[go: up one dir, main page]

WO2024259121A1 - Bicyclic heteroaromatic compounds for treating neurological disorders - Google Patents

Bicyclic heteroaromatic compounds for treating neurological disorders Download PDF

Info

Publication number
WO2024259121A1
WO2024259121A1 PCT/US2024/033833 US2024033833W WO2024259121A1 WO 2024259121 A1 WO2024259121 A1 WO 2024259121A1 US 2024033833 W US2024033833 W US 2024033833W WO 2024259121 A1 WO2024259121 A1 WO 2024259121A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkyl
ring
salt
halogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2024/033833
Other languages
French (fr)
Inventor
Craig William Lindsley
Paul K. SPEARING
Bruce James MELANCON
Katherine Elizabeth CROCKER
Jinming LI
Cayden Jeremiah DODD
Joseph Aron INGER
Stéphane De Lombaert
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.)
Prothena Biosciences Ltd
Vanderbilt University
Original Assignee
Prothena Biosciences Ltd
Vanderbilt University
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
Application filed by Prothena Biosciences Ltd, Vanderbilt University filed Critical Prothena Biosciences Ltd
Publication of WO2024259121A1 publication Critical patent/WO2024259121A1/en
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • This disclosure provides compounds and pharmaceutically acceptable salts thereof, that are useful, e.g., for treating neurological disorder in subject.
  • This disclosure also provides compositions containing the same as well as methods of using and making the same.
  • the subject matter of the present disclosure was created pursuant to a joint research agreement between Prothena Biosciences Limited and V anderbilt University, that was in effect on or before the date the subject matter described herein was made, and the subject matter was made as a result of activities undertaken within the scope of the joint development agreement.
  • Dual-specificity tyrosine phosphorylation-regulated kinase 1 A is a 763 amino acid, 85 kDa serme/threonine/tyrosme kinase located on chromosome 21 (21q22.2).
  • DYRK1A possesses catalytic activity that is regulated by autophosphorylation of a tyrosine residue (Y321) which results in constitutively active serine/threonine kinase activity. See Abbassi, et al., Pharmacology & Therapeutics, 151, 87-98 (2015). Since DYRK1A is constitutively active, its activity is dosage dependent.
  • DYRK1A is also a member of a large family of CMGC kinases, which include cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAPKs), glycogen synthase kinases (GSKs), and CDC-like kinases (CLKs).
  • CDKs cyclin-dependent kinases
  • MAPKs mitogen-activated protein kinases
  • GSKs glycogen synthase kinases
  • CLKs CDC-like kinases
  • DYRK1A additionally has been shown to have a role in cell cycle regulation, at least in part by phosphorylating (and thus inhibiting) the nuclear factor of activated T cells (NFAT) family of transcription factors. Additionally, over 20 substrates of DYRK1A have been identified, including cell signaling, chromatin modulation, gene expression, alternative splicing, cytoskeletal, and synaptic function. See Abassi, et al, (2016). DYRK1A dysregulation is implicated in various disease states such as Alzheimer’s disease, autism, and Down syndrome. In some cases, novel mutations in DYRK1A have been associated with autism phenotypes.
  • DYRK1A is also known to play an important role in brain development. For example, reduced DYRK1A activity (such has having a single copy of loss of function mutation) during neural development results in intellectual disability phenotypes. Conversely, trisomy 21 in Down syndrome individuals is associated with a triplication of the DYRK1A gene, which results in elevated DYRK1A activity. DYRK1A is located on chromosome 21, specifically within the “Down syndrome critical region” a portion of chromosome 21 that includes genes particularly relevant for developing Down syndrome phenotypes.
  • DYRK1A DYRK1A phosphorylates amyloid precursor protein (APP) which promotes the production of pathogenic amyloid- ⁇ peptide (A ⁇ ).
  • APP amyloid precursor protein
  • Dyrk1A also phosphorylates tau both directly and indirectly (see Abassi, et al, (2016)). Both amyloid-P and tau pathologies are associated with Down syndrome phenotypes.
  • DYRK1A gene dosage by crossing Ts65Dn mice (DS model) with DYRK1 A knockout mice mice reverses many Azlheimer’s-like phenotypes. See Garcia-Cerro et al., 2017. In individuals with Down Syndrome, DYRK1 A mRNA levels, protein levels, and kinase activity are increased by -50%, reflecting the number of gene copies. See Liu et al., 2008; see also Wegiel et al., 2011.
  • Alzheimer’s disease Because no treatment is available for these neurological disorders, the prognosis for individuals with, for example, Alzheimer’s disease is poor. This can be particularly devastating because Alzheimer’s disease is responsible for a sharp decline in survival in individuals with Down syndrome that are over 45 years old. Only about 25% of those with Down syndrome live more than 60 years, and most of those have developed Alzheimer’s disease.
  • AD Alzheimer’s disease
  • DYRK1 A inhibitors have been tested in vitro or in animal preclinical models to treat Alzheimer’s disease or Down syndrome, however, since DYRK1A is a member of the highly conserved CMGC family of kinases, identifying compounds that selectively target DYRK1A has proved challenging.
  • D YRK1 A inhibitors to treat Down syndrome, Alzheimer’s disease, Alzheimer’s disease associated with Down syndrome, and other neurodegenerative and neurological diseases.
  • Some embodiments provide a compound represented by the structure of Formula (I):
  • each represents a single or a double bond, such that the bicyclic ring system comprising Y 1 , Y 2 , Y 3 , and Y 4 is an aromatic bicyclic ring system where (i) Y 1 is CR 3 , Y 2 is N, Y 3 is CR 4 , and Y 4 is CR 3 or N; (ii) Y 1 is S, Y 2 is C, Y 3 is CR 4 or N, and Y 4 is CR 3 ; or (iii) Y 1 is N, Y 2 is N, Y 3 is CR 4 , and Y 4 is CR 3 ; L is selected from , , and , wherein * denotes the point of attachment to Ring A, Z is selected from -O-, -NR 1 -, C1-4alkylene, -O-C1-4alkylene, and -NR 1 -C1-4alkylene, Z’ is selected from -NR
  • Some embodiments provide a compound of Formula (II), (II); or a pharmaceutically acceptable salt thereof, wherein: each represents a single or a double bond, such that the bicyclic ring system comprising Y 1 , Y 2 , and Y 3 is an aromatic bicyclic ring system where (i) Y 1 is CR 3 and Y 2 is N, or (ii) Y 1 is S and Y 2 is C; Y 3 is selected from N and CR 4 ; Ring B is selected from (a), (b) and (c): (a) , X 1 is selected from N, CH, and CR 5 ; (b) , X 2 is selected from S and NR 7 ; and (c) , X 3 is selected from S, N, and NH, X 4 is selected from O and CR 9 , X 5 is N or CH, X 6 is N or CH, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system; R 1
  • Ring B is (a), and p is 1, 2, or 3;
  • R 1 is Ci -4 alkyl
  • Ring B is (c); provided that when Ring B is (a), Xi is CH, R A is methyl, Y 1 is CR’, and Y 2 is N, then Ring A is further selected from tetrahydrofuranyl substituted with methyl;
  • R 5 is independently selected at each occurrence from halogen, Ci-4 alkyl, Ct-i haloalkyl, -OR 14 , -SR 13 , -N(R 13 ) 2 , -C(O)R 13 , -C(O)OR 13 , -OC(O)R 13 , -C(O)N(R 13 ) 2 , -N(R 13 )C(O)R 13 , -N(R ! 3 )S(O)2(R !
  • R 6 is independently selected at each occurrence from halogen, Ci-4 alkyl, Ci-4 haloalkyl, -OR 14 , -SR 14 , -N(R 14 )2, -C(O)R 14 , -C(O)OR 14 , -OC(O)R 14 , -C(O)N(R 14 ) 2 ,
  • R/ and R 9 are each independently selected from hydrogen, Ci-4 alkyl, and Ci-4 haloalkyl;
  • R so , R 11 , R l2 , R 13 , and R 14 are each independently selected at each occurrence from hydrogen, Ci- 6 alkyl.
  • Some embodiments provide a compound of Formula (V):
  • R A is selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -CN, Ci-e alkyl optionally substituted with one or more halogen or -OR 10 , Cs-Ce saturated cycloalkyl, and 3- to 6-membered saturated heterocycloalkyl ;
  • Ring A is selected from a C3-C10 saturated cycloalkyl, a C3-C10 partially saturated carbocycle, a 3- to 10-membered saturated heterocycloalkyl, and a 3- to 10-membered partially saturated heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR 11 , -SR”, -N(R”) 2 , -C(O)R”, -C(O)OR U , -OC(O)R”, -OC(O)N(R”) 2 , -C(0)N(R”)2, -N(R”)C(O)R”, -N(R 11 )C(O)OR 11 , -N(R 11 )C(O)N(R 11 )2, -MR ⁇ SCOXR 11 ), -SIOJR 11 , -SlOyR A -S(O) 2 N(R U ) 2 , -S(O)(NR 11 )
  • C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR 11 , -SR 11 , -N(R ! 1 ) 2 , -C(O)R n , -C(0)0R n , -OC(O)R U , -0C(0)N(R u ) 2 , -C(0)N(R !
  • Ring B is selected from a C3-C10 carbocycle and a 3 - to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR A -SR 12 , -N(R 12 ) 2 , -C(())R 12 , -C(0)0R 12 , -0C(0)R 12 , -0C(0)N(R l 2 ) 2 , -C(())N(R 12 )2, -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , -N(R 12 )C(O)N(R 12 ) 2 , -N(R 12 )S(O) 2 (R 12 ), ⁇ S(O)R A -S(O).-R A -S(O).-R A -S(O) 2 N(R 12 )2, -S(O)(NR 12 )R 12
  • C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR 12 , -SR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(0)0R 12 , -0C(0)R 12 , -OC(O)N(R 12 )2, -C(())N(R 12 )2, -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , -N(R 12 )C(O)N(R 12 )2, -N(R 12 )S(O)Z(R 12 ), ⁇ S(O)R . -Sf Oi.-R 2 , -S(0)2N(R i 2 )2, -S(O)(NR 12 )R 12 , -NO.-. O. ⁇ ( N; and
  • R 1 is selected from hydrogen, Ci-4 alkyl, Cu4 haloalkyl, and -C(O)R 1J ;
  • R 2 is independently selected at each occurrence from halogen, Ci-4 alkyl, Ci-4 haloalkyl, -OR 14 , -SR 14 , -N(R 14 )2, -NO2, and -CN;
  • R 3 is independently selected at each occurrence from hydrogen, halogen, Ci -4 alkyl, and Ci-4 haloalkyl;
  • R 4 is selected from hydrogen, halogen, Ci -4 alkyl, and Ci-4 haloalkyl;
  • R 10 , R 11 , R 12 , R 13 , and R 14 are each independently selected at each occurrence from hydrogen, Ci-4 alkyl, Ci-4 haloalkyl, and cycloalkyl optionally substituted with one or more halogen; and n is selected from 0, 1 , and 2; provided that when Ring B is pyrazolyl, then Ring A is not N-Boc pyrrolidinyl.
  • Some embodiments provide a compound of Formula (VI): or a pharmaceutically acceptable salt thereof, wherein:
  • Q 1 is S or CR 3
  • Q 2 is N or C
  • Q J is selected from N and CR 4 , and each represents a single or a double bond, such that the bicyclic ring system comprising Q 1 , Q 2 , and Q 3 is benzo[d]thiazole, imidazofl ,2-a]pyridine, thiazolo[5,4-b]pyridine, or imidazo[l,2-b]pyridazine;
  • R A is selected from halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -CN, C1-6 alkyl, C1-6 haloalkyl, C3-C6 saturated cycloalkyl, and 3- to 6-membered saturated heterocycloalkyl;
  • Ring A is selected from a C3-C10 saturated cycloalkyl, a C3-C10 partially saturated carbocycle, a 3- to 10-membered saturated heterocycloalkyl, and a 3- to 10-membered partially saturated heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR 11 , -SR ! !
  • C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR 11 , -SR 11 , •N(R" r. -C(O)R n , -C(O)OR ! 1 , -OC(O)R ! ! , -OC(O)N(R ! 1 ) 2 , -C(O)N(R’ !
  • C3-6 carbocycle and 3- to 6-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR 11 , -SR 11 , -N(R !! ) 2 , -C(0)R 11 , -C(0)0R ! 1 , -OC(O)R 1!
  • Ring B is selected from a C3-C10 carbocycle and a 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR 12 , -SR 12 , -N(R 12 ) 2 , -C(0)R 12 , -C(0)0R 12 , -0C(0)R 12 , -OC(O)N(R i2 ) 2 , -C(O)N(R 12 ) 2 , -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , -N(R 12 )C(O)N(R 12 ) 2 , -N(R 12 )S(O) 2 (R 12 ), -S(O)R 12 , -S(O) 2 R 12 , -S(O) 2 N( R 12 ): 2, -S(())(NR i2 )R 12
  • C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR 12 , -SR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(())0R 12 , -0C(0)R 12 , -OC(O)N( R 12 ): 2, -C(())N(R 12 )2, -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , -N(R 12 )C(O)N(R 12 ) 2 , -N(R 12 )S(O) 2 (R 12 ), -S(O)R 12 , -S(O) 2 R 12 , -S(O) 2 N( R 12 ): 2, -S(())(NR i2 )R 12 , -N0 2 , O. -CN; and
  • R 1 is selected from hydrogen, C1-4 alkyl, and -C(O)R 13 ;
  • R 2 is independently selected at each occurrence from halogen, Ci-4 alkyl, Ci-4 haloalkyl, -OR 14 , -SR 14 , -N(R 14 )2, -NO2, and -CN;
  • R 3 and R 4 are each selected from hydrogen, halogen, Ci-4 alkyl, and Ci-4 haloalkyl;
  • R 10 , R u , R 12 , R 13 , and R 14 are each independently selected at each occurrence from hydrogen, Ci-4 alkyl, C1-4 haloalkyl, and cycloalkyl optionally substituted with one or more halogen; and n is selected from 0, 1, and 2; provided that when Ring B is pyrazolyl, then Ring A is not A-Boc pyrrolidinyl.
  • composition comprising a compound of Formula
  • a method for treating a neurological disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • Some embodiments provide a method for treating a neurological disorder in a subject in need thereof, the method comprising (a) determining that the neurological disorder is associated with a dysregulation of & DYRK1A gene, a DYRK1A protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • Also provided herein is a method for treating a neurological disorder in a subject in need thereof, the method comprising (a) determining that the neurological disorder is a DYRK1A- associated neurological disorder, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • Also provided herein is a method for treating a neurological disorder in a subject in need thereof, the method comprising (a) determining that the subject has a neurological disorder; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I),
  • DYRKlA-associated disorder in a subject, the method comprising administering to a subject previously determined to have a DYRKlA- associated disorder a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • a method of treating a subject comprising administering a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject having a clinical record that indicates that the subject has a dysregulation of a DYRKIA gene, a DYRKIA protein, or expression or activity or level of any of the same.
  • This disclosure also provides a method for inhibiting DYRKIA activity in a mammalian cell, the method comprising contacting the mammalian cell with a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, sor a pharmaceutically acceptable salt thereof.
  • inhibitor or “inhibition of’ means to reduce by a measurable amount, or to prevent entirely (e.g., 100% inhibition).
  • therapeutically effective amount means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a neurological disorder as described herein, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular neurological disorder, or (iii) delay the onset of one or more symptoms of the particular neurological disorder described herein.
  • the therapeutically effective amount is an amount sufficient to inhibit DYRK1 A activity in brain tissue.
  • treat or “treatment” refer to therapeutic or palliative measures.
  • Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a neurological disorder, diminishment of the extent of a neurological disorder, stabilized (i.e., not worsening) state of a neurological disorder, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the neurological disorder), and remission (whether partial or total), whether detectable or undetectable and can be determined by various clinical assessments including clinical evaluation and self-reporting. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • pharmaceutically acceptable excipient means a. pharmaceutical! y-accep table material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material.
  • each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a formulation of a compound that does not cause significant irritation to an organism to winch it is administered and does not abrogate the biological activity and properties of the compound.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, A-methyl-D-glucamine, tris(hydroxymethyl)methylaniine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, A-methyl-D-glucamine, tris(hydroxymethyl)methylaniine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously
  • Examples of a salt that the compounds described heremform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic ammo acids such as lysine and ornithine; and ammonium salt.
  • the salts may be acid addition salts, which are specifically- exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid
  • organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tart
  • pharmaceutical composition refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “pharmaceutically acceptable carriers”), such as stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or other excipients.
  • pharmaceutically acceptable carriers such as stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or other excipients.
  • pharmaceutical composition facilitates administration of the compound to an organism.
  • subject refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • a primate e.g., human
  • monkey cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • subject and patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human.
  • halo and halogen refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
  • hydroxyl refers to an -OH radical.
  • nitro refers to an –NO 2 radical.
  • cyano refers to a -CN radical.
  • alkyl refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched, containing the indicated number of carbon atoms.
  • C1-10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it.
  • Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl.
  • saturated as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and/or other substituents as defined herein.
  • An “alkylene” group is a divalent alkyl group as described herein.
  • haloalkyl refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen.
  • hydroxyalkyl refers to an alkyl, in which one or more hydrogen atoms is/are replaced with a hydroxyl group, as described herein.
  • alkoxy refers to an -O-alkyl radical (e.g., -OCH 3 ).
  • carbocycle and “carbocyclyl” refer to a 3-20 carbon mono-, bi-, tri- or polycyclic group that can be fully saturated, partially unsaturated, aromatic, and (in multi-ring systems) any combination thereof. Carbocyclyl groups can include fused, bridged, and spiro ring systems. In some embodiments, a carbocyclyl is an aryl as defined herein.
  • carbocyclyl groups include aryl and cycloalkyl groups as described herein.
  • aryl refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system.
  • aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.
  • cycloalkyl refers to cyclic saturated or partially unsaturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons.
  • Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Cycloalkyl groups can include fused and bridged ring systems. Non-limiting examples of fused/bridged cycloalkyl includes: bicyclofl.1.0]butane, bicyclo[2.
  • Cycloalkyl groups can also include spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom).
  • Non-limiting examples of spirocyclic cycloalkyls include spirof2.2]pentane, spiro [2.5] octane, spiro [3.5] nonane, spiro[3.5]nonane, spiro[3.5]nonane, spirof4.4]nonane, spirof2.6]nonane, spiro[4.5]decane, spiro [3.6] decane, spiro[5.5]undecane, and the like.
  • heterocycle and “heterocyclyl” refers to a mono-, bi-, tri-, or polycyclic saturated, partially unsaturated, or aromatic ring systems with 3-20 total ring atoms and having 1 - 4 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic.
  • exemplary heteroatoms include O, N, S, P, Si, and B.
  • a heterocycle comprises 1, 2, 3, or 4 heteroatoms selected from O, N, and S.
  • a heterocycle comprises 1, 2, or 3 (e.g., 1) heteroatoms selected from O, N, and S, In some embodiments, a heterocycle comprises one 0 atom. In some embodiments, a heterocycle comprises one S atom. In some embodiments, a heterocycle comprises one N atom. In some embodiments, for example, a heterocycle comprises 1 , 2, 3, or 4 heteroatoms selected from O, N, and S. In some embodiments, a heterocycle comprises 1 or 2 (e.g., 1) heteroatoms selected from O, N, and S. In some embodiments, a heterocycle comprises one 0 atom. In some embodiments, a heterocycle comprises one S atom. In some embodiments, a heterocycle comprises one N atom.
  • Heterocyclic ring systems can also include 1 -3 ring atoms that are -C(())-, N-oxide, S-oxide, and/or S,S-dioxide groups, valence permitting.
  • a heterocyclyl is a heteroaryl as defined herein.
  • heterocyclyl groups include heteroaryl groups, as described herein, as well as fully and partially saturated groups such as piperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidonyl, tetrahydrothiophenyl 1,1 -dioxide, thiomorpholinyl 1,1 -dioxide, tetrahydrothiophenyl 1,1 -dioxide, thiomorpholinyl 1,1 -dioxide, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihy dr of uranyl, dihydrothiophenyl, and the like.
  • Heterocyclyl groups can include multiple fused and bridged rings.
  • fused/bridged heteorocyclyl includes: 2- azabicyclo [1.1.0]butane, 2-azabicy clo[2.1.0]pentane, 2-azabicyclo[ 1.1.1 ]pentane, 3- aza bicyclo [3.1.0] hexane, 5-azabicyclo[2.1.1 ]hexane, 3 -azabicyclo [3.2.0 ]heptane, octahydrocyclopentalclpvrrole, 3-azabicyclol4.1.Olheptane, 7-azabicyclol2.2.1 lheptane, 6 azabicyclo[3.1.
  • Heterocyclyl groups can also include spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom).
  • spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1- azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2 -azaspiro [4.4] nonane, 6- azaspiro[2.6]nonane, 1 ,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5- diazaspiro[3.6]decane, 3 -azaspiro [5.5] undecane, 2-oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, l-oxaspiro[[
  • heteroaryl means a mono-, bi-, tri- or polycyclic aromatic group (i.e., the entire ring system is aromatic) having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms, wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of O, N, S, P, Si, and B.
  • a heteroaryl comprises 1, 2, 3, or 4 heteroatoms selected from O, N, and S.
  • a heteroaryl comprises 1 or 2 (e.g., 1) heteroatoms selected from 0, N, and S.
  • a heteroaryl comprises one 0 atom.
  • a heteroaryl comprises one S atom. In some embodiments, a heteroaryl comprises one N atom. In some embodiments, for example, a heteroaryl comprises 1, 2, 3, or 4 heteroatoms selected from O, N, and S. In some embodiments, a heteroaryl comprises 1 or 2 (e.g., 1) heteroatoms selected from O, N, and S. In some embodiments, a heteroaryl comprises one O atom. In some embodiments, a heteroaryl comprises one S atom. In some embodiments, a heteroaryl comprises one N atom.
  • heteroaryl examples include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyndo[2,3-r/]pyrimidinyl, pyrrolo[2,3-£]pyridinyl, quinazoiiny
  • heterocycloalkyl refers to a mono-, bi-, tri-, or polycyclic saturated or partially unsaturated ring system with 3-20 total ring atoms and having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic.
  • exemplary heteroatoms include O, N, S, P, Si, and B.
  • a heterocycloalkyl comprises 1, 2, 3, or 4 heteroatoms selected from O, N, and S.
  • a heterocycloalkyl comprises 1, 2, 3, or 4 heteroatoms selected from O, N, and S.
  • a heterocycloalkyl comprises 1 or 2 (e.g., 1) heteroatoms selected from O, N, and S. In some embodiments, a heterocycloalkyl comprises one O atom. In some embodiments, a heterocycloalkyl comprises one S atom. In some embodiments, a heterocycloalkyl comprises one N atom. Heterocycloalkyl ring systems can also include 1-3 ring atoms that are -C(O) ⁇ , N-oxide, S-oxide, and/or S,S-dioxide groups, valence permitting.
  • heterocycloalkyl groups examples include piperazinyl, pyrrolidinyl, pyrrolidonyl, tetrahydrothiophenyl 1,1 -dioxide, thiomorpholinyl 1,1-dioxide, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, and the like.
  • Heterocycloalkyl groups can include multiple fused and bridged rings.
  • Non-limiting examples of fused/bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2- azabicy do [1.1.1 ]pentane, 3-azabicyclo[3.1 .0]hexane, 5-azabicyclo[2.1.1 jhexane, 3- azabi cyclo [3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyc1o[4.1 .0]heptane ; azabicyclo [2.2.1 ]heptane, 6-azabicyclo[3.1.1 [heptane, 7-azabicyclo[4.2.0]octane, aza bicyclo [2.2.2] octane, 3-azabicydo[3.2.1 [octane, 2-oxabicyclo[ 1.1.0] butane, 2- oxabicyclo[2.1.0]pentan
  • Heterocycloalkyl groups can also include spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom).
  • spirocyclic heterocycloalkyls include 2- azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, l-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7- azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, l,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5-diazaspiro[3.6]decane, 3 -azaspiro [5.5] undecane, 2- oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, l-
  • heterocycloalkyl refers to a mono-, bi-, tri-, or polycyclic saturated or partially unsaturated ring system with 3-20 total ring atoms and having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic.
  • exemplary heteroatoms include O, N, S, P, Si, and B.
  • a heterocycloalkyl comprises 1, 2, 3, or 4 heteroatoms selected from O, N, and S.
  • a heterocycloalkyl comprises 1, 2, 3, or 4 heteroatoms selected from O, N, and S.
  • a heterocycloalkyl comprises 1 or 2 (e.g., 1) heteroatoms selected from O, N, and S. In some embodiments, a heterocycloalkyl comprises one O atom. In some embodiments, a heterocycloalkyl comprises one S atom. In some embodiments, a heterocycloalkyl comprises one N atom. Heterocycloalkyl ring systems can also include 1-3 ring atoms that are oxo, N-oxide, S- oxide, and/or S,S-dioxide groups, valence permitting.
  • heterocycloalkyl groups examples include piperazinyl, pyrrolidinyl, pyrrolidonyl, tetrahydrothiophenyl 1,1 -dioxide, thiomorpholinyl 1,1-dioxide, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, and the like.
  • Heterocycloalkyl groups can include multiple fused and bridged rings.
  • Non-limiting examples of fused/bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2- azabicy clo [1.1.1 [pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1 ]hexane, 3- azabicyclo [3.2.0] heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, azabicyclo [2.2.1 [heptane, 6-azabicyclo[3.1.
  • Heterocycloalkyl groups can also include spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom).
  • spirocyclic heterocycloalkyls include 2- azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, l-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7- azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, l,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5-diazaspiro[3.6]decane, 3 -azaspiro [5.5] undecane, 2- oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, l-
  • heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as one or more of
  • saturated 1 as used in this context means only single bonds present between constituent atoms.
  • a ring when a ring is described as being “partially unsaturated,” it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic.
  • additional degrees of unsaturation in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms
  • examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, di hydrothiophene, and the like.
  • rings and cyclic groups e.g., carbocycle, aryl, cycloalkyl, heterocyclyl, heteroaryl, and the like described herein
  • rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x.O] ring systems, in which 0 represents a zero atom bridge (e.g., ))
  • a single ring atom spiro-fused ring systems (e.g., , or ), or
  • any compound or structure given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. These forms of compounds are referred to as “isotopically enriched.” Isotopically enriched compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine, such as 2 H, 13 C, i4 C, 13 N, 15 N, 15 O, 17 O, 18 0, 3i P, 32 P, 35 S, l8 F, 36 C1 , 123 I, and 125 I, respectively.
  • isotopically enriched compounds of the present disclosure for example those into which radioactive isotopes such as 13 C and !4 C are incorporated.
  • Such isotopically enriched compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • the term“isotopically enriched” compounds includes" deuterated” compounds described herein in which one or more hydrogens is/are replaced by deuterium, such as a hydrogen on a carbon atom. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human.
  • Such compounds are synthesized by means known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.
  • isotopically enriched compounds of this disclosure can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically enriched reagent for a non-isotopically enriched reagent.
  • Deuterium enriched compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index relative to the corresponding non-enriched compound.
  • DMPK drug metabolism and pharmacokinetics
  • the concentration of a heavier isotope, such as deuterium, may be defined by an isotopic enrichment factor.
  • the positions noted as “H” or “hydrogen” in the compounds described herein have hydrogen at its natural abundance isotopic composition.
  • the positions noted as “H” or “hydrogen” in the compounds described herein have hydrogen enriched in deuterium above its natural abundance isotopic composition, i.e., the compound is a deuterium enriched compound.
  • deurated groups in the compounds described herein include, but are not limited to deuteromethine ( or monodeuteromethylene ) and dideuteromethylene °x ’ D "''tyr trideuteromethyl (
  • D ⁇ deuterium enriched compounds adjacent to a heteroatom such as, for example and
  • a compound containing the moiety encompasses the tautomeric form containing the moiety: H $ .
  • a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.
  • the compounds provided herein may encompass various stereochemical forms.
  • the compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, as well as mixtures of enantiomers (e.g., R and S isomers) including racemic mixtures and mixtures of diastereomers, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds.
  • enantiomers e.g., R and S isomers
  • diastereomers e.g., R and S isomers
  • mixtures of enantiomers e.g., R and S isomers
  • a disclosed compound is named or depicted by a structure that specifies the stereochemistry (e.g., a structure with “wedge” and/or “dashed” bonds) and has one or more chiral centers, it is understood to represent the indicated stereoisomer of the compound.
  • Dual-specificity tyrosine phosphorylation-regulated kinase 1 A is a member of the dual-specificity tyrosine phosphorylation regulated kinase (DYRK) family, which is also part of the larger CGMC family of kinases.
  • DYRK 1 A is a 763 amino acid, 85 kDa serine/threonine kinase located on chromosome 21.
  • DYRK1A contains a nuclear targeting signal sequence, a protein kinase domain, a leucine zipper motif, and a highly conservative 13-consecutive-histidine repeat.
  • Alternative splicing DYRK 1 A generates several transcript variants differing from each other either in either the 5' untranslated region or in the 3' coding region resulting in at least five different isoforms.
  • DYRKIA possesses catalytic activity that is regulated by autophosphorylation of a tyrosine residue ( ⁇ 321) which results in constitutively active serine/threonine kinase activity. Since DYRK 1 A is constitutively active, its activity is dosage dependent. Thus, both elevated levels and depressed levels of DYRKIA (relative to wild-type levels) have been shown to lead to neurological impairment.
  • DYRKIA displays a broad substrate spectrum (e.g., broad range of targets) including splicing factors, synaptic proteins, and transcription factors. It is ubiquitously expressed in all mammalian tissues and cells, although at different levels, with particularly high levels in embryonic and adult brain tissues.
  • the human DYRKI A gene is a candidate gene to treat several Down syndrome characteristics, including intellectual impairment and Alzheimer’s disease associated with Down syndrome, due to its localization in the Down syndrome critical region on chromosome 21 and its role in brain function.
  • Drosophila with deleterious mutations in the ortholog of DYRKIA (“Minibrain”) have a reduced number of neurons in their central nervous system.
  • mice heterozygous for a disrupted allele of the Dyrkla gene exhibit decreased viability, behavioral alterations, and delayed growth.
  • DYRKIA overexpression indicates that DYRKIA over express! on is central for the deregulation of multiple pathways in the developing and aging brain of individuals with Down syndrome. Identifying DYRKIA cell signaling or transduction pathways can lead to a better understanding of how DYRKIA overexpression (or under expression) leads to the various disease states in which it is known to be involved. Specifically, DYRK1A is known to be active in activated PI3K/Akt signaling, a pathway largely involved in neuronal development, growth, and survival.
  • DYRK1A is also known to be active in ASK1/JNK1 activity and inhibitors of DYRK1A may induce neuronal death and apoptosis.
  • DYRK1A is also known to phosphorylate p53 during embryonic brain development, and inhibitors of DYRK1A can prevent neuronal proliferation alteration.
  • DYRK1A also phosphorylates synaptic proteins Amph 1, Dynamin 1, and Synaptojamn, which are involved in the regulation of endocytosis and inhibitors of DYRK1A can retain synaptic plasticity’ through preventing alteration of the number, size, and morphology of dendritic spines.
  • DYRK1A also phosphorylates inhibit presenilm 1, the catalytic sub-unit of y- secretase. Ryu, et al., J Neurochem., 115(3): 574-84 (2010).
  • DYRK1A over expression leads to structural and functional alterations including intellectual disability’ and dementia, e.g., Alzheimer’s disease.
  • genes involved in learning disorders, synaptic flexibility’ changes, memory loss, and abnormal cell cycles result in neuropathological symptoms similar to dementia associated with Alzheimer’s disease.
  • DYRK1A can also affect the proliferation and differentiation of neuronal progenitors, thus influencing neurogenesis and brain growth. It can also affect neurotransmission and dendritic spine formation through its interaction with synaptic proteins and the cytoskeleton.
  • DYRK1 A One potential source of treatment are inhibitors of DYRK1 A, Inhibitors that can normalize DYRK1A levels in Down syndrome may improve synaptic plasticity' and delay the onset of Alzheimer’s disease pathology, including tau hyperphosphorylation. Therefore, inhibiting DYRK1 A activity in individuals with Down syndrome might counteract the phenotypic effects of its overexpression and is a potential avenue for the treatment of such developmental defects and prevention and/or mitigation of age-associated neurodegeneration, including Alzheimer’s disease associated with Down syndrome. Studies have shown that inhibition of overexpressed DYRK1 A resulted in normal DYRK1 A levels and been found to improve cognitive and behavioral deficits in transgenic models. See, e.g., Stringer, et al..
  • EGCG Epigall ocatechin gallate
  • EGCG is a non- ATP competitive DYRK1A inhibitor and studies have shown that green tea extract comprising 41% EGCG were able to alleviate cognitive decline seen in transgenic mice over expressing DYRK1A.
  • ECGC has also been shown to improve memory recognition and working memory. However, ECGC is not significantly selective and has numerous off-target effects, thus reducing its potential long-term use.
  • SM07883 is an orally bioavailable (%F 92% in mice, 109% in monkey), BBB penetrant, DYRK1A inhibitor (IC50 1.6 nM) that also show's potent inhibition for DYRK1B, CLK4, and GSK3P in kinase assays. It was found to protect against tau hyperphosphorylation in mouse models.
  • This disclosure provides compounds of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, and pharmaceutically acceptable salts thereof, that inhibit Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A).
  • DYRK1A Dual specificity tyrosine-phosphorylation-regulated kinase 1A
  • These chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) DYRK1A activation contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., a neurological disorder in a subject (e.g., a human).
  • This disclosure also provides compositions containing the same as well as methods of using and making the same.
  • Some embodiments provide a compound of Formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein: each represents a single or a double bond, such that the bicyclic ring system comprising Y 1 , Y 2 , Y 3 , and Y 4 is an aromatic bicyclic ring system where (i) Y 1 is CR 3 , Y 2 is N, Y 3 is CR 4 , and Y 4 is CR 3 or N; (ii) Y 1 is S, Y 2 is C, Y 3 is CR 4 or N, and Y 4 is CR 3 ; or (iii) Y 1 is N, Y 2 is N, Y 3 is CR 4 , and Y 4 is CR 3 ; L is selected from , , and , wherein * denotes the point of attachment to Ring A, Z is selected from -O-, -NR 1 -, C1-4alkylene, -O-C1-4alkylene, and -NR 1 -
  • the one or more substituents is 1-4 substituents (e.g., 1- 3, 2-4, 2-3, 1-2, 3-4, 1, 2, 3, or 4 substituents).
  • the one or more substituents is 1-4 substituents.
  • the one or more substituents is one substituent.
  • Y 1 is CR 3
  • Y 2 is N
  • Y 3 is CR 4
  • Y 4 is CR 3 or N.
  • Y 1 is CR 3
  • Y 2 is N
  • Y 3 is CR 4
  • Y 4 is N.
  • Y 1 is CR 3 , Y 2 is N, Y 3 is CR 4 , and Y 4 is CR 3 .
  • Y 1 is S, Y 2 is C, Y 3 is CR 4 or N, and Y 4 is CR 3 .
  • Y 1 is S, Y 2 is C, Y 3 is CR 4 , and Y 4 is CR 3 .
  • Y 1 is S, Y 2 is C, Y 3 is N, and Y 4 is CR 3 .
  • Y 1 is N, Y 2 is N, Y 3 is CR 4 , and Y 4 is CR 3 .
  • Y 1 is CH, Y 2 is N, Y 3 is CH, and Y 4 is CH or N.
  • Y 1 is CH, Y 2 is N, Y 3 is CH, and Y 4 is N.
  • Y 1 is CH, Y 2 is N, Y 3 is CH, and Y 4 is CH.
  • Y 1 is S, Y 2 is C, Y 3 is CH or N, and Y 4 is CH.
  • Y 1 is S, Y 2 is C, Y 3 is CH, and Y 4 is CH.
  • Y 1 is S, Y 2 is C, Y 3 is CH, and Y 4 is CH.
  • Y 1 is S, Y 2 is C, Y 3 is N, and Y 4 is CH.
  • Y 1 is N, Y 2 is N, Y 3 is CH, and Y 4 is CH.
  • the compound is of Formula (IA):
  • the compound is of Formula (IB): (IB), or a pharmaceutically acceptable salt thereof; the compound is of Formula (IC); wherein Y 3 is CH or N, and Y 4 is CH or N. (IC), or a pharmaceutically acceptable salt thereof; wherein Y 3 is CH or N.
  • the compound is of Formula (ID): 10 (ID), or a pharmaceutically acceptable salt thereof; wherein Y 4 is CH or N.
  • L is or . In some embodiments, L is or . In some embodiments, L is or . In some embodiments, L is or . In some embodiments, for the compound of Formula (I), (IA), (IB), (IC), or (ID), Z is selected from -O-, -NR 1 -, C 1-4 alkylene, -O-C 1-4 alkylene, and -NR 1 -C 1-4 alkylene, wherein each C 1- 4 alkylene is optionally substituted with one or more halogen.
  • Z is selected from -O-, -NR 1 -, C 1-4 alkylene, -O-C 1-4 alkylene, and -NR 1 -C 1-4 alkylene, wherein each C 1-4 alkylene is optionally substituted with one or more halogen; and R 1 is independently selected at each occurrence from hydrogen, C1-4 alkyl, and C1-4 haloalkyl.
  • Z is selected from -O-, -NR 1 -, C1-4alkylene, -O-C1-4alkylene, and -NR 1 -C1-4alkylene, wherein each C1-4alkylene is optionally substituted with one or more halogen; and R 1 is independently selected at each occurrence from hydrogen and C 1-4 alkyl.
  • Z is selected from -O-, -NR 1 -, C 1-4 alkylene, -O-C 1-4 alkylene, and -NR 1 -C 1-4 alkylene, wherein each C 1-4 alkylene is optionally substituted with one or more halogen; and each R 1 is hydrogen.
  • Z is selected from -O-, -NR 1 -, C 1-4 alkylene, -O-C 1-4 alkylene, and -NR 1 -C 1-4 alkylene; and each R 1 is hydrogen.
  • Z is selected from -O-, -NR 1 -, C1-2alkylene, -O-C1-2alkylene, and -NR 1 -C1-2alkylene, wherein each C1- 2alkylene is optionally substituted with one or more halogen; and R 1 is independently selected at each occurrence from hydrogen and C1-4 alkyl.
  • Z is selected from -O-, -NR 1 -, C1-2alkylene, -O-C1-2alkylene, and -NR 1 -C1-2alkylene, wherein each C1-2alkylene is optionally substituted with one or more halogen; and each R 1 is hydrogen.
  • Z is selected from -O-, -NR 1 -, C 1-2 alkylene, -O-C 1-2 alkylene, and -NR 1 -C 1-2 alkylene; and each R 1 is hydrogen
  • Z’ is selected from -NR 1 -, -S(O)-, -S(O)2-, C1-4alkylene, -NR 1 -C1-4alkylene, -S(O)-C1-4alkylene, and - S(O)2-C1-4alkylene; wherein each C1-4alkylene is optionally substituted with one or more halogen; and R 1 is independently selected at each occurrene from hydrogen and C1-4 alkyl.
  • Z’ is selected from -NR 1 -, -S(O)-, -S(O) 2 -, C 1-4 alkylene, -NR 1 -C 1-4 alkylene, -S(O)- C1-4alkylene, and -S(O)2-C1-4alkylene; and each R 1 is hydrogen.
  • Z’ is selected from -S(O)2-, C1-4alkylene, and -S(O)2-C1-4alkylene; wherein each C1-4alkylene is optionally substituted with one or more halogen.
  • Z’ is selected from -S(O)2- , C 1-4 alkylene, and -S(O) 2 -C 1-4 alkylene. In some embodiments, Z’ is C 1-4 alkylene, optionally substituted with one or more halogen. In some embodiments, Z’ is C 1-4 alkylene. In some embodiments, Z’ is C 1-4 alkylene, optionally substituted with one or more halogen; and R 1 is hydrogen. In some embodiments, Z’ is C 1-4 alkylene; and R 1 is hydrogen.
  • Z’ is selected from -NR 1 -, -S(O)-, -S(O)2-, C1-2alkylene, -NR 1 -C1-2alkylene, -S(O)-C1-2alkylene, and - S(O)2-C1-2alkylene; wherein each C1-2alkylene is optionally substituted with one or more halogen; and each R 1 is hydrogen.
  • Z’ is selected from -S(O)2-, C1-2alkylene, and - S(O) 2 -C 1-2 alkylene; wherein each C 1-2 alkylene is optionally substituted with one or more halogen, and R 1 is hydrogen.
  • Z’ is C 1-2 alkylene optionally substituted with one or more halogen.
  • Z’ is C 1-2 alkylene.
  • Z’ is C 1-2 alkylene optionally substituted with one or more halogen; and R 1 is hydrogen.
  • Z’ is C1-2alkylene; and R 1 is hydrogen.
  • Z is selected from -O-, -NR 1 -, C1-4alkylene, -O-C1-4alkylene, and -NR 1 -C1-4alkylene; and Z’ is selected from -S(O)2-, C1-4alkylene, and -S(O)2-C1-4alkylene; wherein each C1-4alkylene is optionally substituted with one or more halogen; and R 1 is independently selected at each occurrence from hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl.
  • Z is selected from -O-, -NR 1 -, C 1- 4 alkylene, -O-C 1-4 alkylene, and -NR 1 -C 1-4 alkylene; and Z’ is selected from -NR 1 -, -S(O)-, -S(O) 2 - , C 1-4 alkylene, -NR 1 -C 1-2 alkylene, -S(O)-C 1-4 alkylene, and -S(O) 2 -C 1-4 alkylene, wherein each C 1- 4alkylene is optionally substituted with one or more halogen.
  • Z is selected from -O-, -NR 1 -, C1-4alkylene, -O-C1-4alkylene, and -NR 1 -C1-4alkylene; and Z’ is selected from - NR 1 -, -S(O)-, -S(O)2-, C1-4alkylene, -NR 1 -C1-4alkylene, -S(O)-C1-4alkylene, and -S(O)2-C1- 4alkylene, wherein each C1-4alkylene is optionally substituted with one or more halogen; and R 1 is independently selected at each occurrence from hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl.
  • Z is selected from -O-, -NR 1 -, C 1-4 alkylene, -O-C 1-4 alkylene, and -NR 1 -C 1- 4 alkylene; In some embodiments, Z’ is selected from -S(O) 2 -, C 1-4 alkylene, and -S(O) 2 -C 1- 4alkylene; wherein each C1-4alkylene is optionally substituted with one or more halogen; and R 1 is independently selected at each occurrence from hydrogen and C1-4 alkyl.
  • Z is selected from -O-, -NR 1 -, C1-4alkylene, -O-C1-4alkylene, and -NR 1 -C1-4alkylene; Z’ is C1- 4alkylene, optionally substituted with one or more halogen; wherein each C1-4alkylene is optionally substituted with one or more halogen; and each R 1 is hydrogen.
  • Z is selected from -O-, -NR 1 -, C 1-4 alkylene, -O-C 1-4 alkylene, and -NR 1 -C 1-4 alkylene; Z’ is C 1-4 alkylene; and each R 1 is hydrogen.
  • Z is selected from -O-, -NR 1 -, C1-2alkylene, -O-C1-2alkylene, and -NR 1 -C1-2alkylene; and Z’ is selected from -NR 1 -, -S(O)-, -S(O)2-, C1-2alkylene, -NR 1 -C1-2alkylene, -S(O)-C1-2alkylene, and -S(O)2-C1- 2alkylene, wherein each C1-2alkylene is optionally substituted with one or more halogen; and R 1 is independently selected at each occurrence from hydrogen, C1-4 alkyl, and C1-4 haloalkyl.
  • Z is selected from -O-, -NR 1 -, C 1-2 alkylene, -O-C 1-2 alkylene, and -NR 1 -C 1- 2 alkylene; In some embodiments, Z’ is selected from -S(O) 2 -, C 1-2 alkylene, and -S(O) 2 -C 1- 2 alkylene; wherein each C 1-2 alkylene is optionally substituted with one or more halogen; and R 1 is independently selected at each occurrence from hydrogen and C 1-4 alkyl.
  • Z is selected from -O-, -NR 1 -, C1-2alkylene, -O-C1-2alkylene, and -NR 1 -C1-2alkylene; Z’ is C1- 2alkylene, optionally substituted with one or more halogen; wherein each C1-2alkylene is optionally substituted with one or more halogen; and each R 1 is hydrogen.
  • Z is selected from -O-, -NR 1 -, C1-2alkylene, -O-C1-2alkylene, and -NR 1 -C1-2alkylene; Z’ is C1-4alkylene; and each R 1 is hydrogen.
  • Z is selected from -O-, -NH-, -CH 2 -, -O-CH 2 -, and - NH-CH 2 -; and Z’ is -CH 2 -.
  • L is selected from , , , , , , , , , , , and .
  • L is .
  • L is ;
  • Z is selected from -O-, -NR 1 -, C1- 4alkylene, -O-C1-4alkylene, and -NR 1 -C1-4alkylene, wherein each C1-4alkylene is optionally substituted with 1-2 halogen; and R 1 is independently selected at each occurrence from hydrogen, C1-4 alkyl, and C1-4haloalkyl.
  • L is ; Z is selected from -O-, -NR 1 -, C 1-4 alkylene, -O-C 1-4 alkylene, and -NR 1 -C 1-4 alkylene, wherein each C 1-4 alkylene is optionally substituted with 1-2 halogen; and R 1 is independently selected at each occurrence from hydrogen and C 1-4 alkyl.
  • L is ; Z is selected from -O-, -NR1- , C1-4alkylene, -O-C1-4alkylene, and -NR 1 -C1-4alkylene; and R 1 is independently selected at each occurrence from hydrogen and C1-4 alkyl.
  • L is ; Z is selected from -O-, -NR 1 -, C1-4alkylene, -O-C1-4alkylene, and -NR 1 -C1-4alkylene; and each R 1 is hydrogen.
  • L is ; Z is selected from -O-, -NR 1 -, C 1-2 alkylene, -O-C 1- 2 alkylene, and -NR 1 -C 1-2 alkylene, wherein each C 1-2 alkylene is optionally substituted with 1-2 halogen; and R 1 is independently selected at each occurrence from hydrogen and C 1-4 alkyl.
  • L is ; Z is selected from -O-, -NR 1 -, C1-2alkylene, -O-C1- 2alkylene, and -NR 1 -C1 lk l h i h C lk l i tionally substituted with 1-2 halogen; and each R 1 is hydrogen.
  • L is selected from, , , , , , , and .
  • L is for the compound of Formula (I), (IA), (IB), (IC), or (ID), L is .
  • L is ; Z’ is selected from C 1-4 alkylene optionally substituted with 1-2 halogen; and R 1 is selected from hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl. In some embodiments, L is ; Z’ is selected from C 1-4 alkylene optionally substituted with 1-2 halogen; and R 1 is hydrogen. In some embodiments, L is ; Z’ is selected from C1- 4alkylene; and R 1 is hydrogen. In some embodiments, L is . In some embodiments, for the compound of Formula (I), (IA), (IB), (IC), or (ID), L is .
  • L is ; and R 1 is independently selected at each occurrence from hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl. In some embodiments, L is ; and R 1 is independently selected at each occurrence from hydrogen, C1-4 alkyl, C1-4 haloalkyl. In some embodiments, L is ; and R 1 is independently selected at each occurrence from hydrogen and C 1-4 alkyl. In some embodiments, L is selected from , , , , , and . In some embodiments, L is .
  • Some embodiments provide a compound of Formula (II): (II); or a pharmaceutically acceptable salt thereof, wherein: each represents a single or a double bond, such that the bicyclic ring system comprising Y 1 , Y 2 , and Y 3 is an aromatic bicyclic ring system where (i) Y 1 is CR 3 and Y 2 is N, or (ii) Y 1 is S and Y 2 is C; Y 3 is selected from N and CR 4 ; Ring B is selected from (a), (b) and (c): (a) , X 1 is selected from N, CH, and CR 5 ; (b) , X 2 is selected from S and NR 7 ; and (c) , X 3 is selected from S, N, and NH, X 4 is selected from O and CR 9 , X 5 is N or CH, X 6 is N or CH, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system; R
  • Y 1 is CR 3 ; Y 2 is N; and Y 3 is N. In some embodiments, Y 1 is CR 3 ; Y 2 is N; and Y 3 is CR 4 . In some embodiments, Y 1 is CR 3 ; Y 2 is N; and Y 3 is CH. In some embodiments, Y 1 is CR 3 , Y 2 is N, and Y 4 is CR 3 . In some embodiments, Y 1 is CR 3 ; Y 2 is N; Y 3 is N; and Ring B is (a). In some embodiments, Y 1 is CR 3 ; Y 2 is N; Y 3 is CR 4 ; and Ring B is (a).
  • Y 1 is S and Y 2 is C. In some embodiments, Y 1 is S; Y 2 is C; and Y 3 is N. In some embodiments, Y 1 is S; Y 2 is C; and Y 3 is CR 4 . In some embodiments, Y 1 is S; Y 2 is C; and Y 3 is CH. In some embodiments, Y 3 is N. In some embodiments, Y 3 is CR 4 ; and R 4 is selected from hydrogen and halogen. In some embodiments, Y 3 is CH.In some embodiments, Y 1 is S; Y 2 is C; and X 1 is N.
  • Y 1 is S; Y 2 is C; and R A is selected from C 1-4 alkyl.
  • Y 1 is CR 3 , Y 2 is N, Y 3 is CR 4 , and Y 4 is N.
  • Y 1 is CR 3 , Y 2 is N, Y 3 is CH, and Y 4 is N.
  • Y 1 is CR 3 , Y 2 is N, Y 3 is CR 4 , and Y 4 is N.
  • Y 1 is CH, Y 2 is N, Y 3 is CR 4 , and Y 4 is N; and R 4 is selected from hydrogen, halogen, and C1-4 alkyl.
  • the compound is of Formula (IIA): (IIA), or a pharmaceutically acceptable salt thereof; wherein Y 3 is CH or N, and Y 4 is CH or N.
  • the compound is of Formula (IIA-1): (IIA-1), or a pharmaceutically acceptable salt thereof; wherein Y 3 is CH or N.
  • the compound is of Formula (IIB): (IIB), or a pharmaceutically acceptable salt thereof; wherein Y 3 is CH or N, and Y 4 is CH or N.
  • R 3 is selected from selected from hydrogen, halogen, and C1-4 alkyl.
  • the compound is of Formula (IIB-1): (IIB-1), or a pharmaceutically acceptable salt thereof; wherein Y 3 is CH or N.
  • R 3 is selected from selected from hydrogen, halogen, and C1-4 alkyl.
  • the compound is of Formula (IIC): (IIC), or a pharmaceutically acceptable salt thereof; wherein Y 3 is CH or N.
  • the compound is of Formula (IIC-1): (IIC-1), or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (IID): (IID), or a pharmaceutically acceptable salt thereof; wherein Y 4 is CH or N.
  • the compound is of Formula (IID-1): (IID-1), or a pharmaceutically acceptable salt thereof.
  • each R 3 is selected from selected from hydrogen, halogen, and C1-4 alkyl. In some embodiments, each R 3 is selected from selected from hydrogen and halogen. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is halogen. In some embodiments, R 3 is fluoro. In some embodiments, R 3 is chloro. In some embodiments, R 3 is C 1-4 alkyl. In some embodiments, R 3 is methyl.
  • R 3 is C1-4 haloalkyl. In some embodiments, R 3 is trifluoromethyl.
  • R 1 is independently selected at each occurrence from hydrogen, C1-4 alkyl, and C1-4 haloalkyl. In some embodiments, R 1 is independently selected at each occurrence from hydrogen and C1-4 alkyl. R 1 is independently selected at each occurrence from hydrogen, -CH3, -CF3, -CH2CH3, , and .
  • R 1 is -CH3. In some embodiments, R 1 is -CH2CH3. In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, each R 1 is hydrogen. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), Formula (II), (IIA), (IIA-1), (IIB), (IIB-1), (IIC), (IIC-1), (IID), or (IID-1), R 2 is independently selected at each occurrence from halogen and C 1-4 alkyl. In some embodiments, R 2 is halogen. In some embodiments, R 2 is C 1-4 alkyl.
  • R 2 is C 1-4 haloalkyl. In some embodiments, R 2 is -OR 10 . In some embodiments, R 2 is -SR 10 . In some embodiments, R 2 is -N(R 10 ) 2 . In some embodiments, R 2 is NO2. In some embodiments, R 2 is –CN. In some embodiments, R 2 is independently selected at each occurrence from C1-4 alkyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), Formula (II), (IIA), (IIA-1), (IIB), (IIB-1), (IIC), (IIC-1), (IID), or (IID-1), m is 0 or 1. .
  • Ring B is selected from (a), (b) and (c): (a) , X 1 is selected from N, CH, and CR 5 ; (b) , X 2 is selected from S and NR 7 ; and (c) , X 3 is selected from S, N, and NH, X 4 is selected from O and CR 9 , X 5 is N or CH, X 6 is N or CH, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system, provided that when Ring B is (a), Y 1 is CR 3 , Y 2 is N, Y 3 is CR
  • Ring B is selected from (a) and (c): (a) , X 1 is selected from N, CH, and CR 5 ; (c) , X 3 is selected from S, N, and NH, X 4 is selected from O and CR 9 , X 5 is N or CH, X 6 is N or CH, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system.
  • Ring B is selected from: (b)
  • X 2 is selected from S and NR 7 .
  • Ring B is selected from (a) and (c): (a) , X 1 is selected from N, CH, and CH; and (c) , X 3 is selected from S, N, and NH, X 4 is selected from O and CR 9 , and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system selected from benzothiazole, benzimidazole, and benzofurazan; wherein: R A is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -N(R 11 )2, -SR 11
  • Ring B is selected from (a) and (c): (a) , X 1 is selected from N, CH, and CR 5 ; and (c) , X 3 is selected from S, N, and NH, X 4 is selected from O and CR 9 , and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system selected from benzothiazole, benzimidazole, and benzofurazan; wherein: R A is selected from -F, -Cl, -CN, -NH2, -CH3, -CF3, -CHF2, , , , , , , ,
  • Ring B is selected from: (a) , and X 1 is selected from N, CH, and CR 5 ; provided that when Y 1 is CR 3 , Y 2 is N, Y 3 is CR 4 , and Y 4 is N, then p is 0, In some embodiments, X 1 is selected from N and CH. In some embodiments, X 1 is N.
  • R A is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, -N(R 11 ) 2 , -SR 11 , -N(R 11 )C(O)R 11 , -CN, C 3-5 cycloalkyl, and 5- to 6-membered heterocycloalkyl, provided that: when Y 1 is CR 3 , Y 2 is N, and Y 4 is CR 3 , or when Y 1 is CR 3 , Y 2 is N, and Y 4 is N, then R A is further selected from -OR 11
  • R A is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, -N(R 11 ) 2 , -SR 11 , -N(R 11 )C(O)R 11 , -CN, C 3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; and Y 1 is CR 3 , Y 2 is N, and Y 4 is CR 3 or when Y 1 is CR 3 , Y 2 is N, and Y 4 is N, then R A is further selected from - OR 11 ; R 11 is
  • R A is halogen.
  • R A is C 1-4 alkyl.
  • R A is methyl.
  • R A is ethyl.
  • R A is C1-4 haloalkyl.
  • R A is C1-4 hydroxyalkyl.
  • R A is -N(R 11 )2.
  • R A is -SR 11 . In some embodiments, R A is -N(R 11 )C(O)R 11 . In some embodiments, R A is -CN. In some embodiments, R A is C3-6 cycloalkyl. In some embodiments, R A is 3- to 6-membered heterocycloalkyl.
  • Y 1 is CR 3 and Y 2 is N; and R A is further selected from -OR 11 , provided that when R A is -OR 11 , then R 5 is not -OR 13 .
  • Y 1 is CR 3 , Y 2 is N, and Y 4 is N, and R A is further selected from - OR 11 .
  • Y 1 is CR 3 , Y 2 is N, Y 3 is CH, Ring B is (a), p is 0, X 1 is N, and Ring A is 1-fluoro-1-tetrahydropyranyl; and R A is further selected from hydrogen.
  • Y 1 is S, Y 2 is C, and X 1 is N; and R A is further selected from hydrogen.
  • R A is selected from -F, -Cl, -CN, -NH2, -CH3, -CF3, -CHF2, , , , , and ; and when Y 1 is CR 3 and Y 2 is N, then R A is further selected from -OH, -OCH3, and . In some embodiments, R A is -F.
  • R A is -Cl. In some embodiments, R A is -CN. In some embodiments, R A is -NH 2 . In some embodiments, R A is -OH. In some embodiments, R A is -OCH3. In some embodiment, R A is . In some embodiments, R A is -CH 3 . In some embodiments, R A is -CF 3 . In some embodiments, R A is -CHF 2 . In some embodiments, R A is . In some embodiments, R A is . In some embodiments, R A is . In some embodiments, R A is . In some embodiments, R A is and .
  • p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.
  • R 5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR 13 , -SR 13 , -N(R 13 ) 2 , -C(O)OR 13 , -C(O)N(R 13 ) 2 , -NO 2 , and -CN, provided that when R A is -OR 11 , then R 5 is not -OR 13 ; and R 13 is independently selected at each occurrence from hydrogen, C 1-4 alkyl, and C 1- 4 haloalkyl.
  • R 5 is independently selected at each occurrence from halogen, C 1-4 alkyl, C 1-4 haloalkyl, -SR 13 , -N(R 13 ) 2 , -C(O)OR 13 , -C(O)N(R 13 ) 2 , -NO 2 , and -CN; and R 13 is independently selected at each occurrence from hydrogen, C1-4alkyl, and C1-4 haloalkyl.
  • R 5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1- 4 haloalkyl, -OR 13 , -N(R 13 )2, and -CN, provided that when R A is -OR 11 , then R 5 is not -OR 13 ; and R 13 is independently selected at each occurrence from hydrogen and C1-4alkyl.
  • R 5 is independently selected at each occurrence from halogen, C 1-4 alkyl, C 1- 4 haloalkyl, -N(R 13 ) 2 , and -CN; and R 13 is independently selected at each occurrence from hydrogen and C 1-4 alkyl.
  • R 5 is independently selected at each occurrence from halogen, C 1-4 alkyl, C 1-4 haloalkyl, and -OR 13 , provided that when R A is -OR 11 , then R 5 is not -OR 13 ; and R 13 is independently selected at each occurrence from hydrogen and C1-4alkyl. In some embodiments, R 5 is independently selected at each occurrence from halogen, C1-4 alkyl, and C1- 4 haloalkyl. In some emb di R 5 i i d d l l d ach occurrence from halogen. In some embodiments, R 5 is independently selected at each occurrence from C 1-4 alkyl.
  • Ring B is selected from (b)
  • X 2 is selected from S and NR 7 .
  • X 2 is S.
  • X 2 is NR 7 .
  • X 2 is S or NH.
  • X 2 is NH.
  • X 2 is S.
  • R 7 is selected from hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl.
  • R 7 is selected from hydrogen, and C 1-4 alkyl.
  • q is 0 or 1.
  • q is 1.
  • q is 0.
  • q is 1 or 2.
  • q is 2.
  • R 6 is independently selected at each occurrence from halogen, C 1-4 alkyl, C 1-4 haloalkyl, -OR 14 , -SR 14 , -N(R 14 ) 2 , -C(O)R 14 , -C(O)OR 14 , -OC(O)R 14 , -C(O)N(R 14 ) 2 , -N(R 14 )C(O)R 14 , -N(R 14 )S(O) 2 (R 14 ), -S(O) 2 R 14 , -S(O) 2 N(R 14 ) 2 ,
  • R 6 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR 14 , -SR 14 , -N(R 14 )2, -C(O)OR 14 , -S(O)2N(R 14 )2, -NO2, and -CN; and R 14 is independently selected at each occurrence from hydrogen, C1-4alkyl, and C1-4 haloalkyl.
  • R 6 is independently selected at each occurrence from halogen, C 1-4 alkyl, C 1-4 haloalkyl, -OR 14 , -SR 14 , -N(R 14 ) 2 , and -CN; and R 14 is independently selected at each occurrence from hydrogen and C1-4alkyl.
  • R 6 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR 14 , and -N(R 14 )2, and R 14 is independently selected at each occurrence from hydrogen and C1-4alkyl.
  • R 6 is independently selected at each occurrence from halogen, C1-4 alkyl, and C 1-4 haloalkyl.
  • R 6 is independently selected at each occurrence from halogen and C 1-4 alkyl. In some embodiments, R 6 is independently selected at each occurrence from halogen. In some embodiments, R 6 is independently selected at each occurrence from C 1-4 alkyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), R 6 is halogen. In some embodiments, R 6 is C1-4 alkyl.
  • R 6 is C1-4 haloalkyl. In some embodiments, R 6 is -OR 14 . In some embodiments, R 6 is -SR 14 . In some embodiments, R 6 is -N(R 14 ) 2 . In some embodiments, R 6 is -C(O)R 14 . In some embodiments, R 6 is -C(O)OR 14 . In some embodiments, R 6 is -OC(O)R 14 . In some embodiments, R 6 is -C(O)N(R 14 ) 2 . In some embodiments, R 6 is -N(R 14 )C(O)R 14 . In some embodiments, R 6 is -N(R 14 )S(O) 2 (R 14 ).
  • Ring B is selected from (c) , X 3 is selected from S, N, and NH, X 4 is selected from O and CR 9 , and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system.
  • Ring B is an aromatic bicyclic ring system selected from benzothiazole, benzimidazole, and benzofurazan;
  • X3 is selected from S, N, and NH
  • X 4 is selected from O and CR 9
  • X 5 is N or CH
  • X 6 is N or CH, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system selected from benzothiazole, benzimidazole, and benzofurazan.
  • Ring B is an aromatic bicyclic ring system selected from benzothiazole, and benzofurazan. In some embodiments, Ring B is an aromatic bicyclic ring system selected from benzothiazole and benzimidazole. Ring B is an aromatic bicyclic ring system selected from benzimidazole and benzofurazan. In some embodiments, Ring B is a benzothiazole. In some embodiments, Ring B is abenzimidazole. In some embodiments, Ring B is a benzofurazan.
  • X 3 is S.
  • X 3 is N.
  • X 3 is NH.
  • X 4 is O.
  • X 4 is CR 9 .
  • X 3 is S and X 4 is O.
  • X 3 is S and X 4 is CR 9 .
  • X 3 is N and X 4 is O. In some embodiments, X 3 is N and X 4 is CR 9 . In some embodiments, X 3 is NH and X 4 is O. In some embodiments, X 3 is NH and X 4 is CR 9 . In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), r is 0 or 1. In some embodiments, r is 1.
  • R 8 is independently selected at each occurrence from halogen, C2-4 alkyl, C1-4 haloalkyl, -OR 14 , -SR 14 , -N(R 14 )2, -C(O)R 14 , -C(O)OR 14 , -OC(O)R 14 , -C(O)N(R 14 )2, -N(R 14 )C(O)R 14 , -N(R 14 )S(O)2(R 14 ), - S(O)2(R 14 ), - S(O)2(R 14 ), - S(
  • R 8 is independently selected at each occurrence from halogen, C 2-4 alkyl, C 1-4 haloalkyl, -OR 14 , -SR 14 , -N(R 14 ) 2 , -C(O)OR 14 , - C(O)N(R 14 ) 2 , -N(R 14 )C(O)R 14 , -N(R 14 )S(O) 2 (R 14 ), -S(O) 2 R 14 , -S(O) 2 N(R 14 ) 2 , -NO 2 , and -CN; and R 14 is independently selected at each occurrence from hydrogen, C1-4alkyl, and C1-4 haloalkyl.
  • R 8 is independently selected at each occurrence from halogen, C2-4 alkyl, C1- 4 haloalkyl, -OR 14 , -SR 14 , -N(R 14 )2, and -CN; and R 14 is independently selected at each occurrence from hydrogen and C1-4alkyl. In some embodiments, R 8 is independently selected at each occurrence from halogen, C 1-4 haloalkyl, -OR 14 , -SR 14 , -N(R 14 ) 2 , and -CN; and R 14 is independently selected at each occurrence from hydrogen and C 1-4 alkyl.
  • R 8 is independently selected at each occurrence from halogen, C 2-4 alkyl, C 1-4 haloalkyl, -OR 14 , and - N(R 14 )2; and R 14 is independently selected at each occurrence from hydrogen and C1-4alkyl. In some embodiments, R 8 is independently selected at each occurrence from halogen, C1-4 haloalkyl, -OR 14 , and -N(R 14 )2, and R 14 is independently selected at each occurrence from hydrogen and C1- 4alkyl. In some embodiments, R 8 is independently selected at each occurrence from halogen, C2-4 alkyl, and C 1-4 haloalkyl.
  • R 8 is independently selected at each occurrence from halogen and C 1-4 haloalkyl. In some embodiments, R 8 is independently selected at each occurrence from halogen. In some embodiments, R 8 is independently selected at each occurrence from C 2-4 alkyl. In some embodiments, R 8 is independently selected at each occurrence from C 1- 4 haloalkyl. In some embodiments, R 8 is not methyl.
  • R 9 is selected from hydrogen, C1-4 alkyl, and C1-4 haloalkyl. In some embodiments, R 9 is selected from hydrogen, and C 1-4 alkyl. In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is C 1- 4 alkyl. . In some embodiments, R 9 is methyl. In some emboimdnets, R 9 is hydrogen.
  • R 5 is independently selected at each occurrence from halogen and C1-4 alkyl.
  • R 6 and R 8 are each independently selected at each occurrence from halogen and C1-4 alkyl.
  • R 7 and R 9 are each independently selected from hydrogen, and C1-4 alkyl.
  • Ring B is selected from (a) and (c): (a) , X 1 is selected from N, CH, and CR 5 ; and (c) , X 3 is selected from S, N, and NH, X 4 is selected from O and CR 9 , and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system selected from benzothiazole, benzimidazole, and benzofurazan; wherein: R A is selected from -F, -Cl, -CN, -NH 2 , -CH 3 , -CF 3 , -CHF 2 ,
  • Ring B is selected from (a) and (c): (a) , X 1 is selected from N, CH, and CR 5 ; and (c) , X 3 is selected from S, N, and NH, X 4 is selected from O and CR 9 , and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system selected from benzothiazole, benzimidazole, and benzofurazan; wherein: R A is selected from -F, -Cl, -CN, -NH2, -CH3, -CF3, -CHF2, , , , , , , ,
  • Ring B is selected from (a) and (c): (a) , X 1 is selected from N, CH, and CR 5 ; and (c) , X 3 is selected from S, N, and NH, X 4 is selected from O and CR 9 , and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system selected from benzothiazole, benzimidazole, and benzofurazan; wherein: R A is selected from -F, -Cl, -CN, -NH2, -CH3, -CF3, -CHF2, , , , , , , ,
  • Y 1 is CR 3 and Y 2 is N, and R A is –OH. In some embodiments, Y 1 is CR 3 and Y 2 is N, and R A is -OCH3. In some embodiments, Y 1 is CR 3 and Y 2 is N, and R A is . In some embodiments, when R A is -OR 11 , then R 5 is not -OR 13 .
  • Ring B is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
  • Ring B is selected from (a) ;
  • R A is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -N(R 11 )2, -N(R 11 )C(O)R 11 , -CN, C3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl, and when Y 1 is CR 3 and Y 2 is N, then R A is further selected from -OR 11 ; R 11 is independently selected at each occurrence from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, and C 3-6 cycloal
  • Ring B is selected from: (a) ; R A is selected from -F, -Cl, -CN, -NH 2 , -CH 3 , -CF 3 , -CHF 2 , , , , , and ; and when Y 1 is CR 3 and Y 2 is N, then R A is further selected from -OH, -OCH 3 , and ; and X 1 is selected from N, CH, and CR 5 ; R5 is selected from -F and -CH3; p is 0 or 1, provided that when Y 1 is CR 3 , Y 2 is N, Y 3 is CR 4 , and Y 4 is N, then p is 0.
