WO2019053090A1 - DIPHENYL DERIVATIVES AND USES THEREOF - Google Patents

DIPHENYL DERIVATIVES AND USES THEREOF Download PDF

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WO2019053090A1
WO2019053090A1 PCT/EP2018/074662 EP2018074662W WO2019053090A1 WO 2019053090 A1 WO2019053090 A1 WO 2019053090A1 EP 2018074662 W EP2018074662 W EP 2018074662W WO 2019053090 A1 WO2019053090 A1 WO 2019053090A1
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Prior art keywords
methyl
carboxamide
phenyl
biphenyl
triazole
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English (en)
French (fr)
Inventor
Natalie Dales
Paul GORMISKY
John Ryan Kerrigan
Lei Shu
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Novartis AG
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Novartis AG
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Priority to ES18769353T priority Critical patent/ES2985747T3/es
Priority to CN201880058862.6A priority patent/CN111094278B/zh
Priority to JP2020514550A priority patent/JP7394747B2/ja
Priority to EP18769353.6A priority patent/EP3681883B1/en
Publication of WO2019053090A1 publication Critical patent/WO2019053090A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen 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
    • C07D401/10—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 aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—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 carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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

Definitions

  • the disclosure provides diphenyl compounds and the use thereof as growth factor pathway activators.
  • Growth factors are signaling molecules which bind their cognate cell surface receptors initiating signaling cascades that stimulate a variety of cellular processes including growth, metabolism, survival, migration and differentiation.
  • PI3K Phosphoinositide 3 Kinase
  • Akt also called Protein Kinase B, PKB
  • Akt is a serine/threonine kinase that mediates growth factor signaling by phosphorylating multiple cellular targets.
  • Impaired growth factor signaling can lead to various disease conditions including skeletal muscle loss, hearing loss, degeneration of a number of organ systems and delayed wound healing.
  • IGF-1 Insulin-like growth factor 1
  • PI3K/Akt/mTOR signaling axis show accelerated wound closure.
  • Recombinant PDGF has several drawbacks as a treatment for chronic wounds, including its short half-life in the protease-rich hostile wound microenvironment and insufficient delivery mechanisms. A need remains for growth factor pathway activators that bypass growth factor receptors (which are downregulated in chronic wounds), have increased stability, and pose no risk for immunogenicity.
  • the disclosure provides compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof and combinations thereof.
  • the compounds can or may activate growth factor pathways, including the PI3K/Akt/mTOR pathway.
  • the disclosure provides a compound of formula (I):
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, e.g., in a
  • the disclosure provides a pharmaceutical combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, e.g., in a
  • therapeutically effective amount and one or more other therapeutic agents.
  • the disclosure provides a method of activating a growth factor pathway in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the compound or a pharmaceutically acceptable salt thereof.
  • the disclosure provides a method of promoting wound healing, promoting tissue repair, or treating hearing loss, skeletal muscle loss, organ degeneration, tissue damage, neurodegeneration, or muscular atrophy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the compound or a pharmaceutically acceptable salt thereof.
  • the compounds or methods described herein may be used for research (e.g., studying growth factor signaling pathways) and other non-therapeutic purposes.
  • the disclosure provides a compound of formula (I) or a
  • X is CH or N
  • R is H, halo, -OH, C 1-4 alkyl, Ci -4 alkoxy, d ⁇ haloalkyl or C 1-4 haloalkoxy;
  • R 1 is H, Ci. 4 alkyl, C ⁇ haloalkyl, or 3-6 membered cycloalkyl;
  • R 2 and R 3 are each, independently, H or C - alkyl;
  • R 4 is halo, -C ⁇ C-R 6 , -C 6 H 4 -R 6 , -(4-10 membered heterocyclyl)-R 6 , a 5-10 membered heteroaryi optionally substituted with 1-3 R 6 groups, -(4-10 membered carbocyclyl)-R 6 , a 6-10 membered fused heterocyclyl-aryl optionally substituted with 1 -3 C -4 alkyl groups, or a 6-10 membered fused heterocyclyl-heteroaryl optionally substituted with 1-3 C 1 4 alkyl groups;
