WO2023196720A2 - Lrrk2 inhibitors - Google Patents

Lrrk2 inhibitors Download PDF

Info

Publication number
WO2023196720A2
WO2023196720A2 PCT/US2023/063745 US2023063745W WO2023196720A2 WO 2023196720 A2 WO2023196720 A2 WO 2023196720A2 US 2023063745 W US2023063745 W US 2023063745W WO 2023196720 A2 WO2023196720 A2 WO 2023196720A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
compound
pharmaceutically acceptable
solvate
tautomer
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.)
Ceased
Application number
PCT/US2023/063745
Other languages
English (en)
French (fr)
Other versions
WO2023196720A3 (en
Inventor
Volodymyr KYSIL
Vladislav Zenonovich PARCHINSKY
Alexei Pushechnikov
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
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority to JP2024559442A priority Critical patent/JP2025511875A/ja
Priority to KR1020247036645A priority patent/KR20240171138A/ko
Priority to CA3247536A priority patent/CA3247536A1/en
Priority to EP23785521.8A priority patent/EP4504722A4/en
Priority to AU2023249498A priority patent/AU2023249498B2/en
Priority to CN202380040105.7A priority patent/CN119183452A/zh
Application filed by Brenig Therapeutics Inc filed Critical Brenig Therapeutics Inc
Priority to US18/854,031 priority patent/US20250248998A1/en
Publication of WO2023196720A2 publication Critical patent/WO2023196720A2/en
Publication of WO2023196720A3 publication Critical patent/WO2023196720A3/en
Priority to MX2024012306A priority patent/MX2024012306A/es
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K31/33—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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems

