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WO2025235687A1 - Lrrk2 inhibitors - Google Patents

Lrrk2 inhibitors

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Publication number
WO2025235687A1
WO2025235687A1 PCT/US2025/028256 US2025028256W WO2025235687A1 WO 2025235687 A1 WO2025235687 A1 WO 2025235687A1 US 2025028256 W US2025028256 W US 2025028256W WO 2025235687 A1 WO2025235687 A1 WO 2025235687A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
cycloalkyl
compound
heterocycle
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/028256
Other languages
French (fr)
Inventor
Alexei Pushechnikov
Vladislav Zenonovich PARCHINSKY
Volodymyr KYSIL
Alexandre Vasilievich IVACHTCHENKO
Nikolay Savchuk
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Brenig Therapeutics Inc
Original Assignee
Brenig Therapeutics Inc
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Filing date
Publication date
Application filed by Brenig Therapeutics Inc filed Critical Brenig Therapeutics Inc
Publication of WO2025235687A1 publication Critical patent/WO2025235687A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K31/13—Amines
    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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

Definitions

  • LRRK2 Inhibitors CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application claims priority to and benefit of U.S. Provisional Patent Application Serial No. 63/644,490 filed May 08, 2024, entitled “LRRK2 Inhibitors” the disclosure of which are incorporated by reference in its entirety for all purposes.
  • FIELD OF INVENTION [0002] The present invention is directed to inhibitors leucine-rich repeat kinase 2 (LRRK2).
  • LRRK2 leucine-rich repeat kinase 2
  • the inhibitors described herein can be useful in the treatment of diseases or disorders associated with LRRK2, such as Parkinson disease (PD).
  • PD Parkinson disease
  • the invention is concerned with compounds and pharmaceutical compositions inhibiting LRRK2, methods of treating diseases or disorders associated with LRRK2, and methods of synthesizing these compounds.
  • PD Parkinson’s disease
  • LRRK2 Leucine-rich repeat kinase 2
  • LRRK2 Leucine-rich repeat kinase 2
  • LRRK2 armadillo (ARM), ankyrin (ANK), leucine rich repeat (LRR), Ras of complex domain (Roc), c-terminal of Roc (COR), map kinase (MAPK) and tryptophan-aspartate repeat domain (WD40).
  • LRRK2 exists primarily as a dimeric protein either associated with membrane structures or cytoplasmic localized.
  • the armadillo, ankyrin, LRR and WD40 protein-protein interaction domains enables LRRK2 to interact with a host of different protein partners to impact its own as well as its partner proteins subcellular localization.
  • LRRK2 The central enzymatic core of the LRRK2 protein containing the Roc-COR and the MAPK domain have distinct GTPase and ATPase enzymatic activities enabling LRRK2 to phosphorylate and control the function of intracellular substrates.
  • LRRK2 impacts, via its enzymatic activity and substrate interactions, various subcellular processes and biological mechanisms important for 1. ASB Brenig.24.0001.W trafficking of intracellular vesicular structures and organelles such as lysosomes, endosomes, autophagosomes, the Golgi and mitochondria. [0006] Rare protein-encoding variants in the LRRK2 gene cause Parkinson’s disease.
  • the most common pathogenic variant causing autosomal dominant familial Parkinson’s disease is the p.G2019S substitution which changes a glycine to a serine in the activation loop of the LRRK2 kinase domain rendering the p.G2019S variant more active than the wild type LRRK2 protein.
  • p.G2019S seven additional rare LRRK2 exonic variants having non-synonymous amino acid substitutions in the central enzymatic core (p.N1437H; p.R1441C/G/H; p.Y1699C; p.S1761R; p.I2020T) also cause autosomal dominant Parkinson’s disease.
  • LRRK2 Common protein-coding variants in the LRRK2 gene are also associated with risk of Parkinson’s disease. Variants such as p.A419V, p.M1646T, p.R1628P and p.G2385R increase the risk of Parkinson’s disease and have increased kinase activity. [0007] Evidence that LRRK2 also plays a role in sporadic Parkinson’s disease comes from both genetic studies as well as postmortem analyses of PD brains. A single nucleotide polymorphism (SNP) at the LRRK2 genetic locus is genome-wide associated with risk of Parkinson’s disease.
  • SNP single nucleotide polymorphism
  • This particular SNP variant is associated with increased LRRK2 expression which is in agreement with the increased LRRK2 kinase activity observed in surviving dopamine neurons from postmortem brains of sporadic PD patients.
  • inhibitors ofLRRK2 kinase activity can be used as therapies for both sporadic PD patients as well as for PD patients with LRRK2 mutations or Rab29/Rab7Ll polymorphisms.
  • Developing selective inhibitors of LRRK2 has been a major focus in treating LRRK2-associated PD.
  • LRRK2-specific type I kinase inhibitors are available, and type II inhibitors are under active exploration.
  • LRRK2 inhibitors including DNL201 and DNL151, are currently in clinical trials.
  • MoA mode of action
  • a first aspect of the invention relates to compounds of Formula (A): , or a pharmaceutically solvate, or tautomer thereof, wherein each A is independently selected from CR 4 and N; B is selected from CH and N, provided that anyone from B is N, and another B is CH; R 1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; 3.
  • A is independently selected from CR 4 and N
  • B is selected from CH and N, provided that anyone from B is N, and another B is CH
  • R 1 is selected from C1-C
  • R 2 is selected ;
  • R 3 is selected C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl-C(O)-, C 1 -C 6 alkyl-S(O) 2 -, heterocycle, aryl, and heteroaryl; each R 4 is independently selected from H, OH, halogen, CN, C1-C6 alkyl, C3-C10 cycloalkyl, wherein the alkyl
  • a second aspect of the invention relates to compounds of Formula (B): 4. ASB Brenig.24.0001.W F 3 C R 2 B , or a pharmaceutically solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; E is selected from CH and N, provided that anyone from E is N, and another E is CH; R 1 is selected from C 1 -C 6 alkyl, and C 3 -C 10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, heterocycle, aryl, and heteroaryl; R 2 is selected ; R 3 is selected C 2 -C 6 alkynyl
  • cycloalkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl;
  • u is an integer selected from 0, 1 and 2; wherein, aryl is cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings; heterocyclyl is saturated or partially unsaturated 3–10 membered monocyclic, 7– 12 membered bicyclic (fused, bridged, or spiro rings), or 11–14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms selected from O, N, S, P, Se, or B; heteroaryl is a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being
  • R 1 is selected from C 1 -C 6 alkyl, and C 3 -C 10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, heterocycle, aryl, and heteroaryl; and R b and R c together form a bond;
  • R 1 is selected from C 1 -C 6 alkyl, and C 3 -C 10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C
  • aryl is cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings; heterocyclyl is saturated or partially unsaturated 3–10 membered monocyclic, 7– 12 membered bicyclic (fused, bridged, or spiro rings), or 11–14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms selected from O, N, S, P, Se, or B; heteroaryl is a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C.
  • a fifth aspect of the invention relates to compounds of Formula (E): , or a pharmaceutically or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; R e is selected from H, -(CH 2 ) n -NR 6 R 7 , -(CH 2 ) n -OR 6 ; R f is H; R g is H; or R f and R g together form a bond; R h is H; or R e and R h together with the atoms to which they are attached, may come together to form 5-7 membered heterocycle, optionally substituted with one or more substitutients independently selected from halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(
  • R 1 is selected from C 1 -C 6 alkyl, and C 3 -C 10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, heterocycle, aryl, and heteroaryl;
  • R 2 is selected from H ;
  • R 6 is selected from H, C 1 -C 6 alkyl;
  • R 7 is selected from OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl-C(O)-;
  • n is an integer selected from 0, 1, 2, 3, 4, 5, and 6; wherein, aryl is cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings; heterocyclyl
  • a sixth aspect of the invention relates to compounds of Formula (F): , ASB Brenig.24.0001.W or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; R 1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; R 2 is selected ; each R 8 is halogen, OH, NH 2 , CN, C 1 -C 6 alkyl,
  • heterocyclyl is saturated or partially unsaturated 3–10 membered monocyclic, 7– 12 membered bicyclic (fused, bridged, or spiro rings), or 11–14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms selected from O, N, S, P, Se, or B;
  • heteroaryl is a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C.
  • a seventh aspect of the invention relates to compounds of Formula (G): , or a pharmaceutically solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; R 1 is selected from C 1 -C 6 alkyl, and C 3 -C 10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, heterocycle, aryl, and heteroaryl; R 2 is selected ; R 11 is selected C1-C6 alkoxy; R 12 is selected from C 1 -C 6 alkyl substituted with one or more substitutients independently selected from N(R 14 )2, -CN; or 12.
  • R 11 and R 12 together with the atoms to which they are attached, may come together to form 5-7 membered heterocycle, optionally substituted with one or more substitutients independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl-C(O)-, heterocycle, aryl, -(CH 2 ) n - aryl and heteroaryl;
  • R 13 is halogen; each R 14 is independently selected from H and C 1 -C 6 alkyl;
  • k is an integer selected from 0 and 1; wherein, aryl is cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings; heterocyclyl is saturated or partially unsaturated 3–10 membered monocyclic, 7– 12 membered bicyclic (fused
  • An eighth aspect of the invention relates to compounds of Formula (H): , or a pharmaceutically solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; R 1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected 13.
  • a ninth aspect of the invention relates to compounds of Formula (J): , ASB Brenig.24.0001.W or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; R 1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; R 2 is selected ; R 3 is selected C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl,
  • a tenth aspect of the invention relates to compounds of Formula (K): 15. ASB Brenig.24.0001.W , or a pharmaceutically solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; R 1 is selected from C 1 -C 6 alkyl, and C 3 -C 10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, heterocycle, aryl, and heteroaryl; R 2 is selected ; each R 15 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3 -C 10
  • heteroaryl is a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C.
  • An eleventh aspect of the invention relates to compounds of Formula (L): , or a pharmaceutically solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; each G is independently selected from O, S, S(O), S(O)2, NH; R 1 is selected from C 1 -C 6 alkyl, and C 3 -C 10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, heterocycle, aryl, and heteroaryl; R 2 is selected ; each R 3 is C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
  • a twelfth aspect of the invention relates to compounds of Formula (M): , or a pharmaceutically solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; G is selected from O, S, S(O), S(O)2, NH; R 1 is selected from C 1 -C 6 alkyl, and C 3 -C 10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; 18.
  • B is selected from CH and N, provided that anyone from B is N, and another B is CH
  • G is selected from O, S, S(O), S(
  • R 2 is selected ; each R 3 is C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3 -C 10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl-C(O)-, C 1 -C 6 alkyl- S(O) 2 -, heterocycle, aryl, and heteroaryl; q is an integer selected from 1, 2, and 3; r is an integer selected from 1, 2, and 3; wherein, aryl is cyclic
  • Another aspect of the invention relates to compounds of Formula (N): , ASB Brenig.24.0001.W or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; R 1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; R 2 is selected ; R 16 is selected C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C
  • Another aspect of the invention is directed to pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable 20. ASB Brenig.24.0001.W carrier.
  • the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (B), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (C), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (D), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (E), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (F), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable 21. ASB Brenig.24.0001.W carrier.
  • the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (G), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (H), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (J), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (K), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (L), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (M), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable 22.
  • the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • Another aspect of the invention relates to a method of treating a disease or disorder associated with LRRK2.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders associated with LRRK2 an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention relates to a method of treating a disease or disorder associated with LRRK2.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders associated with LRRK2 an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention relates to a method of treating a disease or disorder associated with LRRK2.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders associated with LRRK2 an effective amount of a compound of Formula (B), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention relates to a method of treating a disease or disorder associated with LRRK2.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders associated with LRRK2 an effective amount of a compound of Formula (C), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention relates to a method of treating a disease or disorder associated with LRRK2.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders associated with LRRK2 an effective amount of a compound of Formula (D), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention relates to a method of treating a disease or disorder associated with LRRK2.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders associated with LRRK2 an effective amount of a 23. ASB Brenig.24.0001.W compound of Formula (E), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention relates to a method of treating a disease or disorder associated with LRRK2.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders associated with LRRK2 an effective amount of a compound of Formula (F), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention relates to a method of treating a disease or disorder associated with LRRK2.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders associated with LRRK2 an effective amount of a compound of Formula (G), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention relates to a method of treating a disease or disorder associated with LRRK2.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders associated with LRRK2 an effective amount of a compound of Formula (H), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention relates to a method of treating a disease or disorder associated with LRRK2.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders associated with LRRK2 an effective amount of a compound of Formula (J), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention relates to a method of treating a disease or disorder associated with LRRK2.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders associated with LRRK2 an effective amount of a compound of Formula (K), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention relates to a method of treating a disease or disorder associated with LRRK2.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders associated with LRRK2 an effective amount of a 24.
  • Another aspect of the invention relates to a method of treating a disease or disorder associated with LRRK2.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders associated with LRRK2 an effective amount of a compound of Formula (M), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of inhibiting of LRRK2.
  • the method involves administering to a patient in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of inhibiting of LRRK2.
  • the method involves administering to a patient in need thereof an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of inhibiting of LRRK2.
  • the method involves administering to a patient in need thereof an effective amount of a compound of Formula (B), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of inhibiting of LRRK2.
  • the method involves administering to a patient in need thereof an effective amount of a compound of Formula (C), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of inhibiting of LRRK2.
  • the method involves administering to a patient in need thereof an effective amount of a compound of Formula (D), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of inhibiting of LRRK2.
  • the method involves administering to a patient in need thereof an effective amount of a compound of Formula (E), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. 25. ASB Brenig.24.0001.W [0057] Another aspect of the invention is directed to a method of inhibiting of LRRK2. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (F), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0058] Another aspect of the invention is directed to a method of inhibiting of LRRK2.
  • the method involves administering to a patient in need thereof an effective amount of a compound of Formula (G), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of inhibiting of LRRK2.
  • the method involves administering to a patient in need thereof an effective amount of a compound of Formula (H), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of inhibiting of LRRK2.
  • the method involves administering to a patient in need thereof an effective amount of a compound of Formula (J), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of inhibiting of LRRK2.
  • the method involves administering to a patient in need thereof an effective amount of a compound of Formula (K), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of inhibiting of LRRK2.
  • the method involves administering to a patient in need thereof an effective amount of a compound of Formula (L), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of inhibiting of LRRK2.
  • the method involves administering to a patient in need thereof an effective amount of a compound of Formula (M), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the present invention relates to compounds disclosed herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, 26.
  • Another aspect of the present invention relates to compounds of Formula (A), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting LRRK2.
  • Another aspect of the present invention relates to compounds of Formula (B), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting LRRK2.
  • Another aspect of the present invention relates to compounds of Formula (C), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting LRRK2.
  • Another aspect of the present invention relates to compounds of Formula (D), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting LRRK2.
  • Another aspect of the present invention relates to compounds of Formula (E), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting LRRK2.
  • Another aspect of the present invention relates to compounds of Formula (F), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting LRRK2.
  • Another aspect of the present invention relates to compounds of Formula (J), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting LRRK2.
  • Another aspect of the present invention relates to compounds of Formula (K), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting LRRK2.
  • Another aspect of the present invention relates to compounds of Formula (L), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting LRRK2.
  • Another aspect of the present invention relates to compounds of Formula (M), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting LRRK2.
  • Another aspect of the present invention relates to the use of compounds disclosed herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with LRRK2.
  • Another aspect of the present invention relates to the use of compounds of Formula (A), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with LRRK2.
  • Another aspect of the present invention relates to the use of compounds of Formula (B), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, 28.
  • Another aspect of the present invention relates to the use of compounds of Formula (C), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with LRRK2.
  • Another aspect of the present invention relates to the use of compounds of Formula (D), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with LRRK2.
  • Another aspect of the present invention relates to the use of compounds of Formula (E), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with LRRK2.
  • Another aspect of the present invention relates to the use of compounds of Formula (F), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with LRRK2.
  • Another aspect of the present invention relates to the use of compounds of Formula (G), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with LRRK2.
  • Another aspect of the present invention relates to the use of compounds of Formula (H), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with LRRK2.
  • Another aspect of the present invention relates to the use of compounds of Formula (L), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with LRRK2.
  • Another aspect of the present invention relates to the use of compounds of Formula (M), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with LRRK2.
  • Another aspect of the present invention relates to compounds disclosed herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • Another aspect of the present invention relates to compounds of Formula (A), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • Another aspect of the present invention relates to compounds of Formula (B), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • Another aspect of the present invention relates to compounds of Formula (C), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • Another aspect of the present invention relates to compounds of Formula (D), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, 30. ASB Brenig.24.0001.W or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • Another aspect of the present invention relates to compounds of Formula (E), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • Another aspect of the present invention relates to compounds of Formula (F), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • Another aspect of the present invention relates to compounds of Formula (G), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • Another aspect of the present invention relates to compounds of Formula (H), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • Another aspect of the present invention relates to compounds of Formula (J), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • Another aspect of the present invention relates to compounds of Formula (K), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • Another aspect of the present invention relates to compounds of Formula (L), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. 31.
  • Another aspect of the present invention relates to compounds of Formula (M), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof.
  • the method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof.
  • the method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (B), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof.
  • the method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (C), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof.
  • the method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (D), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof.
  • the method involves 32. ASB Brenig.24.0001.W administering to a patient in need of the treatment an effective amount of a compound of Formula (E), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof.
  • the method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (F), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof.
  • the method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (G), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof.
  • the method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (H), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof.
  • the method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (J), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof.
  • the method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (K), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof.
  • the method involves administering to a patient in need of the treatment an effective amount of a compound of 33.
  • Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof.
  • the method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (M), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the present invention relates to the use of compounds of the invention disclosed herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.
  • Another aspect of the present invention relates to the use of compounds of Formula (A), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.
  • Another aspect of the present invention relates to the use of compounds of Formula (B), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.
  • Another aspect of the present invention relates to the use of compounds of Formula (C), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.
  • Another aspect of the present invention relates to the use of compounds of Formula (D), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.
  • Another aspect of the present invention relates to the use of compounds of Formula (E), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein. 34. ASB Brenig.24.0001.W [0122] Another aspect of the present invention relates to the use of compounds of Formula (F), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.
  • Another aspect of the present invention relates to the use of compounds of Formula (G), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.
  • Another aspect of the present invention relates to the use of compounds of Formula (H), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.
  • Another aspect of the present invention relates to the use of compounds of Formula (J), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.
  • Another aspect of the present invention relates to the use of compounds of Formula (K), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.
  • Another aspect of the present invention relates to the use of compounds of Formula (L), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.
  • Another aspect of the present invention relates to the use of compounds of Formula (M), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.
  • the present invention further provides methods of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of the disclosure, or a pharmaceutically 35. ASB Brenig.24.0001.W acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • the present invention further provides methods of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • the present invention further provides methods of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (B), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • the present invention further provides methods of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (C), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • the present invention further provides methods of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (D), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • the present invention further provides methods of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (E), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • the present invention further provides methods of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (F), or a pharmaceutically acceptable 36.
  • the present invention further provides methods of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (G), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • the present invention further provides methods of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (H), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • the present invention further provides methods of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (J), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • the present invention further provides methods of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (K), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • the present invention further provides methods of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (L), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • the present invention further provides methods of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (M), or a pharmaceutically acceptable 37. ASB Brenig.24.0001.W salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • M compound of Formula
  • the present invention provides inhibitors of LRRK2 that are therapeutic agents in the treatment of diseases and disorders.
  • the present invention further provides compounds and compositions with an improved efficacy and safety profile relative to known inhibitors of LRRK2.
  • the present disclosure also provides agents with novel mechanisms of action toward LRRK2 in the treatment of various types of diseases.
  • the present invention provides inhibitors of LRRK2 that are therapeutic agents in the treatment of diseases and disorders.
  • the present invention further provides methods of treating a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early- Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson Disease
  • MSA1
  • ASB Brenig.24.0001.W System Disease; Amyotrophic Lateral Sclerosis 1 (ALS1); Mitochondrial Complex I Deficiency, Nuclear Type 1 (MC1DN1) comprising administering to a patient suffering from at least one of said diseases or disorders a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • the present invention further provides methods of treating a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early- Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson Disease 10 (PARK10); Tremor; Frontotemporal Dementia (FTD); Postencephalitic Parkinson
  • the present invention further provides methods of treating a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early- Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson Disease 10 (PARK10); Tremor; Frontotemporal Dementi
  • MSA1 Middle System Atrophy 1
  • the present invention further provides methods of treating a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile 40.
  • LOPD Hereditary Late-Onset Parkinson Disease
  • KFS1 Autosomal Dominant
  • SCA Autosomal Dominant Cerebellar Ataxia
  • Parkinson Disease Late-Onset
  • Parkinson Disease 2 Autosomal Recessive Juvenile 40.
  • PARK2 Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early- Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson Disease 10 (PARK10); Tremor; Frontotemporal Dementia (FTD); Postencephalitic Parkinson Disease; Vascular Parkinsonism; Aphasia; Parkinson Disease 1, Autosomal Dominant (PARK1); Athetosis; Klippel-Feil Syndrome (KFS); Kufor-Rakeb Syndrome (KRS); Leprosy 3 (LPRS3); Alzheimer Disease 8 (AD8); Crohn's Disease; Rheumatoid Arthritis (RA); Alzheimer Disease (AD); Color Agnosia; Gaucher Disease, Type
  • the present invention further provides methods of treating a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early- Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson Disease 10 (PARK10); Tremor; Frontotemporal Dementia (FTD); 41.
  • the present invention further provides methods of treating a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early- Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson Disease 10 (PARK10); Tremor; Frontotemporal Dementia (FTD); Postencephalitic Parkinson
  • the present invention further provides methods of treating a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early- Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson Disease 10 (PARK10); Tremor; Frontotemporal Dementia (FTD); Postencephalitic Parkinson
  • the present invention further provides methods of treating a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early- Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson Disease 10 (PARK10); Tremor; Frontotemporal Dementia (FTD); Postencephalitic Parkinson
  • the present invention further provides methods of treating a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early- Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-
  • MSA1 Multiple System Atrophy 1
  • MSA1 Essential Tremor
  • Movement Disease Supranuclear Palsy, Progressive, 1
  • PSNP1 Klippel
  • the present invention further provides methods of treating a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 45.
  • a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 45.
  • the present invention further provides methods of treating a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early- Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; 46.
  • PARK8 Autosomal Dominant
  • LOPD Hereditary Late-Onset Parkinson Disease
  • SCA Autosomal Dominant Cerebellar Ataxia
  • PARK2 Parkinson Disease, Late-Onset
  • Parkinson Disease 2 Autosomal Recessive
  • the present invention further provides methods of treating a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early- Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson Disease 10 (PARK10); Tremor; Frontotemporal Dementia (FTD); Postencephalitic Parkinson
  • the present invention further provides methods of treating a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early- Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson Disease 10 (PARK10); Tremor; Frontotemporal Dementia (FTD); Postencephalitic Parkinson
  • the present disclosure provides a compound obtainable by, or obtained by, a method for preparing compounds described herein (e.g., a method comprising one or more steps described in General Procedure A, B or C).
  • a method for preparing compounds described herein e.g., a method comprising one or more steps described in General Procedure A, B or C.
  • the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in Preparative part – P1-P44).
  • the present disclosure provides a method of preparing compounds of the present disclosure.
  • the present disclosure provides a method of preparing compounds of the present disclosure, comprising one or more steps described herein.
  • an alkyl group can (but is not required to) be bonded other substituents (e.g., heteroatoms).
  • substituents e.g., heteroatoms
  • an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e., a pure hydrocarbon).
  • the same optionally substituted alkyl group can have one or more substituents different from hydrogen.
  • any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein.
  • the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups but 50. ASB Brenig.24.0001.W does not necessarily have any further functional groups.
  • Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, – OH, –CN, –COOH, –CH2CN, –O-(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1- C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, –O-(C 2 -C 6 )alkenyl, –O-(C 2 -C 6 )alkynyl, (C 2 -C 6 )alkenyl, (C2-C6)alkynyl, –OH, –OP(O)(OH)2, –OC(O)(C1-C6)alkyl, –C(O)(C1-C6)alkyl, – OC(O)O(C1-C6)alkyl, —NH2, –NH((C1-C6)alkyl
  • substituents can themselves be optionally substituted. “Optionally substituted” as used herein also refers to substituted or unsubstituted whose meaning is described below. [0169] As used herein, the term “substituted” means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.
  • aryl refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment.
  • substituents include, but are not limited to, –H, -halogen, –O-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, – O-(C2-C6)alkenyl, –O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, –OH, – OP(O)(OH)2, –OC(O)(C1-C6)alkyl, –C(O)(C1-C6) alkyl, –OC(O)O(C1-C6)alkyl, —NH2, – NH((C 1 -C 6 )alkyl), –N((C 1 -C 6 )alkyl) 2 , –S(O) 2 -(C 1 -C 6 )alkyl, –S(O)NH(C 1 -C 6 )alkyl, and — S(
  • the substituents can themselves be optionally substituted.
  • the aryl groups herein defined may have one or more saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring.
  • Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, 51. ASB Brenig.24.0001.W biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.
  • heteroaryl means a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C.
  • a polycyclic aromatic radical includes two or more fused rings and may further include two or more spiro-fused rings, e.g., bicyclic, tricyclic, tetracyclic, and the like.
  • fused means two rings sharing two ring atoms.
  • spiro-fused means two rings sharing one ring atom.
  • Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, S, P, or B. Heteroaryl as herein defined also means a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B. Heteroaryl as herein defined also means a tetracyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B. The aromatic radical is optionally substituted independently with one or more substituents described herein.
  • Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2- yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyri
  • the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring fused with one or more fully unsaturated aromatic ring.
  • a saturated or partially unsaturated ring may further be fused with a saturated or partially unsaturated ring described herein.
  • the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring spiro-fused. Any saturated or partially unsaturated ring described herein is optionally substituted with one or more oxo.
  • Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H--isoquinolinyl, 2,3- dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, 1,6-dihydro-7H- pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, 8H-pyrido[3,2- b]pyrrolizinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-
  • Halogen or “halo” refers to fluorine, chlorine, bromine, or iodine.
  • Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examples of a (C1-C6)alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.
  • Alkoxy refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, i.e., -O(alkyl). Examples of 53. ASB Brenig.24.0001.W alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.
  • Alkenyl refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkenyl” group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group.
  • alkenyl groups examples include ethenyl, propenyl, n-butenyl, iso- butenyl, pentenyl, or hexenyl.
  • An alkenyl group can be unsubstituted or substituted.
  • Alkenyl, as herein defined, may be straight or branched.
  • Alkynyl refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkynyl” group contains at least one triple bond in the chain.
  • alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl.
  • An alkynyl group can be unsubstituted or substituted.
  • alkylene or “alkylenyl” refers to a divalent alkyl radical. Any of the above-mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. As herein defined, alkylene may also be a C1-C6 alkylene. An alkylene may further be a C1-C4 alkylene.
  • Typical alkylene groups include, but are not limited to, -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -, - CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.
  • Cycloalkyl means mono or polycyclic saturated carbon rings containing 3-18 carbon atoms. Polycyclic cycloalkyl may be fused bicyclic cycloalkyl, bridged bicyclic cycloalkyl, or spiro-fused bicyclic cycloalkyl.
  • a polycyclic cycloalkyl comprises at least one non-aromatic ring.
  • cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norborenyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, spiro[3.5]nonyl, spiro [5.5]undecyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.
  • Heterocyclyl “heterocycle” or “heterocycloalkyl” mono or polycyclic rings containing 3-24 atoms which include carbon and one or more heteroatoms selected from N, O, S, P, or B and wherein the rings are not aromatic.
  • the heterocycloalkyl ring structure may be substituted by one or more substituents.
  • the substituents can themselves be optionally substituted.
  • Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, 54.
  • haloalkyl refers to an alkyl group, as defined herein, which is substituted one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.
  • haloalkoxy refers to an alkoxy group, as defined herein, which is substituted with one or more halogen.
  • haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.
  • cyano as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., C ⁇ N.
  • Spirocycloalkyl or spirocyclyl means carbogenic bicyclic ring systems with both rings connected through a single atom. The ring can be different in size and nature, or identical in size and nature.
  • Examples include spiropentane, spriohexane, spiroheptane, spirooctane, spirononane, or spirodecane.
  • One or both of the rings in a spirocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring.
  • One or more of the carbon atoms in the spirocycle can be substituted with a heteroatom (e.g., O, N, S, or P).
  • a (C3-C12) spirocycloalkyl is a spirocycle containing between 3 and 12 carbon atoms.
  • One or more of the carbon atoms can be substituted with a heteroatom.
  • spiroheterocycloalkyl is understood to mean a spirocycle wherein at least one of the rings is a heterocycle (e.g., at least one of the rings is furanyl, morpholinyl, or piperidinyl).
  • solvate refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the disclosure may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are 55.
  • Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.
  • the term "isomer” refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the compounds of Formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.
  • the present disclosure also contemplates isotopically-labelled compounds of Formula I (e.g., those labeled with 2 H and 14 C).
  • Deuterated (i.e., 2 H or D) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labelled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.
  • the disclosure also includes pharmaceutical compositions comprising a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier.
  • salts include, e.g., water- soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2- disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate
  • a "patient” or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus.
  • an "effective amount" when used in connection with a compound is an amount effective for treating or preventing a disease in a subject as described herein.
  • carrier encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.
  • the term “treating” with regard to a subject refers to improving at least one symptom of the subject's disorder.
  • Treating includes curing, improving, or at least partially ameliorating the disorder.
  • disorder is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
  • administer refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.
  • prodrug means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound.
  • salt refers to pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt also refers to a salt of the compositions of the present disclosure having an acidic functional group, such as a carboxylic acid functional group, and a base. 57. ASB Brenig.24.0001.W [0200] “LRRK2 inhibitor” as used herein refer to a compound of the present disclosure and/or a composition comprising a compound of present disclosure which inhibits LRRK2 kinase.
  • LRRK2 inhibitor refers to a compound of Formula (A) and/or a composition comprising a compound of Formula (A) which inhibits LRRK2 kinase.
  • LRRK2 inhibitor refers to a compound of Formula (B) and/or a composition comprising a compound of Formula (B) which inhibits LRRK2 kinase.
  • LRRK2 inhibitor refers to a compound of Formula (C) and/or a composition comprising a compound of Formula (C) which inhibits LRRK2 kinase.
  • LRRK2 inhibitor refers to a compound of Formula (D) and/or a composition comprising a compound of Formula (D) which inhibits LRRK2 kinase.
  • LRRK2 inhibitor refers to a compound of Formula (E) and/or a composition comprising a compound of Formula (E) which inhibits LRRK2 kinase.
  • LRRK2 inhibitor refers to a compound of Formula (F) and/or a composition comprising a compound of Formula (F) which inhibits LRRK2 kinase.
  • LRRK2 inhibitor refers to a compound of Formula (G) and/or a composition comprising a compound of Formula (G) which inhibits LRRK2 kinase.
  • LRRK2 inhibitor refers to a compound of Formula (H) and/or a composition comprising a compound of Formula (H) which inhibits LRRK2 kinase.
  • LRRK2 inhibitor refers to a compound of Formula (J) and/or a composition comprising a compound of Formula (J) which inhibits LRRK2 kinase.
  • LRRK2 inhibitor refers to a compound of Formula (K) and/or a composition comprising a compound of Formula (K) which inhibits LRRK2 kinase.
  • LRRK2 inhibitor refers to a compound of Formula (L) and/or a composition comprising a compound of Formula (L) which inhibits LRRK2 kinase.
  • LRRK2 inhibitor refers to a compound of Formula (M) and/or a composition comprising a compound of Formula (M) which inhibits LRRK2 kinase.
  • the amount of compound of composition described herein needed for achieving a therapeutic effect may be determined empirically in accordance with conventional procedures for the particular purpose.
  • therapeutic agents e.g. compounds or compositions of Formula I (and/or additional agents) described herein
  • ASB Brenig.24.0001.W therapeutic purposes the therapeutic agents are given at a pharmacologically effective dose.
  • a “pharmacologically effective amount,” “pharmacologically effective dose,” “therapeutically effective amount,” or “effective amount” refers to an amount sufficient to produce the desired physiological effect or amount capable of achieving the desired result, particularly for treating the disorder or disease.
  • An effective amount as used herein would include an amount sufficient to, for example, delay the development of a symptom of the disorder or disease, alter the course of a symptom of the disorder or disease (e.g., slow the progression of a symptom of the disease), reduce or eliminate one or more symptoms or manifestations of the disorder or disease, and reverse a symptom of a disorder or disease.
  • administration of therapeutic agents to a subject suffering from cancer provides a therapeutic benefit not only when the underlying condition is eradicated or ameliorated, but also when the subject reports a decrease in the severity or duration of the symptoms associated with the disease, e.g., a decrease in tumor burden, a decrease in circulating tumor cells, an increase in progression free survival.
  • Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is realized.
  • Compounds of the Present Disclosure [0214]
  • the present disclosure provides compounds of Formula (A) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: , wherein A, B, R 1 , R 2 , and [0215] It is understood that, for a compound of Formula (A), A, B, R 1 , R 2 , and R 3 can each be, where applicable, selected from the groups described herein, and any group described herein for any A, B, R 1 , R 2 , and R 3 can be combined, where applicable, with any group described herein for one or more of the remainders of A, B, R 1 , R 2 , and R 3 .
  • the present disclosure provides compounds of Formula (A) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: F 3 C R 2 B , wherein B, E, R 1 , R 2 , and [0217] It is understood a , B, E, R 1 , R 2 , and R 5 can each be, where applicable, selected from the groups described herein, and any group described herein for any B, E, R 1 , R 2 , and R 5 can be combined, where applicable, with any group described herein for one or more of the remainders of B, E, R 1 , R 2 , and R 5 .
  • the present disclosure provides compounds of Formula (C) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: , wherein B, G, R 1 , R 2 , R 3 , herein.
  • B, G, R 1 , R 2 , R 3 , R a , R b , R c , R d , and R A can each be, where applicable, selected from the groups described herein, and any group described herein for any B, G, R 1 , R 2 , R 3 , R a , R b , R c , R d , and R A can be combined, where applicable, with any group described herein for one or more of the remainders of B, G, R 1 , R 2 , R 3 , R a , R b , R c , R d , and R A .
  • the present disclosure provides compounds of Formula (D) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: 60. ASB Brenig.24.0001.W , wherein B, R 1 , R 2 , R 3 , R A , [0221] It is understood a , B, R 1 , R 2 , R 3 , R A , R c and R d can each be, where applicable, selected from the groups described herein, and any group described herein for any B, R 1 , R 2 , R 3 , R A , R c and R d can be combined, where applicable, with any group described herein for one or more of the remainders of B, R 1 , R 2 , R 3 , R A , R c and R d .
