WO2017189823A2 - Isoquinolin-3-yl carboxamides and preparation and use thereof - Google Patents

Isoquinolin-3-yl carboxamides and preparation and use thereof Download PDF

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Publication number
WO2017189823A2
WO2017189823A2 PCT/US2017/029797 US2017029797W WO2017189823A2 WO 2017189823 A2 WO2017189823 A2 WO 2017189823A2 US 2017029797 W US2017029797 W US 2017029797W WO 2017189823 A2 WO2017189823 A2 WO 2017189823A2
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Prior art keywords
isoquinolin
methyl
carboxamide
pyrazol
piperidine
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PCT/US2017/029797
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French (fr)
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WO2017189823A3 (en
Inventor
Sunil Kumar Kc
Gopi Kumar Mittapalli
Brian Joseph HOFILENA
Joseph Timothy Marakovits
Chandramouli CHIRUTA
Chi Ching Mak
Jianguo Cao
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Samumed, Llc
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Publication date
Priority to KR1020187034080A priority Critical patent/KR102399206B1/en
Priority to AU2017258187A priority patent/AU2017258187B2/en
Application filed by Samumed, Llc filed Critical Samumed, Llc
Priority to EP21181038.7A priority patent/EP3943086A1/en
Priority to BR112018072190-5A priority patent/BR112018072190A2/en
Priority to JP2018556921A priority patent/JP7023243B2/en
Priority to CN201780037470.7A priority patent/CN109311819B/en
Priority to MX2018013173A priority patent/MX2018013173A/en
Priority to EP17790411.7A priority patent/EP3448838B1/en
Priority to PE2018002175A priority patent/PE20190260A1/en
Priority to MA43605A priority patent/MA43605B1/en
Priority to RU2018141379A priority patent/RU2018141379A/en
Priority to SG11201809310PA priority patent/SG11201809310PA/en
Priority to CA3022044A priority patent/CA3022044A1/en
Publication of WO2017189823A2 publication Critical patent/WO2017189823A2/en
Publication of WO2017189823A3 publication Critical patent/WO2017189823A3/en
Priority to IL262495A priority patent/IL262495B/en
Priority to PH12018502259A priority patent/PH12018502259A1/en
Priority to CONC2018/0012655A priority patent/CO2018012655A2/en

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/02—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing not further condensed quinolizine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged 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 an isoquinoline 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 ⁇ -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.
  • Dual specificity tyrosine-phosphorylation-regulated kinase 1A is an enzyme that in humans is encoded by the DYRKIA gene.
  • DYRKIA is a member of the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family.
  • DYRKIA contains a nuclear targeting signal sequence, a protein kinase domain, a leucine zipper motif, and a highly conservative 13 - consecutive-histidine repeat.
  • DYRKIA 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.
  • DYRKIA 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. DYRKIA is also expressed in adult brain neurons, indicating that DYRKIA may play a role in the mature central nervous system. Thus, several lines of evidence point to some synaptic functions of DYRKIA.
  • DYRKIA 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.
  • a polymorphism (SNP) in DYRKIA 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 .
  • the present disclosure provides methods and reagents, involving contacting a cell with an agent, such as an isoquinoline 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 an isoquinoline compound
  • the present disclosure also provides methods and reagents, involving contacting a cell with an agent, such as an isoquinoline compound, in a sufficient amount to antagonize DYRKIA 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 an isoquinoline compound
  • Some embodiments disclosed herein include Wnt and/or DYRKIA inhibitors containing an isoquinoline 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 , R 2 , R 4 , and R 5 are independently selected from the group consisting of H, halide, unsubstituted -(C1-3 haloalkyl), and unsubstituted -(C1-3 alkyl);
  • R 3 is a 5-membered heteroaryl optionally substituted with 1-4 R 45 ;
  • R 6 is selected from the group consisting of -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R 36 , -(C1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 37 , -(C1-4 alkylene)N(R 46 )(R 47 ), and -CF(Ci -9 alkyl) 2 ; wherein each alkyl of -CF(Ci -9 alkyl) 2 is, independently, optionally substituted with one or more halides; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; each R 36 is independently selected from the group consisting of halide, unsubstituted -(Ci- 9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C 1-9 haloalky
  • each R 38 is independently selected from the group consisting of halide, unsubstituted -(Ci-
  • each R 39 independently is selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 44 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • each R 40 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene) p carbocyclyl optionally substituted with 1 -12 R 44 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • each R 41 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -CN;
  • each R 42 is independently selected from the group consisting of unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and - (Ci-4 alkylene) p carbocyclyl optionally substituted with 1 -12 R 44 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; each R 43 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene) p carbocyclyl optional
  • each R 44 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -CN;
  • each R 45 is independently selected from the group consisting of H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(Ci-4 alkylene) p heterocyclyl optionally substituted with 1 -10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • two adjacent R 45 taken together form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1 -10 R 40 and -carbocyclyl optionally substituted with 1-12 R 41 ;
  • R 46 is attached to the nitrogen and is selected from the group consisting of H, unsubstituted -(Ci-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene ) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein -(Ci-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
  • R 47 is attached to the nitrogen and is selected from the group consisting of unsubstituted - (Ci-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
  • each p is independently 0 or 1.
  • R 1 , R 2 , R 4 , and R 5 are independently selected from the group consisting of H, halide, unsubstituted -(C1-3 haloalkyl), and unsubstituted -(C1-3 alkyl);
  • R 3 is selected from the roup consisting of:
  • each of R 7 -R 35 is, independently, a substituent as defined anywhere herein or a single bond connecting R 3 to the isoquinoline ring; wherein only one of R 7 -R 10 (when present) is a bond, only one of R n -R 14 (when present) is a bond, only one of R 15 -R 17 (when present) is a bond, only one of R 18 -R 20 (when present) is a bond, only one of R 21 -R 23 (when present) is a bond, only one of R 24 -R 26 (when present) is a bond, only one of R 27 -R 29 (when present) is a bond, only one of R 0 -R 31 (when present) is a bond, only one of R 2 -R 33 (when present) is a bond, and only one of R 4 -R 35 (when present) is a bond; for purposes of clarification, any one of the nitrogen atoms attached to R 7 , R 11 , R 15 , R 18
  • R 7 when the nitrogen atom to which R 7 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 7 is a single bond connecting R 3 to the isoquinoline ring;
  • R 8 when the carbon atom to which R 8 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 8 is a single bond connecting R 3 to the isoquinoline ring; when the carbon atom to which R 9 is attached serves as the point of attachment of R to the isoquinoline ring, then R 9 is a single bond connecting R 3 to the isoquinoline ring;
  • R 10 when the carbon atom to which R 10 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 10 is a single bond connecting R 3 to the isoquinoline ring;
  • R 11 when the nitrogen atom to which R 11 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 11 is a single bond connecting R 3 to the isoquinoline ring;
  • R 12 when the carbon atom to which R 12 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 12 is a single bond connecting R 3 to the isoquinoline ring;
  • R 13 when the carbon atom to which R 13 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 13 is a single bond connecting R 3 to the isoquinoline ring;
  • R 14 when the carbon atom to which R 14 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 14 is a single bond connecting R 3 to the isoquinoline ring;
  • R 15 when the nitrogen atom to which R 15 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 15 is a single bond connecting R 3 to the isoquinoline ring;
  • R 16 when the carbon atom to which R 16 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 16 is a single bond connecting R 3 to the isoquinoline ring;
  • R 17 when the carbon atom to which R 17 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 17 is a single bond connecting R 3 to the isoquinoline ring;
  • R 18 when the nitrogen atom to which R 18 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 18 is a single bond connecting R 3 to the isoquinoline ring;
  • R 19 when the carbon atom to which R 19 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 19 is a single bond connecting R 3 to the isoquinoline ring;
  • R 20 when the carbon atom to which R 20 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 20 is a single bond connecting R 3 to the isoquinoline ring;
  • R 21 when the nitrogen atom to which R 21 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 21 is a single bond connecting R 3 to the isoquinoline ring;
  • R 22 when the carbon atom to which R 22 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 22 is a single bond connecting R 3 to the isoquinoline ring;
  • R 23 is a single bond connecting R 3 to the isoquinoline ring;
  • R 24 is a single bond connecting R 3 to the isoquinoline ring;
  • R 25 when the carbon atom to which R 25 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 25 is a single bond connecting R 3 to the isoquinoline ring; when the carbon atom to which R 26 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 26 is a single bond connecting R 3 to the isoquinoline ring;
  • R 27 when the carbon atom to which R 27 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 27 is a single bond connecting R 3 to the isoquinoline ring;
  • R 28 when the carbon atom to which R 28 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 28 is a single bond connecting R 3 to the isoquinoline ring;
  • R 29 is a single bond connecting R 3 to the isoquinoline ring;
  • R 30 is a single bond connecting R 3 to the isoquinoline ring;
  • R 31 is a single bond connecting R 3 to the isoquinoline ring;
  • R 32 is a single bond connecting R 3 to the isoquinoline ring;
  • R 33 is a single bond connecting R 3 to the isoquinoline ring;
  • R 34 is a single bond connecting R 3 to the isoquinoline ring;
  • R 35 is a single bond connecting R 3 to the isoquinoline ring;
  • R 6 is selected from the group consisting of -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R 36 , -(C1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 37 , -(C1-4 alkylene)N(R 46 )(R 47 ), and -CF(Ci- 9 alkyl) 2 ; wherein each alkyl of -CF(Ci- 9 alkyl) 2 is, independently, optionally substituted with one or more halides; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • R 7 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
  • R 8 , R 9 , and R 10 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene ) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; alternatively, one of R 7 and R 8 , R 8 and R 9 , or R 9 and R 10 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 40 and -carbocyclyl optionally substituted
  • R 11 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene ) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
  • R 12 , R 13 , and R 14 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene ) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; alternatively, one of R 11 and R 12 , R 12 and R 13 , or R 14 and R 11 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 40 and -carbocyclyl optionally substituted
  • R 15 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
  • R 16 and R 17 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene ) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; alternatively, one of R 15 and R 16 or R 16 and R 17 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 40 and - carbocyclyl optionally substituted with 1-12 R 41 ;
  • R 18 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein -(Ci-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
  • R 19 and R 20 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene ) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; alternatively, one of R 18 and R 19 or R 18 and R 20 are taken together to form a heterocyclyl optionally substituted with 1-10 R 40 ;
  • R 21 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
  • R 22 and R 23 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene ) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; alternatively, R 22 and R 23 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 40 and -carbocyclyl optionally substituted with 1-12 R 41 ;
  • R 24 , R 25 , and R 26 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene ) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; alternatively, one of R 24 and R 25 or R 25 and R 26 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 40 and - carbocyclyl optionally substituted with 1-12 R 41 ;
  • R 27 , R 28 , and R 29 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene ) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; alternatively, R 27 and R 28 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 40 and -carbocyclyl optionally substituted with 1-12 R 41 ;
  • R 30 and R 31 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene ) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; alternatively, R 30 and R 1 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 40 and -carbocyclyl optionally substituted with 1-12 R 41 ;
  • R 32 and R 33 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene ) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • R 34 and R 35 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene ) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; alternatively, R 34 and R 35 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 40 and -carbocyclyl optionally substituted with 1-12 R 41 ;
  • each R 36 is independently selected from the group consisting of halide, unsubstituted -(Ci- 9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -(Ci-4 alkylene) p OR 42 , -(C1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 43 , and -(Ci- 4 alkylene) p carbocyclyl optionally substituted with 1-12 R 44 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; each R 37 is independently selected from the group consisting of halide, unsubstituted -(Ci- 9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9
  • each R 39 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene) p carbocyclyl optionally substituted with 1 -12 R 44 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • each R 40 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene) p carbocyclyl optionally substituted with 1 -12 R 44 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • each R 41 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -CN;
  • each R 42 is independently selected from the group consisting of unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and - (Ci-4 alkylene) p carbocyclyl optionally substituted with 1 -12 R 44 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; each R 43 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene) p carbocyclyl optional
  • each R 44 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -CN;
  • R 46 is attached to the nitrogen and is selected from the group consisting of H, unsubstituted -(Ci-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene ) p heterocyclyl optionally substituted with 1 -10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
  • R 47 is attached to the nitrogen and is selected from the group consisting of unsubstituted - (Ci-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene ) p heterocyclyl optionally substituted with 1 -10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
  • each X is O or S
  • each p is independently 0 or 1.
  • R 1 , R 2 , R 4 , and R 5 are independently selected from the group consisting of H, halide, unsubstituted -(C1-3 haloalkyl), and unsubstituted -(C1-3 alkyl);
  • R 3 is a 5-membered heteroaryl optionally substituted with 1-4 R 45 ; with the proviso that R 3 is not
  • R 6 is selected from the group consisting of -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R 36 , -(C1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 37 , -(C1-4 alkylene)N(R 46 )(R 47 ), -N(R 48 )(R 49 ), -CF(Ci- 9 alkyl) 2 , -(C1-4 alkylene)pO(C 3 -9 alkyl), and alkynyl) optionally substituted with one or more halides; wherein each alkyl of -CF(Ci-9 alkyl) 2 is, independently, optionally substituted with one or more halides; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; with the proviso that R 6 is not unsubstituted -(Ctytetrahydropyranyl;
  • each R 38 independently is selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene) p carbocyclyl optionally substituted with 1 -12 R 44 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • each R 39 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene) p carbocyclyl optionally substituted with 1 -12 R 44 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • each R 40 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene) p carbocyclyl optionally substituted with 1 -12 R 44 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • each R 41 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -CN;
  • each R 42 is independently selected from the group consisting of H, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -(C 1-4 alky lene) p carbocyclyl optionally substituted with 1-12 R 44 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; each R 43 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene) p carbocycly
  • each R 45 is independently selected from the group consisting of H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R 5 ) 2 , -(Ci- 4 alkylene) p OR 42 , -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; alternatively, two adjacent R 45 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 40 and -carbocyclyl optionally substituted with 1-12 R 41 ;
  • R 46 is attached to the nitrogen and is selected from the group consisting of H, unsubstituted -(Ci-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene ) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
  • R 47 is attached to the nitrogen and is selected from the group consisting of unsubstituted - (Ci-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene ) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
  • R 48 is attached to the nitrogen and selected from the group consisting of H, unsubstituted - (Ci-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), and unsubstituted -(C1-5 haloalkyl);
  • R 49 is attached to the nitrogen and is selected from the group consisting of -(C1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and— (C1-4 alkylene ) p carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • R 50 is selected from the group consisting of H, unsubstituted -(C3-5 alkyl), unsubstituted - (C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -(C1-4 alkylene) p aryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), and -(Ci-4 alkylene)pheterocyclyl optionally substituted with one or more halides or one or more unsubstituted -(C1-5 alkyl); wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • R 51 is selected from the group consisting of H, unsubstituted -(C1-5 alkyl), unsubstituted - (C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -(C1-4 alkylene) p aryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), and -(Ci-4 alkylene)pheterocyclyl optionally substituted with one or more halides or one or more unsubstituted -(C1-5 alkyl); wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • R 52 is selected from the group consisting of unsubstituted -(C1-5 alkyl), unsubstituted -(C2- 5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -(C1-4 alkylene) p aryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), and -(Ci-4 alkylene)pheterocyclyl optionally substituted with one or more halides or one or more unsubstituted -(C1-5 alkyl); wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
  • each R 53 is independently selected from the group consisting of H, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), and unsubstituted -(C2-5 alkynyl);
  • each p is independently 0 or 1 ;
  • R 1 , R 2 , R 4 , and R 5 are independently selected from the group consisting of H, halide, unsubstituted -(C1-3 haloalkyl), and unsubstituted -(C1-3 alkyl);
  • R 3 is selected from the roup consisting of:
  • each of R 7 -R 35 is, independently, a substituent as defined anywhere herein or a single bond connecting R 3 to the isoquinoline ring; wherein only one of R 7 -R 10 (when present) is a bond, only one of R n -R 14 (when present) is a bond, only one of R 15 -R 17 (when present) is a bond, only one of R 18 -R 20 (when present) is a bond, only one of R 21 -R 23 (when present) is a bond, only one of R 24 -R 26 (when present) is a bond, only one of R 27 -R 29 (when present) is a bond, only one of R 0 -R 31 (when present) is a bond, only one of R 2 -R 33 (when present) is a bond, and only one of R 4 -R 35 (when present) is a bond; for purposes of clarification, any one of the nitrogen atoms attached to R 7 , R 11 , R 15 , R 18
  • R 7 when the nitrogen atom to which R 7 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 7 is a single bond connecting R 3 to the isoquinoline ring;
  • R 8 when the carbon atom to which R 8 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 8 is a single bond connecting R 3 to the isoquinoline ring;
  • R 9 when the carbon atom to which R 9 is attached serves as the point of attachment of R to the isoquinoline ring, then R 9 is a single bond connecting R 3 to the isoquinoline ring;
  • R 10 when the carbon atom to which R 10 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 10 is a single bond connecting R 3 to the isoquinoline ring;
  • R 11 when the nitrogen atom to which R 11 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 11 is a single bond connecting R 3 to the isoquinoline ring;
  • R 12 when the carbon atom to which R 12 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 12 is a single bond connecting R 3 to the isoquinoline ring;
  • R 13 when the carbon atom to which R 13 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 13 is a single bond connecting R 3 to the isoquinoline ring;
  • R 14 when the carbon atom to which R 14 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 14 is a single bond connecting R 3 to the isoquinoline ring;
  • R 15 when the nitrogen atom to which R 15 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 15 is a single bond connecting R 3 to the isoquinoline ring;
  • R 16 when the carbon atom to which R 16 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 16 is a single bond connecting R 3 to the isoquinoline ring;
  • R 17 when the carbon atom to which R 17 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 17 is a single bond connecting R 3 to the isoquinoline ring; when the nitrogen atom to which R 18 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 18 is a single bond connecting R 3 to the isoquinoline ring;
  • R 19 when the carbon atom to which R 19 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 19 is a single bond connecting R 3 to the isoquinoline ring;
  • R 20 when the carbon atom to which R 20 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 20 is a single bond connecting R 3 to the isoquinoline ring;
  • R 21 when the nitrogen atom to which R 21 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 21 is a single bond connecting R 3 to the isoquinoline ring;
  • R 22 when the carbon atom to which R 22 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 22 is a single bond connecting R 3 to the isoquinoline ring;
  • R 23 is a single bond connecting R 3 to the isoquinoline ring;
  • R 24 is a single bond connecting R 3 to the isoquinoline ring;
  • R 25 is a single bond connecting R 3 to the isoquinoline ring;
  • R 26 when the carbon atom to which R 26 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 26 is a single bond connecting R 3 to the isoquinoline ring;
  • R 27 when the carbon atom to which R 27 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 27 is a single bond connecting R 3 to the isoquinoline ring;
  • R 28 when the carbon atom to which R 28 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 28 is a single bond connecting R 3 to the isoquinoline ring;
  • R 29 is a single bond connecting R 3 to the isoquinoline ring;
  • R 30 is a single bond connecting R 3 to the isoquinoline ring;
  • R 31 is a single bond connecting R 3 to the isoquinoline ring;
  • R 32 is a single bond connecting R 3 to the isoquinoline ring;
  • R 33 is a single bond connecting R 3 to the isoquinoline ring;
  • R 34 when the carbon atom to which R 34 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 34 is a single bond connecting R 3 to the isoquinoline ring; when the carbon atom to which R 35 is attached serves as the point of attachment of R 3 to the isoquinoline ring, then R 35 is a single bond connecting R 3 to the isoquinoline ring;
  • R 6 is selected from the group consisting of -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R 36 , -(C1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 37 , -(C1-4 alkylene)N(R 46 )(R 47 ), -N(R 48 )(R 49 ), -CF(Ci- 9 alkyl) 2 , -(C1-4 alkylene) p O(C 3 - 9 alkyl), and -(C2-9 alkynyl) optionally substituted with one or more halides; wherein each alkyl of -CF(Ci-9 alkyl)2 is, independently, optionally substituted with one or more halides; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; with the proviso that R 6 is not unsubstituted -(CH2)tetrahydropyr
  • R 7 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)OR 42 , -(C 1-4 alky lene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
  • R 8 , R 9 , and R 10 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R 5 )2, -(C1-4 alkylene ) p OR 42 , -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • R 7 and R 8 , R 8 and R 9 , or R 9 and R 10 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 40 and -carbocyclyl optionally substituted with 1-12 R 41 ;
  • R 11 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)OR 42 , -(C 1-4 alky lene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
  • R 12 , R 13 , and R 14 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R 5 )2, -(C1-4 alkylene ) p OR 42 , -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; alternatively, one of R 11 and R 12 , R 12 and R 13 , or R 14 and R 11 are taken together to form a ring which is selected from the group consisting of -heter
  • R 15 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)OR 42 , -(C 1-4 alky lene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein -(Ci-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
  • R 16 and R 17 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R 5 )2, -(C1-4 alkylene) p OR 42 , -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • R 15 and R 16 or R 16 and R 17 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 40 and - carbocyclyl optionally substituted with 1-12 R 41 ;
  • R 18 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)OR 42 , -(C 1-4 alky lene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
  • R 19 and R 20 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R 5 )2, -(C1-4 alkylene ) p OR 42 , -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • R 18 and R 19 or R 18 and R 20 are taken together to form a heterocyclyl optionally substituted with 1-10 R 40 ;
  • R 21 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)OR 42 , -(C 1-4 alky lene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein -(Ci-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
  • R 22 and R 23 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R 5 )2, -(C1-4 alkylene) p OR 42 , -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • R 22 and R 23 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 40 and -carbocyclyl optionally substituted with 1-12 R 41 ;
  • R 24 , R 25 , and R 26 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R 5 )2, -(C1-4 alkylene ) p OR 42 , -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • R 24 and R 25 or R 25 and R 26 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 40 and - carbocyclyl optionally substituted with 1-12 R 41 ;
  • R 27 , R 28 , and R 29 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R 5 )2, -(C1-4 alkylene ) p OR 42 , -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • R 27 and R 28 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 40 and -carbocyclyl optionally substituted with 1-12 R 41 ;
  • R 30 and R 31 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R 5 )2, -(C1-4 alkylene ) p OR 42 , -(C1-4 alkylene)pheterocyclyl optionally substituted with 1 -10 R 38 , and -carbocyclyl optionally substituted with 1 -12 R 39 ; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • R 30 and R 1 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 40 and -carbocyclyl optionally substituted with 1-12 R 41 ;
  • R 32 and R 33 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R 5 )2, -(C1-4 alkylene ) p OR 42 , -(C1-4 alkylene)pheterocyclyl optionally substituted with 1 -10 R 38 , and -carbocyclyl optionally substituted with 1 -12 R 39 ; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • R 34 and R 35 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R 5 )2, -(C1-4 alkylene ) p OR 42 , -(C1-4 alkylene)pheterocyclyl optionally substituted with 1 -10 R 38 , and -carbocyclyl optionally substituted with 1 -12 R 39 ; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • R 34 and R 35 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1 -10 R 40 and -carbocyclyl optionally substituted with 1-12 R 41 ;
  • each R 38 independently is selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene) p carbocyclyl optionally substituted with 1 -12 R 44 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • each R 39 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene) p carbocyclyl optionally substituted with 1 -12 R 44 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • each R 40 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene) p carbocyclyl optionally substituted with 1 -12 R 44 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • each R 41 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -CN;
  • each R 42 is independently selected from the group consisting of unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and - (Ci-4 alkylene) p carbocyclyl optionally substituted with 1 -12 R 44 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; each R 43 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene) p carbocyclyl optional
  • each R 44 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -CN;
  • R 46 is attached to the nitrogen and is selected from the group consisting of H, unsubstituted -(Ci-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined
  • R 47 is attached to the nitrogen and is selected from the group consisting of unsubstituted - (Ci-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
  • R 48 is attached to the nitrogen and selected from the group consisting of H, unsubstituted - (Ci-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), and unsubstituted -(C1-5 haloalkyl);
  • R 49 is attached to the nitrogen and is selected from the group consisting of -(C1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and— (C1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • R 50 is selected from the group consisting of H, unsubstituted -(C3-5 alkyl), unsubstituted - (C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -(C1-4 alkylene) p aryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), -(C1-4 alkylene) p heteroaryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), and -(Ci-4 alkylene)pheterocyclyl optionally substituted with one or more halides or one or more unsubstituted -(C1-5 alkyl); wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • R 51 is selected from the group consisting of H, unsubstituted -(C1-5 alkyl), unsubstituted - (C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -(C1-4 alkylene) p aryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), -(C1-4 alkylene) p heteroaryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), and -(Ci-4 alkylene)pheterocyclyl optionally substituted with one or more halides or one or more unsubstituted -(C1-5 alkyl); wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
  • R 52 is selected from the group consisting of unsubstituted -(C1-5 alkyl), unsubstituted -(C2- 5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -(C1-4 alkylene) p aryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), and -(Ci-4 alkylene)pheterocyclyl optionally substituted with one or more halides or one or more unsubstituted -(C1-5 alkyl); wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
  • each R 53 is independently selected from the group consisting of H, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), and unsubstituted -(C2-5 alkynyl);
  • each X is O or S
  • each p is independently 0 or 1 ;
  • Formula I is not a structure selected from the group consisting of:
  • 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.
  • DYRKIA 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 DYRKIA 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
  • 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, Mullerian-duct regression and virilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome, Al-Awadi/R
  • 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.
  • Other Wnt inhibitors and methods for using the same are disclosed in U.S. Application Ser. Nos. 13/614,296; 14/019,229; and 14/664,517, all of which are incorporated by reference in their entirety herein.
  • compositions and methods for inhibiting DYRK1A are provided herein.
  • Other DYRK1A inhibitors and methods for using the same are disclosed in U.S. Application Ser. No. 14/664,517, which is incorporated by reference in its entirety 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, Mullerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Sch
  • 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 DYRK1A 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).
  • 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.
  • alkenyl groups can either be unsubstituted or substituted with one or more substituents.
  • 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).
  • 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 ethynylene, 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-0— 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.
  • 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, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3- ⁇ f]pyrimidinyl, pyrrolo[2,3-6]pyridinyl, quinazolinyl,
  • the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.
  • 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 3-1 1 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 azetidiny
  • heterocyclic 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.
  • 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.
  • 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 4-1 1 members with the heteroatom(s) being selected from one to five of O, N or S. Examples of bicyclic heterocyclyls include 2 -azabicyclo[ 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 5-1 1 members with the heteroatom(s) being selected from one to five of O, N or S.
  • spirocyclic heterocyclyls examples 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.
  • 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, -NH2, -NH(Ci-3 alkyl), and -N(Ci-3 alkyl)2; -(C1-9 haloalkyl); a halide; a hydroxyl; a carbonyl [such as -C(0)OR, 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"; -NR
  • the substituent is selected from -(Ci-6 alkyl), -(Ci- ⁇ haloalkyl), a halide (e.g., F), a hydroxyl, -C(0)OR, -C(0)R, -(Ci-e alkoxyl), -NRR', -C(0)NRR', and a cyano, in which each occurrence of R and R' is independently selected from H and -(C1-5 alkyl).
  • a halide e.g., F
  • a hydroxyl -C(0)OR, -C(0)R, -(Ci-e alkoxyl), -NRR', -C(0)NRR', and a cyano, in which each occurrence of R and R' is independently selected from H and -(C1-5 alkyl).
  • 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 H (tritium), carbon, such as n C, 1 C and 14 C, chlorine, such as 6 C1, fluorine, such as 18 F, iodine, such as 12 I and 125 I, nitrogen, such as 1 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 2 P, and sulfur, such as 5 S.
  • isotopes of hydrogen such as 2 H (deuterium) and H (tritium)
  • carbon such as n C, 1 C and 14 C
  • chlorine such as 6 C1
  • fluorine such as 18 F
  • iodine such as 12 I and 125 I
  • nitrogen such as 1 N and 15 N
  • oxygen such as 15 0, 17 0 and 18 0, phosphorus, such as 2 P
  • sulfur such as 5 S.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, gly colic 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, ethane sulfonic 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 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 , R 2 , R 4 , and R 5 are independently selected from the group consisting of H, halide, unsubstituted -(Ci-3 haloalkyl), and unsubstituted -(Ci-3 alkyl); [069] In some embodiments, R 1 , R 2 , R 4 , and R 5 are independently selected from the group consisting of H and halide.
  • R 1 , R 2 , R 4 , and R 5 are independently selected from the group consisting of H and F.
  • R 1 , R 2 , R 4 , and R 5 are all H.
  • R 1 is F
  • R 2 , R 4 , and R 5 are all H.
  • R 2 is F
  • R 1 , R 4 , and R 5 are all H.
  • R 4 is F
  • R 1 , R 2 , and R 5 are all H.
  • R 5 is F, and R 1 , R 2 , and R 4 are all H.
  • R 3 is a 5-membered heteroaryl ring optionally substituted as defined anywhere herein.
  • R 3 is 5-membered heteroaryl ring optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R 45 ;
  • R 3 is selected from the group consisting of: furanyl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R 45 , thiophenyl optionally substituted with 1-4 -3, 1-2, 1) R 45 , pyrrolyl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R 45 , / N- y t ? ⁇ Hff H tf tUf
  • each m is independently 1 to 4 (e.g., 1-3, 1-2, 1).
  • R 3 is selected from the group consisting of:
  • each of R 7 -R 35 is, independently, a substituent as defined anywhere herein or a single bond connecting R 3 to the isoquinoline ring; wherein only one of R 7 -R 10 (when present) is a bond, only one of R n -R 14 (when present) is a bond, only one of R 15 -R 17 (when present) is a bond, only one of R 18 -R 20 (when present) is a bond, only one of R 21 -R 23 (when present) is a bond, only one of R 24 -R 26 (when present) is a bond, only one of R 27 -R 29 (when present) is a bond, only one of R 0 -R 31 (when present) is a bond, only one of R 2 -R 33 (when present) is a bond, and only one of R 4 -R 35 (when present) is a bond; for purposes of clarification, any one of the nitrogen atoms attached to R 7 , R 11 , R 15 , R 18
  • R 6 is selected from the group consisting of -(C1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 36 , -(Ci-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 37 , -(C1-4 alkylene)N(R 46 )(R 47 ), -N(R 48 )(R 49 ), -CF(Ci- 9 alkyl) 2 , -(C1-4 alkylene) p O(C3-9 alkyl), and -(C2-9 alkynyl) optionally substituted with one or more halides; wherein each alkyl of -CF(Ci-9 alkyl) 2 is, independently, optionally substituted with one or more halides; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • R 6 is not unsubstituted - (CH 2 )tetrahydropyranyl .
  • R 7 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(Ci-9 haloalkyl), -(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 38 , and -carbocyclyl optionally substituted with 1-12 (e.g., 1-1 1, 1-10, 1-9, 1 -8, 1 -7, 1-6, 1 -5, 1-4, 1-3, 1-2, 1)
  • R 7 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene) OR 42 , -(C1-4 alkylene ) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1 -12 R 39 ; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.
  • R 8 , R 9 , and R 10 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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 38 , and -carbocyclyl optionally substituted with 1-12 (e.g., 1-1 1, 1-10, 1 -9, 1-8, 1-7, 1-6, 1 -5, 1-4, 1-3, 1-2, 1) R 39 ; wherein each -(C 1 -4 alkylene) is, independently, optionally substituted with one or more substitu
  • R 8 , R 9 , and R 10 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R 5 )2, -(C1-4 alkylene) p OR 42 , -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R 38 , and - carbocyclyl optionally substituted with 1 -12 R 39 ; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • one of R 7 and R 8 , R 8 and R 9 , or R 9 and R 10 are taken together to form a ring which is selected from the group consisting of -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 40 and -carbocyclyl optionally substituted with 1-12 (e.g., 1-1 1, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 41 .
  • R 11 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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 38 , and -carbocyclyl optionally substituted with 1-12 (e.g., 1-1 1, 1 -10, 1-9, 1 -8, 1-7, 1-6, 1 -5, 1-4, 1 -3, 1-2, 1) R 39 ; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.
  • 1-10 e.g., 1-9, 1-8,
  • R 11 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)OR 42 , -(C1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1 -12 R 39 ; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.
  • R 12 , R 13 , and R 14 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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 38 , and -carbocyclyl optionally substituted with 1-12 (e.g., 1-1 1, 1-10, 1 -9, 1-8, 1-7, 1-6, 1 -5, 1-4, 1-3, 1-2, 1) R 39 ; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituent
  • R 12 , R 13 , and R 14 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R 5 )2, -(C1-4 alkylene) p OR 42 , -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R 38 , and - carbocyclyl optionally substituted with 1 -12 R 39 ; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • one of R 11 and R 12 , R 12 and R 13 , or R 14 and R 11 are taken together to form a ring which is selected from the group consisting of -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 40 and -carbocyclyl optionally substituted with 1-12 (e.g., 1-1 1, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 41 .
  • 1-10 e.g., 1-9, 1 -8, 1-7, 1 -6, 1 -5, 1-4, 1-3, 1-2, 1
  • R 40 and -carbocyclyl optionally substituted with 1-12 e.g., 1-1 1, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 41 .
  • R 15 is selected from the group consisting of H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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 38 , and -carbocyclyl optionally substituted with 1-12 (e.g., 1-1 1, 1 -10, 1-9, 1 -8, 1-7, 1-6, 1 -5, 1-4, 1 -3, 1-2, 1) R 39 ; 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
  • R 15 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene) OR 42 , -(C1-4 alkylene ) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1 -12 R 39 ; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.
  • R 16 and R 17 are independently selected from the group consisting of H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted - (C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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) R 38 , and -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 39 ; wherein each -(C 1 -4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • R 16 and R 17 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R 5 )2, -(C1-4 alkylene) p OR 42 , -(Ci- 4 alkylene)pheterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • one of R 15 and R 16 or R 16 and R 17 are taken together to form a ring which is selected from the group consisting of -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 40 and -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 41 .
  • R 18 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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 38 , and -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 39 ; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.
  • R 18 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene) OR 42 , -(C1-4 alkylene ) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.
  • R 19 and R 20 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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 38 , and -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 39 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • R 19 and R 20 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R 5 )2, -(C1-4 alkylene) p OR 42 , -(Ci- 4 alkylene)pheterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein
  • one of R 18 and R 19 or R 18 and R 20 are taken together to form a 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 40 .
  • 1-10 e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1
  • R 40 e.g., 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 40 .
  • R 21 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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 38 , and -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 39 ; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.
  • R 21 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene) OR 42 , -(C1-4 alkylene ) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.
  • R 22 and R 23 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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 38 , and -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 39 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • R 22 and R 23 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R 5 )2, -(C1-4 alkylene) p OR 42 , -(Ci- 4 alkylene)pheterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • R 22 and R 23 are taken together to form a ring which is selected from the group consisting of -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 40 and -carbocyclyl optionally substituted with 1-12 (e.g., 1-1 1, 1- 10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 41 .
  • R 24 , R 25 , and R 26 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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 38 , and -carbocyclyl optionally substituted with 1-12 (e.g., 1-1 1, 1-10, 1 -9, 1-8, 1-7, 1-6, 1 -5, 1-4, 1-3, 1-2, 1) R 39 ; wherein each -(C 1 -4 alkylene) is, independently, optionally substituted with one or more substitu
  • R 24 , R 25 , and R 26 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R 5 )2, -(C1-4 alkylene) p OR 42 , -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R 38 , and - carbocyclyl optionally substituted with 1 -12 R 39 ; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • R 25 is a single bond connecting R 3 to the isoquinoline ring, R 24 and R 26 are not methyls.
  • R 25 is a single bond connecting R 3 to the isoquinoline ring, R 24 and R 26 are not both methyls.
  • R 25 is a single bond connecting R 3 to the isoquinoline ring
  • R 24 and R 26 are not selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-2 alkyl), unsubstituted -(C2 alkenyl), unsubstituted -(C2 alkynyl), unsubstituted -(C1-2 haloalkyl).
  • one of R 24 and R 25 or R 25 and R 26 are taken together to form a ring which is selected from the group consisting of -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 40 and -carbocyclyl optionally substituted with 1-12 (e.g., 1-1 1, 1-10, 1-9, 1-8, 1 -7, 1 -6, 1 -5, 1 -4, 1 -3, 1-2, 1) R 41 .
  • R 27 , R 28 , and R 29 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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) R 38 , and -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 39 ; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined
  • R 27 , R 28 , and R 29 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R 5 )2, -(C1-4 alkylene) p OR 42 , -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R 38 , and - carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • R 27 and R 28 are taken together to form a ring which is selected from the group consisting of-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 40 and -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 41 .
  • R 30 and R 31 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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 38 , and -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 39 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • R 30 and R 31 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R 5 )2, -(C1-4 alkylene) p OR 42 , -(Ci- 4 alkylene)pheterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • R 30 and R 31 are taken together to form a ring which is selected from the group consisting of-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 40 and -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 41 .
  • 1-10 e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1
  • R 40 and -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 41 .
  • R 32 and R 33 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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 38 , and -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 39 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • R 32 and R 33 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R 5 )2, -(C1-4 alkylene) p OR 42 , -(Ci- 4 alkylene)pheterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • R 34 and R 35 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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 38 , and -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 39 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • R 34 and R 35 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R 5 )2, -(C1-4 alkylene) p OR 42 , -(Ci- 4 alkylene)pheterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • R 34 and R 35 are taken together to form a ring which is selected from the group consisting of-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 40 and -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 41 .
  • each R 36 is independently selected from the group consisting of halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene ) p OR 42 , -(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 43 , and -(C1-4 alkylene) p 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 44 ; wherein each -(C 1 -4 alkylene) is, independently, optionally substituted
  • halides e.
  • each R 37 is independently selected from the group consisting of halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene ) p OR 42 , -(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 43 , and -(C1-4 alkylene) p 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 44 ; wherein each -(C 1 -4 alkylene) is, independently, optionally substituted
  • each R 38 is independently selected from the group consisting of halide, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene ) p 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 44 ; wherein each - (Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • each R 39 is independently selected from the group consisting of halide, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene ) p 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 44 ; wherein each - (Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • each R 40 is independently selected from the group consisting of halide, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene ) p 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 44 ; wherein each - (Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • each R 41 is independently selected from the group consisting of halide, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -CN.
  • each R 42 is independently selected from the group consisting of unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -(C1-4 alkylene) p 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 44 ; wherein each -(Ci- 4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • each R 43 is independently selected from the group consisting of halide, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene ) p 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 44 ; wherein each - (Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • each R 44 is independently selected from the group consisting of halide, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -CN.
  • each R 45 is independently selected from the group consisting of H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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 38 , and -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 39 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • each R 45 is independently selected from the group consisting of H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R 5 )2, -(C1-4 alkylene) p OR 42 , -(C1-4 alkylene)pheterocyclyl optionally substituted with 1 -10 R 38 , and -carbocyclyl optionally substituted with 1 -12 R 39 ; wherein each -(C 1 -4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • two adjacent R 45 groups are taken together to form a ring which is selected from the group consisting of -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 40 and -carbocyclyl optionally substituted with 1-12 (e.g., 1-1 1, 1 -10, 1 -9, 1 -8, 1-7, 1-6, 1-5, 1-4, 1-3, 1 -2, 1) R 41 .
  • R 46 is attached to the nitrogen and is selected from the group consisting of H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2- 9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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 38 , and -carbocyclyl optionally substituted with 1-12 (e.g., 1-1 1, 1-10, 1-9, 1-8, 1 -7, 1 -6, 1 -5, 1 -4, 1 -3, 1-2, 1) R 39 ; wherein -(Ci- 4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.
  • 1-10 e.g., 1
  • R 47 is attached to the nitrogen and is selected from the group consisting of unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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 38 , and -carbocyclyl optionally substituted with 1-12 (e.g., 1 -1 1, 1-10, 1-9, 1-8, 1 -7, 1 -6, 1 -5, 1 -4, 1 -3, 1-2, 1) R 39 ; wherein -(Ci- 4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.
  • R 48 is attached to the nitrogen and selected from the group consisting of H, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2- 5 alkynyl), and unsubstituted -(C1-5 haloalkyl).
  • R 49 is attached to the nitrogen and is selected from the group consisting of -(Ci-4 alkylene)pheterocyclyl optionally substituted with 1 -10 R 38 , and— (C1-4 alkylene) p carbocyclyl optionally substituted with 1 -12 R 39 ; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
  • R 50 is selected from the group consisting of H, unsubstituted -(C3-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -(C1-4 alkylene) p aryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), and -(C1-4 alkylene ) p heterocyclyl optionally substituted with one or more halides or one or more unsubstituted -(C1-5 alkyl); wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein
  • R 51 is selected from the group consisting of H, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -(C1-4 alkylene) p aryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), and -(C1-4 alkylene) p heterocyclyl optionally substituted with one or more halides or one or more unsubstituted -(C1-5 alkyl); wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein
  • R 52 is selected from the group consisting of unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -(C1-4 alkylene) p aryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), and -(C1-4 alkylene ) p heterocyclyl optionally substituted with one or more halides or one or more unsubstituted -(C1-5 alkyl); wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.
  • each R 53 is independently selected from the group consisting of H, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), and unsubstituted -(C2-5 alkynyl).
  • Formula I is not a structure ng of:
  • the carbocyclyl of -(C1-4 alkylene) p carbocyclyl is optionally substituted with 1 -12 R 37 .
  • the -(C1-4 alkylene) of -(C1-4 alkylene ) p carbocyclyl is optionally substituted with 1 -12 R 37 .
  • the heterocyclyl of -(C1-4 alkylene ) p heterocyclyl is optionally substituted with 1 -10 R 38 .
  • the -(C 1-4 alkylene) of -(C1-4 alkylene ) p heterocyclyl is optionally substituted with 1 -10 R 38 .
  • the carbocyclyl of -(C1-4 alkylene) p carbocyclyl is optionally substituted with 1 -12 R 44 .
  • the -(C1-4 alkylene) of -(C1-4 alkylene ) p carbocyclyl is optionally substituted with 1 -12 R 44 .
  • the heterocyclyl of -(C1-4 alkylene) p heterocyclyl is optionally substituted with 1-10 R 43 .
  • the -(C1-4 alkylene) of -(C1-4 alkylene) p heterocyclyl is optionally substituted with 1-10 R 43 .
  • -(C1-4 alkylene) is optionally substituted with 1 -5 halide or 1-5 unsubstituted -(Ci- 3 alkyl).
  • -(C1-4 alkylene) is substituted with 1-2 fluorines.
  • -(C1-4 alkylene) is substituted with 1-2 methyls.
  • each X is O or S.
  • each m is independently 1 to 4 (e.g., 1-3, 1-2, 1).
  • each n is independently 0 to 3 (e.g., 0-2, 0-1, 0).
  • each p is independently 0 or 1.
  • each q is independently 0 to 12 (e.g., 0-11, 0-10, 0-9, 0-8, 0-7, 0-6, 0-5, 0-4, 0-3, 0-2, 0-1, 0).
  • R 3 is
  • R 9 is a single bond connecting R 3 to the isoquinoline ring, i.e., R 3 has the following formula:
  • R 3 is and n is 1 to 3.
  • R 7 is selected from the group consisting of H, unsubstituted -(C1-3 alkyl), unsubstituted -(C1-2 haloalkyl), and -(C3-4 carbocyclyl) optionally substituted with 1-2 R 39 .
  • R 7 is selected from the group consisting of H, methyl, -CF3, and cyclopropyl optionally substituted with 1-2 R 39 . [0171] In some embodiments, R 7 is selected from the group consisting of H and methyl.
  • R 7 is methyl
  • R 7 is -CD3.
  • R 8 is selected from the group consisting of H, halide, unsubstituted -(C1-2 alkyl), unsubstituted -(Ci-2 haloalkyl), and -(C1-2 alkylene)OR 42 .
  • R 8 is selected from the group consisting of H, F, methyl, -CF 3 , -(CH 2 )OH, and -(CH 2 )OMe.
  • R 8 is selected from the group consisting of H, F, and methyl.
  • R 8 is H.
  • R 10 is selected from the group consisting of H and halide.
  • R 10 is selected from the group consisting of H and F.
  • R 10 is H.
  • R 3 is
  • R 12 is a single bond connecting R 3 to the isoquinoline ring, i.e., R 3 has the following formula:
  • R 3 is and n is i to 3.
  • R 11 is selected from the group consisting of H, unsubstituted -(C1-3 alkyl), unsubstituted -(C1-2 haloalkyl), and -(C3-4 carbocyclyl) optionally substituted with 1-2 R 39 .
  • R 11 is selected from the group consisting of H, methyl, -CF3, and cyclopropyl optionally substituted with 1 -2 R 39 . [0186] In some embodiments, R 11 is selected from the group consisting of H and methyl.
  • R 11 is methyl
  • R 11 is -CD3.
  • R 13 is selected from the group consisting of H and halide.
  • R 13 is selected from the group consisting of H and F.
  • R 14 is selected from the group consisting of H, halide, unsubstituted -(C 1 - 2 alkyl), and unsubstituted -(Ci- 2 haloalkyl).
  • R 14 is selected from the group consisting of H, F, methyl, and -CF3.
  • R 14 is selected from the group consisting of H and methyl.
  • R 11 and R 14 are both methyl.
  • R 3 is
  • R 3 is
  • R 3 is and X is O.
  • R 27 is a single bond connecting R 3 to the isoquinoline ring, i.e., R 3 has the following formula:
  • R 3 is [0200] In some embodiments, R 3 is
  • R 28 is selected from the group consisting of H and halide.
  • R 28 is selected from the group consisting of H and F.
  • R 29 is selected from the group consisting of H, halide, unsubstituted -(C1-2 alkyl), and unsubstituted -(Ci-2 haloalkyl).
  • R 29 is selected from the group consisting of H, F, methyl, and -CF
  • R 3 is
  • R 3 is and X is S.
  • R 3 is and X is O.
  • R 33 is a single bond connecting R 3 to the isoquinoline e.
  • R 3 has the following formula:
  • R 3 is
  • R 32 is selected from the group consisting of H, halide, unsubstituted -(C1-2 alkyl), unsubstituted -(Ci-2 haloalkyl), and -N(R 5 )2.
  • R 32 is selected from the group consisting of H, F, methyl, -CF 3 , -NHMe, and -NMe 2 .
  • R 32 is selected from the group consisting of H and methyl.
  • R 32 is methyl
  • R 3 is
  • R 20 is a single bond connecting R 3 to the isoquinoline e., R 3 has the following formula: [0217] In some embodiments, R 3 is
  • R 16 is a single bond connecting R 3 to the isoquinoline R 3 has the following formula:
  • R 17 is a single bond connecting R 3 to the isoquinoline .
  • R 3 has the following formula:
  • R 15 is selected from the group consisting of H and unsubstituted -(C1-2 alkyl).
  • R 15 is selected from the group consisting of H and methyl. [0222] In some embodiments, R 15 is methyl.
  • R 15 is -CD3.
  • R is and n is 1 to 3.
  • R 18 is selected from the group consisting of H, unsubstituted -(C1-3 alkyl), unsubstituted -(C1-2 haloalkyl), and -(C3-4 carbocyclyl) optionally substituted with 1-2 R 39 .
  • R 18 is selected from the group consisting of H, methyl, -CF3, and cyclopropyl optionally substituted with 1-2 R 39 .
  • R 18 is selected from the group consisting of H and methyl.
  • R 19 is selected from the group consisting of H, halide, unsubstituted -(C1-2 alkyl), and unsubstituted -(C 1-2 haloalkyl).
  • R 19 is selected from the group consisting of H, F, methyl, and -CF3.
  • R 39 is selected from the group consisting of halide, unsubstituted -(C1-3 alkyl), and unsubstituted -(C 1-2 haloalkyl).
  • R 39 is selected from the group consisting of F, methyl,
  • R 40 is selected from the group consisting of H and unsubstituted -(C1-2 alkyl).
  • R 40 is selected from the group consisting of H and methyl.
  • R 6 is selected from the group consisting of -(C1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 36 , and -(C1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 37 .
  • R 6 is a -heterocyclyl optionally substituted with 1-2
  • R 6 is selected from the group consisting of:
  • R 6 is selected from the group consisting of:
  • R 6 is a -carbocyclyl optionally substituted with 1 -2 R 37
  • R 6 is a -(CH2)carbocyclyl optionally substituted with -2 R 37
  • R 6 is a -(Ci- 4 alkylene)N(R 46 )(R 47 ).
  • R 6 is a -(CH 2 )N(R 46 )(R 47 ).
  • R 6 is a -(CH 2 )NH(Ci- 5 alkyl).
  • R 6 is a -(CH 2 )NH(Ci- 4 alkyl). [0244] In some embodiments, R 6 is a -(CH 2 )NH(Ci- 3 alkyl).
  • R 6 is a -(CH 2 )NHEt.
  • R 6 is a -(CH 2 )NHMe.
  • R 6 is a -(CH 2 )NHcarbocyclyl.
  • R 6 is a -(CH 2 )NH(CH 2 )carbocyclyl .
  • R 6 is a -(CH 2 )N(Ci- 5 alkyl) 2 .
  • R 6 is a -(CH 2 )N(Ci- 4 alkyl) 2 .
  • R 6 is a -(CH 2 )N(Ci- 3 alkyl) 2 .
  • R 6 is a -(CH 2 )N(Ci- 2 alkyl) 2 .
  • R 6 is a -(CH 2 )NMe 2 .
  • R 6 is a -(CH 2 )N(Ci-5 alkyl)carbocyclyl.
  • R 6 is a -(CH 2 )N(Ci- 5 alkyl)(CH 2 )carbocyclyl.
  • R 6 is a -(CH 2 )N(Ci-4 alkyl)carbocyclyl.
  • R 6 is a -(CH 2 )N(Ci- 4 alkyl)(CH 2 )carbocyclyl.
  • R 6 is a -(CH 2 )N(Ci-3 alkyl)carbocyclyl.
  • R 6 is a -(CH 2 )N(Ci- 3 alkyl)(CH 2 )carbocyclyl.
  • R 6 is a -(CH 2 )N(Ci- 2 alkyl)carbocyclyl.
  • R 6 is a -(CH 2 )N(Ci- 2 alkyl)(CH 2 )carbocyclyl.
  • R 6 is a -(CH 2 )N(Me)carbocyclyl .
  • R 6 is a -(CH 2 )NMe(CH 2 )carbocyclyl.
  • R 6 is CF(Ci-9 alkyl) 2 ; wherein each alkyl of alkyl) 2 is, independently, optionally substituted with one or more halides.
  • R 6 is -CF(Ci-9 alkyl) 2 ; wherein each alkyl of -CF(Ci-9 alkyl) 2 is, independently, optionally substituted with one or more fluorines.
  • R 6 is -CF(Ci-7 alkyl) 2
  • R 6 is -CF(Ci-5 alkyl) 2
  • R 6 is -CF(Ci-4 alkyl) 2
  • R 6 is -CF(Ci-3 alkyl) 2
  • R 6 is -CF(Ci- 2 alkyl) 2
  • R 6 is -CFMe 2 .
  • R 6 is -CF(Me)(Et).
  • R 6 is -CFEt 2 .
  • R 6 is -CF(Et)( n Pr).
  • R 6 is -CF n Pr 2 .
  • R 6 is -CF(Me)( n Pr).
  • R 6 is -CF'Pr 2 .
  • R 6 is -CF(Et)OPr).
  • R 6 is -CF(Me)OPr).
  • R 36 is selected from the group consisting of halide, unsubstituted -(C1-5 alkyl), unsubstituted -(C1-5 haloalkyl), -(CFbCtyOR 42 , -heterocyclyl optionally substituted with 1 -2 R 43 , -(CH2)heterocyclyl optionally substituted with 1 -2 R 43 , -(C3-4 carbocyclyl) optionally substituted with 1 -2 R 44 , and -(CH2XC3-4 carbocyclyl) optionally substituted with 1-2 R 44 .
  • R 37 is selected from the group consisting of halide, unsubstituted -(C1-5 alkyl), unsubstituted -(C1-5 haloalkyl), -OR 42 , -heterocyclyl optionally substituted with 1-2 R 43 , and -(Ctyheterocyclyl optionally substituted with 1 -2 R 43 .
  • the heterocyclyl is selected from the group consisting of azetidinyl, oxetanyl, pyrrolidinyl, tetrahydroiuranyl, piperidinyl, piperazinyl, morpholinyl, and tetrahydropyranyl .
  • R 42 is selected from the group consisting of unsubstituted -(C1-3 alkyl), and unsubstituted -(C1-3 haloalkyl).
  • R 42 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, -CF3.
  • R 43 is selected from the group consisting of halide, unsubstituted -(C1-2 alkyl), and unsubstituted -(C 1-2 haloalkyl).
  • R 43 is selected from the group consisting of F, methyl, ethyl, -CF 3 .
  • R 44 is selected from the group consisting of halide, unsubstituted -(C1-2 alkyl), and unsubstituted -(C 1-2 haloalkyl).
  • R 44 is selected from the group consisting of F, methyl, ethyl, -CF 3 .
  • R 36 is selected from the group consisting of F, methyl, ethyl, n-propyl, isopropyl, isobutyl, fert-butyl, neopentyl, -CH2CH2F, -CH2CHF2, -CH2CF3, - -CH 2 C(CH 3 ) 2 F, -CH 2 CH 2 CF 3 , -(CH 2 CH 2 )0(Ci- 3 alkyl),
  • R 37 is selected from the group consisting of F, methyl,
  • R 3 is selected from the group consisting of:
  • R 6 is selected from the roup consisting of:
  • R 3 is selected from the group consisting of:
  • R 6 is selected from the group consisting of -carbocyclyl optionally substituted with 1-2 R 37 and -(CH 2 )carbocyclyl optionally substituted with 1-2 R 37 .
  • 3 is selected from the group consisting of:
  • X is S or O and R 6 is -CF(Ci-9 alkyl)2; wherein the alkyl of -CF(Ci-9 alkyl)2 is optionally substituted with one or more halides.
  • R 3 is selected from the group consisting of:
  • R 6 is selected from the roup consisting of:
  • R 3 is selected from the group consisting of:
  • R 3 is selected from the group consisting of
  • R is selected from the group consisting of:
  • R 6 is selected from the group consisting of -cyclopropyl, - cyclobutyl, -cyclopentyl, -cyclohexyl each independently optionally substituted with 1 -2 R 37 and -(CH2)cyclopropyl, -(CH2)cyclobutyl, -(CH2)cyclopentyl, and -(CH2)cyclohexyl, each independently optionally substituted with 1-2 R 37 .
  • R 3 is selected from the group consisting of:
  • R 6 is selected from the group consisting of:
  • R 3 is selected from the group consisting of:
  • R 3 is selected from the group consisting of
  • R 6 is selected from the group consisting of -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl each optionally substituted with 1 -2 R 37 and -(CH2)cyclopropyl, -(CH2)cyclobutyl, -(CH2)cyclopentyl, and - (CH2)cyclohexyl, each optionally substituted with 1-2 R 37 .
  • R 3 is selected from the group consisting of:
  • alkyl)2 wherein the alkyl of -CF(Ci-5 alkyl)2 is optionally substituted with 1-4 fluorines.
  • R 3 is selected from the group consisting of:
  • R 36 is selected from the group consisting of F, methyl, ethyl, n-propyl, isopropyl, isobutyl, tert- butyl, neopentyl, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CH 3 , -CH 2 C(CH 3 ) 2 F, - -(CH 2 CH 2 )0(Ci-3 alkyl),
  • R 3 is selected from the group consisting of:
  • each R 36 is independently selected from the group consisting of F, methyl, and -CF3.
  • R 3 is selected from the group consisting of:
  • each R 37 is independently selected from the group consisting of F, methyl, -CF3, -OCF3, and -OMe.
  • R 3 is selected from the group consisting of: ,
  • R 36 is selected from the group consisting of F, methyl, ethyl, n-propyl, isopropyl, isobutyl, tert- butyl, neopentyl, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CH 3 , -CH 2 C(CH 3 ) 2 F,
  • R 6 is selected from the group consisting of:
  • R 36 is selected from the group consisting of methyl, ethyl, isopropyl, isobutyl, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CF2CH3, -
  • R 3 is selected from the group consisting of:
  • R 6 is selected from the group consisting of -(C1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 36 and -(C1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 37 .
  • R 3 is selected from the group consisting of: , R 6 is selected from the group consisting of -(Ctyheterocyclyl optionally substituted with 1-2 R 36 -heterocyclyl optionally substituted with 1-2 R 36 , and - carbocyclyl optionally substituted with 1 -2 R 37 , and R 36 is selected from the group consisting of halide and unsubstituted -(C1-9 alkyl), and R 37 is selected from the group consisting of halide and unsubstituted -(C1-9 alkyl), -N(R 5 )2, and -heterocyclyl optionally substituted with 1-2 R 43 . diments, R 3 is selected from the group consisting of:
  • R 6 is selected from the group consisting of -(CH2)heterocyclyl optionally substituted with 1 R 36 -heterocyclyl optionally substituted with 1 R 36 , and -carbocyclyl substituted with 1 R 37 , and R 36 is unsubstituted -(C1-5 alkyl), and R 37 is selected from the group consisting of -N(Ci-3 alkyl)2, and an unsubsituted -heterocyclyl.
  • R 3 is selected from the group consisting of:
  • R 36 is selected from the group consisting of
  • R 3 is selected from the group consisting of:
  • R 6 is selected from the group consisting of:
  • R 36 is selected from the group consisting methyl, ethyl, isopropyl, isobutyl, -CH2CH2F, -CH2CHF2, -CH2C -CH2CF2CH3,
  • R 6 is selected from the group consisting of
  • R 36 is selected from the group consisting of methyl, ethyl, isopropyl, isobutyl, -CH2CH2F, -CH2CH -CH2 -CH2CF2CH3, -
  • R 3 is selected from the group consisting of: ,
  • each R 36 is independently selected from the group consisting of F, methyl, and -
  • R 3 is selected from the group consisting of: ,
  • R 6 is selected from the group consisting of -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl each optionally substituted with 1-2 R 37 and -(Ctycyclopropyl, - (Ctycyclobutyl, -(Ctycyclopentyl, and -(Ctycyclohexyl, each optionally substituted with 1-2 R 37 , and each R 37 is independently selected from the group consisting of F, methyl,-CF3, -OCF3, and -OMe.
  • R 3 is selected from the rou consistin of: , , , and R 6 is -CF(Ci- 3 alkyl) 2 ; wherein the alkyl of -CF(Ci optionally substituted with 1-2 fluorines.
  • 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
  • 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.
  • Hormone therapy such as aromatase inhibitors, LHRH [luteinizing hormone-releasing hormone]
  • 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- ⁇ 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 antiinflammatory 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 antiinflammatory 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 ® ), verteporfin (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 ®
  • verteporfin 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 films by methods such as precipitation, crystallization, milling, grinding, supercritical fluid processing, coacervation, complex coacervation, encapsulation, emulsification, complexation, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may 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 ⁇ -, ⁇ , and ⁇ -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).
  • 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. [0345] 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 1 1 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. [0359] 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.
  • 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.
  • 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.
  • aerosols intended for delivery to the nasal mucosa are provided for inhalation through the nose.
  • inhaled particle sizes of about 5 to about 100 microns are useful, with particle sizes of about 10 to about 60 microns being preferred.
  • 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 ⁇ 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. 1 1/337,815).
  • 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, film-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 (ALS), 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, Mullerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al- Awadi/Raas-Rothschild/Sch
  • 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,
  • 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.
  • 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 filum terminale.
  • DNET dysembryoplastic neuroepithelial tumor
  • DNET dysplastic gangliocytoma of the cerebellum
  • desmoplastic infantile astrocytoma/ganglioglioma central neurocytoma
  • anaplastic ganglioglioma extraventricular neuro
  • 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 primitive 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 infar
  • 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, Mullerian-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, IL-6, IL-1, IFNy) 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, IL-6, IL-1, IFNy
  • 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 DYRKl 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), my
  • 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, Coffin-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 claim 1, 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 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.
  • 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 mycotic or viral infection.
  • 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 (CML), chronic myelomonocytic leukemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia, acute lymphocytic leukemia, Hodgkin lymphoma, lymphoma, sarcoma and ovarian cancer.
  • CML chronic myeloid leukemia
  • CLL 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 (CML).
  • CML chronic myeloid leukemia
  • the cancer is chronic myelomonocytic leukemia.
  • the cancer is chronic lymphocytic leukemia (CLL)
  • the cancer is acute myeloid leukemia.
  • the cancer is acute lymphocytic leukemia.
  • the cancer is Hodgkin lymphoma.
  • the cancer is lymphoma.
  • the cancer is sarcoma.
  • the cancer is ovarian cancer.
  • the cancer is lung cancer - non-small cell.
  • the cancer is lung cancer - small cell.
  • the cancer is multiple myeloma. [0493] In some embodiments, 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 gallbladder cancer.
  • the cancer is eye cancer (melanoma and lymphoma)
  • 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. [0527] In some embodiments, 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 or 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.
  • 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,
  • the disorder or disease is a neurological disease or disorder 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
  • TDP-43 Tar DNA-binding Protein of 43KDa
  • Prion protein PrP fused in sarcoma
  • the disorder or 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.
  • 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 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.
  • 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.
  • CDKs cyclin-dependent kinases
  • the compounds and compositions 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.
  • 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 ⁇ -catenin and promoting growth of stem cells.
  • Assays for biological activity of Wnt include stabilization of ⁇ -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 ⁇ -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 ⁇ -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-SY5Y 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).
  • nuclear magnetic resonance spectra were measured in the indicated solvents on a Bruker NMR spectrometer (Avance TM DRX300, 300 MHz for 3 ⁇ 4 or Avance TM DRX500, 500 MHz for 3 ⁇ 4) or Varian NMR spectrometer (Mercury 400BB, 400 MHz for 3 ⁇ 4). 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.
  • DIPEA N,N-diisopropylethylamine
  • HATU l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
  • LAH Lithium aluminium hydride
  • LC/MS Liquid chromatography-mass spectrometry
  • MgS04 magnesium sulfate
  • MsCl mesyl chloride or methane sulfonyl chloride
  • NaB3 ⁇ 4CN sodium cyanoborohydride
  • Pd(dppf)Cl2 1, r-bis(diphenylphosphino)ferrocene-palladium(II)dichloride
  • Pd(PPli3)4 tetrakis(triphenylphosphine)palladium(0)
  • SPhos Pd G3 [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl-l,r- biphenyl)-2-(2'-amino-l, r -biphenyl)]palladium(II) methanesulfonate methane sulfonate
  • SPhos Pd G4 Methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-tri-i- propyl- 1 , 1 '-biphenyl)(2'-methylamino- 1 , 1 '-biphenyl-2-yl)palladium(II)
  • TBAF Tetra-n-butylammonium fluoride
  • Scheme 1 describes a method for preparation of isoquinoline-3-carboxamide derivatives (IX) by first coupling the amine with a variety of acids (III) to produce amide IV. The bromo derivative IV is then reacted with bis(pinacolato)diboron to give the pinacol ester (V). Suzuki coupling with a variety of 5-membered heteroaryl bromides (VIII) yields the desired R 3 substituted isoquinoline IX. Alternatively, the bromo derivative IV is Suzuki coupled with a variety of 5-membered heteroaryl pinacol esters (VI) or coupled to a variety of 5-membered heteroaryl stannanes (VII) to produce the final R 3 substituted isoquinoline IX. [0571] In some embodiments, compounds of Formula I of the present disclosure can be pre
  • A C, N, O, or S,
  • Scheme 2 describes a method for preparation of isoquinoline-3-carboxamide intermediate (IVa) by first coupling the amine 4-nitrophenyl carbonochloridate followed by coupling with a variety of R 6 NH heterocyclyls. Intermediate IVa could then be used in place of IV in Scheme 1 or 3.
  • N or C wherein N or C may be
  • Scheme 3 describes a method for preparation of isoquinoline-3-carboxamide derivatives (IXa) starting with bromo intermediate IV or IVa and couple with the nitrogen of a variety of R 3 NH heteroaryls to produce the final R 3 substituted isoquinoline IXa.
  • reaction mixture was absorbed on silica and was purified by ISCO using EtOAc/hexanes (0 ⁇ 100%) and then with CHCh/MeOH (0 ⁇ 100% to recover unreacted starting material).
  • the pure fractions were combined, concentrated, the residue suspended in diethylether, sonicated and the solid were collected by filtration and dried under high vacuo to obtain N-(6-bromoisoquinolin-3-yl)-l -(3,3,3- trifluoropropyl)piperidine-4-carboxamide (XXX) as an off-white solid (0.31 g, 0.720 mmol, 31.3% yield).
  • N2 gas was bubbled into the mixture for 10 min and then the mixture was heated to 95°C for 5 h to produce N-(6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)isoquinolin-3-yl)-l-(3,3,3-trifluoropropyl) piperidine-4-carboxamide (XXXI).
  • ESIMS found for C24H31BF3N3O3 mlz 478.1 (M+l). Use for next step without work up or further purification.
  • reaction mixture was absorbed on silica and purified by ISCO using CHC1 3 /7N NH 3 in Me OH (0 ⁇ 5%) followed by preparative TLC to obtain N-(6-(l -methyl- 1H- l,2,3-triazol-4-yl)isoquinolin-3-yl)-l-(3,3,3-trifluoropropyl) piperidine-4-carboxamide (271) as a beige solid (0.01 1 g, 0.025 mmol, 6.44% yield).
  • reaction mixture was filtered through Celite and to the filtrates, water was added and extracted with EtOAc. The organics were separated, washed with brine, dried over anhydrous Na 2 S04, and evaporated under vacuo.
  • the crude products were purified by RP-HPLC.
  • N2 gas was bubbled into the mixture for 10 min and then the solution was heated to 110°C for 30 min in a microwave.
  • the organic layer was carefully separated, absorbed on silica gel and purified by column chromatography (0 ⁇ 50% CHCI3/IO %7N NH 3 Me OH in CHC1 3 ).

Abstract

Isoquinoline compounds for treating various diseases and pathologies are disclosed. More particularly, the present disclosure concerns the use of an isoquinoline compound 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 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

ISOQUINOLIN-3-YL CARBOX AMIDE S AND PREPARATION AND USE
THEREOF
RELATED APPLICATIONS
[001] This application claims the benefit of U.S. Provisional Application No. 62/328,210, filed April 27, 2016, which is incorporated herein by reference in its 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 an isoquinoline 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 β-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 DYRKIA gene. DYRKIA is a member of the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family. DYRKIA 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. DYRKIA 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. DYRKIA is also expressed in adult brain neurons, indicating that DYRKIA may play a role in the mature central nervous system. Thus, several lines of evidence point to some synaptic functions of DYRKIA. For instance, it has been found that DYRKIA 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 DYRKIA 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 an isoquinoline 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 an isoquinoline compound, in a sufficient amount to antagonize DYRKIA 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 DYRKIA inhibitors containing an isoquinoline 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
I
as well as prodrugs and pharmaceutically acceptable salts thereof.
[009] In some embodiments of Formula (I):
R1, R2, R4, and R5 are independently selected from the group consisting of H, halide, unsubstituted -(C1-3 haloalkyl), and unsubstituted -(C1-3 alkyl);
R3 is a 5-membered heteroaryl optionally substituted with 1-4 R45;
R6 is selected from the group consisting of -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R36, -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R37, -(C1-4 alkylene)N(R46)(R47), and -CF(Ci-9 alkyl)2; wherein each alkyl of -CF(Ci-9 alkyl)2 is, independently, optionally substituted with one or more halides; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; each R36 is independently selected from the group consisting of halide, unsubstituted -(Ci- 9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -(Ci-4 alkylene)pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R43, and -(Ci- 4 alkylene)pcarbocyclyl optionally substituted with 1-12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; each R37 is independently selected from the group consisting of halide, unsubstituted -(Ci- 9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -(Ci-4 alkylene)pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R43, and -(Ci-
4 alkylene)pcarbocyclyl optionally substituted with 1-12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; each R38 is independently selected from the group consisting of halide, unsubstituted -(Ci-
5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R39 independently is selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R40 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R41 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -CN;
each R42 is independently selected from the group consisting of unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and - (Ci-4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; each R43 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R44 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -CN;
each R45 is independently selected from the group consisting of H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(Ci-4 alkylene)pheterocyclyl optionally substituted with 1 -10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
alternatively, two adjacent R45 taken together form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1 -10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
R46 is attached to the nitrogen and is selected from the group consisting of H, unsubstituted -(Ci-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene )pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(Ci-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
R47 is attached to the nitrogen and is selected from the group consisting of unsubstituted - (Ci-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein
Figure imgf000006_0001
alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
each p is independently 0 or 1.
[010] In another embodiment of Formula (I) :
R1, R2, R4, and R5 are independently selected from the group consisting of H, halide, unsubstituted -(C1-3 haloalkyl), and unsubstituted -(C1-3 alkyl);
R3 is selected from the roup consisting of:
Figure imgf000006_0002
wherein each of R7-R35 is, independently, a substituent as defined anywhere herein or a single bond connecting R3 to the isoquinoline ring; wherein only one of R7-R10 (when present) is a bond, only one of Rn-R14 (when present) is a bond, only one of R15-R17 (when present) is a bond, only one of R18-R20 (when present) is a bond, only one of R21-R23 (when present) is a bond, only one of R24-R26 (when present) is a bond, only one of R27-R29 (when present) is a bond, only one of R 0-R31 (when present) is a bond, only one of R 2-R33 (when present) is a bond, and only one of R 4-R35 (when present) is a bond; for purposes of clarification, any one of the nitrogen atoms attached to R7, R11, R15, R18, or R21 can serve as the point of attachment of R3 to the isoquinoline ring; likewise, any one of the carbon atoms attached to R8, R9, R10, R12, R13, R14, R16, R17, R19, R20, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, or R35 can serve as the point of attachment of R3 to the isoquinoline ring; so that:
when the nitrogen atom to which R7 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R7 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R8 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R8 is a single bond connecting R3 to the isoquinoline ring; when the carbon atom to which R9 is attached serves as the point of attachment of R to the isoquinoline ring, then R9 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R10 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R10 is a single bond connecting R3 to the isoquinoline ring;
when the nitrogen atom to which R11 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R11 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R12 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R12 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R13 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R13 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R14 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R14 is a single bond connecting R3 to the isoquinoline ring;
when the nitrogen atom to which R15 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R15 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R16 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R16 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R17 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R17 is a single bond connecting R3 to the isoquinoline ring;
when the nitrogen atom to which R18 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R18 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R19 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R19 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R20 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R20 is a single bond connecting R3 to the isoquinoline ring;
when the nitrogen atom to which R21 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R21 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R22 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R22 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R23 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R23 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R24 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R24 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R25 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R25 is a single bond connecting R3 to the isoquinoline ring; when the carbon atom to which R26 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R26 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R27 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R27 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R28 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R28 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R29 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R29 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R30 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R30 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R31 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R31 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R32 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R32 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R33 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R33 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R34 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R34 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R35 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R35 is a single bond connecting R3 to the isoquinoline ring;
R6 is selected from the group consisting of -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R36, -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R37, -(C1-4 alkylene)N(R46)(R47), and -CF(Ci-9 alkyl)2; wherein each alkyl of -CF(Ci-9 alkyl)2 is, independently, optionally substituted with one or more halides; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
R7 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
R8, R9, and R10 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene )pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; alternatively, one of R7 and R8, R8 and R9, or R9 and R10 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
R11 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene )pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
R12, R13, and R14 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene )pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; alternatively, one of R11 and R12, R12 and R13, or R14 and R11 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
R15 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
R16 and R17 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene )pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; alternatively, one of R15 and R16 or R16 and R17 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and - carbocyclyl optionally substituted with 1-12 R41;
R18 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(Ci-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
R19 and R20 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene )pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; alternatively, one of R18 and R19 or R18 and R20 are taken together to form a heterocyclyl optionally substituted with 1-10 R40;
R21 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
R22 and R23 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene )pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; alternatively, R22 and R23 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
R24, R25, and R26 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene )pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; alternatively, one of R24 and R25 or R25 and R26 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and - carbocyclyl optionally substituted with 1-12 R41;
R27, R28, and R29 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene )pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; alternatively, R27 and R28 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
R30 and R31 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene )pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; alternatively, R30 and R 1 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
R32 and R33 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene )pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
R34 and R35 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene )pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; alternatively, R34 and R35 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
each R36 is independently selected from the group consisting of halide, unsubstituted -(Ci- 9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -(Ci-4 alkylene)pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R43, and -(Ci- 4 alkylene)pcarbocyclyl optionally substituted with 1-12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; each R37 is independently selected from the group consisting of halide, unsubstituted -(Ci- 9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -(Ci-4 alkylene)pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R43, and -(Ci- 4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; each R38 independently is selected from the group consisting of halide, unsubstituted -(Ci-
5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R39 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R40 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R41 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -CN;
each R42 is independently selected from the group consisting of unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and - (Ci-4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; each R43 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R44 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -CN;
R46 is attached to the nitrogen and is selected from the group consisting of H, unsubstituted -(Ci-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene )pheterocyclyl optionally substituted with 1 -10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
R47 is attached to the nitrogen and is selected from the group consisting of unsubstituted - (Ci-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene )pheterocyclyl optionally substituted with 1 -10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
each X is O or S; and
each p is independently 0 or 1.
[Oil] In another embodiment of Formula (I) :
R1, R2, R4, and R5 are independently selected from the group consisting of H, halide, unsubstituted -(C1-3 haloalkyl), and unsubstituted -(C1-3 alkyl);
R3 is a 5-membered heteroaryl optionally substituted with 1-4 R45; with the proviso that R3 is not
Figure imgf000013_0001
R6 is selected from the group consisting of -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R36, -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R37, -(C1-4 alkylene)N(R46)(R47), -N(R48)(R49), -CF(Ci-9 alkyl)2, -(C1-4 alkylene)pO(C3-9 alkyl), and alkynyl) optionally substituted with one or more halides; wherein each alkyl of -CF(Ci-9 alkyl)2 is, independently, optionally substituted with one or more halides; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; with the proviso that R6 is not unsubstituted -(Ctytetrahydropyranyl;
each R36 is independently selected from the group consisting of halide, unsubstituted -(Ci- 9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -(Ci-4 alkylene)pOR42, -(C1-4 alkylene )pheterocyclyl optionally substituted with 1 -10 R43, -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R44, -C(=0)(R50), -(C1-4 alkylene) C(=0) OR51, -(C1-4 alkylene)aryl optionally substituted with one or more halides, -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides, and -S02(R52); wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
alternatively, two R36 attached to the same carbon atom can together represent =0 to form a carbonyl group; each R37 is independently selected from the group consisting of halide, unsubstituted -(Ci- 9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(Ci-9 haloalkyl), -(Ci-4 alkylene)pOR42, -N(R53)2, -C(=0)(R50), -C(=0)OR51, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1 -10 R43, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R38 independently is selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R39 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R40 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R41 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -CN;
each R42 is independently selected from the group consisting of H, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -(C 1-4 alky lene)pcarbocyclyl optionally substituted with 1-12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; each R43 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; each R44 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -CN;
each R45 is independently selected from the group consisting of H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(Ci-4 alkylene)pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; alternatively, two adjacent R45 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
R46 is attached to the nitrogen and is selected from the group consisting of H, unsubstituted -(Ci-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene )pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
R47 is attached to the nitrogen and is selected from the group consisting of unsubstituted - (Ci-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene )pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
R48 is attached to the nitrogen and selected from the group consisting of H, unsubstituted - (Ci-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), and unsubstituted -(C1-5 haloalkyl);
R49 is attached to the nitrogen and is selected from the group consisting of -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and— (C1-4 alkylene )pcarbocyclyl optionally substituted with 1-12 R39; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
R50 is selected from the group consisting of H, unsubstituted -(C3-5 alkyl), unsubstituted - (C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -(C1-4 alkylene)paryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), and -(Ci-4 alkylene)pheterocyclyl optionally substituted with one or more halides or one or more unsubstituted -(C1-5 alkyl); wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
R51 is selected from the group consisting of H, unsubstituted -(C1-5 alkyl), unsubstituted - (C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -(C1-4 alkylene)paryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), and -(Ci-4 alkylene)pheterocyclyl optionally substituted with one or more halides or one or more unsubstituted -(C1-5 alkyl); wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
R52 is selected from the group consisting of unsubstituted -(C1-5 alkyl), unsubstituted -(C2- 5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -(C1-4 alkylene)paryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), and -(Ci-4 alkylene)pheterocyclyl optionally substituted with one or more halides or one or more unsubstituted -(C1-5 alkyl); wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
each R53 is independently selected from the group consisting of H, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), and unsubstituted -(C2-5 alkynyl);
each p is independently 0 or 1 ; and
is not a structure selected from the group consisting of:
Figure imgf000016_0001
[012] In another embodiment of Formula (I):
R1, R2, R4, and R5 are independently selected from the group consisting of H, halide, unsubstituted -(C1-3 haloalkyl), and unsubstituted -(C1-3 alkyl);
R3 is selected from the roup consisting of:
Figure imgf000016_0002
wherein each of R7-R35 is, independently, a substituent as defined anywhere herein or a single bond connecting R3 to the isoquinoline ring; wherein only one of R7-R10 (when present) is a bond, only one of Rn-R14 (when present) is a bond, only one of R15-R17 (when present) is a bond, only one of R18-R20 (when present) is a bond, only one of R21-R23 (when present) is a bond, only one of R24-R26 (when present) is a bond, only one of R27-R29 (when present) is a bond, only one of R 0-R31 (when present) is a bond, only one of R 2-R33 (when present) is a bond, and only one of R 4-R35 (when present) is a bond; for purposes of clarification, any one of the nitrogen atoms attached to R7, R11, R15, R18, or R21 can serve as the point of attachment of R3 to the isoquinoline ring; likewise, any one of the carbon atoms attached to R8, R9, R10, R12, R13, R14, R16, R17, R19, R20, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, or R35 can serve as the point of attachment of R3 to the isoquinoline ring; so that:
when the nitrogen atom to which R7 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R7 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R8 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R8 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R9 is attached serves as the point of attachment of R to the isoquinoline ring, then R9 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R10 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R10 is a single bond connecting R3 to the isoquinoline ring;
when the nitrogen atom to which R11 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R11 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R12 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R12 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R13 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R13 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R14 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R14 is a single bond connecting R3 to the isoquinoline ring;
when the nitrogen atom to which R15 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R15 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R16 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R16 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R17 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R17 is a single bond connecting R3 to the isoquinoline ring; when the nitrogen atom to which R18 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R18 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R19 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R19 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R20 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R20 is a single bond connecting R3 to the isoquinoline ring;
when the nitrogen atom to which R21 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R21 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R22 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R22 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R23 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R23 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R24 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R24 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R25 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R25 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R26 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R26 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R27 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R27 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R28 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R28 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R29 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R29 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R30 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R30 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R31 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R31 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R32 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R32 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R33 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R33 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R34 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R34 is a single bond connecting R3 to the isoquinoline ring; when the carbon atom to which R35 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R35 is a single bond connecting R3 to the isoquinoline ring;
R6 is selected from the group consisting of -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R36, -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R37, -(C1-4 alkylene)N(R46)(R47), -N(R48)(R49), -CF(Ci-9 alkyl)2, -(C1-4 alkylene)pO(C3-9 alkyl), and -(C2-9 alkynyl) optionally substituted with one or more halides; wherein each alkyl of -CF(Ci-9 alkyl)2 is, independently, optionally substituted with one or more halides; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; with the proviso that R6 is not unsubstituted -(CH2)tetrahydropyranyl;
R7 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)OR42, -(C 1-4 alky lene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
R8, R9, and R10 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene )pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
alternatively, one of R7 and R8, R8 and R9, or R9 and R10 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
R11 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)OR42, -(C 1-4 alky lene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
R12, R13, and R14 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene )pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; alternatively, one of R11 and R12, R12 and R13, or R14 and R11 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
R15 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)OR42, -(C 1-4 alky lene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(Ci-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
R16 and R17 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene)pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
alternatively, one of R15 and R16 or R16 and R17 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and - carbocyclyl optionally substituted with 1-12 R41;
R18 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)OR42, -(C 1-4 alky lene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
R19 and R20 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene )pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
alternatively, one of R18 and R19 or R18 and R20 are taken together to form a heterocyclyl optionally substituted with 1-10 R40;
R21 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)OR42, -(C 1-4 alky lene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(Ci-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
R22 and R23 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene)pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
alternatively, R22 and R23 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
R24, R25, and R26 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene )pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
with the proviso that when R25 is a single bond connecting R3 to the isoquinoline ring, R24 and R26 are not methyls;
alternatively, one of R24 and R25 or R25 and R26 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and - carbocyclyl optionally substituted with 1-12 R41;
R27, R28, and R29 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene )pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
alternatively, R27 and R28 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
R30 and R31 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene )pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1 -10 R38, and -carbocyclyl optionally substituted with 1 -12 R39; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
alternatively, R30 and R 1 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
R32 and R33 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene )pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1 -10 R38, and -carbocyclyl optionally substituted with 1 -12 R39; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
R34 and R35 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene )pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1 -10 R38, and -carbocyclyl optionally substituted with 1 -12 R39; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
alternatively, R34 and R35 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1 -10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
each R36 is independently selected from the group consisting of halide, unsubstituted -(Ci- 9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -(Ci-4 alkylene)pOR42, -(C1-4 alkylene )pheterocyclyl optionally substituted with 1 -10 R43, -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R44, -C(=0)(R50), -(C1-4 alkylene)C(=0)OR51, -(C1-4 alkylene)aryl optionally substituted with one or more halides, -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides, and -S02(R52); wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
alternatively, two R36 attached to the same carbon atom can together represent =0 to form a carbonyl group;
each R37 is independently selected from the group consisting of halide, unsubstituted -(Ci- 9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -(CM alkylene)pOR42, -N(R5 )2, -C(=0)(R50), -C(=0)OR51, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1 -10 R43, and -(Ci-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R44; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R38 independently is selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R39 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R40 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R41 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -CN;
each R42 is independently selected from the group consisting of unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and - (Ci-4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; each R43 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R44 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -CN; R46 is attached to the nitrogen and is selected from the group consisting of H, unsubstituted -(Ci-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
R47 is attached to the nitrogen and is selected from the group consisting of unsubstituted - (Ci-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
R48 is attached to the nitrogen and selected from the group consisting of H, unsubstituted - (Ci-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), and unsubstituted -(C1-5 haloalkyl);
R49 is attached to the nitrogen and is selected from the group consisting of -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and— (C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R39; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
R50 is selected from the group consisting of H, unsubstituted -(C3-5 alkyl), unsubstituted - (C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -(C1-4 alkylene)paryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), and -(Ci-4 alkylene)pheterocyclyl optionally substituted with one or more halides or one or more unsubstituted -(C1-5 alkyl); wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
R51 is selected from the group consisting of H, unsubstituted -(C1-5 alkyl), unsubstituted - (C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -(C1-4 alkylene)paryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), and -(Ci-4 alkylene)pheterocyclyl optionally substituted with one or more halides or one or more unsubstituted -(C1-5 alkyl); wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
R52 is selected from the group consisting of unsubstituted -(C1-5 alkyl), unsubstituted -(C2- 5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -(C1-4 alkylene)paryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), and -(Ci-4 alkylene)pheterocyclyl optionally substituted with one or more halides or one or more unsubstituted -(C1-5 alkyl); wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
each R53 is independently selected from the group consisting of H, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), and unsubstituted -(C2-5 alkynyl);
each X is O or S; and
each p is independently 0 or 1 ; and
with the proviso that Formula I is not a structure selected from the group consisting of:
Figure imgf000025_0001
[013] 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).
[014] Some embodiments include pro-drugs of a compound of Formula (I).
[015] Some embodiments of the present disclosure include pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier, diluent, or excipient.
[016] 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.
[017] Other embodiments disclosed herein include methods of inhibiting DYRKIA by administering to a patient affected by a disorder or disease in which DYRKIA 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.
[018] 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, Mullerian-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.
[019] Some embodiments of the present disclosure include methods to prepare compounds of Formula (I).
[020] 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
[021] Provided herein are compositions and methods for inhibiting one or more members of the Wnt pathway, including one or more Wnt proteins. Other Wnt inhibitors and methods for using the same are disclosed in U.S. Application Ser. Nos. 13/614,296; 14/019,229; and 14/664,517, all of which are incorporated by reference in their entirety herein.