Definitions

  • LRRK2 Inhibitors FIELD OF INVENTION [0001]
  • 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).
  • 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.
  • LRRK2 Leucine-rich repeat kinase 2
  • LRRK2 is a crucial factor to understanding the etiology of PD.
  • LRRK2 is a large, widely expressed, multi-domain and multifunctional protein.
  • LRRK2 mutations are the major cause to inherited and sporadic PD.
  • wild-type LRRK2 is also considered as a potential target.
  • LRRK2 mutations, and particularly the most common mutation Gly2019Ser are observed in patients with autosomal dominant PD and in those with apparent sporadic PD, who are clinically indistinguishable from those with idiopathic PD.
  • LRRK2 pathogenic mutations in the LRRK2 gene increase LRRK2 kinase activity and that small-molecule LRRK2 kinase inhibitors can be neuroprotective in preclinical models of PD have placed LRRK2 at the centre of disease modification efforts in PD.
  • LRRK2 controls multiple processes in brain immune cells, microglia and astrocytes, and suggests that deregulated LRRK2 activity in these cells, due to gene mutation, might be directly associated with pathological mechanisms underlying PD.
  • LRRK2 has a role in the pathogenesis of idiopathic PD and that LRRK2 therapies (LRRK2 mutated and wild) might, therefore, be beneficial in this common subtype of PD.
  • DBS deep brain stimulation
  • STN subthalamic nucleus
  • Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (I), 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 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 (I), 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 (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the present invention relates to compounds of Formula (I), 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 of Formula (I), 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 of Formula (I), 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 Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • a compound of Formula (I) 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 Formula (I), 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 Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • 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 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 (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • 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 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 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. 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.
  • 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, (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, —C(O)(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. [0031] 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-(C1-C6)alkyl, (C1-C6)alkyl, – O-(C 2 -C 6 )alkenyl, –O-(C 2 -C 6 ) alkynyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )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
  • 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, 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 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 C 1 -C 6 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-, - CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, 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 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.
  • heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl.
  • 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 (C 3 -C 12 ) spirocycloalkyl is a spirocycle containing between 3 and 12 carbon atoms.
  • 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.
  • suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH.
  • Solvates wherein water is the solvent molecule are typically referred to as hydrates. 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).
  • 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.
  • treating 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.
  • LRRK2 inhibitor refer to compounds of Formula I and/or compositions comprising a compound of Formula I 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
  • 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 [0064]
  • the present disclosure provides compounds of Formula (I) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: (I), Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , V, W, X, Y, Z, Q, m, n, r and u as described herein.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , V, W, X, Y, Z, Q, m, n, r and u can each be, where applicable, selected from the groups described herein, and any group described herein for any R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , V, W, X, Y, Z, Q, m, n, r and u can be combined, where applicable, with any group described herein for one or more of the remainder of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , V, W, X, Y, Z, Q, m, n, r and u.
  • V is C or N. In some embodiments, V is C. In some embodiments, V is N.
  • W is C or N. In some embodiments, W is C. In some embodiments, W is N.
  • V is N, bond V N is a single bond, bond W N is a double bond, W is C.
  • V is C, bond V N is a double bond, bond W N is a single bond, W is N.
  • X is CR 8 or N. In some embodiments, X is CR 8 . In some embodiments, X is N.
  • R 1 is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, heterocycle, aryl, heteroaryl, NR 10 R 11 , and S(O) 2 R 12 wherein the alkyl, alkoxy, 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
  • R 1 is hydrogen. [0090] In some embodiments, R 1 is halogen. [0091] In some embodiments, R 1 is F. In some embodiments, R 1 is Cl. In some embodiments, R 1 is Br. In some embodiments, R 1 is I. [0092] In some embodiments, R 1 is F. [0093] In some embodiments, R 1 is C 1 -C 6 alkyl. [0094] In some embodiments, R 1 is -CH 3 . In some embodiments, R 1 is -CH 2 CH 3 . In some embodiments, R 1 is -CH2CH2CH3. In some embodiments, R 1 is -CH(CH3)2. [0095] In some embodiments, R 1 is methyl.
  • R 1 is -CH 2 F. In some embodiments, R 1 is -CHF 2 . In some embodiments, R 1 is -CF3. [0097] In some embodiments, R 1 is C1-C6 alkoxy. [0098] In some embodiments, R 1 is -OCH 3 . In some embodiments, R 1 is -OCH 2 CH 3 . In some embodiments, R 1 is -OCH2CH2CH3. In some embodiments, R 1 is -OCH(CH3)2. [0099] In some embodiments, R 1 is -OMe. [0100] In some embodiments, R 1 is methoxy. [0101] In some embodiments, R 1 is -OCH(CH 3 ) 2 .
  • R 1 is iso-propoxy. [0103] In some embodiments, R 1 is -OC(CH3)3. [0104] In some embodiments, R 1 is -OCF 3 . In some embodiments, R 1 is -OCF 2 CF 3 .
  • R 1 and R 2 together with the atoms to which they are attached and intervening atoms form a 5 membered heterocycle, comprising one heteroatom selected from O, N, S.
  • R 1 and R 2 together with the atoms to which they are attached and intervening atoms form a 5 membered heterocycle, comprising one heteroatom – O.
  • R 1 and R 2 together with the atoms to which they are attached and intervening atoms form a 6 membered heterocycle, comprising one heteroatom selected from O, N, S.
  • R 1 and R 2 together with the atoms to which they are attached and intervening atoms, form a 6 membered heterocycle, comprising one heteroatom – O. [0110] In some embodiments, R 1 and R 2 together with the atoms to which they are attached and intervening atoms, form . [0111] In some embodiments, R 2 is H. In some embodiments, R 2 is halogen.
  • R 2 is NR 10 R 11 .
  • R 2 is S(O) 2 R 12 .
  • R 2 is H.
  • R 2 is C1-C6 alkyl.
  • R 2 is methyl.
  • R 2 is ethyl. In some embodiments, R 2 is propyl. In some embodiments, R 2 is n-propyl. In some embodiments, R 2 is isopropyl. In some embodiments, R 2 is butyl. In some embodiments, R 2 is n-butyl. In some embodiments, R 2 is iso-butyl. In some embodiments, R 2 is sec-butyl. In some embodiments, R 2 is tert-butyl. In some embodiments, R 2 is pentyl. In some embodiments, R 2 is hexyl. [0115] In some embodiments, R 2 is C1-C6 alkyl substituted with one or more halogen.
  • R 2 is C 1 -C 6 alkyl substituted with one or more F.
  • R 2 is -CH2F. In some embodiments, R 2 is -CHF2. In some embodiments, R 2 is -CF3. In some embodiments, R 2 is -CF2CH3. In some embodiments, R 2 is -CH 2 CF 3 . In some embodiments, R 2 is -CF 2 CF 3 . In some embodiments, R 2 is -CF2CH(CH3)2. [0118] In some embodiments, R 2 is . [0119] In some embodiments, R 2 is C1-C6 alkyl substituted with one or more CN.
  • R 2 is -CH 2 CN. In some embodiments, R 2 is -CH(CH 3 )CN. In some embodiments, R 2 is -C(CH 3 ) 2 CN. [0121] In some embodiments, R 2 is . [0122] In some embodiments, R 2 is . [0123] In some embodiments, R 2 is C 1 -C 6 alkoxy. [0124] In some embodiments, R 2 is -OCH3. In some embodiments, R 2 is -OCH2CH3. In some embodiments, R 2 is -OCH2CH2CH3. In some embodiments, R 2 is -OCH(CH3)2.
  • R 2 is -OCH 2 CH 2 CH 2 CH 3 . In some embodiments, R 2 is -OCH 2 CH(CH 3 ) 2 . In some embodiments, R 2 is -OCH(CH 3 )CH 2 CH 3 . In some embodiments, R 2 is -OC(CH3)3. [0125] In some embodiments, R 2 is -OCH(CH 3 ) 2 . [0126] In some embodiments, R 2 is is iso-propoxy. [0127] In some embodiments, R 2 is -OC(CH3)3. [0128] In some embodiments, R 2 is tert-butoxy. [0129] In some embodiments, R 2 is C 1 -C 6 alkoxy substituted with one or more halogen.
  • R 2 is -OCH 2 F. In some embodiments, R 2 is -OCHF 2 . In some embodiments, R 2 is -OCF3. In some embodiments, R 2 is -OCF2CH3. In some embodiments, R 2 is -OCH2CF3. In some embodiments, R 2 is -OCF2CF3. [0131] In some embodiments, R 2 is . [0132] In some embodiments, R 2 is . [0133] In some embodiments, R 2 is C 3 -C 10 monocyclic cycloalkyl. [0134] In some embodiments, R 2 is cyclopropyl. In some embodiments, R 2 is cyclobutyl.
  • R 2 is cyclopentyl. In some embodiments, R 2 is cyclohexyl. In some embodiments, R 2 is cycloheptyl. [0135] In some embodiments, R 2 is C 3 -C 10 monocyclic cycloalkyl substituted with one or more halogen. [0136] In some embodiments, R 2 is C 3 -C 10 monocyclic cycloalkyl substituted with one or more F. [0137] In some embodiments, R 2 is C3-C10 monocyclic cycloalkyl substituted with one halogen. [0138] In some embodiments, R 2 is C 3 -C 10 monocyclic cycloalkyl substituted with one F.
  • R 2 is cyclopropyl substituted with one F. In some embodiments, R 2 is cyclobutyl substituted with one F. In some embodiments, R 2 is cyclopentyl substituted with one F. In some embodiments, R 2 is cyclohexyl substituted with one F. In some embodiments, R 2 is cycloheptyl substituted with one F. [0140] In some embodiments, R 2 is . [0141] In some embodiments, R 2 is C3-C10 monocyclic cycloalkyl substituted with one or more CN. [0142] In some embodiments, R 2 is C 3 -C 10 monocyclic cycloalkyl substituted with one CN.
  • R 2 is cyclopropyl substituted with one -CN. In some embodiments, R 2 is cyclobutyl substituted with one -CN. In some embodiments, R 2 is cyclopentyl substituted with one -CN. In some embodiments, R 2 is cyclohexyl substituted with one -CN. In some embodiments, R 2 is cycloheptyl substituted with one -CN. [0144] In some embodiments, R 2 is . [0145] In some embodiments, R 2 is . [0146] In some embodiments, R 2 is . [0147] In some embodiments, R 2 is . [0148] In some embodiments, R 2 is .
  • R 2 is . [0150] In some embodiments, R 2 is . [0151] In some embodiments, R 2 is . [0152] In some embodiments, R 2 is C3-C10 cycloalkoxy. [0153] In some embodiments, R 2 is cyclopropoxy. In some embodiments, R 2 is cyclobutoxy. In some embodiments, R 2 is cyclopentoxy. In some embodiments, R 2 is cyclohexoxy. In some embodiments, R 2 is cycloheptoxy. [0154] In some embodiments, R 2 is . [0155] In some embodiments, R 2 is . [0156] In some embodiments, R 2 is .
  • R 2 is . [0158] In some embodiments, R 2 is C3-C10 cycloalkoxy substituted with one or more C1- C 6 alkyl. [0159] In some embodiments, R 2 is C 3 -C 10 cycloalkoxy substituted with one C 1 -C 6 alkyl. [0160] In some embodiments, R 2 is C3-C10 cycloalkoxy substituted with one methyl. [0161] In some embodiments, R 2 is . [0162] In some embodiments, R 2 is . [0163] In some embodiments, R 2 is . [0164] In some embodiments, R 2 is . [0165] In some embodiments, R 2 is .
  • R 2 is . [0167] In some embodiments, R 2 is . [0168] In some embodiments, R 2 is . [0169] In some embodiments, R 2 is . [0170] In some embodiments, R 2 is . [0171] In some embodiments, R 2 is . [0172] In some embodiments, R 2 is . [0173] In some embodiments, R 2 is heterocycle.
  • R 2 is .
  • R 2 is .
  • R 2 is heteroaryl comprising at least one heteroatom selected from N, O, S.
  • R 2 is 5-membered heteroaryl.
  • R 2 is 6-membered heteroaryl.
  • R 2 is 5-membered heteroaryl comprising O.
  • R 2 is 5-membered heteroaryl comprising N.
  • R 2 is 5-membered heteroaryl comprising S.
  • R 2 is 5-membered heteroaryl comprising O and N. [0189] In some embodiments, R 2 is 5-membered heteroaryl comprising two N.