  • R 5 is H, or R 4 and R 5 together with the carbon atoms to which they are attached form a 5-12 membered carbocyclic, heterocyclic, aryl, heteroaryi, fused heterocyclyl-aryl, fused heterocyclyl-heteroaryl, fused carbocyciyl-aryl, or fused carbocyclyl-heteroaryl ring, wherein said carbocyclic, heterocyclic, aryl, heteroaryi, fused heterocyclyl-aryl, fused heterocyclyl-heteroaryl , fused carbocyciyl-aryl, or fused carbocyclyl-heteroaryl ring is optionally substituted with 1-3 d- 4 alkyl groups;
  • each R 6 is independently -(CH 2 ) m -(CO) n -(CH 2 ) p -R 6a , -0-R 6a , -(CH 2 ) m -(CO) n -(CH 2 ) p -R 6b , - 0-R 6b , -(CH 2 ) m -(CO) n -(CH 2 ) p -R 6c , -0-R 6c , -(CH 2 ) m -(CO) n -(CH 2 ) p -R 6d , or -0-R 6d ;
  • R 6a is H, -OH, -NR 7 R 8 , -CN, oxo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, -CH(NR 7 R 8 )- d-ahaloalkyl, -CH(NR 7 R 8 )-d- 3 alkyl, -C(CH 3 )(NR 7 R 8 )-C 1 . 3 alkyl, -S0 2 C 1-4 alkyl, -S0 2 d_
  • R eb is a 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from a group consisting of halo, -OH, -NR 7 R 8 , Ci_ 4 alkyl, -C 1-4 haloalkyl, - C 1-4 hydroxyalkyl, -C 1 . 4 alkyl-NR 7 R 8 , -S0 2 C 1 . 4 alkyl, and 4-6 membered heterocyclyl;
  • R 6c is a 5-10 membered heteroaryi optionally substituted with 1-3 substituents independently selected from a group consisting of -NR 7 R 8 , C 1- alkyl, -C ⁇ hydroxyalkyl, and -d- 4 alkyl-NR 7 R 8 ;
  • R 6d is a 4-10 membered carbocyclyl optionally substituted with 1-3 substituents independently selected from a group consisting of halo, -OH, -NR 7 R 8 , Ci. 4 alkyl, -d_ 4 haloalkyl, - d. 4 hydroxyalkyl, -d. 4 alkyl-NR 7 R 8 , -S0 2 C 1-4 alkyl, and 4-6 membered heterocyclyl;
  • R 7 and R 8 are each, independently, selected from a group consisting of H, d. alkyl, d- 4 hydroxyalkyl, a 4-6 membered heterocyclyl, and a 4-6 membered cycloalkyl;
  • n 0 or 1 ;
  • n 0 or 1 ;
  • p 0 or 1.
  • the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • X is CH or N
  • R is H, halo, -OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl or C1.4 haloalkoxy;
  • R 1 is H, Ci. 4 alkyl, C 1-4 haloalkyl, or 3-6 membered cycloalkyl;
  • R 2 and R 3 are each, independently, H or C -4 a!kyl
  • R 4 is halo, -C 6 H -R 6 , -(4-10 membered heterocyclyl)-R 6 , -(5-10 membered heteroaryl)- R 6 , -(4-6 membered carbocyclyl)-R 6 , a 6-10 membered fused heterocyclyl-aryl optionally substituted with 1 -3 C 1-4 alkyl groups, or a 6-10 membered fused heterocyclyl-heteroaryl optionally substituted with 1 -3 C 1-4 alkyl groups;
  • R 5 is H, or R 4 and R 5 together with the carbon atoms to which they are attached form a 5-12 membered carbocyclic, heterocyclic, aryl, heteroaryl, fused heterocyclyl-aryl, fused heterocyclyl-heteroaryl, fused carbocyclyl-aryl, or fused carbocyclyl-heteroaryl ring, wherein said carbocyclic, heterocyclic, aryl, heteroaryl, fused heterocyclyl-aryl, fused heterocyclyl-heteroaryl, fused carbocyclyl-aryl, or fused carbocyclyl-heteroaryl ring is optionally substituted with 1 -3 4 alkyl groups;
  • R 6 is -(CH 2 ) m -(CO) n -(CH 2 ) p -R 6a , -(CH 2 ) m -(CO) n -(CH 2 ) p -R 6b , or -(CH 2 ) m -(CO) n -(CH 2 ) p -R 6c ;
  • R 6a is H, -OH, -NR 7 R 8 , -CN, oxo, C 1-4 alkyl, C 1-4 haloalkyl, -CHiNRWj-C ⁇ haloalkyl, - CH(NR 7 R 8 )-Ci. 3 alkyl, -S0 2 C 1 . 4 alkyl, or -S0 2 NR 7 R 8 ;
  • R 6b is a 4-10 membered heterocyclyl optionally substituted with 1 -3 substituents independently selected from a group consisting of -NR 7 R 8 , d. alkyl, -C 1-4 hydroxyalkyl, and -Cv 4 alkyl-NR 7 R 8 ;
  • R 6c is a 5-10 membered heteroaryl optionally substituted with 1 -3 substituents independently selected from a group consisting of -NR 7 R 8 , C -4 alkyl, -Ci_ 4 hydroxyalkyl, and -Ci. 4 alkyl-NR 7 R 8 ;
  • R 7 and R 8 are each, independently, selected from a group consisting of H, C -4 alkyl, d. 4 hydroxyalkyl, a 4-6 membered heterocyclyl, and a 4-6 membered cycloalkyl;
  • n 0 or 1 ;
  • a line traversing a ring and bonded to a substituent group means that the substituent may be bound in place of hydrogen to any ring atom where the valency of the atom allows.
  • the R group in formula (I) may be bound to any carbon atom of the phenyl ring traversed by the line, except for the carbon atom bound to the rest of the molecule through the methylene group and the carbon atom bound to the R 4 substituent.
  • the substituent group may be bound to any ring atom in any ring of the system.
  • the term "compound(s) disclosed herein” refers to compound(s) of formula (I), and subformulae thereof.