[022] Provided herein are compositions and methods for inhibiting DYRK1A. Other DYRK1A inhibitors and methods for using the same are disclosed in U.S. Application Ser. No. 14/664,517, which is incorporated by reference in its entirety herein.
[023] 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, Mullerian-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, Norrie disease, and Rett syndrome.
[024] 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.
[025] 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.
[026] 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. [027] 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.
[028] 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 DYRK1A overexpression. The composition includes a pharmaceutically acceptable carrier and a compound as described herein.
Definitions
[029] 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.
[030] 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).
[031] 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).
[032] 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).
[033] 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).
[034] 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).
[035] 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 ethynylene, 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).
[036] As used herein, "alkoxy" means an alkyl-0— 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.
[037] 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.
[038] 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.
[039] 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.
[040] 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.
[041] 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, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-<f]pyrimidinyl, pyrrolo[2,3-6]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-6]pyridinyl, pyrazolo[3,4- c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-6]pyridinyl, tetrazolyl, chromane, 2,3- dihydrobenzo[6] [l,4]dioxine, benzo[<f] [ l,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[6] [l,4]oxathiine, isoindoline, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.
[042] 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.
[043] 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.
[044] 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 3-1 1 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.
[045] 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.
[046] 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 4-1 1 members with the heteroatom(s) being selected from one to five of O, N or S. Examples of bicyclic heterocyclyls include 2 -azabicyclo[ 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.
[047] 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 5-1 1 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.
[048] 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, -NH2, -NH(Ci-3 alkyl), and -N(Ci-3 alkyl)2; -(C1-9 haloalkyl); a halide; a hydroxyl; a carbonyl [such as -C(0)OR, 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; -OS02(OR); a sulfonate [such as -S02(OH) and -S02(OR)]; -S02NR'R"; and -SO2R; 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), -(C1-5 haloalkyl), ahalide (e.g., F), a hydroxyl, -C(0)OR, -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-β haloalkyl), a halide (e.g., F), a hydroxyl, -C(0)OR, -C(0)R, -(Ci-e alkoxyl), -NRR', -C(0)NRR', and a cyano, in which each occurrence of R and R' is independently selected from H and -(C1-5 alkyl).
[049] 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. [050] 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.
[051] 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.
[052] 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 H (tritium), carbon, such as nC, 1 C and 14C, chlorine, such as 6C1, fluorine, such as 18F, iodine, such as 12 I and 125I, nitrogen, such as 1 N and 15N, oxygen, such as 150, 170 and 180, phosphorus, such as 2P, and sulfur, such as 5S.
[053] 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, intracisternally, 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.
[054] 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.
[055] 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.
[056] The term "pharmaceutically acceptable carrier", "pharmaceutically acceptable diluent" or "pharmaceutically acceptable excipient" includes any and all solvents, co-solvents, complexing agents, dispersion media, coatings, isotonic and absorption delaying agents and the like which are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. In addition, various adjuvants such as are commonly used in the art may be included. These and other such compounds are described in the literature, e.g., in the Merck Index, Merck & Company, Rahway, NJ. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g. , in Gilman et al. (Eds.) (2010); Goodman and Gilman's: The Pharmacological Basis of Therapeutics. 12th Ed.. The McGraw-Hill Companies.
[057] 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, gly colic 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, ethane sulfonic 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.
[058] "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.
[059] 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.
[060] A therapeutic effect relieves, to some extent, one or more of the symptoms of the disease.
[061] "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.
[062] "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. [063] "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.
[064] "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
[065] 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.
[066] 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.
[067] Some embodiments of the present disclosure include compounds of Formula
I:
Figure imgf000036_0001
I
or salts, pharmaceutically acceptable salts, or prodrugs thereof.
[068] In some embodiments, R1, R2, R4, and R5 are independently selected from the group consisting of H, halide, unsubstituted -(Ci-3 haloalkyl), and unsubstituted -(Ci-3 alkyl); [069] In some embodiments, R1, R2, R4, and R5 are independently selected from the group consisting of H and halide.
[070] In some embodiments, R1, R2, R4, and R5 are independently selected from the group consisting of H and F.
[071] In some embodiments, R1, R2, R4, and R5 are all H.
[072] In some embodiments, R1 is F, and R2, R4, and R5 are all H.
[073] In some embodiments, R2 is F, and R1, R4, and R5 are all H.
[074] In some embodiments, R4 is F, and R1, R2, and R5 are all H.
[075] In some embodiments, R5 is F, and R1, R2, and R4 are all H.
[076] In some embodiments, R3 is a 5-membered heteroaryl ring optionally substituted as defined anywhere herein.
[077] In some embodiments, R3 is 5-membered heteroaryl ring optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R45;
N-0
[078] In some embodiments, there is the proviso that R3 is not ·~1~·
[079] In some embodiments, R3 is selected from the group consisting of: furanyl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R45, thiophenyl optionally substituted with 1-4 -3, 1-2, 1) R45, pyrrolyl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R45,
Figure imgf000037_0001
/ N- y t ? ~ Hff H tf tUf
Figure imgf000037_0002
wherein each m is independently 1 to 4 (e.g., 1-3, 1-2, 1).
[080] In some embodiments, R3 is selected from the group consisting of:
Figure imgf000038_0001
wherein each of R7-R35 is, independently, a substituent as defined anywhere herein or a single bond connecting R3 to the isoquinoline ring; wherein only one of R7-R10 (when present) is a bond, only one of Rn-R14 (when present) is a bond, only one of R15-R17 (when present) is a bond, only one of R18-R20 (when present) is a bond, only one of R21-R23 (when present) is a bond, only one of R24-R26 (when present) is a bond, only one of R27-R29 (when present) is a bond, only one of R 0-R31 (when present) is a bond, only one of R 2-R33 (when present) is a bond, and only one of R 4-R35 (when present) is a bond; for purposes of clarification, any one of the nitrogen atoms attached to R7, R11, R15, R18, or R21 can serve as the point of attachment of R3 to the isoquinoline ring; likewise, any one of the carbon atoms attached to R8, R9, R10, R12, R13, R14, R16, R17, R19, R20, R22, R23, R24, R25, 26, R27, R28, R29, R30, R31, R32, R33, R34, or R35 can serve as the point of attachment of R3 to the
Figure imgf000038_0002
In some embodiments, R6 is selected from the group consisting of -(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) R36, -(Ci-4 alkylene)pcarbocyclyl 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) R37, -(Ci-4 alkylene)N(R46)(R47), and -CF(Ci-9 alkyl)2; wherein each alkyl of -CF(Ci-9 alkyl)2 is, independently, optionally substituted with one or more halides; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[082] In some embodiments, R6 is selected from the group consisting of -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R36, -(Ci-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R37, -(C1-4 alkylene)N(R46)(R47), -N(R48)(R49), -CF(Ci-9 alkyl)2, -(C1-4 alkylene)pO(C3-9 alkyl), and -(C2-9 alkynyl) optionally substituted with one or more halides; wherein each alkyl of -CF(Ci-9 alkyl)2 is, independently, optionally substituted with one or more halides; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[083] In some embodiments, there is the proviso that R6 is not unsubstituted - (CH2)tetrahydropyranyl . [084] In some embodiments, R7 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(Ci-9 haloalkyl), -(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) R38, and -carbocyclyl optionally substituted with 1-12 (e.g., 1-1 1, 1-10, 1-9, 1 -8, 1 -7, 1-6, 1 -5, 1-4, 1-3, 1-2, 1) R39; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[085] In some embodiments, R7 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene) OR42, -(C1-4 alkylene )pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1 -12 R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.
[086] In some embodiments, R8, R9, and R10 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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) R38, and -carbocyclyl optionally substituted with 1-12 (e.g., 1-1 1, 1-10, 1 -9, 1-8, 1-7, 1-6, 1 -5, 1-4, 1-3, 1-2, 1) R39; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[087] In some embodiments, R8, R9, and R10 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene)pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and - carbocyclyl optionally substituted with 1 -12 R39; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[088] In some embodiments, one of R7 and R8, R8 and R9, or R9 and R10 are taken together to form a ring which is selected from the group consisting of -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) R40 and -carbocyclyl optionally substituted with 1-12 (e.g., 1-1 1, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R41.
[089] In some embodiments, R11 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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) R38, and -carbocyclyl optionally substituted with 1-12 (e.g., 1-1 1, 1 -10, 1-9, 1 -8, 1-7, 1-6, 1 -5, 1-4, 1 -3, 1-2, 1) R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein. [090] In some embodiments, R11 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)OR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1 -12 R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.
[091] In some embodiments, R12, R13, and R14 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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) R38, and -carbocyclyl optionally substituted with 1-12 (e.g., 1-1 1, 1-10, 1 -9, 1-8, 1-7, 1-6, 1 -5, 1-4, 1-3, 1-2, 1) R39; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[092] In some embodiments, R12, R13, and R14 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene)pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and - carbocyclyl optionally substituted with 1 -12 R39; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[093] In some embodiments, one of R11 and R12, R12 and R13, or R14 and R11 are taken together to form a ring which is selected from the group consisting of -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) R40 and -carbocyclyl optionally substituted with 1-12 (e.g., 1-1 1, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R41.
[094] In some embodiments, R15 is selected from the group consisting of H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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) R38, and -carbocyclyl optionally substituted with 1-12 (e.g., 1-1 1, 1 -10, 1-9, 1 -8, 1-7, 1-6, 1 -5, 1-4, 1 -3, 1-2, 1) R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.
[095] In some embodiments, R15 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene) OR42, -(C1-4 alkylene )pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1 -12 R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein. [096] In some embodiments, R16 and R17 are independently selected from the group consisting of H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted - (C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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) R38, and -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) R39; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[097] In some embodiments, R16 and R17 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene)pOR42, -(Ci- 4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[098] In some embodiments, one of R15 and R16 or R16 and R17 are taken together to form a ring which is selected from the group consisting of -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) R40 and -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) R41.
[099] In some embodiments, R18 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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) R38, and -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) R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.
[0100] In some embodiments, R18 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene) OR42, -(C1-4 alkylene )pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.
[0101] In some embodiments, R19 and R20 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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) R38, and -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) R39; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0102] In some embodiments, R19 and R20 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene)pOR42, -(Ci- 4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein
[0103] In some embodiments, one of R18 and R19 or R18 and R20 are taken together to form a 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) R40.
[0104] In some embodiments, R21 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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) R38, and -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) R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.
[0105] In some embodiments, R21 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene) OR42, -(C1-4 alkylene )pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.
[0106] In some embodiments, R22 and R23 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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) R38, and -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) R39; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0107] In some embodiments, R22 and R23 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene)pOR42, -(Ci- 4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0108] In some embodiments, R22 and R23 are taken together to form a ring which is selected from the group consisting of -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) R40 and -carbocyclyl optionally substituted with 1-12 (e.g., 1-1 1, 1- 10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R41.
[0109] In some embodiments, R24, R25, and R26 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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) R38, and -carbocyclyl optionally substituted with 1-12 (e.g., 1-1 1, 1-10, 1 -9, 1-8, 1-7, 1-6, 1 -5, 1-4, 1-3, 1-2, 1) R39; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0110] In some embodiments, R24, R25, and R26 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene)pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and - carbocyclyl optionally substituted with 1 -12 R39; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0111] In some embodiments, there is the proviso that when R25 is a single bond connecting R3 to the isoquinoline ring, R24 and R26 are not methyls.
[0112] In some embodiments, there is the proviso that when R25 is a single bond connecting R3 to the isoquinoline ring, R24 and R26 are not both methyls.
[0113] In some embodiments, there is the proviso that when R25 is a single bond connecting R3 to the isoquinoline ring, R24 and R26 are not selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-2 alkyl), unsubstituted -(C2 alkenyl), unsubstituted -(C2 alkynyl), unsubstituted -(C1-2 haloalkyl).
[0114] In some embodiments, one of R24 and R25 or R25 and R26 are taken together to form a ring which is selected from the group consisting of -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) R40 and -carbocyclyl optionally substituted with 1-12 (e.g., 1-1 1, 1-10, 1-9, 1-8, 1 -7, 1 -6, 1 -5, 1 -4, 1 -3, 1-2, 1) R41.
[0115] In some embodiments, R27, R28, and R29 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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) R38, and -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) R39; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0116] In some embodiments, R27, R28, and R29 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene)pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and - carbocyclyl optionally substituted with 1-12 R39; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0117] In some embodiments, R27 and R28 are taken together to form a ring which is selected from the group consisting of-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) R40 and -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) R41.
[0118] In some embodiments, R30 and R31 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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) R38, and -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) R39; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0119] In some embodiments, R30 and R31 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene)pOR42, -(Ci- 4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0120] In some embodiments, R30 and R31 are taken together to form a ring which is selected from the group consisting of-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) R40 and -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) R41.
[0121] In some embodiments, R32 and R33 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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) R38, and -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) R39; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0122] In some embodiments, R32 and R33 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene)pOR42, -(Ci- 4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0123] In some embodiments, R34 and R35 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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) R38, and -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) R39; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0124] In some embodiments, R34 and R35 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene)pOR42, -(Ci- 4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0125] In some embodiments, R34 and R35 are taken together to form a ring which is selected from the group consisting of-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) R40 and -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) R41.
[0126] In some embodiments, each R36 is independently selected from the group consisting of halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene )pOR42, -(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) R43, and -(C1-4 alkylene)pcarbocyclyl 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) R44; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein. [0127] In some embodiments, each R36 is independently selected from the group consisting of halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R43, -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R44, -C(=0)(R50), -(Ci-4 alkylene)C(=0)OR51, -(C1-4 alkylene)aryl optionally substituted with one or more halides, -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides (e.g. F, CI, Br, I), and -S02(R52); wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0128] In some embodiments, two R36 that are attached to the same carbon atom can together represent =0 to form a carbonyl group.
[0129] In some embodiments, each R37 is independently selected from the group consisting of halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene )pOR42, -(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) R43, and -(C1-4 alkylene)pcarbocyclyl 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) R44; wherein each -(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0130] In some embodiments, each R37 is independently selected from the group consisting of halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)pOR42, -N(R5 )2, -C(=0)(R50), - C(=0)OR51, -(Ci-4 alkylene)pheterocyclyl optionally substituted with 1-10 R43, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0131] In some embodiments, each R38 is independently selected from the group consisting of halide, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene )pcarbocyclyl 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) R44; wherein each - (Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0132] In some embodiments, each R39 is independently selected from the group consisting of halide, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene )pcarbocyclyl 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) R44; wherein each - (Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0133] In some embodiments, each R40 is independently selected from the group consisting of halide, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene )pcarbocyclyl 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) R44; wherein each - (Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0134] In some embodiments, each R41 is independently selected from the group consisting of halide, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -CN.
[0135] In some embodiments, each R42 is independently selected from the group consisting of unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -(C1-4 alkylene)pcarbocyclyl 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) R44; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0136] In some embodiments, each R43 is independently selected from the group consisting of halide, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene )pcarbocyclyl 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) R44; wherein each - (Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0137] In some embodiments, each R44 is independently selected from the group consisting of halide, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -CN.
[0138] In some embodiments, each R45 is independently selected from the group consisting of H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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) R38, and -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) R39; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0139] In some embodiments, each R45 is independently selected from the group consisting of H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene)pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1 -10 R38, and -carbocyclyl optionally substituted with 1 -12 R39; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0140] In some embodiments, two adjacent R45 groups are taken together to form a ring which is selected from the group consisting of -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) R40 and -carbocyclyl optionally substituted with 1-12 (e.g., 1-1 1, 1 -10, 1 -9, 1 -8, 1-7, 1-6, 1-5, 1-4, 1-3, 1 -2, 1) R41.
[0141] In some embodiments, R46 is attached to the nitrogen and is selected from the group consisting of H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2- 9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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) R38, and -carbocyclyl optionally substituted with 1-12 (e.g., 1-1 1, 1-10, 1-9, 1-8, 1 -7, 1 -6, 1 -5, 1 -4, 1 -3, 1-2, 1) R39; wherein -(Ci-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.
[0142] In some embodiments, R47 is attached to the nitrogen and is selected from the group consisting of unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(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) R38, and -carbocyclyl optionally substituted with 1-12 (e.g., 1 -1 1, 1-10, 1-9, 1-8, 1 -7, 1 -6, 1 -5, 1 -4, 1 -3, 1-2, 1) R39; wherein -(Ci-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.
[0143] In some embodiments, R48 is attached to the nitrogen and selected from the group consisting of H, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2- 5 alkynyl), and unsubstituted -(C1-5 haloalkyl).
[0144] In some embodiments, R49 is attached to the nitrogen and is selected from the group consisting of -(Ci-4 alkylene)pheterocyclyl optionally substituted with 1 -10 R38, and— (C1-4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R39; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0145] In some embodiments, R50 is selected from the group consisting of H, unsubstituted -(C3-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -(C1-4 alkylene)paryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), and -(C1-4 alkylene )pheterocyclyl optionally substituted with one or more halides or one or more unsubstituted -(C1-5 alkyl); wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein. [0146] In some embodiments, R51 is selected from the group consisting of H, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -(C1-4 alkylene)paryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), and -(C1-4 alkylene)pheterocyclyl optionally substituted with one or more halides or one or more unsubstituted -(C1-5 alkyl); wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.
[0147] In some embodiments, R52 is selected from the group consisting of unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -(C1-4 alkylene)paryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), and -(C1-4 alkylene )pheterocyclyl optionally substituted with one or more halides or one or more unsubstituted -(C1-5 alkyl); wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.
[0148] In some embodiments, each R53 is independently selected from the group consisting of H, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), and unsubstituted -(C2-5 alkynyl).
[0149] In some embodiments, there is the proviso that Formula I is not a structure ng of:
Figure imgf000049_0001
[0150] In some embodiments, the carbocyclyl of -(C1-4 alkylene)pcarbocyclyl is optionally substituted with 1 -12 R37.
[0151] In some embodiments, the -(C1-4 alkylene) of -(C1-4 alkylene )pcarbocyclyl is optionally substituted with 1 -12 R37.
[0152] In some embodiments, the heterocyclyl of -(C1-4 alkylene )pheterocyclyl is optionally substituted with 1 -10 R38.
[0153] In some embodiments, the -(C 1-4 alkylene) of -(C1-4 alkylene )pheterocyclyl is optionally substituted with 1 -10 R38.
[0154] In some embodiments, the carbocyclyl of -(C1-4 alkylene)pcarbocyclyl is optionally substituted with 1 -12 R44.
[0155] In some embodiments, the -(C1-4 alkylene) of -(C1-4 alkylene )pcarbocyclyl is optionally substituted with 1 -12 R44. [0156] In some embodiments, the heterocyclyl of -(C1-4 alkylene)pheterocyclyl is optionally substituted with 1-10 R43.
[0157] In some embodiments, the -(C1-4 alkylene) of -(C1-4 alkylene)pheterocyclyl is optionally substituted with 1-10 R43.
[0158] In some embodiments, -(C1-4 alkylene) is optionally substituted with 1 -5 halide or 1-5 unsubstituted -(Ci-3 alkyl).
[0159] In some embodiments, -(C1-4 alkylene) is substituted with 1-2 fluorines.
[0160] In some embodiments, -(C1-4 alkylene) is substituted with 1-2 methyls.
[0161] In some embodiments, each X is O or S.
[0162] In some embodiments, each m is independently 1 to 4 (e.g., 1-3, 1-2, 1).
[0163] In some embodiments, each n is independently 0 to 3 (e.g., 0-2, 0-1, 0).
[0164] In some embodiments, each p is independently 0 or 1.
[0165] In some embodiments, each q is independently 0 to 12 (e.g., 0-11, 0-10, 0-9, 0-8, 0-7, 0-6, 0-5, 0-4, 0-3, 0-2, 0-1, 0).
[0166] In some embodiments, R3 is
Figure imgf000050_0001
[0167] In certain embodiments, R9 is a single bond connecting R3 to the isoquinoline ring, i.e., R3 has the following formula:
Figure imgf000050_0002
[0168] In some embodiments, R3 is and n is 1 to 3.
[0169] In some embodiments, R7 is selected from the group consisting of H, unsubstituted -(C1-3 alkyl), unsubstituted -(C1-2 haloalkyl), and -(C3-4 carbocyclyl) optionally substituted with 1-2 R39.
[0170] In some embodiments, R7 is selected from the group consisting of H, methyl, -CF3, and cyclopropyl optionally substituted with 1-2 R39. [0171] In some embodiments, R7 is selected from the group consisting of H and methyl.
[0172] In some embodiments, R7 is methyl.
[0173] In some embodiments, R7 is -CD3.
[0174] In some embodiments, R8 is selected from the group consisting of H, halide, unsubstituted -(C1-2 alkyl), unsubstituted -(Ci-2 haloalkyl), and -(C1-2 alkylene)OR42.
[0175] In some embodiments, R8 is selected from the group consisting of H, F, methyl, -CF3, -(CH2)OH, and -(CH2)OMe.
[0176] In some embodiments, R8 is selected from the group consisting of H, F, and methyl.
[0177] In some embodiments, R8 is H.
[0178] In some embodiments, R10 is selected from the group consisting of H and halide.
[0179] In some embodiments, R10 is selected from the group consisting of H and F.
[0180] In some embodiments, R10 is H.
[0181] In some embodiments, R3 is
Figure imgf000051_0001
[0182] In certain embodiments, R12 is a single bond connecting R3 to the isoquinoline ring, i.e., R3 has the following formula:
Figure imgf000051_0002
[0183] In some embodiments, R3 is and n is i to 3.
[0184] In some embodiments, R11 is selected from the group consisting of H, unsubstituted -(C1-3 alkyl), unsubstituted -(C1-2 haloalkyl), and -(C3-4 carbocyclyl) optionally substituted with 1-2 R39.
[0185] In some embodiments, R11 is selected from the group consisting of H, methyl, -CF3, and cyclopropyl optionally substituted with 1 -2 R39. [0186] In some embodiments, R11 is selected from the group consisting of H and methyl.
[0187] In some embodiments, R11 is methyl.
[0188] In some embodiments, R11 is -CD3.
[0189] In some embodiments, R13 is selected from the group consisting of H and halide.
[0190] In some embodiments, R13 is selected from the group consisting of H and F.
[0191] In some embodiments, R14 is selected from the group consisting of H, halide, unsubstituted -(C1-2 alkyl), and unsubstituted -(Ci-2 haloalkyl).
[0192] In some embodiments, R14 is selected from the group consisting of H, F, methyl, and -CF3.
[0193] In some embodiments, R14 is selected from the group consisting of H and methyl.
[0194] In some embodiments, R11 and R14 are both methyl.
[0195] In some embodiments, R3 is
[0196] In some embodiments, R3 is
[0197] In some embodiments, R3 is
Figure imgf000052_0001
and X is O.
[0198] In certain embodiments, R27 is a single bond connecting R3 to the isoquinoline ring, i.e., R3 has the following formula:
Figure imgf000052_0002
[0199] In some embodiments, R3 is [0200] In some embodiments, R3 is
Figure imgf000053_0001
[0201] In some embodiments, R28 is selected from the group consisting of H and halide.
[0202] In some embodiments, R28 is selected from the group consisting of H and F.
[0203] In some embodiments, R29 is selected from the group consisting of H, halide, unsubstituted -(C1-2 alkyl), and unsubstituted -(Ci-2 haloalkyl).
[0204] In some embodiments, R29 is selected from the group consisting of H, F, methyl, and -CF
[0205] In some embodiments, R3 is
[0206] In some embodiments, R3 is and X is S.
[0207] In some embodiments, R3 is
Figure imgf000053_0002
and X is O.
[0208] In certain embodiments, R33 is a single bond connecting R3 to the isoquinoline e. R3 has the following formula:
Figure imgf000053_0003
[0209] In some embodiments, R ? 3 ie
[0210] In some embodiments, R3 is
Figure imgf000053_0004
[0211] In some embodiments, R32 is selected from the group consisting of H, halide, unsubstituted -(C1-2 alkyl), unsubstituted -(Ci-2 haloalkyl), and -N(R5 )2. [0212] In some embodiments, R32 is selected from the group consisting of H, F, methyl, -CF3, -NHMe, and -NMe2.
[0213] In some embodiments, R32 is selected from the group consisting of H and methyl.
[0214] In some embodiments, R32 is methyl.
[0215] In some embodiments, R3 is
Figure imgf000054_0001
[0216] In certain embodiments, R20 is a single bond connecting R3 to the isoquinoline e., R3 has the following formula:
Figure imgf000054_0002
[0217] In some embodiments, R3 is
[0218] In certain embodiments, R16 is a single bond connecting R3 to the isoquinoline R3 has the following formula:
Figure imgf000054_0003
[0219] In certain embodiments, R17 is a single bond connecting R3 to the isoquinoline ., R3 has the following formula:
Figure imgf000054_0004
[0220] In some embodiments, R15 is selected from the group consisting of H and unsubstituted -(C1-2 alkyl).
[0221] In some embodiments, R15 is selected from the group consisting of H and methyl. [0222] In some embodiments, R15 is methyl.
[0223] In some embodiments, R15 is -CD3.
[0224] In some embodiments, R is
Figure imgf000055_0001
and n is 1 to 3.
[0225] In some embodiments, R18 is selected from the group consisting of H, unsubstituted -(C1-3 alkyl), unsubstituted -(C1-2 haloalkyl), and -(C3-4 carbocyclyl) optionally substituted with 1-2 R39.
[0226] In some embodiments, R18 is selected from the group consisting of H, methyl, -CF3, and cyclopropyl optionally substituted with 1-2 R39.
[0227] In some embodiments, R18 is selected from the group consisting of H and methyl.
[0228] In some embodiments, R19 is selected from the group consisting of H, halide, unsubstituted -(C1-2 alkyl), and unsubstituted -(C 1-2 haloalkyl).
[0229] In some embodiments, R19 is selected from the group consisting of H, F, methyl, and -CF3.
[0230] In some embodiments, R39 is selected from the group consisting of halide, unsubstituted -(C1-3 alkyl), and unsubstituted -(C 1-2 haloalkyl).
[0231] In some embodiments, R39 is selected from the group consisting of F, methyl,
[0232] In some embodiments, R40 is selected from the group consisting of H and unsubstituted -(C1-2 alkyl).
[0233] In some embodiments, R40 is selected from the group consisting of H and methyl.
[0234] In some embodiments, R6 is selected from the group consisting of -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R36, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R37.
[0235] In some embodiments, R6 is a -heterocyclyl optionally substituted with 1-2
R36.
[0236] In some embodiments, R6 is selected from the group consisting of:
Figure imgf000056_0001
[0237] In some embodiments, R6 is selected from the group consisting of:
Figure imgf000056_0002
[0238] In some embodiments, R6 is a -carbocyclyl optionally substituted with 1 -2 R 37
[0239] In some embodiments, R6 is a -(CH2)carbocyclyl optionally substituted with -2 R 37
[0240] In some embodiments, R6 is a -(Ci-4 alkylene)N(R46)(R47).
[0241] In some embodiments, R6 is a -(CH2)N(R46)(R47).
[0242] In some embodiments, R6 is a -(CH2)NH(Ci-5 alkyl).
[0243] In some embodiments, R6 is a -(CH2)NH(Ci-4 alkyl). [0244] In some embodiments, R6 is a -(CH2)NH(Ci-3 alkyl).
[0245] In some embodimenAts, R6 is a -(CH2)NHEt.
[0246] In some embodiments, R6 is a -(CH2)NHMe.
[0247] In some embodiments, R6 is a -(CH2)NHcarbocyclyl.
[0248] In some embodiments, R6 is a -(CH2)NH(CH2)carbocyclyl .
[0249] In some embodiments, R6 is a -(CH2)N(Ci-5 alkyl)2.
[0250] In some embodiments, R6 is a -(CH2)N(Ci-4 alkyl)2.
[0251] In some embodiments, R6 is a -(CH2)N(Ci-3 alkyl)2.
[0252] In some embodiments, R6 is a -(CH2)N(Ci-2 alkyl)2.
[0253] In some embodiments, R6 is a -(CH2)NMe2.
[0254] In some embodiments, R6 is a -(CH2)N(Ci-5 alkyl)carbocyclyl.
[0255] In some embodiments, R6 is a -(CH2)N(Ci-5 alkyl)(CH2)carbocyclyl.
[0256] In some embodiments, R6 is a -(CH2)N(Ci-4 alkyl)carbocyclyl.
[0257] In some embodiments, R6 is a -(CH2)N(Ci-4 alkyl)(CH2)carbocyclyl.
[0258] In some embodiments, R6 is a -(CH2)N(Ci-3 alkyl)carbocyclyl.
[0259] In some embodiments, R6 is a -(CH2)N(Ci-3 alkyl)(CH2)carbocyclyl.
[0260] In some embodiments, R6 is a -(CH2)N(Ci-2 alkyl)carbocyclyl.
[0261] In some embodiments, R6 is a -(CH2)N(Ci-2 alkyl)(CH2)carbocyclyl.
[0262] In some embodiments, R6 is a -(CH2)N(Me)carbocyclyl .
[0263] In some embodiments, R6 is a -(CH2)NMe(CH2)carbocyclyl.
[0264] In some embodiments, R6 is CF(Ci-9 alkyl)2; wherein each alkyl of alkyl)2 is, independently, optionally substituted with one or more halides.
[0265] In some embodiments, R6 is -CF(Ci-9 alkyl)2; wherein each alkyl of -CF(Ci-9 alkyl)2 is, independently, optionally substituted with one or more fluorines.
[0266] In some embodiments, R6 is -CF(Ci-7 alkyl)2
[0267] In some embodiments, R6 is -CF(Ci-5 alkyl)2
[0268] In some embodiments, R6 is -CF(Ci-4 alkyl)2
[0269] In some embodiments, R6 is -CF(Ci-3 alkyl)2
[0270] In some embodiments, R6 is -CF(Ci-2 alkyl)2
[0271] In some embodiments, R6 is -CFMe2.
[0272] In some embodiments, R6 is -CF(Me)(Et).
[0273] In some embodiments, R6 is -CFEt2.
[0274] In some embodiments, R6 is -CF(Et)(nPr).
[0275] In some embodiments, R6 is -CFnPr2. [0276] In some embodiments, R6 is -CF(Me)(nPr).
[0277] In some embodiments, R6 is -CF'Pr2.
[0278] In some embodiments, R6 is -CF(Et)OPr).
[0279] In some embodiments, R6 is -CF(Me)OPr).
[0280] In some embodiments, R36 is selected from the group consisting of halide, unsubstituted -(C1-5 alkyl), unsubstituted -(C1-5 haloalkyl), -(CFbCtyOR42, -heterocyclyl optionally substituted with 1 -2 R43, -(CH2)heterocyclyl optionally substituted with 1 -2 R43, -(C3-4 carbocyclyl) optionally substituted with 1 -2 R44, and -(CH2XC3-4 carbocyclyl) optionally substituted with 1-2 R44.
[0281] In some embodiments, R37 is selected from the group consisting of halide, unsubstituted -(C1-5 alkyl), unsubstituted -(C1-5 haloalkyl), -OR42, -heterocyclyl optionally substituted with 1-2 R43, and -(Ctyheterocyclyl optionally substituted with 1 -2 R43.
[0282] In some embodiments, the heterocyclyl is selected from the group consisting of azetidinyl, oxetanyl, pyrrolidinyl, tetrahydroiuranyl, piperidinyl, piperazinyl, morpholinyl, and tetrahydropyranyl .
[0283] In some embodiments, R42 is selected from the group consisting of unsubstituted -(C1-3 alkyl), and unsubstituted -(C1-3 haloalkyl).
[0284] In some embodiments, R42 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, -CF3.
[0285] In some embodiments, R43 is selected from the group consisting of halide, unsubstituted -(C1-2 alkyl), and unsubstituted -(C 1-2 haloalkyl).
[0286] In some embodiments, R43 is selected from the group consisting of F, methyl, ethyl, -CF3.
[0287] In some embodiments, R44 is selected from the group consisting of halide, unsubstituted -(C1-2 alkyl), and unsubstituted -(C 1-2 haloalkyl).
[0288] In some embodiments, R44 is selected from the group consisting of F, methyl, ethyl, -CF3.
[0289] In some embodiments, R36 is selected from the group consisting of F, methyl, ethyl, n-propyl, isopropyl, isobutyl, fert-butyl, neopentyl, -CH2CH2F, -CH2CHF2, -CH2CF3, - -CH2C(CH3)2F, -CH2CH2CF3, -(CH2CH2)0(Ci-3 alkyl),
Figure imgf000059_0001
Figure imgf000059_0002
[0290] In some embodiments, R37 is selected from the group consisting of F, methyl,
ethyl, -CF3, -OCF3, -OMe,
Figure imgf000059_0003
0291] In some embodiments, R3 is selected from the group consisting of:
Figure imgf000059_0004
, where in X is S or O and R6 is selected from the roup consisting of:
Figure imgf000059_0005
to 2.
0292] In some embodiments, R3 is selected from the group consisting of:
Figure imgf000059_0006
, where in X is S or O and R6 is selected from the group consisting of -carbocyclyl optionally substituted with 1-2 R37 and -(CH2)carbocyclyl optionally substituted with 1-2 R37. 3 is selected from the group consisting of:
Figure imgf000060_0001
, where in X is S or O and R6 is -CF(Ci-9 alkyl)2; wherein the alkyl of -CF(Ci-9 alkyl)2 is optionally substituted with one or more halides.
0294] In some embodiments, R3 is selected from the group consisting of:
Figure imgf000060_0002
, where in X is S or O and R6 is selected from the roup consisting of:
Figure imgf000060_0003
and q is 0 to 2.
0295] In some embodiments, R3 is selected from the group consisting of:
Figure imgf000060_0004
Figure imgf000061_0001
Figure imgf000061_0002
0297] In some embodiments, R3 is selected from the group consisting
Figure imgf000061_0003
optionally substituted with one or more fluorines. 0298] In some embodiments, R is selected from the group consisting of:
Figure imgf000062_0001
, and R6 is selected from the group consisting of -cyclopropyl, - cyclobutyl, -cyclopentyl, -cyclohexyl each independently optionally substituted with 1 -2 R37 and -(CH2)cyclopropyl, -(CH2)cyclobutyl, -(CH2)cyclopentyl, and -(CH2)cyclohexyl, each independently optionally substituted with 1-2 R37.
0299] In some embodiments, R3 is selected from the group consisting of:
Figure imgf000062_0002
and R6 is selected from the group consisting of:
Figure imgf000062_0003
0300] In some embodiments, R3 is selected from the group consisting of:
Figure imgf000062_0004
from the group consisting of:
Figure imgf000063_0001
0 to 2.
[0301] In some embodiments, R3 is selected from the group consisting
Figure imgf000063_0002
, and R6 is selected from the group consisting of -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl each optionally substituted with 1 -2 R37 and -(CH2)cyclopropyl, -(CH2)cyclobutyl, -(CH2)cyclopentyl, and - (CH2)cyclohexyl, each optionally substituted with 1-2 R37.
[0302] In some embodiments, R3 is selected from the group consisting of:
Figure imgf000063_0003
alkyl)2; wherein the alkyl of -CF(Ci-5 alkyl)2 is optionally substituted with 1-4 fluorines.
0303] In some embodiments R3 is selected from the group consisting of:
Figure imgf000063_0004
R36 is selected from the group consisting of F, methyl, ethyl, n-propyl, isopropyl, isobutyl, tert- butyl, neopentyl, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CF2CH3, -CH2C(CH3)2F, - -(CH2CH2)0(Ci-3 alkyl),
Figure imgf000064_0001
Figure imgf000064_0002
0304] In some embodiments, R3 is selected from the group consisting of:
Figure imgf000064_0003
2, and each R36 is independently selected from the group consisting of F, methyl, and -CF3.
0305] In some embodiments, R3 is selected from the group consisting of:
Figure imgf000064_0004
from the group consisting of -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl each optionally substituted with 1-2 R37 and -(CH2)cyclopropyl, -(CH2)cyclobutyl, -(CH2)cyclopentyl, and - (CH2)cyclohexyl, each optionally substituted with 1-2 R37, and each R37 is independently selected from the group consisting of F, methyl, -CF3, -OCF3, and -OMe.
[0306] In some embodiments, R3 is selected from the group consisting of:
Figure imgf000065_0001
,
Figure imgf000065_0002
R36 is selected from the group consisting of F, methyl, ethyl, n-propyl, isopropyl, isobutyl, tert- butyl, neopentyl, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CF2CH3, -CH2C(CH3)2F,
-CH2CH2CF . -(CH2CH2)0(Ci-3 alkyl). -*~· . and 3 is se
Figure imgf000065_0003
lected from the group consisting of:
Figure imgf000065_0004
, R6 is selected from the group consisting of:
Figure imgf000066_0001
, and , and R36 is selected from the group consisting of methyl, ethyl, isopropyl, isobutyl, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CF2CH3, -
CH2C(CH3)2F, -CH2CH2CF3, -(CH2CH2)OMe, -(CH2CH2)OiPr,
Figure imgf000066_0002
, and
some embodiments, R3 is selected from the group consisting of:
Figure imgf000066_0003
Figure imgf000066_0004
R6 is selected from the group consisting of -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R36 and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R37. diments, R3 is selected from the group consisting of:
Figure imgf000066_0005
Figure imgf000066_0006
, R6 is selected from the group consisting of -(Ctyheterocyclyl optionally substituted with 1-2 R36 -heterocyclyl optionally substituted with 1-2 R36, and - carbocyclyl optionally substituted with 1 -2 R37, and R36 is selected from the group consisting of halide and unsubstituted -(C1-9 alkyl), and R37 is selected from the group consisting of halide and unsubstituted -(C1-9 alkyl), -N(R5 )2, and -heterocyclyl optionally substituted with 1-2 R43. diments, R3 is selected from the group consisting of:
Figure imgf000067_0001
Figure imgf000067_0002
, R6 is selected from the group consisting of -(CH2)heterocyclyl optionally substituted with 1 R36 -heterocyclyl optionally substituted with 1 R36, and -carbocyclyl substituted with 1 R37, and R36 is unsubstituted -(C1-5 alkyl), and R37 is selected from the group consisting of -N(Ci-3 alkyl)2, and an unsubsituted -heterocyclyl.
[0311] In some embodiments, R3 is selected from the group consisting of:
Figure imgf000067_0003
Figure imgf000067_0004
and and R36 is selected from the group consisting of
methyl, ethyl, isopropyl, isobutyl, -NMe2, and .ΛΛΛΙΛΛ
, R3 is selected from the group consisting of:
Figure imgf000068_0001
R6 is selected from the group consisting of:
Figure imgf000068_0002
, and R36 is selected from the group consisting methyl, ethyl, isopropyl, isobutyl, -CH2CH2F, -CH2CHF2, -CH2C -CH2CF2CH3,
CH2C(CH3)2F, -CH2CH2CF3, -(CH2CH2)OMe, -(CH2CH2)OiPr, **<~ , and
Figure imgf000068_0003
0313] In some embodiments, R6 is selected from the group consisting
Figure imgf000068_0004
, and R36 is selected from the group consisting of methyl, ethyl, isopropyl, isobutyl, -CH2CH2F, -CH2CH -CH2 -CH2CF2CH3, -
CH2C(CH3)2F, -CH2CH2CF3, -(CH2CH2)OMe, -(CH2CH2)OiPr,
Figure imgf000068_0005
[0314] [0315] In some embodiments, R3 is selected from the group consisting of:
Figure imgf000069_0001
,
Figure imgf000069_0002
2, and each R36 is independently selected from the group consisting of F, methyl, and -
[0316] In some embodiments, R3 is selected from the group consisting of:
Figure imgf000069_0003
,
Figure imgf000069_0004
, , and R6 is selected from the group consisting of -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl each optionally substituted with 1-2 R37 and -(Ctycyclopropyl, - (Ctycyclobutyl, -(Ctycyclopentyl, and -(Ctycyclohexyl, each optionally substituted with 1-2 R37, and each R37 is independently selected from the group consisting of F, methyl,-CF3, -OCF3, and -OMe.
[0317] In some embodiments, R3 is selected from the rou consistin of:
Figure imgf000069_0005
,
Figure imgf000069_0006
Figure imgf000070_0001
, , and R6 is -CF(Ci-3 alkyl)2; wherein the alkyl of -CF(Ci optionally substituted with 1-2 fluorines.
[0318] Illustrative compounds of Formula (I) are shown in Table 1.
Table 1.
Figure imgf000070_0002
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Administration and Pharmaceutical Compositions
[0319] 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.
[0320] The compounds provided herein may also be useful in combination (administered together or sequentially) with other known agents.
[0321] 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.
[0322] 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).
[0323] 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).
[0324] 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.
[0325] 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).
[0326] 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-γ 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.
[0327] 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. [0328] In some embodiments, a compound of Formula (I) can be used to treat osteoarthritis in combination with any of the following methods: (a) Nonsteroidal antiinflammatory 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.
[0329] 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®), verteporfin (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.
[0330] 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.
[0331] 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, intracisternally, 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.
[0332] 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 films by methods such as precipitation, crystallization, milling, grinding, supercritical fluid processing, coacervation, complex coacervation, encapsulation, emulsification, complexation, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may 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.
[0333] 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 α-, β, and γ-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).
[0334] 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.
[0335] 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).
[0336] In some embodiments, the unit dosage of compounds of Formula (I) is about 0.25 mg/Kg to about 50 mg/Kg in humans.
[0337] In some embodiments, the unit dosage of compounds of Formula (I) is about 0.25 mg/Kg to about 20 mg/Kg in humans.
[0338] In some embodiments, the unit dosage of compounds of Formula (I) is about 0.50 mg/Kg to about 19 mg/Kg in humans.
[0339] In some embodiments, the unit dosage of compounds of Formula (I) is about 0.75 mg/Kg to about 18 mg/Kg in humans.
[0340] In some embodiments, the unit dosage of compounds of Formula (I) is about 1.0 mg/Kg to about 17 mg/Kg in humans.
[0341] In some embodiments, the unit dosage of compounds of Formula (I) is about 1.25 mg/Kg to about 16 mg/Kg in humans.
[0342] In some embodiments, the unit dosage of compounds of Formula (I) is about 1.50 mg/Kg to about 15 mg/Kg in humans.
[0343] In some embodiments, the unit dosage of compounds of Formula (I) is about 1.75 mg/Kg to about 14 mg/Kg in humans.
[0344] In some embodiments, the unit dosage of compounds of Formula (I) is about 2.0 mg/Kg to about 13 mg/Kg in humans. [0345] In some embodiments, the unit dosage of compounds of Formula (I) is about 3.0 mg/Kg to about 12 mg/Kg in humans.
[0346] In some embodiments, the unit dosage of compounds of Formula (I) is about 4.0 mg/Kg to about 1 1 mg/Kg in humans.
[0347] In some embodiments, the unit dosage of compounds of Formula (I) is about 5.0 mg/Kg to about 10 mg/Kg in humans.
[0348] In some embodiments, the compositions are provided in unit dosage forms suitable for single administration.
[0349] In some embodiments, the compositions are provided in unit dosage forms suitable for twice a day administration.
[0350] In some embodiments, the compositions are provided in unit dosage forms suitable for three times a day administration.
[0351] 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.
[0352] In some embodiments, the composition will comprise about 0.1 -10% of the active agent in solution.
[0353] In some embodiments, the composition will comprise about 0.1-5% of the active agent in solution.
[0354] In some embodiments, the composition will comprise about 0.1 -4% of the active agent in solution.
[0355] In some embodiments, the composition will comprise about 0.15-3% of the active agent in solution.
[0356] In some embodiments, the composition will comprise about 0.2-2% of the active agent in solution.
[0357] 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.
[0358] 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. [0359] 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.
[0360] 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.
[0361] 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.
[0362] 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.
[0363] 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.
[0364] 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.
[0365] 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.
[0366] 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.
[0367] 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.
[0368] 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.
[0369] 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.
[0370] 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.
[0371] 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. [0372] 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 μιη 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.
[0373] 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.
[0374] 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.
[0375] 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).
[0376] 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).
[0377] 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.
[0378] Other options include delivery via a pump through a thin film 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.
[0379] 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. 1 1/337,815).
[0380] 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.
[0381] 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.
[0382] 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.
[0383] 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.
[0384] Examples of single units which may be used as dosage forms for the solid composition include tablets, such as compressed tablets, film-like units, foil-like units, wafers, lyophilized matrix units, and the like. In 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.
[0385] 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.
[0386] 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.
[0387] 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, Mullerian-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, Norrie disease, and Rett syndrome.
Methods of Treatment
[0388] 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 (ALS), 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, Mullerian-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, Norrie disease and Rett syndrome.
[0389] 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.
[0390] Other cancers can also be treated with the compounds and compositions described herein.
[0391] More particularly, cancers that may be treated by the compounds, compositions and methods described herein include, but are not limited to, the following:
[0392] 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.
[0393] 2) Cardiac cancers, including, for example sarcoma, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma; fibroma; lipoma and teratoma.
[0394] 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.
[0395] 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.
[0396] 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.
[0397] 6) Liver cancers, including, for example, hepatoma, e.g., hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hepatocellular adenoma; and hemangioma.
[0398] 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.
[0399] 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.
[0400] 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.
[0401] 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.
[0402] 1 1) 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.
[0403] 12) Adrenal gland cancers, including, for example, neuroblastoma.
[0404] More particularly, tumors of the central nervous system that may be treated by the compounds, compositions and methods described herein include:
[0405] 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.
[0406] 2) Oligodendroglial tumors, e.g., oligodendroglioma and anaplastic oligodendroglioma.
[0407] 3) Oligoastrocytic tumors, e.g., oligoastrocytoma and anaplastic oligoastrocytoma.
[0408] 4) Ependymal tumors, e.g., subependymoma, myxopapillary ependymoma, ependymoma, (cellular, papillary, clear cell, tanycytic), and anaplastic (malignant) ependymoma.
[0409] 5) Choroid plexus tumors, e.g., choroid plexus papilloma, atypical choroid plexus papilloma, and choroid plexus carcinoma.
[0410] 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 filum terminale.
[0411] 7) Pineal tumors, e.g., pineocytoma, pineoblastoma, papillary tumors ofthe pineal region, and pineal parenchymal tumor of intermediate differentiation.
[0412] 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.
[0413] 9) Neuroblastic tumors, e.g., olfactory (esthesioneuroblastoma), olfactory neuroepithelioma, and neuroblastomas of the adrenal gland and sympathetic nervous system.
[0414] 10) Glial tumors, e.g., astroblastoma, chordoid glioma of the third ventricle, and angiocentric glioma.
[0415] 11) Tumors of cranial and paraspinal nerves, e.g., schwannoma, neurofibroma Perineurioma, and malignant peripheral nerve sheath tumor.
[0416] 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.
[0417] 13) Tumors of the hematopoietic system, e.g., malignant Lymphomas, plasmocytoma, and granulocytic sarcoma.
[0418] 14) Germ cell tumors, e.g., germinoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma, and mixed germ cell tumors.
[0419] 15) Tumors of the sellar region, e.g., craniopharyngioma, granular cell tumor, pituicytoma, and spindle cell oncocytoma of the adenohypophysis.
[0420] 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.
[0421] 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.
[0422] 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.
[0423] 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.
[0424] 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, Mullerian-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, Norrie disease and Rett syndrome.
[0425] 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, IL-6, IL-1, IFNy) 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.
[0426] The compounds and compositions provided herein can be used as inhibitors and/or modulators of the enzyme DYRKl 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.
[0427] 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, Coffin-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, Kearns- Sayre syndrome, Kennedy disease, Kinsbourne syndrome, Klippel Feil 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.
[0428] The compounds and compositions may also be useful in the inhibition of the development of invasive cancer, tumor angiogenesis and metastasis.
[0429] 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.
[0430] 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 claim 1, or a pharmaceutically acceptable salt thereof.
[0431] 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.
[0432] 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.
[0433] In some embodiments, the disorder or disease is the pain and inflammation associated with cancer.
[0434] In some embodiments, the disorder or disease is the pain and inflammation associated with a joint.
[0435] In some embodiments, the disorder or disease is the pain and inflammation associated with the knee.
[0436] In some embodiments, the disorder or disease is the pain and inflammation associated with the hip.
[0437] In some embodiments, the disorder or disease is the pain and inflammation associated with the shoulder.
[0438] In some embodiments, the disorder or disease is the pain and inflammation associated with arthritis.
[0439] In some embodiments, the disorder or disease is the pain and inflammation associated with gastrointestinal disorders.
[0440] In some embodiments, the disorder or disease is the pain and inflammation associated with pulmonary disorders.
[0441] In some embodiments, the disorder or disease is the pain and inflammation associated with allergies.
[0442] In some embodiments, the disorder or disease is the pain and inflammation associated with skin disorders.
[0443] In some embodiments, the disorder or disease is the pain and inflammation associated with diabetes.
[0444] In some embodiments, the disorder or disease is the pain and inflammation associated with pancreatitis.
[0445] In some embodiments, the disorder or disease is the pain and inflammation associated with tendonitis.
[0446] In some embodiments, the disorder or disease is the pain and inflammation associated with heart disease.
[0447] In some embodiments, the disorder or disease is the pain and inflammation associated with lupus.
[0448] In some embodiments, the disorder or disease is the pain and inflammation associated with a neurological disorder. [0449] In some embodiments, the disorder or disease is the pain and inflammation associated with multiple sclerosis.
[0450] In some embodiments, the disorder or disease is the pain and inflammation associated with Parkinson's.
[0451] In some embodiments, the disorder or disease is cancer.
[0452] In some embodiments, the disorder or disease is systemic inflammation.
[0453] In some embodiments, the disorder or disease is metastatic melanoma.
[0454] In some embodiments, the disorder or disease is fatty liver disease.
[0455] In some embodiments, the disorder or disease is liver fibrosis.
[0456] In some embodiments, the disorder or disease is tendon regeneration.
[0457] In some embodiments, the disorder or disease is diabetes.
[0458] In some embodiments, the disorder or disease is degenerative disc disease.
[0459] In some embodiments, the disorder or disease is osteoarthritis.
[0460] In some embodiments, the disorder or disease is diabetic retinopathy.
[0461] In some embodiments, the disorder or disease is pulmonary fibrosis.
[0462] In some embodiments, the disorder or disease is idiopathic pulmonary fibrosis
[0463] In some embodiments, the disorder or disease is degenerative disc disease.
[0464] In some embodiments, the disorder or disease is rheumatoid arthritis.
[0465] In some embodiments, the disorder or disease is scleroderma.
[0466] In some embodiments, the disorder or disease is a mycotic or viral infection.
[0467] In some embodiments, the disorder or disease is a bone or cartilage disease.
[0468] In some embodiments, the disorder or disease is a neurological disorder.
[0469] In some embodiments, the disorder or disease is Alzheimer's disease.
[0470] In some embodiments, the disorder or disease is osteoarthritis.
[0471] In some embodiments, the disorder or disease is lung disease.
[0472] 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.
[0473] In some embodiments, the patient is a human.
[0474] In some embodiments, the cancer is chosen from: hepatocellular carcinoma, colon cancer, breast cancer, pancreatic cancer, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia, acute lymphocytic leukemia, Hodgkin lymphoma, lymphoma, sarcoma and ovarian cancer.
[0475] 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.
[0476] In some embodiments, the cancer is hepatocellular carcinoma.
[0477] In some embodiments, the cancer is colon cancer.
[0478] In some embodiments, the cancer is colorectal cancer.
[0479] In some embodiments, the cancer is breast cancer.
[0480] In some embodiments, the cancer is pancreatic cancer.
[0481] In some embodiments, the cancer is chronic myeloid leukemia (CML).
[0482] In some embodiments, the cancer is chronic myelomonocytic leukemia.
[0483] In some embodiments, the cancer is chronic lymphocytic leukemia (CLL)
[0484] In some embodiments, the cancer is acute myeloid leukemia.
[0485] In some embodiments, the cancer is acute lymphocytic leukemia.
[0486] In some embodiments, the cancer is Hodgkin lymphoma.
[0487] In some embodiments, the cancer is lymphoma.
[0488] In some embodiments, the cancer is sarcoma.
[0489] In some embodiments, the cancer is ovarian cancer.
[0490] In some embodiments, the cancer is lung cancer - non-small cell.
[0491] In some embodiments, the cancer is lung cancer - small cell.
[0492] In some embodiments, the cancer is multiple myeloma. [0493] In some embodiments, the cancer is nasopharyngeal cancer.
[0494] In some embodiments, the cancer is neuroblastoma.
[0495] In some embodiments, the cancer is osteosarcoma.
[0496] In some embodiments, the cancer is penile cancer.
[0497] In some embodiments, the cancer is pituitary tumors.
[0498] In some embodiments, the cancer is prostate cancer.
[0499] In some embodiments, the cancer is retinoblastoma.
[0500] In some embodiments, the cancer is rhabdomyosarcoma.
[0501] In some embodiments, the cancer is salivary gland cancer.
[0502] In some embodiments, the cancer is skin cancer - basal and squamous cell.
[0503] In some embodiments, the cancer is skin cancer - melanoma.
[0504] In some embodiments, the cancer is small intestine cancer.
[0505] In some embodiments, the cancer is stomach (gastric) cancers.
[0506] In some embodiments, the cancer is testicular cancer.
[0507] In some embodiments, the cancer is thymus cancer.
[0508] In some embodiments, the cancer is thyroid cancer.
[0509] In some embodiments, the cancer is uterine sarcoma.
[0510] In some embodiments, the cancer is vaginal cancer.
[0511] In some embodiments, the cancer is vulvar cancer.
[0512] In some embodiments, the cancer is Wilms tumor.
[0513] In some embodiments, the cancer is laryngeal or hypopharyngeal cancer.
[0514] In some embodiments, the cancer is kidney cancer.
[0515] In some embodiments, the cancer is Kaposi sarcoma.
[0516] In some embodiments, the cancer is gestational trophoblastic disease.
[0517] In some embodiments, the cancer is gastrointestinal stromal tumor.
[0518] In some embodiments, the cancer is gastrointestinal carcinoid tumor.
[0519] In some embodiments, the cancer is gallbladder cancer.
[0520] In some embodiments, the cancer is eye cancer (melanoma and lymphoma)
[0521] In some embodiments, the cancer is Ewing tumor.
[0522] In some embodiments, the cancer is esophagus cancer.
[0523] In some embodiments, the cancer is endometrial cancer.
[0524] In some embodiments, the cancer is colorectal cancer.
[0525] In some embodiments, the cancer is cervical cancer.
[0526] In some embodiments, the cancer is brain or spinal cord tumor. [0527] In some embodiments, the cancer is bone metastasis.
[0528] In some embodiments, the cancer is bone cancer.
[0529] In some embodiments, the cancer is bladder cancer.
[0530] In some embodiments, the cancer is bile duct cancer.
[0531] In some embodiments, the cancer is anal cancer.
[0532] In some embodiments, the cancer is adrenal cortical cancer.
[0533] In some embodiments, the disorder or disease is a neurological condition, disorder or 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.
[0534] In some embodiments, the disorder or disease is a neurological disease or disorder associated with tau protein, amyloid,alpha-synuclein pathology, Tar DNA-binding Protein of 43KDa (TDP-43), Prion protein PrP or fused in sarcoma (FUS).
[0535] In some embodiments, the disorder or 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.
[0536] In some embodiments, a compound of Formula (I) inhibits DYRK1A.
[0537] In some embodiments, a compound of Formula (I) inhibits GSK3.
[0538] In some embodiments, a compound of Formula (I) inhibits GSK3 .
[0539] In some embodiments, a compound of Formula (I) inhibits DYRK1A and
GSK3 .
[0540] In some embodiments, the compound of Formula (I) inhibits one or more proteins in the Wnt pathway.
[0541] In some embodiments, the compound of Formula (I) inhibits signaling induced by one or more Wnt proteins. [0542] 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.
[0543] In some embodiments, the compound of Formula (I) inhibits a kinase activity.
[0544] 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.
[0545] In some embodiments, the compound of Formula (I) inhibits one or more Wnt proteins.
[0546] 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.
[0547] In some embodiments, the disease or disorder comprises tumor growth, cell proliferation, or angiogenesis.
[0548] 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.
[0549] 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.
[0550] 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.
[0551] 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.
[0552] 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. [0553] 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.
[0554] 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
[0555] 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.
[0556] 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.
[0557] In another example, one may utilize in vitro assays for Wnt biological activity, e.g. stabilization of β-catenin and promoting growth of stem cells. Assays for biological activity of Wnt include stabilization of β-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 β-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 β-catenin.
[0558] 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).
[0559] 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-SY5Y 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).
[0560] 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).
[0561] 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
[0562] 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.
[0563] 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.
[0564] 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.
[0565] 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.
[0566] (¾) nuclear magnetic resonance spectra (NMR) were measured in the indicated solvents on a Bruker NMR spectrometer (Avance TM DRX300, 300 MHz for ¾ or Avance TM DRX500, 500 MHz for ¾) or Varian NMR spectrometer (Mercury 400BB, 400 MHz for ¾). 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.
[0567] The following abbreviations have the indicated meanings:
brine = saturated aqueous sodium chloride
CDCh = deuterated chloroform
DCE = dichloroethane
DCM = dichloromethane
DIPEA = N,N-diisopropylethylamine
DMAP = 4-dimethylaminopyridine
DMF = N,N-dimethylformamide
DMSO- 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
HC1 = hydrochloric acid
HO Ac = acetic acid
ISCO = Teledyne ISCO, Inc brand CombiFlash® Rf 200
KOAc = potassium acetate
LAH = Lithium aluminium hydride
LC/MS = Liquid chromatography-mass spectrometry
MeCN = acetonitrile
Me OH = methanol
MgS04 = magnesium sulfate
MsCl = mesyl chloride or methane sulfonyl chloride
MTBE = methyl tert-butyl ether
MW = microwave irradiation
NaB¾CN = sodium cyanoborohydride
NaHC03 = sodium bicarbonate
Na(OAc)3BH = Sodium triacetoxyborohydride
NMR = nuclear magnetic resonance
ON = overnight
Pd(dppf)Cl2 = 1, r-bis(diphenylphosphino)ferrocene-palladium(II)dichloride
Pd(PPli3)4 = tetrakis(triphenylphosphine)palladium(0)
r.t. = room temperature
SPhos Pd G3 = [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl-l,r- biphenyl)-2-(2'-amino-l, r -biphenyl)]palladium(II) methanesulfonate methane sulfonate
SPhos Pd G4 = Methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-tri-i- propyl- 1 , 1 '-biphenyl)(2'-methylamino- 1 , 1 '-biphenyl-2-yl)palladium(II)
TBAF = Tetra-n-butylammonium fluoride,
TEA = triethylamine
TFA = trifluoroacetic acid
THF = tetrahydrofuran
TLC = thin layer chromatography
[0568] 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
[0569] Compounds of Formula I of the present disclosure can be prepared as depicted in Scheme 1.
Figure imgf000130_0001
Scheme 1
[0570] Scheme 1 describes a method for preparation of isoquinoline-3-carboxamide derivatives (IX) by first coupling the amine with a variety of acids (III) to produce amide IV. The bromo derivative IV is then reacted with bis(pinacolato)diboron to give the pinacol ester (V). Suzuki coupling with a variety of 5-membered heteroaryl bromides (VIII) yields the desired R3 substituted isoquinoline IX. Alternatively, the bromo derivative IV is Suzuki coupled with a variety of 5-membered heteroaryl pinacol esters (VI) or coupled to a variety of 5-membered heteroaryl stannanes (VII) to produce the final R3 substituted isoquinoline IX. [0571] In some embodiments, compounds of Formula I of the present disclosure can be pre
Figure imgf000131_0001
A = C, N, O, or S,
wherein C or N may be substituted
as defined for R6 herein
Scheme 2
[0572] Scheme 2 describes a method for preparation of isoquinoline-3-carboxamide intermediate (IVa) by first coupling the amine 4-nitrophenyl carbonochloridate followed by coupling with a variety of R6 NH heterocyclyls. Intermediate IVa could then be used in place of IV in Scheme 1 or 3.
[0573] In other embodiments, compounds of Formula I of the present disclosure can be prepared as depicted in Scheme 3.
A = N or C, wherein N or C may be
substituted as defined for R3 herein
Figure imgf000131_0002
IV or IVa IXa
Scheme 3
[0574] Scheme 3 describes a method for preparation of isoquinoline-3-carboxamide derivatives (IXa) starting with bromo intermediate IV or IVa and couple with the nitrogen of a variety of R3 NH heteroaryls to produce the final R3 substituted isoquinoline IXa. Illustrative Compound Examples
[0575] Preparation of intermediate 6-bromoisoquinolin-l-<i-3 -amine (XI) is depicted below in Scheme 4.
Figure imgf000132_0001
XI
Scheme 4
Step 1
[0576] To a mixture of l,6-dibromoisoquinolin-3-amine (X) (0.5 g, 1.66 mmol), ammonium formate-dj (0.56 g, 8.28 mmol) and Pd(PPh3)4 (191.3 mg, 0.170 mmol) in DMF (5 mL) was heated to 50°C for 48 h. The solvents were concentrated and the residue was suspended in chloroform. The solid was collected by filtration and washed with water and EtOAc. The solid were dried under high vacuo to obtain 6-bromo-l-deuterio-isoquinolin-3 -amine (XI) (115 mg,0.513 mmol, 31.0% yield) as a pale yellow solid. ¾ NMR (500 MHz, DMSO-t¾) δ ppm 6.11 (2 H, s), 6.55 (1 H, s), 7.22 (1 H, dd, J=8.78, 1.92 Hz), 7.73 (1 H, d, J=8.51 Hz), 7.79 (1 H, d, J=1.92 Hz); ESIMS found for C9H6DBrN2 mlz 224.0 (79BrM+H).
[0577] Preparation of intermediate 6-bromo-4-chloroisoquinolin-3-amine (XIII) is depicted below in Scheme 5.
Figure imgf000132_0002
XII XIII
Scheme 5 Step 1
[0578] To a stirred suspension of 6-bromoisoquinolin-3-amine (XII) (1.0 g, 4.48 mmol) in DMF (15 mL) at 0°C was added l-chloropyrrolidine-2,5-dione (598.6 mg, 4.48 mmol) portionwise. The mixture was stirred at 0°C for 6 h. The reaction mixture was added to water (150 mL), stirred for 1 h and the resulting solids were collected by filtration and air dried overnight to obtain 64oromo-4-chloro-isoquinolin-3-amine (XIII) (922 mg, 3.58 mmol, 79.9% yield) as a beige solid which was used for next step without purification. ¾ MR (499 MHz, DMSO-i¾) δ ppm 6.55 (2 H, s), 7.40 (1 H, dd, J=8.64, 1.78 Hz), 7.88 (1 H, d, 7=8.51 Hz), 7.90 (1 H, d, 7=1.10 Hz), 8.86 (1 H, s); ESIMS found for C9H6BrClN2 mlz 256.9 (79BrM+H).
[0579] Preparation of intermediate 64oromo-4-methylisoquinolin-3 -amine (XV) is depicted below in Scheme 6.
Figure imgf000133_0001
XII XIV XV
Scheme 6
Step 1
[0580] To a stirred suspension of 6-bromoisoquinolin-3-amine (XII) (2.g, 8.97mmol) in DMF (25.1 mL) at 0°C was added l -iodopyrrolidine-2,5-dione (2.02 g, 8.97 mmol) portionwise, The mixture was stirred at 0°C for 1 hr. LC-MS of the mixture showed completion of the reaction and the desired product. The solvent was removed under vacuum, the residue was purified by C 18 Silica gel (240g) [0→100% H20/MeCN (0.1%Formic acid)] to produce 6-bromo-4-iodo-isoquinolin-3-amine (XIV) (1.95 g, 5.58 mmol, 62.2% yield) as a brown solid. ¾ NMR (499 MHz, DMSO- 6) δ ppm 6.41 (2 H, br s), 7.40 (1 H, dd, J=8.64, 1.78 Hz), 7.76 - 7.81 (1 H, m), 7.82 ( 1 H, d, J=8.51 Hz), 8.81 (1 H, s); ESIMS found for C9H6BrIN2 mlz 348.9 (79BrM+H).
Step 2
[0581] A stirred solution of 6-bromo-4-iodo-isoquinolin-3-amine (XIV) ( 1.0 g, 2.87 mmol), 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (0.72 g, 2.87 mmol), Pd(dppf)Cl2 (0.23 g, 0.29 mmol), and K3PO4 (5.73 mL, 5.73 mmol) in 1,4-dioxane ( 10 mL) was heated to 90°C for 3 days. The solvent was removed under high vacuum and the residue was purified by C 18 silica gel (240g) [0→20% H20/MeCN (0.1%Formic acid)] to produce 6-bromo-4-methyl-isoquinolin-3-amine (XV) (74 mg, 0.312 mmol, 10.9% yield) as an off-white solid. ¾ NMR (499 MHz, DMSO- 6) δ ppm 2.23 (3 H, br s), 5.91 (2 H, br s), 7.27 ( 1 H, br d, J=2.20 Hz), 7.71 - 7.82 ( 1 H, m), 7.92 ( 1 H, br s), 8.72 ( 1 H, br s); ESIMS found for Ci0H9BrN2 mlz 239.0 (81BrM+H).
[0582] Preparation of intermediate 6-bromo-7-fluoroisoquinolin-3-amine (XVIII) is depicted below in Scheme 7.
Figure imgf000134_0001
Scheme 7 Step 1
[0583] To a vial was added 2,2-diethoxyacetonitrile (XVI) (1.0 g, 7.74 mmol) dissolved MeOH (7.74 mL) followed by addition of MeONa/MeOH (0.18 mL, 0.77 mmol) dropwise. The reaction was stirred at room temperature for 20 h. HO Ac (44.3 μί, 0.77 mmol) was added until pH=7-8 (using pH strips). (4-Bromo-3-fluoro-phenyl)methanamine hydrochloride (XVII) (1.86 g, 7.74 mmol) was added and stirred at 40°C for 4 h. The solvent was removed under vacuum. Sulfuric acid (12.6 mL, 232.3 mmol) was added and stirred at 40°C for 16 h. NH4OH (30.8 mL, 240.0 mmol) was added dropwise at 0°C. The solvent was removed under vacuum and the residue was purified by C18 silica gel (240g) [0→50% H20/MeCN (0.1%Formic acid)] to produce 6-bromo-7-fluoro-isoquinolin-3-amine (XVIII) (1.33 g, 5.50 mmol, 71.1% yield) as an off-white solid. ¾ MR (499 MHz, DMSO-d6) δ ppm 6.07 (2 H, s), 6.61 (1 H, s), 7.76 (1 H, d, J=9.33 Hz), 8.01 (1 H, d, J=6.86 Hz), 8.80 (1 H, s); ESIMS found for C9H6BrFN2 mlz 242.9 (81BrM+H).
[0584] Preparation of intermediates 6-bromo-7-chloroisoquinolin-3 -amine (XX) and 6-bromo-5-chloroisoquinolin-3 -amine (XXI) is depicted below in Scheme 8.
Figure imgf000135_0001
Scheme 8
Step 1
[0585] To a stirred solution of 2,2-diethoxyacetonitrile (XVI) (0.59 g, 4.57 mmol) in a vial containing MeOH (4.57 mL) was added MeONa (0.1 mL, 0.46 mmol) dropwise. The reaction was stirred at 35°C for 20 h. HOAc was added (26.1 μί, 0.46 mmol) (checked that the pH is 7-8 using pH strips) followed by (4-bromo-3-chloro-phenyl)methanamine (XIX) (1.01 g, 4.57 mmol). The mixture was stirred at 35°C for 40 h. The solvent was removed under vacuum. Sulfuric Acid (7.43 mL, 137.0 mmol) was then added and stirred at 35°C for 16 h. NH4OH (60.6 mL, 141.6 mmol) was added at 0°C. The reaction was filtered through Celite and purified by C18 silica gel (240g) [0→30% H20/MeCN (0. l%Formic acid)] to produce a 1 : 1 mixture (by nmr) of 6-bromo-7-chloro- isoquinolin-3 -amine (XX) and 6-bromo-5-chloroisoquinolin-3-amine (XXI) (633.7 mg, 2.46 mmol, 53.9% yield). ¾ MR (499 MHz, DMSO-d6) δ ppm 6.23 (2 H, s), 6.46 (2 H, s), 6.57 (1 H, s), 6.83 (1 H, s), 7.40 (1 H, d, J=8.51 Hz), 7.74 (1 H, d, J=8.51 Hz), 8.05 (1 H, s), 8.09 (1 H, s), 8.81 (1 H, s), 8.88 (1 H, s); ESIMS found for C9H6BrClN2 mlz 256.9 (79BrM+H).
[0586] Preparation of intermediates 6-bromo-7-methylisoquinolin-3-amine (XXIII) and -bromo-5-methylisoquinolin-3-amine (XXIV) is depicted below in Scheme 9.
Figure imgf000136_0001
XXII
Scheme 9
Step 1
[0587] To a stirred solution of 2,2-diethoxyacetonitrile (XVI) (0.33 g, 2.52 mmol) in a vial containing MeOH (2.52 mL) was added MeONa (0.23 mL, 0.25 mmol) dropwise. The reaction was stirred at 22°C for 20 h. HO Ac was added (14.4 μί, 0.25 mmol) (checked that the pH is 7-8 using pH strips) followed by (4-bromo-3-methyl-phenyl)methanamine (XXII) (0.5 g, 2.52 mmol). The mixture was stirred at 40°C for 40 h. The solvent was removed under vacuum. Sulfuric Acid (4.09 mL, 75.49 mmol) was then added and stirred at 40°C for 16 h. NH4OH (33.4 mL, 78 mmol) was added at 0°C. The reaction was filtered through Celite and purified by CI 8 silica gel (240g) [0→30% H20/MeCN (0.1%Formic acid)] to produce a 1 : 1 mixture (by nmr) of 6-bromo- 7-methylisoquinolin-3-amine (XXIII) and 6-bromo-5-methylisoquinolin-3-amine (XXIV) (378 mg, 1.59 mmol, 63.4% yield). ¾ NMR (499 MHz, DMSO-i&) δ ppm 2.40 (3 H, s), 2.52 (3 H, s), 5.96 (2 H, s), 6.12 (1 H, s), 6.54 (1 H, s), 6.71 (1 H, s), 7.27 (1 H, d, J=8.78 Hz), 7.58 (1 H, d, J=8.78 Hz), 7.73 (1 H, s), 7.86 (1 H, s), 8.74 (1 H, s), 8.79 (1 H, s); ESIMS found for CioH9BrN2 mlz 237.0 (79BrM+H).
[0588] Preparation of intermediate l-(bromomethyl)-l-(trifluoromethyl) cyclopropane (XXVII) is depicted below in Scheme 10.
Figure imgf000137_0001
XXV XXVI XXVII
Scheme 10
Step 1
[0589] l-(Trifluoromethyl)cyclopropane-l -carboxylic acid (XXV) (3.7334 g, 24.23 mmol) was dissolved in THF ( 162 mL) and cooled to 0°C. LAH (1.1614 g, 29.07 mmol) was then added and the reaction heated to 40°C overnight. The reaction was cooled to 0°C. Water (2 mL) was added to quench the reaction followed by 2 N NaOH (0.3 mL). The reaction was stirred forming a precipitate which was filtered off and washed with ether. The aqueous phase was removed and the organic phase was was washed with brine, dried, and carefully concentrated to give ( l-(trifluoromethyl)cyclopropyl)methanol (XXVI) ( 1.5376 g, 10.98 mmol, 45.3% yield) as a clear, volatile liquid.
Step 2
[0590] To a solution of (l -(Trifluoromethyl)cyclopropyl)methanol (XXVI) (1.6 g, 1 1.42 mmol) in DCM (23 mL) was added Et3N (1.9 mL, 13.7 mmol). The reaction was cooled to 0°C and MsCl was added dropwise. The reaction was stirred at 0°C for 1 h. The reaction was poured into water, and extracted with DCM. The organic phase was separated, washed with brine, dried, and concentrated. The crude mesylate was then dissolved in acetone (22 mL). LiBr (4.96 g, 57.1 mmol) was added, and the reaction stirred at room temperature overnight. The acetone was carefully removed, and the residue was partitioned between water and ether. The aqueous phase was separated and reextracted with ether. The organic phases were combined, washed with brine, dried, and carefully concentrated to give l-(bromomethyl)-l -(trifluoromethyl)cyclopropane (XXVII) (1.2867 g, 6.34 mmol, 55.5% yield) as a gold liquid with residual amounts of acetone. ¾ NMR (499 MHz, DMSO- 6) δ ppm 1.04 (2 H, tquin, J=5.17, 5.17, 1.74, 1.74, 1.74, 1.74 Hz), 1.23 - 1.27 (2 H, m), 3.77 (2 H, s).
Example 1.
[0591] Preparation of N-(6-( l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)-l- (3,3,3-trifluoropropyl)piperidine-4-carboxamide (271) is depicted below in Scheme 11.
Figure imgf000139_0001
Scheme 11
Step 1
[0592] To a stirred solution of l-(fert-butoxycarbonyl)piperidine-4-carboxylic acid (XXVIII) (1.542 g, 6.72 mmol) and HATU (2.56 g, 6.72 mmol) was added DIPEA (2.349 mL, 13.45 mmol). After 10 min, 6-bromoisoquinolin-3-amine (XII) (1 g, 4.48 mmol) was added followed by the addition of DMAP (0.110 g, 0.897 mmol) and the mixture was heated to 70°C overnight. The LC/MS of mixture showed complete conversion of the amine to the product. The solvents were concentrated in vacuo, the residue taken into EtOAc, washed with water, sat. aq. NaHCC and brine solution. The organic layer was dried over anhydrous Na2SC>4, solvents removed in vacuo and the residue was dried under high vacuo to obtain crude fert-butyl 4-((6- bromoisoquinolin-3-yl)carbamoyl)piperidine-l-carboxylate (XXIX) as a brown gummy solid (2.29 g, 5.27 mmol, 11.8% yield). Used for next step without purification.
Step 2
[0593] To a stirred solution of fert-butyl 4-((6-bromoisoquinolin-3- yl)carbamoyl)piperidine-l-carboxylate (XXIX) (1.0 g, 2.302 mmol) in DCM (4.0 mL) was added TFA (4.0 mL, 51.9 mmol) dropwise and the mixture was stirred at room temperature for 2 h. The solvent were evaporated in vacuo, the residue was neutralized with 7 N NLL/MeOH, concentrated and dried under high vacuo to obtain N-(6-bromoisoquinolin-3-yl)piperidine-4-carboxamide as a dark brown solid (0.769 g, 2.302 mmol, 100% yield). Used for next step without purification. ESIMS found for Ci5Hi6BrN30 mlz 336.1 (81BrM+H). Step 3
[0594] To a stirred suspension of N-(6-bromoisoquinolin-3-yl)piperidine-4- carboxamide (0.769 g, 2.30 mmol) and potassium carbonate (1.271 g, 9.20 mmol) in MeCN (10 ml) was added l, l, l -trifluoro-3-iodopropane (0.270 mL, 2.300 mmol). The mixture was then heated to 90°C overnight. Another equivalents of l, l, l-trifluoro-3-iodopropane (0.270 mL, 2.300 mmol) was added and heating continued at 90°C over a 2nd night. The reaction mixture was absorbed on silica and was purified by ISCO using EtOAc/hexanes (0→100%) and then with CHCh/MeOH (0→100% to recover unreacted starting material). The pure fractions were combined, concentrated, the residue suspended in diethylether, sonicated and the solid were collected by filtration and dried under high vacuo to obtain N-(6-bromoisoquinolin-3-yl)-l -(3,3,3- trifluoropropyl)piperidine-4-carboxamide (XXX) as an off-white solid (0.31 g, 0.720 mmol, 31.3% yield). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 1.57 - 1.71 (m, 2 H), 1.79 (br d, J=l 1.80 Hz, 2 H), 1.89 - 2.01 (m, 2 H), 2.41 - 2.60 (m, 5 H), 2.88 - 2.98 (m, 2 H), 7.63 (dd, J=8.78, 1.92 Hz, 1 H), 8.00 (d, J=8.78 Hz, 1 H), 8.18 (d, J=1.37 Hz, 1 H), 8.45 (s, 1 H), 9.14 (s, 1 H), 10.61 (s, 1 H); ESIMS found for Ci8Hi9BrF3N30 mlz 432.3 (81BrM+H).
Step 4
[0595] To a solution of N-(6-bromoisoquinolin-3-yl)-l-(3,3,3-trifluoropropyl) piperidine-4-carboxamide (XXX) (0.170 g, 0.395 mmol), bis(pinacolato)diboron (0.150 g, 0.593 mmol), potassium acetate (0.1 16 g, 1.185 mmol) and PdidppQC -G bC adduct (0.032 g, 0.040 mmol) was taken in dioxane (2.5 mL). N2 gas was bubbled into the mixture for 10 min and then the mixture was heated to 95°C for 5 h to produce N-(6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)isoquinolin-3-yl)-l-(3,3,3-trifluoropropyl) piperidine-4-carboxamide (XXXI). ESIMS found for C24H31BF3N3O3 mlz 478.1 (M+l). Use for next step without work up or further purification.
Step 5
[0596] To the above solution was added 4-bromo-l -methyl-lH-l,2,3-triazole (XXXII) (0.064 g, 0.395 mmol), Pd(dppf)Cl2-CH2Cl2 adduct (0.032 g, 0.040 mmol) and 2 M aqueous solution of potassium carbonate (0.395 mL, 0.790 mmol). The reaction mixture was heated overnight at 95 °C. The reaction mixture was absorbed on silica and purified by ISCO using CHC13/7N NH3 in Me OH (0→5%) followed by preparative TLC to obtain N-(6-(l -methyl- 1H- l,2,3-triazol-4-yl)isoquinolin-3-yl)-l-(3,3,3-trifluoropropyl) piperidine-4-carboxamide (271) as a beige solid (0.01 1 g, 0.025 mmol, 6.44% yield). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 1.60 - 1.73 (m, 2 H), 1.76 - 1.84 (m, 2 H), 1.92 - 2.01 (m, 2 H), 2.41 - 2.60 (m, 5 H), 2.94 (br d, J=1 1.25 Hz, 2 H), 4.14 (s, 3 H), 8.01 (dd, J=8.51, 1.37 Hz, 1 H), 8.11 (d, J=8.51 Hz, 1 H), 8.28 (s, 1 H), 8.50 (s, 1 H), 8.73 (s, 1 H), 9.11 (s, 1 H), 10.55 (s, 1 H); ESIMS found for C2iH23F3N60 mlz 433.2 (M+l).
Example 2.
[0597] Preparation of N-(6-(l -methyl- lH-pyrazol-4-yl)isoquinolin-3-yl)-l-(oxetan- 3-yl
Figure imgf000141_0001
Scheme 12
Step 1
[0598] To a solution of N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine- 4-carboxamide (72) (0.095 g, 0.283 mmol) in MeOH (1.5 mL) was added oxetan-3-one (0.027 mL, 0.425 mmol) followed by the addition of HOAc (0.081 mL, 1.416 mmol). The mixture was stirred for 20 min, then, sodium cyanoborohydride (0.027 g, 0.425 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo, the residue partitioned between EtOAc/sat. aq. NaHCC , the organic layer separated, washed with water and brine. The organic layer was dried over anhydrous Na2S04, solvents removed in vacuo and the crude product was purified by ISCO (0→5% CHC¾/7 N N¾ in MeOH). The pure fractions were combined, concentrated, the residue suspended in DCM, sonicated and the solids were collected by filtration to obtain N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-l-(oxetan-3-yl)piperidine-4- carboxamide (86) off-white solid (62.0 mg, 0.158 mmol, 56.0% yield). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 1.62 - 1.73 (m, 2 H), 1.74 - 1.86 (m, 4 H), 2.52 - 2.60 (m, 1 H), 2.71 - 2.80 (m, 2 H), 3.38 (quin, J=6.45 Hz, 1 H), 3.90 (s, 3 H), 4.43 (t, J=6.17 Hz, 2 H), 4.53 (t, J=6.59 Hz, 2 H), 7.74 (dd, J=8.51, 1.37 Hz, 1 H), 8.00 (d, J=8.51 Hz, 1 H), 8.04 (s, 1 H), 8.08 (s, 1 H), 8.35 (s, 1 H), 8.45 (s, 1 H), 9.02 (s, 1 H), 10.48 (s, 1 H); ESIMS found for C22H25N502 mlz 392.2 (M+l).
Example 3.
[0599] Preparation of N-(6-(5-(Dimethylamino)-l,3,4-oxadiazol-2-yl)isoquinolin-3- yl)piperidine-4-carboxamide (1075) and N-(6-(5-(dimethylamino)-l,3,4-oxadiazol-2-yl) isoquinolin-3-yl)-l-methylpiperidine-4-carboxamide (1076) is depicted below in Scheme 13.
Figure imgf000142_0001
1076
Scheme 13
Step 1
[0600] To a mixture of fert-butyl 4-[(6-bromo-3 -isoquinolyl)carbamoyl]piperidine- 1 - carboxylate (XXXIII) (1 g, 2.3 mmol), NaOAc (566.6 mg, 6.91 mmol), molybdenumhexacarbonyl (953 mg, 3.45 mmol) and Pd(dppf)Cl2 (376 mg, 0.46 mmol) in MeOH (20 mL) was heated to 75°C overnight. The reaction mixture was absorbed on silica gel and was purified by column chromatography using (25%→100% EtOAc/hexanes) to obtain methyl 3-[(\-tert- butoxycarbonylpiperidine-4-carbonyl)amino]isoquinoline-6-carboxylate (XXXIV) (950 mg, 2.30 mmol, 99.8% yield) as a grey solid. ESIMS found for C22H27N305 mlz 414.2 (M+1). Step 2
[0601] To a stirred solution of methyl 3-[(l-fert-butoxycarbonylpiperidine-4- carbonyl)amino]isoquinoline-6-carboxylate (XXXIV) (950.mg, 2.3 mmol) in MeOH (15 mL) was added 2N aqueous solution of NaOH (2.3 mL, 4.6 mmol) and the mixture was heated to 50°C. The reaction mixture was concentrated, the residue taken up in water and acidified with IN HCl and the resulting solid was collected by filtration, washed with water and dried under high vacuo to obtain 3 -[( 1 -ter^butoxycarbonylpiperidine-4-carbonyl)amino]isoquinoline-6-carboxylic acid (XXXV) (900 mg, 2.25 mmol, 98.1% yield) as a brown solid. ESIMS found for C2iH25N305 mlz 400.2 (M+l).
Step 3
[0602] To a mixture of 3-[(l-fer^butoxycarbonylpiperidine-4-carbonyl)amino] isoquinoline-6-carboxylic acid (XXXV) (0.5 g, 1.26 mmol), HATU (0.48 g, 1.26 mmol) and N- ethyl-N-isopropyl-propan-2-amine (0.66 mL, 3.77 mmol) in DMF (10 mL) was stirred for 10 min. Then 3-amino-l,l-dimethylthiourea (0.18 g, 1.51 mmol) was added and the mixture was stirred at room temperture for 5h. The reaction mixture was concentrated, the residue taken in CHCh, washed with sat. NaHCC , H2O and brine. The organic layer was separated and dried (MgSC ) before concentration to dryness to obtain fert-butyl 4-[[6-[(dimethylcarbamothioylamino)carbamoyl]-3- isoquinolyl]carbamoyl]piperidine-l-carboxylate (XXXVI) (600 mg, 1.20 mmol, 95.4% yield) as a brown solid which was used for next step without purification. ESIMS found for C24H32N6O4S mlz 501.2 (M+l).