  • the present disclosure provides compounds of Formula (E) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: , wherein B, R 1 , R 2 , R e , [0223] It is understood that, for a compound of Formula (E), B, R 1 , R 2 , R e , R f , R g and R h can each be, where applicable, selected from the groups described herein, and any group described herein for any B, R 1 , R 2 , R e , R f , R g and R h can be combined, where applicable, with any group described herein for one or more of the remainders of B, R 1 , R 2 , R e , R f , R g and R h .
  • the present disclosure provides compounds of Formula (F) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: 61. ASB Brenig.24.0001.W , wherein B, R 1 , R 2 , R 8 , R 9 , [0225] It is understood that, a , B, R 1 , R 2 , R 8 , R 9 , R 10 and m can each be, where applicable, selected from the groups described herein, and any group described herein for any B, R 1 , R 2 , R 8 , R 9 , R 10 and m can be combined, where applicable, with any group described herein for one or more of the remainders of B, R 1 , R 2 , R 8 , R 9 , R 10 and m.
  • the present disclosure provides compounds of Formula (G) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: , wherein B, R 1 , R 2 , R 11 , [0227] It is understood that, for a compound of Formula (G), B, R 1 , R 2 , R 11 , R 12 , R 13 and k can each be, where applicable, selected from the groups described herein, and any group described herein for any B, R 1 , R 2 , R 11 , R 12 , R 13 and k can be combined, where applicable, with any group described herein for one or more of the remainders of B, R 1 , R 2 , R 11 , R 12 , R 13 and k.
  • the present disclosure provides compounds of Formula (H) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: 62. ASB Brenig.24.0001.W , wherein B, R 1 , R 2 , and R 3 as [0229] It is understood that, a (H), B, R 1 , R 2 , and R 3 can each be, where applicable, selected from the groups described herein, and any group described herein for any B, R 1 , R 2 , and R 3 can be combined, where applicable, with any group described herein for one or more of the remainders of B, R 1 , R 2 , and R 3 .
  • the present disclosure provides compounds of Formula (J) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: , wherein B, R 1 , R 2 , and R 3 as [0231] It is understood that, for a compound of Formula (J), B, R 1 , R 2 , and R 3 can each be, where applicable, selected from the groups described herein, and any group described herein for any B, R 1 , R 2 , and R 3 can be combined, where applicable, with any group described herein for one or more of the remainders of B, R 1 , R 2 , and R 3 .
  • the present disclosure provides compounds of Formula (K) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: 63. ASB Brenig.24.0001.W , wherein B, R 1 , R 2 , and R 15 [0233] It is understood that, a , B, R 1 , R 2 , and R 14 can each be, where applicable, selected from the groups described herein, and any group described herein for any B, R 1 , R 2 , and R 14 can be combined, where applicable, with any group described herein for one or more of the remainders of B, R 1 , R 2 , and R 14 .
  • the present disclosure provides compounds of Formula (L) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: , wherein B, R 1 , R 2 , R 3 , G [0235] It is understood that, for a compound of Formula (L), B, R 1 , R 2 , R 3 , G and p can each be, where applicable, selected from the groups described herein, and any group described herein for any B, R 1 , R 2 , R 3 , G and p can be combined, where applicable, with any group described herein for one or more of the remainders of B, R 1 , R 2 , R 3 , G and p.
  • the present disclosure provides compounds of Formula (M) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: 64. ASB Brenig.24.0001.W , wherein B, R 1 , R 2 , R 3 , G, r [0237] It is understood that, a (M), B, R 1 , R 2 , R 3 , G, r and q can each be, where applicable, selected from the groups described herein, and any group described herein for any B, R 1 , R 2 , R 3 , G, r and q can be combined, where applicable, with any group described herein for one or more of the remainders of B, R 1 , R 2 , R 3 , G, r and q.
  • each A is independently selected from CR 4 and N. [0239] In some embodiments, A is CR 4 . [0240] In some embodiments, A is N. [0241] In some embodiments, compound of Formula (A) comprises moiety: Brenig.24.0001.W [0244] In some embodiments, compound of Formula (A) comprises moiety: . embodiments, compound of Formula (A) comprises moiety: . embodiments, compound of Formula (A) comprises moiety: . embodiments, B is CH. In some embodiments, B is N. [0248] In some embodiments, a compound of the invention comprises moiety: . embodiments, a compound of the invention comprises moiety: .
  • R 1 is selected from C 1 -C 6 alkyl, and C 3 -C 10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, heterocycle, aryl, and heteroaryl. 66.
  • R 1 is C 1 -C 6 alkyl optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl.
  • R 1 is C 1 -C 6 alkyl.
  • R 1 is methyl.
  • R 1 is C3-C10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl.
  • R 1 is C3-C10 cycloalkyl optionally substituted with one or more C 1 -C 6 alkyl.
  • R 1 is cyclopropyl optionally substituted with one or more C1-C6 alkyl.
  • R 1 is cyclopropyl optionally substituted with one or more methyl.
  • R 1 is cyclopropyl substituted with one or more methyl.
  • R 1 is cyclopropyl substituted with one methyl.
  • R 1 is .
  • R 2 is selected .
  • R 2 is H. [0263] In some .
  • C2-C6 alkenyl C2-C6 alkynyl, C 3 -C 10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, 67.
  • alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl- S(O) 2 -, heterocycle, aryl, and heteroaryl.
  • substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl- S(O) 2 -, heterocycle, aryl,
  • R 3 is C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl-C(O)-, C 1 -C 6 alkyl- S(O)2-, heterocycle, aryl, and heteroaryl.
  • R 3 is C1-C6 alkyl.
  • R 3 is methyl.
  • R68 In some .
  • R 3 is C 1 -C 6 alkyl substituted with one or more C 1 -C 6 alkoxy.
  • R 3 is . [0279] In some with one or more C 3 -C 10 cycloalkyl.
  • R 3 is C 1 -C 6 alkyl substituted with one C 1 -C 6 alkyl-S(O) 2 -.
  • R 3 is C 1 -C 6 alkyl substituted with one C 1 -C 6 alkyl-S(O) 2 -.
  • R 3 is C 1 -C 6 alkyl substituted with one C 1 -C 6 alkyl-S(O) 2 -.
  • R 3 is C 1 -C 6 alkyl substituted with one C 1 -C 6 alkyl-S(O) 2 -.
  • R 3 is C2-C6 alkenyl.
  • R 3 is C 3 -C 10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl- S(O) 2 -, heterocycle, aryl, and heteroaryl.
  • R 3 is C3-C10 cycloalkyl.
  • R 3 is cyclopropyl. [0294] In some embodiments, R 3 is cyclobutyl. [0295] In some embodiments, R 3 is cyclopentyl. [0296] In some embodiments, R 3 is cyclohexyl. [0297] In some embodiments, R 3 is cycloheptyl.
  • R 3 is heterocycle optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl- S(O) 2 -, heterocycle, aryl, and heteroaryl.
  • R 3 is heterocycle.
  • R 3 is heterocycle selected from four membered heterocycle, five membered heterocycle, six membered heterocycle, seven membered heterocycle comprising from 1 to 3 heteroatoms selected from O, S, N.
  • R 3 is heterocycle selected from four membered heterocycle, five membered heterocycle, six membered heterocycle, seven membered heterocycle comprising from 1 to 3 heteroatoms selected from O, S, N.
  • [0301] In some . [0302] In some . . selected from H, OH, halogen, CN, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, C 1 -C 6 alkyl, C1-C6 alkoxy, cycloalkyl, and heterocycle. 70.
  • R 4 is H. [0307] In some embodiments, R 4 is halogen. [0308] In some embodiments, R 4 is F. [0309] In some embodiments, R 4 is Cl. [0310] In some embodiments, R 4 is C1-C6 alkyl. [0311] In some embodiments, R 4 is methyl. [0312] In some embodiments, E is CH. In some embodiments, E is N.
  • R 5 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl.
  • R 5 is C 1 -C 6 alkyl optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl.
  • R 5 is methyl.
  • R 5 is methyl.
  • substituents independently selected from halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl.
  • substituents independently selected from halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl.
  • R 5 is C 3 -C 10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl.
  • R 5 is . [0323] In some . [0324] In some . [0325] In some . [0326] In some . [0327] In some .
  • R A and R c together form a bond. [0353] In some embodiments, R A and R c together form a second bond. [0354] In some embodiments, R A and R c together form a double bond. [0355] In some embodiments, R C is H. [0356] In some embodiments, R D is H or C1-C6 alkyl. [0357] In some embodiments, R D is H. [0358] In some embodiments, R D is methyl. [0359] In some embodiments, R a is H. [0360] In some embodiments, R b is H. [0361] In some embodiments, R d is H.
  • R a and R d together with the atoms to which they are attached may come together to form 5-7 membered cycloalkyl or heterocycle, wherein cycloalkyl or heterocycle is optionally substituted with one or more substitutients independently selected from halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl; and R b and R c together form a bond.
  • R a and R d together with the atoms to which they are attached may come together to form 5-7 membered cycloalkyl optionally substituted with one or more substitutients independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1- C 6 alkoxy, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl; and R b and R c together form a bond.
  • R a , R b , R c , and R d may come together to form 5-7 membered heterocycle, wherein heterocycle is optionally substituted with one or more substitutients independently selected from halogen, OH, NH2, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl; and R b and R c together form a bond.
  • R a , R b , R c , and R d are selected from -(CH2)n-OR 6 .
  • R e is H.
  • R e is -(CH2)n-NR 6 R 7 .
  • R e is -NH(C1-C6 alkyl).
  • R e is -NHCH 3 .
  • R e is -NHOH.
  • R e is -NH(OC1-C6 alkyl).
  • R e is -NHOCH 3 .
  • R e is -N(C 1 -C 6 alkyl)OH. 75. ASB Brenig.24.0001.W
  • R e is -N(CH 3 )OH.
  • R e is -N(C1-C6 alkyl)2.
  • R e is -N(CH3)2.
  • R e is -NHC(O)C 1 -C 6 alkyl.
  • R e is -(CH2)n-OR 6 .
  • R e is -O(C1-C6 alkyl). [0383] In some embodiments, R e is -OCH 3 . [0384] In some embodiments, R f is H. [0385] In some embodiments, R g is H. [0386] In some embodiments, R f and R g together form a bond. [0387] In some embodiments, R f and R g together form a second bond. [0388] In some embodiments, R f and R g together form a double bond. [0389] In some embodiments, R h is H.
  • R e and R h together with the atoms to which they are attached may come together to form 5-7 membered heterocycle, optionally substituted with one or more substitutients independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1- C 6 alkoxy, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl-C(O)-, heterocycle, aryl, -(CH2)n-aryl and heteroaryl.
  • substitutients independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1- C 6 alkoxy, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl-C(O)-, heterocycle, aryl, -(CH2)n-
  • R e and R h together with the atoms to which they are attached may come together to .
  • R e and R h together with the atoms to which they are attached may come together to .
  • R e and R h together with the atoms to which they are attached may come together to .
  • R e and R h together with the atoms to which they are attached may come together to .
  • R 6 is selected from H, C 1 -C 6 alkyl.
  • R 6 is H.
  • R 6 is C1-C6 alkyl.
  • R 6 is C 1 -C 6 alkyl.
  • R 6 is methyl.
  • R 7 is selected from OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C(O)-. [0400] In some embodiments, R 7 is OH. [0401] In some embodiments, R 7 is C1-C6 alkyl. [0402] In some embodiments, R 7 is methyl. [0403] In some embodiments, R 7 is C 1 -C 6 alkoxy. [0404] In some embodiments, R 7 is methoxy. [0405] In some embodiments, R 7 is C1-C6 alkyl-C(O)-. [0406] In some embodiments, R 7 is CH 3 C(O)-.
  • each R 8 is independently selected from H, halogen, OH, NH2, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl.
  • R 8 is H. [0409] In some embodiments, any two R 8 together form C1-C3 alkanediyl. [0410] In some embodiments, each R 9 is independently selected from H, C1-C6 alkyl. [0411] In some embodiments, two R 9 together form C 1 -C 3 alkanediyl. [0412] In some embodiments, two R 9 together form C1 alkanediyl. [0413] In some embodiments, two R 9 together form C2 alkanediyl. [0414] In some embodiments, two R 9 together form C 3 alkanediyl.
  • R 10 is selected from C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the cycloalkyl, heterocycle, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH 2 , 77. ASB Brenig.24.0001.W CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl.
  • R 10 is C3-C10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl.
  • substituents independently selected from halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl.
  • R 11 is selected from SO 2 C 1 -C 6 alkyl, halogen, C 1 -C 6 alkoxy.
  • R 11 is SO 2 C 1 -C 6 alkyl.
  • R 11 is Cl.
  • R 12 is C 1 -C 6 alkyl substituted with one or more substitutients independently selected from N(R 14 )2, -CN. [0425] In some . [0426] In some .
  • atoms to which they are attached may come together to form 5-7 membered heterocycle, optionally substituted with one or more substitutients independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl-C(O)-, heterocycle, aryl, -(CH 2 ) n -aryl and heteroaryl.
  • substitutients independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl-C(O)-, heterocycle, aryl, -(CH 2 ) n -
  • R 11 and R 12 together with the atoms to which they are attached, .
  • R 13 is halogen.
  • R 13 is F.
  • R 13 is Cl.
  • R 13 is Br.
  • each R 14 is independently selected from H and C 1 -C 6 alkyl.
  • R 14 is H.
  • R 14 is C1-C6 alkyl.
  • one R 14 is H, another R 14 is C 1 -C 6 alkyl.
  • both R 14 are H. [0438] In some embodiments, both R 14 are C1-C6 alkyl. [0439] In some embodiments, R 14 is methyl. [0440] In some embodiments, one R 14 is H, another R 14 is methyl.
  • each R 15 is independently selected from H, C1-C6 alkyl, C2- C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl-C(O)-, C 1 -C 6 alkyl-S(O) 2 -, heterocycle, aryl, and heteroaryl.
  • R 15 is H. [0443] In some embodiments, both R 15 are H. [0444] In some embodiments, R 15 is C 1 -C 6 alkyl optionally substituted with one or more substituents independently selected from halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl- S(O) 2 -, heterocycle, aryl, and heteroaryl.
  • substituents independently selected from halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-,
  • R 15 is C 1 -C 6 alkyl. [0446] In some embodiments, R 15 is methyl. [0447] In some embodiments, both R 15 are methyl. 79. ASB Brenig.24.0001.W [0448] In some embodiments, R 16 is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH 2 , CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C
  • R 16 is . [0450] In some . [0451] In some selected from O, S, S(O), S(O)2, NH. [0452] In some embodiments, G is independently selected from O, S, S(O), S(O) 2 , NH. [0453] In some embodiments, G is O. [0454] In some embodiments, G is S. [0455] In some embodiments, G is S(O). [0456] In some embodiments, G is S(O)2. [0457] In some embodiments, G is NH. [0458] In some embodiments, n is an integer selected from 0, 1, 2, 3, 4, 5, and 6. [0459] In some embodiments, n is 0.
  • n is 1. [0461] In some embodiments, n is 2. [0462] In some embodiments, n is 3. [0463] In some embodiments, n is 4. [0464] In some embodiments, n is 5. [0465] In some embodiments, n is 6. [0466] In some embodiments, each m is an integer independently selected from 1, 2, and 3. [0467] In some embodiments, k is an integer selected from 0 and 1. [0468] In some embodiments, k is 0. [0469] In some embodiments, k is 1. 80. ASB Brenig.24.0001.W [0470] In some embodiments, p is an integer selected from 0, 1, 2, and 3. [0471] In some embodiments, p is 0.
  • p is 1. [0473] In some embodiments, p is 2. [0474] In some embodiments, p is 3. [0475] In some embodiments, q is an integer selected from 1, 2, and 3. [0476] In some embodiments, q is 1. [0477] In some embodiments, q is 2. [0478] In some embodiments, q is 3. [0479] In some embodiments, r is an integer selected from 1, 2, and 3. [0480] In some embodiments, r is 1. [0481] In some embodiments, r is 2. [0482] In some embodiments, r is 3. [0483] In some embodiments, u is an integer selected from 0, 1 and 2. [0484] In some embodiments, u is 0.
  • u is 1. [0486] In some embodiments, u is 2. [0487] In some embodiments, the compound is of Formula (A-I): I), or a pharmaceutically isotopic derivative, or tautomer thereof wherein all variables are as defined herein. [0488] In some embodiments, the compound is of Formula (A-I-a): 81. ASB Brenig.24.0001.W , or a pharmaceutically isotopic derivative, or tautomer thereof are as [0489] In some embodiments, the compound is of Formula (A-I-a-1): , or a isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (A-I-a-1-A): N H CF 3 , or a isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (A-I-a-1-B): 82. ASB Brenig.24.0001.W , or a isotopic derivative, or tautomer thereof are as [0492]
  • the compound is of Formula (A-I-a-1-C): N H CF 3 , or a isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (A-I-a-2): , or a pharmaceutically isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (A-I-a-2-A): 83. ASB Brenig.24.0001.W , or a pharmaceutically isotopic derivative, or tautomer thereof are as [0495]
  • the compound is of Formula (A-I-a-2-B): , or a isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (A-I-b): , or a pharmaceutically isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (A-I-b-1): 84. ASB Brenig.24.0001.W , or a isotopic derivative, or tautomer thereof are as [0498]
  • the compound is of Formula (A-I-b-1-A): , or a isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (A-II): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof wherein all variables are as defined herein. 85. ASB Brenig.24.0001.W [0500] In some embodiments, the compound is of Formula (A-II-a): , or a pharmaceutically isotopic derivative, or tautomer thereof are as [0501] In some embodiments, the compound is of Formula (A-II-a-1): , or a pharmaceutically isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (A-II-a-1-A): H N CF3 , or a isotopic derivative, or tautomer thereof wherein all variables are as defined herein.
  • the compound is of Formula (A-III): 86. ASB Brenig.24.0001.W , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (A-III-a): a), or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (A-III-a-1): , or a isotopic derivative, or tautomer thereof.
  • the compound is of Formula (A-III-a-1-A): 87. ASB Brenig.24.0001.W N H CF 3 , or a isotopic derivative, or tautomer thereof.
  • the compound is of Formula (A-III-a-1-B): N H CF 3 , or a isotopic derivative, or tautomer thereof.
  • the compound is of Formula (B-I): I), or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (B-I-a): 88.
  • the compound is of Formula (B-I-a-1): H N N CF 3 , or a isotopic derivative, or tautomer thereof.
  • the compound is of Formula (B-I-a-1-A): , or a isotopic derivative, or tautomer thereof.
  • the compound is of Formula (B-I-a-1-B): , ASB Brenig.24.0001.W or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (B-I-a-2): , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (B-I-a-2-A): , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (B-I-a-2-B): , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (B-II): 90. ASB Brenig.24.0001.W , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (B-II-a): , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (B-II-a-1): H N , or a isotopic derivative, or tautomer thereof.
  • the compound is of Formula (B-II-a-1-A): 91. ASB Brenig.24.0001.W , or a isotopic derivative, or tautomer thereof.
  • the compound is of Formula (B-II-a-2): , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (B-II-a-2-A): , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (B-III): 92. ASB Brenig.24.0001.W , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (B-III-a): , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (B-III-a-1): , or a isotopic derivative, or tautomer thereof.
  • the compound is of Formula (B-III-a-1-A): 93. ASB Brenig.24.0001.W III-a-1-A), or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (B-III-a-1-B): , or a isotopic derivative, or tautomer thereof.
  • the compound is of Formula (B-III-a-2): , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (B-III-a-2-A): 94.
  • the compound is of Formula (B-III-a-2-B): , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (C-I): F 3 C , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (C-I-a): 95. ASB Brenig.24.0001.W F 3 C B , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (C-I-a-1): F 3 C , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (C-I-a-1-A): , or a isotopic derivative, or tautomer thereof, wherein w is an integer selected from 0, 1, 2, and 3; and each R w is independently selected from halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl.
  • the compound is of Formula (C-I-a-1-A-I): N H CF 3 I), or a isotopic derivative, or tautomer w an 3; and each R w is independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl.
  • the compound is of Formula (C-I-a-1-A-I-a): a), or a isotopic derivative, or tautomer thereof.
  • the compound is of Formula (C-I-a-1-B): , or a isotopic derivative, or tautomer thereof, wherein W is selected from O, S, S(O), S(O)2, NH; w is an integer selected from 0, 1, 2, and 3; and each R w is independently selected from halogen, OH, NH2, 97.
  • the compound is of Formula (C-I-a-1-B-I): N H CF 3 I), or a isotopic derivative, or tautomer , 2, NH; w is an integer selected from 0, 1, 2, and 3; and each R w is independently selected from halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl.
  • the compound is of Formula (C-I-a-1-B-I-a): N H CF 3 a), or a isotopic derivative, or tautomer thereof, wherein w is an integer selected from 0, 1, 2, and 3; and each R w is independently selected from halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl.
  • the compound is of Formula (C-I-a-1-B-I-a-1): , ASB Brenig.24.0001.W or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein w is an integer selected from 0, 1, 2, and 3; and each R w is independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl.
  • the compound is of Formula (C-I-a-1-C): , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (C-I-a-1-C-I): I), or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (C-I-a-1-C-II): , ASB Brenig.24.0001.W or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (C-II): F 3 C B , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (C-II-a): F 3 C , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (C-II-a-1): F 3 C , or a pharmaceutically isotopic derivative, or tautomer thereof. 100.
  • the compound is of Formula (C-II-a-1-A): , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (C-II-a-1-A-I): I), or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (C-II-a-1-A-II): , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (D-I): 101.
  • the compound is of Formula (D-I-a): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (D-I-a-1): , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (D-I-a-2): , ASB Brenig.24.0001.W or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (D-II): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (D-II-a): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (D-II-a-1): , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (D-II-a-2): 103. ASB Brenig.24.0001.W , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (E-I): I), or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (E-I-a): , or a isotopic derivative, or tautomer thereof.
  • the compound is of Formula (E-I-a-1): 104. ASB Brenig.24.0001.W , or a isotopic derivative, or tautomer thereof.
  • the compound is of Formula (E-I-a-1-A): , or a isotopic derivative, or tautomer thereof.
  • the compound is of Formula (E-I-a-1-B): , or a isotopic derivative, or tautomer thereof.
  • the compound is of Formula (E-I-a-2): 105.
  • ASB Brenig.24.0001.W 2 ASB Brenig.24.0001.W 2
  • a derivative, or tautomer is selected from halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 - C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, -(CH2)n-aryl and heteroaryl and e is an integer selected from 0, 1, 2, and 3.
  • the compound is of Formula (E-I-a-2-A): , or a derivative, or tautomer thereof, wherein R e2 is selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl-C(O)-, heterocycle, aryl, -(CH 2 ) n -aryl and heteroaryl.
  • the compound is of Formula (E-I-b): , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (E-I-a-3): 106. ASB Brenig.24.0001.W H N N CF 3 , or a isotopic derivative, or tautomer thereof.
  • the compound is of Formula (E-I-a-3-A): , or a isotopic derivative, or tautomer thereof.
  • the compound is of Formula (F-I): I), or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (F-I-a): 107.
  • the compound is of Formula (F-I-a-1): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (F-I-a-1-A): , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (F-I-b): 108. ASB Brenig.24.0001.W , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (F-I-b-1): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (F-I-b-1-A): , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (G-I): 109. ASB Brenig.24.0001.W I), or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (G-I-a): , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (G-I-a-1): , or a pharmaceutically isotopic derivative, or tautomer thereof, wherein Hal is selected from F, Cl, and Br, and all other variables are as defined herein.
  • the compound is of Formula (G-I-a-1-A): 110. ASB Brenig.24.0001.W , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof, Br, and all other variables are as defined herein.
  • the compound is of Formula (G-I-a-2): , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (G-I-a-2-A): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. 111. ASB Brenig.24.0001.W [0580]
  • the compound is of Formula (G-I-a-3): , or a pharmaceutically isotopic derivative, or tautomer thereof, each R G , if present, is independently selected from halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, -(CH2)n- aryl and heteroaryl; g is an integer selected from 0, 1, 2 and 3; and all other variables are as defined herein.
  • the compound is of Formula (G-I-a-3-A): , or a pharmaceutically isotopic derivative, or tautomer thereof, wherein each R G , if present, is independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, -(CH2)n-aryl and heteroaryl; g is an integer selected from 0, 1, 2 and 3; and all other variables are as defined herein.
  • the compound is of Formula (G-I-a-3-A-I): 112. ASB Brenig.24.0001.W I), or a pharmaceutically isotopic derivative, or tautomer thereof, selected from halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, -(CH2)n-aryl and heteroaryl; g is an integer selected from 0, 1, 2 and 3; and all other variables are as defined herein.
  • the compound is of Formula (H-I): I), or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (H-I-a): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. 113. ASB Brenig.24.0001.W
  • the compound is of Formula (H-I-b): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (J-I): I) or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (J-I-a): a) or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (J-I-b): 114. ASB Brenig.24.0001.W b) or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (K-I): I), or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (K-I-a): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (K-I-b): 115. ASB Brenig.24.0001.W , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (L-I): I) or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (L-I-a): a) or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (L-I-a-1): 116.
  • the compound is of Formula (L-I-a-1-A): or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (L-I-a-1-B): or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (L-I-b): 117. ASB Brenig.24.0001.W b) or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (L-I-b-1): 1) or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (L-I-b-1-A): or a pharmaceutically isotopic derivative, or tautomer thereof. 118. ASB Brenig.24.0001.W [0600]
  • the compound is of Formula (L-I-b-1-B): or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (M-I): I), or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (M-I-a): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (M-I-a-1): 119. ASB Brenig.24.0001.W , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (M-I-a-1-A): , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (M-I-a-1-A-I): I), or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (M-I-a-1-A-I-a): 120. ASB Brenig.24.0001.W , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (M-I-a-1-A-I-a*): , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (M-I-a-1-A-I-a**): , or a isotopic derivative, or tautomer thereof.
  • the compound is of Formula (M-I-b): 121. ASB Brenig.24.0001.W , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • R 1 is selected from C 1 -C 6 alkyl, and C 3 -C 10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, heterocycle, aryl, and heteroaryl;
  • R 2 is selected ; each R 3 is C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents
  • u is an integer selected from 0, 1 and 2; q is an integer selected from 1, 2, and 3; r is an integer selected from 1, 2, and 3; wherein, aryl is cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings; heterocyclyl is saturated or partially unsaturated 3–10 membered monocyclic, 7– 12 membered bicyclic (fused, bridged, or spiro rings), or 11–14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms selected from O, N, S, P, Se, or B; heteroaryl is a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C.
  • the compound is of Formula (I-I): I), or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-A): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-A-1): , ASB Brenig.24.0001.W or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-A-2): , or a isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-B): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-B-1): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-B-2): , or a isotopic derivative, or tautomer thereof. 127.
  • the compound is of Formula (I-II): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-A): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-A-1): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-A-2): , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-B): 128. ASB Brenig.24.0001.W , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-B-1): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-B-2): , or a pharmaceutically isotopic derivative, or tautomer thereof.
  • the compound of Formula I is a compound of Formula A.
  • the compound of Formula I is a compound of Formula B.
  • the compound of Formula I is a compound of Formula C.
  • the compound of Formula I is a compound of Formula D.
  • the compound of Formula I is a compound of Formula E.
  • the compound of Formula I is a compound of Formula F.
  • the compound of Formula I is a compound of Formula G.
  • the compound of Formula I is a compound of Formula H. 129. ASB Brenig.24.0001.W [0633]
  • the compound of Formula I is a compound of Formula J.
  • the compound of Formula I is a compound of Formula K.
  • the compound of Formula I is a compound of Formula L.
  • the compound of Formula I is a compound of Formula M.
  • the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof.
  • the compound is selected from the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.
  • the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.
  • the compound is selected from the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.
  • the compound is selected from the compounds described in Table 1.
  • Table 1 Non-limiting illustrative compounds of the present disclosure # Compound IUPAC name - - - 130. ASB Brenig.24.0001.W # Compound IUPAC name - - - e- )- - - - - - - 131. ASB Brenig.24.0001.W # Compound IUPAC name N4-methyl-N2-(8-methyl-23- - )- - - - - 132.
  • the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 1.
  • the compound is a lithium salt, sodium salt, potassium salt, calcium salt, or magnesium salt of any one of the compounds described in Table 1.
  • the compound is a salt of any acid described in the Table 2 and any one of the compounds described in Table 1.
  • Table 2 Pharmaceutical acceptable acid forming salts with the Compound of Formula (I). 1-hydroxy-2-naphthoic acid glycolic acid 2,2-dichloroacetic acid hippuric acid 160. ASB Brenig.24.0001.W [0647]
  • the compound is a salt of acetic acid and any one of the compounds described in Table 1.
  • the compound is a salt of adipic acid and any one of the compounds described in Table 1.
  • the compound is a salt of ascorbic acid (L) and any one of the compounds described in Table 1.
  • the compound is a salt of hydrobromic acid and any one of the compounds described in Table 1.
  • the compound is a salt of hydrochloric acid and any one of the compounds described in Table 1.
  • the compound is a salt of citric acid and any one of the compounds described in Table 1.
  • the compound is a salt of glutamic acid and any one of the compounds described in Table 1.
  • the compound is a salt of oxalic acid and any one of the compounds described in Table 1.
  • the compound is a salt of formic acid and any one of the compounds described in Table 1.
  • the compound is a salt of sulfuric acid and any one of the compounds described in Table 1.
  • the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of any one of the compounds of the Formulae disclosed herein.
  • the compound is an isotopic derivative of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.
  • the compound is an isotopic derivative of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof. 161. ASB Brenig.24.0001.W [0660] In some embodiments, the compound is an isotopic derivative of any one of prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof. [0661] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1. [0662] It is understood that the isotopic derivative can be prepared using any of a variety of art-recognized techniques.
  • the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • the isotopic derivative is a deuterium labeled compound.
  • the isotopic derivative is a deuterium labeled compound of any one of the compounds of the Formulae disclosed herein.
  • an isotopic derivative of a compound of Formula (I) is isotopically enriched with regard to, or labelled with, one or more isotopes as compared to the corresponding compound of Formula (I).
  • the isotopic derivative is enriched with regard to, or labelled with, one or more atoms selected from 2 H, 13 C, 14 C, 15 N, 18 O, 29 Si, 31 P, and 34 S.
  • the isotopic derivative is a deuterium labeled compound (i.e., being enriched with 2 H with regard to one or more atoms thereof).
  • the compound is a deuterium labeled compound of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.
  • the compound is a deuterium labeled compound of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.
  • the compound is a deuterium labeled compound of any one of the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.
  • the compound is a deuterium labeled compound of any one of the compounds described in Table 1. 162.
  • the deuterium labeled compound comprises a deuterium atom having an abundance of deuterium that is substantially greater than the natural abundance of deuterium, which is 0.015%.
  • the deuterium labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • the term “deuterium enrichment factor” means the ratio between the deuterium abundance and the natural abundance of a deuterium.
  • the deuterium labeled compound can be prepared using any of a variety of art-recognized techniques.
  • the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting a deuterium labeled reagent for a non- deuterium labeled reagent.
  • a compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof that contains the aforementioned deuterium atom(s) is within the scope of the disclosure.
  • the compound is a 18 F labeled compound.
  • the compound is a 123 I labeled compound, a 124 I labeled compound, a 125 I labeled compound, a 129 I labeled compound, a 131 I labeled compound, a 135 I labeled compound, or any combination thereof.
  • the compound is a 33 S labeled compound, a 34 S labeled compound, a 35 S labeled compound, a 36 S labeled compound, or any combination thereof.
  • the 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 33 S, 34 S, 35 S, and/or 36 S labeled compound can be prepared using any of a variety of art-recognized techniques.
  • the deuterium labeled compound can generally be prepared by carrying out 163.
  • substitution with isotope may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.
  • isotope e.g., 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 33 S, 34 S, 35 S, and/or 36 S
  • isotope e.g., 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 33 S, 34 S, 35 S, and/or 36 S
  • isotope e.g., 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 33 S, 34 S, 35 S, and/or 36 S
  • substitution with isotope e.g., 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 33 S, 34 S, 35 S, and/or 36 S
  • the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650 Daltons. More conveniently, the molecular weight is less than 600 and, for example, is 550 Daltons or less, for example 500 Daltons or less, for example 450 Daltons or less.
  • a suitable pharmaceutically acceptable salt of a compound of the disclosure is, for example, an acid-addition salt of a compound of the disclosure, which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid.
  • an acid-addition salt of a compound of the disclosure which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid.
  • a suitable pharmaceutically acceptable salt of a compound of the disclosure which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers.
  • racemic mixture A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”
  • chiral center refers to a carbon atom bonded to four nonidentical substituents.
  • chiral isomer means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center.
  • Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center.
  • the substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).
  • the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3- cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules. [0687] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers.
  • Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.
  • the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerisation is possible, a chemical equilibrium of the tautomers will be reached.
  • tautomerism The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.
  • -CHO aldehyde group
  • -OH hydroxy groups
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”.
  • enantiomers When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterised by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • a mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
  • the compounds of this disclosure may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J.
  • a salt for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein.
  • Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, 167.
  • the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt.
  • a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein.
  • Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion or diethylamine ion.
  • the substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.
  • the compounds of the present disclosure can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules.
  • Nonlimiting examples of hydrates include monohydrates, dihydrates, etc.
  • Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.
  • solvate means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate.
  • the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H 2 O.
  • the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group).
  • an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.
  • the term “derivative” refers to compounds that have a common core structure and are substituted with various groups as described herein.
  • bioisostere refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group 168. ASB Brenig.24.0001.W of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based.
  • carboxylic acid bioisosteres include, but are not limited to, acyl sulfonamides, tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.
  • a suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate.
  • tautomeric forms include keto- , enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro. 169. ASB Brenig.24.0001.W H O OH H+ O- C C C C C C [0705] Compounds of any one of the Formulae disclosed herein containing an amine function may also form N-oxides. A reference herein to a compound of Formula (I) or (II) that contains an amine function also includes the N-oxide.
  • N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • N-oxides can be formed by treatment of the corresponding amine with an oxidising agent such as hydrogen peroxide or a peracid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm.
  • the compounds of any one of the Formulae disclosed herein may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure.
  • a prodrug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the disclosure.
  • a prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property-modifying group can be attached.
  • prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the ester or amide group in any one of the Formulae disclosed herein.
  • the present disclosure includes those compounds of any one of the Formulae disclosed herein as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof.
  • the present disclosure includes those compounds of any one of the Formulae disclosed herein that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism 170.
  • ASB Brenig.24.0001.W of a precursor compound, that is a compound of any one of the Formulae disclosed herein may be a synthetically produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H.
  • Bundgaard (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S.
  • a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
  • An in vivo cleavable ester or ether of a compound of any one of the Formulae disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound.
  • Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include C1-C10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1-C10 alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C 1 -C 6 alkyl) 2 carbamoyl, 2- dialkylaminoacetyl and 2-carboxyacetyl groups.
  • inorganic esters such as phosphate esters (including phosphoramidic cyclic esters).
  • Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include C1-C10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzo
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C 1 -C 4 alkyl)piperazin-1-ylmethyl.
  • Suitable pharmaceutically acceptable ether forming groups for 171. ASB Brenig.24.0001.W a hydroxy group include ⁇ -acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
  • a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C 1-4 alkylamine such as methylamine, a (C 1 -C 4 alkyl) 2 amine such as dimethylamine, N- ethyl-N-methylamine or diethylamine, a C1-C4 alkoxy-C2-C4 alkylamine such as 2-methoxyethylamine, a phenyl-C 1 -C 4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
  • an amine such as ammonia
  • a C 1-4 alkylamine such as methylamine
  • a (C 1 -C 4 alkyl) 2 amine such as dimethylamine, N- ethyl-N-methylamine or
  • a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-C10 alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl,morpholinomethyl,piperazin-1-ylmethyl and 4-(C1-C4 alkyl)piperazin-1-ylmethyl.
  • the in vivo effects of a compound of any one of the Formulae disclosed herein may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of any one of the Formulae disclosed herein. As stated hereinbefore, the in vivo effects of a compound of any one of the Formulae disclosed herein may also be exerted by way of metabolism of a precursor compound (a prodrug).
  • the compounds of the present invention may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below.
  • the compounds of Formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. 172. ASB Brenig.24.0001.W Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999).
  • the present invention includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well.
  • a compound When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art.
  • the compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes. Preparation of Compounds [0716]
  • the compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Suitable methods include but are not limited to those methods described below.
  • the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity.
  • high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art. General methodologies for performing high- throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No.5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below. 174.
  • compositions may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.
  • Pharmaceutical Compositions [0722] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient.
  • the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulae described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients.
  • the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1.
  • the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component.
  • the active component In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • Solid form preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions. 175.
  • Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia.
  • Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents.
  • Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • the compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol.
  • oily or nonaqueous carriers, diluents, solvents or vehicles examples include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
  • the compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions.
  • the compounds of present disclosure can also be formulated for intravenous (bolus or in-fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • the formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle.
  • the aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient.
  • Suitable acceptable excipients include 176. ASB Brenig.24.0001.W those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity/suspending agent, buffer, and pH modifying agent, and a mixture thereof. [0729] Any suitable solubility enhancing agent can be used.
  • solubility enhancing agent examples include cyclodextrin, such as those selected from the group consisting of hydroxypropyl- ⁇ -cyclodextrin, methyl- ⁇ -cyclodextrin, randomly methylated- ⁇ - cyclodextrin, ethylated- ⁇ -cyclodextrin, triacetyl- ⁇ -cyclodextrin, peracetylated- ⁇ - cyclodextrin, carboxymethyl- ⁇ -cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin, 2-hydroxy-3- (trimethylammonio)propyl- ⁇ -cyclodextrin, glucosyl- ⁇ -cyclodextrin, sulfated ⁇ - cyclodextrin (S- ⁇ -CD), maltosyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin sulfobutyl ether, branched- ⁇ -cyclodextrin
  • Any suitable chelating agent can be used.
  • a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.
  • Any suitable preservative can be used.
  • Examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.
  • quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethon
  • examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.
  • quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenyl
  • the aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure).
  • the tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof.
  • the tonicity agent is selected from the group consisting of a glycol (such as propylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof.
  • a glycol such as propylene glycol, triethylene glycol
  • glycerol such as propylene glycol, triethylene glycol
  • dextrose such as glycerin
  • mannitol such as sodium chloride
  • sodium chloride such as sodium chloride
  • the aqueous vehicle may also contain a viscosity/suspending agent.
  • Suitable viscosity/suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof.
  • cellulose derivatives such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose
  • polyethylene glycols such as polyethylene glycol 300, polyethylene glycol 400
  • carboxymethyl cellulose such as polyethylene glycol 300, polyethylene glycol 400
  • carboxymethyl cellulose such as polyethylene
  • the formulation may contain a pH modifying agent.
  • the pH modifying agent is typically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and/or hydrochloric acid.
  • the aqueous vehicle may also contain a buffering agent to stabilize the pH.
  • the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and ⁇ -aminocaproic acid, and mixtures thereof. 178.
  • the formulation may further comprise a wetting agent.
  • wetting agents include those selected from the group consisting of polyoxypropylene- polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.
  • Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition described herein may further comprise one or more additional pharmaceutically active agents.
  • compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration 179.
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs
  • topical use for example as creams, ointments, gels, or aqueous or oily solutions or suspensions
  • inhalation for example as a finely divided powder or a liquid aerosol
  • compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.
  • a therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent a LRRK2 related condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • a therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat an LRRK2 related condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of Formula (I) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or subject and the route of administration, according to well- known principles of medicine.
  • the present disclosure provides a method of inhibiting of LRRK2 (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a 180. ASB Brenig.24.0001.W pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the disease or disorder is associated with LRRK2.
  • the disease or disorder is a disease or disorder in which LRRK2 is implicated.
  • the compounds of the invention are also useful in treating diseases associated with LRRK2.
  • diseases and conditions treatable according to the methods of the invention include Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late- Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early-Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson Disease 10 (PARK10); Tremor; Frontotemporal Dementia (FTD); Postencephalitic Parkinson Disease; Vascular Parkinsonis
  • the disease or disorder is a Parkinson Disease (PD). 181. ASB Brenig.24.0001.W [0752] In some aspects, the present disclosure provides a method of treating or preventing a Parkinson Disease (PD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0753] In some aspects, the present disclosure provides a method of treating a Parkinson Disease (PD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in inhibiting of LRRK2 (e.g., in vitro or in vivo).
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a Parkinson Disease (PD) in a subject in need thereof.
  • PD Parkinson Disease
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating Parkinson Disease (PD) in a subject in need thereof.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting of LRRK2 (e.g., in vitro or in vivo).
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. 182.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing Parkinson Disease (PD) in a subject in need thereof.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating Parkinson Disease (PD) in a subject in need thereof.
  • the present disclosure provides compounds that function as inhibitors of LRRK2 (e.g., in vitro or in vivo).
  • the present disclosure therefore provides a method of inhibiting of LRRK2 in vitro or in vivo, said method comprising contacting a cell with a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein.
  • the inhibitor of LRRK2 is a compound of the present disclosure.
  • Effectiveness of compounds of the disclosure can be determined by industry- accepted assays/ disease models according to standard practices of elucidating the same as described in the art and are found in the current general knowledge.
  • the present disclosure also provides a method of treating a disease or disorder in which LRRK2 is implicated in a subject in need of such treatment, said method comprising administering to said subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.
  • the subject is a mammal.
  • the subject is a human.
  • Routes of Administration [0769] The compounds of the disclosure or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action). 183.
  • Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitone
  • Methylamine hydrochloride (3.11 g, 46 mmol) was added to the mixture of 2,4-dichloro- 5-(trifluoromethyl)pyrimidine (10 g, 46 mmol) and DIPEA (17.7 mL, 102 mmol) at 0°C and the reaction mixture was stirred at 0°C for 16 h. The reaction mixture was evaporated to dryness, DCM (100 mL) and H 2 O (100 mL) were added. Layers were separated, organic layer was washed with water, brine, dried over Na 2 SO 4 , and concentrated under reduced pressure.
  • Diisopropyl azodicarboxylate (0.9 mL, 4.6 mmol) was added dropwise at 0°C to a mixture of 6-chloro-3(2H)-pyridazinone (0.5 g, 3.83 mmol), compound P20 (0.6 g, 4.6 mmol) and triphenylphosphine (1.2 g, 4.6 mmol) in THF (10 mL) and the reaction mixture was stirred at ambient temperature overnight. Volatiles were removed under reduced pressure and the residue was subjected to prep.
  • Example 32 N-(1-Methylcyclopropyl)-N-[2-[(1-tetrahydro-2H-pyran-4-yl-1H- pyrazol-4-yl)amino]-5-(trifluoromethyl)-4-pyrimidinyl]amine (Compound 102). 248.
  • Example 36 1-Methyl-1-[4-[4-(methylamino)-5-(trifluoromethyl)-2- pyrimidinyl]amino-6-oxo-1(6H)-pyridazinyl]ethyl cyanide (Compound 106).
  • Example 38 N 4 -[1-(2,2-difluoroethyl)-5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl]- N 2 -(1-methylcyclopropyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 39). The in Example 37 with 17% yield as slightly brown solid.
  • Example A Primary Assays Used to Determine Potency of the LRRK2 Inhibition. Assay for determining enzymatic activity inhibition against LRRK2[G2019S].
  • Compound activity was determined using recombinant LRRK2[G2019S] protein (SignalChem Biotech, Inc., Cat# L10-12GG-10) and LRRKtide substrate (SignalChem Biotech, Inc., Cat#L10-58) in an in vitro enzymatic reaction.
  • the enzymatic reaction was carried out in assay buffer (40 mM TRIS-HCl pH 7.4, 20 mM MgCl 2 , 0.05 mM DTT, 0.1 mg/mL BSA).
  • the compounds were dispensed into a 384 well Diamond Well Plate (Axigen, Cat# P-384-120SQ-C-S) using the Biomek FX liquid handling system at the 80x 253.
  • Ki values are shown in Table A, wherein “A” corresponds to Ki ⁇ 10.0 nM, “B” corresponds to 10.0 nM ⁇ Ki ⁇ 50.0 nM, “C” 50.0 nM ⁇ Ki ⁇ 100.0 nM, “D” corresponds to 100.0 nM ⁇ Ki ⁇ 500.0 nM and “E” corresponds to Ki>500.0 nM.
  • Table A LRRK2 (G2019S) Activity Inhibition Assays Compound Compound Comp nM * ound Ki, Ki, nM * Ki, nM * N mb r N mb r N mb r 254.
  • Example B Primary Assays Used to Determine Potency of the LRRK2 Inhibition. Assay for determining enzymatic activity inhibition against LRRK2 WT.
  • Compound activity was determined using recombinant LRRK2 WT protein (SignalChem Biotech, Inc., Cat#L10-11G-10) and LRRKtide substrate (SignalChem Biotech, Inc., Cat#L10-58) in an in vitro enzymatic reaction.
  • the enzymatic reaction was carried out in assay buffer (40 mM TRIS-HCl pH 7.4, 20 mM MgCl2, 0.05 mM DTT, 0.1 mg/mL BSA).
  • the compounds were dispensed into a 384 well Diamond Well Plate (Axigen, Cat# P-384- 120SQ-C-S) using the Biomek FX liquid handling system at 80x solutions of compounds in DMSO.
  • the 2x Protein-Substrate mix (final concentration 36 nM of LRRK2 WT and 0.8 ⁇ g/ ⁇ L of LRRKtide) was prepared in the 1x Assay buffer and 4 ⁇ L of mixture per well was added into the 384-well white Reaction plate with NBS (Corning, Cat#CLS4513). The 4 ⁇ L of LRRKtide substrate w/o LRRK2 WT in the 1x buffer was used for a negative control. Plates were centrifuged for 1 min at 200 g.
  • Ki values The average Ki values are shown in Table B, wherein “A” corresponds to Ki ⁇ 10.0 nM, “B” corresponds to 10.0 nM ⁇ Ki ⁇ 50.0 nM, “C” 50.0 nM ⁇ Ki ⁇ 100.0 nM, “D” corresponds to 100.0 nM ⁇ Ki ⁇ 500.0 nM and “E” corresponds to Ki>500.0 nM.
  • Table B LRRK2 (WT) Activity Inhibition Assays Compound * Compound * Compound Ki, nM Ki, nM Ki, nM* Number Number Number Ki values are determined through a series of experiments with varying amounts of inhibitor present. Ki: A ⁇ 10 nM; 10 nM ⁇ B ⁇ 20 nM; 20 nM ⁇ C ⁇ 50 nM; 50 nM ⁇ D ⁇ 100 nM; E > 100 nM [0856]
  • Example C Pharmacokinetics in mice. [0857] Table C: Pharmacokinetics in mice. 256.

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Abstract

The present invention is directed to the compounds of Formula (I) - inhibitors of LRRK2. The inhibitors described herein can be useful in the treatment of diseases or disorders associated with LRRK2, such as Parkinson disease (PD). In particular, the invention is concerned with compounds and pharmaceutical compositions inhibiting LRRK2, methods of treating diseases or disorders associated with LRRK2, and methods of synthesizing these compounds.

Description

Brenig.24.0001.W LRRK2 Inhibitors CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to and benefit of U.S. Provisional Patent Application Serial No. 63/644,490 filed May 08, 2024, entitled “LRRK2 Inhibitors” the disclosure of which are incorporated by reference in its entirety for all purposes. FIELD OF INVENTION [0002] The present invention is directed to inhibitors leucine-rich repeat kinase 2 (LRRK2). The inhibitors described herein can be useful in the treatment of diseases or disorders associated with LRRK2, such as Parkinson disease (PD). In particular, the invention is concerned with compounds and pharmaceutical compositions inhibiting LRRK2, methods of treating diseases or disorders associated with LRRK2, and methods of synthesizing these compounds. BACKGROUND [0003] Parkinson’s disease (PD), like many common age-related conditions, has been recognized to have a substantial genetic component. Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects around 2% of individuals over 60 years old. [0004] Leucine-rich repeat kinase 2 (LRRK2) is a 2527 amino acid protein with a molecular weight of 286 kDa that is encoded by the LRRK2 gene. It consists of the following functional and structural proteins domains: armadillo (ARM), ankyrin (ANK), leucine rich repeat (LRR), Ras of complex domain (Roc), c-terminal of Roc (COR), map kinase (MAPK) and tryptophan-aspartate repeat domain (WD40). LRRK2 exists primarily as a dimeric protein either associated with membrane structures or cytoplasmic localized. [0005] The armadillo, ankyrin, LRR and WD40 protein-protein interaction domains enables LRRK2 to interact with a host of different protein partners to impact its own as well as its partner proteins subcellular localization. The central enzymatic core of the LRRK2 protein containing the Roc-COR and the MAPK domain have distinct GTPase and ATPase enzymatic activities enabling LRRK2 to phosphorylate and control the function of intracellular substrates. LRRK2 impacts, via its enzymatic activity and substrate interactions, various subcellular processes and biological mechanisms important for 1. ASB Brenig.24.0001.W trafficking of intracellular vesicular structures and organelles such as lysosomes, endosomes, autophagosomes, the Golgi and mitochondria. [0006] Rare protein-encoding variants in the LRRK2 gene cause Parkinson’s disease. The most common pathogenic variant causing autosomal dominant familial Parkinson’s disease is the p.G2019S substitution which changes a glycine to a serine in the activation loop of the LRRK2 kinase domain rendering the p.G2019S variant more active than the wild type LRRK2 protein. Besides p.G2019S seven additional rare LRRK2 exonic variants having non-synonymous amino acid substitutions in the central enzymatic core (p.N1437H; p.R1441C/G/H; p.Y1699C; p.S1761R; p.I2020T) also cause autosomal dominant Parkinson’s disease. Common protein-coding variants in the LRRK2 gene are also associated with risk of Parkinson’s disease. Variants such as p.A419V, p.M1646T, p.R1628P and p.G2385R increase the risk of Parkinson’s disease and have increased kinase activity. [0007] Evidence that LRRK2 also plays a role in sporadic Parkinson’s disease comes from both genetic studies as well as postmortem analyses of PD brains. A single nucleotide polymorphism (SNP) at the LRRK2 genetic locus is genome-wide associated with risk of Parkinson’s disease. This particular SNP variant is associated with increased LRRK2 expression which is in agreement with the increased LRRK2 kinase activity observed in surviving dopamine neurons from postmortem brains of sporadic PD patients. [0008] Thus, inhibitors ofLRRK2 kinase activity can be used as therapies for both sporadic PD patients as well as for PD patients with LRRK2 mutations or Rab29/Rab7Ll polymorphisms. [0009] Developing selective inhibitors of LRRK2 has been a major focus in treating LRRK2-associated PD. Various targeting strategies are currently being explored, including ATP-competitive type I and type II inhibitors, LRRK2 dimerization inhibitors, LRRK2 G2019S selective inhibitors, antisense oligonucleotide, proteolysis targeting chimeras (PROTACs), and LRRK2-targeting nanobodies. Currently, LRRK2-specific type I kinase inhibitors are available, and type II inhibitors are under active exploration. LRRK2 inhibitors, including DNL201 and DNL151, are currently in clinical trials. [0010] But the lack of co-structures of LRRK2 and small-molecule inhibitors largely hinders our understanding of the mode of action (MoA) of known inhibitors and ongoing 2. ASB Brenig.24.0001.W efforts for structure-based drug discovery. Structural information on drug targets with inhibitors enables medicinal chemists to understand the structure-activity relationship (SAR) and facilitates lead optimization and computation-aided drug discovery. However, experimental methods that enable the determination of high-resolution LRRK2 structures with different types of inhibitors are lacking. SUMMARY [0011] The present invention in general related to compounds of Formula (I): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0012] A first aspect of the invention relates to compounds of Formula (A): , or a pharmaceutically solvate, or tautomer thereof, wherein each A is independently selected from CR4 and N; B is selected from CH and N, provided that anyone from B is N, and another B is CH; R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; 3. ASB Brenig.24.0001.W R2 is selected ; R3 is selected C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl-S(O)2-, heterocycle, aryl, and heteroaryl; each R4 is independently selected from H, OH, halogen, CN, C1-C6 alkyl, C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl, and heterocycle; wherein, aryl is cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings; heterocyclyl is saturated or partially unsaturated 3–10 membered monocyclic, 7– 12 membered bicyclic (fused, bridged, or spiro rings), or 11–14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms selected from O, N, S, P, Se, or B; heteroaryl is a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C. [0013] A second aspect of the invention relates to compounds of Formula (B): 4. ASB Brenig.24.0001.W F3C R2 B , or a pharmaceutically solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; E is selected from CH and N, provided that anyone from E is N, and another E is CH; R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; R2 is selected ; R3 is selected C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl-S(O)2-, heterocycle, aryl, and heteroaryl; R5 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 5. ASB Brenig.24.0001.W cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl; u is an integer selected from 0, 1 and 2; wherein, aryl is cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings; heterocyclyl is saturated or partially unsaturated 3–10 membered monocyclic, 7– 12 membered bicyclic (fused, bridged, or spiro rings), or 11–14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms selected from O, N, S, P, Se, or B; heteroaryl is a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C. [0014] A third aspect of the invention relates to compounds of Formula (C): , or a pharmaceutically solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; U is selected from CRBRC and NRB; RA is H; RB is H; or RA and RB together form a bond; RC is H; Ra is H; Rb is H; and Rc and Rd together form =O; or Ra and Rd together with the atoms to which they are attached, may come together to form 5-7 membered cycloalkyl or heterocycle, wherein cycloalkyl or heterocycle 6. ASB Brenig.24.0001.W optionally substituted with one or more substitutients independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl; and Rb and Rc together form a bond; R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; R2 is selected ; R3 is selected C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl-S(O)2-, heterocycle, aryl, and heteroaryl; wherein, aryl is cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings; heterocyclyl is saturated or partially unsaturated 3–10 membered monocyclic, 7– 12 membered bicyclic (fused, bridged, or spiro rings), or 11–14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms selected from O, N, S, P, Se, or B; heteroaryl is a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C. [0015] A fourth aspect of the invention relates to compounds of Formula (D): 7. ASB Brenig.24.0001.W , or a pharmaceutically solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; RA is H; or RA and Rc together form a bond; Rd is H; or Rc and Rd together form =O; RD is selected from H and C1-C6 alkyl; R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; R2 is selected ; R3 is selected C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl-S(O)2-, heterocycle, aryl, and heteroaryl; wherein, 8. ASB Brenig.24.0001.W aryl is cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings; heterocyclyl is saturated or partially unsaturated 3–10 membered monocyclic, 7– 12 membered bicyclic (fused, bridged, or spiro rings), or 11–14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms selected from O, N, S, P, Se, or B; heteroaryl is a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C. [0016] A fifth aspect of the invention relates to compounds of Formula (E): , or a pharmaceutically or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; Re is selected from H, -(CH2)n-NR6R7, -(CH2)n-OR6; Rf is H; Rg is H; or Rf and Rg together form a bond; Rh is H; or Re and Rh together with the atoms to which they are attached, may come together to form 5-7 membered heterocycle, optionally substituted with one or more substitutients independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, -(CH2)n- aryl and heteroaryl; 9. ASB Brenig.24.0001.W R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; R2 is selected from H ; R6 is selected from H, C1-C6 alkyl; R7 is selected from OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C(O)-; n is an integer selected from 0, 1, 2, 3, 4, 5, and 6; wherein, aryl is cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings; heterocyclyl is saturated or partially unsaturated 3–10 membered monocyclic, 7– 12 membered bicyclic (fused, bridged, or spiro rings), or 11–14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms selected from O, N, S, P, Se, or B; heteroaryl is a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C. [0017] A sixth aspect of the invention relates to compounds of Formula (F): , ASB Brenig.24.0001.W or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; R2 is selected ; each R8 is halogen, OH, NH2, CN, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl; or any two R8 together form C1-C3 alkanediyl; each R9 is independently selected from H, C1-C6 alkyl; or two R9 together form C1-C3 alkanediyl; or any one R8 and any one R9 together form C1-C3 alkanediyl; R10 is selected from C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the cycloalkyl, heterocycle, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl; each m is an integer independently selected from 1, 2, and 3; wherein, aryl is cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings; 11. ASB Brenig.24.0001.W heterocyclyl is saturated or partially unsaturated 3–10 membered monocyclic, 7– 12 membered bicyclic (fused, bridged, or spiro rings), or 11–14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms selected from O, N, S, P, Se, or B; heteroaryl is a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C. [0018] A seventh aspect of the invention relates to compounds of Formula (G): , or a pharmaceutically solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; R2 is selected ; R11 is selected C1-C6 alkoxy; R12 is selected from C1-C6 alkyl substituted with one or more substitutients independently selected from N(R14)2, -CN; or 12. ASB Brenig.24.0001.W R11 and R12 together with the atoms to which they are attached, may come together to form 5-7 membered heterocycle, optionally substituted with one or more substitutients independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, -(CH2)n- aryl and heteroaryl; R13 is halogen; each R14 is independently selected from H and C1-C6 alkyl; k is an integer selected from 0 and 1; wherein, aryl is cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings; heterocyclyl is saturated or partially unsaturated 3–10 membered monocyclic, 7– 12 membered bicyclic (fused, bridged, or spiro rings), or 11–14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms selected from O, N, S, P, Se, or B; heteroaryl is a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C. [0019] An eighth aspect of the invention relates to compounds of Formula (H): , or a pharmaceutically solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected 13. ASB Brenig.24.0001.W from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; R2 is selected ; R3 is selected C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl-S(O)2-, heterocycle, aryl, and heteroaryl; wherein, aryl is cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings; heterocyclyl is saturated or partially unsaturated 3–10 membered monocyclic, 7– 12 membered bicyclic (fused, bridged, or spiro rings), or 11–14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms selected from O, N, S, P, Se, or B; heteroaryl is a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C. [0020] A ninth aspect of the invention relates to compounds of Formula (J): , ASB Brenig.24.0001.W or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; R2 is selected ; R3 is selected C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl-S(O)2-, heterocycle, aryl, and heteroaryl; wherein, aryl is cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings; heterocyclyl is saturated or partially unsaturated 3–10 membered monocyclic, 7– 12 membered bicyclic (fused, bridged, or spiro rings), or 11–14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms selected from O, N, S, P, Se, or B; heteroaryl is a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C. [0021] A tenth aspect of the invention relates to compounds of Formula (K): 15. ASB Brenig.24.0001.W , or a pharmaceutically solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; R2 is selected ; each R15 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl- S(O)2-, heterocycle, aryl, and heteroaryl; wherein, aryl is cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings; heterocyclyl is saturated or partially unsaturated 3–10 membered monocyclic, 7– 12 membered bicyclic (fused, bridged, or spiro rings), or 11–14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms selected from O, N, S, P, Se, or B; 16. ASB Brenig.24.0001.W heteroaryl is a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C. [0022] An eleventh aspect of the invention relates to compounds of Formula (L): , or a pharmaceutically solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; each G is independently selected from O, S, S(O), S(O)2, NH; R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; R2 is selected ; each R3 is C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 17. ASB Brenig.24.0001.W alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl- S(O)2-, heterocycle, aryl, and heteroaryl; p is an integer selected from 0, 1, 2, and 3; wherein, aryl is cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings; heterocyclyl is saturated or partially unsaturated 3–10 membered monocyclic, 7– 12 membered bicyclic (fused, bridged, or spiro rings), or 11–14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms selected from O, N, S, P, Se, or B; heteroaryl is a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C. [0023] A twelfth aspect of the invention relates to compounds of Formula (M): , or a pharmaceutically solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; G is selected from O, S, S(O), S(O)2, NH; R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; 18. ASB Brenig.24.0001.W R2 is selected ; each R3 is C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl- S(O)2-, heterocycle, aryl, and heteroaryl; q is an integer selected from 1, 2, and 3; r is an integer selected from 1, 2, and 3; wherein, aryl is cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings; heterocyclyl is saturated or partially unsaturated 3–10 membered monocyclic, 7– 12 membered bicyclic (fused, bridged, or spiro rings), or 11–14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms selected from O, N, S, P, Se, or B; heteroaryl is a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C. [0024] Another aspect of the invention relates to compounds of Formula (N): , ASB Brenig.24.0001.W or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; R2 is selected ; R16 is selected C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl- S(O)2-, heterocycle, aryl, and heteroaryl; wherein, aryl is cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings; heterocyclyl is saturated or partially unsaturated 3–10 membered monocyclic, 7– 12 membered bicyclic (fused, bridged, or spiro rings), or 11–14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms selected from O, N, S, P, Se, or B; heteroaryl is a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C. [0025] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable 20. ASB Brenig.24.0001.W carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. [0026] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. [0027] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (B), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. [0028] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (C), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. [0029] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (D), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. [0030] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (E), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. [0031] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (F), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable 21. ASB Brenig.24.0001.W carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. [0032] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (G), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. [0033] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (H), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. [0034] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (J), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. [0035] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (K), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. [0036] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (L), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. [0037] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (M), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable 22. ASB Brenig.24.0001.W carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. [0038] Another aspect of the invention relates to a method of treating a disease or disorder associated with LRRK2. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with LRRK2 an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0039] Another aspect of the invention relates to a method of treating a disease or disorder associated with LRRK2. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with LRRK2 an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0040] Another aspect of the invention relates to a method of treating a disease or disorder associated with LRRK2. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with LRRK2 an effective amount of a compound of Formula (B), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0041] Another aspect of the invention relates to a method of treating a disease or disorder associated with LRRK2. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with LRRK2 an effective amount of a compound of Formula (C), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0042] Another aspect of the invention relates to a method of treating a disease or disorder associated with LRRK2. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with LRRK2 an effective amount of a compound of Formula (D), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0043] Another aspect of the invention relates to a method of treating a disease or disorder associated with LRRK2. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with LRRK2 an effective amount of a 23. ASB Brenig.24.0001.W compound of Formula (E), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0044] Another aspect of the invention relates to a method of treating a disease or disorder associated with LRRK2. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with LRRK2 an effective amount of a compound of Formula (F), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0045] Another aspect of the invention relates to a method of treating a disease or disorder associated with LRRK2. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with LRRK2 an effective amount of a compound of Formula (G), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0046] Another aspect of the invention relates to a method of treating a disease or disorder associated with LRRK2. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with LRRK2 an effective amount of a compound of Formula (H), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0047] Another aspect of the invention relates to a method of treating a disease or disorder associated with LRRK2. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with LRRK2 an effective amount of a compound of Formula (J), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0048] Another aspect of the invention relates to a method of treating a disease or disorder associated with LRRK2. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with LRRK2 an effective amount of a compound of Formula (K), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0049] Another aspect of the invention relates to a method of treating a disease or disorder associated with LRRK2. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with LRRK2 an effective amount of a 24. ASB Brenig.24.0001.W compound of Formula (L), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0050] Another aspect of the invention relates to a method of treating a disease or disorder associated with LRRK2. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with LRRK2 an effective amount of a compound of Formula (M), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0051] Another aspect of the invention is directed to a method of inhibiting of LRRK2. The method involves administering to a patient in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0052] Another aspect of the invention is directed to a method of inhibiting of LRRK2. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0053] Another aspect of the invention is directed to a method of inhibiting of LRRK2. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (B), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0054] Another aspect of the invention is directed to a method of inhibiting of LRRK2. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (C), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0055] Another aspect of the invention is directed to a method of inhibiting of LRRK2. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (D), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0056] Another aspect of the invention is directed to a method of inhibiting of LRRK2. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (E), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. 25. ASB Brenig.24.0001.W [0057] Another aspect of the invention is directed to a method of inhibiting of LRRK2. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (F), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0058] Another aspect of the invention is directed to a method of inhibiting of LRRK2. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (G), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0059] Another aspect of the invention is directed to a method of inhibiting of LRRK2. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (H), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0060] Another aspect of the invention is directed to a method of inhibiting of LRRK2. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (J), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0061] Another aspect of the invention is directed to a method of inhibiting of LRRK2. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (K), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0062] Another aspect of the invention is directed to a method of inhibiting of LRRK2. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (L), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0063] Another aspect of the invention is directed to a method of inhibiting of LRRK2. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (M), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0064] Another aspect of the present invention relates to compounds disclosed herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, 26. ASB Brenig.24.0001.W or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting LRRK2. [0065] Another aspect of the present invention relates to compounds of Formula (A), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting LRRK2. [0066] Another aspect of the present invention relates to compounds of Formula (B), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting LRRK2. [0067] Another aspect of the present invention relates to compounds of Formula (C), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting LRRK2. [0068] Another aspect of the present invention relates to compounds of Formula (D), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting LRRK2. [0069] Another aspect of the present invention relates to compounds of Formula (E), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting LRRK2. [0070] Another aspect of the present invention relates to compounds of Formula (F), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting LRRK2. [0071] Another aspect of the present invention relates to compounds of Formula (G), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting LRRK2. 27. ASB Brenig.24.0001.W [0072] Another aspect of the present invention relates to compounds of Formula (H), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting LRRK2. [0073] Another aspect of the present invention relates to compounds of Formula (J), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting LRRK2. [0074] Another aspect of the present invention relates to compounds of Formula (K), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting LRRK2. [0075] Another aspect of the present invention relates to compounds of Formula (L), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting LRRK2. [0076] Another aspect of the present invention relates to compounds of Formula (M), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting LRRK2. [0077] Another aspect of the present invention relates to the use of compounds disclosed herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with LRRK2. [0078] Another aspect of the present invention relates to the use of compounds of Formula (A), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with LRRK2. [0079] Another aspect of the present invention relates to the use of compounds of Formula (B), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, 28. ASB Brenig.24.0001.W tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with LRRK2. [0080] Another aspect of the present invention relates to the use of compounds of Formula (C), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with LRRK2. [0081] Another aspect of the present invention relates to the use of compounds of Formula (D), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with LRRK2. [0082] Another aspect of the present invention relates to the use of compounds of Formula (E), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with LRRK2. [0083] Another aspect of the present invention relates to the use of compounds of Formula (F), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with LRRK2. [0084] Another aspect of the present invention relates to the use of compounds of Formula (G), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with LRRK2. [0085] Another aspect of the present invention relates to the use of compounds of Formula (H), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with LRRK2. [0086] Another aspect of the present invention relates to the use of compounds of Formula (J), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with LRRK2. 29. ASB Brenig.24.0001.W [0087] Another aspect of the present invention relates to the use of compounds of Formula (K), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with LRRK2. [0088] Another aspect of the present invention relates to the use of compounds of Formula (L), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with LRRK2. [0089] Another aspect of the present invention relates to the use of compounds of Formula (M), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with LRRK2. [0090] Another aspect of the present invention relates to compounds disclosed herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. [0091] Another aspect of the present invention relates to compounds of Formula (A), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. [0092] Another aspect of the present invention relates to compounds of Formula (B), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. [0093] Another aspect of the present invention relates to compounds of Formula (C), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. [0094] Another aspect of the present invention relates to compounds of Formula (D), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, 30. ASB Brenig.24.0001.W or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. [0095] Another aspect of the present invention relates to compounds of Formula (E), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. [0096] Another aspect of the present invention relates to compounds of Formula (F), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. [0097] Another aspect of the present invention relates to compounds of Formula (G), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. [0098] Another aspect of the present invention relates to compounds of Formula (H), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. [0099] Another aspect of the present invention relates to compounds of Formula (J), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. [0100] Another aspect of the present invention relates to compounds of Formula (K), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. [0101] Another aspect of the present invention relates to compounds of Formula (L), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. 31. ASB Brenig.24.0001.W [0102] Another aspect of the present invention relates to compounds of Formula (M), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. [0103] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0104] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0105] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (B), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0106] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (C), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0107] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (D), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0108] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves 32. ASB Brenig.24.0001.W administering to a patient in need of the treatment an effective amount of a compound of Formula (E), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0109] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (F), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0110] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (G), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0111] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (H), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0112] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (J), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0113] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (K), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0114] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of 33. ASB Brenig.24.0001.W Formula (L), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0115] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (M), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0116] Another aspect of the present invention relates to the use of compounds of the invention disclosed herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein. [0117] Another aspect of the present invention relates to the use of compounds of Formula (A), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein. [0118] Another aspect of the present invention relates to the use of compounds of Formula (B), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein. [0119] Another aspect of the present invention relates to the use of compounds of Formula (C), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein. [0120] Another aspect of the present invention relates to the use of compounds of Formula (D), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein. [0121] Another aspect of the present invention relates to the use of compounds of Formula (E), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein. 34. ASB Brenig.24.0001.W [0122] Another aspect of the present invention relates to the use of compounds of Formula (F), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein. [0123] Another aspect of the present invention relates to the use of compounds of Formula (G), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein. [0124] Another aspect of the present invention relates to the use of compounds of Formula (H), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein. [0125] Another aspect of the present invention relates to the use of compounds of Formula (J), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein. [0126] Another aspect of the present invention relates to the use of compounds of Formula (K), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein. [0127] Another aspect of the present invention relates to the use of compounds of Formula (L), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein. [0128] Another aspect of the present invention relates to the use of compounds of Formula (M), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein. [0129] The present invention further provides methods of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of the disclosure, or a pharmaceutically 35. ASB Brenig.24.0001.W acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0130] The present invention further provides methods of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0131] The present invention further provides methods of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (B), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0132] The present invention further provides methods of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (C), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0133] The present invention further provides methods of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (D), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0134] The present invention further provides methods of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (E), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0135] The present invention further provides methods of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (F), or a pharmaceutically acceptable 36. ASB Brenig.24.0001.W salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0136] The present invention further provides methods of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (G), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0137] The present invention further provides methods of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (H), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0138] The present invention further provides methods of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (J), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0139] The present invention further provides methods of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (K), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0140] The present invention further provides methods of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (L), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0141] The present invention further provides methods of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (M), or a pharmaceutically acceptable 37. ASB Brenig.24.0001.W salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0142] The present invention provides inhibitors of LRRK2 that are therapeutic agents in the treatment of diseases and disorders. [0143] The present invention further provides compounds and compositions with an improved efficacy and safety profile relative to known inhibitors of LRRK2. The present disclosure also provides agents with novel mechanisms of action toward LRRK2 in the treatment of various types of diseases. [0144] The present invention provides inhibitors of LRRK2 that are therapeutic agents in the treatment of diseases and disorders. [0145] The present invention further provides methods of treating a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early- Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson Disease 10 (PARK10); Tremor; Frontotemporal Dementia (FTD); Postencephalitic Parkinson Disease; Vascular Parkinsonism; Aphasia; Parkinson Disease 1, Autosomal Dominant (PARK1); Athetosis; Klippel-Feil Syndrome (KFS); Kufor-Rakeb Syndrome (KRS); Leprosy 3 (LPRS3); Alzheimer Disease 8 (AD8); Crohn's Disease; Rheumatoid Arthritis (RA); Alzheimer Disease (AD); Color Agnosia; Gaucher Disease, Type I (GD1); Parkinson Disease 15, Autosomal Recessive Early-Onset (PARK15); Von Economo's Disease; Gerstmann-Straussler Disease (GSD); Amyotrophic Lateral Sclerosis- Parkinsonism/dementia Complex 1 (ALS-PDC1); Dystonia; Sphingolipidosis; Radial Nerve Lesion; Toxic Encephalopathy; Sleep Disorder; Pick Disease of Brain (PIDB); Ophthalmomyiasis; Gaucher's Disease (GD); Optic Atrophy 7 with or Without Auditory Neuropathy (OPA7); Ulnar Nerve Lesion; Inflammatory Bowel Disease 4 (IBD4); Inflammatory Bowel Disease; 3-Methylglutaconic Aciduria, Type Iii (MGCA3); Nervous 38. ASB Brenig.24.0001.W System Disease; Amyotrophic Lateral Sclerosis 1 (ALS1); Mitochondrial Complex I Deficiency, Nuclear Type 1 (MC1DN1) comprising administering to a patient suffering from at least one of said diseases or disorders a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0146] The present invention further provides methods of treating a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early- Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson Disease 10 (PARK10); Tremor; Frontotemporal Dementia (FTD); Postencephalitic Parkinson Disease; Vascular Parkinsonism; Aphasia; Parkinson Disease 1, Autosomal Dominant (PARK1); Athetosis; Klippel-Feil Syndrome (KFS); Kufor-Rakeb Syndrome (KRS); Leprosy 3 (LPRS3); Alzheimer Disease 8 (AD8); Crohn's Disease; Rheumatoid Arthritis (RA); Alzheimer Disease (AD); Color Agnosia; Gaucher Disease, Type I (GD1); Parkinson Disease 15, Autosomal Recessive Early-Onset (PARK15); Von Economo's Disease; Gerstmann-Straussler Disease (GSD); Amyotrophic Lateral Sclerosis- Parkinsonism/dementia Complex 1 (ALS-PDC1); Dystonia; Sphingolipidosis; Radial Nerve Lesion; Toxic Encephalopathy; Sleep Disorder; Pick Disease of Brain (PIDB); Ophthalmomyiasis; Gaucher's Disease (GD); Optic Atrophy 7 with or Without Auditory Neuropathy (OPA7); Ulnar Nerve Lesion; Inflammatory Bowel Disease 4 (IBD4); Inflammatory Bowel Disease; 3-Methylglutaconic Aciduria, Type Iii (MGCA3); Nervous System Disease; Amyotrophic Lateral Sclerosis 1 (ALS1); Mitochondrial Complex I Deficiency, Nuclear Type 1 (MC1DN1) comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. 39. ASB Brenig.24.0001.W [0147] The present invention further provides methods of treating a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early- Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson Disease 10 (PARK10); Tremor; Frontotemporal Dementia (FTD); Postencephalitic Parkinson Disease; Vascular Parkinsonism; Aphasia; Parkinson Disease 1, Autosomal Dominant (PARK1); Athetosis; Klippel-Feil Syndrome (KFS); Kufor-Rakeb Syndrome (KRS); Leprosy 3 (LPRS3); Alzheimer Disease 8 (AD8); Crohn's Disease; Rheumatoid Arthritis (RA); Alzheimer Disease (AD); Color Agnosia; Gaucher Disease, Type I (GD1); Parkinson Disease 15, Autosomal Recessive Early-Onset (PARK15); Von Economo's Disease; Gerstmann-Straussler Disease (GSD); Amyotrophic Lateral Sclerosis- Parkinsonism/dementia Complex 1 (ALS-PDC1); Dystonia; Sphingolipidosis; Radial Nerve Lesion; Toxic Encephalopathy; Sleep Disorder; Pick Disease of Brain (PIDB); Ophthalmomyiasis; Gaucher's Disease (GD); Optic Atrophy 7 with or Without Auditory Neuropathy (OPA7); Ulnar Nerve Lesion; Inflammatory Bowel Disease 4 (IBD4); Inflammatory Bowel Disease; 3-Methylglutaconic Aciduria, Type Iii (MGCA3); Nervous System Disease; Amyotrophic Lateral Sclerosis 1 (ALS1); Mitochondrial Complex I Deficiency, Nuclear Type 1 (MC1DN1) comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (B), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0148] The present invention further provides methods of treating a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile 40. ASB Brenig.24.0001.W (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early- Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson Disease 10 (PARK10); Tremor; Frontotemporal Dementia (FTD); Postencephalitic Parkinson Disease; Vascular Parkinsonism; Aphasia; Parkinson Disease 1, Autosomal Dominant (PARK1); Athetosis; Klippel-Feil Syndrome (KFS); Kufor-Rakeb Syndrome (KRS); Leprosy 3 (LPRS3); Alzheimer Disease 8 (AD8); Crohn's Disease; Rheumatoid Arthritis (RA); Alzheimer Disease (AD); Color Agnosia; Gaucher Disease, Type I (GD1); Parkinson Disease 15, Autosomal Recessive Early-Onset (PARK15); Von Economo's Disease; Gerstmann-Straussler Disease (GSD); Amyotrophic Lateral Sclerosis- Parkinsonism/dementia Complex 1 (ALS-PDC1); Dystonia; Sphingolipidosis; Radial Nerve Lesion; Toxic Encephalopathy; Sleep Disorder; Pick Disease of Brain (PIDB); Ophthalmomyiasis; Gaucher's Disease (GD); Optic Atrophy 7 with or Without Auditory Neuropathy (OPA7); Ulnar Nerve Lesion; Inflammatory Bowel Disease 4 (IBD4); Inflammatory Bowel Disease; 3-Methylglutaconic Aciduria, Type Iii (MGCA3); Nervous System Disease; Amyotrophic Lateral Sclerosis 1 (ALS1); Mitochondrial Complex I Deficiency, Nuclear Type 1 (MC1DN1) comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (C), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0149] The present invention further provides methods of treating a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early- Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson Disease 10 (PARK10); Tremor; Frontotemporal Dementia (FTD); 41. ASB Brenig.24.0001.W Postencephalitic Parkinson Disease; Vascular Parkinsonism; Aphasia; Parkinson Disease 1, Autosomal Dominant (PARK1); Athetosis; Klippel-Feil Syndrome (KFS); Kufor-Rakeb Syndrome (KRS); Leprosy 3 (LPRS3); Alzheimer Disease 8 (AD8); Crohn's Disease; Rheumatoid Arthritis (RA); Alzheimer Disease (AD); Color Agnosia; Gaucher Disease, Type I (GD1); Parkinson Disease 15, Autosomal Recessive Early-Onset (PARK15); Von Economo's Disease; Gerstmann-Straussler Disease (GSD); Amyotrophic Lateral Sclerosis- Parkinsonism/dementia Complex 1 (ALS-PDC1); Dystonia; Sphingolipidosis; Radial Nerve Lesion; Toxic Encephalopathy; Sleep Disorder; Pick Disease of Brain (PIDB); Ophthalmomyiasis; Gaucher's Disease (GD); Optic Atrophy 7 with or Without Auditory Neuropathy (OPA7); Ulnar Nerve Lesion; Inflammatory Bowel Disease 4 (IBD4); Inflammatory Bowel Disease; 3-Methylglutaconic Aciduria, Type Iii (MGCA3); Nervous System Disease; Amyotrophic Lateral Sclerosis 1 (ALS1); Mitochondrial Complex I Deficiency, Nuclear Type 1 (MC1DN1) comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (D), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0150] The present invention further provides methods of treating a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early- Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson Disease 10 (PARK10); Tremor; Frontotemporal Dementia (FTD); Postencephalitic Parkinson Disease; Vascular Parkinsonism; Aphasia; Parkinson Disease 1, Autosomal Dominant (PARK1); Athetosis; Klippel-Feil Syndrome (KFS); Kufor-Rakeb Syndrome (KRS); Leprosy 3 (LPRS3); Alzheimer Disease 8 (AD8); Crohn's Disease; Rheumatoid Arthritis (RA); Alzheimer Disease (AD); Color Agnosia; Gaucher Disease, Type I (GD1); Parkinson Disease 15, Autosomal Recessive Early-Onset (PARK15); Von 42. ASB Brenig.24.0001.W Economo's Disease; Gerstmann-Straussler Disease (GSD); Amyotrophic Lateral Sclerosis- Parkinsonism/dementia Complex 1 (ALS-PDC1); Dystonia; Sphingolipidosis; Radial Nerve Lesion; Toxic Encephalopathy; Sleep Disorder; Pick Disease of Brain (PIDB); Ophthalmomyiasis; Gaucher's Disease (GD); Optic Atrophy 7 with or Without Auditory Neuropathy (OPA7); Ulnar Nerve Lesion; Inflammatory Bowel Disease 4 (IBD4); Inflammatory Bowel Disease; 3-Methylglutaconic Aciduria, Type Iii (MGCA3); Nervous System Disease; Amyotrophic Lateral Sclerosis 1 (ALS1); Mitochondrial Complex I Deficiency, Nuclear Type 1 (MC1DN1) comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (E), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0151] The present invention further provides methods of treating a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early- Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson Disease 10 (PARK10); Tremor; Frontotemporal Dementia (FTD); Postencephalitic Parkinson Disease; Vascular Parkinsonism; Aphasia; Parkinson Disease 1, Autosomal Dominant (PARK1); Athetosis; Klippel-Feil Syndrome (KFS); Kufor-Rakeb Syndrome (KRS); Leprosy 3 (LPRS3); Alzheimer Disease 8 (AD8); Crohn's Disease; Rheumatoid Arthritis (RA); Alzheimer Disease (AD); Color Agnosia; Gaucher Disease, Type I (GD1); Parkinson Disease 15, Autosomal Recessive Early-Onset (PARK15); Von Economo's Disease; Gerstmann-Straussler Disease (GSD); Amyotrophic Lateral Sclerosis- Parkinsonism/dementia Complex 1 (ALS-PDC1); Dystonia; Sphingolipidosis; Radial Nerve Lesion; Toxic Encephalopathy; Sleep Disorder; Pick Disease of Brain (PIDB); Ophthalmomyiasis; Gaucher's Disease (GD); Optic Atrophy 7 with or Without Auditory Neuropathy (OPA7); Ulnar Nerve Lesion; Inflammatory Bowel Disease 4 (IBD4); 43. ASB Brenig.24.0001.W Inflammatory Bowel Disease; 3-Methylglutaconic Aciduria, Type Iii (MGCA3); Nervous System Disease; Amyotrophic Lateral Sclerosis 1 (ALS1); Mitochondrial Complex I Deficiency, Nuclear Type 1 (MC1DN1) comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (F), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0152] The present invention further provides methods of treating a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early- Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson Disease 10 (PARK10); Tremor; Frontotemporal Dementia (FTD); Postencephalitic Parkinson Disease; Vascular Parkinsonism; Aphasia; Parkinson Disease 1, Autosomal Dominant (PARK1); Athetosis; Klippel-Feil Syndrome (KFS); Kufor-Rakeb Syndrome (KRS); Leprosy 3 (LPRS3); Alzheimer Disease 8 (AD8); Crohn's Disease; Rheumatoid Arthritis (RA); Alzheimer Disease (AD); Color Agnosia; Gaucher Disease, Type I (GD1); Parkinson Disease 15, Autosomal Recessive Early-Onset (PARK15); Von Economo's Disease; Gerstmann-Straussler Disease (GSD); Amyotrophic Lateral Sclerosis- Parkinsonism/dementia Complex 1 (ALS-PDC1); Dystonia; Sphingolipidosis; Radial Nerve Lesion; Toxic Encephalopathy; Sleep Disorder; Pick Disease of Brain (PIDB); Ophthalmomyiasis; Gaucher's Disease (GD); Optic Atrophy 7 with or Without Auditory Neuropathy (OPA7); Ulnar Nerve Lesion; Inflammatory Bowel Disease 4 (IBD4); Inflammatory Bowel Disease; 3-Methylglutaconic Aciduria, Type Iii (MGCA3); Nervous System Disease; Amyotrophic Lateral Sclerosis 1 (ALS1); Mitochondrial Complex I Deficiency, Nuclear Type 1 (MC1DN1) comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (G), or a 44. ASB Brenig.24.0001.W pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0153] The present invention further provides methods of treating a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early- Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson Disease 10 (PARK10); Tremor; Frontotemporal Dementia (FTD); Postencephalitic Parkinson Disease; Vascular Parkinsonism; Aphasia; Parkinson Disease 1, Autosomal Dominant (PARK1); Athetosis; Klippel-Feil Syndrome (KFS); Kufor-Rakeb Syndrome (KRS); Leprosy 3 (LPRS3); Alzheimer Disease 8 (AD8); Crohn's Disease; Rheumatoid Arthritis (RA); Alzheimer Disease (AD); Color Agnosia; Gaucher Disease, Type I (GD1); Parkinson Disease 15, Autosomal Recessive Early-Onset (PARK15); Von Economo's Disease; Gerstmann-Straussler Disease (GSD); Amyotrophic Lateral Sclerosis- Parkinsonism/dementia Complex 1 (ALS-PDC1); Dystonia; Sphingolipidosis; Radial Nerve Lesion; Toxic Encephalopathy; Sleep Disorder; Pick Disease of Brain (PIDB); Ophthalmomyiasis; Gaucher's Disease (GD); Optic Atrophy 7 with or Without Auditory Neuropathy (OPA7); Ulnar Nerve Lesion; Inflammatory Bowel Disease 4 (IBD4); Inflammatory Bowel Disease; 3-Methylglutaconic Aciduria, Type Iii (MGCA3); Nervous System Disease; Amyotrophic Lateral Sclerosis 1 (ALS1); Mitochondrial Complex I Deficiency, Nuclear Type 1 (MC1DN1) comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (H), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0154] The present invention further provides methods of treating a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 45. ASB Brenig.24.0001.W 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early- Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson Disease 10 (PARK10); Tremor; Frontotemporal Dementia (FTD); Postencephalitic Parkinson Disease; Vascular Parkinsonism; Aphasia; Parkinson Disease 1, Autosomal Dominant (PARK1); Athetosis; Klippel-Feil Syndrome (KFS); Kufor-Rakeb Syndrome (KRS); Leprosy 3 (LPRS3); Alzheimer Disease 8 (AD8); Crohn's Disease; Rheumatoid Arthritis (RA); Alzheimer Disease (AD); Color Agnosia; Gaucher Disease, Type I (GD1); Parkinson Disease 15, Autosomal Recessive Early-Onset (PARK15); Von Economo's Disease; Gerstmann-Straussler Disease (GSD); Amyotrophic Lateral Sclerosis- Parkinsonism/dementia Complex 1 (ALS-PDC1); Dystonia; Sphingolipidosis; Radial Nerve Lesion; Toxic Encephalopathy; Sleep Disorder; Pick Disease of Brain (PIDB); Ophthalmomyiasis; Gaucher's Disease (GD); Optic Atrophy 7 with or Without Auditory Neuropathy (OPA7); Ulnar Nerve Lesion; Inflammatory Bowel Disease 4 (IBD4); Inflammatory Bowel Disease; 3-Methylglutaconic Aciduria, Type Iii (MGCA3); Nervous System Disease; Amyotrophic Lateral Sclerosis 1 (ALS1); Mitochondrial Complex I Deficiency, Nuclear Type 1 (MC1DN1) comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (J), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0155] The present invention further provides methods of treating a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early- Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; 46. ASB Brenig.24.0001.W Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson Disease 10 (PARK10); Tremor; Frontotemporal Dementia (FTD); Postencephalitic Parkinson Disease; Vascular Parkinsonism; Aphasia; Parkinson Disease 1, Autosomal Dominant (PARK1); Athetosis; Klippel-Feil Syndrome (KFS); Kufor-Rakeb Syndrome (KRS); Leprosy 3 (LPRS3); Alzheimer Disease 8 (AD8); Crohn's Disease; Rheumatoid Arthritis (RA); Alzheimer Disease (AD); Color Agnosia; Gaucher Disease, Type I (GD1); Parkinson Disease 15, Autosomal Recessive Early-Onset (PARK15); Von Economo's Disease; Gerstmann-Straussler Disease (GSD); Amyotrophic Lateral Sclerosis- Parkinsonism/dementia Complex 1 (ALS-PDC1); Dystonia; Sphingolipidosis; Radial Nerve Lesion; Toxic Encephalopathy; Sleep Disorder; Pick Disease of Brain (PIDB); Ophthalmomyiasis; Gaucher's Disease (GD); Optic Atrophy 7 with or Without Auditory Neuropathy (OPA7); Ulnar Nerve Lesion; Inflammatory Bowel Disease 4 (IBD4); Inflammatory Bowel Disease; 3-Methylglutaconic Aciduria, Type Iii (MGCA3); Nervous System Disease; Amyotrophic Lateral Sclerosis 1 (ALS1); Mitochondrial Complex I Deficiency, Nuclear Type 1 (MC1DN1) comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (K), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0156] The present invention further provides methods of treating a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early- Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson Disease 10 (PARK10); Tremor; Frontotemporal Dementia (FTD); Postencephalitic Parkinson Disease; Vascular Parkinsonism; Aphasia; Parkinson Disease 1, Autosomal Dominant (PARK1); Athetosis; Klippel-Feil Syndrome (KFS); Kufor-Rakeb Syndrome (KRS); Leprosy 3 (LPRS3); Alzheimer Disease 8 (AD8); Crohn's Disease; 47. ASB Brenig.24.0001.W Rheumatoid Arthritis (RA); Alzheimer Disease (AD); Color Agnosia; Gaucher Disease, Type I (GD1); Parkinson Disease 15, Autosomal Recessive Early-Onset (PARK15); Von Economo's Disease; Gerstmann-Straussler Disease (GSD); Amyotrophic Lateral Sclerosis- Parkinsonism/dementia Complex 1 (ALS-PDC1); Dystonia; Sphingolipidosis; Radial Nerve Lesion; Toxic Encephalopathy; Sleep Disorder; Pick Disease of Brain (PIDB); Ophthalmomyiasis; Gaucher's Disease (GD); Optic Atrophy 7 with or Without Auditory Neuropathy (OPA7); Ulnar Nerve Lesion; Inflammatory Bowel Disease 4 (IBD4); Inflammatory Bowel Disease; 3-Methylglutaconic Aciduria, Type Iii (MGCA3); Nervous System Disease; Amyotrophic Lateral Sclerosis 1 (ALS1); Mitochondrial Complex I Deficiency, Nuclear Type 1 (MC1DN1) comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (L), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0157] The present invention further provides methods of treating a disease, disorder, or condition selected from Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early- Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson Disease 10 (PARK10); Tremor; Frontotemporal Dementia (FTD); Postencephalitic Parkinson Disease; Vascular Parkinsonism; Aphasia; Parkinson Disease 1, Autosomal Dominant (PARK1); Athetosis; Klippel-Feil Syndrome (KFS); Kufor-Rakeb Syndrome (KRS); Leprosy 3 (LPRS3); Alzheimer Disease 8 (AD8); Crohn's Disease; Rheumatoid Arthritis (RA); Alzheimer Disease (AD); Color Agnosia; Gaucher Disease, Type I (GD1); Parkinson Disease 15, Autosomal Recessive Early-Onset (PARK15); Von Economo's Disease; Gerstmann-Straussler Disease (GSD); Amyotrophic Lateral Sclerosis- Parkinsonism/dementia Complex 1 (ALS-PDC1); Dystonia; Sphingolipidosis; Radial Nerve Lesion; Toxic Encephalopathy; Sleep Disorder; Pick Disease of Brain (PIDB); 48. ASB Brenig.24.0001.W Ophthalmomyiasis; Gaucher's Disease (GD); Optic Atrophy 7 with or Without Auditory Neuropathy (OPA7); Ulnar Nerve Lesion; Inflammatory Bowel Disease 4 (IBD4); Inflammatory Bowel Disease; 3-Methylglutaconic Aciduria, Type Iii (MGCA3); Nervous System Disease; Amyotrophic Lateral Sclerosis 1 (ALS1); Mitochondrial Complex I Deficiency, Nuclear Type 1 (MC1DN1) comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (M), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0158] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, a method for preparing compounds described herein (e.g., a method comprising one or more steps described in General Procedure A, B or C). [0159] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in Preparative part – P1-P44). [0160] In some aspects, the present disclosure provides a method of preparing compounds of the present disclosure. [0161] In some aspects, the present disclosure provides a method of preparing compounds of the present disclosure, comprising one or more steps described herein. [0162] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control. 49. ASB Brenig.24.0001.W [0163] Other features and advantages of the disclosure will be apparent from the following detailed description and claims. DETAILED DESCRIPTION [0164] The present disclosure provides methods of treating, preventing, or ameliorating a disease or disorder associated with the inhibition LRRK2 by administering to a subject in need thereof a therapeutically effective amount of a compound as disclosed herein. [0165] The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties. Definitions [0166] The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. [0167] The term "and/or" is used in this disclosure to mean either "and" or "or" unless indicated otherwise. [0168] The term “optionally substituted” is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have one or more substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups but 50. ASB Brenig.24.0001.W does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, – OH, –CN, –COOH, –CH2CN, –O-(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1- C6)haloalkyl, (C1-C6)haloalkoxy, –O-(C2-C6)alkenyl, –O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, –OH, –OP(O)(OH)2, –OC(O)(C1-C6)alkyl, –C(O)(C1-C6)alkyl, – OC(O)O(C1-C6)alkyl, –NH2, –NH((C1-C6)alkyl), –N((C1-C6)alkyl)2, –NHC(O)(C1- C6)alkyl, –C(O)NH(C1-C6)alkyl, –S(O)2(C1-C6)alkyl, –S(O)NH(C1-C6)alkyl, and – S(O)N((C1-C6)alkyl)2. The substituents can themselves be optionally substituted. “Optionally substituted” as used herein also refers to substituted or unsubstituted whose meaning is described below. [0169] As used herein, the term “substituted” means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms. [0170] As used herein, the term “unsubstituted” means that the specified group bears no substituents. [0171] Unless otherwise specifically defined, the term "aryl" refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, –H, -halogen, –O-(C1-C6)alkyl, (C1-C6)alkyl, – O-(C2-C6)alkenyl, –O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, –OH, – OP(O)(OH)2, –OC(O)(C1-C6)alkyl, –C(O)(C1-C6) alkyl, –OC(O)O(C1-C6)alkyl, –NH2, – NH((C1-C6)alkyl), –N((C1-C6)alkyl)2, –S(O)2-(C1-C6)alkyl, –S(O)NH(C1-C6)alkyl, and – S(O)N((C1-C6)alkyl)2. The substituents can themselves be optionally substituted. Furthermore, when containing two fused rings the aryl groups herein defined may have one or more saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, 51. ASB Brenig.24.0001.W biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like. [0172] Unless otherwise specifically defined, "heteroaryl" means a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C. A polycyclic aromatic radical includes two or more fused rings and may further include two or more spiro-fused rings, e.g., bicyclic, tricyclic, tetracyclic, and the like. Unless otherwise specifically defined, “fused” means two rings sharing two ring atoms. Unless otherwise specifically defined, “spiro-fused” means two rings sharing one ring atom. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, S, P, or B. Heteroaryl as herein defined also means a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B. Heteroaryl as herein defined also means a tetracyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2- yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3- b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4- b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro- 2H-1-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2- c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzooxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2- 52. ASB Brenig.24.0001.W b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2- a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H- pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4- d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore, when containing two or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring fused with one or more fully unsaturated aromatic ring. In heteroaryl ring systems containing more than two fused rings, a saturated or partially unsaturated ring may further be fused with a saturated or partially unsaturated ring described herein. Furthermore, when containing three or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring spiro-fused. Any saturated or partially unsaturated ring described herein is optionally substituted with one or more oxo. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H--isoquinolinyl, 2,3- dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, 1,6-dihydro-7H- pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, 8H-pyrido[3,2- b]pyrrolizinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H- pyrido[3,2-b]pyrrolizine, pyrazolo[1,5-a]pyrimidin-7(4H)-only, 3,4-dihydropyrazino[1,2- a]indol-1(2H)-onyl, benzo[c][1,2]oxaborol-1(3H)-olyl, 6,6a,7,8-tetrahydro-9H- pyrido[2,3-b]puyrrolo[1,2-d][1,4]oxazin-9-onyl, or 6a’,7’-dihydro-6’H,9’H- spiro[cyclopropane-1,8’-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9’-onyl. [0173] Halogen or “halo” refers to fluorine, chlorine, bromine, or iodine. [0174] Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examples of a (C1-C6)alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. [0175] “Alkoxy” refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, i.e., -O(alkyl). Examples of 53. ASB Brenig.24.0001.W alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups. [0176] “Alkenyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkenyl” group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso- butenyl, pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted. Alkenyl, as herein defined, may be straight or branched. [0177] “Alkynyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkynyl” group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. An alkynyl group can be unsubstituted or substituted. [0178] The term “alkylene” or “alkylenyl” refers to a divalent alkyl radical. Any of the above-mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. As herein defined, alkylene may also be a C1-C6 alkylene. An alkylene may further be a C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, - CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. [0179] “Cycloalkyl” means mono or polycyclic saturated carbon rings containing 3-18 carbon atoms. Polycyclic cycloalkyl may be fused bicyclic cycloalkyl, bridged bicyclic cycloalkyl, or spiro-fused bicyclic cycloalkyl. A polycyclic cycloalkyl comprises at least one non-aromatic ring. Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norborenyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, spiro[3.5]nonyl, spiro [5.5]undecyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl. [0180] “Heterocyclyl”, “heterocycle” or “heterocycloalkyl” mono or polycyclic rings containing 3-24 atoms which include carbon and one or more heteroatoms selected from N, O, S, P, or B and wherein the rings are not aromatic. The heterocycloalkyl ring structure may be substituted by one or more substituents. The substituents can themselves be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, 54. ASB Brenig.24.0001.W oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl. [0181] The term “aromatic” means a planar ring having 4n + 2 electrons in a conjugated system. As used herein, “conjugated system” means a system of connected p-orbitals with delocalized electrons, and the system may include lone electron pairs. [0182] The term “haloalkyl” as used herein refers to an alkyl group, as defined herein, which is substituted one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc. [0183] The term “haloalkoxy” as used herein refers to an alkoxy group, as defined herein, which is substituted with one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc. [0184] The term “cyano” as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., C≡N. [0185] “Spirocycloalkyl” or “spirocyclyl” means carbogenic bicyclic ring systems with both rings connected through a single atom. The ring can be different in size and nature, or identical in size and nature. Examples include spiropentane, spriohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both of the rings in a spirocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more of the carbon atoms in the spirocycle can be substituted with a heteroatom (e.g., O, N, S, or P). A (C3-C12) spirocycloalkyl is a spirocycle containing between 3 and 12 carbon atoms. One or more of the carbon atoms can be substituted with a heteroatom. [0186] The term “spiroheterocycloalkyl”, “spiroheterocycle”, or “spiroheterocyclyl” is understood to mean a spirocycle wherein at least one of the rings is a heterocycle (e.g., at least one of the rings is furanyl, morpholinyl, or piperidinyl). [0187] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the disclosure may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are 55. ASB Brenig.24.0001.W typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water. [0188] The term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the compounds of Formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. [0189] The present disclosure also contemplates isotopically-labelled compounds of Formula I (e.g., those labeled with 2H and 14C). Deuterated (i.e., 2H or D) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labelled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent. [0190] The disclosure also includes pharmaceutical compositions comprising a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier. Representative "pharmaceutically acceptable salts" include, e.g., water- soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2- disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N- methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p- 56. ASB Brenig.24.0001.W toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts. [0191] A "patient" or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus. [0192] An "effective amount" when used in connection with a compound is an amount effective for treating or preventing a disease in a subject as described herein. [0193] The term "carrier", as used in this disclosure, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject. [0194] The term "treating" with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder. [0195] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated. [0196] The term "administer", "administering", or "administration" as used in this disclosure refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body. [0197] The term "prodrug," as used in this disclosure, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound. [0198] The term “salt’ refers to pharmaceutically acceptable salts. [0199] The term “pharmaceutically acceptable salt” also refers to a salt of the compositions of the present disclosure having an acidic functional group, such as a carboxylic acid functional group, and a base. 57. ASB Brenig.24.0001.W [0200] “LRRK2 inhibitor” as used herein refer to a compound of the present disclosure and/or a composition comprising a compound of present disclosure which inhibits LRRK2 kinase. [0201] “LRRK2 inhibitor” as used herein refer to a compound of Formula (A) and/or a composition comprising a compound of Formula (A) which inhibits LRRK2 kinase. [0202] “LRRK2 inhibitor” as used herein refer to a compound of Formula (B) and/or a composition comprising a compound of Formula (B) which inhibits LRRK2 kinase. [0203] “LRRK2 inhibitor” as used herein refer to a compound of Formula (C) and/or a composition comprising a compound of Formula (C) which inhibits LRRK2 kinase. [0204] “LRRK2 inhibitor” as used herein refer to a compound of Formula (D) and/or a composition comprising a compound of Formula (D) which inhibits LRRK2 kinase. [0205] “LRRK2 inhibitor” as used herein refer to a compound of Formula (E) and/or a composition comprising a compound of Formula (E) which inhibits LRRK2 kinase. [0206] “LRRK2 inhibitor” as used herein refer to a compound of Formula (F) and/or a composition comprising a compound of Formula (F) which inhibits LRRK2 kinase. [0207] “LRRK2 inhibitor” as used herein refer to a compound of Formula (G) and/or a composition comprising a compound of Formula (G) which inhibits LRRK2 kinase. [0208] “LRRK2 inhibitor” as used herein refer to a compound of Formula (H) and/or a composition comprising a compound of Formula (H) which inhibits LRRK2 kinase. [0209] “LRRK2 inhibitor” as used herein refer to a compound of Formula (J) and/or a composition comprising a compound of Formula (J) which inhibits LRRK2 kinase. [0210] “LRRK2 inhibitor” as used herein refer to a compound of Formula (K) and/or a composition comprising a compound of Formula (K) which inhibits LRRK2 kinase. [0211] “LRRK2 inhibitor” as used herein refer to a compound of Formula (L) and/or a composition comprising a compound of Formula (L) which inhibits LRRK2 kinase. [0212] “LRRK2 inhibitor” as used herein refer to a compound of Formula (M) and/or a composition comprising a compound of Formula (M) which inhibits LRRK2 kinase. [0213] The amount of compound of composition described herein needed for achieving a therapeutic effect may be determined empirically in accordance with conventional procedures for the particular purpose. Generally, for administering therapeutic agents (e.g. compounds or compositions of Formula I (and/or additional agents) described herein) for 58. ASB Brenig.24.0001.W therapeutic purposes, the therapeutic agents are given at a pharmacologically effective dose. A “pharmacologically effective amount,” “pharmacologically effective dose,” “therapeutically effective amount,” or “effective amount” refers to an amount sufficient to produce the desired physiological effect or amount capable of achieving the desired result, particularly for treating the disorder or disease. An effective amount as used herein would include an amount sufficient to, for example, delay the development of a symptom of the disorder or disease, alter the course of a symptom of the disorder or disease (e.g., slow the progression of a symptom of the disease), reduce or eliminate one or more symptoms or manifestations of the disorder or disease, and reverse a symptom of a disorder or disease. For example, administration of therapeutic agents to a subject suffering from cancer provides a therapeutic benefit not only when the underlying condition is eradicated or ameliorated, but also when the subject reports a decrease in the severity or duration of the symptoms associated with the disease, e.g., a decrease in tumor burden, a decrease in circulating tumor cells, an increase in progression free survival. Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is realized. Compounds of the Present Disclosure [0214] In one aspect, the present disclosure provides compounds of Formula (A) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: , wherein A, B, R1, R2, and [0215] It is understood that, for a compound of Formula (A), A, B, R1, R2, and R3 can each be, where applicable, selected from the groups described herein, and any group described herein for any A, B, R1, R2, and R3 can be combined, where applicable, with any group described herein for one or more of the remainders of A, B, R1, R2, and R3. 59. ASB Brenig.24.0001.W [0216] In one aspect, the present disclosure provides compounds of Formula (A) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: F3C R2 B , wherein B, E, R1, R2, and [0217] It is understood a , B, E, R1, R2, and R5 can each be, where applicable, selected from the groups described herein, and any group described herein for any B, E, R1, R2, and R5 can be combined, where applicable, with any group described herein for one or more of the remainders of B, E, R1, R2, and R5. [0218] In one aspect, the present disclosure provides compounds of Formula (C) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: , wherein B, G, R1, R2, R3, herein. [0219] It is understood that, for a compound of Formula (C), B, G, R1, R2, R3, Ra, Rb, Rc, Rd, and RA can each be, where applicable, selected from the groups described herein, and any group described herein for any B, G, R1, R2, R3, Ra, Rb, Rc, Rd, and RA can be combined, where applicable, with any group described herein for one or more of the remainders of B, G, R1, R2, R3, Ra, Rb, Rc, Rd, and RA. [0220] In one aspect, the present disclosure provides compounds of Formula (D) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: 60. ASB Brenig.24.0001.W , wherein B, R1, R2, R3, RA, [0221] It is understood a , B, R1, R2, R3, RA, Rc and Rd can each be, where applicable, selected from the groups described herein, and any group described herein for any B, R1, R2, R3, RA, Rc and Rd can be combined, where applicable, with any group described herein for one or more of the remainders of B, R1, R2, R3, RA, Rc and Rd. [0222] In one aspect, the present disclosure provides compounds of Formula (E) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: , wherein B, R1, R2, Re, [0223] It is understood that, for a compound of Formula (E), B, R1, R2, Re, Rf, Rg and Rh can each be, where applicable, selected from the groups described herein, and any group described herein for any B, R1, R2, Re, Rf, Rg and Rh can be combined, where applicable, with any group described herein for one or more of the remainders of B, R1, R2, Re, Rf, Rg and Rh. [0224] In one aspect, the present disclosure provides compounds of Formula (F) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: 61. ASB Brenig.24.0001.W , wherein B, R1, R2, R8, R9, [0225] It is understood that, a , B, R1, R2, R8, R9, R10 and m can each be, where applicable, selected from the groups described herein, and any group described herein for any B, R1, R2, R8, R9, R10 and m can be combined, where applicable, with any group described herein for one or more of the remainders of B, R1, R2, R8, R9, R10 and m. [0226] In one aspect, the present disclosure provides compounds of Formula (G) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: , wherein B, R1, R2, R11, [0227] It is understood that, for a compound of Formula (G), B, R1, R2, R11, R12, R13 and k can each be, where applicable, selected from the groups described herein, and any group described herein for any B, R1, R2, R11, R12, R13 and k can be combined, where applicable, with any group described herein for one or more of the remainders of B, R1, R2, R11, R12, R13 and k. [0228] In one aspect, the present disclosure provides compounds of Formula (H) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: 62. ASB Brenig.24.0001.W , wherein B, R1, R2, and R3 as [0229] It is understood that, a (H), B, R1, R2, and R3 can each be, where applicable, selected from the groups described herein, and any group described herein for any B, R1, R2, and R3 can be combined, where applicable, with any group described herein for one or more of the remainders of B, R1, R2, and R3. [0230] In one aspect, the present disclosure provides compounds of Formula (J) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: , wherein B, R1, R2, and R3 as [0231] It is understood that, for a compound of Formula (J), B, R1, R2, and R3 can each be, where applicable, selected from the groups described herein, and any group described herein for any B, R1, R2, and R3 can be combined, where applicable, with any group described herein for one or more of the remainders of B, R1, R2, and R3. [0232] In one aspect, the present disclosure provides compounds of Formula (K) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: 63. ASB Brenig.24.0001.W , wherein B, R1, R2, and R15 [0233] It is understood that, a , B, R1, R2, and R14 can each be, where applicable, selected from the groups described herein, and any group described herein for any B, R1, R2, and R14 can be combined, where applicable, with any group described herein for one or more of the remainders of B, R1, R2, and R14. [0234] In one aspect, the present disclosure provides compounds of Formula (L) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: , wherein B, R1, R2, R3, G [0235] It is understood that, for a compound of Formula (L), B, R1, R2, R3, G and p can each be, where applicable, selected from the groups described herein, and any group described herein for any B, R1, R2, R3, G and p can be combined, where applicable, with any group described herein for one or more of the remainders of B, R1, R2, R3, G and p. [0236] In one aspect, the present disclosure provides compounds of Formula (M) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: 64. ASB Brenig.24.0001.W , wherein B, R1, R2, R3, G, r [0237] It is understood that, a (M), B, R1, R2, R3, G, r and q can each be, where applicable, selected from the groups described herein, and any group described herein for any B, R1, R2, R3, G, r and q can be combined, where applicable, with any group described herein for one or more of the remainders of B, R1, R2, R3, G, r and q. [0238] In some embodiments, each A is independently selected from CR4 and N. [0239] In some embodiments, A is CR4. [0240] In some embodiments, A is N. [0241] In some embodiments, compound of Formula (A) comprises moiety: Brenig.24.0001.W [0244] In some embodiments, compound of Formula (A) comprises moiety: . embodiments, compound of Formula (A) comprises moiety: . embodiments, compound of Formula (A) comprises moiety: . embodiments, B is CH. In some embodiments, B is N. [0248] In some embodiments, a compound of the invention comprises moiety: . embodiments, a compound of the invention comprises moiety: . embodiments, R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl. 66. ASB Brenig.24.0001.W [0251] In some embodiments, R1 is C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl. [0252] In some embodiments, R1 is C1-C6 alkyl. [0253] In some embodiments, R1 is methyl. [0254] In some embodiments, R1 is C3-C10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl. [0255] In some embodiments, R1 is C3-C10 cycloalkyl optionally substituted with one or more C1-C6 alkyl. [0256] In some embodiments, R1 is cyclopropyl optionally substituted with one or more C1-C6 alkyl. [0257] In some embodiments, R1 is cyclopropyl optionally substituted with one or more methyl. [0258] In some embodiments, R1 is cyclopropyl substituted with one or more methyl. [0259] In some embodiments, R1 is cyclopropyl substituted with one methyl. [0260] In some embodiments, R1 is . [0261] In some embodiments, R2 is selected . [0262] In some embodiments, R2 is H. [0263] In some . [0264] In some C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, 67. ASB Brenig.24.0001.W alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl- S(O)2-, heterocycle, aryl, and heteroaryl. [0265] In some embodiments, R3 is C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl- S(O)2-, heterocycle, aryl, and heteroaryl. [0266] In some embodiments, R3 is C1-C6 alkyl. [0267] In some embodiments, R3 is methyl. [0268] In some . [0269] In some . [0270] In some . [0271] In some substituted with one or more halogen. [0272] In some . [0273] In some . [0274] In some . [0275] In some substituted with one or more CN. [0276] In some . 68. ASB Brenig.24.0001.W [0277] In some embodiments, R3 is C1-C6 alkyl substituted with one or more C1-C6 alkoxy. [0278] In some embodiments, R3 is . [0279] In some with one or more C3-C10 cycloalkyl. [0280] In some . [0281] In some . [0282] In some substituted with one or more C1-C6 alkyl- S(O)2-. [0283] In some embodiments, R3 is C1-C6 alkyl substituted with one C1-C6 alkyl-S(O)2-. [0284] In some substituted with one CH3S(O)2-. [0285] In some . [0286] In some optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl- S(O)2-, heterocycle, aryl, and heteroaryl. [0287] In some embodiments, R3 is C2-C6 alkenyl. [0288] In some . [0289] In some optionally substituted with one or more halogen. [0290] In some . 69. ASB Brenig.24.0001.W [0291] In some embodiments, R3 is C3-C10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl- S(O)2-, heterocycle, aryl, and heteroaryl. [0292] In some embodiments, R3 is C3-C10 cycloalkyl. [0293] In some embodiments, R3 is cyclopropyl. [0294] In some embodiments, R3 is cyclobutyl. [0295] In some embodiments, R3 is cyclopentyl. [0296] In some embodiments, R3 is cyclohexyl. [0297] In some embodiments, R3 is cycloheptyl. [0298] In some embodiments, R3 is heterocycle optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl- S(O)2-, heterocycle, aryl, and heteroaryl. [0299] In some embodiments, R3 is heterocycle. [0300] In some embodiments, R3 is heterocycle selected from four membered heterocycle, five membered heterocycle, six membered heterocycle, seven membered heterocycle comprising from 1 to 3 heteroatoms selected from O, S, N. [0301] In some . [0302] In some . . selected from H, OH, halogen, CN, C1-C6 alkyl, C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl, and heterocycle. 70. ASB Brenig.24.0001.W [0306] In some embodiments, R4 is H. [0307] In some embodiments, R4 is halogen. [0308] In some embodiments, R4 is F. [0309] In some embodiments, R4 is Cl. [0310] In some embodiments, R4 is C1-C6 alkyl. [0311] In some embodiments, R4 is methyl. [0312] In some embodiments, E is CH. In some embodiments, E is N. [0313] In some embodiments, R5 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl. [0314] In some embodiments, R5 is C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl. [0315] In some embodiments, R5 is methyl. [0316] In some . [0317] In some . [0318] In some . [0319] In some optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl. [0320] In some . 71. ASB Brenig.24.0001.W [0321] In some embodiments, R5 is C3-C10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl. [0322] In some embodiments, R5 is . [0323] In some . [0324] In some . [0325] In some . [0326] In some . [0327] In some . [0328] In some optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl. [0329] In some . [0330] In some . [0331] In some . 72. ASB Brenig.24.0001.W [0332] In some . . . . . [0339] In some . [0340] In some . 73. ASB Brenig.24.0001.W [0341] In some . [0342] In some . [0343] In some . [0344] In some CRBRC B and NR . [0345] In some embodiments, U is CRBRC. [0346] In some embodiments, U is NRB. [0347] In some embodiments, RA is H. [0348] In some embodiments, RB is H. [0349] In some embodiments, RA and RB together form a bond. [0350] In some embodiments, RA and RB together form a second bond. [0351] In some embodiments, RA and RB together form a double bond. [0352] In some embodiments, RA and Rc together form a bond. [0353] In some embodiments, RA and Rc together form a second bond. [0354] In some embodiments, RA and Rc together form a double bond. [0355] In some embodiments, RC is H. [0356] In some embodiments, RD is H or C1-C6 alkyl. [0357] In some embodiments, RD is H. [0358] In some embodiments, RD is methyl. [0359] In some embodiments, Ra is H. [0360] In some embodiments, Rb is H. [0361] In some embodiments, Rd is H. [0362] In some embodiments, Rc and Rd together is =O. 74. ASB Brenig.24.0001.W [0363] In some embodiments, Ra and Rd together with the atoms to which they are attached, may come together to form 5-7 membered cycloalkyl or heterocycle, wherein cycloalkyl or heterocycle is optionally substituted with one or more substitutients independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl; and Rb and Rc together form a bond. [0364] In some embodiments, Ra and Rd together with the atoms to which they are attached, may come together to form 5-7 membered cycloalkyl optionally substituted with one or more substitutients independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1- C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl; and Rb and Rc together form a bond. [0365] In some embodiments, Ra, Rb, Rc, and Rd . [0366] In some embodiments, Ra and Rd together they are attached, may come together to form 5-7 membered heterocycle, wherein heterocycle is optionally substituted with one or more substitutients independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl; and Rb and Rc together form a bond. [0367] In some embodiments, Ra, Rb, Rc, and Rd . [0368] In some embodiments, Re is selected from -(CH2)n-OR6. [0369] In some embodiments, Re is H. [0370] In some embodiments, Re is -(CH2)n-NR6R7. [0371] In some embodiments, Re is -NH(C1-C6 alkyl). [0372] In some embodiments, Re is -NHCH3. [0373] In some embodiments, Re is -NHOH. [0374] In some embodiments, Re is -NH(OC1-C6 alkyl). [0375] In some embodiments, Re is -NHOCH3. [0376] In some embodiments, Re is -N(C1-C6 alkyl)OH. 75. ASB Brenig.24.0001.W [0377] In some embodiments, Re is -N(CH3)OH. [0378] In some embodiments, Re is -N(C1-C6 alkyl)2. [0379] In some embodiments, Re is -N(CH3)2. [0380] In some embodiments, Re is -NHC(O)C1-C6 alkyl. [0381] In some embodiments, Re is -(CH2)n-OR6. [0382] In some embodiments, Re is -O(C1-C6 alkyl). [0383] In some embodiments, Re is -OCH3. [0384] In some embodiments, Rf is H. [0385] In some embodiments, Rg is H. [0386] In some embodiments, Rf and Rg together form a bond. [0387] In some embodiments, Rf and Rg together form a second bond. [0388] In some embodiments, Rf and Rg together form a double bond. [0389] In some embodiments, Rh is H. [0390] In some embodiments, Re and Rh together with the atoms to which they are attached, may come together to form 5-7 membered heterocycle, optionally substituted with one or more substitutients independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1- C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, -(CH2)n-aryl and heteroaryl. [0391] In some embodiments, Re and Rh together with the atoms to which they are attached, may come together to . [0392] In some together with the atoms to which they are attached, may come together to . [0393] In some with the atoms to which they are attached, may come together to . 76. ASB Brenig.24.0001.W [0394] In some embodiments, R6 is selected from H, C1-C6 alkyl. [0395] In some embodiments, R6 is H. [0396] In some embodiments, R6 is C1-C6 alkyl. [0397] In some embodiments, R6 is C1-C6 alkyl. [0398] In some embodiments, R6 is methyl. [0399] In some embodiments, R7 is selected from OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C(O)-. [0400] In some embodiments, R7 is OH. [0401] In some embodiments, R7 is C1-C6 alkyl. [0402] In some embodiments, R7 is methyl. [0403] In some embodiments, R7 is C1-C6 alkoxy. [0404] In some embodiments, R7 is methoxy. [0405] In some embodiments, R7 is C1-C6 alkyl-C(O)-. [0406] In some embodiments, R7 is CH3C(O)-. [0407] In some embodiments, each R8 is independently selected from H, halogen, OH, NH2, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl. [0408] In some embodiments, R8 is H. [0409] In some embodiments, any two R8 together form C1-C3 alkanediyl. [0410] In some embodiments, each R9 is independently selected from H, C1-C6 alkyl. [0411] In some embodiments, two R9 together form C1-C3 alkanediyl. [0412] In some embodiments, two R9 together form C1 alkanediyl. [0413] In some embodiments, two R9 together form C2 alkanediyl. [0414] In some embodiments, two R9 together form C3 alkanediyl. [0415] In some embodiments, R10 is selected from C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the cycloalkyl, heterocycle, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, 77. ASB Brenig.24.0001.W CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl. [0416] In some embodiments, R10 is C3-C10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl. [0417] In some . [0418] In some optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl. [0419] In some embodiments, R11 is selected from SO2C1-C6 alkyl, halogen, C1-C6 alkoxy. [0420] In some embodiments, R11 is SO2C1-C6 alkyl. [0421] In some . [0422] In some [0423] In some embodiments, R11 is Cl. [0424] In some embodiments, R12 is C1-C6 alkyl substituted with one or more substitutients independently selected from N(R14)2, -CN. [0425] In some . [0426] In some . [0427] In some with the atoms to which they are attached, may come together to form 5-7 membered heterocycle, optionally substituted with one or more substitutients independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, -(CH2)n-aryl and heteroaryl. 78. ASB Brenig.24.0001.W [0428] In some embodiments, R11 and R12 together with the atoms to which they are attached, . [0429] In R13 is halogen. [0430] In some embodiments, R13 is F. [0431] In some embodiments, R13 is Cl. [0432] In some embodiments, R13 is Br. [0433] In some embodiments, each R14 is independently selected from H and C1-C6 alkyl. [0434] In some embodiments, R14 is H. [0435] In some embodiments, R14 is C1-C6 alkyl. [0436] In some embodiments, one R14 is H, another R14 is C1-C6 alkyl. [0437] In some embodiments, both R14 are H. [0438] In some embodiments, both R14 are C1-C6 alkyl. [0439] In some embodiments, R14 is methyl. [0440] In some embodiments, one R14 is H, another R14 is methyl. [0441] In some embodiments, each R15 is independently selected from H, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl-S(O)2-, heterocycle, aryl, and heteroaryl. [0442] In some embodiments, R15 is H. [0443] In some embodiments, both R15 are H. [0444] In some embodiments, R15 is C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl- S(O)2-, heterocycle, aryl, and heteroaryl. [0445] In some embodiments, R15 is C1-C6 alkyl. [0446] In some embodiments, R15 is methyl. [0447] In some embodiments, both R15 are methyl. 79. ASB Brenig.24.0001.W [0448] In some embodiments, R16 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl-S(O)2-, heterocycle, aryl, and heteroaryl. [0449] In some embodiments, R16 is . [0450] In some . [0451] In some selected from O, S, S(O), S(O)2, NH. [0452] In some embodiments, G is independently selected from O, S, S(O), S(O)2, NH. [0453] In some embodiments, G is O. [0454] In some embodiments, G is S. [0455] In some embodiments, G is S(O). [0456] In some embodiments, G is S(O)2. [0457] In some embodiments, G is NH. [0458] In some embodiments, n is an integer selected from 0, 1, 2, 3, 4, 5, and 6. [0459] In some embodiments, n is 0. [0460] In some embodiments, n is 1. [0461] In some embodiments, n is 2. [0462] In some embodiments, n is 3. [0463] In some embodiments, n is 4. [0464] In some embodiments, n is 5. [0465] In some embodiments, n is 6. [0466] In some embodiments, each m is an integer independently selected from 1, 2, and 3. [0467] In some embodiments, k is an integer selected from 0 and 1. [0468] In some embodiments, k is 0. [0469] In some embodiments, k is 1. 80. ASB Brenig.24.0001.W [0470] In some embodiments, p is an integer selected from 0, 1, 2, and 3. [0471] In some embodiments, p is 0. [0472] In some embodiments, p is 1. [0473] In some embodiments, p is 2. [0474] In some embodiments, p is 3. [0475] In some embodiments, q is an integer selected from 1, 2, and 3. [0476] In some embodiments, q is 1. [0477] In some embodiments, q is 2. [0478] In some embodiments, q is 3. [0479] In some embodiments, r is an integer selected from 1, 2, and 3. [0480] In some embodiments, r is 1. [0481] In some embodiments, r is 2. [0482] In some embodiments, r is 3. [0483] In some embodiments, u is an integer selected from 0, 1 and 2. [0484] In some embodiments, u is 0. [0485] In some embodiments, u is 1. [0486] In some embodiments, u is 2. [0487] In some embodiments, the compound is of Formula (A-I): I), or a pharmaceutically isotopic derivative, or tautomer thereof wherein all variables are as defined herein. [0488] In some embodiments, the compound is of Formula (A-I-a): 81. ASB Brenig.24.0001.W , or a pharmaceutically isotopic derivative, or tautomer thereof are as [0489] In some embodiments, the compound is of Formula (A-I-a-1): , or a isotopic derivative, or tautomer thereof wherein all variables are as defined herein. [0490] In some embodiments, the compound is of Formula (A-I-a-1-A): N H CF3 , or a isotopic derivative, or tautomer thereof wherein all variables are as defined herein. [0491] In some embodiments, the compound is of Formula (A-I-a-1-B): 82. ASB Brenig.24.0001.W , or a isotopic derivative, or tautomer thereof are as [0492] In some embodiments, the compound is of Formula (A-I-a-1-C): N H CF3 , or a isotopic derivative, or tautomer thereof wherein all variables are as defined herein. [0493] In some embodiments, the compound is of Formula (A-I-a-2): , or a pharmaceutically isotopic derivative, or tautomer thereof wherein all variables are as defined herein. [0494] In some embodiments, the compound is of Formula (A-I-a-2-A): 83. ASB Brenig.24.0001.W , or a pharmaceutically isotopic derivative, or tautomer thereof are as [0495] In some embodiments, the compound is of Formula (A-I-a-2-B): , or a isotopic derivative, or tautomer thereof wherein all variables are as defined herein. [0496] In some embodiments, the compound is of Formula (A-I-b): , or a pharmaceutically isotopic derivative, or tautomer thereof wherein all variables are as defined herein. [0497] In some embodiments, the compound is of Formula (A-I-b-1): 84. ASB Brenig.24.0001.W , or a isotopic derivative, or tautomer thereof are as [0498] In some embodiments, the compound is of Formula (A-I-b-1-A): , or a isotopic derivative, or tautomer thereof wherein all variables are as defined herein. [0499] In some embodiments, the compound is of Formula (A-II): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof wherein all variables are as defined herein. 85. ASB Brenig.24.0001.W [0500] In some embodiments, the compound is of Formula (A-II-a): , or a pharmaceutically isotopic derivative, or tautomer thereof are as [0501] In some embodiments, the compound is of Formula (A-II-a-1): , or a pharmaceutically isotopic derivative, or tautomer thereof wherein all variables are as defined herein. [0502] In some embodiments, the compound is of Formula (A-II-a-1-A): H N CF3 , or a isotopic derivative, or tautomer thereof wherein all variables are as defined herein. [0503] In some embodiments, the compound is of Formula (A-III): 86. ASB Brenig.24.0001.W , or a pharmaceutically isotopic derivative, or tautomer thereof. [0504] In some embodiments, the compound is of Formula (A-III-a): a), or a pharmaceutically isotopic derivative, or tautomer thereof. [0505] In some embodiments, the compound is of Formula (A-III-a-1): , or a isotopic derivative, or tautomer thereof. [0506] In some embodiments, the compound is of Formula (A-III-a-1-A): 87. ASB Brenig.24.0001.W N H CF3 , or a isotopic derivative, or tautomer thereof. [0507] In some embodiments, the compound is of Formula (A-III-a-1-B): N H CF3 , or a isotopic derivative, or tautomer thereof. [0508] In some embodiments, the compound is of Formula (B-I): I), or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0509] In some embodiments, the compound is of Formula (B-I-a): 88. ASB Brenig.24.0001.W , or a pharmaceutically isotopic derivative, or tautomer thereof. [0510] In some embodiments, the compound is of Formula (B-I-a-1): H N N CF3 , or a isotopic derivative, or tautomer thereof. [0511] In some embodiments, the compound is of Formula (B-I-a-1-A): , or a isotopic derivative, or tautomer thereof. [0512] In some embodiments, the compound is of Formula (B-I-a-1-B): , ASB Brenig.24.0001.W or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0513] In some embodiments, the compound is of Formula (B-I-a-2): , or a pharmaceutically isotopic derivative, or tautomer thereof. [0514] In some embodiments, the compound is of Formula (B-I-a-2-A): , or a pharmaceutically isotopic derivative, or tautomer thereof. [0515] In some embodiments, the compound is of Formula (B-I-a-2-B): , or a pharmaceutically isotopic derivative, or tautomer thereof. [0516] In some embodiments, the compound is of Formula (B-II): 90. ASB Brenig.24.0001.W , or a pharmaceutically isotopic derivative, or tautomer thereof. [0517] In some embodiments, the compound is of Formula (B-II-a): , or a pharmaceutically isotopic derivative, or tautomer thereof. [0518] In some embodiments, the compound is of Formula (B-II-a-1): H N , or a isotopic derivative, or tautomer thereof. [0519] In some embodiments, the compound is of Formula (B-II-a-1-A): 91. ASB Brenig.24.0001.W , or a isotopic derivative, or tautomer thereof. [0520] In some embodiments, the compound is of Formula (B-II-a-2): , or a pharmaceutically isotopic derivative, or tautomer thereof. [0521] In some embodiments, the compound is of Formula (B-II-a-2-A): , or a pharmaceutically isotopic derivative, or tautomer thereof. [0522] In some embodiments, the compound is of Formula (B-III): 92. ASB Brenig.24.0001.W , or a pharmaceutically isotopic derivative, or tautomer thereof. [0523] In some embodiments, the compound is of Formula (B-III-a): , or a pharmaceutically isotopic derivative, or tautomer thereof. [0524] In some embodiments, the compound is of Formula (B-III-a-1): , or a isotopic derivative, or tautomer thereof. [0525] In some embodiments, the compound is of Formula (B-III-a-1-A): 93. ASB Brenig.24.0001.W III-a-1-A), or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0526] In some embodiments, the compound is of Formula (B-III-a-1-B): , or a isotopic derivative, or tautomer thereof. [0527] In some embodiments, the compound is of Formula (B-III-a-2): , or a pharmaceutically isotopic derivative, or tautomer thereof. [0528] In some embodiments, the compound is of Formula (B-III-a-2-A): 94. ASB Brenig.24.0001.W , or a pharmaceutically isotopic derivative, or tautomer thereof. [0529] In some embodiments, the compound is of Formula (B-III-a-2-B): , or a pharmaceutically isotopic derivative, or tautomer thereof. [0530] In some embodiments, the compound is of Formula (C-I): F3C , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0531] In some embodiments, the compound is of Formula (C-I-a): 95. ASB Brenig.24.0001.W F3C B , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0532] In some embodiments, the compound is of Formula (C-I-a-1): F3C , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0533] In some embodiments, the compound is of Formula (C-I-a-1-A): , or a isotopic derivative, or tautomer thereof, wherein w is an integer selected from 0, 1, 2, and 3; and each Rw is independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl. 96. ASB Brenig.24.0001.W [0534] In some embodiments, the compound is of Formula (C-I-a-1-A-I): N H CF3 I), or a isotopic derivative, or tautomer w an 3; and each Rw is independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl. [0535] In some embodiments, the compound is of Formula (C-I-a-1-A-I-a): a), or a isotopic derivative, or tautomer thereof. [0536] In some embodiments, the compound is of Formula (C-I-a-1-B): , or a isotopic derivative, or tautomer thereof, wherein W is selected from O, S, S(O), S(O)2, NH; w is an integer selected from 0, 1, 2, and 3; and each Rw is independently selected from halogen, OH, NH2, 97. ASB Brenig.24.0001.W CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl. [0537] In some embodiments, the compound is of Formula (C-I-a-1-B-I): N H CF3 I), or a isotopic derivative, or tautomer , 2, NH; w is an integer selected from 0, 1, 2, and 3; and each Rw is independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl. [0538] In some embodiments, the compound is of Formula (C-I-a-1-B-I-a): N H CF3 a), or a isotopic derivative, or tautomer thereof, wherein w is an integer selected from 0, 1, 2, and 3; and each Rw is independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl. [0539] In some embodiments, the compound is of Formula (C-I-a-1-B-I-a-1): , ASB Brenig.24.0001.W or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein w is an integer selected from 0, 1, 2, and 3; and each Rw is independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl. [0540] In some embodiments, the compound is of Formula (C-I-a-1-C): , or a pharmaceutically isotopic derivative, or tautomer thereof. [0541] In some embodiments, the compound is of Formula (C-I-a-1-C-I): I), or a pharmaceutically isotopic derivative, or tautomer thereof. [0542] In some embodiments, the compound is of Formula (C-I-a-1-C-II): , ASB Brenig.24.0001.W or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0543] In some embodiments, the compound is of Formula (C-II): F3C B , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0544] In some embodiments, the compound is of Formula (C-II-a): F3C , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0545] In some embodiments, the compound is of Formula (C-II-a-1): F3C , or a pharmaceutically isotopic derivative, or tautomer thereof. 