  • the terms “compound” and “pharmaceutically acceptable salt” include the specified compounds and pharmaceutically acceptable salts in any form, including any solid form thereof (including any polymorphic form thereof), any solvate or hydrate form thereof, and any solution thereof.
  • C 1 . 4 alkyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to four carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • Examples of C 1-4 alkyl groups include, but are not limited to, methyl, ethyl, /7-propyl, n-butyl, 1 -methylethyl (/so-propyl), 1 -methylpropyl (sec-butyl), 2-methyl propyl (/so-butyl), 1 ,1 - dimethylethyl (f-butyl), and the like.
  • Analogous terms referring to a Iky I groups having different numbers of carbon atoms e.g., "C ⁇ alkyl” refer to analogous alkyl groups having the specified numbers of carbon atoms.
  • u -Ci- 4 alkyl- refers to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to four carbon atoms, and which is attached to the rest of the molecule by single bonds.
  • Examples of -Ci -4 alkyl- groups include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, 1 -methylethylene, and the like.
  • Analogous terms referring to groups having different numbers of carbon atoms e.g., "-C 1-6 alkyl-" refer to analogous groups having the specified numbers of carbon atoms.
  • d ⁇ haloalkyl refers to a C 1-4 alkyl group, wherein one or more of the hydrogen atoms of the C ⁇ alkyl group are replaced by a halo group.
  • C 1-4 haloalkyl include, but are not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 1 ,1 -difluoroethyl, and the like.
  • Analogous terms referring to haloalkyl groups having different numbers of carbon atoms e.g., "Ci -6 haloalkyl” refer to analogous haloalkyl groups having the specified numbers of carbon atoms.
  • the term refers to a C 1 _ 4 alkyl group, wherein one or more of the hydrogen atoms (e.g., one hydrogen atom) of the C 1-4 aSkyS group is replaced by an NR 7 R 8 group.
  • NR 7 R 8 group e.g., one hydrogen atom
  • Analogous terms referring to alkyl-NR 7 R 8 groups having different numbers of carbon atoms e.g., refer to analogous alkyl-NR 7 R B groups having the specified numbers of carbon atoms.
  • halo refers to bromo, chloro, fluoro or iodo.
  • C 1-4 alkoxy refers to a radical of the formula -OR a where R a is a C 1-4 alkyi group.
  • Examples of C 1-4 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and the like.
  • Analogous terms referring to alkoxy groups having different numbers of carbon atoms e.g., "C 1-6 alkoxy” refer to analogous alkoxy groups having the specified numbers of carbon atoms.
  • C 1-4 haloalkoxy refers to a d. 4 alkoxy group, wherein one or more of the hydrogen atoms of the C 1-4 alkyl group are each independently replaced by a halo group.
  • Examples of C ⁇ haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2- trifluoroethoxy, 1 ,1 -difluoroethoxy, and the like.
  • Analogous terms referring to haloalkoxy groups having different numbers of carbon atoms e.g., "C ⁇ haloalkoxy” refer to analogous haloalkoxy groups having the specified numbers of carbon atoms.
  • C ⁇ hydroxyaikyl refers to a C -4 alkyl group, wherein one or more of the hydrogen atoms (e.g., one hydrogen atom) of the C h alky I group are each replaced by OH.
  • Examples of C ⁇ hydroxyalkyl include, but are not limited to, hydroxy-methyl,
  • cycloalkyl refers to a stable, non-aromatic, mono- or bicyclic (fused, bridged, or spiro) saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, having the specified number of carbon ring atoms, and which is attached to the rest of the molecule by a single bond.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • carbocyclyl refers to a stable, saturated or unsaturated, non-aromatic, mono- or bicyclic (fused, bridged, or spiro) ring radical having the specified number of ring carbon atoms.
  • carbocyclyl groups include, but are not limited to, the cycloalkyl groups identified above, cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like.
  • carbocyclyl group likewise refers to a stable, saturated or unsaturated, non-aromatic, mono- or bicyclic (fused, bridged, or spiro) ring having the specified number of ring carbon atoms.
  • heterocyclyl refers to a stable, saturated or unsaturated, non-aromatic, mono- or bicyclic (fused, bridged, or spiro) ring radical having the specified number of ring atoms and comprising one or more heteroatoms individually selected from nitrogen, oxygen and sulfur.
  • the heterocyclyl radical may be bonded via a carbon atom or heteroatom.
  • heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, pyrrol inyl, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl, piperazinyl, tetrahydropyranyl, morpholinyl, perhydroazepinyl, tetrahydropyridinyl, tetrahydroazepinyl, octahydropyrrolopyrrolyl, and the like.
  • heterocyclic ring likewise refers to a stable, saturated or unsaturated, non-aromatic, mono- or bicyclic (fused, bridged, or spiro) ring having the specified number of ring atoms and comprising one or more heteroatoms individually selected from nitrogen, oxygen and sulfur.
  • aryl refers to a stable, aromatic, mono- or bicyclic ring radical having the specified number of ring carbon atoms.