  • Ring B is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring H N O N B is . In some embodiments, Ring B is N .
  • Ring B is selected from (b) , and X 2 is selected from S and NR 7 ; q is 0 or 1; R 6 is selected from halogen, C1-4 alkyl, and C1-4 haloalkyl; and R 7 is selected from hydrogen, C1-4 alkyl, and C1-4 haloalkyl.
  • Ring B is selected from (c) , X 3 is selected from S, N, and NH, X 4 is selected from O and CR 9 , and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system; R 8 is selected from halogen, C 2-4 alkyl, and C 1-4 haloalkyl.
  • R 9 is selected from hydrogen, halogen, C 1-4 alkyl, and C 1-4 haloalkyl.; and r is 0 or 1.
  • Ring B is selected from (c) , X 3 is selected from S, N, and NH, X 4 is selected from O and CR 9 , and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system selected from benzothiazole, benzimidazole, and benzofurazan; R 9 is selected from hydrogen and -CH 3 ; and r is 0.
  • Ring B is selected from: , , , and .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is and .
  • Ring B is (a) and R A is selected from halogen, C 1-4 haloalkyl, C 3- 6 cycloalkyl, -NR 11 , and -OR 11 ; (ii) Y 1 is S, Y 2 is C, Ring B is (a), and X 1 is N; (iii) Y 1 is S, Y 2 is C, Ring B is (a), and R A is C1-4 alkyl; (iv) Ring B is (a),
  • Ring B is (a) and R A is selected from halogen, C1-4 haloalkyl, C3-6 cycloalkyl, -NR 11 , and -OR 11 .
  • Y 1 is S
  • Y 2 is C
  • Ring B is (a)
  • X 1 is N.
  • Y 1 is S, Y 2 is C, Ring B is (a), and R A is C1-4 alkyl. In some embodiments, Ring B is (a), and p is 1, 2, or 3. In some embodiments, R 1 is C 1-4 alkyl or C 1-4 haloalkyl. In some embodiments, Ring B is (c). In some embodiments, Y 1 is CR 3 , Y 2 is N, Y 3 is CR 3 , and Y 4 is N. In some embodiments, Y 1 is N, Y 2 is N, Y 3 is CR 4 , Y 4 is CR 3 , and Ring B is (a) or (c).
  • one or more (e.g., 1-3 (e.g., 1-2 (e.g., 1))) of (i), (ii), (ii), (iv), and (v) apply: (vii) Ring B is (a) and R A is selected from halogen, C1-4 haloalkyl, C3-6 cycloalkyl, -NR 11 , and -OR 11 ; (viii) Y 1 is S, Y 2 is C, Ring B is (a), and X 1 is N; (ix) Y 1 is S, Y 2 is C, Ring B is (a), and R A is C 1-4 alkyl; (x) Ring B is (a), and p is 1, 2, or 3; (xi) R 1 is C 1-4 alkyl; and (xii) Ring B is (c).
  • 1-3 e.g., 1-2 (e.g., 1)
  • Ring B is (a) and R A is selected from halogen, C1-4 haloalkyl, C3-6
  • Ring B is: , wherein X 3 is selected from S and N, X 4 is selected from O and CR 9 , and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system selected from benzothiazole, benzimidazole, and benzofurazan; wherein: R 8 is independently selected at each occurrence from halogen, C2-4 alkyl, C1-4 haloalkyl, and -CN; R 9 is selected from hydrogen and C 1-4 alkyl; p is selected from 0 and 1; and r is selected from 0 and 1.
  • Ring B is , wherein X 1 is selected from N, CH, and CR 5 .
  • Ring B is (a) and R A is selected from halogen, C 1-4 haloalkyl, C 3- 6 cycloalkyl, -NR 11 , and -OR 11 ; (ii) Y 1 is S, Y 2 is C, Ring B is (a), and X 1 is N; (iii) Y 1 is S, Y 2 is C, Ring B is (a), and R A is C1-4 alkyl; (iv) Ring B is (a)
  • Ring B is (a) and R A is selected from halogen, C 1-4 haloalkyl, C 3- 6 cycloalkyl, -NR 11 , and -OR 11 ; (ii) Y 1 is S, Y 2 is C, Ring B is (a), and X 1 is N; (iii) Y 1 is S, Y 2 is C, Ring B is (a), and R A is C1-4 alkyl; (iv) Ring B is (a)
  • Ring B is (a) and R A is selected from halogen, C 1-4 haloalkyl, C 3- 6 cycloalkyl, -NR 11 , and -OR 11 ; (ii) Y 1 is S, Y 2 is C, Ring B is (a), and X 1 is N; (iii) Y 1 is S, Y 2 is C, Ring B is (a), and R A is C 1-4 alkyl; (iv) Ring B is (
  • Ring B is (a) and R A is selected from halogen, C1-4 haloalkyl, C3- 6 cycloalkyl, -NR 11 , and -OR 11 ;
  • (x) Y 1 is S, Y 2 is C, Ring B is (a), and X 1 is N;
  • Y 1 is S, Y 2 is C, Ring B is (a), and R A is C 1-4 alkyl;
  • (xii) Ring B is (a)
  • m is selected from 0 and 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, p is selected from 0 and 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, q is selected from 0 and 1. In some embodiments, q is 0. In some embodiments, q is 1.
  • r is selected from 0 and 1. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, the compound is of Formula (IIA-3): O A N HN R 5 p S Y 3 X 1 N R A (IIA-3), or a pharmaceutically acceptable salt thereof; wherein X 1 is selected from N, CH, and CR 5 . In some embodiments, the compound is of Formula (IIB-3): (IIB-3), or a pharmaceutically acceptable salt thereof; wherein X 1 is selected from N, CH, and CR 5 .
  • the compound is of Formula (IIB-3): (IIB-3), or a pharmaceutically acceptable salt thereof; wherein Ring A is C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is substituted with one or more halogen, and is optionally substituted with one or more substituents independently selected from: C1-6 alkyl, C1-6 haloalkyl, -OR 12 , -SR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -OC(O)N(R 12 )2, -C(O)N(R 12 )2, -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , -N(R 12 )C(O)N(R 12 ) 2 , -N(R 12 )S(O) 2 (R 12 ), -S(O)R 12 , -S
  • the compound is of Formula (IIB-4): (IIB-4), or a pharmaceutically acceptable salt thereof, wherein X 1 is selected from N, CH, and CR 5 .
  • the compound is of Formula (IIC-3): (IIC-3),or a pharmaceutically acceptable salt thereof, wherein X 1 is selected from N, CH, and CR 5 .
  • the compound is of Formula (ID-3): (ID-3), or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (IIB-5): (IIB-5), or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (IIB-6) (IIB-6), or a pharmaceutically acceptable salt thereof.
  • Ring A is selected from: cyclopropyl substituted with one or more C1-6 alkyl or -CN, C3-6 carbocycle substituted with one or more halogen, 3- to 6-membered heterocycle substituted with one or more halogen, C5-6 spirocyclic carbocycle, and 5- to 6-membered spirocyclic heterocycle, any of which is optionally substituted with one or more substituents independently selected from: C1-6 alkyl, C1- 6 haloalkyl,
  • Ring A is selected from: C4-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1- 6 haloalkyl, -OR 12 , -SR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -OC(O)
  • Ring A is selected from: C 4-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with 1-4 substituents independently selected from: halogen, C 1-6 alkyl, C 1-6 haloalkyl, -OR 12 , -SR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -OC(O)N(
  • Ring A is saturated C3-6 carbocycle or saturated 3- to 6- membered heterocycle, each of which is substituted with one or more halogen, and is optionally substituted with one or more substituents independently selected from: C1-6 alkyl, C1-6 haloalkyl, -OR 12 , -SR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -OC(O)N
  • Ring A is saturated C 3-6 carbocycle or saturated 3- to 6-membered heterocycle comprising one O ring member, each of which is substituted with one or more halogen, and is optionally substituted with one or more substituents independently selected from: C1-6 alkyl, C1-6 haloalkyl, -OR 12 , -SR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -OC(O)N(R 12 )2, -C(O)N(R 12 )2, -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , -N(R 12 )C(O)N(R 12 ) 2 , -N(R 12 )S(O) 2 (R 12 ), -S(O)R 12 , -S(O) 2 R 12 , -S(O) 2 R 12 ,
  • Ring A is C3-6 carbocycle substituted with one or more halogen, and optionally substituted with one or more substituents independently selected from: C1- 6 alkyl, C1-6 haloalkyl, -OR 12 , -SR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -OC(O)N(R 12 ) 2, -C(O)N(R 12 )
  • Ring A is 5- to 6-membered heterocycle substituted with one -F, and optionally substituted with one or more substituents independently selected from: C 1- 6 alkyl, C 1-6 haloalkyl, -OR 12 , -SR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -OC(O)N(R 12 ) 2, -C(O)N(R 12 )2, -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , -N(R 12 )C(O)N(R 12 )2, -N(R 12 )S(O)2(R 12 ), -S(O)R 12 , -S(O)2R 12 , -S(O)2N(R 12 )2, -S(O)(NR 12 )R 12 ,
  • Ring A is selected from: C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is substituted with one or more halogen, and is optionally substituted with one or more substituents independently selected from: C 1-6 alkyl, C 1-6 haloalkyl, -OR 12 , -SR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -OC(O)N(R 12 ) 2, -C(O)N(R 12 ) 2 , -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , -N(R 12 )C(O)N(R 12 ) 2 , -N(R 12 )S(O) 2 (R 12 ), -S(O)R 12 , -S(O) 2 R 12 , -S(O) 2 N
  • the Ring A heterocycle comprises 1-4 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A heterocycle comprises 1-3 heteroatoms independently selected from O, N, and S.
  • the Ring A heterocycle comprises 1-2 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A heterocycle comprises 2-3 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A heterocycle comprises 1 heteroatom selected from O, N, and S. In some embodiments, the Ring A heterocycle comprises 2 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A heterocycle comprises 3 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A heterocycle comprises 4 heteroatoms independently selected from O, N, and S.
  • the Ring A heterocycle comprises 1-4 heteroatoms independently selected from O and N. In some embodiments, the Ring A heterocycle comprises 1-3 heteroatoms independently selected from O and N.
  • the Ring A heterocycle comprises 1-2 heteroatoms independently selected from O and N. In some embodiments, the Ring A heterocycle comprises 2-3 heteroatoms independently selected from O and N. In some embodiments, the Ring A heterocycle comprises 1 heteroatom selected from O and N. In some embodiments, the Ring A heterocycle comprises 2 heteroatoms independently selected from O and N. In some embodiments, the Ring A heterocycle comprises 3 heteroatoms independently selected from O and N. In some embodiments, the Ring A heterocycle comprises 4 heteroatoms independently selected from O and N.
  • the Ring A heterocycle comprises 4 N heteroatoms. In some embodiments, the Ring A heterocycle comprises 3 N heteroatoms. In some embodiments, the Ring A heterocycle comprises 3 N heteroatoms and 1 O heteroatom.
  • the Ring A heterocycle comprises 2 N heteroatoms and 1 O heteroatom. In some embodiments, the Ring A heterocycle comprises 2 N heteroatoms and 1 S heteroatom. In some embodiments, the Ring A heterocycle comprises 1 O heteroatom and 1 N heteroatom. In some embodiments, the Ring A heterocycle comprises 1 O heteroatom and 1 S heteroatom. In some embodiments, the Ring A heterocycle comprises 1 S heteroatom and 1 N heteroatom. In some embodiments, the Ring A heterocycle comprises 2 N heteroatoms. In some embodiments, the Ring A heterocycle comprises 1 heteroatom that is O. In some embodiments, the Ring A heterocycle comprises 1 heteroatom that is N. In some embodiments, the Ring A heterocycle comprises 1 heteroatom that is S.
  • Ring A as described herein is substituted with 1-4 substituents as described herein. In some embodiments, Ring A as described herein is unsubstituted.
  • Ring A is selected from: cyclopropyl substituted with one or more -CH3 or -CN; cyclobutyl, cyclohexyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl pyrrolidinyl, and piperidinyl, each of which is substituted with one or more -F, and is optionally substituted with one or more substituents independently selected from: -F,
  • Ring A is selected from: phenyl, tetrahydrofuanyl, tetrahydropyranyl, azetidinyl; pyrrolidinyl, piperidinyl, and 1,9-dioxaspiro[5.5]undecanyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR 12 , -SR 12 ,
  • Ring A is selected from: phenyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, and 1,9-dioxaspiro[5.5]undecanyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, C 1-6 alkyl, -C(O)OR 12 , and 3- to 6-membered heterocycle optionally
  • Ring A is selected from: phenyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, and 1,9-dioxaspiro[5.5]undecanyl, each of which is optionally substituted with 1-4 substituents independently selected from: halogen, C1- 6 alkyl, -C(O)OR 12 , and 3- to 6-membered heterocycle optionally substituted with one or more C 1- 4 alkyl; and R 12 is independently selected at each occurrence from hydrogen and C 1-6 alkyl.
  • the halogen substituent on Ring A is bonded to the ring member of Ring A that is bonded to –L-.
  • Ring A is bonded to the ring member of Ring A that is bonded to –L-.
  • Ring A is selected from: cyclopropyl, phenyl, tetrahydrofuanyl, tetrahydropyranyl, azetidinyl pyrrolidinyl, and piperidinyl, each of which is substituted with one or more -F, and is optionally substituted with one or more substituents independently selected from
  • Ring A is selected from: cyclopropyl, phenyl, tetrahydrofuanyl, tetrahydropyranyl, azetidinyl pyrrolidinyl, and piperidinyl, each of which is substituted with 1-4 -F, and is optionally substituted with one or more substituents independently selected from: halogen, C 1-6 alkyl, C 1-6 haloalkyl, -OR 12 , -SR 12 , -
  • Ring A is selected from: cyclobutyl, cyclohexyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl; pyrrolidinyl, piperidinyl, and 1,9- dioxaspiro[5.5]undecanyl, each of which is optionally substituted with one or more substituents independently selected from: -F, -OH, -CH3, , , , ,
  • Ring A is selected from: cyclopropyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl; pyrrolidinyl, piperidinyl, and 1,9-dioxaspiro[5.5]undecanyl, each of which is optionally substituted with one or more substituents independently selected from: -F, - CH3, , , , , and .
  • Ring A is selected from: cyclopropyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl; pyrrolidinyl, piperidinyl, and 1,9-dioxaspiro[5.5]undecanyl, each of which is optionally substituted with 1-4 substituents independently selected from: -F, -CH3, , , , , and .
  • Ring A is cyclopropyl optionally substituted with 1-4 substituents independently selected from: -F, -CH 3 , , , , , and .
  • Ring A is cyclopropyl optionally substituted with 1-4 substituents independently selected from: -F and -CH 3 .
  • Ring A is phenyl optionally substituted with 1-4 substituents independently selected from: -F, -CH3, , , , , and .
  • Ring A is tetrahydrofuranyl optionally substituted with 1-4 substituents independently selected from: -F, -CH3, , , , , and . In some embodiments, Ring A is tetrahydrofuranyl optionally substituted with 1-4 substituents independently selected from: -F and -CH3. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with 1-4 substituents independently selected from: -F, -CH3, , , , , and . In some embodiments, Ring A is tetrahydropyranyl optionally substituted with 1- 4 substituents independently selected from: -F and -CH3.
  • Ring A is azetidinyl optionally substituted with 1-4 substituents independently selected from: -F, -CH3, , , , , and .
  • Ring A is pyrrolidinyl optionally substituted with 1-4 substituents independently selected from: -F, -CH 3 , , , , , and .
  • Ring A is piperidinyl optionally substituted with 1-4 substituents independently selected from: -F, -CH3, , , , , and .
  • Ring A is 1,9-dioxaspiro[5.5]undecanyl optionally substituted with 1-4 substituents independently selected from: -F, -CH3, , , , , and .
  • Ring A is selected from: F , , , , , , , HO , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
  • Ring A is selected from: cyclopropyl substituted with one or more C1-6 alkyl or -CN, C3-6 carbocycle substituted with one or more halogen, 3- to 6-membered heterocycle substituted with one or more halogen, C5-6 spirocyclic carbocycle, and 5- to 6-membered spirocyclic heterocycle, any of which is optionally substituted with one or more substituents independently selected from: C 1-6 alkyl, C 1- 6 haloalkyl,
  • Ring A is selected from: cyclopropyl substituted with one or more -halogen, C1-6 alkyl or -CN; cyclobutyl, cyclohexyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl pyrrolidinyl, and piperidinyl, each of which is substituted with one or more halogen; and spiro[2.2]pentanyl, spir
  • Ring A is not chromane.
  • Ring A is selected from: cyclopropyl substituted with one or more -F, -CH3, or -CN; cyclobutyl, cyclohexyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl pyrrolidinyl, and piperid
  • Ring A is selected from: F , , , , HO , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
  • Ring A is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
  • Ring A is selected from: , , , , , , , , and .
  • Ring A is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .
  • Ring A is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .
  • Ring A is .
  • Ring A is .
  • Ring A is .
  • Ring A is .
  • Ring A is .
  • Ring A is .
  • Ring A is .
  • Ring A is .
  • Ring A is .
  • Ring A is .
  • Ring A is .
  • Ring A is .
  • Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is
  • Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is .
  • Ring A is tetrahydropyranyl optionally substituted with 1-4 halogen. In some embodiments, Ring A is tetrahydropyranyl substituted with 1-4 halogen.
  • Ring A is tetrahydropyranyl optionally substituted with 1-4 fluorine. In some embodiments, Ring A is tetrahydropyranyl substituted with 1-4 fluorine. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with one halogen. In some embodiments, Ring A is tetrahydropyranyl substituted with one halogen. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with one fluorine. In some embodiments, Ring A is tetrahydropyranyl substituted with one fluorine. In some embodiments, Ring A is unsubstituted tetrahydropyranyl.
  • Ring A is tetrahydropyranyl optionally substituted with 1-4 C 1-6 alkyl. In some embodiments, Ring A is tetrahydropyranyl substituted with 1-4 C 1-6 alkyl. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with 1-4 methyl. In 20 some embodiments, Ring A is tetrahydropyranyl substituted with 1-4 methyl. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with one C 1-6 alkyl. In some embodiments, Ring A is tetrahydropyranyl substituted with one C1-6 alkyl.
  • Ring A is tetrahydropyranyl optionally substituted with one methyl. In some embodiments, Ring A is tetrahydropyranyl substituted with one methyl. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with four C1-6 alkyl. In some embodiments, Ring A is tetrahydropyranyl substituted with four C 1-6 alkyl. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with four methyl. In some embodiments, Ring A is tetrahydropyranyl substituted with four methyl.
  • Ring A is unsubstituted tetrahydrofuranyl.
  • Ring A is tetrahydrofuranyl optionally substituted with 1-4 C1-6 alkyl.
  • Ring A is tetrahydrofuranyl substituted with 1-4 C1-6 alkyl. In some embodiments, Ring A is tetrahydrofuranyl optionally substituted with 1-4 methyl. In some embodiments, Ring A is tetrahydrofuranyl substituted with 1-4 methyl. In some embodiments, Ring A is tetrahydrofuranyl optionally substituted with one C 1-6 alkyl. In some embodiments, Ring A is tetrahydrofuranyl substituted with one C 1-6 alkyl. In some embodiments, Ring A is tetrahydrofuranyl optionally substituted with one methyl. In some embodiments, Ring A is tetrahydrofuranyl substituted with one methyl.
  • Ring A is tetrahydrofuranyl optionally substituted with four C1-6 alkyl. In some embodiments, Ring A is tetrahydrofuranyl substituted with four C1-6 alkyl. In some embodiments, Ring A is tetrahydrofuranyl optionally substituted with four methyl. In some embodiments, Ring A is tetrahydrofuranyl substituted with four methyl.
  • the compound is of Formula (IIIA): (IIIA), or a pharmaceutically acceptable salt thereof; wherein R 5 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, and -C(O)OR 12 ; and R 16 is selected from halogen, -OR 12 , and C 1-6 alkyl optionally substituted with 1-4 halogen; and Q is O, NH, or S.
  • the compound is of Formula (IIIB) (IIIB), or a pharmaceutically acceptable salt thereof; wherein R 16 is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -C(O)OR 12 ; and Q is O, NH, or S.
  • Q is O.
  • the compound is of Formula (IIIA-1): (III-A1), or a pharmaceutically acceptable salt thereof; wherein R 5 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, and -C(O)OR 12 ; and R 16 is selected from halogen, -OR 12 , and C 1-6 alkyl optionally substituted with 1-4 halogen; and Q is O, NH, or S.
  • the compound is of Formula (IIIB-1): (IIIB-1), or a pharmaceutically acceptable salt thereof; wherein R 16 is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -C(O)OR 12 ; and Q is O, NH, or S. In some embodiments, Q is O. In some embodiments, p is 0. In some embodiments, the compound is of Formula (IIIC-1): (IIIC-1), or a pharmaceutically acceptable salt thereof; wherein R 16 is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -C(O)OR 12 ; and Q is O, NH, or S. In some embodiments, Q is O.
  • the compound is of Formula (IIIA-2): (IIIA-2), or a pharmaceutically acceptable salt thereof; wherein R 5 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, and -C(O)OR 12 ; and R 16 is selected from halogen, -OR 12 , and C 1-6 alkyl optionally substituted with 1-4 halogen; and Q is O, NH, or S.
  • the compound is of Formula (IIIA-3): (IIIA-3), or a pharmaceutically acceptable salt thereof; wherein R 5 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR 12 ; and R 16 is selected from halogen, -OR 12 , and C 1-6 alkyl optionally substituted with 1-4 halogen; and Q is O, NH, or S.
  • the compound is of Formula (IIIA-4): (IIIA-4), or a pharmaceutically acceptable salt thereof; wherein R 5 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR 12 ; and R 16 is selected from halogen, -OR 12 , and C 1-6 alkyl optionally substituted with 1-4 halogen; and Q is O, NH, or S.
  • the compound is of Formula (IIIA-5): (IIIA-5), or a pharmaceutically acceptable salt thereof; wherein R 5 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR 12 ; and R 16 is selected from halogen, -OR 12 , and C1-6 alkyl optionally substituted with 1-4 halogen; and Q is O, NH, or S.
  • R A is selected from halogen, C 1-4 alkyl, C 1- 4 haloalkyl, C 1-4 hydroxyalkyl, -OR 11 , -N(R 11 ) 2 , -SR 11 , -N(R 11 )C(O)R 11 , -CN, C 3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; and R 11 is selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and C3-6 cycloalkyl.
  • R A is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -N(R 11 )2, -SR 11 , -N(R 11 )C(O)R 11 , -CN, C3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; and R 11 is selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and C3-6 cycloalkyl.
  • R A is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -N(R 11 ) 2 , -SR 11 , -N(R 11 )C(O)R 11 , and -CN, and R 11 is selected from hydrogen, C 1-4 alkyl, C 1- 4 haloalkyl, and C 3-6 cycloalkyl.
  • R A is selected from halogen, C 1-4 alkyl, C 1- 4 haloalkyl, C 1-4 hydroxyalkyl, -N(R 11 ) 2 , -SR 11 , -N(R 11 )C(O)R 11 , and -CN, and R 11 is selected from hydrogen, and C1-4 alkyl.
  • R A is selected from halogen, C1-4 alkyl, C1- 4 haloalkyl, and C1-4 hydroxyalkyl.
  • R A is selected from halogen, C1-4 alkyl, and C1-4 haloalkyl.
  • R A is selected from halogen and C1-4 alkyl. .
  • R A is selected from C1-4 alkyl.
  • R A is selected from -F, -Cl, -CN, -NH 2 , -OH, - OCH 3 , , -CH 3 , -CF 3 , -CHF 2 , , , , , and .
  • R A is selected from -F, -Cl, -CN, -NH2, -CH3, -CF3, -CHF2, , , , , and .
  • R A is selected from -F, - Cl, -CN, -NH2, -CH3, -CF3, and -CHF2. In some embodiments, R A is selected from -F, -Cl, -CH3, -CF3, and -CHF2. In some embodiments, R A is selected from -F and -Cl. In some embodiments, R A is selected from -CH 3 , -CF 3 , and -CHF 2 . In some embodiments, R A is selected from -CH 3 .
  • p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1.
  • R 5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -SR 13 , -N(R 13 )2, -C(O)R 13 , -C(O)OR 13 , -OC(O)R 13 , - C(O)N(R 13 )2, -N(R 13 )C(O)R 13 , -N(R 13 )S(O)2(R 13 ), -S(O)2R 13 , -S(O)2N(R 13 )2, -NO2, and -CN.
  • R 5 is independently selected at each occurrence from halogen, C 1-4 alkyl, C 1- 4 haloalkyl, -SR 13 , -N(R 13 ) 2 , -C(O)OR 13 , -OC(O)R 13 , -C(O)N(R 13 ) 2 , -N(R 13 )C(O)R 13 , and -CN.
  • R 5 is independently selected at each occurrence from halogen, C 1-4 alkyl, C 1- 4 haloalkyl, -SR 13 , -N(R 13 ) 2 , and -CN.
  • R 5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, and -CN. In some embodiments, R 5 is halogen. In some embodiments, R 5 is C1-4 alkyl. In some embodiments, R 5 is C1-4 haloalkyl. In some embodiments, R 5 is -OR 13 . In some embodiments, R 5 is -SR 13 . In some embodiments, R 5 is -N(R 13 ) 2 . In some embodiments, R 5 is -C(O)R 13 . In some embodiments, R 5 is -C(O)OR 13 . In some embodiments, R 5 is -OC(O)R 13 .
  • R 5 is -C(O)N(R 13 )2. In some embodiments, R 5 is -N(R 13 )C(O)R 13 . In some embodiments, R 5 is -N(R 13 )S(O)2(R 13 ). In some embodiments, R 5 is -S(O)2R 13 . In some embodiments, R 5 is -S(O)2N(R 13 )2. In some embodiments, R 5 is -NO2. In some embodiments, R 5 is -CN.
  • the compound is of Formula (IIIB-2): (IIIB-2), or a pharmaceutically acceptable salt thereof; wherein R 16 is selected from halogen, C 1- 4 alkyl, and C 1-4 haloalkyl; and Q is O, NH, or S. In some embodiments, Q is O. In some embodiments, R 16 is selected from -F and -CH 3 ; Q is O; and X 1 is CH or N. In some embodiments, the compound is of Formula (IIIB-3): (IIIB-3), or a pharmaceutically acceptable salt thereof; wherein R 16 is selected from halogen, C 1- 4 alkyl, and C 1-4 haloalkyl; and Q is O, NH, or S. In some embodiments, Q is O.
  • R 16 is selected from -F and -CH 3 ; Q is O; and X 1 is CH or N.
  • X 1 is selected from N, CH, and CR 5 .
  • X 1 is selected from N and CH.
  • X 1 is selected from CH, and CR 5 .
  • X 1 is N.
  • X 1 is CH.
  • X 1 is CR 5 .
  • Q is O, NH, or S. In some embodiments, Q is O. In some embodiments, for the compound of Formulae (IIIA), (IIIA-1), (IIIA-2), (IIIA-3), (IIIA-4), (IIIA-5), (IIIB), (IIIB-1), (IIIB-2), (IIIB-3), or (IIIC-1), each R 16 is independently selected from halogen, C1-4 alkyl, and C1-4 haloalkyl.
  • each R 16 is independently selected from halogen and C1-4 alkyl. In some embodiments, each R 16 is independently selected from halogen and C1-4 alkyl. In some embodiments, each R 16 is independently selected from -F and C 1-4 alkyl. In some embodiments, each R 16 is independently selected from -F and -CH 3 . In some embodiments, each R 16 is independently selected from C 1-4 alkyl. In some embodiments, each R 16 is -CH 3 . In some embodiments, each R 16 is independently selected from halogen. In some embodiments, each R 16 is -F.
  • the compound has 0, 1, 2, 3, or 4 R 16 groups. In some embodiments, the compound has 0, 1, 2, or 3 R 16 groups. In some embodiments, the compound has 0, 1, or 2 R 16 groups. In some embodiments, the compound has 0 or 1 R 16 groups. In some embodiments, the compound has 1, 2, 3, or 4 R 16 groups. In some embodiments, the compound has 1, 2, or 3 R 16 groups. In some embodiments, the compound has 1 or 2 R 16 groups. In some embodiments, the compound has 0 R 16 groups.
  • the compound has 1 R 16 groups. In some embodiments, the compound has 2 R 16 groups. In some embodiments, the compound has 3 R 16 groups. In some embodiments, the compound has 4 R 16 groups. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is cyclopropyl optionally substituted with 1-4 halogen.
  • Ring A is cyclopropyl substituted with 1-4 halogen. In some embodiments, Ring A is cyclopropyl optionally substituted with 1-4 fluorine. In some embodiments, Ring A is cyclopropyl substituted with 1-4 fluorine. In some embodiments, Ring A is cyclopropyl optionally substituted with one halogen. In some embodiments, Ring A is cyclopropyl substituted with one halogen. In some embodiments, Ring A is cyclopropyl optionally substituted with one fluorine. In some embodiments, Ring A is cyclopropyl substituted with one fluorine. In some embodiments, Ring A is not chromane.
  • the compound is of Formula (IVA): (IVA), or a pharmaceutically acceptable salt thereof; wherein R 15 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, and -C(O)OR 12 .
  • the compound is of Formula (IVA-1): (IVA-1), or a pharmaceutically acceptable salt thereof; wherein R 15 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, and -C(O)OR 12 .
  • the compound is of Formula (IVB-1): (IVB-1), or a pharmaceutically acceptable salt thereof; wherein R 15 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, and - C(O)OR 12 .
  • the compound is of Formula (IVA-2): (IVA-2), or a pharmaceutically acceptable salt thereof; wherein R 15 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, and -C(O)OR 12 .
  • the compound is of Formula (IVA-3): (IVA-3), or a pharmaceutically acceptable salt thereof; wherein R 15 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, and -C(O)OR 12 .
  • R A is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, -OR 11 , - N(R 11 )2, -SR 11 , -N(R 11 )C(O)R 11 , -CN, C3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; and R 11 is selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and C3-6 cycloalkyl.
  • R A is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -N(R 11 )2, -SR 11 , -N(R 11 )C(O)R 11 , -CN, C3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; and R 11 is selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and C3-6 cycloalkyl.
  • R A is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, -N(R 11 ) 2 , -SR 11 , - N(R 11 )C(O)R 11 , and -CN, and R 11 is selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, and C 3-6 cycloalkyl.
  • R A is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1- 4 hydroxyalkyl, -N(R 11 )2, -SR 11 , -N(R 11 )C(O)R 11 , and -CN, and R 11 is selected from hydrogen, and C1-4 alkyl.
  • R A is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, and C1- 4 hydroxyalkyl.
  • R A is selected from halogen, C1-4 alkyl, and C1-4 haloalkyl.
  • R A is selected from halogen and C1-4 alkyl. .
  • R A is selected from C1-4 alkyl.
  • R A is selected from -F, -Cl, -CN, -NH2, -OH, -OCH3, , -CH3, -CF3, -CHF2, , , , , and .
  • R A is selected from -F, -Cl, -CN, -NH 2 , -CH 3 , -CF 3 , -CHF 2 , , , , , and .
  • R A is selected from -F, -Cl, -CN, -NH 2 , -CH 3 , -CF 3 , and -CHF 2 . In some embodiments, R A is selected from -F, -Cl, -CH 3 , -CF 3 , and -CHF 2 . In some embodiments, R A is selected from -F and -Cl. In some embodiments, R A is selected from -CH3, -CF3, and -CHF2. In some embodiments, R A is selected from -CH3. In some embodiments, for the compound of Formulae (IVA), (IVA-1), (IVA-2), (IVA-3), or (IVB-1), p is 0, 1, or 2.
  • R 5 is independently selected at each occurrence from halogen, C 1-4 alkyl, C 1- 4 haloalkyl, -SR 13 , -N(R 13 ) 2 , -C(O)R 13 , -C(O)OR 13 , -OC(O)R 13 , -C(O)N(R 13 ) 2 , -N(R 13 )C(O)R 13 , -N(R 13 )S(O)2(R 13 ), -S(O)2R 13 , -S(O)2N(R 13 )2, -NO2, and -CN.
  • R 5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -SR 13 , -N(R 13 )2, -C(O)OR 13 , -OC(O)R 13 , -C(O)N(R 13 )2, -N(R 13 )C(O)R 13 , and -CN.
  • R 5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -SR 13 , -N(R 13 )2, and -CN.
  • R 5 is independently selected at each occurrence from halogen, C1- 4 alkyl, C 1-4 haloalkyl, and -CN. In some embodiments, R 5 is halogen. In some embodiments, R 5 is C 1-4 alkyl. In some embodiments, R 5 is C 1-4 haloalkyl. In some embodiments, R 5 is -OR 13 . In some embodiments, R 5 is -SR 13 . In some embodiments, R 5 is -N(R 13 ) 2 . In some embodiments, R 5 is -C(O)R 13 . In some embodiments, R 5 is -C(O)OR 13 . In some embodiments, R 5 is -OC(O)R 13 .
  • R 5 is -C(O)N(R 13 )2. In some embodiments, R 5 is -N(R 13 )C(O)R 13 . In some embodiments, R 5 is -N(R 13 )S(O)2(R 13 ). In some embodiments, R 5 is -S(O)2R 13 . In some embodiments, R 5 is -S(O)2N(R 13 )2. In some embodiments, R 5 is -NO2. In some embodiments, R 5 is -CN. In some embodiments, R A is C 1-4 alkyl. In some embodiments, R 16 is selected from -F and -CH 3 ; Q is O; and X 1 is CH or N.
  • the compound is of Formula (IVA-4): (IVA-4), or a pharmaceutically acceptable salt thereof; wherein R 15 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, and -C(O)OR 12 .
  • the compound is of Formula (IVB-2): (IVB-2), or a pharmaceutically acceptable salt thereof; wherein R 15 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR 12 .
  • the compound is of Formula (IVB-3): R 15 0-4 F O N 1-4 N HN N X 1 N (IVB-3), or a pharmaceutically acceptable salt thereof; wherein X 1 is CH or N, and R 15 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR 12 .
  • the compound is of Formula (IVB-4): R15 0-4 F O N N HN N X 1 N (IVB-4), or a pharmaceutically acceptable salt thereof; wherein X 1 is CH or N, and R 15 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR 12 .
  • X 1 is selected from N, CH, and CR 5 . In some embodiments, X 1 is selected from N and CH. In some embodiments, X 1 is selected from CH, and CR 5 . In some embodiments, X 1 is N. In some embodiments, X 1 is CH. In some embodiments, X 1 is CR 5 .
  • X 1 is CR 5 , and R 5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -SR 13 , -N(R 13 )2, and -CN.
  • X 1 is CR 5 , and R 5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, and -CN.
  • X 1 is CR 5 , and R 5 is halogen.
  • X 1 is CR 5 , and R 5 is C1-4 alkyl. In some embodiments, X 1 is CR 5 , and R 5 is C1- 4 haloalkyl. In some embodiments, the compound is of Formula (IVA-5): (IVA-5), or a pharmaceutically acceptable salt thereof; wherein R 15 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR 12 .
  • each R 15 is independently selected from halogen, C 1-4 alkyl, and C 1-4 haloalkyl. In some embodiments, each R 15 is independently selected from halogen and C 1-4 alkyl. In some embodiments, each R 15 is independently selected from halogen and C1-4 alkyl. In some embodiments, each R 15 is independently selected from -F and C1- 4 alkyl. In some embodiments, each R 15 is independently selected from -F and -CH3.
  • each R 15 is independently selected from C1-4 alkyl. In some embodiments, each R 15 is -CH3. In some embodiments, each R 15 is independently selected from halogen. In some embodiments, each R 15 is -F. In some embodiments, R 15 is hydrogen. In some embodiments, R 15 is C 1-6 alkyl. In some embodiments, R 15 is C 1-6 haloalkyl. In some embodiments, R 15 is -C(O)OR 12 .
  • the compound has 0, 1, 2, 3, or 4 R 15 groups. In some embodiments, the compound has 0, 1, 2, or 3 R 15 groups. In some embodiments, the compound has 0, 1, or 2 R 15 groups. In some embodiments, the compound has 0 or 1 R 15 groups. In some embodiments, the compound has 1, 2, 3, or 4 R 15 groups. In some embodiments, the compound has 1, 2, or 3 R 15 groups. In some embodiments, the compound has 1 or 2 R 15 groups. In some embodiments, the compound has 0 R 15 groups.
  • the compound has 1 R 15 groups. In some embodiments, the compound has 2 R 15 groups. In some embodiments, the compound has 3 R 15 groups. In some embodiments, the compound has 4 R 15 groups. In some embodiments, for the compound of any of the preceding FormulaeR 10 , R 11 , R 12 , R 13 , and R 14 are each independently selected at each occurrence from hydrogen and C 1-6 alkyl. In some embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 are each independently selected at each occurrence from hydrogen and C 1-4 alkyl. In some embodiments, each R 10 is independently selected from hydrogen and C 1-6 alkyl. In some embodiments, each R 10 is independently hydrogen.
  • each R 10 is independently C1-6 alkyl.
  • each R 11 is independently selected from hydrogen and C1-6 alkyl. In some embodiments, each R 11 is independently hydrogen. In some embodiments, each R 11 is independently C1-6 alkyl.
  • each R 12 is independently selected from hydrogen and C1-6 alkyl. In some embodiments, each R 12 is independently hydrogen. In some embodiments, each R 12 is independently C 1-6 alkyl. In some embodiments, each R 13 is independently selected from hydrogen and C 1-6 alkyl. In some embodiments, each R 13 is independently hydrogen. In some embodiments, each R 13 is independently C 1-6 alkyl. In some embodiments, each R 14 is independently selected from hydrogen and C1-6 alkyl.
  • each R 14 is independently hydrogen. In some embodiments, each R 14 is independently C1-6 alkyl. In some embodiments, the compound is of Formula (IVA-6): (IVA-6), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (IVA-7): (IVA-7), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (IVA-8): (IVA-8), or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (IIC-10): (IIC-10), or a pharmaceutically acceptable salt thereof, wherein: Ring B is selected from (a), (b) and (c): (a) , X 1 is selected from N, CH, and CR 5 ; (b) , X 2 is selected from S and NR 7 ; and (c) , X 3 is selected from S, N, and NH, X 4 is selected from O and CR 9 , X 5 is N or CH, X 6 is N or CH, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system; R 1 is selected from hydrogen, C1-4 alkyl, and –C(O)C3-6 cycloalkyl optionally substituted with one or more halogen; R 2 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR 10 , -SR 10 , -N(R 10 )2, NO2,
  • R A is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, -N(R 11 ) 2 , -SR 11 , -N(R 11 )C(O)R 11 , -CN, C 3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; and when Y 1 is CR 3 and Y 2 is N, then R A is further selected from -OR 11 ; R 11 is selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and C3-6 cycloalkyl; R 5 is independently selected at each occurrence from halogen, and C1-4 alkyl; and p is selected from 0 and 1.
  • R A is selected from -F, -Cl, -CN, -NH2, -CH3, -CF3, -CHF2, , , , and ; and when Y 1 is CR 3 and Y 2 is N, then R A is further selected from - OH, -OCH 3 , and ; R 5 is selected at each occurrence from -F, -Cl, and -CH 3 ; p is selected from 0 and 1.
  • the compound of Formula (II) is a compound of: (II), or a pharmaceutically acceptable salt thereof, wherein: each represents a single or a double bond, such that the bicyclic ring system comprising Y 1 , Y 2 , and Y 3 is an aromatic bicyclic ring system where (i) Y 1 is CR 3 and Y 2 is N, or (ii) Y 1 is S and Y 2 is C; Y 3 is selected from N and CR 4 ; Ring B is selected from (a), (b) and (c): (a) , X 1 is selected from N, CH, and CR 5 ; (b) , X 2 is selected from S and NR 7 ; and (c) , X 3 is selected from S, N, and NH, X 4 is selected from O and CR 9 , X 5 is N or CH, X 6 is N or CH, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system where (
  • R A is further selected from -OR 11 .
  • Y 1 is CR 3 and Y 2 is N; and R A is further selected from -OR 11 , provided that when R A is -OR 11 , then R 5 is not -OR 13 ;.
  • R A is further selected from hydrogen.
  • Y 1 is CR 3 , Y 2 is N, Y 3 is CH, Ring B is (a), p is 0, X 1 is N, and Ring A is 1-fluoro-1- tetrahydropyranyl
  • R A is further selected from hydrogen.
  • Y 1 is CR 3 , Y 2 is N, Y 3 is CH, Ring B is (a), p is 0, X 1 is N, and Ring A is 1-fluoro-1-tetrahydropyranyl; and R A is further selected from hydrogen.
  • R A is further selected from hydrogen.
  • Y 1 is S, Y 2 is C, and X 1 is N; and R A is further selected from hydrogen.
  • Ring A is further selected from C 4-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: C 1-6 alkyl, C 1-6 haloalkyl, -OR 12 , -SR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -OC(O)N(R 12 )2, -C(O)N(R 12 )2, -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , -N(R 12 )C(O)N(R 12 )2, -N(R 12 )C(O)OR 12 , -N(R 12 )C(O)N(R 12 )2, -N(R 12 )S(O)2
  • Ring A is further selected from C 4-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: C 1-6 alkyl, C 1-6 haloalkyl, -OR 12 , -SR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -OC(O)N(R 12 )2, -C(O)N(R 12 )2, -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , -N(R 12 )C(O)N(R 12 )2, -N(R 12 )C(O)OR 12 , -N(R 12 )C(O)N(R 12 )2, -N(R 12 )S(O)2(R 12 , -N(R 12 )C(O)N(R
  • Ring B when Ring B is (a), X 1 is CH, R A is methyl, Y 1 is CR 3 , and Y 2 is N, then Ring A is further selected from tetrahydrofuranyl substituted with methyl. In some embodiments, Ring B is (a), X 1 is CH, R A is methyl, Y 1 is CR 3 , and Y 2 is N; and Ring A is further selected from tetrahydrofuranyl substituted with methyl. In some embodiments, for the compound of Formulae (I), (II), or sub-formulae thereof, when R A is -OR 11 , then R 5 is chloro.
  • R A is -OR 11 ; and R 5 is chloro.
  • Formulae (V) and (VI) Compounds Some embodiments provide a compound of Formula (V): (V), or a pharmaceutically acceptable salt thereof, wherein: Q 1 is N, S, O or CR 3 , Q 2 is N or C, Q 3 is N or CR 4 , Q 4 is N or CR 3 , Q 5 is C or N, and each represents a single or a double bond, such that the bicyclic ring system comprising Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 is benzo[d]thiazole, benzo[d]oxazole, imidazo[1,2-a]pyridine, thiazolo[5,4- b]pyridine, imidazo[1,2-b]pyridazine, pyrazolo[1,5-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, or [1,2,4]triazolo[[
  • Q 1 is CR 3 .
  • Q 1 is N.
  • Q 1 is S.
  • Q 1 is O.
  • Q 2 is C.
  • Q 3 is CR 4 .
  • Q 3 is N.
  • Q 4 is CR 3 .
  • Q 4 is N.
  • Q 5 is C.
  • the bicyclic ring system comprising Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 is benzo[d]thiazole, benzo[d]oxazole, or thiazolo[5,4- b]pyridine.
  • the the bicyclic ring system comprising Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 is imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, or pyrazolo[1,5-a]pyridine.
  • the the bicyclic ring system comprising Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 is [1,2,4]triazolo[1,5- a]pyridine or [1,2,4]triazolo[1,5-b]pyridazine.
  • the bicyclic ring system comprising Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 is benzo[d]thiazole.
  • the bicyclic ring system comprising Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 is benzo[d]oxazole.
  • the the bicyclic ring system comprising Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 is imidazo[1,2-a]pyridine. In some embodiments, the the bicyclic ring system comprising Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 is thiazolo[5,4- b]pyridine. In some embodiments, the the bicyclic ring system comprising Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 is imidazo[1,2-b]pyridazine.
  • the the bicyclic ring system comprising Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 is pyrazolo[1,5-a]pyridine. In some embodiments, the the bicyclic ring system comprising Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 is [1,2,4]triazolo[1,5-a]pyridine. In some embodiments, the the bicyclic ring system comprising Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 is [1,2,4]triazolo[1,5-b]pyridazine. Some embodiments provide a compound of Formula (VA): (VA), or a pharmaceutically acceptable salt thereof.
  • Q 3 is CR 4 . In some emboidments, Q 3 is N. In some embodiments, Q 4 is CR 3 . In some emboidments, Q 4 is N. In some embodiments, Q 3 is CR 4 and Q 4 is N. In some embodiments, Q 3 is CR 4 and Q 4 is CR 3 . In some embodiments, Q 3 is N and Q 4 is CR 3 . Some embodiments provide a compound of Formula (VB): (VB), or a pharmaceutically acceptable salt thereof. In some embodiments, Q 3 is CR 4 . In some emboidments, Q 3 is N. Some embodiments provide a compound of Formula (VC): (VC), or a pharmaceutically acceptable salt thereof.
  • Q 4 is CR 3 . In some emboidments, Q 4 is N. Some embodiments provide a compound of Formula (VD): (VD), or a pharmaceutically acceptable salt thereof. In some embodiments, Q 3 is CR 4 . In some emboidments, Q 3 is N. Some embodiments provide a compound of Formula (VE): (VE), or a pharmaceutically acceptable salt thereof. In some embodiments, Q 3 is CR 4 . In some emboidments, Q 3 is N.
  • Some embodiments provide a compound of Formula (VF): (VF), or a pharmaceutically acceptable salt thereof
  • R 1 is selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, and -C(O)R 13 ; and R 13 is selected at from C 1-4 alkyl and cycloalkyl. In some embodiments, R 1 is selected from hydrogen and C 1-4 alkyl.
  • R 1 is selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, and -C(O)R 13 ; and R 13 is selected from C 1-4 alkyl and cyclopropyl optionally substituted with one or more -F.
  • R 1 is selected from hydrogen, C1-4 alkyl, and C1-4 haloalkyl.
  • R 1 is selected from hydrogen and C1-4 alkyl.
  • R 1 is selected from hydrogen, -CH 3 , -CF 3 , and .
  • R 1 is hydrogen.
  • R 2 is independently selected at each occurrence from halogen, C 1-4 alkyl, C 1-4 haloalkyl, and -CN. In some embodiments, R 2 is independently selected at each occurrence from halogen and C1-4 alkyl. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), or (VF), R 3 is independently selected at each occurrence from hydrogen, halogen, and C1-4 alkyl. In some embodiments, R 3 is independently selected at each occurrence from hydrogen and C 1-4 alkyl. In some embodiments, each R 3 is independently hydrogen.
  • R 4 is selected from hydrogen, halogen, and C 1-4 alkyl. In some embodiments, R 4 is selected from hydrogen and C1-4 alkyl. R 4 is selected from hydrogen and -CH3. In some embodiments, R 4 is hydrogen. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), or (VF), n is 0 or 1. In some embodiments, n is 0.
  • Some embodiments provide a compound of Formula (VI): (VI), or a pharmaceutically acceptable salt thereof, wherein: Q 1 is S or CR 3 , Q 2 is N or C, Q 3 is selected from N and CR 4 , and each represents a single or a double bond, such that the bicyclic ring system comprising Q 1 , Q 2 , and Q 3 is benzo[d]thiazole, imidazo[1,2-a]pyridine, thiazolo[5,4-b]pyridine, or imidazo[1,2-b]pyridazine; R A is selected from halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3- C 6 saturated cycloalkyl, and 3- to 6-membered saturated heterocycloalkyl; Ring A is selected from a C3-C10 saturated cycloalkyl, a C3-C10 partially saturated carbocycle
  • the one or more substituents do not include and are in addition to the R A group.
  • the one or more substituents when a moiety or a list of moieties is optionally substituted or substituted with one or more substituents, the one or more substituents is 1-4 substituents (e.g., 1- 3, 2-4, 2-3, 1-2, 3-4, 1, 2, 3, or 4 substituents).
  • the one or more substituents is 1-4 substituents.
  • the one or more substituents is one substituent.
  • Q 1 is CR 3 and Q 2 is N.
  • Q 1 is CR 3 ; Q 2 is N; and Q 3 is N. In some embodiments, Q 1 is CR 3 ; Q 2 is N; and Q 3 is CR 4 . In some embodiments, Q 1 is CR 3 ; Q 2 is N; and Q 3 is CH. In some embodiments, Q 1 is S and Q 2 is C. In some embodiments, Q 1 is S; Q 2 is C; and Q 3 is N. In some embodiments, Q 1 is S; Q 2 is C; and Q 3 is CR 4 . In some embodiments, Q 1 is S; Q 2 is C; and Q 3 is CH. In some embodiments, Q 3 is N. In some embodiments, Q 3 is CR 4 .
  • Q 3 is CR 4 ; and R 4 is selected from hydrogen and halogen. In some embodiments, R 4 is selected from hydrogen and C 1-4 alkyl. In some embodiments, R 4 is selected from hydrogen and -CH 3 . In some embodiments, Q 3 is CH. In some embodiments, Q 4 is CR 3 . In some embodiments, Q 4 is N. In some embodiments, Q 4 is CR 3 .and R 3 is selected from hydrogen and halogen. In some embodiments, R 3 is selected from hydrogen and C1-4 alkyl. In some embodiments, R 3 is selected from hydrogen and -CH3. In some embodiments, Q 4 is CH.
  • Q 1 is CR 3 ; Q 2 is N; Q 3 is N; and Q 4 is CR 3 .
  • Q 1 is CR 3 ; Q 2 is N; Q 3 is CR 4 ; and Q 4 is CR 3 .
  • Q 1 is CR 3 ; Q 2 is N; and Q 3 is CR 4 ; and Q 4 is CR 3 .
  • Q 1 is CR 3 ; Q 2 is N; and Q 3 is CR 4 ; and Q 4 is N.
  • Q 1 is CH; Q 2 is N; and Q 3 is CH; and Q 4 is N.
  • the compound is of Formula (VIA): (VIA), or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (VIA-1): (VIA-1), or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (VIB): (VIB), or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (VIC): (VIC), or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (VIC-1): (VIC-1), or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (VIC-2): (VIC-2), or a pharmaceutically acceptable salt thereof.
  • R 1 is selected from hydrogen, C 1-4 alkyl, and -C(O)R 13 .
  • R 1 is selected from hydrogen and C 1-4 alkyl.
  • R 1 is hydrogen.
  • R 1 is C 1-4 alkyl.
  • R 1 is -C(O)R 13 .
  • R 1 is selected from hydrogen, -CH3, and .
  • n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIB), (VIC), (VIC-1), or (VIC-2), R 2 is independently selected at each occurrence from halogen and C1-4 alkyl. In some embodiments.
  • R 2 is halogen. In some embodiments, R 2 is C1-4 alkyl. In some embodiments, R 2 is C1-4 haloalkyl. In some embodiments, R 2 is -OR 14 . In some embodiments, R 2 is -SR 14 . In some embodiments, R 2 is -N(R 14 ) 2 . In some embodiments, R 2 is NO 2 . In some embodiments, R 2 is –CN. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIB), (VIC), (VIC-1), or (VIC-2), R 3 is hydrogen. In some embodiments, R 3 is halogen.
  • R 3 is fluoro. In some embodiments, R 3 is chloro. In some embodiments, R 3 is C1-4 alkyl. In some embodiments, R 3 is methyl. In some embodiments, R 3 is C1-4 haloalkyl. In some embodiments, R 3 is trifluoromethyl.
  • R 2 is independently selected at each occurrence from halogen and C 1-4 alkyl. In some embodiments. In some embodiments, R 2 is halogen.
  • R 2 is C 1-4 alkyl. In some embodiments, R 2 is C 1-4 haloalkyl. In some embodiments, R 2 is -OR 14 . In some embodiments, R 2 is -SR 14 . In some embodiments, R 2 is -N(R 14 ) 2 . In some embodiments, R 2 is NO 2 . In some embodiments, R 2 is –CN. In some embodiments, the compound is of Formula (VIA-2): (VIA-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (VIA-3): (VIA-3), or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (VIB-1): R A O A N HN S B (VIB-1), or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (VIB-2): (VIB-2), or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (VIC-3): (VIC-3), or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (VID-1): (VID-1); or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (ID-2): (VID-2); or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (VIE-1): (VIE-1), or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (VIE-2): (VIE-2), or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (VIF): (VIF), or a pharmaceutically acceptable salt thereof.
  • Ring B is selected from a C3-C10 carbocycle and a 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR 12 , -SR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)
  • the Ring B heterocycle comprises 1-4 heteroatoms independently selected from O, N, and S.
  • the Ring B heterocycle comprises 1-3 heteroatoms independently selected from O, N, and S.
  • the Ring B heterocycle comprises 1-2 heteroatoms independently selected from O, N, and S.
  • the Ring B heterocycle comprises 2-3 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring B heterocycle comprises 1 heteroatom selected from O, N, and S. In some embodiments, the Ring B heterocycle comprises 2 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring B heterocycle comprises 3 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring B heterocycle comprises 4 heteroatoms independently selected from O, N, and S.
  • the Ring B heterocycle comprises 1-4 heteroatoms independently selected from O and N.
  • the Ring B heterocycle comprises 1-3 heteroatoms independently selected from O and N.
  • the Ring B heterocycle comprises 1-2 heteroatoms independently selected from O and N.
  • the Ring B heterocycle comprises 2-3 heteroatoms independently selected from O and N. In some embodiments, the Ring B heterocycle comprises 1 heteroatom selected from O and N. In some embodiments, the Ring B heterocycle comprises 2 heteroatoms independently selected from O and N. In some embodiments, the Ring B heterocycle comprises 3 heteroatoms independently selected from O and N. In some embodiments, the Ring B heterocycle comprises 4 heteroatoms independently selected from O and N.
  • the Ring B heterocycle comprises 4 N heteroatoms.
  • the Ring B heterocycle comprises 3 N heteroatoms.
  • the Ring B heterocycle comprises 3 N heteroatoms and 1 O heteroatom.
  • the Ring B heterocycle comprises 2 N heteroatoms and 1 O heteroatom.
  • the Ring B heterocycle comprises 2 N heteroatoms and 1 S heteroatom. In some embodiments, the Ring B heterocycle comprises 1 O heteroatom and 1 N heteroatom. In some embodiments, the Ring B heterocycle comprises 1 O heteroatom and 1 S heteroatom. In some embodiments, the Ring B heterocycle comprises 1 S heteroatom and 1 N heteroatom. In some embodiments, the Ring B heterocycle comprises 2 N heteroatoms. In some embodiments, the Ring B heterocycle comprises 1 heteroatom that is O. In some embodiments, the Ring B heterocycle comprises 1 heteroatom that is N. In some embodiments, the Ring B heterocycle comprises 1 heteroatom that is S.
  • Ring B is C 3 -C 10 carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR 12 , -SR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)OR 12 , -C(O)N(R 12 )2, -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , - N(R 12 )C(O)N(R 12 )2, -N(R 12 )C(O)OR 12 , - N(R 12 )C(O)N(R 12 )2, -N(R 12 )N(R 12 )OR 12 , - N(R 12 )C(O)N(R 12 )2, -N(R 12 )
  • Ring B is 3- to 12-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR 12 , -SR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(O)OR 12 , -C(O)N(R 12 ) 2 , -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , - N(R 12 )C(O)N(R 12 ) 2 , -N(R 12 )C(O)OR 12 , - N(R 12 )C(O)N(R 12 ) 2 , -N(R 12 )C(O)OR 12 , - N(R 12 )C(O)N(R 12 ) 2 , -N
  • Ring B is selected from a C 3 -C 10 carbocycle and a 3- to 12-membered heterocycle, each of which is optionally substituted with 1-4 substituents independently selected from: halogen, -OR 12 , -SR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)OR 12 , -C(O)N(R 12 )2, -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , - N(R 12 )
  • Ring B is selected from a C 6 -C 10 aryl and a 3- to 12-membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR 12 , -SR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)OR 12 , -C(O)N(R 12 )2, -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , - N(R 12 ,
  • Ring B is selected from a C6-C10 aryl and a 3- to 12-membered heteroaryl, each of which is optionally substituted with 1-4 substituents independently selected from: halogen, -OR 12 , -SR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(O)OR 12 , -C(O)N(R 12 ) 2 , -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , - N(R 12 )OR 12 , - N(
  • Ring B is selected from a C6-C10 aryl and a 3- to 12-membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR 12 , -N(R 12 )2, -C(O)N(R 12 )2, -N(R 12 )C(O)R 12 , - N(R 12 )S(O) 2 (R 12 ), -S(O) 2 R 12 , -S(O) 2 N(R 12 ) 2 , -S(O) 2 , -S(O) 2 N(R 12 ) 2 , -S(O)
  • Ring B is selected from a C 6 -C 10 aryl and a 3- to 12-membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR 12 , -N(R 12 )2, -C(O)N(R 12 )2, -N(R 12 )C(O)R 12 , -N(R 12 )S(O)2(R 12 ), -S(O)2R 12 , -S(O)2N(R 12 )2, -S(O)2N(R 12 )2, -S(O)2N(R 12 )2, -S(O)2N(R 12 )2, -S(O)O), -S(O)2R 12 , -S(O)2N(R 12 )2, -S(O)(O), -S(O)2R 12 , -S(O)2N(R 12 )2, -S(O)
  • Ring B is selected from a C 6 -C 10 aryl and a 3- to 12-membered heteroaryl, each of which is optionally substituted with 1-4 substituents independently selected from: halogen, -OR 12 , -N(R 12 )2, -C(O)N(R 12 )2, -N(R 12 )C(O)R 12 , -N(R 12 )S(O)2(R 12 ), -S(O)2R 12 , -S(O)2N(R 12 )2, -S(O)2N(R 12 )2, -S(O)2N(R 12 )2, -S(O)2N(R 12 )2, -S(O)
  • Ring B is not pyrazolyl.
  • Ring B is selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, indolyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, 2,1,3- benzoxadiazolyl benzfurazanyl, thiazolo[4,5-b]pyridinyl, pyrrolo[2,3-b]pyridinyl, imidazo[1,5- a]pyridinyl, quinolinyl, isoquinolinyl, quin
  • Ring B is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , O S O , , , , , , , , , , , , , , , , , , F N , , , , , , , , , , , , , , , , , , , , , , , , , F N , , , , , , , , , , , , , , , , , , , , , , , , , , , , F N , , , , , , , , , , ,
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is .
  • Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is O S O . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is .
  • Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is
  • Ring B is . In some embodiments, F Ring B is . In some embodiments, Ring B is N . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B
  • Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), Ring B is selected from (a), (b) and (c): (a) , wherein X 1 is selected
  • p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.
  • q is 0, 1, or 2.
  • q is 0 or 1.
  • q is 1 or 2.
  • q is 0.
  • p is 1.
  • q is 2.
  • r is 0, 1, or 2. In some embodiments, r is 0 or 1. In some embodiments, r is 1 or 2. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2.
  • X 1 is N.
  • X 1 is CH.
  • X 1 is CH.
  • X 2 is S.
  • X 2 is NR 7 .
  • X 2 is NH.
  • X 3 is S.
  • X 3 is N. In some embodiments, X 3 is NH. In some embodiments, X 4 is O. In some embodiments, X 4 is CR 9 . In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), X 3 is S and X 4 is O. In some embodiments, X 3 is S and X 4 is CR 9 .
  • X 3 is N and X 4 is O. In some embodiments, X 3 is N and X 4 is CR 9 . In some embodiments, X 3 is NH and X 4 is O. In some embodiments, X 3 is NH and X 4 is CR 9 . In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), R 9 is hydrogen.
  • R 9 is C 1- 4 alkyl. In some embodiments, R 9 is methyl. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- X 1 N 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), Ring B is RB . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is .
  • Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), R B is selected from halogen, C 1-6 alkyl, C 1- 6 haloalkyl, -OR 12 , -SR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -OC(O)N(R 12 ) 2 , -C(O)N(R 12 ) 2 , -N(R 12 )C
  • R B is selected from halogen, C1-6 alkyl, C1-6 haloalkyl, and -OR 12 .
  • R B is selected from halogen, methyl, C 1-6 haloalkyl, and -OR 12 .
  • R B is halogen.
  • R B is C 1-4 alkyl.
  • R B is methyl.
  • R B is C 1-4 haloalkyl.
  • R B is -OR 12 .
  • R B is -SR 12 .
  • R B is -N(R 12 ) 2 .
  • R B is -C(O)R 12 .
  • R B is -C(O)OR 12 .
  • R B is -OC(O)R 12 .
  • R B is -C(O)N(R 12 )2. In some embodiments, R B is -N(R 12 )C(O)R 12 . In some embodiments, R B is -N(R 12 )S(O)2(R 12 ). In some embodiments, R B is -S(O)2R 12 . In some embodiments, R B is -S(O)2N(R 12 )2. In some embodiments, R B is -NO2. In some embodiments, R B is -CN.
  • Ring B is , wherein X 1 is selected from N, CH, and CR 5 .
  • Ring B is , and X 2 is selected from S and NR 7 .
  • Ring B is , and X 3 is selected from S, N, and NH, X 4 is selected from O and CR 9 , X 5 is N or CH, X 6 is N or CH, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system
  • X 3 is selected from S, N, and NH
  • X 4 is selected from O and CR 9
  • X 5 is N or CH
  • X 6 is N or CH, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system
  • R 7 is hydrogen. In some embodiments, R 7 is C 1-4 alkyl. In some embodiments, R 7 is C1-4 haloalkyl. In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is C1-4 alkyl. In some embodiments, R 9 is C1-4 haloalkyl.
  • R 6 and R 8 are each independently selected at each occurrence from halogen and C 1-4 alkyl.
  • R 5 is independently selected at each occurrence from halogen and C1-4 alkyl.
  • R 5 is halogen.
  • R 5 is C1- 4 alkyl.
  • R 5 is C 1-4 haloalkyl.
  • R 5 is -OR 12 .
  • R 5 is -SR 12 . In some embodiments, R 5 is -N(R 12 )2. In some embodiments, R 5 is -C(O)R 12 . In some embodiments, R 5 is -C(O)OR 12 . In some embodiments, R 5 is -OC(O)R 12 . In some embodiments, R 5 is -C(O)N(R 12 )2. In some embodiments, R 5 is -N(R 12 )C(O)R 12 . In some embodiments, R 5 is -N(R 12 )S(O)2(R 12 ). In some embodiments, R 5 is -S(O)2R 12 .
  • R 5 is -S(O) 2 N(R 12 ) 2 . In some embodiments, R 5 is -NO 2 . In some embodiments, R 5 is -CN. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), R 6 is halogen. In some embodiments, R 6 is C1-4 alkyl.
  • R 6 is C1-4 haloalkyl. In some embodiments, R 6 is -OR 12 . In some embodiments, R 6 is -SR 12 . In some embodiments, R 6 is -N(R 12 )2. In some embodiments, R 6 is -C(O)R 12 . In some embodiments, R 6 is -C(O)OR 12 . In some embodiments, R 6 is -OC(O)R 12 . In some embodiments, R 6 is -C(O)N(R 12 ) 2 . In some embodiments, R 6 is -N(R 12 )C(O)R 12 . In some embodiments, R 6 is -N(R 12 )S(O) 2 (R 12 ).
  • R 6 is -S(O) 2 R 12 . In some embodiments, R 6 is -S(O) 2 N(R 12 ) 2 . In some embodiments, R 6 is -NO 2 . In some embodiments, R 6 is -CN. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), R 8 is halogen.
  • R 8 is C1-4 alkyl. In some embodiments, R 8 is C1-4 haloalkyl. In some embodiments, R 8 is -OR 12 . In some embodiments, R 8 is -SR 12 . In some embodiments, R 8 is -N(R 12 ) 2 . In some embodiments, R 8 is - C(O)R 12 . In some embodiments, R 8 is -C(O)OR 12 . In some embodiments, R 8 is -OC(O)R 12 . In some embodiments, R 8 is -C(O)N(R 12 ) 2 . In some embodiments, R 8 is -N(R 12 )C(O)R 12 .
  • R 8 is -N(R 12 )S(O) 2 (R 12 ). In some embodiments, R 8 is -S(O) 2 R 12 . In some embodiments, R 8 is -S(O)2N(R 12 )2. In some embodiments, R 8 is -NO2. In some embodiments, R 8 is -CN.
  • R 10 is hydrogen.
  • R 10 is C 1-6 alkyl.
  • R 10 is C 1-4 haloalkyl.
  • R 10 is cycloalkyl optionally substituted with one or more halogen.
  • R 10 is hydrogen.
  • R 10 is C1-6 alkyl. In some embodiments, R 10 is C1-4 haloalkyl. In some embodiments, R 10 is cycloalkyl optionally substituted with 1-4 halogen. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), R 11 is independently selected at each occurrence from hydrogen and C 1-4 alkyl.
  • R 11 is hydrogen. In some embodiments, R 11 is C 1-6 alkyl. In some embodiments, R 11 is C 1-4 haloalkyl. In some embodiments, R 11 is cycloalkyl optionally substituted with one or more halogen. In some embodiments, R 11 is independently selected at each occurrence from hydrogen, and C1-4 alkyl. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is C1-6 alkyl. In some embodiments, R 11 is C1-4 haloalkyl. In some embodiments, R 11 is cycloalkyl optionally substituted with 1-4 halogen.
  • R 12 is hydrogen.
  • R 12 is C 1-6 alkyl.
  • R 12 is C 1-4 haloalkyl.
  • R 12 is cycloalkyl optionally substituted with one or more halogen.
  • R 12 is -CH 3 .
  • R 12 is CH2CF3. In some embodiments, R 12 is cyclopropyl. In some embodiments, R 12 is independently selected at each occurrence from hydrogen, -CH3, -CH2CH2CH3, -CH2CH(CH3)2, -CH2CF3, and cyclopropyl. In some embodiments, R 12 is hydrogen. In some embodiments, R 12 is C1-6 alkyl. In some embodiments, R 12 is C1-4 haloalkyl. In some embodiments, R 12 is cycloalkyl optionally substituted with 1-4 halogen. In some embodiments, R 12 is -CH 3 . In some embodiments, R 12 is CH 2 CF 3 . In some embodiments, R 12 is cyclopropyl.
  • R 13 is selected from C1-4 alkyl and cyclopropyl optionally substituted with one or more -F.
  • R 13 is hydrogen.
  • R 13 is C1-6 alkyl.
  • R 13 is C1-4 haloalkyl.
  • R 13 is cycloalkyl optionally substituted with one or more halogen.
  • R 14 is hydrogen.
  • R 14 is C1-6 alkyl. In some embodiments, R 14 is C1-4 haloalkyl.
  • R 14 is cycloalkyl optionally substituted with one or more halogen.
  • the compound is of Formula (VIA-4): (VIA-4), or a pharmaceutically acceptable salt thereof; wherein X 1 is selected from N, CH, and CR 5 .
  • X 1 is N.
  • X 1 is CH.
  • the compound is of Formula (VIA-5): (VIA-5), or a pharmaceutically acceptable salt thereof; wherein X1 is selected from N, CH, and CR5.
  • the compound is of Formula (VIA-6): (VIA-6), or a pharmaceutically acceptable salt thereof; wherein X 1 is selected from N, CH, and CR 5 .
  • X 1 is N. In some embodiments, X 1 is CH. In some embodiments, the compound is of Formula (VIA-7): (VIA-7), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (VIB-3): (VIB-3), or a pharmaceutically acceptable salt thereof; wherein X 1 is selected from N, CH, and CR 5 . In some embodiments, X 1 is N. In some embodiments, X 1 is CH. In some embodiments, the compound is of Formula (VIC-4): (VIC-4), or a pharmaceutically acceptable salt thereof; wherein X 1 is selected from N, CH, and CR 5 . In some embodiments, X 1 is N. In some embodiments, X 1 is CH.
  • the compound is of Formula (VID-3): (VID-3); or a pharmaceutically acceptable salt thereof; wherein X 1 is selected from N, CH, and CR 5 . In some embodiments, X 1 is N. In some embodiments, X 1 is CH. In some embodiments, the compound is of Formula (VID-4): (VID-4); or a pharmaceutically acceptable salt thereof; wherein X 1 is selected from N, CH, and CR 5 . In some embodiments, X 1 is N. In some embodiments, X 1 is CH.
  • R 5 is independently selected at each occurrence from halogen and C 1-4 alkyl.
  • R 5 is halogen.
  • R 5 is C 1-4 alkyl.
  • R 5 is C 1-4 haloalkyl.
  • R 5 is -OR 12 .
  • R 5 is -SR 12 .
  • R 5 is -N(R 12 ) 2 .
  • R 5 is - C(O)R 12 .
  • R 5 is -C(O)OR 12 . In some embodiments, R 5 is -OC(O)R 12 . In some embodiments, R 5 is -C(O)N(R 12 )2. In some embodiments, R 5 is -N(R 12 )C(O)R 12 . In some embodiments, R 5 is -N(R 12 )S(O)2(R 12 ). In some embodiments, R 5 is -S(O)2R 12 . In some embodiments, R 5 is -S(O)2N(R 12 )2. In some embodiments, R 5 is -NO2. In some embodiments, R 5 is -CN.