100. ASB Brenig.24.0001.W [0546] In some embodiments, the compound is of Formula (C-II-a-1-A): , or a pharmaceutically isotopic derivative, or tautomer thereof. [0547] In some embodiments, the compound is of Formula (C-II-a-1-A-I): I), or a pharmaceutically isotopic derivative, or tautomer thereof. [0548] In some embodiments, the compound is of Formula (C-II-a-1-A-II): , or a pharmaceutically isotopic derivative, or tautomer thereof. [0549] In some embodiments, the compound is of Formula (D-I): 101. ASB Brenig.24.0001.W , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0550] In some embodiments, the compound is of Formula (D-I-a): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0551] In some embodiments, the compound is of Formula (D-I-a-1): , or a pharmaceutically isotopic derivative, or tautomer thereof. [0552] In some embodiments, the compound is of Formula (D-I-a-2): , ASB Brenig.24.0001.W or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0553] In some embodiments, the compound is of Formula (D-II): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0554] In some embodiments, the compound is of Formula (D-II-a): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0555] In some embodiments, the compound is of Formula (D-II-a-1): , or a pharmaceutically isotopic derivative, or tautomer thereof. [0556] In some embodiments, the compound is of Formula (D-II-a-2): 103. ASB Brenig.24.0001.W , or a pharmaceutically isotopic derivative, or tautomer thereof. [0557] In some embodiments, the compound is of Formula (E-I): I), or a pharmaceutically isotopic derivative, or tautomer thereof. [0558] In some embodiments, the compound is of Formula (E-I-a): , or a isotopic derivative, or tautomer thereof. [0559] In some embodiments, the compound is of Formula (E-I-a-1): 104. ASB Brenig.24.0001.W , or a isotopic derivative, or tautomer thereof. [0560] In some embodiments, the compound is of Formula (E-I-a-1-A): , or a isotopic derivative, or tautomer thereof. [0561] In some embodiments, the compound is of Formula (E-I-a-1-B): , or a isotopic derivative, or tautomer thereof. [0562] In some embodiments, the compound is of Formula (E-I-a-2): 105. ASB Brenig.24.0001.W 2), or a derivative, or tautomer is selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, -(CH2)n-aryl and heteroaryl and e is an integer selected from 0, 1, 2, and 3. [0563] In some embodiments, the compound is of Formula (E-I-a-2-A): , or a derivative, or tautomer thereof, wherein Re2 is selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, -(CH2)n-aryl and heteroaryl. [0564] In some embodiments, the compound is of Formula (E-I-b): , or a pharmaceutically isotopic derivative, or tautomer thereof. [0565] In some embodiments, the compound is of Formula (E-I-a-3): 106. ASB Brenig.24.0001.W H N N CF3 , or a isotopic derivative, or tautomer thereof. [0566] In some embodiments, the compound is of Formula (E-I-a-3-A): , or a isotopic derivative, or tautomer thereof. [0567] In some embodiments, the compound is of Formula (F-I): I), or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0568] In some embodiments, the compound is of Formula (F-I-a): 107. ASB Brenig.24.0001.W , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0569] In some embodiments, the compound is of Formula (F-I-a-1): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0570] In some embodiments, the compound is of Formula (F-I-a-1-A): , or a pharmaceutically isotopic derivative, or tautomer thereof. [0571] In some embodiments, the compound is of Formula (F-I-b): 108. ASB Brenig.24.0001.W , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0572] In some embodiments, the compound is of Formula (F-I-b-1): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0573] In some embodiments, the compound is of Formula (F-I-b-1-A): , or a pharmaceutically isotopic derivative, or tautomer thereof. [0574] In some embodiments, the compound is of Formula (G-I): 109. ASB Brenig.24.0001.W I), or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0575] In some embodiments, the compound is of Formula (G-I-a): , or a pharmaceutically isotopic derivative, or tautomer thereof. [0576] In some embodiments, the compound is of Formula (G-I-a-1): , or a pharmaceutically isotopic derivative, or tautomer thereof, wherein Hal is selected from F, Cl, and Br, and all other variables are as defined herein. [0577] In some embodiments, the compound is of Formula (G-I-a-1-A): 110. ASB Brenig.24.0001.W , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof, Br, and all other variables are as defined herein. [0578] In some embodiments, the compound is of Formula (G-I-a-2): , or a pharmaceutically isotopic derivative, or tautomer thereof. [0579] In some embodiments, the compound is of Formula (G-I-a-2-A): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. 111. ASB Brenig.24.0001.W [0580] In some embodiments, the compound is of Formula (G-I-a-3): , or a pharmaceutically isotopic derivative, or tautomer thereof, each RG, if present, is independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, -(CH2)n- aryl and heteroaryl; g is an integer selected from 0, 1, 2 and 3; and all other variables are as defined herein. [0581] In some embodiments, the compound is of Formula (G-I-a-3-A): , or a pharmaceutically isotopic derivative, or tautomer thereof, wherein each RG, if present, is independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, -(CH2)n-aryl and heteroaryl; g is an integer selected from 0, 1, 2 and 3; and all other variables are as defined herein. [0582] In some embodiments, the compound is of Formula (G-I-a-3-A-I): 112. ASB Brenig.24.0001.W I), or a pharmaceutically isotopic derivative, or tautomer thereof, selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, -(CH2)n-aryl and heteroaryl; g is an integer selected from 0, 1, 2 and 3; and all other variables are as defined herein. [0583] In some embodiments, the compound is of Formula (H-I): I), or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0584] In some embodiments, the compound is of Formula (H-I-a): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. 113. ASB Brenig.24.0001.W [0585] In some embodiments, the compound is of Formula (H-I-b): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0586] In some embodiments, the compound is of Formula (J-I): I) or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0587] In some embodiments, the compound is of Formula (J-I-a): a) or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0588] In some embodiments, the compound is of Formula (J-I-b): 114. ASB Brenig.24.0001.W b) or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0589] In some embodiments, the compound is of Formula (K-I): I), or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0590] In some embodiments, the compound is of Formula (K-I-a): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0591] In some embodiments, the compound is of Formula (K-I-b): 115. ASB Brenig.24.0001.W , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0592] In some embodiments, the compound is of Formula (L-I): I) or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0593] In some embodiments, the compound is of Formula (L-I-a): a) or a pharmaceutically isotopic derivative, or tautomer thereof. [0594] In some embodiments, the compound is of Formula (L-I-a-1): 116. ASB Brenig.24.0001.W 1) or a pharmaceutically isotopic derivative, or tautomer thereof. [0595] In some embodiments, the compound is of Formula (L-I-a-1-A): or a pharmaceutically isotopic derivative, or tautomer thereof. [0596] In some embodiments, the compound is of Formula (L-I-a-1-B): or a pharmaceutically isotopic derivative, or tautomer thereof. [0597] In some embodiments, the compound is of Formula (L-I-b): 117. ASB Brenig.24.0001.W b) or a pharmaceutically isotopic derivative, or tautomer thereof. [0598] In some embodiments, the compound is of Formula (L-I-b-1): 1) or a pharmaceutically isotopic derivative, or tautomer thereof. [0599] In some embodiments, the compound is of Formula (L-I-b-1-A): or a pharmaceutically isotopic derivative, or tautomer thereof. 118. ASB Brenig.24.0001.W [0600] In some embodiments, the compound is of Formula (L-I-b-1-B): or a pharmaceutically isotopic derivative, or tautomer thereof. [0601] In some embodiments, the compound is of Formula (M-I): I), or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0602] In some embodiments, the compound is of Formula (M-I-a): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0603] In some embodiments, the compound is of Formula (M-I-a-1): 119. ASB Brenig.24.0001.W , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0604] In some embodiments, the compound is of Formula (M-I-a-1-A): , or a pharmaceutically isotopic derivative, or tautomer thereof. [0605] In some embodiments, the compound is of Formula (M-I-a-1-A-I): I), or a pharmaceutically isotopic derivative, or tautomer thereof. [0606] In some embodiments, the compound is of Formula (M-I-a-1-A-I-a): 120. ASB Brenig.24.0001.W , or a pharmaceutically isotopic derivative, or tautomer thereof. [0607] In some embodiments, the compound is of Formula (M-I-a-1-A-I-a*): , or a pharmaceutically isotopic derivative, or tautomer thereof. [0608] In some embodiments, the compound is of Formula (M-I-a-1-A-I-a**): , or a isotopic derivative, or tautomer thereof. [0609] In some embodiments, the compound is of Formula (M-I-b): 121. ASB Brenig.24.0001.W , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0610] In some embodiments, the compound is of Formula (I): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof, wherein , , Brenig.24.0001.W A is selected from CR4 and N, provided that anyone from A is N, and two remaining A are CR4; B is selected from CH and N, provided that anyone from B is N, and another B is CH; E is selected from CH and N, provided that anyone from E is N, and another E is CH; U is selected from CRBRC and NRB; each G is independently selected from O, S, S(O), S(O)2, NH; RA is H; or RA and Rc together form a bond; Rd is H; or Rc and Rd together form =O; RB is H; or RA and RB together form a bond; RC is H; Ra is H; Rb is H; and Rc and Rd together form =O; or Ra and Rd together with the atoms to which they are attached, may come together to form 5-7 membered cycloalkyl or heterocycle, wherein cycloalkyl or heterocycle optionally substituted with one or more substitutients independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl; and Rb and Rc together form a bond; Re is selected from H, -(CH2)n-NR6R7, -(CH2)n-OR6; Rf is H; Rg is H; or Rf and Rg together form a bond; Rh is H; or Re and Rh together with the atoms to which they are attached, may come together to form 5-7 membered heterocycle, optionally substituted with one or more substitutients independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, -(CH2)n- aryl and heteroaryl; 123. ASB Brenig.24.0001.W R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; R2 is selected ; each R3 is C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl- S(O)2-, heterocycle, aryl, and heteroaryl; each R4 is independently selected from H, OH, halogen, CN, C1-C6 alkyl, C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl, and heterocycle; R5 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl; R6 is selected from H, C1-C6 alkyl; R7 is selected from OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C(O)-; each R8 is independently selected from H, halogen, OH, NH2, CN, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 124. ASB Brenig.24.0001.W alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl; or any two R8 together form C1-C3 alkanediyl; each R9 is independently selected from H, C1-C6 alkyl; or two R9 together form C1-C3 alkanediyl; or any one R8 and any one R9 together form C1-C3 alkanediyl; R10 is selected from C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the cycloalkyl, heterocycle, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl; R11 is selected from SO2C1-C6 alkyl, halogen, C1-C6 alkoxy; R12 is selected from C1-C6 alkyl substituted with one or more substitutients independently selected from N(R14)2, -CN; or R11 and R12 together with the atoms to which they are attached, may come together to form 5-7 membered heterocycle, optionally substituted with one or more substitutients independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, -(CH2)n- aryl and heteroaryl; R13 is halogen; each R14 is independently selected from H and C1-C6 alkyl; each R15 is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl- S(O)2-, heterocycle, aryl, and heteroaryl; k is an integer selected from 0 and 1; each m is an integer independently selected from 1, 2, and 3; n is an integer selected from 0, 1, 2, 3, 4, 5, and 6; p is an integer selected from 0, 1, 2, and 3; 125. ASB Brenig.24.0001.W u is an integer selected from 0, 1 and 2; q is an integer selected from 1, 2, and 3; r is an integer selected from 1, 2, and 3; wherein, aryl is cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings; heterocyclyl is saturated or partially unsaturated 3–10 membered monocyclic, 7– 12 membered bicyclic (fused, bridged, or spiro rings), or 11–14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms selected from O, N, S, P, Se, or B; heteroaryl is a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C. [0611] In some embodiments, the compound is of Formula (I-I): I), or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0612] In some embodiments, the compound is of Formula (I-I-A): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0613] In some embodiments, the compound is of Formula (I-I-A-1): , ASB Brenig.24.0001.W or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0614] In some embodiments, the compound is of Formula (I-I-A-2): , or a isotopic derivative, or tautomer thereof. [0615] In some embodiments, the compound is of Formula (I-I-B): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0616] In some embodiments, the compound is of Formula (I-I-B-1): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0617] In some embodiments, the compound is of Formula (I-I-B-2): , or a isotopic derivative, or tautomer thereof. 127. ASB Brenig.24.0001.W [0618] In some embodiments, the compound is of Formula (I-II): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0619] In some embodiments, the compound is of Formula (I-II-A): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0620] In some embodiments, the compound is of Formula (I-II-A-1): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0621] In some embodiments, the compound is of Formula (I-II-A-2): , or a pharmaceutically isotopic derivative, or tautomer thereof. [0622] In some embodiments, the compound is of Formula (I-II-B): 128. ASB Brenig.24.0001.W , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0623] In some embodiments, the compound is of Formula (I-II-B-1): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof. [0624] In some embodiments, the compound is of Formula (I-II-B-2): , or a pharmaceutically isotopic derivative, or tautomer thereof. [0625] In some embodiments, the compound of Formula I is a compound of Formula A. [0626] In some embodiments, the compound of Formula I is a compound of Formula B. [0627] In some embodiments, the compound of Formula I is a compound of Formula C. [0628] In some embodiments, the compound of Formula I is a compound of Formula D. [0629] In some embodiments, the compound of Formula I is a compound of Formula E. [0630] In some embodiments, the compound of Formula I is a compound of Formula F. [0631] In some embodiments, the compound of Formula I is a compound of Formula G. [0632] In some embodiments, the compound of Formula I is a compound of Formula H. 129. ASB Brenig.24.0001.W [0633] In some embodiments, the compound of Formula I is a compound of Formula J. [0634] In some embodiments, the compound of Formula I is a compound of Formula K. [0635] In some embodiments, the compound of Formula I is a compound of Formula L. [0636] In some embodiments, the compound of Formula I is a compound of Formula M. [0637] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof. [0638] In some embodiments, the compound is selected from the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof. [0639] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof. [0640] In some embodiments, the compound is selected from the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof. [0641] In some embodiments, the compound is selected from the compounds described in Table 1. [0642] Table 1. Non-limiting illustrative compounds of the present disclosure # Compound IUPAC name - - - 130. ASB Brenig.24.0001.W # Compound IUPAC name - - - e- )- - - - - - - 131. ASB Brenig.24.0001.W # Compound IUPAC name N4-methyl-N2-(8-methyl-23- - )- - - - - 132. ASB Brenig.24.0001.W # Compound IUPAC name N2-[3-(dimethylamino)-11-dioxo- - - - - b- - 133. ASB Brenig.24.0001.W # Compound IUPAC name N4-meth l-N2-(2-meth l-44- - o- - - - 134. ASB Brenig.24.0001.W # Compound IUPAC name N2-(11-dioxobenzothio hen-5- - l- 135. ASB Brenig.24.0001.W # Compound IUPAC name l- 136. ASB Brenig.24.0001.W # Compound IUPAC name 2-methyl-2-[3-[[2-[(1- - ]- l- - ]- 137. ASB Brenig.24.0001.W # Compound IUPAC name ]- - - - - - - - 138. ASB Brenig.24.0001.W # Compound IUPAC name - )- l- 139. ASB Brenig.24.0001.W # Compound IUPAC name l- l- l- 140. ASB Brenig.24.0001.W # Compound IUPAC name l- l- - )- 4- l- 5- - - 141. ASB Brenig.24.0001.W # Compound IUPAC name CF 5-[[4-[(1- - - 142. ASB Brenig.24.0001.W # Compound IUPAC name - - l- l- 143. ASB Brenig.24.0001.W # Compound IUPAC name 144. ASB Brenig.24.0001.W # Compound IUPAC name 2-[(2S 6R)-26- - ]- l- - ]- ]- - - - - 145. ASB Brenig.24.0001.W # Compound IUPAC name - - - - - - 146. ASB Brenig.24.0001.W # Compound IUPAC name - - - - ]- - 1- - ]- - 147. ASB Brenig.24.0001.W # Compound IUPAC name - 5- - - - - - - - - 148. ASB Brenig.24.0001.W # Compound IUPAC name N - - 3- - 3- - - 149. ASB Brenig.24.0001.W # Compound IUPAC name 4 1 l- l- l- - )- 4- 150. ASB Brenig.24.0001.W # Compound IUPAC name l- 5- - - )- l- 151. ASB Brenig.24.0001.W # Compound IUPAC name - 4- - - - - - - - - 152. ASB Brenig.24.0001.W # Compound IUPAC name )- - - - 4- - 153. ASB Brenig.24.0001.W # Compound IUPAC name N2-[1- ]- - - - - - 1- - - 5- - 154. ASB Brenig.24.0001.W # Compound IUPAC name N2-(1-cyclopropyl-7-methyl- - - - - - - 5- - - - - 155. ASB Brenig.24.0001.W # Compound IUPAC name - - ]- 4- - - - - - - 156. ASB Brenig.24.0001.W # Compound IUPAC name l- 5- - 157. ASB Brenig.24.0001.W # Compound IUPAC name ]- - - - 158. ASB Brenig.24.0001.W # Compound IUPAC name - - - - 159. ASB Brenig.24.0001.W [0643] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 1. [0644] In some embodiments, the compound is a lithium salt, sodium salt, potassium salt, calcium salt, or magnesium salt of any one of the compounds described in Table 1. [0645] In some embodiments, the compound is a salt of any acid described in the Table 2 and any one of the compounds described in Table 1. [0646] Table 2. Pharmaceutical acceptable acid forming salts with the Compound of Formula (I). 1-hydroxy-2-naphthoic acid glycolic acid 2,2-dichloroacetic acid hippuric acid 160. ASB Brenig.24.0001.W [0647] In some embodiments, the compound is a salt of acetic acid and any one of the compounds described in Table 1. [0648] In some embodiments, the compound is a salt of adipic acid and any one of the compounds described in Table 1. [0649] In some embodiments, the compound is a salt of ascorbic acid (L) and any one of the compounds described in Table 1. [0650] In some embodiments, the compound is a salt of hydrobromic acid and any one of the compounds described in Table 1. [0651] In some embodiments, the compound is a salt of hydrochloric acid and any one of the compounds described in Table 1. [0652] In some embodiments, the compound is a salt of citric acid and any one of the compounds described in Table 1. [0653] In some embodiments, the compound is a salt of glutamic acid and any one of the compounds described in Table 1. [0654] In some embodiments, the compound is a salt of oxalic acid and any one of the compounds described in Table 1. [0655] In some embodiments, the compound is a salt of formic acid and any one of the compounds described in Table 1. [0656] In some embodiments, the compound is a salt of sulfuric acid and any one of the compounds described in Table 1. [0657] In some aspects, the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of any one of the compounds of the Formulae disclosed herein. [0658] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof. [0659] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof. 161. ASB Brenig.24.0001.W [0660] In some embodiments, the compound is an isotopic derivative of any one of prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof. [0661] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1. [0662] It is understood that the isotopic derivative can be prepared using any of a variety of art-recognized techniques. For example, the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. [0663] In some embodiments, the isotopic derivative is a deuterium labeled compound. [0664] In some embodiments, the isotopic derivative is a deuterium labeled compound of any one of the compounds of the Formulae disclosed herein. [0665] The term “isotopic derivative”, as used herein, refers to a derivative of a compound in which one or more atoms are isotopically enriched or labelled. For example, an isotopic derivative of a compound of Formula (I) is isotopically enriched with regard to, or labelled with, one or more isotopes as compared to the corresponding compound of Formula (I). In some embodiments, the isotopic derivative is enriched with regard to, or labelled with, one or more atoms selected from 2H, 13C, 14C, 15N, 18O, 29Si, 31P, and 34S. In some embodiments, the isotopic derivative is a deuterium labeled compound (i.e., being enriched with 2H with regard to one or more atoms thereof). [0666] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof. [0667] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof. [0668] In some embodiments, the compound is a deuterium labeled compound of any one of the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof. [0669] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1. 162. ASB Brenig.24.0001.W [0670] It is understood that the deuterium labeled compound comprises a deuterium atom having an abundance of deuterium that is substantially greater than the natural abundance of deuterium, which is 0.015%. [0671] In some embodiments, the deuterium labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). As used herein, the term “deuterium enrichment factor” means the ratio between the deuterium abundance and the natural abundance of a deuterium. [0672] It is understood that the deuterium labeled compound can be prepared using any of a variety of art-recognized techniques. For example, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting a deuterium labeled reagent for a non- deuterium labeled reagent. [0673] A compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof that contains the aforementioned deuterium atom(s) is within the scope of the disclosure. Further, substitution with deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements. [0674] In some embodiments, the compound is a 18F labeled compound. [0675] In some embodiments, the compound is a 123I labeled compound, a 124I labeled compound, a 125I labeled compound, a 129I labeled compound, a 131I labeled compound, a 135I labeled compound, or any combination thereof. [0676] In some embodiments, the compound is a 33S labeled compound, a 34S labeled compound, a 35S labeled compound, a 36S labeled compound, or any combination thereof. [0677] It is understood that the 18F, 123I, 124I, 125I, 129I, 131I, 135I, 33S, 34S, 35S, and/or 36S labeled compound, can be prepared using any of a variety of art-recognized techniques. For example, the deuterium labeled compound can generally be prepared by carrying out 163. ASB Brenig.24.0001.W the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting a 18F, 123I, 124I, 125I, 129I, 131I, 135I, 3S, 34S, 35S, and/or 36S labeled reagent for a non-isotope labeled reagent. [0678] A compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof that contains one or more of the aforementioned 18F, 123I, 124I, 125I, 129I, 131I, 135I, 33S, 34S, 35S, and 36S atom(s) is within the scope of the disclosure. Further, substitution with isotope (e.g,, 18F, 123I, 124I, 125I, 129I, 131I, 135I, 33S, 34S, 35S, and/or 36S) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements. [0679] For the avoidance of doubt, it is to be understood that, where in this specification a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group. [0680] The various functional groups and substituents making up the compounds of the Formula (I) are typically chosen such that the molecular weight of the compound does not exceed 1000 Daltons. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650 Daltons. More conveniently, the molecular weight is less than 600 and, for example, is 550 Daltons or less, for example 500 Daltons or less, for example 450 Daltons or less. [0681] A suitable pharmaceutically acceptable salt of a compound of the disclosure is, for example, an acid-addition salt of a compound of the disclosure, which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the disclosure which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. [0682] It will be understood that the compounds of any one of the Formulae disclosed herein and any pharmaceutically acceptable salts thereof, comprise stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of said compounds. 164. ASB Brenig.24.0001.W [0683] As used herein, the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.” [0684] As used herein, the term “chiral center” refers to a carbon atom bonded to four nonidentical substituents. [0685] As used herein, the term “chiral isomer” means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116). [0686] As used herein, the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3- cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules. [0687] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the 165. ASB Brenig.24.0001.W compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity. [0688] It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It is also to be understood that not all atropic isomers may have the same level of activity. [0689] As used herein, the term “atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases. [0690] As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerisation is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose. [0691] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others. [0692] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed 166. ASB Brenig.24.0001.W “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterised by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. [0693] The compounds of this disclosure may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the disclosure may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present disclosure encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess inflammasome inhibitory activity. [0694] The present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions. [0695] It is to be understood that the compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, 167. ASB Brenig.24.0001.W tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate). [0696] As used herein, the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion or diethylamine ion. The substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms. [0697] It is to be understood that the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc. [0698] As used herein, the term “solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O. [0699] As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound. [0700] As used herein, the term “derivative” refers to compounds that have a common core structure and are substituted with various groups as described herein. [0701] As used herein, the term “bioisostere” refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group 168. ASB Brenig.24.0001.W of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonamides, tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996. [0702] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. A suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate. It is to be understood that the disclosure encompasses all such solvated forms that possess inflammasome inhibitory activity. [0703] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exhibit polymorphism, and that the disclosure encompasses all such forms, or mixtures thereof, which possess inflammasome inhibitory activity. It is generally known that crystalline materials may be analysed using conventional techniques such as X-Ray Powder Diffraction analysis, Differential Scanning Calorimetry, Thermal Gravimetric Analysis, Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and/or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials may be determined by Karl Fischer analysis. [0704] Compounds of any one of the Formulae disclosed herein may exist in a number of different tautomeric forms and references to compounds of Formula (I) or (II) include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula (I) or (II). Examples of tautomeric forms include keto- , enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro. 169. ASB Brenig.24.0001.W H O OH H+ O- C C C C C C [0705] Compounds of any one of the Formulae disclosed herein containing an amine function may also form N-oxides. A reference herein to a compound of Formula (I) or (II) that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-oxides can be formed by treatment of the corresponding amine with an oxidising agent such as hydrogen peroxide or a peracid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane. [0706] The compounds of any one of the Formulae disclosed herein may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure. A prodrug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the disclosure. A prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the ester or amide group in any one of the Formulae disclosed herein. [0707] Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof. Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism 170. ASB Brenig.24.0001.W of a precursor compound, that is a compound of any one of the Formulae disclosed herein may be a synthetically produced compound or a metabolically-produced compound. [0708] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity. Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987. [0709] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of any one of the Formulae disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include C1-C10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1-C10 alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-C6 alkyl)2carbamoyl, 2- dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for 171. ASB Brenig.24.0001.W a hydroxy group include ^-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups. [0710] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1-4alkylamine such as methylamine, a (C1-C4 alkyl)2amine such as dimethylamine, N- ethyl-N-methylamine or diethylamine, a C1-C4 alkoxy-C2-C4 alkylamine such as 2-methoxyethylamine, a phenyl-C1-C4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof. [0711] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-C10 alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl,morpholinomethyl,piperazin-1-ylmethyl and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. [0712] The in vivo effects of a compound of any one of the Formulae disclosed herein may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of any one of the Formulae disclosed herein. As stated hereinbefore, the in vivo effects of a compound of any one of the Formulae disclosed herein may also be exerted by way of metabolism of a precursor compound (a prodrug). Method of Synthesizing the Compounds [0713] The compounds of the present invention may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below. [0714] The compounds of Formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. 172. ASB Brenig.24.0001.W Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of those skilled in the art will recognize if a stereocenter exists in the compounds of Formula (I). Accordingly, the present invention includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994). [0715] The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes. Preparation of Compounds [0716] The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Suitable methods include but are not limited to those methods described below. Compounds of the present invention can be synthesized by following the steps outlined in General Procedure. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated below. GENERAL PROCEDURE [0717] In general, the compound of the Formula (I) can be prepared using sequences of reactions presented at the Scheme 1: 173. ASB Brenig.24.0001.W Scheme 1 of synthesis from commercially available reagents. For preparation of these reagents may be used one step or multistep synthetic procedures, including but not limited procedures described herein in preparative part. Biological Assays [0719] Compounds designed, selected and/or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity. [0720] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art. General methodologies for performing high- throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No.5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below. 174. ASB Brenig.24.0001.W [0721] Various in vitro or in vivo biological assays may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein. Pharmaceutical Compositions [0722] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulae described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1. [0723] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. [0724] Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. Solid form preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. [0725] Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions. 175. ASB Brenig.24.0001.W These include solid form preparations which are intended to be converted to liquid form preparations shortly before use. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. [0726] The compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water. [0727] The compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of present disclosure on can also be formulated for intravenous (bolus or in-fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts. [0728] The formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include 176. ASB Brenig.24.0001.W those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity/suspending agent, buffer, and pH modifying agent, and a mixture thereof. [0729] Any suitable solubility enhancing agent can be used. Examples of a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β- cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β- cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3- (trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated β- cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ- cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof. [0730] Any suitable chelating agent can be used. Examples of a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof. [0731] Any suitable preservative can be used. Examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof. [0732] In some embodiments, examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof. 177. ASB Brenig.24.0001.W [0733] The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof. In some embodiments, the tonicity agent is selected from the group consisting of a glycol (such as propylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof. [0734] The aqueous vehicle may also contain a viscosity/suspending agent. Suitable viscosity/suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof. [0735] In order to adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH modifying agent. The pH modifying agent is typically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and/or hydrochloric acid. These acidic and/or basic pH modifying agents are added to adjust the formulation to the target acceptable pH range. Hence it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range. [0736] The aqueous vehicle may also contain a buffering agent to stabilize the pH. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and ε-aminocaproic acid, and mixtures thereof. 178. ASB Brenig.24.0001.W [0737] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene- polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof. [0738] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. [0739] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier. [0740] In some embodiments, a pharmaceutical composition described herein may further comprise one or more additional pharmaceutically active agents. [0741] The compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration 179. ASB Brenig.24.0001.W by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing). [0742] The compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents. [0743] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent a LRRK2 related condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition. [0744] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat an LRRK2 related condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition. [0745] The size of the dose for therapeutic or prophylactic purposes of a compound of Formula (I) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or subject and the route of administration, according to well- known principles of medicine. Methods of Use [0746] In some aspects, the present disclosure provides a method of inhibiting of LRRK2 (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. [0747] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0748] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a 180. ASB Brenig.24.0001.W pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0749] In some embodiments, the disease or disorder is associated with LRRK2. In some embodiments, the disease or disorder is a disease or disorder in which LRRK2 is implicated. [0750] The compounds of the invention are also useful in treating diseases associated with LRRK2. For example, diseases and conditions treatable according to the methods of the invention include Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late- Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early-Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson Disease 10 (PARK10); Tremor; Frontotemporal Dementia (FTD); Postencephalitic Parkinson Disease; Vascular Parkinsonism; Aphasia; Parkinson Disease 1, Autosomal Dominant (PARK1); Athetosis; Klippel-Feil Syndrome (KFS); Kufor-Rakeb Syndrome (KRS); Leprosy 3 (LPRS3); Alzheimer Disease 8 (AD8); Crohn's Disease; Rheumatoid Arthritis (RA); Alzheimer Disease (AD); Color Agnosia; Gaucher Disease, Type I (GD1); Parkinson Disease 15, Autosomal Recessive Early-Onset (PARK15); Von Economo's Disease; Gerstmann-Straussler Disease (GSD); Amyotrophic Lateral Sclerosis- Parkinsonism/dementia Complex 1 (ALS-PDC1); Dystonia; Sphingolipidosis; Radial Nerve Lesion; Toxic Encephalopathy; Sleep Disorder; Pick Disease of Brain (PIDB); Ophthalmomyiasis; Gaucher's Disease (GD); Optic Atrophy 7 with or Without Auditory Neuropathy (OPA7); Ulnar Nerve Lesion; Inflammatory Bowel Disease 4 (IBD4); Inflammatory Bowel Disease; 3-Methylglutaconic Aciduria, Type Iii (MGCA3); Nervous System Disease; Amyotrophic Lateral Sclerosis 1 (ALS1); Mitochondrial Complex I Deficiency, Nuclear Type 1 (MC1DN1). [0751] In some embodiments, the disease or disorder is a Parkinson Disease (PD). 181. ASB Brenig.24.0001.W [0752] In some aspects, the present disclosure provides a method of treating or preventing a Parkinson Disease (PD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0753] In some aspects, the present disclosure provides a method of treating a Parkinson Disease (PD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0754] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in inhibiting of LRRK2 (e.g., in vitro or in vivo). [0755] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein. [0756] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein. [0757] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a Parkinson Disease (PD) in a subject in need thereof. [0758] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating Parkinson Disease (PD) in a subject in need thereof. [0759] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting of LRRK2 (e.g., in vitro or in vivo). [0760] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. 182. ASB Brenig.24.0001.W [0761] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein. [0762] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing Parkinson Disease (PD) in a subject in need thereof. [0763] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating Parkinson Disease (PD) in a subject in need thereof. [0764] The present disclosure provides compounds that function as inhibitors of LRRK2 (e.g., in vitro or in vivo). The present disclosure therefore provides a method of inhibiting of LRRK2 in vitro or in vivo, said method comprising contacting a cell with a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein. [0765] In some embodiments, the inhibitor of LRRK2 is a compound of the present disclosure. [0766] Effectiveness of compounds of the disclosure can be determined by industry- accepted assays/ disease models according to standard practices of elucidating the same as described in the art and are found in the current general knowledge. [0767] The present disclosure also provides a method of treating a disease or disorder in which LRRK2 is implicated in a subject in need of such treatment, said method comprising administering to said subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. [0768] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. Routes of Administration [0769] The compounds of the disclosure or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action). 183. ASB Brenig.24.0001.W [0770] Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. EXAMPLES General synthetical procedures and examples of the compound’s preparation. [0771] All reagents were commercial and were used without further purification. Yields refer to purified and spectroscopically pure compounds. Thin layer chromatography (TLC) was performed using Merck TLC Aluminum sheets silica gel 60 F254 plates and visualized by fluorescence quenching under UV light. Flash chromatography was performed using silica gel (Chromatorex, MB 70-40/75, 40-75^^m) purchased by Fuji Silysia Chemicals. NMR spectra were recorded on a Varian-400MR operating at 400 MHz for 1H. Chemical shifts are reported in ppm with the solvent resonance as the internal standard. Data is reported as follows: s = singlet, br = broad, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets; coupling constants in Hz; integration. The purities were recorded on Waters e2695 separations Module/2998 PDA Detector HPLC system (Column: XBridge C18, 5 μm, 4.6 mm (ID) x 150 mm (L), Eluent: the mixture of mobile phase A and B, mobile phase A: 100% acetonitrile; mobile phase B: pure water containing 0.1% formic acid and 10 mM NH4OAc, Flow rate: 0.5 mL/min. detection: UV, 254 nm) [0772] Abbreviations used in the following examples and elsewhere herein are: AcOH acetic acid anh. anhydrous aq. aqueous br. broad BSA bovine serum albumin CC column chromatography 184. ASB Brenig.24.0001.W d duplet DCM dichloromethane DIPEA diisopropylethylamine DMEM Dulbecco’s modified Eagle’s medium DMF N,N-dimethyl formamide DMSO dimethyl sulfoxide DPPA diphenylphosphoryl azide DTT dithiothreitol EA ethyl acetate FBS fetal bovine serum h hour(s) HPLC high pressure (or performance) liquid chromatography LCMS liquid chromatography mass spectrometry m multiplet M molar MHz megahertz min minutes NBS N-bromosuccinimide NMR nuclear magnetic resonance Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) Py pyridine q quadruplet rt room temperature s singlet s solid sat. saturated t temperature, triplet TBTU 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TRIS 2-amino-2-(hydroximethyl)propane-1,3-diol XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene Synthesis of Building Blocks Synthesis of N-[2-amino-5-(trifluoromethyl)-4-pyrimidinyl]-N-(1- methylcyclopropyl)amine (P3) and N-[4-amino-5-(trifluoromethyl)-2-pyrimidinyl]-N-(1- methylcyclopropyl)amine (P4) 185. ASB Brenig.24.0001.W (1- methylcyclopropyl)amine (P1) and N-[4-chloro-5-(trifluoromethyl)-2-pyrimidinyl]-N-(1- methylcyclopropyl)amine (P2). 1-methylcyclopropylamine hydrochloride (9.91 g, 92 mmol) was added to the mixture of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (20 g, 92 mmol) and DIPEA (35.3 mL, 203 mmol) at 0°C and the reaction mixture was stirred 0°C for 16 h. The reaction mixture was evaporated to dryness, DCM (200 mL) and H2O (200 mL) were added. Layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica CC eluting with DCM to afford 9.3 g (40%) of P1 and 9.3 g (40%) of P2. P1: 1H NMR (400 MHz, DMSO- d6), δ: 8.37 (s, 1H), 8.15 (s, 1H), 1.36 (s, 3H), 0.80 – 0.67 (m, 4H). P2: 1H NMR (400 MHz, DMSO-d6), δ: 8.78 (s, 1H), 8.63 (d, J = 62.3 Hz, 1H), 1.35 (s, 3H), 0.69 (d, J = 29.4 Hz, 4H). [0774] Preparation 2. N-[2-amino-5-(trifluoromethyl)-4-pyrimidinyl]-N-(1- methylcyclopropyl)amine (P3) and N-[4-amino-5-(trifluoromethyl)-2-pyrimidinyl]-N-(1- methylcyclopropyl)amine (P4). NH4OH (30 mL) was added to the solution of P1 (4 g, 15.9 mmol) in dioxane (30 mL) and the reaction mixture was stirred at 120°C for 20 h in a glass autoclave. Then reaction 186. ASB Brenig.24.0001.W mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was subjected to silica CC eluting with DCM to afford 3.5 g (94%) of P3. P4 was synthesized using the same procedure, yield was 3.5 g (94%). Synthesis of N-[2-amino-5-(trifluoromethyl)-4-pyrimidinyl]-N-methylamine (P7) and N- [4-amino-5-(trifluoromethyl)-2-pyrimidinyl]-N-methylamine (P8) (P5) and N-[4-chloro-5-(trifluoromethyl)-2-pyrimidinyl]-N-methylamine (P6). Methylamine hydrochloride (3.11 g, 46 mmol) was added to the mixture of 2,4-dichloro- 5-(trifluoromethyl)pyrimidine (10 g, 46 mmol) and DIPEA (17.7 mL, 102 mmol) at 0°C and the reaction mixture was stirred at 0°C for 16 h. The reaction mixture was evaporated to dryness, DCM (100 mL) and H2O (100 mL) were added. Layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica CC eluting with DCM to afford 3.5 g (36%) of P5 and 3.5 g (36%) of P6. [0776] Preparation 4. N-[2-Amino-5-(trifluoromethyl)-4-pyrimidinyl]-N-methylamine (P7) and N-[4-amino-5-(trifluoromethyl)-2-pyrimidinyl]-N-methylamine (P8). 187. ASB Brenig.24.0001.W NH4OH (15 mL) was added to the solution of P5 (1.5 g, 7.1 mmol) in dioxane (15 mL) and the reaction mixture was stirred at 120°C for 20 h in a glass autoclave. Then reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was subjected to silica CC eluting with DCM to afford 1.3 g (95%) of P7. P8 was synthesized using the same procedure, yield was 1.3 g (95%). Synthesis of 1-[4-chloro-6-oxo-1(6H)-pyridazinyl]-1-methylethyl cyanide (P10) NH O O 2 O N [0777] Preparation 5. 5-Chloro-2-tetrahydro-3-furanyl-3(2H)-pyridazinone (P9) A mixture of 5-chloro-3(2H)-pyridazinone (1 g, 7.66 mmol), 2-bromo-2- methylpropanamide (1.4 g, 8.43 mmol) and Cs2CO3 (4.99 g, 15.32 mmol) in ACN (10 mL) was stirred at 80°C for 20 h, then cooled to ambient temperature. EA (20 mL) and water (20 mL) were added. Layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica CC eluting with DCM to afford 0.5 g (30%) of compound P9. [0778] Preparation 6. 1-[4-Chloro-6-oxo-1(6H)-pyridazinyl]-1-methylethyl cyanide (P10) To a stirred solution of P9 (0.5 g, 2.3 mmol) and Py (0.46 mL, 5.75 mmol) in DCM (5 mL) was added TFA (0.36 mL, 2.53 mmol) at 0°C under N2. The mixture was warmed to ambient temperature for 10 h, then washed with sat. aq. NaHCO3 (10 mL), H2O (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was subjected to silica CC eluting with DCM to afford 0.4 g (87%) of the title compound P10. Synthesis of 5-chloro-2-tetrahydro-3-furanyl-3(2H)-pyridazinone (P11) 188. ASB Brenig.24.0001.W [0779] Preparation (P11) Diisopropyl azodicarboxylate (3.02 mL, 15.32 mmol) was added dropwise at 0°C to a mixture of 5-chloro-3(2H)-pyridazinone (1 g, 7.66 mmol), tetrahydro-3-furanol (1.35 g, 15.32 mmol) and triphenylphosphine (4.01 g, 15.32 mmol) in THF (10 mL) and the reaction mixture was stirred at ambient temperature overnight. Volatiles were removed under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.6 g (38%) of compound P11. Synthesis of 6-chloro-2-tetrahydro-2H-pyran-4-yl-3(2H)-pyridazinone (P12) [0780] Preparation 8. 6-Chloro-2-tetrahydro-2H-pyran-4-yl-3(2H)-pyridazinone (P12) Diisopropyl azodicarboxylate (1.81 mL, 9.2 mmol) was added dropwise at 0°C to a mixture of 6-chloro-3(2H)-pyridazinone (1 g, 7.66 mmol), tetrahydro-2H-pyran-4-ol (0.94 g, 9.2 mmol) and triphenylphosphine (2.41 g, 9.2 mmol) in THF (10 mL) and the reaction mixture was stirred at ambient temperature overnight. Volatiles were removed under reduced pressure and the residue was subjected to prep. HPLC purification to afford 1 g (61%) of compound P12. Synthesis of 6-chloro-2-methyl-3(2H)-pyridazinone (P13) 189. ASB Brenig.24.0001.W [0781] Preparation 9. 6- (P13) A mixture of 6-chloro-3(2H)-pyridazinone (1 g, 7.66 mmol), methyl iodide (5.44 g, 38.3 mmol) and Cs2CO3 (3.12 g, 9.57 mmol) in DMF (10 mL) was stirred at 80°C for 20 h, then cooled to ambient temperature. EA (20 mL) and water (20 mL) were added. Layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica CC eluting with DCM to afford 0.9 g (81%) of compound P13. Synthesis of 5-chloro-2-methyl-3(2H)-pyridazinone (P14) [0782] Preparation 10. 5-Chloro-2-methyl-3(2H)-pyridazinone (P14). A mixture of 5-chloro-3(2H)-pyridazinone (1 g, 7.66 mmol), methyl iodide (3.26 g, 23 mmol) and Cs2CO3 (2.99 g, 9.2 mmol) in DMF (10 mL) was stirred at 80°C for 20 h, then cooled to ambient temperature. EA (20 mL) and water (20 mL) were added. Layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica CC eluting with DCM to afford 0.8 g (72%) of compound P14. Synthesis of 5-chloro-2-cyclopropyl-3(2H)-pyridazinone (P15) 190. ASB Brenig.24.0001.W [0783] Preparation 11. 5-Chloro-2-cyclopropyl-3(2H)-pyridazinone (P15). To a mixture of 5-chloro-3(2H)-pyridazinone (2 g, 15.32 mmol), cyclopropyl boronic acid (2.63 g, 30.64 mmol), pyridine (3.08 mL, 38.3 mmol), sodium carbonate (2 g, 18.4 mmol) in dichloroethane (30 mL) diacetoxycopper (6.74 g, 33.7 mmol) was added under inert atmosphere at ambient temperature and the reaction mixture was stirred at 70°C for 48 h, then cooled to ambient temperature. DCM (50 mL) and water (50 mL) were added. Layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica CC eluting with DCM to afford 1 g (38%) of P15. Synthesis of 5-chloro-2-isopropyl-3(2H)-pyridazinone (P16) [0784] Preparation 12. 5-Chloro-2-isopropyl-3(2H)-pyridazinone (P16). To a solution of 5-isopropoxy-1H-indazole (P3, 3.0 g, 17 mmol) in DCM (30 mL) was added N-bromosuccinimide (3.32 g, 18.8 mmol) at 0°C. The mixture was stirred at rt for overnight. The reaction was directly concentrated and purified by silica gel column chromatography (n-hexane: EtOAc = 1:1) to give P18 (4.11 g, 95% yield). 1H NMR (400 MHz, CDCl3), δ: 10.37 (br. s, 1H), 7.38 (d, J = 9.0 Hz, 1H), 7.10 (dd, J = 1H), 6.97 (d, J = 2.4 Hz, 1H), 4.62 (septet, J = 6.0 Hz, 1H), 1.38 (d, J = 6.0 Hz, 6H). Synthesis of 1-[3-chloro-6-oxo-1(6H)-pyridazinyl]-1-methylethyl cyanide (P18) 191. ASB Brenig.24.0001.W [0785] (P17). A mixture of 6-chloro-3(2H)-pyridazinone (1 g, 7.66 mmol), 2-bromo-2- methylpropanamide (1.4 g, 8.43 mmol) and Cs2CO3 (4.99 g, 15.32 mmol) in ACN (10 mL) was stirred at 80°C for 20 h, then cooled to ambient temperature. EA (20 mL) and water (20 mL) were added. Layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica CC eluting with DCM to afford 0.5 g (30%) of compound P17. [0786] Preparation 14. 1-[3-chloro-6-oxo-1(6H)-pyridazinyl]-1-methylethyl cyanide (P18). To a stirred solution compound P17 (0.5 g, 2.3 mmol) and Py (0.46 mL, 5.75 mmol) in DCM (5 mL) was added TFA (0.36 mL, 2.53 mmol) at 0°C under N2. The mixture was warmed to ambient temperature for 10 h, then washed with sat. aq. NaHCO3 (10 mL), H2O (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was subjected to silica CC eluting with DCM to afford 0.4 g (87%) of the title compound P18. Synthesis of 5-chloro-2-cyclopentyl-3(2H)-pyridazinone (P19) [0787] Preparation - (P19). 192. ASB Brenig.24.0001.W A mixture of 5-chloro-3(2H)-pyridazinone (0.7 g, 5.36 mmol), cyclopentyl bromide (0.96 g, 6.43 mmol) and Cs2CO3 (2.18 g, 6.7 mmol) in DMF (10 mL) was stirred at 80°C for 20 h, then cooled to ambient temperature. EA (20 mL) and water (20 mL) were added. Layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica CC eluting with DCM to afford 0.4 g (37%) of compound P19. Synthesis of 6-chloro-2-[(2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-3(2H)- pyridazinone (P21) [0788] To a solution of 2,6-dimethyl-4H-pyran-4-one (10 g, 80.5 mmol) in EtOH (100 mL) was added a catalytic amount of 10% Pd/C (10% wt.).The mixture was stirred at 35°C for 20 h under an atmosphere of H2. The mixture was then filtered through a pad of celite and solvent was evaporated under reduced pressure to afford 5 g (48%) of compound P20. [0789] Preparation 17. 6-Chloro-2-[(2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]- 3(2H)-pyridazinone (P21). Diisopropyl azodicarboxylate (0.9 mL, 4.6 mmol) was added dropwise at 0°C to a mixture of 6-chloro-3(2H)-pyridazinone (0.5 g, 3.83 mmol), compound P20 (0.6 g, 4.6 mmol) and triphenylphosphine (1.2 g, 4.6 mmol) in THF (10 mL) and the reaction mixture was stirred at ambient temperature overnight. Volatiles were removed under reduced pressure and the residue was subjected to prep. HPLC purification to afford 0.2 g (22%) of compound P21. Synthesis of 5-chloro-2-tetrahydro-2H-pyran-4-yl-3(2H)-pyridazinone (P22) 193. ASB Brenig.24.0001.W [0790] -pyridazinone (P22). A mixture of 5-chloro-3(2H)-pyridazinone (1 g, 7.66 mmol), 4-bromotetrahydro-2H-pyran (1.51 g, 9.2 mmol) and Cs2CO3 (3.12 g, 9.6 mmol) in DMF (10 mL) was stirred at 80°C for 20 h, then cooled to ambient temperature. EA (20 mL) and water (20 mL) were added. Layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica CC eluting with DCM to afford 1 g (61%) of compound P22. Synthesis of 5-chloro-2-[(2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-3(2H)- pyridazinone (P23) [0791] pyran-4-yl]- 3(2H)-pyridazinone (P23). Diisopropyl azodicarboxylate (1.81 mL, 9.2 mmol) was added dropwise at 0°C to a mixture of 5-chloro-3(2H)-pyridazinone (1 g, 7.66 mmol), compound P20 (1.2 g, 9.2 mmol) and triphenylphosphine (2.41 g, 9.2 mmol) in THF (20 mL) and the reaction mixture was stirred at ambient temperature overnight. Volatiles were removed under reduced pressure and the residue was subjected to prep. HPLC purification to afford 0.9 g (48%) of compound P23. Synthesis of 5-chloro-2-(2-methoxyethyl)-3(2H)-pyridazinone (P24) 194. ASB Brenig.24.0001.W [0792] - - (P24). A mixture of 5-chloro-3(2H)-pyridazinone (0.5 g, 3.83 mmol), 2-bromoethyl methyl ether (0.64 g, 4.6 mmol) and Cs2CO3 (1.56 g, 4.8 mmol) in ACN (10 mL) was stirred at 80°C for 20 h, then cooled to ambient temperature. EA (20 mL) and water (20 mL) were added. Layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica CC eluting with DCM to afford 0.7 g (97%) of compound P24. Synthesis of 5-chloro-2-(tetrahydro-2-furanylmethyl)-3(2H)-pyridazinone (P25) [0793] -3(2H)-pyridazinone (P25). Diisopropyl azodicarboxylate (0.9 mL, 4.6 mmol) was added dropwise at 0°C to a mixture of 5-chloro-3(2H)-pyridazinone (0.5 g, 3.83 mmol), tetrahydro-2-furanylmethanol (0.47 g, 4.6 mmol) and triphenylphosphine (1.2 g, 4.6 mmol) in THF (10 mL) and the reaction mixture was stirred at ambient temperature overnight. Volatiles were removed under reduced pressure and the residue was subjected to prep. HPLC purification to afford 0.4 g (49%) of compound P25. Synthesis of 4-amino-1-tetrahydro-2H-pyran-4-yl-2-pyrrolidinone hydrochloride (P28). 195. ASB Brenig.24.0001.W pyran- (P26). A suspension of tetrahydro-2H-pyran-4-amine (1 g, 9.88 mmol) and 2-methylenesuccinic acid (1.28 g, 9.88 mmol) was stirred at 170°C for 2 h. The reaction mixture was cooled to rt, then diluted with EA (20 mL) and water (20 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The product was purified by trituration with EtOH, filtered and dried to afford 1.05 g (50%) of the title compound P26. [0795] Preparation 23. tert-Butyl N-(5-oxo-1-tetrahydro-2H-pyran-4-yltetrahydro-1H- pyrrol-3-yl)carbamate (P27). To a solution of compound P26 (1 g, 4.69 mmol) in t-BuOH (30 mL) was added TEA (1 mL, 7 mmol) and DPPA (1.67 g, 6.1 mmol) and the reaction mixture was stirred at 90°C for 36 h. The reaction mixture was cooled to rt, was then diluted with EA (20 mL) and water (20 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica CC eluting with DCM to afford 0.65 g (49%) of compound P27. [0796] Preparation 24. 4-Amino-1-tetrahydro-2H-pyran-4-yl-2-pyrrolidinone hydrochloride (P28). To a solution of compound P27 (0.6 g, 2.1 mmol) in DCM (30 mL) was added 3M solution of HCl/dioxane (5 mL) and the reaction mixture was stirred for 8 h. The reaction mixture was diluted by Et2O (50 mL), formed precipitate was filtered and dried off to afford 0.45 g (97%) of compound P28 as HCl salt. 196. ASB Brenig.24.0001.W Synthesis of 3-amino-N1-tetrahydro-2H-pyran-4-ylbicyclo[1.1.1]pentane-1-carboxamide hydrochloride (P32) 1- carboxylate (P29). To a solution of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (5 g, 29 mmol) in t-BuOH (50 mL) was added TEA (4 mL, 29 mmol) and DPPA (8.1 g, 38 mmol) and the reaction mixture was stirred at 90°C for 16 h. The reaction mixture was cooled to rt, then diluted with EA (100 mL) and water (200 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica CC eluting with DCM^Et2O to afford 5.1 g (73%) of compound P29. [0798] Preparation 26. 3-[(tert-Butoxycarbonyl)amino]bicyclo[1.1.1]pentane-1- carboxylic acid (P30). LiOHxH2O (0.21 g, 5 mmol) was added to the solution of compound P29 (0.5 g, 2 mmol) in THF/H2O (10 mL/2 mL) and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then evaporated under reduced pressure, H2O (20 mL) and DCM (20 mL) were added, mixture was acidified with aq. HCl, precipitate was filtered off, washed with water and dried on air to afford 0.33 g (73 %) of the title compound P30 that was used in the next step without purification. [0799] Preparation 27. tert-Butyl N-3-[(tetrahydro-2H-pyran-4- ylamino)carbonyl]bicyclo[1.1.1]pent-1-ylcarbamate (P31). 197. ASB Brenig.24.0001.W To a solution of compound P30 (0.33 g, 1.45 mmol) in DCM (10 mL) was added DIPEA (0.76 mL, 4.4 mmol), TBTU (0.7 g, 2.2 mmol) and tetrahydro-2H-pyran-4-amine hydrochloride (0.26 mL, 1.9 mmol) and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was cooled to rt, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica CC eluting with DCM^EA to afford 0.33 g (50%) of compound P31. [0800] Preparation 28. 3-Amino-N1-tetrahydro-2H-pyran-4-ylbicyclo[1.1.1]pentane-1- carboxamide hydrochloride (P32). To a solution of compound P31 (0.33 g, 1 mmol) in dioxane (10 mL) was added 3M solution of HCl/dioxane (5 mL) and the reaction mixture was stirred for 8 h. The reaction mixture was diluted by Et2O (20 mL), formed precipitate was filtered and dried off to afford 0.22 g (89%) of compound P32 as HCl salt. Synthesis of 2-allyl-5-chloro-3(2H)-pyridazinone (P33) [0801] Preparation 29. 2-Allyl-5-chloro-3(2H)-pyridazinone (P33). A mixture of 5-chloro-3(2H)-pyridazinone (0.5 g, 3.83 mmol), allyl bromide (0.56 g, 4.6 mmol) and Cs2CO3 (1.62 g, 4.6 mmol) in ACN (10 mL) was stirred at 80°C for 20 h, then cooled to ambient temperature. EA (20 mL) and water (20 mL) were added. Layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica CC eluting with DCM to afford 0.45 g (69%) of compound P33. Synthesis of 1-isopropylpyrrolo[2,3-b]pyridin-3-amine (P36) 198. ASB Brenig.24.0001.W [0802] Preparation 30. 3-Nitro-7-azoindole (P34). 7-Azoindole (1.10 g, 9.3 mmol) was added to 10 ml of red fuming nitric acid at 0°C within 20 min, and then the reaction mixture was stirred at rt for 1 h. Then the mixture was poured to 50 ml of ice. Formed precipitate was filtered, washed with water (2x10 ml) and dried on air to give P34 (1.20 g, 80 % yield) as slight brown solid.1H NMR (400 MHz, DMSO-d6), δ: 13.23 (br., 1H), 8.81 (s, 1H), 8.44-8.42 (m, 2H), 7.41 (q, J1=5.4 Hz, J2=2.9 Hz, 1H). [0803] Preparation 31. 1-Isopropyl-3-nitro-1H-pyrrolo[2,3-b]pyridine (P35). To a mixture of P34 (0.500 g, 3.07 mmol) and K2CO3 (0.845 g, 6.13 mmol) in DMF (5 ml) isopropyl bromide (0.754 g, 6.13 mmol) was added. The mixture was stirred at 50-60°C for 16 h. Then the mixture was diluted with water (20 ml). A solid was filtered, washed with water (2x10 ml) and dried on air and give P35 (0.46 g, 74 % yield) as slight brown solid.1H NMR (400 MHz, CDCl3), δ: 8.56 (d, J=Hz, 1H), 8.47-8.46 (m, 1H), 8.32 (s, 1H), 7.38-7.36 (m, 1H), 5.28(t, J=6.7 Hz, 1H), 1.62 (d, J=6.7 Hz, 6H). [0804] Preparation 32. 1-Isopropylpyrrolo[2,3-b]pyridin-3-amine (P36). To a solution of the compound P35 (125 mg, 0.6 mmol) in EtOH (10 ml) a 10% Pd/C (10 mg) was added and the mixture was stirred under atmosphere of H2 (1 bar) at rt for 3 h, then solids were filtered-off through Celite and filtrate was evaporated to dryness to give crude compound P36 as dark-red oil. The product was used on next step without purification. Synthesis of 1-(2,2,2-trifluoroethyl)pyrrolo[2,3-b]pyridin-3-amine (P38), 1-(2,2- difluoroethyl)pyrrolo[2,3-b]pyridin-3-amine (P40), and 1-(oxetan-3-yl)pyrrolo[2,3- b]pyridin-3-amine (P42) 199. ASB Brenig.24.0001.W described in preparations Preparation 30 - Preparation 32 and were used in the further steps without isolation and purification. In the Table 3 below presented yields and 1H- NMRs for the compounds P37, P39, and P41. [0806] Table 3. Compound Yield, % 1H-NMR (400 MHz, CDCl3), δ , , 200. ASB Brenig.24.0001.W 1H), 6.21 (tt, J1=55.3 Hz, J2=4.0 Hz, 1H), 4.76 (td, J1=10.0 Hz, J2=4.0 Hz, 2H) , , , , in preparations Preparation 30 - Preparation 32 and was used in the preparation of final compound without isolation and purification. In the Table 4 below presented yields and 1H-NMRs for the compounds P43, and P44. [0808] Table 4. Compound Yield, % 1H-NMR ), , , Examples of the Final Compound [0809] In the Table 4 presented certain non-limiting examples of the compound of Formula (I). [0810] Table 4. Selected examples of the compound of Formula (I) 201. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 202. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 203. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 204. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 205. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 206. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 207. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 208. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 209. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 210. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 211. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 212. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 213. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 214. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 215. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 216. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 217. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 218. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 219. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 220. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 221. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 222. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 223. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 224. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 225. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 226. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 227. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found 228. ASB Brenig.24.0001.W [MH]+ [MH]+ # Structure Calc. Found y es s o e ep ese a e a p es o e co pou [0811] Example 1. 1-Methyl-1-[4-[2-[(1-methylcyclopropyl)amino]-5-(trifluoromethyl)- 4-pyrimidinyl]amino-6-oxo-1(6H)-pyridazinyl]ethyl cyanide (Compound 25). A mixture (0.7 g, 1.52 mmol), XantPhos (0.066 g, 0.11 mmol) and Pd(OAc)2 (0.008 g, 0.038 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 2 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.024 g (8 %) of the title compound 25. 1H NMR (400 MHz, DMSO-d6), δ: 8.77 (s, 1H), 8.42 (d, J = 2.5 Hz, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 8.01 (s, 1H), 1.86 (s, 6H), 1.34 (s, 3H), 0.82 – 0.66 (m, 4H). [0812] Example 2. 5-[2-[(1-Methylcyclopropyl)amino]-5-(trifluoromethyl)-4- pyrimidinyl]amino-2-tetrahydro-3-furanyl-3(2H)-pyridazinone (Compound 26). 229. ASB Brenig.24.0001.W A mixture of g, 1.55 mmol), XantPhos (0.044 g, 0.076 mmol) and Pd2(dba)3 (0.069 g, 0.038 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.015 g (5%) of the title compound 26. 1H NMR (400 MHz, DMSO-d6), δ: 8.67 (s, 1H), 8.38 (s, 1H), 8.33 (s, 1H), 8.25 (s, 1H), 7.86 (s, 1H), 5.50 – 5.37 (m, 1H), 4.02 – 3.86 (m, 2H), 3.80 (dd, J = 7.9, 5.5 Hz, 1H), 3.70 (dd, J = 9.2, 4.2 Hz, 1H), 2.37 – 2.04 (m, 2H), 1.32 (s, 3H), 0.81 – 0.57 (m, 4H). [0813] Example 3. 6-[2-[(1-Methylcyclopropyl)amino]-5-(trifluoromethyl)-4- pyrimidinyl]amino-2-tetrahydro-2H-pyran-4-yl-3(2H)-pyridazinone (Compound 28). A mixture of P12 , , (0.1 g, 0.91 mmol), XantPhos (0.042 g, 0.073 mmol) and Pd2(dba)3 (0.067 g, 0.073 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to 230. ASB Brenig.24.0001.W prep. HPLC purification to afford 0.047 g (16%) of the title compound 28. 1H NMR (400 MHz, DMSO-d6), δ: 9.13 (s, 1H), 8.24 (s, 1H), 8.06 (s, 1H), 7.78 (d, J = 9.8 Hz, 1H), 6.98 (d, J = 9.8 Hz, 1H), 5.11 – 4.91 (m, 1H), 3.96 (dd, J = 11.6, 4.3 Hz, 2H), 3.46 (t, J = 11.8 Hz, 2H), 2.03 – 1.89 (m, 2H), 1.67 (d, J = 12.6 Hz, 2H), 1.14 (s, 3H), 0.63 (s, 2H), 0.44 (s, 2H). [0814] Example 4. 2-Methyl-6-[2-[(1-methylcyclopropyl)amino]-5-(trifluoromethyl)-4- pyrimidinyl]amino-3(2H)-pyridazinone (Compound 29). A mixture of P13 (0.097 g, 0.86 mmol), XantPhos (0.04 g, 0.069 mmol) and Pd2(dba)3 (0.063 g, 0.069 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.037 g (15%) of the title compound 29. 1H NMR (400 MHz, DMSO-d6), δ: 9.07 (s, 1H), 8.23 (s, 1H), 8.02 (s, 1H), 7.82 (d, J = 9.7 Hz, 1H), 6.98 (d, J = 9.7 Hz, 1H), 3.62 (s, 3H), 1.16 (s, 3H), 0.64 (s, 2H), 0.46 (s, 2H). [0815] Example 5. 2-Methyl-5-[2-[(1-methylcyclopropyl)amino]-5-(trifluoromethyl)-4- pyrimidinyl]amino-3(2H)-pyridazinone (Compound 30). 231. ASB Brenig.24.0001.W A mixture of (0.09 g, 0.81 mmol), XantPhos (0.037 g, 0.065 mmol) and Pd2(dba)3 (0.059 g, 0.065 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.021 g (9%) of the title compound 30. 1H NMR (400 MHz, DMSO-d6), δ: 8.65 (s, 1H), 8.40 – 8.31 (m, 2H), 8.26 (s, 1H), 7.87 (s, 1H), 3.59 (s, 3H), 1.33 (s, 3H), 0.80 – 0.58 (m, 4H). [0816] Example 6. 2-Cyclopropyl-5-[2-[(1-methylcyclopropyl)amino]-5- (trifluoromethyl)-4-pyrimidinyl]amino-3(2H)-pyridazinone (Compound 31). A mixture of g, 1.3 mmol), XantPhos (0.056 g, 0.098 mmol) and Pd(OAc)2 (0.008 g, 0.025 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 2 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.111 g (47 %) of the title compound 31. 1H NMR (400 232. ASB Brenig.24.0001.W MHz, DMSO-d6), δ: 8.66 (s, 1H), 8.33 (s, 1H), 8.30 (s, 1H), 8.26 (s, 1H), 7.85 (d, J = 2.5 Hz, 1H), 4.02 – 3.89 (m, 1H), 1.32 (s, 3H), 1.00 – 0.85 (m, 4H), 0.80 – 0.57 (m, 4H). [0817] Example 7. 2-Isopropyl-5-[2-[(1-methylcyclopropyl)amino]-5-(trifluoromethyl)- 4-pyrimidinyl]amino-3(2H)-pyridazinone (Compound 32). A mixture of , KOAc (0.12 g, 1.07 mmol), XantPhos (0.05 g, 0.086 mmol) and Pd2(dba)3 (0.078 g, 0.086 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.045 g (14%) of the title compound 32. 1H NMR (400 MHz, DMSO-d6), δ: 8.61 (s, 1H), 8.36 (s, 1H), 8.32 (s, 1H), 8.21 (s, 1H), 7.81 (s, 1H), 5.10 (p, J = 6.7 Hz, 1H), 1.32 (s, 3H), 1.25 (d, J = 6.6 Hz, 6H), 0.80 – 0.54 (m, 4H). [0818] Example 8. 1-Methyl-1-[3-[2-[(1-methylcyclopropyl)amino]-5-(trifluoromethyl)- 4-pyrimidinyl]amino-6-oxo-1(6H)-pyridazinyl]ethyl cyanide (Compound 34). ASB Brenig.24.0001.W A mixture of compound P18 (0.127 g, 0.65 mmol), P4 (0.15 g, 0.65 mmol), KOAc (0.09 g, 0.81 mmol), XantPhos (0.037 g, 0.065 mmol) and Pd2(dba)3 (0.059 g, 0.065 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.018 g (7%) of the title compound 34. 1H NMR (400 MHz, DMSO-d6), δ: 9.11 (s, 1H), 8.24 (s, 1H), 8.05 (s, 1H), 7.90 (d, J = 9.7 Hz, 1H), 7.09 (d, J = 9.7 Hz, 1H), 1.86 (s, 6H), 1.15 (s, 3H), 0.63 (s, 2H), 0.45 (s, 2H). [0819] Example 9. 2-Cyclopentyl-5-[2-[(1-methylcyclopropyl)amino]-5- (trifluoromethyl)-4-pyrimidinyl]amino-3(2H)-pyridazinone (Compound 35). A mixture of (0.14 g, 1.25 mmol), XantPhos (0.057 g, 0.1 mmol) and Pd2(dba)3 (0.091 g, 0.1 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.09 g (23%) of the title compound 35. 1H NMR (400 MHz, DMSO-d6), δ: 8.63 (s, 1H), 8.37 (s, 1H), 8.32 (s, 1H), 8.22 (s, 1H), 7.78 (d, J = 2.4 Hz, 1H), 5.31 – 5.17 (m, 1H), 2.02 – 1.86 (m, 2H), 1.76 (s, 4H), 1.68 – 1.45 (m, 2H), 1.31 (s, 3H), 0.79 – 0.56 (m, 4H). [0820] Example 10. 2-[(2R,6S)-2,6-Dimethyltetrahydro-2H-pyran-4-yl]-6-[2-[(1- methylcyclopropyl)amino]-5-(trifluoromethyl)-4-pyrimidinyl]amino-3(2H)-pyridazinone (Compound 36). 234. ASB Brenig.24.0001.W A mixture of , KOAc (0.096 g, 0.86 mmol), XantPhos (0.04 g, 0.069 mmol) and Pd2(dba)3 (0.063 g, 0.069 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 4 h, then the mixture was diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.032 g (11%) of the title compound 36. 1H NMR (400 MHz, DMSO-d6), δ: 8.65 (s, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 8.06 (s, 1H), 7.34 (d, J = 9.4 Hz, 1H), 5.51 (s, 1H), 3.90 – 3.74 (m, 2H), 2.04 – 1.87 (m, 2H), 1.59 – 1.36 (m, 2H), 1.14 – 1.02 (m, 9H), 0.73 – 0.50 (m, 4H). [0821] Example 11. 5-[2-[(1-Methylcyclopropyl)amino]-5-(trifluoromethyl)-4- pyrimidinyl]amino-2-tetrahydro-2H-pyran-4-yl-3(2H)-pyridazinone (Compound 37). A mixture , KOAc (0.09 g, 0.81 mmol), XantPhos (0.037 g, 0.065 mmol) and Pd2(dba)3 (0.059 g, 0.065 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with 235. ASB Brenig.24.0001.W water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.007 g (3%) of the title compound 37. [0822] Example 12. 2-[(2R,6S)-2,6-Dimethyltetrahydro-2H-pyran-4-yl]-5-[2-[(1- methylcyclopropyl)amino]-5-(trifluoromethyl)-4-pyrimidinyl]amino-3(2H)-pyridazinone (Compound 38). A (0.066 g, 0.59 mmol), XantPhos (0.027 g, 0.047 mmol) and Pd2(dba)3 (0.043 g, 0.047 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.086 g (41%) of the title compound 38. 1H NMR (400 MHz, DMSO-d6), δ: 8.66 (s, 1H), 8.38 (d, J = 2.5 Hz, 1H), 8.33 (s, 1H), 8.23 (s, 1H), 7.75 (d, J = 2.6 Hz, 1H), 5.02 – 4.91 (m, 1H), 3.92 (td, J = 7.3, 6.9, 3.5 Hz, 2H), 1.87 (d, J = 14.2 Hz, 2H), 1.64 – 1.47 (m, 2H), 1.31 (s, 3H), 1.05 (d, J = 6.1 Hz, 6H), 0.82 – 0.56 (m, 4H). [0823] Example 13. 2-(2-Methoxyethyl)-5-[2-[(1-methylcyclopropyl)amino]-5- (trifluoromethyl)-4-pyrimidinyl]amino-3(2H)-pyridazinone (Compound 48). 236. ASB Brenig.24.0001.W A (0.17 g, 1.55 mmol), XantPhos (0.074 g, 0.129 mmol) and Pd2(dba)3 (0.118 g, 0.129 mmol) in toluene (10 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.105 g (21%) of the title compound 48. 1H NMR (400 MHz, DMSO-d6), δ: 8.62 (s, 1H), 8.32 (s, 2H), 8.23 (s, 1H), 7.83 (s, 1H), 4.16 (t, J = 5.7 Hz, 2H), 3.64 (t, J = 5.6 Hz, 2H), 3.23 (s, 3H), 1.32 (s, 3H), 0.73 (d, J = 6.0 Hz, 4H). [0824] Example 14. 