  • aryl groups include, but are not limited to, phenyl, 1 -naphthyl, 2-naphthyl, and the like.
  • aryl ring likewise refers to a stable, aromatic, mono- or bicyclic ring having the specified number of ring carbon atoms.
  • heteroaryl refers to a stable, aromatic, mono- or bicyclic ring radical having the specified number of ring atoms and comprising one or more heteroatoms individually selected from nitrogen, oxygen and sulfur.
  • the heteroaryl radical may be bonded via a carbon atom or heteroatom.
  • heteroaryl groups include, but are not limited to, fury I, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, indazolyl, oxadiazolyl, benzothiazolyl, quinoxalinyl, and the like.
  • heteroaryl ring likewise refers to a stable, aromatic, mono- or bicyclic ring having the specified number of ring atoms and comprising one or more heteroatoms individually selected from nitrogen, oxygen and sulfur.
  • fused heterocyclyl-aryl refers to a stable bicyclic ring radical having the specified number of ring atoms and comprising a heterocyclyl ring (as defined above) fused to an aryl ring (as defined above).
  • the specified number of ring atoms refers to the total number of ring atoms in the heterocyclyl and aryl rings.
  • the radical may be bonded via a carbon atom or heteroatom on either the heterocyclyl ring or the aryl ring.
  • fused heterocyclyl-aryl groups include, but are not limited to, the following: , and the like.
  • fused heterocyclyl-aryl ring refers to a stable bicyclic ring having the specified number of ring atoms and comprising a heterocyclyl ring (as defined above) fused to an aryl ring (as defined above).
  • fused heterocyclyl-heteroaryl refers to a stable bicyclic ring radical having the specified number of ring atoms and comprising a heterocyclyl ring (as defined above) fused to a heteroaryl ring (as defined above).
  • the specified number of ring atoms refers to the total number of ring atoms in the heterocyclyl and heteroaryl rings.
  • the radical may be bonded via a carbon atom or heteroatom on either the heterocyclyl ring or the heteroaryl ring.
  • fused heterocyclyl-heteroaryl groups include, but are not limited to,
  • heterocyclyl-heteroaryl ring refers to a stable bicyclic ring having the specified number of ring atoms and comprising a heterocyclyl ring (as defined above) fused to a heteroaryl ring (as defined above).
  • fused carbocyclyl-aryl refers to a stable bicyclic ring radical having the specified number of ring atoms and comprising a carbocyclyl ring (as defined above) fused to an aryl ring (as defined above).
  • the specified number of ring atoms refers to the total number of ring atoms in the carbocyclyl and aryl rings.
  • the radical may be bonded via a carbon atom on either the carbocyclyl ring or the aryl ring.
  • fused carbocyclyl-aryl ring refers to a stable bicyclic ring having the specified number of ring atoms and comprising a carbocyclyl ring (as defined above) fused to an aryl ring (as defined above).
  • fused carbocyclyl-heteroaryl refers to a stable bicyclic ring radical having the specified number of ring atoms and comprising a carbocyclyl ring (as defined above) fused to a heteroaryl ring (as defined above).
  • the specified number of ring atoms refers to the total number of ring atoms in the carbocyclyl and heteroaryl rings.
  • the radical may be bonded via a carbon atom on the carbocyclyl ring or a carbon atom or heteroatom on the heteroaryl ring.
  • fused carbocyclyl-heteroaryl groups include, but are not limited to, the following:
  • fused carbocyclyl-heteroaryl ring refers to a stable bicyclic ring having the specified number of ring atoms and comprising a carbocyclyl ring (as defined above) fused to a heteroaryl ring (as defined above).
  • the term "optionally substituted” means that the group in question may be substituted, for example, with the specified number of identified groups, but that such substitution is not required.
  • a group that is “optionally substituted with 1 -3 4 alkyl groups” may be unsubstituted or may be substituted with 1 , 2, or 3 C 1- alkyl groups.
  • X is CH or N
  • R is H, halo, -OH, C 4 alkyl, d- 4 alkoxy, d. 4 haloalkyl or C 1 4 haloalkoxy;
  • R 1 is H, C 1-4 alkyl, C 1-4 haloalkyl, or 3-6 membered cycloalkyl;
  • R 2 and R 3 are each, independently, H or C 1-4 alkyl
  • R 4 is halo, -OC-R 6 , -C 6 H 4 -R 6 , -(4-10 membered heterocyclyl)-R 6 , a 5-10 membered heteroaryl optionally substituted with 1-3 R 6 groups, -(4-10 membered carbocyclyl)-R 6 , a 6-10 membered fused heterocyclyl-aryl optionally substituted with 1 -3 C -4 alkyl groups, or a 6-10 membered fused heterocyclyl-heteroaryl optionally substituted with 1 -3 C 1- alkyl groups;
  • R 5 is H, or R 4 and R 5 together with the carbon atoms to which they are attached form a 5-12 membered carbocyclic, heterocyclic, aryl, heteroaryl, fused heterocyclyl-aryl, fused heterocyclyl-heteroaryl, fused carbocyclyl-aryl, or fused carbocyclyl-heteroaryl ring, wherein said carbocyclic, heterocyclic, aryl, heteroaryl, fused heterocyclyl-aryl, fused heterocyclyl-heteroaryl, fused carbocyclyl-aryl, or fused carbocyclyl-heteroaryl ring is optionally substituted with 1 -3 4 alkyl groups;
  • R 6 is -(CH 2 ) m -(CO) n -(CH 2 ) p -R 6a , -0-R 6a , -(CH 2 ) m -(CO) justify-(CH 2 ) p -R 6b , -0-R 6b , -(CH 2 ) m -(CO) admir- (CH 2 ) P -R 6c , -0-R 6c , -(CH 2 ) m -(CO) n -(CH 2 ) p -R 6d , or -0-R 6d ;
  • R 6a is H, -OH, -NR 7 R 8 , -CN, oxo, C 1-4 alkyl, d_ 4 haloalkyl, d ⁇ hydroxyalkyl, -CH(NR 7 R 8 )- d. 3 haloalkyl, -CH(NR 7 R 8 )-C,. 3 alkyl, -C(CH 3 )(NR 7 R 8 )-d- 3 alkyl, -S0 2 C ⁇ alkyl, -S0 2 Ci.