  • R 2 is 5-membered heteroaryl comprising S and N. [0191] In some embodiments, R 2 is 6-membered heteroaryl comprising O. [0192] In some embodiments, R 2 is 6-membered heteroaryl comprising N. [0193] In some embodiments, R 2 is 6-membered heteroaryl comprising S. [0194] In some embodiments, R 2 is 6-membered heteroaryl comprising O and N. [0195] In some embodiments, R 2 is 6-membered heteroaryl comprising two N. [0196] In some embodiments, R 2 is 6-membered heteroaryl comprising S and N. [0197] In some embodiments, R 2 is heteroaryl substituted with -CH 3 .
  • R 2 is heteroaryl substituted with halogen. [0199] In some embodiments, R 2 is heteroaryl substituted with -CN. [0200] In some embodiments, R 2 is . [0201] In some embodiments, R 2 is . [0202] In some embodiments, R 2 is . [0203] In some embodiments, R 2 is . [0204] In some embodiments, R 2 is -NR 10 R 11 . [0205] In some embodiments, R 2 is -NHS(O)2R 12 .
  • R 2 is -NHS(O) 2 R 12 , wherein R 12 is C 1 -C 6 alkyl optionally substituted with one or more halogen.
  • R 2 is -NHS(O)2R 12 , wherein R 12 is C1-C6 alkyl optionally substituted with one or more F.
  • R 2 is -NHS(O) 2 CHF 2 .
  • R 2 is -S(O) 2 R 12 .
  • R 2 is -S(O)2R 12 , wherein R 12 is C1-C6 alkyl optionally substituted with one or more halogen. [0211] In some embodiments, R 2 is -S(O) 2 CH 3 .
  • R 2 and R 3 together with the atoms to which they are attached and intervening atoms form a 5 membered heterocycle, comprising one heteroatom selected from O, N, S.
  • R 2 and R 3 together with the atoms to which they are attached and intervening atoms form a 5 membered heterocycle, comprising one heteroatom – O.
  • R 2 and R 3 together with the atoms to which they are attached and intervening atoms form a 6 membered heterocycle, comprising one heteroatom selected from O, N, S.
  • R 2 and R 3 together with the atoms to which they are attached and intervening atoms, form a 6 membered heterocycle, comprising one heteroatom – O.
  • R 3 is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C 3 -C 10 monocyclic cycloalkyl, C 3 -C 10 cycloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, heterocycle, aryl, heteroaryl, C 1 -C 6 alkyl-aryl, C 1 -C 6 alkyl-heteroaryl, C 2 -C 6 alkenyl-aryl, C2-C6 alkenyl-heteroaryl, C2-C6 alkynyl-aryl, C2-C6 alkynyl-heteroaryl, NR 10 R 11 , and S(O) 2 R 12 wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents
  • R 3 is C1-C6 alkyl. [0221] In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is propyl. In some embodiments, R 3 is n-propyl. In some embodiments, R 3 is isopropyl. In some embodiments, R 3 is butyl. In some embodiments, R 3 is n-butyl. In some embodiments, R 3 is isobutyl. In some embodiments, R 3 is sec-butyl. In some embodiments, R 3 is tert-butyl. In some embodiments, R 3 is pentyl. In some embodiments, R 3 is hexyl.
  • R 3 is -CH3.
  • R 4 is selected from H, OH, CN, C1-C6 alkyl, C3-C10 cycloalkyl, C 1 -C 6 alkyl-C 1 -C 6 alkoxy, C 1 -C 6 alkyl-NR 10 R 11 , C(O)OC 1 -C 6 alkyl, OC(O)C 1 - C6 alkyl wherein the alkyl, cycloalkyl or alkyl-alkoxy is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle; [0224] In some embodiments, R 4 is H.
  • R 4 when V is C, R 4 is halogen. [0226] In some embodiments, R 4 is F. In some embodiments, R 4 is Cl. In some embodiments, R 4 is Br. In some embodiments, R 4 is I. [0227] In some embodiments, when V is C, R 4 is CN. [0228] In some embodiments, when V is N, R 4 is C(O)OC 1 -C 6 alkyl. [0229] In some embodiments, when V is N, R 4 is C(O)O-tert-butyl.
  • R 5 is selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, heterocycle, aryl, or heteroaryl wherein the alkyl, cycloalkyl, alkenyl, alkynyl, heterocycle, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.
  • R 5 is H.
  • R 5 is C1-C6 alkyl. [0233] In some embodiments, R 5 is CH 3 . In some embodiments, R 5 is C 2 H 5 . In some embodiments, R 5 is CH 2 CH 2 CH 3 . In some embodiments, R 5 is CH(CH 3 ) 2 . In some embodiments, R 5 is CH2CH2CH2CH3. In some embodiments, R 5 is CH2CH(CH3)2. [0234] In some embodiments, R 5 is methyl. [0235] In some embodiments, R 5 is ethyl. [0236] In some embodiments, R 5 is is iso-propyl. [0237] In some embodiments, R 5 is iso-butyl.
  • R 5 is C 1 -C 6 alkyl substituted with one or more halogen. [0239] In some embodiments, R 5 is C1-C6 alkyl substituted with one or more F. [0240] In some embodiments, R 5 is -CHF2. [0241] In some embodiments, R 5 is -CF 3 . [0242] In some embodiments, R 5 is C 3 -C 10 cycloalkyl. [0243] In some embodiments, R 5 is cyclopropyl. [0244] In some embodiments, R 5 is cyclobutyl. [0245] In some embodiments, R 5 is cyclopentyl. [0246] In some embodiments, Q is CH2.
  • Q is NR 5 . In some embodiments, Q is O. In some embodiments, Q is S. In some embodiments, Q is S(O). In some embodiments, Q is S(O) 2 . [0247] In some embodiments, Q is CH2, optionally substituted with one or two R 6 . [0248] In some embodiments, Q is CH2. [0249] In some embodiments, Q is CHR 6 . [0250] In some embodiments, Q is C(R 6 ) 2 . [0251] In some embodiments, Q is O. [0252] In some embodiments, Q is NR 5 . [0253] In some embodiments, Q is NH.
  • Q is N(C 1 -C 6 alkyl). [0255] In some embodiments, Q is NCH3. [0256] In some embodiments, Q is NCH(CH3)2. [0257] In some embodiments, Q is N(C 1 -C 6 halogenalkyl). [0258] In some embodiments, Q is NCH2CF3. [0259] In some embodiments, Q is N(C1-C6 hydroxyalkyl). [0260] In some embodiments, Q is . [0261] In some embodiments, Q is S(O)2. [0262] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.
  • n is 1. [0264] In some embodiments, m is 2. [0265] In some embodiments, m is 3. [0266] In some embodiments, m is 4. [0267] In some embodiments, n is 0. In some embodiments, n is 1.In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. [0268] In some embodiments, n is 0. [0269] In some embodiments, n is 1. [0270] In some embodiments, n is 2. [0271] In some embodiments, n is 3. [0272] In some embodiments, n is 4.
  • combination of m and n is selected from the table below: [0274] In some embodiments, m is 1 and n is 2. [0275] In some embodiments, m is 1, n is 2, and Q is CH2. [0276] In some embodiments, m is 1, n is 2, and Q is CHR 6 . [0277] In some embodiments, m is 1, n is 2, and Q is C(R 6 ) 2 . [0278] In some embodiments, m is 1, n is 2, and Q is C(CH3)2. [0279] In some embodiments, m is 1, n is 2, and Q is . [0280] In some embodiments, m is 1, n is 2, and Q is .
  • m is 2 and n is 2. [0282] In some embodiments, m is 2, n is 2, and Q is O. [0283] In some embodiments, m is 2, n is 2, and Q is NR 5 . [0284] In some embodiments, m is 2, n is 2, and Q is S(O)2. [0285] In some embodiments, m is 2, n is 2, and Q is CH 2 . [0286] In some embodiments, m is 3 and n is 2. [0287] In some embodiments, m is 3, n is 2, and Q is O. [0288] In some embodiments, m is 3, n is 2, and Q is NR 5 .
  • m is 3, n is 2, and Q is NH. [0290] In some embodiments, m is 3, n is 2, and Q is NCH3. [0291] In some embodiments, m is 3, n is 2, and Q is NCH(CH3)2. [0292] In some embodiments, m is 3, n is 2, and Q is NCH 2 CF 3 . [0293] In some embodiments, m is 3, n is 2, and Q is . [0294] In some embodiments, m is 3, n is 2, and Q is CH 2 . [0295] In some embodiments, m is 3, n is 2, and Q is CHCH3.
  • m is 3, n is 2, and Q is C(CH3)2.
  • m is 3, n is 2, and Q is CH(halogen).
  • m is 3, n is 2, and Q is CHF.
  • m is 3, n is 2, and Q is CH(OH).
  • m is 3, n is 2, and Q is C(CH 3 )OH.
  • m is 3, n is 2, and Q is S(O)2.
  • u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments u is 3.
  • u is 4. In some embodiments, u is 5. In some embodiments, u is 6. [0303] In some embodiments, u is 0. [0304] In some embodiments, u is 1. [0305] In some embodiments, u is 2. [0306] In some embodiments, u is 3. [0307] In some embodiments, u is 4.
  • each R 6 is independently selected from halogen, OH, oxo, CN, CONR 10 R 11 , NR 10 R 11 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-C3-C8 cycloalkoxy, O-C1-C6 alkyl-C(O)NR 10 R 11 , NR 10 C(O)R 11 , -S(O)2-C1-C6 alkyl, -C 1 -C 6 alkanediyl-S(O) 2 -C 1 -C 6 alkyl, wherein the alkyl, or alkoxy is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl, and hetero
  • R 6 is selected from halogen. In some embodiments, R 6 is OH. In some embodiments, R 6 is oxo. In some embodiments, R 6 is CN. In some embodiments, R 6 is CONR 10 R 11 . In some embodiments, R 6 is NR 10 R 11 . In some embodiments, R 6 is C1-C6 alkyl. In some embodiments, R 6 is C1-C6 alkoxy. In some embodiments, R 6 is O-C 1 -C 6 alkyl-C(O)NR 10 R 11 . In some embodiments, R 6 is NR 10 C(O)R 11 . [0310] In some embodiments, R 6 is halogen.
  • R 6 is F. [0312] In some embodiments, R 6 is OH. [0313] In some embodiments, R 6 is C 1 -C 6 alkyl. [0314] In some embodiments, R 6 is -CH3. [0315] In some embodiments, R 6 is C1-C6 halogenalkyl. [0316] In some embodiments, R 6 is -CF 3 . [0317] In some embodiments, R6 is -CH2Cl. [0318] In some embodiments, R 6 is C1-C6 hydroxyalkyl. [0319] In some embodiments, R 6 is -CH 2 OH. [0320] In some embodiments, R 6 is .
  • R 6 is C 1 -C 6 alkyl-C 1 -C 6 alkoxy. [0322] In some embodiments, R 6 is -CH 2 -O-CH 3 . [0323] In some embodiments, R 6 is -CH2-O-CH2CH3.
  • two R 6 together with the atoms to which they are attached and any intervening atoms form a 3-14 membered cycloalkyl, an aryl, a 3-14 membered heterocycle, or a 5-10 membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl-C 1 -C 6 alkoxy, S(O)2R 12 .
  • two geminal R 6 together with the atoms to which they are attached and any intervening atoms form a 3-14 membered cycloalkyl, or a 3-14 membered heterocycle, wherein the cycloalkyl, or heterocycle is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C1-C6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl-C 1 -C 6 alkoxy, S(O) 2 R 12 .
  • two vicinal R 6 together with the atoms to which they are attached and any intervening atoms form a 3-14 membered cycloalkyl, an aryl, a 3-14 membered heterocycle, or a 5-10 membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 .
  • two isolated R 6 together with the atoms to which they are attached and any intervening atoms form a 5-14 membered cycloalkyl, or 5-14 membered heterocycle, wherein the cycloalkyl, or heterocycle is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl-C 1 -C 6 alkoxy, S(O) 2 R 12 .
  • two R 6 together with the atoms to which they are attached O and intervening atoms form .
  • two R 6 together with the atom to which they are attached form .
  • two R 6 together with the atom to which they are attached form .
  • two R 6 together with the atom to which they are attached form .
  • two R 6 together with the atom to which they are attached form .
  • two R 6 together with the atom to which they are attached form .
  • two R 6 together with the atom to which they are attached form .
  • R 7 is H. In some embodiments, R 7 is C 1 -C 6 alkyl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.
  • R 7 is C 3 -C 10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.
  • R 7 is C1-C6 alkoxy optionally substituted with one or more substituents independently selected from halogen, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.
  • R 7 is C2-C6 alkenyl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.
  • R 7 is C 2 -C 6 alkynyl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.
  • R 7 is heterocycle optionally substituted with one or more substituents independently selected from halogen, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.
  • R 7 is aryl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, NH 2 , C 1 -C 6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.
  • R 7 is heteroaryl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle. [0346] In some embodiments, R 7 is H. [0347] In some embodiments, R 8 is H.
  • R 8 is C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.
  • R 8 is C 3 -C 10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.
  • R 8 is C1-C6 alkoxy optionally substituted with one or more substituents independently selected from halogen, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.
  • R 8 is C2-C6 alkenyl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.
  • R 8 is C2-C6 alkynyl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.
  • R 8 is heterocycle optionally substituted with one or more substituents independently selected from halogen, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.
  • R 8 is aryl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, NH 2 , C 1 -C 6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.
  • R 8 is heteroaryl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.
  • R 8 is H.
  • R 8 is C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle. [0350] In some embodiments, R 8 is C1-C6 alkyl. [0351] In some embodiments, R 8 is -CH3. [0352] In some embodiments, R 9 is H.
  • R 9 is C 1 -C 6 alkyl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.
  • R 9 is C 3 -C 10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.
