[go: up one dir, main page]

WO2025117599A1 - Composés hétéroaryle bicycliques utilisés en tant qu'activateurs de trem2 - Google Patents

Composés hétéroaryle bicycliques utilisés en tant qu'activateurs de trem2 Download PDF

Info

Publication number
WO2025117599A1
WO2025117599A1 PCT/US2024/057550 US2024057550W WO2025117599A1 WO 2025117599 A1 WO2025117599 A1 WO 2025117599A1 US 2024057550 W US2024057550 W US 2024057550W WO 2025117599 A1 WO2025117599 A1 WO 2025117599A1
Authority
WO
WIPO (PCT)
Prior art keywords
cycloalkyl
heterocycloalkyl
alkyl
compound
haloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2024/057550
Other languages
English (en)
Inventor
Cheryl A. Grice
Andrew Stewart TASKER
Julio C. Medina
Shiyan XU
Anuska SHRESTHA
Christopher Michael Tegley
Moumita SINGHA ROY
Ulhas Bhatt
Thirupataiah AVULLALA
Guo Li
Kendelyn BONE
Chaowei Hu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nura Bio Inc
Original Assignee
Nura Bio Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nura Bio Inc filed Critical Nura Bio Inc
Publication of WO2025117599A1 publication Critical patent/WO2025117599A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/28—Cinnolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—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