  • p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, the compound is of Formula (VIC-5): (VIC-5), or a pharmaceutically acceptable salt thereof; wherein X 1 is selected from N, CH, and CR 5 . In some embodiments, X 1 is N. In some embodiments, X 1 is CH.
  • the compound is of Formula (VIA-8): (VIA-8), or a pharmaceutically acceptable salt thereof.
  • R B is selected from halogen, C1- 6 alkyl, C1-6 haloalkyl, -OR 12 , -SR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -OC(O)N(R 12 ) 2, -C(O)N(R 12 ) 2 , -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , - N(R 12 )C(O)N(R 12 ) 2 , -N(R 12 )C(O)OR 12 , - N(R 12 )C(O)N(R 12 ) 2 , -N(R 12 )N(O)OR 12 , - N(R 12 )C(O)N(R 12
  • R B is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and - OR 12 .
  • R B is selected from halogen, methyl, C1-6 haloalkyl, and -OR 12 .
  • R B is halogen.
  • R B is C1-4 alkyl.
  • R B is methyl.
  • R B is C1-4 haloalkyl.
  • R B is -OR 12 .
  • R B is -SR 12 .
  • R B is -N(R 12 )2.
  • R B is -C(O)R 12 .
  • R B is -C(O)OR 12 .
  • R B is -OC(O)R 12 .
  • R B is -C(O)N(R 12 )2. In some embodiments, R B is -N(R 12 )C(O)R 12 . In some embodiments, R B is -N(R 12 )S(O)2(R 12 ). In some embodiments, R B is -S(O)2R 12 . In some embodiments, R B is -S(O)2N(R 12 )2. In some embodiments, R B is -NO2. In some embodiments, R B is -CN. In some embodiments, the compound is of Formula (VIC-6): (VIC-6), or a pharmaceutically acceptable salt thereof; wherein X 1 is selected from N, CH, and CR 5 .
  • X 1 is N. In some embodiments, X 1 is CH. In some embodiments, the compound is of Formula (VIC-7): (VIC-7), or a pharmaceutically acceptable salt thereof; wherein X 1 is selected from N, CH, and CR 5 . In some embodiments, X 1 is N. In some embodiments, X 1 is CH. In some embodiments, the compound is of Formula (VID-5): (VID-5); or a pharmaceutically acceptable salt thereof; wherein X 1 is selected from N, CH, and CR 5 . In some embodiments, X 1 is N. In some embodiments, X 1 is CH.
  • the compound is of Formula (VID-6): (VID-6); or a pharmaceutically acceptable salt thereof; wherein X 1 is selected from N, CH, and CR 5 .
  • X 1 is N.
  • X 1 is CH.
  • the compound is of Formula (VIE-3): (VIE-3); or a pharmaceutically acceptable salt thereof; wherein X 1 is selected from N, CH, and CR 5 .
  • X 1 is N.
  • X 1 is CH.
  • the compound is of Formula (VIE-4): (VIE-4); or a pharmaceutically acceptable salt thereof; wherein X 1 is selected from N, CH, and CR 5 .
  • X 1 is N. In some embodiments, X 1 is CH. In some embodiments, the compound is of Formula (VIE-5): (VIE-5); or a pharmaceutically acceptable salt thereof; wherein X 1 is selected from N, CH, and CR 5 . In some embodiments, X 1 is N. In some embodiments, X 1 is CH. In some embodiments, the compound is of Formula (VIE-6): (VIE-6); or a pharmaceutically acceptable salt thereof; wherein X 1 is selected from N, CH, and CR 5 . In some embodiments, X 1 is N. In some embodiments, X 1 is CH.
  • the compound is of Formula (VIF-1): (V1F-1); or a pharmaceutically acceptable salt thereof; wherein X 1 is selected from N, CH, and CR 5 . In some embodiments, X 1 is N. In some embodiments, X 1 is CH. In some embodiments, the compound is of Formula (VIF-2): (VIF-2), or a pharmaceutically acceptable salt thereof; wherein X 1 is selected from N, CH, and CR 5 . In some embodiments, X 1 is N. In some embodiments, X 1 is CH.
  • the Ring A saturated heterocycloalkyl comprises 1- 4 heteroatoms independently selected from O, N, and S.
  • the Ring A saturated heterocycloalkyl comprises 1-3 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A saturated heterocycloalkyl comprises 1-2 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A saturated heterocycloalkyl comprises 2-3 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A saturated heterocycloalkyl comprises 1 heteroatom selected from O, N, and S. In some embodiments, the Ring A saturated heterocycloalkyl comprises 2 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A saturated heterocycloalkyl comprises 3 heteroatoms independently selected from O, N, and S.
  • the Ring A saturated heterocycloalkyl comprises 4 heteroatoms independently selected from O, N, and S.
  • the Ring A saturated heterocycloalkyl comprises 1- 4 heteroatoms independently selected from O, N, and S.
  • the Ring A saturated heterocycloalkyl comprises 1- 4 heteroatoms independently selected from O, N, and S.
  • the Ring A saturated heterocycloalkyl comprises 1- 4 heteroatoms independently selected from O, N, and S.
  • the Ring A saturated heterocycloalkyl comprises 1- 4 heteroatoms independently selected from O, N, and S.
  • the Ring A saturated heterocycloalkyl comprises 1- 4 heteroatoms independently selected from O, N, and S.
  • the Ring A saturated heterocycloalkyl comprises 1-3 heteroatoms independently selected from O and N. In some embodiments, the Ring A saturated heterocycloalkyl comprises 1-2 heteroatoms independently selected from O and N. In some embodiments, the Ring A saturated heterocycloalkyl comprises 2-3 heteroatoms independently selected from O and N. In some embodiments, the Ring A saturated heterocycloalkyl comprises 1 heteroatom selected from O and N. In some embodiments, the Ring A saturated heterocycloalkyl comprises 2 heteroatoms independently selected from O and N. In some embodiments, the Ring A saturated heterocycloalkyl comprises 3 heteroatoms independently selected from O and N. In some embodiments, the Ring A saturated heterocycloalkyl comprises 4 heteroatoms independently selected from O and N.
  • the Ring A saturated heterocycloalkyl comprises 3 N heteroatoms. In some embodiments, the Ring A saturated heterocycloalkyl comprises 3 N heteroatoms and 1 O heteroatom. In some embodiments, the Ring A saturated heterocycloalkyl comprises 2 N heteroatoms and 1 O heteroatom. In some embodiments, the Ring A saturated heterocycloalkyl comprises 2 N heteroatoms and 1 S heteroatom. In some embodiments, the Ring A saturated heterocycloalkyl comprises 1 O heteroatom and 1 N heteroatom. In some embodiments, the Ring A saturated heterocycloalkyl comprises 1 O heteroatom and 1 S heteroatom. In some embodiments, the Ring A saturated heterocycloalkyl comprises 1 S heteroatom and 1 N heteroatom.
  • the Ring A saturated heterocycloalkyl comprises 2 N heteroatoms. In some embodiments, the Ring A saturated heterocycloalkyl comprises 1 heteroatom that is O. In some embodiments, the Ring A saturated heterocycloalkyl comprises 1 heteroatom that is N. In some embodiments, the Ring A saturated heterocycloalkyl comprises 1 heteroatom that is S.
  • the Ring A partially saturated heterocycle comprises 1-4 heteroatoms independently selected from O, N, and S.
  • the Ring A partially saturated heterocycle comprises 1-3 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A partially saturated heterocycle comprises 1-2 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A partially saturated heterocycle comprises 2-3 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A partially saturated heterocycle comprises 1 heteroatom selected from O, N, and S. In some embodiments, the Ring A partially saturated heterocycle comprises 2 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A partially saturated heterocycle comprises 3 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A partially saturated heterocycle comprises 4 heteroatoms independently selected from O, N, and S.
  • the Ring A partially saturated heterocycle comprises 1-4 heteroatoms independently selected from O and N.
  • the Ring A partially saturated heterocycle comprises 1-3 heteroatoms independently selected from O and N. In some embodiments, the Ring A partially saturated heterocycle comprises 1-2 heteroatoms independently selected from O and N. In some embodiments, the Ring A partially saturated heterocycle comprises 2-3 heteroatoms independently selected from O and N. In some embodiments, the Ring A partially saturated heterocycle comprises 1 heteroatom selected from O and N. In some embodiments, the Ring A partially saturated heterocycle comprises 2 heteroatoms independently selected from O and N. In some embodiments, the Ring A partially saturated heterocycle comprises 3 heteroatoms independently selected from O and N. In some embodiments, the Ring A partially saturated heterocycle comprises 4 heteroatoms independently selected from O and N.
  • the Ring A partially saturated heterocycle comprises 3 N heteroatoms. In some embodiments, the Ring A partially saturated heterocycle comprises 3 N heteroatoms and 1 O heteroatom. In some embodiments, the Ring A partially saturated heterocycle comprises 2 N heteroatoms and 1 O heteroatom. In some embodiments, the Ring A partially saturated heterocycle comprises 2 N heteroatoms and 1 S heteroatom. In some embodiments, the Ring A partially saturated heterocycle comprises 1 O heteroatom and 1 N heteroatom. In some embodiments, the Ring A partially saturated heterocycle comprises 1 O heteroatom and 1 S heteroatom. In some embodiments, the Ring A partially saturated heterocycle comprises 1 S heteroatom and 1 N heteroatom. In some embodiments, the Ring A partially saturated heterocycle comprises 2 N heteroatoms.
  • the Ring A partially saturated heterocycle comprises 1 heteroatom that is O. In some embodiments, the Ring A partially saturated heterocycle comprises 1 heteroatom that is N. In some embodiments, the Ring A partially saturated heterocycle comprises 1 heteroatom that is S. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC- 7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), (VIE-5), (VIE-6), (VIE
  • Ring A is selected from C3-C10 saturated cycloalkyl, and 3- to 10-membered saturated heterocycloalkyl, each of which is optionally substituted with 1- 4
  • Ring A is C 3 -C 10 saturated cycloalkyl optionally substituted with 1-4 substituents independently selected from: halogen, -OR 11 , -SR 11
  • Ring A is 3- to 10-membered saturated heterocycloalkyl optionally substituted with 1-4 substituents independently selected from: halogen, -OR 11 , -SR 11
  • Ring A is selected from C3-C6 saturated cycloalkyl, and 3- to 6-membered saturated heterocycloalkyl, each of which is optionally substituted with one or
  • Ring A is selected from C 3 -C 6 saturated cycloalkyl, and 3- to 6-membered saturated heterocycloalkyl, each of which is optionally substituted with 1-4 substituents independently selected from halogen, -C(O)OR 11 , C1-6 alkyl, C1-6 haloalkyl, and 3- to 6-membered heterocycloalkyl, optionally substituted with 1-4 C1-6 alkyl.
  • Ring A is selected from: cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl,
  • Ring A is selected from: cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and tetrahydrofuranyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -C(O)OR 11 , C 1-6 alkyl, C 1-6 haloalkyl, and 3- to 6-membered heterocycloalkyl, optionally substituted with one or more C1-6 alkyl; provided that when Ring B is pyrazolyl, then Ring A is not N-Boc pyrrolidinyl; and R 11 is independently selected at each occurrence from hydrogen, and C1-4 alkyl.
  • Ring A is selected from: cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl,
  • Ring A is selected from: cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and tetrahydrofuranyl, each of which is optionally substituted with 1-4 substituents independently selected from halogen, -C(O)OR 11 , C 1-6 alkyl, C 1-6 haloalkyl, and 3- to 6-membered heterocycloalkyl, optionally substituted with 1-4 C 1-6 alkyl; provided that when Ring B is pyrazolyl, then Ring A is not N-Boc pyrrolidinyl.
  • Ring A is selected from: cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl,
  • Ring A is selected from: cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and tetrahydrofuranyl, each of which is optionally substituted with 1-4 substituents independently selected from -F, -CH 3 , O O , O , O , , and ; provided that when Ring B is pyrazolyl, then Ring A is not N-Boc pyrrolidinyl.
  • Ring A is selected from: cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl
  • Ring A is selected from: cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and tetrahydrofuranyl, each of which is optionally substituted with 1-4 substituents independently selected from -F, -CH3, , , , , and ; provided that when Ring B is pyrazolyl, then Ring A is not N-Boc pyrrolidinyl; R A is selected from -F, -CN, -CH3, -CHF2, -CF3, -CH2OCH3, -OCH3, and .
  • Ring A is selected from: cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl
  • Ring A is selected from: cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and tetrahydrofuranyl, each of which is optionally substituted with 1-4 substituents independently selected from -F, -CH 3 , , , , , and ; provided that when Ring B is pyrazolyl, then Ring A is not N-Boc pyrrolidinyl; R A is selected from -F, -CN, -CH3, -CHF2, -CF3, -CH2OCH3, -OCH3, and .
  • R A is selected from halogen, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, and C 3- C 6 saturated cycloalkyl.
  • R A is halogen. In some embodiments, R A is fluoro. In some embodiments, R A is -OR 10 . In some embodiments, R A is -SR 10 . In some embodiments, R A is -N(R 10 )2. In some embodiments, R A is -CN. In some embodiments, R A is C1-6 alkyl. In some embodiments, R A is C1-6 haloalkyl. In some embodiments, R A is C3-C6 saturated cycloalkyl.
  • R A is 3- to 6-membered saturated heterocycloalkyl.
  • R A is selected from -F, -CN, -CH3, -CHF2, -CF3, -CH2OCH3, -OCH3, and .
  • R A is selected from -F, CN, -CH3, -CHF2, -CF 3 , and .
  • R A is selected from -F.
  • R A is CN.
  • R A is -CH 3 .
  • R A is -CHF 2 .
  • R A is -CF 3 .
  • R A is .
  • Ring A is unsubstituted tetrahydropyranyl.
  • Ring A is tetrahydropyranyl optionally substituted with 1-4 C1-6 alkyl. In some embodiments, Ring A is tetrahydropyranyl substituted with 1-4 C1-6 alkyl. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with 1-4 methyl. In some embodiments, Ring A is tetrahydropyranyl substituted with 1-4 methyl. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with one C 1-6 alkyl. In some embodiments, Ring A is tetrahydropyranyl substituted with one C 1-6 alkyl.
  • Ring A is tetrahydropyranyl optionally substituted with one methyl. In some embodiments, Ring A is tetrahydropyranyl substituted with one methyl. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with four C1-6 alkyl. In some embodiments, Ring A is tetrahydropyranyl substituted with four C1-6 alkyl. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with four methyl.
  • Ring A is tetrahydropyranyl substituted with four methyl
  • Ring A is unsubstituted tetrahydrofuranyl.
  • Ring A is tetrahydrofuranyl optionally substituted with 1-4 C 1-6 alkyl. In some embodiments, Ring A is tetrahydrofuranyl substituted with 1-4 C 1-6 alkyl. In some embodiments, Ring A is tetrahydrofuranyl optionally substituted with 1-4 methyl. In some embodiments, Ring A is tetrahydrofuranyl substituted with 1-4 methyl. In some embodiments, Ring A is tetrahydrofuranyl optionally substituted with one C1-6 alkyl. In some embodiments, Ring A is tetrahydrofuranyl substituted with one C1-6 alkyl.
  • Ring A is tetrahydrofuranyl optionally substituted with one methyl. In some embodiments, Ring A is tetrahydrofuranyl substituted with one methyl. In some embodiments, Ring A is tetrahydrofuranyl optionally substituted with four C 1-6 alkyl. In some embodiments, Ring A is tetrahydrofuranyl substituted with four C 1-6 alkyl. In some embodiments, Ring A is tetrahydrofuranyl optionally substituted with four methyl. In some embodiments, Ring A is tetrahydrofuranyl substituted with four methyl. In some embodiments, Ring A is not N-Boc pyrrolidinyl.
  • Ring A is tetrahydropyranyl optionally substituted with 1-4 halogen.
  • Ring A is tetrahydropyranyl substituted with 1-4 halogen. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with 1-4 fluorine. In some embodiments, Ring A is tetrahydropyranyl substituted with 1-4 fluorine. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with one halogen. In some embodiments, Ring A is tetrahydropyranyl substituted with one halogen. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with one fluorine. In some embodiments, Ring A is tetrahydropyranyl substituted with one fluorine.
  • the compound is of Formula (VIA-9): (VIA-9), or a pharmaceutically acceptable salt thereof; wherein R 5 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR 11 ; and R 16 is selected from halogen, -OR 11 , and C1-6 alkyl optionally substituted with 1-4 halogen; and Q is O, NH, or S.
  • the compound is of Formula (VIA-10): (VIA-10), or a pharmaceutically acceptable salt thereof; wherein R 5 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR 11 ; and R 16 is selected from halogen, -OR 11 , and C 1-6 alkyl optionally substituted with 1-4 halogen; and Q is O, NH, or S.
  • the compound is of Formula (VIA-11): (VIA-11), or a pharmaceutically acceptable salt thereof; wherein R 5 is selected from hydrogen C1 6 alkyl C1 6 haloalkyl and -C(O)OR 11 ; and R 16 is selected from halogen, -OR 11 , and C 1-6 alkyl optionally substituted with 1-4 halogen; and Q is O, NH, or S.
  • the compound is of Formula (VIA-12): (VIA-12), or a pharmaceutically acceptable salt thereof; wherein R 5 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, and -C(O)OR 11 ; and R 16 is selected from halogen, -OR 11 , and C 1-6 alkyl optionally substituted with 1-4 halogen; and Q is O, NH, or S.
  • R 5 is independently selected at each occurrence from halogen and C 1-4 alkyl. In some embodiments, R 5 is halogen.
  • R 5 is C1-4 alkyl. In some embodiments, R 5 is C1-4 haloalkyl. In some embodiments, R 5 is -CN. In some embodiments, for the compound of Formulae (VIA-9), (VIA-10), ), (VIA-11), or (VIA-12), p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.
  • the compound is of Formula (VIA-13): (VIA-13), or a pharmaceutically acceptable salt thereof; wherein R 5 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR 11 ; and R 16 is selected from halogen, -OR 11 , and C1-6 alkyl optionally substituted with 1-4 halogen; and Q is O, NH, or S.
  • R B is selected from halogen, C1-6 alkyl, C1-6 haloalkyl, and -CN.
  • R B is selected from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R B is selected from halogen, methyl, and halomethyl. In some embodiments, R B is halogen. In some embodiments, R B is C1-4 alkyl. In some embodiments, R B is methyl. In some embodiments, R B is C 1-4 haloalkyl. In some embodiments, R B is -CN.
  • each R 16 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -C(O)OR 11 ; and R 11 is selected from hydrogen and C 1-4 alkyl. In some embodiments, each R 16 is independently is selected from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, each R 16 is independently is selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.
  • each R 16 is independently is selected from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, each R 16 is independently is selected from hydrogen and C1-6 alkyl. In some embodiments, each R 16 is independently is selected from -F, C 1-4 alkyl, and C 1-4 fluroalkyl. In some embodiments, R 16 is hydrogen. In some embodiments, R 16 is C 1-6 alkyl. In some embodiments, R 16 is C 1-6 haloalkyl. In some embodiments, R 16 is -C(O)OR 11 . In some embodiments, each R 16 is independently is selected from -F and methyl. In some embodiments, each R 16 is independently is selected from halogen.
  • each R 16 is -F. In some embodiments, each R 16 is independently is selected from C1-6 alkyl. In some embodiments, each R 16 is independently is selected from methyl. In some embodiments, for the compound of Formulae (VIA-9), (VIA-10), ), (VIA-11), (VIA-12), ir (VIA-13), the compound has 0, 1, 2, or 3 R 16 groups. In some embodiments, the compound has 0, 1, or 2, R 16 groups. In some embodiments, the compound has 0 or 1 R 16 groups. In some embodiments, the compound has 0 R 16 groups. In some embodiments, the compound has 1, 2, or 3 R 16 groups. In some embodiments, the compound has 1 or 2, R 16 groups. In some embodiments, the compound has 1 R 16 groups.
  • the compound has 2 R 16 groups.
  • Ring A is cyclopropyl optionally substituted with 1-4 halogen.
  • Ring A is cyclopropyl substituted with 1-4 halogen. In some embodiments, Ring A is cyclopropyl optionally substituted with 1-4 fluorine. In some embodiments, Ring A is cyclopropyl substituted with 1-4 fluorine. In some embodiments, Ring A is cyclopropyl optionally substituted with one halogen. In some embodiments, Ring A is cyclopropyl substituted with one halogen. In some embodiments, Ring A is cyclopropyl optionally substituted with one fluorine. In some embodiments, Ring A is cyclopropyl substituted with one fluorine.
  • the compound is of Formula (VIA-14): (VIA-14), or a pharmaceutically acceptable salt thereof; wherein Q 3 is selected from N and CH; and X 1 is selected from N, CH, and CR 5 .
  • X 1 is N.
  • X 1 is CH.
  • the compound is of Formula (VIA-15): (VIA-15), or a pharmaceutically acceptable salt thereof; wherein Q 3 is selected from N and CH; X 1 is selected from N, CH, and CR 5 .
  • X 1 is N.
  • X 1 is CH.
  • R 5 is independently selected at each occurrence from halogen and C 1-4 alkyl. In some embodiments, R 5 is halogen. In some embodiments, R 5 is C1-4 alkyl. In some embodiments, R 5 is C1-4 haloalkyl. In some embodiments, R 5 is -CN. In some embodiments, for the compound of Formulae (VIA-14) or (VIA-15), p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.
  • the compound is of Formula (VIA-16): (VIA-16), or a pharmaceutically acceptable salt thereof; wherein Q 3 is selected from N and CH; and X 1 is selected from N, CH, and CR 5 .
  • R B is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -CN.
  • R B is selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.
  • R B is selected from halogen, methyl, and halomethyl.
  • R B is halogen.
  • R B is C1-4 alkyl. In some embodiments, R B is methyl. In some embodiments, R B is C1-4 haloalkyl. In some embodiments, R B is -CN. In some embodiments, the compound is of Formula (VIA-17): (VIA-17), or a pharmaceutically acceptable salt thereof; wherein Q 3 is selected from N and CH; X 1 is selected from N, CH, and CR 5 . In some embodiments, X 1 is N. In some embodiments, X 1 is CH.
  • each R 15 is independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, and - C(O)OR 11 ; and R 11 is selected from hydrogen and C1-4 alkyl.
  • each R 15 is independently is selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • each R 15 is independently is selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • each R 15 is independently is selected from halogen C 1 6 alkyl, and C 1-6 haloalkyl.
  • each R 15 is independently is selected from hydrogen and C 1-6 alkyl. In some embodiments, each R 15 is independently is selected from -F, C1-4 alkyl, and C1-4 fluroalkyl. In some embodiments, R 15 is hydrogen. In some embodiments, R 15 is C1-6 alkyl. In some embodiments, R 15 is C1-6 haloalkyl. In some embodiments, R 15 is -C(O)OR 11 . In some embodiments, each R 15 is independently is selected from -F and methyl. In some embodiments, each R 15 is independently is selected from halogen. In some embodiments, each R 15 is -F. In some embodiments, each R 15 is independently is selected from C 1-6 alkyl.
  • each R 15 is independently is selected from methyl.
  • the compound of Formulae (VIA-14), (VIA-15), (VIA-16), or (VIA-17) has 0, 1, 2, or 3 R 15 groups. In some embodiments, the compound has 0, 1, or 2, R 15 groups. In some embodiments, the compound has 0 or 1 R 15 groups. In some embodiments, the compound has 0 R 15 groups. In some embodiments, the compound has 1, 2, or 3 R 15 groups. In some embodiments, the compound has 1 or 2, R 15 groups. In some embodiments, the compound has 1 R 15 groups. In some embodiments, the compound has 2 R 15 groups.
  • the compound is of Formula (VIA-18): (VIA-18), or a pharmaceutically acceptable salt thereof; wherein Q 3 is selected from N and CH.
  • the compound is of Formula (VIA-19): (VIA-19), or a pharmaceutically acceptable salt thereof.
  • the compound is of Formula (VIA-20): (VIA-20), or a pharmaceutically acceptable salt thereof.
  • Non-Limiting Exemplary Compounds the compound is selected from the group consisting of the compounds in Examples 1-11 (e.g., Compounds 1-152), or a pharmaceutically acceptable salt thereof.
  • the compound is selected from the group consisting of the compounds delineated in Table 1, or a pharmaceutically acceptable salt thereof.
  • Some embodiments provide a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or any pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • DYRK1A useful for treating disorders associated with dysregulation of a DYRKL4 gene, a DYRK1A protein, or the expression or activity or level of any of the same (i.e., a DYRK1A- associated disorder), such as a DYRK1 A-associated neurological disorder.
  • a “DYRK1A inhibitor” as used herein includes any compound exhibiting DYRK1A inactivation activity (e.g., inhibiting or decreasing).
  • DYRK1 A inhibitor such as DYRK1 A-associated disorders, e.g., neurological disorders such as those described herein.
  • a method for treating a neurological disorder 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 as provided herein.
  • Neurological disorder refers to any disorder of the nervous system and/or visual system.
  • Neurological disease or “neurological disorder” are used interchangeably herein, and include diseases or disorders that involve the central nervous system (CNS; e.g., brain, brainstem and cerebellum), the peripheral nervous system (PNS; including cranial nerves), and the autonomic nervous system (parts of which are located in both the CN S and PNS), including both structural and/or functional disorders (e.g., neurological syndrome).
  • CNS central nervous system
  • PNS peripheral nervous system
  • autonomic nervous system parts of which are located in both the CN S and PNS
  • structural and/or functional disorders e.g., neurological syndrome
  • neurological disorders include, but are not limited to, headache, stupor and coma, dementia, seizure, sleep disorders, trauma, infections, neoplasms, neuroopthalmology, movement disorders, demyelinating diseases, spinal cord disorders, tauopathies, synucleinopathies, and disorders of peripherai nerves, muscle and neuromuscular junctions.
  • Addiction and mental illness include, but are not limited to, bipolar disorder and schizophrenia, are also included in the definition of neurological disorder.
  • compositions and methods that can be treated using compositions and methods according to the present invention: acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; agenesis of the corpus callosum; agnosia: Aicardi syndrome; Alexander disease; Alpers’ disease; alternating hemiplegia; vascular dementia; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Anronl-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia telegiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet's disease; Bell's palsy; benign essential blepharospasm; benign focal; amy
  • the neurological disease is a tauopathy.
  • the neurological disease is a synuclemopathy.
  • the neurological disease or neurological disorder is Alzheimer’s disease, Down syndrome, Alzheimer’s disease associated with Down syndrome, Parkinson’s disease, ALS, dementia, Huntington’s disease, multiple sclerosis, proximal lateral sclerosis, stroke, stroke, or mild cognitive impairment. In some embodiments, the neurological disease or neurological disorder is Alzheimer’s disease.
  • the dementia may be Alzheimer’s dementia, cerebrovascular dementia, dementia due to head injury, multi-infarct dementia, mixed or alcoholic dementia of Alzheimer’s disease and multi-infarct dementia.
  • a method for treating a metabolic disorder 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 as provided herein.
  • the metabolic disorder is diabetes (e.g., Type 1 diabetes or Type 2 diabetes).
  • the metabolic disorder is Metabolic Dysfunction- Associated Steatotic Liver Disease (MASLD).
  • the cancer is a hemotological cancer (e.g., a leukemia, a lymophoma, or myeloma) or a solid tumor (e.g., carcinoma or sarcoma).
  • a hemotological cancer e.g., a leukemia, a lymophoma, or myeloma
  • a solid tumor e.g., carcinoma or sarcoma
  • the cancer is selected from Acute Lymphocytic Leukemia (ALL, Acute Lymphoblastic Leukemia, Colorectal Cancer: Non-Small Ceil Lung Cancer, Glioblastoma Muitiforme (GBM), Prostate Cancer, and Pancreatic Cancer.
  • ALL Acute Lymphocytic Leukemia
  • Colorectal Cancer Non-Small Ceil Lung Cancer
  • Glioblastoma Muitiforme Glioblastoma Muitiforme
  • Prostate Cancer Prostate Cancer
  • Pancreatic Cancer Pancreatic Cancer
  • an immunological disorder or disease e.g., an autoimmune disorder
  • the method 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 as provided herein.
  • the immunological disorder is an autoimmune disorder.
  • the immunological disorder is selected from Psoriasis; Rheumatoid Arthritis; Systemic Lupus Erythematosus, osteoarthritis, degenerative disc disease, and inflammatory bowel disease.
  • the immunological disorder is atopic dermatitis (atopic eczema).
  • a method for treating a cardiovascular disease or disorder 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 as provided herein.
  • the cardiovascular disease or disorder comprises heart failure.
  • the cardiovascular disease or disorder is myocardial infarct restoration.
  • the treatment of the cardiovascular disease or disorder comprises stimulating cardiomyocyte proliferation.
  • test compounds to act as inhibitors of DYRK1A may be demonstrated by assays known in the art.
  • the activity of the compounds and compositions provided herein as DYRK1 A inhibitors can be assayed in vitro, in vivo, or in a cell line.
  • In vitro assay s include assays that determine inhibition of the kinase.
  • Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase and can be measured either by radio labeling the compound prior to binding, isolating the compound/kinase complex and determining the amount of radiolabel bound, or by running a competition experiment where new compounds are incubated with the kinase bound to known radio ligands.
  • Potency of a DYRK1A inhibitor as provided herein can be determined by ECso or ICso values.
  • a compound with a lower ECso or ICso value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher ECso or ICso value.
  • the substantially similar conditions comprise determining a DYRK1A-dependent phosphorylation level, in vitro or in vivo (e.g., in neural cells, such as neurons, astrocytes, oligodendrocytes, microglia, ependymal cells, Schwann cells, and satellite cells, expressing a wild type DYRK1A, a mutant DYRK1 A, or a fragment of any thereof).
  • neural cells such as neurons, astrocytes, oligodendrocytes, microglia, ependymal cells, Schwann cells, and satellite cells, expressing a wild type DYRK1A, a mutant DYRK1 A, or a fragment of any thereof.
  • Potency of a DYRK1 A inhibitor as provided herein can also be determined by ICso value.
  • a compound with a lower ICso value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher ICso value.
  • the substantially similar conditions comprise determining a DYRK1 A-dependent phosphorylation level, in vitro or in vivo (e.g., in neural cells, such as neurons, astrocytes, oligodendrocytes, microglia, ependymal cells, Schwann cells, and satellite cells, expressing a wild type DYRK1 A, a mutant DYRK1A, or a fragment of any thereof).
  • the selectivity between DYRK1 A and other kinases can also be measured using in vitro assays such as surface plasmon resonance and fhiorence-based binding assays, and cellular assays.
  • the compounds of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof can selectively target DYRKIA.
  • a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof can selectively target DYRK1 A over another kinase or non-kinase target, for example, GSK3p.
  • a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof can exhibit greater inhibition of DYRKl A relative to inhibition of GSK3p.
  • a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater inhibition of DYRK1A relative to inhibition of GSK3p.
  • a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof can exhibit up to 1000-fold greater inhibition of DYRKl A relative to inhibition of GSK3p.
  • a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof can exhibit up to lOOOO-fold greater inhibition of DYRKl A relative to inhibition of GSK3 p.
  • the compounds described herein e.g., compounds of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof readily cross the blood-brain barrier. In some embodiments, the compounds described herein (e.g,, compounds of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, cross the blood-brain barrier in an amount sufficient to inhibit DYRKl A activity in brain tissue.
  • the subject is at risk of developing a neurological disorder, e.g., a DYRKl A-associated neurological disorder.
  • the subject is suspected of having a neurological disorder, e.g., a DYRKl A- associated neurological disorder.
  • the subject has been previously determined to have a neurological disorder associated with a dysregulation of a DY/iKlA gene, a DYRKl A protein, or expression or activity, or level of any of the same (a DYRKlA-associated neurological disorder) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
  • a DYRKlA-associated neurological disorder e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit.
  • the subject is suspected of having a DYRKlA-associated neurological disorder.
  • the subject has a clinical record indicating that the subject has a dysregulation of a DYRKIA gene, a neurological disorder protein, or expression or activity, or level of any of the same (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).
  • the subject is at risk of developing a DYRKlA-associated neurological disorder.
  • DYRKlA-associated disorder refers to disorders associated with or having a dysregulation of a DYRKIA gene, a DYRK1 A protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a DYRKIA gene, or a DYRKIA protein, or the expression or activity or level of any of the same described herein).
  • DYRKlA-associated neurological disorder refers to neurological disorders associated with or having a dysregulation of a DYRKIA gene, a DYRKIA protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a DYRKIA gene, or a DYRKIA protein, or the expression or activity or level of any of the same described herein).
  • Non-limiting examples of a DYRK1 A -associated neurological disorders are described herein.
  • DYRKIA gene a DYRKIA protein, or the expression or activity' or level of any of the same
  • a genetic mutation e.g., a mutation in a DYRKIA gene that results in the expression of a DYRK1 A that includes a deletion of at least one amino acid as compared to a wild type DYRK1 A, a mutation in a DYRKIA gene that results in the expression of DYRKIA with one or more point mutations as compared to a wild type DYRKIA, a mutation in a DYRKIA gene that results in the expression of DYRK1 A with at least one inserted amino acid as compared to a wild type DYRKIA, a gene duplication that results in an increased level of DYRKIA in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in an increased level of DYRKI A in
  • a dysregulation of a DYRKIA gene, a DYRKIA protein, or expression or activity, or level of any of the same can be a mutation in a DYRKIA gene that encodes a DY U.K I A that is constitutively active or has increased activity as compared to a protein encoded by a DYRKIA gene that does not include the mutation.
  • the dysregulation of a DYRKI A gene, a DYRKI A protein, or expression or activity or level of any of the same includes at least one point mutation in a DYRKI A gene that results in the production of a DYRKI A protein that has one or more ammo acid substitutions or insertions or deletions in a DYRKIA gene that results in the production of a DYRKI A protein that has one or more amino acids inserted or removed, as compared to the wild type DYRKIA protein.
  • the resulting mutant DYRKIA protein has increased activity’, as compared to a wild type DYRKIA protein or a DYRKIA protein not including the same mutation.
  • compounds of Formula (I), (II), (III), (IV), fV), or (VI), or any subformulae thereof, or pharmaceutically acceptable thereof are useful for treating a neurological disorder that has been identified as having one or more DYRKIA mutations. Accordingly, provided herein are methods for treating a subject diagnosed with (or identified as having) a neurological disorder that include administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof.
  • Some embodiments provide a method for treating a neurological disorder in a subject in need thereof, the method comprising (a) determining that the neurological disorder is associated with a dysregulation of 3.DYRK1A gene, a DYRK1A protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • Also provided herein is a method for treating a neurological disorder in a subject in need thereof, the method comprising (a) determining that the neurological disorder is a DYRK1A- associated neurological disorder; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • a method of treating a DYRK1 A -associated disorder in a subject comprising administering to a subject previously determined to have a DYRK1A- associated disorder a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • the subject that has been previously determined to have a DYRK1 A-associated neurological disorder through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying dysregulation of a DYRK.1A gene, a DYRK1 A protein, or expression or activity or level of any of the same, in a subject or a sample from the subject.
  • a regulatory agency-approved e.g., FDA-approved test or assay for identifying dysregulation of a DYRK.1A gene, a DYRK1 A protein, or expression or activity or level of any of the same.
  • the test or assay is provided as a kit.
  • regulatory agency refers to a country's agency for the approval of the medical use of pharmaceutical agents with the country.
  • FDA U.S. Food and Drug Administration
  • a method of treating a subject comprising administering a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject having a clinical record that indicates that the subject has a dysregulation of a DYRK1A gene, a DYRKI A protein, or expression or activity or level of any of the same.
  • a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof for use in the treatment of a neurological disorder in a subject in need thereof, or a subject previously determined to have a DY1RK1 A-associated neurological disorder. Also provided is the use of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a neurological disorder in a subject previously determined to have a DYRKI A-associated neurological disorder.
  • Compounds of the present disclosure can be used for the treatment of additional DYRKI A-mediated diseases an disorders, including the following: musculoskeletal disorders, genetic disorders (e.g., Fragile X syndrome), CNS disorders (e.g., pain, tauopathies, Attention Deficit Hyperactivity Disorder (ADHD); Depression; Post-Traumatic Stress Disorder (PTSD), traumatic brain injury, epilepsy), gastrointestinal disorders (e.g., irritiable bowel syndrome), metabolic disorders, cancer, immunological disorders and dermatological disorders.
  • musculoskeletal disorders e.g., Fragile X syndrome
  • CNS disorders e.g., pain, tauopathies, Attention Deficit Hyperactivity Disorder (ADHD); Depression; Post-Traumatic Stress Disorder (PTSD), traumatic brain injury, epilepsy), gastrointestinal disorders (e.g., irritiable bowel syndrome), metabolic disorders, cancer, immunological disorders and dermatological disorders.
  • ADHD Attention Deficit Hyperactivity Disorder
  • PTSD Post-Traumatic Stress Disorder
  • the compounds of Formula (I), (II), (III), (IV), (V). or (VI), or any subformulae thereof, including pharmaceutically acceptable salts thereof, can be administered in the form of pharmaceutical compositions as described herein.
  • Some embodiments provide a method of inhibiting DYRK 1 A activity in a mammalian cell comprising a DYRK LA protein, the method comprising contacting the mammalian cell with a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof.
  • Also provided herein is a method for inhibiting DYRKI A activity in a mammalian cell comprising contacting the mammalian cell with a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof.
  • the mammalian cell comprises DYRK1A.
  • the mammalian ceil is a mammalian neural cell.
  • Also provided herein is a method for inhibiting DYRK1 A activity comprising contacting a D YRK1 A protein with a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof
  • the mammalian cell comprises DYRK1A.
  • the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, to a subject having a cell having aberrant DYRK1 A activity. In some embodiments, the cell is a neural cell.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • “contacting” a DYRK1A protein with a compound provided herein includes the administration of a compound provided herein to a subject, such as a human, having a DYRK1A protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the DYRK1 A protein.
  • the contacting occurs after a compound described herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, has crossed the blood-brain barrier.
  • a compound described herein e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, has crossed the blood-brain barrier.
  • the compound of Formula (I), (II), (III), (FV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, contacting a mammalian cell and/or DYRK1A protein is present in an amount effective to inhibit the activity of a DYRK1 A protein. In some embodiments, the amount is a therapeutically effective amount.
  • the compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or in light of the teachings herein.
  • the synthesis of the compounds disclosed herein can be achieved by generally following the schemes provided herein, with modification for specific desired substituents.
  • Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M.
  • the synthetic processes disclosed herein can tolerate a wide variety of functional groups; therefore, various substituted starting materials can be used.
  • the processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.
  • P3 is purified using one or more of any standard methods, including but not limited to reverse phase high pressure liquid chromatography (RP- HPLC, HPLC, or semi-prep HPLC) using standard eluents and additives, silica gel chromatography using automated instruments and pre-packed silica gel cartridges of various sizes and common normal phase organic solvents. The desired fractions are combined, concentrated to drymess to provide the intermediate P3.
  • RP- HPLC reverse phase high pressure liquid chromatography
  • HPLC HPLC
  • semi-prep HPLC silica gel chromatography
  • silica gel chromatography using automated instruments and pre-packed silica gel cartridges of various sizes and common normal phase organic solvents.
  • the desired fractions are combined, concentrated to drymess to provide the intermediate P3.
  • P3 is then combined with a boronic acid or ester like P4, and a series of reagents to perform a carbon-carbon bond forming reaction similar to a palladium mediated Suzuki coupling, such as a palladium (II) salt coordinated to one or more ligands, an inorganic or organic base, and a mixture of organic and aqueous solvents.
  • a palladium mediated Suzuki coupling such as a palladium (II) salt coordinated to one or more ligands, an inorganic or organic base, and a mixture of organic and aqueous solvents.
  • the reaction is heated and stirred for a period of time and monitored for the formation of P5.
  • the mixture is purified using similar methods as described for P3
  • P6 is then combined with a halogen containing reagent like P7, and a series of reagents to perform a carbon-carbon bond forming reaction similar to a palladium mediated Suzuki coupling, such as a palladium (II) salt coordinated to one or more ligands, an inorganic or organic base, and a mixture of organic and aqueous solvents.
  • a palladium mediated Suzuki coupling such as a palladium (II) salt coordinated to one or more ligands, an inorganic or organic base, and a mixture of organic and aqueous solvents.
  • the reaction is heated and stirred for a period of time and monitored for the formation of PS.
  • the mixture is purified using similar methods as described for P3.
  • P9 is purified using one or more of any standard methods, including but not limited to reverse phase high pressure liquid chromatography (RP- HPLC, HPLC, or semi-prep HPLC) using standard eluents and additives, silica gel chromatography using automated instruments and pre-packed silica gel cartridges of various sizes and common normal phase organic solvents. The desired fractions are combined, concentrated to dryness to provide the intermediate P9.
  • RP- HPLC reverse phase high pressure liquid chromatography
  • HPLC HPLC
  • semi-prep HPLC silica gel chromatography
  • P9 is then combined with a boronic acid or ester like P4, and a series of reagents to perform a carbon-carbon bond forming reaction similar to a palladium mediated Suzuki coupling, such as a palladium (II) salt coordinated to one or more ligands, an inorganic or organic base, and a mixture of organic and aqueous solvents.
  • a palladium mediated Suzuki coupling such as a palladium (II) salt coordinated to one or more ligands, an inorganic or organic base, and a mixture of organic and aqueous solvents.
  • the reaction is heated and stirred for a period of time and monitored for the formation of PIO.
  • the mixture is purified using similar methods as described for P9.
  • P12 is purified using one or more of any standard methods, including but not limited to reverse phase high pressure liquid chromatography (RP- HPLC, HPLC, or semi-prep HPLC) using standard eluents and additives, silica gel chromatography using automated instruments and pre-packed silica gel cartridges of various sizes and common normal phase organic solvents. The desired fractions are combined, concentrated to dryness to provide the intermediate P12.
  • RP- HPLC reverse phase high pressure liquid chromatography
  • HPLC HPLC
  • semi-prep HPLC silica gel chromatography
  • P12 is then combined with a boronic acid or ester like P4, and a series of reagents to perform a carbon-carbon bond forming reaction similar to a pailadium mediated Suzuki coupling, such as a palladium (II) salt coordinated to one or more ligands, an inorganic or organic base, and a mixture of organic and aqueous solvents.
  • a pailadium mediated Suzuki coupling such as a palladium (II) salt coordinated to one or more ligands, an inorganic or organic base, and a mixture of organic and aqueous solvents.
  • the reaction is heated and stirred for a period of time and monitored for the formation of 1’13.
  • the mixture is purified using similar methods as described for P12. Benzthiazoles and benzoxazoles were synthesized in an analogous manner.
  • the regent When using an acid such as P2, the regent is stirred with an amide bond forming regeant similar to l-[Bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-Z>]pyridinium 3-oxide hexafluoro-phosphate (HATU), a mild base, and a solvent.
  • HATU hexafluoro-phosphate
  • the mixture is stirred at ambient temperature or with heating to progress the formation of the product of similar type P15.
  • PIS is purified using one or more of any standard methods, including but not limited to reverse phase high pressure liquid chromatography (RP- HPLC, HPLC, or semi-prep HPLC) using standard eluents and additives, silica gel chromatography using automated instruments and pre-packed silica gel cartridges of various sizes and common normal phase organic solvents. The desired fractions are combined, concentrated to dryness to provide the intermediate PIS.
  • RP- HPLC reverse phase high pressure liquid chromatography
  • HPLC HPLC
  • semi-prep HPLC silica gel chromatography
  • silica gel chromatography using automated instruments and pre-packed silica gel cartridges of various sizes and common normal phase organic solvents.
  • the desired fractions are combined, concentrated to dryness to provide the intermediate PIS.
  • PIS is then combined with a boronic acid or ester like P4, and a series of reagents to perform a carbon-carbon bond forming reaction similar to a palladium mediated Suzuki coupling, such as a palladium (II) salt coordinated to one or more ligands, an inorganic or organic base, and a mixture of organic and aqueous solvents.
  • a palladium mediated Suzuki coupling such as a palladium (II) salt coordinated to one or more ligands, an inorganic or organic base, and a mixture of organic and aqueous solvents.
  • the reaction is heated and stirred for a period of time and monitored for the formation of 1’16.
  • the mixture is purified using similar methods as described for PIS.
  • the regent When using an acid such as P2, the regent is stirred with an amide bond forming reg eant similar to 1 - (Bis(dimethylamino)methylene] -1H- 1,2,3 - triazolo[4,5 ⁇ i]pyndinium 3-oxide hexafluoro-phosphate (HATU), a mild base, and a solvent.
  • HATU hydroxyamino triazolo[4,5 ⁇ i]pyndinium 3-oxide hexafluoro-phosphate
  • Pl 8 is purified using one or more of any standard methods, including but not limited to reverse phase high pressure liquid chromatography (RP- HPL.C, HPL.C, or semi-prep HPLC) using standard eluents and additives, silica gel chromatography using automated instruments and pre-packed silica gel cartridges of various sizes and common normal phase organic solvents. The desired fractions are combined, concentrated to dryness to provide the intermediate P18.
  • reverse phase high pressure liquid chromatography RP- HPL.C, HPL.C, or semi-prep HPLC
  • silica gel chromatography using automated instruments and pre-packed silica gel cartridges of various sizes and common normal phase organic solvents.
  • the desired fractions are combined, concentrated to dryness to provide the intermediate P18.
  • P18 is then combined with a boronic acid or ester like P4, and a series of reagents to perform a carbon-carbon bond forming reaction similar to a palladium mediated Suzuki coupling, such as a palladium (II) salt coordinated to one or more ligands, an inorganic or organic base, and a mixture of organic and aqueous solvents.
  • a palladium mediated Suzuki coupling such as a palladium (II) salt coordinated to one or more ligands, an inorganic or organic base, and a mixture of organic and aqueous solvents.
  • the reaction is heated and stirred for a period of time and monitored for the formation of P19.
  • the mixture is purified using similar methods as described for PIS.
  • P21 is purified using one or more of any standard methods, including but not limited to reverse phase high pressure liquid chromatography (RP- HPLC, HPLC, or semi-prep HPLC) using standard eluents and additives, silica gel chromatography using automated instruments and pre-packed silica gel cartridges of various sizes and common normal phase organic solvents. The desired fractions are combined, concentrated to dryness to provide the intermediate P21.
  • RP- HPLC reverse phase high pressure liquid chromatography
  • HPLC HPLC
  • semi-prep HPLC silica gel chromatography
  • the desired fractions are combined, concentrated to dryness to provide the intermediate P21.
  • P21 is then combined with a boronic acid or ester like P4, and a series of reagents to perform a carbon-carbon bond forming reaction similar to a palladium mediated Suzuki coupling, such as a palladium (II) salt coordinated to one or more ligands, an inorganic or organic base, and a mixture of organic and aqueous solvents.
  • a palladium mediated Suzuki coupling such as a palladium (II) salt coordinated to one or more ligands, an inorganic or organic base, and a mixture of organic and aqueous solvents.
  • the reaction is heated and stirred for a period of time and monitored for the formation of P22.
  • the mixture is purified using similar methods as described for P3.
  • General Scheme 8 Synthesis of Pyrazoio
  • P24 is purified using one or more of any standard methods, including but not limited to reverse phase high pressure liquid chromatography (RP- HPLC, HPLC, or semi-prep HPLC) using standard eluents and additives, silica gel chromatography using automated instruments and pre-packed silica gel cartridges of various sizes and common normal phase organic solvents. The desired fractions are combined, concentrated to dryness to provide the intermediate P24.
  • RP- HPLC reverse phase high pressure liquid chromatography
  • HPLC HPLC
  • semi-prep HPLC silica gel chromatography
  • the desired fractions are combined, concentrated to dryness to provide the intermediate P24.
  • P24 is then combined with a boronic acid or ester like P4, and a series of reagents to perform a carbon-carbon bond forming reaction similar to a palladium mediated Suzuki coupling, such as a palladium (II) salt coordinated to one or more ligands, an inorganic or organic base, and a mixture of organic and aqueous solvents.
  • a palladium mediated Suzuki coupling such as a palladium (II) salt coordinated to one or more ligands, an inorganic or organic base, and a mixture of organic and aqueous solvents.
  • the reaction is heated and stirred for a period of time and monitored for the formation of P24.
  • the mixture is purified using similar methods as described for P3.
  • B. Preparation of Intermediates Preparation of N-(6-bromoimidazo[1,2-a]pyridin-2-yl)-4-fluorooxane-4-carboxamide (Intermediate A1).
  • HATU (1.45 g, 3.82 mmol) was added to 4-fluorooxane-4-carboxylic acid (471 mg, 3.18 mmol) and 2- amino-6-bromoimidazo[1,2-a]pyidine (540 mg, 2.55 mmol) in DMA (10 mL) at RT then stirred at RT for 20 min.
  • the solution was purified by semi-prep HPLC (2-60% MeCN in 0.05% NH4OH (aq) over 10 min) to give N-(6-bromoimidazo[1,2-a]pyridin-2-yl)-4-fluorooxane- 4-carboxamide (540 mg, 62% yield) as an off-white solid.
  • HATU (448 mg, 1.18 mmol) was added to 1-fluorocyclopropane-1-carboxamide (92 mg, 0.88 mmol), 2-amino-6-bromoimidazo[1,2-a]pyridine (250 mg, 0.59 mmol) and N,N- diisopropylethylamine (308 uL, 1.77 mmol) in DMF (3 mL) at RT then stirred at RT for 1 hr.
  • Example 3 1-fluoro-N-(6-(6-methylpyridazin-4-yl)imidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxamide N-(6-bromoimidazo[1,2-a]pyridin-2-yl)-1-fluorocyclopropane-1-carboxamide (15 mg, 0.05 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine (17 mg, 0.08 mmol), dichloro[1,1’-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (4 mg, 5 ⁇ mol), and potassium carbonate (11 mg, 0.08 mmol) were suspended in DMA (0.5 mL) and H 2 O (0.1 mL).
  • N-(6-Chloroimidazo[1,2-b]pyridazin-2-yl)-3-fluorotetrahydrofuran-3-carboxamide (24.0 mg, 0.084 mmol)
  • benzo[d]thiazol-6-ylboronic acid (22.6 mg, 0.126 mmol)
  • K 2 CO 3 (35.5 mg, 0.253 mmol)
  • RuPhos-Pd-G3 7.1 mg, 0.009 mmol
  • N-(5-bromo-[1,3]thiazolo[5,4-b]pyridin-2-yl)-2,2-difluorocyclopropane-1-carboxamide (20 mg, 0.06 mmol), picoline-4-boronic acid (13 mg, 0.09 mmol), dichloro[1,1- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (5 mg, 0.01 mmol) and potassium carbonate (26 mg, 0.18 mmol) in DMA (0.5 mL) and water (0.1 mL) was stirred at 90 o C for 3 hr.
  • N-benzyl-6-(2-methylpyridin-4-yl)benzo[d]thiazol-2-amine 6-bromo-2-chloro-1,3-benzothiazole (100 mg, 0.40 mmol), benzylamine (43 mg, 0.40 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.80 mmol) in DMSO (2 mL) was stirred at 80 o C for 2 hr.
  • N-benzyl-6-bromo-1,3-benzothiazol-2-amine (15 mg, 0.05 mmol), picoline-4-boronic acid (10 mg, 0.07 mmol), dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (4 mg, 0.04 mmol), and potassium carbonate (20 mg, 0.14 mmol) in DMA (0.5 mL) and water (0.1 mL) was stirred at 100 o C for 3 hr.
  • N-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-(1-methylpyrazol-4-yl)acetamide (20 mg, 0.06 mmol), 1,3-benzothiazol-6-yl boronic acid (21 mg, 0.12 mmol), dichloro[1,1- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (4 mg, 0.01 mmol) and potassium carbonate (25 mg, 0.18 mmol) in DMA (0.5 mL) and water (0.1 mL) was stirred at 90 o C for 1 hr.
  • N-(6-methylpyridin-3-yl)-6-(2-methylpyridin-4-yl)imidazo[1,2-a]pyridin-2-amine 6-bromo-2-chloroimidazo[1,2-a]pyridine 250 mg, 1.08 mmol
  • picoline-4-boronic acid 222 mg, 1.62 mmol
  • potassium carbonate 227 mg, 1.62 mmol
  • dichloro[1,1- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (79 mg, 0.11 mmol) in DMA (5 mL) and water (1 ml) was stirred at 90 o C for 2 hr.
  • N-benzyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (5 mg, 0.02 mmol), 3- methylpyridazine-5-boronic acid pinacol ester (6 mg, 0.02 mmol), potassium carbonate (7 mg, 0.05 mmol) and Ruphos Palladacycle Gen3 (1 mg, 0.01 mmol) in THF (0.6 mL) and water (0.15 mL) was stirred at 90 o C for 1 hr.
  • the solution was purified by semi-prep HPLC (eluting with 10- 88% MeCN in 0.05% NH4OH (aq) over 10 min) to afford the title compound (2 mg, 32% yield) as a white solid.
  • N-(6-bromoimidazo[1,2-a]pyridin-2-yl)spiro[2.2]pentane-2-carboxamide (15 mg, 0.05 mmol), picoline-4-boronic acid (10 mg, 0.07 mmol), dichloro[1,1- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (4 mg, 0.01 mmol) and potassium carbonate (21 mg, 0.15 mmol) in DMA (0.5 mL) and water (0.1 mL) was stirred at 100 o C for 3 hr.
  • Benzylamine (30 mg, 0.28 mmol) was added and the solution stirred at RT for 2 hr.
  • the solution was purified by semi-prep HPLC (eluting with 5-90% MeCN in 0.05% NH4OH (aq) over 10 min) to afford 1- benzyl-3-(6-bromoimidazo[1,2-a]pyridin-2-yl)urea (36 mg, 74% yield) as a white solid.
  • Oxolan-3-yl N-(6-bromoimidazo[1,2-a]pyridin-2-yl)carbamate (30 mg, 0.09 mmol), picoline-4-boronic acid (25 mg, 0.18 mmol), potassium carbonate (39 mg, 0.27 mmol) and dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (7 mg, 0.01 mmol) in DMF (1 mL) and water (0.2 mL) was stirred at 80 o C for 30 min.
  • N-(6-bromoimidazo[1,2-a]pyridin-2-yl)-1-fluorocyclopropane-1-carboxamide (20 mg, 0.07 mmol), 1-methyl-6-(4455-tetramethyl-132-dioxaborolan-2-yl)benzimidazole (34 mg, 0.13 mmol), potassium carbonate (28 mg, 0.20 mmol) and Ruphos Palladacycle Gen3 (6 mg, 0.01 mmol) in THF (0.5 mL) and water (0.1 mL) was stirred at 90 o C for 1 hr.
  • N-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-1-fluorocyclopropane-1-carboxamide 34 mg, 0.11 mmol
  • quinoline-6-boronic acid 39 mg, 0.23 mmol
  • dichloro[1,1- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (8 mg, 0.01 mmol) and potassium carbonate (48 mg, 0.34 mmol) in DMA (1 mL) and water (0.2 mL) was stirred at 90 o C for 1 hr.
  • Example 27 1-fluoro-N-(6-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-b]pyridazin-2-yl)cyclopropane- 1-carboxamide 6-bromo-[1,2,4]triazolo[1,5-b]pyridazin-2-amine (50 mg, 0.24 mmol), 1- fluorocyclopropane carboxylic acid (26 mg, 0.26 mmol), N,N-diisopropylethylamine (0.12 mL, 0.70 mmol) and HATU (133 mg, 0.35 mmol) in pyridine (1 mL) was stirred at RT for 1 hr.
  • N-(6-bromo-[1,2,4]triazolo[1,5-b]pyridazin-2-yl)-1-fluorocyclopropane-1-carboxamide (9 mg, 0.03 mmol), 2-picoline-4-boronic acid pinacol ester (10 mg, 0.04 mmol), potassium carbonate (13 mg, 0.09 mmol) and Ruphos Palladacycle Gen3 (3 mg, 0.01 mmol) in THF (0.6 mL) and water (0.15 mL) was stirred at 90 o C for 1 hr.
  • 6-bromo-[1,2,4]triazolo[1,5-b]pyridazin-2-amine 60 mg, 0.28 mmol
  • 4-fluoroxane-4- carboxylic acid 42 mg, 0.28 mmol
  • 4-dimethylaminopyridine 103 mg, 0.84 mmol
  • HATU HATU (213 mg, 0.56 mmol) in DMA (1 mL) was stirred at 50 o C for 90 min.
  • the mixture was diluted with DCM and water. The organics were separated and concentrated.
  • N-(6-bromo-[1,2,4]triazolo[1,5-b]pyridazin-2-yl)-4-fluorooxane-4-carboxamide (18 mg, 0.05 mmol), 3-methylpyridazine-5-boronic acid pinacol ester (16 mg, 0.07 mmol), potassium carbonate (18 mg, 0.13 mmol) and dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (3 mg, 0.01 mmol) in DMA (0.5 mL) and water (0.1 mL) was stirred at 100 o C for 30 min.
  • reaction was syringe filtered, washing with DMSO and purified via RP-HPLC, 0-40% MeCN/0.05% aqueous NH 4 OH. Fractions containing the product were concentrated and repurified via flash column chromatography on silica gel (0- 100% EtOAc/Hexanes) to afford 6 mg (30% yield) of the title compound as a white solid.
  • N-(6-Chloroimidazo[1,2-b]pyridazin-2-yl)-3-fluorotetrahydrofuran-3-carboxamide (24.0 mg, 0.084 mmol)
  • benzo[d]thiazol-6-ylboronic acid (22.6 mg, 0.126 mmol)
  • K 2 CO 3 (35.5 mg, 0.253 mmol)
  • RuPhos-Pd-G3 7.1 mg, 0.009 mmol
  • N-(1-fluorocyclopropyl)-6-(2-methylpyridin-4-yl)benzo[d]oxazole-2-carboxamide 6-bromo-1,3-benzoxazol-2-amine (100 mg, 0.47 mmol), 1-fluorocyclopropanecarboxylic acid (59 mg, 0.56 mmol), N,N-diisoproplyethylamine (0.24 mL, 1.41 mmol) and HATU (268 mg, 0.7 mmol) in DMA (2 mL) was stirred at RT for 30 min.
  • N-(6-bromo-1,3-benzoxazol-2-yl)-1-fluorocyclopropane-1-carboxamide (20 mg, 0.07 mmol), picoline-4-boronic acid (14 mg, 0.10 mmol), potassium carbonate (28 mg, 0.01 mmol) and dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (6 mg, 0.01 mmol) in DMA (0.5 mL) and water (0.1 mL) was stirred at 90 o C for 4 hr.
  • N-(6-bromoimidazo[1,2-a]pyrimidin-2-yl)-2-fluoro-5-methoxybenzamide (5 mg, 0.01 mmol), Ruphos Palladacycle Gen3 (1 mg, 0.001 mmol), potassium carbonate (6 mg, 0.04 mmol) and picoline-4-boronic acid (3 mg, 0.02 mmol) in THF (0.6 mL) and water (0.1 mL) was stirred at 90 o C for 1 hr. The mixture was purified by semi-prep HPLC (eluting with 10-88% MeCN in 0.05% NH4OH (aq) over 10 min) to afford the title compound (1.3 mg, 25% yield) as a pale yellow solid.
  • N-(6-bromoimidazo[1,2-a]pyrazine-2-yl)-4-cyanooxane-4-carboxamide (8 mg, 0.02 mmol), potassium carbonate (10 mg, 0.07 mml), Ruphos Palladacycle Gen3 (2 mg, 0.002 mmol), and picoline-4-boronic acid (5 mg, 0.03 mmol) in THF (0.6 mL) and water (0.1 mL) was stirred at 120 o C for hr. The mixture was filtered and the filtrate purified by semi-prep HPLC (eluting with 10-88% MeCN in 0.05% NH4OH (aq) over 10 min) to afford the title compound (3.6 mg, 42% yield) as a white solid.
  • Example 43 2-(4,4-difluorocyclohexyl)-N-(6-(2-methylpyridin-4-yl)imidazo[1,2-a]pyrazin-2- yl)acetamide
  • the compound was prepared as previously exemplified by General Scheme 7 in a manner analogous to Example 41 using Suzuki coupling to afford the title compound (9 mg, 75% yield) as a white solid.
  • LCMS: RT 0.59 min; ES-MS [M+1] + : 386.3.
  • Example 44 2-(4,4-difluorocyclohexyl)-N-(6-(2-methylpyridin-4-yl)imidazo[1,2-a]pyrazin-2- yl)acetamide
  • Example 45 1-fluoro-N-(6-(6-methylpyridazin-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1- carboxamide
  • the compound was prepared as previously exemplified by General Scheme 7 in a manner analogous to Example 41 using Suzuki coupling to afford the title compound (4 mg, 21% yield) as a white solid.
  • LCMS: RT 0.55 min; ES-MS [M+1] + : 313.2.
  • Example 46 Example 46.
  • Example 47 N-(6-(benzo[d]thiazol-6-yl)imidazo[1,2-a]pyrazin-2-yl)-2,2-dimethylcyclopropane-1- carboxamide
  • the compound was prepared as previously exemplified by General Scheme 7 in a manner analogous to Example 41 using Suzuki coupling to afford the title compound (6 mg, 30% yield) as a white solid.
  • LCMS: RT 0.64 min; ES-MS [M+1] + : 364.3.
  • Example 48 N-(6-(benzo[d]thiazol-6-yl)imidazo[1,2-a]pyrazin-2-yl)-2,2-dimethylcyclopropane-1- carboxamide
  • Example 49 4,4-difluoro-N-(6-(2-methylpyridin-4-yl)imidazo[1,2-a]pyridin-2-yl)piperidine-1- carboxamide
  • the compound was prepared as previously exemplified by General Scheme 1 in a manner analogous to Example 4 using Suzuki coupling to afford the title compound (3.2 mg, 21% yield) as a white solid.
  • LCMS: RT 0.54 min; ES-MS [M+1] + : 372.3.
  • Example 50 4.
  • Example 53 1-fluoro-N-(6-(7-fluoro-1H-benzo[d]imidazol-5-yl)imidazo[1,2-a]pyridin-2- yl)cyclopropane-1-carboxamide
  • the compound was prepared as previously exemplified by General Scheme 2 in a manner analogous to Example 24 using Suzuki coupling to afford the title compound (1.5 mg, 14% yield) as a white solid.
  • LCMS: RT 0.50 min; ES-MS [M+1] + : 354.1.
  • Example 54 Example 54.
  • Table 2 provides an exemplary list of general schemes and corresponding compounds that were synthesized using these intermediates in amide coupling reactions, urea couplings reactions, carbamate coupling reactions, and alkylation reactions analogous to those provided herein.
  • Assay buffer 50 mM HEPES pH7.5, W mM MgCh, 1 mM EGTA, 0.01% Bnj-35
  • Test compounds were diluted to ImM in DMSO
  • Percent phosphorylation is calculated using the formula below, and curve fitting and ICso generated using a four-parameter logistic model (GraphPad Prism).
  • the biological activity of certain compounds using the assay described above is shown in Table 3.
  • the ICso of the compounds is categorized as follows: A ⁇ 1 nM ⁇ B ⁇ 10 nM ⁇ C ⁇ 100 Al ⁇ D ⁇ 1 ⁇ M ⁇ F