  • R 9 is C1-C6 alkoxy optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.
  • R 9 is C 2 -C 6 alkenyl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.
  • R 9 is C2-C6 alkynyl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.
  • R 9 is heterocycle optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.
  • R 9 is aryl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C 1 -C 6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.
  • R 9 is heteroaryl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.
  • R 9 is H.
  • R 9 is C 1 -C 6 alkyl.
  • R 9 is -CH3.
  • R 10 is H.
  • R 10 is C1-C6 alkyl, optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy.
  • R 10 is C3-C10 cycloalkyl, optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy.
  • R 10 is S(O) 2 R 12 .
  • R 10 is H. [0358] In some embodiments, R 10 is C1-C6 alkyl. [0359] In some embodiments, R 10 is methyl. [0360] In some embodiments, R 10 is -S(O) 2 R 12 . [0361] In some embodiments, R 10 is -S(O)2C1-C6 alkyl. [0362] In some embodiments, R 10 is -S(O)2CH3. [0363] In some embodiments, R 10 is -S(O) 2 CHF 2 . [0364] In some embodiments, R 11 is H.
  • R 11 is C1-C6 alkyl, optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy. In some embodiments, R 11 is C 3 -C 10 cycloalkyl, optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy. [0365] In some embodiments, R 11 is H. [0366] In some embodiments, R 11 is C 1 -C 6 alkyl. [0367] In some embodiments, R 11 is methyl.
  • R 12 is C1-C6 alkyl, -NH2, -NH(C1-C3 alkyl), or -N(C1-C3 alkyl) 2 wherein the alkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy.
  • R 12 is C1-C6 alkyl optionally substituted with one or more halogen.
  • R 12 is -CHF 2 .
  • the compound is of Formula (I-I): (I-I), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein all variables are as defined herein. [0372] In some embodiments, the compound is of Formula (I-II):
  • the compound is of Formula (I-O): (I-O), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-N): (I-N), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-S): (I-S), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-QN): (I-I-QN), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein the fragment is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , N N , , , , O S N , O , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
  • the compound is of Formula (I-I-A): (I-I-A), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-B): (I-I-B), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-C):
  • the compound is of Formula (I-I-D): (I-I-D), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D): (I-I-D), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein: Q is selected from CH2, NR 5 , O, S, S(O), S(O)2 R 1 is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, C 3 - C10 cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, NR 10 R 11 , and S(O)2R 12 wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH,
  • the compound is of Formula (I-II-A): (I-II-A), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-B): (I-II-B), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-C):
  • the compound is of Formula (I-II-D): (I-II-D), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-A-M): (I-I-A-M), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-B-M): (I-I-B-M), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-C-M): (I-I-C-M), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-I):
  • the compound is of Formula (I-I-D-M): (I-I-D-M), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-M-H): (I-I-D-M-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-M-A): (I-I-D-M-A), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-M-1): (I-I-D-M-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-M-1*):
  • the compound is of Formula (I-I-D-M-1**): (I-I-D-M-1**), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O): (I-I-D-O), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-H): (I-I-D-O-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-A): (I-I-D-O-A), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-A-H):
  • the compound is of Formula (I-I-D-O-A-1): (I-I-D-O-A-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-A-1-H): (I-I-D-O-A-1-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-A--2): (I-I-D-O-A-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-A-2-H): (I-I-D-O-A-2-H), or a pharmaceu tically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-A-3):
  • the compound is of Formula (I-I-D-O-3-A-H): (I-I-D-O-3-A-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-B): (I-I-D-O-B), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-B-H): (I-I-D-O-B-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-B-1): (I-I-D-O-B-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-B-1*):
  • the compound is of Formula (I-I-D-O-B-1**): (I-I-D-O-B-1**), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-B-1***): (I-I-D-O-B-1***), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-B-1****): (I-I-D-O-B-1****), or a pharmaceuti cally acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-C): (I-I-D-O-C), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-C-H): (I-I-D-O-C-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-C-1): (I-I-D-O-C-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-C-1*): (I-I-D-O-C-1*), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-C-1**): (I-I-D-O-C-1**), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-D): (I-I-D-O-D), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-D-H): (I-I-D-O-D-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-D-1): (I-I-D-O-D-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-D-1*): (I-I-D-O-D-1*), [0424] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D- O-D-l): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-E): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-E-H):
  • the compound is of Formula (I-I-D-O-E-1): (I-I-D-O-E-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-F): (I-I-D-O-F), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-F-H): (I-I-D-O-F-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-F-1): (I-I-D-O-F-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-F-1*):
  • the compound is of Formula (I-I-D-O-F-1**): (I-I-D-O-F-1**), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-F-2): (I-I-D-O-F-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-F-2*): (I-I-D-O-F-2*), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-O-F-2): (I-I-D-O-F-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-II):
  • the compound is of Formula (I-I-D-Z): (I-I-D-Z) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-Z-H): (I-I-D-Z-H) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-Z-0): (I-I-D-Z-0) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-Z-1): (I-I-D-Z-1) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-Z-1-H):
  • the compound is of Formula (I-I-D-Z-1-A): (I-I-D-Z-1-A) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-Z-1-a):
  • the compound is of Formula (I-I-D-Z-1-a*): (I-I-D-Z-1-a*) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-Z-1-a**):
  • the compound is of Formula (I-I-D-D): (I-I-D-D) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-H):
  • the compound is of Formula (I-I-D-D-0): (I-I-D-D-0) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-D-0-H): (I-I-D-D-0-H) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-D-0-A): (I-I-D-D-0-A) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-D-0-a): (I-I-D-D-0-a) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-D-0-B):
  • the compound is of Formula (I-I-D-D-0-b): (I-I-D-D-0-b) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-D-0-C): (I-I-D-D-0-C) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-D-0-c): (I-I-D-D-0-c) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-D-0-cc): (I-I-D-D-0-cc) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-D-0-ccc):
  • the compound is of Formula (I-I-D-D-0-D): R 3 R 2 R 4 1 N R N HN N 6 N R N O R 5 (I-I-D-D-0-D) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-D-0-d): (I-I-D-D-0-d) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-D-1): (I-I-D-D-1) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-D-1-H): (I-I-D-D-1-H) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0462] In some embodiments, the compound is of Formula (I-I-D-D-1-A):
  • the compound is of Formula (I-I-D-D-1-a): (I-I-D-D-1-a) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-D-1-B): (I-I-D-D-1-B) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-D-1-b): (I-I-D-D-1-b) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-D-1-C): (I-I-D-D-1-C) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-D-1-c):
  • the compound is of Formula (I-I-D-D-1-cc): (I-I-D-D-1-cc) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-D-2):
  • the compound is of Formula (I-I-D-D-2-H): (I-I-D-D-2-H) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-D-3): (I-I-D-D-3) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-D-3-H): (I-I-D-D-3-H) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-D-4): (I-I-D-D-4) or a pharma ceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-D-4-H): (I-I-D-D-4-H) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-III): (I-I-D-III), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P): (I-I-D-P), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-H): (I-I-D-P-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-0): (I-I-D-P-0), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0479] In some embodiments, the compound is of Formula (I-I-D-P-0-1):
  • the compound is of Formula (I-I-D-P-1): (I-I-D-P-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-1-H): (I-I-D-P-1-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-2): (I-I-D-P-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-2-H): (I-I-D-P-2-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-2-1):
  • the compound is of Formula (I-I-D-P-3): (I-I-D-P-3), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-H): (I-I-D-P-3-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-1): (I-I-D-P-3-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-1-a): (I-I-D-P-3-1-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-1-a-1):
  • the compound is of Formula (I-I-D-P-3-1-a-2): (I-I-D-P-3-1-a-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-2): (I-I-D-P-3-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein q is an integer selected from 1, 2, 3, 4 and 5; p is an integer selected from 0, 1, and 2; R 66 is selected from halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl-C 1 -C 6 alkoxy, S(O) 2 R 12 ; and all other variables are as described herein.
  • the compound is of Formula (I-I-D-P-3-2-a): (I-I-D-P-3-2-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 0, 1, and 2; R 66 is selected from halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 ; and all other variables are as described herein.
  • the compound is of Formula (I-I-D-P-3-2-a-H): (I-I-D-P-3-2-a-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0494] In some embodiments, the compound is of Formula (I-I-D-P-3-2-a-1):
  • the compound is of Formula (I-I-D-P-3-2-a-1-a): (I-I-D-P-3-2-a-1-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-2-b): (I-I-D-P-3-2-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 0, 1, and 2; R 66 is selected from halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O) 2 R 12 ; and all other variables are as described herein.
  • the compound is of Formula (I-I-D-P-3-2-b-H): (I-I-D-P-3-2-b-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-2-b-1): (I-I-D-P-3-2-b-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-2-b-1-H):
  • the compound is of Formula (I-I-D-P-3-2-b-2): (I-I-D-P-3-2-b-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-2-b-2-H):
  • the compound is of Formula (I-I-D-P-3-2-b-3): (I-I-D-P-3-2-b-3), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-2-b-3-H): (I-I-D-P-3-2-b-3-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-2-b-4): (I-I-D-P-3-2-b-4), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-2-b-4-H): (I-I-D-P-3-2-b-4-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-2-b-5):
  • R 66 is selected from halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O) 2 R 12 ;
  • R 67 is selected from H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl; and all other variables are as described herein.
  • the compound is of Formula (I-I-D-P-3-2-b-5-H): (I-I-D-P-3-2-b-5-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R 67 is selected from H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl; and all other variables are as described herein.
  • the compound is of Formula (I-I-D-P-3-2-b-5-a):
  • R 66 is selected from halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O) 2 R 12 ; and all other variables are as described herein.
  • the compound is of Formula (I-I-D-P-3-2-b-5-a-H): (I-I-D-P-3-2-b-5-a-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-2-b-5-b):