  • Described herein are compounds and compositions, and associated methods, useful for activation of TREM2 activity and/or for treating or preventing a neurological disorder.
  • AD Alzheimer’s disease
  • FDD Frontotemporal Dementia
  • ALS Amyotrophic Lateral Sclerosis
  • TREM2 Triggering receptor expressed on myeloid cells 2
  • the R47H TREM2 rare variant was identified as a significant risk factor for late-onset AD and is associated with loss-of-function of the protein.
  • TREM2 loss-of-function of TREM2 results in an exacerbation of symptoms in preclinical models of AD.
  • TREM2 over-expression or treatment with TREM2 activating antibodies restores microglial function in preclinical models of AD.
  • modalities that can more easily cross the blood-brain barrier like CNS-penetrant small molecules are highly desirable.
  • ring A is a 5- or 6-membered heteroaryl ring or phenyl
  • X is N or C(R 7 ); each R 1 is independently selected from halogen, -CN, -OR 10 , -SR 10 , -C(O)OR 10 , - OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O) 2 R 13 , - C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), - N(R 12 )C(O)R 13 , -S(O) 2 R 13 , -S(O) 2 N(R 10 )(R 11 )-, C 1-6 alkyl, C 1-6 haloalkyl,
  • R 2 is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl, wherein C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-4 R 3 groups; each R 3 is independently selected from halogen, -CN, C 1-6 alkyl, C 1 -6 haloalky 1, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, and -CH 2 -C 2-9 heterocycloalkyl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl,
  • R 4 is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl, wherein C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-4 R 5 groups; each R 5 is independently selected from halogen, -CN, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), - C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , - N(R 12 )S(O) 2 R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(
  • R 7 is selected from hydrogen and C 1-6 alkyl
  • R 8 and R 9 are independently selected from hydrogen, halogen, C 1-6 alkyl, and C 1-6 haloalkyl; each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1- 9 heteroaryl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1- 6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloal
  • a compound of Formula (I), wherein X is N. In some embodiments is a compound of Formula (I), wherein X is C(R 7 ). In some embodiments is a compound of Formula (I), wherein X is C(R 7 ) and R 7 is hydrogen. In some embodiments is a compound of Formula (I), wherein X is C(R 7 ) and R 7 is C 1-6 alkyl. [0006] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula (la):
  • R 8 is a compound of Formula (I), (la), (lb), or (Ic), wherein R 8 is halogen.
  • R 8 is C 1-6 alkyl.
  • R 9 is hydrogen.
  • X is N or C(R 7 ); each R 1 is independently selected from halogen, -CN, -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , - OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O) 2 R 13 , - C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), - N(R 12 )C(O)R 13 , -S(O) 2 R 13 , -S(O) 2 N(R 10 )(R 11 )-, C 1-6 alkyl, C 1-6
  • R 2 is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl, wherein C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-4 R 3 groups; each R 3 is independently selected from halogen, -CN, -OR 10 , C 1-6 alkyl, C 1 -6 haloalky 1, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, and -CH 2 -C 2-9 heterocycloalkyl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6
  • R 4 is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl, wherein C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-4 R 5 groups; each R 5 is independently selected from halogen, -CN, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), - C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , - N(R 12 )S(O) 2 R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(
  • R 6 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl
  • R 7 is selected from hydrogen and C 1-6 alkyl; each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1- 9 heteroaryl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1- 6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl
  • X is N. In some embodiments is a compound of Formula (II), wherein X is C(R 7 ). In some embodiments is a compound of Formula (II), wherein R 7 is hydrogen. In some embodiments is a compound of Formula (II), wherein R 7 is C 1-6 alkyl.
  • [0012] is a compound of Formula (I), (la), (lb), (Ic), or (II) wherein R 4 is C 1-9 heteroaryl optionally substituted with 1-4 R 5 groups.
  • R 4 is a compound of Formula (I), (la), (lb), (Ic), or (II) wherein R 4 is pyridyl optionally substituted with 1-4 R 5 groups.
  • R 4 is a compound of Formula (I), (la), (lb), (Ic), or (II) wherein R 4 is pyridyl substituted with 1 R 5 group.
  • R 4 is a compound of Formula (I), (la), (lb), (Ic), or (II) wherein R 4 is phenyl substituted with 1 R 5 group.
  • each R 5 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , wherein C 1-6 alkyl, C 1-6 haloalkyl, C 3- 6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • each R 5 is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted C 2- 9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13
  • each R 10 is independently selected from C 1-6 alkyl, C 1- 6 haloalkyl, and C 3-6 cycloalkyl
  • each R 13 is independently selected from C 1-6 alkyl and C 1- 6 haloalkyl.
  • R 4 is selected from: some embodiments is a compound of Formula (I), (la), (lb), (Ic), or
  • R 4 is selected from:
  • ring A is a 5- or 6-membered heteroaryl ring or phenyl
  • ring B is a 5- or 6-membered heteroaryl ring or phenyl
  • X is N or C(R 7 );
  • Y is O, S, or N(R 7a );
  • each R 1 and each R 1a is independently selected from halogen, -CN, -OR 10 , -SR 10 , - N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), - N(R 12 )C(O)OR 13 , -N(R 12 )S(O) 2 R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), - C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O) 2 R 13 , -S(O) 2 N(R 10 )(R 11 )-, C(O)C(O)N(R
  • R 2 is selected from C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl, wherein C 2- 9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-4 R 3 groups; each R 3 is independently selected from halogen, -CN, -OR 10 , C 1-6 alkyl, C 1 -6 haloalky 1, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, and -CH 2 -C 2-9 heterocycloalkyl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalky
  • R 7 , R 7a , and R 7b are independently selected from hydrogen and C 1-6 alkyl; each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1- 9 heteroaryl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1- 6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 hetero
  • Y is O.
  • Y is S.
  • Z is N.
  • Z is C(H).
  • ring B is a 6-membered heteroaryl ring.
  • ring B is a compound of Formula (III) or (Illa), wherein ring B is a pyridyl ring.
  • each R 1a is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , wherein C 1-6 alkyl, C 1- 6 haloalkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • each R 1a is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 , and each R 10 is independently selected from C 1-6 alkyl.
  • each R 1a is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10
  • each R 10 is independently selected from C 1-6 alkyl.
  • p is 1.
  • R 4a is selected from
  • X is N or C(R 7 );
  • each R 1 is independently selected from halogen, -CN, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), - C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , - N(R 12 )S(O) 2 R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), - C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O) 2 R 13 , -S(O) 2 N(R 10 )(R 11 )-, C(O)(O)(O)(R 11 ),
  • R 4b is C 1-9 heteroaryl optionally substituted with 1-4 R 5a groups; each R 5a is independently selected from halogen, -CN, -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , - OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O) 2 R 13 , - C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), - N(R 12 )C(O)R 13 , -S(O) 2 R 13 , -S(O) 2 N(R 10 )(R 11 )
  • R 7 is selected from hydrogen and C 1-6 alkyl; each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1- 9 heteroaryl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1- 6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl
  • X is N.
  • X is C(R 7 ) and R 7 is hydrogen.
  • each R 1 is independently selected from halogen, -CN, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), - C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , - N(R 12 )S(O) 2 R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), - C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O) 2 R 13 , -S(O) 2 N(R 10 )(R 11 )-, C 1-6 alkyl, C 1- 6
  • R 2 is selected from C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl, wherein C 2- 9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-4 R 3 groups; each R 3 is independently selected from halogen, -CN, -OR 10 , C 1-6 alkyl, C 1 -6 haloalky 1, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, and -CH 2 -C 2-9 heterocycloalkyl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalky
  • R 4b is C 1-9 heteroaryl optionally substituted with 1-4 R 5a groups; each R 5a is independently selected from halogen, -CN, -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , - OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O) 2 R 13 , - C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), - N(R 12 )C(O)R 13 , -S(O) 2 R 13 , -S(O) 2 N(R 10 )(R 11 )
  • [0022] is a compound of Formula (IV), (IVa), (IVb), or (V), wherein R 4b is C 1-9 heteroaryl optionally substituted with 1-4 R 5a groups, wherein the C 1-9 heteroaryl is a bicyclic heteroaryl.
  • R 4b is C 1-9 heteroaryl substituted with 1 R 5a group, wherein the C 1-9 heteroaryl is a bicyclic heteroaryl.
  • each R 5a is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , wherein C 1-6 alkyl, C 1-6 haloalkyl, C 3- 6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • each R 5a is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted C 2- 9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13
  • each R 10 is independently selected from C 1-6 alkyl, C 1- 6 haloalkyl, and C 3-6 cycloalkyl
  • each R 13 is independently selected from C 1-6 alkyl and C 1- 6 haloalkyl.
  • each R 5a is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, and - OR 10 , and each R 10 is independently selected from C 1-6 alkyl.
  • each R 4b is selected from
  • [0023] is a compound of Formula (I), (la), (lb), (Ic), (II), (III), (Illa), (IV), (IVa), (IVb), or (V), wherein R 2 is phenyl optionally substituted with 1-4 R 3 groups.
  • R 2 is phenyl substituted with 1-4 R 3 groups.
  • R 2 is phenyl substituted with 1 or 2 R 3 groups.
  • R 3 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • each R 3 is independently selected from halogen.
  • R 2 is selected from: compound of Formula (I), (la), (lb), (Ic), (II), (III), (Illa), (IV), (IVa), (IVb), or (V), wherein each R 1 is independently selected from C 1-6 alkyl.
  • R 1 is a compound of Formula (I), (la), (lb), (Ic), (II), (III), (Illa), (IV), (IVa), (IVb), or (V), wherein each R 1 is -CH 3 .
  • composition comprising at least one pharmaceutically acceptable carrier and a compound described herein, or a pharmaceutically acceptable salt thereof.
  • a method of treating a neurological disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
  • a method of treating a neurological disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the neurological disorder is a neurodegenerative disease.
  • a method of treating a neurodegenerative disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease is selected from Alzheimer’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis.
  • a method of treating a neurodegenerative disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease is Alzheimer’s disease.
  • a method of treating a neurological disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with a further pharmaceutically active agent.
  • a compound described herein, or a pharmaceutically acceptable salt thereof in treating a neurological disorder in a patient in need thereof.
  • a compound described herein, or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for treating a neurological disorder in a patient in need thereof.
  • a compound described herein, or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for treating Alzheimer’s disease, frontotemporal dementia, or amyotrophic lateral sclerosis.
  • a compound described herein, or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for treating Alzheimer’s disease in a patient in need thereof.
  • AD Alzheimer’s disease
  • a progressive neurofibrillary tangles and amyloid plaques Changes in inflammatory response accompanies AD pathology, observed by the increase in activated astrocytes and microglia in the brain.
  • Microglia known as the resident immune cells of the brain, play an active role in immune surveillance and signaling, including the release of pro-inflammatory cytokines that influence surrounding neurons and astrocytes.
  • Genome-wide association studies for AD risk have identified several microglial genes that indicate a causative role for immune cell response in disease.
  • TREM2 triggering receptor expressed on myeloid cells 2
  • PLOSL polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy
  • FTD frontotemporal dementia
  • ALS amyotrophic lateral sclerosis
  • MS multiple sclerosis
  • PD Parkinson’s disease
  • TREM2 is a V-type immunoglobulin (Ig) domain-containing transmembrane protein that is highly expressed in microglia, macrophages and osteoclasts.
  • TREM2 is 230 amino acid protein containing a single-pass transmembrane region with a large extracellular domain and short cytoplasmic tail.
  • Putative ligands of TREM2 include phospholipids and lipoproteins, and when activated, TREM2 signals through the transmembrane receptor protein TYROBP/DAP12, an adaptor protein that contains an immunoreceptor tyrosine-bases activation motif (IT AM) which then leads to SYK phosphorylation and activation.
  • IT AM immunoreceptor tyrosine-bases activation motif
  • TREM2 signaling promotes microglial activation and survival.
  • Microglial functions regulated by TREM2 include migration, phagocytosis and cytokine release.
  • TREM2 deficiency and haploinsufficiency results in decreased microglial clustering around amyloid ⁇ (a ⁇ ) plaques indicating the requirement of TREM2 for microglial activation and response to amyloid plaques.
  • a ⁇ amyloid ⁇
  • TREM2 activator compounds that specifically bind to TREM2 and activate signaling in a cellular context.
  • TREM2 activation by small molecules has implications for the treatment of age-associated neurodegenerative diseases such as Alzheimer’s disease (AD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and rare microgliopathies.
  • AD Alzheimer’s disease
  • FDD frontotemporal dementia
  • ALS amyotrophic lateral sclerosis
  • rare microgliopathies rare microgliopathies.
  • ring A is a 5- or 6-membered heteroaryl ring or phenyl
  • X is N or C(R 7 ); each R 1 is independently selected from halogen, -CN, -OR 10 , -SR 10 , -C(O)OR 10 , - OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O) 2 R 13 , - C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), - N(R 12 )C(O)R 13 , -S(O) 2 R 13 , -S(O) 2 N(R 10 )(R 11 )-, C 1-6 alkyl, C 1-6 haloalkyl,
  • R 2 is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl, wherein C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-4 R 3 groups; each R 3 is independently selected from halogen, -CN, C 1-6 alkyl, C 1 -6 haloalky 1, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, and -CH 2 -C 2-9 heterocycloalkyl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl,
  • R 4 is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl, wherein C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-4 R 5 groups; each R 5 is independently selected from halogen, -CN, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), - C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , - N(R 12 )S(O) 2 R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(
  • R 7 is selected from hydrogen and C 1-6 alkyl
  • R 8 and R 9 are independently selected from hydrogen, halogen, C 1-6 alkyl, and C 1-6 haloalkyl; each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1- 9 heteroaryl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1- 6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloal
  • X is N. In some embodiments is a compound of Formula (I), wherein X is C(R 7 ). In some embodiments is a compound of Formula (I), wherein R 7 is hydrogen. In some embodiments is a compound of Formula (I), wherein R 7 is C 1-6 alkyl.
  • ring A is a 6-membered heteroaryl ring.
  • ring A is a compound of Formula (I), wherein ring A is a pyridyl ring.
  • ring A is a compound of Formula (I), wherein ring A is a pyrazinyl ring.
  • ring A is a compound of Formula (I), wherein ring A is a pyrimidinyl ring.
  • ring A is a pyridazinyl ring.
  • ring A is a 5-membered heteroaryl ring. In some embodiments is a compound of Formula (I), wherein ring A is a furanyl ring. In some embodiments is a compound of Formula (I), wherein ring A is a thienyl ring. In some embodiments is a compound of Formula (I), wherein ring A is a pyrrolyl ring.
  • ring A is phenyl
  • R 8 is hydrogen. In some embodiments is a compound of Formula (I), wherein R 8 is halogen. In some embodiments is a compound of Formula (I), wherein R 8 is C 1-6 alkyl. In some embodiments is a compound of Formula (I), wherein R 8 is -CH 3 .
  • R 9 is hydrogen. In some embodiments is a compound of Formula (I), wherein R 9 is halogen. In some embodiments is a compound of Formula (I), wherein R 9 is C 1-6 alkyl. In some embodiments is a compound of Formula (I), wherein R 9 is -CH 3 .
  • R 4 is pyridinyl optionally substituted with 1-4 R 5 groups.
  • R 4 is pyridinyl optionally substituted with 1-4 R 5 groups and each R 5 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , wherein C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • R 4 is pyridinyl optionally substituted with 1-4 R 5 groups and each R 5 is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted C 2-9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , each R 10 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, and each R 13 is independently selected from C 1-6 alkyl and C 1- 6 haloalkyl.
  • R 4 is pyridinyl substituted with 1 or 2 R 5 groups and each R 5 is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted C 2- 9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , each R 10 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, and each R 13 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
  • R 4 is pyridinyl substituted with 1 R 5 group and R 5 is unsubstituted C 2-9 heterocycloalkyl.
  • R 4 is pyridinyl substituted with 1 R 5 group, R 5 is -OR 10 , and R 10 is C 1-6 alkyl.
  • R 4 is pyridinyl substituted with 1 R 5 group, R 5 is -OR 10 , and R 10 is C 3-6 cycloalkyl.
  • R 4 is selected from:
  • R 4 is selected from:
  • R 4 is selected from:
  • R 4 is phenyl optionally substituted with 1-4 R 5 groups.
  • R 4 is phenyl optionally substituted with 1-4 R 5 groups and each R 5 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , wherein C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • R 4 is phenyl optionally substituted with 1-4 R 5 groups and each R 5 is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted C 2-9 heterocycloalkyl, -OR 10 , and - S(O) 2 R 13 , each R 10 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, and each R 13 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
  • R 4 is phenyl substituted with 1 or 2 R 5 groups and each R 5 is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, unsubstituted C 3- 6 cycloalkyl, unsubstituted C 2-9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , each R 10 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, and each R 13 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
  • R 4 is phenyl substituted with 1 R 5 group and R 5 is unsubstituted C 2-9 heterocycloalkyl.
  • R 4 is phenyl substituted with 1 R 5 group, R 5 is -OR 10 , and R 10 is C 1-6 alkyl.
  • R 4 is phenyl substituted with 1 R 5 group, R 5 is -OR 10 , and R 10 is C 3-6 cycloalkyl.
  • a compound of Formula (I) wherein R 4 is phenyl substituted with 1 R 5 group, R 5 is -S(O) 2 R 13 , and R 13 is C 1-6 alkyl. In some embodiments is a compound of Formula (I), wherein R 4 is phenyl substituted with 1 R 5 group, R 5 is -S(O) 2 R 13 , and R 13 is C 1-6 haloalkyl. In some embodiments is a compound of Formula (I),