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

This disclosure provides compounds and pharmaceutically acceptable salts thereof, that are useful, e.g., for treating neurological disorder in subject. This disclosure also provides compositions containing the same as well as methods of using and making the same.

Description

BICYCLIC HETEROAROMAT NEUROLOGICAL DISORDERS
TECHNICAL FIELD
This disclosure provides compounds and pharmaceutically acceptable salts thereof, that are useful, e.g., for treating neurological disorder in subject. This disclosure also provides compositions containing the same as well as methods of using and making the same.
SEQUENCE LISTING
This application contains a Sequence Listing that has been submitted electronically as an XML file named “50887-0043W01.XML.” The XML file, created on June 12, 2024, is 4,096 bytes in size. The material in the XML file is hereby incorporated by reference in its entirety.
PARTIES TO A JOINT RESEARCH AGREEMENT
The subject matter of the present disclosure was created pursuant to a joint research agreement between Prothena Biosciences Limited and V anderbilt University, that was in effect on or before the date the subject matter described herein was made, and the subject matter was made as a result of activities undertaken within the scope of the joint development agreement.
PRIORITY CLAIM
The application claims the benefit of U.S. Provisional Patent Application Serial No. 63/508,131 filed June 14, 2023, U.S. Provisional Patent Application Serial No. 63/508,137 filed June 14, 2023, U.S. Provisional Patent Application Serial No. 63/508,139 filed June 14, 2023, U.S. Provisional Patent Application Serial No. 63/510,695 filed June 28, 2023, U.S. Provisional Patent Application Serial No. 63/510,696 filed June 28, 2023, U.S. Provisional Patent Application Serial No. 63/510,711 filed June 28, 2023, U.S. Provisional Patent Application Serial No. 63/656,038 filed June 4, 2024, and U.S. Provisional Patent Application Serial No. 63/656,070 filed June 4, 2024, each of which is incorporated by reference herein in its entirety.
BACKGROUND
Dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1 A) is a 763 amino acid, 85 kDa serme/threonine/tyrosme kinase located on chromosome 21 (21q22.2). DYRK1A possesses catalytic activity that is regulated by autophosphorylation of a tyrosine residue (Y321) which results in constitutively active serine/threonine kinase activity. See Abbassi, et al., Pharmacology & Therapeutics, 151, 87-98 (2015). Since DYRK1A is constitutively active, its activity is dosage dependent. Thus, both elevated levels and depressed levels of DYRK1A, (relative to wild-type levels) have been shown to lead to neurological impairment. See Duchon and Herault, Front Behav. Neurosci. 10, 104-104 (2016). DYRK1A is also a member of a large family of CMGC kinases, which include cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAPKs), glycogen synthase kinases (GSKs), and CDC-like kinases (CLKs). DYRK1A additionally has been shown to have a role in cell cycle regulation, at least in part by phosphorylating (and thus inhibiting) the nuclear factor of activated T cells (NFAT) family of transcription factors. Additionally, over 20 substrates of DYRK1A have been identified, including cell signaling, chromatin modulation, gene expression, alternative splicing, cytoskeletal, and synaptic function. See Abassi, et al, (2016). DYRK1A dysregulation is implicated in various disease states such as Alzheimer’s disease, autism, and Down syndrome. In some cases, novel mutations in DYRK1A have been associated with autism phenotypes. See e.g., Dang, et al., Molecular Psychiatry, 23, 747-758 (2018). DYRK1A is also known to play an important role in brain development. For example, reduced DYRK1A activity (such has having a single copy of loss of function mutation) during neural development results in intellectual disability phenotypes. Conversely, trisomy 21 in Down syndrome individuals is associated with a triplication of the DYRK1A gene, which results in elevated DYRK1A activity. DYRK1A is located on chromosome 21, specifically within the “Down syndrome critical region” a portion of chromosome 21 that includes genes particularly relevant for developing Down syndrome phenotypes. As a result, individuals with Down syndrome have three copies of DYRK1A, and since DYRK1A is dosage sensitive, the elevated levels of DYRK1A in such individuals markedly affects the localization and function of the DYRK1A protein. The expression of DYRK1A is also elevated in the CNS in individuals with neurodegenerative diseases, such as Parkinson’s disease, Pick’s disease, and Alzheimer’s disease. Moreover, approximately 50% of individuals with Down syndrome ultimately develop Alzheimer’s disease, with symptoms generally beginning between the ages of 40 and 60. DYRK1A phosphorylates amyloid precursor protein (APP) which promotes the production of pathogenic amyloid-ȕ peptide (Aȕ). Dyrk1A also phosphorylates tau both directly and indirectly (see Abassi, et al, (2016)). Both amyloid-P and tau pathologies are associated with Down syndrome phenotypes.
Normalization of DYRK1A gene dosage by crossing Ts65Dn mice (DS model) with DYRK1 A knockout mice mice reverses many Azlheimer’s-like phenotypes. See Garcia-Cerro et al., 2017. In individuals with Down Syndrome, DYRK1 A mRNA levels, protein levels, and kinase activity are increased by -50%, reflecting the number of gene copies. See Liu et al., 2008; see also Wegiel et al., 2011.
Because no treatment is available for these neurological disorders, the prognosis for individuals with, for example, Alzheimer’s disease is poor. This can be particularly devastating because Alzheimer’s disease is responsible for a sharp decline in survival in individuals with Down syndrome that are over 45 years old. Only about 25% of those with Down syndrome live more than 60 years, and most of those have developed Alzheimer’s disease.
Across all individuals, dementia remains a significant leading unmet medical need and a costly burden on public health. Currently, 1 in 3 seniors develops dementia, and about 70% of dementia cases are attributed to Alzheimer’s disease. Some 11% of Americans over age 65 has AD, which constitutes over 6.2 million in 2021, This figure is projected to exceed 12 million in 2050 (www.AIz.org).
Presently, no therapies have been approved to treat Alzheimer’s disease associated with Down syndrome, which represents a significant unmet medical need. Some DYRK1 A inhibitors have been tested in vitro or in animal preclinical models to treat Alzheimer’s disease or Down syndrome, however, since DYRK1A is a member of the highly conserved CMGC family of kinases, identifying compounds that selectively target DYRK1A has proved challenging. Thus, there remains a need to identify D YRK1 A inhibitors to treat Down syndrome, Alzheimer’s disease, Alzheimer’s disease associated with Down syndrome, and other neurodegenerative and neurological diseases.
SUMMARY
Some embodiments provide a compound represented by the structure of Formula (I):
(I), or a pharmaceutically acceptable salt thereof, wherein: each represents a single or a double bond, such that the bicyclic ring system comprising Y1, Y2, Y3, and Y4 is an aromatic bicyclic ring system where (i) Y1 is CR3, Y2 is N, Y3 is CR4, and Y4 is CR3 or N; (ii) Y1 is S, Y2 is C, Y3 is CR4 or N, and Y4 is CR3; or (iii) Y1 is N, Y2 is N, Y3 is CR4, and Y4 is CR3; L is selected from , , and , wherein * denotes the point of attachment to Ring A, Z is selected from -O-, -NR1-, C1-4alkylene, -O-C1-4alkylene, and -NR1-C1-4alkylene, Z’ is selected from -NR1-, -S(O)-, -S(O)2-, C1-4alkylene, -NR1-C1-4alkylene, -S(O)-C1-4alkylene, and -S(O)2-C1-4alkylene; wherein each C1-4alkylene is optionally substituted with one or more halogen; Ring B is selected from (a), (b) and (c): (a) , X1 is selected from N, CH, and CR5; (b) , X2 is selected from S and NR7; and (c) , X3 is selected from S, N, and NH, X4 is selected from O and CR9, X5 is N or CH, X6 is N or CH, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system, provided that when Ring B is (a), Y1 is CR3, Y2 is N, Y3 is CR4, and Y4 is N, then p is 0; R1 is independently selected at each occurrence from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and –C(O)C3-6 cycloalkyl optionally substituted with one or more halogen; R2 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, - OR10, -SR10, -N(R10)2, NO2, and -CN; R3 and R4 are each independently selected at each occurrence from hydrogen, halogen, C1- 4 alkyl, and C1-4 haloalkyl; Ring A is selected from: cyclopropyl substituted with one or more C1-6 alkyl or -CN, C3-6 carbocycle substituted with one or more halogen, 3- to 6-membered heterocycle substituted with one or more halogen, C5-6 spirocyclic carbocycle, and 5- to 6-membered spirocyclic heterocycle, any of which is optionally substituted with one or more substituents independently selected from: C1-6 alkyl, C1- 6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl; C7-12 carbocycle and 7- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1- 6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, -CN, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl, provided that when Ring B is selected from (b), then Ring A is not chromane; provided that when one or more of (i), (ii), (ii), (iv), (v), (vi), (vii), and (viii) apply, then Ring A is further selected from C4-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: C1-6 alkyl, C1- 6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, -CN, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl: (i) Ring B is (a) and RA is selected from halogen, C1-4 haloalkyl, C3-6 cycloalkyl, -NR11, and -OR11; (ii) Y1 is S, Y2 is C, Ring B is (a), and X1 is N; (iii) Y1 is S, Y2 is C, Ring B is (a), and RA is C1-4 alkyl; (iv) Ring B is (a), and p is 1, 2, or 3; (v) R1 is C1-4 alkyl or C1-4 haloalkyl; (vi) Ring B is (c); and (vii) Y1 is CR3, Y2 is N, Y3 is CR3, and Y4 is N; (viii) Y1 is N, Y2 is N, Y3 is CR4, Y4 is CR3, and Ring B is (a) or (c); provided that when Ring B is (a), X1 is CH, RA is methyl, Y1 is CR3, and Y2 is N, then Ring A is further selected from tetrahydrofuranyl substituted with methyl; R5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)S(O)2(R13), -S(O)2R13, -S(O)2N(R13)2, -NO2, and -CN, provided that when RA is -OR11, then R5 is not -OR13; R6 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -N(R14)S(O)2(R14), -S(O)2R14, -S(O)2N(R14)2, -NO2, =O, and -CN; R8 is independently selected at each occurrence from halogen, C2-4 alkyl, C1-4 haloalkyl, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -N(R14)S(O)2(R14), -S(O)2R14, -S(O)2N(R14)2, -NO2, =O, and -CN; R7 and R9 are each independently selected from hydrogen, C1-4 alkyl, and C1-4 haloalkyl; R10, R11, R12, R13, and R14 are each independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl; m is selected from 0 and 1; p is selected from 0, 1, and 2; q is selected from 0, 1, and 2; and r is selected from 0, 1, and 2. Some embodiments provide a compound of Formula (II), (II); or a pharmaceutically acceptable salt thereof, wherein: each represents a single or a double bond, such that the bicyclic ring system comprising Y1, Y2, and Y3 is an aromatic bicyclic ring system where (i) Y1 is CR3 and Y2 is N, or (ii) Y1 is S and Y2 is C; Y3 is selected from N and CR4; Ring B is selected from (a), (b) and (c): (a) , X1 is selected from N, CH, and CR5; (b) , X2 is selected from S and NR7; and (c) , X3 is selected from S, N, and NH, X4 is selected from O and CR9, X5 is N or CH, X6 is N or CH, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system; R1 is selected from hydrogen, C1-4 alkyl, and –C(O)C3-6 cycloalkyl optionally substituted with one or more halogen; R2 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR10, -SR10, -N(R10)2, NO2, and -CN; R3 and R4 are each independently selected from hydrogen, halogen, C1-4 alkyl, and C1- 4 haloalkyl; RA is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -N(R11)2, -SR11, -N(R11)C(O)R11, -CN, -S(O)2C1-4 alkyl, C3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl, provided that: when Y1 is CR3 and Y2 is N, then RA is further selected from -OR11, when Y1 is CR3, Y2 is N, Y3 is CH, Ring B is (a), p is 0, X1 is N, and Ring A is 1-fluoro- 1-tetrahydropyranyl, then RA is further selected from hydrogen, and when Y1 is S, Y2 is C, and X1 is N, then RA is further selected from hydrogen; Ring A is selected from: C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is substituted with one or more halogen, and is optionally substituted with one or more substituents independently selected from: C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and 3- to 6- membered heterocycle optionally substituted with one or more C1-4 alkyl; C7-12 carbocycle and 7- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1- 6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, - C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, -CN, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl, provided that when Ring B is selected from (b), then Ring A is not chromane; provided that when one or more of (i), (ii), (ii), (iv), and (v) apply, then Ring A is further selected from C4-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, -CN, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl: (i) Ring B is (a) and RA is selected from halogen, C1-4 haloalkyl, C3-6 cycloalkyl, -NR11, and -OR11; (ii) Y1 is S, Y2 is C, Ring B is (a), and X1 is N; (iii) Y1 is S, Y2 is C, Ring B is (a), and RA is Ci-4 alkyl;
(iv) Ring B is (a), and p is 1, 2, or 3;
(v) R1 is Ci -4 alkyl; and
(vi)Ring B is (c); provided that when Ring B is (a), Xi is CH, RA is methyl, Y1 is CR’, and Y2 is N, then Ring A is further selected from tetrahydrofuranyl substituted with methyl;
R5 is independently selected at each occurrence from halogen, Ci-4 alkyl, Ct-i haloalkyl, -OR14, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R! 3)S(O)2(R! 3), -S(O)2R1J, -S(O)2N(R1J)2, ~NO2, and -CN, provided that when RA is -OR11, then R' is not -OR13;
R6 is independently selected at each occurrence from halogen, Ci-4 alkyl, Ci-4 haloalkyl, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2,
-N(R! 4)C(O)R14, -N(R14)S(O)2(R14), -S(O)2R14, -S(O)2N(R14)2, -NO2, =0, and -CN;
R8 is independently selected at each occurrence from halogen, C2-4 alkyl, Ci-4 haloalkyl, -OR14, -SR14, -N(R14)2, -C(0)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -N(R14)S(O)2(R14), -S(O)2R14, -S(O)2N(R14)2, -NO2, =0, and -CN;
R/ and R9 are each independently selected from hydrogen, Ci-4 alkyl, and Ci-4 haloalkyl;
Rso, R11, Rl2, R13, and R14 are each independently selected at each occurrence from hydrogen, Ci- 6 alkyl. Ci- 6 haloalkyl, and C3 -6 cycloalkyl; m is selected from 0, 1, and 2; p is selected from 0, 1 , and 2; q is selected from 0, 1, and 2; and r is selected from 0, 1 , and 2.
Some embodiments provide a compound of Formula (V):
(v), or a pharmaceutically acceptable salt thereof, wherein: Q! is N, S, O or CR3, Q2 is N or C, Q3 is N or CR4, Q4 is N or CR3, Q3 is C or N, and each represents a single or a double bond, such that the bicyclic ring system comprising Q1, Q2, Q3, Q4, and Q5 is benzo [djthiazole, benzo[d]oxazole, imidazo[l,2-a]pyridine, thiazolo[5,4- bjpyridine, imidazofl ,2-b]pyridazine, pyrazolo[l,5-a]pyridine, [l,2,4]triazolo[l,5-a]pyridine, or [l,2,4]triazolo[l,5-b]pyridazine;
RA is selected from halogen, -OR10, -SR10, -N(R10)2, -CN, Ci-e alkyl optionally substituted with one or more halogen or -OR10, Cs-Ce saturated cycloalkyl, and 3- to 6-membered saturated heterocycloalkyl ;
Ring A is selected from a C3-C10 saturated cycloalkyl, a C3-C10 partially saturated carbocycle, a 3- to 10-membered saturated heterocycloalkyl, and a 3- to 10-membered partially saturated heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR”, -N(R”)2, -C(O)R”, -C(O)ORU, -OC(O)R”, -OC(O)N(R”)2, -C(0)N(R”)2, -N(R”)C(O)R”, -N(R11)C(O)OR11, -N(R11)C(O)N(R11)2, -MR^SCOXR11), -SIOJR11, -SlOyR A -S(O)2N(RU)2, -S(O)(NR11)R11, -NO2, and =0;
C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R! 1)2, -C(O)Rn, -C(0)0Rn, -OC(O)RU, -0C(0)N(Ru)2, -C(0)N(R! 1)2, -N(R: \)C(O)R A -N(R11)C(0)0R11, -N(R11)C(0)N(R11)2, -N(R11)S(0)2(R11), -S(O)R!1, -S(O)2R!1, -S(O)2N(RU)2, -S(0)(NR11)R11, -N02, =0, -CN; and
C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR11, -SR11, -N(Rii)2, -C(0)R”, -CfC^OR11, -OC(O)R”, -0C(0)N(Rn)2, -C(0)N(R11)2, -N(R11)C(())R11, -N(R11)C(0)0R11, -N(R11)C(())N(R11)2, -N(R11)S(())2(R11), -S(O)R”, -S(0) R A -S(O)2N(R11)2, -S(0)(NR11)Rii, -NO: 2, 0 and -CN;
Ring B is selected from a C3-C10 carbocycle and a 3 - to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR A -SR12, -N(R12)2, -C(())R12, -C(0)0R12, -0C(0)R12, -0C(0)N(Rl 2)2, -C(())N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), ■S(O)R A -S(O).-R A -S(O)2N(R12)2, -S(O)(NR12)R12, -NOZ, O. and -CN;
C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(0)0R12, -0C(0)R12, -OC(O)N(R12)2, -C(())N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)Z(R12), ■S(O)R . -Sf Oi.-R 2, -S(0)2N(Ri 2)2, -S(O)(NR12)R12, -NO.-. O. ■( N; and
C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, Ci-e alkyl, Ci-e haloalkyl, -OR12, -SR12, -N(RI2)2, -C(O)R12, -C(())OR12, -OC(O)R12, ■O('{O)N( Ri 2) -C(O)N(R!2)2, -N(R12)C(())R12, -N(R12)C(O)OR12, -N(R12)C(())N(R12)2, -N(R12)S(())2(R12), -S(O)R12, -S(O) 2R12, -S(O) 2N(R! 2)2, -S(O)(NR12)R12, -NO: 2, O. and -CN;
R1 is selected from hydrogen, Ci-4 alkyl, Cu4 haloalkyl, and -C(O)R1J;
R2 is independently selected at each occurrence from halogen, Ci-4 alkyl, Ci-4 haloalkyl, -OR14, -SR14, -N(R14)2, -NO2, and -CN;
R3 is independently selected at each occurrence from hydrogen, halogen, Ci -4 alkyl, and Ci-4 haloalkyl;
R4 is selected from hydrogen, halogen, Ci -4 alkyl, and Ci-4 haloalkyl;
R10, R11, R12, R13, and R14 are each independently selected at each occurrence from hydrogen, Ci-4 alkyl, Ci-4 haloalkyl, and cycloalkyl optionally substituted with one or more halogen; and n is selected from 0, 1 , and 2; provided that when Ring B is pyrazolyl, then Ring A is not N-Boc pyrrolidinyl.
Some embodiments provide a compound of Formula (VI): or a pharmaceutically acceptable salt thereof, wherein:
Q1 is S or CR3, Q2 is N or C, QJ is selected from N and CR4, and each represents a single or a double bond, such that the bicyclic ring system comprising Q1, Q2, and Q3 is benzo[d]thiazole, imidazofl ,2-a]pyridine, thiazolo[5,4-b]pyridine, or imidazo[l,2-b]pyridazine;
RA is selected from halogen, -OR10, -SR10, -N(R10)2, -CN, C1-6 alkyl, C1-6 haloalkyl, C3-C6 saturated cycloalkyl, and 3- to 6-membered saturated heterocycloalkyl; Ring A is selected from a C3-C10 saturated cycloalkyl, a C3-C10 partially saturated carbocycle, a 3- to 10-membered saturated heterocycloalkyl, and a 3- to 10-membered partially saturated heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR! !, -N(Rll)2, -C(O)Rn, -C(O)ORn, -OC(O)RU, OC{O)X( Ri : } -C(0)N(R1 !)2, •X{ R: i )('(())()R: i. -N(R11)C(0)N(R11)2, -X-: R: : ;-S(()) -: R.: : ;-.
-S(O)Rn, -S(O)2Rn, -S(O)2N(R!1)2, -S(O)(NR11)R11, -NO2, and ();
C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, •N(R" r. -C(O)Rn, -C(O)OR! 1, -OC(O)R! !, -OC(O)N(R! 1 )2, -C(O)N(R’! 1)2, -N(R11)C(O)R11, -N(RH)C(O)OR51, -N(Rn)C(O)N(Rn)2, -N(Rn)S(O)2(Rn), -S(O)Rn, -S(O)2Rn, -S(O)2N(R! ! )2, -S(O)(NR”)Rn, -NO2, =0, -CN; and
C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR11, -SR11, -N(R!!)2, -C(0)R11, -C(0)0R! 1, -OC(O)R1! , -0C(0)N(RU)2, -C(0)N(Rn)2, -\iR KW -N^'^OR11, -N(R11)C(0)N(R11)2, -N(Rll)S(0)2(R11), -S(O)R!!, -S(O)2R! 1, -S(O)2N(RH)2, -S(0)(NRll)R!!, -NO2, =0, and -CN;
Ring B is selected from a C3-C10 carbocycle and a 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(0)R12, -C(0)0R12, -0C(0)R12, -OC(O)N(Ri2)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N( R12): 2, -S(())(NRi2)R12, -N02, O. and -CN;
C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(())0R12, -0C(0)R12, -OC(O)N( R12): 2, -C(())N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N( R12): 2, -S(())(NRi2)R12, -N02, O. -CN; and
C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, Ci-e alkyl, Ci-e haloalkyl, -OR12, -SR12, -N(R12)2, -C(())R12, -C(())0R12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(())R12, -N(R12)C(O)OR12, -N(R12)C(())N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(0) 2R12, -S(0) 2N(R12)2, -S(O)(NR12)R12, -NO: 2, O, and -CN;
R1 is selected from hydrogen, C1-4 alkyl, and -C(O)R13; R2 is independently selected at each occurrence from halogen, Ci-4 alkyl, Ci-4 haloalkyl, -OR14, -SR14, -N(R14)2, -NO2, and -CN;
R3 and R4 are each selected from hydrogen, halogen, Ci-4 alkyl, and Ci-4 haloalkyl;
R10, Ru, R12, R13, and R14 are each independently selected at each occurrence from hydrogen, Ci-4 alkyl, C1-4 haloalkyl, and cycloalkyl optionally substituted with one or more halogen; and n is selected from 0, 1, and 2; provided that when Ring B is pyrazolyl, then Ring A is not A-Boc pyrrolidinyl.
Also provided herein is a pharmaceutical composition comprising a compound of Formula
(I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Provided herein is a method for treating a neurological disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
Some embodiments provide a method for treating a neurological disorder in a subject in need thereof, the method comprising (a) determining that the neurological disorder is associated with a dysregulation of & DYRK1A gene, a DYRK1A protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
Also provided herein is a method for treating a neurological disorder in a subject in need thereof, the method comprising (a) determining that the neurological disorder is a DYRK1A- associated neurological disorder, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
Also provided herein is a method for treating a neurological disorder in a subject in need thereof, the method comprising (a) determining that the subject has a neurological disorder; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I),
(II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Provided herein is a method of treating a DYRKlA-associated disorder in a subject, the method comprising administering to a subject previously determined to have a DYRKlA- associated disorder a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
Provided herein is a method of treating a subject, the method comprising administering a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject having a clinical record that indicates that the subject has a dysregulation of a DYRKIA gene, a DYRKIA protein, or expression or activity or level of any of the same.
This disclosure also provides a method for inhibiting DYRKIA activity in a mammalian cell, the method comprising contacting the mammalian cell with a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, sor a pharmaceutically acceptable salt thereof.
The details of one or more embodiments of this disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the present disclosure will be apparent from the description and the claims.
Additional Definitions
To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties. In case of conflict, the present specification, including definitions, wall control.
The term “about” w'hen referring to a number or a numerical range means that the number or numerical range referred to is an approximation, for example, within experimental variability and/or statistical experimental error, and thus the number or numerical range may vary up to ±10% of the stated number or numerical range.
The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.
The term “inhibit” or “inhibition of’ means to reduce by a measurable amount, or to prevent entirely (e.g., 100% inhibition).
The phrase “therapeutically effective amount” means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a neurological disorder as described herein, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular neurological disorder, or (iii) delay the onset of one or more symptoms of the particular neurological disorder described herein. In some embodiments, the therapeutically effective amount is an amount sufficient to inhibit DYRK1 A activity in brain tissue.
As used herein, terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a neurological disorder, diminishment of the extent of a neurological disorder, stabilized (i.e., not worsening) state of a neurological disorder, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the neurological disorder), and remission (whether partial or total), whether detectable or undetectable and can be determined by various clinical assessments including clinical evaluation and self-reporting. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.
The term “pharmaceutically acceptable excipient” means a. pharmaceutical! y-accep table material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.: Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th edg Rowe eta!., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.\ Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.. Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.
The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to winch it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, A-methyl-D-glucamine, tris(hydroxymethyl)methylaniine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salt s not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described heremform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic ammo acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically- exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.
The term “pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “pharmaceutically acceptable carriers”), such as stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or other excipients. The pharmaceutical composition facilitates administration of the compound to an organism. The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human. The terms “halo” and “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). The term “oxo” refers to a divalent doubly bonded oxygen atom (i.e., “=O”). As used herein, oxo groups are attached to carbon atoms to form carbonyls. The term “hydroxyl” refers to an -OH radical. The term “nitro” refers to an –NO2 radical. The term “cyano” refers to a -CN radical. The term “alkyl” refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched, containing the indicated number of carbon atoms. For example, C1-10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and/or other substituents as defined herein. An “alkylene” group is a divalent alkyl group as described herein. The term “haloalkyl” refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen. The term “hydroxyalkyl” refers to an alkyl, in which one or more hydrogen atoms is/are replaced with a hydroxyl group, as described herein. The term “alkoxy” refers to an -O-alkyl radical (e.g., -OCH3). The terms “carbocycle” and “carbocyclyl” refer to a 3-20 carbon mono-, bi-, tri- or polycyclic group that can be fully saturated, partially unsaturated, aromatic, and (in multi-ring systems) any combination thereof. Carbocyclyl groups can include fused, bridged, and spiro ring systems. In some embodiments, a carbocyclyl is an aryl as defined herein. Examples of carbocyclyl groups include aryl and cycloalkyl groups as described herein. The term “aryl” refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like. The term “cycloalkyl” as used herein refers to cyclic saturated or partially unsaturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups can include fused and bridged ring systems. Non-limiting examples of fused/bridged cycloalkyl includes: bicyclofl.1.0]butane, bicyclo[2. l.Ojpentane, bicyclofl.1.1 ]pentane, bicyclof 3.1.0] hexane, bicyclo[2.1.1 ]hexane, bicyclof3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclof2.2. l]heptane, bicyclofS.1. Ijheptane, bicyclof4.2.0]octane, bicyclof3.2.1]octane, bicyclof2.2.2]octane, and the like. Cycloalkyl groups can also include spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic cycloalkyls include spirof2.2]pentane, spiro [2.5] octane, spiro [3.5] nonane, spiro[3.5]nonane, spiro[3.5]nonane, spirof4.4]nonane, spirof2.6]nonane, spiro[4.5]decane, spiro [3.6] decane, spiro[5.5]undecane, and the like.
The terms “heterocycle” and “heterocyclyl” refers to a mono-, bi-, tri-, or polycyclic saturated, partially unsaturated, or aromatic ring systems with 3-20 total ring atoms and having 1 - 4 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic. Exemplary heteroatoms include O, N, S, P, Si, and B. In some embodiments, for example, a heterocycle comprises 1, 2, 3, or 4 heteroatoms selected from O, N, and S. In some embodiments, a heterocycle comprises 1, 2, or 3 (e.g., 1) heteroatoms selected from O, N, and S, In some embodiments, a heterocycle comprises one 0 atom. In some embodiments, a heterocycle comprises one S atom. In some embodiments, a heterocycle comprises one N atom. In some embodiments, for example, a heterocycle comprises 1 , 2, 3, or 4 heteroatoms selected from O, N, and S. In some embodiments, a heterocycle comprises 1 or 2 (e.g., 1) heteroatoms selected from O, N, and S. In some embodiments, a heterocycle comprises one 0 atom. In some embodiments, a heterocycle comprises one S atom. In some embodiments, a heterocycle comprises one N atom. Heterocyclic ring systems can also include 1 -3 ring atoms that are -C(())-, N-oxide, S-oxide, and/or S,S-dioxide groups, valence permitting. In some embodiments, a heterocyclyl is a heteroaryl as defined herein. Examples of heterocyclyl groups include heteroaryl groups, as described herein, as well as fully and partially saturated groups such as piperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidonyl, tetrahydrothiophenyl 1,1 -dioxide, thiomorpholinyl 1,1 -dioxide, tetrahydrothiophenyl 1,1 -dioxide, thiomorpholinyl 1,1 -dioxide, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihy dr of uranyl, dihydrothiophenyl, and the like. Heterocyclyl groups can include multiple fused and bridged rings. Non-limiting examples of fused/bridged heteorocyclyl includes: 2- azabicyclo [1.1.0]butane, 2-azabicy clo[2.1.0]pentane, 2-azabicyclo[ 1.1.1 ]pentane, 3- aza bicyclo [3.1.0] hexane, 5-azabicyclo[2.1.1 ]hexane, 3 -azabicyclo [3.2.0 ]heptane, octahydrocyclopentalclpvrrole, 3-azabicyclol4.1.Olheptane, 7-azabicyclol2.2.1 lheptane, 6 azabicyclo[3.1. 1 ]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3- azabicyclo[3.2. l]octane, 2-oxabicyclo[ 1.1.0]butane, 2-oxabicyclo[2.1.01 pentane, 2- oxabicyclo[ 1.1.1 ]pentane, 3 -oxabicy clo[3.1.0]hexane, 5-oxabicyclo[2.1.1 ]hexane, 3- oxabicy clo[3.2.0] heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1 ]heptane, 6- oxabicy clo[3.1.1 ] heptane, 7-oxabicy clo[4.2.0] octane, 2-oxabicyclo[2.2.2]octane, 3- oxabicyclo[3.2.1]octane, and the like. Heterocyclyl groups can also include spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1- azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2 -azaspiro [4.4] nonane, 6- azaspiro[2.6]nonane, 1 ,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5- diazaspiro[3.6]decane, 3 -azaspiro [5.5] undecane, 2-oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, l-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6- oxaspiro[2.6]nonane, l,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1 - oxaspiro[5.5] undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5jundecane and the like.
The term “heteroaryl”, as used herein, means a mono-, bi-, tri- or polycyclic aromatic group (i.e., the entire ring system is aromatic) having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms, wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of O, N, S, P, Si, and B. In some embodiments, for example, a heteroaryl comprises 1, 2, 3, or 4 heteroatoms selected from O, N, and S. In some embodiments, a heteroaryl comprises 1 or 2 (e.g., 1) heteroatoms selected from 0, N, and S. In some embodiments, a heteroaryl comprises one 0 atom. In some embodiments, a heteroaryl comprises one S atom. In some embodiments, a heteroaryl comprises one N atom. In some embodiments, for example, a heteroaryl comprises 1, 2, 3, or 4 heteroatoms selected from O, N, and S. In some embodiments, a heteroaryl comprises 1 or 2 (e.g., 1) heteroatoms selected from O, N, and S. In some embodiments, a heteroaryl comprises one O atom. In some embodiments, a heteroaryl comprises one S atom. In some embodiments, a heteroaryl comprises one N atom. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyndo[2,3-r/]pyrimidinyl, pyrrolo[2,3-£]pyridinyl, quinazoiinyl, quinolinyl, thieno[2,3- c[pyridinyl, pyrazolo[3,4-i?]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-6]pyridinyl, tetrazolyl, and the like.
The term “heterocycloalkyl” refers to a mono-, bi-, tri-, or polycyclic saturated or partially unsaturated ring system with 3-20 total ring atoms and having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic. Exemplary heteroatoms include O, N, S, P, Si, and B. In some embodiments, for example, a heterocycloalkyl comprises 1, 2, 3, or 4 heteroatoms selected from O, N, and S. In some embodiments, for example, a heterocycloalkyl comprises 1, 2, 3, or 4 heteroatoms selected from O, N, and S. In some embodiments, a heterocycloalkyl comprises 1 or 2 (e.g., 1) heteroatoms selected from O, N, and S. In some embodiments, a heterocycloalkyl comprises one O atom. In some embodiments, a heterocycloalkyl comprises one S atom. In some embodiments, a heterocycloalkyl comprises one N atom. Heterocycloalkyl ring systems can also include 1-3 ring atoms that are -C(O)~, N-oxide, S-oxide, and/or S,S-dioxide groups, valence permitting. Examples of heterocycloalkyl groups include piperazinyl, pyrrolidinyl, pyrrolidonyl, tetrahydrothiophenyl 1,1 -dioxide, thiomorpholinyl 1,1-dioxide, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, and the like. Heterocycloalkyl groups can include multiple fused and bridged rings. Non-limiting examples of fused/bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2- azabicy do [1.1.1 ]pentane, 3-azabicyclo[3.1 .0]hexane, 5-azabicyclo[2.1.1 jhexane, 3- azabi cyclo [3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyc1o[4.1 .0]heptane; azabicyclo [2.2.1 ]heptane, 6-azabicyclo[3.1.1 [heptane, 7-azabicyclo[4.2.0]octane, aza bicyclo [2.2.2] octane, 3-azabicydo[3.2.1 [octane, 2-oxabicyclo[ 1.1.0] butane, 2- oxabicyclo[2.1.0]pentane, 2-oxabicy clo[ 1.1.1 ]pentane, 3-oxabicyclo[3.1.0]hexane, oxabicy clo[2.1.1 ]hexane, 3-oxabicyclo[3.2.0]heptane, 3 -oxabicy clo[4.1 ,0]heptane, 7- oxabicy clo[2.2.1 ]heptane, 6-oxabicyclo[3.1.1 [heptane, 7-oxabicyclo[4.2.0]octane, oxabicyclo[2.2,2]octane, 3-oxabicyclo[3.2.1]octane, and the like. Heterocycloalkyl groups can also include spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocycloalkyls include 2- azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, l-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7- azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, l,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5-diazaspiro[3.6]decane, 3 -azaspiro [5.5] undecane, 2- oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, l-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7- oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, l,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, l-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9- azaspiro[5.5]undecane and the like.
The term “heterocycloalkyl” refers to a mono-, bi-, tri-, or polycyclic saturated or partially unsaturated ring system with 3-20 total ring atoms and having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic. Exemplary heteroatoms include O, N, S, P, Si, and B. In some embodiments, for example, a heterocycloalkyl comprises 1, 2, 3, or 4 heteroatoms selected from O, N, and S. In some embodiments, for example, a heterocycloalkyl comprises 1, 2, 3, or 4 heteroatoms selected from O, N, and S. In some embodiments, a heterocycloalkyl comprises 1 or 2 (e.g., 1) heteroatoms selected from O, N, and S. In some embodiments, a heterocycloalkyl comprises one O atom. In some embodiments, a heterocycloalkyl comprises one S atom. In some embodiments, a heterocycloalkyl comprises one N atom. Heterocycloalkyl ring systems can also include 1-3 ring atoms that are oxo, N-oxide, S- oxide, and/or S,S-dioxide groups, valence permitting. Examples of heterocycloalkyl groups include piperazinyl, pyrrolidinyl, pyrrolidonyl, tetrahydrothiophenyl 1,1 -dioxide, thiomorpholinyl 1,1-dioxide, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, and the like. Heterocycloalkyl groups can include multiple fused and bridged rings. Non-limiting examples of fused/bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2- azabicy clo [1.1.1 [pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1 ]hexane, 3- azabicyclo [3.2.0] heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, azabicyclo [2.2.1 [heptane, 6-azabicyclo[3.1. l]heptane, 7-azabicyclo[4.2.0]octane, aza bicyclo [2.2.2] octane, 3-azabicyclo[3.2. l]octane, 2-oxabicyclo[ 1.1.0] butane, 2- oxabicyclo[2.1.0]pentane, 2-oxabicy clo[ 1.1.1 [pentane, 3-oxabicyclo[3.1.0]hexane, oxabicyclo[2.1.1 Jhexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7- oxabicyclo[2.2.1 ]heptane, 6-oxabicyclo[3.1.1 ]heptane, 7-oxabicyclo[4.2.0]octane, 2- oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, and the like. Heterocycloalkyl groups can also include spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocycloalkyls include 2- azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, l-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7- azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, l,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5-diazaspiro[3.6]decane, 3 -azaspiro [5.5] undecane, 2- oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, l-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7- oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, l,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, l-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9- azaspiro[5.5]undecane and the like.
For purposes of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as one or more of
| y O i ), and imidazolone (e.g., ’), wherein each ring nitrogen adjacent to a carbonyl is tertiary (i.e., the oxo group (i.e., “=O”) herein is a constituent part of the heteroaryl ring).
The term “saturated’1 as used in this context means only single bonds present between constituent atoms.
As used herein, when a ring is described as being “partially unsaturated,” it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, di hydrothiophene, and the like.
For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., carbocycle, aryl, cycloalkyl, heterocyclyl, heteroaryl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x.O] ring systems, in which 0 represents a zero atom bridge (e.g., ))•
J J
(ii) a single ring atom (spiro-fused ring systems) (e.g., , or ), or
(in) a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.g,,
In addition, any compound or structure given herein, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. These forms of compounds are referred to as “isotopically enriched.” Isotopically enriched compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine, such as 2H, 13C, i4C, 13N, 15N, 15O, 17O, 180, 3iP, 32P, 35S, l8F, 36C1 , 123I, and 125I, respectively. Various isotopically enriched compounds of the present disclosure, for example those into which radioactive isotopes such as 13C and !4C are incorporated. Such isotopically enriched compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients. The term“isotopically enriched” compounds includes" deuterated” compounds described herein in which one or more hydrogens is/are replaced by deuterium, such as a hydrogen on a carbon atom. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. Such compounds are synthesized by means known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium. Indeed, isotopically enriched compounds of this disclosure can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically enriched reagent for a non-isotopically enriched reagent.
Deuterium enriched compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index relative to the corresponding non-enriched compound.
The concentration of a heavier isotope, such as deuterium, may be defined by an isotopic enrichment factor. In some embodiments, the positions noted as “H” or “hydrogen” in the compounds described herein have hydrogen at its natural abundance isotopic composition. In some embodiments, the positions noted as “H” or “hydrogen” in the compounds described herein have hydrogen enriched in deuterium above its natural abundance isotopic composition, i.e., the compound is a deuterium enriched compound. Examples of deurated groups in the compounds described herein include, but are not limited to deuteromethine ( or monodeuteromethylene ) and dideuteromethylene °x ’D"''tyr trideuteromethyl (
CD,
Q tri deuteromethoxy (' ), and the like. Compounds of the present disclosure also include
O deuterium enriched compounds at the alpha position of an oxo group, such as D H ; O o D o
D D , U ? and Compounds of the present disclosure also include
D \ deuterium enriched compounds adjacent to a heteroatom, such as, for example and
N<- J-L J
In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety: encompasses the tautomeric form containing the moiety: H $. Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.
The compounds provided herein may encompass various stereochemical forms. The compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, as well as mixtures of enantiomers (e.g., R and S isomers) including racemic mixtures and mixtures of diastereomers, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry (e.g., a “flat” structure) and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Likewise, unless otherwise indicated, when a disclosed compound is named or depicted by a structure that specifies the stereochemistry (e.g., a structure with “wedge” and/or “dashed” bonds) and has one or more chiral centers, it is understood to represent the indicated stereoisomer of the compound.
The details of one or more embodiments of this disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the present disclosure wall be apparent from the description and from the claims. DETAILED DESCRIPTION
Dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRKIA) is a member of the dual-specificity tyrosine phosphorylation regulated kinase (DYRK) family, which is also part of the larger CGMC family of kinases. DYRK 1 A is a 763 amino acid, 85 kDa serine/threonine kinase located on chromosome 21. DYRK1A contains a nuclear targeting signal sequence, a protein kinase domain, a leucine zipper motif, and a highly conservative 13-consecutive-histidine repeat. Alternative splicing DYRK 1 A generates several transcript variants differing from each other either in either the 5' untranslated region or in the 3' coding region resulting in at least five different isoforms.
DYRKIA possesses catalytic activity that is regulated by autophosphorylation of a tyrosine residue (¥321) which results in constitutively active serine/threonine kinase activity. Since DYRK 1 A is constitutively active, its activity is dosage dependent. Thus, both elevated levels and depressed levels of DYRKIA (relative to wild-type levels) have been shown to lead to neurological impairment.
DYRKIA displays a broad substrate spectrum (e.g., broad range of targets) including splicing factors, synaptic proteins, and transcription factors. It is ubiquitously expressed in all mammalian tissues and cells, although at different levels, with particularly high levels in embryonic and adult brain tissues. The human DYRKI A gene is a candidate gene to treat several Down syndrome characteristics, including intellectual impairment and Alzheimer’s disease associated with Down syndrome, due to its localization in the Down syndrome critical region on chromosome 21 and its role in brain function. Notably, Drosophila with deleterious mutations in the ortholog of DYRKIA (“Minibrain”) have a reduced number of neurons in their central nervous system. Likewise, mice heterozygous for a disrupted allele of the Dyrkla gene exhibit decreased viability, behavioral alterations, and delayed growth. Fotaki, et al., Mol Cell Biol., 22(18): 6636- 6647 (2014).
The identification of hundreds of genes deregulated by DYRKIA overexpression and numerous cytosolic, cytoskeletal and nuclear proteins, including transcription factors, phosphorylated by DYRKIA, indicates that DYRKIA over express! on is central for the deregulation of multiple pathways in the developing and aging brain of individuals with Down syndrome. Identifying DYRKIA cell signaling or transduction pathways can lead to a better understanding of how DYRKIA overexpression (or under expression) leads to the various disease states in which it is known to be involved. Specifically, DYRK1A is known to be active in activated PI3K/Akt signaling, a pathway largely involved in neuronal development, growth, and survival. DYRK1A is also known to be active in ASK1/JNK1 activity and inhibitors of DYRK1A may induce neuronal death and apoptosis. DYRK1A is also known to phosphorylate p53 during embryonic brain development, and inhibitors of DYRK1A can prevent neuronal proliferation alteration. DYRK1A also phosphorylates synaptic proteins Amph 1, Dynamin 1, and Synaptojamn, which are involved in the regulation of endocytosis and inhibitors of DYRK1A can retain synaptic plasticity’ through preventing alteration of the number, size, and morphology of dendritic spines. DYRK1A also phosphorylates inhibit presenilm 1, the catalytic sub-unit of y- secretase. Ryu, et al., J Neurochem., 115(3): 574-84 (2010).
DYRK1A over expression leads to structural and functional alterations including intellectual disability’ and dementia, e.g., Alzheimer’s disease. In particular, genes involved in learning disorders, synaptic flexibility’ changes, memory loss, and abnormal cell cycles, result in neuropathological symptoms similar to dementia associated with Alzheimer’s disease. DYRK1A can also affect the proliferation and differentiation of neuronal progenitors, thus influencing neurogenesis and brain growth. It can also affect neurotransmission and dendritic spine formation through its interaction with synaptic proteins and the cytoskeleton.
One potential source of treatment are inhibitors of DYRK1 A, Inhibitors that can normalize DYRK1A levels in Down syndrome may improve synaptic plasticity' and delay the onset of Alzheimer’s disease pathology, including tau hyperphosphorylation. Therefore, inhibiting DYRK1 A activity in individuals with Down syndrome might counteract the phenotypic effects of its overexpression and is a potential avenue for the treatment of such developmental defects and prevention and/or mitigation of age-associated neurodegeneration, including Alzheimer’s disease associated with Down syndrome. Studies have shown that inhibition of overexpressed DYRK1 A resulted in normal DYRK1 A levels and been found to improve cognitive and behavioral deficits in transgenic models. See, e.g., Stringer, et al.. Mol Genet Genomic Med, 5, 451 -465 (2017) and Feki and Hibaoui, Brain Sci, 8, 187 (2018). However, despite promising results there is considerable variation across studies in terms of outcomes. Discrepancies were attributed to differences in model, dose, route of administration, the composition of the inhibitor, and timing of administration. Epigall ocatechin gallate (EGCG) is the primary flavonoid of green tea and has been investigated for its therapeutic effects, which include anti- oxi dative, anti-inflammatory, anticancer, anti -infective and neuroprotective activity. See, Bhat, et al. Towards the discovery of druglike epigallocatechin gallate analogs as Hsp90 inhibitors, Bioorg Med Chem Lett, 24, 2263-2266 (2014). EGCG is a non- ATP competitive DYRK1A inhibitor and studies have shown that green tea extract comprising 41% EGCG were able to alleviate cognitive decline seen in transgenic mice over expressing DYRK1A. ECGC has also been shown to improve memory recognition and working memory. However, ECGC is not significantly selective and has numerous off-target effects, thus reducing its potential long-term use.
SM07883 is an orally bioavailable (%F 92% in mice, 109% in monkey), BBB penetrant, DYRK1A inhibitor (IC50 1.6 nM) that also show's potent inhibition for DYRK1B, CLK4, and GSK3P in kinase assays. It was found to protect against tau hyperphosphorylation in mouse models. SM07883 wv.s tested for treatment of Alzheimer’s disease in a phase 1 study in Australia (ACTRN12619000327189). However, according to the study description page at www.anzctr.org.au, the date of last data collection was in May 2019 and no results have been published for the trial.
This disclosure provides compounds of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, and pharmaceutically acceptable salts thereof, that inhibit Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A). These chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) DYRK1A activation contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., a neurological disorder in a subject (e.g., a human). This disclosure also provides compositions containing the same as well as methods of using and making the same.
Formulae (I), (II), (HI), and (IV) Compounds
Some embodiments provide a compound of Formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein: each represents a single or a double bond, such that the bicyclic ring system comprising Y1, Y2, Y3, and Y4 is an aromatic bicyclic ring system where (i) Y1 is CR3, Y2 is N, Y3 is CR4, and Y4 is CR3 or N; (ii) Y1 is S, Y2 is C, Y3 is CR4 or N, and Y4 is CR3; or (iii) Y1 is N, Y2 is N, Y3 is CR4, and Y4 is CR3; L is selected from , , and , wherein * denotes the point of attachment to Ring A, Z is selected from -O-, -NR1-, C1-4alkylene, -O-C1-4alkylene, and -NR1-C1-4alkylene, Z’ is selected from -NR1-, -S(O)-, -S(O)2-, C1-4alkylene, -NR1-C1-4alkylene, -S(O)-C1-4alkylene, and -S(O)2-C1-4alkylene; wherein each C1-4alkylene is optionally substituted with one or more halogen; Ring B is selected from (a), (b) and (c): (a) , X1 is selected from N, CH, and CR5; (b) , X2 is selected from S and NR7; and (c) , X3 is selected from S, N, and NH, X4 is selected from O and CR9, X5 is N or CH, X6 is N or CH, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system, provided that when Ring B is (a), Y1 is CR3, Y2 is N, Y3 is CR4, and Y4 is N, then p is 0; R1 is independently selected at each occurrence from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and –C(O)C3-6 cycloalkyl optionally substituted with one or more halogen; R2 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, - OR10, -SR10, -N(R10)2, NO2, and -CN; R3 and R4 are each independently selected at each occurrence from hydrogen, halogen, C1- 4 alkyl, and C1-4 haloalkyl; RA is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -N(R11)2, -SR11, -N(R11)C(O)R11, -CN, -S(O)2C1-4 alkyl, C3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl, provided that: when Y1 is CR3, Y2 is N, and Y4 is CR3, or when Y1 is CR3, Y2 is N, and Y4 is N, then RA is further selected from -OR11, when Y1 is CR3, Y2 is N, Y3 is CH, Ring B is (a), p is 0, X1 is N, and Ring A is 1- fluoro-1-tetrahydropyranyl, then RA is further selected from hydrogen, and when Y1 is S, Y2 is C, and X1 is N, then RA is further selected from hydrogen; Ring A is selected from: cyclopropyl substituted with one or more C1-6 alkyl or -CN, C3-6 carbocycle substituted with one or more halogen, 3- to 6-membered heterocycle substituted with one or more halogen, C5-6 spirocyclic carbocycle, and 5- to 6-membered spirocyclic heterocycle, any of which is optionally substituted with one or more substituents independently selected from: C1-6 alkyl, C1- 6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl; C7-12 carbocycle and 7- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-
6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, -CN, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl, provided that when Ring B is 5 selected from (b), then Ring A is not chromane; provided that when one or more of (i), (ii), (ii), (iv), (v), (vi), (vii), and (viii) apply, then Ring A is further selected from C4-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: C1-6 alkyl, C1- 6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, -CN, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl: (i) Ring B is (a) and RA is selected from halogen, C1-4 haloalkyl, C3-6 cycloalkyl, -NR11, and -OR11; (ii) Y1 is S, Y2 is C, Ring B is (a), and X1 is N; (iii) Y1 is S, Y2 is C, Ring B is (a), and RA is C1-4 alkyl; (iv) Ring B is (a), and p is 1, 2, or 3; (v) R1 is C1-4 alkyl or C1-4 haloalkyl; (vi) Ring B is (c); and (vii) Y1 is CR3, Y2 is N, Y3 is CR3, and Y4 is N; (viii) Y1 is N, Y2 is N, Y3 is CR4, Y4 is CR3, and Ring B is (a) or (c); provided that when Ring B is (a), X1 is CH, RA is methyl, Y1 is CR3, and Y2 is N, then Ring A is further selected from tetrahydrofuranyl substituted with methyl; R5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)S(O)2(R13), -S(O)2R13, -S(O)2N(R13)2, -NO2, and -CN, provided that when RA is -OR11, then R5 is not -OR13; R6 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, 30 -N(R14)C(O)R14, -N(R14)S(O)2(R14), -S(O)2R14, -S(O)2N(R14)2, -NO2, =O, and -CN; 31 R8 is independently selected at each occurrence from halogen, C2-4 alkyl, C1-4 haloalkyl, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -N(R14)S(O)2(R14), -S(O)2R14, -S(O)2N(R14)2, -NO2, =O, and -CN; R7 and R9 are each independently selected from hydrogen, C1-4 alkyl, and C1-4 haloalkyl; R10, R11, R12, R13, and R14 are each independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl; m is selected from 0 and 1; p is selected from 0, 1, and 2; q is selected from 0, 1, and 2; and r is selected from 0, 1, and 2. In some embodiments, when a moiety or a list of moieties is optionally substituted or substituted with one or more substituents, the one or more substituents is 1-4 substituents (e.g., 1- 3, 2-4, 2-3, 1-2, 3-4, 1, 2, 3, or 4 substituents). For example, the one or more substituents is 1-4 substituents. For example, the one or more substituents is one substituent. In some embodiments, for the compound of Formula (I), Y1 is CR3, Y2 is N, Y3 is CR4, and Y4 is CR3 or N. In some embodiments, Y1 is CR3, Y2 is N, Y3 is CR4, and Y4 is N. In some embodiments, Y1 is CR3, Y2 is N, Y3 is CR4, and Y4 is CR3. In some embodiments, Y1 is S, Y2 is C, Y3 is CR4 or N, and Y4 is CR3. In some embodiments, Y1 is S, Y2 is C, Y3 is CR4, and Y4 is CR3. In some embodiments, Y1 is S, Y2 is C, Y3 is N, and Y4 is CR3. In some embodiments, Y1 is N, Y2 is N, Y3 is CR4, and Y4 is CR3. In some embodiments, for the compound of Formula (I), Y1 is CH, Y2 is N, Y3 is CH, and Y4 is CH or N. In some embodiments, Y1 is CH, Y2 is N, Y3 is CH, and Y4 is N. In some embodiments, Y1 is CH, Y2 is N, Y3 is CH, and Y4 is CH. In some embodiments, Y1 is S, Y2 is C, Y3 is CH or N, and Y4 is CH. In some embodiments, Y1 is S, Y2 is C, Y3 is CH, and Y4 is CH. In some embodiments, Y1 is S, Y2 is C, Y3 is N, and Y4 is CH. In some embodiments, Y1 is N, Y2 is N, Y3 is CH, and Y4 is CH. In some embodiments, the compound is of Formula (IA):
(IA), or a pharmaceutically acceptable salt thereof; wherein Y3 is CH or N, and Y4 is CH or N. In some embodiments, Y3 is CH, and Y4 is CH. In some embodiments, the compound is of Formula (IB): (IB), or a pharmaceutically acceptable salt thereof; the compound is of Formula (IC); wherein Y3 is CH or N, and Y4 is CH or N. (IC), or a pharmaceutically acceptable salt thereof; wherein Y3 is CH or N. In some embodiments, the compound is of Formula (ID): 10 (ID), or a pharmaceutically acceptable salt thereof; wherein Y4 is CH or N. 33 In some embodiments, for the compound of Formula (I), (IA), (IB), (IC), or (ID), L is or . In some embodiments, L is or . In some embodiments, L is or . In some embodiments, for the compound of Formula (I), (IA), (IB), (IC), or (ID), Z is selected from -O-, -NR1-, C1-4alkylene, -O-C1-4alkylene, and -NR1-C1-4alkylene, wherein each C1- 4alkylene is optionally substituted with one or more halogen. In some embodiments, Z is selected from -O-, -NR1-, C1-4alkylene, -O-C1-4alkylene, and -NR1-C1-4alkylene, wherein each C1-4alkylene is optionally substituted with one or more halogen; and R1 is independently selected at each occurrence from hydrogen, C1-4 alkyl, and C1-4 haloalkyl. In some embodiments, Z is selected from -O-, -NR1-, C1-4alkylene, -O-C1-4alkylene, and -NR1-C1-4alkylene, wherein each C1-4alkylene is optionally substituted with one or more halogen; and R1 is independently selected at each occurrence from hydrogen and C1-4 alkyl. In some embodiments, Z is selected from -O-, -NR1-, C1-4alkylene, -O-C1-4alkylene, and -NR1-C1-4alkylene, wherein each C1-4alkylene is optionally substituted with one or more halogen; and each R1 is hydrogen. In some embodiments, Z is selected from -O-, -NR1-, C1-4alkylene, -O-C1-4alkylene, and -NR1-C1-4alkylene; and each R1 is hydrogen. In some embodiments, for the compound of Formula (I), (IA), (IB), (IC), or (ID), Z is selected from -O-, -NR1-, C1-2alkylene, -O-C1-2alkylene, and -NR1-C1-2alkylene, wherein each C1- 2alkylene is optionally substituted with one or more halogen; and R1 is independently selected at each occurrence from hydrogen and C1-4 alkyl. In some embodiments, Z is selected from -O-, -NR1-, C1-2alkylene, -O-C1-2alkylene, and -NR1-C1-2alkylene, wherein each C1-2alkylene is optionally substituted with one or more halogen; and each R1 is hydrogen. In some embodiments, Z is selected from -O-, -NR1-, C1-2alkylene, -O-C1-2alkylene, and -NR1-C1-2alkylene; and each R1 is hydrogen In some embodiments, for the compound of Formula (I), (IA), (IB), (IC), or (ID), Z’ is selected from -NR1-, -S(O)-, -S(O)2-, C1-4alkylene, -NR1-C1-4alkylene, -S(O)-C1-4alkylene, and - S(O)2-C1-4alkylene; wherein each C1-4alkylene is optionally substituted with one or more halogen; and R1 is independently selected at each occurrene from hydrogen and C1-4 alkyl. In some embodiments, Z’ is selected from -NR1-, -S(O)-, -S(O)2-, C1-4alkylene, -NR1-C1-4alkylene, -S(O)- C1-4alkylene, and -S(O)2-C1-4alkylene; and each R1 is hydrogen. In some embodiments, for the compound of Formula (I), (IA), (IB), (IC), or (ID), Z’ is selected from -S(O)2-, C1-4alkylene, and -S(O)2-C1-4alkylene; wherein each C1-4alkylene is optionally substituted with one or more halogen. In some embodiments, Z’ is selected from -S(O)2- , C1-4alkylene, and -S(O)2-C1-4alkylene. In some embodiments, Z’ is C1-4alkylene, optionally substituted with one or more halogen. In some embodiments, Z’ is C1-4alkylene. In some embodiments, Z’ is C1-4alkylene, optionally substituted with one or more halogen; and R1 is hydrogen. In some embodiments, Z’ is C1-4alkylene; and R1 is hydrogen. In some embodiments, for the compound of Formula (I), (IA), (IB), (IC), or (ID), Z’ is selected from -NR1-, -S(O)-, -S(O)2-, C1-2alkylene, -NR1-C1-2alkylene, -S(O)-C1-2alkylene, and - S(O)2-C1-2alkylene; wherein each C1-2alkylene is optionally substituted with one or more halogen; and each R1 is hydrogen. In some embodiments, Z’ is selected from -S(O)2-, C1-2alkylene, and - S(O)2-C1-2alkylene; wherein each C1-2alkylene is optionally substituted with one or more halogen, and R1 is hydrogen. In some embodiments, Z’ is C1-2alkylene optionally substituted with one or more halogen. In some embodiments, Z’ is C1-2alkylene. In some embodiments, Z’ is C1-2alkylene optionally substituted with one or more halogen; and R1 is hydrogen. In some embodiments, Z’ is C1-2alkylene; and R1 is hydrogen. In some embodiments, for the compound of Formula (I), (IA), (IB), (IC), or (ID), Z is selected from -O-, -NR1-, C1-4alkylene, -O-C1-4alkylene, and -NR1-C1-4alkylene; and Z’ is selected from -S(O)2-, C1-4alkylene, and -S(O)2-C1-4alkylene; wherein each C1-4alkylene is optionally substituted with one or more halogen; and R1 is independently selected at each occurrence from hydrogen, C1-4 alkyl, and C1-4 haloalkyl. In some embodiments, Z is selected from -O-, -NR1-, C1- 4alkylene, -O-C1-4alkylene, and -NR1-C1-4alkylene; and Z’ is selected from -NR1-, -S(O)-, -S(O)2- , C1-4alkylene, -NR1-C1-2alkylene, -S(O)-C1-4alkylene, and -S(O)2-C1-4alkylene, wherein each C1- 4alkylene is optionally substituted with one or more halogen. In some embodiments, Z is selected from -O-, -NR1-, C1-4alkylene, -O-C1-4alkylene, and -NR1-C1-4alkylene; and Z’ is selected from - NR1-, -S(O)-, -S(O)2-, C1-4alkylene, -NR1-C1-4alkylene, -S(O)-C1-4alkylene, and -S(O)2-C1- 4alkylene, wherein each C1-4alkylene is optionally substituted with one or more halogen; and R1 is independently selected at each occurrence from hydrogen, C1-4 alkyl, and C1-4 haloalkyl. In some embodiments, Z is selected from -O-, -NR1-, C1-4alkylene, -O-C1-4alkylene, and -NR1-C1- 4alkylene; In some embodiments, Z’ is selected from -S(O)2-, C1-4alkylene, and -S(O)2-C1- 4alkylene; wherein each C1-4alkylene is optionally substituted with one or more halogen; and R1 is independently selected at each occurrence from hydrogen and C1-4 alkyl. In some embodiments, Z is selected from -O-, -NR1-, C1-4alkylene, -O-C1-4alkylene, and -NR1-C1-4alkylene; Z’ is C1- 4alkylene, optionally substituted with one or more halogen; wherein each C1-4alkylene is optionally substituted with one or more halogen; and each R1 is hydrogen. In some embodiments, Z is selected from -O-, -NR1-, C1-4alkylene, -O-C1-4alkylene, and -NR1-C1-4alkylene; Z’ is C1-4alkylene; and each R1 is hydrogen. In some embodiments, for the compound of Formula (I), (IA), (IB), (IC), or (ID), Z is selected from -O-, -NR1-, C1-2alkylene, -O-C1-2alkylene, and -NR1-C1-2alkylene; and Z’ is selected from -NR1-, -S(O)-, -S(O)2-, C1-2alkylene, -NR1-C1-2alkylene, -S(O)-C1-2alkylene, and -S(O)2-C1- 2alkylene, wherein each C1-2alkylene is optionally substituted with one or more halogen; and R1 is independently selected at each occurrence from hydrogen, C1-4 alkyl, and C1-4 haloalkyl. In some embodiments, Z is selected from -O-, -NR1-, C1-2alkylene, -O-C1-2alkylene, and -NR1-C1- 2alkylene; In some embodiments, Z’ is selected from -S(O)2-, C1-2alkylene, and -S(O)2-C1- 2alkylene; wherein each C1-2alkylene is optionally substituted with one or more halogen; and R1 is independently selected at each occurrence from hydrogen and C1-4 alkyl. In some embodiments, Z is selected from -O-, -NR1-, C1-2alkylene, -O-C1-2alkylene, and -NR1-C1-2alkylene; Z’ is C1- 2alkylene, optionally substituted with one or more halogen; wherein each C1-2alkylene is optionally substituted with one or more halogen; and each R1 is hydrogen. In some embodiments, Z is selected from -O-, -NR1-, C1-2alkylene, -O-C1-2alkylene, and -NR1-C1-2alkylene; Z’ is C1-4alkylene; and each R1 is hydrogen. In some embodiments, Z is selected from -O-, -NH-, -CH2-, -O-CH2-, and - NH-CH2-; and Z’ is -CH2-. In some embodiments, for the compound of Formula (I), (IA), (IB), (IC), or (ID), L is selected from , , , , , , , , , , , , , and . In some embodiments, for the compound of Formula (I), (IA), (IB), (IC), or (ID), L is . In some embodiments, L is ; Z is selected from -O-, -NR1-, C1- 4alkylene, -O-C1-4alkylene, and -NR1-C1-4alkylene, wherein each C1-4alkylene is optionally substituted with 1-2 halogen; and R1 is independently selected at each occurrence from hydrogen, C1-4 alkyl, and C1-4haloalkyl. In some embodiments, L is ; Z is selected from -O-, -NR1-, C1-4alkylene, -O-C1-4alkylene, and -NR1-C1-4alkylene, wherein each C1-4alkylene is optionally substituted with 1-2 halogen; and R1 is independently selected at each occurrence from hydrogen and C 1-4 alkyl. In some embodiments, L is ; Z is selected from -O-, -NR1- , C1-4alkylene, -O-C1-4alkylene, and -NR1-C1-4alkylene; and R1 is independently selected at each occurrence from hydrogen and C1-4 alkyl. In some embodiments, L is ; Z is selected from -O-, -NR1-, C1-4alkylene, -O-C1-4alkylene, and -NR1-C1-4alkylene; and each R1 is hydrogen. In some embodiments, L is ; Z is selected from -O-, -NR1-, C1-2alkylene, -O-C1- 2alkylene, and -NR1-C1-2alkylene, wherein each C1-2alkylene is optionally substituted with 1-2 halogen; and R1 is independently selected at each occurrence from hydrogen and C1-4 alkyl. In some embodiments, L is ; Z is selected from -O-, -NR1-, C1-2alkylene, -O-C1- 2alkylene, and -NR1-C1 lk l h i h C lk l i tionally substituted with 1-2 halogen; and each R1 is hydrogen. In some embodiments, L is selected from, , , , , , , and . In some embodiments, for the compound of Formula (I), (IA), (IB), (IC), or (ID), L is . In some embodiments, L is ; Z’ is selected from C1-4alkylene optionally substituted with 1-2 halogen; and R1 is selected from hydrogen, C1-4 alkyl, and C1-4haloalkyl. In some embodiments, L is ; Z’ is selected from C1-4alkylene optionally substituted with 1-2 halogen; and R1 is hydrogen. In some embodiments, L is ; Z’ is selected from C1- 4alkylene; and R1 is hydrogen. In some embodiments, L is . In some embodiments, for the compound of Formula (I), (IA), (IB), (IC), or (ID), L is . In some embodiments, L is ; and R1 is independently selected at each occurrence from hydrogen, C1-4 alkyl, and C1-4 haloalkyl. In some embodiments, L is ; and R1 is independently selected at each occurrence from hydrogen, C1-4 alkyl, C1-4 haloalkyl. In some embodiments, L is ; and R1 is independently selected at each occurrence from hydrogen and C1-4 alkyl. In some embodiments, L is selected from , , , , , and . In some embodiments, L is . Some embodiments provide a compound of Formula (II): (II); or a pharmaceutically acceptable salt thereof, wherein: each represents a single or a double bond, such that the bicyclic ring system comprising Y1, Y2, and Y3 is an aromatic bicyclic ring system where (i) Y1 is CR3 and Y2 is N, or (ii) Y1 is S and Y2 is C; Y3 is selected from N and CR4; Ring B is selected from (a), (b) and (c): (a) , X1 is selected from N, CH, and CR5; (b) , X2 is selected from S and NR7; and (c) , X3 is selected from S, N, and NH, X4 is selected from O and CR9, X5 is N or CH, X6 is N or CH, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system; R1 is selected from hydrogen, C1-4 alkyl, and –C(O)C3-6 cycloalkyl optionally substituted with one or more halogen; R2 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, - OR10, -SR10, -N(R10)2, NO2, and -CN; R3 and R4 are each independently selected from hydrogen, halogen, C1-4 alkyl, and C1- 4 haloalkyl; RA is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -N(R11)2, -SR11, -N(R11)C(O)R11, -CN, -S(O)2C1-4 alkyl, C3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl, provided that: when Y1 is CR3 and Y2 is N, then RA is further selected from -OR11, when Y1 is CR3, Y2 is N, Y3 is CH, Ring B is (a), p is 0, X1 is N, and Ring A is 1-fluoro- 1-tetrahydropyranyl, then RA is further selected from hydrogen, and when Y1 is S, Y2 is C, and X1 is N, then RA is further selected from hydrogen; Ring A is selected from: C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is substituted with one or more halogen, and is optionally substituted with one or more substituents independently selected from: C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, - OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, - N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and 3- to 6- membered heterocycle optionally substituted with one or more C1-4 alkyl; C7-12 carbocycle and 7- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1- 6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, - C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), - S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, -CN, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl, provided that when Ring B is selected from (b), then Ring A is not chromane; provided that when one or more of (i), (ii), (ii), (iv), and (v) apply, then Ring A is further selected from C4-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, -CN, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl: (i) Ring B is (a) and RA is selected from halogen, C1-4 haloalkyl, C3-6 cycloalkyl, -NR11, and -OR11; (ii) Y1 is S, Y2 is C, Ring B is (a), and X1 is N; (iii) Y1 is S, Y2 is C, Ring B is (a), and RA is C1-4 alkyl; (iv) Ring B is (a), and p is 1, 2, or 3; (v) R1 is C1-4 alkyl; and (vi) Ring B is (c); provided that when Ring B is (a), X1 is CH, RA is methyl, Y1 is CR3, and Y2 is N, then Ring A is further selected from tetrahydrofuranyl substituted with methyl; R5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)S(O)2(R13), -S(O)2R13, -S(O)2N(R13)2, -NO2, and -CN, provided that when RA is -OR11, then R5 is not -OR13; R6 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -N(R14)S(O)2(R14), -S(O)2R14, -S(O)2N(R14)2, -NO2, =O, and -CN; R8 is independently selected at each occurrence from halogen, C2-4 alkyl, C1-4 haloalkyl, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -N(R14)S(O)2(R14), -S(O)2R14, -S(O)2N(R14)2, -NO2, =O, and -CN; R7 and R9 are each independently selected from hydrogen, C1-4 alkyl, and C1-4 haloalkyl; R10, R11, R12, R13, and R14 are each independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl; m is selected from 0, 1, and 2; p is selected from 0, 1, and 2; q is selected from 0, 1, and 2; and r is selected from 0, 1, and 2. In some embodiments for the compound of Formula (II), Y1 is CR3; Y2 is N; and Y3 is N. In some embodiments, Y1 is CR3; Y2 is N; and Y3 is CR4. In some embodiments, Y1 is CR3; Y2 is N; and Y3 is CH. In some embodiments, Y1 is CR3, Y2 is N, and Y4 is CR3. In some embodiments, Y1 is CR3; Y2 is N; Y3 is N; and Ring B is (a). In some embodiments, Y1 is CR3; Y2 is N; Y3 is CR4; and Ring B is (a). In some embodiments, Y1 is S and Y2 is C. In some embodiments, Y1 is S; Y2 is C; and Y3 is N. In some embodiments, Y1 is S; Y2 is C; and Y3 is CR4. In some embodiments, Y1 is S; Y2 is C; and Y3 is CH. In some embodiments, Y3 is N. In some embodiments, Y3 is CR4; and R4 is selected from hydrogen and halogen. In some embodiments, Y3 is CH.In some embodiments, Y1 is S; Y2 is C; and X1 is N. In some embodiments, Y1 is S; Y2 is C; and RA is selected from C1-4 alkyl. In some embodiments, Y1 is CR3, Y2 is N, Y3 is CR4, and Y4 is N. In some embodiments, Y1 is CR3, Y2 is N, Y3 is CH, and Y4 is N. In some embodiments, Y1 is CR3, Y2 is N, Y3 is CR4, and Y4 is N. In some embodiments, Y1 is CH, Y2 is N, Y3 is CR4, and Y4 is N; and R4 is selected from hydrogen, halogen, and C1-4 alkyl. In some embodiments, the compound is of Formula (IIA): (IIA), or a pharmaceutically acceptable salt thereof; wherein Y3 is CH or N, and Y4 is CH or N. In some embodiments, the compound is of Formula (IIA-1): (IIA-1), or a pharmaceutically acceptable salt thereof; wherein Y3 is CH or N.
