaryl optionally substituted with 1-4 R13; wherein heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, 5,6,7,8-tetrahydroimidazo[l,2- a]pyrazinyl, 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridinyl, 1,2,3,4-tetrahydroisoquinolinyl,
Figure imgf000257_0001
isoquinolinyl, and quinolinyl; wherein is only substituted at positions 4 and 7;
each R4 is halide;
each R5 is independently selected from the group consisting of halide, Me, and Et;
each R6 is independently selected from the group consisting of methyl, -CFfiF, -CHF2, - CF3, -OR15a, and -(Ci-4 alkylene)pN(R16a)(R16b); wherein -(C1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein;
each R7 is independently selected from the group consisting of F, methyl, -CFfiF, -CHF2, -CF3, -CF2CH3, -OR15a, -CO2R17, -NR18(C=0)R19, — (Ci-4 alkylene)pheterocyclyl optionally substituted with 1-10 R20b, and -(C1-4 alkylene)pN(R16a)(R16b); wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
R8 is unsubstituted -(C1-9 alkyl);
R9 is unsubstituted -(C1-9 alkyl);
R10 is -aryl optionally substituted with 1-5 R21;
each R11 is independently selected from the group consisting of halide, methyl, and ethyl; each R12 is independently selected from the group consisting of -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R20a, -aryl optionally substituted with 1-5 R22,— (Ci-4 alkylene)N(R16a)(R16b), and -OR23a; wherein heterocyclyl selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; each R13 is independently selected from the group consisting of F, methyl, -CFfiF, -CHF2, -CF3,— (Ci-4 alkylene)pN(R16a)2, -OR23b, -(Cw alkylene)pheterocyclyl optionally substituted with 1-10 R20b, -aryl optionally substituted with 1-5 R22, and -heteroaryl substituted with 1-4 R24; wherein -(C1-4 alkylene) is optionally substituted with one or more substituents as defined anywhere herein;
R14 is selected from the group consisting of unsubstituted -(Cw alkyl) and -aryl optionally substituted with 1-5 R22; each R15a is independently selected from the group consisting of unsubstituted -(C2-3 alkyl), and -heterocyclyl optionally substituted with 1-10 R20b;
each R15b is independently selected from the group consisting of H, unsubstituted -(C2-9 alkyl), and -heterocyclyl optionally substituted with 1-10 R20b;
each R16a is independently selected from the group consisting of H and unsubstituted -(Ci-
2 alkyl);
each R16b is unsubstituted -(C1-2 alkyl);
each R17 is unsubstituted -(C1-9 alkyl);
each R18 is independently selected from the group consisting of H and Me;
each R19 is unsubstituted -(C1-9 alkyl);
each R20a is independently selected from the group consisting of halide and unsubstituted -(C2-9 alkyl);
each R20b is independently selected from the group consisting of halide and unsubstituted -(Ci-9 alkyl);
each R21 is independently selected from the group consisting of halide and unsubstituted - (Ci-9 alkyl);
each R22 is independently selected from the group consisting of halide and unsubstituted - (Ci-9 alkyl);
each R23a is independently selected from the group consisting of unsubstituted -(C2-9 alkyl), — (Ci-4 alkylene)OR25, and -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R20b; wherein each -(Cw alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R23b is independently selected from the group consisting of unsubstituted -(C1-9 alkyl), — (Ci-4 alkylene)OR25, and -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R20b; wherein each -(Cw alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R24 is independently selected from the group consisting of halide and unsubstituted - (Ci-9 alkyl);
each R25 is independently selected from the group consisting of H and unsubstituted -(Ci-
9 alkyl);
, — CºC—
L1 is selected from the group consisting of a bond, -CH=CH-, , -
(CH2)PNR18(C=0)-, -(C=0)NR18(CH2)p-, -NR18(C=0)NR18-, -NH(CH2)p-, and -(CH2)PNH-; L2 is selected from the group consisting of a bond, -(C=0)NR18-, -NR18(C=0)-, - NHCH2-, and -CH2NH-;
each p is independently an integer of 0 or 1 ; and
with the proviso that a compound of Formula (I) is not a compound selected from the group consisting of:
Figure imgf000259_0001
Figure imgf000260_0001
Figure imgf000261_0001
2. The compound of claim 1, wherein R1 is H.
3. The compound according to any one of claims 1-2, wherein L1 is selected from the
Figure imgf000261_0002
group consisting of a bond, -CH=CH-, , -NH(C=0)-, and -NH(C=0)NH-.
4. The compound according to any one of claims 1-3, wherein L2 is selected from the group consisting of a bond and -(C=0)NH-.
5. The compound according to any one of claims 1-4, wherein R2 is selected from the group consisting of unsubstituted -(C1-3 alkyl), -(CThXcyclopropyl), -(cyclopropyl), -monocyclic heterocyclyl optionally substituted with 1 R5, -phenyl substituted with 1-2 R6, and -pyridinyl optionally substituted with 1 R7.
6. The compound according to any one of claims 1-5, wherein R2 is -pyridinyl optionally substituted with 1 R7.
7. The compound according to any one of claims 1-6, wherein R3 is selected from the group consisting of-heterocyclyl substituted with 1 R11, -(Ci-4alkylene)pphenyl substituted with 1 R12, -heteroaryl optionally substituted with 1 R13, and -(C2-3 alkylene)0(Ci-3 alkyl).