  • each R 3 is independently selected from halogen, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, C 3-6 cycloalkyl, -OR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -C(O)N(R 10 )(R 11 ), -S(O) 2 R 13 , and - S(O)2N(R 10 )(R 11 )-, wherein C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1 -6 haloalky 1, - OR 10 , and -N(R 10 )(R 11 ).
  • each R 3 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl, wherein C 1-6 alkyl and C 1- 6 haloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 3 is independently selected from halogen, C 1-6 alkyl, and C 1- 6 haloalkyl.
  • each R 3 is independently selected from halogen, unsubstituted C 1-6 alkyl, and unsubstituted C 1-6 haloalkyl. In some embodiments is a compound of Formula (I), wherein each R 3 is independently selected from halogen. In some embodiments is a compound of Formula (I), wherein each R 3 is independently selected from unsubstituted C 1-6 alkyl. In some embodiments is a compound of Formula (I), wherein each R 3 is independently selected from unsubstituted C 1-6 haloalkyl. [0045] In some embodiments is a compound of Formula (I), wherein R 2 is selected from
  • each R 1 is independently selected from C 1-6 alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, C 1-9 heteroaryl, -OR 10 , and - N(R 10 )(R 11 ).
  • each R 1 is independently selected from unsubstituted C 1-6 alkyl.
  • each R 1 is -CH 3 .
  • X is N or C(R 7 ); each R 1 is independently selected from halogen, -CN, -OR 10 , -SR 10 , -C(O)OR 10 , - OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O) 2 R 13 , - C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), - N(R 12 )C(O)R 13 , -S(O) 2 R 13 , -S(O) 2 N(R 10 )(R 11 )-, C 1-6 alkyl, C 1-6 haloalkyl,
  • R 2 is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl, wherein C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-4 R 3 groups; each R 3 is independently selected from halogen, -CN, C 1-6 alkyl, C 1 -6 haloalky 1, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, and -CH 2 -C 2-9 heterocycloalkyl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl,
  • R 4 is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl, wherein C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-4 R 5 groups; each R 5 is independently selected from halogen, -CN, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), - C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , - N(R 12 )S(O) 2 R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(
  • R 7 is selected from hydrogen and C 1-6 alkyl
  • R 8 and R 9 are independently selected from hydrogen, halogen, C 1-6 alkyl, and C 1-6 haloalkyl; each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1- 9 heteroaryl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1- 6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloal
  • a compound of Formula (la), wherein R 8 is hydrogen. In some embodiments is a compound of Formula (la), wherein R 8 is halogen. In some embodiments is a compound of Formula (la), wherein R 8 is C 1-6 alkyl. In some embodiments is a compound of Formula (la), wherein R 8 is -CH 3 .
  • a compound of Formula (la), wherein R 9 is hydrogen. In some embodiments is a compound of Formula (la), wherein R 9 is halogen. In some embodiments is a compound of Formula (la), wherein R 9 is C 1-6 alkyl. In some embodiments is a compound of Formula (la), wherein R 9 is -CH 3 .
  • a compound of Formula (la) wherein R 4 is C 1-9 heteroaryl optionally substituted with 1-4 R 5 groups.
  • R 4 is pyridinyl optionally substituted with 1-4 R 5 groups.
  • R 4 is pyridinyl optionally substituted with 1-4 R 5 groups and each R 5 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , wherein C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • R 4 is pyridinyl optionally substituted with 1-4 R 5 groups and each R 5 is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted C 2-9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , each R 10 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, and each R 13 is independently selected from C 1-6 alkyl and C 1- 6 haloalkyl.
  • R 4 is pyridinyl substituted with 1 or 2 R 5 groups and each R 5 is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted C 2- 9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , each R 10 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, and each R 13 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
  • R 4 is pyridinyl substituted with 1 R 5 group, R 5 is -OR 10 , and R 10 is C 1-6 alkyl.
  • R 4 is pyridinyl substituted with 1 R 5 group, R 5 is -OR 10 , and R 10 is C 3-6 cycloalkyl.
  • R 4 is selected from:
  • R 4 is selected from:
  • R 4 is selected from:
  • R 4 is phenyl optionally substituted with 1-4 R 5 groups.
  • a compound of Formula (la) wherein R 4 is phenyl optionally substituted with 1-4 R 5 groups and each R 5 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -OR 10 , and - S(O) 2 R 13 , wherein C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, and C 1- 6 haloalkyl.
  • R 4 is phenyl optionally substituted with 1-4 R 5 groups and each R 5 is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted C 2- 9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , each R 10 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, and each R 13 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
  • R 4 is phenyl substituted with 1 or 2 R 5 groups and each R 5 is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1- 6 haloalkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted C 2-9 heterocycloalkyl, -OR 10 , and - S(O) 2 R 13 , each R 10 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, and each R 13 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
  • R 4 is phenyl substituted with 1 R 5 group, R 5 is -OR 10 , and R 10 is C 1-6 alkyl.
  • R 4 is phenyl substituted with 1 R 5 group, R 5 is -OR 10 , and R 10 is C 3-6 cycloalkyl.
  • each R 3 is independently selected from halogen, -CN, C 1- 6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, -OR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -C(O)N(R 10 )(R 11 ), - S(O) 2 R 13 , and -S(O)2N(R 10 )(R 11 )-, wherein C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 3 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl, wherein C 1-6 alkyl and C 1-6 haloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 3 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • each R 3 is independently selected from halogen, unsubstituted C 1-6 alkyl, and unsubstituted C 1-6 haloalkyl. In some embodiments is a compound of Formula (la), wherein each R 3 is independently selected from halogen. In some embodiments is a compound of Formula (la), wherein each R 3 is independently selected from unsubstituted C 1-6 alkyl. In some embodiments is a compound of Formula (la), wherein each R 3 is independently selected from unsubstituted C 1 -6 haloalky 1. [0063] In some embodiments is a compound of Formula (la), wherein R 2 is selected from
  • each R 1 is independently selected from C 1-6 alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, C 1-9 heteroaryl, -OR 10 , and - N(R 10 )(R 11 ).
  • each R 1 is independently selected from unsubstituted C 1-6 alkyl.
  • each R 1 is -CH 3 .
  • X is N or C(R 7 ); each R 1 is independently selected from halogen, -CN, -OR 10 , -SR 10 , -C(O)OR 10 , - OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O) 2 R 13 , - C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), - N(R 12 )C(O)R 13 , -S(O) 2 R 13 , -S(O) 2 N(R 10 )(R 11 )-, C 1-6 alkyl, C 1-6 haloalkyl,
  • R 2 is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl, wherein C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-4 R 3 groups; each R 3 is independently selected from halogen, -CN, C 1-6 alkyl, C 1 -6 haloalky 1, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, and -CH 2 -C 2-9 heterocycloalkyl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl,
  • R 4 is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl, wherein C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-4 R 5 groups; each R 5 is independently selected from halogen, -CN, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), - C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , - N(R 12 )S(O) 2 R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(
  • R 7 is selected from hydrogen and C 1-6 alkyl
  • R 8 and R 9 are independently selected from hydrogen, halogen, C 1-6 alkyl, and C 1-6 haloalkyl; each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1- 9 heteroaryl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and Ci - 9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1- 6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cyclo
  • a compound of Formula (lb), wherein R 8 is hydrogen. In some embodiments is a compound of Formula (lb), wherein R 8 is halogen. In some embodiments is a compound of Formula (lb), wherein R 8 is C 1-6 alkyl. In some embodiments is a compound of Formula (lb), wherein R 8 is -CH 3 .
  • R 9 is hydrogen. In some embodiments is a compound of Formula (lb), wherein R 9 is halogen. In some embodiments is a compound of Formula (lb), wherein R 9 is C 1-6 alkyl. In some embodiments is a compound of Formula (lb), wherein R 9 is -CH 3 .
  • [0075] is a compound of Formula (lb), wherein R 4 is Ci - 9 heteroaryl optionally substituted with 1-4 R 5 groups. In some embodiments is a compound of Formula (lb), wherein R 4 is pyridinyl optionally substituted with 1-4 R 5 groups.
  • R 4 is pyridinyl optionally substituted with 1-4 R 5 groups and each R 5 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , wherein C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • R 4 is pyridinyl optionally substituted with 1-4 R 5 groups and each R 5 is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted C 2-9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , each R 10 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, and each R 13 is independently selected from C 1-6 alkyl and C 1- 6 haloalkyl.
  • R 4 is pyridinyl substituted with 1 or 2 R 5 groups and each R 5 is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted C 2- 9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , each R 10 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, and each R 13 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
  • R 4 is pyridinyl substituted with 1 R 5 group, R 5 is -OR 10 , and R 10 is C 1-6 alkyl.
  • R 4 is pyridinyl substituted with 1 R 5 group, R 5 is -OR 10 , and R 10 is C 3-6 cycloalkyl.
  • R 4 is selected from:
  • R 4 is selected from:
  • R 4 is selected from:
  • R 4 is phenyl optionally substituted with 1-4 R 5 groups.
  • R 4 is phenyl optionally substituted with 1-4 R 5 groups and each R 5 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -OR 10 , and - S(O) 2 R 13 , wherein C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, and C 1- 6 haloalkyl.
  • R 4 is phenyl optionally substituted with 1-4 R 5 groups and each R 5 is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted C 2- 9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , each R 10 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, and each R 13 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
  • R 4 is phenyl substituted with 1 or 2 R 5 groups and each R 5 is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1- 6 haloalkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted C 2-9 heterocycloalkyl, -OR 10 , and - S(O) 2 R 13 , each R 10 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, and each R 13 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
  • R 4 is phenyl substituted with 1 R 5 group, R 5 is -OR 10 , and R 10 is C 1-6 alkyl.
  • R 4 is phenyl substituted with 1 R 5 group, R 5 is -OR 10 , and R 10 is C 3-6 cycloalkyl.
  • each R 3 is independently selected from halogen, -CN, C 1- 6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, -OR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -C(O)N(R 10 )(R 11 ), - S(O) 2 R 13 , and -S(O)2N(R 10 )(R 11 )-, wherein C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 3 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl, wherein C 1-6 alkyl and C 1-6 haloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 3 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • each R 3 is independently selected from halogen, unsubstituted C 1-6 alkyl, and unsubstituted C 1-6 haloalkyl. In some embodiments is a compound of Formula (lb), wherein each R 3 is independently selected from halogen. In some embodiments is a compound of Formula (lb), wherein each R 3 is independently selected from unsubstituted C 1-6 alkyl. In some embodiments is a compound of Formula (lb), wherein each R 3 is independently selected from unsubstituted C 1 -6 haloalky 1. [0081] In some embodiments is a compound of Formula (lb), wherein R 2 is selected from
  • each R 1 is independently selected from C 1-6 alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, C 1-9 heteroaryl, -OR 10 , and - N(R 10 )(R 11 ).
  • each R 1 is independently selected from unsubstituted C 1-6 alkyl.
  • each R 1 is -CH 3 .
  • n is a compound of Formula (lb), wherein m is 2. In some embodiments is a compound of Formula (lb), wherein m is 1. In some embodiments is a compound of Formula (lb), wherein m is 0.
  • X is N or C(R 7 ); each R 1 is independently selected from halogen, -CN, -OR 10 , -SR 10 , -C(O)OR 10 , - OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O) 2 R 13 , - C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), - N(R 12 )C(O)R 13 , -S(O) 2 R 13 , -S(O) 2 N(R 10 )(R 11 )-, C 1-6 alkyl, C 1-6 haloalkyl,
  • R 2 is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl, wherein C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-4 R 3 groups; each R 3 is independently selected from halogen, -CN, C 1-6 alkyl, C 1 -6 haloalky 1, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, and -CH 2 -C 2-9 heterocycloalkyl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl,
  • R 7 is selected from hydrogen and C 1-6 alkyl
  • R 8 and R 9 are independently selected from hydrogen, halogen, C 1-6 alkyl, and C 1-6 haloalkyl; each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1- 9 heteroaryl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1- 6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloal
  • a compound of Formula (Ic), wherein R 8 is hydrogen. In some embodiments is a compound of Formula (Ic), wherein R 8 is halogen. In some embodiments is a compound of Formula (Ic), wherein R 8 is C 1-6 alkyl. In some embodiments is a compound of Formula (Ic), wherein R 8 is -CH 3 .
  • a compound of Formula (Ic), wherein R 9 is hydrogen. In some embodiments is a compound of Formula (Ic), wherein R 9 is halogen. In some embodiments is a compound of Formula (Ic), wherein R 9 is C 1-6 alkyl. In some embodiments is a compound of Formula (Ic), wherein R 9 is -CH 3 .
  • a compound of Formula (Ic) wherein R 4 is C 1-9 heteroaryl optionally substituted with 1-4 R 5 groups. In some embodiments is a compound of Formula (Ic), wherein R 4 is pyridinyl optionally substituted with 1-4 R 5 groups.
  • R 4 is pyridinyl optionally substituted with 1-4 R 5 groups and each R 5 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , wherein C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • R 4 is pyridinyl optionally substituted with 1-4 R 5 groups and each R 5 is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted C 2-9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , each R 10 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, and each R 13 is independently selected from C 1-6 alkyl and C 1- 6 haloalkyl.
  • R 4 is pyridinyl substituted with 1 or 2 R 5 groups and each R 5 is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted C 2- 9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , each R 10 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, and each R 13 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
  • a compound of Formula (Ic) wherein R 4 is pyridinyl substituted with 1 R 5 group and R 5 is unsubstituted C 2-9 heterocycloalkyl.
  • R 4 is pyridinyl substituted with 1 R 5 group, R 5 is -OR 10 , and R 10 is C 1-6 alkyl.
  • R 4 is pyridinyl substituted with 1 R 5 group, R 5 is -OR 10 , and R 10 is C 3-6 cycloalkyl.
  • R 4 is selected from:
  • R 4 is selected from:
  • R 4 is phenyl optionally substituted with 1-4 R 5 groups.
  • R 4 is phenyl optionally substituted with 1-4 R 5 groups and each R 5 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -OR 10 , and - S(O) 2 R 13 , wherein C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, and C 1- 6 haloalkyl.
  • R 4 is phenyl optionally substituted with 1-4 R 5 groups and each R 5 is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted C 2- 9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , each R 10 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, and each R 13 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
  • R 4 is phenyl substituted with 1 or 2 R 5 groups and each R 5 is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1- 6 haloalkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted C 2-9 heterocycloalkyl, -OR 10 , and - S(O) 2 R 13 , each R 10 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, and each R 13 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
  • a compound of Formula (Ic) wherein R 4 is phenyl substituted with 1 R 5 group and R 5 is unsubstituted C 2-9 heterocycloalkyl.
  • R 4 is phenyl substituted with 1 R 5 group, R 5 is -OR 10 , and R 10 is C 1-6 alkyl.
  • R 4 is phenyl substituted with 1 R 5 group, R 5 is -OR 10 , and R 10 is C 3-6 cycloalkyl.
  • a compound of Formula (Ic) wherein R 4 is phenyl substituted with 1 R 5 group, R 5 is -S(O) 2 R 13 , and R 13 is C 1-6 alkyl. In some embodiments is a compound of Formula (Ic), wherein R 4 is phenyl substituted with 1 R 5 group, R 5 is -S(O) 2 R 13 , and R 13 is C 1-6 haloalkyl. In some embodiments is a compound of Formula (Ic), wherein R 4 is . In some embodiments is a compound of Formula (Ic), wherein R 4 is a compound of Formula (Ic), wherein R 4 is
  • R 2 is phenyl substituted with 1-4 R 3 groups.
  • R 2 is phenyl substituted with 1 or 2 R 3 groups.
  • each R 3 is independently selected from halogen, -CN, C 1- 6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, -OR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -C(O)N(R 10 )(R 11 ), - S(O) 2 R 13 , and -S(O)2N(R 10 )(R 11 )-, wherein C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1- 6 haloalkyl,
  • each R 3 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl, wherein C 1-6 alkyl and C 1-6 haloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 3 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • each R 3 is independently selected from halogen, unsubstituted C 1-6 alkyl, and unsubstituted C 1-6 haloalkyl. In some embodiments is a compound of Formula (Ic), wherein each R 3 is independently selected from halogen. In some embodiments is a compound of Formula (Ic), wherein each R 3 is independently selected from unsubstituted C 1-6 alkyl. In some embodiments is a compound of Formula (Ic), wherein each R 3 is independently selected from unsubstituted C 1 -6 haloalky 1. [0099] In some embodiments is a compound of Formula (Ic), wherein R 2 is selected from [0100] In some embodiments is a compound of Formula (Ic), wherein R 2 is
  • each R 1 is independently selected from C 1-6 alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, C 1-9 heteroaryl, -OR 10 , and - N(R 10 )(R 11 ).
  • each R 1 is independently selected from unsubstituted C 1-6 alkyl.
  • each R 1 is -CH 3 .
  • X is N or C(R 7 ); each R 1 is independently selected from halogen, -CN, -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , - OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O) 2 R 13 , - C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), - N(R 12 )C(O)R 13 , -S(O) 2 R 13 , -S(O) 2 N(R 10 )(R 11 )-, C 1-6 alkyl, C 1-6
  • R 2 is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl, wherein C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-4 R 3 groups; each R 3 is independently selected from halogen, -CN, -OR 10 , C 1-6 alkyl, C 1 -6 haloalky 1, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, and -CH 2 -C 2-9 heterocycloalkyl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6
  • R 4 is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl, wherein C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-4 R 5 groups; each R 5 is independently selected from halogen, -CN, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), - C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , - N(R 12 )S(O) 2 R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(
  • R 6 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl
  • R 7 is selected from hydrogen and C 1-6 alkyl; each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1- 9 heteroaryl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1- 6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl
  • X is N. In some embodiments is a compound of Formula (II), wherein X is C(R 7 ). In some embodiments is a compound of Formula (II), wherein R 7 is hydrogen. In some embodiments is a compound of Formula (II), wherein R 7 is C 1-6 alkyl.
  • a compound of Formula (II) wherein R 4 is C 1-9 heteroaryl optionally substituted with 1-4 R 5 groups.
  • a compound of Formula (II) wherein R 4 is pyridinyl optionally substituted with 1-4 R 5 groups.
  • R 4 is pyridinyl optionally substituted with 1-4 R 5 groups and each R 5 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , wherein C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • R 4 is pyridinyl optionally substituted with 1-4 R 5 groups and each R 5 is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted C 2-9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , each R 10 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, and each R 13 is independently selected from C 1-6 alkyl and C 1- 6 haloalkyl.
  • R 4 is pyridinyl substituted with 1 or 2 R 5 groups and each R 5 is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted C 2- 9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , each R 10 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, and each R 13 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
  • R 4 is pyridinyl substituted with 1 R 5 group, R 5 is -OR 10 , and R 10 is C 1-6 alkyl.
  • R 4 is pyridinyl substituted with 1 R 5 group, R 5 is -OR 10 , and R 10 is C 3-6 cycloalkyl.
  • R 4 is selected from:
  • R 4 is selected from:
  • R 4 is selected from:
  • R 4 is phenyl optionally substituted with 1-4 R 5 groups.
  • a compound of Formula (II) wherein R 4 is phenyl optionally substituted with 1-4 R 5 groups and each R 5 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -OR 10 , and - S(O) 2 R 13 , wherein C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, and C 1- 6 haloalkyl.
  • R 4 is phenyl optionally substituted with 1-4 R 5 groups and each R 5 is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted C 2- 9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , each R 10 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, and each R 13 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
  • R 4 is phenyl substituted with 1 or 2 R 5 groups and each R 5 is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1- 6 haloalkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted C 2-9 heterocycloalkyl, -OR 10 , and - S(O) 2 R 13 , each R 10 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, and each R 13 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
  • R 4 is phenyl substituted with 1 R 5 group, R 5 is -OR 10 , and R 10 is C 1-6 alkyl.
  • R 4 is phenyl substituted with 1 R 5 group, R 5 is -OR 10 , and R 10 is C 3-6 cycloalkyl.
  • R 6 is hydrogen. In some embodiments is a compound of Formula (II), R 6 is C 1-6 alkyl. In some embodiments is a compound of Formula (II), R 6 is -CH 3 . In some embodiments is a compound of Formula (II), R 6 is C 1-6 haloalkyl.
  • each R 3 is independently selected from halogen, -CN, C 1- 6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, -OR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -C(O)N(R 10 )(R 11 ), - S(O) 2 R 13 , and -S(O)2N(R 10 )(R 11 )-, wherein C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 3 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl, wherein C 1-6 alkyl and C 1-6 haloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 3 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • each R 3 is independently selected from halogen, unsubstituted C 1-6 alkyl, and unsubstituted C 1-6 haloalkyl.
  • each R 3 is independently selected from halogen.
  • each R 3 is independently selected from unsubstituted C 1-6 alkyl.
  • each R 3 is independently selected from unsubstituted C 1-6 haloalkyl.
  • R 2 is selected from
  • each R 1 is independently selected from C 1-6 alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, C 1-9 heteroaryl, -OR 10 , and - N(R 10 )(R 11 ).
  • each R 1 is independently selected from unsubstituted C 1-6 alkyl.
  • each R 1 is -CH 3 .
  • ring A is a 5- or 6-membered heteroaryl ring or phenyl
  • ring B is a 5- or 6-membered heteroaryl ring or phenyl
  • X is N or C(R 7 );
  • Y is O, S, or N(R 7a );
  • each R 1 and each R 1a is independently selected from halogen, -CN, -OR 10 , -SR 10 , - N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), - N(R 12 )C(O)OR 13 , -N(R 12 )S(O) 2 R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), - C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O) 2 R 13 , -S(O) 2 N(R 10 )(R 11 )-, C(O)C(O)N(R
  • R 2 is selected from C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl, wherein C 2- 9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-4 R 3 groups; each R 3 is independently selected from halogen, -CN, -OR 10 , C 1-6 alkyl, C 1 -6 haloalky 1, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, and -CH 2 -C 2-9 heterocycloalkyl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalky
  • R 7 , R 7a , and R 7b are independently selected from hydrogen and C 1-6 alkyl; each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1- 9 heteroaryl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1- 6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 hetero
  • ring A is a 6-membered heteroaryl ring.
  • ring A is a compound of Formula (III), wherein ring A is a pyridyl ring.
  • ring A is a compound of Formula (III), wherein ring A is a pyrazinyl ring.
  • ring A is a compound of Formula (III), wherein ring A is a pyrimidinyl ring.
  • ring A is a pyridazinyl ring.
  • ring A is a 5-membered heteroaryl ring.
  • ring A is a furanyl ring.
  • ring A is a compound of Formula (III), wherein ring A is a thienyl ring.
  • ring A is a pyrrolyl ring.
  • ring A is a compound of Formula (III), wherein ring A is phenyl.
  • ring B is a 6-membered heteroaryl ring.
  • ring B is a pyridyl ring.
  • ring B is a compound of Formula (III), wherein ring B is a pyrazinyl ring.
  • ring B is a compound of Formula (III), wherein ring B is a pyrimidinyl ring.
  • ring B is a pyridazinyl ring.
  • ring B is a 5-membered heteroaryl ring. In some embodiments is a compound of Formula (III), wherein ring B is a furanyl ring. In some embodiments is a compound of Formula (III), wherein ring B is a thienyl ring. In some embodiments is a compound of Formula (III), wherein ring B is a pyrrolyl ring. [0132] In some embodiments is a compound of Formula (III), wherein ring B is phenyl.
  • X is N.
  • X is C(R 7 ).
  • R 7 is hydrogen.
  • R 7 is C 1-6 alkyl.
  • Y is O. In some embodiments is a compound of Formula (III), wherein Y is S. In some embodiments is a compound of Formula (III), wherein Y is N(R 7a ). In some embodiments is a compound of Formula (III), wherein R 7a is hydrogen. In some embodiments is a compound of Formula (III), wherein R 7a is C 1-6 alkyl.
  • a compound of Formula (III) wherein Z is N. In some embodiments is a compound of Formula (III), wherein Z is C(R 7b ). In some embodiments is a compound of Formula (III), wherein Z is C(H).
  • each R 1a is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , wherein C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, and C 1- 6 haloalkyl.
  • each R 1a is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, unsubstituted C 3- 6 cycloalkyl, unsubstituted C 2-9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , each R 10 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, and each R 13 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
  • each R 1a is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 , and each R 10 is independently selected from C 1-6 alkyl.
  • each R 1a is independently selected from halogen.
  • each R 1a is independently selected from unsubstituted C 1-
  • each R 1a is -CH 3 .
  • each R 1a is independently selected from C 1-6 haloalkyl.
  • each R 1a is a compound of Formula (III), wherein each R 1a is -CF3.
  • each R 1a is independently selected from -OR 10 , and R 10 is C 1-6 alkyl.
  • each R 1a is -OR 10 , and R 10 is -CH 3 .
  • p is 1.
  • a compound of Formula (III) wherein R 2 is phenyl optionally substituted with 1-4 R 3 groups. In some embodiments is a compound of Formula (III), wherein R 2 is phenyl substituted with 1-4 R 3 groups. In some embodiments is a compound of Formula (III), wherein R 2 is phenyl substituted with 1 or 2 R 3 groups.
  • each R 3 is independently selected from halogen, -CN, C 1- 6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, -OR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -C(O)N(R 10 )(R 11 ), - S(O) 2 R 13 , and -S(O)2N(R 10 )(R 11 )-, wherein C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 3 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl, wherein C 1-6 alkyl and C 1-6 haloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 3 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • each R 3 is independently selected from halogen, unsubstituted C 1-6 alkyl, and unsubstituted C 1-6 haloalkyl. In some embodiments is a compound of Formula (III), wherein each R 3 is independently selected from halogen. In some embodiments is a compound of Formula (III), wherein each R 3 is independently selected from unsubstituted C 1-6 alkyl. In some embodiments is a compound of Formula (III), wherein each R 3 is independently selected from unsubstituted C 1 -6 haloalky 1. [0140] In some embodiments is a compound of Formula (III), wherein R 2 is selected from some embodiments is a compound of Formula (III), wherein In some embodiments is a compound of
  • each R 1 is independently selected from C 1-6 alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, C 1-9 heteroaryl, -OR 10 , and - N(R 10 )(R 11 ).
  • each R 1 is independently selected from unsubstituted C 1-6 alkyl.
  • each R 1 is -CH 3 .
  • a compound of Formula (III) wherein m is 0, 1, or 2. In some embodiments is a compound of Formula (III), wherein m is 2. In some embodiments is a compound of Formula (III), wherein m is 1. In some embodiments is a compound of Formula (III), wherein m is 0.
  • ring B is a 5- or 6-membered heteroaryl ring or phenyl
  • Y is O, S, or N(R 7a );
  • each R 1 and each R 1a is independently selected from halogen, -CN, -OR 10 , -SR 10 , - N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), - N(R 12 )C(O)OR 13 , -N(R 12 )S(O) 2 R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), - C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O) 2 R 13 , -S(O) 2 N(R 10 )(R 11 )-, C(O)C(O)N(R
  • R 2 is selected from C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl, wherein C 2- 9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-4 R 3 groups; each R 3 is independently selected from halogen, -CN, -OR 10 , C 1-6 alkyl, C 1 -6 haloalky 1, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, and -CH 2 -C 2-9 heterocycloalkyl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalky
  • R 7a and R 7b are independently selected from hydrogen and C 1-6 alkyl; each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1- 9 heteroaryl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1- 6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl,
  • ring B is a 6-membered heteroaryl ring.
  • ring B is a pyridyl ring.
  • ring B is a compound of Formula (Illa), wherein ring B is a pyrazinyl ring.
  • ring B is a compound of Formula (Illa), wherein ring B is a pyrimidinyl ring.
  • ring B is a pyridazinyl ring.
  • ring B is a 5-membered heteroaryl ring.
  • ring B is a furanyl ring.
  • ring B is a thienyl ring.
  • ring B is a compound of Formula (Illa), wherein ring B is a pyrrolyl ring.
  • ring B is a compound of Formula (Illa), wherein ring B is phenyl.
  • Y is O.
  • Y is S. In some embodiments is a compound of Formula (Illa), wherein Y is N(R 7a ). In some embodiments is a compound of Formula (Illa), wherein R 7a is hydrogen. In some embodiments is a compound of Formula (II), wherein R 7a is C 1-6 alkyl.
  • each R 1a is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , wherein C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • each R 1a is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted C 2-9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , each R 10 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, and each R 13 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
  • each R 1a is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1- 6 haloalkyl, and -OR 10 , and each R 10 is independently selected from C 1-6 alkyl.
  • each R 1a is independently selected from halogen.
  • each R 1a is independently selected from unsubstituted C 1-6 alkyl.
  • each R 1a is -CH 3 .
  • each R 1a is independently selected from C 1-6 haloalkyl. In some embodiments is a compound of Formula (Illa), wherein each R 1a is -CF3. In some embodiments is a compound of Formula (Illa), wherein each R 1a is independently selected from -OR 10 , and R 10 is C 1-6 alkyl. In some embodiments is a compound of Formula (Illa), wherein each R 1a is -OR 10 , and R 10 is - CH 3 .
  • each R 3 is independently selected from halogen, -CN, C 1- 6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, -OR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -C(O)N(R 10 )(R 11 ), - S(O) 2 R 13 , and -S(O)2N(R 10 )(R 11 )-, wherein C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 3 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl, wherein C 1-6 alkyl and C 1-6 haloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 3 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • each R 3 is independently selected from halogen, unsubstituted C 1-6 alkyl, and unsubstituted C 1-6 haloalkyl. In some embodiments is a compound of Formula (Illa), wherein each R 3 is independently selected from halogen. In some embodiments is a compound of Formula (Illa), wherein each R 3 is independently selected from unsubstituted C 1-6 alkyl. In some embodiments is a compound of Formula (Illa), wherein each R 3 is independently selected from unsubstituted C 1 -6 haloalky 1. [0158] In some embodiments is a compound of Formula (Illa), wherein R 2 is selected from some embodiments is a compound of Formula (Illa), wherein In some embodiments is a compound of
  • each R 1 is independently selected from C 1-6 alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, C 1-9 heteroaryl, - OR 10 , and -N(R 10 )(R 11 ).
  • each R 1 is independently selected from unsubstituted C 1-6 alkyl.
  • each R 1 is -CH 3 .
  • X is N or C(R 7 );
  • each R 1 is independently selected from halogen, -CN, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), - C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , - N(R 12 )S(O) 2 R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), - C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O) 2 R 13 , -S(O) 2 N(R 10 )(R 11 )-, C(O)(O)(O)(R 11 ),
  • R 2 is selected from C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl, wherein C 2- 9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-4 R 3 groups; each R 3 is independently selected from halogen, -CN, -OR 10 , C 1-6 alkyl, C 1 -6 haloalky 1, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, and -CH 2 -C 2-9 heterocycloalkyl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalky
  • R 4b is C 1-9 heteroaryl optionally substituted with 1-4 R 5a groups; each R 5a is independently selected from halogen, -CN, -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -
  • R 7 is selected from hydrogen and C 1-6 alkyl; each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1- 9 heteroaryl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1- 6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl
  • a compound of Formula (IV) wherein J is C(H). In some embodiments is a compound of Formula (IV), wherein J is C(R 1 ). In some embodiments is a compound of Formula (IV), wherein J is N.
  • X is N. In some embodiments is a compound of Formula (IV), wherein X is C(R 7 ). In some embodiments is a compound of Formula (IV), wherein R 7 is hydrogen. In some embodiments is a compound of Formula (IV), wherein R 7 is C 1-6 alkyl.
  • a compound of Formula (IV) wherein R 4b is C 1-9 heteroaryl optionally substituted with 1-4 R 5a groups, wherein the C 1-9 heteroaryl is a bicyclic heteroaryl.
  • R 4b is C 1-9 heteroaryl substituted with 1-4 R 5a groups, wherein the C 1-9 heteroaryl is a bicyclic heteroaryl.
  • R 4b is C 1-9 heteroaryl substituted with 1 or 2 R 5a groups, wherein the C 1-9 heteroaryl is a bicyclic heteroaryl.
  • R 4b is C 5- 9 heteroaryl substituted with 1 or 2 R 5a groups, wherein the C 5-
  • 9 heteroaryl is a bicyclic heteroaryl.
  • R 4b is C 1-9 heteroaryl substituted with 1 R 5a group, wherein the C 1-9 heteroaryl is a bicyclic heteroaryl.
  • R 4b is C 5-
  • R 4b is a C 1-9 heteroaryl selected from oxazolo[4,5-c]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4- c]pyridine, imidazo[4,5-c]pyridine, benzoxazole, benzothiazole, and benzimidazole.
  • R 4b is an oxazolo[4,5-c]pyridine.
  • R 4b is an oxazolo[5,4-c]pyridine. In some embodiments is a compound of Formula (IV), wherein R 4b is a thiazolo[4,5-c]pyridine. In some embodiments is a compound of Formula (IV), wherein R 4b is a thiazolo[5,4-c]pyridine. In some embodiments is a compound of Formula (IV), wherein R 4b is an imidazo[4,5-c]pyridine, benzoxazole, benzothiazole, and benzimidazole. In some embodiments is a compound of Formula (IV), wherein R 4b is a benzoxazole. In some embodiments is a compound of Formula (IV), wherein R 4b is a benzothiazole. In some embodiments is a compound of Formula (IV), wherein R 4b is a compound of Formula (IV), wherein R 4b is a benzimidazole.
  • each R 5a is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , wherein C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, and C 1- 6 haloalkyl.
  • each R 5a is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, unsubstituted C 3 . 6 cycloalkyl, unsubstituted C 2-9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , each R 10 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, and each R 13 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
  • each R 5a is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 , and each R 10 is independently selected from C 1-6 alkyl.
  • R 4b is substituted with 1 R 5a group and R 5a is halogen.
  • R 4b is substituted with 1 R 5a group and R 5a is unsubstituted C 1-6 alkyl.
  • R 4b is substituted with 1 R 5a group and R 5a is -CH 3 .
  • a compound of Formula (IV) wherein R 4b is substituted with 1 R 5a group and R 5a is C 1-6 haloalkyl. In some embodiments is a compound of Formula (IV), wherein R 4b is substituted with 1 R 5a group and R 5a is -CF 3 . In some embodiments is a compound of Formula (IV), wherein R 4b is substituted with 1 R 5a group and R 5a is unsubstituted C 3-6 cycloalkyl. In some embodiments is a compound of Formula (IV), wherein R 4b is substituted with 1 R 5a group, R 5a is -OR 10 , and R 10 is C 1-6 alkyl. In some embodiments is a compound of Formula (IV), wherein R 4b is substituted with 1 R 5a group, R 5a is -OR 10 , and R 10 is C 3-6 cycloalkyl.
  • R 4b is selected from:
  • a compound of Formula (IV) wherein R 2 is phenyl optionally substituted with 1-4 R 3 groups. In some embodiments is a compound of Formula (IV), wherein R 2 is phenyl substituted with 1-4 R 3 groups. In some embodiments is a compound of Formula (IV), wherein R 2 is phenyl substituted with 1 or 2 R 3 groups.
  • each R 3 is independently selected from halogen, -CN, C 1- 6 alkyl, C 1-6 haloalkyl, C 3.6 cycloalkyl, -OR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -C(O)N(R 10 )(R 11 ), - S(O) 2 R 13 , and -S(O)2N(R 10 )(R 11 )-, wherein C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 3 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl, wherein C 1-6 alkyl and C 1-6 haloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 3 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • each R 3 is independently selected from halogen, unsubstituted C 1-6 alkyl, and unsubstituted C 1-6 haloalkyl. In some embodiments is a compound of Formula (IV), wherein each R 3 is independently selected from halogen. In some embodiments is a compound of Formula (IV), wherein each R 3 is independently selected from unsubstituted C 1-6 alkyl. In some embodiments is a compound of Formula (IV), wherein each R 3 is independently selected from unsubstituted C 1 -6 haloalky 1. [0173] In some embodiments is a compound of Formula (IV), wherein R 2 is selected from embodiments is a compound of Formula (IV), wherein R 2 is