In some embodiments, the compound is of Formula (IIB): (IIB), or a pharmaceutically acceptable salt thereof; wherein Y3 is CH or N, and Y4 is CH or N. In some embodiments, R3 is selected from selected from hydrogen, halogen, and C1-4 alkyl. In some embodiments, the compound is of Formula (IIB-1): (IIB-1), or a pharmaceutically acceptable salt thereof; wherein Y3 is CH or N. In some embodiments, R3 is selected from selected from hydrogen, halogen, and C1-4 alkyl. In some embodiments, the compound is of Formula (IIC): (IIC), or a pharmaceutically acceptable salt thereof; wherein Y3 is CH or N. In some embodiments, the compound is of Formula (IIC-1): (IIC-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (IID): (IID), or a pharmaceutically acceptable salt thereof; wherein Y4 is CH or N. In some embodiments, the compound is of Formula (IID-1): (IID-1), or a pharmaceutically acceptable salt thereof. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), Formula (II), (IIA), (IIA-1), (IIB), (IIB-1), (IIC), (IIC-1), (IID), or (IID-1), each R3 is selected from selected from hydrogen, halogen, and C1-4 alkyl. In some embodiments, each R3 is selected from selected from hydrogen and halogen. In some embodiments, R3 is hydrogen. In some embodiments, R3 is halogen. In some embodiments, R3 is fluoro. In some embodiments, R3 is chloro. In some embodiments, R3 is C1-4 alkyl. In some embodiments, R3 is methyl. In some embodiments, R3 is C1-4 haloalkyl. In some embodiments, R3 is trifluoromethyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), Formula (II), (IIA), (IIA-1), (IIB), (IIB-1), (IIC), (IIC-1), (IID), or (IID-1), R1 is independently selected at each occurrence from hydrogen, C1-4 alkyl, and C1-4 haloalkyl. In some embodiments, R1 is independently selected at each occurrence from hydrogen and C1-4 alkyl. R1 is independently selected at each occurrence from hydrogen, -CH3, -CF3, -CH2CH3, , and . In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), Formula (II), (IIA), (IIA-1), (IIB), (IIB-1), (IIC), (IIC-1), (IID), or (IID-1), R1 is selected from hydrogen, - CH3, -CH2CH3, d I b di R1 is hydrogen In some embodiments, R1 is C1-4 alkyl. In some embodiments, R1 is –C(O)C3-6 cycloalkyl optionally substituted with one or more halogen. In some embodiments, R1 is –C(O)C3-6 cycloalkyl substituted with one or more fluoro. In some embodiments, R1 is -CH3. In some embodiments, R1 is -CH2CH3. In some embodiments, R1 is . In some embodiments, R1 is . In some embodiments, each R1 is hydrogen. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), Formula (II), (IIA), (IIA-1), (IIB), (IIB-1), (IIC), (IIC-1), (IID), or (IID-1), R2 is independently selected at each occurrence from halogen and C1-4 alkyl. In some embodiments, R2 is halogen. In some embodiments, R2 is C1-4 alkyl. In some embodiments, R2 is C1-4 haloalkyl. In some embodiments, R2 is -OR10. In some embodiments, R2 is -SR10. In some embodiments, R2 is -N(R10)2. In some embodiments, R2 is NO2. In some embodiments, R2 is –CN. In some embodiments, R2 is independently selected at each occurrence from C1-4 alkyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), Formula (II), (IIA), (IIA-1), (IIB), (IIB-1), (IIC), (IIC-1), (IID), or (IID-1), m is 0 or 1. . In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), Formula (II), (IIA), (IIA-1), (IIB), (IIB-1), (IIC), (IIC-1), (IID), or (IID-1), R3 and R4 are each independently selected at each occurrence from hydrogen, halogen, and C1-4 alkyl. In some embodiments, R3 and R4 are each independently selected at each occurrence from hydrogen and halogen. In some embodiments, R3 and R4 are each independently selected at each occurrence from hydrogen and C1-4 alkyl. In some embodiments, each R3 is hydrogen. In some embodiments, each R4 is hydrogen. In some embodiments, the compound is of Formula (IIA-2): (IIA-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (IIB-2): (IIB-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (IIC-2): (IIC-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (IID-2): (IID-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IIE-2): (IIE-2), or a pharmaceutically acceptable salt thereof. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), Ring B is selected from (a), (b) and (c): (a) , X1 is selected from N, CH, and CR5; (b) , X2 is selected from S and NR7; and (c) , X3 is selected from S, N, and NH, X4 is selected from O and CR9, X5 is N or CH, X6 is N or CH, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system, provided that when Ring B is (a), Y1 is CR3, Y2 is N, Y3 is CR4, and Y4 is N, then p is 0. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), Ring B is selected from (a) and (c): (a) , X1 is selected from N, CH, and CR5; (c) , X3 is selected from S, N, and NH, X4 is selected from O and CR9, X5 is N or CH, X6 is N or CH, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), Ring B is selected from: (b) , and X2 is selected from S and NR7. In some embodiments, Ring B is selected from: (c) , X3 is selected from S, N, and NH, X4 is selected from O and CR9, X5 is N or CH, X6 is N or CH, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system,. provided that when Ring B is (a), Y1 is CR3, Y2 is N, Y3 is CR4, and Y4 is N, then p is 0. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), Ring B is selected from (a) and (c): (a) , X1 is selected from N, CH, and CH; and (c) , X3 is selected from S, N, and NH, X4 is selected from O and CR9, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system selected from benzothiazole, benzimidazole, and benzofurazan; wherein: RA is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -N(R11)2, -SR11, -N(R11)C(O)R11, -CN, C3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; and when Y1 is CR3 and Y2 is N, then RA is further selected from -OR11; R11 is selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and C3-6 cycloalkyl; R5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, and -CN; R8 is independently selected at each occurrence from halogen, C2-4 alkyl, C1-4 haloalkyl, and -CN; R9 is selected from hydrogen and C1-4 alkyl; p is selected from 0 and 1; and r is selected from 0 and 1. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), Ring B is selected from (a) and (c): (a) , X1 is selected from N, CH, and CR5; and (c) , X3 is selected from S, N, and NH, X4 is selected from O and CR9, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system selected from benzothiazole, benzimidazole, and benzofurazan; wherein: RA is selected from -F, -Cl, -CN, -NH2, -CH3, -CF3, -CHF2, , , , , and ; and when Y1 is CR3 and Y2 is N, then RA is further selected from - OH, -OCH3, and ; R5 is selected at each occurrence from -F, -Cl, and -CH3; R9 is selected from hydrogen and -CH3; p is selected from 0 and 1; and r is 0. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), Ring B is selected from: (a) , and X1 is selected from N, CH, and CR5; provided that when Y1 is CR3, Y2 is N, Y3 is CR4, and Y4 is N, then p is 0, In some embodiments, X1 is selected from N and CH. In some embodiments, X1 is N. In some embodiment, X1 is CH. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), RA is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -N(R11)2, -SR11, - N(R11)C(O)R11, -CN, -S(O)2C1-4 alkyl, C3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl, provided that: when Y1 is CR3, Y2 is N, and Y4 is CR3, or when Y1 is CR3, Y2 is N, and Y4 is N, then RA is further selected from -OR11, when Y1 is CR3, Y2 is N, Y3 is CH, Ring B is (a), p is 0, X1 is N, and Ring A is 1- fluoro-1-tetrahydropyranyl, then RA is further selected from hydrogen, and when Y1 is S, Y2 is C, and X1 is N, then RA is further selected from hydrogen. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), RA is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -N(R11)2, -SR11, -N(R11)C(O)R11, -CN, -S(O)2C1-4 alkyl, C3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl, provided that: when Y1 is CR3, Y2 is N, and Y4 is CR3, or when Y1 is CR3, Y2 is N, and Y4 is N, then RA is further selected from -OR11; and wherein R11 is independently selected at each occurrence from hydrogen, C1-4alkyl, C1-4 haloalkyl; and C3-6 cycloalkyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), RA is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -N(R11)2, -SR11, -N(R11)C(O)R11, -CN, C3-5 cycloalkyl, and 5- to 6-membered heterocycloalkyl, provided that: when Y1 is CR3, Y2 is N, and Y4 is CR3, or when Y1 is CR3, Y2 is N, and Y4 is N, then RA is further selected from -OR11; and wherein R11 is independently selected at each occurrence from hydrogen, C1-4alkyl, C1-4 haloalkyl, and C3-6 cycloalkyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), RA is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -N(R11)2, -SR11, -N(R11)C(O)R11, -CN, C3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; and Y1 is CR3, Y2 is N, and Y4 is CR3 or when Y1 is CR3, Y2 is N, and Y4 is N, then RA is further selected from - OR11; R11 is selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and C3-6 cycloalkyl. In some embodiments, RA is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -N(R11)2, -SR11, -N(R11)C(O)R11, -CN, C3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; and when Y1 is CR3 and Y2 is N, then RA is further selected from -OR11; R11 is selected from hydrogen, C1- 4 alkyl, C1-4 haloalkyl, and C3-6 cycloalkyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), RA is halogen. In some embodiments, RA is C1-4 alkyl. In some embodiments, RA is methyl. In some embodiments, RA is ethyl. In some embodiments, RA is C1-4 haloalkyl. In some embodiments, RA is C1-4 hydroxyalkyl. In some embodiments, RA is -N(R11)2. In some embodiments, RA is -SR11. In some embodiments, RA is -N(R11)C(O)R11. In some embodiments, RA is -CN. In some embodiments, RA is C3-6 cycloalkyl. In some embodiments, RA is 3- to 6-membered heterocycloalkyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), Y1 is CR3 and Y2 is N; and RA is further selected from -OR11, provided that when RA is -OR11, then R5 is not -OR13. In some embodiments, Y1 is CR3, Y2 is N, and Y4 is N, and RA is further selected from - OR11. In some embodiments, Y1 is CR3, Y2 is N, Y3 is CH, Ring B is (a), p is 0, X1 is N, and Ring A is 1-fluoro-1-tetrahydropyranyl; and RA is further selected from hydrogen. In some embodiments, Y1 is S, Y2 is C, and X1 is N; and RA is further selected from hydrogen. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), RA is selected from -F, -Cl, -CN, -NH2, -CH3, -CF3, -CHF2, , , , , and ; and when Y1 is CR3 and Y2 is N, then RA is further selected from -OH, -OCH3, and . In some embodiments, RA is -F. In some embodiments, RA is -Cl. In some embodiments, RA is -CN. In some embodiments, RA is -NH2. In some embodiments, RA is -OH. In some embodiments, RA is -OCH3. In some embodiment, RA is . In some embodiments, RA is -CH3. In some embodiments, RA is -CF3. In some embodiments, RA is -CHF2. In some embodiments, RA is . In some embodiments, RA is . In some embodiments, RA is . In some embodiments, RA is . In some embodiments, RA is and . In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), R5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR13, -SR13, -N(R13)2, -C(O)OR13, -C(O)N(R13)2, -NO2, and -CN, provided that when RA is -OR11, then R5 is not -OR13; and R13 is independently selected at each occurrence from hydrogen, C1-4alkyl, and C1- 4 haloalkyl. In some embodiments, R5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -SR13, -N(R13)2, -C(O)OR13, -C(O)N(R13)2, -NO2, and -CN; and R13 is independently selected at each occurrence from hydrogen, C1-4alkyl, and C1-4 haloalkyl. In some embodiments, R5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1- 4 haloalkyl, -OR13, -N(R13)2, and -CN, provided that when RA is -OR11, then R5 is not -OR13; and R13 is independently selected at each occurrence from hydrogen and C1-4alkyl. In some embodiments, R5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1- 4 haloalkyl, -N(R13)2, and -CN; and R13 is independently selected at each occurrence from hydrogen and C1-4alkyl. In some embodiments, R5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, and -OR13, provided that when RA is -OR11, then R5 is not -OR13; and R13 is independently selected at each occurrence from hydrogen and C1-4alkyl. In some embodiments, R5 is independently selected at each occurrence from halogen, C1-4 alkyl, and C1- 4 haloalkyl. In some emb di R5 i i d d l l d ach occurrence from halogen. In some embodiments, R5 is independently selected at each occurrence from C1-4 alkyl. In some embodiments, R5 is independently selected at each occurrence from C1-4 haloalkyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), R13 is independently selected at each occurrence from hydrogen, C1-4alkyl, and C1-4 haloalkyl. In some embodiments, R13 is independently selected at each occurrence from hydrogen and C1-4alkyl. In some embodiments, each R13 is hydrogen. In some embodiments, or the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), Ring B is selected from (b) , and X2 is selected from S and NR7. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), X2 is S. In some embodiments, X2 is NR7. In some embodiments, X2 is S or NH. In some embodiments, X2 is NH. In some embodiments, X2 is S. In some embodiments, R7 is selected from hydrogen, C1-4 alkyl, and C1-4 haloalkyl. In some embodiments, R7 is selected from hydrogen, and C1-4 alkyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), q is 0 or 1. In some embodiments, q is 1. In some embodiments, q is 0. In some embodiments, q is 1 or 2. In some embodiments, q is 2. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), R6 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -N(R14)S(O)2(R14), -S(O)2R14, -S(O)2N(R14)2, -NO2, and -CN; and R14 is independently selected at each occurrence from hydrogen, C1-4alkyl, and C1-4 haloalkyl. In some embodiments, R6 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR14, -SR14, -N(R14)2, -C(O)OR14, -S(O)2N(R14)2, -NO2, and -CN; and R14 is independently selected at each occurrence from hydrogen, C1-4alkyl, and C1-4 haloalkyl. In some embodiments, R6 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR14, -SR14, -N(R14)2, and -CN; and R14 is independently selected at each occurrence from hydrogen and C1-4alkyl. In some embodiments, R6 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR14, and -N(R14)2, and R14 is independently selected at each occurrence from hydrogen and C1-4alkyl. In some embodiments, R6 is independently selected at each occurrence from halogen, C1-4 alkyl, and C1-4 haloalkyl. In some embodiments, R6 is independently selected at each occurrence from halogen and C1-4 alkyl. In some embodiments, R6 is independently selected at each occurrence from halogen. In some embodiments, R6 is independently selected at each occurrence from C1-4 alkyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), R6 is halogen. In some embodiments, R6 is C1-4 alkyl. In some embodiments, R6 is C1-4 haloalkyl. In some embodiments, R6 is -OR14. In some embodiments, R6 is -SR14. In some embodiments, R6 is -N(R14)2. In some embodiments, R6 is -C(O)R14. In some embodiments, R6 is -C(O)OR14. In some embodiments, R6 is -OC(O)R14. In some embodiments, R6 is -C(O)N(R14)2. In some embodiments, R6 is -N(R14)C(O)R14. In some embodiments, R6 is -N(R14)S(O)2(R14). In some embodiments, R6 is -S(O)2R14. In some embodiments, R6 is -S(O)2N(R14)2. In some embodiments, R6 is -NO2. In some embodiments, R6 is =O. In some embodiments, R6 is -CN. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), Ring B is selected from (c) , X3 is selected from S, N, and NH, X4 is selected from O and CR9, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system. In some embodiments, Ring B is an aromatic bicyclic ring system selected from benzothiazole, benzimidazole, and benzofurazan; In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), X3 is selected from S, N, and NH, X4 is selected from O and CR9, X5 is N or CH, X6 is N or CH, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system selected from benzothiazole, benzimidazole, and benzofurazan. In some embodiments, Ring B is an aromatic bicyclic ring system selected from benzothiazole, and benzofurazan. In some embodiments, Ring B is an aromatic bicyclic ring system selected from benzothiazole and benzimidazole. Ring B is an aromatic bicyclic ring system selected from benzimidazole and benzofurazan. In some embodiments, Ring B is a benzothiazole. In some embodiments, Ring B is abenzimidazole. In some embodiments, Ring B is a benzofurazan. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), X3 is S. In some embodiments, X3 is N. In some embodiments, X3 is NH. In some embodiments, X4 is O. In some embodiments, X4 is CR9. In some embodiments, X3 is S and X4 is O. In some embodiments, X3 is S and X4 is CR9. In some embodiments, X3 is N and X4 is O. In some embodiments, X3 is N and X4 is CR9. In some embodiments, X3 is NH and X4 is O. In some embodiments, X3 is NH and X4 is CR9. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), r is 0 or 1. In some embodiments, r is 1. In some embodiments, r is 0. In some embodiments, r is 1 or 2. In some embodiments, r is 2. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), R8 is independently selected at each occurrence from halogen, C2-4 alkyl, C1-4 haloalkyl, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -N(R14)S(O)2(R14), - S(O)2R14, -S(O)2N(R14)2, -NO2, and -CN; R14 is independently selected at each occurrence from hydrogen, C1-4alkyl, and C1-4 haloalkyl. In some embodiments, R8 is independently selected at each occurrence from halogen, C2-4 alkyl, C1-4 haloalkyl, -OR14, -SR14, -N(R14)2, -C(O)OR14, - C(O)N(R14)2, -N(R14)C(O)R14, -N(R14)S(O)2(R14), -S(O)2R14, -S(O)2N(R14)2, -NO2, and -CN; and R14 is independently selected at each occurrence from hydrogen, C1-4alkyl, and C1-4 haloalkyl. In some embodiments, R8 is independently selected at each occurrence from halogen, C2-4 alkyl, C1- 4 haloalkyl, -OR14, -SR14, -N(R14)2, and -CN; and R14 is independently selected at each occurrence from hydrogen and C1-4alkyl. In some embodiments, R8 is independently selected at each occurrence from halogen, C1-4 haloalkyl, -OR14, -SR14, -N(R14)2, and -CN; and R14 is independently selected at each occurrence from hydrogen and C1-4alkyl. In some embodiments, R8 is independently selected at each occurrence from halogen, C2-4 alkyl, C1-4 haloalkyl, -OR14, and - N(R14)2; and R14 is independently selected at each occurrence from hydrogen and C1-4alkyl. In some embodiments, R8 is independently selected at each occurrence from halogen, C1-4 haloalkyl, -OR14, and -N(R14)2, and R14 is independently selected at each occurrence from hydrogen and C1- 4alkyl. In some embodiments, R8 is independently selected at each occurrence from halogen, C2-4 alkyl, and C1-4 haloalkyl. In some embodiments, R8 is independently selected at each occurrence from halogen and C1-4 haloalkyl. In some embodiments, R8 is independently selected at each occurrence from halogen. In some embodiments, R8 is independently selected at each occurrence from C2-4 alkyl. In some embodiments, R8 is independently selected at each occurrence from C1- 4 haloalkyl. In some embodiments, R8 is not methyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), R9 is selected from hydrogen, C1-4 alkyl, and C1-4 haloalkyl. In some embodiments, R9 is selected from hydrogen, and C1-4 alkyl. In some embodiments, R9 is hydrogen. In some embodiments, R9 is C1- 4 alkyl. . In some embodiments, R9 is methyl. In some emboimdnets, R9 is hydrogen. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), R5 is independently selected at each occurrence from halogen and C1-4 alkyl. In some embodiments, R6 and R8 are each independently selected at each occurrence from halogen and C1-4 alkyl. In some embodiments, R7 and R9 are each independently selected from hydrogen, and C1-4 alkyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), Ring B is selected from (a) and (c): (a) , X1 is selected from N, CH, and CR5; and (c) , X3 is selected from S, N, and NH, X4 is selected from O and CR9, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system selected from benzothiazole, benzimidazole, and benzofurazan; wherein: RA is selected from -F, -Cl, -CN, -NH2, -CH3, -CF3, -CHF2, , , , , and ; and when Y1 is CR3 and Y2 is N, then RA is further selected from - OH, -OCH3, and ; R5 is selected at each occurrence from -F, -Cl, and -CH3; R9 is selected from hydrogen and -CH3; p is selected from 0 and 1; and r is 0; provided that when Ring B is (a), Y1 is CR3, Y2 is N, Y3 is CR4, and Y4 is N, then p is 0. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), Ring B is selected from (a) and (c): (a) , X1 is selected from N, CH, and CR5; and (c) , X3 is selected from S, N, and NH, X4 is selected from O and CR9, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system selected from benzothiazole, benzimidazole, and benzofurazan; wherein: RA is selected from -F, -Cl, -CN, -NH2, -CH3, -CF3, -CHF2, , , , , and ; and when Y1 is CR3 and Y2 is N, then RA is further selected from - OH, -OCH3, and ; R5 is selected at each occurrence from -F, -Cl, and -CH3; R9 is selected from hydrogen and -CH3; p is selected from 0 and 1; and r is 0; provided that when Ring B is (a), Y1 is CR3, Y2 is N, Y3 is CR4, and Y4 is N, then p is 0. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), Ring B is selected from (a) and (c): (a) , X1 is selected from N, CH, and CR5; and (c) , X3 is selected from S, N, and NH, X4 is selected from O and CR9, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system selected from benzothiazole, benzimidazole, and benzofurazan; wherein: RA is selected from -F, -Cl, -CN, -NH2, -CH3, -CF3, -CHF2, , , , , and ; and when Y1 is CR3 and Y2 is N, then RA is further selected from - OH, -OCH3, and ; R5 is selected at each occurrence from -F, -Cl, and -CH3; R9 is selected from hydrogen and -CH3; p is selected from 0 and 1; and r is 0; provided that when Ring B is (a), Y1 is CR3, Y2 is N, Y3 is CR4, and Y4 is N, then p is 0. In some embodiments, Y1 is CR3 and Y2 is N, and RA is –OH. In some embodiments, Y1 is CR3 and Y2 is N, and RA is -OCH3. In some embodiments, Y1 is CR3 and Y2 is N, and RA is . In some embodiments, when RA is -OR11, then R5 is not -OR13. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), Ring B is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), Ring B is selected from (a) ; RA is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -N(R11)2, -N(R11)C(O)R11, -CN, C3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl, and when Y1 is CR3 and Y2 is N, then RA is further selected from -OR11; R11 is independently selected at each occurrence from hydrogen, C1-4alkyl, C1-4 haloalkyl, and C3-6 cycloalkyl; p is 0 or 1, provided that when Y1 is CR3, Y2 is N, Y3 is CR4, and Y4 is N, then p is 0; X is selected from N, CH, and CR5; and R5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl. In some embodiments, Ring B is selected from: (a) ; RA is selected from -F, -Cl, -CN, -NH2, -CH3, -CF3, -CHF2, , , , , and ; and when Y1 is CR3 and Y2 is N, then RA is further selected from -OH, -OCH3, and ; and X1 is selected from N, CH, and CR5; R5 is selected from -F and -CH3; p is 0 or 1, provided that when Y1 is CR3, Y2 is N, Y3 is CR4, and Y4 is N, then p is 0. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), Ring B is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , and . In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring H N O N B is . In some embodiments, Ring B is N . In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), Ring B is selected from (b) , and X2 is selected from S and NR7; q is 0 or 1; R6 is selected from halogen, C1-4 alkyl, and C1-4 haloalkyl; and R7 is selected from hydrogen, C1-4 alkyl, and C1-4 haloalkyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), Ring B is selected from (c) , X3 is selected from S, N, and NH, X4 is selected from O and CR9, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system; R8 is selected from halogen, C2-4 alkyl, and C1-4 haloalkyl. R9 is selected from hydrogen, halogen, C1-4 alkyl, and C1-4 haloalkyl.; and r is 0 or 1. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), Ring B is selected from (c) , X3 is selected from S, N, and NH, X4 is selected from O and CR9, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system selected from benzothiazole, benzimidazole, and benzofurazan; R9 is selected from hydrogen and -CH3; and r is 0. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), Ring B is selected from: , , , and . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is and . In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), at least one of the (i), (ii), (ii), (iv), (v), (vi), (vii), and (viii) applies: (i) Ring B is (a) and RA is selected from halogen, C1-4 haloalkyl, C3- 6 cycloalkyl, -NR11, and -OR11; (ii) Y1 is S, Y2 is C, Ring B is (a), and X1 is N; (iii) Y1 is S, Y2 is C, Ring B is (a), and RA is C1-4 alkyl; (iv) Ring B is (a), and p is 1, 2, or 3; (v) R1 is C1-4 alkyl or C1-4 haloalkyl; (vi) Ring B is (c); (vii) Y1 is CR3, Y2 is N, Y3 is CR3, and Y4 is N; and (viii) Y1 is N, Y2 is N, Y3 is CR4, Y4 is CR3, and Ring B is (a) or (c). In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), Ring B is (a) and RA is selected from halogen, C1-4 haloalkyl, C3-6 cycloalkyl, -NR11, and -OR11. In some embodiments, Y1 is S, Y2 is C, Ring B is (a), and X1 is N. In some embodiments, Y1 is S, Y2 is C, Ring B is (a), and RA is C1-4 alkyl. In some embodiments, Ring B is (a), and p is 1, 2, or 3. In some embodiments, R1 is C1-4 alkyl or C1-4 haloalkyl. In some embodiments, Ring B is (c). In some embodiments, Y1 is CR3, Y2 is N, Y3 is CR3, and Y4 is N. In some embodiments, Y1 is N, Y2 is N, Y3 is CR4, Y4 is CR3, and Ring B is (a) or (c). In some embodiments, one or more (e.g., 1-3 (e.g., 1-2 (e.g., 1))) of (i), (ii), (ii), (iv), and (v) apply: (vii) Ring B is (a) and RA is selected from halogen, C1-4 haloalkyl, C3-6 cycloalkyl, -NR11, and -OR11; (viii) Y1 is S, Y2 is C, Ring B is (a), and X1 is N; (ix) Y1 is S, Y2 is C, Ring B is (a), and RA is C1-4 alkyl; (x) Ring B is (a), and p is 1, 2, or 3; (xi) R1 is C1-4 alkyl; and (xii) Ring B is (c). In some embodiments, Ring B is: , wherein X3 is selected from S and N, X4 is selected from O and CR9, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system selected from benzothiazole, benzimidazole, and benzofurazan; wherein: R8 is independently selected at each occurrence from halogen, C2-4 alkyl, C1-4 haloalkyl, and -CN; R9 is selected from hydrogen and C1-4 alkyl; p is selected from 0 and 1; and r is selected from 0 and 1. In some embodiments, Ring B is , wherein X1 is selected from N, CH, and CR5. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), when at least one of the (i), (ii), (ii), (iv), (v), (vi), (vii), and (viii) applies: (i) Ring B is (a) and RA is selected from halogen, C1-4 haloalkyl, C3- 6 cycloalkyl, -NR11, and -OR11; (ii) Y1 is S, Y2 is C, Ring B is (a), and X1 is N; (iii) Y1 is S, Y2 is C, Ring B is (a), and RA is C1-4 alkyl; (iv) Ring B is (a), and p is 1, 2, or 3; (v) R1 is C1-4 alkyl or C1-4 haloalkyl; (vi) Ring B is (c); (vii) Y1 is CR3, Y2 is N, Y3 is CR3, and Y4 is N; and (viii) Y1 is N, Y2 is N, Y3 is CR4, Y4 is CR3, and Ring B is (a) or (c); Ring A is selected from cyclopropyl substituted with one or more halogen, C1-6 alkyl, or -CN; C4-12 carbocycle; and 3- to 12-membered heterocycle; any of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, -CN, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl; and R12 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl; and provided that when Ring B is (a), X1 is CH, RA is methyl, Y1 is CR3, and Y2 is N, then Ring A is further selected from tetrahydrofuranyl substituted with methyl; and when Ring B is selected from (b), then Ring A is not chromane. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), when at least one of the (i), (ii), (ii), (iv), (v), (vi), (vii), and (viii) applies: (i) Ring B is (a) and RA is selected from halogen, C1-4 haloalkyl, C3- 6 cycloalkyl, -NR11, and -OR11; (ii) Y1 is S, Y2 is C, Ring B is (a), and X1 is N; (iii) Y1 is S, Y2 is C, Ring B is (a), and RA is C1-4 alkyl; (iv) Ring B is (a), and p is 1, 2, or 3; (v) R1 is C1-4 alkyl or C1-4 haloalkyl; (vi) Ring B is (c); (vii) Y1 is CR3, Y2 is N, Y3 is CR3, and Y4 is N; and (viii) Y1 is N, Y2 is N, Y3 is CR4, Y4 is CR3, and Ring B is (a) or (c); Ring A is selected from: cyclopropyl substituted with one or more halogen, C1-6 alkyl or -CN, C4-12 carbocycle, and 3- to 12-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, =O, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl; and R12 is independently selected at each occurrence from hydrogen and C1-6 alkyl; provided that when Ring B is (a), X1 is CH, RA is methyl, Y1 is CR3, and Y2 is N, then Ring A is further selected from tetrahydrofuranyl substituted with methyl; and when Ring B is selected from (b), then Ring A is not chromane. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), when at least one of the (i), (ii), (ii), (iv), (v), (vi), (vii), and (viii) applies: (i) Ring B is (a) and RA is selected from halogen, C1-4 haloalkyl, C3- 6 cycloalkyl, -NR11, and -OR11; (ii) Y1 is S, Y2 is C, Ring B is (a), and X1 is N; (iii) Y1 is S, Y2 is C, Ring B is (a), and RA is C1-4 alkyl; (iv) Ring B is (a), and p is 1, 2, or 3; (v) R1 is C1-4 alkyl or C1-4 haloalkyl; (vi) Ring B is (c); (vii) Y1 is CR3, Y2 is N, Y3 is CR3, and Y4 is N; and (viii) Y1 is N, Y2 is N, Y3 is CR4, Y4 is CR3, and Ring B is (a) or (c); Ring A is selected from: cyclobutyl, cyclohexyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, sulfolanyl, azetidinyl, pyrrolidinyl, piperidinyl, spiro[2.2]pentanyl, spiro[3.2]hexanyl, spiro[4.2]heptanyl, 6-oxaspiro[2.5]octanyl, 2-oxabicyclo[2.2.1]heptanyl, 8- oxabicyclo[3.2.1]octanyl, 1-Oxaspiro[5.5]undecanyl, adamantanyl, 2-azaspiro[3.3]heptanyl, and 1,9-dioxaspiro[5.5]undecanyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, =O, -CN, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl; and R12 is independently selected at each occurrence from hydrogen, C1-6 alkyl, and phenyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), when at least one of the (i), (ii), (ii), (iv), (v), (vi), (vii), and (viii) applies: (ix) Ring B is (a) and RA is selected from halogen, C1-4 haloalkyl, C3- 6 cycloalkyl, -NR11, and -OR11; (x) Y1 is S, Y2 is C, Ring B is (a), and X1 is N; (xi) Y1 is S, Y2 is C, Ring B is (a), and RA is C1-4 alkyl; (xii) Ring B is (a), and p is 1, 2, or 3; (xiii) R1 is C1-4 alkyl or C1-4 haloalkyl; (xiv) Ring B is (c); (xv) Y1 is CR3, Y2 is N, Y3 is CR3, and Y4 is N; and (xvi) Y1 is N, Y2 is N, Y3 is CR4, Y4 is CR3, and Ring B is (a) or (c); and Ring A is selected from: cyclopropyl substituted with one or more -CH3 or -CN, cyclobutyl, cyclohexyl, phenyl, oxepanyl, sulfolanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, spiro[2.2]pentanyl, spiro[3.2]hexanyl, spiro[4.2]heptanyl, 6- oxaspiro[2.5]octanyl, 2-Oxabicyclo[2.2.1]heptanyl, 8-Oxabicyclo[3.2.1]octanyl, 1- Oxaspiro[5.5]undecanyl, adamantanyl, 2-Azaspiro[3.3]heptanyl, and 1,9- dioxaspiro[5.5]undecanyl, each of which is optionally substituted with one or more substituents independently selected from: -F, -OH, -OCH3, -CH3, -CF3, =O, -CN, , , , , , , and . In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIB), (IIB-1), (IIB-2), (IIC), (IIC-1), (IIC-2), (IID), (IID-1), or (IID-2), m is selected from 0 and 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, p is selected from 0 and 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, q is selected from 0 and 1. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, r is selected from 0 and 1. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, the compound is of Formula (IIA-3): O A N HN R5 p S Y3 X1 N RA (IIA-3), or a pharmaceutically acceptable salt thereof; wherein X1 is selected from N, CH, and CR5. In some embodiments, the compound is of Formula (IIB-3): (IIB-3), or a pharmaceutically acceptable salt thereof; wherein X1 is selected from N, CH, and CR5. In some embodiments, the compound is of Formula (IIB-3): (IIB-3), or a pharmaceutically acceptable salt thereof; wherein Ring A is C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is substituted with one or more halogen, and is optionally substituted with one or more substituents independently selected from: C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl. In some embodiments, the compound is of Formula (IIB-4): (IIB-4), or a pharmaceutically acceptable salt thereof, wherein X1 is selected from N, CH, and CR5. In some embodiments, the compound is of Formula (IIC-3): (IIC-3),or a pharmaceutically acceptable salt thereof, wherein X1 is selected from N, CH, and CR5. In some embodiments, the compound is of Formula (ID-3): (ID-3), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (IIB-5): (IIB-5), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (IIB-6) (IIB-6), or a pharmaceutically acceptable salt thereof. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is selected from: cyclopropyl substituted with one or more C1-6 alkyl or -CN, C3-6 carbocycle substituted with one or more halogen, 3- to 6-membered heterocycle substituted with one or more halogen, C5-6 spirocyclic carbocycle, and 5- to 6-membered spirocyclic heterocycle, any of which is optionally substituted with one or more substituents independently selected from: C1-6 alkyl, C1- 6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl; C7-12 carbocycle and 7- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1- 6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, -CN, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl, provided that when Ring B is selected from (b), then Ring A is not chromane; provided that when one or more of (i), (ii), (ii), (iv), (v), (vi), (vii), and (viii) apply, then Ring A is further selected from C4-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: C1-6 alkyl, C1- 6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, -CN, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl: (i) Ring B is (a) and RA is selected from halogen, C1-4 haloalkyl, C3-6 cycloalkyl, -NR11, and -OR11; (ii) Y1 is S, Y2 is C, Ring B is (a), and X1 is N; (iii) Y1 is S, Y2 is C, Ring B is (a), and RA is C1-4 alkyl; (iv) Ring B is (a), and p is 1, 2, or 3; (v) R1 is C1-4 alkyl or C1-4 haloalkyl; (vi) Ring B is (c); and (vii) Y1 is CR3, Y2 is N, Y3 is CR3, and Y4 is N; (viii) Y1 is N, Y2 is N, Y3 is CR4, Y4 is CR3, and Ring B is (a) or (c); provided that when Ring B is (a), X1 is CH, RA is methyl, Y1 is CR3, and Y2 is N, then Ring A is further selected from tetrahydrofuranyl substituted with methyl; and R12 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl. In some embodiments, In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB- 6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is selected from: C4-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1- 6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl, provided that when Ring B is selected from (b), then Ring A is not chromane; and R12 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl. In some embodiments, In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB- 6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is selected from: C4-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with 1-4 substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl, provided that when Ring B is selected from (b), then Ring A is not chromane; and R12 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is selected from: C4-12 carbocycle and 3- to 12- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, =O, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl; and R12 is independently selected at each occurrence from hydrogen and C1-6 alkyl, provided that when Ring B is selected from (b), then Ring A is not chromane. In some embodiments, Ring A is selected from: C4-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1- 6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, =O, and 3- to 6-membered heterocycle optionally substituted with 1-4 C1-4 alkyl; and R12 is independently selected at each occurrence from hydrogen and C1-6 alkyl, provided that when Ring B is selected from (b), then Ring A is not chromane. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is selected from: C4-6 carbocycle and 3- to 6-membered heterocycle, each of which is substituted with one or more -F, and is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, =O, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl; 7- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, =O, -CN, provided that when Ring B is selected from (b), then Ring A is not chromane; and R12 is independently selected at each occurrence from hydrogen and C1-6 alkyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is selected from: C4-6 carbocycle and 3- to 6-membered heterocycle, each of which is substituted with one or more -F, and is optionally substituted with 1-4 substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, =O, and 3- to 6- membered heterocycle optionally substituted with one or more C1-4 alkyl; 7- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, =O, provided that when Ring B is selected from (b), then Ring A is not chromane; and R12 is independently selected at each occurrence from hydrogen and C1-6 alkyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is saturated C3-6 carbocycle or saturated 3- to 6- membered heterocycle, each of which is substituted with one or more halogen, and is optionally substituted with one or more substituents independently selected from: C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl. In some embodiments, Ring A is saturated C3-6 carbocycle or saturated 3- to 6-membered heterocycle comprising one O ring member, each of which is substituted with one or more halogen, and is optionally substituted with one or more substituents independently selected from: C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is C3-6 carbocycle substituted with one or more halogen, and optionally substituted with one or more substituents independently selected from: C1- 6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and 3- to 6- membered heterocycle optionally substituted with one or more C1-4 alkyl. In some embodiments, Ring A is C3-5 carbocycle substituted with one -F, and optionally substituted with one or more substituents independently selected from: C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl. In some embodiments, Ring A is 5- to 6-membered heterocycle substituted with one -F, and optionally substituted with one or more substituents independently selected from: C1- 6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl. In some embodiments, Ring A is selected from: C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is substituted with one or more halogen, and is optionally substituted with one or more substituents independently selected from: C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), the Ring A heterocycle comprises 1-4 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A heterocycle comprises 1-3 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A heterocycle comprises 1-2 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A heterocycle comprises 2-3 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A heterocycle comprises 1 heteroatom selected from O, N, and S. In some embodiments, the Ring A heterocycle comprises 2 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A heterocycle comprises 3 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A heterocycle comprises 4 heteroatoms independently selected from O, N, and S. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), the Ring A heterocycle comprises 1-4 heteroatoms independently selected from O and N. In some embodiments, the Ring A heterocycle comprises 1-3 heteroatoms independently selected from O and N. In some embodiments, the Ring A heterocycle comprises 1-2 heteroatoms independently selected from O and N. In some embodiments, the Ring A heterocycle comprises 2-3 heteroatoms independently selected from O and N. In some embodiments, the Ring A heterocycle comprises 1 heteroatom selected from O and N. In some embodiments, the Ring A heterocycle comprises 2 heteroatoms independently selected from O and N. In some embodiments, the Ring A heterocycle comprises 3 heteroatoms independently selected from O and N. In some embodiments, the Ring A heterocycle comprises 4 heteroatoms independently selected from O and N. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), the Ring A heterocycle comprises 4 N heteroatoms. In some embodiments, the Ring A heterocycle comprises 3 N heteroatoms. In some embodiments, the Ring A heterocycle comprises 3 N heteroatoms and 1 O heteroatom. In some embodiments, the Ring A heterocycle comprises 2 N heteroatoms and 1 O heteroatom. In some embodiments, the Ring A heterocycle comprises 2 N heteroatoms and 1 S heteroatom. In some embodiments, the Ring A heterocycle comprises 1 O heteroatom and 1 N heteroatom. In some embodiments, the Ring A heterocycle comprises 1 O heteroatom and 1 S heteroatom. In some embodiments, the Ring A heterocycle comprises 1 S heteroatom and 1 N heteroatom. In some embodiments, the Ring A heterocycle comprises 2 N heteroatoms. In some embodiments, the Ring A heterocycle comprises 1 heteroatom that is O. In some embodiments, the Ring A heterocycle comprises 1 heteroatom that is N. In some embodiments, the Ring A heterocycle comprises 1 heteroatom that is S. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3),, Ring A as described herein is substituted with 1-4 substituents as described herein. In some embodiments, Ring A as described herein is unsubstituted. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is selected from: cyclopropyl substituted with one or more -CH3 or -CN, optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, =O, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl; cyclobutyl, cyclohexyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl pyrrolidinyl, and piperidinyl, each of which is substituted with one or more -F, and is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1- 6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, =O, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl; and spiro[2.2]pentanyl, spiro[3.2]hexanyl, spiro[4.2]heptanyl, 6-oxaspiro[2.5]octanyl, 2- oxabicyclo[2.2.1]heptanyl, 8-oxabicyclo[3.2.1]octanyl, 1-Oxaspiro[5.5]undecanyl, adamantanyl, 2-azaspiro[3.3]heptanyl, and 1,9-dioxaspiro[5.5]undecanyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, =O, -CN, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl; and provided that when one or more of (i), (ii), (ii), (iv), (v), (vi), (vii), and (viii) apply, then Ring A is further selected from cyclobutyl, cyclohexyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, sulfolanyl, azetidinyl, pyrrolidinyl, piperidinyl, spiro[2.2]pentanyl, spiro[3.2]hexanyl, spiro[4.2]heptanyl, 6-oxaspiro[2.5]octanyl, 2-Oxabicyclo[2.2.1]heptanyl, 8- Oxabicyclo[3.2.1]octanyl, 1-Oxaspiro[5.5]undecanyl, adamantanyl, 2-Azaspiro[3.3]heptanyl, and 1,9-dioxaspiro[5.5]undecanyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, -C(O)OR12, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl; (i) Ring B is (a) and RA is selected from halogen, C1-4 haloalkyl, C3-6 cycloalkyl, -NR11, and -OR11; (ii) Y1 is S, Y2 is C, Ring B is (a), and X1 is N; (iii) Y1 is S, Y2 is C, Ring B is (a), and RA is C1-4 alkyl; (iv) Ring B is (a), and p is 1, 2, or 3; (v) R1 is C1-4 alkyl or C1-4 haloalkyl; (vi) Ring B is (c); and (vii) Y1 is CR3, Y2 is N, Y3 is CR3, and Y4 is N; (viii) Y1 is N, Y2 is N, Y3 is CR4, Y4 is CR3, and Ring B is (a) or (c); provided that when Ring B is (a), X1 is CH, RA is methyl, Y1 is CR3, and Y2 is N, then Ring A is further selected from tetrahydrofuranyl substituted with methyl; and R12 is independently selected at each occurrence from hydrogen and C1-6 alkyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is selected from: cyclopropyl substituted with one or more -CH3 or -CN; cyclobutyl, cyclohexyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl pyrrolidinyl, and piperidinyl, each of which is substituted with one or more -F, and is optionally substituted with one or more substituents independently selected from: -F, -OH, -OCH3, -CH3, , , , , , and ;and spiro[2.2]pentanyl, spiro[3.2]hexanyl, spiro[4.2]heptanyl, 6-oxaspiro[2.5]octanyl, 2- oxabicyclo[2.2.1]heptanyl, 8-oxabicyclo[3.2.1]octanyl, 1-Oxaspiro[5.5]undecanyl, adamantanyl, 2-azaspiro[3.3]heptanyl, and 1,9-dioxaspiro[5.5]undecanyl, any of which is optionally substituted with one or more substituents independently selected from: -F, -OH, and -CH3, and provided that when one or more of (i), (ii), (ii), (iv), (v), (vi), (vii), and (viii) apply, then Ring A is further selected from cyclobutyl, cyclohexyl, phenyl, oxepanyl, sulfolanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, spiro[2.2]pentanyl, spiro[3.2]hexanyl, spiro[4.2]heptanyl, 6-oxaspiro[2.5]octanyl, 2-Oxabicyclo[2.2.1]heptanyl, 8- Oxabicyclo[3.2.1]octanyl, 1-Oxaspiro[5.5]undecanyl, adamantanyl, 2-Azaspiro[3.3]heptanyl, and 1,9-dioxaspiro[5.5]undecanyl, each of which is optionally substituted with one or more substituents independently selected from: -F, -OH, -OCH3, -CH3, -CF3, =O, , and ; (i) Ring B is (a) and RA is selected from halogen, C1-4 haloalkyl, C3-6 cycloalkyl, -NR11, and -OR11; (ii) Y1 is S, Y2 is C, Ring B is (a), and X1 is N; (iii) Y1 is S, Y2 is C, Ring B is (a), and RA is C1-4 alkyl; (iv) Ring B is (a), and p is 1, 2, or 3; (v) R1 is C1-4 alkyl or C1-4 haloalkyl; (vi) Ring B is (c); and (vii) Y1 is CR3, Y2 is N, Y3 is CR3, and Y4 is N; (viii) Y1 is N, Y2 is N, Y3 is CR4, Y4 is CR3, and Ring B is (a) or (c); provided that Ring A is selected from tetrahydrofuranyl substituted with methyl only when Ring B is (a), X1 is CH, RA is methyl, Y1 is CR3, and Y2 is N. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is selected from: phenyl, tetrahydrofuanyl, tetrahydropyranyl, azetidinyl; pyrrolidinyl, piperidinyl, and 1,9-dioxaspiro[5.5]undecanyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, =O, and 3- to 6- membered heterocycle optionally substituted with one or more C1-4 alkyl; and R12 is independently selected at each occurrence from hydrogen and C1-6 alkyl. In some embodiments, Ring A is selected from: phenyl, tetrahydrofuanyl, tetrahydropyranyl, azetidinyl; pyrrolidinyl, piperidinyl, and 1,9-dioxaspiro[5.5]undecanyl, each of which is optionally substituted with 1-4 substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, =O, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl; and R12 is independently selected at each occurrence from hydrogen and C1-6 alkyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is selected from: phenyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, and 1,9-dioxaspiro[5.5]undecanyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, -C(O)OR12, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl; and R12 is independently selected at each occurrence from hydrogen and C1-6 alkyl. In some embodiments, Ring A is selected from: phenyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, and 1,9-dioxaspiro[5.5]undecanyl, each of which is optionally substituted with 1-4 substituents independently selected from: halogen, C1- 6 alkyl, -C(O)OR12, and 3- to 6-membered heterocycle optionally substituted with one or more C1- 4 alkyl; and R12 is independently selected at each occurrence from hydrogen and C1-6 alkyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), the halogen substituent on Ring A is bonded to the ring member of Ring A that is bonded to –L-. In some embodiments, the -F substituent on Ring A is bonded to the ring member of Ring A that is bonded to –L-. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is selected from: cyclopropyl, phenyl, tetrahydrofuanyl, tetrahydropyranyl, azetidinyl pyrrolidinyl, and piperidinyl, each of which is substituted with one or more -F, and is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, =O, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl; and 1,9-dioxaspiro[5.5]undecanyl optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, =O, -CN; and R12 is independently selected at each occurrence from hydrogen and C1-6 alkyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is selected from: cyclopropyl, phenyl, tetrahydrofuanyl, tetrahydropyranyl, azetidinyl pyrrolidinyl, and piperidinyl, each of which is substituted with 1-4 -F, and is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, =O, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl; and 1,9-dioxaspiro[5.5]undecanyl optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, =O, -CN; and R12 is independently selected at each occurrence from hydrogen and C1-6 alkyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is selected from: cyclobutyl, cyclohexyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl; pyrrolidinyl, piperidinyl, and 1,9- dioxaspiro[5.5]undecanyl, each of which is optionally substituted with one or more substituents independently selected from: -F, -OH, -CH3, , , , , and . In some embodiments, Ring A is selected from: cyclopropyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl; pyrrolidinyl, piperidinyl, and 1,9-dioxaspiro[5.5]undecanyl, each of which is optionally substituted with one or more substituents independently selected from: -F, - CH3, , , , , and . In some embodiments, Ring A is selected from: cyclopropyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl; pyrrolidinyl, piperidinyl, and 1,9-dioxaspiro[5.5]undecanyl, each of which is optionally substituted with 1-4 substituents independently selected from: -F, -CH3, , , , , and . In some embodiments, Ring A is cyclopropyl optionally substituted with 1-4 substituents independently selected from: -F, -CH3, , , , , and . In some embodiments, Ring A is cyclopropyl optionally substituted with 1-4 substituents independently selected from: -F and -CH3. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is phenyl optionally substituted with 1-4 substituents independently selected from: -F, -CH3, , , , , and . In some embodiments, Ring A is tetrahydrofuranyl optionally substituted with 1-4 substituents independently selected from: -F, -CH3, , , , , and . In some embodiments, Ring A is tetrahydrofuranyl optionally substituted with 1-4 substituents independently selected from: -F and -CH3. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with 1-4 substituents independently selected from: -F, -CH3, , , , , and . In some embodiments, Ring A is tetrahydropyranyl optionally substituted with 1- 4 substituents independently selected from: -F and -CH3. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is azetidinyl optionally substituted with 1-4 substituents independently selected from: -F, -CH3, , , , , and . In some embodiments, Ring A is pyrrolidinyl optionally substituted with 1-4 substituents independently selected from: -F, -CH3, , , , , and . In some embodiments, Ring A is piperidinyl optionally substituted with 1-4 substituents independently selected from: -F, -CH3, , , , , and . In some embodiments, Ring A is 1,9-dioxaspiro[5.5]undecanyl optionally substituted with 1-4 substituents independently selected from: -F, -CH3, , , , , and . In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is selected from: F , , , , , , HO , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is selected from: cyclopropyl substituted with one or more C1-6 alkyl or -CN, C3-6 carbocycle substituted with one or more halogen, 3- to 6-membered heterocycle substituted with one or more halogen, C5-6 spirocyclic carbocycle, and 5- to 6-membered spirocyclic heterocycle, any of which is optionally substituted with one or more substituents independently selected from: C1-6 alkyl, C1- 6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl; C7-12 carbocycle and 7- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1- 6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, -CN, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl, provided that when Ring B is selected from (b), then Ring A is not chromane; and R12 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is selected from: cyclopropyl substituted with one or more -halogen, C1-6 alkyl or -CN; cyclobutyl, cyclohexyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl pyrrolidinyl, and piperidinyl, each of which is substituted with one or more halogen; and spiro[2.2]pentanyl, spiro[3.2]hexanyl, spiro[4.2]heptanyl, 6-oxaspiro[2.5]octanyl, 2- oxabicyclo[2.2.1]heptanyl, 8-oxabicyclo[3.2.1]octanyl, 1-Oxaspiro[5.5]undecanyl, adamantanyl, 2-azaspiro[3.3]heptanyl, and 1,9-dioxaspiro[5.5]undecanyl; any of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, =O, -CN, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl; and R12 is independently selected at each occurrence from hydrogen and C1-6 alkyl. In some embodiments, for the compound of any of the preceding Formulae, when Ring B is selected from (b), then Ring A is not chromane. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is selected from: cyclopropyl substituted with one or more -F, -CH3, or -CN; cyclobutyl, cyclohexyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl pyrrolidinyl, and piperidinyl, each of which is substituted with one or more -F; and spiro[2.2]pentanyl, spiro[3.2]hexanyl, spiro[4.2]heptanyl, 6-oxaspiro[2.5]octanyl, 2- oxabicyclo[2.2.1]heptanyl, 8-oxabicyclo[3.2.1]octanyl, 1-Oxaspiro[5.5]undecanyl, adamantanyl, 2-azaspiro[3.3]heptanyl, and 1,9-dioxaspiro[5.5]undecanyl; any of which is optionally substituted with one or more substituents independently selected from: -F, -OH, -OCH3, -CH3, -CF3, =O, -CN, , , , , , , , and . In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is selected from: F , , , , HO , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is selected from: , , , , , , , , and . In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is selected from: , , , , , , , , , , , , , , , , , , , , , , , and . In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is selected from: , , , , , , , , , , , , , , , , , , , , , , , and . In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is tetrahydropyranyl optionally substituted with 1-4 halogen. In some embodiments, Ring A is tetrahydropyranyl substituted with 1-4 halogen. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with 1-4 fluorine. In some embodiments, Ring A is tetrahydropyranyl substituted with 1-4 fluorine. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with one halogen. In some embodiments, Ring A is tetrahydropyranyl substituted with one halogen. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with one fluorine. In some embodiments, Ring A is tetrahydropyranyl substituted with one fluorine. In some embodiments, Ring A is unsubstituted tetrahydropyranyl. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with 1-4 C1-6 alkyl. In some embodiments, Ring A is tetrahydropyranyl substituted with 1-4 C1-6 alkyl. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with 1-4 methyl. In 20 some embodiments, Ring A is tetrahydropyranyl substituted with 1-4 methyl. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with one C1-6 alkyl. In some embodiments, Ring A is tetrahydropyranyl substituted with one C1-6 alkyl. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with one methyl. In some embodiments, Ring A is tetrahydropyranyl substituted with one methyl. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with four C1-6 alkyl. In some embodiments, Ring A is tetrahydropyranyl substituted with four C1-6 alkyl. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with four methyl. In some embodiments, Ring A is tetrahydropyranyl substituted with four methyl. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is unsubstituted tetrahydrofuranyl. In some embodiments, Ring A is tetrahydrofuranyl optionally substituted with 1-4 C1-6 alkyl. In some embodiments, Ring A is tetrahydrofuranyl substituted with 1-4 C1-6 alkyl. In some embodiments, Ring A is tetrahydrofuranyl optionally substituted with 1-4 methyl. In some embodiments, Ring A is tetrahydrofuranyl substituted with 1-4 methyl. In some embodiments, Ring A is tetrahydrofuranyl optionally substituted with one C1-6 alkyl. In some embodiments, Ring A is tetrahydrofuranyl substituted with one C1-6 alkyl. In some embodiments, Ring A is tetrahydrofuranyl optionally substituted with one methyl. In some embodiments, Ring A is tetrahydrofuranyl substituted with one methyl. In some embodiments, Ring A is tetrahydrofuranyl optionally substituted with four C1-6 alkyl. In some embodiments, Ring A is tetrahydrofuranyl substituted with four C1-6 alkyl. In some embodiments, Ring A is tetrahydrofuranyl optionally substituted with four methyl. In some embodiments, Ring A is tetrahydrofuranyl substituted with four methyl. In some embodiments, the compound is of Formula (IIIA): (IIIA), or a pharmaceutically acceptable salt thereof; wherein R5 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR12; and R16 is selected from halogen, -OR12, and C1-6 alkyl optionally substituted with 1-4 halogen; and Q is O, NH, or S. In some embodiments, the compound is of Formula (IIIB) (IIIB), or a pharmaceutically acceptable salt thereof; wherein R16 is selected from halogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR12; and Q is O, NH, or S. In some embodiments, Q is O. In some embodiments, the compound is of Formula (IIIA-1): (III-A1), or a pharmaceutically acceptable salt thereof; wherein R5 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR12; and R16 is selected from halogen, -OR12, and C1-6 alkyl optionally substituted with 1-4 halogen; and Q is O, NH, or S. In some embodiments, the compound is of Formula (IIIB-1): (IIIB-1), or a pharmaceutically acceptable salt thereof; wherein R16 is selected from halogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR12; and Q is O, NH, or S. In some embodiments, Q is O. In some embodiments, p is 0. In some embodiments, the compound is of Formula (IIIC-1): (IIIC-1), or a pharmaceutically acceptable salt thereof; wherein R16 is selected from halogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR12; and Q is O, NH, or S. In some embodiments, Q is O. In some embodiments, the compound is of Formula (IIIA-2): (IIIA-2), or a pharmaceutically acceptable salt thereof; wherein R5 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR12; and R16 is selected from halogen, -OR12, and C1-6 alkyl optionally substituted with 1-4 halogen; and Q is O, NH, or S. In some embodiments, the compound is of Formula (IIIA-3): (IIIA-3), or a pharmaceutically acceptable salt thereof; wherein R5 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR12; and R16 is selected from halogen, -OR12, and C1-6 alkyl optionally substituted with 1-4 halogen; and Q is O, NH, or S. In some embodiments, the compound is of Formula (IIIA-4): (IIIA-4), or a pharmaceutically acceptable salt thereof; wherein R5 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR12; and R16 is selected from halogen, -OR12, and C1-6 alkyl optionally substituted with 1-4 halogen; and Q is O, NH, or S. In some embodiments, the compound is of Formula (IIIA-5): (IIIA-5), or a pharmaceutically acceptable salt thereof; wherein R5 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR12; and R16 is selected from halogen, -OR12, and C1-6 alkyl optionally substituted with 1-4 halogen; and Q is O, NH, or S. In some embodiments, for the compound of Formulae (IIIA), (IIIA-1), (IIIA-2), (IIIA-3), (IIIA-4), (IIIA-5), (IIIB), (IIIB-1), or (IIIC-1), RA is selected from halogen, C1-4 alkyl, C1- 4 haloalkyl, C1-4 hydroxyalkyl, -OR11, -N(R11)2, -SR11, -N(R11)C(O)R11, -CN, C3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; and R11 is selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and C3-6 cycloalkyl. In some embodiments, RA is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -N(R11)2, -SR11, -N(R11)C(O)R11, -CN, C3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; and R11 is selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and C3-6 cycloalkyl. In some embodiments, RA is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -N(R11)2, -SR11, -N(R11)C(O)R11, and -CN, and R11 is selected from hydrogen, C1-4 alkyl, C1- 4 haloalkyl, and C3-6 cycloalkyl. In some embodiments, RA is selected from halogen, C1-4 alkyl, C1- 4 haloalkyl, C1-4 hydroxyalkyl, -N(R11)2, -SR11, -N(R11)C(O)R11, and -CN, and R11 is selected from hydrogen, and C1-4 alkyl. In some embodiments, RA is selected from halogen, C1-4 alkyl, C1- 4 haloalkyl, and C1-4 hydroxyalkyl. In some embodiments, RA is selected from halogen, C1-4 alkyl, and C1-4 haloalkyl. In some embodiments, RA is selected from halogen and C1-4 alkyl. . In some embodiments, RA is selected from C1-4 alkyl. In some embodiments, for the compound of Formulae (IIIA), (IIIA-1), (IIIA-2), (IIIA-3), (IIIA-4), (IIIA-5), (IIIB), (IIIB-1), or (IIIC-1), RA is selected from -F, -Cl, -CN, -NH2, -OH, - OCH3, , -CH3, -CF3, -CHF2, , , , , and . In some embodiments, RA is selected from -F, -Cl, -CN, -NH2, -CH3, -CF3, -CHF2, , , , , and . In some embodiments, RA is selected from -F, - Cl, -CN, -NH2, -CH3, -CF3, and -CHF2. In some embodiments, RA is selected from -F, -Cl, -CH3, -CF3, and -CHF2. In some embodiments, RA is selected from -F and -Cl. In some embodiments, RA is selected from -CH3, -CF3, and -CHF2. In some embodiments, RA is selected from -CH3. In some embodiments, for the compound of Formulae (IIIA), (IIIA-1), (IIIA-2), (IIIA-3), (IIIA-4), (IIIA-5), (IIIB), (IIIB-1), or (IIIC-1), p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, for the compound of Formulae (IIIA), (IIIA-1), (IIIA-2), (IIIA-3), (IIIA-4), (IIIA-5), (IIIB), (IIIB-1), or (IIIC-1), R5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, - C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)S(O)2(R13), -S(O)2R13, -S(O)2N(R13)2, -NO2, and -CN. In some embodiments, R5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1- 4 haloalkyl, -SR13, -N(R13)2, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, and -CN. In some embodiments, R5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1- 4 haloalkyl, -SR13, -N(R13)2, and -CN. In some embodiments, R5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, and -CN. In some embodiments, R5 is halogen. In some embodiments, R5 is C1-4 alkyl. In some embodiments, R5 is C1-4 haloalkyl. In some embodiments, R5 is -OR13. In some embodiments, R5 is -SR13. In some embodiments, R5 is -N(R13)2. In some embodiments, R5 is -C(O)R13. In some embodiments, R5 is -C(O)OR13. In some embodiments, R5 is -OC(O)R13. In some embodiments, R5 is -C(O)N(R13)2. In some embodiments, R5 is -N(R13)C(O)R13. In some embodiments, R5 is -N(R13)S(O)2(R13). In some embodiments, R5 is -S(O)2R13. In some embodiments, R5 is -S(O)2N(R13)2. In some embodiments, R5 is -NO2. In some embodiments, R5 is -CN. In some embodiments, the compound is of Formula (IIIB-2): (IIIB-2), or a pharmaceutically acceptable salt thereof; wherein R16 is selected from halogen, C1- 4 alkyl, and C1-4 haloalkyl; and Q is O, NH, or S. In some embodiments, Q is O. In some embodiments, R16 is selected from -F and -CH3; Q is O; and X1 is CH or N. In some embodiments, the compound is of Formula (IIIB-3): (IIIB-3), or a pharmaceutically acceptable salt thereof; wherein R16 is selected from halogen, C1- 4 alkyl, and C1-4 haloalkyl; and Q is O, NH, or S. In some embodiments, Q is O. In some embodiments, R16 is selected from -F and -CH3; Q is O; and X1 is CH or N. In some embodiments, for the compound of Formulae (IIIA), (IIIA-1), (IIIB), (IIIB-1), (IIIB-2), (IIIB-3), or (IIIC-1), X1 is selected from N, CH, and CR5. In some embodiments, X1 is selected from N and CH. In some embodiments, X1 is selected from CH, and CR5. In some embodiments, X1 is N. In some embodiments, X1 is CH. In some embodiments, X1 is CR5. In some embodiments, for the compound of Formulae (IIIA), (IIIA-1), (IIIA-2), (IIIA-3), (IIIA-4), (IIIA-5), (IIIB), (IIIB-1), (IIIB-2), (IIIB-3), or (IIIC-1), Q is O, NH, or S. In some embodiments, Q is O. In some embodiments, for the compound of Formulae (IIIA), (IIIA-1), (IIIA-2), (IIIA-3), (IIIA-4), (IIIA-5), (IIIB), (IIIB-1), (IIIB-2), (IIIB-3), or (IIIC-1), each R16 is independently selected from halogen, C1-4 alkyl, and C1-4 haloalkyl. In some embodiments, each R16 is independently selected from halogen and C1-4 alkyl. In some embodiments, each R16 is independently selected from halogen and C1-4 alkyl. In some embodiments, each R16 is independently selected from -F and C1-4 alkyl. In some embodiments, each R16 is independently selected from -F and -CH3. In some embodiments, each R16 is independently selected from C1-4 alkyl. In some embodiments, each R16 is -CH3. In some embodiments, each R16 is independently selected from halogen. In some embodiments, each R16 is -F. In some embodiments, for the compound of Formulae (IIIA), (IIIA-1), (IIIA-2), (IIIA-3), (IIIA-4), (IIIA-5), (IIIB), (IIIB-1), (IIIB-2), (IIIB-3), or (IIIC-1), the compound has 0, 1, 2, 3, or 4 R16 groups. In some embodiments, the compound has 0, 1, 2, or 3 R16 groups. In some embodiments, the compound has 0, 1, or 2 R16 groups. In some embodiments, the compound has 0 or 1 R16 groups. In some embodiments, the compound has 1, 2, 3, or 4 R16 groups. In some embodiments, the compound has 1, 2, or 3 R16 groups. In some embodiments, the compound has 1 or 2 R16 groups. In some embodiments, the compound has 0 R16 groups. In some embodiments, the compound has 1 R16 groups. In some embodiments, the compound has 2 R16 groups. In some embodiments, the compound has 3 R16 groups. In some embodiments, the compound has 4 R16 groups. In some embodiments, for the compound of Formulae (I), (IA), (IB), (IC), (ID), (II), (IIA), (IIA-1), (IIA-2) (IIA-3), (IIB), (IIB-1), (IIB-2), (IIB-3), (IIB-5), (IIB-6), (IIC), (IIC-1), (IIC-2), (IIC-3), (IID), (IID-1), (IID-2), or (IID-3), Ring A is cyclopropyl optionally substituted with 1-4 halogen. In some embodiments, Ring A is cyclopropyl substituted with 1-4 halogen. In some embodiments, Ring A is cyclopropyl optionally substituted with 1-4 fluorine. In some embodiments, Ring A is cyclopropyl substituted with 1-4 fluorine. In some embodiments, Ring A is cyclopropyl optionally substituted with one halogen. In some embodiments, Ring A is cyclopropyl substituted with one halogen. In some embodiments, Ring A is cyclopropyl optionally substituted with one fluorine. In some embodiments, Ring A is cyclopropyl substituted with one fluorine. In some embodiments, Ring A is not chromane. In some embodiments, the compound is of Formula (IVA): (IVA), or a pharmaceutically acceptable salt thereof; wherein R15 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR12. In some embodiments, the compound is of Formula (IVA-1): (IVA-1), or a pharmaceutically acceptable salt thereof; wherein R15 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR12. In some embodiments, the compound is of Formula (IVB-1): (IVB-1), or a pharmaceutically acceptable salt thereof; wherein R15 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, and - C(O)OR12. In some embodiments, the compound is of Formula (IVA-2): (IVA-2), or a pharmaceutically acceptable salt thereof; wherein R15 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR12. In some embodiments, the compound is of Formula (IVA-3): (IVA-3), or a pharmaceutically acceptable salt thereof; wherein R15 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR12. In some embodiments, for the compound of Formulae (IVA), (IVA-1), (IVA-2), (IVA-3), or (IVB-1), RA is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -OR11, - N(R11)2, -SR11, -N(R11)C(O)R11, -CN, C3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; and R11 is selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and C3-6 cycloalkyl. In some embodiments, RA is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -N(R11)2, -SR11, -N(R11)C(O)R11, -CN, C3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; and R11 is selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and C3-6 cycloalkyl. In some embodiments, RA is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -N(R11)2, -SR11, - N(R11)C(O)R11, and -CN, and R11 is selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and C3-6 cycloalkyl. In some embodiments, RA is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1- 4 hydroxyalkyl, -N(R11)2, -SR11, -N(R11)C(O)R11, and -CN, and R11 is selected from hydrogen, and C1-4 alkyl. In some embodiments, RA is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, and C1- 4 hydroxyalkyl. In some embodiments, RA is selected from halogen, C1-4 alkyl, and C1-4 haloalkyl. In some embodiments, RA is selected from halogen and C1-4 alkyl. . In some embodiments, RA is selected from C1-4 alkyl. In some embodiments, for the compound of Formulae (IVA), (IVA-1), (IVA-2), (IVA-3), or (IVB-1), RA is selected from -F, -Cl, -CN, -NH2, -OH, -OCH3, , -CH3, -CF3, -CHF2, , , , , and . In some embodiments, RA is selected from -F, -Cl, -CN, -NH2, -CH3, -CF3, -CHF2, , , , , and . In some embodiments, RA is selected from -F, -Cl, -CN, -NH2, -CH3, -CF3, and -CHF2. In some embodiments, RA is selected from -F, -Cl, -CH3, -CF3, and -CHF2. In some embodiments, RA is selected from -F and -Cl. In some embodiments, RA is selected from -CH3, -CF3, and -CHF2. In some embodiments, RA is selected from -CH3. In some embodiments, for the compound of Formulae (IVA), (IVA-1), (IVA-2), (IVA-3), or (IVB-1), p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, for the compound of Formulae (IVA), (IVA-1), (IVA-2), (IVA-3), or (IVB-1), R5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1- 4 haloalkyl, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)S(O)2(R13), -S(O)2R13, -S(O)2N(R13)2, -NO2, and -CN. In some embodiments, R5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -SR13, -N(R13)2, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, and -CN. In some embodiments, R5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -SR13, -N(R13)2, and -CN. In some embodiments, R5 is independently selected at each occurrence from halogen, C1- 4 alkyl, C1-4 haloalkyl, and -CN. In some embodiments, R5 is halogen. In some embodiments, R5 is C1-4 alkyl. In some embodiments, R5 is C1-4 haloalkyl. In some embodiments, R5 is -OR13. In some embodiments, R5 is -SR13. In some embodiments, R5 is -N(R13)2. In some embodiments, R5 is -C(O)R13. In some embodiments, R5 is -C(O)OR13. In some embodiments, R5 is -OC(O)R13. In some embodiments, R5 is -C(O)N(R13)2. In some embodiments, R5 is -N(R13)C(O)R13. In some embodiments, R5 is -N(R13)S(O)2(R13). In some embodiments, R5 is -S(O)2R13. In some embodiments, R5 is -S(O)2N(R13)2. In some embodiments, R5 is -NO2. In some embodiments, R5 is -CN. In some embodiments, RA is C1-4 alkyl. In some embodiments, R16 is selected from -F and -CH3; Q is O; and X1 is CH or N. In some embodiments, p is 0. In some embodiments, the compound is of Formula (IVA-4): (IVA-4), or a pharmaceutically acceptable salt thereof; wherein R15 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR12. In some embodiments, the compound is of Formula (IVB-2): (IVB-2), or a pharmaceutically acceptable salt thereof; wherein R15 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR12. In some embodiments, the compound is of Formula (IVB-3): R15 0-4 F O N 1-4 N HN N X1 N (IVB-3), or a pharmaceutically acceptable salt thereof; wherein X1 is CH or N, and R15 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR12. In some embodiments, the compound is of Formula (IVB-4): R15 0-4 F O N N HN N X1 N (IVB-4), or a pharmaceutically acceptable salt thereof; wherein X1 is CH or N, and R15 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR12. In some embodiments, for the compound of Formulae (IVA), (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVB-1), (IVB-2), (IVB-3), or (IVB-4), X1 is selected from N, CH, and CR5. In some embodiments, X1 is selected from N and CH. In some embodiments, X1 is selected from CH, and CR5. In some embodiments, X1 is N. In some embodiments, X1 is CH. In some embodiments, X1 is CR5. In some embodiments, for the compound of Formulae (IVA), (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVB-1), (IVB-2), (IVB-3), or (IVB-4), X1 is CR5, and R5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -SR13, -N(R13)2, and -CN. In some embodiments, X1 is CR5, and R5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, and -CN. In some embodiments, X1 is CR5, and R5 is halogen. In some embodiments, X1 is CR5, and R5 is C1-4 alkyl. In some embodiments, X1 is CR5, and R5 is C1- 4 haloalkyl. In some embodiments, the compound is of Formula (IVA-5): (IVA-5), or a pharmaceutically acceptable salt thereof; wherein R15 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR12. In some embodiments, for the compound of Formulae (IVA), (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVB-1), (IVB-2), (IVB-3), or (IVB-4), each R15 is independently selected from halogen, C1-4 alkyl, and C1-4 haloalkyl. In some embodiments, each R15 is independently selected from halogen and C1-4 alkyl. In some embodiments, each R15 is independently selected from halogen and C1-4 alkyl. In some embodiments, each R15 is independently selected from -F and C1- 4 alkyl. In some embodiments, each R15 is independently selected from -F and -CH3. In some embodiments, each R15 is independently selected from C1-4 alkyl. In some embodiments, each R15 is -CH3. In some embodiments, each R15 is independently selected from halogen. In some embodiments, each R15 is -F. In some embodiments, R15 is hydrogen. In some embodiments, R15 is C1-6 alkyl. In some embodiments, R15 is C1-6 haloalkyl. In some embodiments, R15 is -C(O)OR12. In some embodiments, for the compound of Formulae (IVA), (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVB-1), (IVB-2), (IVB-3), or (IVB-4), the compound has 0, 1, 2, 3, or 4 R15 groups. In some embodiments, the compound has 0, 1, 2, or 3 R15 groups. In some embodiments, the compound has 0, 1, or 2 R15 groups. In some embodiments, the compound has 0 or 1 R15 groups. In some embodiments, the compound has 1, 2, 3, or 4 R15 groups. In some embodiments, the compound has 1, 2, or 3 R15 groups. In some embodiments, the compound has 1 or 2 R15 groups. In some embodiments, the compound has 0 R15 groups. In some embodiments, the compound has 1 R15 groups. In some embodiments, the compound has 2 R15 groups. In some embodiments, the compound has 3 R15 groups. In some embodiments, the compound has 4 R15 groups. In some embodiments, for the compound of any of the preceding FormulaeR10, R11, R12, R13, and R14 are each independently selected at each occurrence from hydrogen and C1-6 alkyl. In some embodiments, R10, R11, R12, R13, and R14 are each independently selected at each occurrence from hydrogen and C1-4 alkyl. In some embodiments, each R10 is independently selected from hydrogen and C1-6 alkyl. In some embodiments, each R10 is independently hydrogen. In some embodiments, each R10 is independently C1-6 alkyl. In some embodiments, each R11 is independently selected from hydrogen and C1-6 alkyl. In some embodiments, each R11 is independently hydrogen. In some embodiments, each R11 is independently C1-6 alkyl. In some embodiments, each R12 is independently selected from hydrogen and C1-6 alkyl. In some embodiments, each R12 is independently hydrogen. In some embodiments, each R12 is independently C1-6 alkyl. In some embodiments, each R13 is independently selected from hydrogen and C1-6 alkyl. In some embodiments, each R13 is independently hydrogen. In some embodiments, each R13 is independently C1-6 alkyl. In some embodiments, each R14 is independently selected from hydrogen and C1-6 alkyl. In some embodiments, each R14 is independently hydrogen. In some embodiments, each R14 is independently C1-6 alkyl. In some embodiments, the compound is of Formula (IVA-6): (IVA-6), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (IVA-7): (IVA-7), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (IVA-8): (IVA-8), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (IIC-10): (IIC-10), or a pharmaceutically acceptable salt thereof, wherein: Ring B is selected from (a), (b) and (c): (a) , X1 is selected from N, CH, and CR5; (b) , X2 is selected from S and NR7; and (c) , X3 is selected from S, N, and NH, X4 is selected from O and CR9, X5 is N or CH, X6 is N or CH, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system; R1 is selected from hydrogen, C1-4 alkyl, and –C(O)C3-6 cycloalkyl optionally substituted with one or more halogen; R2 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR10, -SR10, -N(R10)2, NO2, and -CN; R3 and R4 are each independently selected at each occurrence from hydrogen, halogen, C1-4 alkyl, and C1-4 haloalkyl; RA is selected from hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, -OR11, -N(R11)2, -SR11, -N(R11)C(O)R11, -CN, -S(O)2C1-4 alkyl, C3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; Ring A is selected from: cyclopropyl substituted with one or more halogen, C4-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and -CN; R5, R6, andR8 are each independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)S(O)2(R13), -S(O)2R13, -S(O)2N(R13)2, -NO2, and -CN; R7 and R9 are each independently selected from hydrogen, C1-4 alkyl, and C1-4 haloalkyl; R10, R11, R12, R13, and R14 are each independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl; m is selected from 0, 1, and 2; p is selected from 0, 1, and 2; q is selected from 0, 1, and 2; and r is selected from 0, 1, and 2. In some embodiments, for the compound of Formula (IIC-10), RA is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -N(R11)2, -SR11, -N(R11)C(O)R11, -CN, C3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; and when Y1 is CR3 and Y2 is N, then RA is further selected from -OR11; R11 is selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and C3-6 cycloalkyl; R5 is independently selected at each occurrence from halogen, and C1-4 alkyl; and p is selected from 0 and 1. In some embodiments, for the compound of Formula (IIC-10), RA is selected from -F, -Cl, -CN, -NH2, -CH3, -CF3, -CHF2, , , , , and ; and when Y1 is CR3 and Y2 is N, then RA is further selected from - OH, -OCH3, and ; R5 is selected at each occurrence from -F, -Cl, and -CH3; p is selected from 0 and 1. In some embodiments, the compound of Formula (II) is a compound of: (II), or a pharmaceutically acceptable salt thereof, wherein: each represents a single or a double bond, such that the bicyclic ring system comprising Y1, Y2, and Y3 is an aromatic bicyclic ring system where (i) Y1 is CR3 and Y2 is N, or (ii) Y1 is S and Y2 is C; Y3 is selected from N and CR4; Ring B is selected from (a), (b) and (c): (a) , X1 is selected from N, CH, and CR5; (b) , X2 is selected from S and NR7; and (c) , X3 is selected from S, N, and NH, X4 is selected from O and CR9, X5 is N or CH, X6 is N or CH, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system; R1 is selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and –C(O)C3-6 cycloalkyl optionally substituted with one or more halogen; R2 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR10, -N(R10)2,, and -CN; R3 and R4 are each independently selected from hydrogen, halogen, C1-4 alkyl, and C1- 4 haloalkyl; RA is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -N(R11)2, -SR11, -N(R11)C(O)R11, -CN, -S(O)2C1-4 alkyl, C3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl, provided that: when Y1 is CR3, Y2 is N, and Y4 is CR3, or when Y1 is CR3, Y2 is N, and Y4 is N, then RA is further selected from -OR11, when Y1 is CR3, Y2 is N, Y3 is CH, Ring B is (a), p is 0, X1 is N, and Ring A is 1- fluoro-1-tetrahydropyranyl, then RA is further selected from hydrogen, and when Y1 is S, Y2 is C, and X1 is N, then RA is further selected from hydrogen; Ring A is selected from cyclopropyl substituted with one or more C1-6 alkyl or -CN, C3-6 carbocycle substituted with one or more halogen, 3- to 6-membered heterocycle substituted with one or more halogen, C5-6 spirocyclic carbocycle, and 5- to 6-membered spirocyclic heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, =O, -CN, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl; C7-12 carbocycle and 7- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1- 6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, =O, -CN, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl; provided that when Ring B is selected from (b), then Ring A is not chromane; provided that when one or more of (i), (ii), (ii), (iv), (v), (vi), (vii), and (viii) apply, then Ring A is further selected from C4-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: C1-6 alkyl, C1- 6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, =O, -CN, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl;, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl: (i) Ring B is (a) and RA is selected from halogen, C1-4 haloalkyl, C3-6 cycloalkyl, -NR11, and -OR11; (ii) Y1 is S, Y2 is C, Ring B is (a), and X1 is N; (iii) Y1 is S, Y2 is C, Ring B is (a), and RA is C1-4 alkyl; (iv) Ring B is (a), and p is 1, 2, or 3; (v) R1 is C1-4 alkyl or C1-4 haloalkyl; (vi) Ring B is (c); and (vii) Y1 is CR3, Y2 is N, Y3 is CR3, and Y4 is N; (viii) Y1 is N, Y2 is N, Y3 is CR4, Y4 is CR3, and Ring B is (a) or (c); provided that when Ring B is (a), X1 is CH, RA is methyl, Y1 is CR3, and Y2 is N, then Ring A is further selected from tetrahydrofuranyl substituted with methyl; and R5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, and -OR13, provided that when RA is -OR11, then R5 is not -OR13; R6 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR14, and -N(R14)2; R7 is selected from hydrogen and C1-4 alkyl; R8 is independently selected at each occurrence from halogen, C2-4 alkyl, C1-4 haloalkyl, -OR14, and -N(R14)2; R9 is selected from hydrogen, C1-4 alkyl, and C1-4 haloalkyl; R10, R11, R12, R13, R14 are each independently selected at each occurrence from hydrogen and C1-4alkyl; m, p, q, and r are each independently selected from 0, and 1. In some embodiments, for the compound of Formulae (I), (II), or sub-formulae thereof, when Y1 is CR3 and Y2 is N, then RA is further selected from -OR11. In some embodiments, Y1 is CR3 and Y2 is N; and RA is further selected from -OR11, provided that when RA is -OR11, then R5 is not -OR13;. In some embodiments, for the compound of Formulae (I), (II), or sub-formulae thereof, when Y1 is CR3, Y2 is N, Y3 is CH, Ring B is (a), p is 0, X1 is N, and Ring A is 1-fluoro-1- tetrahydropyranyl, then RA is further selected from hydrogen. In some embodiments, Y1 is CR3, Y2 is N, Y3 is CH, Ring B is (a), p is 0, X1 is N, and Ring A is 1-fluoro-1-tetrahydropyranyl; and RA is further selected from hydrogen. In some embodiments, for the compound of Formulae (I), (II), or sub-formulae thereof, when Y1 is S, Y2 is C, and X1 is N, then RA is further selected from hydrogen. In some embodiments, Y1 is S, Y2 is C, and X1 is N; and RA is further selected from hydrogen. In some embodiments, for the compound of Formulae (I), (II), or sub-formulae thereof, when one or more of (i), (ii), (ii), (iv), and (v) apply, then Ring A is further selected from C4-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, -CN, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl: (i) Ring B is (a) and RA is selected from halogen, C1-4 haloalkyl, C3-6 cycloalkyl, -NR11, and -OR11; (ii) Y1 is S, Y2 is C, Ring B is (a), and X1 is N; (iii) Y1 is S, Y2 is C, Ring B is (a), and RA is C1-4 alkyl; (iv) Ring B is (a), and p is 1, 2, or 3; (v) R1 is C1-4 alkyl; and (vi) Ring B is (c). In some embodiments, for the compound of Formulae (I), (II), or sub-formulae thereof, one or more of (i), (ii), (ii), (iv), and (v) apply; and Ring A is further selected from C4-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, -CN, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl: (i) Ring B is (a) and RA is selected from halogen, C1-4 haloalkyl, C3-6 cycloalkyl, -NR11, and -OR11; (ii) Y1 is S, Y2 is C, Ring B is (a), and X1 is N; (iii) Y1 is S, Y2 is C, Ring B is (a), and RA is C1-4 alkyl; (iv) Ring B is (a), and p is 1, 2, or 3; (v) R1 is C1-4 alkyl; and (vi) Ring B is (c). In some embodiments, for the compound of Formulae (I), (II), or sub-formulae thereof, when Ring B is (a), X1 is CH, RA is methyl, Y1 is CR3, and Y2 is N, then Ring A is further selected from tetrahydrofuranyl substituted with methyl. In some embodiments, Ring B is (a), X1 is CH, RA is methyl, Y1 is CR3, and Y2 is N; and Ring A is further selected from tetrahydrofuranyl substituted with methyl. In some embodiments, for the compound of Formulae (I), (II), or sub-formulae thereof, when RA is -OR11, then R5 is chloro. In some embodiments, RA is -OR11; and R5 is chloro. Formulae (V) and (VI) Compounds Some embodiments provide a compound of Formula (V): (V), or a pharmaceutically acceptable salt thereof, wherein: Q1 is N, S, O or CR3, Q2 is N or C, Q3 is N or CR4, Q4 is N or CR3, Q5 is C or N, and each represents a single or a double bond, such that the bicyclic ring system comprising Q1, Q2, Q3, Q4, and Q5 is benzo[d]thiazole, benzo[d]oxazole, imidazo[1,2-a]pyridine, thiazolo[5,4- b]pyridine, imidazo[1,2-b]pyridazine, pyrazolo[1,5-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, or [1,2,4]triazolo[1,5-b]pyridazine, RA is selected from halogen, -OR10, -SR10, -N(R10)2, -CN, C1-6 alkyl optionally substituted with one or more halogen or -OR10, C3-C6 saturated cycloalkyl, and 3- to 6-membered saturated heterocycloalkyl; Ring A is selected from a C3-C10 saturated cycloalkyl, a C3-C10 partially saturated carbocycle, a 3- to 10-membered saturated heterocycloalkyl, and a 3- to 10-membered partially saturated heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -OC(O)R11, -OC(O)N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)C(O)N(R11)2, -N(R11)S(O)2(R11), -S(O)R11, -S(O)2R11, -S(O)2N(R11)2, -S(O)(NR11)R11, -NO2, and =O; C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -OC(O)R11, -OC(O)N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)C(O)N(R11)2, -N(R11)S(O)2(R11), -S(O)R11, -S(O)2R11, -S(O)2N(R11)2, -S(O)(NR11)R11, -NO2, =O, -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -OC(O)R11, -OC(O)N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)C(O)N(R11)2, -N(R11)S(O)2(R11), -S(O)R11, -S(O)2R11, -S(O)2N(R11)2, -S(O)(NR11)R11, -NO2, =O, and -CN; Ring B is selected from a C3-C10 carbocycle and a 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and -CN; R1 is selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and -C(O)R13; R2 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR14, -SR14, -N(R14)2, -NO2, and -CN; R3 is independently selected at each occurrence from hydrogen, halogen, C1-4 alkyl, and C1-4 haloalkyl; R4 is selected from hydrogen, halogen, C1-4 alkyl, and C1-4 haloalkyl; R10, R11, R12, R13, and R14 are each independently selected at each occurrence from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and cycloalkyl optionally substituted with one or more halogen; and n is selected from 0, 1, and 2; provided that when Ring B is pyrazolyl, then Ring A is not N-Boc pyrrolidinyl. In some embodiments, for the compound of Formula (V), Q1 is CR3. In some emboidments, Q1 is N. In some emboidments, Q1 is S. In some emboidments, Q1 is O. In some embodiments, Q2 is C. In some emboidments, Q2 is N. In some embodiments, Q3 is CR4. In some emboidments, Q3 is N. In some embodiments, Q4 is CR3. In some emboidments, Q4 is N. In some embodiments, Q5 is C. In some embodiments, for the compound of Formula (V), the the bicyclic ring system comprising Q1, Q2, Q3, Q4, and Q5 is benzo[d]thiazole, benzo[d]oxazole, or thiazolo[5,4- b]pyridine. In some embodiments, the the bicyclic ring system comprising Q1, Q2, Q3, Q4, and Q5 is imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, or pyrazolo[1,5-a]pyridine. In some embodiments, the the bicyclic ring system comprising Q1, Q2, Q3, Q4, and Q5 is [1,2,4]triazolo[1,5- a]pyridine or [1,2,4]triazolo[1,5-b]pyridazine. In some embodiments, for the compound of Formula (V), the the bicyclic ring system comprising Q1, Q2, Q3, Q4, and Q5 is benzo[d]thiazole. In some embodiments, the the bicyclic ring system comprising Q1, Q2, Q3, Q4, and Q5 is benzo[d]oxazole. In some embodiments, the the bicyclic ring system comprising Q1, Q2, Q3, Q4, and Q5 is imidazo[1,2-a]pyridine. In some embodiments, the the bicyclic ring system comprising Q1, Q2, Q3, Q4, and Q5 is thiazolo[5,4- b]pyridine. In some embodiments, the the bicyclic ring system comprising Q1, Q2, Q3, Q4, and Q5 is imidazo[1,2-b]pyridazine. In some embodiments, the the bicyclic ring system comprising Q1, Q2, Q3, Q4, and Q5 is pyrazolo[1,5-a]pyridine. In some embodiments, the the bicyclic ring system comprising Q1, Q2, Q3, Q4, and Q5 is [1,2,4]triazolo[1,5-a]pyridine. In some embodiments, the the bicyclic ring system comprising Q1, Q2, Q3, Q4, and Q5 is [1,2,4]triazolo[1,5-b]pyridazine. Some embodiments provide a compound of Formula (VA): (VA), or a pharmaceutically acceptable salt thereof. In some embodiments, Q3 is CR4. In some emboidments, Q3 is N. In some embodiments, Q4 is CR3. In some emboidments, Q4 is N. In some embodiments, Q3 is CR4 and Q4 is N. In some embodiments, Q3 is CR4 and Q4 is CR3. In some embodiments, Q3 is N and Q4 is CR3. Some embodiments provide a compound of Formula (VB): (VB), or a pharmaceutically acceptable salt thereof. In some embodiments, Q3 is CR4. In some emboidments, Q3 is N. Some embodiments provide a compound of Formula (VC): (VC), or a pharmaceutically acceptable salt thereof. In some embodiments, Q4 is CR3. In some emboidments, Q4 is N. Some embodiments provide a compound of Formula (VD): (VD), or a pharmaceutically acceptable salt thereof. In some embodiments, Q3 is CR4. In some emboidments, Q3 is N. Some embodiments provide a compound of Formula (VE): (VE), or a pharmaceutically acceptable salt thereof. In some embodiments, Q3 is CR4. In some emboidments, Q3 is N. Some embodiments provide a compound of Formula (VF): (VF), or a pharmaceutically acceptable salt thereof In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), or (VF), R1 is selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and -C(O)R13; and R13 is selected at from C1-4 alkyl and cycloalkyl. In some embodiments, R1 is selected from hydrogen and C1-4 alkyl. In some embodiments, R1 is selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and -C(O)R13; and R13 is selected from C1-4 alkyl and cyclopropyl optionally substituted with one or more -F. In some embodiments, R1 is selected from hydrogen, C1-4 alkyl, and C1-4 haloalkyl. In some embodiments, R1 is selected from hydrogen and C1-4 alkyl. In some embodiments, R1 is selected from hydrogen, -CH3, -CF3, and . In some embodiments, R1 is hydrogen. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), or (VF), R2 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, and -CN. In some embodiments, R2 is independently selected at each occurrence from halogen and C1-4 alkyl. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), or (VF), R3 is independently selected at each occurrence from hydrogen, halogen, and C1-4 alkyl. In some embodiments, R3 is independently selected at each occurrence from hydrogen and C1-4 alkyl. In some embodiments, each R3 is independently hydrogen. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), or (VF), R4 is selected from hydrogen, halogen, and C1-4 alkyl. In some embodiments, R4 is selected from hydrogen and C1-4 alkyl. R4 is selected from hydrogen and -CH3. In some embodiments, R4 is hydrogen. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), or (VF), n is 0 or 1. In some embodiments, n is 0. Some embodiments provide a compound of Formula (VI): (VI), or a pharmaceutically acceptable salt thereof, wherein: Q1 is S or CR3, Q2 is N or C, Q3 is selected from N and CR4, and each represents a single or a double bond, such that the bicyclic ring system comprising Q1, Q2, and Q3 is benzo[d]thiazole, imidazo[1,2-a]pyridine, thiazolo[5,4-b]pyridine, or imidazo[1,2-b]pyridazine; RA is selected from halogen, -OR10, -SR10, -N(R10)2, -CN, C1-6 alkyl, C1-6 haloalkyl, C3-C6 saturated cycloalkyl, and 3- to 6-membered saturated heterocycloalkyl; Ring A is selected from a C3-C10 saturated cycloalkyl, a C3-C10 partially saturated carbocycle, a 3- to 10-membered saturated heterocycloalkyl, and a 3- to 10-membered partially saturated heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -OC(O)R11, -OC(O)N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)C(O)N(R11)2, -N(R11)S(O)2(R11), -S(O)R11, -S(O)2R11, -S(O)2N(R11)2, -S(O)(NR11)R11, -NO2, and =O; C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -OC(O)R11, -OC(O)N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)C(O)N(R11)2, -N(R11)S(O)2(R11), -S(O)R11, -S(O)2R11, -S(O)2N(R11)2, -S(O)(NR11)R11, -NO2, =O, -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -OC(O)R11, -OC(O)N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)C(O)N(R11)2, -N(R11)S(O)2(R11), -S(O)R11, -S(O)2R11, -S(O)2N(R11)2, -S(O)(NR11)R11, -NO2, =O, and -CN; Ring B is selected from a C3-C10 carbocycle and a 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and -CN; R1 is selected from hydrogen, C1-4 alkyl, and -C(O)R13; R2 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR14, -SR14, -N(R14)2, -NO2, and -CN; R3 and R4 are each selected from hydrogen, halogen, C1-4 alkyl, and C1-4 haloalkyl; R10, R11, R12, R13, and R14 are each independently selected at each occurrence from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and cycloalkyl optionally substituted with one or more halogen; and n is selected from 0, 1, and 2; provided that when Ring B is pyrazolyl, then Ring A is not N-Boc pyrrolidinyl. For purposes of clarification, when Ring A is substituted with one or more substituents, the one or more substituents do not include and are in addition to the RA group. In some embodiments, when a moiety or a list of moieties is optionally substituted or substituted with one or more substituents, the one or more substituents is 1-4 substituents (e.g., 1- 3, 2-4, 2-3, 1-2, 3-4, 1, 2, 3, or 4 substituents). For example, in some embodiments, the one or more substituents is 1-4 substituents. In some embodiments, the one or more substituents is one substituent. In some embodiments, for the compound of Formula (VI), Q1 is CR3 and Q2 is N. In some embodiments, Q1 is CR3; Q2 is N; and Q3 is N. In some embodiments, Q1 is CR3; Q2 is N; and Q3 is CR4. In some embodiments, Q1 is CR3; Q2 is N; and Q3 is CH. In some embodiments, Q1 is S and Q2 is C. In some embodiments, Q1 is S; Q2 is C; and Q3 is N. In some embodiments, Q1 is S; Q2 is C; and Q3 is CR4. In some embodiments, Q1 is S; Q2 is C; and Q3 is CH. In some embodiments, Q3 is N. In some embodiments, Q3 is CR4. In some embodiments, Q3 is CR4; and R4 is selected from hydrogen and halogen. In some embodiments, R4 is selected from hydrogen and C1-4 alkyl. In some embodiments, R4 is selected from hydrogen and -CH3. In some embodiments, Q3 is CH. In some embodiments, Q4 is CR3. In some embodiments, Q4 is N. In some embodiments, Q4 is CR3.and R3 is selected from hydrogen and halogen. In some embodiments, R3 is selected from hydrogen and C1-4 alkyl. In some embodiments, R3 is selected from hydrogen and -CH3. In some embodiments, Q4 is CH. In some embodiments, for the compound of Formula (VI), Q1 is CR3; Q2 is N; Q3 is N; and Q4 is CR3. In some embodiments, Q1 is CR3; Q2 is N; Q3 is CR4; and Q4 is CR3. In some embodiments, Q1 is CR3; Q2 is N; and Q3 is CR4; and Q4 is CR3. In some embodiments, Q1 is CR3; Q2 is N; and Q3 is CR4; and Q4 is N. In some embodiments, Q1 is CH; Q2 is N; and Q3 is CH; and Q4 is N. In some embodiments, the compound is of Formula (VIA): (VIA), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (VIA-1): (VIA-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (VIB): (VIB), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (VIC): (VIC), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (VIC-1): (VIC-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (VIC-2): (VIC-2), or a pharmaceutically acceptable salt thereof. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIB), (VIC), (VIC-1), or (VIC-2), R1 is selected from hydrogen, C1-4 alkyl, and -C(O)R13.In some embodiments, R1 is selected from hydrogen and C1-4 alkyl. In some embodiments, R1 is hydrogen. In some embodiments, R1 is C1-4 alkyl. In some embodiments, R1 is -C(O)R13. In some embodiments, R1 is selected from hydrogen, -CH3, and . In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIB), (VIC), (VIC-1), or (VIC-2), n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIB), (VIC), (VIC-1), or (VIC-2), R2 is independently selected at each occurrence from halogen and C1-4 alkyl. In some embodiments. In some embodiments, R2 is halogen. In some embodiments, R2 is C1-4 alkyl. In some embodiments, R2 is C1-4 haloalkyl. In some embodiments, R2 is -OR14. In some embodiments, R2 is -SR14. In some embodiments, R2 is -N(R14)2. In some embodiments, R2 is NO2. In some embodiments, R2 is –CN. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIB), (VIC), (VIC-1), or (VIC-2), R3 is hydrogen. In some embodiments, R3 is halogen. In some embodiments, R3 is fluoro. In some embodiments, R3 is chloro. In some embodiments, R3 is C1-4 alkyl. In some embodiments, R3 is methyl. In some embodiments, R3 is C1-4 haloalkyl. In some embodiments, R3 is trifluoromethyl. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIB), (VIC), (VIC-1), or (VIC-2), R2 is independently selected at each occurrence from halogen and C1-4 alkyl. In some embodiments. In some embodiments, R2 is halogen. In some embodiments, R2 is C1-4 alkyl. In some embodiments, R2 is C1-4 haloalkyl. In some embodiments, R2 is -OR14. In some embodiments, R2 is -SR14. In some embodiments, R2 is -N(R14)2. In some embodiments, R2 is NO2. In some embodiments, R2 is –CN. In some embodiments, the compound is of Formula (VIA-2): (VIA-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (VIA-3): (VIA-3), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (VIB-1): RA O A N HN S B (VIB-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (VIB-2): (VIB-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (VIC-3): (VIC-3), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (VID-1): (VID-1); or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (ID-2): (VID-2); or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (VIE-1): (VIE-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (VIE-2): (VIE-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (VIF): (VIF), or a pharmaceutically acceptable salt thereof. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), Ring B is selected from a C3-C10 carbocycle and a 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, - N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, =O, -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, =O, and -CN. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), the Ring B heterocycle comprises 1-4 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring B heterocycle comprises 1-3 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring B heterocycle comprises 1-2 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring B heterocycle comprises 2-3 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring B heterocycle comprises 1 heteroatom selected from O, N, and S. In some embodiments, the Ring B heterocycle comprises 2 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring B heterocycle comprises 3 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring B heterocycle comprises 4 heteroatoms independently selected from O, N, and S. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), the Ring B heterocycle comprises 1-4 heteroatoms independently selected from O and N. In some embodiments, the Ring B heterocycle comprises 1-3 heteroatoms independently selected from O and N. In some embodiments, the Ring B heterocycle comprises 1-2 heteroatoms independently selected from O and N. In some embodiments, the Ring B heterocycle comprises 2-3 heteroatoms independently selected from O and N. In some embodiments, the Ring B heterocycle comprises 1 heteroatom selected from O and N. In some embodiments, the Ring B heterocycle comprises 2 heteroatoms independently selected from O and N. In some embodiments, the Ring B heterocycle comprises 3 heteroatoms independently selected from O and N. In some embodiments, the Ring B heterocycle comprises 4 heteroatoms independently selected from O and N. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), the Ring B heterocycle comprises 4 N heteroatoms. In some embodiments, the Ring B heterocycle comprises 3 N heteroatoms. In some embodiments, the Ring B heterocycle comprises 3 N heteroatoms and 1 O heteroatom. In some embodiments, the Ring B heterocycle comprises 2 N heteroatoms and 1 O heteroatom. In some embodiments, the Ring B heterocycle comprises 2 N heteroatoms and 1 S heteroatom. In some embodiments, the Ring B heterocycle comprises 1 O heteroatom and 1 N heteroatom. In some embodiments, the Ring B heterocycle comprises 1 O heteroatom and 1 S heteroatom. In some embodiments, the Ring B heterocycle comprises 1 S heteroatom and 1 N heteroatom. In some embodiments, the Ring B heterocycle comprises 2 N heteroatoms. In some embodiments, the Ring B heterocycle comprises 1 heteroatom that is O. In some embodiments, the Ring B heterocycle comprises 1 heteroatom that is N. In some embodiments, the Ring B heterocycle comprises 1 heteroatom that is S. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), Ring B is C3-C10 carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, - N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, =O, -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, =O, and -CN. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), Ring B is 3- to 12-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, - N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, =O, -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, =O, and -CN. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), Ring B is selected from a C3-C10 carbocycle and a 3- to 12-membered heterocycle, each of which is optionally substituted with 1-4 substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, - N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and -CN; C1-6 alkyl optionally substituted with 1-4 substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, =O, -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with 1-4 substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, =O, and -CN. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), Ring B is selected from a C6-C10 aryl and a 3- to 12-membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, - N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, =O, and -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, =O, and -CN. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), Ring B is selected from a C6-C10 aryl and a 3- to 12-membered heteroaryl, each of which is optionally substituted with 1-4 substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, - N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and -CN; C1-6 alkyl optionally substituted with 1-4 substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, =O, and -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with 1-4 substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, =O, and -CN. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), Ring B is selected from a C6-C10 aryl and a 3- to 12-membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, - N(R12)S(O)2(R12), -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, =O, -CN, C3-6 carbocycle and 3- to 6-membered heterocycle, and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen and -OR12. In some embodiments, Ring B is selected from a C6-C10 aryl and a 3- to 12-membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)N(R12)2, - N(R12)C(O)R12, -N(R12)S(O)2(R12), -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, =O, -CN, C3-6 carbocycle and 3- to 6-membered heterocycle, and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen and -OR12; and R12 is selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and C3-6 cycloalkyl. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), Ring B is selected from a C6-C10 aryl and a 3- to 12-membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2(R12), -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, =O, -CN, C3-6 carbocycle and 3- to 6-membered heterocycle, and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen and -OR12; and R12 is selected from hydrogen, -CH3, -CH2CH2CH3, -CH2CH(CH3)2, -CH2CF3, and cyclopropyl. In some embodiments, Ring B is selected from a C6-C10 aryl and a 3- to 12-membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2(R12), -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, =O, -CN, C3-6 carbocycle and 3- to 6-membered heterocycle, and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen and -OR12. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), Ring B is selected from a C6-C10 aryl and a 3- to 12-membered heteroaryl, each of which is optionally substituted with 1-4 substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2(R12), -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, =O, -CN, C3-6 carbocycle and 3- to 6-membered heterocycle, and C1-6 alkyl optionally substituted with 1-4 substituents independently selected from halogen and -OR12. In some embodiments, Ring B is selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, benzthiazolyl, benzimidazolyl, and benzfurazanyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2(R12), -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, =O, -CN, C3-6 carbocycle and 3- to 6-membered heterocycle, and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen and - OR12. In some embodiments, Ring B is not pyrazolyl. In some embodiments, Ring B is selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, benzthiazolyl, benzimidazolyl, and benzfurazanyl, each of which is optionally substituted with 1-4 substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2(R12), -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, =O, -CN, C3-6 carbocycle and 3- to 6-membered heterocycle, and C1-6 alkyl optionally substituted with 1-4 substituents independently selected from halogen and -OR12. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), Ring B is selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, indolyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, 2,1,3- benzoxadiazolyl benzfurazanyl, thiazolo[4,5-b]pyridinyl, pyrrolo[2,3-b]pyridinyl, imidazo[1,5- a]pyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, and quinoxalinyl, each of which is optionally substituted with one or more substituents independently selected from: -F, -Cl, -CN, -OH, -NH2, =O, -CH3, -OCH3, -CF3, -CHF2, , , , , , , , , , , , , , , , , and . In some embodiments, Ring B is selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, benzthiazolyl, benzimidazolyl, and benzfurazanyl, each of which is optionally substituted with one or more substituents independently selected from: -F, -Cl, -CN, -OH, -NH2, =O, -CH3, -OCH3, -CF3, -CHF2, , , , , , , , , , , , , and . In some embodiments, Ring B is selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, benzthiazolyl, benzimidazolyl, and benzfurazanyl, each of which is optionally substituted with 1- 4 substituents independently selected from: -F, -Cl, -CN, -OH, -NH2, =O, -CH3, -OCH3, -CF3, - CHF2, , , , , , , , , , , , , and . In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), Ring B is phenyl optionally substituted with 1- 4 substituents independently selected from: -F, -Cl, -CN, -OH, -NH2, =O, -CH3, -OCH3, -CF3, -CHF2, , , , , , , , , , , , , and . In some embodiments, Ring B is pyridinyl optionally substituted with 1-4 substituents independently selected from: -F, -Cl, -CN, -OH, -NH2, =O, -CH3, -OCH3, -CF3, -CHF2, , , , , , , , , , , , , and . In some embodiments, Ring B is pyridazinyl optionally substituted with 1-4 substituents independently selected from: -F, -Cl, -CN, -OH, -NH2, =O, -CH3, -OCH3, -CF3, -CHF2, , , , , , , , , , , , , and . In some embodiments, Ring B is pyrimidinyl optionally substituted with 1-4 substituents independently selected from: -F, -Cl, -CN, -OH, -NH2, =O, -CH3, -OCH3, -CF3, -CHF2, , , , , , , , , , , , , and . In some embodiments, Ring B is benzthiazolyl optionally substituted with 1-4 substituents independently selected from: -F, -Cl, -CN, -OH, -NH2, =O, -CH3, -OCH3, -CF3, -CHF2, , , , , , , , , , , , , and . In some embodiments, Ring B is benzimidazolyl optionally substituted with 1-4 substituents independently selected from: -F, -Cl, -CN, -OH, -NH2, =O, -CH3, -OCH3, -CF3, - CHF2, , , , , , , , , , , , , and . In some embodiments, Ring B is benzfurazanyl optionally substituted with 1-4 substituents independently selected from: -F, -Cl, -CN, -OH, -NH2, =O, -CH3, -OCH3, -CF3, -CHF2, , , , , , , , , , , , , and . In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), Ring B is selected from: , , , , , , , , , , , , , , , , , , , , , , , O S O , , , , , , , , , , , , , , , , , , , , , , , , F N , , , , , , , , , , , , , , , , , , , , , , and . In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is O S O . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, F Ring B is . In some embodiments, Ring B is N . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), Ring B is selected from (a), (b) and (c): (a) , wherein X1 is selected from N, CH, and CR5; (b) , wherein X2 is selected from S and NR7; and (c) , wherein X3 is selected from S, N, and NH, X4 is selected from O and CR9, X5 is N or CH, X6 is N or CH, each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system; and each occurrence of R5, R6, and R8 are halogen, C1- 6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, - N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and –CN. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), q is 0, 1, or 2. In some embodiments, q is 0 or 1. In some embodiments, q is 1 or 2. In some embodiments, q is 0. In some embodiments, p is 1. In some embodiments, q is 2. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), r is 0, 1, or 2. In some embodiments, r is 0 or 1. In some embodiments, r is 1 or 2. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), X1 is N. In some embodiments, X1 is CH. In some embodiments, X1 is CH. In some embodiments, X2 is S. In some embodiments, X2 is NR7. In some embodiments, X2 is NH. In some embodiments, X3 is S. In some embodiments, X3 is N. In some embodiments, X3 is NH. In some embodiments, X4 is O. In some embodiments, X4 is CR9. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), X3 is S and X4 is O. In some embodiments, X3 is S and X4 is CR9. In some embodiments, X3 is N and X4 is O. In some embodiments, X3 is N and X4 is CR9. In some embodiments, X3 is NH and X4 is O. In some embodiments, X3 is NH and X4 is CR9. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), R9 is hydrogen. In some embodiments, R9 is C1- 4 alkyl. In some embodiments, R9 is methyl. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- X1 N 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), Ring B is RB . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), RB is selected from halogen, C1-6 alkyl, C1- 6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, - N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and -CN. In some embodiments, RB is selected from halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2(R12), -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, =O, and -CN. In some embodiments, RB is selected from halogen, C1-6 alkyl, C1-6 haloalkyl, and -OR12. In some embodiments, RB is selected from halogen, methyl, C1-6 haloalkyl, and -OR12. In some embodiments, RB is halogen. In some embodiments, RB is C1-4 alkyl. In some embodiments, RB is methyl. In some embodiments, RB is C1-4 haloalkyl. In some embodiments, RB is -OR12. In some embodiments, RB is -SR12. In some embodiments, RB is -N(R12)2. In some embodiments, RB is -C(O)R12. In some embodiments, RB is -C(O)OR12. In some embodiments, RB is -OC(O)R12. In some embodiments, RB is -C(O)N(R12)2. In some embodiments, RB is -N(R12)C(O)R12. In some embodiments, RB is -N(R12)S(O)2(R12). In some embodiments, RB is -S(O)2R12. In some embodiments, RB is -S(O)2N(R12)2. In some embodiments, RB is -NO2. In some embodiments, RB is -CN. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), Ring B is , wherein X1 is selected from N, CH, and CR5. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), Ring B is , and X2 is selected from S and NR7. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), Ring B is , and X3 is selected from S, N, and NH, X4 is selected from O and CR9, X5 is N or CH, X6 is N or CH, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), R7 and R9 are each independently selected from hydrogen, and C1-4 alkyl. In some embodiments, R7 is hydrogen. In some embodiments, R7 is C1-4 alkyl. In some embodiments, R7 is C1-4 haloalkyl. In some embodiments, R9 is hydrogen. In some embodiments, R9 is C1-4 alkyl. In some embodiments, R9 is C1-4 haloalkyl. In some embodiments,, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), R6 and R8 are each independently selected at each occurrence from halogen and C1-4 alkyl. In some embodiments,, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), R5 is independently selected at each occurrence from halogen and C1-4 alkyl. In some embodiments, R5 is halogen. In some embodiments, R5 is C1- 4 alkyl. In some embodiments, R5 is C1-4 haloalkyl. In some embodiments, R5 is -OR12. In some embodiments, R5 is -SR12. In some embodiments, R5 is -N(R12)2. In some embodiments, R5 is -C(O)R12. In some embodiments, R5 is -C(O)OR12. In some embodiments, R5 is -OC(O)R12. In some embodiments, R5 is -C(O)N(R12)2. In some embodiments, R5 is -N(R12)C(O)R12. In some embodiments, R5 is -N(R12)S(O)2(R12). In some embodiments, R5 is -S(O)2R12. In some embodiments, R5 is -S(O)2N(R12)2. In some embodiments, R5 is -NO2. In some embodiments, R5 is -CN. In some embodiments,, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), R6 is halogen. In some embodiments, R6 is C1-4 alkyl. In some embodiments, R6 is C1-4 haloalkyl. In some embodiments, R6 is -OR12. In some embodiments, R6 is -SR12. In some embodiments, R6 is -N(R12)2. In some embodiments, R6 is -C(O)R12. In some embodiments, R6 is -C(O)OR12. In some embodiments, R6 is -OC(O)R12. In some embodiments, R6 is -C(O)N(R12)2. In some embodiments, R6 is -N(R12)C(O)R12. In some embodiments, R6 is -N(R12)S(O)2(R12). In some embodiments, R6 is -S(O)2R12. In some embodiments, R6 is -S(O)2N(R12)2. In some embodiments, R6 is -NO2. In some embodiments, R6 is -CN. In some embodiments,, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), R8 is halogen. In some embodiments, R8 is C1-4 alkyl. In some embodiments, R8 is C1-4 haloalkyl. In some embodiments, R8 is -OR12. In some embodiments, R8 is -SR12. In some embodiments, R8 is -N(R12)2. In some embodiments, R8 is - C(O)R12. In some embodiments, R8 is -C(O)OR12. In some embodiments, R8 is -OC(O)R12. In some embodiments, R8 is -C(O)N(R12)2. In some embodiments, R8 is -N(R12)C(O)R12. In some embodiments, R8 is -N(R12)S(O)2(R12). In some embodiments, R8 is -S(O)2R12. In some embodiments, R8 is -S(O)2N(R12)2. In some embodiments, R8 is -NO2. In some embodiments, R8 is -CN. In some embodiments,, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), R10 is hydrogen. In some embodiments, R10 is C1-6 alkyl. In some embodiments, R10 is C1-4 haloalkyl. In some embodiments, R10 is cycloalkyl optionally substituted with one or more halogen. In some embodiments, R10 is hydrogen. In some embodiments, R10 is C1-6 alkyl. In some embodiments, R10 is C1-4 haloalkyl. In some embodiments, R10 is cycloalkyl optionally substituted with 1-4 halogen. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), R11 is independently selected at each occurrence from hydrogen and C1-4 alkyl. In some embodiments, R11 is hydrogen. In some embodiments, R11 is C1-6 alkyl. In some embodiments, R11 is C1-4 haloalkyl. In some embodiments, R11 is cycloalkyl optionally substituted with one or more halogen. In some embodiments, R11 is independently selected at each occurrence from hydrogen, and C1-4 alkyl. In some embodiments, R11 is hydrogen. In some embodiments, R11 is C1-6 alkyl. In some embodiments, R11 is C1-4 haloalkyl. In some embodiments, R11 is cycloalkyl optionally substituted with 1-4 halogen. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), R12 is hydrogen. In some embodiments, R12 is C1-6 alkyl. In some embodiments, R12 is C1-4 haloalkyl. In some embodiments, R12 is cycloalkyl optionally substituted with one or more halogen. In some embodiments, R12 is -CH3. In some embodiments, R12 is CH2CF3. In some embodiments, R12 is cyclopropyl. In some embodiments, R12 is independently selected at each occurrence from hydrogen, -CH3, -CH2CH2CH3, -CH2CH(CH3)2, -CH2CF3, and cyclopropyl. In some embodiments, R12 is hydrogen. In some embodiments, R12 is C1-6 alkyl. In some embodiments, R12 is C1-4 haloalkyl. In some embodiments, R12 is cycloalkyl optionally substituted with 1-4 halogen. In some embodiments, R12 is -CH3. In some embodiments, R12 is CH2CF3. In some embodiments, R12 is cyclopropyl. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), R13 is selected from C1-4 alkyl and cyclopropyl optionally substituted with one or more -F. In some embodiments, R13 is hydrogen. In some embodiments, R13 is C1-6 alkyl. In some embodiments, R13 is C1-4 haloalkyl. In some embodiments, R13 is cycloalkyl optionally substituted with one or more halogen. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIB), (VIB-1), (VIB-2), (VIC), (VIC-1), (VIC-2), (VIC- 3), (VID-1), (VID-2), (VIE-1), (VIE-2), or (VIF), R14 is hydrogen. In some embodiments, R14 is C1-6 alkyl. In some embodiments, R14 is C1-4 haloalkyl. In some embodiments, R14 is cycloalkyl optionally substituted with one or more halogen. In some embodiments, the compound is of Formula (VIA-4): (VIA-4), or a pharmaceutically acceptable salt thereof; wherein X1 is selected from N, CH, and CR5. In some embodiments, X1 is N. In some embodiments, X1 is CH. In some embodiments, the compound is of Formula (VIA-5): (VIA-5), or a pharmaceutically acceptable salt thereof; wherein X1 is selected from N, CH, and CR5. In some embodiments, the compound is of Formula (VIA-6): (VIA-6), or a pharmaceutically acceptable salt thereof; wherein X1 is selected from N, CH, and CR5. In some embodiments, X1 is N. In some embodiments, X1 is CH. In some embodiments, the compound is of Formula (VIA-7): (VIA-7), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (VIB-3): (VIB-3), or a pharmaceutically acceptable salt thereof; wherein X1 is selected from N, CH, and CR5. In some embodiments, X1 is N. In some embodiments, X1 is CH. In some embodiments, the compound is of Formula (VIC-4): (VIC-4), or a pharmaceutically acceptable salt thereof; wherein X1 is selected from N, CH, and CR5. In some embodiments, X1 is N. In some embodiments, X1 is CH. In some embodiments, the compound is of Formula (VID-3): (VID-3); or a pharmaceutically acceptable salt thereof; wherein X1 is selected from N, CH, and CR5. In some embodiments, X1 is N. In some embodiments, X1 is CH. In some embodiments, the compound is of Formula (VID-4): (VID-4); or a pharmaceutically acceptable salt thereof; wherein X1 is selected from N, CH, and CR5. In some embodiments, X1 is N. In some embodiments, X1 is CH. In some embodiments, for the compound of Formulae (VIA-4), (VIA-5), (VIA-6), (VIA- 7), (VIB-3), (VIC-4), (VID-3), or (VID-4), R5 is independently selected at each occurrence from halogen and C1-4 alkyl. In some embodiments, R5 is halogen. In some embodiments, R5 is C1-4 alkyl. In some embodiments, R5 is C1-4 haloalkyl. In some embodiments, R5 is -OR12. In some embodiments, R5 is -SR12. In some embodiments, R5 is -N(R12)2. In some embodiments, R5 is - C(O)R12. In some embodiments, R5 is -C(O)OR12. In some embodiments, R5 is -OC(O)R12. In some embodiments, R5 is -C(O)N(R12)2. In some embodiments, R5 is -N(R12)C(O)R12. In some embodiments, R5 is -N(R12)S(O)2(R12). In some embodiments, R5 is -S(O)2R12. In some embodiments, R5 is -S(O)2N(R12)2. In some embodiments, R5 is -NO2. In some embodiments, R5 is -CN. In some embodiments, for the compound of Formulae (VIA-4), (VIA-5), (VIA-6), (VIA- 7), (VIB-3), (VIC-4), (VID-3), or (VID-4), p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, the compound is of Formula (VIC-5): (VIC-5), or a pharmaceutically acceptable salt thereof; wherein X1 is selected from N, CH, and CR5. In some embodiments, X1 is N. In some embodiments, X1 is CH. In some embodiments, the compound is of Formula (VIA-8): (VIA-8), or a pharmaceutically acceptable salt thereof. In some embodiments, for the compound of Formulae (VIA-4), (VIA-5), (VIA-6), (VIA- 7), (VIA-8), (VIB-3), (VIC-4), (VIC-5), (VID-3), or (VID-4), RB is selected from halogen, C1- 6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, - N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and -CN. In some embodiments, RB is selected from halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2(R12), -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, =O, and -CN. In some embodiments, RB is selected from halogen, C1-6 alkyl, C1-6 haloalkyl, and - OR12. In some embodiments, RB is selected from halogen, methyl, C1-6 haloalkyl, and -OR12. In some embodiments, RB is halogen. In some embodiments, RB is C1-4 alkyl. In some embodiments, RB is methyl. In some embodiments, RB is C1-4 haloalkyl. In some embodiments, RB is -OR12. In some embodiments, RB is -SR12. In some embodiments, RB is -N(R12)2. In some embodiments, RB is -C(O)R12. In some embodiments, RB is -C(O)OR12. In some embodiments, RB is -OC(O)R12. In some embodiments, RB is -C(O)N(R12)2. In some embodiments, RB is -N(R12)C(O)R12. In some embodiments, RB is -N(R12)S(O)2(R12). In some embodiments, RB is -S(O)2R12. In some embodiments, RB is -S(O)2N(R12)2. In some embodiments, RB is -NO2. In some embodiments, RB is -CN. In some embodiments, the compound is of Formula (VIC-6): (VIC-6), or a pharmaceutically acceptable salt thereof; wherein X1 is selected from N, CH, and CR5. In some embodiments, X1 is N. In some embodiments, X1 is CH. In some embodiments, the compound is of Formula (VIC-7): (VIC-7), or a pharmaceutically acceptable salt thereof; wherein X1 is selected from N, CH, and CR5. In some embodiments, X1 is N. In some embodiments, X1 is CH. In some embodiments, the compound is of Formula (VID-5): (VID-5); or a pharmaceutically acceptable salt thereof; wherein X1 is selected from N, CH, and CR5. In some embodiments, X1 is N. In some embodiments, X1 is CH. In some embodiments, the compound is of Formula (VID-6): (VID-6); or a pharmaceutically acceptable salt thereof; wherein X1 is selected from N, CH, and CR5. In some embodiments, X1 is N. In some embodiments, X1 is CH. In some embodiments, the compound is of Formula (VIE-3): (VIE-3); or a pharmaceutically acceptable salt thereof; wherein X1 is selected from N, CH, and CR5. In some embodiments, X1 is N. In some embodiments, X1 is CH. In some embodiments, the compound is of Formula (VIE-4): (VIE-4); or a pharmaceutically acceptable salt thereof; wherein X1 is selected from N, CH, and CR5. In some embodiments, X1 is N. In some embodiments, X1 is CH. In some embodiments, the compound is of Formula (VIE-5): (VIE-5); or a pharmaceutically acceptable salt thereof; wherein X1 is selected from N, CH, and CR5. In some embodiments, X1 is N. In some embodiments, X1 is CH. In some embodiments, the compound is of Formula (VIE-6): (VIE-6); or a pharmaceutically acceptable salt thereof; wherein X1 is selected from N, CH, and CR5. In some embodiments, X1 is N. In some embodiments, X1 is CH. In some embodiments, the compound is of Formula (VIF-1): (V1F-1); or a pharmaceutically acceptable salt thereof; wherein X1 is selected from N, CH, and CR5. In some embodiments, X1 is N. In some embodiments, X1 is CH. In some embodiments, the compound is of Formula (VIF-2): (VIF-2), or a pharmaceutically acceptable salt thereof; wherein X1 is selected from N, CH, and CR5. In some embodiments, X1 is N. In some embodiments, X1 is CH. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC- 7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), (VIE-5), (VIE-6), (VIF), (VIF-1), or (VIF-2), the Ring A saturated heterocycloalkyl comprises 1- 4 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A saturated heterocycloalkyl comprises 1-3 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A saturated heterocycloalkyl comprises 1-2 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A saturated heterocycloalkyl comprises 2-3 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A saturated heterocycloalkyl comprises 1 heteroatom selected from O, N, and S. In some embodiments, the Ring A saturated heterocycloalkyl comprises 2 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A saturated heterocycloalkyl comprises 3 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A saturated heterocycloalkyl comprises 4 heteroatoms independently selected from O, N, and S. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC- 7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), (VIE-5), (VIE-6), (VIF), (VIF-1), or (VIF-2), the Ring A saturated heterocycloalkyl comprises 1- 4 heteroatoms independently selected from O and N. In some embodiments, the Ring A saturated heterocycloalkyl comprises 1-3 heteroatoms independently selected from O and N. In some embodiments, the Ring A saturated heterocycloalkyl comprises 1-2 heteroatoms independently selected from O and N. In some embodiments, the Ring A saturated heterocycloalkyl comprises 2-3 heteroatoms independently selected from O and N. In some embodiments, the Ring A saturated heterocycloalkyl comprises 1 heteroatom selected from O and N. In some embodiments, the Ring A saturated heterocycloalkyl comprises 2 heteroatoms independently selected from O and N. In some embodiments, the Ring A saturated heterocycloalkyl comprises 3 heteroatoms independently selected from O and N. In some embodiments, the Ring A saturated heterocycloalkyl comprises 4 heteroatoms independently selected from O and N. In some embodiments, t for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC- 7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), (VIE-5), (VIE-6), (VIF), (VIF-1), or (VIF-2), he Ring A saturated heterocycloalkyl comprises 4 N heteroatoms. In some embodiments, the Ring A saturated heterocycloalkyl comprises 3 N heteroatoms. In some embodiments, the Ring A saturated heterocycloalkyl comprises 3 N heteroatoms and 1 O heteroatom. In some embodiments, the Ring A saturated heterocycloalkyl comprises 2 N heteroatoms and 1 O heteroatom. In some embodiments, the Ring A saturated heterocycloalkyl comprises 2 N heteroatoms and 1 S heteroatom. In some embodiments, the Ring A saturated heterocycloalkyl comprises 1 O heteroatom and 1 N heteroatom. In some embodiments, the Ring A saturated heterocycloalkyl comprises 1 O heteroatom and 1 S heteroatom. In some embodiments, the Ring A saturated heterocycloalkyl comprises 1 S heteroatom and 1 N heteroatom. In some embodiments, the Ring A saturated heterocycloalkyl comprises 2 N heteroatoms. In some embodiments, the Ring A saturated heterocycloalkyl comprises 1 heteroatom that is O. In some embodiments, the Ring A saturated heterocycloalkyl comprises 1 heteroatom that is N. In some embodiments, the Ring A saturated heterocycloalkyl comprises 1 heteroatom that is S. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC- 7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), (VIE-5), (VIE-6), (VIF), (VIF-1), or (VIF-2), the Ring A partially saturated heterocycle comprises 1-4 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A partially saturated heterocycle comprises 1-3 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A partially saturated heterocycle comprises 1-2 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A partially saturated heterocycle comprises 2-3 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A partially saturated heterocycle comprises 1 heteroatom selected from O, N, and S. In some embodiments, the Ring A partially saturated heterocycle comprises 2 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A partially saturated heterocycle comprises 3 heteroatoms independently selected from O, N, and S. In some embodiments, the Ring A partially saturated heterocycle comprises 4 heteroatoms independently selected from O, N, and S. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC- 7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), (VIE-5), (VIE-6), (VIF), (VIF-1), or (VIF-2), the Ring A partially saturated heterocycle comprises 1-4 heteroatoms independently selected from O and N. In some embodiments, the Ring A partially saturated heterocycle comprises 1-3 heteroatoms independently selected from O and N. In some embodiments, the Ring A partially saturated heterocycle comprises 1-2 heteroatoms independently selected from O and N. In some embodiments, the Ring A partially saturated heterocycle comprises 2-3 heteroatoms independently selected from O and N. In some embodiments, the Ring A partially saturated heterocycle comprises 1 heteroatom selected from O and N. In some embodiments, the Ring A partially saturated heterocycle comprises 2 heteroatoms independently selected from O and N. In some embodiments, the Ring A partially saturated heterocycle comprises 3 heteroatoms independently selected from O and N. In some embodiments, the Ring A partially saturated heterocycle comprises 4 heteroatoms independently selected from O and N. In some embodiments, t for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC- 7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), (VIE-5), (VIE-6), (VIF), (VIF-1), or (VIF-2), he Ring A partially saturated heterocycle comprises 4 N heteroatoms. In some embodiments, the Ring A partially saturated heterocycle comprises 3 N heteroatoms. In some embodiments, the Ring A partially saturated heterocycle comprises 3 N heteroatoms and 1 O heteroatom. In some embodiments, the Ring A partially saturated heterocycle comprises 2 N heteroatoms and 1 O heteroatom. In some embodiments, the Ring A partially saturated heterocycle comprises 2 N heteroatoms and 1 S heteroatom. In some embodiments, the Ring A partially saturated heterocycle comprises 1 O heteroatom and 1 N heteroatom. In some embodiments, the Ring A partially saturated heterocycle comprises 1 O heteroatom and 1 S heteroatom. In some embodiments, the Ring A partially saturated heterocycle comprises 1 S heteroatom and 1 N heteroatom. In some embodiments, the Ring A partially saturated heterocycle comprises 2 N heteroatoms. In some embodiments, the Ring A partially saturated heterocycle comprises 1 heteroatom that is O. In some embodiments, the Ring A partially saturated heterocycle comprises 1 heteroatom that is N. In some embodiments, the Ring A partially saturated heterocycle comprises 1 heteroatom that is S. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC- 7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), (VIE-5), (VIE-6), (VIF), (VIF-1), or (VIF-2), Ring A is selected from C3-C10 saturated cycloalkyl, and 3- to 10-membered saturated heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -C(O)N(R11)2, -N(R11)C(O)R11, -NO2, and =O; C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, and =O, -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, C1- 6 alkyl, C1-6 haloalkyl, =O, and -CN. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC- 7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), (VIE-5), (VIE-6), (VIF), (VIF-1), or (VIF-2), Ring A is selected from C3-C10 saturated cycloalkyl, and 3- to 10-membered saturated heterocycloalkyl, each of which is optionally substituted with 1- 4 substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -C(O)N(R11)2, -N(R11)C(O)R11, -NO2, and =O; C1-6 alkyl optionally substituted with 1-4 substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, and =O, -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with 1-4 substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, C1-6 alkyl, C1- 6 haloalkyl, =O, and -CN. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC- 7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), (VIE-5), (VIE-6), (VIF), (VIF-1), or (VIF-2), Ring A is C3-C10 saturated cycloalkyl optionally substituted with 1-4 substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -C(O)N(R11)2, -N(R11)C(O)R11, -NO2, and =O; C1-6 alkyl optionally substituted with 1-4 substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, and =O, -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with 1-4 substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, C1-6 alkyl, C1- 6 haloalkyl, =O, and -CN. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC- 7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), (VIE-5), (VIE-6), (VIF), (VIF-1), or (VIF-2), Ring A is 3- to 10-membered saturated heterocycloalkyl optionally substituted with 1-4 substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -C(O)N(R11)2, -N(R11)C(O)R11, -NO2, and =O; C1-6 alkyl optionally substituted with 1-4 substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, and =O, -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with 1-4 substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, C1-6 alkyl, C1- 6 haloalkyl, =O, and -CN. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC- 7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), (VIE-5), (VIE-6), (VIF), (VIF-1), or (VIF-2), Ring A is selected from C3-C6 saturated cycloalkyl, and 3- to 6-membered saturated heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -C(O)OR11, C1-6 alkyl, C1-6 haloalkyl, and 3- to 6-membered heterocycloalkyl, optionally substituted with one or more C1-6 alkyl. In some embodiments, Ring A is selected from C3-C6 saturated cycloalkyl, and 3- to 6-membered saturated heterocycloalkyl, each of which is optionally substituted with 1-4 substituents independently selected from halogen, -C(O)OR11, C1-6 alkyl, C1-6 haloalkyl, and 3- to 6-membered heterocycloalkyl, optionally substituted with 1-4 C1-6 alkyl. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC- 7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), (VIE-5), (VIE-6), (VIF), (VIF-1), or (VIF-2), Ring A is selected from: cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and tetrahydrofuranyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -C(O)OR11, C1-6 alkyl, C1-6 haloalkyl, and 3- to 6-membered heterocycloalkyl, optionally substituted with one or more C1-6 alkyl; provided that when Ring B is pyrazolyl, then Ring A is not N-Boc pyrrolidinyl. In some embodiments, Ring A is selected from: cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and tetrahydrofuranyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -C(O)OR11, C1-6 alkyl, C1-6 haloalkyl, and 3- to 6-membered heterocycloalkyl, optionally substituted with one or more C1-6 alkyl; provided that when Ring B is pyrazolyl, then Ring A is not N-Boc pyrrolidinyl; and R11 is independently selected at each occurrence from hydrogen, and C1-4 alkyl. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC- 7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), (VIE-5), (VIE-6), (VIF), (VIF-1), or (VIF-2), Ring A is selected from: cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and tetrahydrofuranyl, each of which is optionally substituted with one or more substituents independently selected from halogen, - C(O)OR11, C1-6 alkyl, C1-6 haloalkyl, and 3- to 6-membered heterocycloalkyl, optionally substituted with one or more C1-6 alkyl. In some embodiments, Ring A is selected from: cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and tetrahydrofuranyl, each of which is optionally substituted with 1-4 substituents independently selected from halogen, -C(O)OR11, C1-6 alkyl, C1-6 haloalkyl, and 3- to 6-membered heterocycloalkyl, optionally substituted with 1-4 C1-6 alkyl; provided that when Ring B is pyrazolyl, then Ring A is not N-Boc pyrrolidinyl. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC- 7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), (VIE-5), (VIE-6), (VIF), (VIF-1), or (VIF-2), Ring A is selected from: cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and tetrahydrofuranyl, each of which is optionally substituted with one or more substituents independently selected from -F, -CH3, O O , O , O , , and ; provided that when Ring B is pyrazolyl, then Ring A is not N-Boc pyrrolidinyl. In some embodiments, Ring A is selected from: cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and tetrahydrofuranyl, each of which is optionally substituted with 1-4 substituents independently selected from -F, -CH3, O O , O , O , , and ; provided that when Ring B is pyrazolyl, then Ring A is not N-Boc pyrrolidinyl. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC- 7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), (VIE-5), (VIE-6), (VIF), (VIF-1), or (VIF-2), wherein Ring A is selected from: cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and tetrahydrofuranyl, each of which is optionally substituted with one or more substituents independently selected from -F, -CH3, , , , , and ; provided that when Ring B is pyrazolyl, then Ring A is not N-Boc pyrrolidinyl. In some embodiments, wherein Ring A is selected from: cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and tetrahydrofuranyl, each of which is optionally substituted with 1-4 substituents independently selected from -F, -CH3, , , , , and ; provided that when Ring B is pyrazolyl, then Ring A is not N-Boc pyrrolidinyl; RA is selected from -F, -CN, -CH3, -CHF2, -CF3, -CH2OCH3, -OCH3, and . In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC- 7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), (VIE-5), (VIE-6), (VIF), (VIF-1), or (VIF-2), wherein Ring A is selected from: cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and tetrahydrofuranyl, each of which is optionally substituted with one or more substituents independently selected from -F, - CH3, , , , , and ; provided that when Ring B is pyrazolyl, then Ring A is not N-Boc pyrrolidinyl. In some embodiments, wherein Ring A is selected from: cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and tetrahydrofuranyl, each of which is optionally substituted with 1-4 substituents independently selected from -F, -CH3, , , , , and ; provided that when Ring B is pyrazolyl, then Ring A is not N-Boc pyrrolidinyl; RA is selected from -F, -CN, -CH3, -CHF2, -CF3, -CH2OCH3, -OCH3, and . In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC- 7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), (VIE-5), (VIE-6), (VIF), (VIF-1), or (VIF-2), RA is selected from halogen, -CN, C1-6 alkyl, C1- 6 haloalkyl, and C3-C6 saturated cycloalkyl. In some embodiments, RA is halogen. In some embodiments, RA is fluoro. In some embodiments, RA is -OR10. In some embodiments, RA is -SR10. In some embodiments, RA is -N(R10)2. In some embodiments, RA is -CN. In some embodiments, RA is C1-6 alkyl. In some embodiments, RA is C1-6 haloalkyl. In some embodiments, RA is C3-C6 saturated cycloalkyl. In some embodiments, RA is 3- to 6-membered saturated heterocycloalkyl.In some embodiments, RA is selected from -F, -CN, -CH3, -CHF2, -CF3, -CH2OCH3, -OCH3, and . In some embodiments, RA is selected from -F, CN, -CH3, -CHF2, -CF3, and . In some embodiments, RA is selected from -F. In some embodiments, RA is CN. In some embodiments, RA is -CH3. In some embodiments, RA is -CHF2. In some embodiments, RA is -CF3. In some embodiments, RA is . In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC- 7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), (VIE-5), (VIE-6), (VIF), (VIF-1), or (VIF-2), is selected from: O O F , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC- 7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), (VIE-5), (VIE-6), (VIF), (VIF-1), or (VIF-2), is selected from: O O F , , , , , , , , , , , , , , , , , , , , , , , , , , , and . In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC- 7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), (VIE-5), (VIE-6), (VIF), (VIF-1), or (VIF-2), is selected from: O O F , , , , , , , , , , , , , , , , , , , , , , , , , , and . In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC- 7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), O F (VIE-5), (VIE-6), (VIF), (VIF-1), or (VIF-2), is . In some embodiments, is . In some embodiments, is . In some O embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, F N is . In some embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, is . In some F embodiments, is and . In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC- 7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), (VIE-5), (VIE-6), (VIF), (VIF-1), or (VIF-2), R10, R11, R12, R13, and R14 are each independently selected at each occurrence from hydrogen and C1-6 alkyl. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC- 7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), (VIE-5), (VIE-6), (VIF), (VIF-1), or (VIF-2), Ring A is unsubstituted tetrahydropyranyl. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with 1-4 C1-6 alkyl. In some embodiments, Ring A is tetrahydropyranyl substituted with 1-4 C1-6 alkyl. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with 1-4 methyl. In some embodiments, Ring A is tetrahydropyranyl substituted with 1-4 methyl. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with one C1-6 alkyl. In some embodiments, Ring A is tetrahydropyranyl substituted with one C1-6 alkyl. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with one methyl. In some embodiments, Ring A is tetrahydropyranyl substituted with one methyl. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with four C1-6 alkyl. In some embodiments, Ring A is tetrahydropyranyl substituted with four C1-6 alkyl. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with four methyl. In some embodiments, Ring A is tetrahydropyranyl substituted with four methyl In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC- 7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), (VIE-5), (VIE-6), (VIF), (VIF-1), or (VIF-2), Ring A is unsubstituted tetrahydrofuranyl. In some embodiments, Ring A is tetrahydrofuranyl optionally substituted with 1-4 C1-6 alkyl. In some embodiments, Ring A is tetrahydrofuranyl substituted with 1-4 C1-6 alkyl. In some embodiments, Ring A is tetrahydrofuranyl optionally substituted with 1-4 methyl. In some embodiments, Ring A is tetrahydrofuranyl substituted with 1-4 methyl. In some embodiments, Ring A is tetrahydrofuranyl optionally substituted with one C1-6 alkyl. In some embodiments, Ring A is tetrahydrofuranyl substituted with one C1-6 alkyl. In some embodiments, Ring A is tetrahydrofuranyl optionally substituted with one methyl. In some embodiments, Ring A is tetrahydrofuranyl substituted with one methyl. In some embodiments, Ring A is tetrahydrofuranyl optionally substituted with four C1-6 alkyl. In some embodiments, Ring A is tetrahydrofuranyl substituted with four C1-6 alkyl. In some embodiments, Ring A is tetrahydrofuranyl optionally substituted with four methyl. In some embodiments, Ring A is tetrahydrofuranyl substituted with four methyl. In some embodiments, Ring A is not N-Boc pyrrolidinyl. In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC- 7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), (VIE-5), (VIE-6), (VIF), (VIF-1), or (VIF-2), Ring A is tetrahydropyranyl optionally substituted with 1-4 halogen. In some embodiments, Ring A is tetrahydropyranyl substituted with 1-4 halogen. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with 1-4 fluorine. In some embodiments, Ring A is tetrahydropyranyl substituted with 1-4 fluorine. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with one halogen. In some embodiments, Ring A is tetrahydropyranyl substituted with one halogen. In some embodiments, Ring A is tetrahydropyranyl optionally substituted with one fluorine. In some embodiments, Ring A is tetrahydropyranyl substituted with one fluorine. In some embodiments, the compound is of Formula (VIA-9): (VIA-9), or a pharmaceutically acceptable salt thereof; wherein R5 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR11; and R16 is selected from halogen, -OR11, and C1-6 alkyl optionally substituted with 1-4 halogen; and Q is O, NH, or S. In some embodiments, the compound is of Formula (VIA-10): (VIA-10), or a pharmaceutically acceptable salt thereof; wherein R5 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR11; and R16 is selected from halogen, -OR11, and C1-6 alkyl optionally substituted with 1-4 halogen; and Q is O, NH, or S. In some embodiments, the compound is of Formula (VIA-11): (VIA-11), or a pharmaceutically acceptable salt thereof; wherein R5 is selected from hydrogen C1 6 alkyl C1 6 haloalkyl and -C(O)OR11; and R16 is selected from halogen, -OR11, and C1-6 alkyl optionally substituted with 1-4 halogen; and Q is O, NH, or S. In some embodiments, the compound is of Formula (VIA-12): (VIA-12), or a pharmaceutically acceptable salt thereof; wherein R5 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR11; and R16 is selected from halogen, -OR11, and C1-6 alkyl optionally substituted with 1-4 halogen; and Q is O, NH, or S. In some embodiments, for the compound of Formulae (VIA-9), (VIA-10), ), (VIA-11), or (VIA-12), R5 is independently selected at each occurrence from halogen and C1-4 alkyl. In some embodiments, R5 is halogen. In some embodiments, R5 is C1-4 alkyl. In some embodiments, R5 is C1-4 haloalkyl. In some embodiments, R5 is -CN. In some embodiments, for the compound of Formulae (VIA-9), (VIA-10), ), (VIA-11), or (VIA-12), p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, the compound is of Formula (VIA-13): (VIA-13), or a pharmaceutically acceptable salt thereof; wherein R5 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR11; and R16 is selected from halogen, -OR11, and C1-6 alkyl optionally substituted with 1-4 halogen; and Q is O, NH, or S. In some embodiments, for the compound of Formulae (VIA-9), (VIA-10), ), (VIA-11), (VIA-12), ir (VIA-13), RB is selected from halogen, C1-6 alkyl, C1-6 haloalkyl, and -CN. In some embodiments, RB is selected from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, RB is selected from halogen, methyl, and halomethyl. In some embodiments, RB is halogen. In some embodiments, RB is C1-4 alkyl. In some embodiments, RB is methyl. In some embodiments, RB is C1-4 haloalkyl. In some embodiments, RB is -CN. In some embodiments, for the compound of Formulae (VIA-9), (VIA-10), ), (VIA-11), (VIA-12), ir (VIA-13), each R16 is independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, and -C(O)OR11; and R11 is selected from hydrogen and C1-4 alkyl. In some embodiments, each R16 is independently is selected from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, each R16 is independently is selected from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, each R16 is independently is selected from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, each R16 is independently is selected from hydrogen and C1-6 alkyl. In some embodiments, each R16 is independently is selected from -F, C1-4 alkyl, and C1-4 fluroalkyl. In some embodiments, R16 is hydrogen. In some embodiments, R16 is C1-6 alkyl. In some embodiments, R16 is C1-6 haloalkyl. In some embodiments, R16 is -C(O)OR11. In some embodiments, each R16 is independently is selected from -F and methyl. In some embodiments, each R16 is independently is selected from halogen. In some embodiments, each R16 is -F. In some embodiments, each R16 is independently is selected from C1-6 alkyl. In some embodiments, each R16 is independently is selected from methyl. In some embodiments, for the compound of Formulae (VIA-9), (VIA-10), ), (VIA-11), (VIA-12), ir (VIA-13), the compound has 0, 1, 2, or 3 R16 groups. In some embodiments, the compound has 0, 1, or 2, R16 groups. In some embodiments, the compound has 0 or 1 R16 groups. In some embodiments, the compound has 0 R16 groups. In some embodiments, the compound has 1, 2, or 3 R16 groups. In some embodiments, the compound has 1 or 2, R16 groups. In some embodiments, the compound has 1 R16 groups. In some embodiments, the compound has 2 R16 groups. In some embodiments, In some embodiments, for the compound of Formulae (V), (VA), (VB), (VC), (VD), (VE), (VI), (VIA), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIB), (VIB-1), (VIB-2), (VIB-3), (VIC), (VIC-1), (VIC-2), (VIC-3), (VIC-4), (VIC-5), (VIC-6), (VIC-7), (VID-1), (VID-2), (VID-3), (VID-4), (VID-5), (VID-6), (VIE-1), (VIE-2), (VIE-3), (VIE-4), (VIE-5), (VIE-6), (VIF), (VIF-1), or (VIF-2), Ring A is cyclopropyl optionally substituted with 1-4 halogen. In some embodiments, Ring A is cyclopropyl substituted with 1-4 halogen. In some embodiments, Ring A is cyclopropyl optionally substituted with 1-4 fluorine. In some embodiments, Ring A is cyclopropyl substituted with 1-4 fluorine. In some embodiments, Ring A is cyclopropyl optionally substituted with one halogen. In some embodiments, Ring A is cyclopropyl substituted with one halogen. In some embodiments, Ring A is cyclopropyl optionally substituted with one fluorine. In some embodiments, Ring A is cyclopropyl substituted with one fluorine. In some embodiments, the compound is of Formula (VIA-14): (VIA-14), or a pharmaceutically acceptable salt thereof; wherein Q3 is selected from N and CH; and X1 is selected from N, CH, and CR5. In some embodiments, X1 is N. In some embodiments, X1 is CH. In some embodiments, the compound is of Formula (VIA-15): (VIA-15), or a pharmaceutically acceptable salt thereof; wherein Q3 is selected from N and CH; X1 is selected from N, CH, and CR5. In some embodiments, X1 is N. In some embodiments, X1 is CH. In some embodiments, for the compound of Formulae (VIA-14) or (VIA-15), R5 is independently selected at each occurrence from halogen and C1-4 alkyl. In some embodiments, R5 is halogen. In some embodiments, R5 is C1-4 alkyl. In some embodiments, R5 is C1-4 haloalkyl. In some embodiments, R5 is -CN. In some embodiments, for the compound of Formulae (VIA-14) or (VIA-15), p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, the compound is of Formula (VIA-16): (VIA-16), or a pharmaceutically acceptable salt thereof; wherein Q3 is selected from N and CH; and X1 is selected from N, CH, and CR5. In some embodiments, for the compound of Formulae (VIA-14), (VIA-15), or (VIA-16), RB is selected from halogen, C1-6 alkyl, C1-6 haloalkyl, and -CN. In some embodiments, RB is selected from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, RB is selected from halogen, methyl, and halomethyl. In some embodiments, RB is halogen. In some embodiments, RB is C1-4 alkyl. In some embodiments, RB is methyl. In some embodiments, RB is C1-4 haloalkyl. In some embodiments, RB is -CN. In some embodiments, the compound is of Formula (VIA-17): (VIA-17), or a pharmaceutically acceptable salt thereof; wherein Q3 is selected from N and CH; X1 is selected from N, CH, and CR5. In some embodiments, X1 is N. In some embodiments, X1 is CH. In some embodiments, for the compound of Formulae (VIA-14), (VIA-15), (VIA-16), or (VIA-17), each R15 is independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, and - C(O)OR11; and R11 is selected from hydrogen and C1-4 alkyl. In some embodiments, each R15 is independently is selected from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, each R15 is independently is selected from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, each R15 is independently is selected from halogen C1 6 alkyl, and C1-6 haloalkyl. In some embodiments, each R15 is independently is selected from hydrogen and C1-6 alkyl. In some embodiments, each R15 is independently is selected from -F, C1-4 alkyl, and C1-4 fluroalkyl. In some embodiments, R15 is hydrogen. In some embodiments, R15 is C1-6 alkyl. In some embodiments, R15 is C1-6 haloalkyl. In some embodiments, R15 is -C(O)OR11. In some embodiments, each R15 is independently is selected from -F and methyl. In some embodiments, each R15 is independently is selected from halogen. In some embodiments, each R15 is -F. In some embodiments, each R15 is independently is selected from C1-6 alkyl. In some embodiments, each R15 is independently is selected from methyl. In some embodiments, for the compound of Formulae (VIA-14), (VIA-15), (VIA-16), or (VIA-17), the compound has 0, 1, 2, or 3 R15 groups. In some embodiments, the compound has 0, 1, or 2, R15 groups. In some embodiments, the compound has 0 or 1 R15 groups. In some embodiments, the compound has 0 R15 groups. In some embodiments, the compound has 1, 2, or 3 R15 groups. In some embodiments, the compound has 1 or 2, R15 groups. In some embodiments, the compound has 1 R15 groups. In some embodiments, the compound has 2 R15 groups. In In some embodiments, the compound is of Formula (VIA-18): (VIA-18), or a pharmaceutically acceptable salt thereof; wherein Q3 is selected from N and CH. In some embodiments, the compound is of Formula (VIA-19): (VIA-19), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula (VIA-20): (VIA-20), or a pharmaceutically acceptable salt thereof. Non-Limiting Exemplary Compounds In some embodiments, the compound is selected from the group consisting of the compounds in Examples 1-11 (e.g., Compounds 1-152), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table 1, or a pharmaceutically acceptable salt thereof.
1 O W 3 4 0 0-7 8 3 7 1
Figure imgf000174_0001
4 7 1
Figure imgf000175_0001
1O W 3 4 0 0-7 8
Figure imgf000176_0001
1O W 3 4 0 0-7 8
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
1O W 3 4 0 0-7 8
Figure imgf000181_0001
1 8 1
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
4 8 1
Figure imgf000185_0001
5 8
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
1O W 3 4 0 0-7 8
Figure imgf000189_0001
1O W 3 4 0 0-7 8
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
1O W 3 4 0 0-7 8
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
1O W 3 4 0 0-7 8
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000203_0002
Figure imgf000204_0001
Figure imgf000204_0002
:03
Figure imgf000205_0001
Figure imgf000205_0002
Figure imgf000206_0001
O
Figure imgf000206_0002
Figure imgf000207_0001
Figure imgf000207_0002
:06
Figure imgf000208_0002
O
C-f
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000211_0002
1 0
Figure imgf000212_0001
Figure imgf000212_0002
1 1
Figure imgf000213_0001
ri
Fl
Figure imgf000213_0002
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000215_0002
Figure imgf000216_0001
Figure imgf000217_0002
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000219_0002
Figure imgf000220_0002
Figure imgf000220_0003
cl
Figure imgf000220_0001
Figure imgf000221_0002
Figure imgf000221_0001
Figure imgf000222_0002
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0002
Figure imgf000224_0001
Pharmaceutical Compositions
Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or any pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Methods of Treatment
Provided herein are methods for inhibiting dual specificity tyrosine-phosphorylation- regulated kinase 1 A, encoded by the DYRK1A gene. For example, provided herein are inhibitors of DYRK1A useful for treating disorders associated with dysregulation of a DYRKL4 gene, a DYRK1A protein, or the expression or activity or level of any of the same (i.e., a DYRK1A- associated disorder), such as a DYRK1 A-associated neurological disorder.
A “DYRK1A inhibitor” as used herein includes any compound exhibiting DYRK1A inactivation activity (e.g., inhibiting or decreasing).
Indications
Compounds disclosed herein, including those of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or pharmaceutically acceptable salts thereof, are useful for treating disorders which can be treated with a DYRK1 A inhibitor, such as DYRK1 A-associated disorders, e.g., neurological disorders such as those described herein.
Provided herein is a method for treating a neurological disorder in a subject in need thereof, the method 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 as provided herein.
The term “neurological disorder” refers to any disorder of the nervous system and/or visual system. “Neurological disease” or “neurological disorder” are used interchangeably herein, and include diseases or disorders that involve the central nervous system (CNS; e.g., brain, brainstem and cerebellum), the peripheral nervous system (PNS; including cranial nerves), and the autonomic nervous system (parts of which are located in both the CN S and PNS), including both structural and/or functional disorders (e.g., neurological syndrome).
Examples of neurological disorders include, but are not limited to, headache, stupor and coma, dementia, seizure, sleep disorders, trauma, infections, neoplasms, neuroopthalmology, movement disorders, demyelinating diseases, spinal cord disorders, tauopathies, synucleinopathies, and disorders of peripherai nerves, muscle and neuromuscular junctions. Addiction and mental illness, include, but are not limited to, bipolar disorder and schizophrenia, are also included in the definition of neurological disorder. The following is a list of several neurological disorders, symptoms, signs and syndromes that can be treated using compositions and methods according to the present invention: acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; agenesis of the corpus callosum; agnosia: Aicardi syndrome; Alexander disease; Alpers’ disease; alternating hemiplegia; vascular dementia; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Anronl-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia telegiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet's disease; Bell's palsy; benign essential blepharospasm; benign focal; amyotrophy; benign intracranial hypertension; Binswanger's disease; blepharospasm: Bloch Sulzberger syndrome; brachial plexus injury; brain abscess; brain injury; Brown-Sequard syndrome; Cana van disease; carpal tunnel syndrome; causalgia; central pain syndrome; central pontine myelinolysis: cephalic disorder; cerebral aneurysm; cerebral arteriosclerosis: cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy; chronic pain; chronic regional pain syndrome; Coffin Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration: cranial arteritis; craniosynostosis, Creutzfeldt- Jakob disease; cumulative trauma disorders; Cushing's syndrome; cytomegalic inclusion body disease, cytomegalovirus infection; dancing eyes-dancing feet syndrome, Dandy Walker syndrome, Dawson disease; De Moisier’s syndrome, Dejerine-Klumke palsy; dementia, dermatomyositis; diabetic neuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias, early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephaloceles, encephalotrigeminal angiomatosis; epilepsy; Erb's palsy; essential tremor, Fabry's disease, Fahr's syndrome; fainting; familial spastic paralysis, febrile seizures; Fisher syndrome; Friedreich's ataxia; fronto-temporal dementia; Gaucher's disease; Gerstmann's syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain- Barre syndrome; HTLV-1 -associated myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia: heredopathia atactic a polyneuritiformis; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIVassociated dementia and neuropathy (also neurological manifestations of AIDS); holoprosencephaly; Huntington's disease and other polyglutaniine repeat diseases; hydranencephaly: hydrocephalus; hypercortisolism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; infantile phytanic acid storage disease; infantile spasms; inflammatory myopathy; intracranial cyst; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease Kinsboume syndrome; Klippel Fell syndrome; Krabbe disease; Kugelberg-Welander disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Kleffner syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Leigh's disease; Lennox- Gustaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lewy body dementia; Lissencephaiy; locked-in syndrome; Lou Gehrig's disease (i.e., motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; Lyme disease-neurological sequelae; Machado- Joseph disease; macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieres disease; meningitis; Menkes disease; nietachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; mini-strokes; mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motor neuron disease; Moyamoya disease; mucopolysaccharidoses; milti-mfarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with postural hypotension; p muscular dystrophy; myasthenia gravis; myelmociastic diffuse sclerosis; myoclonic encephalopathy of infants; myoclonus; myopathy; myotonia congenital; narcolepsy: neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of AIDS; neurological sequelae oflupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O'Sullivan-McLeod syndrome; occipital neuralgia; occult spinal dysraphism sequence, Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome, paresthesia, Neurodegen erative disease or disorder (Parkinson's disease, Huntington’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), dementia, multiple sclerosis and other diseases and disorders associated with neuronal cell death); paramyotonia congenital; paraneoplastic diseases; paroxysmal atacks; Parry Romberg syndrome; Pelizaeus-Merzbacher disease; periodic paralyses; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disorders; photic sneeze reflex; phytanic acid storage disease; Pick's disease; pinched nerve; porencephaly; post-polio syndrome; postherpetic neuralgia; postinfectious encephalomy elitis; postural hypotension; Prader- Willi syndrome; primary lateral sclerosis; prion diseases; progressive hemifacial atrophy; progressive multifocalleukoencephalopathy; progressive sclerosing poliodystrophy; progressive supranuclear palsy; Ramsay-Hunt syndrome (types I and II); Rasmussen's encephalitis: reflex sympathetic dystrophy syndrome; Refsum disease; repetitive motion disorders, repetitive stress injuries; restless legs syndrome; retrovirus-associated myelopathy; Rett syndrome; Reye's syndrome; Saint Vitus dance; Sandhoff disease; Schilder’s disease; sclnzencephaly; septo-optic dysplasia: shaken baby syndrome: shingles: Shy-Drager syndrome; Sjogren’s syndrome; Soto's syndrome; spasticity; spina bifida; spinal cord injury; spinal muscular atrophy; Stiff-Person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subcortical arteriosclerotic encephalopathy; Sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; tethered spinal cord syndrome; Thomsen disease; thoracic outlet syndrome; Tic Douloureux; Todd's paralysis; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathies; transverse myelitis; traumatic brain injury; tremor, trigeminal neuralgia; tropical spastic paraparesis: tuberous sclerosis; vascular dementia (multiinfarct dementia); vasculitis including temporal arteritis; Von Hippel -Lindau disease; Wallenberg's syndrome; Werdnig-Hoffman disease; West syndrome; Williams syndrome; Wildons disease; and Zellweger syndrome.
In some embodiments, the neurological disease is a tauopathy.
In some embodiments, the neurological disease is a synuclemopathy.
In some embodiments, the neurological disease or neurological disorder is Alzheimer’s disease, Down syndrome, Alzheimer’s disease associated with Down syndrome, Parkinson’s disease, ALS, dementia, Huntington’s disease, multiple sclerosis, proximal lateral sclerosis, stroke, stroke, or mild cognitive impairment. In some embodiments, the neurological disease or neurological disorder is Alzheimer’s disease.
In some embodiments, the dementia may be Alzheimer’s dementia, cerebrovascular dementia, dementia due to head injury, multi-infarct dementia, mixed or alcoholic dementia of Alzheimer’s disease and multi-infarct dementia.
Provided herein is a method for treating a metabolic disorder in a subject in need thereof, the method 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 as provided herein. In some embodiments, the metabolic disorder is diabetes (e.g., Type 1 diabetes or Type 2 diabetes). In some embodiments, the metabolic disorder is Metabolic Dysfunction- Associated Steatotic Liver Disease (MASLD).
Provided herein is a method for treating a cancer in a subject in need thereof, the method 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 as provided herein. In some embodiments, the cancer is a hemotological cancer (e.g., a leukemia, a lymophoma, or myeloma) or a solid tumor (e.g., carcinoma or sarcoma). In some embodiments, the cancer is selected from Acute Lymphocytic Leukemia (ALL, Acute Lymphoblastic Leukemia, Colorectal Cancer: Non-Small Ceil Lung Cancer, Glioblastoma Muitiforme (GBM), Prostate Cancer, and Pancreatic Cancer.
Provided herein is a method for treating an immunological disorder or disease (e.g., an autoimmune disorder) in a subject in need thereof, the method 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 as provided herein. In some embodiments, the immunological disorder is an autoimmune disorder. In some embodiments, the immunological disorder is selected from Psoriasis; Rheumatoid Arthritis; Systemic Lupus Erythematosus, osteoarthritis, degenerative disc disease, and inflammatory bowel disease.
Provided herein is a method for treating an dermatological disorder or disease in a subject in need thereof, the method 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 as provided herein. In some embodiments, the immunological disorder is atopic dermatitis (atopic eczema).
Provided herein is a method for treating a cardiovascular disease or disorder in a subject in need thereof, the method 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 as provided herein. In some embodiments, the cardiovascular disease or disorder comprises heart failure. In some embodiments, the cardiovascular disease or disorder is myocardial infarct restoration. In some embodiments, the treatment of the cardiovascular disease or disorder comprises stimulating cardiomyocyte proliferation.
Use of compounds of the present disclosure for treatment, as described herein, include the use of any compounds of Formula (I), (II), (III), (IV), (V), or (VI), or a subformula thereof, and ah compounds described herein.
The ability of test compounds to act as inhibitors of DYRK1A may be demonstrated by assays known in the art. The activity of the compounds and compositions provided herein as DYRK1 A inhibitors can be assayed in vitro, in vivo, or in a cell line. In vitro assay s include assays that determine inhibition of the kinase. Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase and can be measured either by radio labeling the compound prior to binding, isolating the compound/kinase complex and determining the amount of radiolabel bound, or by running a competition experiment where new compounds are incubated with the kinase bound to known radio ligands.
Potency of a DYRK1A inhibitor as provided herein can be determined by ECso or ICso values. A compound with a lower ECso or ICso value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher ECso or ICso value. In some embodiments, the substantially similar conditions comprise determining a DYRK1A- dependent phosphorylation level, in vitro or in vivo (e.g., in neural cells, such as neurons, astrocytes, oligodendrocytes, microglia, ependymal cells, Schwann cells, and satellite cells, expressing a wild type DYRK1A, a mutant DYRK1 A, or a fragment of any thereof).
Potency of a DYRK1 A inhibitor as provided herein can also be determined by ICso value. A compound with a lower ICso value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher ICso value. In some embodiments, the substantially similar conditions comprise determining a DYRK1 A-dependent phosphorylation level, in vitro or in vivo (e.g., in neural cells, such as neurons, astrocytes, oligodendrocytes, microglia, ependymal cells, Schwann cells, and satellite cells, expressing a wild type DYRK1 A, a mutant DYRK1A, or a fragment of any thereof).
The selectivity between DYRK1 A and other kinases (e.g., glycogen synthase kmase-3p, GSK3p) can also be measured using in vitro assays such as surface plasmon resonance and fhiorence-based binding assays, and cellular assays.
In some embodiments, the compounds of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, can selectively target DYRKIA. For example, a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, can selectively target DYRK1 A over another kinase or non-kinase target, for example, GSK3p.
In some embodiments, a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, can exhibit greater inhibition of DYRKl A relative to inhibition of GSK3p. In some embodiments, a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater inhibition of DYRK1A relative to inhibition of GSK3p. In some embodiments, a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, can exhibit up to 1000-fold greater inhibition of DYRKl A relative to inhibition of GSK3p. In some embodiments, a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, can exhibit up to lOOOO-fold greater inhibition of DYRKl A relative to inhibition of GSK3 p.