Step 4
[0603] To a mixture of fert-butyl 4-[[6-[(dimethylcarbamothioylamino)carbamoyl]- 3-isoquinolyl]carbamoyl]piperidine-l-carboxylate (XXXVI) (600 mg, 1.2 mmol), 2-chloro-l,3- dimethyl-4,5-dihydroimidazol-l-ium chloride (405.2 mg, 2.4 mmol) and N,N-diethylethanamine (0.5 mL, 3.6 mmol) in DCM (10 mL) was stirred overnight at room temperature. Reaction mixture was concentrated and the residue was purified by column chromatography (0→10% 7N-Nt¼- MeOH/CHCh) to obtain fert-butyl 4-[[6-[5-(dimethylamino)-l,3,4-oxadiazol-2-yl]-3-isoquinolyl] carbamoyl]piperidine-l-carboxylate (XXXVII) (60 mg, 0.129 mmol, 10.7% yield) as a brown solid. ESIMS found for C24H3oN604 mlz 467.2 (M+l). Step 5
[0604] To a stirred solution of fert-butyl 4-[[6-[5-(dimethylamino)-l,3,4-oxadiazol- 2-yl]-3-isoquinolyl]carbamoyl]piperidine-l-carboxylate (XXXVII) (60 mg, 0.130 mmol) in DCM (2 mL) was added TFA (0.2 mL, 2.57 mmol) and the mixture was stirred at room temperature for 5h. Reaction mixture was concentrated and the residue was absorbed on silica gel, purified by flash column chromatography (0-10% 7N-NH3-MeOH/CHCl3) to obtain N-[6-[5-(dimethylamino)- l,3,4-oxadiazol-2-yl]-3-isoquinolyl]piperidine-4-carboxamide (1075) (32 mg, 0.087 mmol, 67.9% yield) as a white solid. ¾ NMR (499 MHz, DMSO-t¾) δ ppm 1.54 (2 H, qd, J=12.17, 4.12 Hz), 1.71 (2 H, br d, J=10.43 Hz), 2.44 - 2.49 (2 H, m), 2.65 (1 H, tt, J=11.49, 3.60 Hz), 2.98 (2 H, br d, J=12.08 Hz), 3.13 (6 H, s), 7.96 (1 H, dd, J=8.51, 1.65 Hz), 8.15 (1 H, d, J=8.51 Hz), 8.35 (1 H, s), 8.59 (1 H, s), 9.17 (1 H, s), 10.55 (1 H, s); ESIMS found for C19H22N6O2 mlz 367.2 (M+l).
Step 6
[0605] To a mixture of N-[6-[5-(dimethylamino)-l,3,4-oxadiazol-2-yl]-3- isoquinolyl]piperidine-4-carboxamide (1075) (27 mg, 0.070 mmol), NaBH3CN (14.03 mg, 0.070 mmol) and catalytic HO Ac in MeOH (2 mL) was stirred for 30 min, formaldehyde (2.21 mg, 0.070 mmol) was added and the stirring was continued 2h. The reaction mixture was quenched with minimum amount of aq. saturated NH4CI, concentrated on under vacuum and the residue was adsorbed on silica gel, purified by chromatography (0→20% 7N.NH3-MeOH/CHCl3) to obtain N- [6-[5-(dimethylamino)-l,3,4-oxadiazol-2-yl]-3-isoquinolyl]-l-methyl-piperidine-4-carboxamide (1076) (25 mg, 0.066 mmol, 89.2% yield) as a white solid. ¾ NMR (499 MHz, DMSO- 6) δ ppm 1.62 - 1.74 (2 H, m), 1.74 - 1.81 (2 H, m), 1.87 (2 H, td, J= 11.66, 2.20 Hz), 2.16 (3 H, s), 2.51 - 2.56 (1 H, m), 2.77 - 2.85 (2 H, m), 3.13 (6 H, s), 7.96 (1 H, dd, J=8.51, 1.65 Hz), 8.15 (1 H, d, J=8.51 Hz), 8.35 (1 H, s), 8.59 (1 H, s), 9.18 (1 H, s), 10.61 (1 H, s); ESIMS found for C20H24N6O2 mlz 381.2 (M+l).
Example 4.
[0606] Preparation of N-(6-(lH-l,2,3-triazol-l-yl)isoquinolin-3-yl)-4-fluoro-l- isobutylpiperidine-4-carboxamide (1074) and N-(6-(2H-l,2,3-triazol-2-yl)isoquinolin-3-yl)-4- fluoro-l-isobutylpiperidine-4-carboxamide (1075) is depicted below in Scheme 14.
Figure imgf000145_0001
Scheme 14
Step 1
[0607] To a mixture of l-teri-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid (XXXVIII) (1.07 mL, 13.99 mmol), HATU (7.09 g, 18.65 mmol) and DIPEA (4.87 mL, 27.97 mmol) in DMF (40 mL) was stirred for 10 min. Then, 6-bromoisoquinolin-3 -amine (XII) (2.08 g, 9.32 mmol) and DMAP (0.23 g, 1.86 mmol) was added then the mixture was heated to 80°C overnight. The reaction mixture was concentrated, the residue partitioned between EtOAc/sat.NaHCC , organic layer separated, washed with water and brine. The organics were then separated and dried (MgSC ) before concentration to dryness. The crude was then purified by flash column chromatography (0→40% EtOAc/hexanes). The desired fractions were concentrated to dryness en vacuo and recrystallized with hexanes to obtain tert-butyl 4-[(6-bromo-3- isoquinolyl)carbamoyl]-4-fluoro-piperidine-l-carboxylate (XXXIX) (2.94 g, 6.50 mmol, 69.7% yield) as a white solid. ESIMS found for C2oH23BrFN303 mlz 452.1 (79BrM+l).
Step 2
[0608] To a suspension of tert-butyl 4-[(6-bromo-3-isoquinolyl)carbamoyl]-4-fluoro- piperidine-l-carboxylate (XXXIX) (1.92 g, 4.24 mmol) in DCM (8 mL) was added TFA (8.mL, 103.84 mmol) at 0°C and the mixture was stirred for 1 h. The solvents were concentrated, triturated with CHCh (3X) and the resulting solids were dried under high vacuo to obtain N-(6-bromo-3- isoquinolyl)-4-fluoro-piperidine-4-carboxamide (XL) (1.979 g, 4.24 mmol, 100% yield) as an off- white solid which was used for next step without further purification. ESIMS found for Ci5Hi5BrFN30 mlz 352.0 (79BrM+l). Step 3
[0609] To a suspension of N-(6-bromo-3-isoquinolyl)-4-fluoro-piperidine-4- carboxamide (XL) (1.98 g, 4.24 mmol) in MeCN (20 mL) was added l-iodo-2 -methyl -propane (0.98 mL, 8.48 mmol) and the mixture was stirred for 30 min. The solvents were concentrated, treated with 7N NH3/MeOH, absorbed on silica gel and purified by column chromatography (0→30% CHC13/10% 7N NH3 Me OH) to obtain N-(6-bromo-3-isoquinolyl)-4-fluoro-l-isobutyl- piperidine-4-carboxamide (XLI) (1.4 g, 3.43 mmol, 80.9% yield) as a beige solid. ESIMS found for Ci9H23BrFN30 mlz 408.1 (79BrM+l).
Step 4
[0610] To a mixture of N-(6-bromo-3-isoquinolyl)-4-fluoro-l-isobutyl-piperidine-4- carboxamide (XLI) (150 mg, 0.370 mmol), lH-triazole (0.04 mL, 0.730 mmol), Cs2C03 (239 mg, 0.730 mmol), N,N-dimethylethylenediamine (6.48 mg, 0.070 mmol) and Cul (O.mL, 0.040 mmol) in DMF (2 mL) was purged with N2 gas for 10 min. The mixture was then heated to 120°C overnight. The reaction mixture was filtered through Celite and to the filtrates, water was added and extracted with EtOAc. The organics were separated, washed with brine, dried over anhydrous Na2S04, and evaporated under vacuo. The crude products were purified by RP-HPLC. The pure fractions were combined and dried under vacuum to obtain N-(6-(2H-l,2,3-triazol-2- yl)isoquinolin-3-yl)-4-fluoro-l-isobutylpiperidine-4-carboxamide (1073) (3.5 mg, 0.008 mmol, 2.2% yield) as an off-white solid; ¾ NMR (499 MHz, DMSO- 6) δ ppm 0.88 (6 H, d, J=6.59 Hz), 1.79 (1 H, dquin, J=13.55, 6.84, 6.84, 6.84, 6.84 Hz), 1.92 - 2.02 (2 H, m), 2.05 - 2.21 (6 H, m), 2.75 - 2.82 (2 H, m), 8.25 (2 H, s), 8.26 - 8.29 (1 H, m), 8.29 - 8.33 (1 H, m), 8.52 (1 H, d, J=1.37 Hz), 8.56 (1 H, s), 9.25 (1 H, s), 10.02 (1 H, br d, J=3.29 Hz); ESIMS found for C2iH25FN60 mlz 397.0 (M+l) and N-(6-(lH-l,2,3-triazol-l-yl)isoquinolin-3-yl)-4-fluoro-l-isobutylpiperidine-4- carboxamide (1074) (2 mg, 0.005 mmol, 1.2% yield) as an off-white solid. ¾ NMR (499 MHz, DMSO- e) δ ppm 0.88 (6 H, d, J=6.59 Hz), 1.79 (1 H, dquin, J=13.46, 6.79, 6.79, 6.79, 6.79 Hz), 1.92 - 2.02 (2 H, m), 2.06 - 2.12 (2 H, m), 2.12 - 2.21 (4 H, m), 2.73 - 2.83 (2 H, m), 8.06 (1 H, d, J=1.10 Hz), 8.19 (1 H, dd, J=8.92, 2.06 Hz), 8.34 (1 H, d, J=9.06 Hz), 8.53 (1 H, d, J=1.92 Hz), 8.58 (1 H, s), 9.03 (1 H, d, J=1.10 Hz), 9.28 (1 H, s), 10.07 (1 H, br d, J=3.84 Hz); ESIMS found for C2iH25FN60 mlz 397.0 (M+l). Example 5.
[0611] Preparation of tra«5-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-4- mo holinocyclohexane-l -carboxamide (1064) is depicted below in Scheme 15.
Figure imgf000147_0001
reflux, 24h
XLIV
Figure imgf000147_0002
1064
Scheme 15
Step 1
[0612] To a mixture of fra«s-4-(fer^butoxycarbonylamino)cyclohexanecarboxylic acid (XLII) ( 1.15 mL, 56.04 mmol), HATU (21.31 g, 56.04 mmol), 6-bromoisoquinolin-3 -amine (XII) (lO.g, 44.83 mmol), and DMAP (1.1 g, 8.97 mmol) in DMF ( 100 mL) was added DIPEA (23.4 mL, 134.49 mmol). The mixture was stirred at 70°C overnight. The reaction mixture was cooled before water (800 mL) was added and stirred for ~2h. The solid was collected by filtration and sequentially washed with aq. sat.NLLCl, water and aq. sat.NaHCC . The solid was dried under high vacuo to obtain tert-butyl tra«5-N-[4-[(6-bromo-3-isoquinolyl)carbamoyl]cyclohexyl] carbamate (XLIII) (17.87 g, 39.86 mmol, 88.9% yield) as a grey solid which was used for next step without further purification. ESIMS found for C2iH26BrN303 m/z 448.1 (79BrM+l). Step 2
[0613] To a stirred solution of fert-butyl tra«s-N-[4-[(6-bromo-3-isoquinolyl) carbamoyl] cyclohexyl] carbamate (XLIII) (5.g, 1 1.15 mmol) in DCM (20 mL) was added TFA (10 mL, 129.8 mmol). The mixture was stirred for 1 h at 25°C. The solvent was concentrated and the residue was treated with 7N NH3/MeOH. The crude product was purified by column chromatography (25→ 100% CHC13/10% 7N NH3 MeOH in CHC13). The pure fractions were combined, concentrated, the residue suspended in EtOAc, sonicated and the solid was collected by filtration, washed with diethyl ether and dried under high vacuo to obtain fra«s-4-amino-N-(6- bromo-3-isoquinolyl)cyclohexanecarboxamide (XLIV) (3 g, 8.61 mmol, 77.2% yield) as a beige solid. ESIMS found for Ci6Hi8BrN30 mlz 348.1 (79BrM+l).
Step 3
[0614] To a mixture of tra«s-4-amino-N-(6-bromo-3-isoquinolyl) cyclohexanecarboxamide (XLIV) (550 mg, 1.58 mmol), l -bromo-2-(2-bromoethoxy)ethane (XLV) (439.53 mg, 1.9 mmol) and K2C03 (654.8 mg, 4.74 mmol) in MeCN (8 mL) was heated to reflux for 24 h. The reaction mixture was concentrated and the residue was taken into DCM, washed with water and brine. The organic layer was then separated and dried (MgSC ) before concentration to dryness. The crude was dissolved in EtOAc, sonicated and the solid was collected by filtration and dried under high vacuo to obtain the desired product tra«5-N-(6-bromo-3-isoquinolyl)-4- morpholino-cyclohexanecarboxamide (XL VI) (320 mg, 0.765 mmol, 48.4% yield) as an off-white solid. ESIMS found for C2oH24BrN302 mlz 418.1 (79BrM+l).
Step 4
[0615] To a mixture of 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) oxazole (XL VII) (62.5 mg, 0.300 mmol), Pd(dppf)Cl2-CH2Cl2 adduct (9.76 mg, 0.010 mmol) and tra«5-N-(6-bromo-3-isoquinolyl)-4-moφholino-cyclohexanecarboxamide (XLVI) ( 100 mg, 0.240 mmol) in MeCN (1 mL) was added a 2 M aqueous solution of K2C03 (0.3 mL, 0.600 mmol). N2 gas was bubbled into the mixture for 10 min and then the solution was heated to 90°C for 0.5 h. The organic layer was carefully separated, absorbed on silica gel and purified by flash column chromatography (0→40% CHC13/10% 7N NH3 in MeOH) followed by preparative TLC. The purified product was suspended in EtOAc, sonicated and the solid was collected by filtration and dried under high vacuo to obtain tra«5-N-[6-(2-methyloxazol-5-yl)-3-isoquinolyl]-4-mo holino- cyclohexanecarboxamide (1064) ( 18 mg, 0.043 mmol, 17.9% yield) as an off-white solid. 'H NMR (499 MHz, DMSO- e) δ ppm 1.16 - 1.27 (2 H, m), 1.42 - 1.56 (2 H, m), 1.91 (4 H, br t, J=11.80 Hz), 2.17 - 2.27 (1 H, m), 2.44 - 2.49 (4 H, m), 2.53 (3 H, s), 3.26 - 3.30 (1 H, m), 3.54 - 3.58 (4 H, m), 7.78 (1 H, s), 7.79 - 7.83 (1 H, m), 8.09 (2 H, dd, J=4.80, 3.98 Hz), 8.50 (1 H, s), 9.10 (1 H, s), 10.51 (1 H, s); ESIMS found for CTAHTXWS mlz 421.2 (M+l).
Example 6.
[0616] Preparation of tra«5-4-(dimethylamino)-N-(6-(2-methyloxazol-5-yl) isoqu
Figure imgf000149_0001
1017
Scheme 16
Step 1
[0617] To a stirred solution of tra«s-4-amino-N-(6-bromo-3-isoquinolyl) cyclohexanecarboxamide (XL VIII) (3 g, 8.61 mmol) in MeOH (50 mL) was added formaldehyde (8.64 mL, 42.93 mmol). After 15 min, Na(OAc)3BH (9.1 g, 42.93 mmol) was added and the mixture was stirred at room temperature for 2 h. The solvents were removed in vacuo, the residue taken in water, basified with IN NaOH solution and extracted with CHCh. The organic layer was separated, washed with water and brine, and dried over anhydrous Na2SC>4. The solvent was concentrated and the crude was suspended in diethyl ether, sonicated and the solid was collected by filtration and dried under high vacuo to obtain the desired product tra«5-N-(6-bromo-3-isoquinolyl)-4- (dimethylamino)cyclohexanecarboxamide (XLIX) (2.28 g,6.06 mmol, 70.3% yield) as a beige solid. ESIMS found for Ci8H22BrN30 mlz 376.1 (79BrM+l). Step 2
[0618] To a mixture of 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) oxazole (L) (138.9 mg, 0.660 mmol), Pd(dppf)Cl2-CH2Cl2 adduct (43.4 mg, 0.050 mmol), a 2 M aqueous solution of K2CO3 (0.66 mL, 1.33 mmol) and fr «5-N-(64oromo-3-isoquinolyl)-4- (dimethylamino)cyclohexanecarboxamide (XLIX) (200 mg, 0.530 mmol) in MeCN (2.5 mL). N2 gas was bubbled into the mixture for 10 min and then the solution was heated to 110°C for 30 min in a microwave. The organic layer was carefully separated, absorbed on silica gel and purified by column chromatography (0→50% CHCI3/IO %7N NH3 Me OH in CHC13). The pure fractions were combined, concentrated and the product was suspended in EtOAc, sonicated and the solid was collected by filtration, washed with diethyl ether and dried under high vacuo to obtain trans- - (dimethylamino)-N-[6-(2-methyloxazol-5-yl)-3-isoquinolyl]cyclohexanecarboxamide (1017) (92 mg, 0.243 mmol, 45.7% yield) as a beige solid. 1H NMR (499 MHz, DMSO- 6) δ ppm 1.14 - 1.23 (2 H, m), 1.43 - 1.54 (2 H, m), 1.83 - 1.95 (4 H, m), 2.10 - 2.16 (1 H, m), 2.18 (6 H, s), 2.44 - 2.49 (1 H, m), 2.53 (3 H, s), 7.78 (1 H, s), 7.79 - 7.84 (1 H, m), 8.06 - 8.13 (2 H, m), 8.50 (1 H, s), 9.10 (1 H, s), 10.49 (1 H, s); ESIMS found for C22H26N4O2 mlz 379.2 (M+l).
Example 7.
[0619] Preparation of tra«5-4-((4-methylpiperazin-l-yl)methyl)-N-(6-(oxazol-5-yl) i
Figure imgf000150_0001
Figure imgf000151_0001
Step 1
[0620] To a mixture of methyl /ra«s-4-(hydroxymethyl)cyclohexanecarboxylate (LI) (5.0 g, 29.03 mmol) imidazole (3.95 g, 58.07 mmol) and fert-butyl-chloro-dimethyl-silane (4.81 g, 31.94 mmol) in DMF (50 mL) was stirred at room temperature for 48 h. The solvents were concentrated to 1/2 volume, water (200 mL) was added and extracted with MTBE. The organic layer was separated and washed with 1 N HCl, ¾0 and brine. The organics were dried over anhydrous Na2SC>4 and the solvent was concentrated to dryness to obtain methyl trans-4-[[tert- butyl(dimethyl)silyl]oxymethyl]cyclohexanecarboxylate (LII) (8.09 g,28.24 mmol, 97.3% yield) as a colorless oil. ESIMS found for Ci5H30O3Si mlz 287.1 (M+l).
Step 2
[0621] To a stirred solution of methyl tra«5-4-[[teri-butyl(dimethyl)silyl]oxymethyl] cyclohexanecarboxylate (LII) (8.05 g, 28.1 mmol) in amixture of THF (20mL) and MeOH (20mL) was added 2 M solution of NaOH (28.1 mL, 56.2 mmol). The mixture was stirred at room temperature for 5 h. The solvent was reduced to 1/3 volume, acidified with 1 N HCl and the resulting solid was filtered, washed with water and dried under high vacuo to obtain 5 grams of the desired product. The filtrates were extracted with EtOAc (2x), washed with water, brine, dried over anhydrous Na2SC>4, concentrated, and dried in vacuo to obtain another 1.1 g of trans-4-[[tert- butyl(dimethyl)silyl]oxymethyl]cyclohexanecarboxylic acid (LIII) (Total 6.1 g, 22.39 mmol, 79.7% yield) as a white solid. ¾ NMR (499 MHz, DMSO- 6) δ ppm 0.01 (6 H, s), 0.83 - 0.87 (8 H, m), 0.88 - 0.96 (2 H, m), 1.19 - 1.32 (2 H, m), 1.32 - 1.43 (1 H, m), 1.74 (2 H, br dd, J=13.31, 3.16 Hz), 1.84 - 1.94 (2 H, m), 2.09 (1 H, tt, J=12.18, 3.46 Hz), 3.38 (2 H, d, J=6.31 Hz), 11.98 (1 H, br s); ESIMS found for Ci4H2803Si mlz 273.1 (M+l).
Step 3
[0622] A mixture of DIPEA (5.86 mL, 33.62 mmol), DMAP (0.27 g, 2.24 mmol) and HATU (5.11 g, 13.45 mmol) in DMF (30mL) was stirred for 10 min. 6-Bromoisoquinolin-3 -amine (XII) (2.5 g, 11.21 mmol) was then added followed by the addition of trans- -[[tert-buty\ (dimethyl)silyl]oxymethyl]cyclohexanecarboxylic acid (LIII) (3.66 g, 13.45 mmol). The mixture was heated to 70°C overnight. An additional 0.5 equiv. of HATU were added and the mixture was continued for additional 6 h. The solvent was concentrated, the residue taken up in EtOAc, washed with sat. NaHCC and brine. The organic layer was then concentrated and the crude product was purified by column chromatography (0→30% EtOAc/hexanes). The pure fractions were combine and concentrated to obtain tra«5-N-(6-bromo-3-isoquinolyl)-4-[[teri-butyl(dimethyl)silyl] oxymethyl]cyclohexanecarboxamide (LIV) (2.25 g, 4.71 mmol, 42.0% yield) as a crystalline off- white solid. ¾ NMR (499 MHz, DMSO-t¾) δ ppm 0.03 (6 H, s), 0.87 (9 H, s), 0.98 (2 H, qd, J=12.72, 3.29 Hz), 1.38 - 1.51 (3 H, m), 1.73 - 1.82 (2 H, m), 1.85 - 1.92 (2 H, m), 2.46 - 2.55 (1 H, m), 3.41 (2 H, d, J=6.04 Hz), 7.62 (1 H, dd, J=8.64, 1.78 Hz), 7.99 (1 H, d, J=8.78 Hz), 8.16 (1 H, d, J=1.65 Hz), 8.44 (1 H, s), 9.13 (1 H, s), 10.53 (1 H, s); ESIMS found for C23H33BrN202Si mlz Ml 2 (79BrM+l).
Step 4
[0623] To a stirred solution of tra«s-N-(6-bromo-3-isoquinolyl)-4-[[fert-butyl (dimethyl)silyl]oxymethyl]cyclohexanecarboxamide (LIV) (2.24 g, 4.69 mmol) in THF (10 mL) was added 1 M solution of TBAF (7.04 mL, 7.04 mmol) in THF. The mixture was stirred at room temperature overnight (monitored by LCMS). Water was added to the reaction mixture and extracted with EtOAc (2x). The organic layer was separated, washed with brine, and dried over anhydrous Na2SC>4. The solvent was concentrated and the crude product was suspended in EtOAc, sonicated and the solid was collected by filtration and dried under high vacuo to obtain trans- - (6-bromo-3-isoquinolyl)-4-(hydroxymethyl)cyclohexanecarboxamide (LV) (1.437 g, 3.96 mmol, 84.3% yield) as a light beige solid. ESIMS found for CivHigBrNzOz mlz 363.1 (79BrM+l). Step 5
[0624] To a stirred solution of DMSO (0.59 mL, 8.26 mmol) in DCM (3 mL) at -78°C was added dropwise under Ar, oxalyl dichloride (0.36 mL, 4.13 mmol) in DCM (1 mL). After 15 min, tra«5-N-(6-bromo-3-isoquinolyl)-4-(hydroxymethyl)cyclohexanecarboxamide (LV) (1.0 g, 2.75 mmol) in a mixture of THF (12 mL) and DMSO (0.5 mL) was added and the mixture was stirred at -78°C for 1 h. Then, TEA (1.15 mL, 8.26 mmol) was added and the mixture was continued to stir for 1 h and warmed to room temperature for 1 h. The reaction mixture was diluted with ¾0 and DCM and the organic layer separated, washed with brine, dried over anhydrous Na2SC>4 and concentrated in vacuo to obtain tra«5-4-formyl-N-[6-( l-methylpyrazol-4-yl)-3-isoquinolyl] cyclohexanecarboxamide (LVI) (215 mg, 0.593 mmol, 108.1% yield) as a white solid which was used for next step without further purification. ESIMS found for Ci7Hi7BrN202 mlz 361.05 (79BrM+ l).
Step 6
[0625] To a mixture of 1-methylpiperazine (0.23 mL, 2.03 mmol), trans-N-{6- bromo-3-isoquinolyl)-4-formyl-cyclohexanecarboxamide (LVI) (490 mg, 1.36 mmol) and in DCE (6 mL) was stirred for 20 min. Then, Na(OAc)3BH (431.2 mg, 2.03 mmol) was added and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM, washed with sat. NaHCC , ¾0 and brine. The organic layer was then separated and dried (MgSO- before concentration to dryness to obtain tra«s-N-(6-bromo-3-isoquinolyl)-4-[(4-methylpiperazin- l-yl)methyl] cyclohexanecarboxamide (LVII) (610 mg, 1.37 mmol, 100% yield) as a beige solid. ESIMS found for C22H29BrN40 mlz 445.1 (79BrM+l).
Step 7
[0626] To a smixture of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)oxazole (LVIII) (54.7 mg, 0.280 mmol), Pd(dppf)Cl2-CH2Cl2 adduct (18.3 mg, 0.020 mmol), and trans- - (6-bromo-3-isoquinolyl)-4-[(4-methylpiperazin-l -yl)methyl]cyclohexanecarboxamide (LVII) (100 mg, 0.220 mmol) was taken in MeCN (1 mL) and was added a 2 M aqueous solution of K2CO3 (0.28 mL, 0.560 mmol). N2 gas was bubbled into the mixture for 10 min and then was heated to 110°C for 0.5 h. The organic layer was separated, absorbed on silica gel and was purified by column chromatography (10→80% CHCL3/10%7N NH3 MeOH in CHC13). The pure fractions were combined, concentrated, the residue suspended in a mixture EtOAc/diethyl ether, sonicated and the resulting solid was collected by filtration and dried under vacuo to obtain trans- -[( - methylpiperazin-l -yl)methyl]-N-(6-oxazol-5-yl-3-isoquinolyl)cyclohexanecarboxamide (1007) (25 mg, 0.058 mmol, 25.7% yield) as a light brown solid. ¾ NMR (499 MHz, DMSO- 6) δ ppm 0.83 - 0.96 (2 H, m), 1.41 - 1.54 (3 H, m), 1.79 - 1.92 (4 H, m), 2.08 (2 H, d, J=7.41 Hz), 2.14 (3 H, s), 2.31 (8 H, br s), 2.52 - 2.56 (1 H, m), 7.86 (1 H, dd, J=8.51, 1.65 Hz), 7.94 (1 H, s), 8.12 (1 H, d, J=8.51 Hz), 8.18 (1 H, s), 8.53 (1 H, s), 8.57 (1 H, s), 9.12 ( 1 H, s), 10.50 (1 H, s); ESIMS found for C25H3iN502 mlz 434.2 (M+l).
Example 8.
[0627] Preparation of l-isobutyl-N-(6-( l-methyl-5-(piperidin-l -ylmethyl)-lH- pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide (822) is depicted below in Scheme 18.
Figure imgf000154_0001
Scheme 18
Steps 1-2
[0628] To a mixture of 6-bromoisoquinolin-3 -amine (XII) (4.0 g, 17.93 mmol), Pd(dppf)Cl2-CH2Cl2 adduct (1.03 g, 1.26 mmol), KOAc (4.39 g, 44.83 mmol) and 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (5.01 g, 19.72 mmol) in 1,4-dioxane (50 mL) was bubbled with N2 for 2 min. The reaction mixture was sealed and heated at 90°C for 1.5 h. The reaction was cooled to room temperature, filtered and washed with EtOAc. The filtrate was concentrated and the residue taken in dioxane (50 mL). To the suspension was added 4-bromo-2-methyl-pyrazole-3-carbaldehyde (LX) (3.39 g, 17.93 mmol) followed by K3P04 (9.52 g, 44.83 mmol), Pd(dppf)Cl2-CH2Cl2 adduct (1.03 g, 1.26 mmol) and water (15 mL). The mixture was purged with N2 for a min, sealed and heated again at 90°C for 19 h. The mixture was cooled to room temperature and concentrated to about 20 mL. The concentrate was diluted with EtOAc and filtered through a pad of Celite. The filtrate was diluted with water and the organic layer separated. The organic layer was washed with brine; dried, filtered and concentrated. The residue was triturated in ether and the resulting solid filtered to afford 4-(3- amino-6-isoquinolyl)-2-methyl-pyrazole-3-carbaldehyde (LXI) (4.1 g, 16.2 mmol, 90.6% yield) as a brown solid. ¾ NMR (499 MHz, DMSO- 6) δ ppm 0.01 (6 H, s), 0.86 (9 H, s), 0.88 - 1.00 (2 H, m), 1.23 - 1.35 (2 H, m), 1.35 - 1.46 (1 H, m), 1.69 - 1.79 (2 H, m), 1.85 - 1.95 (2 H, m), 2.21 (1 H, tt, J=12.21, 3.57 Hz), 3.38 (2 H, d, J=6.31 Hz), 3.57 (3 H, s)ESIMS found for Ci4Hi2N40 mlz 252.95 (M+l).
Step 3
[0629] To a mixture of 4-(3-amino-6-isoquinolyl)-2-methyl-pyrazole-3-carbaldehyde (LXI) (1.07 g, 4.25 mmol), piperidine (0.84 mL, 8.51 mmol) and catalytic HOAc in DCE (10 mL) was stirred for 30 min. Na(OAc)3BH (1.8 g, 8.51 mmol) was added and stirring was continued for 12 h at room temperature. The reaction mixture was quenched with minimum amount of aq. saturated ammonium chloride solution, and concentrated under vacuum. The residue was adsorbed on silica gel and purified by chromatography (0→20% 7N ML-MeOH/CHCh) to obtain 6-[l- methyl-5-(l-piperidylmethyl)pyrazol-4-yl]isoquinolin-3 -amine (LXII) (800 mg, 2.49 mmol, 58.5% yield) as a white solid. ESIMS found for Ci9H23N5 mlz 322.2 (M+l).
Step 4
[0630] To a mixture of l-fert-butoxycarbonylpiperidine-4-carboxylic acid (XXVIII) (1.15mL, 1.63mmol), HATU (703.87 mg, 1.85 mmol) and DIPEA (0.57 mL, 3.27 mmol) in DMF (5mL) was stirred for 10 min. To this mixture was added 6-[l -methyl -5 -(1-piperidylmethyl) pyrazol-4-yl]isoquinolin-3-amine (LXII) (350 mg, 1.09 mmol) and DMAP (26.61 mg, 0.220 mmol) and the mixture was stirred at 50°C overnight. The solvent was concentrated and the residue was taken up in EtOAc, washed with sat. NaHC03, water and brine. The organic layer was then separated and dried (MgS04) before concentrating to dryness. The crude product was purified by column chromatography (25%→100% EtOAc/hexanes). The pure fractions were combined, concentrated, the residue triturated with diethyl ether, sonicated and the solid were collected by filtration and dried under high vacuo to obtain fert-butyl 4-[[6-[ l -methyl -5 -( 1-piperidylmethyl) pyrazol-4-yl]-3-isoquinolyl]carbamoyl]piperidine-l-carboxylate (LXIII) (550 mg, 1.03 mmol, 94.8% yield) as a dark beige solid. ESIMS found for C3oH4oN603 mlz 533.3 (M+l).
Step 5
[0631] To a stirred solution of fert-butyl 4-[[6-[ l-methyl-5-( l-piperidylmethyl) pyrazol-4-yl]-3-isoquinolyl]carbamoyl]piperidine-l-carboxylate (LXIII) (300 mg, 0.560 mmol) in DCM (5 mL) was added TFA (1.23 mL, 15.91 mmol). The mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was adsorbed on silica gel, purified by column chromatography (0-10% 7N.NH4-MeOH/CHCl3), pure fractions were concentrated and the solid were triturated with MeOH, filtered and dried to obtain N-[6-[ 1 -methyl -5 -( 1 -piperidylmethyl) pyrazol-4-yl]-3-isoquinolyl]piperidine-4-carboxamide (LXIV) (191 mg, 0.441 mmol, 78.4% yield) as a white solid. ESIMS found for C25H32N60 mlz 433.3 (M+l).
Step 6
[0632] To stirred mixture of N-[6-[l -methyl-5-(l -piperidylmethyl)pyrazol-4-yl]-3- isoquinolyl]piperidine-4-carboxamide (LXIV) (95 mg, 0.220 mmol) and 2-methylpropanal (0.06 mL, 0.660 mmol) in MeOH (2 mL) was added NaCNBH3 (27.6 mg, 0.440 mmol) at 0°C. The mixture was stirred for 30 min→lh at room temperature. Reaction mixture was quenched with minimum amount of aq. saturated ammonium chloride solution, concentrated under vacuum and the residue was adsorbed on silica gel, purified by chromatography (0→10% 7N.NH3- MeOH/CHCl3) to obtain l -isobutyl-N-[6-[l -methyl-5-( l-piperidylmethyl)pyrazol-4-yl]-3- isoquinolyl]piperidine-4-carboxamide (822) (30 mg, 0.061 mmol, 28.0% yield) as a beige solid. ¾ NMR (499 MHz, DMSO- 6) δ ppm 0.86 (6 H, d, J=6.59 Hz), 1.33 - 1.42 (2 H, m), 1.45 - 1.53 (4 H, m), 1.61 - 1.72 (2 H, m), 1.72 - 1.81 (3 H, m), 1.86 (2 H, td, J=11.60, 1.78 Hz), 2.02 (2 H, d, J=7.41 Hz), 2.36 (4 H, br s), 2.52 - 2.59 (1 H, m), 2.86 (2 H, br d, J=l 1.53 Hz), 3.65 (2 H, s), 3.91 (3 H, s), 7.68 (1 H, dd, J=8.37, 1.51 Hz), 7.79 ( 1 H, s), 8.02 (1 H, d, J=9.33 Hz), 8.03 (1 H, s), 8.46 ( 1 H, s), 9.07 ( 1 H, s), 10.46 (1 H, s); ESIMS found for C29H4oN60 mlz 489.3 (M+l).
Example 9.
[0633] Preparation of 2-[(3R)-3-fluoropyrrolidin-l -yl]-N-[6-( l-methylpyrazol-4-yl)- 3-isoquinolyl]acetamide (274) is depicted below in Scheme 19.
Figure imgf000157_0001
274
Scheme 19
Step 1
[0634] To a stirred suspension of 6-bromoisoquinolin-3-amine (XII) ( 1.0 g, 4.48 mmol) and DMAP ( 109.5 mg, 0.90 mmol) in DCE (35 mL) was added DIPEA (3.12 mL, 17.93 mmol) followed by the addition of 2-chloroacetyl chloride (1.07 mL, 13.45 mmol). The mixture was heated to 75°C overnight. The reaction mixture was then cooled to room temperature, diluted with DCM, washed with H2O and brine, the organic layer were then separated and dried over MgSC>4 before concentrating to dryness. The crude product was then purified by flash column chromatography using EtOAc/hexanes (0→100%) to obtain N-(6-bromo-3-isoquinolyl)-2-chloro- acetamide (LXV) as a light yellow solid (350 mg, 1.16 mmol, 26.1% yield). ESIMS found for CnH8BrClN20 mlz 298.9 (79BrM+H).
Step 2
[0635] To a solution of N-(6-bromo-3-isoquinolyl)-2-chloro-acetamide (LXV) ( 100 mg, 0.33 mmol), (3i?)-3-fluoropyrrolidine hydrochloride (LXVI) (209.6 mg, 1.67 mmol) , KI (0.02 mL, 0.33 mmol) and K2CO3 (461.4 mg, 3.34 mmol) in DMF (2 mL) was heated to 90°C overnight. The reaction was then concentrated to dryness and the residue was taken up in EtOAc and the organic layer was washed with water then brine. The organic layer was then separated and dried over MgSC>4 before concentration to dryness to obtain N-(6-bromo-3-isoquinolyl)-2-[(3R)-3- fluoropyrrolidin-l-yl]acetamide (LXVII) as a dark brown thick gum (1 10 mg, 0.312 mmol, 94.6% yield). Used for next step without purification. ESIMS found for
Figure imgf000157_0002
mlz 352.2 (79BrM+H). Step 3
[0636] To a solution of N-(6-bromo-3-isoquinolyl)-2-[(3R)-3-fluoropyrrolidin-l- yl]acetamide (LXVII) (1 16.2 mg, 0.33 mmol), l-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazolo (LXVIII) (103 mg, 0.50 mmol), Pd(dppf)Cl2 (27 mg, 0.03 mmol) in MeCN (1.5 mL) was added a 2 M aqueous solution of K2CO3 (0.5 mL, 0.99 mmol). N2 gas was bubbled into the mixture for 10 min and then heated to 80°C for 3 h. The organic layer was carefully separated, absorbed on silica gel and purified by flash column chromatography (0→30% CHCl3/10% 7 N NH3 in MeOH). The pure fractions were concentrated, the residue suspended in minimum EtOAc, sonicated and the resulting solid was collected by filtration, washed with diethyl ether and dried to obtain 2-[(3R)-3-fluoropyrrolidin-l -yl]-N-[6-(l -methylpyrazol-4-yl)-3- isoquinolyl]acetamide (274) as a white solid (58.0 mg, 0.164 mmol, 49.7% yield). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 1.88 - 2.03 (m, 1 H), 2.12 - 2.28 (m, 1 H), 2.53 - 2.61 (m, 1 H), 2.86 (ddd, J=32.40, 1 1.80, 4.95 Hz, 1 H), 2.95 - 3.04 (m, 2 H), 3.41 (s, 2 H), 3.90 (s, 3 H), 5.26 (ddd, J=55.80, 6.05, 4.95 Hz, 1 H), 7.77 (dd, J=8.51, 1.37 Hz, 1 H), 8.02 (d, J=8.78 Hz, 1 H), 8.10 (s, 2 H), 8.37 (s, 1 H), 8.44 (s, 1 H), 9.03 (s, 1 H), 10.02 (s, 1 H); ESIMS found for Ci9H2oFN50 mlz 354.1 (M+l).
Example 10.
[0637] Preparation of (S)-N-(6-( l-(methyl-£/3)-lH-pyrazol-4-yl)isoquinolin-3-yl)-2- (pyrrolidin-l-yl)propanamide (971) is depicted below in Scheme 20.
Figure imgf000159_0001
Figure imgf000159_0002
971
Scheme 20
Step 1
[0638] To a stirred suspension of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazole (LXIX) (1.435 g, 7.4 mmol) and Cs2C03 (2.89 g, 8.87 mmol) in DMF ( 15 mL) was added trideuterio(iodo)methane (0.51 mL, 8.13 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filtrates were concentrated and dried under high vacuo to obtain 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l - (trideuteriomethyl)pyrazole (LXX) (3.9 g, 18.48 mmol, 249.8% yield) as a white solid which was used for next step without purification. ESIMS found for CioHi4[2H3]BN202 mlz 212. (M+l).
Step 2
[0639] To a mixture of 6-bromo-3-chloro-isoquinoline (XII) (0.5g, 2.06mmol), 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(trideuteriomethyl)pyrazole (LXX) ( 1.305 g, 6.19 mmol) and SPhos Pd G4 (81.9 mg, 0.100 mmol) in 1,4-dioxane ( 10 mL) and was added a 2 M aqueous solution of K2CO3 (3.88 mL, 7.77 mmol). N2 gas was bubbled into the mixture for 10 min and then the mixture was heated to 1 10°C for 0.5 h in a microwave. The organic layer was carefully separated, absorbed on silica gel and purified by column chromatography (0→100% hexanes/EtOAc) to obtain 3-chloro-6-[ l-(trideuteriomethyl)pyrazol-4-yl]isoquinoline (LXXI) (400 mg, 1.62 mmol, 78.6% yield) as an off-white solid. ESIMS found for Ci3H7[2H3]ClN3 mlz 246.9 (M+l). Step 3
[0640] To a mixture of (S)-2-aminopropanamide HC1 (LXXII) (100 mg, 0.330 mmol), 1,4- dibromobutane (LXXIII) (1.9 mL, 16.06 mmol), K2C03 (4.437 g, 32.1 1 mmol) and KI (266.5 mg, 1.61 mmol) in MeCN (80 mL) was heated to reflux for 40 h. 1 N hydrochloric acid (100 mL) and DCM (100 mL) were added to the reaction mixture. The organic phase is separated off and discarded. The aqueous phase is made basic with a NaOH solution and extracted with CHCh (3x80 ml). The organic layers were combined and dried under high vacuo to obtain (2S)-2-pyrrolidin-l - ylpropanamide (LXXIV) (1.10 g, 7.45 mmol, 46.4% yield) as a white solid which was used for next step without purification. ¾ NMR (499 MHz, DMSO- 6) δ ppm 1.15 (3 H, d, J=6.86 Hz), 1.63 - 1.72 (4 H, m), 2.44 - 2.49 (4 H, m), 2.72 (1 H, q, J=6.68 Hz), 6.88 (1 H, br s), 7.07 (1 H, br s)ESIMS found for C7H14N2O mlz 143.1 (M+l).
Step 4
[0641] To a mixture of (2S)-2-pyrrolidin-l -ylpropanamide (LXXIV) (420.1 mg, 2.95 mmol) BrettPhos Pd G3 (223.2 mg, 0.250 mmol), 3-chloro-6-[l -(trideuteriomethyl)pyrazol-4- yl]isoquinoline (LXXI) (200 mg, 0.810 mmol) and K3PO4 (1.045 g, 4.92 mmol) was taken in 1,4- dioxane (5 mL). N2 gas was bubbled into the mixture for 10 min and then the mixture was heated to 100°C for 16 h. The reaction mixture was filtered through Celite, washed with EtOAc, the filtrates concentrated and the crude product was purified by flash chromatography followed by preparative TLC (50% CHC13/10% 7N NH3 in MeOH) to obtain (2S)-2-pyrrolidin-l-yl-N-[6-[ l- (trideuteriomethyl)pyrazol-4-yl]-3-isoquinolyl]propanamide (971) (150.0 mg, 0.426 mmol, 50.6% yield) as a beige solid. ¾ NMR (499 MHz, DMSO- 6) δ ppm 1.30 (3 H, d, J=6.86 Hz), 1.75 (4 H, br s), 2.59 - 2.69 (4 H, m), 3.29 - 3.32 ( 1 H, m), 7.76 ( 1 H, dd, J=8.51, 1.65 Hz), 8.02 (1 H, d, J=8.51 Hz), 8.08 (2 H, s), 8.35 ( 1 H, s), 8.43 (1 H, s), 9.03 ( 1 H, s), 9.91 (1 H, s); ESIMS found for C2oH2o[2H3]N50 mlz 353.0 (M+l).
Example 11.
[0642] Preparation of N-[6-(3-methylimidazol-4-yl)-3-isoquinolyl]-2-( l-piperidyl) acetamide (275) is depicted below in Scheme 21.
Figure imgf000161_0001
LXXV 275
Scheme 21
Step 1
[0643] To a stirred mixture of N-(6-bromo-3-isoquinolyl)-2-(l-piperidyl)acetamide (LXXV) (100 mg, 0.29 mmol) tributyl-(3-methylimidazol-4-yl)stannane (LXXVI) (117.24 mg, 0.32 mmol) Pd(PPh3)4 (33.2 mg, 0.03 mmol) and cuprous iodide (5.47 mg, 0.03 mmol) in DMF (2 mL) was bubbled N2 gas for 10 min and then heated to 90°C overnight. The reaction mixture was concentrated, absorbed on silica gel and purified by flash column chromatography using CHC13/10% 7 N NH3 in MeOH (0→40%). The pure fractions were concentrated, the residue suspended in diethyl ether, sonicated and the resulting solids were collected by filtration, and dried to obtain N-[6-(3-methylimidazol-4-yl)-3-isoquinolyl]-2-(l-piperidyl)acetamide (275) as a white solid (53.0 mg, 0.152 mmol, 52.3% yield). 'HNMR (DMSO- e, 500 MHz) δ ppm 1.43 (br d, J=4.94 Hz, 2 H), 1.59 (quin, J=5.63 Hz, 4 H), 2.52 (br d, J=5.21 Hz, 4 H), 3.18 (s, 2 H), 3.84 (s, 3 H), 7.33 (br s, 1 H), 7.70 (dd, J=8.51, 1.65 Hz, 1 H), 7.81 (br s, 1 H), 8.06 (s, 1 H), 8.11 (d, J=8.51 Hz, 1 H), 8.53 (s, 1 H), 9.14 (s, 1 H), 9.98 (s, 1 H); ESIMS found for C2oH23N50 mlz 350.2 (M+l).
Example 12.
[0644] Preparation of 1 -methyl -3 -(6-(l -methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)-l - (l-methylpiperidin-4-yl)urea (1037) is depicted below in Scheme 22.
Figure imgf000161_0002
Scheme 22
Step 1
[0645] To a stirred suspension of 6-bromoisoquinolin-3 -amine (XII) (200 mg, 0.900 mmol), DMAP (11 mg, 0.090 mmol) and TEA (0.5 mL, 3.59 mmol) in THF (40 ml) was added trichloromethyl carbonochloridate (0.11 mL, 0.900 mmol) and the mixture was stirred for 1 h at room temperature. N, l-dimethylpiperidin-4-amine (LXXVII) ( 1 15 mg, 0.900 mmol) was then added and the mixture was stirred for 2 h at room temperature. The reaction was concentrated and the residue taken in DCM, washed with water, sat.NaHCC and brine. The organic layer was dried over anhydrous Na2SC>4, solvents removed in vacuo and the crude was purified by colum chromatography (0→10% CHCW7N NH3 in MeOH) to obtain 3-(6-bromo-3-isoquinolyl)-l- methyl-l -( l-methyl-4-piperidyl)urea (LXXVIII) (98 mg, 0.260 mmol, 29.0% yield) as a beige solid. ESIMS found for Ci7H2iBrN40 mlz 377.1 (79BrM+H).
Step 2
[0646] To a mixture of Pd(dppf)Cl2-CH2Cl2 adduct ( 19.6 mg, 0.020 mmol), l-(6- bromo-3-isoquinolyl)-3-(l -methyl-4-piperidyl)urea (LXXVIII) (87 mg, 0.240 mmol), and 1- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (LXVIII) (59.8 mg, 0.290 mmol) in MeCN (5 mL) was added a 2 M aqueous solution of K2CC>3 (0.24 mL, 0.480 mmol). N2 gas was bubbled into the mixture for 10 min and then heated at 1 10°C for 30 min in a microwave. The organic layer was carefully separated, absorbed on silica gel and purified by flash column chromatography (0→10% 7N N¾ in MeOH/CHCh). The pure fractions were combined, concentrated and the residue was triturated from DCM/hexanes. The solid was collected by filtration and dried under high vacuum to obtain 1 -(1 -methyl -4-piperidyl)-3 -[6-(l -methylpyrazol- 4-yl)-3-isoquinolyl]urea (1037) (35 mg, 0.096 mmol, 40.1% yield) as a beige solid. ¾ NMR (499 MHz, DMSO- e) δ ppm 1.52 (2 H, br d, J=10.15 Hz), 1.74 (2 H, qd, J=12.12, 3.70 Hz), 1.93 - 2.02 (2 H, m), 2.17 (3 H, s), 2.82 (2 H, br d, .7=1 1.25 Hz), 2.88 (3 H, s), 3.90 (3 H, s), 4.09 (1 H, tt, J=12.01, 3.91 Hz), 7.65 - 7.72 ( 1 H, m), 7.93 - 7.99 (2 H, m), 8.06 ( 1 H, s), 8.15 (1 H, s), 8.33 (1 H, s), 8.76 (1 H, s), 8.97 ( 1 H, s); ESIMS found for C2iH26N60 mlz 379.2 (M+l).
[0647] The following compounds were prepared in accordance with the procedures described in the above Examples 1-12.
Figure imgf000162_0001
[0648] N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)cyclopropanecarboxamide
1.
[0649] Beige solid (32.0 mg, 0.109 mmol, 31.9% yield). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 0.77 - 0.90 (m, 4 H), 2.03 - 2.12 (m, 1 H), 3.90 (s, 3 H), 7.74 (dd, J=8.51, 1.65 Hz, 1 H), 7.96 - 8.03 (m, 2 H), 8.08 (s, 1 H), 8.35 (s, 1 H), 8.40 (s, 1 H), 9.03 (s, 1 H), 10.83 (s, 1 H); ESIMS found for Ci7Hi6N40 mlz 293.1 (M+l).
Figure imgf000163_0001
3
[0650] 4,4-Difluoro-N-(6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)
cyclohexanecarboxamide 3.
[0651] Beige solid (41.6 mg, 0.1 12 mmol, 56.2% yield). ¾ NMR (DMSO-d6, 500 MHz) δ ppm 1.66 - 1.90 (m, 4 H), 1.91 - 2.00 (m, 2 H), 2.06 - 2.18 (m, 2 H), 2.66 - 2.76 (m, 1 H), 3.90 (s, 3 H), 7.75 (dd, J=8.64, 1.51 Hz, 1 H), 8.00 (d, J=8.51 Hz, 1 H), 8.04 (s, 1 H), 8.08 (s, 1 H), 8.35 (s, 1 H), 8.43 (s, 1 H), 9.03 (s, 1 H), 10.57 (s, 1 H); ESIMS found for C20H20F2N4O mlz 371.2 (M+ l).
Figure imgf000163_0002
4
[0652] tra«5-4-Methoxy-N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl) cyclohexane - 1 -carboxamide 4.
[0653] White solid (101 mg, 0.277 mmol, 62.2% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.07 - 1.17 (2 H, m), 1.43 - 1.56 (2 H, m), 1.84 - 1.95 (2 H, m), 2.03 - 2.1 1 (2 H, m), 2.51 - 2.57 (1 H, m), 3.12 (1 H, tt, J=10.67, 4.15 Hz), 3.25 (3 H, s), 3.90 (3 H, s), 7.74 (1 H, dd, J=8.51, 1.65 Hz), 7.99 ( 1 H, d, J=8.51 Hz), 8.02 (1 H, s), 8.07 (1 H, s), 8.34 ( 1 H, s), 8.42 (1 H, s), 9.02 (1 H, s), 10.42 (1 H, s); ESIMS found for C21H24N4O2 mlz 365.2 (M+l).
Figure imgf000163_0003
[0654] tra«5-N-(6-( l-Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-4- morpholinocyclohexane - 1 -carboxamide 6.
[0655] White solid (36 mg, 0.086 mmol, 30.0% yield). ¾ NMR (499 MHz, DMSO- 6) 5 ppm 1.15 - 1.30 (2 H, m), 1.41 - 1.56 (2 H, m), 1.91 (4 H, br t, J=l 1.1 1 Hz), 2.17 - 2.28 ( 1 H, m), 3.28 (4 H, br s), 3.50 - 3.60 (4 H, m), 3.90 (3 H, s), 7.74 (1 H, dd, J=8.51, 1.65 Hz), 7.99 (1 H, d, .7=8.51 Hz), 8.02 (1 H, s), 8.07 (1 H, s), 8.35 (1 H, s), 8.42 (1 H, s), 9.02 (1 H, s), 10.41 (1 H, s); ESIMS found for C24¾9N502
Figure imgf000164_0001
[0656] trans-4-((3 -Fluoroazetidin- 1 -yl)methyl)-N-(6-( 1 -methyl- lH-pyrazol-4-yl) isoquinolin-3 -yl)cyclohexane - 1 -carboxamide 10.
[0657] White solid (42.0 mg, 0.100 mmol, 36.1% yield). 'HNMR (500 MHz, DMSO- d6) 5 ppm 0.91 (2 H, qd, J=12.67, 3.16 Hz), 1.20 - 1.33 (1 H, m), 1.37 - 1.51 (2 H, m), 1.51 - 1.61 (1 H, m), 1.75 - 1.90 (4 H, m), 2.29 (2 H, d, J=6.86 Hz), 2.96 - 3.08 (2 H, m), 3.48 - 3.60 (2 H, m), 3.90 (3 H, s), 5.02 - 5.22 (1 H, m), 7.73 (1 H, dd, J=8.51, 1.65 Hz), 7.99 (1 H, d, J=8.51 Hz), 8.02 (1 H, s), 8.07 (1 H, s), 8.34 (1 H, s), 8.42 (1 H, s), 9.01 (1 H, s), 10.38 (1 H, s); ESIMS found for C24H28FN5O mlz 422.0 (M+l).
Figure imgf000164_0002
[0658] tra«5-N-(6-(l-Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-4-((4- methylpiperazin-1 -yl)methyl)cyclohexane-l -carboxamide 14.
[0659] White solid (35.0 mg, 0.078 mmol, 28.4% yield). ¾NMR (499 MHz, DMSO- d6) 5 ppm 0.82 - 0.95 (2 H, m), 1.40 - 1.54 (4 H, m), 1.79 - 1.91 (4 H, m), 2.08 (2 H, d, J=7.14 Hz), 2.14 (3 H, s), 2.23 - 2.41 (8 H, m), 3.90 (3 H, s), 7.73 (1 H, dd, J=8.51, 1.37 Hz), 7.99 (1 H, d, J=8.51 Hz), 8.02 (1 H, s), 8.07 (1 H, s), 8.34 (1 H, s), 8.43 (1 H, s), 9.01 (1 H, s), 10.37 (1 H, s); ESIMS found for C26H34N60 mlz 447.0 (M+l).
Figure imgf000164_0003
[0660] N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)azetidine-3 -carboxamide
16.
[0661] Yellow solid (10.8 mg, 0.035 mmol, 62.4% yield). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 3.50 (br s, 2 H), 3.76 (br s, 3 H), 3.90 (s, 3 H), 7.75 (dd, J=8.51, 1.37 Hz, 1 H), 8.00 (d, J=8.51 Hz, 1 H), 8.06 (s, 1 H), 8.09 (s, 1 H), 8.36 (s, 1 H), 8.47 (s, 1 H), 9.02 (s, 1 H), 10.45 (s, 1 H); ESIMS found for Ci7Hi7N50 mlz 308.1 (M+l).
Figure imgf000165_0001
[0662] (S)-2-(3-Fluoropyrrolidin- 1 -yl)-N-(6-( 1 -methyl- lH-pyrazol-4-yl) isoquinolin-3-yl)acetamide 69.
[0663] Off-white solid (70.0 mg, 0.198 mmol, 41.0% yield). 'HNMR (DMSO- 6, 500 MHz) δ ppm 1.87 - 2.04 (m, 1 H), 2.12 - 2.29 (m, 1 H), 2.55 - 2.62 (m, 1 H), 2.81 - 2.94 (m, 1 H), 2.96 - 3.06 (m, 2 H), 3.42 (s, 2 H), 5.17 - 5.35 (m, 1 H), 7.77 (dd, J=8.64, 1.51 Hz, 1 H), 8.02 (d, J=8.78 Hz, 1 H), 8.10 (d, J=0.82 Hz, 2 H), 8.36 (s, 1 H), 8.44 (s, 1 H), 9.03 (s, 1 H), 10.02 (s, 1 H); ESIMS found for Ci9H2oFN50 mlz 354.2 (M+l).
Figure imgf000165_0002
[0664] (S)-N-(6-(l-Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)tetrahydrofuran-2- carboxamide 71.
[0665] Off-white solid (30.0 mg, 0.093 mmol, 59.8% yield). 'HNMR (DMSO- e, 500 MHz) δ ppm 1.83 - 1.96 (m, 2 H), 1.97 - 2.07 (m, 1 H), 2.19 - 2.30 (m, 1 H), 3.83 - 3.88 (m, 1 H), 3.90 (s, 3 H), 3.99 - 4.07 (m, 1 H), 4.53 (dd, J=8.23, 5.76 Hz, 1 H), 7.78 (dd, J=8.51, 1.65 Hz, 1 H), 8.03 (d, J=8.51 Hz, 1 H), 8.10 (s, 2 H), 8.37 (s, 1 H), 8.42 (s, 1 H), 9.05 (s, 1 H), 9.75 (s, 1 H); ESIMS found for Ci8Hi8N402 mlz 323.2 (M+l).
Figure imgf000165_0003
[0666] N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)piperidine -4 -carboxamide
72.
[0667] White solid (75.0 mg, 0.224 mmol, 92.2% yield). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 1.65 (qd, J=12.30, 3.70 Hz, 2 H), 1.81 (br d, J=10.70 Hz, 2 H), 2.64 (td, J=12.28, 2.33 Hz, 2 H), 2.71 (ddt, J=11.32, 7.62, 3.84, 3.84 Hz, 1 H), 3.12 (br d, J=12.35 Hz, 2 H), 3.90 (s, 3 H), 7.75 (dd, J=8.51, 1.37 Hz, 1 H), 8.00 (d, J=8.51 Hz, 1 H), 8.04 (s, 1 H), 8.08 (s, 1 H), 8.35 (s, 1 H), 8.43 (s, 1 H), 9.03 (s, 1 H), 10.50 (s, 1 H); ESIMS found for Ci9H2iN50 mlz 336.1 (M+l).
Figure imgf000166_0001
73
[0668] 1 -Methyl -N-(6 -( 1 -methyl - 1 H-pyrazol -4 -yl)isoquinolin-3 -yl)piperidine -4 - carboxamide 73.
[0669] White solid ( 1 14.0 mg, 0.326 mmol, 42.1% yield). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 1.60 - 1.73 (m, 2 H), 1.73 - 1.80 (m, 2 H), 1.86 (td, J=1 1.66, 2.20 Hz, 2 H), 2.16 (s, 3 H), 2.45 - 2.55 (m, 1 H), 2.81 (br d, J=l 1.53 Hz, 2 H), 3.90 (s, 3 H), 7.74 (dd, J=8.51, 1.65 Hz, 1 H), 8.00 (d, J=8.51 Hz, 1 H), 8.02 (s, 1 H), 8.07 (s, 1 H), 8.35 (s, 1 H), 8.43 (s, 1 H), 9.02 (s, 1 H), 10.46 (s, 1 H); ESIMS found for C2oH23N50 mlz 350.2 (M+l).
Figure imgf000166_0002
75
[0670] l-Isopropyl-N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide 75.
[0671] Off -white solid (43.0 mg, 0.1 14 mmol, 40.22% yield). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 0.97 (d, J=6.31 Hz, 6 H), 1.63 (qd, J=1 1.98, 3.57 Hz, 2 H), 1.78 (br d, J=10.15 Hz, 2 H), 2.1 1 (br t, J=l 1.11 Hz, 2 H), 2.45 - 2.55 (m, 1 H), 2.62 - 2.73 (m, 1 H), 2.83 (br d, J=10.98 Hz, 2 H), 3.90 (s, 3 H), 7.74 (dd, J=8.51, 1.65 Hz, 1 H), 8.00 (d, J=8.51 Hz, 1 H), 8.03 (s, 1 H), 8.08 (d, J=0.82 Hz, 1 H), 8.35 (s, 1 H), 8.44 (s, 1 H), 9.02 (s, 1 H), 10.44 (s, 1 H); ESIMS found for C22H27N50 mlz 378.3 (M+l).
Figure imgf000166_0003
76
[0672] l-Cyclopropyl-N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine- 4-carboxamide 76.
[0673] White solid (42.0 mg, 0.1 12 mmol, 24.6% yield). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 0.25 - 0.33 (m, 2 H), 0.38 - 0.46 (m, 2 H), 1.53 - 1.65 (m, 3 H), 1.76 (br d, J=10.98 Hz, 2 H), 2.1 1 - 2.22 (m, 2 H), 2.51 - 2.60 (m, 1 H), 2.98 (br d, J=1 1.25 Hz, 2 H), 3.90 (s, 3 H), 7.74 (dd, J=8.51, 1.65 Hz, 1 H), 7.99 (d, J=8.51 Hz, 1 H), 8.03 (s, 1 H), 8.07 (s, 1 H), 8.34 (s, 1 H), 8.44 (s, 1 H), 9.02 (s, 1 H), 10.47 (s, 1 H); ESIMS found for C22H25N50 mlz 376.2 (M+l).
Figure imgf000167_0001
77
[0674] l-Isobutyl-N-(6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide 77.
[0675] White solid ( 128 .0 mg, 0.327 mmol, 60.3% yield). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 0.85 (d, J=6.59 Hz, 6 H), 1.60 - 1.73 (m, 2 H), 1.73 - 1.80 (m, 3 H), 1.82 - 1.90 (m, 2 H), 2.01 (d, J=7.41 Hz, 2 H), 2.51 - 2.57 (m, 1 H), 2.86 (br d, J=11.53 Hz, 2 H), 3.90 (s, 3 H), 7.74 (dd, J=8.51, 1.37 Hz, 1 H), 7.99 (d, J=8.51 Hz, 1 H), 8.04 (s, 1 H), 8.08 (s, 1 H), 8.35 (s, 1 H), 8.44 (s, 1 H), 9.02 (s, 1 H), 10.46 (s, 1 H); ESIMS found for C23H29N50 mlz 392.2 (M+l).
Figure imgf000167_0002
78
[0676] N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)-l -neopentylpiperidine-4- carboxamide 78.
[0677] White solid (16.5 mg, 0.041 mmol, 13.7% yield). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 0.85 (s, 9 H), 1.67 - 1.76 (m, 4 H), 2.04 (s, 2 H), 2.16 - 2.26 (m, 2 H), 2.81 (br d, J=1 1.25 Hz, 2 H), 3.90 (s, 3 H), 7.74 (dd, J=8.51, 1.65 Hz, 1 H), 7.99 (d, J=8.51 Hz, 1 H), 8.04 (s, 1 H), 8.08 (s, 1 H), 8.35 (s, 1 H), 8.44 (s, 1 H), 9.02 (s, 1 H), 10.45 (s, 1 H); ESIMS found for C24H3iN50 mlz 406.3 (M+ l).
Figure imgf000167_0003
81
[0678] l-(2-Fluoroethyl)-N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl) piperidine -4 -carboxamide 81.
[0679] White solid (257.0 mg, 0.674 mmol, 62.1% yield). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 1.68 (qd, J=12.12, 3.70 Hz, 2 H), 1.75 - 1.83 (m, 2 H), 2.03 (td, J=11.66, 2.20 Hz, 2 H), 2.51 - 2.56 (m, 1 H), 2.61 (dt, J=28.30, 4.90 Hz, 2 H), 2.91 - 2.99 (m, 2 H), 3.90 (s, 3 H), 4.53 (dt, J=47.75, 4.95 Hz, 2 H), 7.74 (dd, J=8.51, 1.65 Hz, 1 H), 8.00 (d, J=8.51 Hz, 1 H), 8.03 (s, 1 H), 8.07 (s, 1 H), 8.34 (s, 1 H), 8.44 (s, 1 H), 9.02 (s, 1 H), 10.46 (s, 1 H); ESIMS found for C21H24FN5O mlz 382.2 (M+l).
Figure imgf000168_0001
82
[0680] N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)-l -(3,3,3-trifluoropropyl) piperidine-4-carboxamide 82.
[0681] White solid ( 137.0 mg, 0.318 mmol, 54.9% yield). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 1.58 - 1.74 (m, 2 H), 1.79 (br d, J=10.70 Hz, 2 H), 1.92 - 2.02 (m, 2 H), 2.40 - 2.60 (m, 5 H), 2.93 (br d, J=1 1.25 Hz, 2 H), 3.90 (s, 3 H), 7.74 (dd, J=8.51, 1.37 Hz, 1 H), 8.00 (d, J=8.51 Hz, 1 H), 8.03 (s, 1 H), 8.08 (s, 1 H), 8.35 (s, 1 H), 8.44 (s, 1 H), 9.02 (s, 1 H), 10.48 (s, 1 H); ESIMS found for C22H24F
Figure imgf000168_0002
[0682] l-(2,2-Difluoropropyl)-N-(6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl) piperidine-4-carboxamide 83.
[0683] Off-white solid (29.0 mg, 0.070 mmol, 23.5% yield). 'HNMR (DMSO- 6, 500 MHz) δ ppm 1.62 (t, J=19.21 Hz, 3 H), 1.66 - 1.73 (m, 2 H), 1.73 - 1.81 (m, 2 H), 2.21 (td, J=1 1.66, 2.47 Hz, 2 H), 2.50 - 2.57 (m, 1 H), 2.70 (t, J=14.00 Hz, 2 H), 2.94 (br d, J=1 1.53 Hz, 2 H), 3.89 (s, 3 H), 7.74 (dd, J=8.51, 1.65 Hz, 1 H), 7.99 (d, J=8.51 Hz, 1 H), 8.03 (s, 1 H), 8.07 (d, J=0.82 Hz, 1 H), 8.34 (s, 1 H), 8.43 (s, 1 H), 9.01 (s, 1 H), 10.48 (s, 1 H); ESIMS found for C22H25F2N50 mlz 414.2 (M+l).
Figure imgf000168_0003
84
[0684] l-(2,2-Difluoroethyl)-N-(6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl) piperidine-4-carboxamide 84.
[0685] White solid ( 147.0 mg, 0.368 mmol, 7.71% yield). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 1.68 (qd, J=12.12, 3.70 Hz, 2 H), 1.74 - 1.83 (m, 2 H), 2.14 - 2.23 (m, 2 H), 2.52 - 2.59 (m, 1 H), 2.72 (td, J=15.57, 4.25 Hz, 2 H), 2.96 (br d, J=1 1.53 Hz, 2 H), 3.90 (s, 3 H), 6.13 (tt, J=55.75, 4.15 Hz, 1 H), 7.74 (dd, J=8.51, 1.65 Hz, 1 H), 8.00 (d, J=8.51 Hz, 1 H), 8.03 (s, 1 H), 8.07 (s, 1 H), 8.34 (s, 1 H), 8.44 (s, 1 H), 9.02 (s, 1 H), 10.47 (s, 1 H); ESIMS found for C2iH23F2N50 mlz 400.2 (M+l).
Figure imgf000169_0001
85
[0686] l-(2-Fluoro-2-methylpropyl)-N-(6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3- yl)piperidine-4-carboxamide 85.
[0687] Off-white solid (1 10.0 mg, 0.269 mmol, 47.4% yield). ¾ NMR (DMSO- 6, 500 MHz) 5 ppm 1.31 (d, J=21.45 Hz, 6 H), 1.64 - 1.81 (m, 4 H), 2.10 (td, J=l 1.53, 2.74 Hz, 2 H), 2.45 (t, J=22.85 Hz, 2 H), 2.51 - 2.57 (m, 1 H), 2.95 (br d, J=1 1.53 Hz, 2 H), 3.90 (s, 3 H), 7.74 (dd, J=8.51, 1.37 Hz, 1 H), 8.00 (d, J=8.51 Hz, 1 H), 8.04 (s, 1 H), 8.08 (s, 1 H), 8.35 (s, 1 H), 8.44 (s, 1 H), 9.02 (s, 1 H), 10.46 (s, 1 H); ESIMS found for C23H28FN50 mlz 410.2 (M+l).
Figure imgf000169_0002
87
[0688] N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)-l -((3-methyloxetan-3 -yl) methyl)piperidine-4-carboxamide 87.
[0689] White solid (58.0 mg, 0.138 mmol, 57.8% yield). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 1.31 (s, 3 H), 1.59 - 1.70 (m, 2 H), 1.71 - 1.79 (m, 2 H), 1.97 (td, J=l 1.53, 2.47 Hz, 2 H), 2.48 (s, 2 H), 2.51 - 2.57 (m, 1 H), 2.62 (br d, J=l 1.25 Hz, 2 H), 3.90 (s, 3 H), 4.19 (d, J=5.49 Hz, 2 H), 4.36 (d, J=5.76 Hz, 2 H), 7.74 (dd, J=8.51, 1.65 Hz, 1 H), 8.00 (d, J=8.51 Hz, 1 H), 8.04 (s, 1 H), 8.08 (s, 1 H), 8.35 (s, 1 H), 8.44 (s, 1 H), 9.02 (s, 1 H), 10.47 (s, 1 H); ESIMS found for C24H29N502 mlz 420.3 (M+l).
Figure imgf000169_0003
89
[0690] l-(2-Methoxyethyl)-N-(6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl) piperidine-4-carboxamide 89. [0691] White solid (32.0 mg, 0.081 mmol, 28.7% yield). ¾ NMR (OMSO-d6, 500 MHz) 5 ppm 1.59 - 1.71 (m, 2 H), 1.73 - 1.81 (m, 2 H), 1.92 - 2.04 (m, 2 H), 2.46 (t, J=5.90 Hz, 2 H), 2.51 - 2.58 (m, 1 H), 2.92 (br d, J=1 1.25 Hz, 2 H), 3.24 (s, 3 H), 3.43 (t, J=6.04 Hz, 2 H), 3.90 (s, 3 H), 7.74 (dd, J=8.51, 1.65 Hz, 1 H), 8.00 (d, J=8.51 Hz, 1 H), 8.03 (s, 1 H), 8.08 (d, J=0.82 Hz, 1 H), 8.35 (s, 1 H), 8.44 (s, 1 H), 9.02 (s, 1 H), 10.46 (s, 1 H); ESIMS found for C22H27N502 mlz 394.2 (M+l).
Figure imgf000170_0001
90
[0692] l-(2-Isopropoxyethyl)-N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl) piperidine-4-carboxamide 90.
[0693] Off-white solid (71.0 mg, 0.168 mmol, 56.5% yield). 'HNMR (DMSO- e, 500 MHz) 5 ppm 1.08 (d, J=6.04 Hz, 7 H), 1.59 - 1.71 (m, 2 H), 1.73 - 1.82 (m, 2 H), 1.98 (td, J=l 1.60, 2.06 Hz, 2 H), 2.44 (t, J=6.17 Hz, 2 H), 2.51 - 2.58 (m, 1 H), 2.92 (br d, J=l 1.53 Hz, 2 H), 3.46 (t, J=6.31 Hz, 2 H), 3.53 (dt, J=12.14, 6.14 Hz, 1 H), 3.90 (s, 3 H), 7.74 (dd, J=8.64, 1.51 Hz, 1 H), 7.99 (d, J=8.51 Hz, 1 H), 8.03 (s, 1 H), 8.08 (s, 1 H), 8.35 (s, 1 H), 8.44 (s, 1 H), 9.02 (s, 1 H), 10.45 (s, 1 H); ESIMS found for C24H3iN502 mlz 422.2 (M+l).
Figure imgf000170_0002
91
[0694] 4-Fluoro-N-(6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide 91.
[0695] White solid (54.0 mg, 0.153 mmol). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 1.79 - 1.90 (m, 2 H), 1.93 - 2.12 (m, 2 H), 2.74 (td, J=12.28, 2.33 Hz, 2 H), 2.86 - 2.94 (m, 2 H), 3.90 (s, 3 H), 7.81 (dd, J=8.64, 1.51 Hz, 1 H), 8.05 (d, J=8.51 Hz, 1 H), 8.09 (s, 1 H), 8.12 (s, 1 H), 8.36 (s, 1 H), 8.40 (s, 1 H), 9.08 (s, 1 H), 9.78 (d, J=4.39 Hz, 1 H); ESIMS found for Ci9H20FN5O mlz 354.2 (M+l).
Figure imgf000170_0003
92 [0696] 4-Fluoro-l -methyl -N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl) piperidine -4 -carboxamide 92.
[0697] White solid (57.0 mg, 0.155 mmol, 68.5% yield). ¾ NMR DMSO-d6, 500 MHz) δ ppm 1.89 - 2.01 (m, 2 H), 2.05 - 2.20 (m, 4 H), 2.22 (s, 3 H), 2.69 - 2.77 (m, 2 H), 3.91 (s, 3 H), 7.81 (dd, J=8.51, 1.37 Hz, 1 H), 8.05 (d, J=8.78 Hz, 1 H), 8.09 (s, 1 H), 8.1 1 (s, 1 H), 8.36 (s, 1 H), 8.40 (s, 1 H), 9.08 (s, 1 H), 9.87 (d, J=4.12 Hz, 1 H); ESIMS found for C2oH22FN50 mlz 368.2 (M+l).
Figure imgf000171_0001
[0698] 4-Fluoro-l -isobutyl-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl) piperidine -4 -carboxamide 96.
[0699] White solid (37.0 mg, 0.090 mmol, 39.9% yield). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 0.88 (d, J=6.59 Hz, 6 H), 1.74 - 1.85 (m, 1 H), 1.91 - 2.01 (m, 2 H), 2.09 (d, J=7.41 Hz, 2 H), 2.1 1 - 2.21 (m, 4 H), 2.78 (br d, J=8.23 Hz, 2 H), 3.90 (s, 3 H), 7.81 (dd, J=8.51, 1.65 Hz, 1 H), 8.05 (d, J=8.51 Hz, 1 H), 8.10 (s, 1 H), 8.12 (s, 1 H), 8.37 (s, 1 H), 8.40 (s, 1 H), 9.08 (s, 1 H), 9.86 (d, J=4.39 Hz, 1 H); ESIMS found for C23H28FN5O mlz 410.2 (M+l).
Figure imgf000171_0002
110
[0700] (S)-N-(6-(l -Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-3- carboxamide 110.
[0701] White solid (37.7 mg, 0.1 12 mmol, 47.0% yield). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 1.34 - 1.48 (m, 1 H), 1.55 - 1.64 (m, 1 H), 1.64 - 1.73 (m, 1 H), 1.81 - 1.92 (m, 1 H), 2.52 - 2.67 (m, 2 H), 2.71 - 2.85 (m, 2 H), 2.98 (dd, J=l 1.94, 3.16 Hz, 1 H), 3.90 (s, 3 H), 7.74 (dd, J=8.51, 1.65 Hz, 1 H), 8.00 (d, J=8.51 Hz, 1 H), 8.03 (s, 1 H), 8.08 (s, 1 H), 8.35 (s, 1 H), 8.42 (s, 1 H), 9.01 (s, 1 H), 10.75 (s, 1 H); ESIMS found for Ci9H2iN50 mlz 336.1 (M+l).
Figure imgf000171_0003
[0702] (R)-N-(6-(l -Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-3- carboxamide 111.
[0703] White solid (6.5 mg, 0.019 mmol, 44.8% yield). ¾ NMR (DMSO-d6, 500 MHz) δ ppm 1.33 - 1.49 (m, 1 H), 1.55 - 1.64 (m, 1 H), 1.64 - 1.74 (m, 1 H), 1.81 - 1.93 (m, 1 H), 2.52 - 2.66 (m, 2 H), 2.71 - 2.86 (m, 2 H), 2.98 (dd, J=l 1.80, 2.74 Hz, 1 H), 3.90 (s, 3 H), 7.74 (dd, J=8.64, 1.51 Hz, 1 H), 8.00 (d, J=8.51 Hz, 1 H), 8.03 (s, 1 H), 8.08 (s, 1 H), 8.35 (s, 1 H), 8.42 (s, 1 H), 9.01 (s, 1 H), 10.75 (s, 1 H); ESIMS found for Ci9H2iN50 mlz 336.2 (M+1).
Figure imgf000172_0001
112
[0704] (S)-l -Isobutyl-N-(6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine- 3 -carboxamide 112.
[0705] Beige solid (17.8 mg, 0.045 mmol, 4.7% yield). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 0.88 (d, J=6.59 Hz, 3 H), 0.90 (d, J=6.59 Hz, 3 H), 1.48 - 1.60 (m, 2 H), 1.64 - 1.73 (m, 1 H), 1.77 - 1.86 (m, 2 H), 2.07 (d, J=7.41 Hz, 2 H), 2.10 (br dd, J=4.25, 3.16 Hz, 1 H), 2.30 (br d, J=7.14 Hz, 1 H), 2.55 - 2.63 (m, 1 H), 2.76 (br d, J=7.68 Hz, 2 H), 3.90 (s, 3 H), 7.74 (dd, J=8.51, 1.65 Hz, 1 H), 8.00 (d, J=8.78 Hz, 1 H), 8.04 (s, 1 H), 8.08 (s, 1 H), 8.35 (s, 1 H), 8.42 (s, 1 H), 9.01 (s, 1 H), 10.68 (s, 1 H); ESIMS found for C23H29N50 mlz 392.2 (M+1).
Figure imgf000172_0002
113
[0706] (R)-l -Isobutyl-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)piperidine- 3 -carboxamide 113.
[0707] Beige solid (1 10 mg, 0.281 mmol, 26.8% yield). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 0.88 (3 H, d, J=6.59 Hz), 0.90 (3 H, d, J=6.59 Hz), 1.49 - 1.59 (2 H, m), 1.68 (1 H, br dd, J=8.23, 3.29 Hz), 1.76 - 1.88 (2 H, m), 2.07 (2 H, d, J=7.41 Hz), 2.10 (1 H, br s), 2.30 ( 1 H, br d, J=6.59 Hz), 2.55 - 2.62 (1 H, m), 2.76 (2 H, br d, J=7.68 Hz), 3.90 (3 H, s), 7.74 (1 H, dd, J=8.51, 1.37 Hz), 8.00 (1 H, d, J=8.51 Hz), 8.04 ( 1 H, s), 8.08 (1 H, s), 8.35 (1 H, s), 8.42 (1 H, s), 9.01 ( 1 H, s), 10.68 (1 H, s); ESIMS found for C23H29N50 mlz 392.2 (M+1).
Figure imgf000173_0001
114
[0708] N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)tetrahydro-2H-pyran-4- carboxamide 114.
[0709] White solid (95.0 mg, 0.282 mmol, 63.3% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.62 - 1.80 (m, 4 H), 2.76 - 2.87 (m, 1 H), 3.32 - 3.38 (m, 2 H), 3.90 (s, 3 H), 3.91 - 3.95 (m, 2 H), 7.74 (dd, J=8.51, 1.65 Hz, 1 H), 8.00 (d, J=8.51 Hz, 1 H), 8.04 (s, 1 H), 8.08 (s, 1 H), 8.35 (s, 1 H), 8.44 (s, 1 H), 9.03 (s, 1 H), 10.49 (s, 1 H); ESIMS found for C19H20N4O2 mlz 337.15 (M+ l).
Figure imgf000173_0002
[0710] N-(6-(l -Methyl- lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-l-yl) acetamide 115.
[0711] Off-white solid (23.0 mg, 0.066 mmol, 16.5% yield). 'HNMR (DMSO- e, 500 MHz) δ ppm 1.43 (2 H, br d, J=4.39 Hz), 1.59 (4 H, quin, J=5.56 Hz), 2.52 (4 H, br s), 3.17 (2 H, s), 3.90 (3 H, s), 7.77 ( 1 H, dd, J=8.51, 1.37 Hz), 8.02 ( 1 H, d, J=8.51 Hz), 8.10 (2 H, s), 8.37 (1 H, s), 8.43 (1 H, s), 9.04 ( 1 H, s), 9.91 ( 1 H, s); ESIMS found for C2oH23N50 mlz 350.2 (M+l).
Figure imgf000173_0003
116
[0712] 2-(4-Fluoropiperidin-l-yl)-N-(6-(l -methyl- lH-pyrazol-4-yl)isoquinolin-3- yl)acetamide 116.
[0713] Off-white solid (80.0 mg, 0.218 mmol, 44.3% yield). 'HNMR (DMSO- e, 500 MHz) δ ppm 1.73 - 1.86 (2 H, m), 1.87 - 2.01 (2 H, m), 2.54 (2 H, ddd, J=1 1.39, 7.41, 3.70 Hz), 2.67 - 2.76 (2 H, m), 3.24 (2 H, s), 4.66 - 4.83 (1 H, m), 7.77 (1 H, dd, J=8.51, 1.65 Hz), 8.02 ( 1 H, d, J=8.51 Hz), 8.10 (2 H, s), 8.36 ( 1 H, s), 8.44 ( 1 H, s), 9.04 ( 1 H, s), 9.98 (1 H, s); ESIMS found for C2oH22FN50 mlz 368.2 (M+ l).
Figure imgf000174_0001
118
[0714] N-(6-(l -Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-l - yl)acetamide 118.
[0715] Beige solid ( 18.0 mg, 0.049 mmol, 59.8% yield). ¾ NMR DMSO-d6, 500 MHz) δ ppm 2.19 (3 H, s), 2.33 - 2.46 (4 H, m), 2.58 (4 H, br s), 3.22 (2 H, s), 3.90 (3 H, s), 7.77 ( 1 H, dd, J=8.51, 1.65 Hz), 8.02 (1 H, d, J=8.51 Hz), 8.10 (2 H, s), 8.37 (1 H, s), 8.43 ( 1 H, s), 9.04 ( 1 H, s), 9.93 ( 1 H, s); ESIMS found for C2oH24N60 mlz 365.2 (M+l).
Figure imgf000174_0002
119
[0716] N-(6-(l,2-Dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)
cyclopropanecarboxamide 119.
[0717] Beige solid (70.0 mg, 0.228 mmol, 28.9% yield). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 0.78 - 0.91 (4 H, m), 2.02 - 2.13 ( 1 H, m), 2.39 (3 H, s), 3.65 (3 H, s), 7.1 1 ( 1 H, s), 7.59 (1 H, dd, J=8.51, 1.37 Hz), 7.88 (1 H, s), 8.07 (1 H, d, J=8.51 Hz), 8.49 ( 1 H, s), 9.12 (1 H, s), 10.89 (1 H, s); ESIMS found for Ci8Hi8N40 mlz 307.1 (M+l).
Figure imgf000174_0003
120
[0718] N-(6-(l,2-Dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)
cyclohexanecarboxamide 120.
[0719] Beige solid (20.0 mg, 0.056 mmol, 18.7% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.17 - 1.34 (3 H, m), 1.44 (2 H, qd, J=12.21, 2.61 Hz), 1.66 (1 H, br d, J=l 1.53 Hz), 1.71 - 1.79 (2 H, m), 1.83 (2 H, br d, J=13.17 Hz), 2.39 (3 H, br s), 2.52 - 2.62 (1 H, m), 3.66 (3 H, s), 7.13 (1 H, br s), 7.58 ( 1 H, dd, J=8.51, 1.37 Hz), 7.89 (1 H, s), 8.07 ( 1 H, d, J=8.51 Hz), 8.51 (1 H, s), 9.1 1 (1 H, s), 10.43 (1 H, s); ESIMS found for C21H24N4O mlz 349.0 (M+l).
Figure imgf000175_0001
121
[0720] N-(6-(l,2-Dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-4,4- difluorocyclohexanecarboxamide 121.
[0721] Off-white solid (40.0 mg, 0.104 mmol, 38.4% yield). 'HNMR (DMSO-de, 500 MHz) δ ppm 1.66 - 1.76 (2 H, m), 1.77- 1.91 (2 H, m), 1.92-2.01 (2 H, m), 2.08 -2.21 (2 H, m), 2.39 (3 H, s), 2.71 (1 H, br t, J=10.43 Hz), 3.66 (3 H, s), 7.12 (1 H, br s), 7.61 (1 H, dd, J=8.51, 1.37 Hz), 7.91 (1 H, s), 8.08 (1 H, d,J=8.51 Hz), 8.51 (1 H, s), 9.12 (1 H, s), 10.63 (1 H, s); ESIMS found for C21H22F2N4O mlz 385.2 (M+l).
Figure imgf000175_0002
188
[0722] (S)-N-(6-(l,2-Dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)tetrahydrofuran- 2-carboxamide 188.
[0723] Light yellow solid (60.0 mg, 0.178 mmol, 57.3% yield). ¾ NMR (DMSO- 6, 500 MHz)5ppm 1.83 - 1.95 (2 H,m), 1.97 - 2.07 (1 H, m), 2.19 - 2.30 (1 H, m), 2.39 (3 H, s),3.67 (3 H, s), 3.82 - 3.91 (1 H, m), 3.98 - 4.07 (1 H, m), 4.54 (1 H, dd, J=8.23, 5.49 Hz), 7.13 (1 H, s), 7.64 (1 H, dd,J=8.51, 1.65 Hz), 7.96 (1 H, s), 8.11 (1 H, d,J=8.51 Hz), 8.50 (1 H, s), 9.14 (1 H, s), 9.85 (1 H, s); ESIMS foun (M+l).
Figure imgf000175_0003
248
[0724] N-(6-( 1 -Methyl- 1H- 1 ,2,3 -triazol-5 -yl)isoquinolin-3 -yl)- 1 -(3 ,3 ,3 - trifluoropropyl)piperidine-4-carboxamide 248.
[0725] Off-white solid (99.0 mg, 0.229 mmol, 50.3% yield). 'HNMR (DMSO- e, 500 MHz)5ppm 1.61 - 1.74(m,2H), 1.80 (br d, J=10.70 Hz, 2 H), 1.97 (brt, J=ll.ll Hz, 2 H), 2.40 - 2.61 (m, 5 H), 2.89 - 3.00 (m, 2 H), 4.20 (s, 3 H), 7.68 - 7.77 (m, 1 H), 8.10 (s, 1 H), 8.17 - 8.21 (m, 2 H), 8.60 (s, 1 H), 9.21 (s, 1 H), 10.62 (br s, 1 H); ESIMS found for C2iH23F3N60 mlz 433.2 (M+l).
Figure imgf000176_0001
262
[0726] N-(6-( 1 -Methyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-l -(3 ,3 ,3 -trifluoropropyl) piperidine -4 -carboxamide 262.