  • R 6 is a 4-10 membered heterocyclyl optionally substituted with 1 -3 substituents independently selected from a group consisting of halo, -OH, -NR 7 R 8 , d. 4 alkyl, -C 1-4 haloalkyl, - Ci -4 hydroxyalkyl, -C 1 . alkyl-NR 7 R 8 , -S0 2 d. 4 alkyl, and 4-6 membered heterocyclyl;
  • R 6c is a 5-10 membered heteroaryl optionally substituted with 1 -3 substituents independently selected from a group consisting of -NR 7 R 8 , d. alkyl, -C 1-4 hydroxyalkyl, and -Ci. 4 alkyl-NR 7 R 8 ;
  • R is a 4-10 membered carbocyclyl optionally substituted with 1 -3 substituents independently selected from a group consisting of halo, -OH, -NR 7 R 8 , C ⁇ alkyl, -C ⁇ haloalkyl, - Ci. 4 hydroxyalkyl, -C 1 . 4 alkyl-NR 7 R 8 , -S02C 1-4 alkyl, and 4-6 membered heterocyclyl;
  • R 7 and R 8 are each, independently, selected from a group consisting of H, C 1 _ 4 alkyl, Ci. 4 hydroxyalkyl, a 4-6 membered heterocyclyl, and a 4-6 membered cycloalkyl;
  • n 0 or 1 ;
  • n 0 or 1 ;
  • p is 0 or 1 .
  • Embodiment 2 A compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • X is CH or N
  • R is H, halo, -OH, C 1- alkyl, d ⁇ alkoxy, Ci. 4 haloalkyl or Ci- 4 haloalkoxy;
  • R 1 is H, Ci. 4 alkyl, Ci_ haloalkyl, or 3-6 membered cycloalkyl;
  • R 2 and R 3 are each, independently, H or C 1- alkyl
  • R 4 is halo, -C 6 H 4 -R 6 , -(4-10 membered heterocyclyl)-R 6 , -(5-10 membered heteroaryl)- R 6 , -(4-6 membered carbocyclyl )-R 6 , a 6-10 membered fused heterocyclyl-aryl optionally substituted with 1 -3 C 1-4 alkyl groups, or a 6-10 membered fused heterocyclyl-heteroaryl optionally substituted with 1 -3 C 1-4 alkyl groups;
  • R 5 is H, or R 4 and R 5 together with the carbon atoms to which they are attached form a 5-12 membered carbocyclic, heterocyclic, aryl, heteroaryl, fused heterocyclyl-aryl, fused heterocyclyl-heteroaryl, fused carbocyclyl-aryl, or fused carbocyclyl-heteroaryl ring, wherein said carbocyclic, heterocyclic, aryl, heteroaryl, fused heterocyclyl-aryl, fused heterocyclyl-heteroaryl, fused carbocyclyl-aryl, or fused carbocyclyl-heteroaryl ring is optionally substituted with 1 -3 Ci_ 4 alkyl groups;
  • R 6 is -(CH 2 ) m -(C0) n -(CH 2 ) p -R 6a , -(CH 2 ) m -(CO) réelle-(CH 2 ) p -R 6b , or -(CH 2 ) m -(CO) n -(CH 2 ) p -R 6c ;
  • R 6a is H, -OH, -NR 7 R 8 , -CN, oxo, C 1-4 alkyl, C 1-4 haloalkyl, -CH(NR 7 R 8 )-C 1 . 3 haloalkyl, -
  • R 6b is a 4-10 membered heterocyclyl optionally substituted with 1 -3 substituents independently selected from a group consisting of -NR 7 R 8 , C 1-4 alkyl, -Ci. 4 hydroxyalkyl, and -d. 4 alkyl-NR 7 R 8 ;
  • R 6c is a 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from a group consisting of -NR 7 R 8 , Ci -4 alkyl, -C _ 4 hydroxya!kyl, and -Ci. 4 alkyl-NR 7 R 8 ;
  • R 7 and R 8 are each, independently, selected from a group consisting of H , C 1- aSkyl, CL 4 hydroxyalkyl, a 4-6 membered heterocyclyl, and a 4-6 membered cycloalkyi;
  • n 0 or 1 ;
  • n 0 or 1 ;
  • p 0 or 1.