In some embodiments, the compounds described herein (e.g., compounds of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof readily cross the blood-brain barrier. In some embodiments, the compounds described herein (e.g,, compounds of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, cross the blood-brain barrier in an amount sufficient to inhibit DYRKl A activity in brain tissue.
Also provided herein is a method for treating a neurological disorder in a subject in need thereof, the method comprising (a) determining that the subject has a neurological disorder; and (b) administering to the subject, a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. In some embodiments, the subject is at risk of developing a neurological disorder, e.g., a DYRKl A-associated neurological disorder. In some embodiments, the subject is suspected of having a neurological disorder, e.g., a DYRKl A- associated neurological disorder.
In some embodiments, the subject has been previously determined to have a neurological disorder associated with a dysregulation of a DY/iKlA gene, a DYRKl A protein, or expression or activity, or level of any of the same (a DYRKlA-associated neurological disorder) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject is suspected of having a DYRKlA-associated neurological disorder. In some embodiments, the subject has a clinical record indicating that the subject has a dysregulation of a DYRKIA gene, a neurological disorder protein, or expression or activity, or level of any of the same (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is at risk of developing a DYRKlA-associated neurological disorder.
The term “DYRKlA-associated disorder” as used herein refers to disorders associated with or having a dysregulation of a DYRKIA gene, a DYRK1 A protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a DYRKIA gene, or a DYRKIA protein, or the expression or activity or level of any of the same described herein).
The term “DYRKlA-associated neurological disorder” as used herein refers to neurological disorders associated with or having a dysregulation of a DYRKIA gene, a DYRKIA protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a DYRKIA gene, or a DYRKIA protein, or the expression or activity or level of any of the same described herein). Non-limiting examples of a DYRK1 A -associated neurological disorders are described herein.
The phrase “dysregulation of a DYRKIA gene, a DYRKIA protein, or the expression or activity' or level of any of the same” refers to a genetic mutation (e.g., a mutation in a DYRKIA gene that results in the expression of a DYRK1 A that includes a deletion of at least one amino acid as compared to a wild type DYRK1 A, a mutation in a DYRKIA gene that results in the expression of DYRKIA with one or more point mutations as compared to a wild type DYRKIA, a mutation in a DYRKIA gene that results in the expression of DYRK1 A with at least one inserted amino acid as compared to a wild type DYRKIA, a gene duplication that results in an increased level of DYRKIA in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in an increased level of DYRKI A in a cell), an alternative spliced version of DYRKIA mRNA that results in DYRKIA having a deletion of at least one amino acid in the DYRKIA as compared to the wild type DYRKIA), or increased expression (e.g., increased levels) of a wild type DYRKIA in a mammalian cell due to aberrant cell signaling (e.g., as compared to a control cell). As another example, a dysregulation of a DYRKIA gene, a DYRKIA protein, or expression or activity, or level of any of the same, can be a mutation in a DYRKIA gene that encodes a DY U.K I A that is constitutively active or has increased activity as compared to a protein encoded by a DYRKIA gene that does not include the mutation.
In some embodiments, the dysregulation of a DYRKI A gene, a DYRKI A protein, or expression or activity or level of any of the same, includes at least one point mutation in a DYRKI A gene that results in the production of a DYRKI A protein that has one or more ammo acid substitutions or insertions or deletions in a DYRKIA gene that results in the production of a DYRKI A protein that has one or more amino acids inserted or removed, as compared to the wild type DYRKIA protein. In some cases, the resulting mutant DYRKIA protein has increased activity’, as compared to a wild type DYRKIA protein or a DYRKIA protein not including the same mutation.
Exemplary Sequence of Human Dual specificity’ tyrosine-phosphorylation-regulated kinase 1A (UniProtKB entry’ QI 3627) (SEQ ID NO: 1)
MHTGGETSAC KPSSVRLAPS FSFHAAGLQM AGQMPHSHQY SDRRQPNISD
QQVSALSYSD QIQQPLTNQV MPDIVMLQRR MPQTFRDPAT APLRKLSVDL IKTYKHINEV YYA.KKKRRHQ QGQGDDSSHK KERKVYNDGY DDDNYDYIVK NGEKWMDRYE IDSLIGKGSF GQWKAYDRV EQEWVAIKII KNKKAFLNQA
QIEARELELM NKHDTEMKYY IVEILKRHI AH RNHLCLVFEM LSYNLYDLLR
NTNFRGVSLN LTRKFAQQMC TAELFLATPE LSIIHCDLKP ENILLCNPKR
SAIKIVDFGS SCQLGQRIYQ YIQSRFYRSP EVLL.GMPYDL AIDMWSLGCI
LVEMHTGEPL FSGANEVDQM NKIVEVLGIP PAHILDQAPK ARKFFEKLPD
GTWNLKKTKD GKREYKPPGT RKLHNILGVE T GGPGGRRAG ESGHTVADYL
KFKDLILRML DYDPKTRIQP YYALQHSFFK KTADEGTNTS NSVSTSPAME
QSQSSGTTSS TSSSSGGSSG TSNSGRARSD PTHQHRHSGG HFTAAVQAMD CETHSPQVRQ QFPAPLGWSG TEAPTQVTVE THPVQETTFH VAPQQNALHH iniGNSSHHini HHHHHHHI D IG QQ ALGNRTRP RVYNSPTNSS STQDSMEVGH SHHSMTSLSS STTSSSTSSS STGNQGNQAY QNRPVAANTL DFGQNGAMDV
NLTVYSNPRQ ETGLAGHPTY QFSANTGPAH YMTEGHLTMR QGADREESPM
TGVCVQQSPV ASS
In some embodiments, compounds of Formula (I), (II), (III), (IV), fV), or (VI), or any subformulae thereof, or pharmaceutically acceptable thereof, are useful for treating a neurological disorder that has been identified as having one or more DYRKIA mutations. Accordingly, provided herein are methods for treating a subject diagnosed with (or identified as having) a neurological disorder that include administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof.
Some embodiments provide a method for treating a neurological disorder in a subject in need thereof, the method comprising (a) determining that the neurological disorder is associated with a dysregulation of 3.DYRK1A gene, a DYRK1A protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
Also provided herein is a method for treating a neurological disorder in a subject in need thereof, the method comprising (a) determining that the neurological disorder is a DYRK1A- associated neurological disorder; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
Provided herein is a method of treating a DYRK1 A -associated disorder in a subject, the method comprising administering to a subject previously determined to have a DYRK1A- associated disorder a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
In some embodiments, the subject that has been previously determined to have a DYRK1 A-associated neurological disorder through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying dysregulation of a DYRK.1A gene, a DYRK1 A protein, or expression or activity or level of any of the same, in a subject or a sample from the subject. In some embodiments, the test or assay is provided as a kit.
The term “regulatory agency” refers to a country's agency for the approval of the medical use of pharmaceutical agents with the country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).
Provided herein is a method of treating a subject, the method comprising administering a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject having a clinical record that indicates that the subject has a dysregulation of a DYRK1A gene, a DYRKI A protein, or expression or activity or level of any of the same.
Also provided is a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a neurological disorder in a subject in need thereof, or a subject previously determined to have a DY1RK1 A-associated neurological disorder. Also provided is the use of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a neurological disorder in a subject previously determined to have a DYRKI A-associated neurological disorder.
Compounds of the present disclosure (including compounds of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof) or a pharmaceutically acceptable salt thereof, can be used for the treatment of additional DYRKI A-mediated diseases an disorders, including the following: musculoskeletal disorders, genetic disorders (e.g., Fragile X syndrome), CNS disorders (e.g., pain, tauopathies, Attention Deficit Hyperactivity Disorder (ADHD); Depression; Post-Traumatic Stress Disorder (PTSD), traumatic brain injury, epilepsy), gastrointestinal disorders (e.g., irritiable bowel syndrome), metabolic disorders, cancer, immunological disorders and dermatological disorders.
When employed as pharmaceuticals, the compounds of Formula (I), (II), (III), (IV), (V). or (VI), or any subformulae thereof, including pharmaceutically acceptable salts thereof, can be administered in the form of pharmaceutical compositions as described herein.
Methods of Inhibiting DYRK1A Activity
Some embodiments provide a method of inhibiting DYRK 1 A activity in a mammalian cell comprising a DYRK LA protein, the method comprising contacting the mammalian cell with a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof.
Also provided herein is a method for inhibiting DYRKI A activity in a mammalian cell, the method comprising contacting the mammalian cell with a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the mammalian cell comprises DYRK1A. In some embodiments, the mammalian ceil is a mammalian neural cell.
Also provided herein is a method for inhibiting DYRK1 A activity, the method comprising contacting a D YRK1 A protein with a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof In some embodiments, the mammalian cell comprises DYRK1A.
In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, to a subject having a cell having aberrant DYRK1 A activity. In some embodiments, the cell is a neural cell.
As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” a DYRK1A protein with a compound provided herein includes the administration of a compound provided herein to a subject, such as a human, having a DYRK1A protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the DYRK1 A protein. In some embodiments, the contacting occurs after a compound described herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), or (VI), or any subformulae thereof, has crossed the blood-brain barrier.
In some embodiments, the compound of Formula (I), (II), (III), (FV), (V), or (VI), or any subformulae thereof, or a pharmaceutically acceptable salt thereof, contacting a mammalian cell and/or DYRK1A protein is present in an amount effective to inhibit the activity of a DYRK1 A protein. In some embodiments, the amount is a therapeutically effective amount.
EXAMPLES
Compound Preparation
The compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or in light of the teachings herein. The synthesis of the compounds disclosed herein can be achieved by generally following the schemes provided herein, with modification for specific desired substituents. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Smith, M. B., March, J., March' s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001 ; and Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New' York, 1999, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of the present disclosure.
The synthetic processes disclosed herein can tolerate a wide variety of functional groups; therefore, various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.
Procedures
A. Preparation of Intermediates
General Scheme 1: Imidazo[l,2~a]pyridine Synthesis Route 1
Figure imgf000237_0001
:0
Figure imgf000237_0002
Preparation of general imidazo[l,2-a]pyridines of type P5 via Scheme 1. An imidazo pyridine similar to Pl is combined with an acid or acid chloride or activated ester of type P2 that is arrived at either via commercially available reagent or single in situ formation according to usual procedures. When using an acid such as P2, the reagent is stirred with an amide bond forming regent similar to (l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridmium 3-oxide hexafluoro-phosphate (HATU), a mild base, and a solvent. The mixture is stirred at ambient temperature or with heating to progress the formation of the product of similar type P3. P3 is purified using one or more of any standard methods, including but not limited to reverse phase high pressure liquid chromatography (RP- HPLC, HPLC, or semi-prep HPLC) using standard eluents and additives, silica gel chromatography using automated instruments and pre-packed silica gel cartridges of various sizes and common normal phase organic solvents. The desired fractions are combined, concentrated to drymess to provide the intermediate P3. P3 is then combined with a boronic acid or ester like P4, and a series of reagents to perform a carbon-carbon bond forming reaction similar to a palladium mediated Suzuki coupling, such as a palladium (II) salt coordinated to one or more ligands, an inorganic or organic base, and a mixture of organic and aqueous solvents. The reaction is heated and stirred for a period of time and monitored for the formation of P5. When formation of PS is complete, the mixture is purified using similar methods as described for P3
General Scheme 2: Synthesis of Imidazo[l,2-«]pyridines
Figure imgf000238_0001
Preparation of general imidazo|l,2~«|pyridines of type P5 via Scheme 2. An intermediate similar to P3 is combined with a diboron reagent, a palladium (II ) salt coordinated to one or more ligands, an inorganic or organic base, and an organic solvent. The mixture is stirred at ambient temperature or with heating to progress the formation of a product similar to type P6. The mixture is filtered through a PTFE syringe filter or similar type and the solution is concentrated to dryness. The resulting crude material is used without further purification. P6 is then combined with a halogen containing reagent like P7, and a series of reagents to perform a carbon-carbon bond forming reaction similar to a palladium mediated Suzuki coupling, such as a palladium (II) salt coordinated to one or more ligands, an inorganic or organic base, and a mixture of organic and aqueous solvents. The reaction is heated and stirred for a period of time and monitored for the formation of PS. When formation of P5 is complete, the mixture is purified using similar methods as described for P3.
General Scheme 3: Synthesis of Imidazo [1,2-6] pyridazine
Figure imgf000239_0001
Preparation of general imidazo[l,2~a]pyridazines of type PIO via Scheme 3. An imidazo pyridazme similar to PS is combined with an acid or acid chloride or activated ester of type P2 that is arrived at either via commercially available reagent or single in situ formation according to usual procedures. When using an acid such as P2, the reagent is stirred with a amide bond forming reagent similar to l-[Bis(dimethylarnino)methylene]-l H-l,2,3-triazolo[4,5-bjpyridinium 3-oxide hexafluoro-phosphate (HATU), a mild base, and a solvent. The mixture is stirred at ambient temperature or with heating to progress the formation of the product of similar type P9. P9 is purified using one or more of any standard methods, including but not limited to reverse phase high pressure liquid chromatography (RP- HPLC, HPLC, or semi-prep HPLC) using standard eluents and additives, silica gel chromatography using automated instruments and pre-packed silica gel cartridges of various sizes and common normal phase organic solvents. The desired fractions are combined, concentrated to dryness to provide the intermediate P9. P9 is then combined with a boronic acid or ester like P4, and a series of reagents to perform a carbon-carbon bond forming reaction similar to a palladium mediated Suzuki coupling, such as a palladium (II) salt coordinated to one or more ligands, an inorganic or organic base, and a mixture of organic and aqueous solvents. The reaction is heated and stirred for a period of time and monitored for the formation of PIO. When formation of PIO is complete, the mixture is purified using similar methods as described for P9.
General Scheme 4: Synthesis of Thiazolo [5,4-6] pyridines
Figure imgf000240_0001
Figure imgf000240_0002
Preparation of general thiazoio[5,4-6]pyridines of type P13 via Scheme 4. A thiazolopyridine similar to Pl 1 is combined with an acid or acid chloride or activated ester of type P2 that is arrived at either via commercially available reagent or single in situ formation according to usual procedures. When using an acid such as P2, the regent is stirred with an amide bond forming regeant similar to l-[Bis(dimethylamino)methylene]-l/f-l,2,3-triazolo[4,5-6]pyridinium 3-oxide hexafluoro-phosphate (HATU), a mild base, and a solvent. The mixture is stirred at ambient temperature or with heating to progress the formation of the product of similar type P12. P12 is purified using one or more of any standard methods, including but not limited to reverse phase high pressure liquid chromatography (RP- HPLC, HPLC, or semi-prep HPLC) using standard eluents and additives, silica gel chromatography using automated instruments and pre-packed silica gel cartridges of various sizes and common normal phase organic solvents. The desired fractions are combined, concentrated to dryness to provide the intermediate P12. P12 is then combined with a boronic acid or ester like P4, and a series of reagents to perform a carbon-carbon bond forming reaction similar to a pailadium mediated Suzuki coupling, such as a palladium (II) salt coordinated to one or more ligands, an inorganic or organic base, and a mixture of organic and aqueous solvents. The reaction is heated and stirred for a period of time and monitored for the formation of 1’13. When formation of P13 is complete, the mixture is purified using similar methods as described for P12. Benzthiazoles and benzoxazoles were synthesized in an analogous manner.
General Scheme 5: Synthesis of [l,2,4]triazolo[l,5-b]pyridazines
Figure imgf000241_0001
Figure imgf000241_0002
Prep Preparation of general [l,2,4]triazolo[l,5~b]pyridazines of type P16 via Scheme 5. A [l,2,4]triazolo[l,5-b]pyridazine similar to P14 is combined with an acid or acid chloride or activated ester of type P2 that is arrived at either via commercially available reagent or single in situ formation according to usual procedures. When using an acid such as P2, the regent is stirred with an amide bond forming regeant similar to l-[Bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-Z>]pyridinium 3-oxide hexafluoro-phosphate (HATU), a mild base, and a solvent. The mixture is stirred at ambient temperature or with heating to progress the formation of the product of similar type P15. PIS is purified using one or more of any standard methods, including but not limited to reverse phase high pressure liquid chromatography (RP- HPLC, HPLC, or semi-prep HPLC) using standard eluents and additives, silica gel chromatography using automated instruments and pre-packed silica gel cartridges of various sizes and common normal phase organic solvents. The desired fractions are combined, concentrated to dryness to provide the intermediate PIS. PIS is then combined with a boronic acid or ester like P4, and a series of reagents to perform a carbon-carbon bond forming reaction similar to a palladium mediated Suzuki coupling, such as a palladium (II) salt coordinated to one or more ligands, an inorganic or organic base, and a mixture of organic and aqueous solvents. The reaction is heated and stirred for a period of time and monitored for the formation of 1’16. When formation of P16 is complete, the mixture is purified using similar methods as described for PIS.
General Scheme 6: Synthesis of [l,2,4]-triazolo[l,5-a]pyridines
Figure imgf000242_0001
Figure imgf000242_0002
Prep Preparation of general [ 1, 2, 4 |-triazolo[l,5-a] pyridines of type P16 via Scheme 6. A [l,2,4]-triazolo[l,5-a]pyridiness similar to P17 is combined with an acid or acid chloride or activated ester of type P2 that is arrived at either via commercially available reagent or single in situ formation according to usual procedures. When using an acid such as P2, the regent is stirred with an amide bond forming reg eant similar to 1 - (Bis(dimethylamino)methylene] -1H- 1,2,3 - triazolo[4,5~i]pyndinium 3-oxide hexafluoro-phosphate (HATU), a mild base, and a solvent. The mixture is stirred at ambient temperature or with heating to progress the formation of the product of similar type Pl 8. Pl 8 is purified using one or more of any standard methods, including but not limited to reverse phase high pressure liquid chromatography (RP- HPL.C, HPL.C, or semi-prep HPLC) using standard eluents and additives, silica gel chromatography using automated instruments and pre-packed silica gel cartridges of various sizes and common normal phase organic solvents. The desired fractions are combined, concentrated to dryness to provide the intermediate P18. P18 is then combined with a boronic acid or ester like P4, and a series of reagents to perform a carbon-carbon bond forming reaction similar to a palladium mediated Suzuki coupling, such as a palladium (II) salt coordinated to one or more ligands, an inorganic or organic base, and a mixture of organic and aqueous solvents. The reaction is heated and stirred for a period of time and monitored for the formation of P19. When formation of P19 is complete, the mixture is purified using similar methods as described for PIS.
General Scheme 7: Synthesis of Imidazo[l,2-a]pyrazines
Figure imgf000243_0001
P20 some activated ester
Figure imgf000243_0002
Preparation of genera! imidazo[l,2-a] pyrazines of type P22 via Scheme 7. .An imidazo[l ,2- a]pyrazines similar to P20 is combined with an acid or acid chloride or activated ester of type P2 that is arrived at either via commercially available reagent or single in situ formation according to usual procedures. When using an acid such as P2, the reagent is stirred with an amide bond forming regent similar to (1 -[Bis(dimethylamino)methylene]-1 H-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro-phosphate (HATU), a mild base, and a solvent. The mixture is stirred at ambient temperature or with heating to progress the formation of the product of similar type P21. P21 is purified using one or more of any standard methods, including but not limited to reverse phase high pressure liquid chromatography (RP- HPLC, HPLC, or semi-prep HPLC) using standard eluents and additives, silica gel chromatography using automated instruments and pre-packed silica gel cartridges of various sizes and common normal phase organic solvents. The desired fractions are combined, concentrated to dryness to provide the intermediate P21. P21 is then combined with a boronic acid or ester like P4, and a series of reagents to perform a carbon-carbon bond forming reaction similar to a palladium mediated Suzuki coupling, such as a palladium (II) salt coordinated to one or more ligands, an inorganic or organic base, and a mixture of organic and aqueous solvents. The reaction is heated and stirred for a period of time and monitored for the formation of P22. When formation of P22 is complete, the mixture is purified using similar methods as described for P3. General Scheme 8; Synthesis of Pyrazoio|l,5-a| pyridine
Figure imgf000244_0001
P23 some activated ester
Figure imgf000244_0002
Preparation of general pyrazolo[l,5-a]pyridineof type P25 via Scheme 8, A pyrazolo[l ,5- a]pyridine similar to P23 is combined with an acid or acid chloride or activated ester of type P2 that is arrived at either via commercially available reagent or single in situ formation according to usual procedures. When using an acid such as P2, the reagent is stirred with an amide bond forming regent similar to (l-[Bis(dimethylammo)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro-phosphate (HATU), a mild base, and a solvent. The mixture is stirred at ambient temperature or with heating to progress the formation of the product of similar type P24. P24 is purified using one or more of any standard methods, including but not limited to reverse phase high pressure liquid chromatography (RP- HPLC, HPLC, or semi-prep HPLC) using standard eluents and additives, silica gel chromatography using automated instruments and pre-packed silica gel cartridges of various sizes and common normal phase organic solvents. The desired fractions are combined, concentrated to dryness to provide the intermediate P24. P24 is then combined with a boronic acid or ester like P4, and a series of reagents to perform a carbon-carbon bond forming reaction similar to a palladium mediated Suzuki coupling, such as a palladium (II) salt coordinated to one or more ligands, an inorganic or organic base, and a mixture of organic and aqueous solvents. The reaction is heated and stirred for a period of time and monitored for the formation of P24. When formation of P25 is complete, the mixture is purified using similar methods as described for P3. B. Preparation of Intermediates Preparation of N-(6-bromoimidazo[1,2-a]pyridin-2-yl)-4-fluorooxane-4-carboxamide (Intermediate A1). HATU (1.45 g, 3.82 mmol) was added to 4-fluorooxane-4-carboxylic acid (471 mg, 3.18 mmol) and 2- amino-6-bromoimidazo[1,2-a]pyidine (540 mg, 2.55 mmol) in DMA (10 mL) at RT then stirred at RT for 20 min. The solution was purified by semi-prep HPLC (2-60% MeCN in 0.05% NH4OH (aq) over 10 min) to give N-(6-bromoimidazo[1,2-a]pyridin-2-yl)-4-fluorooxane- 4-carboxamide (540 mg, 62% yield) as an off-white solid. 1H NMR (400 MHz, DMSO) į 10.80 (d, J = 2.3 Hz, 1H), 8.92 (dd, J = 2.0, 0.9 Hz, 1H), 8.19 (s, 1H), 7.48 – 7.40 (m, 1H), 7.35 (dd, J = 9.5, 1.9 Hz, 1H), 3.84 (ddd, J = 11.6, 5.3, 2.0 Hz, 2H), 3.60 (td, J = 11.7, 2.3 Hz, 2H), 2.14 (dddd, J = 37.6, 14.2, 12.1, 5.3 Hz, 2H), 1.84 (ddd, J = 14.1, 11.5, 2.2 Hz, 2H). LCMS: RT = 0.55 min, ES-MS [M+H]+ = 342.1/344.1. 4-fluoro-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridin-2- yl)tetrahydro-2H-pyran-4-carboxamide (Intermediate A2). F O B2pin2 F O O N Pd(dppf)Cl2 O N HN KOAc HN N N B O Br 1,4-dioxane O N-(6-Bromoimidazo[1,2-a]pyridin-2-yl)-4-fluorotetrahydro-2H-pyran-4-carboxamide (200 mg, 0.58 mmol), bis(pinacolato)diboron (223 mg, 0.88 mmol), dichloro[1,1’- bis(diphenylphosphino)ferrocene]palladium(II) (43 mg, 0.06 mmol) and potassium acetate (172 mg, 1.75 mmol) in 1,4-dioxane (5 mL) was stirred at 90 oC for 16 hr. The mixture was filtered through celite, washing with EtOAc and the filtrate concentrated in vacuo to afford the title compound as a brown solid which was used without further purification. LCMS: RT = 0.65 min; ES-MS [M+1]+: 390.4. Preparation of N-(6-bromoimidazo[1,2-a]pyridin-2-yl)-2,2,6,6-tetramethyltetrahydro-2H-pyran- 4-carboxamide (Intermediate A3) 2,2,6,6-tetramethyltetrahydro-2H-pyran-4-carboxyic acid (131.75mg, 0.71mmol) and phosphorus(V) oxychloride (0.22mL, 2.36mmol) in MeCN (0.75mL) was allowed to stir at ambient temperature. After 5 minutes, to the mixture was added dropwise, 2-amino-6- bromoimidazo[1,2-a]pyridine (100.mg, 0.47mmol, 1.0 eq) in pyridine (1.5 mL) and allowed to stir for 30 minutes at ambient temperature. The mixture was purified by flash chromatography on silica gel column and eluent using 0-10% MeOH in DCM and 1% NH4OH as an additive. The desired fractions were collected, combined, and concentrated to provide the title compound. LCMS: RT = 0.532 min; ES-MS [M+1]+ = 380.1/382.1 Preparation of N-(6-bromoimidazo[1,2-a]pyridin-2-yl)-1-fluorocyclopropane-1-carboxamide (Intermediate A4). HATU (448 mg, 1.18 mmol) was added to 1-fluorocyclopropane-1-carboxamide (92 mg, 0.88 mmol), 2-amino-6-bromoimidazo[1,2-a]pyridine (250 mg, 0.59 mmol) and N,N- diisopropylethylamine (308 uL, 1.77 mmol) in DMF (3 mL) at RT then stirred at RT for 1 hr. The solution was purified by semi-prep HPLC (2-50% MeCN in 0.05% NH4OH (aq) over 20 min) to give N-(6-bromoimidazo[1,2-a]pyridin-2-yl)-1-fluorocyclopropane-1-carboxamide (155 mg, 88 % yield) as a white solid. LCMS: RT = 0.50 min, ES-MS [M+H]+ = 298.1/300.1 Alternatively, A4 was prepared in a similar manner to Intermediate A1 to provide 155 mg (88%) as a white solid. LCMS: RT = 0.50 min, ES-MS [M+H]+ = 298.1/300.1. Preparation of N-(6-bromoimidazo[1,2-a]pyridin-2-yl)-2,2,5,5-tetramethyloxolane-3- carboxamide (Intermediate A5) To a mixture of 2-amino-6-bromoimidazo[1,2-a]pyridine (50.mg, 0.24mmol), 2,2,5,5- tetramethyltetrahydrofuran-3-carboxylic acid (60.9 mg, 0.35 mmol) and N,N- diisopropylethylamine (0.062 mL, 0.356 mmol) in DMA (0.8 mL) was added HATU (134.4 mg, 0.353 mmol) at ambient temperature. The reaction was stirred for one hour. The reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-100% EtOAc/Hexanes) to afford the title compound as a white solid. LCMS: RT = 0.66 min; ES-MS [M+1]+ = 368.1/370.1. Alternatively, A5 can be prepared in a similar manner to Intermediate A1 to provide 8 mg (9%) as a white solid. LCMS: RT = 0.66 min; ES-MS [M+1]+ = 368.1/370.1. Preparation of N-(6-bromoimidazo[1,2-a]pyridin-2-yl)-3-fluorotetrahydrofuran-3-carboxamide (Intermediate A6) To a mixture of 2-amino-6-bromoimidazo[1,2-a]pyridine (50 mg, 0.24 mmol), 3- fluorooxolane-3-carboxylic acid (31.6 mg, 0.24 mmol) and N,N-diisopropylethylamine (0.062 mL, 0.356 mmol) in DMA (1.0 mL) was added HATU (134.4 mg, 0.353 mmol) at ambient temperature. The reaction was stirred for one hour. The reaction mixture was concentrated in vacuo. The residue was purified by semi-prep HPLC (2-60% MeCN in 0.05% NH4OH (aq) over 10 min) to give the title compound. LCMS: RT = 0.606 min, ES-MS [M+1]+ = 328.1/330.1 Alternatively, A6 was prepared in a similar manner to Intermediate A1 to provide 39 mg (50%) as a white solid. LCMS: RT = 0.606 min, ES-MS [M+1]+ = 328.1/330.1 Preparation of N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-3-fluorotetrahydrofuran-3- carboxamide (Intermediate A7) O O N OH O HATU, DIPEA H2N + N N F N Cl F HN O DMA N N Cl To a mixture of 6-chloroimidazo[1,2-b]pyridazin-2-amine (20.0 mg, 0.119 mmol,), 3- fluorotetrahydrofuran-3-carboxylic acid (17.5 mg, 0.131 mmol), and N,N-diisopropylethylamine (0.062 mL, 0.356 mmol) in DMA (0.8 mL) was added HATU (67.7 mg, 0.178 mmol) at ambient temperature. The reaction was stirred for one hour. The reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-100% EtOAc/Hexanes) to afford the title compound as a white solid. LCMS: RT = 0.52 min, ES-MS [M+1]+ = 285.0. Preparation of N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2,2-dimethyltetrahydro-2H-pyran-4- carboxamide (Intermediate A8) To a mixture of 6-chloroimidazo[1,2-b]pyridazin-2-amine (40.0 mg, 0.237 mmol), 2,2- dimethyltetrahydro-2H-pyran-4-carboxylic acid (56.3 mg, 0.356 mmol), and N,N- diisopropylethylamine (0.124 mL, 0.712 mmol), in DMA (1.2 mL) was added HATU (135.3 mg, 0.356 mmol) at ambient temperature. The reaction was stirred for one hour. The reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-100% EtOAc/Hexanes) to afford the title compound as a white solid. LCMS: RT = 0.56 min, ES-MS [M+1]+ = 309.1. Preparation of N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-2,2,5,5-tetramethyltetrahydrofuran-3- carboxamide (Intermediate A9) To a mixture of 5-bromothiazolo[5,4-b]pyridin-2-amine (100.0 mg, 0.43 mmol), 2,2,5,5- tetramethyltetrahydrofuran-3-carboxylic acid (89.8 mg, 0.52 mmol) in pyridine (1.0 mL) and ethyl acetate (1.0 mL) was added Et3N (181.7 ^L, 1.3 mmol), 1-propanephosphonic anhydride 50 wt. % in ethyl acetate (0.52 mL, 0.87 mmol) at ambient temperature. The reaction was heated to 90 oC. After 2 h, the reaction mixture was cooled and then concentrated under reduced pressure. The residue was diluted with DCM, washed with saturated aq. NaHCO3, and extracted three times with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the crude mixture. The crude mixture was purified using flash silica gel column chromatography(0- 50% EtOAc/hexanes) to give the title compound as a white solid. LCMS: RT = 0.69 min, ES-MS [M+H]+ = 384.1, 386.1. C. Preparation of Compounds Example 1. 4-fluoro-N-(6-(2-methylpyridin-4-yl)imidazo[1,2-a]pyridin-2-yl)tetrahydro-2H-pyran-4- carboxamide picoline-4-boronic acid (324 mg, 2.37 mmol), dichloro[1,1’-bis(diphenylphosphino)- ferrocene]palladium(II) dichloromethane adduct (64 mg, 0.08 mmol) and potassium carbonate (553 mg, 3.95 mmol) in DMA (5 mL) and water (1 mL) was stirred at 90oC for 2 hr. The solution was purified by semi-prep HPLC (2-60% MeCN in 0.05% NH4OH (aq) over 20 min) to give 4- fluoro-N-(6-(2-methylpyridin-4-yl)imidazo[1,2-a]pyridin-2-yl)tetrahydro-2H-pyran-4- carboxamide (221 mg, 39% yield) as a white solid. 1H NMR (400 MHz, DMSO) į 10.82 (s, 1H), 9.17 (s, 1H), 8.53 (d, J = 5.5 Hz, 1H), 8.24 (s, 1H), 7.70 (d, J = 9.5 Hz, 1H), 7.64 (s, 1H), 7.59- 7.53 (m, 2H), 3.90-3.83 (m, 2H), 3.63 (t, J = 11.6 Hz, 2H), 2.56 (s, 3H), 2.27-2.09 (m, 2H), 1.88 (t, J = 12.8 Hz, 2H); LCMS: RT = 0.50 min, ES-MS [M+H]+ = 355.3. Example 2. 1-fluoro-N-[6-(2-methylpyridin-4-yl)imidazo[1,2-a]pyridin-2-yl]cyclopropane-1-carboxamide N-(6-bromoimidazo[1,2-a]pyridin-2-yl)-1-fluorocyclopropane-1-carboxamide (195 mg, 0.65 mmol), picoline-4-boronic acid (134 mg, 0.98 mmol), dichloro[1,1’- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (53 mg, 0.07 mmol) and potassium carbonate (1.31 mmol) in DMA (3mL) and water (0.5mL) was stirred at 90 oC for 60 min. The solution was purified by semi-prep HPLC (2-65% MeCN in 0.1% TFA (aq) over 12 min.) The elutant was pH adjusted with sat. NaHCO3 (aq) then extracted with 3:1 CHCl3:IPA. The organics were combined and washed sequentially with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated to give 1-fluoro-N-[6-(2- methylpyridin-4-yl)imidazo[1,2-a]pyridin-2-yl]cyclopropane-1-carboxamide (122 mg, 60 % yield) as an off-white solid. LCMS: RT = 0.53 min, ES-MS [M+H]+ = 311.1. Example 3. 1-fluoro-N-(6-(6-methylpyridazin-4-yl)imidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxamide N-(6-bromoimidazo[1,2-a]pyridin-2-yl)-1-fluorocyclopropane-1-carboxamide (15 mg, 0.05 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine (17 mg, 0.08 mmol), dichloro[1,1’-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (4 mg, 5 μmol), and potassium carbonate (11 mg, 0.08 mmol) were suspended in DMA (0.5 mL) and H2O (0.1 mL). The suspension was sparged with N2 for several minutes and then stirred at 90 °C for 2 hours under an inert atmosphere in a sealed vial. The mixture was then cooled to RT, diluted with minimal MeOH filtered and purified directly via RP-HPLC 5-45% (MeCN in 0.1% aqueous TFA). Product-cont epurified by RP-HPLC (10-90% CH3CN in 0.05% aqueous NH4OH). Product-containing fractions were combined and concentrated to afford the title compound (15.6 mg, 19.8% yield) as a clear glass. LCMS: RT = 0.397 min; ES-MS [M+1]+: 312.2. Example 4. 3-fluoro-N-(6-(2-methylpyridin-4-yl)imidazo[1,2-a]pyridin-2-yl)tetrahydrofuran-3-carboxamide Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dicloromethane adduct (2.39 mg, 0.0.5 mmol), potassium carbonate (20.5 mg, 0.15 mmol), 2-picoline-4-boronic acid pinacol ester (12.0 mg, 0.09 mmol) and N-(6-bromoimidazo[1,2-a]pyridin-2-yl)-3- fluorotetrahydrofuran-3-carboxamide (19.2 mg, 0.06 mmol, )in DMA (0.5 mL) and water (0.1 mL) was heated to 100 °C while stirring for two hours. The vial was cooled and diluted with DCM. The mixture was filtered using a syringe filter and semi-prep HPLC (2-65% MeCN in 0.05% NH4OH (aq) over 12 min). The desired organic fractions were combined and concentrated to provide the title compound (10.1 mg, 51% yield) as a colorless glass. LCMS: RT = 0.524 min; ES- MS [M+1]+ = 341.1. Example 5. N-(6-(6-Chloropyridazin-4-yl)imidazo[1,2-a]pyridin-2-yl)-4-fluorotetrahydro-2H-pyran-4- carboxamide 4-Fluoro-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridin-2- yl)tetrahy-dro-2H-pyran-4-carboxamide, 5-bromo-3-chloropyridazine, dichloro[1,1’- bis(diphenylphosph t and potassium carbonate were taken up in DMA (0.5 mL) and water (0.1 mL) and stirred at 90 oC for several hours. The reaction was syringe filtered, washing with DMSO and purified via RP-HPLC, 0-40% MeCN/0.05% aqueous NH4OH. Fractions containing the product were concentrated and repurified via flash column chromatography on silica gel (0-100% EtOAc/Hexanes) to afford 26 mg (29%) of the title compound. LCMS: RT=0.50 min; ES-MS [M+1]+: 376.3. Example 6. N-(6-(6-Aminopyridazin-4-yl)imidazo[1,2-a]pyridin-2-yl)-4-fluorotetrahydro-2H-pyran-4- carboxamide Br H2N N N N Pd(dppf)Cl N F HN 2ÂDCM K2CO3 F HN N N O N B O O H 2 O DMA/H O, 90 °C O O 2 N N 4-Fluoro-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridin-2- yl)tetrahy-dro-2H-pyran-4-carboxamide, 5-bromopyridazin-3-amine, dichloro[1,1’- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct, and potassium carbonate were taken up in DMA (0.5 mL) and water (0.1 mL) and stirred at 90 oC for several hours. The reaction was syringe filtered, washing with DMSO and purified via RP-HPLC, 0-40% MeCN/0.05% aqueous NH4OH. Fractions containing the product were concentrated and repurified via flash column chromatography on silica gel (0-100% EtOAc/Hexanes) to afford 82 mg (40%) of the title compound. LCMS: RT=0.41 min; ES-MS [M+1]+: 357.3. Example 7. N-(6-(6-(Cyclopropanecarboxamido)pyridazin-4-yl)imidazo[1,2-a]pyridin-2-yl)-4- fluorotetrahydro-2H-pyran-4-carboxamide N-(6-(6-aminopyridazin-4-yl)imidazo[1,2-a]pyridin-2-yl)-4-fluorotetrahydro-2H-pyran- 4-carboxamide (16 mg, 0.04 mmol), cyclopropanecarboxylic acid (6 mg, 0.7 mmol), HATU (34 mg, 0.09 mmol) and DIEA (23 μL, 0.13 mmol) in DMF (1 mL) was stirred at 90 ^. The reaction was syringe filtered, rinsing with DMSO and purified via RP-HPLC, 5-95% MeCN/0.05% aqueous NH4OH. Fractions containing the product were concentrated to afford 5 mg (25% yield) of the title compound. LCMS: RT=0.51 min; ES-MS [M+1]+: 425.4. Example 8. 4-Fluoro-N-(6-(6-methoxypyridazin-4-yl)imidazo[1,2-a]pyridin-2-yl)tetrahydro-2H-pyran-4- carboxamide To a solution of N-(6-(6-chloropyridazin-4-yl)imidazo[1,2-a]pyridin-2-yl)-4- fluorotetrahydro-2H-pyran-4-carboxamide (10 mg, 0.03 mmol) in MeOH (1 mL) was added sodium methoxide (4 M, 0.01 mL, 0.13 mmol) and the reaction stirred at 60 ^ for 16 hours. The reaction was concentrated and the resulting residue dissolved in DMSO and purified via RP- HPLC, 5-95% MeCN/0.05% aqueous NH4OH. Fractions containing the product were concentrated to afford 4 mg (39% yield) of the title compound. LCMS: RT=0.56 min; ES-MS [M+1]+: 372.3. Example 9. N-(6-(benzo[d]thiazol-6-yl)imidazo[1,2-b]pyridazin-2-yl)-3-fluorotetra-hydrofuran-3- carboxamide N-(6-Chloroimidazo[1,2-b]pyridazin-2-yl)-3-fluorotetrahydrofuran-3-carboxamide (24.0 mg, 0.084 mmol), benzo[d]thiazol-6-ylboronic acid (22.6 mg, 0.126 mmol), K2CO3 (35.5 mg, 0.253 mmol), and RuPhos-Pd-G3 (7.1 mg, 0.009 mmol) in THF (0.6 mL) and water (0.15 mL) was heated at 120 oC ti n was diluted with THF (1 mL) and syringe filtered. The filtrate was purified via RP-HPLC, 5-95% CH3CN/0.05% aqueous NH4OH. Fractions containing the product were concentrated to afford the title compound as a white solid. LCMS: RT = 0.57 min; ES-MS [M+1]+ = 384.1. Example 10. 2,2,5,5-tetramethyl-N-(5-(2-methylpyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)tetrahydrofuran-3- carboxamide N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-2,2,5,5-tetramethyltetrahydrofuran-3- carboxamide (20.0 mg, 0.052 mmol), (2-methylpyridin-4-yl)boronic acid (10.7 mg, 0.078 mmol), K2CO3 (21.9 mg, 0.156 mmol), Pd(dppf)Cl2 (4.3 mg, 0.005 mmol) in DMA (0.5 mL) and water (0.1 mL). was heated to 100 oC. Upon completion, the reaction was cooled to ambient temperature, diluted with DMSO (1 mL), and filtered through a syringe filter to give the crude mixture. The crude product was purified using semi-prep HPLC 5-95% ACN/0.1% aqueous TFA, 10 min run). Fractions containing desired product were adjusted to neutral pH with sat. NaHCO3 then extracted with 3:1 chloroform/IPA (3x). The combined organics were passed through a phase separator and the organic fractions were concentrated to give the title compound as a white solid. Example 11. 2,2,5,5-tetramethyl-N-(5-(2-methylpyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)tetrahydrofuran-3- carboxamide N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-2,2,5,5-tetramethyltetrahydrofuran-3- carboxamide (15.0 mg, 0.039 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridazine (12.9 mg, 0.059 mmol), K2CO3 (16.4 mg, 0.117 mmol), Pd(dppf)Cl2 (3.2 mg, 0.004 mmol) in DMA (0.5 mL) and water (0.1 mL).was heated to 100 oC. Upon completion, the reaction was diluted with DMSO (1 mL) and filtered through a syringe filter to give the crude. Crude product was purified using semi-prep HPLC (5-95% ACN/0.1% aqueous TFA, 10 min run). Fractions containing desired product were adjusted to neutral pH with sat. NaHCO3 and then extracted with 3:1 chloroform/IPA (3x). The combined organics were passed through a phase separator and the solvents were concentrated to give the title compound as a white solid. LCMS: RT = 0.61 min; ES-MS [M+H]+ = 398.2. Example 12. 2,2-difluoro-N-(5-(2-methylpyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)cyclopropane-1- carboxamide 1-propanephosphonic anhydride (0.78 mL, 1.30 mmol) was added to 2,2- difluorocyclopropane carboxylic acid (70 mg, 0.57 mmol), 5-bromothiazolo[5,4-b]pyridine-2- amine (120 mg, 0.52 mmol) and trimethylamine (0.22 mL, 1.56 mmol) in pyridine (1 mL) and stirred at 80oC for 1 hr. The solution was concentrated and the residue purified by flash chromatography (eluting with 10-60% EtOAc in hexanes over 20 min) to afford N-(5-bromo- [1,3]thiazolo[5,4-b]pyridin-2-yl)-2,2-difluorocyclopropane-1-carboxamide (161 mg, 92 % yield) as white solid. LCMS: RT = 0.62 min; ES-MS [M+1]+: 368.0, 370.0. N-(5-bromo-[1,3]thiazolo[5,4-b]pyridin-2-yl)-2,2-difluorocyclopropane-1-carboxamide (20 mg, 0.06 mmol), picoline-4-boronic acid (13 mg, 0.09 mmol), dichloro[1,1- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (5 mg, 0.01 mmol) and potassium carbonate (26 mg, 0.18 mmol) in DMA (0.5 mL) and water (0.1 mL) was stirred at 90oC for 3 hr. The mixture was diluted with DMSO (2 mL), filtered and the filtrate was purified by semi-prep HPLC (eluting with 5-90% MeCN in 0.05% NH4OH (aq) over 10 min) to afford the title compound (7 mg, 33% yield) as a white solid. LCMS: RT = 0.49 min; ES-MS [M+1]+: 347.1. Example 13. N-benzyl-6-(2-methylpyridin-4-yl)benzo[d]thiazol-2-amine 6-bromo-2-chloro-1,3-benzothiazole (100 mg, 0.40 mmol), benzylamine (43 mg, 0.40 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.80 mmol) in DMSO (2 mL) was stirred at 80oC for 2 hr. The reaction was filtered and the filtrate purified by semi-prep HPLC (eluting with 5-90% MeCN in 0.05% NH4OH (aq) over 10 min) to afford N-benzyl-6-bromo-1,3-benzothiazol- 2-amine (101 mg, 79% yield) as a clear oil. LCMS: RT = 0.86 min; ES-MS [M+1]+: 319.1, 321.1. N-benzyl-6-bromo-1,3-benzothiazol-2-amine (15 mg, 0.05 mmol), picoline-4-boronic acid (10 mg, 0.07 mmol), dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (4 mg, 0.04 mmol), and potassium carbonate (20 mg, 0.14 mmol) in DMA (0.5 mL) and water (0.1 mL) was stirred at 100oC for 3 hr. The mixture was filtered and the filtrate purified by semi-prep HPLC (eluting with 5-90% NH4OH (aq) over 10 min) to afford the title compound (4 mg, 28% yield) as a tan solid. LCMS: RT = 0.53 min; ES-MS [M+1]+: 332.2. Example 14. N-(6-(benzo[d]thiazol-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-(1-methyl-1H-pyrazol- 4-yl)acetamide 6-bromo-[1,2,4]-triazolo[1,5-a]pyridine-2-amine (50 mg, 0.23 mmol), 2-(1- methylpyrazol-4-yl)acetic acid (66 mg, 0.47 mmol), HATU (178 mg, 0.47 mmol) and N,N- diisopropylethylamine (0.123 mL, 0.70 mmol) in DMF (1 mL) was stirred at 90oC for 1 hr. The solution was purified by semi-prep HPLC (eluting with 2-50% MeCN in 0.1% TFA (aq) over 10 min) to afford N-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-(1-methylpyrazol-4-yl)acetamide (51 mg, 64% yield) as a tan solid. LCMS: RT = 0.44 min; ES-MS [M+1]+: 335.0, 337.0. N-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-(1-methylpyrazol-4-yl)acetamide (20 mg, 0.06 mmol), 1,3-benzothiazol-6-yl boronic acid (21 mg, 0.12 mmol), dichloro[1,1- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (4 mg, 0.01 mmol) and potassium carbonate (25 mg, 0.18 mmol) in DMA (0.5 mL) and water (0.1 mL) was stirred at 90oC for 1 hr. The mixture was filtered then purified by semi-prep HPLC (eluting with 2-50% MeCN in 0.1% TFA (aq) over 10 min) to afford the title compound (3 mg, 14% yield) as a tan solid. LCMS: RT = 0.57 min; ES-MS [M+1]+: 390.2. Example 15. N-(6-methylpyridin-3-yl)-6-(2-methylpyridin-4-yl)imidazo[1,2-a]pyridin-2-amine 6-bromo-2-chloroimidazo[1,2-a]pyridine (250 mg, 1.08 mmol), picoline-4-boronic acid (222 mg, 1.62 mmol), potassium carbonate (227 mg, 1.62 mmol) and dichloro[1,1- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (79 mg, 0.11 mmol) in DMA (5 mL) and water (1 ml) was stirred at 90oC for 2 hr. The mixture was filtered and the filtrate purified by semi-prep HPLC (eluting with 2-55% MeCN in 0.05% NH4OH(aq) over 12 min) to afford 2-chloro-6-(2-methyl-4-pyridinyl)imidazo[1,2-a]pyridine (108 mg, 41% yield) as a white solid. LCMS: RT = 0.39 min; ES-MS [M+1]+: 244.1. 2-chloro-6-(2-methyl-4-pyridinyl)imidazo[1,2-a]pyridine (20 mg, 0.08 mmol), 5-amino-2- methylpyridine (14 mg, 0.12 mmol), Ruphos Palladacycle Gen3 (7 mg, 0.01mmol) and sodium tert-butoxide (16 mg, 0.16 mmol) in 1,4-dioxane (0.5 mL) was stirred at 90oC for 4 hr. The solution was purified by semi-prep HPLC (eluting with 2-55% MeCN in 0.05% NH4OH (aq) over 10 min) to afford the title compound (3 mg, 10% yield) as a tan solid. LCMS: RT = 0.36 min; ES-MS [M+1]+: 316.2. Example 16. N-benzyl-6-(6-methylpyridazin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine 2,6-dibromo-[1,2,4]triazolo[1,5-a]pyridine (15 mg, 0.05 mmol), benzylamine (0.19 mL, 1.72 mmol), and (1-methyl-1H-pyrazol-4yl)methanamine (180 mg, 1.62 mmol) was stirred at RT for 4 hr. The solution was concentrated and the residue purified by flash chromatography (eluting with 10-60% EtOAc in hexanes over 20 min) to afford N-benzyl-6-bromo-[1,2,4]triazolo[1,5- a]pyridin-2-amine (5 mg, 30% yield) as a white solid. LCMS: RT = 0.64 min; ES-MS [M+1]+: 303.0, 305.0. N-benzyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (5 mg, 0.02 mmol), 3- methylpyridazine-5-boronic acid pinacol ester (6 mg, 0.02 mmol), potassium carbonate (7 mg, 0.05 mmol) and Ruphos Palladacycle Gen3 (1 mg, 0.01 mmol) in THF (0.6 mL) and water (0.15 mL) was stirred at 90oC for 1 hr. The solution was purified by semi-prep HPLC (eluting with 10- 88% MeCN in 0.05% NH4OH (aq) over 10 min) to afford the title compound (2 mg, 32% yield) as a white solid. LCMS: RT = 0.51 min; ES-MS [M+1]+: 317.2. Example 17. benzyl (6-(2-methylpyridin-4-yl)imidazo[1,2-a]pyridin-2-yl)carbamate 2-chloro-6-(2-methyl-4-pyridinyl)imidazo[1,2-a]pyridine (60 mg, 0.25 mmol), sodium 20 iodide (149 mg, 0.98 mmol) and hydroiodic acid (0.6 mL, 8.0 mmol) in MeCN (2 mL) was stirred at 90oC for 5 hr. The solution was cooled to RT and the resulting solids were collected by suction filtration, washed with MeCN then dried to afford 2-iodo-6-(2-methyl-4-pyridinyl)imidazo[1,2- a]pyridine:hydroiodide (78 mg, 68% yield) as yellow solid. LCMS: RT = 0.38 min; ES-MS [M+1]+: 336.0 2-iodo-6-(2-methyl-4-pyridinyl)imidazo[1,2-a]pyridine:hydroiodide (20 mg, 0.04 mmol), benzyl carbamate (8 mg, 0.05 mmol), copper (I) iodide (2 mg, 0.01 mmol), N,N’- dimethylethylenediamine (0.01 mL, 0.01 mmol) and cesium carbonate (43 mg, 0.13 mmol) in 1,4- dioxane (0.25 mL) was stirred at 100oC for 18 hr. The mixture was filtered and the filtrate purified by semi-prep HPLC (eluting with 2-60% MeCN in 0.05% NH4OH (aq) over 12 min) to afford the title compound (3 mg, 19% yield) as a white solid. LCMS: RT = 0.51 min; ES-MS [M+1]+: 359.2. Example 18. 2,2,5,5-tetramethyltetrahydrofuran-3-yl (6-(6-methylpyridazin-4-yl)imidazo[1,2- a]pyridin-2-yl)carbamate 4-nitrophenyl chloroformate (143 mg, 0.71 mmol) was added to 2-amino-6- bromoimidazo[1,2-a]pyridine (75 mg, 0.35 mmol) in pyridine (1 mL) at RT then the solution was stirred at RT for 1 hr. 2,2,5,5-tetramethyloxolan-3-ol (102 mg, 0.70 mmol) was added and the solution stirred at 80oC for 30 min. The solution was concentrated and the residue purified by semi-prep HPLC (5-65% MeCN in 0.05% NH4OH (aq) over 12 min) to afford (2,2,5,5- tetramethyloxolan-3-yl) N-(6-bromoimidazo[1,2-a]pyridin-2-yl)carbamate (51 mg, 38% yield) as a clear glass. LCMS: RT = 0.62 min; ES-MS [M+1]+: 382.1, 384.1. (2,2,5,5-tetramethyloxolan-3-yl) N-(6-bromoimidazo[1,2-a]pyridin-2-yl)carbamate (15 mg, 0.04 mmol), picoline-4-boronic acid (8 mg, 0.06 mmol), potassium carbonate (11 mg, 0.08 mmol) and dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct 3 mg, 0.01 mmol) in DMA (0.5 mL) and water (0.1 mL) was stirred at 90oC for 2 hr. The solution was purified by semi-prep HPLC (eluting with 2-60% MeCN in 0.05% NH4OH (aq) over 10 min) to afford the title compound (3 mg, 20 % yield) as a tan solid. LCMS: RT = 0.51 min; ES-MS [M+1]+: 396.2. Example 19. N-(6-(2-methylpyridin-4-yl)imidazo[1,2-a]pyridin-2-yl)spiro[2.2]pentane-1-carboxamide N-(6-bromoimidazo[1,2-a]pyridin-2-yl)spiro[2.2]pentane-2-carboxamide (15 mg, 0.05 mmol), picoline-4-boronic acid (10 mg, 0.07 mmol), dichloro[1,1- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (4 mg, 0.01 mmol) and potassium carbonate (21 mg, 0.15 mmol) in DMA (0.5 mL) and water (0.1 mL) was stirred at 100oC for 3 hr. The mixture was filtered and the filtrate purified by semi-prep HPLC (5-90% MeCN in 0.1% TFA (aq) over 10 min) to afford the title compound (7 mg, 42% yield) as an off- white solid. LCMS: RT = 0.43 min; ES-MS [M+1]+: 319.2. Example 20. 6-(6-methylpyridazin-4-yl)-N-(tetrahydrofuran-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2- amine 2,6-dibromo-[1,2,4]triazolo[1,5-a]pyridine (40 mg, 0.14 mmol)and oxolan-3-amine (378 mg, 4.3 mmol) were stirred at reflux for 4 hr. The mixture was purified by flash chromatography (eluting with 10-60% EtOAc in hexanes over 20 min) to afford 6-bromo-N-(oxolan-3-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine (20 mg, 49% yield) as a white solid. LCMS: RT = 0.53 min; ES-MS [M+1]+: 283.0, 285.0 6-bromo-N-(oxolan-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (20 mg, 0.07 mmol), 3- methylpyridazine-5-boronic acid pinacol ester (23 mg, 0.11 mmol), potassium carbonate (30 mg, 0.21 mmol) and Ruphos Palladacycle Gen3 (6 mg, 0.01 mmol) in THF (0.6 mL) and water (0.15 mL) was stirred at 90oC for 1 hr. The solution was purified by semi-prep HPLC (eluting with 10- 80% MeCN in 0.1% TFA (aq) over 10 min) to afford the title compound (2 mg, 7% yield) as a white solid. LCMS: RT = 0.39 min; ES-MS [M+1]+: 297.2. Example 21. 1-benzyl-3-(6-(6-methylpyridazin-4-yl)imidazo[1,2-a]pyridin-2-yl)urea 2-amino-6-bromoimidazo[1,2-a]pyridine (30 mg, 0.14 mmol) and 4-nitrophenyl chloroformate (57 mg, 0.28 mmol) in pyridine (1 mL) were stirred at RT for 30 min. Benzylamine (30 mg, 0.28 mmol) was added and the solution stirred at RT for 2 hr. The solution was purified by semi-prep HPLC (eluting with 5-90% MeCN in 0.05% NH4OH (aq) over 10 min) to afford 1- benzyl-3-(6-bromoimidazo[1,2-a]pyridin-2-yl)urea (36 mg, 74% yield) as a white solid. LCMS: RT = 0.64 min; ES-MS [M+1]+: 345.1, 347.1 1-benzyl-3-(6-bromoimidazo[1,2-a]pyridin-2-yl)urea (12 mg, 0.03 mmol), 3- methylpyridazine-5-boronic acid pinacol ester (12 mg, 0.06 mmol), potassium carbonate (15 mg, 0.10 mmol) and dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (3 mg, 0.01 mmol) in DMA (0.5 mL) and water (0.1 mL) was stirred at 100oC for 30 min. The solution was purified by semi-prep HPLC (eluting with 5-70% MeCN in 0.05% NH4OH (aq) over 10 min) to afford the title compound (3 mg, 24% yield) as a white solid. LCMS: RT = 0.49 min; ES-MS [M+1]+: 326.0, 328.0. Example 22. tetrahydrofuran-3-yl (6-(2-methylpyridin-4-yl)imidazo[1,2-a]pyridin-2-yl)carbamate 4-nitrophenyl chloroformate (124 mg, 0.61 mmol) and 2-amino-6-bromoimidazo[1,2- a]pyridine (65 mg, 0.31 mmol) in pyridine (1 mL) was stirred at RT for 30 min. Oxolan-3-ol (27 mg, 0.31 mmol) was added and the solution stirred at 80oC for 30 min. The solution was concentrated and the residue purified by semi-prep HPLC (eluting with 5-65% MeCN in 0.05% NH4OH (aq) over 10 min) to afford oxolan-3-yl N-(6-bromoimidazo[1,2-a]pyridin-2-yl)carbamate (63 mg, 64% yield) as a white solid. LCMS: RT = 0.50 min; ES-MS [M+1]+: 359.2. Oxolan-3-yl N-(6-bromoimidazo[1,2-a]pyridin-2-yl)carbamate (30 mg, 0.09 mmol), picoline-4-boronic acid (25 mg, 0.18 mmol), potassium carbonate (39 mg, 0.27 mmol) and dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (7 mg, 0.01 mmol) in DMF (1 mL) and water (0.2 mL) was stirred at 80oC for 30 min. The solution was purified by semi-prep HPLC (eluting with 5-65% MeCN in 0.05% NH4OH (aq) over 10 min) to afford the title compound (6 mg, 19% yield) as a white solid. LCMS: RT = 0.48 min; ES-MS [M+1]+: 339.3. Example 23. 2-methyl-N-(6-(2-methylpyridin-4-yl)imidazo[1,2-a]pyridin-2-yl)propane-1-sulfonamide 6-(2-methyl-4-pyridinyl)imidazo[1,2-a]pyridin-2-amine (20 mg, 0.09 mmol), isobutanesulfonyl chloride (14 mg, 0.09 mmol) and N,N-diisopropylethylamine (0.03 mL, 0.18 mmol) in DMA (0.5 mL) was stirred at RT for 1 hr. The solution was purified by semi-prep HPLC (eluting with 2-50% MeCN in 0.05% NH4OH (aq) over 10 min) to afford the title compound as a white solid. LCMS: RT = 0.44 min; ES-MS [M+1]+: 345.2. Example 24. (1R,2R)-N-(6-(benzo[d]thiazol-6-yl)imidazo[1,2-a]pyridin-2-yl)-2-cyanocyclopropane-1- carboxamide N-(6-bromoimidazo[1,2-a]pyridin-2-yl)spiro[2.2]pentane-2-carboxamide (15 mg, 0.05 mmol), 1,3-benzothiazol-6-ylboronic acid (11 mg, 0.06 mmol), potassium carbonate (21 mg, 0.15 mmol) and dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (4 mg, 0.01 mmol) in DMA (0.5 mL) and water (0.1 mL) was stirred at 100oC for 2 hr. The solution was purified by semi-prep HPLC (5-90% MeCN in0.1% TFA (aq) over 10 min) to afford the title compound (5 mg, 26 % yield) as a white solid. LCMS: RT = 0.44 min; ES-MS [M+1]+: 345.2. Example 25. 1-(6-(6-methylpyridazin-4-yl)imidazo[1,2-a]pyridin-2-yl)-3-(1-(pyridin-3- yl)cyclopropyl)urea 2-amino-6-bromoimidazo[1,2-a]pyridine (30 mg, 0.14 mmol) and 4- nitrophenylchloroformate (57 mg, 0.28 mmol) in pyridine (1 mL) was stirred at RT for 30 min. 1- (3-pyridyl)cyclopropylamine (57 mg, 0.42 mmol) was added and the mixture stirred at RT for 16 hr. The solution was purified by semi-prep HPLC (eluting with 5-90% MeCN in 0.05% NH4OH (aq) over 10 min) to afford 1-(6-bromoimidazo[1,2-a]pyridin-2-yl)-3-(1-pyridin-3- ylcyclopropyl)urea (40 mg, 76% yield) as a white solid. LCMS: RT = 0.53 min; ES-MS [M+1]+: 372.1, 374.1. 1-(6-bromoimidazo[1,2-a]pyridin-2-yl)-3-(1-pyridin-3-ylcyclopropyl)urea (20 mg, 0.05 mmol), 3-methylpyridazine-5-boronic acid pinacol ester (19 mg, 0.09 mmol), potassium carbonate (23 mg, 0.16 mmol) and dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (4 mg, 0.01 mmol) in DMA (0.5 mL) and water (0.1 mL) was stirred at 100oC at 30 min. The solution was purified by semi-prep HPLC (eluting with 5-70% MeCN in 0.05% NH4OH (aq) over 10 min) to afford the title compound (3 mg, 14% yield) as a white solid. LCMS: RT = 0.42 min; ES-MS [M+1]+: 386.3. Example 24. 1-fluoro-N-(6-(1-methyl-1H-benzo[d]imidazol-6-yl)imidazo[1,2-a]pyridin-2- yl)cyclopropane-1-carboxamide HATU (14.3 g, 38 mmol) was added in portions to 1-fluorocyclopropanecarboxylic acid (2.9 g, 28.3mmol) and 2-amino-6-bromoimidazo[1,2-a]pyridine (4.0 g, 18.9 mmol) in pyridine (40 mL) at 0oC then was stirred at 0oC for 1 hr. The solution concentrated and the residue was dissolved in a minimum of DMSO then purified by semi-prep HPLC (eluting with 2-60% MeCN in 0.1% TFA (aq) over 25 min.) The elutant was basified with sat. Na2CO3 (aq) then extracted with 3:1 CHCl3:IPA (2x). The combined organics were washed with brine, dried over Na2SO4 then concentrated to afford the title compound (1.91g, 34 % yield) as a tan solid. LCMS: RT = 0.50 min; ES-MS [M+1]+: 298.0, 300.0. N-(6-bromoimidazo[1,2-a]pyridin-2-yl)-1-fluorocyclopropane-1-carboxamide (20 mg, 0.07 mmol), 1-methyl-6-(4455-tetramethyl-132-dioxaborolan-2-yl)benzimidazole (34 mg, 0.13 mmol), potassium carbonate (28 mg, 0.20 mmol) and Ruphos Palladacycle Gen3 (6 mg, 0.01 mmol) in THF (0.5 mL) and water (0.1 mL) was stirred at 90oC for 1 hr. The solution was purified by semi-prep HPLC (eluting with 2-60% MeCN in 0.05% NH4OH(aq) over 12 min) to give the title compound (13 mg, 55% yield) as an off-white solid. LCMS: RT = 0.40 min; ES-MS [M+1]+: 350.2. Example 25. 1-fluoro-N-(6-(thiazolo[4,5-b]pyridin-6-yl)imidazo[1,2-a]pyridin-2-yl)cyclopropane-1- carboxamide N-(6-bromoimidazo[1,2-a]pyridin-2-yl)-1-fluorocyclopropane-1-carboxamide (75 mg, 0.25 mmol), potassium acetate (74 mg, 0.76 mmol), dichloro[1,1- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (18 mg, 0.03 mmol), and bis(pinacolato)diboron (96 mg, 0.38 mmol) in 1,4 dioxane (3 mL) was stirred at 100oC for 2 hr. The mixture was filtered then concentrated to give 1-fluoro-N-[6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)imidazo[1,2-a]pyridin-2-yl]cyclopropane-1-carboxamide (85 mg, 98% yield) which was used without purification. LCMS: RT = 0.37 min; ES-MS [M+1]+: 264.1. 1-fluoro-N-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridin-2- yl]cyclopropane-1-carboxamide (13 mg, 0.04 mmol), 6-bromothiazolo[4,5-b]pyridine (10 mg, 0.04 mmol), dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (2 mg, 0.01 mmol), and potassium carbonate (16 mg, 0.11 mmol) in DMA (1 mL) and water (0.2 mL) was stirred at 90oC for 4 hr. The mixture was filtered and the filtrate purified by semi-prep HPLC (eluting with 5-90% MeCN in 0.05% NH4OH (aq) over 10 min) to afford the title compound (5 mg, 40% yield) as a white solid. LCMS: RT = 0.49 min; ES-MS [M+1]+: 354.1. Example 26. 1-fluoro-N-(6-(quinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropane-1- carboxamide 6-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-amine (500 mg, 2.34 mmol), 1- fluorocyclopropane carboxylic acid (488 mg, 4.69 mmol), HATU (1.78 g, 4.69 mmol) and N,N- diisopropylethylamine (1.22 mL, 7.04 mmol) in DMF (9 mL) was stirred at 90oC for 1 hr. The reaction was purified by semi-prep HPLC (eluting with 2-50% MeCN in 0.1% TFA (aq) over 14 min) to afford N-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-1-fluorocyclopropane-1- carboxamide (320 mg, 46% yield) as a tan solid. LCMS: RT = 0.41 min; ES-MS [M+1]+: 299.1, 301.1. N-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-1-fluorocyclopropane-1-carboxamide (34 mg, 0.11 mmol), quinoline-6-boronic acid (39 mg, 0.23 mmol), dichloro[1,1- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (8 mg, 0.01 mmol) and potassium carbonate (48 mg, 0.34 mmol) in DMA (1 mL) and water (0.2 mL) was stirred at 90oC for 1 hr. The solution was purified by semi-prep HPLC (2-50% MeCN in 0.1% TFA (aq) over 10 min) to afford the title compound (13 mg, 32% yield) as a tan solid. LCMS: RT = 0.42 min; ES- MS [M+1]+: 348.2.
Example 27. 1-fluoro-N-(6-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-b]pyridazin-2-yl)cyclopropane- 1-carboxamide 6-bromo-[1,2,4]triazolo[1,5-b]pyridazin-2-amine (50 mg, 0.24 mmol), 1- fluorocyclopropane carboxylic acid (26 mg, 0.26 mmol), N,N-diisopropylethylamine (0.12 mL, 0.70 mmol) and HATU (133 mg, 0.35 mmol) in pyridine (1 mL) was stirred at RT for 1 hr. The solution was concentrated and the residue purified by flash chromatography (eluting with 0-10% MeOH in DCM over 20 min) to afford N-(6-bromo-[1,2,4]triazolo[1,5-b]pyridazin-2-yl)-1- fluorocyclopropane-1-carboxamide (27 mg, 39% yield) as a white solid. LCMS: RT = 0.43 min; ES-MS [M+1]+: 300.0, 302.0. N-(6-bromo-[1,2,4]triazolo[1,5-b]pyridazin-2-yl)-1-fluorocyclopropane-1-carboxamide (9 mg, 0.03 mmol), 2-picoline-4-boronic acid pinacol ester (10 mg, 0.04 mmol), potassium carbonate (13 mg, 0.09 mmol) and Ruphos Palladacycle Gen3 (3 mg, 0.01 mmol) in THF (0.6 mL) and water (0.15 mL) was stirred at 90oC for 1 hr. The solution was purified by semi-prep HPLC (eluting with 10-90% MeCN in 0.05% NH4OH (aq) over 10 min) to afford the title compound (4 mg, 39% yield) as a white solid. LCMS: RT = 0.44 min; ES-MS [M+1]+: 313.2. Example 28. 4-fluoro-N-(6-(6-methylpyridazin-4-yl)-[1,2,4]triazolo[1,5-b]pyridazin-2-yl)tetrahydro- 2H-pyran-4-carboxamide
6-bromo-[1,2,4]triazolo[1,5-b]pyridazin-2-amine (60 mg, 0.28 mmol), 4-fluoroxane-4- carboxylic acid (42 mg, 0.28 mmol), 4-dimethylaminopyridine (103 mg, 0.84 mmol) and HATU (213 mg, 0.56 mmol) in DMA (1 mL) was stirred at 50oC for 90 min. The mixture was diluted with DCM and water. The organics were separated and concentrated. The residue was purified by flash chromatography (eluting with 20-90% EtOAc in hexanes over 20 min) to afford N-(6- bromo-[1,2,4]triazolo[1,5-b]pyridazin-2-yl)-4-fluorooxane-4-carboxamide (18 mg, 19% yield) as a white solid. LCMS: RT = 0.42 min; ES-MS [M+1]+: 344.0, 346.0. N-(6-bromo-[1,2,4]triazolo[1,5-b]pyridazin-2-yl)-4-fluorooxane-4-carboxamide (18 mg, 0.05 mmol), 3-methylpyridazine-5-boronic acid pinacol ester (16 mg, 0.07 mmol), potassium carbonate (18 mg, 0.13 mmol) and dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (3 mg, 0.01 mmol) in DMA (0.5 mL) and water (0.1 mL) was stirred at 100oC for 30 min. The solution was purified by semi-prep HPLC (eluting with 2-70% MeCN in 0.05% NH4OH (aq) over 10 min) to afford the title compound (2 mg, 9% yield) as a white solid. LCMS: RT = 0.37 min; ES-MS [M+1]+: 358.2. Example 29. 4-Fluoro-N-(6-(2-methylpyrimidin-5-yl)imidazo[1,2-a]pyridin-2-yl)tetrahydro-2H-pyran-4- carboxamide 4-Fluoro-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridin-2- yl)tetrahy-dro-2H-pyran-4-carboxamide (23 mg, 0.058 mmol), 5-bromo-2-methylpyrimidine (13 mg, 0.076 mmol), dichloro[1,1’-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (2 mg, 0.003 mmol) and potassium carbonate (25 mg, 0.18 mmol) in DMA (0.5 mL) and water (0.1 mL) was stirred at 90 oC for 3 hr. The reaction was syringe filtered, washing with DMSO and purified via RP-HPLC, 0-40% MeCN/0.05% aqueous NH4OH. Fractions containing the product were concentrated and repurified via flash column chromatography on silica gel (0- 100% EtOAc/Hexanes) to afford 6 mg (30% yield) of the title compound as a white solid. 1H NMR (400 MHz, DMSO) į 10.80 (d, J = 2.2 Hz, 1H), 9.10 (dd, J = 1.9, 1.0 Hz, 1H), 9.06 (s, 2H), 8.20 (d, J = 0.7 Hz, 1H), 7.69 (dd, J = 9.3, 1.9 Hz, 1H), 7.60 (dt, J = 9.3, 0.8 Hz, 1H), 3.90 – 3.81 (m, 2H), 3.61 (td, J = 11.8, 2.3 Hz, 2H), 2.68 (s, 3H), 2.16 (dtd, J = 37.8, 13.3, 12.7, 5.3 Hz, 2H), 1.87 (t, J = 12.6 Hz, 2H). LCMS: RT = 0.45 min; ES-MS [M+1]+: 356.2. Example 30. N-(6-(3-cyano-5-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-4-fluorotetrahydro-2H-pyran-4- carboxamide Prepared in a similar manner to 4-Fluoro-N-(6-(2-methylpyrimidin-5-yl)imidazo[1,2- a]pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide to afford 3 mg (13% yield) of the title compound as a white solid. 1H NMR (400 MHz, DMSO) į 10.78 (d, J = 2.2 Hz, 1H), 9.09 (dd, J = 2.0, 1.0 Hz, 1H), 8.18 (d, J = 0.6 Hz, 1H), 7.79 (t, J = 1.5 Hz, 1H), 7.69 (dd, J = 9.4, 1.9 Hz, 1H), 7.61 (dd, J = 2.5, 1.6 Hz, 1H), 7.55 (dt, J = 9.3, 0.8 Hz, 1H), 7.46 (dd, J = 2.5, 1.3 Hz, 1H), 3.91 (s, 3H), 3.89 – 3.81 (m, 2H), 3.68 – 3.55 (m, 2H), 2.16 (dtd, J = 37.7, 13.3, 12.7, 5.3 Hz, 2H), 1.86 (t, J = 12.6 Hz, 2H). LCMS: RT=0.64 min; ES-MS [M+1]+: 395.4. Example 31. 4-Fluoro-N-(6-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide Prepared in a similar manner to 4-Fluoro-N-(6-(2-methylpyrimidin-5-yl)imidazo[1,2-a]pyridin- 2-yl)tetrahydro-2H-pyran-4-carboxamide to afford 2 mg (8% yield) of the title compound as a white solid. LCMS: RT=0.52 min; ES-MS [M+1]+: 358.3. Example 32. 4-Fluoro-N-(6-(3-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide Prepared in a similar manner to 4-Fluoro-N-(6-(2-methylpyrimidin-5-yl)imidazo[1,2-a]pyridin- 2-yl)tetrahydro-2H-pyran-4-carboxamide to afford 11 mg (50% yield) of the title compound as a white solid. LCMS: RT=0.57 min; ES-MS [M+1]+: 358.1. Example 33. 4-Fluoro-N-(6-(6-oxo-1,6-dihydropyridazin-3-yl)imidazo[1,2-a]pyridin-2-yl)tetrahydro-2H- pyran-4-carboxamide Prepared in a similar manner to 4-Fluoro-N-(6-(2-methylpyrimidin-5-yl)imidazo[1,2-a]pyridin- 2-yl)tetrahydro-2H-pyran-4-carboxamide to afford 4 mg (16%) of the title compound. LCMS: RT=0.40 min; ES-MS [M+1]+: 358.2. Example 34. N-(6-(benzo[d]thiazol-6-yl)imidazo[1,2-b]pyridazin-2-yl)-3-fluorotetra-hydrofuran-3- carboxamide N-(6-Chloroimidazo[1,2-b]pyridazin-2-yl)-3-fluorotetrahydrofuran-3-carboxamide (24.0 mg, 0.084 mmol), benzo[d]thiazol-6-ylboronic acid (22.6 mg, 0.126 mmol), K2CO3 (35.5 mg, 0.253 mmol), and RuPhos-Pd-G3 (7.1 mg, 0.009 mmol) in THF (0.6 mL) and water (0.15 mL) was heated at 120 oC under microwave irradiation for one hour. The reaction was diluted with THF (1 mL) and syringe filtered. The filtrate was purified via RP-HPLC, 5-95% CH3CN/0.05% aqueous NH4OH. Fractions containing the product were concentrated to afford the title compound as a white solid. LCMS: RT = 0.57 min; ES-MS [M+1]+ = 384.1. Example 35. 2,2,5,5-tetramethyl-N-(6-(2-methylpyridin-4-yl)imidazo[1,2-a]pyridin-2-yl)tetrahydrofuran-3- carboxamide N-(6-bromoimidazo[1,2-a]pyridin-2-yl)-2,2,5,5-tetramethyloxolane-3-carboxamide (33 mg, 0.09 mmol) 2-picoline-4-boronic acid pinacol ester (31.7 mg, 0.14mmol), dichloro[1,1'- bis(diphenylphosphino)ferrocene]palladium (II) dicloromethane adduct (3.95 mg, 0.005 mmol) and potassium carbonate (33.8 mg, 0.24 mmol) in DMA (0.5mL) and water (0.1mL) was heated to 90 °C and stirred for 2 hr. The solution was cooled to ambient temperature and was purified by semi-prep HPLC (2-60% MeCN in 0.05% NH4OH (aq) over 12 min) to give the title compound (2.5 mg, 6.8% yield) as a colorless glass. LCMS: RT = 0.61 min; ES-MS [M+1]+ = 379.1. Example 36. 2,2,6,6-tetramethyl-N-[6-(2-methylpyridin-4-yl)imidazo[1,2-a]pyridin-2-yl]oxane-4- carboxamide Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dicloromethane adduct (5.76mg, 0.01mmol), potassium carbonate (20 mg, 0.12 mmol), 2-picoline-4-boronic acid pinacol ester (25.8mg, 0.12mmol) and N-(6-bromoimidazo[1,2-a]pyridin-2-yl)-2,2,6,6-tetramethyloxane-4- carboxamide (29.84 mg, 0.08 mmol)in DMA (0.3 mL) and water (0.08 mL) was heated to 100 °C while stirring for one hour. The vial was cooled and diluted with DCM. The mixture was filtered using a syringe filter and purified by flash column chromatography on silica gel 0-7% MeOH / NH4OH IN DCM). The desired organic fractions were combined and concentrated to provide the title compound (22.1 mg, 72 % yield) as a colorless glass. LCMS: RT = 0.650 min; ES-MS [M+1]+ = 393.1. Example 37. 2,2-dimethyl-N-(6-(2-methylpyridin-4-yl)imidazo[1,2-b]pyridazin-2-yl)tetra-hydro-2H-pyran-4- carboxamide N-(6-Chloroimidazo[1,2-b]pyridazin-2-yl)-2,2-dimethyltetrahydro-2H-pyran-4-carboxamide (70.0 mg, 0.227 mmol), (2-methylpyridin-4-yl)boronic acid (46.6 mg, 0.340 mmol), K2CO3 (95.4 mg, 0.680 mmol), and RuPhos-Pd-G3 (18.9 mg, 0.023 mmol) in THF (0.8 mL) and water (0.2 mL)was heated at 120 oC under microwave irradiation for one hour. The reaction was diluted with THF (1 mL) and syringe filtered. The filtrate was purified via RP-HPLC, 5-95% CH3CN/0.05% aqueous NH4OH. Fractions containing the product were concentrated to afford the title compound as a white solid. LCMS: RT = 0.54 min, ES-MS [M+H]+ = 366.2. Example 38. N-benzyl-6-(6-methylpyridazin-4-yl)benzo[d]thiazol-2-amine
Compound was prepared as previously exemplified according to General Scheme 4 via Suzuki coupling to afford the title compound (9 mg, 58% yield) as a white solid. LCMS: RT = 0.62 min; ES-MS [M+1]+: 332.0. Example 39. N-(1-fluorocyclopropyl)-6-(2-methylpyridin-4-yl)benzo[d]oxazole-2-carboxamide 6-bromo-1,3-benzoxazol-2-amine (100 mg, 0.47 mmol), 1-fluorocyclopropanecarboxylic acid (59 mg, 0.56 mmol), N,N-diisoproplyethylamine (0.24 mL, 1.41 mmol) and HATU (268 mg, 0.7 mmol) in DMA (2 mL) was stirred at RT for 30 min. The solution was purified by semi-prep HPLC (eluting with 5-45% MeCN in 0.05% NH4OH (aq) over 10 min) to afford N-(6-bromo-1,3- benzoxazol-2-yl)-1-fluorocyclopropane-1-carboxamide (71 mg, 51% yield) as a white solid. LCMS: RT = 0.51 min; ES-MS [M+1]+: 299.0, 301.0. N-(6-bromo-1,3-benzoxazol-2-yl)-1-fluorocyclopropane-1-carboxamide (20 mg, 0.07 mmol), picoline-4-boronic acid (14 mg, 0.10 mmol), potassium carbonate (28 mg, 0.01 mmol) and dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (6 mg, 0.01 mmol) in DMA (0.5 mL) and water (0.1 mL) was stirred at 90oC for 4 hr. The mixture was filtered and the filtrate purified by semi-prep HPLC (eluting with 5-80% MeCN in 0.05% NH4OH (aq) over 10 min) to afford the title compound (9 mg, 42% yield) as a white solid. LCMS: RT = 0.44 min; ES-MS [M+1]+: 312.1
Example 40. 2-fluoro-5-methoxy-N-(6-(2-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)benzamide 2-fluoro-5-methoxybenzoic acid (19 mg, 0.11 mmol), 6-bromoimidazol[1,2-a]pyrimidin- 2-amine (20 mg, 0.09 mmol), N,N-diisopropylethylamine (0.05 mL, 0.28 mmol) and HATU (54 mg, 0.14 mmol) in DMF (0.6 ml) was stirred at RT for 2 hr. The solution was purified by semi- prep HPLC (eluting with 2-60% MeCN in 0.05% NH4OH (aq) over 10 min) to afford N-(6- bromoimidazo[1,2-a]pyrimidin-2-yl)-2-fluoro-5-methoxybenzamide (5 mg, 15% yield) as a clear glass. LCMS: RT = 0.58 min; ES-MS [M+1]+: 365.1, 367.1. N-(6-bromoimidazo[1,2-a]pyrimidin-2-yl)-2-fluoro-5-methoxybenzamide (5 mg, 0.01 mmol), Ruphos Palladacycle Gen3 (1 mg, 0.001 mmol), potassium carbonate (6 mg, 0.04 mmol) and picoline-4-boronic acid (3 mg, 0.02 mmol) in THF (0.6 mL) and water (0.1 mL) was stirred at 90oC for 1 hr. The mixture was purified by semi-prep HPLC (eluting with 10-88% MeCN in 0.05% NH4OH (aq) over 10 min) to afford the title compound (1.3 mg, 25% yield) as a pale yellow solid. LCMS: RT = 0.51 min; ES-MS [M+1]+: 378.2. Example 41. 4-cyano-N-(6-(2-methylpyridin-4-yl)imidazo[1,2-a]pyrazin-2-yl)tetrahydro-2H-pyran-4- carboxamide N H O N N O N N N 4-cyanotetrahydro-2H-pyran-4-carboxylic acid (13 mg, 0.08 mmol), 6-bromoimidazo[1,2- a]pyrazin-2-amine (15 mg, 0.07 mmol), N,N-diisopropylethylamine (0.04 mL, 0.21 mmol) and HATU (40 mg, 0.11 mmol) in DMA (0.5 mL) was stirred at RT for 2 hr. The solution was purified by semi-prep HPLC (eluting with 2-60% MeCN in 0.05% NH4OH (aq) over 10 min) to afford N- (6-bromoimidazo[1,2-a]pyrazine-2-yl)-4-cyanooxane-4-carboxamide (8 mg, 32% yield) as a clear glass. LCMS: RT = 0.49 min; ES-MS [M+1]+: 350.0, 352.0. N-(6-bromoimidazo[1,2-a]pyrazine-2-yl)-4-cyanooxane-4-carboxamide (8 mg, 0.02 mmol), potassium carbonate (10 mg, 0.07 mml), Ruphos Palladacycle Gen3 (2 mg, 0.002 mmol), and picoline-4-boronic acid (5 mg, 0.03 mmol) in THF (0.6 mL) and water (0.1 mL) was stirred at 120oC for hr. The mixture was filtered and the filtrate purified by semi-prep HPLC (eluting with 10-88% MeCN in 0.05% NH4OH (aq) over 10 min) to afford the title compound (3.6 mg, 42% yield) as a white solid. LCMS: RT = 0.46 min; ES-MS [M+1]+: 363.2. Example 42. N-(6-(2-methylpyridin-4-yl)imidazo[1,2-a]pyrazin-2-yl)tetrahydrothiophene-3- carboxamide 1,1-dioxide The compound was prepared as previously exemplified by General Scheme 7 in a manner analogous to Example 41 using Suzuki coupling to afford the title compound (3.5 mg, 68% yield) as a white solid. LCMS: RT = 0.46 min; ES-MS [M+1]+: 372.2.
Example 43. 2-(4,4-difluorocyclohexyl)-N-(6-(2-methylpyridin-4-yl)imidazo[1,2-a]pyrazin-2- yl)acetamide The compound was prepared as previously exemplified by General Scheme 7 in a manner analogous to Example 41 using Suzuki coupling to afford the title compound (9 mg, 75% yield) as a white solid. LCMS: RT = 0.59 min; ES-MS [M+1]+: 386.3. Example 44. (1S,2S)-2-fluoro-N-(6-(6-methylpyridazin-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane- 1-carboxamide The compound was prepared as previously exemplified by General Scheme 7 in a manner analogous to Example 41 using Suzuki coupling to afford the title compound (5 mg, 30% yield) as a white solid. LCMS: RT = 0.45 min; ES-MS [M+1]+: 331.2.
Example 45. 1-fluoro-N-(6-(6-methylpyridazin-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1- carboxamide The compound was prepared as previously exemplified by General Scheme 7 in a manner analogous to Example 41 using Suzuki coupling to afford the title compound (4 mg, 21% yield) as a white solid. LCMS: RT = 0.55 min; ES-MS [M+1]+: 313.2. Example 46. N-(6-(2-methylpyridin-4-yl)imidazo[1,2-a]pyridin-2-yl)-6-oxaspiro[2.5]octane-1- carboxamide The compound was prepared as previously exemplified according to General Scheme 1 using a Suzuki coupling to afford the title compound (5.7 mg, 31% yield) as a white solid. LCMS: RT = 0.40 min; ES-MS [M+1]+: 363.2.
Example 47. N-(6-(benzo[d]thiazol-6-yl)imidazo[1,2-a]pyrazin-2-yl)-2,2-dimethylcyclopropane-1- carboxamide The compound was prepared as previously exemplified by General Scheme 7 in a manner analogous to Example 41 using Suzuki coupling to afford the title compound (6 mg, 30% yield) as a white solid. LCMS: RT = 0.64 min; ES-MS [M+1]+: 364.3. Example 48. 1-(6-(2-methylpyridin-4-yl)imidazo[1,2-a]pyridin-2-yl)-3-(thiophen-3-yl)urea The compound was prepared as previously exemplified by General Scheme 7 in a manner analogous to Example 4 using Suzuki couplingand urea coupling to afford the title compound (8 mg, 54% yield) as a white solid. LCMS: RT = 0.58 min; ES-MS [M+1]+: 350.1.
Example 49. 4,4-difluoro-N-(6-(2-methylpyridin-4-yl)imidazo[1,2-a]pyridin-2-yl)piperidine-1- carboxamide The compound was prepared as previously exemplified by General Scheme 1 in a manner analogous to Example 4 using Suzuki coupling to afford the title compound (3.2 mg, 21% yield) as a white solid. LCMS: RT = 0.54 min; ES-MS [M+1]+: 372.3. Example 50. 2,2-dimethyl-N-(6-(quinolin-6-yl)imidazo[1,2-a]pyridin-2-yl)cyclopropane-1- carboxamide The compound was prepared as previously exemplified by General Scheme 1 in a manner analogous to Example 9 using Suzuki coupling to afford the title compound (5 mg, 30% yield) as a white solid. LCMS: RT = 0.64 min; ES-MS [M+1]+: 357.3. Example 51. 3-methyl-N-(6-(quinolin-6-yl)imidazo[1,2-a]pyridin-2-yl)butanamide H N N O N N The compound was prepared as previously exemplified by General Scheme 1 in a manner analogous to Example 41 Suzuki coupling to afford the title compound (12 mg, 68% yield) as a white solid. LCMS: RT = 0.47 min; ES-MS [M+1]+: 345.2. Example 52. N-(6-(benzo[d]thiazol-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-1-methyl-1H-pyrazole-4- carboxamide The compound was prepared as previously exemplified by General Scheme 6 in a manner analogous to Example 14 using Suzuki coupling to afford the title compound (5.6 mg, 33% yield) as a white solid. LCMS: RT = 0.62 min; ES-MS [M+1]+: 376.2.
Example 53. 1-fluoro-N-(6-(7-fluoro-1H-benzo[d]imidazol-5-yl)imidazo[1,2-a]pyridin-2- yl)cyclopropane-1-carboxamide The compound was prepared as previously exemplified by General Scheme 2 in a manner analogous to Example 24 using Suzuki coupling to afford the title compound (1.5 mg, 14% yield) as a white solid. LCMS: RT = 0.50 min; ES-MS [M+1]+: 354.1. Example 54. N-(6-(benzo[c][1,2,5]oxadiazol-5-yl)imidazo[1,2-a]pyridin-2-yl)-1-fluorocyclopropane- 1-carboxamide The compound was prepared as previously exemplified by General Scheme 2 in a manner analogous to Example 24 Suzuki coupling to afford the title compound (5.3 mg, 39% yield) as a white solid. LCMS: RT = 0.66 min; ES-MS [M+1]+: 338.2.
Example 55. l-fluoro-bl-(6-(6-(pyrrolidin-l-yl)pyridazin-4-yl)imidazo[l,2-a]pyridin-2- yl) cyclopropane- 1 -carboxamide
Figure imgf000282_0001
The compound was prepared as previously exemplified by General Scheme 2 in a manner analogous to Example 8 Suzuki coupling to afford the title compound (9 nig, 65% yield) as a white solid. LCMS: RT = 0.54 mm; ES-MS [M+l]+: 367.2.
Example 56.
3-jhu)ro~N~(6-(2-meAhylpyridin~4-yl)imidazo[I/2~a]pyrazin-2-yl)oxeiane~3~carboxamicle
Figure imgf000282_0002
The compound was prepared as previously exemplified by General Scheme 2 in a manner analogous to Example 4 using Suzuki coupling to afford the title compound (4.7 mg, 28% yield) as a white solid. LCMS: RT - 0.44 mm; ES-MS [ M I j . 328.2. Example 57.
The remaining compounds disclosed herein (for example, the compounds disclosed in Tables 1 and 2) whose procedure is not shown above were prepared using procedures similar to those shown above, with appropriate modifications within the purview of one having ordinary skill in the art. For example, Table 2 provides an exemplary list of general schemes and corresponding compounds that were synthesized using these intermediates in amide coupling reactions, urea couplings reactions, carbamate coupling reactions, and alkylation reactions analogous to those provided herein.
Table 2
Figure imgf000283_0001
Figure imgf000284_0001
Remaining compounds were similarly synthesized according to analogous procedures set forth above, e.g., General Schemes 1-8, which will be apparent to those skilled in the art. Calculated and observed mass values for compounds synthesized as described herein herein are provided in Table 3 below.
Example 58: DRYK1A Inhibition Assay
Materials
DYRK I A Invitrogen # - PR7189B Z’ -LYTE Kinase assay kit - Invitrogen #PV4319 5X Kinase Buffer - Invitrogen #PV3189 Ser/Thr 18 peptide - Invitrogen # PV4320 Phos-Ser/Thr 18 peptide - Invitrogen # PV4321 ATP - Invitrogen # PV3227 Development reagent A - Invitrogen # PV3295 Development buffer B- Invitrogen # P3127 Stop reagent - Invitrogen # P3094 Assay plate - Corning # 4514 Final Compound Concentrations
Assay buffer: 50 mM HEPES pH7.5, W mM MgCh, 1 mM EGTA, 0.01% Bnj-35
DYRK1A: 2 n\l
ATP: 20 pM
Ser/Thr 18 peptide: 2 pM
Reaction time: 90 minutes
Compound preparation
1. Test compounds were diluted to ImM in DMSO
2. Stock was serially diluted 1:4 into 10-point concentration response curves in DA-ISO using a Bravo Liquid Handler (Agilent) in a 384 well microplate.
3. 100 nl of the diluted compounds was transferred to columns 3-22 in an assay plate using an Echo plate reformat protocol.
4. 100 nL of DMSO control was added to Columns 1, 2, 23, and 24.
Assay Procedure
1 . Add 5 pL enzyme (2X) to each well in Column 2-23, and 5 pL IX kinase buffer to column 1 and 24 in a 384- well assay plate.
2. Spin the assay plate (100 x g, 1 minute @ 25°C).
3. Incubate enzyme with compounds for 15 minutes at 25°C.
4. Add 5 uL ATP and substrate mixture (2X) to each well in Column 2-23.
5. Add 5 pL ATP and substrate mixture (2X) to Al-Hl and A24-H24 wells for 0% Phosph ory lati on controls .
4. Add 5 pL ATP and phospho substrate mixture (2X) to 11 -PI and I24-P24 wells for 100% Phosphorylation controls .
5. Spin the assay plate (100 x g, 1 minute @ 25°C).
6. Cover the plate with a black lid.
7. Incubate the assay plate for 90 minutes at 25°C with gentle shaking at 35 rpm.
8. Dilute the development reagent A to 1 : 1024 into Development buffer B.
9. Add 5 uL diluted Development solution to each well of the entire plate.
10. Spin the assay plate (100 x g, 1 minute @ 25°C). 11. Incubate the assay plate for 60 minutes at 25°C with gentle shaking at 35rpm.
12. Add 5 pL Stop reagent to each well of the entire plate.
13. Spin the assay plate (100 x g, 1 minute
Figure imgf000286_0001
25 °C).
14. Read assay plates on Envision Plate Reader. 15. FREI' signals were measured at two channels, 445 and 520 nm.
Data analysis
Percent phosphorylation is calculated using the formula below, and curve fitting and ICso generated using a four-parameter logistic model (GraphPad Prism).
Figure imgf000286_0002
The biological activity of certain compounds using the assay described above is shown in Table 3. The ICso of the compounds is categorized as follows: A < 1 nM < B < 10 nM < C < 100 Al < D < 1 μM < F
Table 3
Figure imgf000287_0001
Figure imgf000287_0002
Figure imgf000288_0001
Figure imgf000288_0002
Figure imgf000289_0001
Figure imgf000289_0002
Figure imgf000290_0001
Figure imgf000290_0002
Figure imgf000291_0001
Figure imgf000291_0002
Figure imgf000292_0001
Figure imgf000292_0002
Figure imgf000293_0001
Figure imgf000293_0002
Figure imgf000294_0001
Figure imgf000294_0002
Figure imgf000295_0001
Figure imgf000295_0002