[0727] White solid (82.5 mg, 0.191 mmol, 82.4% yield). ¾ NMR DMSO-d6, 500 MHz) δ ppm 1.68 (qd, J=12.17, 3.57 Hz, 2 H), 1.81 (br d, J=1 1.25 Hz, 2 H), 1.97 - 2.1 1 (m, 2 H), 2.50 (dt, J=3.64, 1.89 Hz, 2 H), 2.52 - 2.62 (m, 3 H), 2.97 (br d, J=10.43 Hz, 2 H), 3.83 (s, 3 H), 7.30 (d, J=0.82 Hz, 1 H), 7.67 (dd, J=8.51, 1.65 Hz, 1 H), 7.80 (s, 1 H), 8.00 (s, 1 H), 8.08 (d, J=8.51 Hz, 1 H), 8.54 (s, 1 H), 9.12 (s, 1 H), 10.55 (s, 1 H); ESIMS found for C22H24F3N50 mlz 432.2 (M+l).
Figure imgf000176_0002
263
[0728] 4,4-Difluoro-N-(6-( l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)
cyclohexanecarboxamide 263.
[0729] White solid (60.0 mg, 0.162 mmol, 46.0% yield). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 1.63 - 1.76 (m, 2 H), 1.76 - 1.91 (m, 2 H), 1.95 (br d, J=12.90 Hz, 2 H), 2.06 - 2.20 (m, 2 H), 2.71 (br t, J=10.84 Hz, 1 H), 3.83 (s, 3 H), 7.30 (d, J=0.82 Hz, 1 H), 7.67 (dd, J=8.37, 1.78 Hz, 1 H), 7.79 (s, 1 H), 8.01 (d, J=0.82 Hz, 1 H), 8.09 (d, J=8.78 Hz, 1 H), 8.53 (s, 1 H), 9.13 (s, 1 H), 10.64 (s, 1 H); ESIMS found for C20H20F2N4O mlz 371.2 (M+l).
Figure imgf000176_0003
264
[0730] 1 -Methyl -N-(6 -( 1 -methyl - 1 H-pyrazol -3 -yl)isoquinolin-3 -yl)piperidine -4 - carboxamide 264.
[0731] White solid (36.5 mg, 0.104 mmol, 48.5% yield). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 1.60 - 1.72 (m, 2 H), 1.74 - 1.80 (m, 2 H), 1.86 (td, J=1 1.60, 2.06 Hz, 2 H), 2.16 (s, 3 H), 2.45 - 2.56 (m, 1 H), 2.81 (br d, J=l 1.25 Hz, 2 H), 3.93 (s, 3 H), 6.93 (d, J=2.20 Hz, 1 H), 7.81 (d, J=2.20 Hz, 1 H), 7.95 - 8.01 (m, 1 H), 8.01 - 8.08 (m, 1 H), 8.20 (s, 1 H), 8.49 (s, 1 H), 9.07 (s, 1 H), 10.49 (s, 1 H); ESIMS found for C2oH23N50 mlz 350.2 (M+l).
Figure imgf000177_0001
265
[0732] N-(6-(5,6,7,8-Tetrahydroimidazo[ l,2- ]pyrazin-3-yl)isoquinolin-3-yl) cyclopropanecarboxamide 265.
[0733] Off-white solid (168.0 mg, 0.504 mmol, 87.3% yield). ¾ NMR (DMSO-d6, 500 MHz) δ ppm 0.78 - 0.90 (m, 4 H), 2.03 - 2.13 (m, 1 H), 2.77 (br s, 1 H), 3.07 (t, J=5.35 Hz, 2 H), 3.95 (s, 2 H), 4.10 (t, J=5.35 Hz, 2 H), 7.28 (s, 1 H), 7.65 (dd, J=8.51, 1.65 Hz, 1 H), 7.91 (s, 1 H), 8.06 (d, J=8.51 Hz, 1 H), 8.49 (s, 1 H), 9.10 (s, 1 H), 10.87 (s, 1 H); ESIMS found for Ci9Hi9N50 mlz 334.1 (M+l).
Figure imgf000177_0002
266
[0734] N-(6-(7-Methyl-5,6,7,8-tetrahydroimidazo[ l,2- ]pyrazin-3-yl)isoquinolin-3- yl)cyclopropanecarboxamide 266.
[0735] White solid (75.0 mg, 0.216 mmol, 69.9% yield). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 0.77 - 0.90 (m, 4 H), 2.01 - 2.13 (m, 1 H), 2.42 (s, 3 H), 2.80 (t, J=5.35 Hz, 2 H), 3.63 (s, 2 H), 4.21 (t, J=5.35 Hz, 2 H), 7.29 (s, 1 H), 7.66 (dd, J=8.51, 1.65 Hz, 1 H), 7.95 (s, 1 H), 8.06 (d, J=8.51 Hz, 1 H), 8.49 (s, 1 H), 9.10 (s, 1 H), 10.87 (s, 1 H); ESIMS found for C2oH2iN50 mlz 348.2 (M+l).
Figure imgf000177_0003
[0736] 3,3-Difluoro-N-(6-(5-methyl-4,5,6,7-tetrahydropyrazolo[l,5- ]pyrazin-3-yl) isoquinolin-3-yl)cyclobutanecarboxamide 267.
[0737] Beige solid (65.0 mg, 0.164 mmol, 28.5% yield). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 2.55 (br s, 2 H), 2.75 - 2.88 (m, 4 H), 2.93 - 3.10 (m, 1 H), 3.94 - 4.10 (m, 1 H), 4.21 (br s, 2 H), 7.66 (dd, J=8.51, 1.65 Hz, 1 H), 7.79 (s, 1 H), 8.02 (s, 1 H), 8.05 (d, J=8.51 Hz, 1 H), 8.52 (s, 1 H), 9.08 (s, 1 H), 10.76 for C2iH2iF2N50 mlz 398.2 (M+l).
Figure imgf000178_0001
268
[0738] N-(6-( 1 ,2-Dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-3 ,3 - difluorocyclobutanecarboxamide 268.
[0739] White solid (67.0 mg, 0.188 mmol, 49.3% yield). ¾ NMR (DMSO- 6, 500 MHz) δ ppm 2.39 (s, 3 H), 2.76 - 2.92 (m, 4 H), 3.27 - 3.36 (m, 1 H), 3.67 (s, 3 H), 7.12 (s, 1 H), 7.62 (dd, J=8.51, 1.65 Hz, 1 H), 7.93 (s, 1 H), 8.09 (d, J=8.51 Hz, 1 H), 8.55 (s, 1 H), 9.13 (s, 1 H), 10.80 (s, 1 H); ESIMS found for C19H18F2N4O mlz 357.1 (M+l).
Figure imgf000178_0002
269
[0740] 2,2,3,3-Tetramethyl-N-[6-(3-methylimidazol-4-yl)-3-isoquinolyl] cyclopropanecarboxamide 269.
[0741] Light yellow solid ( 132.0 mg, 0.379 mmol, 65.3% yield). ¾ NMR (DMSO- d6, 500 MHz) δ ppm 1.19 (s, 6 H), 1.28 (s, 6 H), 1.63 (s, 1 H), 3.83 (s, 3 H), 7.26 - 7.40 (m, 1 H), 7.64 (dd, J=8.51, 1.37 Hz, 1 H), 7.75 - 7.87 (m, 1 H), 8.00 (s, 1 H), 8.06 (d, J=8.51 Hz, 1 H), 8.52 (s, 1 H), 9.09 (s, 1 H), 10.51 (s, 1 H); ESIMS found for C21H24N4O mlz 349.2 (M+l).
Figure imgf000178_0003
270
[0742] N-(6-( 1 -Methyl- lH-pyrazol-5 -yl)isoquinolin-3 -yl)-l -(3 ,3 ,3 -trifluoropropyl) piperidine-4-carboxamide 270.
[0743] Off-white solid (45.0 mg, 0.104 mmol, 44.9% yield). 'HNMR (DMSO- 6, 500 MHz) δ ppm 1.61 - 1.75 (m, 2 H), 1.75 - 1.86 (m, 2 H), 1.98 (br d, J=1.92 Hz, 2 H), 2.42 - 2.63 (m, 5 H), 2.95 (br d, J=1.10 Hz, 2 H), 3.97 (s, 3 H), 6.60 (d, J=1.92 Hz, 1 H), 7.54 (d, J=1.92 Hz, 1 H), 7.66 (dd, J=8.37, 1.51 Hz, 1 H), 8.07 (s, 1 H), 8.14 (d, J=8.51 Hz, 1 H), 8.58 (s, l H), 9.18 (s, 1 H), 10.60 (s, 1 H); ESIMS found for C22H24F3N50 mlz 432.2 (M+l).
Figure imgf000179_0001
272
[0744] 2-(4-Isobutylpiperazin- 1 -yl)-N-[6-( 1 -methylpyrazol-4-yl)-3 -isoquinolyl] acetamide 272.
[0745] Off-white solid (39.0 mg, 0.096 mmol, 29.1% yield). 'HNMR DMSO-d6, 500 MHz) δ ppm 0.85 (d, J=6.59 Hz, 6 H), 1.76 (dquin, J=13.64, 6.81, 6.81, 6.81, 6.81 Hz, 1 H), 2.06 (d, J=7.41 Hz, 2 H), 2.41 (br s, 4 H), 2.58 (br s, 4 H), 3.22 (s, 2 H), 3.90 (s, 3 H), 7.77 (dd, J=8.51, 1.65 Hz, 1 H), 8.02 (d, J=8.51 Hz, 1 H), 8.10 (s, 2 H), 8.37 (s, 1 H), 8.43 (s, 1 H), 9.04 (s, 1 H), 9.92 (s, 1 H); ESIMS found for C23H3oN60 mlz 407.2 (M+l).
Figure imgf000179_0002
[0746] 2-(3,3-Dimethylazetidin-l -yl)-N-[6-( l-methylpyrazol-4-yl)-3-isoquinolyl] acetamide 273.
[0747] Off-white solid (51.0 mg, 0.146 mmol, 44.2% yield). 'HNMR (DMSO- 6, 500 MHz) δ ppm 1.23 (s, 6 H), 3.10 (s, 4 H), 3.31 (s, 2 H), 3.90 (s, 3 H), 7.77 (dd, J=8.51, 1.65 Hz, 1 H), 8.02 (d, J=8.51 Hz, 1 H), 8.10 (s, 2 H), 8.36 (s, 1 H), 8.41 (s, 1 H), 9.04 (s, 1 H), 9.88 (s, 1 H); ESIMS found for C2oH23N50 mlz 350.2 (M+l).
Figure imgf000179_0003
276
[0748] N-(6-(l -methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(piperidin-l -yl) acetamide 276.
[0749] White solid (61.0 mg, 0.174 mmol, 51.2% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.44 (br d, J=5.21 Hz, 2 H), 1.59 (quin, J=5.56 Hz, 4 H), 2.53 (br s, 4 H), 3.18 (s, 2 H), 4.14 (s, 3 H), 8.04 (dd, J=8.51, 1.65 Hz, 1 H), 8.13 (d, J=8.51 Hz, 1 H), 8.34 (s, 1 H), 8.50 (s, 1 H), 8.74 (s, 1 H), 9.13 (s, 1 H), 9.97 (s, 1 H); ESIMS found for C19H22N6O mlz 351.2 (M+l).
Figure imgf000179_0004
277
[0750] 2,2,3,3-Tetramethyl-N-(6-( l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl) cyclopropane -1 -carboxamide 277.
[0751] White solid (6.0 mg, 0.017 mmol, 6.0% yield). ¾ NMR (499 MHz, DMSO- d6) δ ρρηι 1.19 (s, 6 H), 1.29 (s, 6 H), 1.63 (s, 1 H), 4.14 (s, 3 H), 7.99 (dd, J=8.51, 1.37 Hz, 1 H), 8.09 (d, J=8.51 Hz, 1 H), 8.28 (s, 1 H), 8.47 (s, 1 H), 8.69 (s, 1 H), 9.09 (s, 1 H), 10.50 (s, 1 H); ESIMS found for C2oH23N50 mlz 350.2 (M+l).
Figure imgf000180_0001
278
[0752] N-(6-(4-Methyl-4H- 1 ,2,4-triazol-3 -yl)isoquinolin-3 -yl)- 1 -(3 ,3 ,3 - trifluoropropyl)piperidine-4-carboxamide 278.
[0753] Off-white solid (30.0 mg, 0.069 mmol, 30.2% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.60 - 1.74 (m, 2 H), 1.80 (br d, J=10.70 Hz, 2 H), 1.92 - 2.03 (m, 2 H), 2.40 - 2.49 (m, 2 H), 2.51 - 2.62 (m, 3 H), 2.94 (br d, J=1 1.25 Hz, 2 H), 3.88 (s, 3 H), 7.90 (dd, J=8.51, 1.65 Hz, 1 H), 8.19 (d, J=8.51 Hz, 1 H), 8.27 (s, 1 H), 8.63 (s, 1 H), 8.65 (s, 1 H), 9.22 (s, 1 H), 10.63 (s, 1 H); ESIMS found for C2iH23F3N60 mlz 433.2 (M+l).
Figure imgf000180_0002
279
[0754] N-(6-(4,5 -Dimethyl-4H- 1 ,2,4-triazol-3 -yl)isoquinolin-3 -yl)- 1 -(3,3,3- trifluoropropyl)piperidine-4-carboxamide 279.
[0755] Light pink solid (53.0 mg, 0.1 19 mmol, 51.6% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.62 - 1.73 (m, 2 H), 1.80 (br d, J=1 1.53 Hz, 2 H), 1.92 - 2.04 (m, 2 H), 2.40 - 2.49 (m, 5 H), 2.51 - 2.61 (m, 3 H), 2.94 (br d, J=10.98 Hz, 2 H), 3.70 (s, 3 H), 7.82 (dd, J=8.51, 1.65 Hz, 1 H), 8.14 - 8.22 (m, 2 H), 8.62 (s, 1 H), 9.21 (s, 1 H), 10.63 (s, 1 H); ESIMS found for C22H25F3N60 mlz 447.2 (M+l).
Figure imgf000180_0003
280
[0756] 4-Fluoro-l -isobutyl-N-(6-(4-methyl-4H-l,2,4-triazol-3-yl)isoquinolin-3-yl) piperidine-4-carboxamide 280. [0757] White solid (38.0 mg, 0.093 mmol, 25.2% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 0.88 (d, J=6.59 Hz, 6 H), 1.79 (dquin, J=13.46, 6.79, 6.79, 6.79, 6.79 Hz, 1 H), 1.92 - 2.02 (m, 2 H), 2.09 (d, J=7.41 Hz, 3 H), 2.12 - 2.21 (m, 3 H), 2.74 - 2.83 (m, 2 H), 3.89 (s, 3 H), 7.97 (dd, J=8.51, 1.65 Hz, 1 H), 8.24 (d, J=8.51 Hz, 1 H), 8.36 (s, 1 H), 8.60 (s, 1 H), 8.66 (s, 1 H), 9.28 (s, 1 H), 10.06 (d, J=3.84 Hz, 1 H); ESIMS found for C22H27FN6O mlz 41 1.2 (M+l).
Figure imgf000181_0001
281
[0758] 4-Fluoro- 1 -isobutyl-N-(6-( 1 -methyl- 1H- 1 ,2,3 -triazol-4-yl)isoquinolin-3 -yl) piperidine-4-carboxamide 281.
[0759] Off-white solid (31.0 mg, 0.076 mmol, 20.6% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 0.88 (d, J=6.59 Hz, 6 H), 1.79 (dquin, J=13.52, 6.71, 6.71, 6.71, 6.71 Hz, 1 H), 1.91 - 2.01 (m, 2 H), 2.06 - 2.22 (m, 6 H), 2.78 (br d, J=7.96 Hz, 2 H), 4.15 (s, 3 H), 8.07 (dd, J=8.51, 1.65 Hz, 1 H), 8.16 (d, J=8.78 Hz, 1 H), 8.37 (s, 1 H), 8.47 (s, 1 H), 8.74 (s, 1 H), 9.17 (s, 1 H), 9.95 (d, J=4.12 Hz, 1 H); ESIMS found for C22H27FN6O mlz 41 1.2 (M+l).
Figure imgf000181_0002
282
[0760] 1 -Ethyl-4-fluoro-N-(6-( 1 -methyl- 1H- 1 ,2,3 -triazol-4-yl)isoquinolin-3 -yl) piperidine-4-carboxamide 282.
[0761] Beige solid (6.0 mg, 0.016 mmol, 5.6% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.03 (t, J=7.14 Hz, 3 H), 1.93 - 2.02 (m, 2 H), 2.05 - 2.13 (m, 1 H), 2.13 - 2.20 (m, 3 H), 2.39 (q, J=7.14 Hz, 2 H), 2.80 - 2.88 (m, 2 H), 4.15 (s, 3 H), 8.03 - 8.10 (m, 1 H), 8.16 (d, J=8.51 Hz, 1 H), 8.36 (s, 1 H), 8.47 (s, 1 H), 8.73 (s, 1 H), 9.17 (s, 1 H), 9.94 (d, J=4.12 Hz, 1 H); ESIMS found for C20H23FN6O mlz 383.2 (M+l).
Figure imgf000181_0003
283
[0762] 4,4-Difluoro-N-(6-(5-(2-fluoroethyl)-4,5,6,7-tetrahydropyrazolo[l,5-a] pyrazin-3 -yl)isoquinolin-3 -yl)cyclohexane- 1 -carboxamide 283. [0763] Beige solid (7.7 mg, 0.017 mmol, 12.4% yield). 'H NMR (499 MHz, DMSO- d6) 5 ppm 1.66 - 1.77 (m, 2 H), 1.77 - 1.91 (m, 2 H), 1.92 - 2.01 (m, 2 H), 2.08 - 2.19 (m, 2 H), 2.67 - 2.76 (m, 1 H), 2.96 (t, J=4.80 Hz, 1 H), 3.01 (t, J=4.80 Hz, 1 H), 3.07 (t, J=5.35 Hz, 2 H), 4.08 (s, 2 H), 4.18 (t, J=5.35 Hz, 2 H), 4.66 (dt, J=47.85, 4.95 Hz, 2 H), 7.64 (dd, J=8.51, 1.37 Hz, 1 H), 7.76 (s, 1 H), 8.00 (s, 1 H), 8.03 (d, J=8.78 Hz, 1 H), 8.47 (s, 1 H), 9.06 (s, 1 H), 10.58 (s, 1 H); ESIMS found for C24H26F3N50 mlz 458.2 (M+l).
Figure imgf000182_0001
284
[0764] N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)-2-(pyrrolidin- 1 -yl) acetamide 284.
[0765] White gummy paste (53.0 mg, 0.150 mmol, 45.5% yield) . ¾ NMR (499 MHz, DMSO- e) δ ppm 1.78 (dt, J=6.52, 3.19 Hz, 4 H), 2.66 (br t, J=5.90 Hz, 4 H), 3.35 (s, 2 H), 3.90 (s, 3 H), 7.77 (dd, J=8.51, 1.65 Hz, 1 H), 8.02 (d, J=8.51 Hz, 1 H), 8.10 (s, 2 H), 8.37 (s, 1 H), 8.43 (s, 1 H), 9.03 (s, 1 H), 9.92 (s, 1 H); ESIMS found for Ci9H2iN50 mlz 336.2 (M+l).
Figure imgf000182_0002
285
[0766] N-(6-(l-Ethyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-l-yl) acetamide 285.
[0767] Dark pink paste (42.0 mg, 0.114 mmol, 63.6% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.44 (t, J=7.27 Hz, 3 H), 1.78 (dt, J=6.66, 3.12 Hz, 4 H), 2.62 - 2.69 (m, 4 H), 3.35 (s, 2 H), 4.18 (q, J=7.41 Hz, 2 H), 7.78 (dd, J=8.51, 1.65 Hz, 1 H), 8.02 (d, J=8.51 Hz, 1 H), 8.09 - 8.14 (m, 2 H), 8.43 (s, 2 H), 9.03 (s, 1 H), 9.92 (s, 1 H); ESIMS found for C2oH23N50 mlz 350.2 (M+l).
Figure imgf000182_0003
286
[0768] N-(6-( 1 -Cyclopropyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)-2-(pyrrolidin- 1 -yl) acetamide 286. [0769] White paste (68.0 mg, 0.179 mmol, 59.7% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 0.98 - 1.05 (m, 2 H), 1.08 - 1.13 (m, 2 H), 1.78 (dt, J=6.86, 3.16 Hz, 4 H), 2.62 - 2.69 (m, 4 H), 3.35 (s, 2 H), 3.78 (tt, J=7.34, 3.77 Hz, 1 H), 7.79 (dd, J=8.51, 1.65 Hz, 1 H), 8.01 (d, J=8.78 Hz, 1 H), 8.08 - 8.15 (m, 2 H), 8.43 (s, 1 H), 8.48 (s, 1 H), 9.03 (s, 1 H), 9.92 (s, 1 H); ESIMS found for C2iH23N50 mlz 362.2 (M+1).
Figure imgf000183_0001
287
[0770] 2-(Pyrrolidin-l-yl)-N-(6-(5-(trifluoromethyl)-lH-pyrazol-4-yl)isoquinolin-3- yl)acetamide 287.
[0771] White solid (83.0 mg, 0.203 mmol, 45.1% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.78 (dt, J=6.72, 3.22 Hz, 4 H), 2.61 - 2.70 (m, 4 H), 3.36 (s, 2 H), 7.60 (dd, J=8.37, 1.24 Hz, 1 H), 7.93 (s, 1 H), 8.12 (d, J=8.51 Hz, 1 H), 8.40 (s, 1 H), 8.46 (s, 1 H), 9.14 (s, 1 H), 10.01 (s, 1 H); ESIMS found for Ci9Hi8F3
Figure imgf000183_0002
288
[0772] N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)-2-(pyrrolidin- 1 -yl) propanamide 288.
[0773] White solid (58.8 mg, 0.158 mmol, 50.9% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.30 (d, J=6.86 Hz, 3 H), 1.74 (br s, 4 H), 2.57 - 2.69 (m, 4 H), 3.28 (q, J=6.95 Hz, 1 H), 3.90 (s, 3 H), 7.76 (dd, J=8.51, 1.65 Hz, 1 H), 8.02 (d, J=8.51 Hz, 1 H), 8.06 - 8.12 (m, 2 H), 8.36 (s, 1 H), 8.43 (s, 1 H), 9.03 (s, 1 H), 9.95 (s, 1 H); ESIMS found for C2oH23N50 mlz 350.1 (M+1).
Figure imgf000183_0003
289
[0774] (i?)-N-(6-( l-Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(2- methylpyrrolidin- 1 -yl)acetamide 289.
[0775] White paste (79.5 mg, 0.216 mmol, 65.5% yield). 'HNMR (499 MHz, DMSO- d6) δ ppm 1.09 (d, J=6.04 Hz, 3 H), 1.42 (dddd, J=12.25, 10.33, 8.30, 6.45 Hz, 1 H), 1.66 - 1.83 (m, 2 H), 1.91 - 2.02 (m, 1 H), 2.40 (q, J=8.78 Hz, 1 H), 2.56 - 2.66 (m, 1 H), 3.12 (d, J=16.19 Hz, 1 H), 3.14 - 3.19 (m, 1 H), 3.54 (d, J=16.47 Hz, 1 H), 3.90 (s, 3 H), 7.77 (dd, J=8.51, 1.65 Hz, 1 H), 8.02 (d, J=8.51 Hz, 1 H), 8.07 - 8.14 (m, 2 H), 8.37 (s, 1 H), 8.44 (s, 1 H), 9.03 (s, 1 H), 9.89 (s, 1 H); ESIMS found for C2oH23N50 mlz 350.2 (M+l).
Figure imgf000184_0001
290
[0776] (,S)-N-(6-( l-Metliyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(2- methylpyrrolidin- 1 -yl)acetamide 290.
[0777] White solid (77.0 mg, 0.209 mmol, 66.3% yield). 'HNMR (499 MHz, DMSO- d6) δ ppm 1.09 (d, J=6.04 Hz, 3 H), 1.42 (dddd, J=12.32, 10.39, 8.30, 6.31 Hz, 1 H), 1.66 - 1.84 (m, 2 H), 1.91 - 2.01 (m, 1 H), 2.40 (q, J=8.78 Hz, 1 H), 2.57 - 2.66 (m, 1 H), 3.12 (d, J=16.47 Hz, 1 H), 3.14 - 3.19 (m, 1 H), 3.54 (d, J=16.19 Hz, 1 H), 3.90 (s, 3 H), 7.77 (dd, J=8.51, 1.37 Hz, 1 H), 8.02 (d, J=8.51 Hz, 1 H), 8.08 - 8.13 (m, 2 H), 8.37 (s, 1 H), 8.44 (s, 1 H), 9.03 (s, 1 H), 9.88 (s, 1 H); ESIMS found for C2oH23N50 mlz 350.2 (M+l).
Figure imgf000184_0002
291
[0778] 2-(3-Azabicyclo[3.1.0]hexan-3-yl)-N-(6-(l -methyl-lH-pyrazol-4-yl) isoquinolin-3-yl)acetamide 291.
[0779] White solid (72.0 mg, 0.207 mmol, 62.8% yield). 'HNMR (499 MHz, DMSO- d6) δ ppm 0.44 (td, J=7.55, 4.12 Hz, 1 H), 0.70 (q, J=3.84 Hz, 1 H), 1.40 - 1.48 (m, 2 H), 2.57 (br d, J=8.23 Hz, 2 H), 3.04 (d, J=8.78 Hz, 2 H), 3.33 (s, 2 H), 3.90 (s, 3 H), 7.77 (dd, J=8.51, 1.37 Hz, 1 H), 8.02 (d, J=8.51 Hz, 1 H), 8.09 (s, 2 H), 8.36 (s, 1 H), 8.41 (s, 1 H), 9.03 (s, 1 H), 9.77 (s, 1 H); ESIMS found for C2oH2iN50 mlz 348.2 (M+l).
Figure imgf000184_0003
292
[0780] 2-(7-Azabicyclo[2.2.1]heptan-7-yl)-N-(6-(l -methyl-lH-pyrazol-4-yl) isoquinolin-3-yl)acetamide 292.
[0781] Beige solid (64.0 mg, 0.177 mmol, 53.7% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.34 (br d, J=6.86 Hz, 4 H), 1.74 (br d, J=6.59 Hz, 4 H), 3.19 (s, 2 H), 3.34 - 3.39 (m, 2 H), 3.90 (s, 3 H), 7.74 - 7.83 (m, 1 H), 8.02 (d, J=8.78 Hz, 1 H), 8.08 - 8.14 (m, 2 H), 8.37 (s, 1 H), 8.46 (s, 1 H), 9.04 (s, 1 H), 10.08 (s, 1 H); ESIMS found for C2iH23N50 mlz 362.2 (M+l).
Figure imgf000185_0001
293
[0782] N-(6-(l -Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperidin-l - yl)acetamide 293.
[0783] White solid (56.0 mg, 0.146 mmol, 44.4% yield). ¾ NMR (499 MHz, DMSO- d6) 5 ppm 0.93 (d, J=6.59 Hz, 3 H), 1.18 - 1.29 (m, 2 H), 1.32 - 1.43 (m, 1 H), 1.64 (br d, J=1 1.25 Hz, 2 H), 2.20 (td, J=11.53, 1.92 Hz, 2 H), 2.87 (br d, J=1 1.53 Hz, 2 H), 3.18 (s, 2 H), 3.90 (s, 3 H), 7.77 (dd, J=8.51, 1.37 Hz, 1 H), 8.02 (d, J=8.51 Hz, 1 H), 8.10 (s, 2 H), 8.37 (s, 1 H), 8.43 (s, 1 H), 9.04 (s, 1 H), 9.90 (s, 1 H); ESIMS found for C2iH25N50 mlz 364.2 (M+l).
Figure imgf000185_0002
[0784] N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)-2-(4-(trifluoromethyl) piperidin-l-yl)acetamide 294.
[0785] Off-white solid (92.0 mg, 0.209 mmol, 63.4% yield). ¾ NMR (499 MHz, DMSO- e) δ ρρηι 1.56 (qd, J=12.44, 3.84 Hz, 2 H), 1.83 (br d, J=12.62 Hz, 2 H), 2.28 (td, J=1 1.94, 1.92 Hz, 2 H), 2.30 - 2.39 (m, 1 H), 3.00 (br d, J=1 1.53 Hz, 2 H), 3.25 (s, 2 H), 3.90 (s, 3 H), 7.77 (dd, J=8.64, 1.51 Hz, 1 H), 8.02 (d, J=8.51 Hz, 1 H), 8.10 (s, 2 H), 8.37 (s, 1 H), 8.44 (s, 1 H), 9.04 (s, 1 H), 9.98 (s, 1 H); ESIMS found for C2iH22F3N50 mlz 418.2 (M+l).
Figure imgf000185_0003
295
[0786] 2-(4-(Difluoromethyl)piperidin-l -yl)-N-(6-(l -methyl-lH-pyrazol-4-yl) isoquinolin-3-yl)acetamide 295.
[0787] Beige solid (70.0 mg, 0.167 mmol, 62.4% yield). ¾ NMR (499 MHz, DMSO- 6) 5 ppm 1.47 (qd, J=12.44, 3.84 Hz, 2 H), 1.71 (br d, J=12.35 Hz, 2 H), 1.75 - 1.90 (m, 1 H), 2.23 (td, J=1 1.80, 1.92 Hz, 2 H), 2.97 (br d, J=1 1.53 Hz, 2 H), 3.23 (s, 2 H), 3.90 (s, 3 H), 5.95 (td, J=56.90, 4.40 Hz, 1 H), 7.77 (dd, J=8.51, 1.37 Hz, 1 H), 8.02 (d, J=8.51 Hz, 1 H), 8.10 (s, 2 H), 8.37 (s, 1 H), 8.44 (s, 1 H), 9.04 (s, 1 H), 9.93 (s, 1 H); ESIMS found for C2iH23F2N50 mlz 400.2 (M+ l).
Figure imgf000186_0001
296
[0788] N-(6-(l -Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(6-azaspiro[2.5]octan- 6-yl)acetamide 296.
[0789] Off-white solid (60.0 mg, 0.152 mmol, 56.9% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 0.29 (s, 4 H), 1.42 (br s, 4 H), 2.56 - 2.64 (m, 4 H), 3.24 (s, 2 H), 3.90 (s, 3 H), 7.77 (dd, J=8.64, 1.51 Hz, 1 H), 8.02 (d, J=8.51 Hz, 1 H), 8.08 - 8.14 (m, 2 H), 8.37 (s, 1 H), 8.44 (s, 1 H), 9.04 (s, 1 H), 9.96 (s, 1 H); ESIMS found for C22H25N50 mlz 376.2 (M+l).
Figure imgf000186_0002
297
[0790] N-(6-( 1 -Cyclopropyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)- 1 -(3 ,3 ,3 - trifluoropropyl)piperidine-4-carboxamide 297.
[0791] Off-white solid (21.0 mg, 0.046 mmol, 24.7% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 0.97 - 1.06 (m, 2 H), 1.08 - 1.14 (m, 2 H), 1.60 - 1.73 (m, 2 H), 1.79 (br d, J=10.43 Hz, 2 H), 1.92 - 2.02 (m, 2 H), 2.40 - 2.60 (m, 5 H), 2.93 (br d, J=l 1.25 Hz, 2 H), 3.78 (tt, J=7.44, 3.81 Hz, 1 H), 7.76 (dd, J=8.51, 1.37 Hz, 1 H), 7.99 (d, J=8.51 Hz, 1 H), 8.04 - 8.1 1 (m, 2 H), 8.45 (d, J=9.06 Hz, 2 H), 9.02 (s, 1 H), 10.47 (s, 1 H); ESIMS found for C24H26F3N50 mlz 458.2 (M+ l).
Figure imgf000186_0003
298
[0792] N-(6-(5 -(Azetidin- 1 -ylmethyl)- 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)- 4,4-difluorocyclohexane- 1 -carboxamide 298.
[0793] Beige solid (4.4 mg, 0.010 mmol, 3.6% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.67 - 2.02 (m, 8 H), 2.07 - 2.19 (m, 2 H), 2.67 - 2.77 (m, 1 H), 3.1 1 (t, J=6.86 Hz, 4 H), 3.77 (s, 2 H), 3.92 (s, 3 H), 7.67 (dd, J=8.51, 1.37 Hz, 1 H), 7.75 (s, 1 H), 7.93 (s, 1 H), 8.05 (d, J=8.51 Hz, 1 H), 8.46 (s, 1 H), 9.09 (s, 1 H), 10.60 (s, 1 H); ESIMS found for Cz^vFzNsO mlz 440.2 (M+l).
Figure imgf000187_0001
299
[0794] 4,4-Difluoro-N-(6-( 1 -methyl -5 -(pyrrolidin-1 -ylmethyl)- lH-pyrazol-4-yl) isoquinolin-3 -yl)cyclohexane - 1 -carboxamide 299.
[0795] Beige solid (26.4 mg, 0.058 mmol, 23.2% yield). ¾ NMR (499 MHz, DMSO- d6) δ ρρηι 1.67 (br s, 4 H), 1.69 - 1.91 (m, 4 H), 1.95 (br d, J=12.90 Hz, 2 H), 2.06 - 2.18 (m, 2 H), 2.44 (br s, 4 H), 2.71 (br t, J=10.84 Hz, 1 H), 3.83 (s, 2 H), 3.92 (s, 3 H), 7.68 (dd, J=8.51, 1.65 Hz, 1 H), 7.78 (s, 1 H), 7.96 (s, 1 H), 8.03 (d, J=8.51 Hz, 1 H), 8.44 (s, 1 H), 9.08 (s, 1 H), 10.59 (s, 1 H); ESIMS found for CzsHzgF
Figure imgf000187_0002
300
[0796] 4,4-Difluoro-N-(6-( 1 -methyl -5 -(piperidin- 1 -ylmethyl)- lH-pyrazol-4-yl) isoquinolin-3 -yl)cyclohexane - 1 -carboxamide 300.
[0797] White solid (10.6 mg, 0.023 mmol, 18.1% yield). ¾NMR (499 MHz, DMSO- d6) δ ppm 1.38 (br d, J=4.12 Hz, 2 H), 1.44 - 1.53 (m, 4 H), 1.66 - 1.90 (m, 4 H), 1.92 - 2.01 (m, 2 H), 2.06 - 2.18 (m, 2 H), 2.36 (br d, J=1.65 Hz, 4 H), 2.65 - 2.76 (m, 1 H), 3.65 (s, 2 H), 3.91 (s, 3 H), 7.70 (dd, J=8.51, 1.65 Hz, 1 H), 7.80 (s, 1 H), 7.98 - 8.07 (m, 2 H), 8.45 (s, 1 H), 9.08 (s, 1 H), 10.58 (s, 1 H); ESIMS found for C26H3iF2N50 mlz 468.2 (M+l).
Figure imgf000187_0003
301
[0798] 7-(2-Fluoroethyl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-7- azaspiro[3.5]nonane-2 -carboxamide 301. [0799] Beige solid (50.0 mg, 0.1 19 mmol, 18.1% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.53 (br t, J=5.35 Hz, 2 H), 1.59 (br t, J=5.35 Hz, 2 H), 1.97 (d, J=8.51 Hz, 4 H), 2.30 (br s, 2 H), 2.33 - 2.44 (m, 2 H), 2.55 (dt, J=28.30, 5.20 Hz, 2 H), 3.33 - 3.42 (m, 1 H), 3.90 (s, 3 H), 4.50 (dt, J=48.10, 5.25 Hz, 2 H), 7.74 (dd, J=8.51, 1.65 Hz, 1 H), 7.99 (d, J=8.51 Hz, 1 H), 8.03 (s, 1 H), 8.08 (s, 1 H), 8.35 (s, 1 H), 8.46 (s, 1 H), 9.01 (s, 1 H), 10.34 (s, 1 H); ESIMS found for C24H28FN50 mlz 422.2 (M+ l).
Figure imgf000188_0001
302
[0800] 2-(Cyclobutyl(methyl)amino)-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin- 3-yl)acetamide 302.
[0801] Off-white solid (69.0 mg, 0.198 mmol, 59.8% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.53 - 1.69 (m, 2 H), 1.81 - 1.92 (m, 2 H), 1.97 - 2.07 (m, 2 H), 2.23 (s, 3 H), 3.03 - 3.10 (m, 1 H), 3.1 1 (s, 2 H), 3.90 (s, 3 H), 7.77 (dd, J=8.51, 1.37 Hz, 1 H), 8.03 (d, J=8.51 Hz, I H), 8.08 - 8.14 (m, 2 H), 8.37 (s, 1 H), 8.43 (s, 1 H), 9.04 (s, 1 H), 9.91 (s, 1 H); ESIMS found for C2oH23N50 mlz 350.2 (M+l).
Figure imgf000188_0002
303
[0802] 2-(Diethylamino)-N-(6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl) acetamide 303.
[0803] White paste (74.0 mg, 0.219 mmol, 66.5% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.05 (t, J=7.14 Hz, 6 H), 2.65 (q, J=7.14 Hz, 4 H), 3.24 (s, 2 H), 3.90 (s, 3 H), 7.77 (dd, J=8.51, 1.37 Hz, I H), 8.02 (d, J=8.51 Hz, 1 H), 8.08 - 8.14 (m, 2 H), 8.37 (s, 1 H), 8.43 (s, 1 H), 9.03 (s, 1 H), 9.93 (s, 1 H); ESIMS found for Ci9H23N50 mlz 338.2 (M+l).
Figure imgf000188_0003
304
[0804] N-(6-(l -(Methyl-£/3)-lH-pyrazol-4-yl)isoquinolin-3-yl)-l-(3,3,3- trifluoropropyl)piperidine-4-carboxamide 304. [0805] Off-white solid (54.0 mg, 0.124 mmol, 44.6% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.60 - 1.72 (m, 2 H), 1.79 (br d, J=10.15 Hz, 2 H), 1.91 - 2.02 (m, 2 H), 2.39 - 2.60 (m, 5 H), 2.93 (br d, J=1 1.25 Hz, 2 H), 7.74 (dd, J=8.51, 1.65 Hz, 1 H), 8.00 (d, J=8.51 Hz, 1 H), 8.03 (s, 1 H), 8.07 (s, 1 H), 8.34 (s, 1 H), 8.44 (s, 1 H), 9.02 (s, 1 H), 10.47 (s, 1 H) ; ESIMS found for C22H2iD3F3N50 mlz 435.2 (M+l).
Figure imgf000189_0001
305
[0806] N-(6-(l -(Methyl- 3)-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-l -yl) acetamide 305.
[0807] White paste (80.0 mg, 0.236 mmol, 71.6% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.78 (dt, J=6.59, 3.29 Hz, 4 H), 2.62 - 2.70 (m, 4 H), 3.35 (s, 2 H), 7.77 (dd, J=8.51, 1.65 Hz, 1 H), 8.02 (d, J=8.51 Hz, 1 H), 8.10 (s, 2 H), 8.36 (s, 1 H), 8.43 (s, 1 H), 9.03 (s, 1 H), 9.92 (s, 1 H); ESIMS found for Ci9Hi8D3 +l).
Figure imgf000189_0002
306
[0808] N-(6-(l -(Methyl- 3)-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-l -yl) acetamide 306.
[0809] Beige solid (82.0 mg, 0.233 mmol, 70.5% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.43 (br d, J=4.94 Hz, 2 H), 1.59 (quin, J=5.56 Hz, 4 H), 2.52 (br d, J=1.92 Hz, 4 H), 3.17 (s, 2 H), 7.77 (dd, J=8.51, 1.65 Hz, 1 H), 8.02 (d, J=8.78 Hz, 1 H), 8.10 (s, 2 H), 8.36 (s, 1 H), 8.43 (s, 1 H), 9.04 (s, 1 H), 9.91 (s, 1 H); ESIMS found for C2oH2oD3N50 mlz 353.2 (M+l).
Figure imgf000189_0003
307
[0810] N-(6-(3-Methylisoxazol-5-yl)isoquinolin-3-yl)-l-(3,3,3-trifluoropropyl) piperidine-4-carboxamide 307.
[0811] White solid (3.0 mg, 0.007 mmol, 2.4% yield). ¾ NMR (499 MHz, DMSO- £¾) δ ρριη 1.61 - 1.73 (m, 2 H), 1.80 (br d, J=10.43 Hz, 2 H), 1.92 - 2.02 (m, 2 H), 2.41 - 2.61 (m, 5 H), 2.51 (s, 3 H), 2.93 (br d, J=1 1.25 Hz, 2 H), 7.68 (dd, J=8.37, 1.51 Hz, 1 H), 8.04 (s, 1 H), 8.11 (d, J=8.51 Hz, 1 H), 8.54 (s, 1 H), 9.13 (s, 1 H), 9.34 (s, 1 H), 10.56 (s, 1 H); ESIMS found for C22H23F3N402 mlz 433.2 (M+l).
Figure imgf000190_0001
308
[0812] N-(6-(Oxazol-5-yl)isoquinolin-3-yl)-l-(3,3,3-trifluoropropyl)piperidine-4- carboxamide 308.
[0813] Off-white solid (16.0 mg, 0.038 mmol, 16.5% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.58 - 1.72 (m, 2 H), 1.80 (br d, J=10.70 Hz, 2 H), 1.91 - 2.03 (m, 2 H), 2.40 - 2.61 (m, 5 H), 2.94 (br d, J=11.25 Hz, 2 H), 7.87 (dd, J=8.64, 1.51 Hz, 1 H), 7.95 (s, 1 H), 8.13 (d, J=8.51 Hz, 1 H), 8.20 (s, 1 H), 8.54 (s, 1 H), 8.58 (s, 1 H), 9.13 (s, 1 H), 10.58 (s, 1 H); ESIMS found for C2iH2iF3N402 mlz 419.1 (M+l).
Figure imgf000190_0002
309
[0814] 4-Fluoro-l-isobutyl-N-(6-(5-methyl-l,3,4-oxadiazol-2-yl)isoquinolin-3-yl) piperidine-4-carboxamide 309.
[0815] Off-white solid (20.0 mg, 0.049 mmol, 13.2% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 0.88 (d, J=6.59 Hz, 6 H), 1.80 (dquin, J=13.55, 6.84, 6.84, 6.84, 6.84 Hz, 1 H), 1.92 - 2.02 (m, 2 H), 2.09 (d, J=7.41 Hz, 2 H), 2.06 - 2.21 (m, 4 H), 2.64 (s, 3 H), 2.75 - 2.82 (m, 2 H), 8.11 (dd, J=8.51, 1.65 Hz, 1 H), 8.29 (d, J=8.51 Hz, 1 H), 8.57 (s, 1 H), 8.60 (s, 1 H), 9.30 (s, 1 H), 10.11 (d, J=3.57 Hz, 1 H); ESIMS found for C22H26FN502 mlz 412.2 (M+l).
Figure imgf000190_0003
310
[0816] N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)-l -(( 1 -(trifluoromethyl) cyclopropyl)methyl)piperidine -4-carboxamide 310.
[0817] Off-white solid (70.0 mg, 0.153 mmol, 76.5% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 0.73 (s, 2 H), 0.93 - 0.99 (m, 2 H), 1.60 - 1.72 (m, 2 H), 1.73 - 1.82 (m, 2 H), 1.89 - 2.00 (m, 2 H), 2.49 (br s, 2 H), 2.52 - 2.58 (m, 1 H), 2.96 (br d, J=11.25 Hz, 2 H), 3.90 (s, 3 H), 7.74 (dd, J=8.51, 1.65 Hz, 1 H), 8.00 (d, J=8.51 Hz, 1 H), 8.04 (s, 1 H), 8.08 (s, 1 H), 8.35 (s, 1 H), 8.44 (s, 1 H), 9.02 (s, 1 H), 10.46 (s, 1 H); ESIMS found for C24H26F3N50 mlz 458.2 (M+l).
Figure imgf000191_0001
311
[0818] (5)-l-(2-Fluoropropyl)-N-(6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl) piperidine-4-carboxamide 311.
[0819] White solid (71.0 mg, 0.180 mmol, 60.2% yield). ¾ NMR (499 MHz, DMSO- £¾) 5 ppm 1.26 (dd, J=23.95, 6.35 Hz, 3 H), 1.62 - 1.72 (m, 2 H), 1.74 - 1.82 (m, 2 H), 2.00 - 2.12 (m, 2 H), 2.34 - 2.49 (m, 2 H), 2.52 - 2.59 (m, 1 H), 2.93 (br t, J=l 1.80 Hz, 2 H), 3.90 (s, 3 H), 4.75 - 4.94 (m, 1 H), 7.74 (dd, J=8.51, 1.65 Hz, 1 H), 8.00 (d, J=8.78 Hz, 1 H), 8.04 (s, 1 H), 8.07 (s, 1 H), 8.34 (s, 1 H), 8.44 (s, 1 H), 9.02 (s, 1 H), 10.45 (s, 1 H); ESIMS found for C22H26FN50 mlz 396.2 (M+l).
Figure imgf000191_0002
312
[0820] 2-Fluoro-2 -methyl -N-(6-( 1 -methyl- 1H- 1 ,2,3 -triazol-4-yl)isoquinolin-3 -yl) propanamide 312.
[0821] Off-white solid (21.0 mg, 0.067 mmol, 10.5% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.64 (d, J=22.00 Hz, 6 H), 4.15 (s, 3 H), 8.07 (dd, J=8.51, 1.65 Hz, 1 H), 8.16 (d, J=8.51 Hz, 1 H), 8.36 (s, 1 H), 8.46 (s, 1 H), 8.74 (s, 1 H), 9.17 (s, 1 H), 9.91 (d, J=3.57 Hz, 1 H); ESIMS found for Ci6Hi6FN5
Figure imgf000191_0003
313
[0822] (R)- 1 -(2-Fluoropropyl)-N-(6-( 1 -methyl-lH-pyrazol-4-yl)isoquinolin-3 -yl) piperidine-4-carboxamide 313.
[0823] White solid (30.0 mg, 0.076 mmol, 25.4% yield). ¾ NMR (499 MHz, DMSO- 6) 5 ppm 1.26 (dd, J=23.90, 6.30 Hz, 3 H), 1.68 (q, J=l 1.53 Hz, 2 H), 1.74 - 1.81 (m, 2 H), 1.99 - 2.09 (m, 2 H), 2.35 - 2.47 (m, 1 H), 2.52 - 2.57 (m, 1 H), 2.93 (br t, J=1 1.80 Hz, 2 H), 3.90 (s, 3 H), 4.74 - 4.94 (m, 1 H), 7.74 (dd, J=8.51, 1.37 Hz, 1 H), 8.00 (d, J=8.51 Hz, 1 H), 8.03 (s, 1 H), 8.07 (s, 1 H), 8.35 (s, 1 H), 8.44 (s, 1 H), 9.02 (s, 1 H), 10.46 (s, 1 H); ESIMS found for C22H26FN50 mlz 396.2 (M+l).
Figure imgf000192_0001
314
[0824] N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)-2-(piperidin
propanamide 314.
[0825] Off-white solid (57.0 mg, 0.157 mmol, 51.6% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.20 (d, J=7.14 Hz, 3 H), 1.39 - 1.46 (m, 2 H), 1.53 - 1.64 (m, 4 H), 2.52 - 2.58 (m, 2 H), 3.44 (q, J=6.86 Hz, 1 H), 3.90 (s, 3 H), 7.76 (dd, J=8.51, 1.65 Hz, 1 H), 8.02 (d, J=8.51 Hz, 1 H), 8.06 - 8.11 (m, 2 H), 8.36 (s, 1 H), 8.44 (s, 1 H), 9.04 (s, 1 H), 10.09 (s, 1 H); ESIMS found for C2iH25N50 mlz 364.2 (M+l).
Figure imgf000192_0002
315
[0826] N-(6-(l-Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-l-yl-2,2,5,5- <¾)acetamide 315.
[0827] Beige solid (43.0 mg, 0.127 mmol, 42.8% yield). ¾ NMR (499 MHz, DMSO- d6) 5 ppm 1.76 (s, 4 H), 3.36 (s, 2 H), 3.90 (s, 3 H), 7.77 (dd, J=8.64, 1.51 Hz, 1 H), 8.02 (d, J=8.51 Hz, 1 H), 8.10 (s, 2 H), 8.37 (s, 1 H), 8.43 (s, 1 H), 9.03 (s, 1 H), 9.93 (s, 1 H); ESIMS found for Ci9Hi7D4N50 mlz 340.2 (M+l).
Figure imgf000192_0003
316
[0828] 4-Methyl -N-(6 -( 1 -methyl - 1 H-pyrazol -4 -yl)isoquinolin-3 -yl)piperazine - 1 - carboxamide 316.
[0829] Off-white solid (14.0 mg, 0.040 mmol, 46.5% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 2.20 (s, 3 H), 2.29 - 2.35 (m, 4 H), 3.48 - 3.54 (m, 4 H), 3.90 (s, 3 H), 7.68 (dd, J=8.51, 1.65 Hz, I H), 7.94 - 8.00 (m, 2 H), 8.06 (s, 1 H), 8.14 (s, 1 H), 8.33 (s, 1 H), 8.97 (s, 1 H), 9.13 (s, 1 H); ESIMS found for C19H22N6O mlz 351.2 (M+l).
Figure imgf000193_0001
317
[0830] (S)-N-(6-(l-Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-l-yl) propanamide 317.
[0831] White solid (75.0 mg, 0.215 mmol, 65.4% yield). ¾NMR (499 MHz, DMSO- d6) δ ppm 1.30 (3 H, d, J=6.86 Hz), 1.74 (4 H, br s), 2.57 - 2.68 (4 H, m), 3.25 - 3.30 (1 H, m), 3.90 (3 H, s), 7.76 (1 H, dd, J=8.51, 1.65 Hz), 8.02 (1 H, d, J=8.51 Hz), 8.08 (1 H, s), 8.09 (1 H, s), 8.36 (1 H, s), 8.43 (1 H, s), 9.03 (1 H, s), 9.94 (1 H, s); ESIMS found for C2oH23N50 mlz 350.2 (M+l).
Figure imgf000193_0002
318
[0832] (R)-N-(6-(l-Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-l-yl) propanamide 318.
[0833] Light beige solid (89.0 mg, 0.255 mmol, 62.1% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.30 (3 H, d, J=6.86 Hz), 1.74 (4 H, br s), 2.56 - 2.70 (4 H, m), 3.25 - 3.30 (1 H, m), 3.90 (3 H, s), 7.76 (1 H, dd, J=8.51, 1.65 Hz), 8.02 (1 H, d, J=8.51 Hz), 8.08 (1 H, s), 8.09 (1 H, s), 8.36 (1 H, s), 8.43 (1 H, s), 9.03 (1 H, s), 9.94 (1 H, s); ESIMS found for C2oH23N50 mlz 350.2 (M+l).
Figure imgf000193_0003
320
[0834] (R)-N-(6-(l-Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-2- carboxamide 320.
[0835] Brown solid (830.0 mg, 2.58 mmol, 78.2% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.67 (2 H, quin, J=6.86 Hz), 1.79 - 1.90 (1 H, m), 2.04 - 2.16 (1 H, m), 2.87 (1 H, dt, J=10.15, 6.31 Hz), 2.97 (1 H, dt, J=10.15, 6.72 Hz), 3.35 (1 H, br s), 3.80 (1 H, dd, J=9.19, 5.35 Hz), 3.90 (3 H, s), 7.76 (1 H, dd, J=8.51, 1.65 Hz), 8.02 (1 H, d, J=8.51 Hz), 8.09 (1 H, br s), 8.09 (1 H, s), 8.36 (1 H, s), 8.44 (1 H, s), 9.02 (1 H, s), 10.34 (1 H, s); ESIMS found for Ci8Hi9N50 mlz 322.15 (M+l).
Figure imgf000194_0001
[0836] 2-Methyl-N-(6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-azaspiro[3.3] heptane-6-carboxamide 324.
[0837] Off-white solid (32.0 mg, 0.089 mmol, 38.4% yield). ¾ NMR (499 MHz, DMSO- e) 5 ppm 2.15 (3 H, s), 2.21 - 2.35 (4 H, m), 3.04 (2 H, s), 3.14 (2 H, s), 3.21 - 3.28 (1 H, m), 3.90 (3 H, s), 7.74 (1 H, dd, J=8.51, 1.65 Hz), 7.99 (1 H, d, J=8.51 Hz), 8.04 (1 H, s), 8.08 (1 H, s), 8.35 (1 H, s), 8.44 ( 1 H, s), 9.01 (1 H, s), 10.35 (1 H, s); ESIMS found for C2iH23N50 mlz 362.2 (M+l).
Figure imgf000194_0002
325
[0838] N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(2,2,2-trifluoroacetyl)- 2-azaspiro[3.3]heptane-6-carboxamide 325.
[0839] White solid (26.0 mg, 0.059 mmol, 18.0% yield). 'HNMR (500 MHz, DMSO- d6) δ ppm 2.40 - 2.49 (4 H, m), 3.22 - 3.31 ( 1 H, m), 4.06 - 4.15 (2 H, m), 4.44 (2 H, br d, J=17.56 Hz), 7.75 ( 1 H, dd, J=8.51, 1.65 Hz), 8.00 (1 H, d, J=8.51 Hz), 8.06 ( 1 H, s), 8.09 ( 1 H, d, J=1.10 Hz), 8.35 (1 H, d, J=1.65 Hz), 8.46 (1 H, s), 9.02 (1 H, s), 10.47 ( 1 H, s); ESIMS found for C22H2oF3N502 mlz 444.15 (M+l).
Figure imgf000194_0003
326
[0840] 2-(2-Fluoroethyl)-N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2- azaspiro[3.3]heptane-6-carboxamide 326.
[0841] Beige solid ( 10.0 mg, 0.025 mmol, 24.9% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 2.23 - 2.36 (4 H, m), 2.60 (2 H, dt, J=29.00, 5.00 Hz), 3.13 (2 H, s), 3.22 (2 H, s), 3.24 - 3.29 (1 H, m), 4.36 (2 H, dt, J=48.00, 5.00 Hz), 7.74 (1 H, dd, J=8.51, 1.37 Hz), 7.99 ( 1 H, d, J=8.51 Hz), 8.04 (1 H, s), 8.08 (1 H, s), 8.35 (1 H, s), 8.44 (1 H, s), 9.01 (1 H, s), 10.36 (1 H, s); ESIMS found for C22H24FN50
Figure imgf000195_0001
327
[0842] tra«s-4-(Dimethylamino)-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 - yl)cyclohexane-l -carboxamide 327.
[0843] Beige solid (650.0 mg, 1.72 mmol, 46.3% yield). ¾ NMR (499 MHz, DMSO- 6) 5 ppm 1.11 - 1.27 (3 H, m), 1.41 - 1.54 (2 H, m), 1.83 - 1.96 (4 H, m), 2.10 - 2.16 (1 H, m), 2.18 (6 H, s), 2.42 - 2.49 (1 H, m), 3.90 (3 H, s), 7.74 (1 H, dd, J=8.51, 1.37 Hz), 7.99 (1 H, d, J=8.51 Hz), 8.02 (1 H, s), 8.07 (1 H, s), 8.35 (1 H, s), 8.43 (1 H, s), 9.02 (1 H, s), 10.41 (1 H, s); ESIMS found for C22H27N50 mlz 378.2 (M+l).
Figure imgf000195_0002
328
[0844] 1 -Benzoyl -N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)piperidine-4- carboxamide 328.
[0845] White solid (65.0 mg, 0.148 mmol, 55.3% yield). ¾ NMR (499 MHz, DMSO- d6) 5 ppm 1.57 - 1.72 (2 H, m), 1.75 - 2.00 (2 H, m), 2.86 (2 H, tt, J=11.18, 3.77 Hz), 3.04 - 3.19 (1 H, m), 3.57 - 3.75 (1 H, m), 3.90 (3 H, s), 4.43 - 4.63 (1 H, m), 7.38 - 7.43 (2 H, m), 7.43 - 7.49 (3 H, m), 7.75 (1 H, dd, J=8.51, 1.37 Hz), 8.00 (1 H, d, J=8.51 Hz), 8.04 (1 H, s), 8.08 (1 H, s), 8.35 (1 H, s), 8.43 (1 H, s), 9.03 (1 H, s), 10.54 (1 H, s); ESIMS found for CzeHzsNsOz mlz 440.0 (M+l).
Figure imgf000195_0003
329
[0846] 1 -Acetyl -N-(6 -( 1 -methyl - 1 H-pyrazol -4 -yl)isoquinolin-3 -yl)piperidine -4 - carboxamide 329. [0847] White solid (60.0 mg, 0.159 mmol, 59.4% yield). ¾NMR (499 MHz, DMSO- d6) δ ρρηι 1.47 (1 H, qd, J=12.26, 4.39 Hz), 1.56 - 1.69 (1 H, m), 1.77 - 1.91 (2 H, m), 2.02 (3 H, s), 2.58 (1 H, td, J=12.62, 2.47 Hz), 2.75 - 2.84 (1 H, m), 3.03 - 3.11 (1 H, m), 3.88 (1 H, br d, J=13.15 Hz), 3.90 (3 H, s), 4.41 (1 H, br d, J=13.17 Hz), 7.75 (1 H, dd, J=8.51, 1.65 Hz), 8.00 (1 H, d, J=8.51 Hz), 8.04 (1 H, s), 8.08 (1 H, s), 8.35 (1 H, s), 8.43 (1 H, s), 9.03 (1 H, s), 10.53 (1 H, s); ESIMS found for C2iH23N5 +l).
Figure imgf000196_0001
330
[0848] N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)-l -(methylsulfonyl) piperidine-4-carboxamide 330.
[0849] White solid (60.0 mg, 0.145 mmol, 54.2% yield). ¾NMR (499 MHz, DMSO- d6) 5 ppm 1.65 - 1.77 (2 H, m), 1.95 (2 H, br dd, J=13.31, 2.61 Hz), 2.69 (1 H, tt, J=11.25, 3.84 Hz), 2.76 (2 H, td, J=11.94, 2.20 Hz), 2.89 (3 H, s), 3.59 - 3.67 (2 H, m), 3.90 (3 H, s), 7.75 (1 H, dd, J=8.51, 1.65 Hz), 8.01 (1 H, d, J=8.51 Hz), 8.05 (1 H, s), 8.08 (1 H, s), 8.35 (1 H, s), 8.44 (1 H, s), 9.03 (1 H, s), 10.59 (1 H, s); ESIMS found for C2oH23N503S mlz 413.9 (M+l).
Figure imgf000196_0002
331
[0850] Γ -Methyl -N-(6-(l -methyl- lH-pyrazol-4-yl)isoquinolin-3-yl)-[ 1,4'- bipiperidine]-4-carboxamide 331.
[0851] White solid (4.0 mg, 0.009 mmol, 3.1% yield). ¾ NMR (499 MHz, DMSO- d6) 5 ppm 1.44 (2 H, qd, J=11.89, 3.57 Hz), 1.58 - 1.71 (4 H, m), 1.73 - 1.87 (4 H, m), 2.06 - 2.20 (4 H, m), 2.12 (3 H, s), 2.78 (2 H, br d, J=11.53 Hz), 2.91 (2 H, br d, J=11.25 Hz), 3.90 (3 H, s), 7.74 (1 H, dd, J=8.51, 1.37 Hz), 7.99 (1 H, d, J=8.78 Hz), 8.03 (1 H, s), 8.07 (1 H, s), 8.34 (1 H, s), 8.44 (1 H, s), 9.02 (1 H, s), 10.42 (1 H, s); ESIMS found for C25H32N60 mlz 433.0 (M+l).
Figure imgf000196_0003
332 [0852] N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)-l -(tetrahydro-2H-pyran- 4-yl)piperidine -4 -carboxamide 332.
[0853] White solid ( 1 1.0 mg, 0.026 mmol, 8.8% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.43 (2 H, qd, J=12.08, 4.39 Hz), 1.59 - 1.69 (4 H, m), 1.79 (2 H, br d, J=l 1.80 Hz), 2.08 - 2.17 (2 H, m), 2.42 (1 H, tt, J=l 1.35, 3.60 Hz), 2.51 - 2.58 (1 H, m), 2.94 (2 H, br d, J=l 1.53 Hz), 3.22 - 3.29 (2 H, m), 3.87 (2 H, br d, J=3.57 Hz), 3.90 (3 H, s), 7.74 (1 H, dd, J=8.51, 1.65 Hz), 7.99 (1 H, d, J=8.78 Hz), 8.03 (1 H, s), 8.07 (1 H, s), 8.34 (1 H, s), 8.44 ( 1 H, s), 9.02 ( 1 H, s), 10.43 ( 1 H, s); ESIMS found for
Figure imgf000197_0001
mlz 420.0 (M+l).
Figure imgf000197_0002
333
[0854] tra«5-4-(Hydroxymethyl)-N-(6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3- yl)cyclohexane-l -carboxamide 333.
[0855] Light beige solid (215.0 mg, 0.59 mmol, 51.3% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 0.95 (2 H, qd, J=12.72, 3.29 Hz), 1.31 - 1.39 (1 H, m), 1.45 (2 H, qd, J=12.72, 3.02 Hz), 1.80 (2 H, br dd, J=13.17, 2.74 Hz), 1.84 - 1.93 (2 H, m), 3.24 (2 H, t, J=5.76 Hz), 3.90 (3 H, s), 4.37 (1 H, t, J=5.35 Hz), 7.74 (1 H, dd, J=8.51, 1.65 Hz), 7.99 (1 H, d, J=8.51 Hz), 8.02 ( 1 H, s), 8.07 (1 H, s), 8.34 (1 H, s), 8.43 (1 H, s), 9.02 (1 H, s), 10.38 (1 H, s); ESIMS found for C21H24N4O2 mlz 365.0 (M+l).
Figure imgf000197_0003
334
[0856] Methyl 2-(4-((6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl) piperidin-l-yl)acetate 334.
[0857] White solid (20.0 mg, 0.049 mmol, 16.5% yield). 'HNMR (499 MHz, DMSO- d6) 5 ppm 1.62 - 1.73 (2 H, m), 1.74 - 1.82 (2 H, m), 2.22 (2 H, td, J=l 1.53, 2.20 Hz), 2.51 - 2.58 ( 1 H, m), 2.84 - 2.92 (2 H, m), 3.24 (2 H, s), 3.62 (3 H, s), 3.90 (3 H, s), 7.74 ( 1 H, dd, J=8.51, 1.65 Hz), 8.00 ( 1 H, d, J=8.51 Hz), 8.03 (1 H, s), 8.07 (1 H, s), 8.34 (1 H, s), 8.44 (1 H, s), 9.02 (1 H, s), 10.45 (1 H, s); ESIMS found for C22H25N503 mlz 408.0 (M+l).
Figure imgf000198_0001
335
[0858] l-Benzyl-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide 335.
[0859] White solid (22.0 mg, 0.052 mmol, 17.3%yield). 'HNMR (499 MHz, DMSO- d6) δρρηι 1.60 - 1.72 (2 H, m), 1.73 - 1.81 (2 H, m), 1.98 (2 H, td, J= 11.60, 2.06 Hz), 2.51 -2.57 (1 H, m), 2.88 - 2.96 (2 H, m), 3.24 (2 H, s), 3.90 (3 H, s), 7.74 (1 H, dd, J=8.51, 1.65 Hz), 7.99 (1 H, d,J=8.78 Hz), 8.03 (1 H, s), 8.07 (1 H, s), 8.34 (1 H, s), 8.44 (1 H, s), 9.02 (1 H, s), 10.43 (1 H, s); ESIMS found for CzeHzv +l).
Figure imgf000198_0002
336
[0860] N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)-l -(2-(pyrrolidin-l -yl) acetyl)piperidine-4-carboxamide 336.
[0861] White solid (21.0 mg, 0.047 mmol, 15.8%yield). 'HNMR (500 MHz, DMSO- d6)5ppm 1.43 - 1.54(1 H, m), 1.55 - 1.66 (1 H, m), 1.67 - 1.73 (4 H, m), 1.84 (2H, brd,J=10.98 Hz), 2.48 (4 H, br s), 2.56 - 2.66 (1 H, m), 2.76 - 2.87 (1 H, m), 2.97 - 3.07 (1 H, m), 3.32 (2 H, br s), 3.90 (3 H, s), 4.11 (1 H, br d, J=13.17 Hz), 4.40 (1 H, br d, J=12.90 Hz), 7.75 (1 H, dd, J=8.51, 1.65 Hz), 8.00 (1 H, d,J=8.51 Hz), 8.04 (1 H, s), 8.07 (1 H, s), 8.34 (1 H, s), 8.43 (1 H, s), 9.03 (1 H, s), 10.52 (1 H, s); ESIMS found for C25H3oN602 mlz 447.0 (M+l).
Figure imgf000198_0003
338
[0862] N-(6-(l -Methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)-2-morpholinoacetamide [0863] Beige solid (13.0 mg, 0.037 mmol, 33.6% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 2.55 - 2.60 (3 H, m), 3.24 (2 H, s), 3.62 - 3.70 (4 H, m), 3.90 (3 H, s), 7.77 (1 H, dd, J=8.51, 1.65 Hz), 8.02 (1 H, d, J=8.51 Hz), 8.09 (2 H, s), 8.35 (1 H, s), 8.43 (1 H, s), 9.04 (1 H, s), 9.97 (1 H, s); ESIMS found for
Figure imgf000199_0001
340
[0864] (S)-N-(6-(l-Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-2- carboxamide 340.
[0865] Light beige solid (35.0 mg, 0.104 mmol, 56.8% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.31 - 1.41 (1 H, m), 1.41 - 1.47 (2 H, m), 1.47 - 1.56 (1 H, m), 1.72 - 1.79 (1 H, m), 1.84 - 1.91 (1 H, m), 2.58 - 2.64 (1 H, m), 2.93 - 3.00 (1 H, m), 3.34 (1 H, br dd, J=9.19, 3.16 Hz), 3.90 (3 H, s), 7.76 (1 H, dd, J=8.51, 1.65 Hz), 8.01 (1 H, d, J=8.51 Hz), 8.07 (1 H, br s), 8.08 (1 H, s), 8.35 (1 H, s), 8.43 (1 H, s), 9.03 (1 H, s), 9.85 (1 H, br s); ESIMS found for Ci9H2iN50 mlz 336.0 (M+l).
Figure imgf000199_0002
341
[0866] (S)-N-(6-(l-Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(3- methylmorpholino)acetamide 341.
[0867] Beige solid (32.5 mg, 0.089 mmol, 34.2% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 0.95 (3 H, d, J=6.59 Hz), 2.52 - 2.58 (1 H, m), 2.58 - 2.65 (1 H, m), 2.81 (1 H, dt, J=l 1.80, 2.47 Hz), 3.15 - 3.23 (2 H, m), 3.47 (1 H, d, J=16.47 Hz), 3.58 (1 H, td, J=10.70, 2.20 Hz), 3.68 (1 H, dd, J=11.25, 2.74 Hz), 3.71 - 3.79 (1 H, m), 3.90 (3 H, s), 7.77 (1 H, dd, J=8.51, 1.37 Hz), 8.03 (1 H, d, J=8.51 Hz), 8.10 (1 H, s), 8.11 (1 H, br s), 8.37 (1 H, s), 8.44 (1 H, s), 9.04 (1 H, s), 9.97 (1 H, s); ESIMS found for CztJfeNsOz mlz 366.2 (M+l).
Figure imgf000200_0001
342
[0868] (R)-N-(6-(l-Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(3- methylmorpholino)acetamide 342.
[0869] Beige solid (37.0 mg, 0.101 mmol, 38.9% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 0.96 (3 H, d, J=6.59 Hz), 2.55 (1 H, ddd, J=11.80, 10.15, 3.02 Hz), 2.61 (1 H, ddd, J=9.13, 6.24, 3.02 Hz), 2.81 (1 H, dt, J=11.73, 2.50 Hz), 3.13 - 3.23 (2 H, m), 3.47 (1 H, d, J=16.47 Hz), 3.58 (1 H, td, J=10.70, 2.20 Hz), 3.68 (1 H, dd, J=11.25, 3.02 Hz), 3.74 (1 H, dt, J=11.32, 2.71 Hz), 3.90 (3 H, s), 7.77 (1 H, dd, J=8.64, 1.51 Hz), 8.02 (1 H, d, J=8.51 Hz), 8.10 (1 H, s), 8.10 (1 H, br s), 8.36 (1 H, s), 8.43 (1 H, s), 9.04 (1 H, s), 9.97 (1 H, s); ESIMS found for CztJfeNsOz mlz 366.2 (M+l).
Figure imgf000200_0002
343
[0870] (S)-N-(6-(l-Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(2- methylmorpholino)acetamide 343.
[0871] Beige solid (19.0 mg, 0.052 mmol, 15.8% yield). ¾ NMR (499 MHz, DMSO- d6) 5 ppm 1.07 (3 H, d, J=6.31 Hz), 2.00 (1 H, dd, J=10.98, 10.15 Hz), 2.30 (1 H, td, J=l 1.39, 3.02 Hz), 2.73 - 2.79 (1 H, m), 2.83 (1 H, br d, J=l 1.25 Hz), 3.23 (2 H, d, J=1.92 Hz), 3.53 - 3.66 (2 H, m), 3.75 - 3.81 (1 H, m), 3.90 (3 H, s), 7.77 (1 H, dd, J=8.64, 1.51 Hz), 8.02 (1 H, d, J=8.78 Hz), 8.10 (2 H, s), 8.37 (1 H, s), 8.44 (1 H, s), 9.04 (1 H, s), 10.00 (1 H, s); ESIMS found for CztJfeNsOz mlz 366.2 (M+l).
Figure imgf000200_0003
344
[0872] 2-((2Κ,68)-2,6-ϋ™ε ^οφ1ιοΗηο)-Ν-(6-(1 -methyl- lH-pyrazol-4-yl) isoquinolin-3-yl)acetamide 344. [0873] Off-white solid (53.0 mg, 0.140 mmol, 46.6% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.07 (6 H, d, J=6.31 Hz), 1.92 (2 H, t, J=10.84 Hz), 2.82 (2 H, br d, J=10.15 Hz), 3.22 (2 H, s), 3.62 - 3.71 (2 H, m), 3.90 (3 H, s), 7.77 ( 1 H, dd, J=8.51, 1.65 Hz), 8.02 ( 1 H, d, J=8.51 Hz), 8.10 (2 H, s), 8.36 ( 1 H, s), 8.44 (1 H, s), 9.04 ( 1 H, s), 9.98 (1 H, s); ESIMS found for C2iH25N502 mlz 380.2 (M+l).
Figure imgf000201_0001
345
[0874] 2-((l S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(l -methyl-lH- pyrazol-4-yl)isoquinolin-3-yl)acetamide 345.
[0875] Ash colored solid (22.0 mg, 0.061 mmol, 18.3% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.67 (1 H, dt, J=9.61, 1.10 Hz), 1.87 (1 H, dd, J=9.74, 1.78 Hz), 2.62 ( 1 H, d, J=10.43 Hz), 2.95 (1 H, dd, J=10.02, 1.51 Hz), 3.45 (2 H, d, J=5.21 Hz), 3.59 (1 H, dd, J=7.82, 1.78 Hz), 3.63 ( 1 H, s), 3.88 ( 1 H, d, J=7.68 Hz), 3.90 (3 H, s), 4.41 (1 H, s), 7.77 ( 1 H, dd, J=8.64, 1.51 Hz), 8.03 ( 1 H, d, J=8.78 Hz), 8.10 (1 H, s), 8.11 (1 H, br s), 8.37 (1 H, s), 8.44 (1 H, s), 9.04 ( 1 H, s), 9.92 ( 1 H, s); ESIMS found for C2oH2iN502 mlz 364.2 (M+l).
Figure imgf000201_0002
346
[0876] 2-((lR,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(l -methyl-lH- pyrazol-4-yl)isoquinolin-3-yl)acetamide 346.
[0877] Ash colored solid (25.0 mg, 0.069 mmol, 18.3% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.63 - 1.70 ( l H, m), 1.87 (1 H, dd, J=9.74, 1.78 Hz), 2.62 (1 H, d, J=10.15 Hz), 2.95 (1 H, dd, J=10.02, 1.51 Hz), 3.45 (2 H, d, J=4.94 Hz), 3.59 (1 H, dd, J=7.68, 1.92 Hz), 3.63 ( 1 H, s), 3.88 (1 H, d, J=7.68 Hz), 3.90 (3 H, s), 4.41 (1 H, s), 7.77 ( 1 H, dd, J=8.51, 1.65 Hz), 8.03 ( 1 H, d, J=8.51 Hz), 8.10 (1 H, s), 8.11 (1 H, br s), 8.37 ( 1 H, s), 8.44 ( 1 H, s), 9.04 (1 H, s), 9.92 ( 1 H, s); ESIMS found for C2oH2iN502 mlz 364.2 (M+l).
Figure imgf000201_0003
347
[0878] 2-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(6-(l -methyl-lH-pyrazol-4-yl) isoquinolin-3-yl)acetamide 347.
[0879] Off-white solid (8.0 mg, 0.021 mmol, 8.2% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.75 - 1.82 (2 H, m), 1.86 - 1.94 (2 H, m), 3.14 (2 H, s), 3.17 (2 H, br d, J=0.82 Hz), 3.48 - 3.55 (2 H, m), 3.68 (2 H, d, J=10.43 Hz), 3.90 (3 H, s), 7.78 ( 1 H, dd, J=8.51, 1.37 Hz), 8.03 (1 H, d, J=8.51 Hz), 8.10 (1 H, s), 8.1 1 (1 H, s), 8.37 (1 H, s), 8.46 ( 1 H, s), 9.06 ( 1 H, s), 10.15 ( 1 H, s); ESIMS found for C2iH23N502 mlz 378.2 (M+l).
Figure imgf000202_0001
348
[0880] (S)-N-(6-(l -Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2- morpholinopropanamide 348.
[0881] Light yellow solid (68.0 mg, 0.186 mmol, 45.3% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.23 (3 H, d, J=6.86 Hz), 2.51 - 2.57 (2 H, m), 2.57 - 2.65 (2 H, m), 3.45 ( 1 H, q, J=6.77 Hz), 3.64 (4 H, t, J=4.67 Hz), 3.90 (3 H, s), 7.77 ( 1 H, dd, J=8.51, 1.37 Hz), 8.02 (1 H, d, .7=8.51 Hz), 8.08 (1 H, s), 8.09 (1 H, s), 8.36 ( 1 H, s), 8.45 ( 1 H, s), 9.04 (1 H, s), 10.17 ( 1 H, s); ESIMS found for CztJfeNsOz mlz 366.2 (M+l).
Figure imgf000202_0002
349
[0882] N-(6-(l -Methyl- lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(mo holin-2-yl) acetamide 349.
[0883] Off-white solid (275.0 mg, 0.783 mmol, 91.8% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 2.41 - 2.48 (2 H, m), 2.57 - 2.69 (3 H, m), 2.83 ( 1 H, br dd, J=12.21, 2.06 Hz), 3.43 (1 H, td, J=10.63, 3.43 Hz), 3.70 ( 1 H, br d, J=10.70 Hz), 3.78 - 3.85 (1 H, m), 3.90 (3 H, s), 7.74 (1 H, dd, J=8.64, 1.51 Hz), 8.00 (1 H, d, J=8.51 Hz), 8.04 ( 1 H, s), 8.07 (1 H, s), 8.34 ( 1 H, s), 8.43 (1 H, s), 9.02 (1 H, s), 10.41 ( 1 H, s); ESIMS found for Ci9H2iN502 mlz 352.0 (M+l).
Figure imgf000203_0001
350
[0884] N-(6-(l -Methyl- 1Η-ργΓαζο1-4-γ1)ί8ο υίηο1ίη-3-γ1)-2-(4-ηιεΐ1ιγ1ηιοφ1ιο1ίη-2- yl)acetamide 350.
[0885] White solid (71.0 mg, 0.194 mmol, 68.3% yield). ¾NMR (499 MHz, DMSO- d6) δ ρρηι 1.78 (1 H, t, J=11.00 Hz), 1.97 (1 H, td, J=11.32, 3.16 Hz), 2.18 (3 H, s), 2.53 (1 H, br d, J=5.49 Hz), 2.58 (1 H, br dd, J=l 1.25, 1.37 Hz), 2.66 (1 H, dd, J=14.68, 7.82 Hz), 2.74 (1 H, br d, J=11.25 Hz), 3.50 (1 H, td, J=l 1.11, 2.47 Hz), 3.72 - 3.80 (1 H, m), 3.86 - 3.96 (1 H, m), 3.90 (3 H, s), 7.75 (1 H, dd, J=8.51, 1.65 Hz), 8.00 (1 H, d, J=8.51 Hz), 8.04 (1 H, s), 8.07 (1 H, s), 8.34 (1 H, s), 8.44 (1 H, s), 9.02 (1 H, s), 10.45 (1 H, s); ESIMS found for CztJfeNsOz mlz 366.0 (M+l).
Figure imgf000203_0002
351
[0886] 2-(4-Ethylpiperazin- 1 -yl)-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl) acetamide 351.
[0887] Beige solid (52.0 mg, 0.137 mmol, 52.8% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.03 (3 H, br s), 2.30 - 2.47 (4 H, m), 2.53 - 2.74 (6 H, m), 3.24 (2 H, br s), 3.90 (3 H, s), 7.77 (1 H, dd, J=8.51, 1.37 Hz), 8.02 (1 H, d, J=8.51 Hz), 8.10 (2 H, s), 8.37 (1 H, s), 8.43 (1 H, s), 9.04 (1 H, s), 9.96 (1 H, br s); ESIMS found for CziHzeNeO mlz 379.2 (M+l).
Figure imgf000203_0003
352
[0888] 2-(4-Isopropylpiperazin-l-yl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin- 3-yl)acetamide 352.
[0889] Beige solid (66.0 mg, 0.162 mmol, 66.7% yield). ¾ NMR (500 MHz, DMSO- d6) δ ppm 0.99 (6 H, d, J=6.59 Hz), 2.51 - 2.54 (2 H, m), 2.57 (4 H, br s), 2.61 - 2.69 (1 H, m), 3.20 (2 H, s), 3.90 (3 H, s), 7.77 (1 H, dd, J=8.64, 1.51 Hz), 8.02 (1 H, d, J=8.51 Hz), 8.10 (2 H, s), 8.36 (1 H, s), 8.43 (1 H, s), 9.04 (1 H, s), 9.89 (1 H, s); ESIMS found for C22H28N60 mlz 393.0 (M+l).
Figure imgf000204_0001
353
[0890] 2-(4-Cyclopropylpiperazin- 1 -yl)-N-(6-( 1 -methyl-lH-pyrazol-4-yl) isoquinolin-3-yl)acetamide 353.
[0891] Beige solid (44.0 mg, 0.109 mmol, 44.7% yield). ¾ NMR (500 MHz, DMSO- d6) δ ppm 0.26 - 0.32 (2 H, m), 0.39 - 0.45 (2 H, m), 1.66 (1 H, tt, J=6.59, 3.43 Hz), 2.51 - 2.57 (4 H, m), 2.62 (4 H, br s), 3.20 (2 H, s), 3.90 (3 H, s), 7.77 ( 1 H, dd, J=8.51, 1.65 Hz), 8.02 (1 H, d, J=8.78 Hz), 8.09 (2 H, s), 8.36 ( 1 H, s), 8.43 (1 H, s), 9.04 ( 1 H, s), 9.92 ( 1 H, s); ESIMS found for C22H26N6O mlz 391.0 (M+ l).
Figure imgf000204_0002
354
[0892] 2-(4-(2-Fluoroethyl)piperazin- 1 -yl)-N-(6-( 1 -methyl- lH-pyrazol-4-yl) isoquinolin-3-yl)acetamide 354.
[0893] Off-white solid (33.0 mg, 0.083 mmol, 25.9% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 2.54 (4 H, br s), 2.57 - 2.60 (3 H, m), 2.64 (4 H, dt, J=28.60, 4.95 Hz), 3.22 (2 H, s), 3.90 (3 H, s), 4.54 (2 H, dt, J=47.80, 4.70 Hz), 7.77 (1 H, dd, J=8.51, 1.65 Hz), 8.02 (1 H, d, J=8.51 Hz), 8.10 (2 H, s), 8.37 ( 1 H, s), 8.43 (1 H, s), 9.04 ( 1 H, s), 9.93 (1 H, s); ESIMS found for C21H25FN6O mlz 397.2 (M+l).
Figure imgf000204_0003
355
[0894] (S)-2-(2,4-Dimethylpiperazin-l -yl)-N-(6-( l-methyl-lH-pyrazol-4-yl) isoquinolin-3-yl)acetamide 355.
[0895] Beige solid (20.0 mg, 0.053 mmol, 20.3% yield). ¾ NMR (499 MHz, DMSO- 6) 5 ppm 1.01 (3 H, d, J=6.31 Hz), 1.87 (1 H, br t, J=8.51 Hz), 2.1 1 - 2.19 ( 1 H, m), 2.17 (3 H, s), 2.51 - 2.57 (1 H, m), 2.57 - 2.67 (3 H, m), 2.83 (1 H, dt, J=1 1.25, 3.02 Hz), 3.13 (1 H, d, J=16.47 Hz), 3.43 (1 H, d, J=16.74 Hz), 3.90 (3 H, s), 7.77 ( 1 H, dd, J=8.51, 1.65 Hz), 8.02 (1 H, d, J=8.51 Hz), 8.10 (1 H, s), 8.11 (1 H, br s), 8.37 (1 H, s), 8.43 (1 H, s), 9.04 (1 H, s), 9.92 (1 H, s); ESIMS found for CziHzeNeO mlz 379.
Figure imgf000205_0001
358
[0896] 1 -(2-Hydroxyethyl)-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl) piperidine-4-carboxamide 358.
[0897] White solid (41.0 mg, 0.108 mmol, 36.2% yield). ¾NMR (499 MHz, DMSO- £¾) 5 ppm 1.62 - 1.73 (2 H, m), 1.73 - 1.81 (2 H, m), 1.98 (2 H, td, J= 11.46, 2.06 Hz), 2.39 (2 H, t, J=6.31 Hz), 2.52 - 2.57 (1 H, m), 2.92 (2 H, br d, J=11.53 Hz), 3.50 (2 H, q, J=6.04 Hz), 3.90 (3 H, s), 4.30 (1 H, br t, J=5.35 Hz), 7.73 (1 H, dd, J=8.51, 1.65 Hz), 7.99 (1 H, d, J=8.51 Hz), 8.02 (1 H, s), 8.06 (1 H, s), 8.33 (1 H, s), 8.44 (1 H, s), 9.02 (1 H, s), 10.39 (1 H, s); ESIMS found for C2iH25N502 mlz 380.0 (M+l).
Figure imgf000205_0002
359
[0898] N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)- 1 -(pyridin-2-ylmethyl) piperidine-4-carboxamide 359.
[0899] Beige solid (11.0 mg, 0.026 mmol, 8.7% yield). 'H NMR (499 MHz, DMSO- d6) δ ppm 1.66 - 1.77 (2 H, m), 1.77 - 1.84 (2 H, m), 2.01 - 2.12 (2 H, m), 2.53 - 2.62 ( 1 H, m), 2.85 - 2.94 (2 H, m), 3.60 (2 H, s), 3.90 (3 H, s), 7.25 (1 H, dd, J=6.86, 5.49 Hz), 7.46 (1 H, d, J=7.96 Hz), 7.74 (1 H, dd, J=8.51, 1.65 Hz), 7.77 (1 H, td, J=7.62, 1.78 Hz), 7.99 (1 H, d, J=8.51 Hz), 8.03 (1 H, s), 8.07 (1 H, s), 8.33 (1 H, s), 8.44 (1 H, s), 8.49 (1 H, br d, J=4.12 Hz), 9.02 (1 H, s), 10.41 (1 H, s); ESIMS found
Figure imgf000205_0003
360
[0900] N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)- 1 -(oxazol-2-ylmethyl) piperidine-4-carboxamide 360. [0901] White solid (65.0 mg, 0.156 mmol, 52.3% yield). ¾NMR (499 MHz, DMSO- d6) δ ppm 1.68 (2 H, qd, J=12.21, 3.43 Hz), 1.79 (2 H, br d, J=10.43 Hz), 2.07 - 2.18 (2 H, m), 2.51 - 2.57 (1 H, m), 2.85 - 2.94 (2 H, m), 3.67 (2 H, s), 3.90 (3 H, s), 7.17 (1 H, d, J=0.82 Hz), 7.73 (1 H, dd, J=8.64, 1.51 Hz), 7.99 (1 H, d, J=8.51 Hz), 8.02 (1 H, s), 8.06 (1 H, s), 8.06 (1 H, d, J=0.82 Hz), 8.33 (1 H, s), 8.43 (1 H, s), 9.01 (1 H, s), 10.40 (1 H, s); ESIMS found for C23H24N6O2 mlz 416.95 (M+l).