  • R 66 is selected from halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O) 2 R 12 ; and all other variables are as described herein.
  • the compound is of Formula (I-I-D-P-3-2-b-5-b-H): (I-I-D-P-3-2-b-5-b-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-2-b-5-c):
  • R 66 is selected from halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O) 2 R 12 ; and all other variables are as described herein.
  • the compound is of Formula (I-I-D-P-3-2-b-5-c-H): (I-I-D-P-3-2-b-5-c-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-2-c):
  • the compound is of Formula (I-I-D-P-3-3): (I-I-D-P-3-3), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-3-H): (I-I-D-P-3-3-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-4): (I-I-D-P-3-4), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 0, 1, and 2; R 66 is selected from halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 ; Ring H is 3-8 membered saturated or partially unsaturated heterocyclyl, comprising 1-3 heteroatoms, selected from N, O, S; and all other variables are as described herein.
  • the compound is of Formula (I-I-D-P-3-4-H): (I-I-D-P-3-4-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 0, 1, and 2; R 66 is selected from halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 ; Ring H is 3-8 membered saturated or partially unsaturated heterocyclyl, comprising 1-3 heteroatoms, selected from N, O, S; and all other variables are as described herein.
  • the compound is of Formula (I-I-D-P-3-4-a): (I-I-D-P-3-4-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein w is an integer selected from 1, 2, 3, 4 and 5; and all other variables are as described herein.
  • the compound is of Formula (I-I-D-P-3-4-a-H): (I-I-D-P-3-4-a-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein w is an integer selected from 1, 2, 3, 4 and 5; and all other variables are as described herein.
  • the compound is of Formula (I-I-D-P-3-4-a-1):
  • the compound is of Formula (I-I-D-P-3-4-a-H): (I-I-D-P-3-4-a-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-4-b): (I-I-D-P-3-4-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein x and y are integers independently selected from 1, 2, and 3; and all other variables are as described herein.
  • the compound is of Formula (I-I-D-P-3-4-b-H): (I-I-D-P-3-4-b-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein x and y are integers independently selected from 1, 2, and 3; and all other variables are as described herein.
  • the compound is of Formula (I-I-D-P-3-4-b-1): (I-I-D-P-3-4-b-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-4-b-1-H):
  • the compound is of Formula (I-I-D-P-3-4-b-1-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-4-b-2): (I-I-D-P-3-4-b-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-4-b-2-H):
  • the compound is of Formula (I-I-D-P-3-4-b-2-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-4-b-3): (I-I-D-P-3-4-b-3), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-4-b-3-H):
  • the compound is of Formula (I-I-D-P-3-4-c): (I-I-D-P-3-4-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein w is an integer selected from 1, 2, 3, 4 and 5; and all other variables are as described herein.
  • the compound is of Formula (I-I-D-P-3-4-c-H):
  • the compound is of Formula (I-I-D-P-3-4-c-1): (I-I-D-P-3-4-c-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-4-c-1-H):
  • the compound is of Formula (I-I-D-P-3-4-c-2): (I-I-D-P-3-4-c-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 0, 1, and 2; R 66 is selected from halogen, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl-C 1 -C 6 alkoxy, S(O)2R 12 ; and all other variables are as described herein. [0536] In some embodiments, the compound is of Formula (I-I-D-P-3-4-c-2-H
  • R 66 is selected from halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O) 2 R 12 ; and all other variables are as described herein.
  • the compound is of Formula (I-I-D-P-3-4-c-2-a): (I-I-D-P-3-4-c-2-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0538] In some embodiments, the compound is of Formula (I-I-D-P-3-4-c-2-a-H):
  • the compound is of Formula (I-I-D-P-3-4-c-2-b): (I-I-D-P-3-4-c-2-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-4-c-2-b): (I-I-D-P-3-4-c-2-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-4-c-2-b-H):
  • the compound is of Formula (I-I-D-P-3-4-d): ( I-I-D-P-3-4-d), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein x and y are integers independently selected from 1, 2, and 3; p is an integer selected from 0, 1, and 2; R 66 is selected from halogen, OH, CN, C1-C6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl-C 1 -C 6 alkoxy, S(O) 2 R 12 ; and all other variables are as described herein.
  • the compound is of Formula (I-I-D-P-3-4-d-H): (I-I-D-P-3-4-d-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein x and y are integers independently selected from 1, 2, and 3; p is an integer selected from 0, 1, and 2; R 66 is selected from halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 ; and all other variables are as described herein.
  • the compound is of Formula (I-I-D-P-3-4-d-1): (I-I-D-P-3-4-d-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0544] In some embodiments, the compound is of Formula (I-I-D-P-3-4-d-1-H):
  • the compound is of Formula (I-I-D-P-3-4-d-2): (I-I-D-P-3-4-d-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 0, 1, and 2; R 66 is selected from halogen, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl-C 1 -C 6 alkoxy, S(O)2R 12 ; and all other variables are as described herein. [0546] In some embodiments, the compound is of Formula (I-I-D-P-3-4-d-2-H
  • R 66 is selected from halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O) 2 R 12 ; and all other variables are as described herein.
  • the compound is of Formula (I-I-D-P-3-4-d-2-a): (I-I-D-P-3-4-d-2-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-4-d-2-a-H):
  • the compound is of Formula (I-I-D-P-3-4-d-2-b): (I-I-D-P-3-4-d-2-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-4-d-2-b-H): (I-I-D-P-3-4-d-2-b-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-4-e): (I-I-D-P-3-4-e), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein w is an integer selected from 1, 2, 3, 4 and 5; and all other variables are as described herein.
  • the compound is of Formula (I-I-D-P-3-4-e-H): (I-I-D-P-3-4-e-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein w is an integer selected from 1, 2, 3, 4 and 5; and all other variables are as described herein.
  • the compound is of Formula (I-I-D-P-3-4-e-1):
  • the compound is of Formula (I-I-D-P-3-4-e-1-H): (I-I-D-P-3-4-e-1-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-4-e-1-a): (I-I-D-P-3-4-e-1-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-4-e-1-a-H): (I-I-D-P-3-4-e-1-a-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-4-e-2): (I-I-D-P-3-4-e-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-4-e-2-H):
  • the compound is of Formula (I-I-D-P-3-4-e-2-a): (I-I-D-P-3-4-e-2-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-4-e-2-a-H): (I-I-D-P-3-4-e-2-a-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-4-e-2-b): (I-I-D-P-3-4-e-2-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-4-e-2-b-H): (I-I-D-P-3-4-e-2-b-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-4-f):
  • the compound is of Formula (I-I-D-P-3-4-f-H): (I-I-D-P-3-4-f-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein x and y are integers independently selected from 1, 2, and 3; p is an integer selected from 0, 1, and 2; R 66 is selected from halogen, OH, CN, C1-C6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl-C 1 -C 6 alkoxy, S(O) 2 R 12 ; and all other variables are as described herein. [0565] In some embodiments, the compound is of Formula (I-I-D-P-3-4-f-1):
  • the compound is of Formula (I-I-D-P-3-4-f-1-H): (I-I-D-P-3-4-f-1-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-4-f-1-a): (I-I-D-P-3-4-f-1-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-4-f-1-a-H): (I-I-D-P-3-4-f-1-a-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-P-3-4-f-2): (I-I-D-P-3-4-f-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 0, 1, and 2; R 66 is selected from halogen, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl-C 1 -C 6 alkoxy, S(O)2R 12 ; and all other variables are as described herein. [0570] In some embodiments, the compound is of Formula (I-I-D-P-3-4-f-2-H):
  • R 66 is selected from halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O) 2 R 12 ; and all other variables are as described herein.
  • the compound is of Formula (I-I-D-P-3-4-f-2-a): (I-I-D-P-3-4-f-2-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0572] In some embodiments, the compound is of Formula (I-I-D-P-3-4-f-2-a-H):
  • the compound is of Formula (I-I-D-PP): (I-I-D-PP), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-PP-H): (I-I-D-PP-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-PP-1): (I-I-D-PP-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-PP-1-a): (I-I-D-PP-1-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-A):
  • the compound is of Formula (I-I-D-A-H): (I-I-D-A-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-A-1): (I-I-D-A-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-A-2): (I-I-D-A-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-A-3): (I-I-D-A-3), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-A-3*):
  • the compound is of Formula (I-I-D-A-3**): (I-I-D-A-3**), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-A-3***): (I-I-D-A-3***), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-A-3****): (I-I-D-A-3****), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-A-4): (I-I-D-A-4), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-A-4*):
  • the compound is of Formula (I-I-D-A-4**): (I-I-D-A-4**), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-A-5): (I-I-D-A-5), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-A-6): (I-I-D-A-6), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-A-6*): (I-I-D-A-6*), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-A-6**):
  • the compound is of Formula (I-I-D-A-6***): (I-I-D-A-6***), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-A-6****): (I-I-D-A-6****), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-A-7): (I-I-D-A-7), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-A-8): (I-I-D-A-8), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-IV):
  • the compound is of Formula (I-I-D-T): (I-I-D-T), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-T-H): (I-I-D-T-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-TZ): (I-I-D-TZ), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-TZ-H): (I-I-D-TZ-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-A-M):
  • the compound is of Formula (I-II-B-M): (I-II-B-M), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-C-M): (I-II-C-M), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-D-M): (I-II-D-M), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-A-P): (I-I-A-P), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein u is 0 or 1 and all other variables are as defined herein.
  • the compound is of Formula (I-I-B-P): (I-I-B-P), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein u is 0 or 1 and all other variables are as defined herein.
  • the compound is of Formula (I-I-C-P): (I-I-C-P), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein u is 0 or 1 and all other variables are as defined herein.
  • the compound is of Formula (I-I-D-P): (I-I-D-P), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein u is 0 or 1 and all other variables are as defined herein.
  • the compound is of Formula (I-II-A-P):
  • the compound is of Formula (I-II-B-P): (I-II-B-P), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein u is 0 or 1 and all other variables are as defined herein.
  • the compound is of Formula (I-II-B-P): (I-II-B-P), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein u is 0 or 1 and all other variables are as defined herein.
  • the compound is of Formula (I-II-C-P): (I-II-C-P), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein u is 0 or 1 and all other variables are as defined herein.
  • the compound is of Formula (I-II-D-P): (I-II-D-P), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein u is 0 or 1 and all other variables are as defined herein.
  • the compound is of Formula (I-I-A-A): (I-I-A-A), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein u is 0 or 1 and all other variables are as defined herein.
  • the compound is of Formula (I-I-B-A): (I-I-B-A), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein u is 0 or 1 and all other variables are as defined herein.
  • the compound is of Formula (I-I-C-A): (I-I-C-A), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein u is 0 or 1 and all other variables are as defined herein.