  • Embodiment 3 A compound according to embodiment 1 or 2, wherein the compound is of formula (l-A):
  • Embodiment 4 A compound according to embodiment 1 or 2, wherein the compound is of formula (l-B):
  • Embodiment 5 A compound according to embodiment 1 or 2, wherein the compound is of formula (l-C):
  • Embodiment 6 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein X is CH.
  • Embodiment 7 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein X is N.
  • Embodiment 8 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R is H, halo, C - alkyl, or C ⁇ haloalkyl.
  • Embodiment 9 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R is H or C 1-4 alkyl.
  • Embodiment 10 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R is H.
  • Embodiment 1 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 1 is H, d. 4 alkyl, or C ⁇ haloalkyl.
  • Embodiment 12 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 1 is H or C ⁇ alkyl.
  • Embodiment 13 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-4 a!kyl or C ⁇ haloalkyl.
  • Embodiment 14 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 1 is C -4 alkyS.
  • Embodiment 15 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 1 is CH 3 .
  • Embodiment 16 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 1 is H.
  • Embodiment 17 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 2 is H.
  • Embodiment 18 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 2 is d ⁇ alkyl.
  • Embodiment 19 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 2 is H or CH 3 .
  • Embodiment 20 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 2 is CH 3 .
  • Embodiment 21 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 3 is H.
  • Embodiment 22 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 3 is C 1-4 alkyl.
  • Embodiment 23 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 3 is H or CH 3 .
  • Embodiment 24 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 3 is CH 3 .
  • Embodiment 25 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is -C 6 H 4 -R 6 , -(4-10 membered heterocyclyl)-R 6 , -(5-10 membered heteroaryl)-R 6 , -(4-6 membered carbocyclyl)-R 6 , a 6-10 membered fused heterocyclyl-aryl optionally substituted with 1 -3 Ci alkyl groups, or a 6-10 membered fused heterocyclyl-heteroaryl optionally substituted with 1 -3 C 1-4 alky! groups.
  • Embodiment 26 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is halo, -(4-10 membered
  • heterocyclyl)-R 6 -(5-10 membered heteroaryl)-R 6 , -(4-6 membered carbocyclyl)-R 6 , a 6-10 membered fused heterocyclyl-aryl optionally substituted with 1 -3 C 1-4 a!kyl groups, or a 6-10 membered fused heterocyclyl-heteroaryl optionally substituted with 1 -3 d. 4 alkyl groups.
  • Embodiment 27 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is halo, -C 6 H 4 -R 6 , -(5-10 membered heteroaryl)-R 6 , -(4-6 membered carbocyclyl)-R 6 , a 6-10 membered fused heterocyclyl-aryl optionally substituted with 1 -3 C -4 alkyl groups, or a 6-10 membered fused heterocyclyl- heteroaryl optionally substituted with 1 -3 C ⁇ alkyi groups.
  • Embodiment 28 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is halo, -C 6 H 4 -R 6 , -(4-10 membered heterocyclyl)-R 6 , -(4-6 membered carbocyclyl)-R 6 , a 6-10 membered fused heterocyclyl-aryl optionally substituted with 1 -3 C 1-4 a!ky! groups, or a 6-10 membered fused heterocyclyl- heteroaryl optionally substituted with 1 -3 C h alky! groups.
  • Embodiment 29 Embodiment 29.
  • Embodiment 30 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is halo, -C 6 H 4 -R 6 , -(4-10 membered heterocyclyl)-R 6 , -(5-10 membered heteroaryl)-R 6 , -(4-6 membered carbocyclyl)-R 6 , or a 6-10 membered fused heterocyclyl-heteroaryl optionally substituted with 1 -3 C 4 alkyl groups.
  • Embodiment 31 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is halo, -C 6 H 4 -R 6 , -(4-10 membered heterocyclyl)-R 6 , -(5-10 membered heteroaryl)-R 6 , -(4-6 membered carbocyclyl)-R 6 , or a 6-10 membered fused heterocyclyl-aryl optionally substituted with 1 -3 C 1- alkyl groups.
  • Embodiment 32 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is -C ⁇ C-R 6 , -C 6 H -R 6 , -(4-10 membered heterocyclyl)-R 6 , a 5-10 membered heteroaryl optionally substituted with 1 -3 R 6 groups, -(4-10 membered carbocyclyl)-R 6 , a 6-10 membered fused heterocyclyl-aryl optionally substituted with 1 -3 C -4 aikyl groups, or a 6-10 membered fused heterocyclyl-heteroaryl optionally substituted with 1 -3 C 1-4 alkyl groups.