Figure imgf000206_0001
362
[0902] (R)-N-(6-( 1 -Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)- 1 -oxotetrahydro- 1H- pyrrolo [ 1 ,2-c] imidazole-2(3H)-carboxamide 362.
[0903] White solid (120.0 mg, 0.360 mmol, 57.8% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.70 - 1.83 (2 H, m), 2.02 (1 H, dtd, J=12.49, 8.16, 8.16, 3.84 Hz), 2.08 - 2.18 (1 H, m), 2.64 (1 H, td, J=9.33, 6.86 Hz), 3.17 (1 H, ddd, J=9.74, 6.17, 4.12 Hz), 3.90 (3 H, s), 3.96 (1 H, dd, J=9.06, 4.12 Hz), 4.99 - 5.10 (2 H, m), 7.80 (1 H, dd, J=8.51, 1.65 Hz), 8.04 (1 H, d, J=8.51 Hz), 8.11 (1 H, s), 8.13 (1 H, s), 8.38 (1 H, s), 8.60 (1 H, s), 9.09 (1 H, s); ESIMS found for CigHisNsO mlz 334.1 (M+l).
Figure imgf000206_0002
363
[0904] (R)-l-Methyl-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine- 2-carboxamide 363.
[0905] Off-white solid (65.0 mg, 0.194 mmol, 62.3% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.74 - 1.82 (2 H, m), 1.82 - 1.90 (1 H, m), 2.17 - 2.28 (1 H, m), 2.37 - 2.44 (1 H, m), 2.42 (3 H, s), 3.07 (1 H, dd, J=9.88, 5.49 Hz), 3.17 (1 H, ddd, J=8.92, 6.04, 3.16 Hz), 3.90 (3 H, s), 7.77 (1 H, dd, J=8.51, 1.65 Hz), 8.03 (1 H, d, J=8.51 Hz), 8.10 (2 H, s), 8.37 (1 H, s), 8.44 (1 H, s), 9.03 (1 H, s), 9.92 (1 H, s); ESIMS found for Ci9H2iN50 mlz 336.2 (M+l).
Figure imgf000206_0003
364
[0906] N-(4-Chloro-6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)
cyclopropanecarboxamide 364.
[0907] Beige solid (240.0 mg, 0.734 mmol, 95.0% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 0.80 - 0.86 (4 H, m), 1.91 (1 H, quin, J=6.24 Hz), 3.92 (3 H, s), 7.99 (1 H, dd, J=8.51, 1.37 Hz), 8.14 (1 H, s), 8.19 (1 H, d, J=8.78 Hz), 8.22 (1 H, d, J=0.82 Hz), 8.49 (1 H, s), 9.10 (1 H, s), 10.48 (1 H, s); ESIMS found for Ci7Hi5ClN40 mlz 327.1 (M+l).
Figure imgf000207_0001
365
[0908] tra«5-4-Amino-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl) cyclohexane-l-carboxamide 365.
[0909] Beige solid (350.0 mg, 1.00 mmol, 90.1% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 0.99 - 1.11 (2 H, m), 1.42 - 1.64 (4 H, m), 1.82 (4 H, br d, J=l 1.80 Hz), 2.42 - 2.49 (1 H, m), 3.90 (3 H, s), 7.74 (1 H, dd, J=8.51, 1.65 Hz), 7.99 (1 H, d, J=8.51 Hz), 8.02 (1 H, s), 8.07 (1 H, s), 8.35 (1 H, s), 8.42 (1 H, s), 9.02 (1 H, s), 10.40 (1 H, s); ESIMS found for C2oH23N50 mlz 350.2 (M+l).
Figure imgf000207_0002
366
[0910] N-(8-Fluoro-6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide 366.
[0911] White solid (260.0 mg, 0.736 mmol, 73.6% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.53 (2 H, qd, J=12.21, 3.98 Hz), 1.70 (2 H, br d, J=10.98 Hz), 2.42 - 2.49 (2 H, m), 2.60 - 2.70 (1 H, m), 2.97 (2 H, br d, J=14.00 Hz), 3.90 (3 H, s), 7.58 (1 H, dd, J=12.08, 1.10 Hz), 7.92 (1 H, s), 8.11 (1 H, s), 8.39 (1 H, s), 8.49 (1 H, s), 9.14 (1 H, s), 10.56 (1 H, s); ESIMS found for C19H20FN5O mlz 354.15 (M+l).
Figure imgf000208_0001
367
[0912] N-(8-Fluoro-6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-l- isobutylpiperidine-4-carboxamide 367.
[0913] Beige solid (15.0 mg, 0.037 mmol, 16.2% yield). ¾NMR(499 MHz, DMSO- 6)5ppm0.86(6H, d,J=6.59Hz), 1.61 - 1.72 (2H, m), 1.73 - 1.81 (3 H, m), 1.83 - 1.92 (2H, m), 2.02 (2 H, d, J=7.41 Hz), 2.51 - 2.59 (1 H, m), 2.82 - 2.91 (2 H, m), 3.90 (3 H, s), 7.58 (1 H, dd, J=12.08, 1.10 Hz), 7.92 (1 H, s), 8.11 (1 H, s), 8.39 (1 H, s), 8.49 (1 H, s), 9.15 (1 H, s), 10.61 (1 H, s); ESIMS found for C23H2
Figure imgf000208_0002
368
[0914] N-(8-Fluoro-6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-l-(2-fluoroethyl) piperidine-4-carboxamide 368.
[0915] Off-white solid (26.0 mg, 0.065 mmol, 28.8% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.68 (2 H, qd,J=12.21, 3.70 Hz), 1.75 - 1.83 (2 H, m), 2.00 - 2.07 (2 H, m), 2.52 - 2.57 (1 H, m), 2.61 (2 H, dt, J=28.30, 4.95 Hz), 2.94 (2 H, br d, J=l 1.53 Hz), 3.90 (3 H, s), 4.53 (2 H, dt,J=48.10, 5.25 Hz), 7.59 (1 H, dd,J=12.08, 1.37 Hz), 7.92 (1 H, s), 8.11 (1 H, d,J=0.82 Hz), 8.39 (1 H, s), 8.50 (1 H, s), 9.15 (1 H, s), 10.62 (1 H, s); ESIMS found for C2iH23F2N50 mlz 400.2 (M+l).
Figure imgf000208_0003
369
[0916] N-(7-Fluoro-6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide 369.
[0917] Off-white solid (135.0 mg, 0.382 mmol, 74.0% yield). ¾ NMR (499 MHz, DMSO- 6)5ppm 1.53 (2H, qd,J=12.17, 3.84 Hz), 1.70 (2H, brdd,J=12.08, 1.65 Hz), 2.43 - 2.49 (2 H, m), 2.63 ( 1 H, tt, J=11.63, 3.74 Hz), 2.97 (2 H, br d, J=12.08 Hz), 3.93 (3 H, s), 7.89 ( 1 H, d, J=1 1.80 Hz), 8.10 ( 1 H, s), 8.26 ( 1 H, d, J=7.41 Hz), 8.30 ( 1 H, d, J=2.74 Hz), 8.49 (1 H, s), 9.03 ( 1 H, s), 10.44 ( 1 H, s); ESIM 354.15 (M+l).
Figure imgf000209_0001
370
[0918] N-(7-Fluoro-6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-l - isobutylpiperidine-4-carboxamide 370.
[0919] Off-white solid (45.0 mg, 0.106 mmol, 53.4% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 0.86 (6 H, d, J=6.59 Hz), 1.61 - 1.72 (2 H, m), 1.73 - 1.81 (3 H, m), 1.83 - 1.92 (2 H, m), 2.02 (2 H, d, J=7.41 Hz), 2.51 - 2.58 (1 H, m), 2.86 (2 H, br d, J=1 1.25 Hz), 3.93 (3 H, s), 7.89 ( 1 H, d, J=1 1.53 Hz), 8.10 (1 H, d, J=0.82 Hz), 8.27 (1 H, d, J=7.41 Hz), 8.30 (1 H, d, J=2.74 Hz), 8.50 ( 1 H, s), 9.03 ( 1 H, s), 10.49 (1 H, s); ESIMS found for C23H28FN50 mlz 410.2 (M+ l).
Figure imgf000209_0002
371
[0920] N-(7-Fluoro-6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-l -(2-fluoroethyl) piperidine-4-carboxamide 371.
[0921] White solid (30.0 mg, 0.072 mmol, 51.1% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.68 (2 H, qd, J=12.21, 3.70 Hz), 1.76 - 1.83 (2 H, m), 2.04 (2 H, td, J=l 1.80, 2.20 Hz), 2.54 (1 H, td, J=7.62, 3.98 Hz), 2.61 (2 H, dt, J=28.35, 4.95 Hz), 2.94 (2 H, br d, J=l 1.53 Hz), 3.93 (3 H, s), 4.53 (2 H, dt, J=47.80, 4.95 Hz), 7.89 ( 1 H, d, J=1 1.53 Hz), 8.10 (1 H, s), 8.27 ( 1 H, d, J=7.68 Hz), 8.30 (1 H, d, J=2.74 Hz), 8.50 (1 H, s), 9.04 (1 H, s), 10.49 (1 H, s); ESIMS found for C2iH23F2N50 mlz 400.2 (M+l).
Figure imgf000209_0003
372 [0922] N-(7-Fluoro-6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(4- methylpiperazin-1 -yl)acetamide 372.
[0923] Off-white solid (16.0 mg, 0.042 mmol, 13.5% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 2.19 (3 H, s), 2.40 (4 H, br s), 2.58 (4 H, br s), 3.22 (2 H, s), 3.93 (3 H, s), 7.92 (1 H, d, J=11.53 Hz), 8.13 (1 H, s), 8.32 (1 H, d, J=3.02 Hz), 8.34 (1 H, d, J=7.41 Hz), 8.49 (1 H, s), 9.05 (1 H, s), 9.95 (1 H, s); ESIMS found for CztfeFNeO mlz 383.2 (M+l).
Figure imgf000210_0001
[0924] N-(6-( 1 ,2-Dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)- 1 - fluorocyclopropane-1 -carboxamide 376.
[0925] Beige solid (32.0 mg, 0.094 mmol, 19.3% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.33 - 1.42 (2 H, m), 1.43 - 1.53 (2 H, m), 2.39 (3 H, s), 3.67 (3 H, s), 7.13 (1 H, s), 7.67 (1 H, dd, J=8.51, 1.65 Hz), 7.97 (1 H, s), 8.13 (1 H, d, J=8.51 Hz), 8.46 (1 H, s), 9.18 (1 H, s), 10.28 (1 H, s); ESIMS found for (M+l).
Figure imgf000210_0002
433
[0926] N-(6-(l-Methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)
cyclopropanecarboxamide 433.
[0927] Beige solid (14.0 mg, 0.048 mmol, 10.8% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 0.79 - 0.91 (4 H, m), 2.03 - 2.12 (1 H, m), 4.14 (3 H, s), 8.01 (1 H, dd, J=8.51, 1.65 Hz), 8.11 (1 H, d, J=8.78 Hz), 8.26 (1 H, s), 8.47 (1 H, s), 8.72 (1 H, s), 9.12 (1 H, s), 10.90 (1 H, s); ESIMS found for Ci6Hi5N50 mlz 294 A (M+l).
Figure imgf000210_0003
441
[0928] 4,4-Difluoro-N-(6-(l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl) cyclohexane-1 -carboxamide 441. [0929] White solid (57.8 mg, 0.156 mmol, 43.2% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.67 - 1.91 (4 H, m), 1.96 (2 H, br d, J=12.90 Hz), 2.08 - 2.18 (2 H, m), 2.69 - 2.75 (1 H, m), 4.14 (3 H, s), 8.02 (1 H, dd, J=8.51, 1.37 Hz), 8.1 1 (1 H, d, J=8.51 Hz), 8.29 (1 H, s), 8.50 (1 H, s), 8.73 (1 H, s), 9.12 (1 H, s), 10.63 (1 H, s); ESIMS found for Ci9Hi9F2N50 mlz 372.2 (M+1).
Figure imgf000211_0001
443
[0930] tra«s-4-(Dimethylamino)-N-(6-( 1 -methyl- 1H- 1 ,2,3-triazol-4-yl)isoquinolin- 3 -yl)cyclohexane - 1 -carboxamide 443.
[0931] White solid (8.0 mg, 0.021 mmol, 10.9% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.13 - 1.23 (2 H, m), 1.43 - 1.55 (2 H, m), 1.83 - 1.96 (4 H, m), 2.1 1 - 2.16 ( 1 H, m), 2.18 (6 H, s), 2.44 - 2.48 (1 H, m), 4.14 (3 H, s), 8.01 (1 H, dd, J=8.51, 1.65 Hz), 8.10 (1 H, d, J=8.51 Hz), 8.27 (1 H, s), 8.49 (1 H, s), 8.72 ( 1 H, s), 9.11 ( 1 H, s), 10.47 (1 H, s); ESIMS found for C2iH26N60 mlz 379.2 (M+ 1).
Figure imgf000211_0002
448
[0932] tra«5-N-(6-( l-Methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)-4-((4- methylpiperazin-1 -yl)methyl)cyclohexane-l -carboxamide 448.
[0933] Off-white solid (22.0 mg, 0.049 mmol, 14.6% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 0.82 - 0.95 (2 H, m), 1.41 - 1.52 (3 H, m), 1.79 - 1.91 (4 H, m), 2.08 (2 H, d, J=7.14 Hz), 2.14 (3 H, s), 2.31 (8 H, br s), 2.51 - 2.55 (1 H, m), 4.14 (3 H, s), 8.00 (1 H, dd, J=8.51, 1.37 Hz), 8.10 ( 1 H, d, J=8.51 Hz), 8.27 (1 H, s), 8.50 (1 H, s), 8.72 (1 H, s), 9.10 (1 H, s), 10.47 ( 1 H, s); ESIMS found for C25H
Figure imgf000211_0003
452
[0934] N-(6-(l -Methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide 452. [0935] White solid (119.4 mg, 0.355 mmol, 77.9% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.54 (2 H, qd, J=12.17, 3.84 Hz), 1.71 (2 H, br d, J=l 1.25 Hz), 2.45 - 2.49 (2 H, m), 2.65 (1 H, tt, J=11.70, 3.67 Hz), 2.98 (2 H, br d, J=12.08 Hz), 4.14 (3 H, s), 8.01 (1 H, dd, J=8.51, 1.37 Hz), 8.11 (1 H, d,J=8.51 Hz), 8.28 (1 H, s), 8.50 (1 H, s), 8.73 (1 H, s), 9.11 (1 H, s), 10.48 (1 H, s); ESIMS found
Figure imgf000212_0001
470
[0936] N-(6-( 1 -Methyl- 1H- 1 ,2,3 -triazol-4-yl)isoquinolin-3 -yl)- 1 -(( 1 - (trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide 470.
[0937] White solid (75.9 mg, 0.166 mmol, 79.4% yield). ¾NMR(499 MHz, DMSO- d6) 5ppm 0.73 (2 H, br s), 0.93 - 1.00 (2 H, m), 1.63 - 1.74 (2 H, m), 1.78 (2 H, br d,J=10.70 Hz), 1.95 (2 H, br t, J=10.57 Hz), 2.52 - 2.60 (1 H, m), 2.97 (2 H, br d, J=10.98 Hz), 3.28 (2 H, s), 4.14 (3 H, s), 8.01 (1 H, dd, J=8.51, 1.37 Hz), 8.11 (1 H, d, J=8.51 Hz), 8.28 (1 H, s), 8.50 (1 H, s), 8.72 (1 H, s), 9.11 (1 H, s), 10.52 (1 H, s); ESIMS found for C23H25F3N60 mlz 459.2 (M+l).
Figure imgf000212_0002
472
[0938] N-(6-( 1 -Methyl- 1H- 1 ,2,3 -triazol-4-yl)isoquinolin-3 -yl)- 1 -((3 -methyloxetan- 3 -yl)methyl)piperidine-4-carboxamide 472.
[0939] Beige solid (32.0 mg, 0.076 mmol, 21.1%yield). ¾NMR(499 MHz, DMSO- d6) 5ppm 1.31 (3 H, s), 1.60- 1.71 (2 H, m), 1.72- 1.80 (2 H, m), 1.93 -2.02 (2 H, m), 2.48 (2 H, br s), 2.52 - 2.59 (1 H, m), 2.59 - 2.67 (2 H, m), 4.14 (3 H, s), 4.19 (2 H, d, J=5.49 Hz), 4.36 (2 H, d,J=5.76Hz), 8.01 (1 H, dd,J=8.51, 1.37 Hz), 8.11 (1 H, d,J=8.51 Hz), 8.28 (1 H, s), 8.50 (1 H, s), 8.73 (1 H, s), 9.11 (1 H, s), 10.54 (1 H, s); ESIMS found for CzsHzsNeOz mlz 421.2 (M+l).
Figure imgf000212_0003
475
[0940] N-(6-( 1 -Methyl- 1H- 1 ,2,3 -triazol-4-yl)isoquinolin-3 -yl)- 1 -(2-(pyrrolidin- 1 -yl) acetyl)piperidine-4-carboxamide 475. [0941] White solid (7.8 mg, 0.017 mmol, 20.5% yield). ¾ NMR (499 MHz, DMSO- d6) δρρηι 1.44- 1.55 (2 H, m), 1.57 - 1.66 (2 H, m), 1.67 - 1.73 (4 H, m), 1.85 (2H, brd,J=10.43 Hz), 2.58 - 2.65 (1 H, m), 2.82 (1 H, ddd, J=l 1.32, 7.34, 4.39 Hz), 2.99 - 3.06 (1 H, m), 3.16 - 3.21 (2 H, m), 3.30 - 3.38 (2 H, m), 4.10 (1 H, br d, J=1.10 Hz), 4.14 (3 H, s), 4.36 - 4.44 (1 H, m), 8.01 (1 H, dd, J=8.51, 1.37 Hz), 8.11 (1 H, d, J=8.78 Hz), 8.28 (1 H, s), 8.49 (1 H, s), 8.71 (1 H, s), 9.11 (1 H, s), 10.56 (1 H, s); ESIM 448.0 (M+l).
Figure imgf000213_0001
477
[0942] r-Methyl-N-(6-(l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)-[l,4'- bipiperidine]-4-carboxamide 477.
[0943] Off-white solid (65.0 mg, 0.150 mmol, 37.6% yield). ¾ NMR (500 MHz, DMSO- e) δ ppm 1.43 (2 H, qd, J=l 1.94, 3.70 Hz), 1.57 - 1.70 (4 H, m), 1.75 - 1.86 (4 H, m), 2.08 - 2.19 (1 H, m), 2.12 (3 H, s), 2.51 - 2.57 (1 H, m), 2.77 (2 H, br d,J=11.53 Hz), 2.90 (2 H, br d, J=11.25 Hz), 3.17 (2 H, d,J=2.20 Hz), 4.14 (3 H, s), 8.01 (1 H, dd, J=8.51, 1.65 Hz), 8.10 (1 H, d, J=8.51 Hz), 8.28 (1 H, s), 8.51 (1 H, s), 8.72 (1 H, s), 9.10 (1 H, s), 10.51 (1 H, s); ESIMS found for C24H3iN70 mlz 434.25 (M+l).
Figure imgf000213_0002
481
[0944] (R)-N-(6-(l-Methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-3- carboxamide 481.
[0945] White solid (80.4 mg, 0.239 mmol, 87.7% yield). 'HNMR (499 MHz, DMSO- d6) 5ppm 1.36 - 1.46 (1 H, m), 1.56 - 1.64 (1 H, m), 1.64 - 1.72 (1 H, m), 1.84 - 1.92 (1 H, m), 2.53 - 2.60 (1 H, m), 2.63 (1 H, dq, J=8.71, 4.41 Hz), 2.75 (1 H, dd, J=11.94, 8.92 Hz), 2.81 (1 H, dt, J=12.14, 3.95 Hz), 3.00 (1 H, dd, J=11.94, 3.16 Hz), 4.14 (3 H, s), 8.01 (1 H, dd, J=8.51, 1.65 Hz), 8.11 (1 H, d,J=8.51 Hz), 8.28 (1 H, s), 8.49 (1 H, s), 8.73 (1 H, s), 9.10 (1 H, s), 10.81 (1 H, s); ESIMS found for Ci8H2oN60 mlz 337.2 (M+l).
Figure imgf000214_0001
483
[0946] (R)-l -Isobutyl-N-(6-( l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl) piperidine-3-carboxamide 483.
[0947] White solid (45.9 mg, 0.1 17 mmol, 82.3% yield). 'HNMR (499 MHz, DMSO- d6) δ ppm 0.88 (3 H, d, J=6.59 Hz), 0.91 (3 H, d, J=6.59 Hz), 1.50 - 1.61 (2 H, m), 1.65 - 1.73 ( 1 H, m), 1.78 - 1.86 (2 H, m), 2.08 (2 H, br d, J=7.41 Hz), 2.10 - 2.16 ( 1 H, m), 2.25 - 2.33 ( 1 H, m), 2.55 - 2.62 (1 H, m), 2.77 (2 H, br d, J=7.68 Hz), 4.14 (3 H, s), 8.01 (1 H, dd, J=8.51, 1.65 Hz), 8.1 1 (1 H, d, J=8.78 Hz), 8.28 (1 H, s), 8.49 ( 1 H, s), 8.73 (1 H, s), 9.10 ( 1 H, s), 10.73 ( 1 H, s); ESIMS found for C22H28N60 mlz 393.2 (M+l).
Figure imgf000214_0002
487
[0948] N-(6-(l -Methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-l -yl) acetamide 487.
[0949] Off-white solid ( 18.2 mg, 0.054 mmol, 16.0% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.78 (4 H, dt, J=6.52, 3.19 Hz), 2.62 - 2.70 (4 H, m), 3.36 (2 H, s), 4.14 (3 H, s), 8.04 (1 H, dd, J=8.51, 1.37 Hz), 8.13 (1 H, d, J=8.51 Hz), 8.34 (1 H, s), 8.50 (1 H, s), 8.74 (1 H, s), 9.12 (1 H, s), 9.98 (1 H, s); ESIMS found for Ci8H2oN60 mlz 337.15 (M+l).
Figure imgf000214_0003
500
[0950] N-(6-(l -Methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(4- methylpiperazin-1 -yl)acetamide 500.
[0951] Beige solid (5.0 mg, 0.014 mmol, 4.1% yield). ¾ NMR (499 MHz, DMSO- d6) 5 ppm 2.19 (3 H, s), 2.34 - 2.46 (4 H, m), 2.58 (4 H, br s), 3.23 (2 H, s), 4.14 (3 H, s), 8.04 (1 H, dd, J=8.51, 1.65 Hz), 8.14 ( 1 H, d, J=8.51 Hz), 8.34 (1 H, s), 8.50 ( 1 H, s), 8.74 ( 1 H, s), 9.13 ( 1 H, s), 10.00 ( 1 H, s); ESIMS found for C19H23N7O mlz 366.2 (M+l).
Figure imgf000215_0001
[0952] 2-(7-Azabicyclo[2.2.1]heptan-7-yl)-N-(6-(l-methyl-lH-l,2,3-triazol-4-yl) isoquinolin-3-yl)acetamide 513.
[0953] White solid (12.2 mg, 0.034 mmol, 17.8% yield). 'HNMR (499 MHz, DMSO- d6) δ ppm 1.34 (4 H, br d, J=7.14 Hz), 1.75 (4 H, br d, J=6.86 Hz), 3.20 (2 H, s), 3.37 (2 H, br s), 4.14 (3 H, s), 8.05 (1 H, dd, J=8.51, 1.37 Hz), 8.14 (1 H, d, J=8.51 Hz), 8.35 (1 H, s), 8.52 (1 H, s), 8.74 (1 H, s), 9.12 (1 H, s), 10.14 (1 H, s); ESIMS found for C2oH22N60 mlz 363.2 (M+l).
Figure imgf000215_0002
517
[0954] 2-Fluoro-2 -methyl -N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl) propanamide 517.
[0955] Off-white solid (70.0 mg, 0.224 mmol, 50.3% yield). ¾ NMR (499 MHz, DMSO- e) 5 ppm 1.64 (6 H, d, J=21.70 Hz), 3.83 (3 H, s), 7.32 (1 H, d, J=1.10 Hz), 7.73 (1 H, dd, J=8.51, 1.65 Hz), 7.79 (1 H, s), 8.07 (1 H, s), 8.14 (1 H, d, J=8.51 Hz), 8.49 (1 H, s), 9.18 (1 H, s), 9.85 (1 H, br d, J=3.57 Hz) ;ESI mlz 313.0 (M+l).
Figure imgf000215_0003
[0956] l-Fluoro-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)cyclopropane-l- carboxamide 521.
[0957] White solid (100.0 mg, 0.306 mmol, 63.1% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.34 - 1.42 (2 H, m), 1.42 - 1.52 (2 H, m), 3.83 (3 H, s), 7.38 (1 H, br s), 7.73 (1 H, br d, J=8.51 Hz), 7.86 (1 H, br s), 8.06 (1 H, s), 8.14 (1 H, d, J=8.51 Hz), 8.47 (1 H, s), 9.19 (1 H, s), 10.29 (1 H, s); ESIMS found for Ci7Hi5FN40 mlz 311.1 (M+l).
Figure imgf000216_0001
[0958] 2-Methyl-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-azaspiro[3.3] heptane-6-carboxamide 523.
[0959] White solid (5.0 mg, 0.014 mmol, 7.1% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 2.15 (3 H, s), 2.22 - 2.36 (4 H, m), 3.04 (2 H, s), 3.14 (2 H, s), 3.22 - 3.29 (1 H, m), 3.83 (3 H, s), 7.30 (1 H, d, J=1.10 Hz), 7.66 (1 H, dd, J=8.51, 1.65 Hz), 7.79 (1 H, s), 8.00 (1 H, s), 8.08 (1 H, d, J=8.51 Hz), 8.54 (1 H, s), 9.11 (1 H, s), 10.42 (1 H, s); ESIMS found for C2iH23N50 mlz 362.2 (M+l).
Figure imgf000216_0002
527
[0960] 1 -Fluoro-N-(6-( 1 -methyl- 1 H-imidazol-5 -yl)isoquinolin-3 -yl)cyclohexane- 1 - carboxamide 527.
[0961] White solid (16.0 mg, 0.043 mmol, 10.1% yield). ¾NMR (499 MHz, DMSO- d6) 5 ppm 1.30 - 1.42 (1 H, m), 1.50 - 1.63 (2 H, m), 1.68 (3 H, br d, J=9.61 Hz), 1.85 - 2.02 (4 H, m), 3.84 (3 H, s), 7.32 (1 H, d, J=1.10 Hz), 7.73 (1 H, dd, J=8.51, 1.92 Hz), 7.80 (1 H, s), 8.07 (1 H, s), 8.13 (1 H, d, J=8.51 Hz), 8.50 (1 H, s), 9.17 (1 H, s), 9.83 (1 H, d, J=4.12 Hz); ESIMS found for C20H21FN4O mlz 353.15 (M+l).
Figure imgf000216_0003
528
[0962] tra«5-4-Methoxy-N-(6-( 1 -methyl- lH-imidazol-5 -yl)isoquinolin-3 -yl) cyclohexane-1 -carboxamide 528.
[0963] White solid (96.6 mg, 0.265 mmol, 39.6% yield). ¾ NMR (500 MHz, DMSO- 6) 5 ppm 1.06 - 1.18 (2 H, m), 1.44 - 1.56 (2 H, m), 1.86 - 1.95 (2 H, m), 2.04 - 2.12 (2 H, m), 2.52 - 2.58 (1 H, m), 3.07 - 3.16 (1 H, m), 3.25 (3 H, s), 3.82 (3 H, s), 7.30 (1 H, s), 7.66 (1 H, dd, J=8.51, 1.65 Hz), 7.79 (1 H, s), 7.99 (1 H, s), 8.08 (1 H, d, J=8.51 Hz), 8.52 (1 H, s), 9.12 (1 H, s), 10.50 (1 H, s); ESIMS found for C21H24N4O2 mlz 365.2 (M+l).
Figure imgf000217_0001
531
[0964] tra«5-4-(Hydroxymethyl)-N-(6-( l-methyl-lH-imidazol-5-yl)isoquinolin-3- yl)cyclohexane-l -carboxamide 531.
[0965] Off-white solid (17.0 mg, 0.047 mmol, 7.0% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 0.95 (2 H, qd, J=12.81, 3.29 Hz), 1.36 ( 1 H, dtt, J=14.75, 5.90, 5.90, 3.05, 3.05 Hz), 1.45 (2 H, qd, J=12.76, 3.16 Hz), 1.80 (2 H, br dd, J=13.04, 2.61 Hz), 1.84 - 1.93 (2 H, m), 2.51 - 2.54 ( 1 H, m), 3.24 (2 H, t, J=5.76 Hz), 3.82 (3 H, s), 4.38 ( 1 H, t, J=5.35 Hz), 7.30 ( 1 H, d, J=1.10 Hz), 7.66 ( 1 H, dd, J=8.51, 1.65 Hz), 7.79 ( 1 H, s), 7.98 (1 H, d, J=0.82 Hz), 8.08 ( 1 H, d, J=8.51 Hz), 8.53 (1 H, s), 9.12 ( 1 H, s), 10.47 (1 H, s); ESIMS found for C21H24N4O2 mlz 365.2 (M+ l).
Figure imgf000217_0002
535
[0966] N-(6-(l -Methyl-lH-imidazol-5-yl)isoquinolin-3-yl)azetidine-3-carboxamide
535.
[0967] Orange solid (4.0 mg, 0.013 mmol, 3.5% yield). ¾ NMR (500 MHz, DMSO- d6) δ ppm 3.23 - 3.32 (1 H, m), 3.70 - 3.78 (2 H, m), 3.83 (3 H, s), 3.90 - 3.98 (2 H, m), 7.31 ( 1 H, d, J=1.10 Hz), 7.69 (1 H, dd, J=8.51, 1.65 Hz), 7.80 (1 H, s), 8.03 ( 1 H, s), 8.10 (1 H, d, J=8.51 Hz), 8.57 (1 H, s), 9.13 ( 1 H, s), 10.65 (1 H, br s) ESIMS found for Ci7Hi7N50 mlz 308.15 (M+l).
Figure imgf000217_0003
537
[0968] (R)-N-(6-(l -Methyl-lH midazol-5-yl)isoquinolin-3-yl)tetrahydrofuran-2- carboxamide 537.
[0969] Off-white solid ( 100.0 mg, 0.310 mmol, 69.6% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.84 - 1.97 (2 H, m), 1.98 - 2.08 ( 1 H, m), 2.20 - 2.31 (1 H, m), 3.83 (3 H, s), 3.84 - 3.90 (1 H, m), 4.00 - 4.07 (1 H, m), 4.54 (1 H, dd, J=8.23, 5.76 Hz), 7.31 (1 H, d, J=0.82 Hz), 7.70 (1 H, dd,J=8.51, 1.65 Hz), 7.79 (1 H, s), 8.05 (1 H, s), 8.11 (1 H, d,J=8.51 Hz), 8.52 (1 H, s), 9.14 (1 H, s), 9.79 (1 H, s); ESIMS found for mlz 323.0 (M+l).
Figure imgf000218_0001
547
[0970] l-(2-Methoxyethyl)-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl) piperidine -4 -carboxamide 547.
[0971] Yellow-white solid (5.0 mg, 0.013 mmol, 8.5% yield). ¾ NMR (499 MHz, METHANOLS) δ ppm 1.88 - 1.98 (4 H, m), 2.25 (2 H, dt, J=11.05, 7.51 Hz), 2.56 (1 H, dt, J=15.51, 7.62 Hz), 2.66 (2 H, t, J=5.63 Hz), 3.12 (2 H, br d, J=l 1.80 Hz), 3.36 (3 H, s), 3.57 (2 H, t, J=5.63 Hz), 3.85 (3 H, s), 7.28 (1 H, s), 7.64 (1 H, dd, J=8.51, 1.65 Hz), 7.85 (1 H, s), 7.94 (1 H, s), 8.07 (1 H, d, J=8.51 Hz), 8.51 (1 H, s), 9.06 (1 H, s); ESIMS found for C22H27N502 mlz 394.2 (M+l).
Figure imgf000218_0002
554
[0972] 1 -Isobutyl-N-(6 -( 1 -methyl - 1 H-imidazol -5 -yl)isoquinolin-3 -yl)piperidine -4 - carboxamide 554.
[0973] White solid (50.0 mg, 0.121 mmol, 31.6% yield). ¾ NMR (499 MHz, DMSO- d6)5 ppm 0.85 (6H, d,J=6.59Hz), 1.60- 1.73 (2H, m), 1.74-1.81 (3 H, m), 1.83 - 1.91 (2H, m), 2.02 (2 H, d, J=7.41 Hz), 2.52 - 2.60 (1 H, m), 2.86 (2 H, br d, J=11.25 Hz), 3.83 (3 H, s), 7.30 (1 H, d,J=1.10 Hz), 7.66 (1 H, dd, J=8.51, 1.65 Hz), 7.79 (1 H, s), 8.00 (1 H, s), 8.08 (1 H, d, J=8.78 Hz), 8.54 (1 H, s), 9.12 (1 H, s), 10.52 (1 H, s); ESIMS found for C23H29N50 mlz 392.2 (M+l).
Figure imgf000218_0003
561
[0974] N-(6-( 1 -Methyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-l -(methylsulfonyl) piperidine -4 -carboxamide 561.
[0975] Beige solid (15.0 mg, 0.036 mmol, 21.7% yield). ¾NMR(499 MHz, DMSO- d6) 5ppm 1.64 - 1.77 (2 H, m), 1.91 - 1.98 (2 H, m), 2.65 -2.73 (1 H, m), 2.77 (2 H, td, J= 11.94, 2.20 Hz), 2.89 (3 H, s), 3.59 - 3.67 (2 H, m), 3.83 (3 H, s), 7.30 (1 H, d, J=1.10 Hz), 7.67 ( 1 H, dd, J=8.64, 1.51 Hz), 7.78 (1 H, s), 8.01 ( 1 H, s), 8.09 ( 1 H, d, J=8.51 Hz), 8.54 (1 H, s), 9.13 (1 H, s), 10.62 ( 1 H, s); ESIMS found for C2oH23N503S mlz 413.9 (M+l).
579
[0976] N-(6-( 1 -Methyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-2-(pyrrolidin- 1 -yl) propanamide 579.
[0977] White solid (15.0 mg, 0.043 mmol, 10.6% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.30 (3 H, d, J=6.86 Hz), 1.74 (4 H, br s), 2.56 - 2.69 (4 H, m), 3.28 - 3.31 ( 1 H, m), 3.83 (3 H, s), 7.31 (1 H, s), 7.69 ( 1 H, dd, J=8.51, 1.65 Hz), 7.80 (1 H, s), 8.04 (1 H, s), 8.10 (1 H, d, J=8.51 Hz), 8.53 ( 1 H, s), 9.13 (1 H, s), 10.02 ( 1 H, s); ESIMS found for C2oH23N50 mlz 350.2 (M+ l).
Figure imgf000219_0002
643
[0978] N-(6-(lH-Pyrazol-4-yl)isoquinolin-3-yl)-l -isobutylpiperidine-4-carboxamide
643.
[0979] Brown solid (31.0 mg, 0.082 mmol, 32.1% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 0.86 (6 H, d, J=6.59 Hz), 1.62 - 1.73 (2 H, m), 1.73 - 1.80 (3 H, m), 1.82 - 1.91 (2 H, m), 2.02 (2 H, d, J=7.41 Hz), 2.51 - 2.59 (1 H, m), 2.86 (2 H, br d, J=1 1.25 Hz), 7.80 (1 H, dd, J=8.64, 1.51 Hz), 7.99 (1 H, d, J=8.51 Hz), 8.09 (1 H, s), 8.14 (1 H, br s), 8.42 ( 1 H, br s), 8.45 ( 1 H, s), 9.02 (1 H, s), 10.44 (1 H, s), 13.09 (1 H, br s); ESIMS found for C22H27N50 mlz 378.2 (M+ l).
Figure imgf000219_0003
699
[0980] 3,3 -Difluoro-N-(6 -(thiazol-5 -yl)isoquinolin-3 -yl)cyclobutane - 1 -carboxamide
699.
[0981] Beige solid (8.0 mg, 0.023 mmol, 8.5% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 2.75 - 2.90 (5 H, m), 7.89 (1 H, dd, J=8.64, 1.78 Hz), 8.12 ( 1 H, d, J=8.51 Hz), 8.24 (1 H, s), 8.56 (1 H, s), 8.57 (1 H, s), 9.14 (1 H, s), 9.20 (1 H, s), 10.82 (1 H, s); ESIMS found for Ci7Hi3F2N3OS mlz 346.05 (M+l).
Figure imgf000220_0001
700
[0982] 2-Methyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6- carboxamide 700.
[0983] Beige solid (4.0 mg, 0.011 mmol, 12.8% yield). ¾ NMR (499 MHz, METHANOLS) δρρηι 2.39 (3 H, s), 2.42 - 2.55 (4 H, m), 3.22 - 3.29 (1 H, m), 3.41 (2 H, s), 3.48 (2 H, s), 7.83 (1 H, dd, J=8.51, 1.65 Hz), 8.05 (1 H, d, J=8.51 Hz), 8.11 (1 H, d, J=0.82 Hz), 8.40 (1 H, s), 8.50 (1 H, s), 9.02 (1 H, s), 9.06 (1 H, s); ESIMS found for C20H20N4OS mlz 365.1 (M+l).
Figure imgf000220_0002
704
[0984] l-Fluoro-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclohexane-l-carboxamide
704.
[0985] Light pink solid (14.0 mg, 0.039 mmol, 17.9% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.28 - 1.42 (1 H, m), 1.49 - 1.62 (2 H, m), 1.68 (3 H, br d, J=9.61 Hz), 1.85 - 2.02 (4 H, m), 7.93 (1 H, dd, J=8.64, 1.78 Hz), 8.15 (1 H, d, J=8.78 Hz), 8.28 (1 H, s), 8.49 (1 H, s), 8.58 (1 H, s), 9.18 (1 H, s), 9.20 (1 H, s), 9.87 (1 H, d, J=4.12 Hz); ESIMS found for Ci9Hi8FN3OS mlz 355.9 (M+l).
Figure imgf000220_0003
707
[0986] tra«5-4-(Dimethylamino)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclohexane- 1-carboxamide 707.
[0987] White solid (48.0 mg, 0.126 mmol, 25.1% yield). 'HNMR (499 MHz, DMSO- 6)5ppm 1.12-1.22 (2H,m), 1.42 - 1.54 (2 H, m), 1.83 - 1.97 (4 H, m), 2.11 -2.16 (1 H, m),2.18 (6H, s), 2.43 -2.49 (1 H, m), 7.85 (1 H, dd,J=8.64, 1.51 Hz), 8.10 (1 H, d,J=8.51 Hz), 8.19 (1 H, s), 8.52 ( 1 H, s), 8.55 (1 H, s), 9.12 ( 1 H, s), 9.19 (1 H, s), 10.49 ( 1 H, s); ESIMS found for C21H24N4OS mlz 381.2 (M+l).
Figure imgf000221_0001
711
[0988] tra«5-4-((3-Fluoroazetidin-l-yl)methyl)-N-(6-(thiazol-5-yl)isoquinolin-3- yl)cyclohexane-l -carboxamide 711.
[0989] Beige solid (22.0 mg, 0.052 mmol, 21.8% yield). ¾ NMR (499 MHz, DMSO- d6) δ ρρηι 0.84 - 0.97 (2 H, m), 1.21 - 1.33 (1 H, m), 1.44 (2 H, qd, J=12.76, 2.88 Hz), 1.80 (2 H, br dd, J=12.76, 2.33 Hz), 1.86 (2 H, br d, J=10.70 Hz), 2.29 (2 H, d, J=6.86 Hz), 2.45 - 2.49 (1 H, m), 2.97 - 3.08 (2 H, m), 3.48 - 3.60 (2 H, m), 5.12 (1 H, dq, J=58.00, 5.20 Hz), 7.86 (1 H, dd, J=8.51, 1.65 Hz), 8.10 (1 H, d, J=8.51 Hz), 8.19 ( 1 H, s), 8.52 ( 1 H, s), 8.56 ( 1 H, s), 9.12 ( 1 H, s), 9.19 ( 1 H, s), 10.49 (1 H, s); ESIMS found for C23H25FN4OS mlz 425.2 (M+l).
Figure imgf000221_0002
713
[0990] N-(6-(Thiazol-5-yl)isoquinolin-3-yl)azetidine-3-carboxamide 713.
[0991] Orange solid (6.0 mg, 0.019 mmol, 8.4% yield). 'H NMR (500 MHz, DMSO- d6) δ ppm 3.70 (2 H, br t, J=7.96 Hz), 3.82 (1 H, dt, J=15.09, 7.55 Hz), 3.87 - 3.93 (2 H, m), 7.88 ( 1 H, dd, J=8.51, 1.92 Hz), 8.1 1 (1 H, d, J=8.51 Hz), 8.24 ( 1 H, s), 8.57 ( 1 H, br s), 8.57 (1 H, s), 9.13 ( 1 H, s), 9.20 (1 H, s), 10.65 ( 1 H, br s); ESIMS found for Ci6Hi4N4OS mlz 31 1.1 (M+l).
Figure imgf000221_0003
718
[0992] 1 -Methyl -N-(6 -(thiazol-5 -yl)isoquinolin-3 -yl)piperidine -4 -carboxamide 718.
[0993] Beige solid ( 16.0 mg, 0.045 mmol, 21.1% yield). ¾ NMR (500 MHz, DMSO- 6) 5 ppm 1.62 - 1.73 (2 H, m), 1.74 - 1.81 (2 H, m), 1.87 (2 H, td, J=l 1.53, 1.92 Hz), 2.16 (3 H, s), 2.51 - 2.56 (1 H, m), 2.81 (2 H, br d, J=l 1.25 Hz), 7.86 (1 H, dd, J=8.64, 1.51 Hz), 8.10 (1 H, d, .7=8.51 Hz), 8.20 (1 H, s), 8.53 (1 H, s), 8.55 ( 1 H, s), 9.12 ( 1 H, s), 9.19 (1 H, s), 10.54 (1 H, s); ESIMS found for C19H20N4OS mlz 352.9 (M+l).
Figure imgf000222_0001
731
[0994] l-(2,2-Difluoropropyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4- carboxamide 731.
[0995] White solid (54.3 mg, 0.131 mmol, 52.2% yield). ¾NMR(499 MHz, DMSO- d6) δ ppm 1.63 (3 H, t, J=19.07 Hz), 1.68 - 1.75 (2 H, m), 1.75 - 1.81 (2 H, m), 2.22 (2 H, td, J=11.66, 2.47 Hz), 2.51 -2.60 (1 H, m), 2.71 (2 H, t, J=14.00 Hz), 2.95 (2 H, brd,J=11.53 Hz), 7.86 (1 H, dd, J=8.64, 1.78 Hz), 8.10 (1 H, d, J=8.78 Hz), 8.21 (1 H, d, J=0.82 Hz), 8.53 (1 H, s), 8.56 (1 H, s), 9.13 (1 H, s), 9.19 (1 H, s), 10.56 (1 H, s); ESIMS found for C21H22F2N4OS ra/z 417.2 (M+l).
Figure imgf000222_0002
737
[0996] l-(Oxetan-3-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4- carboxamide 737.
[0997] White solid (39.0 mg, 0.099 mmol, 42.9% yield). 'HNMR (499 MHz, DMSO- d6) δ ppm 1.64 - 1.73 (2 H, m), 1.75 - 1.85 (4 H, m), 2.53 - 2.61 (1 H, m), 2.71 - 2.78 (2 H, m), 3.35 - 3.41 (1 H, m), 4.43 (2 H, t,J=6.17 Hz), 4.53 (2 H, t,J=6.45 Hz), 7.86 (1 H, dd,J=8.51, 1.65 Hz), 8.10 (1 H, d,J=8.51 Hz), 8.21 (1 H, d,J=1.10 Hz), 8.55 (1 H, s), 8.56 (1 H, s), 9.12 (1 H, s), 9.19 (1 H, s), 10.56 (1 H, s) ESIM mlz 395.1 (M+l).
Figure imgf000222_0003
741
[0998] l-(2-(Pyrrolidin-l-yl)acetyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine- 4-carboxamide 741.
[0999] White solid (124.6 mg, 0.277 mmol, 69.7% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.42 - 1.55 (1 H, m), 1.57 - 1.68 (1 H, m), 1.72 (4 H, br s), 1.85 (2 H, br d, J=10.98 Hz), 2.55 (4 H, br s), 2.58 - 2.67 (1 H, m), 2.78 - 2.88 (1 H, m), 3.03 (1 H, br t, J=l 1.94 Hz), 3.25 - 3.30 (1 H, m), 3.44 (1 H, br d, J=13.17 Hz), 4.07 (1 H, br d, J=14.00 Hz), 4.40 (1 H, br d, J=12.62 Hz), 7.87 (1 H, dd, J=8.51, 1.65 Hz), 8.11 (1 H, d, J=8.78 Hz), 8.21 (1 H, s), 8.53 (1 H, s), 8.56 (1 H, s), 9.13 (1 H, s), 9.19 (1 H, s), 10.64 (1 H, s); ESIMS found for C24¾7N502S mlz 449.9 (M+l).
Figure imgf000223_0001
743
[01000] r-Methyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)-[l,4'-bipiperidine]-4- carboxamide 743.
[01001] Beige solid (55.0 mg, 0.126 mmol, 36.3% yield). ¾ NMR (499 MHz, DMSO- d6) δ ρρηι 1.43 (2 H, qd, J=11.94, 3.70 Hz), 1.58 - 1.71 (4 H, m), 1.75 - 1.87 (4 H, m), 2.09 - 2.20 (3 H, m), 2.12 (3 H, s), 2.51 - 2.57 ( 1 H, m), 2.77 (2 H, br d, J=l 1.53 Hz), 2.90 (2 H, br d, J=l 1.25 Hz), 7.86 (1 H, dd, J=8.51, 1.65 Hz), 8.10 (1 H, d, J=8.51 Hz), 8.20 (1 H, s), 8.54 (1 H, s), 8.55 (1 H, s), 9.12 (1 H, s), 9.19 (1 H, s), 10.52 (1 H, s); ESIMS found for
Figure imgf000223_0002
mlz 436.2 (M+l).
Figure imgf000223_0003
758
[01002] 2-(Pyrrolidin-l-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)propanamide 758.
[01003] Beige solid (40.0 mg, 0.114 mmol, 26.3% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.30 (3 H, d, J=6.86 Hz), 1.74 (4 H, br s), 2.56 - 2.68 (4 H, m), 3.27 - 3.34 (1 H, m), 7.88 (1 H, dd, J=8.64, 1.78 Hz), 8.12 (1 H, d, J=8.78 Hz), 8.25 (1 H, d, J=0.82 Hz), 8.53 (1 H, s), 8.57 (1 H, s), 9.13 (1 H, s), 9.20 (1 H, s), 10.04 (1 H, s); ESIMS found for C19H20N4OS mlz 353.2 (M+l).
Figure imgf000223_0004
760
[01004] 2-(Piperidin-l-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide 760.
[01005] Yellow-white solid (8.0 mg, 0.023 mmol, 16.1% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.40 - 1.48 (2 H, m), 1.59 (4 H, dt, J=11.05, 5.59 Hz), 2.51 - 2.57 (4 H, m), 3.18 (2 H, s), 7.89 (1 H, dd, J=8.51, 1.92 Hz), 8.13 (1 H, d, J=8.51 Hz), 8.27 (1 H, d, J=1.10 Hz), 8.53 (1 H, s), 8.58 (1 H, d, J=0.82 Hz), 9.14 (1 H, s), 9.20 (1 H, s), 9.99 (1 H, s); ESIMS found for C19H20N4OS mlz 353.1 (M+l).
Figure imgf000224_0001
767
[01006] 2-(4-Methylpiperazin- 1 -yl)-N-(6-(thiazol-5 -yl)isoquinolin-3 -yl)acetamide
767.
[01007] Beige solid ( 10.0 mg, 0.027 mmol, 8.2% yield). 'H NMR (499 MHz, DMSO- d6) δ ppm 2.19 (3 H, s), 2.40 (4 H, br s), 2.59 (4 H, br s), 3.23 (2 H, s), 7.89 (1 H, dd, J=8.51, 1.65 Hz), 8.13 ( 1 H, d, J=8.78 Hz), 8.28 (1 H, s), 8.53 ( 1 H, s), 8.58 ( 1 H, s), 9.14 ( 1 H, s), 9.20 (1 H, s), 10.02 (1 H, s); ESIMS foun (M+l).
Figure imgf000224_0002
773
[01008] 2-Mo holino-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide 773.
[01009] Pale green solid (43.0 mg, 0.121 mmol, 42.5% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 2.54 - 2.62 (4 H, m), 3.26 (2 H, s), 3.62 - 3.69 (4 H, m), 7.89 ( 1 H, dd, J=8.64, 1.78 Hz), 8.13 ( 1 H, d, J=8.51 Hz), 8.27 (1 H, s), 8.53 (1 H, s), 8.58 ( 1 H, s), 9.15 (1 H, s), 9.20 (1 H, s), 10.10 (1 H, s); ESIMS found for C18H18N4O2S mlz 355.1 (M+l).
Figure imgf000224_0003
784
[01010] 2-Fluoro-2-methyl-N-(6-(l -methyl-5-(piperidin-l -ylmethyl)-lH-pyrazol-4- yl)isoquinolin-3 -yl)propanamide 784.
[01011] Beige solid (40.0 mg, 0.098 mmol, 36.9% yield). ¾ NMR (500 MHz, DMSO- d6) δ ppm 1.38 (2 H, br d, J=3.29 Hz), 1.49 (4 H, quin, J=5.21 Hz), 1.64 (6 H, d, J=22.00 Hz), 2.37 (4 H, br s), 3.65 (2 H, s), 3.92 (3 H, s), 7.76 ( 1 H, dd, J=8.51, 1.65 Hz), 7.82 (1 H, s), 8.08 (1 H, d, J=8.51 Hz), 8.13 (1 H, s), 8.42 (1 H, s), 9.13 (1 H, s), 9.85 (1 H, d, J=3.84 Hz); ESIMS found for C23H28FN5O mlz 410.2 (M+l).
Figure imgf000225_0001
785
[01012] 2-(Diethylamino)-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl) isoquinolin-3-yl)acetamide 785.
[01013] Orange gum (200.0 mg, 0.460 mmol, 60.1% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.05 (6 H, t, J=7.14 Hz), 1.34 - 1.42 (2 H, m), 1.44 - 1.54 (4 H, m), 2.36 (4 H, br s), 2.64 (4 H, q, J=6.95 Hz), 3.24 (2 H, s), 3.64 (2 H, s), 3.91 (3 H, s), 7.72 (1 H, dd, J=8.37, 1.51 Hz), 7.81 (1 H, s), 8.04 (1 H, d, J=8.51 Hz), 8.12 (1 H, s), 8.45 (1 H, s), 9.08 (1 H, s), 9.93 (1 H, s); ESIMS found for CZSH
Figure imgf000225_0002
791
[01014] 2-(2-Fluoroethyl)-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl) isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide 791.
[01015] White solid (20.0 mg, 0.041 mmol, 23.2% yield). ¾ NMR (499 MHz, DMSO- d6) 5 ppm 1.38 (2 H, br d, J=3.57 Hz), 1.45 - 1.54 (4 H, m), 2.24 - 2.33 (4 H, m), 2.36 (4 H, br s), 2.60 (2 H, dt, J=28.60, 4.95 Hz), 3.12 (2 H, s), 3.22 (2 H, s), 3.27 (1 H, t, J=8.37 Hz), 3.65 (2 H, s), 3.91 (3 H, s), 4.36 (2 H, dt, J=47.80, 4.95 Hz), 7.69 (1 H, dd, J=8.51, 1.37 Hz), 7.80 (1 H, s), 8.02 (1 H, d, J=8.51 Hz), 8.04 (1 H, s), 8.46 (1 H, s), 9.06 (1 H, s), 10.39 (1 H, s); ESIMS found for C28H35FN60 mlz 491.3 (M+l).
Figure imgf000225_0003
795 [01016] tra«5-4-Methoxy-N-(6-(l -methyl-5-(piperidin-l -ylmethyl)-lH-pyrazol-4- yl)isoquinolin-3 -yl)cyclohexane- 1 -carboxamide 795.
[01017] White solid (33.7 mg, 0.073 mmol, 54.7% yield). ¾ NMR (499 MHz, DMSO- d6) δ ρρηι 1.07 - 1.18 (2 H, m), 1.38 (2 H, br d, J=3.29 Hz), 1.43 - 1.52 (6 H, m), 1.89 (2 H, br d, J=1 1.53 Hz), 2.04 - 2.12 (2 H, m), 2.36 (4 H, br s), 2.51 - 2.57 (1 H, m), 3.12 (1 H, tt, J=10.67, 4.15 Hz), 3.25 (3 H, s), 3.64 (2 H, s), 3.91 (3 H, s), 7.69 (1 H, dd, J=8.37, 1.51 Hz), 7.80 ( 1 H, s), 8.02 (1 H, d, J=8.51 Hz), 8.04 (1 H, br s), 8.45 (1 H, s), 9.07 (1 H, s), 10.46 ( 1 H, s); ESIMS found for C27H35N502 mlz 462.3 (M+ l).
Figure imgf000226_0001
798
[01018] tra«5-4-(Hydroxymethyl)-N-(6-( l-methyl-5-(piperidin-l -ylmethyl)-lH- pyrazol-4-yl)isoquinolin-3 -yl)cyclohexane- 1 -carboxamide 798.
[01019] White solid (50.6 mg, 0.1 10 mmol, 103% yield). nH NMR (499 MHz, DMSO- d6) δ ppm 0.90 - 1.01 (2 H, m), 1.32 - 1.42 (4 H, m), 1.42 - 1.53 (6 H, m), 1.80 (2 H, br dd, J=13.04, 2.61 Hz), 1.85 - 1.91 (2 H, m), 2.36 (4 H, br s), 3.24 (2 H, t, J=5.63 Hz), 3.64 (2 H, s), 3.91 (3 H, s), 4.39 ( 1 H, t, J=5.21 Hz), 7.68 (1 H, dd, J=8.37, 1.51 Hz), 7.80 (1 H, s), 8.00 - 8.06 (2 H, m), 8.46 ( 1 H, s), 9.07 (1 H, s), 10.42 for C27H35N502 mlz 462.3 (M+l).
Figure imgf000226_0002
803
[01020] (R)-N-(6-(l -Methyl-5-(piperidin-l -ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3- yl)pyrrolidine-2-carboxamide 803.
[01021] Off-white solid (40.0 mg, 0.096 mmol, 58.7% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.38 (2 H, br s), 1.46 - 1.52 (4 H, m), 1.67 (2 H, quin, J=6.79 Hz), 1.80 - 1.89 ( 1 H, m), 2.05 - 2.15 (1 H, m), 2.36 (4 H, br s), 2.87 (1 H, dt, J=10.15, 6.31 Hz), 2.97 (1 H, dt, J=10.15, 6.72 Hz), 3.64 (2 H, s), 3.80 ( 1 H, dd, J=9.06, 5.49 Hz), 3.91 (3 H, s), 7.71 (1 H, dd, J=8.51, 1.65 Hz), 7.81 (1 H, s), 8.04 (1 H, d, J=8.51 Hz), 8.10 (1 H, s), 8.46 (1 H, s), 9.07 (1 H, s), 10.36 (1 H, s); ESIMS found for C24H3oN6
Figure imgf000227_0001
826
[01022] N-(6-(l-Methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)- l-(oxetan-3-yl)piperidine-4-carboxamide 826.
[01023] Off-white solid (40.0 mg, 0.082 mmol, 27.2% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.34 - 1.42 (2 H, m), 1.44 - 1.53 (4 H, m), 1.63 - 1.73 (2 H, m), 1.74 - 1.86 (4 H, m), 2.36 (4 H, br s), 2.53 - 2.61 (1 H, m), 2.71 - 2.82 (2 H, m), 3.40 (1 H, br s), 3.65 (2 H, br s), 3.91 (3 H, s), 4.44 (2 H, br t, J=5.90 Hz), 4.50 - 4.57 (2 H, m), 7.69 (1 H, dd, J=8.64, 1.51 Hz), 7.79 (1 H, s), 7.99 - 8.06 (2 H, m), 8.47 (1 H, s), 9.07 (1 H, s), 10.48 (1 H, s); ESIMS found for CZSHMNSOZ mlz 489.3 (M+l).
Figure imgf000227_0002
831
[01024] l-Benzoyl-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl) isoquinolin-3-yl)piperidine-4-carboxamide 831.
[01025] White solid (53.0 mg, 0.099 mmol, 58.6% yield). ¾NMR (499 MHz, DMSO- d6) 5 ppm 1.38 (2 H, br d, J=3.02 Hz), 1.45 - 1.54 (4 H, m), 1.57 - 1.71 (2 H, m), 1.74 - 1.86 (1 H, m), 1.89 - 1.98 (1 H, m), 2.36 (4 H, br s), 2.45 - 2.49 (1 H, m), 2.86 (2 H, ddt, J=11.25, 7.55, 3.77, 3.77 Hz), 3.02 - 3.16 (1 H, m), 3.65 (2 H, s), 3.91 (3 H, s), 4.46 - 4.61 (1 H, m), 7.37 - 7.43 (2 H, m), 7.43 - 7.49 (3 H, m), 7.70 (1 H, dd, J=8.51, 1.37 Hz), 7.80 (1 H, s), 8.03 (1 H, d, J=8.51 Hz), 8.06 (1 H, s), 8.46 (1 H, s), 9.08 (1 H, s), 10.58 (1 H, s); ESIMS found for C^H^NeOz mlz 537.3 (M+l).
Figure imgf000228_0001
839
[01026] N-(6-(l -Methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl) tetrahydro-2H-pyran-4-carboxamide 839.
[01027] White amorphous solid (25.8 mg, 0.060 mmol, 69.3% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.35 - 1.41 (2 H, m), 1.46 - 1.52 (4 H, m), 1.66 - 1.77 (4 H, m), 2.36 (4 H, br d, J=1.65 Hz), 2.77 - 2.88 ( 1 H, m), 3.33 - 3.39 (2 H, m), 3.65 (2 H, s), 3.89 - 3.94 (2 H, m), 3.91 (3 H, s), 7.66 - 7.73 ( 1 H, m), 7.80 (1 H, s), 8.00 - 8.06 (2 H, m), 8.46 (1 H, s), 9.08 (1 H, s), 10.52 ( 1 H, s); ESIMS found for C25H3iN502 mlz 434.2 (M+l).
Figure imgf000228_0002
851
[01028] N-(6-(l -Methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)- 2-(4-methylpiperidin- 1 -yl)acetamide 851.
[01029] Off-white solid ( 180.0 mg, 0.391 mmol, 54.6% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 0.93 (3 H, d, J=6.31 Hz), 1.20 - 1.30 (2 H, m), 1.33 - 1.42 (3 H, m), 1.44 - 1.53 (4 H, m), 1.63 (2 H, br d, J=1 1.53 Hz), 2.16 - 2.24 (2 H, m), 2.36 (4 H, br s), 2.87 (2 H, br d, J=l 1.53 Hz), 3.18 (2 H, s), 3.65 (2 H, s), 3.91 (3 H, s), 7.72 (1 H, dd, J=8.51, 1.37 Hz), 7.82 ( 1 H, s), 8.05 (1 H, d, J=8.78 Hz), 8.12 (1 H, s), 8.45 ( 1 H, s), 9.08 ( 1 H, s), 9.91 ( 1 H, s); ESIMS found for C27H36N60 mlz 461.3 (M+l).
Figure imgf000228_0003
883
[01030] l-Fluoro-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclohexane- 1-carboxamide 883. [01031] Off-white solid (36.5 mg, 0.099 mmol, 63.5% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.31 - 1.40 (1 H, m), 1.51 - 1.62 (2 H, m), 1.69 (3 H, br d, J=9.33 Hz), 1.87 - 2.02 (4 H, m), 2.83 (3 H, s), 8.15 (1 H, dd, J=8.51, 1.65 Hz), 8.24 (1 H, d, J=8.51 Hz), 8.53 (1 H, s), 8.58 (1 H, s), 9.27 ( 1 H, s), 9.97 (1 H, d, J=3.84 Hz); ESIMS found for C19H19FN4OS mlz 371.1 (M+ l).
Figure imgf000229_0001
885
[01032] tra«s-4-Methoxy-N-(6-(5 -methyl- 1, 3, 4-thiadiazol-2-yl)isoquinolin-3-yl) cyclohexane-l -carboxamide 885.
[01033] White solid (33.4 mg, 0.087 mmol, 21.2% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.08 - 1.19 (2 H, m), 1.44 - 1.56 (2 H, m), 1.88 - 1.94 (2 H, m), 2.05 - 2.13 (2 H, m), 2.52 - 2.58 (1 H, m), 2.83 (3 H, s), 3.09 - 3.17 (1 H, m), 3.25 (3 H, s), 8.09 (1 H, dd, J=8.65, 1.51 Hz), 8.19 (1 H, d, J=8.51 Hz), 8.44 ( 1 H, s), 8.60 (1 H, s), 9.21 ( 1 H, s), 10.60 ( 1 H, s); ESIMS found for C20H22N4O2S mlz 383.15 (M+l).
Figure imgf000229_0002
888
[01034] tra«5-4-(Hydroxymethyl)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin- 3 -yl)cyclohexane - 1 -carboxamide 888.
[01035] White solid (12.4 mg, 0.032 mmol, 39.0% yield). 'HNMR (499 MHz, DMSO- d6) 5 ppm 0.90 - 1.02 (2 H, m), 1.30 - 1.40 (1 H, m), 1.46 (2 H, qd, J=12.76, 3.43 Hz), 1.81 (2 H, br dd, J=13.04, 2.61 Hz), 1.86 - 1.93 (2 H, m), 2.52 - 2.56 (1 H, m), 2.83 (3 H, s), 3.24 (2 H, t, J=5.76 Hz), 4.39 ( 1 H, t, J=5.35 Hz), 8.08 (1 H, dd, J=8.51, 1.65 Hz), 8.19 ( 1 H, d, J=8.51 Hz), 8.43 ( 1 H, s), 8.61 (1 H, s), 9.21 (1 H, s), 10.57 (1 H, s); ESIMS found for C20H22N4O2S mlz 383.1 (M+ l).
Figure imgf000229_0003
900 [01036] l-(2-Fluoroethyl)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl) piperidine-4-carboxamide 900.
[01037] Beige solid (41.0 mg, 0.103 mmol, 19.5% yield). ¾ NMR (499 MHz, DMSO- d6) δ ρρηι 1.69 (2 H, qd, J=12.12, 3.70 Hz), 1.76 - 1.85 (2 H, m), 2.02 - 2.09 (2 H, m), 2.52 - 2.57 (1 H, m), 2.62 (2 H, dt, J=28.35, 4.95 Hz), 2.83 (3 H, s), 2.95 (2 H, br d, J=11.53 Hz), 4.54 (2 H, dt, J=47.80, 4.95 Hz), 8.09 (1 H, dd, J=8.51, 1.65 Hz), 8.19 (1 H, d, J=8.51 Hz), 8.44 (1 H, s), 8.63 (1 H, s), 9.21 (1 H, s), 10.62 (1 H, s); ESIMS found for C2oH22FN5OS mlz 400.15 (M+l).
Figure imgf000230_0001
921
[01038] 1 -Benzoyl -N-(6-(5 -methyl- 1 ,3 ,4-thiadiazol-2-yl)isoquinolin-3 -yl)piperidine- 4-carboxamide 921.
[01039] Off-white solid (78.5 mg, 0.172 mmol, 42.8% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.64 (2 H, br s), 1.77 - 1.89 (1 H, m), 1.90 - 2.04 (1 H, m), 2.78 - 2.92 (2 H, m), 2.83 (3 H, s), 3.10 (1 H, tdd, J=5.01, 5.01, 2.88, 1.37 Hz), 3.58 - 3.76 (1 H, m), 4.42 - 4.61 (1 H, m), 7.37 - 7.43 (2 H, m), 7.43 - 7.49 (3 H, m), 8.10 (1 H, dd, J=8.51, 1.65 Hz), 8.19 (1 H, d, J=8.51 Hz), 8.46 (1 H, d, J=0.82 Hz), 8.62 (1 H, s), 9.22 (1 H, s), 10.72 (1 H, s); ESIMS found for C25H23N502S mlz 458.2 (M+l).
Figure imgf000230_0002
932
[01040] N-(6-(5 -Methyl- 1 ,3 ,4-thiadiazol-2-yl)isoquinolin-3 -yl)-2-(pyrrolidin- 1 -yl) acetamide 932.
[01041] Beige solid (46.0 mg, 0.130 mmol, 21.7% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.78 (7 H, dt, J=6.86, 3.16 Hz), 2.62 - 2.70 (4 H, m), 2.83 (3 H, s), 3.38 (2 H, s), 8.12 (1 H, dd, J=8.51, 1.65 Hz), 8.21 (1 H, d, J=8.51 Hz), 8.50 (1 H, s), 8.61 (1 H, s), 9.22 (1 H, s), 10.08 (1 H, s); ESIMS found for Ci8
Figure imgf000230_0003
939
[01042] N-(6-(5 -Methyl- 1 ,3 ,4-thiadiazol-2-yl)isoquinolin-3 -yl)-2-(piperidin- 1 -yl) acetamide 939.
[01043] Beige solid (77.0 mg, 0.210 mmol, 21.0% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.39 - 1.47 (2 H, m), 1.59 (4 H, quin, J=5.56 Hz), 2.52 - 2.57 (4 H, m), 2.83 (3 H, s), 3.19 (2 H, s), 8.12 (1 H, dd, J=8.51, 1.65 Hz), 8.21 (1 H, d, J=8.51 Hz), 8.51 ( 1 H, s), 8.61 ( 1 H, s), 9.22 (1 H, s), 10.06 (1 H, s); ESIMS found for Ci9H2iN5OS mlz 368.2 (M+l).
Figure imgf000231_0001
946
[01044] N-(6-(5-Methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(4- methylpiperazin-1 -yl)acetamide 946.
[01045] Beige solid ( 1 1.0 mg, 0.029 mmol, 8.7% yield). 'H NMR (499 MHz, DMSO- d6) δ ppm 2.19 (3 H, s), 2.40 (4 H, br s), 2.59 (4 H, br s), 2.83 (3 H, s), 3.24 (2 H, s), 8.12 (1 H, dd, J=8.78, 1.65 Hz), 8.21 (1 H, d, J=8.51 Hz), 8.51 ( 1 H, s), 8.61 ( 1 H, s), 9.23 ( 1 H, s), 10.09 (1 H, s); ESIMS found for C19H22N6
Figure imgf000231_0002
952
[01046] N-(6-(5-Methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2- morpholinoacetamide 952.
[01047] Pale yellow solid ( 1 1.0 mg, 0.030 mmol, 9.6% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 2.55 - 2.61 (4 H, m), 2.83 (3 H, s), 3.27 (2 H, s), 3.62 - 3.70 (4 H, m), 8.12 (1 H, dd, J=8.51, 1.65 Hz), 8.21 (1 H, d, J=8.78 Hz), 8.51 (1 H, s), 8.62 ( 1 H, s), 9.23 (1 H, s), 10.17 ( 1 H, s); ESIMS found for Ci8Hi9N
Figure imgf000231_0003
953
[01048] (R)-N-(6-(5-Methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(3- methylmorpholino)acetamide 953. [01049] Beige solid (66.0 mg, 0.172 mmol, 23.1% yield). ¾NMR(499 MHz, DMSO- d6) δ ppm 0.96 (3 H, d, J=6.31 Hz), 2.54 - 2.60 (1 H, m), 2.63 (1 H, ddd, J=9.06, 6.17, 2.88 Hz), 2.80 - 2.82 (1 H, m), 2.83 (3 H, s), 3.19 (1 H, dd, J=ll.ll, 8.92 Hz), 3.21 (1 H, d, J=16.47 Hz), 3.49 (1 H, d, J=16.47 Hz), 3.54 - 3.62 (1 H, m), 3.68 (1 H, dd, J=l 1.25, 3.02 Hz), 3.71 - 3.79 (1 H, m), 8.08 - 8.18 (1 H, m), 8.22 (1 H, d, J=8.51 Hz), 8.51 (1 H, s), 8.62 (1 H, s), 9.23 (1 H, s), 10.13 (1 H, s); ESIMS found for Ci9H2i
Figure imgf000232_0001
959
[01050] 2-(7-Azabicyclo[2.2.1]heptan-7-yl)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl) isoquinolin-3-yl)acetamide 959.
[01051] Beige solid (27.0 mg, 0.071 mmol, 18.7% yield). ¾NMR(499 MHz, DMSO- d6)5ppm 1.34 (4 H, d,J=7.14Hz), 1.71 - 1.79 (4 H, m), 2.83 (3 H, s), 3.21 (2 H, s), 3.35 -3.40 (2 H, m), 8.12 (1 H, dd,J=8.51, 1.65 Hz), 8.22 (1 H, d,J=8.51 Hz), 8.52 (1 H, s), 8.63 (1 H, s), 9.22 (1 H, s), 10.21 (1 H, s); ESIMS mlz 380.1 (M+l).
Figure imgf000232_0002
960
[01052] 2-((lR,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(5-methyl-l,3,4- thiadiazol-2-yl)isoquinolin-3-yl)acetamide 960.
[01053] Off-white solid (110.0 mg, 0.288 mmol, 47.5% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.67 (1 H, dd, J=9.74, 0.96 Hz), 1.87 (1 H, dd, J=9.74, 1.78 Hz), 2.63 (1 H, d, J=9.88 Hz), 2.83 (3 H, s), 2.96 (1 H, dd, J=9.88, 1.65 Hz), 3.48 (2 H, d, J=4.94 Hz), 3.59 (1 H, dd, J=7.68, 1.65 Hz), 3.64 (1 H, s), 3.88 (1 H, d,J=7.41 Hz), 4.41 (1 H, s), 8.12 (1 H, dd,J=8.51, 1.65 Hz), 8.22 (1 H, d, J=8.78 Hz), 8.51 (1 H, s), 8.62 (1 H, s), 9.23 (1 H, s), 10.07 (1 H, s); ESIMS found for Ci9Hi9N502S mlz 382.1 (M+l).
Figure imgf000232_0003
962 [01054] 2-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(6-(5-methyl-l,3,4-thiadiazol-2- yl)isoquinolin-3-yl)acetamide 962.
[01055] Off-white solid ( 175.0 mg, 0.065 mmol, 17.4% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.76 - 1.82 (2 H, m), 1.87 - 1.94 (2 H, m), 2.83 (3 H, s), 3.16 (2 H, s), 3.18 (2 H, br d, J=1.10 Hz), 3.52 (2 H, dd, J=10.57, 1.51 Hz), 3.68 (2 H, d, J=10.43 Hz), 8.13 (1 H, dd, J=8.51, 1.65 Hz), 8.22 ( 1 H, d, J=8.78 Hz), 8.52 (1 H, s), 8.63 (1 H, s), 9.25 ( 1 H, s), 10.28 ( 1 H, s); ESIMS found for C2oH2iN502S mlz 396.15 (M+l).
Figure imgf000233_0001
963
[01056] N-(8-Fluoro-6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2- morpholinoacetamide 963.
[01057] Beige solid (25.0 mg, 0.065 mmol, 17.4% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 2.55 - 2.63 (4 H, m), 2.83 (3 H, s), 3.28 (2 H, s), 3.61 - 3.69 (4 H, m), 7.89 ( 1 H, dd, J=l l . l l, 1.24 Hz), 8.40 (1 H, s), 8.68 (1 H, s), 9.34 ( 1 H, s), 10.32 ( 1 H, s); ESIMS found for CisHisFNsOzS mlz 388.1 (M+l).
Figure imgf000233_0002
964
[01058] N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)-l -(phenylsulfonyl) piperidine-4-carboxamide 964.
[01059] White solid (81.0 mg, 0.170 mmol, 63.7% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.62 - 1.75 (2 H, m), 1.90 (2 H, br dd, J=13.58, 2.88 Hz), 2.27 - 2.36 (2 H, m), 2.51 - 2.56 (1 H, m), 3.69 (2 H, br d, J=12.08 Hz), 3.90 (3 H, s), 7.65 - 7.70 (2 H, m), 7.72 - 7.80 (4 H, m), 7.99 (1 H, d, J=8.51 Hz), 8.03 (1 H, s), 8.07 (1 H, s), 8.34 (1 H, s), 8.39 ( 1 H, s), 9.01 ( 1 H, s), 10.45 ( 1 H, s); ESIMS found for C25H25N503S mlz 475.9 (M+l).
Figure imgf000233_0003
965
[01060] N-(6-(l -Methyl- lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-(methyl- 3) piperazin-l-yl)acetamide 965.
[01061] Beige solid (70.0 mg, 0.191 mmol, 28.9% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 2.40 (4 H, br s), 2.58 (4 H, br s), 3.22 (2 H, s), 3.90 (3 H, s), 7.77 ( 1 H, dd, J=8.51, 1.65 Hz), 8.02 ( 1 H, d, J=8.51 Hz), 8.10 (2 H, s), 8.37 (1 H, s), 8.43 (1 H, s), 9.04 (1 H, s), 9.92 (1 H, s); ESIMS found for C2oH2i[2H3]N60 mlz 368.2 (M+l).
Figure imgf000234_0001
966
[01062] N-(7-Fluoro-6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-l - methylpiperidine -4 -carboxamide 966.
[01063] White solid (65.0 mg, 0.177 mmol, 80.2% yield). ¾ NMR (499 MHz, DMSO- 6) 5 ppm 1.62 - 1.72 (2 H, m), 1.73 - 1.80 (2 H, m), 1.86 (2 H, td, J=1 1.66, 2.20 Hz), 2.16 (3 H, s), 2.45 - 2.55 (1 H, m), 2.76 - 2.85 (2 H, m), 3.93 (3 H, s), 7.89 (1 H, d, J=1 1.80 Hz), 8.10 (1 H, s), 8.26 (1 H, d, J=7.41 Hz), 8.30 (1 H, d, J=2.74 Hz), 8.49 (1 H, s), 9.03 (1 H, s), 10.49 (1 H, s); ESIMS found for C2oH22FN50
Figure imgf000234_0002
967
[01064] 1 -Ethyl-N-(7-fluoro-6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3-yl) piperidine -4 -carboxamide 967.
[01065] White solid (20.0 mg, 0.052 mmol, 26.9% yield). 'HNMR (499 MHz, DMSO- 6) 5 ppm 1.00 (3 H, t, J=7.14 Hz), 1.67 (2 H, td, J=12.21, 3.57 Hz), 1.75 - 1.81 (2 H, m), 1.86 (2 H, td, J=l 1.73, 2.06 Hz), 2.31 (2 H, q, J=7.14 Hz), 2.51 - 2.58 (1 H, m), 2.87 - 2.95 (2 H, m), 3.93 (3 H, s), 7.89 ( 1 H, d, J=1 1.53 Hz), 8.10 ( 1 H, d, J=0.82 Hz), 8.26 (1 H, d, J=7.41 Hz), 8.30 (1 H, d, J=2.47 Hz), 8.50 (1 H, s), 9.03 ( 1 H, s), 10.49 ( 1 H, s); ESIMS found for C2iH24FN50 mlz 382.2 (M+ l).
Figure imgf000235_0001
968
[01066] N-(8-Fluoro-6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(4- methylpiperazin-1 -yl)acetamide 968.
[01067] Beige solid (25.0 mg, 0.065 mmol, 23.1% yield). ¾NMR(500 MHz, DMSO- d6) δ ppm 2.33 (3 H, br s), 2.52 - 2.77 (8 H, m), 3.27 (2 H, s), 3.90 (3 H, s), 7.62 (1 H, dd, J=12.08, 1.37 Hz), 7.99 (1 H, s), 8.14 (1 H, d, J=0.82 Hz), 8.41 (1 H, s), 8.48 (1 H, s), 9.17 (1 H, s), 10.12 (1 H, br s); ESIMS found for CztJfeFNeO mlz 383.2 (M+l).
Figure imgf000235_0002
969
[01068] N-(6-(l-(l-Methylpiperidin-4-yl)-lH-pyrazol-4-yl)isoquinolin-3-yl) cyclohexanecarboxamide 969.
[01069] Beige solid (79.0 mg, 0.189 mmol, 63.0% yield). ¾NMR(499 MHz, DMSO- d6)5ppm 1.13 - 1.34(3 H, m), 1.39-1.51 (2 H, m), 1.66 (1 H, br d, J=l 1.25 Hz), 1.72- 1.79 (2 H, m), 1.82 (2 H, br d, J=12.90 Hz), 1.94-2.11 (6 H, m), 2.22 (3 H, s), 2.52 - 2.60 (1 H, m), 2.87 (2 H, br d, J=11.25 Hz), 4.10 - 4.20 (1 H, m), 7.77 (1 H, dd, J=8.51, 1.37 Hz), 7.99 (1 H, d, J=8.51 Hz), 8.05 (1 H, s), 8.10 (1 H, s), 8.43 (1 H, s), 8.47 (1 H, s), 9.01 (1 H, s), 10.37 (1 H, s) ESIMS found for C25H3iN50 mlz 418.2
Figure imgf000235_0003
970
[01070] N-(6-(Isothiazol-4-yl)isoquinolin-3-yl)-l-methylpiperidine-4-carboxamide
970.
[01071] Beige solid (28.0 mg, 0.079 mmol, 17.7% yield). ¾NMR(499 MHz, DMSO- d6) 5ppm 1.63 - 1.74 (2 H, m), 1.75 - 1.84 (2 H, m), 1.88 (2 H, td, J= 11.46, 2.06 Hz), 2.17 (3 H, s), 2.51 - 2.57 (1 H, m), 2.81 (2 H, br d, J=1 1.53 Hz), 7.95 (1 H, dd, J=8.51, 1.65 Hz), 8.1 1 (1 H, d, J=8.51 Hz), 8.35 (1 H, s), 8.54 (1 H, s), 9.12 ( 1 H, s), 9.25 ( 1 H, s), 9.59 (1 H, s), 10.49 ( 1 H, s); ESIMS found for Ci9H2oN mlz 352.9 (M+l).
Figure imgf000236_0001
972
[01072] l-Isobutyl-N-(6-( l-(methyl-£/3)-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine- 4-carboxamide 972.
[01073] White solid (165.0 mg, 0.418 mmol, 49.8% yield). ¾ NMR (500 MHz, DMSO- e) δ ppm 0.86 (6 H, d, J=6.59 Hz), 1.62 - 1.72 (2 H, m), 1.73 - 1.81 (3 H, m), 1.82 - 1.91 (2 H, m), 2.02 (2 H, d, J=7.41 Hz), 2.51 - 2.59 ( 1 H, m), 2.81 - 2.90 (2 H, m), 7.74 (1 H, dd, J=8.51, 1.65 Hz), 8.00 (1 H, d, J=8.51 Hz), 8.04 ( 1 H, s), 8.08 ( 1 H, d, J=0.82 Hz), 8.35 (1 H, s), 8.44 ( 1 H, s), 9.02 (1 H, s), 10.45 (1 H, s); ESIMS found for C23H26[2H3]N50 mlz 395.2 (M+l).
Figure imgf000236_0002
973
[01074] N-(6-(Oxazol-5-yl)isoquinolin-3-yl)cyclopropanecarboxamide 974.
[01075] Beige solid (34.0 mg, 0.122 mmol, 25.7% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 0.78 - 0.91 (4 H, m), 2.04 - 2.12 ( 1 H, m), 7.86 (1 H, dd, J=8.51, 1.65 Hz), 7.95 ( 1 H, s), 8.13 (1 H, d, J=8.78 Hz), 8.17 (1 H, s), 8.50 ( 1 H, s), 8.57 (1 H, s), 9.14 ( 1 H, s), 10.93 (1 H, s); ESIMS found for Ci6Hi3N302 mlz 280.1 (M+l).
Figure imgf000236_0003
974
[01076] (R)-N-(6-(Oxazol-5-yl)isoquinolin-3-yl)tetrahydrofuran-2-carboxamide 974.
[01077] Light yellow solid (120.0 mg, 0.388 mmol, 41.0% yield). ¾ NMR (500 MHz, DMSO- e) δ ppm 1.83 - 1.97 (2 H, m), 1.98 - 2.08 ( 1 H, m), 2.20 - 2.31 ( 1 H, m), 3.82 - 3.91 ( 1 H, m), 3.97 - 4.06 (1 H, m), 4.54 (1 H, dd, J=8.37, 5.63 Hz), 7.90 (1 H, dd, J=8.64, 1.51 Hz), 7.96 (1 H, s), 8.16 (1 H, d, .7=8.51 Hz), 8.25 (1 H, s), 8.52 (1 H, s), 8.58 ( 1 H, s), 9.15 ( 1 H, s), 9.88 ( 1 H, s); ESIMS found for Ci7Hi5N3 +l).
Figure imgf000237_0001
975
[01078] (R)-N-(6-(Oxazol-5-yl)isoquinolin-3-yl)piperidine-3-carboxamide 975.
[01079] Beige solid ( 19.0 mg, 0.059 mmol, 24.9% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.36 - 1.47 (1 H, m), 1.56 - 1.64 ( 1 H, m), 1.64 - 1.72 ( 1 H, m), 1.87 (1 H, dt, J=8.58, 4.08 Hz), 2.52 - 2.59 (1 H, m), 2.59 - 2.67 ( 1 H, m), 2.75 (1 H, br dd, J=1 1.94, 8.92 Hz), 2.78 - 2.85 (1 H, m), 2.99 (1 H, br dd, J=12.08, 3.02 Hz), 7.86 ( 1 H, dd, J=8.51, 1.65 Hz), 7.95 (1 H, s), 8.13 (1 H, d, J=8.51 Hz), 8.19 (1 H, s), 8.52 ( 1 H, s), 8.58 (1 H, s), 9.12 ( 1 H, s), 10.85 (1 H, s); ESIMS found for Ci8Hi8N402 mlz 323.0 (M+l).
Figure imgf000237_0002
976
[01080] N-(6-(Oxazol-5-yl)isoquinolin-3-yl)tetrahydro-2H-pyran-4-carboxamide 976.
[01081] Beige solid ( 17.5 mg, 0.054 mmol, 24.6% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.63 - 1.78 (4 H, m), 2.78 - 2.87 ( 1 H, m), 3.33 - 3.40 (2 H, m), 3.88 - 3.96 (2 H, m), 7.87 ( 1 H, dd, J=8.64, 1.51 Hz), 7.95 (1 H, s), 8.13 (1 H, d, J=8.78 Hz), 8.20 ( 1 H, s), 8.54 (1 H, s), 8.58 ( 1 H, s), 9.13 ( 1 H, s), 10.60 (1 H, s); ESIMS found for Ci8Hi7N303 mlz 323.9 (M+l).
Figure imgf000237_0003
977
[01082] N-(6-(Oxazol-5-yl)isoquinolin-3-yl)-l -(2-(pyrrolidin-l-yl)acetyl)piperidine- 4-carboxamide 977.
[01083] White solid (33.4 mg, 0.077 mmol, 43.3% yield). ¾ NMR (499 MHz, DMSO- d6) 5 ppm 1.41 - 1.53 ( 1 H, m), 1.55 - 1.66 ( 1 H, m), 1.69 (4 H, br s), 1.84 (2 H, br d, J=10.98 Hz), 2.48 (4 H, br s), 2.56 - 2.66 (1 H, m), 2.82 (1 H, ddt, J=1 1.25, 7.55, 3.91, 3.91 Hz), 3.01 (1 H, br t, J=12.21 Hz), 3.14 - 3.21 ( 1 H, m), 3.33 - 3.37 (1 H, m), 4.1 1 (1 H, br d, J=13.45 Hz), 4.40 (1 H, br d, J=13.17 Hz), 7.87 ( 1 H, dd, J=8.51, 1.10 Hz), 7.95 (1 H, s), 8.13 (1 H, d, J=8.51 Hz), 8.20 (1 H, s), 8.53 (1 H, s), 8.57 (1 H, s), 9.14 (1 H, s), 10.64 (1 H, s); ESIMS found for C24H27N503 mlz 434.0 (M+l).