  • each R 1 is independently selected from C 1-6 alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, C 1-9 heteroaryl, -OR 10 , and - N(R 10 )(R 11 ).
  • each R 1 is independently selected from unsubstituted C 1-6 alkyl.
  • each R 1 is -CH 3 .
  • n is a compound of Formula (IV), wherein m is 2. In some embodiments is a compound of Formula (IV), wherein m is 1. In some embodiments is a compound of Formula (IV), wherein m is 0.
  • X is N or C(R 7 ); each R 1 is independently selected from halogen, -CN, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), - C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , - N(R 12 )S(O) 2 R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), - C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O) 2 R 13 , -S(O) 2 N(R 10 )(R 11 ); each R 1 is independently selected from
  • R 2 is selected from C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl, wherein C 2- 9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-4 R 3 groups; each R 3 is independently selected from halogen, -CN, -OR 10 , C 1-6 alkyl, C 1 -6 haloalky 1, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, and -CH 2 -C 2-9 heterocycloalkyl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalky
  • R 4b is C 1-9 heteroaryl optionally substituted with 1-4 R 5a groups; each R 5a is independently selected from halogen, -CN, -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , - OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O) 2 R 13 , - C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), - N(R 12 )C(O)R 13 , -S(O) 2 R 13 , -S(O) 2 N(R 10 )(R 11 )
  • R 7 is selected from hydrogen and C 1-6 alkyl; each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1- 9 heteroaryl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1- 6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl
  • X is N. In some embodiments is a compound of Formula (IVa), wherein X is C(R 7 ). In some embodiments is a compound of Formula (IVa), wherein R 7 is hydrogen. In some embodiments is a compound of Formula (IVa), wherein R 7 is C 1-6 alkyl.
  • R 4b is C 1-9 heteroaryl substituted with 1-4 R 5a groups, wherein the C 1-9 heteroaryl is a bicyclic heteroaryl.
  • R 4b is C 1-9 heteroaryl substituted with 1 or 2 R 5a groups, wherein the C 1-9 heteroaryl is a bicyclic heteroaryl.
  • R 4b is C 5- 9 heteroaryl substituted with 1 or 2 R 5a groups, wherein the C 5-
  • 9 heteroaryl is a bicyclic heteroaryl.
  • R 4b is C 1-9 heteroaryl substituted with 1 R 5a group, wherein the C 1-9 heteroaryl is a bicyclic heteroaryl.
  • R 4b is C 5-
  • R 4b is a C 1-9 heteroaryl selected from oxazolo[4,5-c]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4- c]pyridine, imidazo[4,5-c]pyridine, benzoxazole, benzothiazole, and benzimidazole.
  • R 4b is an oxazolo[4,5-c]pyridine.
  • each R 5a is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , wherein C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • each R 5a is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted C 2-9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , each R 10 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, and each R 13 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
  • each R 5a is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1- 6 haloalkyl, and -OR 10 , and each R 10 is independently selected from C 1-6 alkyl.
  • each R 4b is substituted with 1 R 5a group and R 5a is halogen.
  • a compound of Formula (IVa) wherein R 4b is substituted with 1 R 5a group and R 5a is unsubstituted C 1-6 alkyl.
  • a compound of Formula (IVa) wherein R 4b is substituted with 1 R 5a group, R 5a is -OR 10 , and R 10 is C 1-6 alkyl. In some embodiments is a compound of Formula (IVa), wherein R 4b is substituted with 1 R 5a group, R 5a is -OR 10 , and R 10 is C 3-6 cycloalkyl.
  • R 4b is selected from:
  • each R 3 is independently selected from halogen, -CN, C 1- 6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, -OR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -C(O)N(R 10 )(R 11 ), - S(O) 2 R 13 , and -S(O)2N(R 10 )(R 11 )-, wherein C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 3 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl, wherein C 1-6 alkyl and C 1-6 haloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 3 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • each R 3 is independently selected from halogen, unsubstituted C 1-6 alkyl, and unsubstituted C 1-6 haloalkyl. In some embodiments is a compound of Formula (IVa), wherein each R 3 is independently selected from halogen. In some embodiments is a compound of Formula (IVa), wherein each R 3 is independently selected from unsubstituted C 1-6 alkyl. In some embodiments is a compound of Formula (IVa), wherein each R 3 is independently selected from unsubstituted C 1 -6 haloalky 1. [0187] In some embodiments is a compound of Formula (IVa), wherein R 2 is selected from embodiments is a compound of Formula (IVa), wherein R 2 is
  • each R 1 is independently selected from C 1-6 alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, C 1-9 heteroaryl, - OR 10 , and -N(R 10 )(R 11 ).
  • each R 1 is independently selected from unsubstituted C 1-6 alkyl.
  • each R 1 is -CH 3 .
  • X is N or C(R 7 ); each R 1 is independently selected from halogen, -CN, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), - C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , - N(R 12 )S(O) 2 R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), - C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O) 2 R 13 , -S(O) 2 N(R 10 )(R 11 ); each R 1 is independently selected from
  • R 2 is selected from C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl, wherein C 2- 9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-4 R 3 groups; each R 3 is independently selected from halogen, -CN, -OR 10 , C 1-6 alkyl, C 1 -6 haloalky 1, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, and -CH 2 -C 2-9 heterocycloalkyl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalky
  • R 4b is C 1-9 heteroaryl optionally substituted with 1-4 R 5a groups; each R 5a is independently selected from halogen, -CN, -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , - OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O) 2 R 13 , - C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), - N(R 12 )C(O)R 13 , -S(O) 2 R 13 , -S(O) 2 N(R 10 )(R 11 )
  • R 7 is selected from hydrogen and C 1-6 alkyl; each R 10 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1- 9 heteroaryl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1- 6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl
  • X is N. In some embodiments is a compound of Formula (IVb), wherein X is C(R 7 ). In some embodiments is a compound of Formula (IVb), wherein R 7 is hydrogen. In some embodiments is a compound of Formula (IVb), wherein R 7 is C 1-6 alkyl.
  • a compound of Formula (IVb) wherein R 4b is C 1-9 heteroaryl optionally substituted with 1-4 R 5a groups, wherein the C 1-9 heteroaryl is a bicyclic heteroaryl.
  • R 4b is C 1-9 heteroaryl substituted with 1-4 R 5a groups, wherein the C 1-9 heteroaryl is a bicyclic heteroaryl.
  • R 4b is C 1-9 heteroaryl substituted with 1 or 2 R 5a groups, wherein the C 1-9 heteroaryl is a bicyclic heteroaryl.
  • R 4b is C 5- 9 heteroaryl substituted with 1 or 2 R 5a groups, wherein the C 5-
  • 9 heteroaryl is a bicyclic heteroaryl.
  • R 4b is C 1-9 heteroaryl substituted with 1 R 5a group, wherein the C 1-9 heteroaryl is a bicyclic heteroaryl.
  • R 4b is C 5-
  • R 4b is a C 1-9 heteroaryl selected from oxazolo[4,5-c]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4- c]pyridine, imidazo[4,5-c]pyridine, benzoxazole, benzothiazole, and benzimidazole.
  • R 4b is an oxazolo[4,5-c]pyridine.
  • R 4b is an oxazolo[5,4-c]pyridine. In some embodiments is a compound of Formula (IVb), wherein R 4b is a thiazolo[4,5-c]pyridine. In some embodiments is a compound of Formula (IVb), wherein R 4b is a thiazolo[5,4-c]pyridine. In some embodiments is a compound of Formula (IVb), wherein R 4b is an imidazo[4,5- c]pyridine, benzoxazole, benzothiazole, and benzimidazole. In some embodiments is a compound of Formula (IVb), wherein R 4b is a benzoxazole.
  • each R 5a is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , wherein C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • each R 5a is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted C 2-9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , each R 10 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, and each R 13 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
  • each R 5a is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1- 6 haloalkyl, and -OR 10 , and each R 10 is independently selected from C 1-6 alkyl.
  • each R 4b is substituted with 1 R 5a group and R 5a is halogen.
  • R 4b is substituted with 1 R 5a group and R 5a is unsubstituted C 1-6 alkyl.
  • a compound of Formula (IVb) wherein R 4b is substituted with 1 R 5a group, R 5a is -OR 10 , and R 10 is C 1-6 alkyl. In some embodiments is a compound of Formula (IVb), wherein R 4b is substituted with 1 R 5a group, R 5a is -OR 10 , and R 10 is C 3-6 cycloalkyl.
  • R 4b is selected from:
  • [0200] is a compound of Formula (IVb), wherein R 2 is phenyl optionally substituted with 1-4 R 3 groups. In some embodiments is a compound of Formula (IVb), wherein R 2 is phenyl substituted with 1-4 R 3 groups. In some embodiments is a compound of Formula (IVb), wherein R 2 is phenyl substituted with 1 or 2 R 3 groups.
  • each R 3 is independently selected from halogen, -CN, C 1- 6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, -OR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -C(O)N(R 10 )(R 11 ), - S(O) 2 R 13 , and -S(O)2N(R 10 )(R 11 )-, wherein C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 3 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl, wherein C 1-6 alkyl and C 1-6 haloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 3 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • each R 3 is independently selected from halogen, unsubstituted C 1-6 alkyl, and unsubstituted C 1-6 haloalkyl. In some embodiments is a compound of Formula (IVb), wherein each R 3 is independently selected from halogen. In some embodiments is a compound of Formula (IVb), wherein each R 3 is independently selected from unsubstituted C 1-6 alkyl. In some embodiments is a compound of Formula (IVb), wherein each R 3 is independently selected from unsubstituted C 1 -6 haloalky 1. [0201] In some embodiments is a compound of Formula (IVb), wherein R 2 is selected from embodiments is a compound of Formula (IVb), wherein R 2 is
  • each R 1 is independently selected from C 1-6 alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, C 1-9 heteroaryl, - OR 10 , and -N(R 10 )(R 11 ).
  • each R 1 is independently selected from unsubstituted C 1-6 alkyl.
  • each R 1 is -CH 3 .
  • m is 2. In some embodiments is a compound of Formula (IVb), wherein m is 1. In some embodiments is a compound of Formula (IVb), wherein m is 0.
  • each R 1 is independently selected from halogen, -CN, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), - C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , - N(R 12 )S(O) 2 R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), - C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O) 2 R 13 , -S(O) 2 N(R 10 )(R 11 )-, C
  • R 2 is selected from C 2-9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl, wherein C 2- 9 heterocycloalkyl, C 6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-4 R 3 groups; each R 3 is independently selected from halogen, -CN, -OR 10 , C 1-6 alkyl, C 1 -6 haloalky 1, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, and -CH 2 -C 2-9 heterocycloalkyl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C 2- 6 heteroalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalky
  • R 4b is C 1-9 heteroaryl optionally substituted with 1-4 R 5a groups; each R 5a is independently selected from halogen, -CN, -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , - OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O) 2 R 13 , - C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), - N(R 12 )C(O)R 13 , -S(O) 2 R 13 , -S(O) 2 N(R 10 )(R 11 )
  • R 4b is C 1-9 heteroaryl substituted with 1-4 R 5a groups, wherein the C 1-9 heteroaryl is a bicyclic heteroaryl.
  • R 4b is C 1-9 heteroaryl substituted with 1 or 2 R 5a groups, wherein the C 1-9 heteroaryl is a bicyclic heteroaryl.
  • R 4b is C 5- 9 heteroaryl substituted with 1 or 2 R 5a groups, wherein the C 5-
  • 9 heteroaryl is a bicyclic heteroaryl.
  • R 4b is C 1-9 heteroaryl substituted with 1 R 5a group, wherein the C 1-9 heteroaryl is a bicyclic heteroaryl.
  • R 4b is C 5-
  • R 4b is a C 1-9 heteroaryl selected from oxazolo[4,5-c]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-c]pyridine, imidazo[4,5-c]pyridine, benzoxazole, benzothiazole, and benzimidazole.
  • R 4b is an oxazolo[4,5-c]pyridine.
  • R 4b is an oxazolo[5,4-c]pyridine. In some embodiments is a compound of Formula (V), wherein R 4b is a thiazolo[4,5-c]pyridine. In some embodiments is a compound of Formula (V), wherein R 4b is a thiazolo[5,4-c]pyridine. In some embodiments is a compound of Formula (V), wherein R 4b is an imidazo[4,5-c]pyridine, benzoxazole, benzothiazole, and benzimidazole. In some embodiments is a compound of Formula (V), wherein R 4b is a benzoxazole. In some embodiments is a compound of Formula (V), wherein R 4b is a benzothiazole. In some embodiments is a compound of Formula (V), wherein R 4b is a compound of Formula (V), wherein R 4b is a benzimidazole.
  • each R 5a is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , wherein C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, and C 1- 6 haloalkyl.
  • each R 5a is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, unsubstituted C 3 . 6 cycloalkyl, unsubstituted C 2-9 heterocycloalkyl, -OR 10 , and -S(O) 2 R 13 , each R 10 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, and each R 13 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
  • each R 5a is independently selected from halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 , and each R 10 is independently selected from C 1-6 alkyl.
  • R 4b is substituted with 1 R 5a group and R 5a is halogen.
  • R 4b is substituted with 1 R 5a group and R 5a is unsubstituted C 1-6 alkyl.
  • R 4b is substituted with 1 R 5a group and R 5a is -CH 3 .
  • R 4b is selected from:
  • each R 3 is independently selected from halogen, -CN, C 1- 6 alkyl, C 1-6 haloalkyl, C 3.6 cycloalkyl, -OR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -C(O)N(R 10 )(R 11 ), - S(O) 2 R 13 , and -S(O)2N(R 10 )(R 11 )-, wherein C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 3 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl, wherein C 1-6 alkyl and C 1-6 haloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 3 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • each R 3 is independently selected from halogen, unsubstituted C 1-6 alkyl, and unsubstituted C 1-6 haloalkyl. In some embodiments is a compound of Formula (V), wherein each R 3 is independently selected from halogen. In some embodiments is a compound of Formula (V), wherein each R 3 is independently selected from unsubstituted C 1-6 alkyl. In some embodiments is a compound of Formula (V), wherein each R 3 is independently selected from unsubstituted C 1-6 haloalkyl. [0214] In some embodiments is a compound of Formula (V), wherein R 2 is selected from embodiments is a compound of Formula (V), wherein R 2 is
  • each R 1 is independently selected from C 1-6 alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10 aryl, C 1-9 heteroaryl, -OR 10 , and - N(R 10 )(R 11 ).
  • each R 1 is independently selected from unsubstituted C 1-6 alkyl.
  • each R 1 is -CH 3 .
  • a compound of Formula (V), wherein m is 2. In some embodiments is a compound of Formula (V), wherein m is 1. In some embodiments is a compound of Formula (V), wherein m is 3. In some embodiments is a compound of Formula (V), wherein m is 4. In some embodiments is a compound of Formula (V), wherein m is 0.
  • [0226] is a compound selected from Table 1, or a pharmaceutically acceptable salt thereof.
  • substituents of compounds described herein are disclosed in groups or in ranges. It is specifically intended that the groups or ranges include each and every individual subcombination of the members of such groups and ranges.
  • the term “C 1-6 alkyl” is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency.
  • pyridinyl “pyridyl,” or “a pyridine ring” may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-
  • n-membered typically describes the number of ringforming atoms in a moiety where the number of ring-forming atoms is “n”.
  • piperidinyl is an example of a 6-membered heterocycloalkyl ring
  • pyrazolyl is an example of a
  • 5-membered heteroaryl ring pyridinyl is an example of a 6-membered heteroaryl ring
  • 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.
  • each variable can be a different moiety independently selected from the group defining the variable.
  • the two R groups can represent different moieties independently selected from the group defined for R.
  • C i-j where i and j are integers, employed in combination with a chemical group, designates a range of the number of carbon atoms in the chemical group with i-j defining the range.
  • C 1-6 alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms.
  • alkyl refers to a saturated hydrocarbon group that may be straight-chain or branched. In some embodiments, the alkyl group contains 1 to 7, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, ec-butyl, tert-butyl, //-pentyl, 2-methyl-l -butyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, //-heptyl, and the like.
  • the alkyl group is methyl, ethyl, or propyl.
  • the alkyl group is methyl.
  • halo or “halogen”, employed alone or in combination with other terms, includes fluoro, chloro, bromo, and iodo. In some embodiments, halo is F or Cl.
  • haloalkyl refers to an alkyl group having up to the full valency of halogen atom substituents, which may either be the same or different.
  • the halogen atoms are fluoro atoms.
  • the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • Example haloalkyl groups include CF3, C 2 F5, CHF2, CCI3, CHCl 2 , C 2 CI5, and the like.
  • alkoxy refers to a group of formula -O-alkyl.
  • Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.
  • the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • haloalkoxy employed alone or in combination with other terms, refers to a group of formula -O-(haloalkyl).
  • the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • An example haloalkoxy group is -OCF3.
  • amino employed alone or in combination with other terms, refers to NH 2 .
  • cycloalkyl employed alone or in combination with other terms, refers to a non-aromatic cyclic hydrocarbon including cyclized alkyl and alkenyl groups.
  • Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) ring systems.
  • cycloalkyl moieties that have one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of cyclopentane, cyclohexene, cyclohexane, and the like, or pyrido derivatives of cyclopentane or cyclohexane. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo. Cycloalkyl groups also include cycloalkylidenes.
  • cycloalkyl also includes bridgehead cycloalkyl groups (e.g., non-aromatic cyclic hydrocarbon moieties containing at least one bridgehead carbon, such as admantan-l-yl) and spirocycloalkyl groups (e.g., non-aromatic hydrocarbon moieties containing at least two rings fused at a single carbon atom, such as spiro[2.5]octane and the like).
  • the cycloalkyl group has 3 to 10 ring members, or 3 to 7 ring members.
  • the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is monocyclic.
  • the cycloalkyl group is a C 3- 7 monocyclic cycloalkyl group.
  • Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcarnyl, tetrahydronaphthalenyl, octahydronaphthalenyl, indanyl, and the like.
  • the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • heterocycloalkyl refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene or alkynylene groups as part of the ring structure, which has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus.
  • Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused, bridged, or spiro rings) ring systems.
  • the heterocycloalkyl group is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur and oxygen.
  • heterocycloalkyl moi eties that have one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having a bond in common with) to the non-aromatic heterocycloalkyl ring, for example, 1,2,3,4-tetrahydro-quinoline and the like.