  • the compound is of Formula (I-I-D-A): (I-I-D-A), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein u is 0 or 1 and all other variables are as defined herein.
  • the compound is of Formula (I-II-A-A):
  • the compound is of Formula (I-II-B-A): (I-II-B-A), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein u is 0 or 1 and all other variables are as defined herein.
  • the compound is of Formula (I-II-B-A): (I-II-B-A), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein u is 0 or 1 and all other variables are as defined herein.
  • the compound is of Formula (I-II-C-A): (I-II-C-A), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein u is 0 or 1 and all other variables are as defined herein.
  • the compound is of Formula (I-II-D-A): (I-II-D-A), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof wherein u is 0 or 1 and all other variables are as defined herein.
  • the compound is of Formula (I-I-A-1): (I-I-A-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-A-1-H): (I-I-A-1-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-A-2): (I-I-A-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-A-2-H): (I-I-A-2-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-A-3):
  • the compound is of Formula (I-I-A-3-H): (I-I-A-3-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-A-4): (I-I-A-4), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-A-4-H): (I-I-A-4-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-A-5): (I-I-A-5), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is integer selected from 1, 2, 3, and 4 and all other variables are as defined herein.
  • the compound is of Formula (I-I-A-5-H): (I-I-A-5-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is integer selected from 1, 2, 3, and 4 and all other variables are as defined herein.
  • the compound is of Formula (I-I-B-1): (I-I-B-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-B-1-H): (I-I-B-1-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-C-1):
  • the compound is of Formula (I-I-C-1-H): (I-I-C-1-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-1): (I-I-D-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-1-H): (I-I-D-1-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-1-H-1): (I-I-D-1-H-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-1-H-2): (I-I-D-1-H-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-1-H-3): (I-I-D-1-H-3), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-2): (I-I-D-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-2-H): (I-I-D-2-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-3): (I-I-D-3), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein b is an integer selected from 1, 2, and 3 and all other integers are as defined herein.
  • the compound is of Formula (I-I-D-3-H): (I-I-D-3-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein b is an integer selected from 1, 2, and 3 and all other variables are as defined herein.
  • the compound is of Formula (I-I-D-3-1):
  • the compound is of Formula (I-I-D-3-1-H): (I-I-D-3-1-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-3-2): (I-I-D-3-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-3-2): (I-I-D-3-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-3-2-H):
  • the compound is of Formula (I-I-D-4): (I-I-D-4), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-4-H): (I-I-D-4-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-4-H): (I-I-D-4-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-5):
  • the compound is of Formula (I-I-D-5-H): (I-I-D-5-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R S is H, halogen, CN, or CH3 and all other variables are as defined herein.
  • the compound is of Formula (I-I-D-5-H): (I-I-D-5-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R S is H, halogen, CN, or CH3 and all other variables are as defined herein.
  • the compound is of Formula (I-I-D-6): (I-I-D-6), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R S is H, halogen, CN, or CH3 and all other variables are as defined herein.
  • the compound is of Formula (I-I-D-6-H): (I-I-D-6-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R S is H, halogen, CN, or CH3 and all other variables are as defined herein.
  • the compound is of Formula (I-I-D-7): (I-I-D-7), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, L is CH 2 , O, S, NH, and all other variables are as defined herein. [0656] In some embodiments, the compound is of Formula (I-I-D-7-H):
  • the compound is of Formula (I-I-D-7-1): (I-I-D-7-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-7-1-H): (I-I-D-7-1-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-8): (I-I-D-8), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein L is CH2, O, S, or NH, and all other variables are as defined herein.
  • the compound is of Formula (I-I-D-8-H): (I-I-D-8-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein L is CH2, O, S, or NH, and all other variables are as defined herein.
  • the compound is of Formula (I-I-D-7-1):
  • the compound is of Formula (I-I-D-7-1-H): (I-I-D-7-1-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-9): (I-I-D-9), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-9-H):
  • the compound is of Formula (I-I-D-9-1): (I-I-D-9-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-9-1-H): (I-I-D-9-1-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-I-D-9-1-H): (I-I-D-9-1-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-A-1):
  • the compound is of Formula (I-II-A-1-H): (I-II-A-1-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R A is selected from H and C1-C3 alkyl and all other variables are as defined herein.
  • the compound is of Formula (I-II-A-1-H): (I-II-A-1-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R A is selected from H and C1-C3 alkyl and all other variables are as defined herein.
  • the compound is of Formula (I-II-A-2): (I-II-A-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 1, 2, 3, 4, and 5 and all other variables are as defined herein.
  • the compound is of Formula (I-II-A-2-H): (I-II-A-2-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 1, 2, 3, 4, and 5, and all other variables are as defined herein.
  • the compound is of Formula (I-II-A-2-H-1): (I-II-A-2-H-1), or a pharmaceuti cally acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-A-2-H-2):
  • the compound is of Formula (I-II-A-2-H-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-A-2-H-3): (I-II-A-2-H-3), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-A-2-H-4): (I-II-A-2-H-4), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-A-2-H-5): (I-II-A-2-H-5), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-A-3-1): (I-II-A-3-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • Ring A is heterocyclyl or heteroaryl
  • v is an integer selected from 0, 1, 2
  • the compound is of Formula (I-II-A-3-1): (I-II-A-3-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-A-3-1-H):
  • the compound is of Formula (I-II-A-3-1-H’): (I-II-A-3-1-H’), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-A-3-1-H”): (I-II-A-3-1-H”), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-A-3-2): (I-II-A-3-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-A-3-2-H): (I-II-A-3-2-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-A-3-3):
  • the compound is of Formula (I-II-A-3-2-H): I-II-A-3-2-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-B-H): (I-II-B-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-C-H): (I-II-C-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-D-1): (I-II-D-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R A is selected from H and C1-C3 alkyl and all other variables are as defined herein.
  • the compound is of Formula (I-II-D-1-H): (I-II-D-1-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R A is selected from H and C1-C3 alkyl and all other variables are as defined herein.
  • the compound is of Formula (I-II-D-1-H-1): (I-II-D-1-H-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-D-1-H-2): (I-II-D-1-H-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0692] In some embodiments, the compound is of Formula (I-II-D-2):
  • the compound is of Formula (I-II-D-2-H): (I-II-D-2-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 1, 2, 3, 4, and 5, and all other variables are as defined herein.
  • the compound is of Formula (I-II-D-2-H): (I-II-D-2-H), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 1, 2, 3, 4, and 5, and all other variables are as defined herein.
  • the compound is of Formula (I-II-D-2-H-1): (I-II-D-2-H-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-D-2-H-2): (I-II-D-2-H-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-D-2-H-3): (I-II-D-2-H-3), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-D-2-H-4): (I-II-D-2-H-4), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-II-D-2-H-5): (I-II-D-2-H-5), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is selected from the compounds is of Formula (I-I-A-M), (I-I-B-M), (I-I-C-M), (I-I-D-M), (I-II-A-M), (I-II-B-M), (I-II-C-M), or (I-II-D- M): (I-I-A-M), (I-I-B-M),
  • the compound is selected from the compounds of Formula (I-I-A-G), (I-I-B-G), (I-I-C-G), or (I-I-D-G):
  • the compound is selected from the compounds of Formula (I-II-A-G), (I-II-B-G), (I-II-C-G), or (I-II-D-G): (I-II-A-G), (I-II-B-G),
  • the compound is compound 27: (27) or a pharmaceutically a cceptable salt, stereoisomer, solvate, or tautomer thereof.
  • the compound is compound 50:
  • the compound is compound 59: (59) or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.
  • the compound is compound 62: (62) or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.
  • the compound is compound 65:
  • the compound is compound 70: (70) or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.
  • the compound is compound 74: (74) or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.
  • the compound is compound 78:
  • the compound is compound 79: (79) or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.
  • the compound is compound 81: (81) or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.
  • the compound is compound 82:
  • the compound is compound 88: (88) or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.
  • the compound is compound 92: (92) or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.
  • the compound is compound 121:
  • the compound is compound 122: (122) or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.
  • the compound is compound 123: (123) or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.
  • the compound is compound 124:
  • the compound is compound 125: (125) or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.
  • the compound is compound 126: (126) or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.
  • the compound is compound 127:
  • the compound is compound 128: (128) or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.
  • the compound is compound 129: (129) or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.
  • the compound is compound 130:
  • the compound is compound 131: (131) or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.
  • the compound is compound 132: (132) or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.
  • the compound is compound 133:
  • the compound is compound 134: (134) or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.
  • 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. [0733] In some embodiments, the compound is selected from the compounds described in Table 1. [0734] Table 1. Non-limiting illustrative compounds of the present disclosure # IUPAC Name 1 1-[5-(5-isopropoxy-1H-indazol-3-yl)pyridazin-3-yl]azetidin-3-ol ⁇ IUPAC Name 2 (R)-1-(5-(5-isopropoxy-1H-indazol-3-yl)pyridazin-3-yl)pyrrolidin-3-ol 3 5-isopropoxy-3-[6-(3-methylpyrrolidin-1-yl)pyridazin-4-yl]-1H-indazole 4 4-[5-(5-isopropoxy-1H-indazol-3-yl)pyridazin-3-yl]morpholine 5 5-isopropy
  • 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).
  • 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.
  • the compound is an isotopic derivative of any one of prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.
  • the compound is an isotopic derivative of any one of the compounds described in Table 1. [0754] 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. [0759] 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. [0760] 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. [0761] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1.
  • 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, 3 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 the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting a 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and/or 36 S labeled reagent for a non-isotope labeled reagent.
  • a compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof that contains one or more of the aforementioned 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and 36 S atom(s) is within the scope of the disclosure.