Figure imgf000238_0001
978
[01084] r-Methyl-N-(6-(oxazol-5-yl)isoquinolin-3-yl)-[l,4'-bipiperidine]-4- carboxamide 978.
[01085] Beige solid (90.0 mg, 0.215 mmol, 61.7% yield). ¾ NMR (499 MHz, DMSO- d6) δ ρρηι 1.43 (2 H, qd, J=11.85, 3.43 Hz), 1.58 - 1.71 (4 H, m), 1.75 - 1.86 (4 H, m), 2.07 - 2.20 (3 H, m), 2.12 (3 H, s), 2.51 - 2.57 ( 1 H, m), 2.77 (2 H, br d, J=l 1.53 Hz), 2.90 (2 H, br d, J=l 1.25 Hz), 7.86 (1 H, dd, J=8.51, 1.65 Hz), 7.94 (1 H, s), 8.12 (1 H, d, J=8.78 Hz), 8.19 (1 H, s), 8.54 (1 H, s), 8.57 (1 H, s), 9.12 (1 H, s), 10.53 (1 H, s); ESIMS found for C24¾9N502 m>z 420·2 (Μ+ 1)·
Figure imgf000238_0002
979
[01086] c/5-4-Mo holino-N-(6-(oxazol-5-yl)isoquinolin-3-yl)cyclohexane-l- carboxamide 979.
[01087] Off-white solid (125.0 mg, 0.308 mmol, 51.7% yield). ¾ NMR (500 MHz, DMSO- e) δ ppm 1.15 - 1.27 (2 H, m), 1.42 - 1.55 (2 H, m), 1.91 (4 H, br t, J=12.62 Hz), 2.17 - 2.26 (1 H, m), 2.45 - 2.49 (4 H, m), 2.51 - 2.53 (1 H, m), 3.52 - 3.59 (4 H, m), 7.86 (1 H, dd, J=8.51, 1.37 Hz), 7.95 (1 H, s), 8.12 (1 H, d, J=8.51 Hz), 8.18 (1 H, s), 8.52 (1 H, s), 8.57 (1 H, s), 9.12 (1 H, s), 10.53 (1 H, s); ESIMS found for
Figure imgf000238_0003
mlz 407.2 (M+l).
Figure imgf000238_0004
980
[01088] 2-(Cyclobutyl(methyl)amino)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)acetamide
980.
[01089] Beige solid (31.5 mg, 0.094 mmol, 49.2% yield). ¾ NMR (500 MHz, DMSO- d6) δ ppm 1.54 - 1.69 (2 H, m), 1.80 - 1.92 (2 H, m), 1.98 - 2.06 (2 H, m), 2.23 (3 H, s), 3.03 - 3.11 (1 H, m), 3.13 (2 H, s), 7.89 (1 H, dd, J=8.51, 1.65 Hz), 7.97 (1 H, s), 8.16 (1 H, d, J=8.51 Hz), 8.27 (1 H, s), 8.53 (1 H, s), 8.58 (1 H, s), 9.15 (1 H, s), 10.01 (1 H, s); ESIMS found for C19H20N4O2 mlz 337.1 (M+l).
Figure imgf000239_0001
981
[01090] N-(6-(Oxazol-5-yl)isoquinolin-3-yl)-2-(pyrrolidin-l-yl)acetamide 981.
[01091] Off-white solid (45.0 mg, 0.140 mmol, 42.3% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.78 (4 H, dt, J=6.79, 3.33 Hz), 2.62 - 2.70 (4 H, m), 3.37 (2 H, s), 7.89 (1 H, dd, J=8.78, 1.65 Hz), 7.96 (1 H, s), 8.15 (1 H, d, J=8.51 Hz), 8.26 (1 H, s), 8.53 (1 H, s), 8.58 (1 H, s), 9.14 (1 H, s), 10.01 (1 H, s); ESIMS found for C18H18N4O2 mlz 323.1 (M+l).
Figure imgf000239_0002
982
[01092] (R)-2-(2-Methylpyrrolidin-l-yl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl) acetamide 982.
[01093] Beige solid (8.0 mg, 0.024 mmol, 23.8% yield). ¾ NMR (500 MHz, DMSO- d6) 5 ppm 1.09 (3 H, d, J=6.04 Hz), 1.41 (1 H, dddd, J=12.32, 10.39, 8.30, 6.31 Hz), 1.67 - 1.84 (2 H, m), 1.91 - 2.02 (1 H, m), 2.40 (1 H, q, J=8.78 Hz), 2.57 - 2.66 (1 H, m), 3.13 (1 H, d, J=16.19 Hz), 3.13 - 3.20 (1 H, m), 3.55 (1 H, d, J=16.19 Hz), 7.89 (1 H, dd, J=8.51, 1.65 Hz), 7.97 (1 H, s), 8.16 (1 H, d, J=8.51 Hz), 8.27 (1 H, s), 8.53 (1 H, s), 8.58 (1 H, s), 9.14 (1 H, s), 9.98 (1 H, s); ESIMS found for C19H20N4O2 mlz 337.2 (M+l).
Figure imgf000239_0003
983
[01094] 2-(4-Methylpiperazin-l-yl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)acetamide
983.
[01095] Pale yellow solid (43.0 mg, 0.122 mmol, 37.1% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 2.19 (3 H, s), 2.40 (4 H, br s), 2.58 (4 H, br s), 3.23 (2 H, s), 7.89 (1 H, dd, J=8.51, 1.65 Hz), 7.96 (1 H, s), 8.15 (1 H, d, J=8.78 Hz), 8.26 (1 H, s), 8.53 (1 H, s), 8.58 (1 H, s), 9.15 (1 H, s), 10.01 (1 H, s); ESIMS found for Ci9H2iN502 mlz 352.2 (M+l).
Figure imgf000240_0001
984
[01096] N-(6-(5-(Hydroxymethyl)-l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl) tetrahydro-2H-pyran-4-carboxamide 984.
[01097] Beige solid (30.0 mg, 0.082 mmol, 25.9% yield). ¾ NMR (499 MHz, DMSO- 6) 5 ppm 1.63 - 1.79 (4 H, m), 2.77 - 2.87 (1 H, m), 3.33 - 3.40 (2 H, m), 3.91 (2 H, br d, J=2.47 Hz), 3.93 (3 H, s), 4.64 (2 H, d, J=5.21 Hz), 5.56 (1 H, t, J=5.35 Hz), 7.68 ( 1 H, dd, J=8.51, 1.37 Hz), 7.81 ( 1 H, s), 7.94 (1 H, s), 8.05 (1 H, d, J=8.51 Hz), 8.48 (1 H, s), 9.09 (1 H, s), 10.54 ( 1 H, s); ESIMS found for C2oH22N403 mlz 367.0 (M+1).
Figure imgf000240_0002
985
[01098] N-(6-(5 -(Hydroxymethyl)- 1 -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)- 1 - methylpiperidine -4 -carboxamide 985.
[01099] Beige solid (26.0 mg, 0.069 mmol, 12.9% yield). ¾ NMR (499 MHz, DMSO- 6) 5 ppm 1.62 - 1.73 (2 H, m), 1.74 - 1.81 (2 H, m), 1.86 (2 H, td, J=1 1.60, 2.06 Hz), 2.16 (3 H, s), 2.46 - 2.55 (1 H, m), 2.77 - 2.85 (2 H, m), 3.93 (3 H, s), 4.63 (2 H, d, J=5.21 Hz), 5.56 ( 1 H, t, J=5.35 Hz), 7.67 (1 H, dd, J=8.51, 1.65 Hz), 7.81 (1 H, s), 7.94 (1 H, s), 8.05 (1 H, d, J=8.51 Hz), 8.48 ( 1 H, s), 9.08 (1 H, s), 10.50 ( 1 H, s); ESIMS found for C2iH25N502 mlz 380.0 (M+1).
Figure imgf000240_0003
986
[01100] 3,3-Difluoro-N-(6-(5,6,7,8-tetrahydroimidazo[l,2-a]pyrazin-3-yl) isoquinolin-3 -yl)cyclobutane - 1 -carboxamide 986.
[01101] White solid (33.0 mg, 0.086 mmol, 28.3% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 2.75 - 2.90 (5 H, m), 3.07 (2 H, br t, J=5.21 Hz), 3.95 (2 H, s), 4.1 1 (2 H, t, J=5.35 Hz), 7.30 (1 H, s), 7.68 (1 H, dd, J=8.51, 1.65 Hz), 7.97 (1 H, s), 8.07 ( 1 H, d, J=8.51 Hz), 8.55 (1 H, s), 9.1 1 (1 H, s), 10.78 (1 H, s); ESIMS found for C2oHi9F2N50 mlz 384.15 (M+l).
Figure imgf000241_0001
987
[01102] (R)-N-(6-(5,6,7,8-Tetrahydroimidazo[l,2-a]pyrazin-3-yl)isoquinolin-3-yl) pyrrolidine-2-carboxamide 987.
[01103] Beige solid (20.0 mg, 0.055 mmol, 34.3% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.67 (2 H, quin, J=6.72 Hz), 1.78 - 1.90 (1 H, m), 2.05 - 2.16 (1 H, m), 2.87 (1 H, dt, J=10.15, 6.45 Hz), 2.97 (1 H, dt, J=10.15, 6.72 Hz), 3.07 (2 H, t, J=5.49 Hz), 3.81 (1 H, dd, J=9.06, 5.49 Hz), 3.95 (2 H, s), 4.12 (2 H, t, J=5.35 Hz), 7.30 (1 H, s), 7.67 (1 H, dd, J=8.51, 1.65 Hz), 7.98 ( 1 H, s), 8.07 ( 1 H, d, J=8.78 Hz), 8.52 (1 H, s), 9.09 (1 H, s), 10.38 ( 1 H, s); ESIMS found for C20H22N6O mlz 363.2 (M+ l).
Figure imgf000241_0002
988
[01104] (R)-N-(6-(5,6,7,8-Tetrahydroimidazo[l,2-a]pyrazin-3-yl)isoquinolin-3-yl) piperidine-3-carboxamide 988.
[01105] Dark brown gum (36.0 mg, 0.096 mmol, 55.2% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.31 - 1.56 (2 H, m), 1.57 - 1.74 (2 H, m), 2.32 - 2.46 ( 1 H, m), 2.52 - 2.66 (2 H, m), 2.70 - 2.88 (2 H, m), 3.07 (2 H, t, J=5.35 Hz), 3.95 (2 H, s), 4.1 1 (2 H, t, J=5.21 Hz), 7.29 (1 H, s), 7.65 (1 H, dd, J=8.51, 1.65 Hz), 7.93 (1 H, s), 8.05 (1 H, d, J=8.51 Hz), 8.51 (1 H, s), 9.08 ( 1 H, s), 10.79 ( 1 H, s); ESIMS found for C2iH24N60 mlz 377.0 (M+l).
Figure imgf000241_0003
989
[01106] 1 -Methyl -N-(6-(5,6,7,8-tetrahydroimidazo[ 1 ,2-a]pyrazin-3 -yl)isoquinolin-3 - yl)piperidine-4-carboxamide 989.
[01107] White solid (3.0 mg, 0.008 mmol, 6.4% yield). ¾ NMR (499 MHz, DMSO- £¾) 5 ppm 1.61 - 1.72 (2 H, m), 1.73 - 1.80 (2 H, m), 1.87 (2 H, td, J=1 1.60, 2.06 Hz), 2.16 (3 H, s), 2.51 - 2.56 (1 H, m), 2.76 - 2.86 (3 H, m), 3.07 (2 H, br t, J=5.21 Hz), 3.95 (2 H, s), 4.10 (2 H, t, J=5.49 Hz), 7.28 (1 H, s), 7.65 ( 1 H, dd, J=8.51, 1.65 Hz), 7.93 (1 H, s), 8.05 (1 H, d, J=8.51 Hz), 8.52 (1 H, s), 9.09 (1 H, s), 10.51 ( 1 H, s); ESIMS found for C22H26N60 mlz 391.2 (M+1).
Figure imgf000242_0001
990
[01108] N-(6-(5,6,7,8-Tetrahydroimidazo[l,2-a]pyrazin-3-yl)isoquinolin-3-yl)-l-(( l- (trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide 990.
[01109] Tan solid (31.0 mg, 0.062 mmol, 49.4% yield). ¾ NMR (499 MHz, DMSO- d6) 5 ppm 0.73 (2 H, br s), 0.93 - 0.98 (2 H, m), 1.62 - 1.71 (2 H, m), 1.77 (2 H, br d, J=10.70 Hz), 1.91 - 1.99 (2 H, m), 2.53 - 2.59 ( 1 H, m), 2.96 (2 H, br d, J=l 1.25 Hz), 3.08 (2 H, br t, J=5.21 Hz), 3.95 (2 H, s), 4.1 1 (2 H, br t, J=5.21 Hz), 7.29 (1 H, s), 7.65 (1 H, dd, J=8.51, 1.65 Hz), 7.94 ( 1 H, s), 8.05 (1 H, d, J=8.51 Hz), 8.52 ( 1 H, s), 9.09 (1 H, s), 10.51 ( 1 H, s); ESIMS found for C26H29F3N60 mlz 499.2 (M+1).
Figure imgf000242_0002
991
[OHIO] l-Benzoyl-N-(6-(5,6,7,8-tetrahydroimidazo[l,2-a]pyrazin-3-yl)isoquinolin- 3 -yl)piperidine -4 -carboxamide 991.
[01111] White solid (27.7 mg, 0.058 mmol, 70.8% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.63 (2 H, br s), 1.75 - 1.98 (2 H, m), 2.69 - 2.96 ( 1 H, m), 2.86 (2 H, ddt, J=1 1.22, 7.51, 3.81, 3.81 Hz), 3.02 - 3.17 (1 H, m), 3.07 (2 H, br t, J=5.08 Hz), 3.95 (2 H, s), 4.1 1 (2 H, t, J=5.21 Hz), 7.29 (1 H, s), 7.36 - 7.43 (2 H, m), 7.43 - 7.50 (3 H, m), 7.66 ( 1 H, dd, J=8.51, 1.65 Hz), 7.94 ( 1 H, s), 8.06 ( 1 H, d, J=8.78 Hz), 8.52 (1 H, s), 9.10 (1 H, s), 10.61 ( 1 H, s); ESIMS found for CzsHzsNeOz mlz 481.2 (M+l).
Figure imgf000243_0001
[01112] fert-Butyl 6-((6-( 1 -methyl-5-(piperidin-l -ylmethyl)- lH-pyrazol-4-yl) isoquinolin-3-yl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate 992.
[01113] White solid (200.0 mg, 0.367 mmol, 78.3% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.37 ( 1 1 H, s), 1.45 - 1.54 (4 H, m), 2.37 (4 H, s), 2.38 (4 H, s), 3.21 - 3.30 ( 1 H, m), 3.65 (2 H, s), 3.81 (2 H, br s), 3.88 (2 H, br s), 3.91 (3 H, s), 7.69 (1 H, dd, J=8.51, 1.65 Hz), 7.80 (1 H, s), 8.02 ( 1 H, d, J=8.78 Hz), 8.05 ( 1 H, s), 8.47 ( 1 H, s), 9.06 (1 H, s), 10.44 ( 1 H, s) ;ESIMS found for C3iH4oN603
Figure imgf000243_0002
993
[01114] N-(6-(2-Methylthiazol-5-yl)isoquinolin-3 -yl)-2-(pyrrolidin- 1 -yl)acetamide
993.
[01115] Beige solid (25.0 mg, 0.071 mmol, 21.6% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.78 (4 H, dt, J=6.79, 3.33 Hz), 2.62 - 2.69 (4 H, m), 2.72 (3 H, s), 3.36 (2 H, s), 7.82 (1 H, dd, J=8.51, 1.92 Hz), 8.10 (1 H, d, J=8.51 Hz), 8.15 ( 1 H, d, J=0.82 Hz), 8.30 ( 1 H, s), 8.50 (1 H, s), 9.1 1 (1 H, s), 9.99 ( 1 H, s); ESIMS found for C19H20N4OS mlz 353.1 (M+l).
Figure imgf000243_0003
994
[01116] N-(6-(2-Methylthiazol-5-yl)isoquinolin-3-yl)-2-mo holinoacetamide 994.
[01117] Beige solid (44.0 mg, 0.1 19 mmol, 41.8% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 2.55 - 2.61 (4 H, m), 2.72 (3 H, s), 3.25 (2 H, s), 3.60 - 3.68 (4 H, m), 7.82 ( 1 H, dd, J=8.64, 1.78 Hz), 8.10 ( 1 H, d, J=8.51 Hz), 8.15 (1 H, d, J=0.82 Hz), 8.30 ( 1 H, s), 8.50 ( 1 H, s), 9.12 ( 1 H, s), 10.08 (1 H, s); ESIMS found for C19H20N4O2S mlz 369.1 (M+l).
Figure imgf000244_0001
995
[01118] 2-(4-Methylpiperazin- 1 -yl)-N-(6-(2-methylthiazol-5-yl)isoquinolin-3 -yl) acetamide 995.
[01119] Brown solid (31.0 mg, 0.081 mmol, 31.3% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 2.19 (3 H, s), 2.40 (4 H, br s), 2.58 (4 H, br s), 2.72 (3 H, s), 3.23 (2 H, s), 7.82 ( 1 H, dd, J=8.51, 1.65 Hz), 8.10 (1 H, d, J=8.51 Hz), 8.15 (1 H, s), 8.30 (1 H, s), 8.50 ( 1 H, s), 9.12 ( 1 H, s), 10.00 ( 1 H, s); ESIMS mlz 382.2 (M+l).
Figure imgf000244_0002
996
[01120] 2-((lR,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(2-methylthiazol-5- yl)isoquinolin-3-yl)acetamide 996.
[01121] Beige solid (50.0 mg, 0.131 mmol, 43.8% yield). ¾ NMR (499 MHz, DMSO- d6) 5 ppm 1.64 - 1.71 (1 H, m), 1.87 (1 H, dd, J=9.47, 1.78 Hz), 2.63 ( 1 H, d, J=9.88 Hz), 2.72 (3 H, s), 2.95 (1 H, dd, J=9.88, 1.65 Hz), 3.46 (2 H, d, J=4.39 Hz), 3.59 (1 H, dd, J=7.68, 1.92 Hz), 3.63 (1 H, s), 3.88 (1 H, d, J=7.68 Hz), 4.41 (1 H, s), 7.82 (1 H, dd, J=8.64, 1.78 Hz), 8.10 (1 H, d, J=8.51 Hz), 8.15 (1 H, d, J=0.82 Hz), 8.30 (1 H, s), 8.50 (1 H, s), 9.12 ( 1 H, s), 9.98 (1 H, s); ESIMS found for C20H20N4O +l).
Figure imgf000244_0003
997
[01122] N-(6-(4,5 ,6,7-Tetrahydropyrazolo [1,5 -a]pyrazin-3 -yl)isoquinolin-3 -yl)- 1 -(( 1 (trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide 997.
[01123] Tan solid (33.6 mg, 0.067 mmol, 47.8% yield). ¾ NMR (499 MHz, DMSO d6) 5 ppm 0.73 (2 H, br s), 0.94 - 0.99 (2 H, m), 1.62 - 1.72 (2 H, m), 1.74 - 1.81 (2 H, m), 1.91 1.99 (2 H, m), 2.53 - 2.58 (1 H, m), 2.93 - 2.99 (2 H, m), 3.16 (2 H, br t, J=5.21 Hz), 4.06 (2 H, br t, J=5.35 Hz), 4.22 (2 H, s), 7.63 (1 H, dd, J=8.51, 1.65 Hz), 7.76 (1 H, s), 7.98 ( 1 H, s), 8.01 (1 H, d, J=8.51 Hz), 8.47 (1 H, s), 9.04 (1 H, s), 10.46 (1 H, s); ESIMS found for CzeHzgFsNeO mlz 499.25 (M+ l).
Figure imgf000245_0001
998
[01124] N-(6-(5-(2-Fluoroethyl)-4,5,6,7-tetrahydropyrazolo[ l,5-a]pyrazin-3-yl) isoquinolin-3 -yl)-l -(( 1 -(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide 998.
[01125] Off-white solid ( 15.0 mg, 0.028 mmol, 41.6% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 0.73 (2 H, br s), 0.94 - 0.99 (2 H, m), 1.62 - 1.72 (2 H, m), 1.74 - 1.82 (2 H, m), 1.91 - 1.99 (2 H, m), 2.52 - 2.59 (1 H, m), 2.93 - 3.03 (4 H, m), 3.07 (2 H, t, J=5.35 Hz), 4.08 (2 H, s), 4.18 (2 H, t, J=5.49 Hz), 4.66 (2 H, dt, J=47.85, 4.70 Hz), 7.64 (1 H, dd, J=8.51, 1.37 Hz), 7.76 ( 1 H, s), 8.00 ( 1 H, s), 8.02 ( 1 H, d, J=8.51 Hz), 8.48 (1 H, s), 9.05 ( 1 H, s), 10.48 (1 H, s); ESIMS found for C28H32F4N60 mlz 545.3 (M+l).
Figure imgf000245_0002
999
[01126] N-(6-(5-(2-Fluoroethyl)-4,5,6,7-tetrahydropyrazolo[ l,5-a]pyrazin-3-yl) isoquinolin-3 -yl)-2-(pyrrolidin- 1 -yl)acetamide 999.
[01127] Yellow oil (5.6 mg, 0.013 mmol, 38.4% yield). ¾ NMR (500 MHz, DMSO- d6) δ ppm 1.78 (4 H, dt, J=6.72, 3.22 Hz), 2.66 (4 H, br s), 2.98 (3 H, dt, J=28.55, 4.95 Hz), 3.07 (2 H, t, J=5.49 Hz), 3.36 (2 H, s), 4.09 (2 H, s), 4.18 (2 H, t, J=5.49 Hz), 4.66 (3 H, dt, J=47.75, 4.95 Hz), 7.65 (1 H, dd, J=8.51, 1.65 Hz), 7.82 (1 H, s), 8.01 (1 H, s), 8.05 (1 H, d, J=8.51 Hz), 8.47 ( 1 H, s), 9.06 (1 H, s), 9.96 ( 1 H, s); ESIMS found for C23H27FN6O mlz 423.2 (M+l).
Figure imgf000246_0001
1000
[01128] 2-(7-Azabicyclo[2.2.1]heptan-7-yl)-N-(6-(5-(2-fluoroethyl)-4,5,6,7- tetrahydropyrazolo [ 1 , 5 -a] pyrazin-3 -yl)isoquinolin-3 -yl)acetamide 1000.
[01129] Yellow solid (26.5 mg, 0.059 mmol, 52.7% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.35 (4 H, br d, J=6.86 Hz), 1.69 - 1.79 (4 H, m), 2.99 (2 H, dt, J=28.90, 4.95 Hz), 3.08 (2 H, br t, J=5.49 Hz), 3.19 (2 H, s), 3.36 (2 H, br s), 4.09 (2 H, s), 4.18 (2 H, br t, J=5.49 Hz), 4.66 (2 H, dt, J=47.85, 4.95 Hz), 7.65 (1 H, dd, J=8.51, 1.65 Hz), 7.82 ( 1 H, s), 8.00 (1 H, s), 8.05 ( 1 H, d, J=8.78 Hz), 8.48 (1 H, s), 9.06 ( 1 H, s), 10.08 (1 H, s); ESIMS found for C25H29FN6O mlz 449.25 (M+l).
Figure imgf000246_0002
1001
[01130] c/'5-4-Methoxy-N-(6-(5 -methyl- 1 ,3,4-thiadiazol-2-yl)isoquinolin-3 -yl) cyclohexane-l -carboxamide 1001.
[01131] White solid (33.4 mg, 0.087 mmol, 21.2% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.08 - 1.18 (2 H, m), 1.45 - 1.55 (2 H, m), 1.88 - 1.94 (2 H, m), 2.05 - 2.1 1 (2 H, m), 2.52 - 2.58 (1 H, m), 2.83 (3 H, s), 3.09 - 3.16 (1 H, m), 3.25 (3 H, s), 8.09 (1 H, dd, J=8.65, 1.51 Hz), 8.19 (1 H, d, J=8.51 Hz), 8.44 ( 1 H, s), 8.60 (1 H, s), 9.21 ( 1 H, s), 10.60 ( 1 H, s); ESIMS found for C20H22N4O2S mlz 383.15 (M+l).
Figure imgf000246_0003
1002
[01132] (R)-N-(6-(5 -(2-Fluoroethyl)-4,5,6,7-tetrahydropyrazolo[ 1 ,5 -a]pyrazin-3 -yl) isoquinolin-3-yl)-l-isobutylpiperidine-3-carboxamide 1002. [01133] Light yellow gum (31.1 mg, 0.065 mmol, 40.7% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 0.89 (6 H, dd,J=ll.ll, 6.45 Hz), 1.50 - 1.58 (2 H, m), 1.69 (1 H, br dd,J=8.37, 3.98 Hz), 1.78 - 1.86 (2 H, m), 2.11 (1 H, d,J=7.14 Hz), 2.09 - 2.17 (1 H, m), 2.28 - 2.37 (1 H, m), 2.60 - 2.66 (1 H, m), 2.75 - 2.84 (2 H, m), 2.98 (3 H, dt, J=28.60, 4.95 Hz), 3.07 (2 H, br t, J=5.49 Hz), 4.07 (2 H, s), 4.18 (2 H, t,J=5.35 Hz), 4.66 (2 H, dt, J=47.80, 4.95 Hz), 7.64 (1 H, dd,J=8.51, 1.65 Hz), 7.75 (1 H, s), 8.00 (1 H, s), 8.02 (1 H, d, J=8.78 Hz), 8.46 (1 H, s), 9.05 (1 H, s), 10.69 (1 H, s); ESIMS found for
Figure imgf000247_0001
1003
[01134] N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)-l -(pyrimidin-2- ylmethyl)piperidine -4 -carboxamide 1003.
[01135] Beige solid (75.0 mg, 0.175 mmol, 29.4% yield). ¾NMR(499 MHz, DMSO- d6) δ ppm 1.63 - 1.74 (2 H, m), 1.74 - 1.82 (2 H, m), 2.18 (2 H, brt, J=10.70 Hz), 2.52 - 2.59 (1 H, m), 2.98 (2 H, br d, J=10.98 Hz), 3.74 (2 H, s), 3.90 (3 H, s), 7.41 (1 H, t, J=4.80 Hz), 7.74 (1 H, dd,J=8.51, 1.65 Hz), 7.99 (1 H, d,J=8.51 Hz), 8.03 (1 H, s), 8.07 (1 H, d,J=0.82Hz), 8.34 (1 H, s), 8.44 (1 H, s), 8.79 (2 H, d, J=4.94 Hz), 9.02 (1 H, s), 10.44 (1 H, s); ESIMS found for C24H25N7O mlz 428.2 (M+l).
Figure imgf000247_0002
1004
[01136] N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)-l -(pyrazin-2- ylmethyl)piperidine -4 -carboxamide 1004.
[01137] Orange solid (20.0 mg, 0.047 mmol, 7.8% yield). 'HNMR (499 MHz, DMSO- 6)5ppm 1.66 - 1.76 (2 H, m), 1.76 - 1.83 (2 H, m), 2.09 (2 H, td, J=l 1.60, 2.33 Hz), 2.52 - 2.61 (1 H, m), 2.90 (2 H, br d, J=l 1.53 Hz), 3.67 (2 H, s), 3.90 (3 H, s), 7.74 (1 H, dd, J=8.51, 1.65 Hz), 7.99 (1 H, d, J=8.51 Hz), 8.03 (1 H, s), 8.07 (1 H, s), 8.35 (1 H, s), 8.44 (1 H, s), 8.54 (1 H, d, J=2.74Hz), 8.58 (1 H, dd,J=2.61, 1.51 Hz), 8.70 (1 H, d,J=1.37Hz), 9.02 (1 H, s), 10.46 (1 H, s); ESIMS found for C24H25N7O mlz 428.2 (M+l).
Figure imgf000248_0001
1005
[01138] l-((5-Methyl-l,2,4-oxadiazol-3-yl)methyl)-N-(6-(l-methyl-lH-pyrazol-4-yl) isoquinolin-3-yl)piperidine-4-carboxamide 1005.
[01139] White solid (45.0 mg, 0.104 mmol, 17.5% yield). 'HNMR (499 MHz, DMSO- d6) δ ρρηι 1.63 - 1.74 (2 H, m), 1.78 - 1.84 (2 H, m), 2.18 (2 H, td, J=l 1.53, 2.20 Hz), 2.35 (3 H, s), 2.52 - 2.57 (1 H, m), 2.89 - 2.96 (2 H, m), 3.87 (2 H, s), 3.90 (3 H, s), 7.74 (1 H, dd, J=8.51, 1.65 Hz), 8.00 (1 H, d, J=8.51 Hz), 8.03 (1 H, s), 8.07 (1 H, s), 8.34 (1 H, s), 8.44 (1 H, s), 9.02 (1 H, s), 10.45 (1 H, s); ESIM (M+l).
Figure imgf000248_0002
1006
[01140] 1 -(2-Hydroxy-2-methylpropyl)-N-(6-( 1 -methyl-lH-pyrazol-4-yl) isoquinolin-3-yl)piperidine-4-carboxamide 1006.
[01141] White solid (45.0 mg, 0.110 mmol, 18.5% yield). 'HNMR (499 MHz, DMSO- d6) δ ppm 1.09 (6 H, s), 1.72 (4 H, br d, J=2.74 Hz), 2.13 (2 H, br s), 2.20 (2 H, br s), 2.46 - 2.55 (1 H, m), 2.99 (2 H, br d, J=9.88 Hz), 3.90 (3 H, s), 4.04 (1 H, br s), 7.74 (1 H, dd, J=8.51, 1.65 Hz), 7.99 (1 H, d, J=8.51 Hz), 8.04 (1 H, s), 8.08 (1 H, d, J=0.82 Hz), 8.35 (1 H, s), 8.44 (1 H, s), 9.02 (1 H, s), 10.44 (1 H, s); ESIMS found for CzsHzgNsOz mlz 408.2 (M+l).
Figure imgf000248_0003
1008
[01142] 2-Isopropoxy-N-(6-( 1 -methyl- lH-imidazol-5-yl)isoquinolin-3 -yl)acetamide
1008.
[01143] White solid (35.0 mg, 0.108 mmol, 18.6% yield). ¾NMR (499 MHz, DMSO- d6) δ ppm 1.20 (6 H, d, J=6.04 Hz), 3.75 (1 H, spt, J=6.13 Hz), 3.91 (3 H, s), 4.15 (2 H, s), 7.69 (1 H, s), 7.73 (1 H, dd, J=8.37, 1.78 Hz), 8.17 (1 H, br s), 8.18 (1 H, d, J=8.78 Hz), 8.51 (1 H, s), 8.57 (1 H, s), 9.20 (1 H, s), 9.80 (1 H, s); ESIMS found for C18H20N4O2 mlz 325.2 (M+l).
Figure imgf000249_0001
1009
[01144] 3 -Isopropoxy-N-(6-( 1 -methyl- lH-imidazol-5 -yl)isoquinolin-3 -yl) propanamide 1009.
[01145] White solid (105.0 mg, 0.310 mmol, 43.5% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.08 (6 H, d, J=6.04 Hz), 2.66 (2 H, t, J=6.31 Hz), 3.58 (1 H, spt, J=6.08 Hz), 3.69 (2 H, t, J=6.17 Hz), 3.84 (3 H, s), 7.34 ( 1 H, s), 7.67 (1 H, dd, J=8.51, 1.65 Hz), 7.87 ( 1 H, s), 8.03 (1 H, d, J=0.82 Hz), 8.09 ( 1 H, d, J=8.51 Hz), 8.55 ( 1 H, s), 9.13 (1 H, s), 10.55 (1 H, s); ESIMS found for C19H22N
Figure imgf000249_0002
1010
[01146] fert-Butyl 2-(4-((6-(l -methyl- lH-pyrazol-4-yl)isoquinolin-3-yl) carbamoyl) piperidin-l-yl)acetate 1010.
[01147] White solid (75.0 mg, 0.167 mmol, 18.7% yield). 'HNMR (499 MHz, DMSO- d6) δ ppm 1.42 (9 H, s), 1.62 - 1.73 (2 H, m), 1.74 - 1.81 (2 H, m), 2.22 (2 H, td, J=l 1.53, 2.20 Hz), 2.51 - 2.57 (1 H, m), 2.83 - 2.91 (2 H, m), 3.10 (2 H, s), 3.90 (3 H, s), 7.74 (1 H, dd, J=8.51, 1.65 Hz), 8.00 ( 1 H, d, J=8.51 Hz), 8.03 (1 H, s), 8.07 (1 H, s), 8.34 (1 H, s), 8.44 ( 1 H, s), 9.02 (1 H, s), 10.46 (1 H, s); ESIMS foun (M+l).
1011
[01148] 2-(4-((6-( l-Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)piperidin-l- yl)acetic acid 1011.
[01149] White solid. ¾ NMR (499 MHz, DMSO- 6) δ ppm 1.76 - 1.90 (4 H, m), 2.41 - 2.48 (2 H, m), 2.57 - 2.66 ( 1 H, m), 3.10 - 3.19 (4 H, m), 3.90 (3 H, s), 7.75 ( 1 H, dd, J=8.51, 1.65 Hz), 8.00 (1 H, d, J=8.51 Hz), 8.04 (1 H, s), 8.08 (1 H, s), 8.36 ( 1 H, br s), 8.44 ( 1 H, s), 9.03 (1 H, s), 10.53 (1 H, s); ESIMS found for C2iH23N503 mlz 394.2 (M+l).
Figure imgf000250_0001
1012
[01150] 2-(4-Methyl-l,4-diazepan-l-yl)-N-(6-(l -methyl-lH-pyrazol-4-yl) isoquinolin-3-yl)acetamide 1012.
[01151] Off-white solid (40.0 mg, 0.106 mmol, 48.0% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.78 (2 H, quin, J=5.97 Hz), 2.28 (3 H, s), 2.56 - 2.64 (4 H, m), 2.79 - 2.87 (4 H, m), 3.36 (2 H, s), 3.90 (3 H, s), 7.77 ( 1 H, dd, J=8.51, 1.65 Hz), 8.02 ( 1 H, d, J=8.51 Hz), 8.08 - 8.13 (2 H, m), 8.36 ( 1 H, s), 8.44 (1 H, s), 9.04 (1 H, s), 9.96 (1 H, s); ESIMS found for C2iH26N60 mlz 379.2 (M+ l).
Figure imgf000250_0002
1013
[01152] N-(7-Chloro-6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide 1013.
[01153] Off-white solid (200.0 mg, 0.541 mmol, 99.9% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.75 - 1.85 (2 H, m), 1.93 - 1.99 (2 H, m), 2.79 - 2.90 (3 H, m), 3.28 - 3.34 (2 H, m), 3.93 (3 H, s), 7.98 ( 1 H, s), 8.1 1 ( 1 H, s), 8.26 (1 H, s), 8.31 ( 1 H, s), 8.47 ( 1 H, s), 9.09 (1 H, s), 10.71 (1 H, s); ESIMS found for Ci9H2oClN50 mlz 370.1 (M+l).
Figure imgf000250_0003
1014
[01154] N-(6-(l -(Methyl-£/3)-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(4- methylpiperazin-1 -yl)acetamide 1014.
[01155] Light brown solid (92.0 mg, 0.250 mmol, 50.1% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 2.24 (3 H, s), 2.46 (4 H, br s), 2.60 (4 H, br s), 3.23 (2 H, s), 7.77 (1 H, dd, J=8.51, 1.65 Hz), 8.02 (1 H, d, J=8.51 Hz), 8.10 (2 H, s), 8.36 ( 1 H, s), 8.43 ( 1 H, s), 9.04 ( 1 H, s), 9.94 ( 1 H, s); ESIMS found for C2oH2i[2H3]N60 mlz 368.2 (M+l).
Figure imgf000251_0001
1015
[01156] N-(7-Fluoro-6-(l-(methyl- 3)-lH-pyrazol-4-yl)isoquinolin-3-yl)-2- (piperidin-l-yl)acetamide 1015.
[01157] Brown solid (20.0 mg, 0.054 mmol, 33.0% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.43 (2 H, br d, J=5.21 Hz), 1.58 (4 H, quin, J=5.56 Hz), 2.52 (4 H, br s), 3.17 (2 H, s), 7.92 (1 H, d, J=11.53 Hz), 8.13 (1 H, s), 8.31 (1 H, d, J=2.47 Hz), 8.33 (1 H, d, J=7.68 Hz), 8.49 (1 H, s), 9.05 (1 H, s), 9.93 (1 H, s); ESIMS found for C2oHi9[2H3]FN50 mlz 371.2 (M+l).
Figure imgf000251_0002
1016
[01158] N-(8-Fluoro-6-(l-(methyl- 3)-lH-pyrazol-4-yl)isoquinolin-3-yl)-2- (piperidin-l-yl)acetamide 1016.
[01159] Pale yellow solid (46.0 mg, 0.124 mmol, 40.1% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.43 (2 H, br d, J=4.94 Hz), 1.58 (4 H, quin, J=5.56 Hz), 2.51 - 2.57 (4 H, m), 3.19 (2 H, s), 7.62 (1 H, dd, J=12.08, 1.10 Hz), 7.99 (1 H, s), 8.13 (1 H, s), 8.40 (1 H, d, J=0.82 Hz), 8.48 (1 H, s), 9.16 (1 H, s), 10.04 (1 H, s); ESIMS found for C2oHi9[2H3]FN50 mlz 371.2 (M+l).
Figure imgf000251_0003
1018
[01160] trans-4-((3 -Fluoroazetidin- 1 -yl)methyl)-N-(6-(2-methyloxazol-5-yl) isoquinolin-3 -yl)cyclohexane - 1 -carboxamide 1018.
[01161] Off-white solid (52.0 mg, 0.123 mmol, 51.7% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 0.91 (2 H, qd, J=12.72, 3.02 Hz), 1.22 - 1.32 (1 H, m), 1.44 (2 H, qd, J=12.72, 3.29 Hz), 1.79 (2 H, br dd, J=13.17, 2.47 Hz), 1.82 - 1.89 (2 H, m), 2.29 (2 H, d, J=6.59 Hz), 2.44 - 2.49 (1 H, m), 2.53 (3 H, s), 2.96 - 3.08 (2 H, m), 3.49 - 3.59 (2 H, m), 5.12 ( 1 H, dq, J=58.00, 5.20 Hz), 7.78 (1 H, s), 7.79 - 7.83 (1 H, m), 8.06 - 8.12 (2 H, m), 8.50 (1 H, s), 9.10 (1 H, s), 10.48 ( 1 H, s); ESIMS found for C24H27FN4O2 mlz 423.2 (M+l).
Figure imgf000252_0001
1019
[01162] N-(6-(2-Methyloxazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-l-yl) acetamide 1019.
[01163] Off-white solid (60.0 mg, 0.164 mmol, 49.8% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 2.19 (3 H, s), 2.40 (4 H, br s), 2.53 (3 H, s), 2.58 (4 H, br s), 3.23 (2 H, s), 7.80 ( 1 H, s), 7.83 (1 H, dd, J=8.51, 1.65 Hz), 8.12 (1 H, d, J=8.51 Hz), 8.16 ( 1 H, s), 8.50 ( 1 H, s), 9.12 ( 1 H, s), 10.00 ( 1 H, s); ESIM 366.2 (M+l).
Figure imgf000252_0002
1020
[01164] 1 -Isobutyl-N-(6-(5 -methyl- 1 ,3 ,4-oxadiazol-2-yl)isoquinolin-3 -yl)piperidine- 4-carboxamide 1020.
[01165] Off-white solid (40.0 mg, 0.102 mmol, 34.3% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 0.86 (6 H, d, J=6.59 Hz), 1.62 - 1.73 (2 H, m), 1.73 - 1.82 (3 H, m), 1.83 - 1.92 (2 H, m), 2.02 (2 H, d, J=7.41 Hz), 2.52 - 2.59 (1 H, m), 2.64 (3 H, s), 2.87 (2 H, br d, J=l 1.25 Hz), 8.04 (1 H, dd, J=8.51, 1.37 Hz), 8.23 (1 H, d, J=8.78 Hz), 8.47 (1 H, s), 8.62 (1 H, s), 9.24 (1 H, s), 10.64 (1 H, s); ESIMS found for C22H27N502 mlz 394.2 (M+l).
Figure imgf000252_0003
1021
[01166] 4-Fluoro-l -isobutyl-N-(6-(5,6,7,8-tetrahydroimidazo[l,2-a]pyrazin-3-yl) isoquinolin-3-yl)piperidine-4-carboxamide 1021.
[01167] White solid (66.0 mg, 0.147 mmol, 47.5% yield). ¾ NMR (499 MHz, DMSO- 6) 5 ppm 0.88 (6 H, d, J=6.59 Hz), 1.75 - 1.86 ( 1 H, m), 1.91 - 2.01 (2 H, m), 2.05 - 2.22 (4 H, m), 2.09 (2 H, d, J=7.41 Hz), 2.78 (2 H, br d, J=7.68 Hz), 3.07 (2 H, br t, J=5.21 Hz), 3.95 (2 H, s), 4.12 (2 H, t, J=5.21 Hz), 7.31 (1 H, s), 7.72 (1 H, dd, J=8.64, 1.51 Hz), 8.02 (1 H, s), 8.11 (1 H, d, J=8.51 Hz), 8.49 (1 H, s), 9.15 (1 H, s), 9.91 (1 H, d, J=4.12 Hz); ESIMS found for C25H3iFN60 iw/z 451.25 (M+l).
Figure imgf000253_0001
1022
[01168] N-(6-(5-(2-Fluoroethyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-3-yl) isoquinolin-3-yl)piperidine-4-carboxamide 1022.
[01169] White solid (14.0 mg, 0.033 mmol, 46.7% yield). ¾NMR (499 MHz, DMSO- d6) δ ppm 1.54 (2 H, qd, J=12.12, 3.70 Hz), 1.70 (2 H, br d, J=10.98 Hz), 2.47 (2 H, br s), 2.64 (1 H, tt, J=l 1.46, 3.50 Hz), 2.93 - 3.04 (4 H, m), 3.07 (2 H, br t, J=5.49 Hz), 4.08 (2 H, s), 4.18 (2 H, t, J=5.35 Hz), 4.66 (2 H, dt, J=47.80, 4.70 Hz), 7.63 (1 H, dd, J=8.51, 1.65 Hz), 7.75 (1 H, s), 8.00 (1 H, s), 8.02 (1 H, d, J=8.78 Hz), 8.48 (1 H, s), 9.05 (1 H, s), 10.42 (1 H, s); ESIMS found for C23H27FN6O mlz 423.2 (M+l).
Figure imgf000253_0002
1023
[01170] 4-Fluoro-N-(6-(5-(2-fluoroethyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-3- yl)isoquinolin-3 -yl)-l -isobutylpiperidine-4-carboxamide 1023.
[01171] White amorphous solid (48.8 mg, 0.098 mmol, 88.2% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 0.88 (6 H, d, J=6.59 Hz), 1.79 (1 H, dt, J=13.52, 6.83 Hz), 1.95 (2 H, br t, J=11.66 Hz), 2.06 - 2.22 (4 H, m), 2.09 (2 H, d, J=7.68 Hz), 2.78 (2 H, br d, J=7.96 Hz), 2.99 (2 H, dt, J=28.60, 4.95 Hz), 3.08 (2 H, t, J=5.49 Hz), 4.09 (2 H, s), 4.18 (2 H, t, J=5.49 Hz), 4.66 (2 H, dt, J=47.85, 4.95 Hz), 7.70 (1 H, dd, J=8.51, 1.65 Hz), 7.84 (1 H, s), 8.01 (1 H, s), 8.08 (1 H, d, J=8.78 Hz), 8.45 (1 H, s), 9.11 (1 H, s), 9.86 (1 H, d, J=4.39 Hz); ESIMS found for CZVHMFZNSO mlz 497.3 (M+l).
Figure imgf000254_0001
1024
[01172] N-(6-(5-(2-Fluoroethyl)-4,5,6,7-tetrahydropyrazolo[ l,5-a]pyrazin-3-yl) isoquinolin-3-yl)-2-(4-methylpiperazin-l -yl)acetamide 1024.
[01173] Orange solid (3.0 mg, 0.007 mmol, 4.5% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 2.19 (3 H, s), 2.40 (4 H, br s), 2.58 (4 H, br s), 2.99 (2 H, dt, J=28.60, 4.95 Hz), 3.07 (2 H, t, J=5.49 Hz), 3.22 (2 H, s), 4.09 (2 H, s), 4.18 (2 H, t, J=5.35 Hz), 4.66 (2 H, dt, J=47.80, 4.95 Hz), 7.66 (1 H, dd, J=8.51, 1.65 Hz), 7.82 (1 H, s), 8.01 ( 1 H, s), 8.05 (1 H, d, J=8.51 Hz), 8.47 ( 1 H, s), 9.07 (1 H, s), 9.94 ( 1 H, s); ESIMS found for C24H3oFN70 mlz 452.2 (M+l).
Figure imgf000254_0002
[01174] fert-Butyl (6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)carbamate 1025.
[01175] White solid (96.0 mg, 0.296 mmol, 28.1% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.51 (9 H, s), 3.90 (3 H, s), 7.71 (1 H, dd, J=8.51, 1.65 Hz), 7.97 (1 H, d, J=8.51 Hz), 8.04 ( 1 H, s), 8.07 ( 1 H, s), 8.10 (1 H, s), 8.33 (1 H, s), 8.97 (1 H, s), 9.78 (1 H, s); ESIMS found for C18H20N4O2 mlz 325.2 (M+ l).
Figure imgf000254_0003
1026
[01176] N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)but-2-ynamide 1026.
[01177] Yellow solid (3.7 mg, 0.013 mmol, 2.8% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 2.05 (3 H, s), 3.90 (3 H, s), 7.78 (1 H, dd, J=8.78, 1.65 Hz), 8.01 (1 H, d, J=8.78 Hz), 8.08 (1 H, s), 8.09 (1 H, s), 8.34 (2 H, s), 9.03 (1 H, s), 1 1.06 (1 H, br s); ESIMS found for C17H14N4O mlz 290.9 (M+ l).
Figure imgf000255_0001
1027
[01178] N-(7-Chloro-6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-l - methylpiperidine -4 -carboxamide 1027.
[01179] White solid (2.0 mg, 0.005 mmol, 1.3% yield). ¾ NMR (499 MHz, DMSO- 6) 5 ppm 1.61 - 1.72 (2 H, m), 1.73 - 1.80 (2 H, m), 1.83 - 1.90 (2 H, m), 2.16 (3 H, s), 2.45 - 2.49 ( 1 H, m), 2.81 (2 H, br d, J=l 1.25 Hz), 3.93 (3 H, s), 7.97 (1 H, s), 8.09 (1 H, s), 8.25 (1 H, s), 8.30 ( 1 H, s), 8.48 ( 1 H, s), 9.08 (1 H, s), 10.56 (1 H, s); ESIMS found for C2oH22ClN50 mlz 384.2 (M+ l).
Figure imgf000255_0002
1028
[01180] N-(6-(2-Methyloxazol-5-yl)isoquinolin-3-yl)-2-(piperidin-l -yl)acetamide
1028.
[01181] Off-white solid (57.0 mg, 0.163 mmol, 32.5% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.43 (2 H, br d, J=5.21 Hz), 1.58 (4 H, quin, J=5.56 Hz), 2.52 (4 H, br s), 2.53 (3 H, s), 3.18 (2 H, s), 7.80 (1 H, s), 7.83 (1 H, dd, J=8.51, 1.65 Hz), 8.12 (1 H, d, J=8.78 Hz), 8.16 ( 1 H, s), 8.50 ( 1 H, s), 9.12 (1 H, s), 9.98 (1 H, s); ESIMS found for C20H22N4O2 mlz 351.15 (M+l).
Figure imgf000255_0003
1029
[01182] 2-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-(6-(5-methyl-l,3,4-thiadiazol-2- yl)isoquinolin-3-yl)acetamide 1029.
[01183] Beige solid (200.0 mg, 0.506 mmol, 56.0% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.80 - 1.88 (2 H, m), 2.00 - 2.06 (2 H, m), 2.48 (2 H, br s), 2.67 (2 H, br d, J=10.98 Hz), 2.83 (3 H, s), 3.20 (2 H, s), 4.27 (2 H, br d, J=1.92 Hz), 8.12 ( 1 H, dd, J=8.51, 1.65 Hz), 8.20 ( 1 H, d, J=8.78 Hz), 8.51 (1 H, s), 8.61 (1 H, s), 9.24 (1 H, s), 10.09 (1 H, s) ; ESIMS found for C2oH2iN502S mlz 396.15 (M+l).
Figure imgf000256_0001
1030
[01184] (R)-2-(2-Methylpyrrolidin-l-yl)-N-(6-(5,6,7,8-tetrahydroimidazo[l,2-a] pyrazin-3 -yl)isoquinolin-3 -yl)acetamide 1030.
[01185] White solid (25.2 mg, 0.065 mmol, 36.0% yield). ¾NMR (499 MHz, DMSO- d6) δ ρρηι 1.09 (3 H, d, J=6.04 Hz), 1.42 (1 H, dddd, J=12.18, 10.26, 8.30, 6.59 Hz), 1.67 - 1.85 (2 H, m), 1.90 - 2.02 (1 H, m), 2.41 (1 H, q, J=8.51 Hz), 2.57 - 2.67 (1 H, m), 3.08 (2 H, br t, J=5.21 Hz), 3.13 - 3.20 (2 H, m), 3.54 (1 H, d, J=16.19 Hz), 3.95 (2 H, s), 4.12 (2 H, t, J=5.21 Hz), 7.30 (1 H, s), 7.68 (1 H, dd, J=8.51, 1.65 Hz), 7.99 (1 H, s), 8.08 (1 H, d, J=8.51 Hz), 8.51 (1 H, s), 9.10 (1 H, s), 9.93 (1 H, s); ESIMS found for C22H26N60 mlz 391.2 (M+1).
Figure imgf000256_0002
1031
[01186] 2-(Cyclobutyl(methyl)amino)-N-(6-(5,6,7,8-tetrahydroimidazo[l,2-a] pyrazin-3 -yl)isoquinolin-3 -yl)acetamide 1031.
[01187] Light olive-colored gum (43.2 mg, 0.111 mmol, 46.4% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.54 - 1.71 (2 H, m), 1.80 - 1.93 (2 H, m), 1.96 - 2.07 (2 H, m), 2.23 (3 H, s), 3.12 (1 H, br d, J=14.27 Hz), 3.06 - 3.09 (2 H, m), 3.12 (2 H, s), 3.95 (2 H, s), 4.12 (2 H, t, J=5.21 Hz), 7.30 (1 H, s), 7.68 (1 H, dd, J=8.51, 1.65 Hz), 7.99 (1 H, s), 8.08 (1 H, d, J=8.51 Hz), 8.51 (1 H, s), 9.11 (1 H, s), 9.96 (1 H, s); ESIMS found for C22H26N60 mlz 391.2 (M+1).
Figure imgf000256_0003
1032
[01188] trans-4-((6-( 1 -Methyl-lH-pyrazol-4-yl)isoquinolin-3 -yl)carbamoyl) cyclohexane-l-carboxylic acid 1032.
[01189] Beige solid (135.0 mg, 0.357 mmol, 70.0% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.29 - 1.40 (2 H, m), 1.49 (2 H, qd, J=12.76, 3.16 Hz), 1.85 - 1.94 (2 H, m), 1.97 (2 H, br dd, J=13.45, 2.74 Hz), 2.22 (1 H, tt, J=12.18, 3.60 Hz), 2.51 - 2.58 (1 H, m), 3.90 (3 H, s), 7.74 (1 H, dd, J=8.51, 1.65 Hz), 8.00 (1 H, d, J=8.51 Hz), 8.03 (1 H, s), 8.08 (1 H, s), 8.35 (1 H, s), 8.42 (1 H, s), 9.02 (1 H, s), 10.43 (1 H, s), 12.07 (1 H, br s); ESIMS found for C2iH22N403 mlz 379.1 (M+l).
Figure imgf000257_0001
1034
[01190] N-(6-(l-Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-3- morpholinopropanamide 1034.
[01191] White solid (12.0 mg, 0.033 mmol, 12.0% yield). ¾NMR (499 MHz, DMSO- d6) δ ppm 2.44 (4 H, br s), 2.57 - 2.63 (2 H, m), 2.63 - 2.70 (2 H, m), 3.59 (4 H, t, J=4.67 Hz), 3.90 (3 H, s), 7.75 (1 H, dd, J=8.51, 1.65 Hz), 8.00 (1 H, d, J=8.51 Hz), 8.06 (1 H, s), 8.09 (1 H, s), 8.36 (1 H, s), 8.44 (1 H, s), 9.03 (1 H, s), 10.74 (1 H, s); ESIMS found for CztJfeNsOz mlz 366.2 (M+l).
Figure imgf000257_0002
[01192] tra«5-N-(6-(l-Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-3- morpholinocyclobutane - 1 -carboxamide 1035.
[01193] White solid (18.0 mg, 0.075 mmol, 23.92% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 2.07 - 2.16 (2 H, m), 2.22 - 2.32 (6 H, m), 2.85 - 2.95 (1 H, m), 3.22 - 3.30 (1 H, m), 3.59 (4 H, t, J=4.39 Hz), 3.91 (3 H, s), 7.74 (1 H, dd, J=8.51, 1.65 Hz), 8.00 (1 H, d, J=8.51 Hz), 8.04 (1 H, s), 8.08 (1 H, s), 8.35 (1 H, s), 8.47 (1 H, s), 9.01 (1 H, s), 10.41 (1 H, s); ESIMS found for C22H25N502 mlz 392. (M+l).
Figure imgf000257_0003
1040
[01194] N-(6-(2-(Methylamino)thiazol-5-yl)isoquinolin-3-yl)piperidine-4- carboxamide 1040. [01195] Beige solid (80.0 mg, 0.218 mmol, 91.1%yield). ¾NMR(499 MHz, DMSO- 6)5ppm 1.46- 1.60 (2H,m), 1.66- 1.74 (2H, m), 2.43 -2.49 (2 H, m), 2.59 - 2.68 (1 H, m), 2.89 (3 H, d, J=4.94 Hz), 2.93 - 3.01 (2 H, m), 7.69 (1 H, s), 7.70 - 7.74 (1 H, m), 7.78 (1 H, s), 7.90 - 7.98 (2 H, m), 8.40 (1 H, s), 8.99 (1 H, s), 10.40 (1 H, s); ESIMS found for Ci9H2iN5OS mlz 368.15 (M+l).
Figure imgf000258_0001
[01196] 1 -Methyl -N-(6 -(2-(methylamino)thiazol -5 -yl)isoquinolin-3 -yl)piperidine -4 - carboxamide 1041.
[01197] Yellow solid (32.0 mg, 0.084 mmol, 77.1% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.60 - 1.72 (2 H, m), 1.73 - 1.80 (2 H, m), 1.86 (2 H, td, J=l 1.60, 2.06 Hz), 2.16 (3 H, s), 2.44 - 2.49 (1 H, m), 2.77 - 2.85 (2 H, m), 2.89 (3 H, d, J=4.94 Hz), 7.69 (1 H, s), 7.72 (1 H, dd, J=8.64, 1.78 Hz), 7.77 (1 H, s), 7.89 - 7.97 (2 H, m), 8.40 (1 H, s), 8.99 (1 H, s), 10.45 (1 H, s); ESIMS found for C2oH2
Figure imgf000258_0002
[01198] N-(6-(2-(Diethylamino)thiazol-5-yl)isoquinolin-3-yl)-2-(4-fluoropiperidin-l- yl)acetamide 1047.
[01199] Yellow solid (22.0 mg, 0.050 mmol, 26.7% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.21 (6 H, t, J=7.14 Hz), 1.73 - 1.85 (2 H, m), 1.86 - 1.99 (2 H, m), 2.52 - 2.58 (2 H, m), 2.66 - 2.75 (2 H, m), 3.24 (2 H, s), 3.52 (4 H, q, J=7.14 Hz), 4.66 - 4.83 (1 H, m), 7.74 (1 H, dd,J=8.51, 1.65 Hz), 7.79 (1 H, s), 7.86 (1 H, s), 7.98 (1 H, d,J=8.51 Hz), 8.40 (1 H, s), 9.01 (1 H, s), 9.97 (1 H, s); ESIM mlz 442.2 (M+l).
Figure imgf000258_0003
1048
[01200] N-(6-(2-(Diethylamino)thiazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperazin- l-yl)acetamide 1048.
[01201] Beige solid (25.0 mg, 0.057 mmol, 30.5% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.21 (6 H, t, J=7.00 Hz), 2.19 (3 H, s), 2.40 (4 H, br s), 2.58 (4 H, br s), 3.21 (2 H, s), 3.52 (4 H, q, J=7.14 Hz), 7.74 ( 1 H, dd, J=8.64, 1.78 Hz), 7.79 (1 H, s), 7.86 ( 1 H, s), 7.98 (1 H, d, J=8.51 Hz), 8.39 (1 H, s), 9.01 (1 H, s), 9.92 (1 H, s); ESIMS found for C23H3oN6OS mlz 439.2 (M+ l).
Figure imgf000259_0001
1049
[01202] N-(6-(5-Methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-( l,4-oxazepan-4-yl) acetamide 1049.
[01203] Beige solid (74.0 mg, 0.193 mmol, 35.1% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.87 (2 H, quin, J=5.83 Hz), 2.83 (3 H, s), 2.83 - 2.86 (4 H, m), 3.43 (2 H, s), 3.66 - 3.70 (2 H, m), 3.74 (2 H, t, J=6.04 Hz), 8.12 (1 H, dd, J=8.51, 1.65 Hz), 8.21 ( 1 H, d, J=8.51 Hz), 8.51 ( 1 H, d, J=0.82 Hz), 8.62 (1 H, s), 9.23 (1 H, s), 10.15 (1 H, s); ESIMS found for Ci9H2iN502S mlz 384.15 (M+l).
Figure imgf000259_0002
1051
[01204] N-(6-(5-Methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2- mo holinoacetamide-2,2-< 2 1051.
[01205] White solid (20.0 mg, 0.054 mmol, 32.5% yield). 'HNMR (499 MHz, DMSO- d6) δ ppm 2.55 - 2.61 (4 H, m), 2.83 (3 H, s), 3.62 - 3.69 (4 H, m), 8.12 (1 H, dd, J=8.64, 1.78 Hz), 8.21 (1 H, d, J=8.51 Hz), 8.51 ( 1 H, s), 8.62 ( 1 H, s), 9.23 (1 H, s), 10.18 (1 H, d, J=3.02 Hz); ESIMS found for Ci8Hi7[2H2]N502S mlz 372.1 (M+l).
Figure imgf000260_0001
1052
[01206] Ν-(6-(5-ΜεΛγ1-1,3,4 ωαάίαζο1-2-γ1)ί8ο ηίηο1ίη-3-γ1)-2-(ηιοφ1ιο1ίηο-£/8) acetamide 1052.
[01207] Off-white solid (22.0 mg, 0.058 mmol, 7.2% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 2.83 (3 H, s), 3.26 (2 H, s), 8.12 (1 H, dd, J=8.51, 1.65 Hz), 8.21 ( 1 H, d, J=8.51 Hz), 8.51 (1 H, s), 8.62 ( 1 H, s), 9.23 (1 H, s), 10.17 (1 H, s); ESIMS found for Ci8Hii[2H8]N502S mlz 378.2 (M+1).
Figure imgf000260_0002
1057
[01208] l-(2,2-Difluoropropyl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)piperidine-4- carboxamide 1057.
[01209] White solid (22.5 mg, 0.056 mmol, 22.8% yield). 'HNMR (499 MHz, DMSO- d6) δ ppm 1.63 (3 H, t, J=19.07 Hz), 1.67 - 1.74 (2 H, m), 1.75 - 1.81 (2 H, m), 2.22 (2 H, td, J=1 1.60, 2.06 Hz), 2.52 - 2.60 ( 1 H, m), 2.71 (2 H, t, J=14.13 Hz), 2.95 (2 H, br d, J=1 1.53 Hz), 7.87 (1 H, dd, J=8.51, 1.65 Hz), 7.95 (1 H, s), 8.13 (1 H, d, J=8.51 Hz), 8.20 ( 1 H, s), 8.54 ( 1 H, s), 8.58 (1 H, s), 9.13 (1 H, s), 10.58 ( 1 H, s); ESIMS found for C21H22F2N4O2 mlz 401.2 (M+1).
Figure imgf000260_0003
1061
[01210] tra«5-N-(6-(2-Methyloxazol-5-yl)isoquinolin-3-yl)-3- morpholinocyclobutane - 1 -carboxamide 1061.
[01211] Grey solid (15.0 mg, 0.038 mmol, 19.9% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 2.07 - 2.16 (2 H, m), 2.22 - 2.32 (6 H, m), 2.54 (3 H, s), 2.90 (1 H, quin, J=7.14 Hz), 3.23 - 3.30 ( 1 H, m), 3.59 (4 H, t, J=4.39 Hz), 7.79 ( 1 H, s), 7.80 - 7.83 ( 1 H, m), 8.07 - 8.13 (2 H, m), 8.54 (1 H, s), 9.10 (1 H, s), 10.50 (1 H, s); ESIMS found for C22H24N403 mlz 393.2 (M+1).
Figure imgf000261_0001
1067
[01212] Ν-(6-(2-Μεΐ1ιγ1οχαζο1-5-γ1)ί8ο ηίηο1ίη-3-γ1)-2-ηιοφ1ιο1ίηοαοεΐαηιίάε 1067.
[01213] Off-white solid (41.0 mg, 0.116 mmol, 40.7% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 2.53 (3 H, s), 2.55 - 2.60 (4 H, m), 3.25 (2 H, s), 3.62 - 3.69 (4 H, m), 7.80 (1 H, s), 7.83 (1 H, dd, J=8.51, 1.65 Hz), 8.12 (1 H, d, J=8.78 Hz), 8.16 (1 H, s), 8.51 (1 H, s), 9.12 (1 H, s), 10.08 (1 H, s); ESIMS found for Ci9H2oN403 mlz 353.15 (M+1).
Figure imgf000261_0002
1068
N-(6-(2-Methyloxazol-5-yl)isoquinolin-3-yl)-3-moφholinopropanamide
1068.
[01215] Beige solid (21.0 mg, 0.057 mmol, 20.9% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 2.44 (4 H, br s), 2.53 (3 H, s), 2.57 - 2.64 (2 H, m), 2.64 - 2.71 (2 H, m), 3.59 (4 H, t, J=4.53 Hz), 7.79 (1 H, s), 7.81 (1 H, dd, J=8.51, 1.65 Hz), 8.10 (1 H, d, J=8.51 Hz), 8.12 (1 H, s), 8.50 (1 H, s), 9.11 (1 H, s), 10.82 (1 H, s); ESIMS found for C2oH22N403 mlz 367.15 (M+1).
Figure imgf000261_0003
1070
[01216] l-(2-Hydroxy-2-methylpropyl)-N-(6-(l-methyl-lH-l,2,3-triazol-4-yl) isoquinolin-3-yl)piperidine-4-carboxamide 1070.
[01217] White solid (26.0 mg, 0.064 mmol, 22.5% yield). 'HNMR (499 MHz, DMSO- 6) 5 ppm 0.86 (6 H, d, J=6.59 Hz), 1.62 - 1.73 (2 H, m), 1.74 - 1.81 (2 H, m), 1.83 - 1.92 (2 H, m), 2.02 (2 H, d, J=7.41 Hz), 2.52 - 2.59 (1 H, m), 2.87 (2 H, br d, J=11.53 Hz), 4.09 (1 H, s), 4.14 (3 H, s), 8.01 (1 H, dd, J=8.51, 1.37 Hz), 8.11 (1 H, d, J=8.51 Hz), 8.28 (1 H, s), 8.51 (1 H, s), 8.73 (1 H, s), 9.11 (1 H, s), 10.52 (1 H, s); ESIMS found for C22H28N6O2 mlz 409.2 (M+1).
Figure imgf000261_0004
1071
[01218] N-(6-(l -Methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)quinuclidine-4- carboxamide 1071.
[01219] Beige solid (27.0 mg, 0.075 mmol, 53.8% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.72 - 1.81 (6 H, m), 2.74 - 2.83 (6 H, m), 3.90 (3 H, s), 7.75 (1 H, dd, J=8.51, 1.65 Hz), 8.01 (1 H, d, J=8.51 Hz), 8.04 ( 1 H, s), 8.07 (1 H, d, J=0.82 Hz), 8.35 ( 1 H, s), 8.41 (1 H, s), 9.04 ( 1 H, s), 9.59 ( 1 H, s); ESIMS found for C2iH23N50 mlz 362.2 (M+l).
Figure imgf000262_0001
1077
[01220] 2-(4-Methoxypiperidin-l-yl)-N-(6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3- yl)acetamide 1077.
[01221] Off-white solid (79.0 mg, 0.208 mmol, 41.6% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.48 - 1.57 (2 H, m), 1.83 - 1.93 (2 H, m), 2.32 - 2.41 (2 H, m), 2.73 - 2.82 (2 H, m), 3.18 - 3.27 ( 1 H, m), 3.20 (2 H, s), 3.24 (3 H, s), 3.90 (3 H, s), 7.77 (1 H, dd, J=8.51, 1.65 Hz), 8.02 (1 H, d, J=8.78 Hz), 8.10 (2 H, s), 8.37 ( 1 H, s), 8.43 (1 H, s), 9.04 (1 H, s), 9.94 ( 1 H, s) ; ESIMS found for C2iH25N502 mlz 380.2 (M+l).
Figure imgf000262_0002
1078
[01222] 2-(4-Hydroxypiperidin-l -yl)-N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3- yl)acetamide 1078.
[01223] Off-white solid (84.0 mg, 0.230 mmol, 46.0% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.49 (2 H, dtd, J=12.66, 9.52, 9.52, 3.70 Hz), 1.73 - 1.82 (2 H, m), 2.28 - 2.35 (2 H, m), 2.76 - 2.83 (2 H, m), 3.19 (2 H, s), 3.47 - 3.56 (1 H, m), 3.90 (3 H, s), 4.60 (1 H, d, J=4.12 Hz), 7.77 (1 H, dd, J=8.51, 1.65 Hz), 8.02 (1 H, d, J=8.51 Hz), 8.10 (2 H, s), 8.37 (1 H, s), 8.43 (1 H, s), 9.04 (1 H, s), 9.93 ( 1 H, s); ESIMS found for C2oH23N502 mlz 366.2 (M+l).
Figure imgf000262_0003
1079 [01224] l-Isobutyl-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)azepane-4- carboxamide 1079.
[01225] Beige solid (12.0 mg, 0.030 mmol, 14.8% yield). ¾NMR(499 MHz, DMSO- 6)5ppm0.86 (3 H, d, J=2.20 Hz), 0.88 (3 H, d,J=2.20Hz), 1.53 - 1.62 (1 H, m), 1.64 - 1.82 (4 H, m), 1.82 - 1.93 (2 H, m), 2.13 - 2.25 (2 H, m), 2.54 - 2.62 (3 H, m), 2.66 - 2.74 (1 H, m), 2.80 - 2.89 (1 H, m), 3.90 (3 H, s), 7.74 (1 H, dd, J=8.51, 1.37 Hz), 7.99 (1 H, d, J=8.51 Hz), 8.02 (1 H, s), 8.07 (1 H, s), 8.35 (1 H, s), 8.42 (1 H, s), 9.02 (1 H, s), 10.42 (1 H, s); ESIMS found for C24H3iN50 mlz 406.25 (M+l).
Figure imgf000263_0001
1080
[01226] l-Methyl-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)azepane-4- carboxamide 1080.
[01227] White solid (11.0 mg, 0.030 mmol, 15.1%yield). 'HNMR (499 MHz, DMSO- 6)5ppm 1.56 - 1.66(1 H, m), 1.71 - 1.82 (2 H, m), 1.82 - 1.93 (3 H, m), 2.27 (3 H, s), 2.45 -2.58 (3 H, m), 2.62 - 2.72 (1 H, m), 2.81 - 2.90 (1 H, m), 3.90 (3 H, s), 7.74 (1 H, dd, J=8.37, 1.51 Hz), 7.99 (1 H, d, J=8.51 Hz), 8.03 (1 H, s), 8.08 (1 H, s), 8.35 (1 H, s), 8.42 (1 H, s), 9.02 (1 H, s), 10.43 (1 H, s); ESIMS found for C2iH25N50 mlz 364.2 (M+l).
Figure imgf000263_0002
1081
[01228] tra«s-4-(Dimethylamino)-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 - yl)cyclohexane-l -carboxamide 1081.
[01229] Beige solid (5.0 mg, 0.013 mmol, 7.7% yield). ¾ NMR (499 MHz, DMSO- 6)5ppm 1.13 - 1.22 (2H,m), 1.43 - 1.54 (2 H, m), 1.84- 1.96 (4 H, m), 2.11 -2.20 (1 H, m),2.18 (6 H, s), 2.42 - 2.49 (1 H, m), 3.90 (3 H, s), 7.74 (1 H, dd, J=8.51, 1.65 Hz), 7.99 (1 H, d, J=8.51 Hz), 8.02 (1 H, s), 8.07 (1 H, d, J=0.82 Hz), 8.35 (1 H, s), 8.42 (1 H, s), 9.02 (1 H, s), 10.41 (1 H, s); ESIMS found for C22H27N50 mlz 378.2 (M+l).
Figure imgf000264_0001
1082
[01230] tra«5-4-(Dimethylamino)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl) cyclohexane - 1 -carboxamide 1082.
[01231] Brown solid (3.0 mg, 0.008 mmol, 4.6% yield). ¾ NMR (499 MHz, METHANOLS) δ ppm 1.35 - 1.46 (2 H, m), 1.60 - 1.72 (2 H, m), 2.04 - 2.12 (4 H, m), 2.37 (6 H, s), 2.39 - 2.44 ( 1 H, m), 2.44 - 2.53 ( 1 H, m), 2.58 (3 H, s), 7.61 (1 H, s), 7.80 (1 H, dd, J=8.51, 1.65 Hz), 8.03 (1 H, d, J=8.51 Hz), 8.10 ( 1 H, s), 8.48 (1 H, s), 9.01 (1 H, s); ESIMS found for C22H26N4O2 mlz 379.2 (M+l).
Figure imgf000264_0002
1083
[01232] 3-(Hydroxymethyl)-N-(6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl) bicyclo[l .1. l]pentane-l-carboxamide 1083.
[01233] White solid (310.4 mg, 0.891 mmol, 96.0% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.97 (6 H, s), 3.41 (2 H, d, J=5.76 Hz), 3.90 (3 H, s), 4.56 (1 H, t, J=5.49 Hz), 7.76 (1 H, dd, J=8.51, 1.65 Hz), 8.02 ( 1 H, d, J=8.51 Hz), 8.04 (1 H, s), 8.09 (1 H, d, J=0.82 Hz), 8.37 ( 1 H, s), 8.40 ( 1 H, s), 9.05 (1 H, s), 10.13 ( 1 H, s); ESIMS found for C20H20N4O2 mlz 349.2 (M+ l).
Figure imgf000264_0003
1084
[01234] Methyl tra«5-4-((6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl) cyclohexane -1 -carboxylate 1084.
[01235] Light yellow solid (350.0 mg, 0.892 mmol, 40.0% yield). ¾ NMR (499 MHz, METHANOLS) δ ppm 1.47 - 1.58 (2 H, m), 1.64 (2 H, qd, J=12.76, 2.88 Hz), 2.04 (2 H, br dd, J=13.31, 2.88 Hz), 2.09 (2 H, br dd, J=13.31, 3.16 Hz), 2.39 (1 H, tt, J=12.08, 3.57 Hz), 2.51 ( 1 H, tt, J=1 1.87, 3.36 Hz), 3.68 (3 H, s), 3.96 (3 H, s), 7.73 (1 H, dd, J=8.51, 1.65 Hz), 7.93 - 7.99 (2 H, m), 8.00 (1 H, s), 8.16 (1 H, s), 8.40 (1 H, s), 8.94 (1 H, s); ESIMS found for C22H24N403 mlz 393.2 (M+l).
Figure imgf000265_0001
1085
[01236] N-(6-(l-Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl-l- )piperidine-4- carboxamide 1085.
[01237] Off-white solid (105.0 mg, 0.312 mmol, 81.1% yield). ¾ NMR (500 MHz, DMSO- 6)5ppm 1.53 (2H, qd,J=12.12, 3.98 Hz), 1.70 (2H, brdd,J=12.21, 1.78 Hz), 2.44 - 2.49 (2 H, m), 2.64 (1 H, tt, J=l 1.60, 3.64 Hz), 2.94 - 3.01 (2 H, m), 3.90 (3 H, s), 7.74 (1 H, dd, J=8.51, 1.65 Hz), 8.00 (1 H, d,J=8.51 Hz), 8.03 (1 H, d,J=1.37Hz), 8.08 (1 H, d,J=0.82Hz), 8.35 (1 H, s), 8.44 (1 H, s), 10.40 (1 H, s); ESIMS found for Ci9H2o[2H]N50 mlz 337.2 (M+l).
Figure imgf000265_0002
1086
[01238] N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin-3-yl)-l-(2-(methyl-£/3)propyl- 1,1,2,3,3,3 -£¾;)piperidine -4-carboxamide 1086.
[01239] Beige solid (160.0 mg, 0.399 mmol, 67.0% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 1.61 - 1.73 (2 H, m), 1.74 - 1.80 (2 H, m), 1.86 (2 H, td, J=l 1.66, 2.20 Hz), 2.51 - 2.58 (1 H, m), 2.86 (2 H, br d, J=11.25 Hz), 3.90 (3 H, s), 7.74 (1 H, dd, J=8.51, 1.65 Hz), 7.99 (1 H, d, .7=8.51 Hz), 8.04 (1 H, s), 8.08 (1 H, s), 8.35 (1 H, s), 8.44 (1 H, s), 9.02 (1 H, s), 10.45 (1 H, s); ESIMS found for C23H2o[2
Figure imgf000265_0003
1087
[01240] l-Isobutyl-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl-l-£/)piperidine- 4-carboxamide 1087.
[01241] White solid (75.0 mg, 0.191 mmol, 64.3%yield). ¾NMR(499 MHz, DMSO- 6)5ppm0.86(6H, d,J=6.59Hz), 1.63 - 1.73 (2H, m), 1.74 - 1.80(3 H, m), 1.83 - 1.90 (2H, m), 2.02 (2 H, d, J=7.41 Hz), 2.51 - 2.57 (1 H, m), 2.86 (2 H, br d, J=11.25 Hz), 3.90 (3 H, s), 7.74 (1 H, dd, J=8.51, 1.65 Hz), 8.00 (1 H, d, J=8.51 Hz), 8.04 ( 1 H, d, J=1.37 Hz), 8.08 ( 1 H, s), 8.35 (1 H, s), 8.44 (1 H, s), 10.45 (1 H, s); ESIMS found for C23H28[2H]N50 mlz 393.25 (M+l).
Figure imgf000266_0001
1088
[01242] N-(6-(l -Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-3-((4-methylpiperazin-l- yl)methyl)bicyclo [ 1.1.1] pentane - 1 -carboxamide 1088.
[01243] Light brown amorphous solid ( 13.9 mg, 0.032 mmol, 30.2% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 2.04 (6 H, s), 2.14 (3 H, s), 2.31 (4 H, br d, J=1.92 Hz), 2.36 - 2.46 (4 H, m), 2.38 (2 H, s), 3.90 (3 H, s), 7.76 (1 H, dd, J=8.51, 1.65 Hz), 8.01 ( 1 H, d, J=8.51 Hz), 8.04 ( 1 H, s), 8.09 (1 H, s), 8.36 ( 1 H, s), 8.39 (1 H, s), 9.04 ( 1 H, s), 10.13 (1 H, s); ESIMS found for C25H3oN60 mlz 431.25 (M+l).
Figure imgf000266_0002
1090
[01244] 1 -(6-( 1 -Methyl-lH-pyrazol-4-yl)isoquinolin-3 -yl)-3-( 1 -methylpiperidin-4- yl)urea 1090.
[01245] Beige solid (35.0 mg, 0.096 mmol, 87.3% yield). ¾ NMR (499 MHz, DMSO- d6) δ ppm 1.35 - 1.49 (2 H, m), 1.77 - 1.88 (2 H, m), 1.98 - 2.09 (2 H, m), 2.17 (3 H, s), 2.63 (2 H, ddd, J=5.35, 3.43, 1.65 Hz), 3.54 (1 H, br dd, J=4.12, 1.65 Hz), 3.90 (3 H, s), 7.15 - 7.24 ( 1 H, m), 7.65 ( 1 H, dd, J=8.51, 1.65 Hz), 7.93 (3 H, d, J=8.51 Hz), 8.07 (1 H, s), 8.34 (1 H, s), 8.88 - 8.96 (2 H, m); ESIMS found for +l).
Figure imgf000266_0003
1091
[01246] fr «5-N-(6-(l -Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-4-(4- methylpiperazine - 1 -carbonyl)cyclohexane - 1 -carboxamide 1091.
[01247] Beige solid (80.0 mg, 0.174 mmol, 50.6% yield). ¾ NMR (499 MHz, DMSO- 6) 5 ppm 1.35 - 1.47 (2 H, m), 1.57 (2 H, qd, J=12.76, 2.88 Hz), 1.69 - 1.75 (2 H, m), 1.84 - 1.93 (2 H, m), 2.18 (3 H, s), 2.23 (2 H, br s), 2.30 (2 H, br s), 2.51 - 2.60 (1 H, m), 2.64 (1 H, tt, J=\ 1.73, 3.22 Hz), 3.44 (2 H, br s), 3.50 (2 H, br s), 3.90 (3 H, s), 7.74 (1 H, dd, J=8.51, 1.65 Hz), 7.99 (1 H, d, J=8.51 Hz), 8.04 (1 H, s), 8.08 (1 H, s), 8.35 (1 H, s), 8.43 (1 H, s), 9.02 (1 H, s), 10.43 (1 H, s); ESIMS found for CzeH^NeOz mlz 461.3 (M+l).
Figure imgf000267_0001
1092
[01248] 1 -Isobutyl-N-(6-( 1 -methyl- lH-tetrazol-5 -yl)isoquinolin-3-yl)piperidine-4- carboxamide 1092. N-(6-( 1 -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl- 1 - )-2-(pyrrolidin- 1 - yl)acetamide
[01249] Off-white solid (18.0 mg, 0.046 mmol, 7.1% yield). ¾ NMR (499 MHz, DMSO- e) δ ppm 0.86 (6 H, d, J=6.59 Hz), 1.61 - 1.72 (2 H, m), 1.74 - 1.82 (3 H, m), 1.82 - 1.94 (2 H, m), 2.02 (2 H, d, J=7.41 Hz), 2.52 - 2.61 (1 H, m), 2.87 (2 H, br d, J=11.53 Hz), 4.29 (3 H, s), 7.92 (1 H, dd, J=8.51, 1.65 Hz), 8.26 (1 H, d, J=8.51 Hz), 8.44 (1 H, s), 8.67 (1 H, s), 9.27 (1 H, s), 10.67 (1 H, s); ESIMS found for C21H27N7O mlz 394.2 (M+l).
Figure imgf000267_0002
1093
[01250] N-(6-(l-Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl-l-£/)-2-(pyrrolidin-l-yl) acetamide 1093.
[01251] Beige solid (45.0 mg, 0.134 mmol, 44.6% yield). ¾ NMR (499 MHz, DMSO-i&) δ ppm 1.78 (4 H, dt, J=6.59, 3.29 Hz), 2.63 - 2.69 (4 H, m), 3.35 (2 H, s), 3.90 (3 H, s), 7.77 (1 H, dd, J=8.64, 1.51 Hz), 8.02 (1 H, d, J=8.51 Hz), 8.10 (2 H, s), 8.37 (1 H, s), 8.43 (1 H, s), 9.92 (1 H, s); ESIMS found for Ci9H2o[2H]N50 mlz 337.2 (M+l).
Example 13.
[01252] 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. [01253] 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 μg/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 μΜ) 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 backfill 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% CO2. Following incubation, 15 μΐ 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). For EC50 of >10 μΜ, the percent inhibition at 10 μΜ is provided.
[01254] Table 2 shows the measured activity for representative compounds of Formula I as described herein.
Table 2.
Figure imgf000268_0001
89 0.765 328 0.804 758 1 .253 1015 3.734
90 1 .100 329 1.173 760 3.970 1016 4.057
91 >10 330 0.449 767 3.225 1017 0.621
92 1 .600 331 2.988 773 6.549 1018 0.608
96 >10 332 0.662 784 5.885 1019 3.799
110 1 .100 333 0.384 785 2.837 1020 1 .142
111 0.743 334 0.787 791 0.212 1021 >10 (16.5%)
112 3.200 335 0.993 795 0.471 1022 1 .370
113 >10 336 0.395 798 0.594 1023 >10 (38.2%)
114 0.835 338 7.369 803 3.551 1024 3.510
115 2.400 340 0.932 822 0.517 1025 >10
116 7.100 341 4.097 826 0.603 1026 0.513
118 3.600 342 7.215 831 0.706 1027 0.875
119 1 .060 343 3.587 839 0.776 1028 3.870
120 2.205 344 5.468 851 >10 (6.4%) 1029 3.336
121 3.500 345 2.123 883 >10 (43.2%) 1030 >10 (44.8%)
188 >10 346 4.358 885 4.475 1031 3.969
248 >10 347 9.442 888 1 .038 1032 >10 (27.4%)
262 1 .700 348 >10 (36.9%) 900 1 .013 1034 2.040
263 1 .300 349 0.712 921 0.779 1035 1 .374
264 >10 350 1.005 932 0.946 1037 3.643
265 1 .243 351 2.521 939 2.072 1040 1 .211
266 2.441 352 2.958 946 1 .881 1041 0.776
267 1 .379 353 5.71 1 952 1 .469 1047 >10 (32.6%)
268 2.072 354 2.320 953 >10 (48.7%) 1048 9.381
269 3.624 355 3.512 959 4.235 1049 2.544
270 >10 358 0.413 960 1 .658 1051 0.480
271 1 .715 359 0.669 962 >10 (45.0%) 1052 2.285
272 3.753 360 0.690 963 1 .199 1057 >10 (5.0%)
273 1 .511 362 0.951 964 1 .449 1061 1 .614
274 3.720 363 2.359 965 3.175 1064 4.1 19
275 1 .917 364 >10 (24.1 %) 966 1 .592 1067 >10 (48.7%)
276 5.183 365 0.381 967 4.423 1068 3.718
277 5.264 366 0.334 968 >10 (38.0%) 1070 0.738
278 0.413 367 0.524 969 3.926 1071 >10 (43.2%)
279 5.650 368 0.689 970 1 .356 1073 >10 (5.9%)
280 2.325 369 0.743 971 0.720 1074 >10 (19.7%)
281 >10 (47.0%) 370 0.608 972 0.420 1075 2.542
282 >10 (49.3%) 371 0.643 973 0.609 1076 0.640
283 2.486 372 3.398 974 3.742 1077 5.189
284 1 .874 376 2.206 975 0.423 1078 4.033
285 3.405 433 0.191 976 2.965 1079 1 .429
286 3.143 441 1.214 977 0.875 1080 1 .218
287 7.330 443 0.397 978 2.223 1081 2.734
288 1 .197 448 0.289 979 4.093 1082 9.902
289 2.647 452 0.787 980 >10 (40.5%) 1083 8.209
290 5.231 468 0.363 981 1 .085 1084 3.407
291 4.641 470 1.184 982 2.709 1085 2.195
292 3.385 472 0.382 983 5.533 1086 0.485
293 3.222 475 0.701 984 2.987 1087 0.514
294 5.186 477 0.327 985 1 .160 1088 7.403
295 2.571 481 1.536 986 1 .380 1090 0.722
296 3.479 483 1.872 987 >10 (10.7%) 1091 2.949
297 4.811 487 0.446 988 >10 (11 .1 %) 1092 0.247
298 3.229 500 3.232 989 4.320 1093 1 .781
299 1 .529 513 6.428 990 2.865
300 1 .1 17 517 >10 (35.8%) 991 1 .705
301 0.467 521 1.805 992 3.209
Example 14.