  • aromatic rings e.g., aryl or heteroaryl rings
  • heteroaryl rings fused (i.e., having a bond in common with) to the non-aromatic heterocycloalkyl ring, for example, 1,2,3,4-tetrahydro-quinoline and the like.
  • Heterocycloalkyl groups can also include bridgehead heterocycloalkyl groups (e.g., a heterocycloalkyl moiety containing at least one bridgehead atom, such as azaadmantan-l-yl and the like) and spiroheterocycloalkyl groups (e.g., a heterocycloalkyl moiety containing at least two rings fused at a single atom, such as [l,4-dioxa-8-aza-spiro[4.5]decan-N-yl] and the like).
  • the heterocycloalkyl group has 3 to 10 ring-forming atoms, 4 to 10 ringforming atoms, or about 3 to 8 ring forming atoms.
  • the heterocycloalkyl group has 2 to 20 carbon atoms, 2 to 15 carbon atoms, 2 to 10 carbon atoms, or about 2 to 8 carbon atoms. In some embodiments, the heterocycloalkyl group has 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms.
  • the carbon atoms or heteroatoms in the ring(s) of the heterocycloalkyl group can be oxidized to form a carbonyl, an N-oxide, or a sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quaternized.
  • the heterocycloalkyl portion is a C 2- 7 monocyclic heterocycloalkyl group.
  • the heterocycloalkyl group is a morpholine ring, pyrrolidine ring, piperazine ring, piperidine ring, tetrahydropyran ring, tetrahydropyridine, azetidine ring, or tetrahydrofuran ring.
  • aryl refers to a monocyclic or polycyclic (e.g., a fused ring system) aromatic hydrocarbon moiety, such as, but not limited to, phenyl, 1 -naphthyl, 2-naphthyl, and the like. In some embodiments, aryl groups have from 6 to 10 carbon atoms or 6 carbon atoms. In some embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, the aryl group is phenyl or naphthyl. In some embodiments, the aryl group is phenyl.
  • heteroaryl refers to a monocyclic or polycyclic (e.g., a fused ring system) aromatic hydrocarbon moiety, having one or more heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • the heteroaryl group is a monocyclic or a bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur and oxygen.
  • the heteroaryl group is a 5-14 membered heteroaryl group.
  • the heteroaryl group is a 5-10 membered heteroaryl group.
  • the heteroaryl group is a 5-6 membered heteroaryl group.
  • Example heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl, azolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo[l,2-b]thiazolyl or the like.
  • the carbon atoms or heteroatoms in the ring(s) of the heteroaryl group can be oxidized to form a carbonyl, an N- oxide, or a sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quatemized, provided the aromatic nature of the ring is preserved.
  • the heteroaryl group has from 3 to 10 carbon atoms, from 3 to 8 carbon atoms, from 3 to 5 carbon atoms, from 1 to 5 carbon atoms, or from 5 to 10 carbon atoms.
  • the heteroaryl group contains 3 to 14, 4 to 12, 4 to 8, 9 to 10, or 5 to 6 ring-forming atoms.
  • the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2 heteroatoms.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • Compounds described herein that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole.
  • Compounds described herein also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, the compounds described herein include at least one deuterium atom. [0250]
  • the term, “compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted, unless otherwise specified.
  • the term “compound” is also not limited by the way in which it was made. Thus, a compound described herein includes molecules that were made by a synthetic process or by a biological process (such as through enzyme conversion or metabolism), or combinations thereof.
  • All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., in the form of hydrates and solvates) or can be isolated.
  • the compounds described herein, or salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected.
  • Partial separation can include, for example, a composition enriched in the compounds described herein.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of a compound described herein, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the compounds described herein include the non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the compounds described herein can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.
  • suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.
  • TREM2 activators are TREM2 activators.
  • the compounds described herein can be used to activate TREM2 in a cell or in an individual or patient in need of inhibition of the enzyme by administering an inhibiting amount of a compound described herein to the cell, individual, or patient.
  • the term “in a cell” includes both inside the cell membrane and on the surface of the cell membrane.
  • the compounds described herein are useful in the treatment and prevention of various diseases which would benefit from TREM2 activation.
  • the compounds described herein are useful in the treatment and prevention of neurodegenerative and neurological disorders.
  • the compounds described herein are useful in the treatment of neurological disorders.
  • the compounds described herein are useful in the prevention of neurological disorders.
  • the compounds described herein are useful in the treatment of neurodegenerative disorders.
  • the compounds described herein are useful in the prevention of neurodegenerative disorders.
  • In some embodiments is a method of treating a neurological disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments is a method of treating a neurological disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the neurological disorder is a neurodegenerative disease.
  • a method of treating a neurodegenerative disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease is selected from Alzheimer’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis.
  • a method of treating a neurodegenerative disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease is Alzheimer’s disease.
  • a method of treating a neurodegenerative disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease is frontotemporal dementia.
  • a method of treating a neurodegenerative disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease is amyotrophic lateral sclerosis.
  • the term “cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo.
  • an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal.
  • an in vitro cell can be a cell in a cell culture.
  • an in vivo cell is a cell living in an organism such as a mammal.
  • contacting TREM2 or “contacting” a cell with a compound described herein includes the administration of a compound described herein to an individual or patient, such as a human, having TREM2, as well as, for example, introducing a compound described herein into a sample containing a cellular or purified preparation containing TREM2.
  • the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • treating refers to 1) inhibiting the disease in an individual who is experiencing or displaying the pathology or symptomatology of the disease (z.e., arresting further development of the pathology and/or symptomatology), or 2) ameliorating the disease in an individual who is experiencing or displaying the pathology or symptomatology of the disease (z.e., reversing the pathology and/or symptomatology).
  • preventing refers to preventing the disease in an individual who may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease.
  • prevention refers to preventing the disease in an individual who may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease.
  • a method of preventing a disease in a patient by administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
  • One or more additional pharmaceutically active agents or treatment methods can be used in combination with the compounds described herein.
  • the agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.
  • additional agents include acamprosate, agomelatine, almotriptan, amantadine, amisulpride, amitriptyline, apomorphine, aripiprazole, asenapine, atomoxetine, baclofen, botulinum toxin type A, bromocriptine, buccal midazolam, buprenorphine, buspirone, cabergoline, carbamazepine, chlordiazepoxide, chlorpromazine, citalopram, clobazam, clomethiazole, clomipramine, clonazepam, clozapine, denzapine, co- beneldopa, co-careldopa, dantrolene
  • the one or more additional pharmaceutically active agent can include a neuroprotective agent.
  • the neuroprotective agent is a dual leucine-zipper kinase (DLK) inhibitor.
  • the neuroprotective agent is a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor.
  • the one or more additional pharmaceutically active agent can be NAD+ or an NAD+ precursor.
  • NAD+ precursors include, for example, nicotinamide riboside (NR), nicotinic acid (NA), nicotinic acid riboside (NaR), nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinic acid mononucleotide (NaMN), tryptophan, vitamin B3, and nicotinic acid adenine dinucleotide (NAAD).
  • NR nicotinamide riboside
  • NA nicotinic acid
  • NaR nicotinic acid riboside
  • NAM nicotinamide
  • NMN nicotinamide mononucleotide
  • NaMN nicotinic acid mononucleotide
  • tryptophan vitamin B3, and nicotinic acid a
  • a pharmaceutical composition refers to a combination of a compound described herein, or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier.
  • compositions described herein are formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Additional details about suitable excipients for pharmaceutical compositions described herein may be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A.
  • Administration may be oral, topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular (e.g., eye drops or intravitreal, subconjunctival, subtenon, or retrobulbar injection), or parenteral.
  • topical including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery
  • pulmonary e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal
  • ocular e.g., eye drops or intravitreal, subconjunctival, subtenon, or retrobulbar injection
  • compositions which contain, as the active ingredient, one or more of the compounds described herein above in combination with one or more pharmaceutically acceptable carriers.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • compositions can be formulated in a unit dosage form.
  • unit dosage form refers to a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid pre-formulation composition containing a homogeneous mixture of a compound described herein.
  • a pharmaceutical excipient for preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid pre-formulation composition containing a homogeneous mixture of a compound described herein.
  • the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid pre-formulation is then subdivided into unit dosage forms of the type described above.
  • the tablets or pills described herein can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the compounds and compositions described herein can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
  • compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the therapeutic dosage of the compounds described herein can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of a compound described herein in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • Compound Int-6a was synthesized using 3-chloro-5,6-dimethylpyrazine-2-carboxylic acid (15 g, 80 mmol, 1 eq.) and 1-ethyl 3-potassium propanedioate (16.4 g, 96 mmol, 1.2 eq.) by following the procedure from Compound Int-la to afford the title compound as a light yellow oil (15 g, 72% yield).
  • Compound Int-7 was synthesized using 3-amino-l-(4-chloro-2-fluorophenyl)-6,7- dimethylpyrazino[2, 3-c]pyridazin-4-one (Int-7a) (500 mg, 1.56 mmol) by following the procedure from Compound Int-2 to afford the title compound as a yellow solid (200 mg, 33% yield).
  • Compound Int-12a was synthesized using 2,4-dichloroaniline (7 g, 43 mmol) and ethyl 3-(3-bromo-5,6-dimethylpyridin-2-yl)-3-oxopropanoate (Int-la) (5.16 g, 17 mmol) by following the procedure from Compound Int-8a to afford the title compound as a yellow solid (5.1 g, 25% yield).
  • Compound Int-12b was synthesized using ethyl (2E)-3-(3-bromo-5,6-dimethylpyridin- 2-yl)-2-(2-(2,4-dichlorophenyl)hydrazin-l-ylidene)-3-oxopropanoate (Int-12a) (5 g, 10.5 mmol) by following the procedure from Compound Int-lc to afford the title compound without further purification.
  • Compound Int-13a was synthesized using 4-chloro-o-toluidine (5.9 g, 41.6 mmol, 2.5 eq.) and ethyl 3-(3-bromo-5, 6-dimethylpyridin-2-yl)-3-oxopropanoate (Int-la) (5 g, 16.7 mmol, 1 eq.) by following the procedure from Compound Int-6b to afford the title compound as a yellow oil (2.68 g, 36% yield).
  • Compound Int-13b was synthesized using ethyl (E)-3-(3-bromo-5,6-dimethylpyridin-2- yl)-2-(2-(4-chloro-2-methylphenyl)hydrazineylidene)-3-oxopropanoate (Int-13a) (2.68 g, 5.92 mmol) by following the procedure from Compound Int-lc to afford the title compound as a yellow oil (3.2 g, crude).
  • Compound Int-14b was synthesized using ethyl (E)-3-(3-bromo-5,6-dimethylpyridin-2- yl)-2-(2-(2,4-difluorophenyl)hydrazineylidene)-3-oxopropanoate (Int-14a) (5.8 g, 13.1 mmol) by following the procedure from Compound Int-lc to afford the title compound as a yellow solid (3.7 g, crude). The crude product was used in the next step directly without further purification.
  • Compound Int-15a was synthesized using 6-(trifluoromethyl) pyridin-3 -amine (8.1 g, 49 mmol, 3 eq.) and ethyl 3-(3-bromo-5,6-dimethylpyridin-2-yl)-3-oxopropanoate (Int-la) (5.0 g, 16 mmol, 1 eq.) by following the procedure from Compound Int-8a to afford the title compound as an orange oil (5.32 g, 67% yield).
  • Compound Int-15b was synthesized using ethyl 3-(3-bromo-5,6-dimethylpyridin-2-yl)- 3-oxo-2-(2-(6-(trifluoromethyl)pyridin-3-yl)hydrazineylidene)propanoate (Int-15a) (5.3 g, 11.1 mmol) by following the procedure from Compound Int-lc to afford the title compound as a brown solid (4.8 g, crude). The crude product was used in the next step directly without further purification.
  • Compound Int-16c was synthesized using l-(4-chlorophenyl)-6-cyclopropyl-4- oxopyridazine-3 -carboxylic acid (Int-16b) (1.75 g, 6 mmol) by following the procedure from Compound Int-2a to afford the title compound as a yellow solid (750 mg, 48% yield).
  • Compound 2 was synthesized using l-(4-chloro-2-fluorophenyl)-N-(5-hydroxy-2- (trifluoromethyl)pyridin-4-yl)-6,7-dimethyl-4-oxo-l,4-dihydropyrido[3,2-c]pyridazine-3- carboxamide (2a) (50 mg, 0.098 mmol) by following the procedure from Compound 1 to afford Compound 2 as a white solid (6.0 mg, 12% yield).
  • Compound 3a was synthesized using 5-amino-2-methylpyridin-4-ol (50 mg, 0.4 mmol, 2.8 eq.) and l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4-oxopyrido [3, 2-c] pyridazine-3- carboxylic acid (Int-1) (50 mg, 0.14 mmol, 1 eq.) by following the procedure from Compound la heating the reaction to 60 °C to afford Compound 3a as a yellow solid (20 mg).
  • Compound 3 was synthesized using l-(4-chl oro-2 -fluorophenyl)-N-(4-hydroxy-6- methylpyridin-3-yl)-6,7-dimethyl-4-oxo-l,4-dihydropyrido[3,2-c]pyridazine-3-carboxamide (3a) (20 mg, 0.044 mmol) by following the procedure from Compound 1 to afford Compound 3 as an off-white solid (2.6 mg, 13% yield).
  • Compound 5a was synthesized using 5-amino-2-methoxypyridin-4-ol (50 mg, 0.36 mmol, 1 eq.) and l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4-oxopyrido[3,2-c]pyridazine-3- carboxylic acid (Int-1) (124 mg, 0.36 mmol, 1 eq.) by following the procedure from Compound 2a to afford Compound 5a as a dark green solid (20 mg, 9% yield).
  • Compound 5 was synthesized using l-(4-chl oro-2 -fluorophenyl)-N-(4-hydroxy-6- methoxypyridin-3-yl)-6,7-dimethyl-4-oxo-l,4-dihydropyrido[3,2-c]pyridazine-3-carboxamide (5a) (20 mg, 0.04 mmol) by following the procedure from Compound 4 to afford Compound 5 as a white solid (1.0 mg, 5% yield).
  • Compound 6a was synthesized using l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4- oxopyrido[3,2-c]pyridazine-3 -carboxylic acid (Int-1) (70 mg, 0.201 mmol, 1 eq.) and 4-amino- 6-methoxypyri din-3 -ol (28.2 mg, 0.201 mmol, 1 eq.) by following the procedure from Compound 4a to afford Compound 6a as an orange solid (35 mg, 37% yield).
  • Compound 7a was synthesized using 5-amino-2-fluoropyridin-4-ol (150 mg, 1.17 mmol, 1.6 eq.) and l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4-oxopyrido[3,2-c]pyridazine-3- carboxylic acid (Int-1) (252 mg, 0.726 mmol, 1 eq.) by following the procedure from Compound la to afford Compound 7a as a red solid (80 mg, 15% yield).
  • Compound 7 was synthesized using l-(4-chloro-2-fluorophenyl)-N-(6-fluoro-4- hydroxypyridin-3-yl)-6,7-dimethyl-4-oxo-l,4-dihydropyrido[3,2-c]pyridazine-3-carboxamide (7a) (80 mg, 0.175 mmol) by following the procedure from Compound 1 to afford Compound 7 as a white solid (9.7 mg, 12% yield).
  • Example 9 Preparation of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(6- (trifluoromethyl)thiazolo[5,4-c]pyridin-2-yl)pyrido[3,2-c]pyridazin-4(lH)-one (Compound 9) [0366] To a stirred solution of DMF (2.1 g, 29.6 mmol, 10 eq.) in DCE (14 mL) was added oxalyl chloride (1.4 g, 11.5 mmol, 4 eq.) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for 5 min at 0 °C.
  • Compound 10a was synthesized using 4-chloro-2-methoxy-5-nitropyridine (800 mg, 4.2 mmol, 1 eq.) and PMB-SH (654 mg, 4.2 mmol, 1 eq.) by following the procedure from Compound 8a to afford Compound 10a as a light-yellow solid (1.2 g, 92% yield).
  • Compound 10b was synthesized using 2 -methoxy -4-((4-methoxybenzyl)thio)-5- nitropyridine (10a) (1.2 g, 3.92 mmol) by following the procedure from Compound 8b to afford Compound 10b as a grey solid (1.1 g, crude).
  • Compound 10c was synthesized using 6-methoxy-4-((4-methoxybenzyl)thio)pyridin-3- amine (10b) (47.7 mg, 0.17 mmol, 1.2 eq.) and l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4- oxopyrido [3, 2-c] pyridazine-3 -carboxylic acid (Int-1) (50 mg, 0.14 mmol, 1 eq.) by following the procedure from Compound 8c to afford Compound 10c as a brown solid (90 mg, 98% yield).
  • Compound 10 was synthesized using l-(4-chloro-2-fluorophenyl)-N-(6-methoxy-4-((4- methoxybenzyl)thio)pyridin-3-yl)-6,7-dimethyl-4-oxo-l,4-dihydropyrido[3,2-c]pyridazine-3- carboxamide (10c) (50 mg, 0.08 mmol) by following the procedure from Compound 8 to afford Compound 10 as a light-yellow solid (7 mg, 18% yield).
  • Compound 11b was synthesized using l-(4-chloro-2-fhiorophenyl)-6,7-dimethyl-4-oxo- l,5-naphthyridine-3-carboxylic acid (Int-3) (55 mg, 0.16 mmol, 1 eq.) and 5-(((4- methoxyphenyl)methyl)sulfanyl)-2-(trifluoromethyl)pyridin-4-amine (Ila) (50 mg, 0.16 mmol, 1 eq.) by following the procedure from Compound 8c to afford Compound 11b as a yellow solid (45 mg, 44% yield).
  • Int-3 l-(4-chloro-2-fhiorophenyl)-6,7-dimethyl-4-oxo- l,5-naphthyridine-3-carboxylic acid
  • Ila 5-(((4- methoxyphenyl)methyl)sulfanyl)-2-(
  • Compound 12a was synthesized by l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4- oxoquinoline-3-carboxylic acid (Int-3) (50 mg, 0.14 mmol, 1 eq.) and 4-([(4- methoxyphenyl)methyl]sulfanyl)-6-(trifluoromethyl)pyridin-3-amine (8b) (45.3 mg, 0.14 mmol, 1 eq.) by following the procedure from Compound 8c to afford Compound 12a as a brown solid (25.2 mg), which was used in the next step directly without further purification.
  • Compound 12 was synthesized using l-(4-chloro-2-fluorophenyl)-N-(4-(((4- methoxyphenyl)methyl)sulfanyl)-6-(trifluoromethyl)pyridin-3-yl)-6,7-dimethyl-4-oxo-l,5- naphthyridine-3 -carboxamide (12a) (25.2 mg, 0.039 mmol) by following the procedure from Compound 11 to afford Compound 12 as an off-white solid (17 mg, 23% yield (2 steps)).
  • Compound 14b was synthesized using methyl 5-(trifluoromethyl)thieno[2,3-c]pyridine- 2-carboxylate (14a) (2.2 g, 8.42 mmol) by following the procedure from Compound 13b to afford Compound 14b as an off-white solid (1.24 g, 59% yield).
  • Compound 14c was synthesized using 5-(trifluoromethyl)thieno[2,3-c]pyridine-2- carboxylic acid (14b) (1 g, 4.04 mmol) by following the procedure from Compound 13c to afford Compound 14c as an off-white solid (680 mg, 82% yield).
  • Compound 14d was synthesized using 5-(trifluoromethyl)thieno[2,3-c]pyridine (14c) (630 mg, 3.1 mmol) by following the procedure from Compound 13d to afford Compound 14d as a light yellow oil (1.2 g, 78% yield).
  • Compound 14 was synthesized using 3-bromo-l-(4-chloro-2-fluorophenyl)-6,7- dimethylpyrido[3,2-c]pyridazin-4-one (Int-2) (50 mg, 0.131 mmol, 1 eq.) and 2- (tributylstannyl)-5-(trifluoromethyl)thieno[2,3-c]pyridine (14d) (90.1 mg, 0.183 mmol, 1.4 eq) by following the procedure from Compound 13 to afford Compound 14 as a light yellow solid (14 mg, 21% yield).