  • 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, 3 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, 3 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, 3 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, 3 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 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. [0779] 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.
  • 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. [0786] The present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions. [0787] 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, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).
  • 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 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. [0794] 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.
  • 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.
  • keto/enol Illustrated below
  • imine/enamine imine/enamine
  • amide/imino alcohol amidine/amidine
  • nitroso/oxime thioketone/enethiol
  • nitro/aci-nitro H O OH H+ O- C C C C + C C H keto enol enolate
  • 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.
  • 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 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. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.
  • 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).
  • ester forming groups for a hydroxy group include C 1 -C 10 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.
  • Suitable pharmaceutically acceptable ether forming groups for 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 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-C 1 -C 4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
  • 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 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. 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 [0808]
  • 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.
  • All reagents may be commercially available compounds itself or products 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.
  • GENERAL PROCEDURE B [0811] In general, the compound of the Formula (I-II) can be prepared using sequences of reactions presented at the Scheme 2: Scheme 2
  • reagents may be used one step or multistep synthetic procedures, including but not limited procedures described herein in preparative part.
  • any of compound of Formula (I) obtained according to the procedures A, B, or C described above may be a subject for further transformation and modification that will led to obtain other compound of Formula (I).
  • Biological Assays 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.
  • 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. [0819] Various in vitro or in vivo biological assays may be suitable for detecting the effect of the compounds of the present disclosure.
  • compositions 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 [0820] 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.
  • 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. 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.
  • 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 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. [0827] 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.
  • 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.
  • 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.
  • 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.
  • Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets.
  • 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 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).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or
  • 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 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 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.
  • 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-
  • the disease or disorder is a Parkinson Disease (PD).
  • 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.
  • 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.
  • 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 [0867] 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). [0868] Routes of administration include, but are not limited to, oral (e.g.
  • 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
  • Tris(dibenzylideneacetone)dipalladium(0) (307 mg, 0.34 mmol) was added to the mixture and the solution was stirred at 80°C for overnight. The mixture was filtered through a pad of celite. The filtrate was treated with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0–20 % EtOAc in n-hexane) to give P27 (1.23 g, 80 %) as an orange oil.
  • N-(4-cyclopropoxy-2-methylphenyl)acetamide (P55).
  • P53 (920 mg, 5.63 mmol, 1.0 eq) in DCM (8.0 mL) was added triethylamine (0.864 mL, 6.20 mmol, 1.1 eq) and acetic anhydride (0.586 mL, 6.20 mmol, 1.1 eq) at 0°C.
  • the reaction solution was stirred at rt for 16 h, the solution was diluted with water and extracted with EtOAc. The organic layers were dried over MgSO 4(s) , filtered, and concentrated under reduced pressure.
  • the mixture solution was degassed with Argon (g) and then added [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (31.8 mg, 0.039 mmol, 0.1 eq). After the reaction solution was stirred at 90°C for 16 h, the solution was filtered through a pad of Celite and washed with EtOAc. The filtrate solution was extracted with EtOAc. The organic layers were washed with water, dried over MgSO 4(s) , filtered, and concentrated under reduced pressure.
  • 1,4-dioxane (5.4 mL) was added bis(pinacolato)diboron (684 mg, 2.70 mmol), potassium acetate (106 mg, 1.08 mmol), XPhos (5.1mg, 0.11 mmol). The mixture was bubbled with argon for 15 min. The mixture was added by [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (39 mg, 0.05 mmol) and then bubbled with argon for 15 min. After the mixture was stirred at 50°C for overnight, the solution was used in the next step without further purification. LCMS (ESI) m/z calc.
  • 1,4-dioxane (5 mL) was added bis(pinacolato)diboron (645 mg, 2.54 mmol), potassium acetate (100 mg, 1.02 mmol), XPhos (48.6 mg, 0.10 mmol). The mixture was degassed with argon for 15 min. The mixture was added by [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37 mg, 0.05 mmol) and then degassed with argon for 15 min. After the mixture was stirred at 50°C for overnight, the solution was used in the next step without further purification. LCMS (ESI) m/z calc.
  • 1,4-dioxane (3.0 mL) was added bis(pinacolato)diboron (418 mg, 1.65 mmol), potassium acetate (65 mg, 0.66 mmol), XPhos (33 mg, 0.07 mmol). The mixture was degassed with argon for 15 min. The mixture was added by [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (22 mg, 0.03 mmol) and then degassed with argon for 15 min. After the mixture was stirred at 50°C for overnight, the solution was used in the next step without further purification. LCMS (ESI) m/z calc.
  • 1,4-dioxane (4 mL) was added bis(pinacolato)diboron (500 mg, 1.97 mmol), potassium acetate (77.3 mg, 0.79 mmol), XPhos (38 mg, 0.08 mmol). The mixture was degassed with argon for 15 min. The mixture was added by [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (29 mg, 0.04 mmol) and then degassed with argon for 15 min. After the mixture was stirred at 50°C for overnight, the solution was used in the next step without further purification. LCMS (ESI) m/z calc.
  • 1,4-dioxane (15 mL) was added morpholine (157 ⁇ L, 1.80 mmol), cesium carbonate (1.27 g, 3.6 mmol), and Xantphos (104.3 mg, 0.18 mmol). The mixture was degassed by argon for 15 min. The mixture was added by tris(dibenzylideneacetone)dipalladium(0) (80 mg, 0.1 mmol) and was degassed with argon again. After the mixture was stirred at 80°C for overnight, the solution was filtered through a pad of celite. The filtrate was treated with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated.
  • tert-Butyl 4-fluoro-3,3-dimethylpyrrolidine-1-carboxylate P123.
  • THF 65 mL
  • dimethyl sulfide borane 26 mL, 51 mmol, 2 M in THF
  • the reaction mixture was cooled to rt, quenched with methanol (100 mL) and concentrated in vacuo.
  • Example 1 1-[5-(5-isopropoxy-1H-indazol-3-yl)pyridazin-3-yl]azetidin-3-ol (Compound 1) To a solution of P8 (47.0 mg, 0.083 mmol, 1.0 eq) in DCM (0.6 mL) was added TFA (0.6 mL) and triethylsilane (0.014 mL, 0.087 mmol, 1.05 eq). After the reaction mixture was stirred at rt for 16 h, the pH value of the mixture was adjusted to 7 by addition of saturated sodium bicarbonate aqueous solution. The solution was extracted with DCM for three times.
  • reaction mixture was warmed to rt and stirred for 30 min.
  • zinc chloride 0.5 M in THF, 0.75 mL, 0.37 mmol, 1.5 eq
  • -20 °C zinc chloride
  • 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 solutions of compounds in DMSO.
  • the 2x Protein-Substrate mix (final concentration 36 nM of LRRK2[G2019S] and 0.8 ⁇ g/ ⁇ L of LRRKtide) was prepared in 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[G2019S] in the 1x buffer was used for a negative control.
  • Ki values are shown in Table A, wherein “A” corresponds to Ki ⁇ 5.0 nM, “B” corresponds to 5.0 nM ⁇ Ki ⁇ 10.0 nM, “C” 10.0 nM ⁇ Ki ⁇ 50.0 nM, “D” corresponds to 50.0 nM ⁇ Ki ⁇ 100.0 nM and “E” corresponds to Ki > 100.0 nM.
  • Table A LRRK2 (G2019S) Activity Inhibition Assays *-K i is the dissociation equilibrium constant of the enzyme-inhibitor complex (E-I). Ki values are determined through a series of experiments with varying amounts of inhibitor present.
  • 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 MgCl 2 , 0.05 mM DTT, 0.1 mg/mL BSA).
  • 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 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 is the dissociation equilibrium constant of the enzyme-inhibitor complex (E-I). 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 [1014]
  • Example C Cell-based NanoBRET Target Engagement Assay in HEK293 cells Transiently Transfected with LRRK2 WT- or LRRK2 (G2019S)-Nano Luc Fusion Vector.
  • HEK293 (ATCC) cells were transfected with 1 ⁇ g LRRK2 WT or LRRK2 (G2019S) and 9 ⁇ g transfection carrier DNA.
  • the transfected cells were treated with the compounds (starting at 1 ⁇ M, 10-dose with 3-fold dilution) and reference compounds CEP-701 or Staurosporine (starting at 1 ⁇ M, 10-dose with 3-fold dilution); compound treatment time: 1 h.
  • LRRK2 WT and LRRK2 (G2019S) target engagement was measured by NanoBRET assay. Curve fits were performed only when % NanoBret signal at the highest concentration of compounds was less than 55%.
  • Assay format 384-well format, 4000 cells/well.
  • IC 50 values are shown in Table C, wherein “A” corresponds to IC 50 ⁇ 50.0 nM, “B” corresponds to 50.0 nM ⁇ IC50 ⁇ 100.0 nM, “C” corresponds to 100.0 nM ⁇ IC50.
  • Table C HEK293 NanoBRET LRRK2[WT] and LRRK2[G2019S] activities.
  • Example D A549 cytotoxicity Assay Used to determine safety of the LRRK2 inhibitors.
  • A549 (ATCC, CCL-185) cells were seeded at a density of 4000 cells per well in a 384-well clear bottom plate (Greiner Cat #781090) in 45 ⁇ L total volume of the complete cell culture medium DMEM (PanEco, Cat# ⁇ 420, Russia) with 10% FBS (HyClone Cat #SV30160.03). The cells were allowed to adhere overnight at 37°C, 5% CO2.
  • the 500x compounds solutions in DMSO (Sigma Cat #D2650) were prepared in the compounds plate (Diamond Well Plate, Axigen, Cat#P-384-120SQ-C-S) and DMSO as a vehicle control was included.
  • the 1 ⁇ L aliquot of 500x compounds (Compounds plate) was added to the 49 ⁇ L culture medium in the Dilution plate (Diamond Well Plate, Axigen, Cat#P-384- 120SQ-C-S), mixed and then the 5 ⁇ L aliquots of the 10x compounds solutions was transferred to cells followed by centrifugation at 100 g for 1 min. Final DMSO concentration was 0.2%. After 3 days of incubation the 10 ⁇ L per well of CellTiter-Glo (Promega, CAT#G7572) was added to the cells, plate was centrifuged at 100 g for 1 min. The luminescence signal was detected with CLARIOstar Plus (BMG LABTECH) microplate reader.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
PCT/US2023/063745 2022-04-04 2023-03-04 Lrrk2 inhibitors Ceased WO2023196720A2 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
KR1020247036645A KR20240171138A (ko) 2022-04-04 2023-03-04 Lrrk2 저해제
CA3247536A CA3247536A1 (en) 2022-04-04 2023-03-04 LEUCINE-RICH KINASE 2 REPETITION INHIBITORS
EP23785521.8A EP4504722A4 (en) 2022-04-04 2023-03-04 LRRK2 INHIBITORS
AU2023249498A AU2023249498B2 (en) 2022-04-04 2023-03-04 Lrrk2 inhibitors
CN202380040105.7A CN119183452A (zh) 2022-04-04 2023-03-04 Lrrk2抑制剂
JP2024559442A JP2025511875A (ja) 2022-04-04 2023-03-04 Ｌｒｒｋ２阻害剤
US18/854,031 US20250248998A1 (en) 2022-04-04 2023-03-04 LRRK2 Inhibitors
MX2024012306A MX2024012306A (es) 2022-04-04 2024-10-03 Inhibidores lrrk2.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202263327058P 2022-04-04 2022-04-04
US63/327,058 2022-04-04