[01255] Representative compounds were screened using the assay procedure DYRKIA kinase activity as described below. [01256] 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 μΜΐο 0.00016 μΜ) and compound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale, CA) into 1536-well black-walled round bottom plates (Corning).
[01257] 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.
[01258] Briefly, recombinant DYRK1A kinase, ATP and Ser/Thr peptide 18 were prepared in IX Kinase buffer to final concentrations of 0.19 μg/mL, 30 μΜ, and 4 μΜ 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.
[01259] 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).
[01260] 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 (F100% - 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).
[01261] Table 3 shows the measured activity for representative compounds of Formula I as described herein.
Table 3.
Figure imgf000270_0001
71 0.0136 310 0.0062 561 0.0015 1001 0.0073
72 0.0025 311 0.0019 579 0.0250 1002 0.0285
73 0.0017 312 0.0127 643 0.0018 1003 0.0021
75 0.0026 313 0.0025 699 0.0021 1004 0.0020
76 0.0023 314 0.0221 700 0.0022 1005 0.0015
77 0.0016 315 0.0123 704 0.0082 1006 0.0030
78 0.0047 316 0.0042 707 0.0009 1007 0.0024
81 0.0015 317 0.0370 711 0.0010 1008 0.0075
82 0.0009 318 0.0588 713 0.0031 1009 0.0062
83 0.0012 320 0.0099 718 0.0013 1010 0.0026
84 0.0013 324 0.0021 731 0.0014 1011 0.0026
85 0.0014 325 0.0021 737 0.0010 1012 0.0130
86 0.0025 326 0.0029 741 0.0009 1013 0.0171
87 0.0033 327 0.0017 743 0.0013 1014 0.0094
89 0.0027 328 0.0019 758 0.0243 1015 0.0058
90 0.0030 329 0.0027 760 0.0038 1016 0.0291
91 0.0105 330 0.0016 767 0.0043 1017 0.0031
92 0.0065 331 0.0018 773 0.0038 1018 0.0025
96 0.0071 332 0.0035 784 0.0108 1019 0.0289
110 0.0047 333 0.0012 785 0.0101 1020 0.0104
111 0.0039 334 0.0016 791 0.0022 1021 0.0422
112 0.0206 335 0.0038 795 0.0024 1022 0.0042
113 0.0241 336 0.0029 798 0.0031 1023 0.0087
114 0.0019 338 0.0062 803 0.0126 1024 0.0170
115 0.0034 340 0.0019 822 0.0041 1025 0.0780
116 0.0043 341 0.0056 826 0.0039 1026 0.0050
118 0.0096 342 0.0065 831 0.0032 1027 0.0500
119 0.0029 343 0.0099 839 0.0038 1028 0.0225
120 0.0048 344 0.0105 851 5.0052 1029 0.0257
121 0.0034 345 0.0040 883 0.0089 1030 0.1938
188 0.0286 346 0.0099 885 0.0346 1031 0.0704
248 0.0374 347 0.0104 888 0.0014 1032 0.0012
262 0.0015 348 0.0775 900 0.0029 1034 0.0019
263 0.0013 349 0.0065 921 0.0021 1035 0.0026
264 0.3476 350 0.0062 932 0.0169 1037 0.0102
265 0.0037 351 0.0136 939 0.0139 1040 0.0048
266 0.0174 352 0.0215 946 0.0230 1041 0.0033
267 0.0294 353 0.0086 952 0.0072 1047 0.4629
268 0.0058 354 0.0044 953 0.0168 1048 0.5407
269 0.0050 355 0.0064 959 0.0154 1049 0.0069
270 0.9524 358 0.0006 960 0.0171 1051 0.0146
271 0.0021 359 0.0030 962 0.0236 1052 0.0180
272 0.0140 360 0.0019 963 0.0267 1057 0.0027
273 0.0107 362 0.1319 964 0.0052 1061 0.0043
274 0.0059 363 0.0503 965 0.0106 1064 0.0067
275 0.0047 364 0.8403 966 0.0020 1067 0.0188
276 0.0051 365 0.0027 967 0.0019 1068 0.0053
277 0.0023 366 0.0106 968 0.0314 1070 0.0076
278 0.0032 367 0.01 11 969 0.0500 1071 0.0165
279 0.0078 368 0.0079 970 0.0023 1073 1.5241
280 0.0108 369 0.0028 971 0.0342 1074 0.0069
281 0.0081 370 0.0031 972 0.0030 1075 0.0137
282 0.01 15 371 0.0024 973 0.0029 1076 0.0084
283 0.0070 372 0.0106 974 0.0135 1077 0.0045
284 0.0071 376 0.0055 975 0.0120 1078 0.0060
285 0.0442 433 0.0019 976 0.0061 1079 0.0057
286 0.0649 441 0.0091 977 0.0032 1080 0.0032
287 5.1353 443 0.0022 978 0.0039 1081 0.0022
288 0.0273 448 0.0012 979 0.0100 1082 0.0102
289 0.0137 452 0.0004 980 0.0191 1083 0.0042
290 0.0058 468 0.0049 981 0.0137 1084 0.0017
291 0.0082 470 0.0027 982 0.0192 1085 0.0024
292 0.0078 472 0.0032 983 0.0223 1086 0.0025
293 0.0050 475 0.0032 984 0.0055 1087 0.0035
294 0.0124 477 0.0011 985 0.0041 1088 0.0093
295 0.0028 481 0.0043 986 0.0110 1090 0.0069 296 0.0143 483 0.01 13 987 0.0428 1091 0.0014
297 0.0237 487 0.0077 988 0.0249 1092 0.0627
298 0.0135 500 0.0106 989 0.0162 1093 0.01 17
299 0.0067 513 0.0104 990 0.0213
300 0.0082 517 0.0096 991 0.0033
301 0.0020 521 0.0016 992 0.0253
Example 15.
[01262] Representative compounds were screened using the assay procedure for GSK3 kinase activity as described below.
[01263] 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 μΜ to 0.0003 μΜ) and compound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale, CA) into 1536-well black-walled round bottom plates (Corning).
[01264] 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.
[01265] Briefly, recombinant GSK3 kinase, ATP and Ser/Thr peptide 09 are prepared in IX Kinase buffer to final concentrations of 0.04 μg/mL, 46 μΜ, and 4 μΜ 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.
[01266] 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 (En Vision Multilabel Plate Reader, PerkinElmer).
[01267] 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 (F100% - F0%)))] .
[01268] 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).
[01269] Table 4 shows the activity of representative compounds of Formula I as provided herein. Table 4.
Figure imgf000273_0001
285 0.149 433 0.001 976 0.146 1079 0.048
286 0.186 441 0.005 977 0.246 1080 0.056
287 9.838 443 0.013 978 0.220 1081 0.082
288 0.020 448 0.01 1 979 0.791 1082 0.210
289 0.062 452 0.007 980 0.389 1083 0.914
290 0.075 468 0.007 981 0.141 1084 0.040
291 0.043 470 0.004 982 0.265 1085 0.083
292 0.173 472 0.008 983 0.303 1086 0.028
293 0.059 475 0.023 984 0.236 1087 0.037
294 0.041 477 0.006 985 0.283 1088 0.937
295 0.020 481 0.004 986 0.021 1090 0.288
296 0.080 483 0.045 987 2.316 1091 0.069
297 0.155 487 0.007 988 1 .093 1092 0.132
298 0.125 500 0.023 989 0.298 1093 0.047
299 0.044 513 0.043 990 0.100
300 0.031 517 0.470 991 0.029
301 0.010 521 0.234 992 0.014
Example 16.
[01270] Representative compounds were screened using the assay procedure for tau phosphorylation activity described below.
[01271] 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.
[01272] The above synthesized compounds were screened using the cell assay procedure to assess decrease Tau phosphorylation at Ser396 (pSer396) described below.
[01273] DMSO-resuspended compounds were dispensed to 8 wells as a serial titration from 10 μΜ 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 (LDH, CytoToxOne kit, Promega) if necessary. As controls, commercially available DYRKIA inhibitors, Harmine and Indy which were shown to have good DYRKIA inhibition in the kinase assay with no CDK1 activity (EC50 18 and 53 nM respectively, 6 μΜ for CDK1) but weak EC50 in the Tau assay >10 μΜ.
[01274] 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. [01275] Blot densitometry for pSer396 and β-actin were analyzed using ImageJ (ΝΠ4) and pSer396 Tau ELISA signal was used to plot, draw the curve fitting, and determine each compounds EC50 in Prism (GraphPad).
[01276] Table 5 shows the activity of representative compounds as provided herein.
Table 5.
Figure imgf000275_0001
274 0.535 360 0.659 960 0.233 1051 0.147
275 0.232 363 0.406 962 0.447 1052 0.254
276 0.150 364 >10 963 0.252 1057 0.342
277 1 .080 365 1 .200 964 0.576 1061 0.058
278 0.076 366 1 .100 965 1 .000 1064 0.109
279 0.498 367 0.258 966 0.236 1067 0.729
280 0.677 368 0.660 967 0.373 1068 0.689
281 0.518 369 0.970 968 2.700 1070 0.091
282 0.973 370 0.256 970 0.862 1071 6.900
283 0.411 371 0.581 971 0.191 1074 1.300
284 0.359 372 1 .100 972 0.355 1075 0.709
285 1 .580 376 7.900 973 0.102 1076 0.041
286 1 .150 433 0.032 974 2.000 1077 0.425
288 0.159 441 0.073 975 4.600 1078 0.458
289 0.185 443 0.289 976 0.536 1079 0.190
290 0.490 448 0.106 977 0.426 1080 0.251
291 0.716 452 0.912 978 0.274 1081 0.470
292 1 .350 468 0.039 979 0.569 1082 1.100
293 0.668 470 0.095 980 2.100 1086 0.168
294 0.905 472 0.200 981 1 .100 1087 0.160
295 0.430 475 1 .800 982 1 .100 1088 8.600
296 0.978 477 0.188 983 1 .500 1090 0.969
297 1 .420 481 0.662 984 2.100 1091 0.869
298 1 .390 483 0.611 985 3.200 1092 0.131
299 0.573 487 0.161 986 0.387 1093 0.422
300 0.222 500 0.388 987 >10
Example 17.
[01277] Representative compounds were screened using the cell-based assay procedure for secreted β-amyloid 40 (Αβ40) peptide in an APP overexpressing cell line described below.
[01278] SH-SY5Y cells (human neuroblastoma) were cultured in 1 : 1 DMEM/F-12 medium supplemented with 15% FBS, 1% non-essential amino acids, and 1% penicillin/streptomycin. HEK293T cells (human kidney) were cultured in DMEM medium supplemented with 10% FBS and 1% penicillin/streptomycin.
[01279] SH-SY5Y cells were infected with lentivirus to overexpress amyloid (A4) beta precursor protein (APP), hereafter referred to as the SH-SY5Y-APP cells. Specifically, in a 10 cm dish, HEK293T cells were seeded at 2.5xl05— and transfected with APP (Myc-DDK-tagged)-
Human amyloid beta (A4) precursor protein (APP), transcript variant 3 pLenti-ORF expression construct (custom modification of RC215147 to include bicistronic IRES-puromycin, OriGene). Culture medium was changed 18 h post-transfection before a first batch of viral supernatant was then harvested at 42 h post-transfection. Culture medium was replenished once more before a second batch of viral supernatant was harvested 66 h post-transfection. The two batches of viral supernatant were combined and spun at 1800g, then filtered through a 0.45μπι PVDF filter.
[01280] SH-SY5Y cells were seeded onto 6-well plates at 5.0xl05 and incubated
Γ well
overnight at 37°C. Cells were then infected with viral supernatant at concentrations ranging from 10%→100% viral supernatant (diluted in Opti-MEM as appropriate), with 10 Polybrene added for permeability (H9268, Sigma). 24 hours post-transfection, the entire volume from each well was replaced with regular SH-SY5Y medium. 4 days post-transfection, APP-overexpressing SH-SY5Y cells were selected for by adding puromycin (Al l 138-03, Gibco) to each well at a final concentration of 2 Puromycin-resistant cell were then expanded, harvested and banked. APP- overexpression was controlled by immunoblotting for total APP and Myc-DDK.
[01281] The cell assay procedure start 18 h prior to treatment, as SH-SY5Y-APP cells were seeded onto 96-well plates at 2.0xl04 lll_ τ¾ε entire 200 uL volume of medium was removed
Γ well r
from all wells, and replenished to reset any Αβ40 peptide that may have been secreted prior to treatment. DMSO-resuspended compounds were dispensed to eight wells as a serial dilution from 10 μΜ to 4.6 nM final concentration in medium. At this time, designated wells were seeded with SH-SY5Y cells that were seeded and treated with puromycin at 10 Cells were exposed overnight (16-18 hours) in a 37°C incubator before supernatant was harvested. Wells were visually checked for cell death before 150 of supernatant was harvested from each well into V-bottom 96-well plates (3894, Corning). The original plates with seeded cells were tested for cytotoxicity by measure of adenosine triphosphate (ATP) release by adding CellTiter-Glo® diluted 1:4 in distilled water (G7573, Promega) and transferring lysed cells to a completely black 96-well plate to be read with the Cytation3. Plates containing supernatant were spun down at 1200g for 10 minutes to remove any cellular debris. Supernatant was then diluted 1 :2 with a diluent from V- PLEX Αβ40 Peptide (6E10) Kit and directly tested for secreted Αβ40 peptide (K150SKE, Meso Scale Discovery). The signal was used to plot, draw the curve fitting, and determine each compounds EC50 in Prism (GraphPad).
[01282] Table 6 shows the activity of representative compounds as provided herein.
Table 6.
Figure imgf000277_0001
Example 18.
[01283] Representative compounds were screened using the assay procedure to assess the effect on cell viability as described below. [01284] 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 μg/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 μΜ to 0.0045 μΜ) 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 backfill for a final DMSO concentration of 0.1%.
[01285] 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.
[01286] After incubation, 10 μΐ^ οΐ 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)".
[01287] 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). For EC50 of >10 μΜ, the percent inhibition at 10 μΜ is provided.
[01288] Table 7 shows the activity of representative compounds of Formula I as provided herein.
Table 7.
Figure imgf000278_0001
76 1 .556 314 1.196 699 0.834 1003 0.804
77 0.767 315 1.251 700 0.623 1004 0.678
78 1 .844 316 2.340 704 >10 (18.1 %) 1005 1 .126
81 0.949 317 6.336 707 0.947 1006 0.584
82 2.710 318 0.940 711 0.706 1007 0.922
83 6.336 320 1.784 713 6.976 1008 >10 (37.2%)
84 1 .954 324 0.266 718 0.483 1009 2.351
85 1 .637 325 0.526 731 1 .103 1010 3.965
86 >10 326 0.400 737 4.342 1011 >10 (25.0%)
87 3.156 327 1.585 741 0.462 1012 3.195
89 0.738 328 0.929 743 1 .544 1013 5.498
90 1 .174 329 4.119 758 1 .336 1014 5.417
91 9.592 330 6.784 760 3.284 1015 6.419
92 0.983 331 3.115 767 9.054 1016 6.136
96 >10 332 1.003 773 >10 (48.4%) 1017 0.659
110 1 .049 333 0.641 784 >10 (39.7%) 1018 0.498
111 0.526 334 7.370 785 2.860 1019 9.381
112 6.425 335 1.120 791 0.137 1020 1 .032
113 >10 336 0.510 795 0.806 1021 >10 (11 .6%)
114 3.892 338 9.332 798 0.613 1022 3.337
115 3.505 340 2.232 803 4.533 1023 >10 (39.9%)
116 6.495 341 >10 (33.9%) 822 0.708 1024 6.773
118 5.936 342 >10 (40.0%) 826 0.897 1026 0.554
119 0.525 343 7.886 831 0.911 1027 0.488
120 2.486 344 7.678 839 1 .177 1028 3.523
121 4.307 345 3.076 851 >10 (30.4%) 1029 >10 (34.6%)
188 >10 346 9.663 883 >10 (35.5%) 1030 >10 (19.3%)
248 >10 347 >10 (48.5%) 885 7.720 1031 3.892
262 1 .391 348 >10 (22.4%) 888 2.471 1032 >10 (34.7%)
263 1 .287 349 0.704 900 3.883 1034 3.242
264 8.750 350 1.081 921 1 .624 1035 2.463
265 4.348 351 6.882 932 5.449 1037 >10 (32.7%)
266 6.316 352 8.599 939 >10 (31 .6%) 1040 2.684
267 2.025 353 8.225 946 >10 (42.6%) 1041 2.763
268 2.774 354 4.992 952 7.090 1047 >10 (41 .7%)
269 2.3303 355 8.634 953 >10 (40.3%) 1048 4.057
270 >10 358 2.372 959 >10 (45.0%) 1049 >10 (31 .3%)
271 2.962 359 0.261 960 6.673 1051 >10 (22.5%)
272 5.869 360 0.570 962 >10 (30.9%) 1052 >10 (40.7%)
273 1 .184 362 5.476 963 >10 (49.2%) 1057 4.505
274 4.051 363 3.057 964 3.828 1061 1 .595
275 1 .275 364 5.601 965 8.630 1064 4.851
276 >10 (29.6%) 365 0.522 966 0.259 1067 >10 (43.1 %)
277 1 .401 366 0.910 967 0.459 1068 >10 (46.0%)
278 1 .232 367 8.240 968 >10 (14.5%) 1070 8.388
279 >10 (52.4%) 368 0.651 969 2.885 1071 >10 (26.2%)
280 9.566 369 0.864 970 1 .255 1073 >10 (8.5%)
281 >10 370 1.246 971 1 .197 1074 >10 (25.0%)
282 6.613 371 1.063 972 0.757 1075 5.281
283 3.121 372 8.816 973 0.391 1076 1 .576
284 2.670 376 4.195 974 3.161 1077 5.246
285 7.023 433 0.615 975 0.334 1078 4.407
286 3.292 441 5.268 976 3.878 1079 2.605
287 >10 (47.8%) 443 1.676 977 0.615 1080 1 .380
288 2.660 448 0.626 978 1 .577 1081 4.648
289 7.755 452 1.453 979 2.223 1082 7.100
290 3.783 468 2.507 980 5.743 1083 0.901
291 >10 (24.4%) 470 4.187 981 0.546 1084 3.666
292 2.821 472 5.093 982 1 .212 1085 1 .240
293 2.857 475 1.063 983 4.619 1086 0.592
294 4.154 477 0.719 984 3.128 1087 0.746
296 3.465 481 1.368 985 1 .722 1088 9.194
297 5.718 483 7.343 986 3.305 1090 0.994
298 2.381 487 2.684 987 >10 (10.6%) 1091 1 .246
299 2.237 500 >10 (25.1 %) 988 >10 (18.0%) 1092 2.984
300 1 .298 513 9.064 989 >10 (36.4%) 301 I 0.550 I 517 | >10 (27.5%) | 990 | 3.547 | Example 19.
[01289] Representative compounds were screened using primary human fibroblasts (derived from IPF patients) treated with TGF-β Ι to determine their ability to inhibit the fibrotic process.
[01290] 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; ^atts, K. L., et.al., "RhoA signaling modulates cyclin D l 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.
[01291] Compound Screening: Each compound was dissolved in DMSO as a 10 mM stock and used to prepare compound source plates. Serial dilution (1 :2, 1 1 -point dose-response curves from 10 μΜ 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 μίΛνεΙΙ F 12 medium supplemented with 1% Fetal Bovine Serum. TGF-βΙ (Peprotech; 20 ng/mL) was added to the plates to induce fibrosis (ref. 1 and 2 above). Wells treated with TGF-βΙ 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 μΜ 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 1 1 wells treated with TGF-βΙ 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 μΜ, the percent inhibition at 10 μΜ is provided.
[01292] Table 8 shows the activity of representative compounds of Formula I as provided herein.
Table 8.
Compound ECso (μΜ) Compound ECso (μΜ) Compound ECso (μΜ) Compound ECso (μΜ)
1 0.135 290 1.056 367 0.211 965 1 .369
3 0.103 291 >10 (49.6%) 368 0.272 966 0.014
4 0.068 292 2.216 369 0.295 967 0.079
6 >10 (45.6%) 293 7.768 370 0.379 968 >10 (24.1 %)
10 >10 (39.6%) 294 >10 (41.3%) 371 0.394 969 0.935
14 0.035 295 4.465 372 0.504 970 1 .239
16 1 .266 296 1.964 376 >10 (21 .0%) 971 0.866
69 0.394 297 0.447 433 0.052 972 0.754
71 >10 (33.4%) 298 1.340 441 0.057 973 0.134
72 0.096 299 1.208 443 0.371 974 >10 (49.6%)
73 0.169 300 0.51 1 448 0.059 975 0.138
75 0.148 301 4.807 452 0.220 976 1 .174
76 0.087 302 0.901 470 0.387 977 0.136
77 0.146 303 0.817 472 0.243 978 0.722
78 0.108 304 0.150 475 0.140 979 1 .032
81 0.104 305 5.510 477 0.077 980 >10 (40.3%)
82 0.156 306 0.282 481 1 .021 981 0.605
83 0.067 307 7.150 483 0.315 982 0.767
84 0.148 308 >10 (27.6%) 487 0.367 983 0.679
85 0.097 309 0.014 500 0.675 984 1 .239
86 >10 (14.6%) 310 0.294 513 1 .353 985 >10 (38.0%)
87 0.081 311 0.076 517 >10 (29.9%) 986 0.158
89 0.137 312 >10 (36.5%) 521 1 .991 987 >10 (42.0%)
90 0.096 313 0.105 523 >10 (32.6%) 988 >10 (46.5%)
91 >10 (17.3%) 314 0.045 527 >10 (37.3%) 989 4.418
92 >10 (16.7%) 315 1.822 528 0.103 990 0.782
96 0.677 316 1.082 531 0.153 991 2.678
110 0.286 317 0.174 535 >10 (17.7%) 992 2.972
111 0.280 318 0.073 537 0.599 993 1 .487
112 0.546 320 0.069 547 0.160 994 0.567
113 2.1 13 324 0.068 554 0.190 995 1 .254
114 0.735 325 1.304 561 0.600 996 1 .204
115 0.605 326 >10 (47.2%) 579 0.167 997 0.567
116 0.830 327 0.058 643 0.138 998 0.260
118 0.821 328 >10 (34.5%) 699 0.234 999 0.779
119 1 .410 329 0.212 700 0.275 1000 2.957
120 2.133 330 0.020 704 4.383 1001 0.065
121 1 .083 331 0.096 707 4.242 1002 >10 (27.5%)
188 >10 (12.4%) 332 0.291 711 0.540 1003 0.049
248 7.922 333 0.061 713 >10 (37.6%) 1004 5.041
262 0.043 334 0.063 718 0.168 1005 0.072
263 0.134 335 0.11 1 737 0.080 1006 0.061
264 >10 (11 .7%) 336 >10 (38.4%) 741 0.175 1007 0.942
265 2.563 338 0.643 743 0.447 1008 0.318 266 0.697 340 0.413 758 0.265 1009 >10 (22.4%)
267 0.590 341 2.372 760 0.765 1010 0.103
268 0.073 342 0.948 767 >10 (33.2%) 1011 >10 (15.9%)
269 0.396 343 0.446 773 >10 (30.3%) 1012 >10 (10.2%)
270 >10 (11 .4%) 344 >10 (24.3%) 784 >10 (37.4%) 1013 2.436
271 0.064 345 >10 (38.0%) 785 1 .174 1014 0.695
272 2.543 346 0.965 791 0.067 1015 >10 (9.7%)
273 0.515 347 5.220 795 0.227 1016 2.132
274 0.195 348 1.457 803 >10 (27.8%) 1017 0.097
275 0.431 349 0.145 822 0.212 1018 0.088
276 0.336 350 0.100 826 0.149 1019 6.529
277 0.245 351 >10 (38.8%) 831 0.244 1020 >10 (30.6%)
278 0.211 352 1.322 851 0.692 1021 4.494
279 1 .202 353 >10 (31.7%) 883 >10 (14.0%) 1022 0.222
280 0.909 354 0.346 885 2.620 1023 4.671
281 0.486 355 6.191 900 0.449 1024 0.549
282 1 .937 358 0.145 921 0.075 1025 >10 (31 .4%)
283 0.782 359 0.127 932 0.594 1026 2.255
284 2.338 360 0.094 939 1 .137 1029 >10 (31 .8%)
285 1 .473 362 0.782 946 0.970 1030 2.806
286 >10 (16.4%) 363 0.387 952 0.741 1031 >10 (39.2%)
287 2.347 364 >10 (15.0%) 960 0.957 1071 0.712
288 0.532 365 4.799 963 1 .187 1073 >10
289 >10 (14.3%) 366 0.173 964 >10 (19.7%) 1074 >10
Example 20.
[01293] Representative compounds were screened using the following assay procedure to determine their ability to inhibit IL-6 and therefore demonstrate their anti -inflammatory properties.
[01294] 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.
[01295] 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 μΜ) 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 μΜ, the percent inhibition at 10 μΜ is provided.
[01296] Table 9 shows the activity of representative compounds of Formula I as provided herein.
Table 9.
Compound ECso (μΜ) Compound ECso (μΜ) Compound ECso (μΜ) Compound ECso (μΜ)
1 0.338 300 2.739 487 3.299 988 >10 (8.8%)
3 0.792 301 0.393 500 >10 (4.0%) 989 >10 (12.5%)
4 1 .131 302 7.698 513 >10 (14.5%) 990 >10 (0%)
6 1 .286 303 5.235 517 9.068 991 3.236
10 0.399 304 1.144 521 3.248 992 >10 (2.6%)
14 0.643 305 1.144 523 0.201 993 8.836
16 2.166 306 2.517 527 9.975 994 >10 (31 .8%)
69 2.157 307 >10 (4.3%) 528 1 .785 995 8.930
71 6.733 308 9.229 531 0.698 996 >10 (10.6%)
72 1 .127 309 >10 (4.5%) 535 >10 (3.1 %) 997 >10 (28.6%)
73 0.963 310 1.167 537 1 .243 998 7.082
75 0.806 311 0.396 547 1 .1 19 999 >10 (30.3%)
76 1 .127 312 >10 (3.9%) 554 0.439 1000 8.724
77 0.958 313 1.009 561 0.634 1001 >10 (49.7%)
78 2.941 314 1.273 579 1 .017 1002 >10 (5.9%)
81 0.395 315 0.819 643 0.129 1003 1 .146
82 1 .186 316 0.395 699 0.410 1004 1 .177
83 2.152 317 1.897 700 0.380 1005 2.890
84 2.463 318 1.031 704 >10 (4.8%) 1006 1 .128
85 1 .148 320 1.264 707 0.446 1007 1 .262
86 1 .772 324 0.321 711 1 .080 1008 7.591
87 2.939 325 0.357 713 3.633 1009 1 .840
89 1 .136 326 0.380 718 0.406 1010 1 .170
90 1 .083 327 0.947 731 1 .179 1011 >10 (15.3%)
91 >10 (40.0%) 328 0.398 737 1 .179 1012 3.122
92 >10 (33.0%) 329 1.158 741 0.380 1013 6.824
96 >10 (5.8%) 330 1.157 743 1 .127 1014 3.201
110 0.484 331 0.882 758 2.871 1015 3.1 19
112 2.989 332 1.066 760 1 .245 1016 >10 (5.4%)
113 1 .917 333 0.790 767 3.817 1017 0.655
114 1 .140 334 0.263 773 3.481 1018 0.441
115 1 .913 335 0.401 784 >10 (3.7%) 1019 8.973
116 1 .334 336 0.569 785 9.147 1020 1 .181
118 3.606 338 4.458 791 0.350 1021 >10 (5.1 %)
119 1 .198 340 0.562 795 1 .218 1022 3.288
120 2.291 341 >10 (46.1 %) 798 1 .268 1023 >10 (20.7%)
121 3.653 342 4.167 803 3.317 1024 >10 (33.1 %)
188 9.975 343 >10 (47.4%) 822 3.260 1025 >10 (13.6%)
248 9.730 344 9.133 826 3.294 1026 9.523
262 1 .092 345 4.167 831 0.812 1027 >10 (0%) 263 0.451 346 9.438 839 3.276 1028 1 .934
264 >10 (4.0%) 347 >10 (4.5%) 851 >10 (2.9%) 1029 >10 (7.3%)
265 2.997 348 >10 (19.0%) 883 >10 (9.1 %) 1030 >10 (7.7%)
266 1 .933 349 0.307 885 >10 (7.0%) 1031 >10 (2.0%)
267 9.407 350 0.578 888 3.944 1032 3.323
268 8.174 351 3.009 900 9.862 1034 3.325
269 3.389 352 5.026 921 >10 (9.9%) 1035 1 .027
270 9.975 353 >10 (39.9%) 932 >10 (7.5%) 1037 7.521
271 3.084 354 7.000 939 >10 (3.6%) 1040 1 .177
272 3.095 355 9.133 946 >10 (18.2%) 1041 0.941
273 0.842 358 0.613 952 >10 (10.1 %) 1047 >10 (4.5%)
274 3.223 359 1.026 959 >10 (6.1 %) 1048 >10 (4.3%)
275 1 .142 360 1.167 960 >10 (8.2%) 1049 >10 (10.4%)
276 2.920 362 9.153 962 >10 (9.6%) 1057 3.202
277 >10 (4.0%) 363 1.223 963 >10 (8.2%) 1061 0.947
278 3.988 364 >10 (5.8%) 964 >10 (6.8%) 1064 3.505
279 >10 14.2%) 365 0.526 965 3.263 1067 8.940
280 >10 (11 .6%) 366 1.120 967 1 .130 1068 3.404
281 >10 (0%) 367 1.153 968 9.238 1070 6.470
282 >10 (2.4%) 368 1.186 969 9.123 1071 >10 (8.8%)
283 5.452 369 1.128 970 1 .132 1073 >10 (3.3%)
284 1 .182 370 3.708 971 1 .220 1074 >10 (5.6%)
285 2.273 371 1.209 972 1 .134 1075 3.266
286 1 .227 372 3.656 973 0.395 1076 >10 (3.0%)
287 9.578 376 >10 (1 1.8%) 974 >10 (45.9%) 1077 3.167
288 1 .236 433 0.41 1 975 0.425 1078 3.242
289 3.195 441 3.351 977 0.404 1079 1 .214
290 4.782 443 3.289 978 3.364 1080 1 .073
291 9.827 448 2.185 979 4.303 1081 1 .097
292 1 .1 16 452 2.973 980 3.680 1082 2.929
293 1 .170 468 5.776 981 1 .104 1083 8.734
294 6.228 470 3.550 982 2.787 1084 0.752
295 >10 (5.9%) 472 5.409 983 >10 (9.1 %) 1085 0.453
296 1 .575 475 2.562 984 8.760 1086 0.394
297 1 .170 477 2.994 985 3.891 1087 0.470
298 5.533 481 1.143 986 >10 (13.4%) 1088 5.978
299 4.528 483 9.616 987 >10 (6.5%) 1090 0.484
Example 21.
[01297] Representative compounds were screened using the cell-based assay procedure for secreted cytokines in a Lipopolysaccharide-stimulated mouse glial cell line described below.
[01298] BV-2 cells (mouse microglial cells) were cultured in 1 : 1 DMEM medium supplemented with 10% FBS, and 1% penicillin/streptomycin.
[01299] Compound Screening: BV-2 cells are plated at 35,000 cells/well in a volume of lOOul for at least 4 hours before compounds are added. DMSO -re suspended compounds were first dispensed in a 96 well plate and serial diluted from 10 μΜ to 4.6 nM final concentration in medium. Compounds were added to cells overnight. Two hundred fifty ng per milliliter of lipopolysaccharide (Escherichia coli 055 :B5, SIGMA) was added for 5 h. Supernatant is removed and saved for further cytokine detection. The original plates with seeded cells were tested for cytotoxicity by measure of adenosine triphosphate (ATP) release by adding CellTiter-Glo® diluted 1 :4 in distilled water (G7573, Promega) and transferring lysed cells to a completely black 96-well plate to be read with the Cytation3. Supernatant was then diluted 1 :2 with a diluent from V-PLEX cytokine Kit and directly tested for the secreted cytokines TNFa, IL-6 and KC-GRO using electrochemiluminescence (Meso Scale Discovery). The standard curve for each cytokine was used to convert the electrochemiluminescent signal into pg of protein per mL. The signal was used to plot, draw the curve fitting, and determine each compounds EC50 in Prism (GraphPad).
[01300] Table 10 shows the activity of representative compounds of Formula I as provided herein.
Table 10.
Figure imgf000285_0001
ND = Not Determined

Claims

WHAT IS CLAIMED IS:
1. A compound, or a pharmaceutically acceptable salt thereof, of Formula I:
Figure imgf000286_0001
I
wherein:
R1, R2, R4, and R5 are independently selected from the group consisting of H, halide, unsubstituted -(C1-3 haloalkyl), and unsubstituted -(C1-3 alkyl);
R3 is a 5-membered heteroaryl optionally substituted with 1-4 R45; with the proviso that R3 is not
Figure imgf000286_0002
R6 is selected from the group consisting of -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R36, -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R37, -(C1-4 alkylene)N(R46)(R47), -N(R48)(R49), -CF(Ci-9 alkyl)2, -(C1-4 alkylene)pO(C3-9 alkyl), and alkynyl) optionally substituted with one or more halides; wherein each alkyl of -CF(Ci-9 alkyl)2 is, independently, optionally substituted with one or more halides; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; with the proviso that R6 is not unsubstituted -(Ctytetrahydropyranyl;
each R36 is independently selected from the group consisting of halide, unsubstituted -(Ci- 9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -(Ci-4 alkylene)pOR42, -(C1-4 alkylene )pheterocyclyl optionally substituted with 1-10 R43, -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R44, -C(=0)(R50), -(C1-4 alkylene) C(=0) OR51, -(C1-4 alkylene)aryl optionally substituted with one or more halides, -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides, and -S02(R52); wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
alternatively, two R36 attached to the same carbon atom can together represent =0 to form a carbonyl group;
each R37 is independently selected from the group consisting of halide, unsubstituted -(Ci- 9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -(Ci-4 alkylene)pOR42, -N(R5 )2, -C(=0)(R50), -C(=0)OR51, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1 -10 R43, and -(Ci-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R44; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R38 independently is selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R39 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R40 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R41 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -CN;
each R42 is independently selected from the group consisting of H, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -(C 1-4 alky lene)pcarbocyclyl optionally substituted with 1-12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; each R43 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R44 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -CN; each R45 is independently selected from the group consisting of H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(Ci-4 alkylene)pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; alternatively, two adjacent R45 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
R46 is attached to the nitrogen and is selected from the group consisting of H, unsubstituted -(Ci-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene )pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
R47 is attached to the nitrogen and is selected from the group consisting of unsubstituted - (Ci-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene )pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
R48 is attached to the nitrogen and selected from the group consisting of H, unsubstituted - (Ci-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), and unsubstituted -(C1-5 haloalkyl);
R49 is attached to the nitrogen and is selected from the group consisting of -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and— (C1-4 alkylene )pcarbocyclyl optionally substituted with 1-12 R39; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
R50 is selected from the group consisting of H, unsubstituted -(C3-5 alkyl), unsubstituted - (C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -(C1-4 alkylene)paryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), and -(Ci-4 alkylene)pheterocyclyl optionally substituted with one or more halides or one or more unsubstituted -(C1-5 alkyl); wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
R51 is selected from the group consisting of H, unsubstituted -(C1-5 alkyl), unsubstituted - (C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -(C1-4 alkylene)paryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), and -(Ci-4 alkylene)pheterocyclyl optionally substituted with one or more halides or one or more unsubstituted -(C1-5 alkyl); wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
R52 is selected from the group consisting of unsubstituted -(C1-5 alkyl), unsubstituted -(C2- 5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -(C1-4 alkylene)paryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), and -(Ci-4 alkylene)pheterocyclyl optionally substituted with one or more halides or one or more unsubstituted -(C1-5 alkyl); wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
each R53 is independently selected from the group consisting of H, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), and unsubstituted -(C2-5 alkynyl);
each p is independently 0 or 1 ; and
is not a structure selected from the group consisting of:
Figure imgf000289_0001
2. The compound of claim 1, wherein R1, R2, R4, and R5 are H.
3. The compound according to any one of claims 1-2, wherein R3 is a pyrazolyl optionally substituted with 1-4 R45.
4. The compound according to any one of claims 1-3, wherein R3 is an unsubstituted pyrazolyl.
5. The compound according to any one of claims 1-3, wherein R3 is a pyrazolyl substituted with one -(C1-3 alkyl).
6. The compound according to any one of claims 1-2, wherein R3 is an imidazolyl optionally substituted with 1-4 R45.
7. The compound according to any one of claims 1-2 and 6, wherein R3 is a imidazolyl substituted with one -(C1-3 alkyl).
8. The compound according to any one of claims 1-2, wherein R3 is a triazolyl optionally substituted with 1-4 R45.
9. The compound according to any one of claims 1-2 and 8, wherein R3 is an unsubstituted triazolyl.
10. The compound according to any one of claims 1-2 and 8, wherein R3 is a triazolyl substituted with one -(Ci-3 alkyl).
11. A compound, or a pharmaceuticall acceptable salt thereof, of Formula I:
Figure imgf000290_0001
I
wherein:
R1, R2, R4, and R5 are independently selected from the group consisting of H, halide, unsubstituted -(Ci-3 haloalkyl), and unsubstituted -(Ci-3 alkyl);
R3 is selected from the roup consisting of:
Figure imgf000290_0002
wherein each of R7-R35 is, independently, a substituent as defined anywhere herein or a single bond connecting R3 to the isoquinoline ring; wherein only one of R7-R10 (when present) is a bond, only one of Rn-R14 (when present) is a bond, only one of R15-R17 (when present) is a bond, only one of R18-R20 (when present) is a bond, only one of R21-R23 (when present) is a bond, only one of R24-R26 (when present) is a bond, only one of R27-R29 (when present) is a bond, only one of R 0-R31 (when present) is a bond, only one of R 2-R33 (when present) is a bond, and only one of R 4-R35 (when present) is a bond; wherein any one of the nitrogen atoms attached to R7, R11, R15, R18, or R21 can serve as the point of attachment of R3 to the isoquinoline ring; wherein any one of the carbon atoms attached to R8, R9, R10, R12, R13, R14, R16, R17, R19, R20, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, or R35 can serve as the point of attachment of R3 to the isoquinoline ring; so that:
when the nitrogen atom to which R7 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R7 is a single bond connecting R3 to the isoquinoline ring; when the carbon atom to which R8 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R8 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R9 is attached serves as the point of attachment of R to the isoquinoline ring, then R9 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R10 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R10 is a single bond connecting R3 to the isoquinoline ring;
when the nitrogen atom to which R11 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R11 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R12 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R12 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R13 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R13 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R14 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R14 is a single bond connecting R3 to the isoquinoline ring;
when the nitrogen atom to which R15 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R15 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R16 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R16 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R17 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R17 is a single bond connecting R3 to the isoquinoline ring;
when the nitrogen atom to which R18 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R18 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R19 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R19 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R20 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R20 is a single bond connecting R3 to the isoquinoline ring;
when the nitrogen atom to which R21 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R21 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R22 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R22 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R23 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R23 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R24 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R24 is a single bond connecting R3 to the isoquinoline ring; when the carbon atom to which R25 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R25 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R26 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R26 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R27 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R27 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R28 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R28 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R29 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R29 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R30 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R30 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R31 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R31 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R32 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R32 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R33 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R33 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R34 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R34 is a single bond connecting R3 to the isoquinoline ring;
when the carbon atom to which R35 is attached serves as the point of attachment of R3 to the isoquinoline ring, then R35 is a single bond connecting R3 to the isoquinoline ring;
R6 is selected from the group consisting of -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R36, -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R37, -(C1-4 alkylene)N(R46)(R47), -N(R48)(R49), -CF(Ci-9 alkyl)2, -(C1-4 alkylene)pO(C3-9 alkyl), and -(C2-9 alkynyl) optionally substituted with one or more halides; wherein each alkyl of -CF(Ci-9 alkyl)2 is, independently, optionally substituted with one or more halides; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; with the proviso that R6 is not unsubstituted -(Ctytetrahydropyranyl;
R7 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)OR42, -(C 1-4 alky lene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein; R8, R9, and R10 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene)pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
alternatively, one of R7 and R8, R8 and R9, or R9 and R10 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
R11 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)OR42, -(C 1-4 alky lene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
R12, R13, and R14 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene )pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
alternatively, one of R11 and R12, R12 and R13, or R14 and R11 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
R15 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)OR42, -(C 1-4 alky lene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
R16 and R17 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene )pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; alternatively, one of R15 and R16 or R16 and R17 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and - carbocyclyl optionally substituted with 1-12 R41;
R18 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)OR42, -(C 1-4 alky lene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(Ci-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
R19 and R20 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene)pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
alternatively, one of R18 and R19 or R18 and R20 are taken together to form a heterocyclyl optionally substituted with 1-10 R40;
R21 is selected from the group consisting of a single bond, H, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene)OR42, -(C 1-4 alky lene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
R22 and R23 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene )pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
alternatively, R22 and R23 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
R24, R25, and R26 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene )pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
with the proviso that when R25 is a single bond connecting R3 to the isoquinoline ring, R24 and R26 are not methyls;
alternatively, one of R24 and R25 or R25 and R26 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and - carbocyclyl optionally substituted with 1-12 R41;
R27, R28, and R29 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene )pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
alternatively, R27 and R28 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
R30 and R31 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene )pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
alternatively, R30 and R 1 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
R32 and R33 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene )pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
R34 and R35 are independently selected from the group consisting of a single bond, H, halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -N(R5 )2, -(C1-4 alkylene )pOR42, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
alternatively, R34 and R35 are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R40 and -carbocyclyl optionally substituted with 1-12 R41;
each R36 is independently selected from the group consisting of halide, unsubstituted -(Ci- 9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(Ci-9haloalkyl), -(Ci-4 alkylene)pOR42, -(C1-4 alkylene )pheterocyclyl optionally substituted with 1-10 R43, -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R44, -C(=0)(R50), -(C1-4 alkylene)C(=0)OR51, -(C1-4 alkylene)aryl optionally substituted with one or more halides, -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides, and -S02(R52); wherein each -(Ci-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
alternatively, two R36 attached to the same carbon atom can together represent =0 to form a carbonyl group;
each R37 is independently selected from the group consisting of halide, unsubstituted -(Ci- 9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(Ci-9haloalkyl), -(CM alkylene)pOR42, -N(R5 )2, -C(=0)(R50), -C(=0)OR51, -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R43, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R38 independently is selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R39 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1-12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R40 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R41 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -CN;
each R42 is independently selected from the group consisting of unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and - (Ci-4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein; each R43 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -CN, and -(C1-4 alkylene)pcarbocyclyl optionally substituted with 1 -12 R44; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
each R44 is independently selected from the group consisting of halide, unsubstituted -(Ci- 5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), and -CN;
R46 is attached to the nitrogen and is selected from the group consisting of H, unsubstituted -(Ci-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene )pheterocyclyl optionally substituted with 1-10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
R47 is attached to the nitrogen and is selected from the group consisting of unsubstituted - (Ci-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -(C1-4 alkylene )pheterocyclyl optionally substituted with 1 -10 R38, and -carbocyclyl optionally substituted with 1-12 R39; wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
R48 is attached to the nitrogen and selected from the group consisting of H, unsubstituted - (Ci-5 alkyl), unsubstituted -(C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), and unsubstituted -(C1-5 haloalkyl);
R49 is attached to the nitrogen and is selected from the group consisting of -(C1-4 alkylene)pheterocyclyl optionally substituted with 1 -10 R38, and— (C1-4 alkylene )pcarbocyclyl optionally substituted with 1-12 R39; wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
R50 is selected from the group consisting of H, unsubstituted -(C3-5 alkyl), unsubstituted - (C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -(C1-4 alkylene)paryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), and -(Ci-4 alkylene)pheterocyclyl optionally substituted with one or more halides or one or more unsubstituted -(C1-5 alkyl); wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
R51 is selected from the group consisting of H, unsubstituted -(C1-5 alkyl), unsubstituted - (C2-5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -(C1-4 alkylene)paryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), and -(Ci-4 alkylene)pheterocyclyl optionally substituted with one or more halides or one or more unsubstituted -(C1-5 alkyl); wherein each -(C1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;
R52 is selected from the group consisting of unsubstituted -(C1-5 alkyl), unsubstituted -(C2- 5 alkenyl), unsubstituted -(C2-5 alkynyl), unsubstituted -(C1-5 haloalkyl), -(C1-4 alkylene)paryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), -(C1-4 alkylene)pheteroaryl optionally substituted with one or more halides or unsubstituted -(C1-5 alkyl), and -(Ci-4 alkylene)pheterocyclyl optionally substituted with one or more halides or one or more unsubstituted -(C1-5 alkyl); wherein -(C1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;
each R53 is independently selected from the group consisting of H, unsubstituted -(C1-5 alkyl), unsubstituted -(C2-5 alkenyl), and unsubstituted -(C2-5 alkynyl);
each X is O or S; and
each p is independently 0 or 1 ; and
is not a structure selected from the group consisting of:
Figure imgf000298_0001
12. The compound of claim 11, wherein R1, R2, R4, and R5 are H.
13. The compound according to any one of claims 11-12, wherein R3 is selected from the group consisting of:
Figure imgf000299_0001
and X is O or S.
14. The compound according to any one of claims 11-13, wherein R3 is selected from
Figure imgf000299_0002
15. The compound according to any one of claims 11-14, wherein R3 is selected from the group consisting of:
Figure imgf000299_0003
R15, R18, R19, R28, R29, and R32 are independently selected from the group consisting of H and -(Ci- s alkyl).
16. The compound according to any one of claims 1-15, wherein R6 is a -(C1-4 alkylene)pheterocyclyl optionally substituted with 1-10 R36.
17. The compound according to any one of claims 1-16, wherein R6 is a -heterocyclyl optionally substituted with 1-2 R36.
18. The compound according to any one of claims 1-16, wherein R6 is a - Grbheterocyclyl optionally substituted with 1-2 R36.
19. The compound according to any one of claims 1-17, wherein R6 is either a piperidinyl or a pyrrolidinyl both optionally substituted with 1-2 R36.
20. The compound according to any one of claims 1-17 and 19, wherein R6 is a piperidinyl substituted with one -(C1-5 alkyl).
21. The compound according to any one of claims 1-17 and 19, wherein R6 is a piperidinyl substituted with one -(Ci-3 haloalkyl).
22. The compound according to any one of claims 1-16, wherein R6 is either a - CFbpiperidinyl or a -CFbpyrrolidinyl optionally substituted with 1-2 R36.
23. The compound according to any one of claims 1-16, and 22, wherein R6 is a - CFbpiperidinyl substituted with one -(C1-5 alkyl).
24. The compound according to any one of claims 1-16, and 22, wherein R6 is a - CFbpiperidinyl substituted with one -(Ci-3 haloalkyl).
25. The compound of claims 1, wherein the compound of Formula I is selected from the group consisting of:
N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)cyclopropanecarboxamide [1] ;
N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)cyclohexanecarboxamide [2] ;
4,4-Difluoro-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-l -carboxamide [3]; fr «5-N-(6-(l-Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-4-moφholinocyclohexane-l- carboxamide [6];
c/5-N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin-3-yl)-4-morpholinocyclohexane- 1 -carboxamide
[7];
fr «5-N-(6-(l-Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-4-(4-methylpiperazin-l-yl)cyclohexane- 1 -carboxamide [8];
c/5-N-(6-(l-Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-4-(4-methylpiperazin-l-yl)cyclohexane-l- carboxamide [9];
trans-4-((3 -Fluoroazetidin- 1 -yl)methyl)-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3- yl)cyclohexane - 1 -carboxamide [10];
cis-4 -((3 -Fluoroazetidin- 1 -yl)methyl) -N-(6 -( 1 -methyl - 1 H-pyrazol -4 -yl)isoquinolin-3 - yl)cyclohexane-l -carboxamide [11];
fr «5-N-(6-(l-Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-4-(mo holinomethyl)cyclohexane-l- carboxamide [12];
c/5-N-(6-(l-Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-4-(moφholinomethyl)cyclohexane-l- carboxamide [13];
fr «5-N-(6-(l-Methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-4-((4-methylpiperazin-l-yl)methyl) cyclohexane - 1 -carboxamide [14];
c/5-N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)-4-((4-methylpiperazin- 1 -yl)methyl)
cyclohexane - 1 -carboxamide [15];
N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)azetidine-3 -carboxamide [16] ;
l-Methyl-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide [17];
l-Ethyl-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide [18]; 1 -Isopropyl-N-(6-( 1 -methyl- 1 H-pyrazol-4-yl)isoquinolin-3 -yl)azetidine-3 -carboxamide [19] ; l-Cyclopropyl-N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide [20]; 1 -Isobutyl-N-(6 -( 1 -methyl - 1 H-pyrazol -4 -yl)isoquinolin-3 -yl)azetidine-3 -carboxamide [21]; N-(6-( 1 -Methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)- 1 -neopentylazetidine-3 -carboxamide [22] ; N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)- 1 -(( 1 -methylcyclopropyl)methyl)azetidine-3- carboxamide [23];
N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)- 1 -(( 1 -
(trifluoromethyl)cyclopropyl)methyl)azetidine -3 -carboxamide [24] ;
1 -(2 -fluoroethyl) -N-(6 -( 1 -methyl - 1 H-pyrazol -4 -yl)isoquinolin-3 -yl)azetidine-3 -carboxamide
[25];
N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)- 1 -(3,3,3-trifluoropropyl)azetidine-3 - carboxamide [26];
l-(2,2-difluoroethyl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide
[27];
l-(2-fluoro-2-methylpropyl)-N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3- carboxamide [28];
N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)- 1 -(oxetan-3-yl)azetidine-3 -carboxamide [29] ; N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)- 1 -((3-methyloxetan-3 -yl)methyl)azetidine-3- carboxamide [30];
N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)- 1 -(oxetan-2-ylmethyl)azetidine-3-carboxamide
[31];
l-(2-methoxyethyl)-N-(6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide
[32];
1 -(2-isopropoxyethyl)-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)azetidine-3-carboxamide
[33];
3-fluoro-N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide [34] ;
3-fluoro-l -methyl-N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide
[35];
l-ethyl-3-fluoro-N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide [36]; 3-fluoro-l -isopropyl-N-(6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide
[37];
l-cyclopropyl-3-fluoro-N-(6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3- carboxamide [38]; 3-fluoro-l-isobutyl-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide
[39];
3-fluoro-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-l-neopentylazetidine-3-carboxamide
[40];
3-fluoro-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-l-((l- methylcyclopropyl)methyl)azetidine-3-carboxamide [41] ;
3-fluoro-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-l-((l-
(trifluoromethyl)cyclopropyl)methyl) azetidine-3-carboxamide [42];
3-fluoro-l-(2-fluoroethyl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3- carboxamide [43];
l-(2,2-difluoroethyl)-3-fluoro-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3- carboxamide [44];
3-fluoro-l-(2-fluoro-2-methylpropyl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3- yl)azetidine-3-carboxamide [45];
3-fluoro-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-l-(oxetan-3-yl)azetidine-3- carboxamide [46];
3-fluoro-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-l-((3-methyloxetan-3- yl)methyl)azetidine-3 -carboxamide [47] ;
3-fluoro-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-l-(oxetan-2-ylmethyl)azetidine-3- carboxamide [48];
3-fluoro-l-(2-methoxyethyl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3- carboxamide [49];
3-fluoro-l-(2-isopropoxyemyl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3- carboxamide [50];
N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)pyrrolidine -3 -carboxamide [51] ;
1 -methyl -N-(6 -( 1 -methyl - 1 H-pyrazol -4 -yl)isoquinolin-3 -yl)pyrrolidine -3 -carboxamide [52] ; l-ethyl-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-3-carboxamide [53];
1 -isopropyl-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)pyrrolidine -3 -carboxamide [54] ; l-cyclopropyl-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-3-carboxamide [55]; 1 -isobutyl-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)pyrrolidine -3 -carboxamide [56] ; N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)- 1 -neopentylpyrrolidine-3 -carboxamide [57] ; N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)- 1 -(( 1 -methylcyclopropyl)methyl)pyrrolidine- 3 -carboxamide [58]; N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)- 1 -(( 1 -
(trifluoromethyl)cyclopropyl)methyl)pyrrolidine -3 -carboxamide [59] ;
1 -(2 -fluoroethyl) -N-(6 -( 1 -methyl - 1 H-pyrazol -4 -yl)isoquinolin-3 -yl)pyrrolidine -3 -carboxamide
[60];
N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-l-(3,3,3-trifluoropropyl)pyrrolidine-3- carboxamide [61];
l-(2,2-difluoroethyl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-3- carboxamide [62];
1 -(2-fluoro-2-methylpropyl)-N-(6-( 1 -methyl-lH-pyrazol-4-yl)isoquinolin-3 -yl)pyrrolidine-3 - carboxamide [63];
N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)- 1 -(oxetan-3-yl)pyrrolidine -3 -carboxamide
[64];
N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)- 1 -((3-methyloxetan-3 -yl)methyl)pyrrolidine-3- carboxamide [65];
N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)- 1 -(oxetan-2-ylmethyl)pyrrolidine-3- carboxamide [66];
l-(2-methoxyethyl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-3-carboxamide
[67];
1 -(2-isopropoxyethyl)-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)pyrrolidine-3- carboxamide [68];
(S)-2-(3-fluoropyrrolidin- 1 -yl)-N-(6-( 1 -methyl-lH-pyrazol-4-yl)isoquinolin-3 -yl)acetamide [69] ; (R)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)tetrahydrofuran-2 -carboxamide [70]; (S)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)tetrahydrofuran-2 -carboxamide [71];
N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)piperidine -4 -carboxamide [72] ;
1 -methyl -N-(6 -( 1 -methyl - 1 H-pyrazol -4 -yl)isoquinolin-3 -yl)piperidine -4 -carboxamide [73] ; 1 -ethyl -N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide [74] ;
1 -isopropyl-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)piperidine-4-carboxamide [75] ; l-cyclopropyl-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide [76]; 1 -isobutyl-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)piperidine-4-carboxamide [77] ; N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)- 1 -neopentylpiperidine-4-carboxamide [78] ; N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)- 1 -(( 1 -methylcyclopropyl)methyl)piperidine-4- carboxamide [79];
N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)- 1 -(( 1 -
(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide [80] ; 1 -(2 -fluoroethyl) -N-(6 -( 1 -methyl - 1 H-pyrazol -4 -yl)isoquinolin-3 -yl)piperidine -4 -carboxamide
[81];
N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)- 1 -(3,3,3-trifluoropropyl)piperidine-4- carboxamide [82];
l-(2,2-difluoropropyl)-N-(6-(l -methyl- lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide [83];
l-(2,2-difluoroethyl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide
[84];
l-(2-fluoro-2-methylpropyl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide [85];
N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)- 1 -(oxetan-3-yl)piperidine-4-carboxamide [86] ; N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)- 1 -((3-methyloxetan-3 -yl)methyl)piperidine-4- carboxamide [87];
N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)- 1 -(oxetan-2-ylmethyl)piperidine-4- carboxamide [88];
l-(2-methoxyethyl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide
[89];
1 -(2-isopropoxyethyl)-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)piperidine-4- carboxamide [90];
4-fluoro-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide [91];
4-fluoro-l -methyl-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide
[92];
l-ethyl-4-fluoro-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4 -carboxamide
[93];
4-fluoro-l -isopropyl-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)piperidine-4-carboxamide
[94];
l-cyclopropyl-4-fluoro-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide [95];
4-fluoro-l -isobutyl-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide
[96];
4-fluoro-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-l-neopentylpiperidine-4-carboxamide
[97];
4-fluoro-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-l-((l- methylcyclopropyl)methyl)piperidine -4 -carboxamide [98] ; 4-fluoro-N-(6-( 1 -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)- 1 -(( 1 -
(trifluoromethyl)cyclopropyl)methyl) piperidine-4-carboxamide [99]; and
4-fluoro-l -(2-fluoroethyl)-N-(6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide [100]; or a pharmaceutically acceptable salt thereof.
26. The compound of claims 1, wherein the compound of Formula I is selected from the group consisting of:
4-fluoro-N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-l-(3,3,3 rifluoropropyl)piperidine-4- carboxamide [101];
l-(2,2-difluoropropyl)-4-fluoro-N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide [102];
1- (2,2-difluoroethyl)-4-fluoro-N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide [103];
4-fluoro-l -(2-fluoro-2-methylpropyl)-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 - yl)piperidine-4-carboxamide [104];
4-fluoro-N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-l-(oxetan-3-yl)piperidine-4- carboxamide [105];
4-fluoro-N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-l-((3-methyloxetan-3- yl)methyl)piperidine-4-carboxamide [106] ;
4-fluoro-N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-l-(oxetan-2-ylmethyl)piperidine-4- carboxamide [107];
4-fluoro-l -(2-methoxyethyl)-N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide [108];
4-fluoro-l -(2-isopropoxyethyl)-N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide [109];
(S)-N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide [110];
(R)-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-3 -carboxamide [111];
(S)-l -isobutyl-N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide [112]; (R)-l -isobutyl-N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide [113]; N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)-2-(piperidin- 1 -yl)acetamide [115];
2- (4-fluoropiperidin-l -yl)-N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)acetamide [116]; N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)-2-(4-methylpiperidin-l -yl)acetamide [117]; N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)-2-(4-methylpiperazin-l -yl)acetamide [118]; N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)cyclopropanecarboxamide [119];
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)cyclohexanecarboxamide [120] ; N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)-4,4-difluorocyclohexane- 1 -carboxamide
[121];
fr «5-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-4-methoxycyclohexane-l - carboxamide [122];
c/5-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-4-methoxycyclohexane-l - carboxamide [123];
fr «5-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-4-mo holinocyclohexane-l- carboxamide [124];
c/5-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-4-mo holinocyclohexane-l - carboxamide [125];
trans-N-(6-( 1 ,2-dimethyl- 1 H-imidazol-5 -yl)isoquinolin-3 -yl)-4-(4-methylpiperazin- 1 - yl)cyclohexane - 1 -carboxamide [126];
c/5-N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)-4-(4-methylpiperazin- 1 - yl)cyclohexane - 1 -carboxamide [127];
fr «5-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-4-((3-fluoroazetidin-l -yl)methyl) cyclohexane - 1 -carboxamide [128] ;
c/5-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-4-((3-fluoroazetidin-l -yl)methyl) cyclohexane - 1 -carboxamide [129] ;
fr «5-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-4-(mo holinomethyl)cyclohexane-
1 -carboxamide [130];
c/5-N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)-4-(moφholinomethyl)cyclohexane- 1 - carboxamide [131];
fr «5-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-4-((4-methylpiperazin-l -yl)methyl) cyclohexane - 1 -carboxamide [132] ;
c/5-N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)-4-((4-methylpiperazin- 1 -yl)methyl) cyclohexane - 1 -carboxamide [133] ;
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)azetidine-3-carboxamide [134] ;
N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)- 1 -methylazetidine-3 -carboxamide [135] ; N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)- 1 -ethylazetidine-3 -carboxamide [136] ; N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)- 1 -isopropylazetidine-3 -carboxamide
[137];
1 -cyclopropyl-N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin -3 -yl)azetidine-3 -carboxamide
[138];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)- 1 -isobutylazetidine-3-carboxamide [139] ; N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)i^
[140];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)- 1 -(( 1 - methylcyclopropyl)methyl)azetidine -3 -carboxamide [141] ;
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)- 1 -(( 1 -
(trifluoromethyl)cyclopropyl)methyl) azetidine -3 -carboxamide [142] ;
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquin^
[143];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)- 1 -(3 ,3 ,3 -trifluoropropyl)azetidine-3 - carboxamide [144];
l-(2,2-difluoroethyl)-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)azetidine-3- carboxamide [145];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)- 1 -(2-fluoro-2-methylpropyl)azetidine-3 - carboxamide [146];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)- 1 -(oxetan-3 -yl)azetidine-3 -carboxamide
[147];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)- 1 -((3 -methyloxetan-3 - yl)methyl)azetidine -3 -carboxamide [148];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)- 1 -(oxetan-2-ylmethyl)azetidine-3 - carboxamide [149];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)- 1 -(2-methoxyethyl)azetidine-3 - carboxamide [150];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)- 1 -(2-isopropoxyethyl)azetidine-3 - carboxamide [151];
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-3-fluoroazetidine-3-carboxamide [152]; N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-3 -fluoro- 1 -methylazetidine-3 - carboxamide [153];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)- 1 -ethyl-3 -fluoroazetidine-3 -carboxamide
[154];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-3 -fluoro- 1 -isopropylazetidine-3 - carboxamide [155];
l-cyclopropyl-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-3-fluoroazetidine-3- carboxamide [156]; N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-3 -fluoro- 1 -isobutylazetidine-3 - carboxamide [157];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-3 -fluoro- 1 -neopentylazetidine-3 - carboxamide [158];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-3 -fluoro- 1 -(( 1 - methylcyclopropyl)methyl) azetidine -3 -carboxamide [159];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-3 -fluoro- 1 -(( 1 -
(trifluoromethyl)cyclopropyl) methyl)azetidine -3 -carboxamide [160] ;
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-3 -fluoro- 1 -(2-fluoroethyl)azetidine-3 - carboxamide [161];
l-(2,2-difluoroethyl)-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-3-fluoroazetidine-3- carboxamide [162];
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-3-fluoro-l-(2-fluoro-2- methylpropyl)azetidine -3 -carboxamide [163];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-3 -fluoro- 1 -(oxetan-3 -yl)azetidine-3 - carboxamide [164];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-3 -fluoro- 1 -((3 -methyloxetan-3 -yl)methyl) azetidine -3 -carboxamide [165];
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-3-fluoro-l-(oxetan-2-ylmethyl)azetidine-
3 -carboxamide [166];
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-3-fluoro-l-(2-methoxyethyl)azetidine-3- carboxamide [167];
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-3-fluoro-l-(2-isopropoxyethyl)azetidine- 3 -carboxamide [168];
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)pyrrolidine-3-carboxamide [169];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)- 1 -methylpyrrolidine-3 -carboxamide
[170];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)- 1 -ethylpyrrolidine-3 -carboxamide [171]; N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)- 1 -isopropylpyrrolidine-3 -carboxamide
[172];
1 -cyclopropyl-N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin -3 -yl)pyrrolidine -3 -carboxamide
[173];
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-l-isobutylpyrrolidine-3-carboxamide
[174]; N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoqum^
[175];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)- 1 -(( 1 - methylcyclopropyl)methyl)pyrrolidine -3 -carboxamide [ 176] ;
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)- 1 -(( 1 -
(trifluoromethyl)cyclopropyl)methyl) pyrrolidine -3 -carboxamide [177];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)- 1 -(2-fluoroethyl)pyrrolidine-3 - carboxamide [178];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)- 1 -(3 ,3 ,3 -trifluoropropyl)pyrrolidine-3 - carboxamide [179];
l-(2,2-difluoroethyl)-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)pyrrolidine-3- carboxamide [180];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)- 1 -(2 -fluoro-2 -methylpropyl)pyrrolidine-
3 -carboxamide [181];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)- 1 -(oxetan-3 -yl)pyrrolidine-3 - carboxamide [182];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)- 1 -((3 -methyloxetan-3 - yl)methyl)pyrrolidine -3 -carboxamide [ 183] ;
N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)- 1 -(oxetan-2-ylmethyl)pyrrolidine-3 - carboxamide [184];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)- 1 -(2-methoxyethyl)pyrrolidine-3- carboxamide [185];
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-l-(2-isopropoxyethyl)pyrrolidine-3- carboxamide [186];
(R)-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)tetrahydrofuran-2 -carboxamide [187]; (S)-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)tetrahydrofuran-2 -carboxamide [188]; N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [189];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)- 1 -methylpiperidine-4-carboxamide [190] ; N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)- 1 -ethylpiperidine-4-carboxamide [191] ; N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)- 1 -isopropylpiperidine-4 -carboxamide
[192];
1 -cyclopropyl-N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)piperidine-4-carboxamide
[193]; N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)- 1 -isobutylpiperidine-4-carboxamide
[194];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)- 1 -neopentylpiperidine-4-carboxamide
[195];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)- 1 -(( 1 - methylcyclopropyl)methyl)piperidine-4-carboxamide [196] ;
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)- 1 -(( 1 -
(trifluoromethyl)cyclopropyl)methyl) piperidine-4-carboxamide [197];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)- 1 -(2-fluoroethyl)piperidine-4- carboxamide [198];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)- 1 -(3,3,3 -trifluoropropyl)piperidine-4- carboxamide [199]; and
l-(2,2-difluoropropyl)-N-(6-( l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)piperidine-4- carboxamide [200]; or a pharmaceutically acceptable salt thereof.
27. The compound of claims 1, wherein the compound of Formula I is selected from the group consisting of:
l-(2,2-difluoroethyl)-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)piperidine-4- carboxamide [201];
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-l-(2-fluoro-2-methylpropyl)piperidine-4- carboxamide [202];
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-l-(oxetan-3-yl)piperidine-4-carboxamide
[203];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)- 1 -((3 -methyloxetan-3 - yl)methyl)piperidine-4-carboxamide [204] ;
N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)- 1 -(oxetan-2-ylmethyl)piperidine-4- carboxamide [205];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)- 1 -(2 -methoxyethyl)piperidine-4- carboxamide [206];
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-l-(2-isopropoxyethyl)piperidine-4- carboxamide [207];
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-4-fluoropiperidine-4-carboxamide [208] ; N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-4-fluoro-l -methylpiperidine-4- carboxamide [209]; N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)- 1 -ethyl -4-fluoropiperidine-4- carboxamide [210];
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-4-fluoro-l-isopropylpiperidine-4- carboxamide [211];
1 -cyclopropyl-N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin -3 -yl)-4-fluoropiperidine-4- carboxamide [212];
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-4-fluoro-l-isobutylpiperidine-4- carboxamide [213];
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-4-fluoro-l-neopentylpiperidine-4- carboxamide [214];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-4-fluoro- 1 -(( 1 - methylcyclopropyl)methyl) piperidine-4-carboxamide [215];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-4-fluoro- 1 -(( 1 -
(trifluoromethyl)cyclopropyl) methyl)piperidine-4-carboxamide [216];
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-4-fluoro-l-(2-fluoroethyl)piperidine-4- carboxamide [217];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-4-fluoro- 1 -(3,3,3- trifluoropropyl)piperidine-4-carboxamide [218] ;
l-(2,2-difluoropropyl)-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-4- fluoropiperidine -4 -carboxamide [219];
l-(2,2-difluoroethyl)-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-4-fluoropiperidine-
4-carboxamide [220];
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-4-fluoro-l-(2-fluoro-2- methylpropyl)piperidine -4 -carboxamide [221] ;
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-4-fluoro-l-(oxetan-3-yl)piperidine-4- carboxamide [222];
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-4-fluoro-l-((3-methyloxetan-3-yl)methyl) piperidine -4 -carboxamide [223];
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-4-fluoro-l-(oxetan-2- ylmethyl)piperidine -4 -carboxamide [224] ;
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-4-fluoro-l-(2-methoxyethyl)piperidine-4- carboxamide [225];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-4-fluoro- 1 -(2- isopropoxyethyl)piperidine-4-carboxamide [226] ; N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)tetrahydro-2H-pyran -4 -carboxamide
[227];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-2-(piperidin- 1 -yl)acetamide [228] ;
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-(4-fluoropiperidin-l-yl)acetamide
[229];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperidin- 1 -yl)acetamide
[230];
N-(6-( 1 -methyl- 1H- 1 ,2,3-triazol-5 -yl)isoquinolin-3-yl)cyclopropanecarboxamide [231] ;
N-(6-( 1 -methyl- 1H- 1 ,2,3 -triazol-5 -yl)isoquinolin-3 -yl)cyclohexanecarboxamide [232] ;
4,4-difluoro-N-(6-(l-methyl-lH-l,2,3-triazol-5-yl)isoquinolin-3-yl)cyclohexane-l-carboxamide
[233];
N-(6-( 1 -methyl- 1H- 1 ,2,3 -triazol-5 -yl)isoquinolin-3 -yl)azetidine-3 -carboxamide [234] ;
1 -methyl -N-(6-( 1 -methyl -IH- 1 ,2, 3 -triazol-5 -yl)isoquinolin-3-yl)azetidine-3 -carboxamide [235] ; N-(6-( 1 -methyl- IH- 1 ,2,3 -triazol-5 -yl)isoquinolin-3 -yl)pyrrolidine-3 -carboxamide [236] ;
1 -methyl -N-(6 -( 1 -methyl - 1 H- 1 ,2, 3 -triazol-5 -yl)isoquinolin-3 -yl)pyrrolidine -3 -carboxamide
[237];
l-(2-fluoroethyl)-N-(6-(l-methyl-lH-l,2,3-triazol-5-yl)isoquinolin-3-yl)pyrrolidine-3- carboxamide [238];
N-(6-( 1 -methyl- IH- 1 ,2,3 -triazol-5 -yl)isoquinolin-3 -yl)- 1 -(3 ,3 ,3 -trifluoropropyl)pyrrolidine-3 - carboxamide [239];
N-(6-( 1 -methyl- IH- 1 ,2,3-triazol-5 -yl)isoquinolin-3-yl)piperidine-4 -carboxamide [240] ;
1 -methyl -N-(6-( 1 -methyl -IH- 1 ,2,3-triazol-5 -yl)isoquinolin-3-yl)piperidine-4-carboxamide [241] ; 1 -ethyl -N-(6-( 1 -methyl- IH- 1 ,2,3-triazol-5 -yl)isoquinolin-3 -yl)piperidine-4 -carboxamide [242] ; l-isopropyl-N-(6-(l-methyl-lH-l,2,3-triazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide
[243];
l-cyclopropyl-N-(6-(l-methyl-lH-l,2,3-triazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide
[244];
1 -isobutyl-N-(6-( 1 -methyl- IH- 1 ,2,3 -triazol-5 -yl)isoquinolin-3 -yl)piperidine-4 -carboxamide
[245];
N-(6-( 1 -methyl- IH- 1 ,2,3-triazol-5 -yl)isoquinolin-3-yl)- 1 -neopentylpiperidine-4 -carboxamide
[246];
1 -(2-fluoroethyl)-N-(6-( 1 -methyl- IH- 1 ,2,3-triazol-5 -yl)isoquinolin-3-yl)piperidine-4- carboxamide [247]; N-(6-( 1 -methyl- 1H- 1 ,2,3-triazol-5 -yl)isoquinolin-3-yl)- 1 -(3,3,3 -trifluoropropyl)piperidine-4- carboxamide [248];
l-(2,2-difluoropropyl)-N-(6-(l-methyl-lH-l,2,3-triazol-5-yl)isoquinolin-3-yl)piperidine-4- carboxamide [249];
l-(2,2-difluoroethyl)-N-(6-(l-methyl-lH-l,2,3-triazol-5-yl)isoquinolin-3-yl)piperidine-4- carboxamide [250];
l-(2-fluoro-2-methylpropyl)-N-(6-(l-methyl-lH-l,2,3-triazol-5-yl)isoquinolin-3-yl)piperidine-4- carboxamide [251];
4-fluoro-N-(6-(l-methyl-lH-l,2,3-triazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [252]; 4-fluoro- 1 -methyl -N-(6-( 1 -methyl- 1H- 1,2,3 -triazol-5 -yl)isoquinolin-3 -yl)piperidine-4- carboxamide [253];
4-fluoro-l-(2-fluoroethyl)-N-(6-(l-methyl-lH-l,2,3-triazol-5-yl)isoquinolin-3-yl)piperidine-4- carboxamide [254];
4-fluoro-N-(6-(l-methyl-lH-l,2,3-triazol-5-yl)isoquinolin-3-yl)-l-(3,3,3- trifluoropropyl)piperidine-4-carboxamide [255] ;
1 -(2,2-difluoropropyl)-4-fluoro-N-(6-( 1 -methyl- 1H- 1 ,2,3 -triazol-5 -yl)isoquinolin-3 -yl)piperidine-
4-carboxamide [256];
1- (2,2-difluoroethyl)-4-fluoro-N-(6-(l-methyl-lH-l,2,3-triazol-5-yl)isoquinolin-3-yl)piperidine-
4-carboxamide [257];
4-fluoro-l-(2-fluoro-2-methylpropyl)-N-(6-(l-methyl-lH-l,2,3-triazol-5-yl)isoquinolin-3- yl)piperidine-4-carboxamide [258];
N-(6-( 1 -methyl- 1H- 1 ,2,3 -triazol-5 -yl)isoquinolin-3 -yl)-2-(piperidin- 1 -yl)acetamide [259] ;
2- (4-fluoropiperidin-l -yl)-N-(6-( 1 -methyl- 1H- 1 ,2,3-triazol-5 -yl)isoquinolin-3-yl)acetamide
[260];
N-(6-( 1 -methyl- 1H- 1 ,2,3-triazol-5 -yl)isoquinolin-3-yl)-2-(4-methylpiperidin- 1 -yl)acetamide
[261];
N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)-l-(3,3,3-trifluoropropyl)piperidine-4- carboxamide [262];
4,4-difluoro-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)cyclohexane-l-carboxamide
[263];
1 -methyl -N-(6 -( 1 -methyl - 1 H-pyrazol -3 -yl)isoquinolin-3 -yl)piperidine -4 -carboxamide [264] ; N-(6-(5,6,7,8-tetrahydroimidazo[l,2-a]pyrazin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide
[265]; N-(6-(7-methyl-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazin-3-yl)isoquinolin-3- yl)cyclopropanecarboxamide [266];
3.3- difluoro-N-(6-(5-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-3-yl)isoquinolin-3- yl)cyclobutane- 1 -carboxamide [267] ;
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-3 ,3 -difluorocyclobutane- 1 -carboxamide
[268];
2,2,3, 3 etramethyl-N-(6-(l-methyl-lH midazol-5-yl)isoquinolin-3-yl)cyclopropane-l- carboxamide [269];
N-(6-( 1 -methyl- lH-pyrazol-5 -yl)isoquinolin-3 -yl)-l -(3,3,3-trifluoropropyl)piperidine-4- carboxamide [270];
N-(6-(l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)-l-(3,3,3-trifluoropropyl)piperidine-4- carboxamide [271];
2-(4-isobutylpiperazin-l-yl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)acetamide [272]; 2-(3,3-dimethylazetidin-l-yl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)acetamide [273]; (R)-2-(3-fluoropyrrolidin- 1 -yl)-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)acetamide
[274];
N-(6-( 1 -methyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-2-(piperidin- 1 -yl)acetamide [275] ;
N-(6-(l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(piperidin-l-yl)acetamide [276];
2,2,3 ,3 -tetramethyl-N-(6-( 1 -methyl- 1H- 1,2,3 -triazol-4-yl)isoquinolin-3 -yl)cyclopropane- 1 - carboxamide [277];
N-(6-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)isoquinolin-3 -yl)- 1 -(3 ,3 ,3 -trifluoropropyl)piperidine-4- carboxamide [278];
N-(6-(4,5-dimethyl-4H-l,2,4-triazol-3-yl)isoquinolin-3-yl)-l-(3,3,3-trifluoropropyl)piperidine-4- carboxamide [279];
4-fluoro-l-isobutyl-N-(6-(4-methyl-4H-l,2,4-triazol-3-yl)isoquinolin-3-yl)piperidine-4- carboxamide [280];
4-fluoro-l-isobutyl-N-(6-(l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide [281];
l-ethyl-4-fluoro-N-(6-(l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide
[282];
4.4- difluoro-N-(6-(5-(2-fluoroethyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-3-yl)isoquinolin-3- yl) cyclohexane-1 -carboxamide [283];
N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)-2-(pyrrolidin- 1 -yl)acetamide [284] ;
N-(6-( 1 -ethyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)-2-(pyrrolidin- 1 -yl)acetamide [285] ; N-(6-(l -cyclopropyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-l -yl)acetamide [286]; 2-(pyrrolidin-l-yl)-N-(6-(5-(trifluoromethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)acetamide [287]; N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)-2-(pyrrolidin- 1 -yl)propanamide [288] ;
(R)-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin- 1 -yl)acetamide
[289];
(S)-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin- 1 -yl)acetamide
[290];
2-(3 -azabicyclo[3.1.0]hexan-3 -yl)-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)acetamide
[291];
2-(7-azabicyclo [2.2.1 ]heptan-7-yl)-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)acetamide
[292];
N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)-2-(4-methylpiperidin-l -yl)acetamide [293] ; N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)-2-(4-(trifluoromethyl)piperidin- 1 -yl)acetamide
[294];
2-(4-(difluoromethyl)piperidin- 1 -yl)-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3-yl)acetamide
[295];
N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)acetamide [296]; N-(6-(l -cyclopropyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-l-(3,3,3-trifluoropropyl)piperidine-4- carboxamide [297];
N-(6-(5-(azetidin-l-ylmethyl)-l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-4,4- difluorocyclohexane - 1 -carboxamide [298] ;
4,4-difluoro-N-(6-( 1 -methyl -5 -(pyrrolidin- 1 -ylmethyl)- lH-pyrazol-4-yl)isoquinolin-3 - yl)cyclohexane-l -carboxamide [299]; and
4,4-difluoro-N-(6-( 1 -methyl -5 -(piperidin- 1 -ylmethyl)- lH-pyrazol-4-yl)isoquinolin-3- yl)cyclohexane-l -carboxamide [300]; or a pharmaceutically acceptable salt thereof.
28. The compound of claims 1, wherein the compound of Formula I is selected from the group consisting of:
7-(2-fluoroethyl)-N-(6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-7-azaspiro[3.5]nonane-2- carboxamide [301];
2-(cyclobutyl(methyl)amino)-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)acetamide [302] ; 2-(diethylamino) -N-(6 -( 1 -methyl - 1 H-pyrazol -4 -yl)isoquinolin-3 -yl)acetamide [303] ;
N-(6-(l -(methyl - 3)-lH-pyrazol-4-yl)isoquinolin-3-yl)-l-(3,3,3-trifluoropropyl)piperidine-4- carboxamide [304];
N-(6-(l -(methyl -£/3)-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-l -yl)acetamide [305]; N-(6-(l -(methyl - 3)-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-l-yl)acetamide [306];
N-(6-(3-methylisoxazol-5-yl)isoquinolin-3-yl)-l-(3,3,3 rifluoropropyl)piperidine-4-carboxamid
[307];
N-(6-(oxazol-5-yl)isoquinolin-3-yl)-l-(3,3,3-trifluoropropyl)piperidine-4-carboxamide [308]; 4-fluoro-l-isobutyl-N-(6-(5-methyl-l,3,4-oxadiazol-2-yl)isoquinolin-3-yl)piperidine-4- carboxamide [309];
N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)-l -(( 1 -
(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide [310];
(S)-l-(2-fluoropropyl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide [311];
2-fluoro-2 -methyl -N-(6-( 1 -methyl- 1H- 1 ,2,3 -triazol-4-yl)isoquinolin-3 -yl)propanamide [312] ; (R)-l-(2-fluoropropyl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide [313];
N-(6-(l -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)-2-(piperidin-l-yl)propanamide [314];
N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-l-yl-2,2,5,5-£/4)acetamide [315]; 4-methyl-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperazine-l -carboxamide [316]; (S)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-l-yl)propanamide [317]; (R)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-l-yl)propanamide [318]; 2-methyl -N-(6 -( 1 -methyl - 1 H-pyrazol -4 -yl)isoquinolin-3 -yl) -2 -(pyrrolidin- 1 -yl)propanamide
[319];
(R)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-2 -carboxamide [320];
2-fluoro-2-methyl-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)propanamide [321];
1 -fluoro-N-(6-( 1 -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane- 1 -carboxamide [322] ; 3,3-difluoro-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)cyclobutane-l-carboxamide [323]; 2-methyl -N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6- carboxamide [324];
N-(6-(l -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)-2-(2,2,2-trifluoroacetyl)-2- azaspiro [3.3] heptane -6 -carboxamide [325] ;
2-(2-fluoroethyl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6- carboxamide [326];
fr «5-4-(dimethylamino)-N-(6-( 1 -methyl-lH-pyrazol-4-yl)isoquinolin-3 -yl)cyclohexane- 1 - carboxamide [327];
l-benzoyl-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide [328]; N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)-l -(methylsulfonyl)piperidine-4-carboxamide
[330];
1 '-methyl -N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3-yl)-[ 1 ,4'-bipiperidine]-4-carboxamide
[331];
N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)-l -(tetrahydro-2H-pyran-4-yl)piperidine-4- carboxamide [332];
fr «5-4-(hydroxymethyl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-l- carboxamide [333];
methyl 2-(4-((6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)carbamoyl)piperidin-l -yl)acetate
[334];
l-benzyl-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide [335]; N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)-l -(2-(pyrrolidin-l -yl)acetyl)piperidine-4- carboxamide [336];
1- fluoro-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)cyclopropane-l-carboxamide [337]; N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)-2-morpholinoacetamide [338] ;
trans A -formyl -N-(6 -( 1 -methyl - 1 H-pyrazol -4 -yl)isoquinolin-3 -yl)cyclohexane - 1 -carboxamide
[339];
(S)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-2 -carboxamide [340];
(S)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(3-methylmo holino)acetamide [341]; (R)-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(3 -methylmorpholino)acetamide [342] ; (S)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-methylmo holino)acetamide [343];
2- ((2R,6S)-2,6-dimethylmo holino)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)acetamide
[344];
2-((lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3- yl)acetamide [345];
2-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin- 3-yl)acetamide [346];
2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3- yl)acetamide [347];
(S)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-moφholinopropanamide [348];
N-(6-(l -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)-2-(moφholin-2-yl)acetamide [349];
N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)-2-(4-methylmoφholin-2-yl)acetamide [350] ; 2-(4-ethylpiperazin-l-yl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)acetamide [351]; 2-(4-isopropylpiperazin- 1 -yl)-N-(6-( 1 -methyl-lH-pyrazol-4-yl)isoquinolin-3 -yl)acetamide [352] ; 2-(4-cyclopropylpiperazin- 1 -yl)-N-(6-( 1 -methyl-lH-pyrazol-4-yl)isoquinolin-3 -yl)acetamide
[353];
2-(4-(2-fluoroethyl)piperazin-l -yl)-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)acetamide
[354];
(S)-2-(2,4-dimethylpiperazin-l-yl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)acetamide
[355];
7-methyl-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-7-azaspiro[3.5]nonane-2- carboxamide [356];
N-(6-(l -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)piperidine-4-carboxamide [357];
1- (2-hydroxyethyl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide
[358];
N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)- 1 -(pyridin-2-ylmethyl)piperidine-4- carboxamide [359];
N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)- 1 -(oxazol-2-ylmethyl)piperidine-4- carboxamide [360];
2- (3,3-dimethylazetidin-l-yl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)acetamide [361]; (R)-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3-yl)- 1 -oxotetrahydro- lH-pyrrolo[ 1 ,2- c]imidazole-2(3H)-carboxamide [362];
(R)-l-methyl-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-2-carboxamide [363]; N-(4-chloro-6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide [364]; fr «5-4-amino-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-l-carboxamide
[365];
N-(8-fluoro-6-(l -methyl -lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide [366]; N-(8-fluoro-6-(l -methyl -lH-pyrazol-4-yl)isoquinolin-3-yl)-l-isobutylpiperidine-4-carboxamide
[367];
N-(8-fluoro-6-(l -methyl - 1 H-pyrazol-4-yl)isoquinolin-3 -yl) - 1 -(2 -fluoroethyl)piperidine -4 - carboxamide [368];
N-(7-fluoro-6-( 1 -methyl -lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide [369]; N-(7-fluoro-6-( 1 -methyl -lH-pyrazol-4-yl)isoquinolin-3-yl)-l-isobutylpiperidine-4-carboxamide
[370];
N-(7-fluoro-6-( 1 -methyl - 1 H-pyrazol-4-yl)isoquinolin-3 -yl) - 1 -(2 -fluoroethyl)piperidine -4 - carboxamide [371];
N-(7-fluoro-6-( 1 -methyl -lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-l-yl)acetamide
[372]; N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolm^ [373]; 2-(diethylamino)-N-(6-( l,2-dimethyl-lH midazol-5-yl)isoquinolin-3-yl)acetamide [374];
2-(cyclobutyl(methyl)amino)-N-(6-( l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)ace
[375];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)- 1 -fluorocyclopropane- 1 -carboxamide
[376];
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-methyl-2-azaspiro[3.3]heptane-6- carboxamide [377];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoqum^
6-carboxamide [378];
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-(2,2,2-trifluoroacetyl)-2- azaspiro [3.3] heptane -6 -carboxamide [379] ;
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-7-methyl-7-azaspiro[3.5]nonane-2- carboxamide [380];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)- 1 -fluorocyclohexane- 1 -carboxamide
[381];
fr «5-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-4-(dimethylamino)cyclohexane-l- carboxamide [382];
trans-N-(6-( 1 ,2-dimethyl- 1 H-imidazol-5 -yl)isoquinolin-3 -yl)-4-formylcyclohexane- 1 - carboxamide [383];
fr «5-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-4-(hydroxymethyl)cyclohexane-l - carboxamide [384];
(R)-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)pyrrolidine-2 -carboxamide [385]; N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [386];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)- 1 -(2-hydroxyethyl)piperidine-4- carboxamide [387];
methyl 2-(4-((6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)carbamoyl)piperidin-l - yl)acetate [388];
(R)-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-l-(2-fluoropropyl)piperidine-4- carboxamide [389];
(S)-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-l-(2-fluoropropyl)piperidine-4- carboxamide [390];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)- 1 -(methylsulfonyl)piperidine-4- carboxamide [391]; N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)- 1 -(2 -(pyrrolidin- 1 -yl)acetyl)piperidine-4- carboxamide [392];
1- benzoyl-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide
[393];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)- 1 '-methyl-[ 1 ,4'-bipiperidine] -4- carboxamide [394];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)- 1 -(tetrahydro-2H-pyran-4-yl)piperidine- 4-carboxamide [395];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)- 1 -(oxazol-2-ylmethyl)piperidine-4- carboxamide [396];
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-l-(pyridin-2-ylmethyl)piperidine-4- carboxamide [397];
(S)-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)piperidine-3-carboxamide [398]; N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-l-isobutylpiperidine-3-carboxamide
[399]; and
(R)-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-l-isobutylpiperidine-3-carboxamide
[400]; or a pharmaceutically acceptable salt thereof.