  • Compound 15a was synthesized using l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4- oxopyrido[3,2-c]pyridazine-3 -carboxylic acid (Int-4) (45 mg, 0.124 mmol, 1 eq.) and 5-amino- 2-methoxypyridin-4-ol (20.8 mg, 0.149 mmol, 1.2 eq.) by following the procedure from Compound 4a. The precipitated solids of Compound 15a were collected by filtration and washed with water (3 x 3 mL) to afford Compound 15a as a light-yellow solid (49 mg, 76% yield).
  • Compound 15 was synthesized using l-(3,4-dichlorophenyl)-N-(4-hydroxy-6- methoxypyridin-3-yl)-6,7-dimethyl-4-oxopyrido[3,2-c]pyridazine-3-carboxamide (15a) (45 mg, 0.093 mmol) by following the procedure from Compound 1. The residue was purified by trituration with ACN (5 mL). The precipitated solids were collected by filtration and washed with ACN (3 x 5 mL) to afford Compound 15 as a yellow solid (25.3 mg, 58% yield).
  • Compound 16a was synthesized using l-(3,4-dichlorophenyl)-6,7-dimethyl-4- oxopyrido[3,2-c]pyridazine-3 -carboxylic acid (Int-4) (127 mg, 0.348 mmol, 1 eq.) and 4-amino- 6-(trifluorom ethyl)pyri din-3 -ol (100 mg, 0.561 mmol, 1.6 eq.) by following the procedure from Compound 4a to afford Compound 16a red solid (60 mg, 20% yield).
  • Compound 16 was synthesized using l-(3,4-dichlorophenyl)-N-(5-hydroxy-2- (trifluoromethyl)pyridin-4-yl)-6,7-dimethyl-4-oxo-l,4-dihydropyrido[3,2-c]pyridazine-3- carboxamide (16a) (60 mg, 0.114 mmol) by following the procedure from Compound 6 to afford Compound 16 as a white solid (0.9 mg, 2% yield).
  • Compound 17a was synthesized using l-(3,4-dichlorophenyl)-6,7-dimethyl-4- oxopyrido[3,2-c]pyridazine-3 -carboxylic acid (Int-4) (80 mg, 0.22 mmol, 1 eq.) and 5-amino-2- (trifluoromethyl)pyridin-4-ol (39.1 mg, 0.22 mmol, 1 eq.) by following the procedure from Compound 4a to afford Compound 17a as a white solid (60 mg, 47% yield).
  • Compound 17 was synthesized using l-(3,4-dichlorophenyl)-N-(4-hydroxy-6- (trifluoromethyl)pyridin-3-yl)-6,7-dimethyl-4-oxo-l,4-dihydropyrido[3,2-c]pyridazine-3- carboxamide (17a) (55 mg, 0.105 mmol) by following the procedure from Compound 1. The residue was purified by trituration with ACN (5 mL). The precipitated solids were collected by filtration and washed with ACN (3 x 2 mL) to afford Compound 17 as a white solid (24.1 mg, 43% yield).
  • Compound 18a was synthesized using 5-((4-methoxybenzyl)thio)-2- (trifluoromethyl)pyridin-4-amine (Ila) (100 mg, 0.32 mmol, 1 eq.) and l-(3,4-dichlorophenyl)- 6,7-dimethyl-4-oxopyrido[3,2-c]pyridazine-3-carboxylic acid (Int-4) (116 mg, 0.32 mmol, 1 eq.) by following the procedure from Compound 8c to afford Compound 18a as a brown solid (70 mg, 28% yield).
  • Compound 19a was synthesized using l-(3,4-dichlorophenyl)-6,7-dimethyl-4- oxopyrido[3,2-c]pyridazine-3 -carboxylic acid (Int-4) (50 mg, 0.137 mmol, 1 eq.) and 4-((4- methoxybenzyl)thio)-6-(trifluoromethyl)pyridin-3-amine (8b) (43.2 mg, 0.137 mmol, 1 eq.) by following the procedure from Compound 8c to afford Compound 19a as a yellow solid (55 mg, 88% yield).
  • Compound 20a was synthesized was using l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4- oxo-1, 4-dihydropyrazino[2,3-c]pyridazine-3-carboxylic acid (Int-6) (97.9 mg, 0.281 mmol, 1 eq.) and 5-amino-2-(trifluoromethyl)pyridin-4-ol (50 mg, 0.281 mmol, 1 eq.) by following the procedure from Compound 4a to afford Compound 20a as a dark green solid (22 mg, 15% yield).
  • Compound 20 was synthesized by using l-(4-chloro-2-fluorophenyl)-N-(4-hydroxy-6- (trifluoromethyl)pyri din-3 -yl)-6,7-dimethyl-4-oxo- 1 ,4-dihydropyrazino[2,3 -c]pyridazine-3 - carboxamide (20a) (20 mg, 0.039 mmol) by following the procedure from Compound 6 to afford Compound 20 as a white solid (1.3 mg, 6% yield).
  • Example 21 Preparation of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(6- (trifluoromethyl)oxazolo[5,4-c]pyridin-2-yl)pyrazino[2,3-c]pyridazin-4(lH)-one
  • Compound 21a was synthesized using l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4- oxopyrazino[2,3-c]pyridazine-3-carboxylic acid (Int-6) (150 mg, 0.431 mmol, 1 eq.) and 4- amino-6-(trifluoromethyl) pyridin-3-ol (120 mg, 0.674 mmol, 1.5 eq.) by following the procedure from Compound 4a to afford Compound 21a as a brown solid (60 mg, 17% yield).
  • Compound 21 was synthesized using l-(4-chloro-2-fluorophenyl)-N-(5-hydroxy-2- (trifluoromethyl)pyridin-4-yl)-6,7-dimethyl-4-oxo- 1 ,4-dihydropyrazino[2,3 -c]pyridazine-3 - carboxamide (21a) (50 mg, 0.098 mmol) by following the procedure from Compound 6 to afford Compound 21 as a light-yellow solid (1.1 mg, 4% yield).
  • Compound 22a was synthesized using l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4- oxopyrazino[2,3-c]pyridazine-3-carboxylic acid (Int-6) (80 mg, 0.23 mmol, 1 eq.) and 5-amino- 2-methoxypyridin-4-ol (48.2 mg, 0.34 mmol, 1.5 eq.) by following the procedure from Compound 4a to afford Compound 22a as a yellow solid (50 mg, 46% yield).
  • Compound 22 was synthesized using l-(4-chloro-2-fluorophenyl)-N-(4-hydroxy-6- methoxypyridin-3-yl)-6,7-dimethyl-4-oxo-l,4-dihydropyrazino[2,3-c]pyridazine-3-carboxamide (22a) by following the procedure from Compound 6 to afford Compound 22 as a yellow solid (10.8 mg, 33% yield).
  • Example 23 Preparation of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(6- (trifluoromethyl)thiazolo[4,5-c]pyridin-2-yl)pyrazino[2,3-c]pyridazin-4(lH)-one
  • Compound 23a was synthesized using l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4- oxopyrazino[2,3-c]pyridazine-3-carboxylic acid (Int-6) (50 mg, 0.143 mmol, 1 eq.) and 4-((4- methoxybenzyl)thio)-6-(trifluoromethyl)pyridin-3-amine (8b) (45.1 mg, 0.143 mmol, 1 eq.) by following the procedure from Compound 8c to afford Compound 23a as an off-white solid (85 mg, 88% yield).
  • Compound 23 was synthesized using l-(4-chloro-2-fluorophenyl)-N-(4-((4- methoxybenzyl)thio)-6-(trifluoromethyl)pyridin-3-yl)-6,7-dimethyl-4-oxo-l,4- dihydropyrazino[2,3-c]pyridazine-3 -carboxamide (23a) (80 mg, 0.07 mmol) by following the procedure from Compound 8 to afford Compound 23 as an off-white solid (38 mg, 56% yield).
  • Example 24 Preparation of l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(6- (trifluoromethyl)thiazolo[5,4-c]pyridin-2-yl)pyrazino[2,3-c]pyridazin-4(lH)-one (Compound 24) [0407] Compound 24a was synthesized using 5-((4-methoxybenzyl)thio)-2- (trifluoromethyl)pyridin-4-amine (Ila) (100 mg, 0.32 mmol, 1 eq.) and l-(4-chloro-2- fluorophenyl)-6,7-dimethyl-4-oxopyrazino[2,3-c]pyridazine-3-carboxylic acid (Int-6) (111 mg, 0.32 mmol, 1 eq.) by following the procedure from Compound 8c to afford Compound 24a as a brown solid (70 mg, 34% yield).
  • Compound 24 was synthesized using l-(4-chloro-2-fluorophenyl)-N-(5-((4- methoxybenzyl)thio)-2-(trifluoromethyl)pyridin-4-yl)-6,7-dimethyl-4-oxo-l,4- dihydropyrazino[2,3-c]pyridazine-3 -carboxamide (24a) (70 mg, 0.11 mmol) by following the procedure from Compound 18 and reacting at 120 °C for 10 min to afford Compound 24 as a light-yellow solid (12.3 mg, 22% yield).
  • Compound 25a was synthesized using l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4- oxopyrazino[2,3-c]pyridazine-3-carboxylic acid (Int-6) (100 mg, 0.29 mmol, 1 eq.) and 6- (trifluoromethyl)pyridine-3,4-diamine (61 mg, 0.34 mmol, 1.2 eq.) by following the procedure from Compound la to afford Compound 25a as a solid (90 mg, crude).
  • Compound 26a was synthesized using l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4- oxopyrido[3,2-c]pyridazine-3 -carboxylic acid (lnt-8) (45 mg, 0.13 mmol, 1 eq.) and 5-amino-2- methoxypyridin-4-ol (21.8 mg, 0.16 mmol, 1.2 eq.) by following the procedure from Compound 4a. The precipitated solids were collected by filtration and washed with water (3 x 3 mL) to afford Compound 26a as a yellow solid (47 mg, 73% yield).
  • Compound 26 was synthesized using l-(4-chloro-2-fluorophenyl)-N-(4-hydroxy-6- methoxypyridin-3-yl)-6,7-dimethyl-4-oxo-l,4-dihydrocinnoline-3-carboxamide (26a) (45 mg, 0.096 mmol) by following the procedure from Compound 1. The residue was purified by trituration with ACN (5 mL). The precipitated solids were collected by filtration and washed with ACN (3 x 5 mL) to afford Compound 26 as an off-white solid (22.1 mg, 50% yield).
  • Compound 27a was synthesized using l-(4-chloro-2-fhiorophenyl)-6,7-dimethyl-4- oxocinnoline-3 -carboxylic acid (lnt-8) (84.5 mg, 0.244 mmol, 1 eq.) and 4-amino-6- (trifluorom ethyl)pyri din-3 -ol (70 mg, 0.393 mmol, 1.6 eq.) by following the procedure from Compound 4a to afford Compound 27a as a brown solid (30 mg, 15% yield).
  • Compound 27 was synthesized using l-(4-chloro-2-fluorophenyl)-N-(5-hydroxy-2- (trifluoromethyl)pyridin-4-yl)-6,7-dimethyl-4-oxo-l,4-dihydrocinnoline-3-carboxamide (27a) (30 mg, 0.059 mmol) by following the procedure from Compound 1 to afford Compound 27 as a white solid (4.1 mg, 14% yield).
  • Compound 28a was synthesized using 5-amino-2-(trifluoromethyl)pyridin-4-ol (30 mg, 0.168 mmol, 1 eq.) and l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4-oxocinnoline-3-carboxylic acid (lnt-8) (58.4 mg, 0.168 mmol, 1 eq.) by following the procedure from Compound 4a. The precipitated solids were collected by filtration and washed with water (3 x 1 mL) to afford Compound 28a as a yellow solid (40 mg, 43% yield).
  • Compound 28 was synthesized using l-(4-chloro-2-fluorophenyl)-N-(4-hydroxy-6- (trifluoromethyl)pyridin-3-yl)-6,7-dimethyl-4-oxo-l,4-dihydrocinnoline-3-carboxamide (28a) (16 mg, 0.032 mmol) by following the procedure from Compound 1 to afford Compound 28 as a white solid (3.4 mg, 21% yield).
  • Compound 29a was synthesized using 5-((4-methoxybenzyl)thio)-2- (trifluoromethyl)pyridin-4-amine (Ila) (50 mg, 0.159 mmol, 1 eq.) and l-(4-chloro-2- fluorophenyl)-6,7-dimethyl-4-oxocinnoline-3-carboxylic acid (lnt-8) (55.2 mg, 0.159 mmol, 1 eq.) by following the procedure from Compound 8c to afford Compound 29a as an off-white solid (65 mg, 55% yield).
  • Ila 5-((4-methoxybenzyl)thio)-2- (trifluoromethyl)pyridin-4-amine
  • lnt-8 l-(4-chloro-2- fluorophenyl)-6,7-dimethyl-4-oxocinnoline-3-carboxylic acid
  • Compound 29 was synthesized using l-(4-chloro-2-fluorophenyl)-N-(5-((4- methoxybenzyl)thio)-2-(trifluoromethyl)pyridin-4-yl)-6,7-dimethyl-4-oxo-l,4-dihydrocinnoline- 3-carboxamide (29a) (60 mg, 0.093 mmol) by following the procedure from Compound 18 and reacting at 140 °C for 15 min to afford Compound 29 as an off-white solid (22.7 mg, 47% yield).
  • Compound 30a was synthesized using l-(4-chloro-2-fhrorophenyl)-6,7-dimethyl-4- oxocinnoline-3 -carboxylic acid (Int-8) (40 mg, 0.12 mmol, 1 eq.) and 4-((4- methoxybenzyl)thio)-6-(trifluoromethyl)pyridin-3-amine (8b) (36.3 mg, 0.12 mmol, 1 eq.) by following the procedure from Compound 8c to afford Compound 30a as a yellow solid (98 mg, 67% yield).
  • Compound 30 was synthesized using l-(4-chloro-2-fluorophenyl)-N-(4-((4- methoxybenzyl)thio)-6-(trifluoromethyl)pyridin-3-yl)-6,7-dimethyl-4-oxo-l,4-dihydrocinnoline- 3-carboxamide (30a) (45 mg, 0.07 mmol) by following the procedure from Compound 8 to afford Compound 30 as an off-white solid (7.1 mg, 20% yield).
  • Compound 31a was synthesized using l-(4-chloro-2-fhrorophenyl)-6,7-dimethyl-4- oxocinnoline-3 -carboxylic acid (Int-8) (100 mg, 0.29 mmol) and 6-(trifluoromethyl)pyridine- 3,4-diamine (61 mg, 0.35 mmol) by following the procedure from Compound 4a and reacting at RT to afford Compound 31a as a yellow solid (90 mg, 59% yield).
  • Compound 31 was synthesized using N-(5-amino-2-(trifluoromethyl)pyridin-4-yl)-l-(4- chloro-2-fluorophenyl)-6,7-dimethyl-4-oxo-l,4-dihydrocinnoline-3-carboxamide (31a) (90 mg, 0.18 mmol) by following the procedure from Compound 25 to afford Compound 31 as a yellow solid (11.0 mg, 12% yield).
  • Compound 56 was synthesized using l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4- oxopyrido[3,2-c]pyridazine-3 -carboxylic acid (Int-1) (94.7 mg, 0.23 mmol, 1 eq.) and 2-fluoro- 6-isopropylpyridin-4-amine (105b) (200 mg, 0.30 mmol, 1.3 eq.) by following the procedure from Compound 32 to afford Compound 105 as a yellow solid (30.3 mg, 15% yield).
  • Int-1 l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4- oxopyrido[3,2-c]pyridazine-3 -carboxylic acid
  • 105b 2-fluoro- 6-isopropylpyridin-4-amine
  • Example 35 Preparation of l-(4-chloro-2-fluorophenyl)-N-(l,2-dimethyl-6-(2- methylpyridin-4-yl)piperidin-4-yl)-6,7-dimethyl-4-oxo-l,4-dihydropyrido[3,2-c]pyridazine- 3-carboxamide (Compound 106)
  • Example 36 Preparation of l-(4-chloro-2-fluorophenyl)-N-(2-methoxypyridin-4-yl)-6,7- dimethyl-4-oxo-l,4-dihydropyrido[3,2-c]pyridazine-3-carboxamide (Compound 107), l-(4- chloro-2-fluorophenyl)-N-[(2R,4S)-l,2-dimethylpiperidin-4-yl]-6,7-dimethyl-4- oxopyrido[3,2-c]pyridazine-3-carboxamide (Compound 108), and l-(4-chloro-2- fluorophenyl)-N-[(2S,4R )-l,2-dimethylpiperidin-4-yl]-6,7-dimethyl-4-o opyrido[3,2- c]pyridazine-3-carboxamide (Compound 109)
  • Compound 107a (300 mg, 90% purity) was purified by Prep-HPLC to afford Compound 107 (44.8 mg, 17% yield, cis-configuration) and Compound 108a (30 mg, 11%, trans-configuration) as off-white solid, which are confirmed by 2D NMRs.
  • Compound 112 was synthesized using l-(4-chloro-2-fluorophenyl)-6,7-dimethyl-4-oxo- l,4-dihydrocinnoline-3 -carboxylic acid (Int-8) (54 mg, 0.16 mmol, 1 eq.) and 3-methoxy-4- (trifluoromethoxy)aniline (39.3 mg, 0.19 mmol, 1.2 eq.) by following the procedure from Compound 106 to afford the title compound (76.7 mg, 98% yield).
  • Compound 113a was synthesized using ethyl 3-(2-chlorofuran-3-yl)-3-oxopropanoate (7.8 g, 36.1 mmol) and (Z)-chloro(4-chloro-2-fluorophenyl) diazene (8.4 g, 43.3 mmol) by following the procedure from Compound Int-4b to afford Compound 113a as a yellow solid (1.2 g, 9% yield).
  • Compound 113 was synthesized using l-(4-chloro-2-fluorophenyl)-4-oxofuro[2,3- c]pyridazine-3-carboxylic acid (113b) (25 mg, 0.08 mmol, 1 eq.) and 3-methoxy-4- (trifluoromethoxy)aniline (25.2 mg, 0.12 mmol, 1.5 eq.) by following the procedure from Compound 32 to afford Compound 113 as an off-white solid (2.4 mg, 6% yield).
  • Compound 114a was synthesized using triacetic acid lactone (9.38 g, 74.3 mmol, 1 eq.) and 4-chloro-2-fluoroaniline (11.4 g, 78.4 mmol, 1.05 eq.) by following the procedure from Compound Int-17a to afford Compound 114a as a light brown solid (13 g, 60% yield).
  • Compound 114 was synthesized l-(4-chloro-2-fluorophenyl)-6-methyl-4- oxopyridazine-3 -carboxylic acid (114a) (80.00 mg, 0.28 mmol, 1 eq.) and 2- (trifluoromethyl)pyridin-4-amine (68 mg, 0.42 mmol, 1.50 eq.) by following the procedure from Compound 32 to afford Compound 114 as an off-white solid (40.4 mg, 33% yield).
  • Compound 115 was synthesized using l-(4-chloro-2-fluorophenyl)-6-methyl-4- oxopyridazine-3 -carboxylic acid (114a) (80 mg, 0.28 mmol, leq.) and 6- (trifluoromethyl)pyridazin-3-amine (69.2 mg, 0.42 mmol, 1.50 eq.) by following the procedure from Compound 32 to afford Compound 115 as an off-white solid (74 mg, 61% yield).
  • Compound 117 was synthesized using l-(4-chlorophenyl)-6-methyl-4-oxo-l,4- dihydropyridazine-3 -carboxylic acid (Int-17a) (179 mg, 0.67 mmol, 1.4 eq.) and 4- difluorom ethanesulfonyl aniline (100 mg, 0.48 mmol, 1 eq.) by following the procedure from Compound 116 to afford Compound 117 (154 mg, 70% yield).
  • Compound 118 was synthesized using l-(4-chlorophenyl)-6-methyl-4-oxo- 1,4- dihydropyridazine-3 -carboxylic acid (Int-17a) (55.5 mg, 0.21 mmol, 1.4 eq.) and 4 amino-N,N- dimethylbenzene- 1 -sulfonamide (30 mg, 0.15 mmol, 1 eq.) by following the procedure from Compound 116 to afford Compound 118 (50.1 mg, 75% yield).
  • Compound 119b was synthesizing using ethyl 6,7-dimethyl-4-oxo-l-(6- (trifluoromethyl)pyridin-2-yl)- 1 ,4-dihydropyrido[3 ,2-c]pyridazine-3 -carboxylate (119a) by following the procedure from Compound Int-1 to afford Compound 119b as a brown solid (28 mg, 83% yield).
  • Compound 119 was synthesized using 6,7-dimethyl-4-oxo-l-[6- (trifluoromethyl)pyridin-2-yl]pyrido[3,2-c]pyridazine-3-carboxylic acid (119b) (28 mg, 0.077 mmol, 1 eq.) and 2-fhioropyridin-4-amine (13 mg, 0.12 mmol, 1.6 eq.) by following the procedure from Compound 32 to afford Compound 119 as a purple solid (10.7 mg, 29% yield).
  • Compound 120b was synthesized using ethyl l-(4-methoxybenzyl)-6,7-dimethyl-4-oxo- l,4-dihydropyrido[3,2-c]pyridazine-3 -carboxylate (120a) (300 mg, 0.81 mmol) by following the procedure from Compound Int-1 to afford Compound 120b as a yellow solid (250 mg, 90% yield).
  • LCMS ESI-MS m/z: 340 [M+H] + .
  • Compound 180 was synthesized using 3-bromo-l-(4,4-difluorocyclohexyl)-6,7- dimethylpyrido[3,2-c]pyridazin-4-one (Int-10) (50 mg, 0.13 mmol, 1 eq.) and 2-methoxy-4- [(lZ)-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)prop-l-en-l-yl]pyridine (180a) (44.4 mg, 0.16 mmol, 1.2 eq.) by following the procedure from Compound 121 to afford Compound 180 as a light-yellow solid (21.5 mg, 35% yield).
  • Example 52 Preparation of (E)-l-(4-chlorophenyl)-6,7-dimethyl-3-(l-(2- (trifluoromethyl)pyridin-4-yl)prop-l-en-2-yl)pyrido[3,2-c]pyridazin-4(lH)-one (Compound 193)
  • Compound 193a was synthesized using 2-methyl-4-(prop-l-yn-l-yl)pyridine (2 g, 10.8 mmol, 1 eq.) and 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (5.53 g, 43.2 mmol, 4 eq.) by following the procedure from Compound 191a to afford Compound 193a yellow oil (2.5 g, 36% yield).
  • Compound 193 was synthesized using 3-bromo-l-(4-chlorophenyl)-6,7- dimethylpyrido[3,2-c] pyridazin-4-one (Int-11) (40 mg, 0.11 mmol, 1 eq.) and 4-[(lZ)-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) prop-l-en-l-yl]-2-(trifluoromethyl) pyridine (193a) (41.2 mg, 0.13 mmol, 1.2 eq.) by following the procedure from Compound 121 to afford Compound 193 as a light yellow solid (15 mg, 27% yield).
  • Compound 194b was synthesized using 4-(2-bromo-2-fluoroethenyl)-2- methoxypyridine (194a) (100 mg, 0.43 mmol) by following the procedure from Compound 121b to afford the Compound 194b as a black liquid (4 mL) and was used in the next step directly without further purification.
  • Compound 194 was synthesized using 4-(2-fluoro-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)ethenyl)-2-methoxypyridine (194b) (4 mL, 1 mmol, 3.5 eq.) and 3-bromo-l- (4-chloro-2-fluorophenyl)-6,7-dimethylpyrido[3,2-c]pyridazin-4-one (Int-2) (110 mg, 0.28 mmol, 1 eq.) by following the procedure from Compound 121 to afford Compound 194 as a white solid (6.4 mg, 3% yield).
  • Example 54 Preparation of (Z)-l-(4-chloro-2-fluorophenyl)-3-(l-fluoro-2-(2- fluoropyridin-4-yl)vinyl)-6,7-dimethylpyrazino[2,3-c]pyridazin-4(lH)-one (Compound 195)
  • Compound 195 was synthesized using 3-bromo-l-(4-chloro-2-fluorophenyl)-6,7- dimethylpyrazino [2, 3-c] pyridazin-4-one (Int-7) (30 mg, 0.08 mmol, 1.3 eq.) and 2-fluoro-4- [2-fluoro-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) ethenyl]pyridine (195a) (16.71 mg, 0.062 mmol, 1 eq.) by following the procedure from Compound 121 to afford Compound 195 as an off-white solid (2.6 mg, 5% yield (2 steps)).
  • Compound 198 was synthesized using of 3-bromo-l-(4-chlorophenyl)-6- methylpyridazin-4-one (Int-17) (150 mg, 0.50 mmol, 1 eq.) and l-phenylprop-l-en-2-ylboronic acid (162 mg, 1 mmol, 2 eq.) by following the procedure from Compound 196 to afford Compound 198 as a white solid (55.7 mg, 33% yield).
  • Activation of TREM2 by agonists results in phosphorylation of Syk (pSyk).
  • pSyk levels were measured using an AlphaLISA reagent kit [Perking Elmer] and following manufacturer- provided instructions.
  • HEK293T cells stably expressing huTREM2 and huDAP12 were plated overnight in 384-well white poly-D-Lysine coated microplates at a density of 20,000 cells/well in DMEM:F12 medium supplemented with 10% Fetal Bovine Serum, IX Penicillin/Streptomycin, and incubated overnight at 37° C, 5% CO2.
  • test buffer phenol-red free DMEM containing diluted test compounds (in 0.5% final DMSO), or 300 nM anti-TREM2 antibody (positive control), or 0.5% DMSO (negative control) at 5 pL/well were added to the plates. The plates were incubated at room temperature for 30 minutes. At the end of the incubation, the buffer was removed and IX lysis buffer supplemented with IX HALT Protease and Phosphatase Inhibitors was dispensed at 10 pL/well. Plates were incubated for 30 minutes at room temperature.
  • Table 2 designated as “++++” demonstrated an EC 5 0 > 0.1 pM and ⁇ 0.5 pM.
  • Compounds designated as “+++” demonstrated an EC 5 0 > 0.5 pM and ⁇ 1.0 pM.
  • Compounds designated as “++” demonstrated an EC 5 0 > 1.0 pM and ⁇ 30.0 pM.
  • Compounds designated as “+” demonstrated an EC 5 0 > 30 pM.