Claims

WHAT IS CLAIMED IS: 1. A compound represented by the structure of Formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein: each represents a single or a double bond, such that the bicyclic ring system comprising Y1, Y2, Y3, and Y4 is an aromatic bicyclic ring system where (i) Y1 is CR3, Y2 is N, Y3 is CR4, and Y4 is CR3 or N; (ii) Y1 is S, Y2 is C, Y3 is CR4 or N, and Y4 is CR3; or (iii) Y1 is N, Y2 is N, Y3 is CR4, and Y4 is CR3; L is selected from , , and , wherein * denotes the point of attachment to Ring A, Z is selected from -O-, -NR1-, C1-4alkylene, -O-C1-4alkylene, and -NR1-C1-4alkylene, Z’ is selected from -NR1-, -S(O)-, -S(O)2-, C1-4alkylene, -NR1-C1-4alkylene, -S(O)-C1-4alkylene, and -S(O)2-C1-4alkylene; wherein each C1-4alkylene is optionally substituted with one or more halogen; Ring B is selected from (a), (b) and (c): (a) , X1 is selected from N, CH, and CR5; (b) , X2 is selected from S and NR7; and (c) , X3 is selected from S, N, and NH, X4 is selected from O and CR9, X5 is N or CH, X6 is N or CH, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system, provided that when Ring B is (a), Y1 is CR3, Y2 is N, Y3 is CR4, and Y4 is N, then p is 0; R1 is independently selected at each occurrence from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and –C(O)C3-6 cycloalkyl optionally substituted with one or more halogen; R2 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, - OR10, -SR10, -N(R10)2, NO2, and -CN; R3 and R4 are each independently selected at each occurrence from hydrogen, halogen, C1- 4 alkyl, and C1-4 haloalkyl; Ring A is selected from: cyclopropyl substituted with one or more C1-6 alkyl or -CN, C3-6 carbocycle substituted with one or more halogen, 3- to 6-membered heterocycle substituted with one or more halogen, C5-6 spirocyclic carbocycle, and 5- to 6-membered spirocyclic heterocycle, any of which is optionally substituted with one or more substituents independently selected from: C1-6 alkyl, C1- 6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl; C7-12 carbocycle and 7- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1- 6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, -CN, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl, provided that when Ring B is selected from (b), then Ring A is not chromane; provided that when one or more of (i), (ii), (ii), (iv), (v), (vi), (vii), and (viii) apply, then Ring A is further selected from C4-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: C1-6 alkyl, C1- 6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, -CN, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl: (ix) Ring B is (a) and RA is selected from halogen, C1-4 haloalkyl, C3-6 cycloalkyl, -NR11, and -OR11; (x) Y1 is S, Y2 is C, Ring B is (a), and X1 is N; (xi) Y1 is S, Y2 is C, Ring B is (a), and RA is C1-4 alkyl; (xii) Ring B is (a), and p is 1, 2, or 3; (xiii) R1 is C1-4 alkyl or C1-4 haloalkyl; (xiv) Ring B is (c); and (xv) Y1 is CR3, Y2 is N, Y3 is CR3, and Y4 is N; (xvi) Y1 is N, Y2 is N, Y3 is CR4, Y4 is CR3, and Ring B is (a) or (c); provided that when Ring B is (a), X1 is CH, RA is methyl, Y1 is CR3, and Y2 is N, then Ring A is further selected from tetrahydrofuranyl substituted with methyl; R5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)S(O)2(R13), -S(O)2R13, -S(O)2N(R13)2, -NO2, and -CN, provided that when RA is -OR11, then R5 is not -OR13; R6 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -N(R14)S(O)2(R14), -S(O)2R14, -S(O)2N(R14)2, -NO2, =O, and -CN; R8 is independently selected at each occurrence from halogen, C2-4 alkyl, C1-4 haloalkyl, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -N(R14)S(O)2(R14), -S(O)2R14, -S(O)2N(R14)2, -NO2, =O, and -CN; R7 and R9 are each independently selected from hydrogen, C1-4 alkyl, and C1-4 haloalkyl; R10, R11, R12, R13, and R14 are each independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl; m is selected from 0 and 1; p is selected from 0, 1, and 2; q is selected from 0, 1 and 2; and r is selected from 0, 1, and 2.
2. The compound or salt of claim 1, wherein Y1 is CR3, Y2 is N, Y3 is CR4, and Y4 is CR3 or N.
3. The compound or salt of claim 1, wherein Y1 is S, Y2 is C, Y3 is CR4 or N, and Y4 is CR3.
4. The compound or salt of claim 1, wherein Y1 is N, Y2 is N, Y3 is CR4, and Y4 is CR3.
5. The compound or salt of claim 1, wherein Y1 is CR3, Y2 is N, Y3 is CR4, and Y4 is N.
6. The compound or salt of any one of claims 1 to 5, wherein L is .
7. The compound or salt of claim 6, wherein Z is selected from -O-, -NR1-, C1- 4alkylene, -O-C1-4alkylene, and -NR1-C1-4alkylene.
8. The compound or salt of any one of claims 1 to 5, wherein L is .
9. The compound or salt of claim 8, wherein Z’ is selected from C1-4alkylene.
10. The compound or salt of any one of claims 1 to 5, wherein L is selected from: , , , , , , , , , , , , , and .
11. The compound or salt of any one of claims 1 to 5, wherein L is .
12. The compound or salt of claim 1, wherein the compound or salt is a compound of Formula (IIA-1): (IIA-1), or a pharmaceutically acceptable salt thereof.
13. The compound or salt of claim 1, wherein the compound or salt is a compound of Formula (IIB): (IIB-1), or a pharmaceutically acceptable salt thereof; wherein R3 is selected from selected from hydrogen, halogen, and C1-4 alkyl.
14. The compound or salt of claim 1, wherein the compound or salt is a compound of Formula (IID-1): (IID-1), or a pharmaceutically acceptable salt thereof; wherein R3 is selected from selected from hydrogen, halogen, and C1-4 alkyl.
15. The compound or salt of claim 1, wherein the compound or salt is a compound of Formula (IIC-1): (IIC-1), or a pharmaceutically acceptable salt thereof; wherein R3 is independently selected at each occurrence from selected from hydrogen, halogen, and C1-4 alkyl.
16. The compound or salt of any one of claims 1 to 15, wherein each R3 is hydrogen.
17. The compound or salt of any one of claims 1 to 16, wherein R1 is independently selected at each occurrence from hydrogen, -CH3, -CF3, -CH2CH3, , and .
18. The compound or salt of any one of claims 1 to 17, wherein each R1 is hydrogen.
19. The compound or salt of any one of claims 1 to 18, wherein m is 0.
20. The compound or salt of any one of claims 1 and 16 to 19, wherein the compound or salt is a compound of Formula (IA-1): (IIA-2), or a pharmaceutically acceptable salt thereof.
21. The compound or salt of any one of claims 1 and 16 to 19, wherein the compound or salt is a compound of Formula (IIB-2): (IIB-2), or a pharmaceutically acceptable salt thereof.
22. The compound or salt of claim 1 and 16 to 19, wherein the compound or salt is a compound of Formula (IC-1): (IIC-2), or a pharmaceutically acceptable salt thereof
23. The compound or salt of any one of claims 1 to 22, wherein Ring B is selected from (a) and (c): (a) , X1 is selected from N, CH, and CR5; and (c) , X3 is selected from S, N, and NH, X4 is selected from O and CR9, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system selected from benzothiazole, benzimidazole, and benzofurazan; wherein: RA is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -N(R11)2, -SR11, -N(R11)C(O)R11, -CN, C3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; and when Y1 is CR3 and Y2 is N, then RA is further selected from -OR11; R11 is selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and C3-6 cycloalkyl; R5 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, and -CN; R8 is independently selected at each occurrence from halogen, C2-4 alkyl, C1-4 haloalkyl, and -CN; R9 is selected from hydrogen and C1-4 alkyl; p is selected from 0 and 1; and r is selected from 0 and 1.
24. The compound or salt of any one of claims 1 to 23, wherein X2 is S.
25. The compound or salt of any one of claims 1 to 24, wherein Ring B is selected from (a) and (c): (a) , X1 is selected from N, CH, and CR5; and Ĩc) , X3 is selected from S, N, and NH, X4 is selected from O and CR9, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system selected from benzothiazole, benzimidazole, and benzofurazan; wherein: RA is selected from -F, -Cl, -CN, -NH2, -CH3, -CF3, -CHF2, , , , , and ; and when Y1 is CR3 and Y2 is N, then RA is further selected from - OH, -OCH3, and ; R5 is selected at each occurrence from -F, -Cl, and -CH3; R9 is selected from hydrogen and -CH3; p is selected from 0 and 1; and r is 0.
26. The compound or salt of any one of claims 1 to 25, wherein Ring B is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .
27. The compound or salt of any one of claims 1 to 22, wherein Ring B is selected from: , wherein X3 is selected from S and N, X4 is selected from O and CR9, and each represents a single or a double bond, such that Ring B is an aromatic bicyclic ring system selected from benzothiazole, benzimidazole, and benzofurazan; wherein: R8 is independently selected at each occurrence from halogen, C2-4 alkyl, C1-4 haloalkyl, and -CN; R9 is selected from hydrogen and C1-4 alkyl; p is selected from 0 and 1; and r is selected from 0 and 1.
28. The compound or salt of any one of claims 1 to 22, wherein Ring B is selected from , wherein X1 is selected from N, CH, and CR5.
29. The compound or salt of claim 28, wherein the compound or salt is a compound of Formula (IIA-3): (IIA-3) or a pharmaceutically acceptable salt thereof; wherein X1 is selected from N, CH, and CR5.
30. The compound or salt of claim 28, wherein the compound or salt is a compound of Formula (IIB-3): (IIB-3), or a pharmaceutically acceptable salt thereof; wherein X1 is selected from N, CH, and CR5.
31. The compound or salt of any one of claims 1 to 30, wherein Y3 is N.
32. The compound or salt of any one of claims 1 to 30, wherein Y3 is CR4; and R4 is selected from hydrogen and halogen.
33. The compound or salt of any one of claims 1 to 30, wherein Y3 is CH.
34. The compound or salt of claim 1, wherein the compound or salt is a compound of Formula (IIC-3): (IIC-3), or a pharmaceutically acceptable salt thereof.
35. The compound or salt of any one of claims 1 to 34, wherein: RA is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, -N(R11)2, -SR11, -N(R11)C(O)R11, -CN, C3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; and Y1 is CR3, Y2 is N, and Y4 is CR3 or when Y1 is CR3, Y2 is N, and Y4 is N, then RA is further selected from - OR11; R11 is selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and C3-6 cycloalkyl; R5 is independently selected at each occurrence from halogen and C1-4 alkyl; and p is selected from 0 and 1.
36. The compound or salt of any one of claims 1 to 35, wherein RA is selected from -F, -Cl, -CN, -NH2, -CH3, -CF3, -CHF2, , , , , and ; and when Y1 is CR3, Y2 is N, and Y4 is CR3 or when Y1 is CR3, Y2 is N, and Y4 is N, then RA is further selected from -OH, -OCH3, and ; R5 is selected at each occurrence from -F, -Cl, and -CH3; p is selected from 0 and 1.
37. The compound or salt of claim 1 to 36, wherein Ring B is selected from: , , , , , , , , , , , , , , , F , , , N , , , , , , , , and .
38. The compound or salt of any one of claim 1 to 19, 23 to 28, 35, 36, and 37, wherein R1 is C1-4 alkyl.
39. The compound or salt of any one of claims 1 to 22 and 28 to 38, wherein RA is selected from halogen, C1-4 haloalkyl, C3-6 cycloalkyl, -NR11, and -OR11.
40. The compound or salt of any one of claims 1 to 22 and 28 to 39, wherein p is 1, 2, or 3.
41. The compound or salt of any one of claims 1 to 22 and 28 to 40, wherein Y1 is S; Y2 is C; and X1 is N.
42. The compound or salt of any one of claims 1 to 22 and 28 to 41, wherein Y1 is S; Y2 is C; and RA is selected from C1-4 alkyl.
43. The compound or salt of any one of claims 1 to 42, wherein Ring A is selected from: cyclopropyl substituted with one or more C1-6 alkyl or -CN, C4-12 carbocycle, and 3- to 12- membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl, provided that when Ring B is selected from (b), then Ring A is not chromane; and R12 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl.
44. The compound or salt of any one of claims 1 to 43, wherein Ring A is selected from: cyclopropyl substituted with one or more C1-6 alkyl or -CN, C4-12 carbocycle, and 3- to 12- membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, =O, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl, provided that when Ring B is selected from (b), then Ring A is not chromane; and R12 is independently selected at each occurrence from hydrogen and C1-6 alkyl.
45. The compound or salt of any one of claims 1 to 44, wherein Ring A is selected from: cyclopropyl substituted with one or more C1-4 alkyl or -CN, cyclobutyl, cyclohexyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, sulfolanyl, azetidinyl, pyrrolidinyl, piperidinyl, spiro[2.2]pentanyl, spiro[3.2]hexanyl, spiro[4.2]heptanyl, 6-oxaspiro[2.5]octanyl, 2- oxabicyclo[2.2.1]heptanyl, 8-oxabicyclo[3.2.1]octanyl, 1-Oxaspiro[5.5]undecanyl, adamantanyl, 2-azaspiro[3.3]heptanyl, and 1,9-dioxaspiro[5.5]undecanyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, - OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, =O, -CN, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl; and R12 is independently selected at each occurrence from hydrogen, C1-6 alkyl, and phenyl.
46. The compound or salt of any one of claims 1 to 45, wherein Ring A is selected from: cyclopropyl substituted with one or more C1-4 alkyl or -CN, cyclobutyl, cyclohexyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, sulfolanyl, azetidinyl, pyrrolidinyl, piperidinyl, spiro[2.2]pentanyl, spiro[3.2]hexanyl, spiro[4.2]heptanyl, 6-oxaspiro[2.5]octanyl, 2- Oxabicyclo[2.2.1]heptanyl, 8-Oxabicyclo[3.2.1]octanyl, 1-Oxaspiro[5.5]undecanyl, adamantanyl, 2-Azaspiro[3.3]heptanyl, and 1,9-dioxaspiro[5.5]undecanyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, - C(O)OR12, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl; and R12 is independently selected at each occurrence from hydrogen and C1-6 alkyl.
47. The compound or salt of any one of claims 1 to 46, wherein Ring A is selected from: cyclopropyl substituted with one or more -CH3 or -CN, cyclobutyl, cyclohexyl, phenyl, oxepanyl, sulfolanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, spiro[2.2]pentanyl, spiro[3.2]hexanyl, spiro[4.2]heptanyl, 6-oxaspiro[2.5]octanyl, 2- Oxabicyclo[2.2.1]heptanyl, 8-Oxabicyclo[3.2.1]octanyl, 1-Oxaspiro[5.5]undecanyl, adamantanyl, 2-Azaspiro[3.3]heptanyl, and 1,9-dioxaspiro[5.5]undecanyl, each of which is optionally substituted with one or more substituents independently selected from: -F, -OH, -OCH3, -CH3, -CF3, =O, -CN, , , , , , , , and .
48. The compound or salt of any one of claims 1 to 47, wherein Ring A is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .
49. The compound or salt of any one of claims 1 to 42, wherein Ring A is selected from: cyclopropyl substituted with one or more C1-6 alkyl or -CN, C3-6 carbocycle substituted with one or more -F, and 3- to 6-membered heterocycle substituted with one or more -F, any of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, =O, -CN, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl; 7- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, =O, -CN, provided that when Ring B is selected from (b), then Ring A is not chromane; and R12 is independently selected at each occurrence from hydrogen and C1-6 alkyl.
50. The compound or salt of any one of claims 1 to 42, wherein Ring A is selected from: cyclopropyl, cyclobutyl, cyclohexyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl pyrrolidinyl, and piperidinyl, each of which is substituted with one or more -F, and is optionally substituted with one or more substituents independently selected from: halogen, C1- 6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, =O, and 3- to 6-membered heterocycle optionally substituted with one or more C1-4 alkyl; and spiro[2.2]pentanyl, spiro[3.2]hexanyl, spiro[4.2]heptanyl, 6-oxaspiro[2.5]octanyl, 2- oxabicyclo[2.2.1]heptanyl, 8-oxabicyclo[3.2.1]octanyl, 1-Oxaspiro[5.5]undecanyl, adamantanyl, 2-azaspiro[3.3]heptanyl, and 1,9-dioxaspiro[5.5]undecanyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12) 2 , -C(O)R12, -C(O)OR12, =O, -CN, and 3- to 6-membered heterocycle optionally substituted with o R12 is independently selected at each occurrence from hydrogen and C1-6 alkyl.
51. The compound or salt of any one of claims 1 to 42, wherein Ring A is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 0 , and .
52. The compound or salt of any one of claims 1 to 51, wherein p is selected from 0 and 1, provided that when RA is -OR11, then p is 0; q is selected from 0 and 1; and r is 0.
53. The compound or salt of any one of claims 1 to 52, wherein R10, R11, R12, R13, and R14 are each independently selected at each occurrence from hydrogen and C1-6 alkyl.
54. A compound represented by the structure of Formula (V): (V), or a pharmaceutically acceptable salt thereof, wherein: Q1 is N, S, O or CR3, Q2 is N or C, Q3 is N or CR4, Q4 is N or CR3, Q5 is C or N, and each represents a single or a double bond, such that the bicyclic ring system comprising Q1, Q2, Q3, Q4, and Q5 is benzo[d]thiazole, benzo[d]oxazole, imidazo[1,2-a]pyridine, thiazolo[5,4- b]pyridine, imidazo[1,2-b]pyridazine, pyrazolo[1,5-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, or [1,2,4]triazolo[1,5-b]pyridazine; RA is selected from halogen, -OR10, -SR10, -N(R10)2, -CN, C1-6 alkyl optionally substituted with one or more halogen or -OR10, C3-C6 saturated cycloalkyl, and 3- to 6-membered saturated heterocycloalkyl; Ring A is selected from a C3-C10 saturated cycloalkyl, a C3-C10 partially saturated carbocycle, a 3- to 10-membered saturated heterocycloalkyl, and a 3- to 10-membered partially saturated heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -OC(O)R11, -OC(O)N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)C(O)N(R11)2, -N(R11)S(O)2(R11), -S(O)R11, -S(O)2R11, -S(O)2N(R11)2, -S(O)(NR11)R11, -NO2, and =O; C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -OC(O)R11, -OC(O)N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)C(O)N(R11)2, -N(R11)S(O)2(R11), -S(O)R11, -S(O)2R11, -S(O)2N(R11)2, -S(O)(NR11)R11, -NO2, =O, -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -OC(O)R11, -OC(O)N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)C(O)N(R11)2, -N(R11)S(O)2(R11), -S(O)R11, -S(O)2R11, -S(O)2N(R11)2, -S(O)(NR11)R11, -NO2, =O, and -CN; Ring B is selected from a C3-C10 carbocycle and a 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, -NO2, =O, and -CN; R1 is selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and -C(O)R13; R2 is independently selected at each occurrence from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR14, -SR14, -N(R14)2, -NO2, and -CN; R3 is independently selected at each occurrence from hydrogen, halogen, C1-4 alkyl, and C1-4 haloalkyl; R4 is selected from hydrogen, halogen, C1-4 alkyl, and C1-4 haloalkyl; R10, R11, R12, R13, and R14 are each independently selected at each occurrence from hydrogen, C1-4 alkyl, C1-4 haloalkyl, and cycloalkyl optionally substituted with one or more halogen; and n is selected from 0, 1, and 2; provided that when Ring B is pyrazolyl, then Ring A is not N-Boc pyrrolidinyl.
55. The compound or salt of claim 54 wherein the compound or salt is a compound of Formula (VA): (VA), or a pharmaceutically acceptable salt thereof.
56. The compound or salt of claim 54, wherein the compound or salt is a compound of Formula (VB): (VB), or a pharmaceutically acceptable salt thereof.
57. The compound or salt of claim 54, wherein the compound or salt is a compound of Formula (VC): (VC), or a pharmaceutically acceptable salt thereof.
58. The compound or salt of claim 54, wherein the compound or salt is a compound of Formula (VD): (VD), or a pharmaceutically acceptable salt thereof.
59. The compound or salt of claim 54, wherein the compound or salt is a compound of Formula (VE): (VE), or a pharmaceutically acceptable salt thereof.
60. The compound or salt of any one of claims 54 to 56, 58, and 59, wherein Q3 is CR4.
61. The compound or salt of any one of claims 54 to 56, 58, and 59, wherein Q3 is N.
62. The compound or salt of any one of claims 54, 55, 57, 60 and 61, wherein Q4 is CR3.
63. The compound or salt of any one of claims 54, 55, 57, 60 and 61, wherein Q4 is N.
64. The compound or salt of claim 54, wherein the compound or salt is a compound of Formula (VF): (VF), or a pharmaceutically acceptable salt thereof.
65. The compound or salt of any one of claims 54 to 64, wherein each R3 is independently hydrogen.
66. The compound or salt of any one of claims 54 to 65, wherein R4 is selected from hydrogen and C1-4 alkyl.
67. The compound or salt of any one of claims 54 to 66, wherein R4 is selected from hydrogen and -CH3.
68. The compound or salt of any one of claims 54 to 67, wherein R1 is selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl and -C(O)R13
69. The compound or salt of any one of claims 54 to 68, wherein R13 is selected from C1-4 alkyl and cyclopropyl optionally substituted with one or more -F.
70. The compound or salt of any one of claims 54 to 69, wherein R1 is selected from F hydrogen, -CH3, -CF3, and O .
71. The compound or salt of any one of claims 54 to 70, wherein n is 0.
72. The compound or salt of claim 54, wherein the compound or salt is a compound of Formula (VIA-1): (VIA-1), or a pharmaceutically acceptable salt thereof.
73. The compound or salt of claim 54, wherein the compound or salt is a compound of Formula (VIA-2): (VIA-2), or a pharmaceutically acceptable salt thereof.
74. The compound or salt of claim 54, wherein the compound or salt is a compound of Formula (VIB-1): RA O A N HN S B (VIB-1), or a pharmaceutically acceptable salt thereof
75. The compound or salt of claim 54, wherein the compound or salt is a compound of Formula (VIB-2): (VIB-2), or a pharmaceutically acceptable salt thereof.
76. The compound or salt of claim 54, wherein the compound or salt is a compound of Formula (VIC-3): (VIC-3), or a pharmaceutically acceptable salt thereof.
77. The compound or salt of claim 54, wherein the compound or salt is a compound of Formula (VID-1): (VID-1); or a pharmaceutically acceptable salt thereof.
78. The compound or salt of claim 54, wherein the compound or salt is a compound of Formula (VID-2): (VID-2); or a pharmaceutically acceptable salt thereof.
79. The compound or salt of claim 54, wherein the compound or salt is a compound of Formula (VIE-1): (VIE-1), or a pharmaceutically acceptable salt thereof.
80. The compound or salt of claim 54, wherein the compound or salt is a compound of Formula (VIE-2): (VIE-2), or a pharmaceutically acceptable salt thereof.
81. The compound or salt of claim 54, wherein the compound or salt is a compound of Formula (VIF): (VIF), or a pharmaceutically acceptable salt thereof.
82. The compound or salt of any one of claims 54 to 81, wherein Ring A is selected from C3-C10 saturated cycloalkyl, and 3- to 10-membered saturated heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -C(O)N(R11)2, -N(R11)C(O)R11, -NO2, and =O; C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, and =O, -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, C1- 6 alkyl, C1-6 haloalkyl, =O, and -CN; provided that when Ring B is pyrazolyl, then Ring A is not N-Boc pyrrolidinyl.
83. The compound or salt of any one of claims 54 to 82, wherein Ring A is selected from C3-C6 saturated cycloalkyl, and 3- to 6-membered saturated heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halogen, - C(O)OR11, C1-6 alkyl, C1-6 haloalkyl, and 3- to 6-membered heterocycloalkyl, optionally substituted with one or more C1-6 alkyl.
84. The compound or salt of any one of claims 54 to 83, wherein Ring A is selected from: cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and tetrahydrofuranyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -C(O)OR11, C1-6 alkyl, C1-6 haloalkyl, and 3- to 6-membered heterocycloalkyl, optionally substituted with one or more C1-6 alkyl; provided that when Ring B is pyrazolyl, then Ring A is not N-Boc pyrrolidinyl.
85. The compound or salt of any one of claims 54 to 84, wherein R11 is independently selected at each occurrence
86. The compound or salt of any one of claims 54 to 85, wherein Ring A is selected from: cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and tetrahydrofuranyl, each of which is optionally substituted with one or more substituents independently selected from -F, -CH3, , , , , and ; provided that when Ring B is pyrazolyl, then Ring A is not N-Boc pyrrolidinyl.
87. The compound or salt of any one of claims 54 to 86, wherein RA is selected from - F, -CN, -CH3, -CHF2, -CF3, -CH2OCH3, -OCH3, and .
88. The compound or salt of any one of claims 54 to 87, wherein is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , F , , , , and .
89. The compound or salt of any one of claims 54 to 88, wherein Ring B is selected from a C3-C10 carbocycle and a 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)C(O)R12, - N(R12)C(O)OR12, - N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, - S(O)(NR12)R12, -NO2, =O, and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, =O, -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, - OR12, -SR12, -N(R12)2, -C(O)R12, =O, and -CN.
90. The compound or salt of any one of claims 54 to 89, wherein Ring B is selected from a C6-C10 aryl and a 3- to 12-membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -N(R12)C(O)R12, - N(R12)C(O)OR12, - N(R12)C(O)N(R12)2, -N(R12)S(O)2(R12), -S(O)R12, -S(O)2R12, -S(O)2N(R12)2, - S(O)(NR12)R12, -NO2, =O, and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, =O, and -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, - OR12, -SR12, -N(R12)2, -C(O)R12, =O, and -CN.
91. The compound or salt of any one of claims 54 to 90, wherein Ring B is selected from a C6-C10 aryl and a 3- to 12-membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, - C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2(R12), -S(O)2R12, -S(O)2N(R12)2, -S(O)(NR12)R12, =O, -CN, C3-6 carbocycle and 3- to 6-membered heterocycle, and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen and -OR12.
92. The compound or salt of any one of claim 54 to 91, wherein Ring B is selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, indolyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, 2,1,3-benzoxadiazolyl, benzfurazanyl, thiazolo[4,5-b]pyridinyl, pyrrolo[2,3-b]pyridinyl, imidazo[1,5-a]pyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, and quinoxalinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, - OR12, -N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2(R12), -S(O)2R12, -S(O)2N(R12)2, - S(O)(NR12)R12, =O, -CN, C3-6 carbocycle and 3- to 6-membered heterocycle, and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen and - OR12.
93. The compound or salt of any one of claims 54 to 92, wherein R12 is selected from hydrogen, -CH3, -CH2CH2CH3, -CH2CH(CH3)2, -CH2CF3, and cyclopropyl.
94. The compound or salt of any one of claims 54 to 93, wherein Ring B is selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, indolyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, 2,1,3-benzoxadiazolyl benzfurazanyl, thiazolo[4,5-b]pyridinyl, pyrrolo[2,3- b]pyridinyl, imidazo[1,5-a]pyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, and quinoxalinyl, each of which is optionally substituted with one or more substituents independently selected from: -F, -Cl, -CN, -OH, -NH2, =O, -CH3, -OCH3, -CF3, -CHF2, , , , , , , , , , , , , N N , , , , and .
95. The compound or salt of any one of claims 54 to 94, wherein Ring B is selected from: , , , , , , , , , , , , , , , , , , , , , , , O S O , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 10 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .
96. A compound selected from a compound in Table 1, or a pharmaceutically acceptable salt thereof.
97. A pharmaceutical composition comprising a compound of any one of claims 1 to 96, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable diluent or carrier.
98. A method for treating a neurological disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 96, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 97.
99. The method of claim 98, wherein the neurological disorder is selected from the group consisting of Down Syndrome, Alzheimer’s disease, and Alzheimer’s disease associated with Down Syndrome.
100. The method of claim 98 or 99, wherein the neurological disorder is selected Alzheimer’s disease associated with Down syndrome.
101. A method for treating a metabolic disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 96, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 97.
102. The method of claim 101, wherein the metabolic disorder is diabetes.
103. A method for treating a cardiovascular disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 96, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 97.
104. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 96, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 97.
105. A method of inhibiting DYRK1A activity in a mammalian cell comprising a DYRK1A protein, the method comprising contacting the mammalian cell with a compound of any one of claims 1 to 96, or a pharmaceutically acceptable salt thereof.
PCT/US2024/033833 2023-06-14 2024-06-13 Bicyclic heteroaromatic compounds for treating neurological disorders Pending WO2024259121A1 (en)

Applications Claiming Priority (16)

Application Number Priority Date Filing Date Title
US202363508137P 2023-06-14 2023-06-14
US202363508131P 2023-06-14 2023-06-14
US202363508139P 2023-06-14 2023-06-14
US63/508,137 2023-06-14
US63/508,139 2023-06-14
US63/508,131 2023-06-14
US202363510696P 2023-06-28 2023-06-28
US202363510695P 2023-06-28 2023-06-28
US202363510711P 2023-06-28 2023-06-28
US63/510,711 2023-06-28
US63/510,696 2023-06-28
US63/510,695 2023-06-28
US202463656038P 2024-06-04 2024-06-04
US202463656070P 2024-06-04 2024-06-04
US63/656,070 2024-06-04
US63/656,038 2024-06-04

Publications (1)

Publication Number Publication Date
WO2024259121A1 true WO2024259121A1 (en) 2024-12-19

Family

ID=91969304

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/033833 Pending WO2024259121A1 (en) 2023-06-14 2024-06-13 Bicyclic heteroaromatic compounds for treating neurological disorders

Country Status (2)

Country Link
TW (1) TW202515543A (en)
WO (1) WO2024259121A1 (en)

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009027283A1 (en) * 2007-08-31 2009-03-05 Merck Serono S.A. Triazolopyridine compounds and their use as ask inhibitors
US20090318425A1 (en) * 2008-06-24 2009-12-24 Takeda Pharmaceutical Company Limited Apoptosis signal-regulating kinase 1 inhibitors
WO2010024903A1 (en) * 2008-08-29 2010-03-04 Yangbo Feng BENZO[d]OXAZOLES AND BENZO[d]THIAZOLES AS KINASE INHIBITORS
WO2016046530A1 (en) * 2014-09-23 2016-03-31 Mission Therapeutics Ltd Novel compounds
WO2017040993A1 (en) * 2015-09-03 2017-03-09 The Arizona Board Of Regents On Behalf Of The University Of Arizona Small molecule inhibitors of dyrk1a and uses thereof
WO2017109488A1 (en) * 2015-12-23 2017-06-29 Mission Therapeutics Limited Cyanopyrrolidine dervivatives as inhibitors for dubs
WO2019165192A1 (en) * 2018-02-23 2019-08-29 Samumed, Llc 5-heteroaryl substituted indazole-3-carboxamides and preparation and use thereof
WO2023107722A1 (en) * 2021-12-10 2023-06-15 Prothena Biosciences Limited Compounds for use in treating neurological disorders

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009027283A1 (en) * 2007-08-31 2009-03-05 Merck Serono S.A. Triazolopyridine compounds and their use as ask inhibitors
US20090318425A1 (en) * 2008-06-24 2009-12-24 Takeda Pharmaceutical Company Limited Apoptosis signal-regulating kinase 1 inhibitors
WO2010024903A1 (en) * 2008-08-29 2010-03-04 Yangbo Feng BENZO[d]OXAZOLES AND BENZO[d]THIAZOLES AS KINASE INHIBITORS
WO2016046530A1 (en) * 2014-09-23 2016-03-31 Mission Therapeutics Ltd Novel compounds
WO2017040993A1 (en) * 2015-09-03 2017-03-09 The Arizona Board Of Regents On Behalf Of The University Of Arizona Small molecule inhibitors of dyrk1a and uses thereof
WO2017109488A1 (en) * 2015-12-23 2017-06-29 Mission Therapeutics Limited Cyanopyrrolidine dervivatives as inhibitors for dubs
WO2019165192A1 (en) * 2018-02-23 2019-08-29 Samumed, Llc 5-heteroaryl substituted indazole-3-carboxamides and preparation and use thereof
WO2023107722A1 (en) * 2021-12-10 2023-06-15 Prothena Biosciences Limited Compounds for use in treating neurological disorders

Also Published As

Publication number Publication date
TW202515543A (en) 2025-04-16

Similar Documents

Publication Publication Date Title
CN104910137B (en) CDK kinase inhibitor
AU2003221500B9 (en) Heteroaryl substituted 2-pyridinyl and 2-pyrimidinyl -6,7,8,9-tetrahydropyrimido[1,2-a] pyrimidin-4-one derivatives
BR112014031730B1 (en) PHARMACEUTICALLY ACCEPTABLE COMPOUNDS OR SALTS THEREOF AND THEIR USE
AU2017374721B2 (en) CDK4/6 inhibitor
EP3573955A1 (en) Compounds for inhibiting lrrk2 kinase activity
US9777020B2 (en) Furo-3-carboxamide derivatives and methods of use
US20250099442A1 (en) Compounds for use in treating neurological disorders
WO2023107723A2 (en) Methods for treating neurological disorders
AU2018300091B2 (en) Substituted benzoxazole and benzofuran compounds as PDE7 inhibitors
AU2021349904B2 (en) A class of fused ring compounds, and preparation and use thereof
AU2022407173A1 (en) Heterocyclic compounds as dyrk1a inhibitors
WO2024259121A1 (en) Bicyclic heteroaromatic compounds for treating neurological disorders
RU2619932C1 (en) SUBSTITUTED PYRAZOLO[1.5-a]PYRIDO[3.4-e]PYRIMIDINES AND THEIR USE AS PROTEINQUINASE INHIBITORS
WO2024259116A1 (en) 5-(cinnolin-6-yl)thiazole compounds for treating neurological disorders
EP3573980A1 (en) Compounds
CN120004901A (en) Triazolocyclic compounds as WRN helicase inhibitors
HK40008902B (en) Cdk4/6 inhibitor

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: 24746840

Country of ref document: EP

Kind code of ref document: A1