  • Embodiment 33 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is halo, -C 6 H 4 -R 6 , -(4-10 membered heterocyclyl)-R 6 , a 5-10 membered heteroaryl optionally substituted with 1-3 R 6 groups, -(4-10 membered carbocyclyl)-R 6 , a 6-10 membered fused heterocyclyl-aryl optionally substituted with 1 -3 C -4 alkyl groups, or a 6-10 membered fused heterocyclyl-heteroaryl optionally substituted with 1 -3 C 1- a!kyl groups.
  • Embodiment 34 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is halo, -C ⁇ C-R 6 , -(4-10 membered heterocyclyl)-R 6 , a 5-10 membered heteroaryl optionally substituted with 1 -3 R 6 groups, -(4-10 membered carbocyclylJ-R 6 , a 6-10 membered fused heterocyclyl-aryl optionally substituted with 1 -3 C 1-4 alkyl groups, or a 6-10 membered fused heterocyclyl-heteroaryl optionally substituted with 1 -3 Ci_ 4 alkyl groups.
  • Embodiment 35 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is halo, -C ⁇ C-R 6 , -C 6 H -R 6 , a 5-10 membered heteroaryl optionally substituted with 1-3 R 6 groups, -(4-10 membered carbocyclyl)- R 6 , a 6-10 membered fused heterocyclyl-aryl optionally substituted with 1-3 C 1-4 alkyl groups, or a 6-10 membered fused heterocyclyl-heteroaryl optionally substituted with 1 -3 C -4 alkyl groups.
  • Embodiment 36 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is halo, -C ⁇ C-R 6 , -C 6 H 4 -R 6 , -(4-10 membered heterocyclyl)-R 6 , -(4-10 membered carbocyclyl )-R 6 , a 6-10 membered fused heterocyclyl-aryl optionally substituted with 1-3 C 1-4 alkyl groups, or a 6-10 membered fused heterocyclyl-heteroaryl optionally substituted with 1-3 Ci. 4 alkyl groups.
  • Embodiment 37 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is halo, -OC-R 6 , -C 6 H 4 -R 6 , -(4-10 membered heterocyclyl)-R 6 , a 5-10 membered heteroaryl optionally substituted with 1-3 R 6 groups, a 6-10 membered fused heterocyclyl-aryl optionally substituted with 1 -3 C -4 alkyl groups, or a 6-10 membered fused heterocyclyl-heteroaryl optionally substituted with 1-3 Ci. alkyl groups.
  • Embodiment 38 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is halo, -C ⁇ C-R 6 , -C 6 H 4 -R 6 , -(4-10 membered heterocyclyl)-R 6 , a 5-10 membered heteroaryl optionally substituted with 1-3 R 6 groups, -(4-10 membered carbocyclyl )-R 6 , or a 6-10 membered fused heterocyclyl-heteroaryl optionally substituted with 1-3 Ci. alkyl groups.
  • Embodiment 39 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is halo, -C ⁇ C-R 6 , -C 6 H 4 -R 6 , -(4-10 membered heterocyclyl)-R 6 , a 5-10 membered heteroaryl optionally substituted with 1-3 R 6 groups, -(4-10 membered carbocyclyl)-R 6 , or a 6-10 membered fused heterocyclyl-aryl optionally substituted with 1-3 d. 4 alkyl groups.
  • Embodiment 40 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is halo.
  • Embodiment 41 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is -C 6 H 4 -R 6 .
  • Embodiment 42 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is -(4-10 membered heterocyclyl)-R 6 .
  • Embodiment 43 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is -(5-10 membered heteroaryl )-R 6 .
  • Embodiment 44 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is -(4-6 membered carbocyclyl)-R 6 .
  • Embodiment 45 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is a 6-10 membered fused
  • heterocyclyl-aryl optionally substituted with 1 -3 C 1-4 alkyl groups.
  • Embodiment 46 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is a 6-10 membered fused
  • heterocyclyl-heteroaryl optionally substituted with 1 -3 C,. 4 alkyl groups.
  • Embodiment 47 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is -C ⁇ C-R 6 .
  • Embodiment 48 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is a 5-10 membered heteroaryl optionally substituted with 1 -3 R 6 groups.
  • Embodiment 49 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is -(4-10 membered carbocyclyl)-R 6 .
  • Embodiment 50 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • Embodiment 51 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • g 0, 1 , 2, or 3.
  • Embodiment 52 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is F or CI.
  • Embodiment 53 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is F.
  • Embodiment 54 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is CI.
  • Embodiment 55 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • Embodiment 56 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • Embodiment 56 may also be described as a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is -C 6 H 4 -R 6 .
