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WO2024259121A1 - Composés hétéroaromatiques bicycliques pour le traitement de troubles neurologiques - Google Patents

Composés hétéroaromatiques bicycliques pour le traitement de troubles neurologiques Download PDF

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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
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compound
alkyl
ring
salt
halogen
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Craig William Lindsley
Paul K. SPEARING
Bruce James MELANCON
Katherine Elizabeth CROCKER
Jinming LI
Cayden Jeremiah DODD
Joseph Aron INGER
Stéphane De Lombaert
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Prothena Biosciences Ltd
Vanderbilt University
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Prothena Biosciences Ltd
Vanderbilt University
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    • 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

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Abstract

La présente invention concerne des composés et des sels pharmaceutiquement acceptables de ceux-ci, qui sont utiles, par exemple, pour traiter un trouble neurologique chez un sujet. La présente invention concerne également des compositions les contenant ainsi que des procédés d'utilisation et de fabrication associés.
PCT/US2024/033833 2023-06-14 2024-06-13 Composés hétéroaromatiques bicycliques pour le traitement de troubles neurologiques Pending WO2024259121A1 (fr)

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WO2010024903A1 (fr) * 2008-08-29 2010-03-04 Yangbo Feng Benzo[d]oxazoles et benzo[d]thiazoles comme inhibiteurs de la kinase
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WO2017040993A1 (fr) * 2015-09-03 2017-03-09 The Arizona Board Of Regents On Behalf Of The University Of Arizona Petites molécules inhibitrices de dyrk1a et leurs utilisations
WO2017109488A1 (fr) * 2015-12-23 2017-06-29 Mission Therapeutics Limited Dérivés de cyanopyrrolidine comme inhibiteurs de dub
WO2019165192A1 (fr) * 2018-02-23 2019-08-29 Samumed, Llc Indazole-3-carboxamides substitués par hétéroaryle en position 5, préparation et utilisation associées
WO2023107722A1 (fr) * 2021-12-10 2023-06-15 Prothena Biosciences Limited Composés destinés à être utilisés dans le traitement de troubles neurologiques

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WO2009027283A1 (fr) * 2007-08-31 2009-03-05 Merck Serono S.A. Composés de triazolopyridine et leur utilisation comme inhibiteurs de ask
US20090318425A1 (en) * 2008-06-24 2009-12-24 Takeda Pharmaceutical Company Limited Apoptosis signal-regulating kinase 1 inhibitors
WO2010024903A1 (fr) * 2008-08-29 2010-03-04 Yangbo Feng Benzo[d]oxazoles et benzo[d]thiazoles comme inhibiteurs de la kinase
WO2016046530A1 (fr) * 2014-09-23 2016-03-31 Mission Therapeutics Ltd Nouveaux composés
WO2017040993A1 (fr) * 2015-09-03 2017-03-09 The Arizona Board Of Regents On Behalf Of The University Of Arizona Petites molécules inhibitrices de dyrk1a et leurs utilisations
WO2017109488A1 (fr) * 2015-12-23 2017-06-29 Mission Therapeutics Limited Dérivés de cyanopyrrolidine comme inhibiteurs de dub
WO2019165192A1 (fr) * 2018-02-23 2019-08-29 Samumed, Llc Indazole-3-carboxamides substitués par hétéroaryle en position 5, préparation et utilisation associées
WO2023107722A1 (fr) * 2021-12-10 2023-06-15 Prothena Biosciences Limited Composés destinés à être utilisés dans le traitement de troubles neurologiques

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