8. The compound according to any one of claims 1-7, wherein R3 is -pyridinyl optionally substituted with 1 R13.
9. The compound according to any one of claims 1-7, wherein R3 is -benzimidazolyl optionally substituted with 1 R13.
10. The compound according to any one of claims 1-9, wherein the optional R7 is independently selected from the group consisting of F, methyl, -CF3, -Oheterocyclyl optionally substituted with 1 R20b, -(CH2)heterocyclyl optionally substituted with 1-2 R20b, -NMe2, and - (CH2)NMe2.
11. The compound according to any one of claims 1-10, wherein the optional R13 is independently selected from the group consisting of F, methyl, -CF3, -OMe, -Oheterocyclyl optionally substituted with 1 R20b, -heterocyclyl optionally substituted with 1-2 R20b, - (CH2)heterocyclyl optionally substituted with 1-2 R20b, -(CH2CH2)heterocyclyl optionally substituted with 1-2 R20b, -phenyl optionally substituted with 1 R22, and -heteroaryl substituted with 1 R24.
12. The compound according to any one of claims 1-11, wherein the compound of
Formula (I) is selected from the group consisting of:
Figure imgf000262_0001
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001
Figure imgf000269_0001
Figure imgf000270_0001
, a pharmaceutically acceptable salt thereof.
13. A compound having the structure of:
Figure imgf000271_0001
Figure imgf000272_0001
Figure imgf000273_0001
Figure imgf000274_0001
acceptable salt thereof.
14. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
15. A method of treating a disorder or disease in a patient, wherein the disorder or disease is selected from the group consisting of: chronic inflammation, systemic inflammation, diabetes, cancer, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), degenerative disc disease, bone/osteoporotic fractures, a bone or cartilage disease, a neurological condition/disorder/disease, osteoarthritis, lung disease, a fibrotic disorder, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1-13, or a pharmaceutically acceptable salt, or a pharmaceutical composition; wherein the patient is a human
16. The method of claim 14, wherein the cancer is selected from the group consisting of: osteoma, hemangioma, granuloma, xanthoma, osteitis deformans, meningioma, meningiosarcoma, and gliomatosis, astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, oligodendrocytoma, schwannoma, retinoblastoma, and congenital tumors, neurofibroma, meningioma, glioma, and sarcoma.
17. The method of claim 14, wherein the disorder or disease is a neurological condition/disorder/disease, wherein the neurological condition/disorder/disease is selected from the group consisting of: frontotemporal dementias, dementia with lewy bodies, prion diseases, multiple system atrophy, inclusion body myositis, degenerative myopathies, diabetic neuropathy, other metabolic neuropathies, endocrine neuropathies, orthostatic hypotension, Charcot-Marie-Tooth disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), down syndrome, frontotemporal dementia (FTD) including FTD with Parkinsonism- 17 (FTDP-17), behavioural variant frontotemporal dementia (bvFTD), FTD in patients with motor neuron disease (MND) (typically amyotrophic lateral sclerosis, also called FTD-ALS), corticobasal degeneration (CBD) (also called corticobasal ganglionic degeneration), progressive supranuclear palsy, primary progressive aphasia (PPA), Prion Diseases, globular glial tauopathy (GGT), myotonic dystrophy type 1 (DM1) (also called Steinert disease), myotonic dystrophy type 2 (DM2) (also called proximal myotonic myopathy), Guam complex, argyrophilic grain disease, dementia pugilistica, post-encephalitic parkinsonism, lewy body dementia, Parkinson’s disease, Pick's disease, and additional diseases with pronounced neurodegeneration such as autism, dementia, epilepsy, Huntington’s disease, multiple sclerosis; diseases and disorders associated with acquired brain injury such as chronic traumatic encephalopathy, traumatic brain injury, tumor, and stroke.
18. The method of claim 14, wherein the disorder or disease is a neurological condition/disorder/disease associated with tau protein, amyloid, alpha-synuclein, Tar DNA-binding Protein of 43KDa (TDP-43), Prion protein PrP or fused in sarcoma (FUS) pathology.
19. The method of claim 14, wherein the disorder or disease is a fibrotic disorder, wherein the fibrotic disorder is selected from the group consisting of: skin fibrosis; scleroderma; progressive systemic fibrosis; lung fibrosis; muscle fibrosis; kidney fibrosis; glomerulosclerosis; glomerulonephritis; hypertrophic scar formation; uterine fibrosis; renal fibrosis; cirrhosis of the liver, liver fibrosis; adhesions; chronic obstructive pulmonary disease; fibrosis following myocardial infarction; pulmonary fibrosis; fibrosis and scarring associated with diffuse/interstitial lung disease; central nervous system fibrosis; fibrosis associated with proliferative vitreoretinopathy (PVR); restenosis; endometriosis; ischemic disease, and radiation fibrosis.
20. The method of claim 14, wherein the disorder or disease is chronic inflammation associated eye disorders, joint pain, arthritis (rheumatoid, osteo, psoriatic gout), cancers (colon, breast, lung, pancreas, and others), gastrointestinal disorders (ulcerative colitis and inflammatory bowel diseases), pulmonary disorders (chronic obstructive pulmonary disorder and asthma), allergies, skin disorders (atopic dermatitis and psoriasis), diabetes, pancreatitis, tendonitis, hepatitis, heart disease, myocarditis, stroke, lupus, and neurological disorders such as multiple A method of preventing or reducing angiogenesis in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 - 13, or a pharmaceutically acceptable salt, or a pharmaceutical composition.
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