Publications (2)

Publication Number Publication Date
WO2023196720A2 true WO2023196720A2 (en) 2023-10-12
WO2023196720A3 WO2023196720A3 (en) 2023-12-07

Family

ID=88243544

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2023/063745 Ceased WO2023196720A2 (en) 2022-04-04 2023-03-04 Lrrk2 inhibitors

Country Status (11)

Country Link
US (1) US20250248998A1 (https=)
EP (1) EP4504722A4 (https=)
JP (1) JP2025511875A (https=)
KR (1) KR20240171138A (https=)
CN (1) CN119183452A (https=)
AU (1) AU2023249498B2 (https=)
CA (1) CA3247536A1 (https=)
CL (1) CL2024003023A1 (https=)
MX (1) MX2024012306A (https=)
TW (1) TWI867484B (https=)
WO (1) WO2023196720A2 (https=)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12071428B2 (en) 2020-12-30 2024-08-27 Tyra Biosciences, Inc. Indazole compounds as kinase inhibitors
WO2024209363A1 (en) 2023-04-06 2024-10-10 Pfizer Inc. Substituted indazole propionic acid derivative compounds and uses thereof as ampk activators
WO2025123046A1 (en) * 2023-12-07 2025-06-12 Arvinas Operations, Inc. Synthesis of leucine-rich repeat kinase 2 modulators
WO2025247357A1 (zh) * 2024-05-31 2025-12-04 中国医学科学院药物研究所 一类氧代芳杂环结构的cd73抑制剂、及其制法和药物组合物与用途

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2489663A1 (en) * 2011-02-16 2012-08-22 Almirall, S.A. Compounds as syk kinase inhibitors
WO2014134774A1 (en) * 2013-03-04 2014-09-12 Merck Sharp & Dohme Corp. Compounds inhibiting leucine-rich repeat kinase enzyme activity
WO2019074809A1 (en) * 2017-10-11 2019-04-18 Merck Sharp & Dohme Corp. INDAZOLYL-SPIRO [2.2] PENTANE-CARBONITRILE DERIVATIVES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
US20210361774A1 (en) * 2018-10-16 2021-11-25 Dana-Farber Cancer Institute, Inc. Degraders of wild-type and mutant forms of lrrk2
JP2024512501A (ja) * 2021-03-19 2024-03-19 アルヴィナス・オペレーションズ・インコーポレイテッド インダゾール系化合物及び関連使用方法
TW202317561A (zh) * 2021-07-01 2023-05-01 美商羅曼德生物治療公司 作為治療劑的具有１ｈ—吡唑并［４，３—ｃ］吡啶—６—胺基的化合物

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12071428B2 (en) 2020-12-30 2024-08-27 Tyra Biosciences, Inc. Indazole compounds as kinase inhibitors
US12264149B2 (en) 2020-12-30 2025-04-01 Tyra Biosciences, Inc. Indazole compounds as kinase inhibitors
WO2024209363A1 (en) 2023-04-06 2024-10-10 Pfizer Inc. Substituted indazole propionic acid derivative compounds and uses thereof as ampk activators
WO2025123046A1 (en) * 2023-12-07 2025-06-12 Arvinas Operations, Inc. Synthesis of leucine-rich repeat kinase 2 modulators
WO2025247357A1 (zh) * 2024-05-31 2025-12-04 中国医学科学院药物研究所 一类氧代芳杂环结构的cd73抑制剂、及其制法和药物组合物与用途

Also Published As

Publication number Publication date
CN119183452A (zh) 2024-12-24
EP4504722A4 (en) 2026-03-18
AU2023249498A1 (en) 2024-10-17
EP4504722A2 (en) 2025-02-12
JP2025511875A (ja) 2025-04-16
CL2024003023A1 (es) 2024-12-20
CA3247536A1 (en) 2023-10-12
TWI867484B (zh) 2024-12-21
KR20240171138A (ko) 2024-12-06
AU2023249498B2 (en) 2026-01-29
MX2024012306A (es) 2025-01-09
TW202339722A (zh) 2023-10-16
WO2023196720A3 (en) 2023-12-07
US20250248998A1 (en) 2025-08-07

Similar Documents

Publication Publication Date Title
AU2023249498B2 (en) Lrrk2 inhibitors
WO2025170938A1 (en) Kras(g12d) inhibitors
EP4511376A2 (en) Egfr inhibitors in cancer treatment
US20250163066A1 (en) PROTACs of MALT1
AU2024211236A1 (en) Inhibitors of nlrp3
JP2025539787A (ja) Ｔｙｋ２阻害剤
EA052127B1 (ru) Ингибиторы lrrk2
WO2025175258A1 (en) Inhibitors of cdk2
WO2025175264A1 (en) Inhibitors of cdk2
WO2025251058A1 (en) Egfr inhibitors in cancer treatment
WO2025199376A1 (en) Cdk2 inhibitors
WO2025235687A1 (en) Lrrk2 inhibitors
EP4444313A1 (en) Inhibitors of menin-mll interaction
EP4637738A2 (en) Inhibitors of jak2
US20250163061A1 (en) Inhibitors of menin-mll interaction
BR112024017282B1 (pt) Compostos protacs de malt1, composição farmacêutica e usos dos mesmos para tratar uma doença ou distúrbio associado a malt1, linfoma e uma imunodeficiência

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23785521

Country of ref document: EP

Kind code of ref document: A2

WWE Wipo information: entry into national phase

Ref document number: MX/A/2024/012306

Country of ref document: MX

Ref document number: P2024-02622

Country of ref document: AE

Ref document number: AU2023249498

Country of ref document: AU

Ref document number: 18854031

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 2024559442

Country of ref document: JP

Ref document number: 202492298

Country of ref document: EA

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112024020335

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 2023249498

Country of ref document: AU

Date of ref document: 20230304

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 20247036645

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1020247036645

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 2023785521

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2023785521

Country of ref document: EP

Effective date: 20241104

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23785521

Country of ref document: EP

Kind code of ref document: A2

ENP Entry into the national phase

Ref document number: 112024020335

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20240930

WWP Wipo information: published in national office

Ref document number: 18854031

Country of ref document: US