29. The compound of claims 1, wherein the compound of Formula I is selected from the group consisting of:
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-4-methylpiperazine- 1 -carboxamide [401] ; N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-(3,3-dimethylazetidin-l -yl)acetamide
[402];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-2-(pyrrolidin- 1 -yl)acetamide [403] ; (S)-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-(3-fluoropyrrolidin-l-yl)acetamide
[404];
(R)-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-(3-fluoropyrrolidin-l-yl)acetamide
[405];
(R)-N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin- 1 -yl)acetamide
[406];
(S)-N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin- 1 -yl)acetamide
[407];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-2-(pyrrolidin- 1 -yl)propanamide [408] ;
2- (3 -azabicyclo[3.1.0]hexan-3 -yl)-N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3 - yl)acetamide [409]; 2-(4-(difluoromethyl)piperidin- 1 -yl)-N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3 - yl)acetamide [410];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)-2-(4-(trifluoromethyl)piperidin- 1 - yl)acetamide [411];
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)acetamide
[412];
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-(piperidin-l-yl)propanamide [413]; N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperazin- 1 -yl)acetamide
[414];
N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-(4-ethylpiperazin-l-yl)acetamide [415]; N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-2-(4-(2-fluoroethyl)piperazin- 1 - yl)acetamide [416];
(S)-N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)-2-(2,4-dimethylpiperazin- 1 - yl)acetamide [417];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5-yl)isoquinolin-3-yl)-2-(4-isopropylpiperazin- 1 -yl)acetamide
[418];
2-(4-cyclopropylpiperazin-l-yl)-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3- yl)acetamide [419];
N-(6-( 1 ,2-dimethyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-2-moφholinoacetamide [420] ;
(R)-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-(3-methylmo holino)acetamide
[421];
(S)-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-(3-methylmo holino)acetamide
[422];
(S)-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-(2-methylmo holino)acetamide
[423];
(S)-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-moφholinopropanamide [424]; N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-(moφholin-2-yl)acetamide [425]; N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-(4-methylmoφholin-2-yl)acetamide
[426];
2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3- yl)acetamide [427];
2-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(l,2-dimethyl-lH-imidazol-5- yl)isoquinolin-3 -yl)acetamide [428] ; 2-((lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(l,2-dimethyl-lH-imidazol-5- yl)isoquinolin-3 -yl)acetamide [429] ;
2-(3-oxa-8-azabicyclo[3.2. l]octan-8-yl)-N-(6-(l,2-dimethyl-lH-imidazol-5-yl)isoquinolin-3- yl)acetamide [430];
2-(diethylamino)-N-(6-(l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)acetamide [431];
2-(cyclobutyl(methyl)amino)-N-(6-(l-methyl-lH-l,2,3 riazol-4-yl)isoquinolin-3-yl)acetam
[432];
N-(6-( 1 -methyl- 1H- 1 ,2,3-triazol-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide [433] ;
1 -fluoro-N-(6-( 1 -methyl-lH-1 ,2,3 -triazol-4-yl)isoquinolin-3 -yl)cyclopropane-l -carboxamide
[434];
3.3- difluoro-N-(6-(l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)cyclobutane-l -carboxamide
[435];
2-methyl-N-(6-(l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6- carboxamide [436];
2-(2-fluoroethyl)-N-(6-(l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-
6-carboxamide [437];
N-(6-(l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(2,2,2-trifluoroacetyl)-2- azaspiro [3.3] heptane -6 -carboxamide [438] ;
7-methyl-N-(6-(l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)-7-azaspiro[3.5]nonane-2- carboxamide [439];
1 -fluoro-N-(6-( 1 -methyl-lH-1 ,2,3 -triazol-4-yl)isoquinolin-3 -yl)cyclohexane-l -carboxamide
[440];
4.4- difluoro-N-(6-(l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)cyclohexane-l-carboxamide
[441];
fr «5-4-methoxy-N-(6-( 1 -methyl- 1H- 1 ,2,3 -triazol-4-yl)isoquinolin-3 -yl)cyclohexane- 1 - carboxamide [442];
trans A -(dimethylamino) -N-(6 -( 1 -methyl - 1 H- 1 ,2, 3 -triazol -4 -yl)isoquinolin-3 -yl)cyclohexane - 1 - carboxamide [443];
fr «5-4-formyl-N-(6-(l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)cyclohexane-l- carboxamide [444];
fr «5-4-(hydroxymethyl)-N-(6-( 1 -methyl- 1H- 1 ,2,3 -triazol-4-yl)isoquinolin-3 -yl)cyclohexane- 1 - carboxamide [445];
fr «5-N-(6-(l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)-4-mo holinocyclohexane-l- carboxamide [446]; trans-4-((3 -fluoroazetidin- 1 -yl)methyl)-N-(6-( 1 -methyl- lH-1 ,2,3 -triazol-4-yl)isoquinolin-3-yl) cyclohexane-l -carboxamide [447] ;
fr «5-N-(6-(l -methyl-lH-l ,2,3-triazol-4-yl)isoquinolin-3-yl)-4-((4-methylpiperazin-l - yl)methyl)cyclohexane- 1 -carboxamide [448] ;
N-(6-(l -methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide [449] ;
(R)-N-(6-( 1 -methyl- 1H- 1 ,2,3-triazol-4-yl)isoquinolin-3-yl)pyrrolidine-2 -carboxamide [450] ; (R)-N-(6-( 1 -methyl- 1H- 1 ,2,3-triazol-4-yl)isoquinolin-3-yl)tetrahydrofuran-2 -carboxamide [451] ; N-(6-(l -methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide [452];
N-(6-(l -methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide [453];
l-methyl-N-(6-( l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide [454]; 4-fluoro- 1 -methyl -N-(6-( 1 -methyl- 1H- 1,2,3 -triazol-4-yl)isoquinolin-3 -yl)piperidine-4- carboxamide [455];
l-(2-fluoroethyl)-N-(6-( l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide [456];
4-fluoro-l -(2-fluoroethyl)-N-(6-( l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide [457];
l-(2,2-difluoroethyl)-N-(6-(l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide [458];
1 -(2-hydroxyethyl)-N-(6-( 1 -methyl-lH-1 ,2,3 -triazol-4-yl)isoquinolin-3 -yl)piperidine-4- carboxamide [459];
l-(2-methoxyethyl)-N-(6-( l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide [460];
methyl 2-(4-((6-(l -methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)carbamoyl)piperidin-l - yl)acetate [461];
1 -isopropyl-N-(6-( 1 -methyl- 1H- 1,2,3 -triazol-4-yl)isoquinolin-3 -yl)piperidine-4-carboxamide
[462];
1 -cyclopropyl-N-(6-( 1 -methyl-lH-1 ,2,3 -triazol-4-yl)isoquinolin-3 -yl)piperidine-4-carboxamide
[463];
(R)-l -(2-fluoropropyl)-N-(6-(l -methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide [464];
(S)-l -(2-fluoropropyl)-N-(6-( l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide [465];
l-(2,2-difluoropropyl)-N-(6-( l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide [466]; N-(6-(l-methyl-lH-l,2,3 riazol-4-yl)isoquinolin-3-yl)-l-(3,3,3 rifluoropropyl)piperidine-4- carboxamide [467];
l-isobutyl-N-(6-(l-methyl-lH-l,2,3 riazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide
[468];
l-(2-fluoro-2-methylpropyl)-N-(6-(l-methyl-lH-l,2,3 riazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide [469];
N-(6-( 1 -methyl- IH- 1 ,2,3 -triazol-4-yl)isoquinolin-3 -yl)- 1 -(( 1 -
(trifluoromethyl)cyclopropyl)methyl) piperidine -4-carboxamide [470] ;
N-(6-( 1 -methyl- IH- 1 ,2,3 -triazol-4-yl)isoquinolin-3 -yl)- 1 -(oxetan-3 -yl)piperidine-4-carboxamide
[471];
N-(6-( 1 -methyl- IH- 1 ,2,3 -triazol-4-yl)isoquinolin-3 -yl)- 1 -((3 -methyloxetan-3 - yl)methyl)piperidine-4-carboxamide [472] ;
N-(6-( 1 -methyl- IH- 1 ,2,3-triazol-4-yl)isoquinolin-3-yl)- 1 -neopentylpiperidine-4-carboxamide
[473];
N-(6-( 1 -methyl- IH- 1 ,2,3-triazol-4-yl)isoquinolin-3-yl)- 1 -(methylsulfonyl)piperidine-4- carboxamide [474];
N-(6-( 1 -methyl- IH- 1 ,2,3-triazol-4-yl)isoquinolin-3-yl)- 1 -(2-(pyrrolidin- 1 -yl)acetyl)piperidine-4- carboxamide [475];
1 -benzoyl -N-(6-( 1 -methyl- IH- 1 ,2,3-triazol-4-yl)isoquinolin-3 -yl)piperidine-4-carboxamide
[476];
r-methyl-N-(6-(l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)-[l,4'-bipiperidine]-4- carboxamide [477];
N-(6-( 1 -methyl- IH- 1 ,2,3-triazol-4-yl)isoquinolin-3-yl)- 1 -(tetrahydro-2H-pyran-4-yl)piperidine-4- carboxamide [478];
N-(6-( 1 -methyl- IH- 1 ,2,3 -triazol-4-yl)isoquinolin-3 -yl)- 1 -(oxazol-2-ylmethyl)piperidine-4- carboxamide [479];
N-(6-( 1 -methyl- IH- 1 ,2,3-triazol-4-yl)isoquinolin-3-yl)- 1 -(pyridin-2-ylmethyl)piperidine-4- carboxamide [480];
(R)-N-(6-(l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide [481]; 1 -isobutyl-N-(6-( 1 -methyl- IH- 1 ,2,3 -triazol-4-yl)isoquinolin-3 -yl)piperidine-3 -carboxamide
[482];
(R)-l-isobutyl-N-(6-(l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide
[483];
N-(6-(l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)tetrahydro-2H-pyran-4-carboxamide [484]; 4-methyl-N-(6-( 1 -methyl-lH- 1 ,2,3-triazol-4-yl)isoquinolin-3-yl)piperazine- 1 -carboxamide [485] ; 2-(3,3-dimethylazetidin-l -yl)-N-(6-( l-methyl-lH-l,2,3 riazol-4-yl)isoquinolin-3-yl)acetamide
[486];
N-(6-( 1 -methyl- IH- 1 ,2,3 -triazol-4-yl)isoquinolin-3 -yl)-2-(pyrrolidin- 1 -yl)acetamide [487] ; (S)-2-(3-fluoropyrrolidin-l-yl)-N-(6-( l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)acetamide
[488];
(R)-2-(3-fluoropyrrolidin- 1 -yl)-N-(6-( 1 -methyl- IH- 1 ,2,3-triazol-4-yl)isoquinolin-3-yl)acetamide
[489];
(R)-N-(6-( 1 -methyl- IH- 1 ,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin- 1 -yl)acetamide
[490];
(S)-N-(6-( 1 -methyl- IH- 1 ,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin- 1 -yl)acetamide
[491];
N-(6-( 1 -methyl- IH- 1 ,2,3 -triazol-4-yl)isoquinolin-3 -yl)-2-(pyrrolidin- 1 -yl)propanamide [492] ; 2-(3 -azabicyclo [3.1.0]hexan-3 -yl)-N-(6-( 1 -methyl- IH- 1 ,2,3 -triazol-4-yl)isoquinolin-3 - yl)acetamide [493];
2-(4-fluoropiperidin-l -yl)-N-(6-(l -methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)acetamide
[494];
N-(6-( 1 -methyl- IH- 1 ,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperidin- 1 -yl)acetamide
[495];
2-(4-(difluoromethyl)piperidin- 1 -yl)-N-(6-( 1 -methyl- IH- 1,2,3 -triazol-4-yl)isoquinolin-3 - yl)acetamide [496];
N-(6-(l -methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(4-(trifluoromethyl)piperidin-l - yl)acetamide [497];
N-(6-(l -methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)acetamide
[498];
N-(6-(l -methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(piperidin-l -yl)propanamide [499]; and N-(6-( 1 -methyl- IH- 1 ,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin- 1 -yl)acetamide
[500]; or a pharmaceutically acceptable salt thereof.
30. The compound of claims 1, wherein the compound of Formula I is selected from the group consisting of:
2-(4-ethylpiperazin- 1 -yl)-N-(6-( 1 -methyl- IH- 1,2,3 -triazol-4-yl)isoquinolin-3 -yl)acetamide [501] ; 2-(4-(2-fluoroethyl)piperazin-l -yl)-N-(6-( 1 -methyl- IH- 1 ,2,3-triazol-4-yl)isoquinolin-3 - yl)acetamide [502]; (S)-2-(2,4-dimethylpiperazin-l-yl)-N-(6-(l-methyl-lH-l,2,3 riazol-4-yl)isoquinolin-3- yl)acetamide [503];
2-(4 sopropylpiperazin-l-yl)-N-(6-(l-methyl-lH-l,2,3 riazol-4-yl)isoquinolin-3-yl)acetami
[504];
2-(4-cyclopropylpiperazin-l-yl)-N-(6-(l-methyl-lH-l,2,3 riazol-4-yl)isoquinolin-3-yl)acetami
[505];
N-(6-(l-methyl-lH-l,2,3 riazol-4-yl)isoquinolin-3-yl)-2-moφholinoacetamide [506];
(R)-N-(6-( 1 -methyl- IH- 1 ,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(3 -methylmo holino)acetamide
[507];
(S)-N-(6-(l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(3-methylmoφholino)acetamide
[508];
(S)-N-(6-(l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(2-methylmoφholino)acetamide
[509];
(S)-N-(6-(l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)-2-moφholinopropanamide [510]; N-(6-( 1 -methyl- IH- 1 ,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(moφholin-2-yl)acetamide [511]; N-(6-(l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(4-methylmoφholin-2-yl)acetamide
[512];
2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(6-(l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3- yl)acetamide [513];
2-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(l-methyl-lH-l,2,3-triazol-4- yl)isoquinolin-3 -yl)acetamide [514] ;
2-((lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(l-methyl-lH-l,2,3-triazol-4- yl)isoquinolin-3 -yl)acetamide [515] ;
2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(6-(l-methyl-lH-l,2,3-triazol-4-yl)isoquinolin-3- yl)acetamide [516];
2-fluoro-2-methyl-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)propanamide [517]; 2-(diethylamino) -N-(6 -( 1 -methyl - 1 H-imidazol -5 -yl)isoquinolin-3 -yl)acetamide [518];
2-(cyclobutyl(methyl)amino)-N-(6-( 1 -methyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)acetamide
[519];
N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)cyclopropanecarboxamide [520];
1 -fluoro-N-(6-( 1 -methyl-lH-imidazol-5-yl)isoquinolin-3 -yl)cyclopropane- 1 -carboxamide [521] ; 3,3-difluoro-N-(6-( 1 -methyl-lH-imidazol-5 -yl)isoquinolin-3 -yl)cyclobutane- 1 -carboxamide
[522]; 2-methyl-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6- carboxamide [523];
2-(2-fluoroethyl)-N-(6-(l-methyl-lH midazol-5-yl)isoquinolin-3-yl)-2-azaspiro[3 ]heptane-6- carboxamide [524];
N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-(2,2,2-trifluoroacetyl)-2- azaspiro [3.3] heptane -6 -carboxamide [525] ;
7-methyl-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)-7-azaspiro[3.5]nonane-2- carboxamide [526];
l-fluoro-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)cyclohexane-l -carboxamide [527]; fr «5-4-methoxy-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)cyclohexane-l -carboxamide
[528];
fr «5-4-(dimethylamino)-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)cyclohexane-l- carboxamide [529];
trans A -formyl -N-(6 -( 1 -methyl - 1 H-imidazol -5 -yl)isoquinolin-3 -yl)cyclohexane - 1 -carboxamide
[530];
fr «5-4-(hydroxymethyl)-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)cyclohexane-l- carboxamide [531];
fr «5-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)-4-moφholinocyclohexane-l- carboxamide [532];
trans-4-((3 -fluoroazetidin- 1 -yl)methyl)-N-(6-( 1 -methyl- lH-imidazol-5-yl)isoquinolin-3- yl)cyclohexane-l -carboxamide [533];
fr «5-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)-4-((4-methylpiperazin-l- yl)methyl)cyclohexane- 1 -carboxamide [534] ;
N-(6-( 1 -methyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)azetidine-3 -carboxamide [535] ;
(R)-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)pyrrolidine-2 -carboxamide [536];
(R)-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)tetrahydrofuran-2 -carboxamide [537]; N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [538];
N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [539];
l-methyl-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [540]; 4-fluoro-l-methyl-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide
[541];
l-ethyl-4-fluoro-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)piperidine-4 -carboxamide
[542]; 1 -(2 -fluoroethyl) -N-(6 -( 1 -methyl - 1 H-imidazol -5 -yl)isoquinolin-3 -yl)piperidine -4-carboxamide
[543];
4-fluoro-l-(2-fluoroethyl)-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)piperidine-4- carboxamide [544];
l-(2,2-difluoroethyl)-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)piperidine-4- carboxamide [545];
l-(2-hydroxyethyl)-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide
[546];
l-(2-methoxyethyl)-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide
[547];
methyl 2-(4-((6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)carbamoyl)piperidin-l-yl)acetate
[548];
l-isopropyl-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [549]; l-cyclopropyl-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide
[550];
(R)-l-(2-fluoropropyl)-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)piperidine-4- carboxamide [551];
(S)-l-(2-fluoropropyl)-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)piperidine-4- carboxamide [552];
1 -(2,2-difluoropropyl)-N-(6-( 1 -methyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)piperidine-4- carboxamide [553];
1 -isobutyl-N-(6-( 1 -methyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)piperidine-4-carboxamide [554] ; 4-fluoro-l-isobutyl-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide
[555];
l-(2-fluoro-2-methylpropyl)-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)piperidine-4- carboxamide [556];
N-(6-( 1 -methyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)- 1 -((1 -(trifluoromethyl)cyclopropyl)methyl) piperidine -4-carboxamide [557];
N-(6-( 1 -methyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)- 1 -(oxetan-3 -yl)piperidine-4-carboxamide
[558];
N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)-l-((3-methyloxetan-3-yl)methyl)piperidine- 4-carboxamide [559];
N-(6-( 1 -methyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)- 1 -neopentylpiperidine-4-carboxamide [560] ; N-(6-( 1 -methyl- lH-imidazol-5 -yl)isoquin^
[561];
N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)-l-(2-(pyrrolidin-l-yl)acetyl)piperidine-4- carboxamide [562];
1 -benzoyl -N-(6-( 1 -methyl- lH-imidazol -5 -yl)isoquinolin-3-yl)piperidine-4-carboxamide [563] ; 1 '-methyl -N-(6-( 1 -methyl- lH-imidazol-5-yl)isoquinolin -3 -yl)-[ 1 ,4'-bipiperidine] -4-carboxamide
[564];
N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)-l-(tetrahydro-2H-pyran-4-yl)piperidine-4- carboxamide [565];
N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)-l-(oxazol-2-ylmethyl)piperidine-4- carboxamide [566];
N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)-l-(pyridin-2-ylmethyl)piperidine-4- carboxamide [567];
(S)-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)piperidine-3-carboxamide [568];
1- isobutyl-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)piperidine-3-carboxamide [569]; (R)-l-isobutyl-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)piperidine-3-carboxamide
[570];
N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)tetrahydro-2H-pyran-4-carboxamide [571]; 4-methyl-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)piperazine-l-carboxamide [572];
2- (3,3-dimethylazetidin-l-yl)-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)acetamide
[573];
N-(6-( 1 -methyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-2-(pyrrolidin- 1 -yl)acetamide [574] ;
(S)-2-(3-fluoropyrrolidin- 1 -yl)-N-(6-( 1 -methyl-lH-imidazol-5 -yl)isoquinolin-3 -yl)acetamide
[575];
(R)-2-(3-fluoropyrrolidin- 1 -yl)-N-(6-( 1 -methyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)acetamide
[576];
(R)-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin-l-yl)acetamide
[577];
(S)-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin-l-yl)acetamide
[578];
N-(6-( 1 -methyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-2-(pyrrolidin- 1 -yl)propanamide [579] ; 2-(3 -azabicyclo[3.1.0]hexan-3 -yl)-N-(6-( 1 -methyl- lH-imidazol-5 -yl)isoquinolin-3-yl)acetamide
[580];
2-(4-fluoropiperidin-l-yl)-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)acetamide [581]; N-(6-(l -methyl-lH-imidazol-5-yl)isoqum^ [582]; 2-(4-(difluoromethyl)piperidin- 1 -yl)-N-(6-( 1 -methyl- lH-imidazol-5-yl)isoquinolin-3 - yl)acetamide [583];
N-(6-(l -methyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-(4-(trifluoromethyl)piperidin-l - yl)acetamide [584];
N-(6-(l -methyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)acetamide
[585];
N-(6-(l -methyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-(piperidin-l-yl)propanamide [586] ;
N-(6-( 1 -methyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)-2-(4-methylpiperazin- 1 -yl)acetamide [587] ; 2-(4-ethylpiperazin-l -yl)-N-(6-(l -methyl-lH-imidazol-5-yl)isoquinolin-3-yl)acetamide [588]; 2-(4-(2-fluoroethyl)piperazin-l -yl)-N-(6-( l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)acetamide
[589];
(S)-2-(2,4-dimethylpiperazin-l-yl)-N-(6-(l -methyl-lH-imidazol-5-yl)isoquinolin-3-yl)acetamide
[590];
2-(4-isopropylpiperazin- 1 -yl)-N-(6-( 1 -methyl-lH-imidazol-5 -yl)isoquinolin-3 -yl)acetamide
[591];
2-(4 -cyclopropylpiperazin- 1 -yl) -N-(6 -( 1 -methyl - 1 H-imidazol -5 -yl)isoquinolin-3 -yl)acetamide
[592];
N-(6-(l -methyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-mo holinoacetamide [593];
(R)-N-(6-(l -methyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-(3-methylmo holino)acetamide [594]; (S)-N-(6-(l -methyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-(3-methylmo holino)acetamide [595]; (S)-N-(6-(l -methyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-(2-methylmo holino)acetamide [596]; (S)-N-(6-(l -methyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-moφholinopropanamide [597] ;
N-(6-(l -methyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-(moφholin-2-yl)acetamide [598];
N-(6-(l -methyl-lH-imidazol-5-yl)isoquinolin-3-yl)-2-(4-methylmoφholin-2-yl)acetamide [599];
and
2-(7-azabicyclo [2.2.1 ]heptan-7-yl)-N-(6-( 1 -methyl- lH-imidazol-5 -yl)isoquinolin-3 -yl)acetamide
[600]; or a pharmaceutically acceptable salt thereof.
31. The compound of claims 1, wherein the compound of Formula I is selected from the group consisting of:
2-(( lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(l -methyl-lH-imidazol-5-yl)isoquinolin- 3-yl) acetamide [601] ;
2-(( l S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(l -methyl-lH-imidazol-5-yl)isoquinolin- 3-yl) acetamide [602] ; 2-(3-oxa-8-azabicyclo[3.2. l]octan-8-yl)-N-(6-( l-methyl-lH-imidazol-5-yl)isoquinolin-3- yl)acetamide [603];
N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-2-fluoro-2-methylpropanamide [604];
N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(diethylamino)acetamide [605] ;
N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(cyclobutyl(methyl)amino)acetamide [606] ;
N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide [607] ;
N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-l-fluorocyclopropane-l -carboxamide [608] ;
N-(6-( lH-pyrazol-4-yl)isoquinolin-3-yl)-3,3 -difluorocyclobutane- 1 -carboxamide [609] ;
N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-2-methyl-2-azaspiro[3.3]heptane-6-carboxamide [610]; N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-fluoroethyl)-2-azaspiro[3.3]heptane-6-carboxamide
[611];
N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(2,2,2-trifluoroacetyl)-2-azaspiro[3.3]heptane-6- carboxamide [612];
N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-7-methyl-7-azaspiro[3.5]nonane-2 -carboxamide [613]; N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-l-fluorocyclohexane-l-carboxamide [614] ;
N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-4,4-difluorocyclohexane-l -carboxamide [615];
fr «5-N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-4-(dimethylamino)cyclohexane-l-carboxamide
[617];
fr «5-N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-4-formylcyclohexane-l-carboxamide [618] ;
fr «5-N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-4-(hydroxymethyl)cyclohexane-l-carboxamide
[619];
trans-N-(6-( lH-pyrazol-4-yl)isoquinolin-3-yl)-4-moφholinocyclohexane- 1 -carboxamide [620] ; fr «5-N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-4-((3-fluoroazetidin-l -yl)methyl)cyclohexane-l- carboxamide [621];
fr «5-N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-4-((4-methylpiperazin-l -yl)methyl)cyclohexane-l - carboxamide [622];
N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide [623];
(R)-N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-2 -carboxamide [624];
(R)-N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)tetrahydrofuran-2 -carboxamide [625] ;
N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide [626];
N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide [627];
N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-l-methylpiperidine-4-carboxamide [628] ;
N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-4-fluoro-l -methylpiperidine-4-carboxamide [629]; N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-l-ethyl-4-fluoropiperidine-4-carboxamide [630] ; N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-l-(2-fluoroethyl)piperidine-4-carboxamide [631]; N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-4-fluoro-l-(2-fluoroethyl)piperidine-4-carboxamide
[632];
N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-l-(2,2-difluoroethyl)piperidine-4-carboxamide [633]; N-(6-( lH-pyrazol-4-yl)isoquinolin-3-yl)- 1 -(2-hydroxyethyl)piperidine-4-carboxamide [634] ; N-(6-( lH-pyrazol-4-yl)isoquinolin-3-yl)- 1 -(2-methoxyethyl)piperidine-4-carboxamide [635] ; methyl 2-(4-((6-( lH-pyrazol-4-yl)isoquinolin-3 -yl)carbamoyl)piperidin- 1 -yl)acetate [636] ; N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-l-isopropylpiperidine-4-carboxamide [637];
N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-l-cyclopropylpiperidine-4-carboxamide [638];
(R)-N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-l-(2-fluoropropyl)piperidine-4-carboxamide [639]; (S)-N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-l-(2-fluoropropyl)piperidine-4-carboxamide [640]; N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-l-(2,2-difluoropropyl)piperidine-4-carboxamide [641]; N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-l-(3,3,3 rifluoropropyl)piperidine-4-carboxamide
[642];
N-(6-( lH-pyrazol-4-yl)isoquinolin-3-yl)- 1 -isobutylpiperidine-4-carboxamide [643] ;
N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-4-fluoro-l-isobutylpiperidine-4-carboxamide [644]; N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-l-(2-fluoro-2-methylpropyl)piperidine-4-carboxami
[645];
N-(6-( lH-pyrazol-4-yl)isoquinolin-3-yl)- 1 -(( 1 -(trifluoromethyl)cyclopropyl)methyl)piperidine-4- carboxamide [646];
N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-l-(oxetan-3-yl)piperidine-4-carboxamide [647];
N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-l-((3-methyloxetan-3-yl)methyl)piperidine-4- carboxamide [648];
N-(6-( lH-pyrazol-4-yl)isoquinolin-3-yl)- 1 -neopentylpiperidine-4-carboxamide [649] ;
N-(6-( lH-pyrazol-4-yl)isoquinolin-3-yl)- 1 -(methylsulfonyl)piperidine-4-carboxamide [650] ; N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-l-(2-(pyrrolidin-l-yl)acetyl)piperidine-4-carboxamide
[651];
N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-l-benzoylpiperidine-4-carboxamide [652];
N-(6-( lH-pyrazol-4-yl)isoquinolin-3 -yl)-l '-methyl-[ 1 ,4'-bipiperidine] -4-carboxamide [653] ; N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-l-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxamide
[654];
N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-l-(oxazol-2-ylmethyl)piperidine-4-carboxamide [655]; N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-l-(pyridin-2-ylmethyl)piperidine-4-carboxamide [656]; (S)-N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide [657]; N 6-( lH-pyrazol-4-yl)isoquinolin-3-yl)- 1 -isobutylpiperidine-3-carboxamide [658] ;
(R: -N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-l-isobutylpiperidine-3-carboxamide [659];
N 6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-4-methylpiperazine-l-carboxamide [661] ;
N 6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(3,3-dimethylazetidin-l-yl)acetamide [662] ;
N 6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-l-yl)acetamide [663];
(S -N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(3-fluoropyrrolidin-l-yl)acetamide [664];
(R: -N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(3-fluoropyrrolidin-l-yl)acetamide [665];
(R -N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin-l-yl)acetamide [666] ; (s -N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin-l-yl)acetamide [667] ;
N 6- ((llHH--ppyvrraazzooll--44--yvll ))iissooqquuiinnoolliinn--33--yvll))-2-(pyrrolidin-l-yl)propanamide [668] ;
N 6- ((llHH--ppyvrraazzooll--44--yvll ))iissooqquuiinnoolliinn--33--yvll))-2-(3-azabicyclo[3.1.0]hexan-3-yl)acetamide [669] ; N 6- ((llHH--ppyvrraazzooll--44--yvll ))iissooqquuiinnoolliinn--33--yyll))-2-(piperidin-l-yl)acetamide [670];
N 6- ((llHH--ppyvrraazzooll--44--yvll ))iissooqquuiinnoolliinn--33--yvll))-2-(4-fluoropiperidin-l-yl)acetamide [671];
N (lH-pyrazol-4-yl )isoquinolin-3-yl))-2-(4-methylpiperidin- 1 -yl)acetamide [672] ;
N (lH-pyrazol-4-yl )isoquinolin-3-yl))-2-(4-(difluoromethyl)piperidin- 1 -yl)acetamide [673] ; N (lH-pyrazol-4-yl )isoquinolin-3-yl))-2-(4-(trifluoromethyl)piperidin- 1 -yl)acetamide [674] ; N (lH-pyrazol-4-yl )isoquinolin-3-yl))-2-(6-azaspiro[2.5]octan-6-yl)acetamide [675] ;
N (lH-pyrazol-4-yl )isoquinolin-3-yl))-2-(piperidin-l-yl)propanamide [676] ;
N (lH-pyrazol-4-yl )isoquinolin-3-yl))-2-(4-methylpiperazin- 1 -yl)acetamide [677] ;
N (lH-pyrazol-4-yl )isoquinolin-3-yl))-2-(4-ethylpiperazin- 1 -yl)acetamide [678] ;
N (lH-pyrazol-4-yl )isoquinolin-3-yl))-2-(4-(2-fluoroethyl)piperazin- 1 -yl)acetamide [679] ;
(S (6-(lH-pyrazol yl)isoquinolin- yl)-2-(2,4-dimethylpiperazin-l-yl)acetamide [680]; N (lH-pyrazol-4-yl )isoquinolin-3-yl)) -2-(4 -isopropylpiperazin- 1 -yl)acetamide [681] ;
N (lH-pyrazol-4-yl )isoquinolin-3-yl))-2-(4-cyclopropylpiperazin-l -yl)acetamide [682] ; N (lH-pyrazol-4-yl )isoquinolin-3-yl))-2^οφηο1πκ^οεΐ3Γτ^ε [683];
(R -N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(3-methylmoφholino)acetamide [684];
(s -N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(3-methylmoφholino)acetamide [685];
(S -N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-methylmoφholino)acetamide [686];
(S -N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-2-moφholinopropanamide [687];
N 6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(moφholin-2-yl)acetamide [688] ;
N 6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylmoφholin-2-yl)acetamide [689];
N 6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(7-azabicyclo[2.2.1]heptan-7-yl)acetamide [690]; N 6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-2-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5- yl)acetamide [691]; N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(( l S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5- yl)acetamide [692];
N-(6-(lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)acetamide [693]; 2-fluoro-2-methyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)propanamide [694] ;
2-(diethylamino)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide [695];
2-(cyclobutyl(methyl)amino)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide [696] ;
N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclopropanecarboxamide [697] ;
1- fluoro-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclopropane-l -carboxamide [698];
3.3- difluoro-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclobutane-l-carboxamide [699]; and
2- methyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide [700]; or a pharmaceutically acceptable salt thereof.
32. The compound of claims 1, wherein the compound of Formula I is selected from the group consisting of:
2-(2-fluoroethyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide
[701];
N-(6-(thiazol-5-yl)isoquinolin-3-yl)-2-(2,2,2-trifluoroacetyl)-2-azaspiro[3.3]heptane-6- carboxamide [702];
7-methyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)-7-azaspiro[3.5]nonane-2-carboxamide [703];
l-fluoro-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclohexane-l -carboxamide [704] ;
4.4- difluoro-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclohexane-l-carboxamide [705] ;
fr «5-4-methoxy-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclohexane-l -carboxamide [706];
fr «5-4-(dimethylamino)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclohexane-l -carboxamide [707]; fr «5-4-formyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclohexane-l-carboxamide [708];
fr «5-4-(hydroxymethyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclohexane-l-carboxamide [709] ; fr «5-4-mo holino-N-(6-(thiazol-5-yl)isoquinolin-3 -yl)cyclohexane- 1 -carboxamide [710] ;
trans-4-((3 -fluoroazetidin- 1 -yl)methyl)-N-(6-(thiazol-5 -yl)isoquinolin-3 -yl)cyclohexane- 1 - carboxamide [711];
fr «5-4-((4-methylpiperazin-l -yl)methyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclohexane-l- carboxamide [712];
N-(6-(thiazol-5-yl)isoquinolin-3-yl)azetidine-3-carboxamide [713] ;
(R)-N-(6-(thiazol-5 -yl)isoquinolin-3 -yl)pyrrolidine -2 -carboxamide [714] ;
(R)-N-(6-(thiazol-5 -yl)isoquinolin-3 -yl)tetrahydrofuran -2 -carboxamide [715] ;
N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [716];
N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [717]; l-methyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [718];
4-fluoro-l-methyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [719];
l-ethyl-4-fluoro-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [720];
1 -(2 -fluoroethyl) -N-(6 -(thiazol -5 -yl)isoquinolin-3 -yl)piperidine -4 -carboxamide [721 ] ;
4-fluoro-l-(2-fluoroethyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [722]; l-(2,2-difluoroethyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [723];
l-(2-hydroxyethyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [724];
l-(2-methoxyethyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [725];
methyl 2-(4-((6-(thiazol-5 -yl)isoquinolin-3-yl)carbamoyl)piperidin- 1 -yl)acetate [726] ;
1 -isopropyl-N-(6-(thiazol-5 -yl)isoquinolin-3 -yl)piperidine -4 -carboxamide [727] ;
1 -cyclopropyl-N-(6-(thiazol-5 -yl)isoquinolin-3 -yl)piperidine -4 -carboxamide [728] ;
(R)-l-(2-fluoropropyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [729]; (S)-l-(2-fluoropropyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [730]; l-(2,2-difluoropropyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [731]; N-(6-(thiazol-5-yl)isoquinolin-3-yl)-l-(3,3,3-trifluoropropyl)piperidine-4-carboxamide [732]; l-isobutyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [733];
4-fluoro-l-isobutyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [734];
1 -(2-fluoro-2-methylpropyl)-N-(6-(thiazol-5 -yl)isoquinolin-3 -yl)piperidine-4 -carboxamide [735] ; N-(6-(thiazol-5 -yl)isoquinolin-3 -yl)- 1 -(( 1 -(trifluoromethyl)cyclopropyl)methyl)piperidine-4- carboxamide [736];
1 -(oxetan-3-yl)-N-(6-(thiazol-5 -yl)isoquinolin-3 -yl)piperidine-4-carboxamide [737] ;
l-((3-methyloxetan-3-yl)methyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide
[738];
l-neopentyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [739];
l-(methylsulfonyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [740];
1 -(2-(pyrrolidin-l -yl)acetyl)-N-(6-(thiazol-5 -yl)isoquinolin-3 -yl)piperidine-4 -carboxamide [741] ; 1 -benzoyl -N-(6-(thiazol-5-yl)isoquinolin -3 -yl)piperidine -4 -carboxamide [742];
r-methyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)-[l,4'-bipiperidine]-4-carboxamide [743];
l-(tetrahydro-2H-pyran-4-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4 -carboxamide
[744];
l-(oxazol-2-ylmethyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [745]; l-(pyridin-2-ylmethyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [746]; (S)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-3 -carboxamide [747];
l-isobutyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-3-carboxamide [748]; (R)-l -isobutyl-N-(6-(thiazol-5 -yl)isoquinolin-3 -yl)piperidine-3 -carboxamide [749] ;
N-(6-(thiazol-5-yl)isoquinolin-3-yl)tetrahydro-2H-pyran-4-carboxamide [750];
4-methyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperazine-l -carboxamide [751];
2-(3 ,3 -dimethylazetidin- 1 -yl)-N-(6-(thiazol-5 -yl)isoquinolin-3 -yl)acetamide [752] ;
2-(pyrrolidin-l-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide [753];
(S)-2-(3-fluoropyrrolidin-l-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide [754];
(R)-2-(3-fluoropyrrolidin-l-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide [755];
(R)-2-(2-methylpyrrolidin- 1 -yl)-N-(6-(thiazol-5 -yl)isoquinolin-3-yl)acetamide [756] ;
(S)-2-(2-methylpyrrolidin-l-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide [757];
2-(pyrrolidin-l-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)propanamide [758];
2-(3 -azabicyclo [3.1.0]hexan-3 -yl)-N-(6-(thiazol-5 -yl)isoquinolin-3 -yl)acetamide [759] ;
2-(piperidin- 1 -yl)-N-(6-(thiazol-5 -yl)isoquinolin-3 -yl)acetamide [760] ;
2-(4-fluoropiperidin-l-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide [761];
2-(4-methylpiperidin- 1 -yl)-N-(6-(thiazol-5 -yl)isoquinolin-3 -yl)acetamide [762] ;
2-(4-(difluoromethyl)piperidin-l-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide [763]; N-(6-(thiazol-5-yl)isoquinolin-3-yl)-2-(4-(trifluoromethyl)piperidin-l-yl)acetami [764]; 2-(6-azaspiro[2.5]octan-6-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide [765];
2-(piperidin- 1 -yl)-N-(6-(thiazol-5 -yl)isoquinolin-3 -yl)propanamide [766] ;
2-(4-methylpiperazin- 1 -yl)-N-(6-(thiazol-5 -yl)isoquinolin-3 -yl)acetamide [767] ;
2-(4-ethylpiperazin-l-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide [768];
2-(4-(2-fluoroethyl)piperazin-l-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide [769];
(S)-2-(2,4-dimethylpiperazin-l-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide [770];
2-(4 sopropylpiperazin-l-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide [771];
2-(4-cyclopropylpiperazin-l-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide [772];
2-moφholino-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide [773];
(R)-2-(3-methylmo holino)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide [774];
(S)-2-(3-methylmo holino)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide [775];
(S)-2-(2-methylmo holino)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide [776];
(S)-2-moφholino-N-(6-(thiazol-5-yl)isoquinolin-3-yl)propanamide [777];
2-(moφholin-2-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide [778];
2-(4-methylmoφholin-2-yl)-N-(6-(thiazol-5 -yl)isoquinolin-3 -yl)acetamide [779] ;
2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide [780];
2-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide
[781]; 2-((lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide
[782];
2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide [783]; 2-fluoro-2-methyl-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl) propanamide [784];
2-(diethylamino)-N-(6-( 1 -methyl -5 -(piperidin- 1 -ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3 - yl)acetamide [785];
2-(cyclobutyl(methyl)amino)-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4- yl)isoquinolin-3-yl) acetamide [786];
N-(6-( 1 -methyl-5 -(piperidin- 1 -ylmethyl)- lH-pyrazol-4-yl)isoquinolin-3 - yl)cyclopropanecarboxamide [787];
1 -fluoro-N-(6-( 1 -methyl-5 -(piperidin- 1 -ylmethyl)- lH-pyrazol-4-yl)isoquinolin-3- yl)cyclopropane-l -carboxamide [788];
3,3-difluoro-N-(6-( 1 -methyl-5 -(piperidin- 1 -ylmethyl)- lH-pyrazol-4-yl)isoquinolin-3- yl)cyclobutane- 1 -carboxamide [789] ;
2-methyl -N-(6 -( 1 -methyl -5 -(piperidin- 1 -ylmethyl) - 1 H-pyrazol -4 -yl)isoquinolin-3 -yl) -2 - azaspiro[3.3] heptane-6-carboxamide [790];
2-(2-fluoroethyl)-N-(6-( 1 -methyl-5 -(piperidin- 1 -ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3 -yl)-2- azaspiro [3.3]heptane-6-carboxamide [791];
N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(2,2,2- trifluoroacetyl) -2-azaspiro [3.3] heptane -6 -carboxamide [792] ;
7-methyl -N-(6 -( 1 -methyl -5 -(piperidin- 1 -ylmethyl) - 1 H-pyrazol -4 -yl)isoquinolin-3 -yl) -7 - azaspiro[3.5] nonane-2-carboxamide [793];
1 -fluoro-N-(6-( 1 -methyl-5 -(piperidin- 1 -ylmethyl)- lH-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-
1 -carboxamide [794];
fr «5-4-methoxy-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3- yl)cyclohexane-l -carboxamide [795];
fr «5-4-(dimethylamino)-N-(6-( 1 -methyl-5 -(piperidin- 1 -ylmethyl)-lH-pyrazol-4-yl)isoquinolin-
3-yl) cyclohexane-1 -carboxamide [796];
fr «5-4-formyl-N-(6-( 1 -methyl-5 -(piperidin- 1 -ylmethyl)- lH-pyrazol-4-yl)isoquinolin-3- yl)cyclohexane-l -carboxamide [797];
fr «5-4-(hydroxymethyl)-N-(6-( 1 -methyl-5 -(piperidin- 1 -ylmethyl)- lH-pyrazol-4-yl)isoquinolin-
3-yl) cyclohexane-1 -carboxamide [798]; trans-N-(6-(l -methyl -5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)-4- mo holinocyclohexane-l -carboxamide [799]; and
trans-4-((3 -fluoroazetidin- 1 -yl)methyl)-N-(6-( 1 -methyl-5-(piperidin-l -ylmethyl)- lH-pyrazol-4- yl) isoquinolin-3-yl)cyclohexane-l -carboxamide [800]; or a pharmaceutically acceptable salt thereof.
33. The compound of claims 1, wherein the compound of Formula I is selected from the group consisting of:
trans-N-(6-(\ -methyl -5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)-4-((4- methylpiperazin-l -yl)methyl)cyclohexane-l -carboxamide [801];
N-(6-( 1 -methyl-5-(piperidin- 1 -ylmethyl)- lH-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3 - carboxamide [802];
(R)-N-(6-(l -methyl-5-(piperidin-l -ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-2- carboxamide [803];
(R)-N-(6-(l -methyl-5-(piperidin-l -ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)tetrahydrofuran-
2- carboxamide [804];
N-(6-(l -methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide [805];
N-(6-(l -methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide [806];
1 -methyl -N-(6-( 1 -methyl -5 -(piperidin- 1 -ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine- 4-carboxamide [807];
4-fluoro-l -methyl-N-(6-(l -methyl-5-(piperidin-l -ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3- yl)piperidine-4-carboxamide [808];
1 -ethyl -4-fluoro-N-(6-( 1 -methyl -5 -(piperidin- 1 -ylmethyl)- lH-pyrazol-4-yl)isoquinolin-3- yl)piperidine-4-carboxamide [809];
1 -(2-fluoroethyl)-N-(6-( 1 -methyl -5 -(piperidin- 1 -ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3 - yl)piperidine-4-carboxamide [810];
4-fluoro-l -(2-fluoroethyl)-N-(6-( l-methyl-5-(piperidin-l -ylmethyl)-lH-pyrazol-4-yl)isoquinolin-
3- yl) piperidine-4-carboxamide [811];
1 -(2,2-difluoroethyl)-N-(6-( 1 -methyl -5 -(piperidin- 1 -ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl) piperidine -4 -carboxamide [812];
1 -(2-hydroxyethyl)-N-(6-( 1 -methyl -5 -(piperidin- 1 -ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl) piperidine -4 -carboxamide [813]; l-(2-methoxyethyl)-N-(6-(l-methyl-5-(piperidin-l-ylm
piperidine -4 -carboxamide [814];
methyl 2-(4-((6-(l -methyl -5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl) carbamoyl)piperidin-l-yl)acetate [815];
l-isopropyl-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3- yl)piperidine-4-carboxamide [816];
1 -cyclopropyl-N-(6-( 1 -methyl -5 -(piperidin- 1 -ylmethyl)- lH-pyrazol-4-yl)isoquinolin-3- yl)piperidine-4-carboxamide [817];
(R)-l-(2-fluoropropyl)-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3- yl) piperidine -4 -carboxamide [818];
(S)-l-(2-fluoropropyl)-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3- yl) piperidine -4 -carboxamide [819];
1 -(2,2-difluoropropyl)-N-(6-( 1 -methyl-5 -(piperidin- 1 -ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3 - yl) piperidine -4 -carboxamide [820];
N-(6-( 1 -methyl-5 -(piperidin- 1 -ylmethyl)- lH-pyrazol-4-yl)isoquinolin-3 -yl)- 1 -(3 ,3 ,3 - trifluoropropyl)piperidine-4-carboxamide [821] ;
l-isobutyl-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-
4-carboxamide [822];
4-fluoro-l-isobutyl-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl) piperidine -4 -carboxamide [823];
1 -(2-fluoro-2-methylpropyl)-N-(6-( 1 -methyl-5 -(piperidin-1 -ylmethyl)- lH-pyrazol-4- yl)isoquinolin-3-yl) piperidine -4 -carboxamide [824];
N-(6-( 1 -methyl-5 -(piperidin- 1 -ylmethyl)- lH-pyrazol-4-yl)isoquinolin-3 -yl)- 1 -(( 1 -
(trifluoromethyl) cyclopropyl)methyl)piperidine -4 -carboxamide [825] ;
N-(6-( 1 -methyl-5 -(piperidin- 1 -ylmethyl)- lH-pyrazol-4-yl)isoquinolin-3 -yl)- 1 -(oxetan-3 - yl)piperidine-4-carboxamide [826];
N-(6-( 1 -methyl-5 -(piperidin- 1 -ylmethyl)- lH-pyrazol-4-yl)isoquinolin-3 -yl)- 1 -((3 -methyloxetan-
3-yl) methyl)piperidine -4 -carboxamide [827];
N-(6-( 1 -methyl-5 -(piperidin- 1 -ylmethyl)- lH-pyrazol-4-yl)isoquinolin-3 -yl)- 1 - neopentylpiperidine-4-carboxamide [828] ;
N-(6-( 1 -methyl-5 -(piperidin- 1 -ylmethyl)- lH-pyrazol-4-yl)isoquinolin-3 -yl)- 1 -
(methylsulfonyl)piperidine-4-carboxamide [829] ;
N-(6-( 1 -methyl-5 -(piperidin- 1 -ylmethyl)- lH-pyrazol-4-yl)isoquinolin-3 -yl)- 1 -(2-(pyrrolidin- 1 - yl)acetyl) piperidine -4 -carboxamide [830]; 1 -benzoyl -N-(6-( 1 -methyl-5-(piperidin- 1 -yto
4-carboxamide [831];
r-methyl-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)-[l,4'- bipiperidine] -4-carboxamide [832];
N-(6-( 1 -methyl-5 -(piperidin- 1 -ylmethyl)- lH-pyrazol-4-yl)isoquinolin-3 -yl)- 1 -(tetrahydro-2H- pyran-4-yl) piperidine -4-carboxamide [833];
N-(6-( 1 -methyl-5 -(piperidin- 1 -ylmethyl)- lH-pyrazol-4-yl)isoquinolin-3 -yl)- 1 -(oxazol-2- ylmethyl) piperidine-4-carboxamide [834];
N-(6-( 1 -methyl-5 -(piperidin- 1 -ylmethyl)- lH-pyrazol-4-yl)isoquinolin-3-yl)- 1 -(pyridin-2- ylmethyl) piperidine -4-carboxamide [835];
(R)-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-3- carboxamide [836];
1- isobutyl-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-
3- carboxamide [837];
(R)-l -isobutyl-N-(6-( 1 -methyl-5 -(piperidin- 1 -ylmethyl)- lH-pyrazol-4-yl)isoquinolin-3- yl)piperidine-3-carboxamide [838];
N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)tetrahydro-2H-pyran-
4- carboxamide [839];
4-methyl -N-(6 -( 1 -methyl -5 -(piperidin- 1 -ylmethyl) - 1 H-pyrazol -4 -yl)isoquinolin-3 -yl)piperazine - 1-carboxamide [840];
2- (3,3-dimethylazetidin-l-yl)-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4- yl)isoquinolin-3-yl) acetamide [841];
N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-l- yl)acetamide [842];
( S) -2 -(3 -fluoropyrrolidin- 1 -yl) -N-(6 -( 1 -methyl -5 -(piperidin- 1 -ylmethyl)- 1 H-pyrazol-4 - yl)isoquinolin-3 -yl)acetamide [843] ;
(R) -2 -(3 -fluoropyrrolidin- 1 -yl) -N-(6 -( 1 -methyl-5 -(piperidin- 1 -ylmethyl) - 1 H-pyrazol-4 - yl)isoquinolin-3 -yl)acetamide [844] ;
(R)-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(2- methylpyrrolidin- 1 -yl)acetamide [845] ;
(S)-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(2- methylpyrrolidin- 1 -yl)acetamide [846] ;
N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-l-yl) propanamide [847]; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4- yl)isoquinolin-3 -yl)acetamide [848] ;
N-(6-( 1 -methyl-5 -(piperidin- 1 -ylmethyl)- lH-pyrazol-4-yl)isoquinolin-3 -yl)-2-(piperidin- 1 - yl)acetamide [849];
2-(4-fluoropiperidin-l-yl)-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-
3-yl) acetamide [850];
N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(4- methylpiperidin-l-yl) acetamide [851];
2-(4-(difluoromethyl)piperidin-l-yl)-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl) isoquinolin-3-yl)acetamide [852];
N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-
(trifluoromethyl) piperidin- l-yl)acetamide [853];
N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(6- azaspiro[2.5]octan-6-yl) acetamide [854];
N-(6-( 1 -methyl-5 -(piperidin- 1 -ylmethyl)- lH-pyrazol-4-yl)isoquinolin-3 -yl)-2-(piperidin- 1 -yl) propanamide [855];
N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(4- methylpiperazin-l-yl) acetamide [856];
2-(4-ethylpiperazin-l-yl)-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-
3-yl) acetamide [857];
2-(4-(2-fluoroethyl)piperazin-l-yl)-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl) isoquinolin-3-yl)acetamide [858];
( S) -2 -(2,4 -dimethylpiperazin- 1 -yl) -N-(6-( 1 -methyl -5 -(piperidin- 1 -ylmethyl) - 1 H-pyrazol -4 - yl)isoquinolin-3 -yl)acetamide [859] ;
2-(4-isopropylpiperazin- 1 -yl)-N-(6-( 1 -methyl-5 -(piperidin- 1 -ylmethyl)-lH-pyrazol-4- yl)isoquinolin-3-yl) acetamide [860];
2-(4-cyclopropylpiperazin- 1 -yl)-N-(6-( 1 -methyl-5 -(piperidin-1 -ylmethyl)- lH-pyrazol-4- yl)isoquinolin-3 -yl)acetamide [861] ;
N-(6-( 1 -methyl-5 -(piperidin- 1 -ylmethyl)- lH-pyrazol-4-yl)isoquinolin-3 -yl)-2- mo holinoacetamide [862];
(R)-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(3- methylmo holino) acetamide [863];
(S)-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(3- methylmo holino) acetamide [864]; (S)-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(2- methylmorpholino)acetamide [865];
(S)-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)-2- mo holinopropanamide [866] ;
N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lHφyrazol-4-yl)isoquinolin-3-yl)-2-(mo holin-2- yl)acetamide [867];
N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(4- methylmc^holin-2-yl) acetamide [868];
2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(6-(l -methyl -5-(piperidin-l-ylmethyl)-lH-pyrazol-4- yl)isoquinolin-3 -yl)acetamide [869] ;
2-((lR,4R)-2-oxa-5-azabicyclo[2 ]heptan-5-yl)-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH- pyrazol-4-yl)isoquinolin-3 -yl)acetamide [870] ;
2-((lS,4S)-2-oxa-5-azabicyclo[2 ]heptan-5-yl)-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH- pyrazol-4-yl)isoquinolin-3-yl)acetamide [871];
2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(6-(l-methyl-5-(piperidin-l-ylmethyl)-lH-pyrazol-4- yl) isoquinolin-3-yl)acetamide [872];
2-fluoro-2-methyl-N-(6-(5-methyl-l,3,4 hiadiazol-2-yl)isoquinolin-3-yl)propanamide [873]; 2-(diethylamino)-N-(6-(5-methyl-l,3,4 hiadiazol-2-yl)isoquinolin-3-yl)acetamide [874];
2-(cyclobutyl(methyl)amino)-N-(6-(5-methyl^^
[875];
N-(6-(5 -methyl- 1 ,3 ,4-thiadiazol-2-yl)isoquinolin-3 -yl)cyclopropanecarboxamide [876] ;
1- fluoro-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclopropane-l-carboxamide
[877];
3,3-difluoro-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclobutane-l-carboxamide
[878];
2- methyl-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6- carboxamide [879];
2-(2-fluoroethyl)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-
6-carboxamide [880];
N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(2,2,2-trifluoroacetyl)-2- azaspiro [3.3] heptane -6 -carboxamide [881 ] ;
7-methyl-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-7-azaspiro[3.5]nonane-2- carboxamide [882]; 1 -fluoro-N-(6-(5 -methyl- 1 ,3 ,4-thiadiazol-2-yl)isoquinolin-3 -yl)cyclohexane- 1 -carboxamide
[883];
4,4-difluoro-N-(6-(5 -methyl-1 ,3,4-thiadiazol-2-yl)isoquinolin -3 -yl)cyclohexane- 1 -carboxamide
[884];
fr «5-4-methoxy-N-(6-(5 -methyl- 1 ,3 ,4-thiadiazol-2-yl)isoquinolin-3 -yl)cyclohexane- 1 - carboxamide [885];
fr «5-4-(dimethylamino)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclohexane-l- carboxamide [886];
fr «5-4-formyl-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclohexane-l- carboxamide [887];
fr «5-4-(hydroxymethyl)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclohexane-l - carboxamide [888];
trans-N-(6-(5 -methyl-1 ,3,4-thiadiazol-2-yl)isoquinolin-3 -yl)-4-morpholinocyclohexane- 1 - carboxamide [889];
trans-4-((3 -fluoroazetidin- 1 -yl)methyl)-N-(6-(5 -methyl- 1 ,3,4-thiadiazol-2-yl)isoquinolin-3-yl) cyclohexane-1 -carboxamide [890] ;
trans-N-(6-(5 -methyl-1 ,3,4-thiadiazol-2-yl)isoquinolin-3 -yl)-4-((4-methylpiperazin- 1 -yl)methyl) cyclohexane-1 -carboxamide [891] ;
N-(6-(5 -methyl- 1 ,3 ,4-thiadiazol-2-yl)isoquinolin-3 -yl)azetidine-3 -carboxamide [892] ;
(R)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)pyrrolidine-2 -carboxamide [893]; (R)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)tetrahydrofuran-2 -carboxamide [894] ; N-(6-(5 -methyl- 1 ,3,4-thiadiazol-2-yl)isoquinolin-3 -yl)piperidine-4-carboxamide [895] ;
N-(6-(5 -methyl- 1 ,3,4-thiadiazol-2-yl)isoquinolin-3 -yl)piperidine-4-carboxamide [896] ;
l-methyl-N-(6-(5-methyl-l ,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide [897] ; 4-fluoro-l -methyl-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4- carboxamide [898];
l-ethyl-4-fluoro-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide
[899]; and
l-(2-fluoroethyl)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4- carboxamide [900]; or a pharmaceutically acceptable salt thereof.
34. The compound of claims 1, wherein the compound of Formula I is selected from the group consisting of:
4-fluoro-l -(2-fluoroethyl)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4- carboxamide [901]; l-(2,2-difluoroethyl)-N-(6-(5-methyl-l,3,4 hiadiazol-2-yl)isoquinolin-3-yl)piperidin^ carboxamide [902];
l-(2-hydroxyethyl)-N-(6-(5-methyl-l,3,4 hiadiazol-2-yl)isoquinolin-3-yl)piperidine-4- carboxamide [903];
l-(2-methoxyethyl)-N-(6-(5-methyl-l,3,4 hiadiazol-2-yl)isoquinolin-3-yl)piperidine-4- carboxamide [904];
methyl 2-(4-((6-(5 -methyl- 1 ,3 ,4-thiadiazol-2-yl)isoquinolin-3 -yl)carbamoyl)piperidin- 1 - yl)acetate [905];
l-isopropyl-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide
[906];
l-cyclopropyl-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide
[907];
(R)-l-(2-fluoropropyl)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4- carboxamide [908];
(S)-l-(2-fluoropropyl)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4- carboxamide [909];
l-(2,2-difluoropropyl)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4- carboxamide [910];
N-(6-(5 -methyl- 1 ,3 ,4-thiadiazol-2-yl)isoquinolin-3 -yl)- 1 -(3 ,3 ,3 -trifluoropropyl)piperidine-4- carboxamide [911];
1 -isobutyl-N-(6-(5 -methyl- 1 ,3,4-thiadiazol-2-yl)isoquinolin-3 -yl)piperidine-4-carboxamide [912] ; 4-fluoro-l-isobutyl-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4- carboxamide [913];
l-(2-fluoro-2-methylpropyl)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4- carboxamide [914];
N-(6-(5 -methyl- 1 ,3 ,4-thiadiazol-2-yl)isoquinolin-3 -yl)- 1 -(( 1 -
(trifluoromethyl)cyclopropyl)methyl) piperidine-4-carboxamide [915];
N-(6-(5 -methyl- 1 ,3,4-thiadiazol-2-yl)isoquinolin-3 -yl)- 1 -(oxetan-3 -yl)piperidine-4-carboxamide
[916];
N-(6-(5 -methyl- 1 ,3,4-thiadiazol-2-yl)isoquinolin-3 -yl)- 1 -((3 -methyloxetan-3 - yl)methyl)piperidine-4-carboxamide [917] ;
N-(6-(5 -methyl- 1 ,3,4-thiadiazol-2-yl)isoquinolin-3 -yl)- 1 -neopentylpiperidine-4-carboxamide
[918]; N-(6-(5 -methyl- 1 ,3,4-thiadiazol-2-yl)isoquinolin-3 -yl)-l -(methylsulfonyl)piperidine-4- carboxamide [919];
N-(6-(5 -methyl- 1 ,3 ,4-thiadiazol-2-yl)isoquinolin-3 -yl)-l -(2-(pyrrolidin- 1 -yl)acetyl)piperidine-4- carboxamide [920];
1- benzoyl-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide [921]; l'-methyl-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-[l,4'-bipiperidine]-4- carboxamide [922];
N-(6-(5 -methyl- 1 ,3,4-thiadiazol-2-yl)isoquinolin-3 -yl)-l -(tetrahydro-2H-pyran-4-yl)piperidine-4- carboxamide [923];
N-(6-(5 -methyl- 1 ,3,4-thiadiazol-2-yl)isoquinolin-3 -yl)-l -(oxazol-2-ylmethyl)piperidine-4- carboxamide [924];
N-(6-(5 -methyl- 1 ,3,4-thiadiazol-2-yl)isoquinolin-3 -yl)-l -(pyridin-2-ylmethyl)piperidine-4- carboxamide [925];
(S)-N-(6-(5 -methyl- 1 ,3 ,4-thiadiazol-2-yl)isoquinolin-3 -yl)piperidine-3 -carboxamide [926] ;
1 -isobutyl-N-(6-(5 -methyl- 1 ,3 ,4-thiadiazol-2-yl)isoquinolin-3 -yl)piperidine-3 -carboxamide [927] ; (R)-l-isobutyl-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-3-carboxamide
[928];
N-(6-(5 -methyl- 1 ,3 ,4-thiadiazol-2-yl)isoquinolin-3 -yl)tetrahydro-2H-pyran-4-carboxamide [929] ; 4-methyl-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperazine-l -carboxamide [930];
2- (3,3-dimethylazetidin-l-yl)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide
[931];
N-(6-(5 -methyl- 1 ,3,4-thiadiazol-2-yl)isoquinolin-3 -yl)-2-(pyrrolidin- 1 -yl)acetamide [932] ;
(S)-2-(3-fluoropyrrolidin-l-yl)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide
[933];
(R)-2-(3-fluoropyrrolidin-l-yl)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide
[934];
(R)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin-l-yl)acetamide
[935];
(S)-N-(6-(5 -methyl- 1 ,3,4-thiadiazol-2-yl)isoquinolin-3 -yl)-2-(2-methylpyrrolidin-l -yl)acetamide
[936];
N-(6-(5 -methyl- 1 ,3,4-thiadiazol-2-yl)isoquinolin-3 -yl)-2-(pyrrolidin- 1 -yl)propanamide [937] ; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)
acetamide [938];
N-(6-(5 -methyl- 1 ,3,4-thiadiazol-2-yl)isoquinolin-3 -yl)-2-(piperidin- 1 -yl)acetamide [939] ; 2-(4-fluoropiperidin-l -yl)-N-(6-(5 -methyl- 1 ,3,4-thiadiazol-2-yl)isoquinolin-3 -yl)acetamide [940] ; N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(4-methylpiperidin-l-yl)acetami
[941];
2-(4-(difluoromethyl)piperidin- 1 -yl)-N-(6-(5 -methyl- 1 ,3 ,4-thiadiazol-2-yl)isoquinolin-3 -yl)
acetamide [942];
N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(4-(trifluoromethyl)piperidin-l-yl) acetamide [943];
N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)acetamide
[944];
N-(6-(5 -methyl- 1 ,3,4-thiadiazol-2-yl)isoquinolin-3 -yl)-2-(piperidin- 1 -yl)propanamide [945] ; N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-l-yl)acetamide
[946];
2-(4-ethylpiperazin-l-yl)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide [947]; 2-(4-(2-fluoroethyl)piperazin-l-yl)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)
acetamide [948];
(S)-2-(2,4-dimethylpiperazin- 1 -yl)-N-(6-(5 -methyl-1 ,3,4-thiadiazol-2-yl)isoquinolin-3 -yl)
acetamide [949];
2-(4-isopropylpiperazin-l-yl)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide
[950];
2-(4-cyclopropylpiperazin-l-yl)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide
[951];
N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-mo holinoacetamide [952];
(R)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(3-methylmoφholino)acetamide
[953];
(S)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(3-methylmo holino)acetamide
[954];
(S)-N-(6-(5 -methyl- 1 ,3,4-thiadiazol-2-yl)isoquinolin-3 -yl)-2-(2-methylmo holino)acetamide
[955];
(S)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-moφholinopropanamide [956]; N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(moφholin-2-yl)acetamide [957];
N-(6-(5 -methyl- 1 ,3,4-thiadiazol-2-yl)isoquinolin-3 -yl)-2-(4-methylmoφholin-2-yl)acetamide
[958];
2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)
acetamide [959]; 2-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl) isoquinolin-3-yl)acetamide [960];
2-((lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)
isoquinolin-3-yl)acetamide [961];
2-(3-oxa-8-azabicyclo[3.2 ]octan-8-yl)-N-(6-(5-methyl-l,3,4 hiadiazol-2-yl)isoquinolin-3-yl) acetamide [962];
N-(8-fluoro-6-(5-methyl-l,3,4 hiadiazol-2-yl)isoquinolin-3-yl)-2-mo holinoacetamide [963]; N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)- 1 -(phenylsulfonyl)piperidine-4-carboxamide
[964];
N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)-2-(4-(methyl-£/3)piperazin- 1 -yl)acetamide
[965];
N-(7-fluoro-6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-l-methylpiperidine-4-carboxamide
[966];
l-ethyl-N-(7-fluoro-6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide
[967];
N-(8-fluoro-6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-l-yl)acetamide
[968];
N-(6-( 1 -( 1 -methylpiperidin-4-yl)- lH-pyrazol-4-yl)isoquinolin-3-yl)cyclohexanecarboxamide
[969];
N-(6-(isothiazol-4-yl)isoquinolin-3-yl)-l-methylpiperidine-4-carboxamide [970];
(S)-N-(6-(l -(methyl - 3)-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-l-yl)propanamide
[971];
1- isobutyl-N-(6-(l-(methyl-£/3)-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide
[972];
N-(6-(oxazol-5 -yl)isoquinolin-3 -yl)cyclopropanecarboxamide [973] ;
(R)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)tetrahydrofuran-2-carboxamide [974];
(R)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)piperidine-3-carboxamide [975];
N-(6-(oxazol-5 -yl)isoquinolin-3 -yl)tetrahydro-2H-pyran-4-carboxamide [976] ;
N-(6-(oxazol-5 -yl)isoquinolin-3 -yl)-l -(2-(pyrrolidin- 1 -yl)acetyl)piperidine-4-carboxamide [977] ; r-methyl-N-(6-(oxazol-5-yl)isoquinolin-3-yl)-[l,4'-bipiperidine]-4-carboxamide [978];
c/5-4-moφholino-N-(6-(oxazol-5-yl)isoquinolin-3-yl)cyclohexane-l-carboxamide [979];
2- (cyclobutyl(methyl)amino)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)acetamide [980];
N-(6-(oxazol-5 -yl)isoquinolin-3 -yl)-2-(pyrrolidin- 1 -yl)acetamide [981] ;
(R)-2-(2-methylpyrrolidin-l-yl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)acetamide [982]; 2-(4-methylpiperazin- 1 -yl)-N-(6-(oxazol-5 -yl)isoquinolin-3 -yl)acetamide [983] ;
N-(6-(5 -(hydroxymethyl)- 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)tetrahydro-2H-pyran-4- carboxamide [984];
N-(6-(5 -(hydroxymethyl)- 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)-l -methylpiperidine-4- carboxamide [985];
3,3-difluoro-N-(6-(5,6J,8-tetrahydroimidazo[l,2-a]pyrazin-3-yl)isoquinolin-3-yl)cyclobutane-l - carboxamide [986];
(R)-N-(6-(5,6J,8-tetrahydroimidazo[ l,2-a]pyrazin-3-yl)isoquinolin-3-yl)pyrrolidine-2- carboxamide [987];
(R)-N-(6-(5,6,7,8-tetrahydroimidazo[ l,2-a]pyrazin-3-yl)isoquinolin-3-yl)piperidine-3- carboxamide [988];
l-methyl-N-(6-(5,6,7,8-tetrahydroimidazo[l,2-a]pyrazin-3-yl)isoquinolin-3-yl)piperidine-4- carboxamide [989];
N-(6-(5,6J,8-tetrahydroimidazo[ l,2-a]pyrazin-3-yl)isoquinolin-3-yl)-l-(( l-(trifluoromethyl) cyclopropyl)methyl)piperidine-4-carboxamide [990] ;
1- benzoyl-N-(6-(5,6J,8-tetrahydroimidazo[ l,2-a]pyrazin-3-yl)isoquinolin-3-yl)piperidine-4- carboxamide [991];
N-(6-(2-methylthiazol-5-yl)isoquinolin-3-yl)-2-(pyrrolidin-l -yl)acetamide [993];
N-(6-(2-methylthiazol-5-yl)isoquinolin-3-yl)-2-moφholinoacetamide [994];
2- (4-methylpiperazin-l-yl)-N-(6-(2-methylthiazol-5-yl)isoquinolin-3-yl)acetamide [995];
2-(( lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(2-methylthiazol-5-yl)isoquinolin-3-yl) acetamide [996];
N-(6-(4,5,6,7-tetrahydropyrazolo[ l,5-a]pyrazin-3-yl)isoquinolin-3-yl)-l -((l-(trifluoromethyl) cyclopropyl)methyl)piperidine-4-carboxamide [997] ;
N-(6-(5-(2-fluoroethyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-3-yl)isoquinolin-3-yl)-l-(( l-
(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide [998] ;
N-(6-(5-(2-fluoroethyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-3-yl)isoquinolin-3-yl)-2-
(pyrrolidin-l-yl)acetamide [999]; and
2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(6-(5-(2-fluoroethyl)-4,5,6,7-tetrahydropyrazolo[l,5-a] pyrazin-3-yl)isoquinolin-3-yl)acetamide [1000]; or a pharmaceutically acceptable salt thereof.
35. The compound of claims 1, wherein the compound of Formula I is selected from the group consisting of:
c/s-4-methoxy-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclohexane-l -carboxamide
[1001] ; (R)-N-(6-(5 -(2-fluoroethyl)-4,5,6,7-tetrahydropyrazolo[ 1 ,5 -a]pyrazin-3 -yl)isoquinolin-3 -yl)-l - isobutylpiperidine-3-carboxamide [1002] ;
N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)-l -(pyrimidin-2-ylmethyl)piperidine-4- carboxamide [1003];
N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)-l -(pyrazin-2-ylmethyl)piperidine-4- carboxamide [1004];
l-((5-methyl-l,2,4-oxadiazol-3-yl)methyl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl) piperidine -4 -carboxamide [ 1005] ;
1- (2 -hydroxy -2 -methylpropyl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4- carboxamide [1006];
fr «5-4-((4-methylpiperazin-l-yl)methyl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)cyclohexane-l- carboxamide [1007];
2- isopropoxy-N-(6-(l-methyl-lH-imidazol-5-yl)isoquinolin-3-yl)acetamide [1008];
3 -isopropoxy-N-(6 -( 1 -methyl - 1 H-imidazol -5 -yl)isoquinolin-3 -yl)propanamide [ 1009] ;
fert-butyl 2-(4-((6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)carbamoyl)piperidin-l -yl)acetate
[1010];
2-(4-((6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)piperidin-l-yl)acetic acid [1011]; 2-(4-methyl- 1 ,4-diazepan- 1 -yl)-N-(6-( 1 -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)acetamide
[1012];
N-(7-chloro-6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide [1013]; N-(6-(l -(methyl -£/3)-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-l-yl)acetamide
[1014];
N-(7-fluoro-6-(l-(methyl- 3)-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-l-yl)acetamide
[1015];
N-(8-fluoro-6-(l-(methyl- 3)-lH-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-l-yl)acetamide
[1016];
fr «5-4-(dimethylamino)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-l- carboxamide [1017];
trans-4-((3 -fluoroazetidin- 1 -yl)methyl)-N-(6-(2-methyloxazol-5 -yl)isoquinolin-3 -yl)cyclohexane- 1 -carboxamide [1018];
N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-l -yl)acetamide [1019] ;
l-isobutyl-N-(6-(5-methyl-l,3,4-oxadiazol-2-yl)isoquinolin-3-yl)piperidine-4 -carboxamide
[1020]; 4-fluoro-l -isobutyl-N-(6-(5,6,7,8 etrahydroimidazo[l,2-a]pyrazin-3-yl)isoquinolin-3- yl)piperidine -4-carboxamide [ 1021 ] ;
N-(6-(5-(2-fluoroe1hyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-3-yl)isoquinolin-3- yl)piperidine -4-carboxamide [ 1022] ;
4-fluoro-N-(6-(5-(2-fluoroethyl)-4,5,6,7-tetrahydropyrazolo[ l,5-a]pyrazin-3-yl)isoquinolin-3-yl)-
1 -isobutylpiperidine-4-carboxamide [1023] ;
N-(6-(5-(2-fluoroethyl)-4,5,6J-tetrahydropyrazolo[l,5-a]pyrazin-3-yl)isoquinolin-3-yl)-2-(4- methylpiperazin- 1 -yl)acetamide [ 1024] ;
fert-butyl (6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3-yl)carbamate [1025] ;
N-(6-(l -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)but-2-ynamide [1026] ;
N-(7-chloro-6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-l -methylpiperidine-4-carboxamide
[1027] ;
N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-2-(piperidin-l-yl)acetamide [1028];
2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3- yl)acetamide [1029];
(R)-2-(2-methylpyrrolidin-l-yl)-N-(6-(5,6J,8-tetrahydroimidazo[l,2-a]pyrazin-3-yl)isoquinolin- 3-yl)acetamide [1030];
2-(cyclobutyl(methyl)amino)-N-(6-(5,6,7,8-tetrahydroimidazo[l,2-a]pyrazin-3-yl)isoquinolin-3- yl)acetamide [1031];
fr «5-4-((6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)cyclohexane-l-carboxylic acid [1032];
N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)-2-(4-methylpiperazin-l -yl)acetamide-2,2-<i2
[1033] ;
N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-3-moφholinopropanamide [1034];
trans-N-(6-( 1 -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-3 -morpholinocyclobutane- 1 - carboxamide [1035];
1 -( 1 -isobutylpiperidin-4-yl)-3-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)urea [1036] ;
l-methyl-3-(6-( l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-l -( l-methylpiperidin-4-yl)urea
[1037] ;
l-isobutyl-N-(6-(4-methyl-4H-l,2,4-triazol-3-yl)isoquinolin-3-yl)piperidine-4 -carboxamide
[1038] ;
1 -isobutyl-N-(6-( 1 -methyl- lH-tetrazol-5-yl)isoquinolin -3 -yl)piperidine-4-carboxamide [1039] ;
N-(6-(2-(methylamino)thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [1040] ;
1 -methyl -N-(6 -(2-(methylamino)thiazol -5 -yl)isoquinolin-3 -yl)piperidine -4 -carboxamide [1041 ] ; N-(6-(2-(dimethylamino)thiazol-5-yl)isoquinolin-3-yl)quinuclidine-4-carboxamide [1042]; N-(6-(2-(dimethylamino)thiazol-5-yl)isoquinolin-3-yl)-2-(piperidin-l-yl)acetamide [1043]; N-(6-(2-(dimethylamino)thiazol-5-yl)isoquinolin-3-yl)-2-(4-fluoropiperidin-l-yl)acetamide
[1044];
N-(6-(2-(dimethylamino)thiazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-l-yl)acetamide
[1045];
N-(6-(2-(die1hylamino)thiazol-5-yl)isoquinolin-3-yl)-2-(piperidin-l-yl)acetamid [1046];
N-(6-(2-(diemylamino)thiazol-5-yl)isoquinolm^ [1047]; N-(6-(2-(diethylamino)thiazol-5-yl)isoqum^
[1048];
N-(6-(5-methyl-l,3,4 hiadiazol-2-yl)isoquinolin-3-yl)-2-(l,4-oxazepan-4-yl)acetamide [1049]; N-(6-(5 -methyl- 1 ,3 ,4-thiadiazol-2-yl)isoquinolin-3 -yl)-2-(piperidin- 1 -yl)acetamide-2,2- 2
[1050];
N-(6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-mo holinoacetamide-2,2-ί [1051];
Figure imgf000351_0001
[1052] ; N-(7-fluoro-6-(5-methyl-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-mo holinoacetamide [1053]; N-(6-(5-(dimethylamino)-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide
[1054];
N-(6-(5-(dimethylamino)-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-l-methylpiperidine-4- carboxamide [1055];
N-(6-(5-(dimethylamino)-l,3,4-thiadiazol-2-yl)isoquinolin-3-yl)quinuclidine-4-carboxamide
[1056];
l-(2,2-difluoropropyl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide [1057]; l-((3-methyloxetan-3-yl)methyl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide
[1058];
4-methyl-N-(6-(2-methyloxazol-5 -yl)isoquinolin-3 -yl)piperazine- 1 -carboxamide [1059] ;
fr «5-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-3-(4-methylpiperazin-l-yl)cyclobutane-l- carboxamide [1060];
fr «5-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-3-moφholinocyclobutane-l -carboxamide
[1061];
fr «5-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-3-(moφholinomethyl)bicyclo[l .1. l]pentane-
1 -carboxamide [1062];
fr «5-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-3-((4-methylpiperazin-l- yl)methyl)bicycle[ 1.1.1] pentane-1 -carboxamide [1063]; fra«s-N-(6-(2-methyloxazol-5 -yl)isoquinolin-3 -yl)-4-morpholinocyclohexane- 1 -carboxamide
[1064];
fra«s-N-(6-(2-methyloxazol-5 -yl)isoquinolin-3 -yl)-4-(4-methylpiperazin-l -yl)cyclohexane- 1 - carboxamide [1065];
(S)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-2-(pyrrolidin-l-yl)propanamide [1066];
N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-2-mo holinoacetamide [1067];
N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-3-mo holinopropanamide [1068];
N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-3-(4-methylpiperazin-l-yl)propanamide [1069];
1- (2 -hydroxy -2 -methylpropyl)-N-(6-(5-methyl-l,3,4-oxadiazol-2-yl)isoquinolin-3-yl)piperidine-
4-carboxamide [1070];
N-(6-(l -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)quinuclidine-4-carboxamide [1071];
1 -(2-hydroxy-2-methylpropyl)-N-(6-( 1 -methyl- 1H- 1 ,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-
4-carboxamide [1072];
N-(6-(2H-l ,2,3 -triazol-2-yl)isoquinolin-3 -yl)-4-fluoro- 1 -isobutylpiperidine-4-carboxamide
[1073];
N-(6-( lH-1 ,2,3 -triazol- 1 -yl)isoquinolin-3 -yl)-4-fluoro- 1 -isobutylpiperidine-4-carboxamide
[1074];
N-(6-(5-(Dimethylamino)-l,3,4-oxadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide
[1075];
N-(6-(5 -(Dimethylamino)- 1 ,3,4-oxadiazol-2-yl)isoquinolin-3-yl)- 1 -methylpiperidine-4- carboxamide [1076];
2- (4-Methoxypiperidin- 1 -yl)-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3-yl)acetamide [1077] ;
2- (4-Hydroxypiperidin-l-yl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)acetamide [1078]; 1 -Isobutyl-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3-yl)azepane-4-carboxamide [1079] ; l-Methyl-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)azepane-4-carboxamide [1080]; c/5-4-(Dimethylamino)-N-(6-( 1 -methyl-lH-pyrazol-4-yl)isoquinolin-3 -yl)cyclohexane- 1 - carboxamide [1081];
c/5-4-(dimethylamino)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-l-carboxamide
[1082];
3- (hydroxymethyl)-N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)bicyclo[l . l . l]pentane-l- carboxamide [1083];
methyl fr «5-4-((6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)cyclohexane-l- carboxylate [1084];
N-(6-(l-methyl-lH-pyrazol-4-yl)isoquinolin-3-yl-l-£/)piperidine-4-carboxamide [1085]; N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin-3 -yl)- 1 -(2-(methyl-£/3)propyl- 1 , 1 ,2,3, 3,3-
£/e)piperidine -4-carboxamide [ 1086] ;
1 -isobutyl-N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl-1 -d)piperidine-4-carboxamide
[1087] ;
N-(6-( 1 -methyl- lH-pyrazol-4-yl)isoquinolin -3 -yl)-3-((4-methylpiperazin- 1 - yl)methyl)bicyclo[ 1.1.1] pentane-l-carboxamide [1088];
N-(6-(5 -methyl- 1 ,3 ,4-thiadiazol-2-yl)isoquinolin-3 -yl)-2-(pyrrolidin- 1 -yl)acetamide-2,2-<i2
[1089] ;
1 -(6-( 1 -methyl-lH-pyrazol-4-yl)isoquinolin-3 -yl)-3 -( 1 -methylpiperidin-4-yl)urea [1090] ;
fr «5-N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl)-4-(4-methylpiperazine-l -carbonyl)
cyclohexane-l -carboxamide [1091]; and
1 -isobutyl-N-(6-( 1 -methyl- lH-tetrazol-5-yl)isoquinolin -3 -yl)piperidine-4-carboxamide [1092] ; N-(6-(l -methyl-lH-pyrazol-4-yl)isoquinolin-3-yl-l -£/)-2-(pyrrolidin-l-yl)acetamide [1093] ; or a pharmaceutically acceptable salt thereof.
36. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any of claims 1 -35, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
37. 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, diabetes, cancer, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), degenerative disc disease, bone/osteoporotic fractures, a bone or cartilage disease, a neurological disorder, 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 1-35, or a pharmaceutically acceptable salt, or a pharmaceutical composition according to claim 36 thereof.
38. A method of claim 37, wherein the disorder or disease is cancer.
39. A method of claim 37, wherein the disorder or disease is pulmonary fibrosis.
40. A method of claim 37, wherein the disorder or disease is idiopathic pulmonary fibrosis (IPF).
41. The method of claim 37, wherein the disorder or disease is lung disease.
42. A method of claim 37, wherein the disorder or disease is degenerative disc disease.
43. A method of claim 37, wherein the disorder or disease is a bone/osteoporotic fracture .
44. A method of claim 37, wherein the disorder or disease is a bone or cartilage disease.
45. A method of claim 37, wherein the disorder or disease is osteoarthritis.
46. A method of claim 37, wherein the disorder or disease is a neurological disorder.
47. The method according to any one of claims 37-38, 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.
48. The method according to any one of claims 37 and 46, wherein the disorder or disease is a neurological disorder, 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, and Charcot-Marie- Tooth disease.
49. The method according to any one of claims 37 and 46, wherein the disorder or disease is selected from the group consisting of: 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.
50. A method according to any one of claims 37, 46 and 49, wherein the disorder or disease is Alzheimer's disease.
51. The method according to any one of claims 37, 46 and 48-50, wherein the disorder or disease is a neurological disorder associated with tau protein, amyloid, alpha-synuclein, Tar DNA -binding Protein of 43KDa (TDP-43), Prion protein PrP or fused in sarcoma (FUS) pathology.
52. The method of claim 37, 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.
53. The method according to any one of claims claims 37-52, wherein the patient is a human.
54. The method according to any one of claims 37-53, wherein the compound inhibits one or more proteins in the Wnt pathway.
55. The method according to any one of claims 37-54, wherein the compound inhibits signaling induced by one or more Wnt proteins.
56. The method according to any one of claims 37-55, wherein the compound inhibits DYRK1A.
57. The method according to any one of claims 37-55, wherein the compound inhibits
GSK3 .
58. The method according to any one of claims 37-55, wherein the compound inhibits DYRK1A and GSK3 .
59. The method according to any one of claims 37-58, wherein the compound inhibits a kinase activity.
60. 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 -35, or a pharmaceutically acceptable salt, or a pharmaceutical composition according to claim 36 thereof.
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