5-[2-[(1-Methylcyclopropyl)amino]-5-(trifluoromethyl)-4- pyrimidinyl]amino-2-(tetrahydro-2-furanylmethyl)-3(2H)-pyridazinone (Compound 49). A (0.09 g, 0.81 mmol), XantPhos (0.037 g, 0.065 mmol) and Pd2(dba)3 (0.059 g, 0.065 mmol) in toluene (10 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.041 g (15%) of the title compound 49. 1H 237. ASB Brenig.24.0001.W NMR (400 MHz, DMSO-d6), δ: 8.55 (s, 1H), 8.33 (s, 2H), 8.23 (s, 1H), 7.83 (s, 1H), 4.27 – 4.15 (m, 1H), 4.09 (dd, J = 13.0, 7.4 Hz, 1H), 3.94 (dd, J = 13.0, 5.4 Hz, 1H), 3.81 – 3.68 (m, 1H), 3.68 – 3.55 (m, 1H), 1.99 – 1.70 (m, 3H), 1.70 – 1.55 (m, 1H), 1.32 (s, 3H), 0.80 – 0.56 (m, 4H). [0825] Example 15. 4-[2-[(1-Methylcyclopropyl)amino]-5-(trifluoromethyl)-4- pyrimidinyl]amino-1-tetrahydro-2H-pyran-4-yl-2-pyrrolidinone (Compound 53). H2N F O A mixture KOAc (0.11 g, 0.99 mmol), XantPhos (0.026 g, 0.045 mmol) and Pd2(dba)3 (0.041 g, 0.045 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.051 g (28%) of the title compound 53. 1H NMR (400 MHz, DMSO-d6), δ: 8.02 (s, 1H), 7.71 (s, 1H), 6.84 (s, 1H), 4.83 – 4.62 (m, 1H), 4.11 – 3.95 (m, 1H), 3.88 (d, J = 11.4 Hz, 2H), 3.83 – 3.67 (m, 1H), 3.45 – 3.32 (m, 2H), 2.82 – 2.56 (m, 3H), 1.73 – 1.55 (m, 2H), 1.50 (d, J = 12.5 Hz, 2H), 1.36 (s, 3H), 0.77 – 0.53 (m, 4H). [0826] Example 16. 3-[2-[(1-Methylcyclopropyl)amino]-5-(trifluoromethyl)-4- pyrimidinyl]amino-N1-tetrahydro-2H-pyran-4-ylbicyclo[1.1.1]pentane-1-carboxamide (Compound 54). 238. ASB Brenig.24.0001.W A (0.22 g, 1.96 mmol), XantPhos (0.051 g, 0.089 mmol) and Pd2(dba)3 (0.081 g, 0.089 mmol) in toluene (10 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (20 mL) and water (20 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.04 g (11%) of the title compound 54. 1H NMR (400 MHz, DMSO-d6), δ: 7.99 (s, 1H), 7.65 (s, 1H), 7.59 (s, 1H), 7.23 (s, 1H), 3.89 – 3.67 (m, 3H), 3.40 – 3.23 (m, 2H), 2.34 (s, 6H), 1.62 (d, J = 12.6 Hz, 2H), 1.47 (tt, J = 12.2, 6.0 Hz, 2H), 1.36 (s, 3H), 0.76 – 0.52 (m, 4H). [0827] Example 17. N-(1-Methylcyclopropyl)-N-[4-[(1-tetrahydro-2H-pyran-4-yl-1H- pyrazol-4-yl)amino]-5-(trifluoromethyl)-2-pyrimidinyl]amine (Compound 55). A mmol), intermediate P4 (0.2 g, 0.79 mmol), KOAc (0.11 g, 0.98 mmol), XantPhos (0.046 g, 0.079 mmol) and Pd2(dba)3 (0.072 g, 0.079 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and 239. ASB Brenig.24.0001.W concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.075 g (25%) of the title compound 55. 1H NMR (400 MHz, DMSO-d6), δ: 8.61 (s, 1H), 8.28 (s, 1H), 8.09 (s, 1H), 7.90 – 7.68 (m, 2H), 4.41 – 4.26 (m, 1H), 3.95 (d, J = 11.3 Hz, 2H), 3.54 – 3.39 (m, 2H), 2.05 – 1.79 (m, 4H), 1.40 (s, 3H), 0.83 – 0.57 (m, 4H). [0828] Example 18. N-[1-(3-Methoxypropyl)-1H-pyrazol-4-yl]-N-[2-[(1- methylcyclopropyl)amino]-5-(trifluoromethyl)-4-pyrimidinyl]amine (Compound 56). A (0.24 g, 0.95 mmol), KOAc (0.13 g, 1.18 mmol), XantPhos (0.055 g, 0.095 mmol) and Pd2(dba)3 (0.087 g, 0.095 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.1 g (28%) of the title compound 56. 1H NMR (400 MHz, DMSO-d6), δ: 8.64 (s, 1H), 8.30 (s, 2H), 8.09 (s, 1H), 7.82 (s, 1H), 4.08 (t, J = 6.7 Hz, 2H), 3.36 – 3.17 (m, 5H), 1.98 (q, J = 6.7 Hz, 2H), 1.40 (s, 3H), 0.83 – 0.57 (m, 4H). [0829] Example 19. 1-Methyl-1-[4-[2-(methylamino)-5-(trifluoromethyl)-4- pyrimidinyl]amino-6-oxo-1(6H)-pyridazinyl]ethyl cyanide (Compound 45). ASB Brenig.24.0001.W A mixture of compound P10 (0.154 g, 0.78 mmol), P8 (0.15 g, 0.78 mmol), KOAc (0.105 g, 0.94 mmol), XantPhos (0.045 g, 0.078 mmol) and Pd2(dba)3 (0.071 g, 0.078 mmol) in toluene (10 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.045 g (16%) of the title compound 45. 1H NMR (400 MHz, DMSO-d6), δ: 8.74 (s, 1H), 8.49 – 8.30 (m, 2H), 7.91 (s, 1H), 7.50 (d, J = 13.9 Hz, 1H), 2.83 (s, 3H), 1.86 (s, 6H). [0830] Example 20.1-Methyl-1-[4-[4-[(1-methylcyclopropyl)amino]-5-(trifluoromethyl)- 2-pyrimidinyl]amino-6-oxo-1(6H)-pyridazinyl]ethyl cyanide (Compound 64). A mixture of g, 0.76 mmol), Cs2CO3 (0.7 g, 1.52 mmol), Xantphos (0.066 g, 0.11 mmol) and Pd(OAc)2 (0.008 g, 0.038 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 2 h, then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.068 g (23 %) of the title compound 64. 1H NMR (400 MHz, DMSO-d6), δ: 10.34 (s, 1H), 8.32 (s, 1H), 8.09 (d, J = 2.5 Hz, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.74 (s, 1H), 1.85 (s, 6H), 1.44 (s, 3H), 0.84 (s, 4H). [0831] Example 21. 5-[4-[(1-Methylcyclopropyl)amino]-5-(trifluoromethyl)-2- pyrimidinyl]amino-2-tetrahydro-3-furanyl-3(2H)-pyridazinone (Compound 65). 241. ASB Brenig.24.0001.W A mixture of , KOAc (0.17 g, 1.55 mmol), XantPhos (0.044 g, 0.076 mmol) and Pd2(dba)3 (0.069 g, 0.038 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.05 g (17%) of the title compound 65. 1H NMR (400 MHz, DMSO-d6), δ: 10.22 (s, 1H), 8.30 (s, 1H), 8.09 (d, J = 2.5 Hz, 1H), 7.93 (d, J = 2.5 Hz, 1H), 7.68 (s, 1H), 5.49 – 5.35 (m, 1H), 4.02 – 3.85 (m, 2H), 3.81 (dd, J = 8.0, 5.5 Hz, 1H), 3.69 (dd, J = 9.2, 4.2 Hz, 1H), 2.29 – 2.07 (m, 2H), 1.42 (s, 3H), 0.83 (s, 4H). [0832] Example 22. 6-[4-[(1-Methylcyclopropyl)amino]-5-(trifluoromethyl)-2- pyrimidinyl]amino-2-tetrahydro-2H-pyran-4-yl-3(2H)-pyridazinone (Compound 66). A mixture , , KOAc (0.12 g, 1.08 mmol), XantPhos (0.049g, 0.086 mmol) and Pd2(dba)3 (0.079 g, 0.086 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted 242. ASB Brenig.24.0001.W with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.042 g (12%) of the title compound 66. 1H NMR (400 MHz, DMSO-d6), δ: 9.94 (s, 1H), 8.31 – 8.21 (m, 1H), 8.19 (s, 1H), 7.39 (s, 1H), 6.99 (d, J = 9.8 Hz, 1H), 5.05 – 4.90 (m, 1H), 3.96 (dd, J = 11.1, 4.4 Hz, 2H), 3.46 (t, J = 11.9 Hz, 2H), 1.96 (qd, J = 12.2, 4.5 Hz, 2H), 1.74 – 1.59 (m, 2H), 1.31 (s, 3H), 0.82 – 0.48 (m, 4H). [0833] Example 22. 2-Methyl-6-[4-[(1-methylcyclopropyl)amino]-5-(trifluoromethyl)-2- pyrimidinyl]amino-3(2H)-pyridazinone (Compound 67). A mixture of , KOAc (0.097 g, 0.86 mmol), XantPhos (0.04 g, 0.069 mmol) and Pd2(dba)3 (0.063 g, 0.069 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.015 g (7%) of the title compound 67. [0834] Example 23. 2-Methyl-5-[4-[(1-methylcyclopropyl)amino]-5-(trifluoromethyl)-2- pyrimidinyl]amino-3(2H)-pyridazinone (Compound 68). ASB Brenig.24.0001.W A mixture of compound P14 (0.1 g, 0.69 mmol), P3 (0.17 g, 0.76 mmol), KOAc (0.097 g, 0.86 mmol), XantPhos (0.04g, 0.069 mmol) and Pd2(dba)3 (0.063 g, 0.069 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.048 g (22%) of the title compound 68. 1H NMR (400 MHz, DMSO-d6), δ: 10.18 (s, 1H), 8.30 (s, 1H), 8.07 (d, J = 2.5 Hz, 1H), 7.88 (d, J = 2.5 Hz, 1H), 7.68 (s, 1H), 3.56 (s, 3H), 1.42 (s, 3H), 0.83 (s, 4H). [0835] Example 24. 2-Cyclopropyl-5-[4-[(1-methylcyclopropyl)amino]-5- (trifluoromethyl)-2-pyrimidinyl]amino-3(2H)-pyridazinone (Compound 69). A mixture of , Cs2CO3 (0.41 g, 1.3 mmol), XantPhos (0.056 g, 0.098 mmol) and Pd(OAc)2 (0.008 g, 0.025 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 2 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.007 g (3 %) of the title compound 69. [0836] Example 25. 2-Isopropyl-5-[4-[(1-methylcyclopropyl)amino]-5-(trifluoromethyl)- 2-pyrimidinyl]amino-3(2H)-pyridazinone (Compound 70). ASB Brenig.24.0001.W A mixture of compound P16 (0.148 g, 0.86 mmol), P3 (0.2 g, 0.86 mmol), KOAc (0.12 g, 1.07 mmol), XantPhos (0.05 g, 0.086 mmol) and Pd2(dba)3 (0.078 g, 0.086 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 4h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.025 g (8%) of the title compound 70. 1H NMR (400 MHz, DMSO-d6), δ: 10.17 (s, 1H), 8.30 (s, 1H), 8.09 (d, J = 2.6 Hz, 1H), 7.91 (d, J = 2.6 Hz, 1H), 7.67 (s, 1H), 5.09 (p, J = 6.6 Hz, 1H), 1.42 (s, 3H), 1.24 (d, J = 6.7 Hz, 6H), 0.83 (s, 4H). [0837] Example 26.1-Methyl-1-[3-[4-[(1-methylcyclopropyl)amino]-5-(trifluoromethyl)- 2-pyrimidinyl]amino-6-oxo-1(6H)-pyridazinyl]ethyl cyanide (Compound 71). A mixture of , KOAc (0.09 g, 0.81 mmol), XantPhos (0.037 g, 0.065 mmol) and Pd2(dba)3 (0.059 g, 0.065 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.037 g (14%) of the title compound 71. 1H NMR (400 MHz, DMSO-d6), δ: 10.04 (s, 1H), 8.43 – 8.31 (m, 1H), 8.20 (s, 1H), 7.43 (s, 1H), 7.11 (d, J = 9.9 Hz, 1H), 1.85 (s, 6H), 1.32 (s, 3H), 0.88 – 0.61 (m, 4H). [0838] Example 27. 2-Cyclopentyl-5-[4-[(1-methylcyclopropyl)amino]-5- (trifluoromethyl)-2-pyrimidinyl]amino-3(2H)-pyridazinone (Compound 72). 245. ASB Brenig.24.0001.W A mixture (0.14 g, 1.25 mmol), XantPhos (0.057 g, 0.1 mmol) and Pd2(dba)3 (0.091 g, 0.1 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.042 g (11%) of the title compound 72. 1H NMR (400 MHz, DMSO-d6), δ: 10.17 (s, 1H), 8.30 (s, 1H), 8.08 (d, J = 2.5 Hz, 1H), 7.89 (d, J = 2.6 Hz, 1H), 7.67 (s, 1H), 5.30 – 5.15 (m, 1H), 2.04 – 1.83 (m, 2H), 1.83 – 1.68 (m, 4H), 1.68 – 1.52 (m, 2H), 1.42 (s, 3H), 0.83 (s, 4H). [0839] Example 28. 2-[(2R,6S)-2,6-Dimethyltetrahydro-2H-pyran-4-yl]-6-[4-[(1- methylcyclopropyl)amino]-5-(trifluoromethyl)-2-pyrimidinyl]amino-3(2H)-pyridazinone (Compound 73). A (0.096 g, 0.86 mmol), XantPhos (0.04 g, 0.069 mmol) and Pd2(dba)3 (0.063 g, 0.069 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was 246. ASB Brenig.24.0001.W subjected to prep. HPLC purification to afford 0.064 g (21%) of the title compound 73. 1H NMR (400 MHz, DMSO-d6), δ: 10.09 (s, 1H), 8.35 – 8.24 (m, 1H), 8.20 (s, 1H), 7.39 (s, 1H), 6.98 (d, J = 9.9 Hz, 1H), 5.00 (s, 1H), 4.21 – 4.06 (m, 2H), 1.82 (d, J = 14.3 Hz, 2H), 1.60 – 1.45 (m, 2H), 1.33 (s, 3H), 1.04 (d, J = 6.1 Hz, 6H), 0.83 – 0.62 (m, 4H). [0840] Example 29. 5-[4-[(1-Methylcyclopropyl)amino]-5-(trifluoromethyl)-2- pyrimidinyl]amino-2-tetrahydro-2H-pyran-4-yl-3(2H)-pyridazinone (Compound 74). A KOAc (0.09 g, 0.81 mmol), XantPhos (0.037 g, 0.065 mmol) and Pd2(dba)3 (0.059 g, 0.065 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.042 g (16%) of the title compound 74. 1H NMR (400 MHz, DMSO-d6), δ: 10.20 (s, 1H), 8.30 (s, 1H), 8.11 (d, J = 2.6 Hz, 1H), 7.91 (d, J = 2.6 Hz, 1H), 7.68 (s, 1H), 5.02 – 4.87 (m, 1H), 3.96 (dd, J = 11.3, 4.4 Hz, 2H), 3.52 – 3.35 (m, 2H), 1.87 (qd, J = 12.5, 4.7 Hz, 2H), 1.67 (dd, J = 11.8, 3.9 Hz, 2H), 1.42 (s, 3H), 0.83 (s, 4H). [0841] Example 30. 2-(2-Methoxyethyl)-5-[4-[(1-methylcyclopropyl)amino]-5- (trifluoromethyl)-2-pyrimidinyl]amino-3(2H)-pyridazinone (Compound 97). ASB Brenig.24.0001.W A mixture of compound P24 (0.29 g, 1.55 mmol), P3 (0.3 g, 1.29 mmol), KOAc (0.17 g, 1.55 mmol), XantPhos (0.074 g, 0.129 mmol) and Pd2(dba)3 (0.118 g, 0.129 mmol) in toluene (10 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.085 g (17%) of the title compound 97. 1H NMR (400 MHz, DMSO-d6), δ: 10.19 (s, 1H), 8.30 (s, 1H), 8.07 (d, J = 2.5 Hz, 1H), 7.89 (d, J = 2.5 Hz, 1H), 7.68 (s, 1H), 4.14 (t, J = 5.7 Hz, 2H), 3.64 (t, J = 5.7 Hz, 2H), 3.23 (s, 3H), 1.42 (s, 3H), 0.83 (s, 4H). [0842] Example 31. 5-[4-[(1-Methylcyclopropyl)amino]-5-(trifluoromethyl)-2- pyrimidinyl]amino-2-(tetrahydro-2-furanylmethyl)-3(2H)-pyridazinone (Compound 98). A (0.09 g, 0.81 mmol), XantPhos (0.037 g, 0.065 mmol) and Pd2(dba)3 (0.059 g, 0.065 mmol) in toluene (10 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.025 g (9%) of the title compound 98. 1H NMR (400 MHz, DMSO-d6), δ: 10.19 (s, 1H), 8.30 (s, 1H), 8.06 (d, J = 2.5 Hz, 1H), 7.89 (d, J = 2.5 Hz, 1H), 7.68 (s, 1H), 4.20 (p, J = 6.2 Hz, 1H), 4.07 (dd, J = 13.0, 7.3 Hz, 1H), 3.91 (dd, J = 13.0, 5.5 Hz, 1H), 3.75 (q, J = 7.1 Hz, 1H), 3.68 – 3.53 (m, 1H), 2.02 – 1.73 (m, 3H), 1.70 – 1.54 (m, 1H), 1.42 (s, 3H), 0.82 (s, 4H). [0843] Example 32. N-(1-Methylcyclopropyl)-N-[2-[(1-tetrahydro-2H-pyran-4-yl-1H- pyrazol-4-yl)amino]-5-(trifluoromethyl)-4-pyrimidinyl]amine (Compound 102). 248. ASB Brenig.24.0001.W A , P3 (0.2 g, 0.79 mmol), KOAc (0.11 g, 0.98 mmol), XantPhos (0.046 g, 0.079 mmol) and Pd2(dba)3 (0.072 g, 0.079 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.03 g (10%) of the title compound 102. 1H NMR (400 MHz, DMSO-d6), δ: 9.61 (s, 1H), 8.09 (s, 2H), 7.61 (s, 1H), 7.15 (s, 1H), 4.42 – 4.23 (m, 1H), 4.01 – 3.88 (m, 2H), 3.57 – 3.39 (m, 2H), 2.07 – 1.77 (m, 4H), 1.47 (s, 3H), 0.90 – 0.70 (m, 4H). [0844] Example 33. N-[1-(3-Methoxypropyl)-1H-pyrazol-4-yl]-N-[4-[(1- methylcyclopropyl)amino]-5-(trifluoromethyl)-2-pyrimidinyl]amine (Compound 103). A , g, 0.95 mmol), KOAc (0.13 g, 1.18 mmol), XantPhos (0.055 g, 0.095 mmol) and Pd2(dba)3 (0.087 g, 0.095 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.013 g 249. ASB Brenig.24.0001.W (4%) of the title compound 103. 1H NMR (400 MHz, DMSO-d6), δ: 9.61 (s, 1H), 8.10 (s, 2H), 7.58 (s, 1H), 7.16 (s, 1H), 4.09 (d, J = 6.8 Hz, 2H), 3.25 (d, J = 6.2 Hz, 2H), 3.20 (s, 3H), 1.96 (p, J = 6.5 Hz, 2H), 1.46 (s, 3H), 0.90 – 0.70 (m, 4H). [0845] Example 34. 2-Allyl-5-[4-[(1-methylcyclopropyl)amino]-5-(trifluoromethyl)-2- pyrimidinyl]amino-3(2H)-pyridazinone (Compound 112). A mixture g, , g, , KOAc (0.10 g, 0.91 mmol), XantPhos (0.042 g, 0.073 mmol) and Pd2(dba)3 (0.067 g, 0.073 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.075 g (28%) of the title compound 112. 1H NMR (400 MHz, DMSO-d6), δ: 10.20 (s, 1H), 8.30 (s, 1H), 8.09 (d, J = 2.5 Hz, 1H), 7.91 (d, J = 2.5 Hz, 1H), 7.68 (s, 1H), 6.01 – 5.85 (m, 1H), 5.21 – 5.04 (m, 2H), 4.59 (d, J = 5.6 Hz, 2H), 1.42 (s, 3H), 0.89 – 0.76 (m, 4H). [0846] Example 35. 2-Cyclopropyl-5-{[4-(methylamino)-5-(trifluoromethyl)-2- pyrimidinyl]amino}-3(2H)-pyridazinone (Compound 61). A mixture of , , Cs2CO3 (0.5 g, 1.56 mmol), XantPhos (0.045 g, 0.078 mmol) and Pd(OAc)2 (0.008 g, 0.039 mmol) in toluene (5 mL) was subjected to microwave irradiation at 110°C for 2 h, was then diluted 250. ASB Brenig.24.0001.W with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.011 g (4 %) of the title compound 61. [0847] Example 36. 1-Methyl-1-[4-[4-(methylamino)-5-(trifluoromethyl)-2- pyrimidinyl]amino-6-oxo-1(6H)-pyridazinyl]ethyl cyanide (Compound 106). A mixture KOAc (0.105 g, 0.94 mmol), XantPhos (0.045 g, 0.078 mmol) and Pd2(dba)3 (0.071 g, 0.078 mmol) in toluene (10 mL) was subjected to microwave irradiation at 110°C for 4 h, was then diluted with EA (10 mL) and water (10 mL), layers were separated, organic layer was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to prep. HPLC purification to afford 0.068 g (25%) of the title compound 106. 1H NMR (400 MHz, DMSO-d6), δ: 10.30 (s, 1H), 8.33 (s, 1H), 8.13 (d, J = 2.5 Hz, 1H), 7.57 (d, J = 2.5 Hz, 1H), 7.54 – 7.45 (m, 1H), 2.95 (s, 3H), 1.84 (s, 6H). [0848] Example 37. N4-(1-Isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N2-(1- methylcyclopropyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 42). Through a , (110 mg, 0.437 mmol) and Cs2CO3 (284 mg, 0.874 mmol) in toluene (5 ml) Ar was bubbled for 5 min. 251. ASB Brenig.24.0001.W Then Pd(OAc)2 (5 mg, 0.022 mmol) and XantPhos (25 mg, 0.044 mmol) were added and the mixture was stirred in capped tube at 80°C for a 16 h. The mixture was cooled, diluted with EA (10 ml), washed with water. Then was dried under Na2SO4 and concentrated to give a residue. The residue was purified by silica gel CC (DCM-Et2O 10-1 to 5-1) to give compound 42 (31 mg, 18% yield) as slight brown solid. [0849] Example 38. N4-[1-(2,2-difluoroethyl)-5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl]- N2-(1-methylcyclopropyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 39). The in Example 37 with 17% yield as slightly brown solid. 1H NMR (400 MHz, DMSO-d6), δ: 8.36-8.14 (m, 3H), 7.98-7.89 (m, 2H), 7.71-7.48 (m, 1H), 7.14 (dd, J1=7.9 Hz, J2=4.9 Hz, 1H), 6.58-6.25 (m, 1H), 4.76-4.69 (m, 2H), 1.32-1.06 (m, 3H), 0.57-0.52 (m, 2H), 0.33-0.27 (m , 2H). [0850] Example 39. Other examples of the final compounds from the Table 4 were prepared using the procedures described herein directly or with slight modifications. 1H- NMR spectra for these compounds are presented in the Table 6. [0851] Table 6. Compound Yield, % 1H NMR (400 MHz, DMSO-d6), δ ), , , ) 252. ASB Brenig.24.0001.W Compound Yield, % 1H NMR (400 MHz, DMSO-d6), δ 10.05 (br. 1H) 8.53 (d J=7.7 Hz 1H) 8.33-8.31 (m 2H) 3 0 , ) 0 ), , ), , ) Biological Assays [0852] Example A. Primary Assays Used to Determine Potency of the LRRK2 Inhibition. Assay for determining enzymatic activity inhibition against LRRK2[G2019S]. Compound activity was determined using recombinant LRRK2[G2019S] protein (SignalChem Biotech, Inc., Cat# L10-12GG-10) and LRRKtide substrate (SignalChem Biotech, Inc., Cat#L10-58) in an in vitro enzymatic reaction. The enzymatic reaction was carried out in assay buffer (40 mM TRIS-HCl pH 7.4, 20 mM MgCl2, 0.05 mM DTT, 0.1 mg/mL BSA). The compounds were dispensed into a 384 well Diamond Well Plate (Axigen, Cat# P-384-120SQ-C-S) using the Biomek FX liquid handling system at the 80x 253. ASB Brenig.24.0001.W solutions of compounds in DMSO. The 2x Protein-Substrate mix (final concentration 36 nM of LRRK2[G2019S] and 0.8 µg/µL of LRRKtide) was prepared in 1x Assay buffer and 4 µL of mixture per well was added into the 384-well white Reaction plate with NBS (Corning, Cat#CLS4513). The 4 µL of LRRKtide substrate w/o LRRK2[G2019S] in the 1x buffer was used for a negative control. Plates were centrifuged for 1 min at 200 g. Next the compounds were added to the reaction plate using Biomek station via following steps: 1 µL of 80x compounds (in DMSO) were mixed thoroughly with 39 µL of 2x 10 µM ATP in Assay Buffer, then 4 µL of this mixture was added to Reaction plate with 4 µL of Protein- Substrate mix. Plates were centrifuged for 1 min at 200 g and incubated for 1 h at rt. Then, 4 µL per well of ADP-Glo reagent (Promega, ADP-Glo™ Kinase Assay, Cat# V9102) was added. Plates were incubated for 30 min at rt. Then, 8 µL per well of Kinase detection reagent (Promega, ADP-Glo™ Kinase Assay, Cat# V9102) was added and the luminescence signal was measured with a microplate reader. The luminescence signal was detected with CLARIOstar Plus (BMG LABTECH) microplate reader. The % inhibition was then used to calculate the Ki values. The average Ki values are shown in Table A, wherein “A” corresponds to Ki≤10.0 nM, “B” corresponds to 10.0 nM<Ki≤50.0 nM, “C” 50.0 nM<Ki≤100.0 nM, “D” corresponds to 100.0 nM<Ki≤500.0 nM and “E” corresponds to Ki>500.0 nM. [0853] Table A: LRRK2 (G2019S) Activity Inhibition Assays Compound Compound Comp nM* ound Ki, Ki, nM* Ki, nM* N mb r N mb r N mb r 254. ASB Brenig.24.0001.W Compound * Compound * Compound Ki * Number , nM Number Ki, nM Number Ki, nM Ki tor present. Ki: A ≤ 10 nM; 10 nM < B ≤ 50 nM; 50 nM < C ≤ 100 nM; 100 nM < D ≤ 500 nM; E > 500 nM. [0854] Example B. Primary Assays Used to Determine Potency of the LRRK2 Inhibition. Assay for determining enzymatic activity inhibition against LRRK2 WT. Compound activity was determined using recombinant LRRK2 WT protein (SignalChem Biotech, Inc., Cat#L10-11G-10) and LRRKtide substrate (SignalChem Biotech, Inc., Cat#L10-58) in an in vitro enzymatic reaction. The enzymatic reaction was carried out in assay buffer (40 mM TRIS-HCl pH 7.4, 20 mM MgCl2, 0.05 mM DTT, 0.1 mg/mL BSA). The compounds were dispensed into a 384 well Diamond Well Plate (Axigen, Cat# P-384- 120SQ-C-S) using the Biomek FX liquid handling system at 80x solutions of compounds in DMSO. The 2x Protein-Substrate mix (final concentration 36 nM of LRRK2 WT and 0.8 µg/µL of LRRKtide) was prepared in the 1x Assay buffer and 4 µL of mixture per well was added into the 384-well white Reaction plate with NBS (Corning, Cat#CLS4513). The 4 µL of LRRKtide substrate w/o LRRK2 WT in the 1x buffer was used for a negative control. Plates were centrifuged for 1 min at 200 g. Next the compounds were added to Reaction plate using Biomek station via following steps: 1 µL of 80x compounds (in DMSO) were mixed thoroughly with 39 µL of 2x 10 µM ATP in Assay Buffer, then 4 µL of this mixture was added to Reaction plate with 4 µL of Protein-Substrate mix. Plates were centrifuged for 1 min at 200 g and incubated for 1 h at rt. Then, 4 µL per well of ADP-Glo reagent (Promega, ADP-Glo™ Kinase Assay, Cat# V9102) was added. Plates were incubated for 30 minutes at rt. Then, 8 µL per well of Kinase detection reagent (Promega, 255. ASB Brenig.24.0001.W ADP-Glo™ Kinase Assay, Cat# V9102) was added and the luminescence signal was measured with a microplate reader. The % inhibition was then used to calculate the Ki values. The average Ki values are shown in Table B, wherein “A” corresponds to Ki≤10.0 nM, “B” corresponds to 10.0 nM<Ki≤50.0 nM, “C” 50.0 nM<Ki≤100.0 nM, “D” corresponds to 100.0 nM<Ki≤500.0 nM and “E” corresponds to Ki>500.0 nM. [0855] Table B: LRRK2 (WT) Activity Inhibition Assays Compound * Compound * Compound Ki, nM Ki, nM Ki, nM* Number Number Number Ki values are determined through a series of experiments with varying amounts of inhibitor present. Ki: A ≤ 10 nM; 10 nM < B ≤ 20 nM; 20 nM < C ≤ 50 nM; 50 nM < D ≤ 100 nM; E > 100 nM [0856] Example C. Pharmacokinetics in mice. [0857] Table C: Pharmacokinetics in mice. 256. ASB Brenig.24.0001.W PK in mouse plasma, PO, 10 mg/kg Compound # Cmax, AUClast, Fabs, Example of Pharmaceutical composition: 1000 Tablets Component Mass, g Component Mass, g Component Mass, g C d I 5 L t 30 Sili 1 Equivalents [0858] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims. 257. ASB

Claims

Brenig.24.0001.W CLAIMS What is claimed is: 1. A compound of Formula (I): , or a pharmaceutically prodrug, isotopic derivative, or tautomer thereof, wherein , , A are CR4; B is selected from CH and N, provided that anyone from B is N, and another B is CH; E is selected from CH and N, provided that anyone from E is N, and another E is CH; 258. ASB Brenig.24.0001.W U is selected from CRBRC and NRB; each G is independently selected from O, S, S(O), S(O)2, NH; RA is H; or RA and Rc together form a bond; Rd is H; or Rc and Rd together form =O; RB is H; or RA and RB together form a bond; RC is H; Ra is H; Rb is H; and Rc and Rd together form =O; or Ra and Rd together with the atoms to which they are attached, may come together to form 5-7 membered cycloalkyl or heterocycle, wherein cycloalkyl or heterocycle optionally substituted with one or more substitutients independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl; and Rb and Rc together form a bond; Re is selected from H, -(CH2)n-NR6R7, -(CH2)n-OR6; Rf is H; Rg is H; or Rf and Rg together form a bond; Rh is H; or Re and Rh together with the atoms to which they are attached, may come together to form 5-7 membered heterocycle, optionally substituted with one or more substitutients independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, -(CH2)n- aryl and heteroaryl; R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; 259. ASB Brenig.24.0001.W R2 is selected ; each R3 is C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl- S(O)2-, heterocycle, aryl, and heteroaryl; each R4 is independently selected from H, OH, halogen, CN, C1-C6 alkyl, C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl, and heterocycle; R5 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl; R6 is selected from H, C1-C6 alkyl; R7 is selected from OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C(O)-; each R8 is independently selected from H, halogen, OH, NH2, CN, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl; or any two R8 together form C1-C3 alkanediyl; each R9 is independently selected from H, C1-C6 alkyl; or 260. ASB Brenig.24.0001.W two R9 together form C1-C3 alkanediyl; or any one R8 and any one R9 together form C1-C3 alkanediyl; R10 is selected from C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the cycloalkyl, heterocycle, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl; R11 is selected from SO2C1-C6 alkyl, halogen, C1-C6 alkoxy; R12 is selected from C1-C6 alkyl substituted with one or more substitutients independently selected from N(R14)2, -CN; or R11 and R12 together with the atoms to which they are attached, may come together to form 5-7 membered heterocycle, optionally substituted with one or more substitutients independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, -(CH2)n- aryl and heteroaryl; R13 is halogen; each R14 is independently selected from H and C1-C6 alkyl; each R15 is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl- S(O)2-, heterocycle, aryl, and heteroaryl; k is an integer selected from 0 and 1; each m is an integer independently selected from 1, 2, and 3; n is an integer selected from 0, 1, 2, 3, 4, 5, and 6; p is an integer selected from 0, 1, 2, and 3; u is an integer selected from 0, 1 and 2; q is an integer selected from 1, 2, and 3; r is an integer selected from 1, 2, and 3; wherein, 261. ASB Brenig.24.0001.W aryl is cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings; heterocyclyl is saturated or partially unsaturated 3–10 membered monocyclic, 7– 12 membered bicyclic (fused, bridged, or spiro rings), or 11–14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms selected from O, N, S, P, Se, or B; heteroaryl is a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C. 2. The compound of claim 1, wherein the compound is of Formula (A): , or a pharmaceutically solvate, or tautomer thereof, wherein each A is independently selected from CR4 and N; B is selected from CH and N, provided that anyone from B is N, and another B is CH; R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; R2 is selected ; 262. ASB Brenig.24.0001.W R3 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl-S(O)2-, heterocycle, aryl, and heteroaryl; each R4 is independently selected from H, OH, halogen, CN, C1-C6 alkyl, C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl, and heterocycle. 3. The compound of claim 1, wherein the compound is of Formula (B): F3C , or a pharmaceutically solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; E is selected from CH and N, provided that anyone from E is N, and another E is CH; R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; 263. ASB Brenig.24.0001.W R2 is selected ; R3 is selected C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl-S(O)2-, heterocycle, aryl, and heteroaryl; R5 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl; u is an integer selected from 0, 1 and 2. 4. The compound of claim 1, wherein the compound is of Formula (C): , or a pharmaceutically solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; U is selected from CRBRC and NRB; 264. ASB Brenig.24.0001.W RA is H; RB is H; or RA and RB together form a bond; RC is H; Ra is H; Rb is H; and Rc and Rd together form =O; or Ra and Rd together with the atoms to which they are attached, may come together to form 5-7 membered cycloalkyl or heterocycle, wherein cycloalkyl or heterocycle optionally substituted with one or more substitutients independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl; and Rb and Rc together form a bond; R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; R2 is selected ; R3 is selected C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl-S(O)2-, heterocycle, aryl, and heteroaryl. 5. The compound of claim 1, wherein the compound is of Formula (D): 265. ASB Brenig.24.0001.W , or a pharmaceutically solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; RA is H; or RA and Rc together form a bond; Rd is H; or Rc and Rd together form =O; RD is selected from H and C1-C6 alkyl; R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; R2 is selected ; R3 is selected C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl-S(O)2-, heterocycle, aryl, and heteroaryl. 6. The compound of claim 1, wherein the compound is of Formula (E): 266. ASB Brenig.24.0001.W , or a pharmaceutically or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; Re is selected from H, -(CH2)n-NR6R7, -(CH2)n-OR6; Rf is H; Rg is H; or Rf and Rg together form a bond; Rh is H; or Re and Rh together with the atoms to which they are attached, may come together to form 5-7 membered heterocycle, optionally substituted with one or more substitutients independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, -(CH2)n- aryl and heteroaryl; R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; R2 is selected ; R6 is selected 267. ASB Brenig.24.0001.W R7 is selected from OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C(O)-; n is an integer selected from 0, 1, 2, 3, 4, 5, and 6. 7. The compound of claim 1, wherein the compound is of Formula (F): , or a pharmaceutically solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; R2 is selected ; each R8 is halogen, OH, NH2, CN, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl; or any two R8 together form C1-C3 alkanediyl; 268. ASB Brenig.24.0001.W each R9 is independently selected from H, C1-C6 alkyl; or two R9 together form C1-C3 alkanediyl; or any one R8 and any one R9 together form C1-C3 alkanediyl; R10 is selected from C3-C10 cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the cycloalkyl, heterocycle, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, and heteroaryl; each m is an integer independently selected from 1, 2, and 3. 8. The compound of claim 1, wherein the compound is of Formula (G): , or a pharmaceutically solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; R2 is selected ; 269. ASB Brenig.24.0001.W R11 is selected from SO2C1-C6 alkyl, halogen, C1-C6 alkoxy; R12 is selected from C1-C6 alkyl substituted with one or more substitutients independently selected from N(R14)2, -CN; or R11 and R12 together with the atoms to which they are attached, may come together to form 5-7 membered heterocycle, optionally substituted with one or more substitutients independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, heterocycle, aryl, -(CH2)n- aryl and heteroaryl; R13 is halogen; each R14 is independently selected from H and C1-C6 alkyl; k is an integer selected from 0 and 1. 9. The compound of claim 1, wherein the compound is of Formula (H): , or a pharmaceutically solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; 270. ASB Brenig.24.0001.W R2 is selected ; R3 is selected C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl-S(O)2-, heterocycle, aryl, and heteroaryl. 10. The compound of claim 1, wherein the compound is of Formula (J): , or a pharmaceutically solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; 271. ASB Brenig.24.0001.W R2 is selected ; R3 is selected C2-C6 alkynyl, C3-C10 cycloalkyl, heterocycle, aryl, and alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl-S(O)2-, heterocycle, aryl, and heteroaryl. 11. The compound of claim 1, wherein the compound is of Formula (K): , or a pharmaceutically solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; 272. ASB Brenig.24.0001.W R2 is selected ; each R15 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl- S(O)2-, heterocycle, aryl, and heteroaryl. 12. The compound of claim 1, wherein the compound is of Formula (L): , or a pharmaceutically solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; each G is independently selected from O, S, S(O), S(O)2, NH; R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; 273. ASB Brenig.24.0001.W R2 is selected ; each R3 is C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl- S(O)2-, heterocycle, aryl, and heteroaryl; p is an integer selected from 0, 1, 2, and 3. 13. The compound of claim 1, wherein the compound is of Formula (M): , or a pharmaceutically solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; G is selected from O, S, S(O), S(O)2, NH; R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; 274. ASB Brenig.24.0001.W R2 is selected ; each R3 is C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, wherein the alkyl, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl- S(O)2-, heterocycle, aryl, and heteroaryl; q is an integer selected from 1, 2, and 3; r is an integer selected from 1, 2, and 3. 14. Another aspect of the invention relates to compounds of Formula (N): , or a pharmaceutically solvate, or tautomer thereof, wherein B is selected from CH and N, provided that anyone from B is N, and another B is CH; R1 is selected from C1-C6 alkyl, and C3-C10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; 275. ASB Brenig.24.0001.W R2 is selected ; R16 is selected C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, the alkyl, alkenyl, alkynyl, alkoxy, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-C(O)-, C1-C6 alkyl- S(O)2-, heterocycle, aryl, and heteroaryl; wherein, aryl is cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings; heterocyclyl is saturated or partially unsaturated 3–10 membered monocyclic, 7– 12 membered bicyclic (fused, bridged, or spiro rings), or 11–14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms selected from O, N, S, P, Se, or B; heteroaryl is a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C. 15. A compound is selected from: # Compound IUPAC name )- 276. ASB Brenig.24.0001.W # Compound IUPAC name - - - - - e- )- - - - - - 277. ASB Brenig.24.0001.W # Compound IUPAC name N2-(6-fluoro-23- - - )- - - 278. ASB Brenig.24.0001.W # Compound IUPAC name - - o- - - - - 279. ASB Brenig.24.0001.W # Compound IUPAC name F3 C HN b- - - o- - - 280. ASB Brenig.24.0001.W # Compound IUPAC name N4-methyl-N2-[3- - - l- 281. ASB Brenig.24.0001.W # Compound IUPAC name l- 282. ASB Brenig.24.0001.W # Compound IUPAC name 2-methyl-2-[3-[[2-[(1- - ]- l- - ]- 283. ASB Brenig.24.0001.W # Compound IUPAC name ]- - - - - - - - 284. ASB Brenig.24.0001.W # Compound IUPAC name - )- l- 285. ASB Brenig.24.0001.W # Compound IUPAC name l- l- l- 286. ASB Brenig.24.0001.W # Compound IUPAC name l- l- - )- 4- l- 5- - - 287. ASB Brenig.24.0001.W # Compound IUPAC name CF 5-[[4-[(1- - - 288. ASB Brenig.24.0001.W # Compound IUPAC name - - l- l- 289. ASB Brenig.24.0001.W # Compound IUPAC name 290. ASB Brenig.24.0001.W # Compound IUPAC name 2-[(2S 6R)-26- - ]- l- - ]- ]- - - - - 291. ASB Brenig.24.0001.W # Compound IUPAC name - - - - - - 292. ASB Brenig.24.0001.W # Compound IUPAC name - - - - ]- - 1- - ]- - 293. ASB Brenig.24.0001.W # Compound IUPAC name - 5- - - - - - - - - 294. ASB Brenig.24.0001.W # Compound IUPAC name N - - 3- - 3- - - 295. ASB Brenig.24.0001.W # Compound IUPAC name 4 1 l- l- l- - )- 4- 296. ASB Brenig.24.0001.W # Compound IUPAC name l- 5- - - )- l- 297. ASB Brenig.24.0001.W # Compound IUPAC name - 4- - - - - - - - - 298. ASB Brenig.24.0001.W # Compound IUPAC name )- - - - 4- - 299. ASB Brenig.24.0001.W # Compound IUPAC name N2-[1- ]- - - - - - 1- - - 5- - 300. ASB Brenig.24.0001.W # Compound IUPAC name N2-(1-cyclopropyl-7-methyl- - - - - - - 5- - - - - 301. ASB Brenig.24.0001.W # Compound IUPAC name - - ]- 4- - - - ]- - - - 302. ASB Brenig.24.0001.W # Compound IUPAC name l- 5- - 303. ASB Brenig.24.0001.W # Compound IUPAC name ]- - - - 304. ASB Brenig.24.0001.W # Compound IUPAC name - - - - 305. ASB Brenig.24.0001.W # Compound IUPAC name N2-[7-(22- - , , , . 16. A pharmaceutical composition comprising the compound of any one of claims 1– 15 or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, and a pharmaceutically acceptable carrier. 17. The pharmaceutical composition of claim 16, further comprising one or more additional pharmaceutically active agents. 18. A method of inhibiting of LRRK2 in a cell, comprising contacting the cell with a compound of any one of claims 1–15 or a pharmaceutical composition of claim 16 or 17. 19. A method for the treatment or prevention of a disease or disorder associated with LRRK2 comprising administering to a subject in need thereof a compound of any one of claims 1–15 or a pharmaceutical composition of claim 16 or 17. 20. The method of claim 19, wherein the disease or disorder is selected from the group consisting of Parkinson Disease 8, Autosomal Dominant (PARK8); Hereditary Late-Onset Parkinson Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant (KFS1); Autosomal Dominant Cerebellar Ataxia (SCA); Parkinson Disease, Late-Onset (PD); Parkinson Disease 2, Autosomal Recessive Juvenile (PARK2); Parkinsonism; Rem Sleep Behavior Disorder; Dementia, Lewy Body (DLB); Lrrk2 Parkinson Disease; Parkinson Disease 3, Autosomal Dominant (PARK3); Early-Onset Parkinson's Disease; Multiple System Atrophy 1 (MSA1); Essential Tremor; Movement Disease; Supranuclear Palsy, Progressive, 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson Disease 10 (PARK10); Tremor; Frontotemporal Dementia (FTD); 306. ASB Brenig.24.0001.W Postencephalitic Parkinson Disease; Vascular Parkinsonism; Aphasia; Parkinson Disease 1, Autosomal Dominant (PARK1); Athetosis; Klippel-Feil Syndrome (KFS); Kufor-Rakeb Syndrome (KRS); Leprosy 3 (LPRS3); Alzheimer Disease 8 (AD8); Crohn's Disease; Rheumatoid Arthritis (RA); Alzheimer Disease (AD); Color Agnosia; Gaucher Disease, Type I (GD1); Parkinson Disease 15, Autosomal Recessive Early-Onset (PARK15); Von Economo's Disease; Gerstmann-Straussler Disease (GSD); Amyotrophic Lateral Sclerosis- Parkinsonism/dementia Complex 1 (ALS-PDC1); Dystonia; Sphingolipidosis; Radial Nerve Lesion; Toxic Encephalopathy; Sleep Disorder; Pick Disease of Brain (PIDB); Ophthalmomyiasis; Gaucher's Disease (GD); Optic Atrophy 7 with or Without Auditory Neuropathy (OPA7); Ulnar Nerve Lesion; Inflammatory Bowel Disease 4 (IBD4); Inflammatory Bowel Disease; 3-Methylglutaconic Aciduria, Type Iii (MGCA3); Nervous System Disease; Amyotrophic Lateral Sclerosis 1 (ALS1); Mitochondrial Complex I Deficiency, Nuclear Type 1 (MC1DN1). 21. The method of claim 20, wherein the disease or disorder is Parkinson Disease (PD). 22. The method of any one of claims 18-21, wherein the subject is a mammal. 23. The method of claim 22, wherein the subject is a human. 307. ASB
PCT/US2025/028256 2024-05-08 2025-05-07 Lrrk2 inhibitors Pending WO2025235687A1 (en)

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