Landscapes

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

Abstract

La présente divulgation concerne des composés hétéroaryle bicycliques, des compositions de ceux-ci, et des procédés associés, utiles pour l'activation de l'activité TREM2 et/ou pour le traitement de troubles neurologiques.
PCT/US2024/057550 2023-11-30 2024-11-26 Composés hétéroaryle bicycliques utilisés en tant qu'activateurs de trem2 Pending WO2025117599A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363604802P 2023-11-30 2023-11-30
US63/604,802 2023-11-30

Publications (1)

Publication Number Publication Date
WO2025117599A1 true WO2025117599A1 (fr) 2025-06-05

Family

ID=95898179

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/057550 Pending WO2025117599A1 (fr) 2023-11-30 2024-11-26 Composés hétéroaryle bicycliques utilisés en tant qu'activateurs de trem2

Country Status (1)

Country Link
WO (1) WO2025117599A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12459953B2 (en) 2024-01-04 2025-11-04 Muna Therapeutics Aps TREM2 modulators
US12459952B2 (en) 2024-01-04 2025-11-04 Muna Therapeutics Aps TREM2 modulators

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007105751A1 (fr) * 2006-03-16 2007-09-20 Astellas Pharma Inc. Derive de quinolone ou sel pharmaceutiquement acceptable de celui-ci
WO2009053799A1 (fr) * 2007-10-24 2009-04-30 Glenmark Pharmaceuticals, S.A. Nouveaux ligands du récepteur cannobinoïde, compositions pharmaceutiques les contenant et leur procédé de préparation
WO2022236272A2 (fr) * 2021-05-04 2022-11-10 Vigil Neuroscience, Inc. Composés hétérocycliques utilisés en tant que récepteur de déclenchement exprimé sur des agonistes de cellules myéloïdes 2 et procédés d'utilisation
WO2023086799A1 (fr) * 2021-11-09 2023-05-19 Vigil Neuroscience, Inc. Composés hétérocycliques utilisés en tant que récepteur de déclenchement exprimé sur des agonistes de cellules myéloïdes 2

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007105751A1 (fr) * 2006-03-16 2007-09-20 Astellas Pharma Inc. Derive de quinolone ou sel pharmaceutiquement acceptable de celui-ci
WO2009053799A1 (fr) * 2007-10-24 2009-04-30 Glenmark Pharmaceuticals, S.A. Nouveaux ligands du récepteur cannobinoïde, compositions pharmaceutiques les contenant et leur procédé de préparation
WO2022236272A2 (fr) * 2021-05-04 2022-11-10 Vigil Neuroscience, Inc. Composés hétérocycliques utilisés en tant que récepteur de déclenchement exprimé sur des agonistes de cellules myéloïdes 2 et procédés d'utilisation
WO2023086799A1 (fr) * 2021-11-09 2023-05-19 Vigil Neuroscience, Inc. Composés hétérocycliques utilisés en tant que récepteur de déclenchement exprimé sur des agonistes de cellules myéloïdes 2

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY 18 June 2019 (2019-06-18), XP093332936, Database accession no. 2337685-28-4 *
DATABASE REGISTRY 5 March 2006 (2006-03-05), XP093332935, Database accession no. 875864-32-7 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12459953B2 (en) 2024-01-04 2025-11-04 Muna Therapeutics Aps TREM2 modulators
US12459952B2 (en) 2024-01-04 2025-11-04 Muna Therapeutics Aps TREM2 modulators

Similar Documents

Publication Publication Date Title
US11884680B2 (en) Bromodomain inhibitors
JP7088983B2 (ja) キナーゼ阻害剤としてのビアリールアミド化合物
JP7392164B2 (ja) ヘテロアリール誘導体、その製造方法およびその使用
TWI617559B (zh) ２－芳基咪唑并［１，２－ｂ］嗒．２－苯基咪唑并［１，２－ａ］吡啶，和２－苯基咪唑并［１，２－ａ］吡衍生物
JP2021098753A (ja) １，４−二置換ピリダジン誘導体およびｓｍｎ欠損に関連する状態を処置するためのその使用
KR20210013145A (ko) 키나아제 억제제로서 헤테로시클릭 화합물, 헤테로시클릭 화합물을 포함하는 조성물 및 그 사용 방법
CN110022875A (zh) 治疗性抑制化合物
WO2025117599A1 (fr) Composés hétéroaryle bicycliques utilisés en tant qu'activateurs de trem2
KR20110039383A (ko) ｃＭＥＴ 억제제
WO2014026327A1 (fr) Composés d'acide benzoïque à substitution 4-hétéroaryle en tant qu'inhibiteurs de rorgammat et leurs utilisations
EP2763976A1 (fr) Inhibiteurs de tyrosine kinase de la rate (syk) contenant un 2-pyridyl carboxamide
MX2013010315A (es) Compuestos de tiazolopirimidina.
TW201302713A (zh) 化合物及其作為β－位置ＡＰＰ裂解酶（ＢＡＣＥ）抑制劑之用途
CN110156770A (zh) 作为tam族激酶抑制剂的氨基吡啶衍生物
JP2007507546A (ja) キナーゼ阻害剤としての１，６−二置換アザベンゾイミダゾールの調製
KR20230026288A (ko) Sos1 억제제 및 이의 용도
WO2022199662A1 (fr) Composé polycyclique et son application
KR20180110132A (ko) 무스카린성 아세틸콜린 수용체 m1의 양성 알로스테릭 조절제
WO2002102807A1 (fr) Nouveaux derives d'isoxazolopyridone et leur utilisation
TW201217362A (en) Heteroaryls and uses thereof
AU2018326734B2 (en) Substituted 2-azabicyclo(3.1.1)heptane and 2-azabicyclo(3.2.1)octane derivatives as orexin receptor antagonists
TWI508968B (zh) 用於治療呼吸道融合性病毒感染的化合物
TW202339721A (zh) Bcl-xL抑制劑
JP2022515309A (ja) 置換アリール化合物、その製造方法及び用途
CN101663276A (zh) 用作激酶抑制剂的2-氨基吡啶衍生物

Legal Events

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

Ref document number: 24898672

Country of ref document: EP

Kind code of ref document: A1