  • Embodiment 57 A compound according to any one of the preceding embodiments,
  • Embodiment 58 A compound according to any one of the preceding embodiments,
  • Embodiment 59 A compound according to any one of the preceding embodiments,
  • Embodiment 60 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • Embodiment 61 A compound according to any one of the preceding embodiments,
  • Embodiment 63 A compound according to any eding embodiments,
  • Embodiment 65 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • Embodiment 66 A compound according to an preceding embodiments,
  • Embodiment 67 A compound according to any one of the preceding embodiments,
  • Embodiment 68 A compound according to any one of the preceding embodiments,
  • Embodiment 69 A compound according to any one of the preceding embodiments,
  • Embodiment 70 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • Embodiment 71 A compound according to any preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is
  • Embodiment 72 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is
  • Embodiment 73 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • Embodiment 74 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • Embodiment 75 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R is
  • Embodiment 76 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R is [00115] Embodiment 77. A compound according to any one of the preceding embodiments,
  • Embodiment 78 A compound according to any one of the preceding embodiments,
  • Embodiment 79 A compound according to any one of the preceding embodiments,
  • Embodiment 80 A compound according to any one of the receding embodiments,
  • Embodiment 81 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof wherein 4 is selected from a roup consisting of:
  • Embodiment 82 A compound according to any one of the preceding embodiments,
  • Embodiment 83 A compound according to any one of the preceding embodiments,
  • Embodiment 85 A compound according to any one of the preceding embodiments,
  • Embodiment 86 A compound according to any one of the preceding embodiments,
  • Embodiment 87 A compound according to any ing embodiments,
  • Embodiment 88 A compound according to any one of the preceding embodiments, harmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • Embodiment 89 A compound according to any one of the preceding embodiments,
  • Embodiment 90 A compound according to any one of the preceding embodiments,
  • Embodiment 91 A compound according to any one of the preceding embodiments,
  • Embodiment 92 A compound according to any one of the preceding embodiments,
  • Embodiment 93 A compound according to any one of the preceding embodiments, ble salt thereof, wherein R 4 is selected from a group consisting of:
  • Embodiment 94 A compound according to any one of the receding embodiments,
  • Embodiment 95 A compound according to any ing embodiments,
  • Embodiment 96 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • Embodiment 97 A compound according to any one of the preceding embodiments,
  • Embodiment 99 A compound according to any ceding embodiments,
  • Embodiment 100 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • Embodiment 101 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • Embodiment 02. A compound according to a preceding embodiments,
  • Embodiment 103 A compound according to any one of the receding embodiments,
  • Embodiment 104 A compound according to any one of the preceding embodiments,
  • Embodiment 105 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • Embodiment 106 A compound according to any one of the preceding embodiments,
  • Embodiment 107 A compound according to any one of the preceding embodiments,
  • Embodiment 108 A compound according to any one of the preceding embodiments,
  • Embodiment 109 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a roup consisting of:
  • Embodiment 1 10. A compound according to any one of the preceding embodiments, r a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a roup consisting of:
  • Embodiment 1 1 A compound according to any one of the preceding embodiments,
  • Embodiment 1 13 A compound according to any one of the preceding embodiments,
  • Embodiment 1 A compound according to any one of the preceding embodiments,
  • Embodiment 1 15. A compound according to any one of the preceding embodiments,
  • Embodiment 1 16. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • Embodiment 1 A compound according to any one of the preceding embodiments,
  • Embodiment 1 18. A compound according to any one of the preceding embodiments,
  • Embodiment 120 A compound according to any one of the preceding embodiments,
  • Embodiment 121 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • Embodiment 122 A compound according to any one of the preceding embodiments,
  • Embodiment 123 A compound according to any one of the preceding embodiments,
  • Embodiment 124 A compound according to any one of the preceding embodiments,
  • Embodiment 126 A compound according to any one of the preceding embodiments,
  • Embodiment 127 A compound according to any one of the preceding embodiments,
  • Embodiment 128 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • Embodiment 129 A compound according to any one of the preceding embodiments,
  • Embodiment 130 A compound according to any one of the preceding embodiments,
  • Embodiment 131 A compound according to any one of the preceding embodiments,
  • Embodiment 133 A compound according to any one of the preceding embodiments,
  • Embodiment 134 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • Embodiment 135. A compound according to any one of the preceding embodiments,
  • Embodiment 136 A compound according to any one of the preceding embodiments,
  • Embodiment 137 A compound according to any one of the preceding embodiments,
  • Embodiment 139 A compound according to any one of the preceding embodiments,
  • Embodiment 140 A compound according to any one of the preceding embodiments,
  • Embodiment 141 A compound according to any one of the preceding embodiments, harmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • Embodiment 142 A compound according to any one of the preceding embodiments, harmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • Embodiment 143 A compound according to any ne of the preceding embodiments,
  • Embodiment 144 A compound according to any one of the preceding embodiments,
  • Embodiment 146 A compound according to any one of the preceding embodiments,
  • Embodiment 147 A compound according to any one of the preceding embodiments,
  • Embodiment 148 A compound according to any one of the preceding embodiments, d from a group consisting of:
  • Embodiment 149 A compound according to any on of the preceding embodiments,
  • Embodiment 150 A compound according to any one of the preceding embodiments,
  • Embodiment 151 A compound according to any ne of the preceding embodiments,
  • Embodiment 153 A compound according to any one of the preceding embodiments,
  • R 4 is R 6 .
  • Embodiment 154 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • Embodiment 55 A compound according to any one of the preceding embodiments,
  • Embodiment 156 A compound according to any one of the preceding embodiments,
  • Embodiment 157 A compound according to any one of the preceding embodiments,
  • Embodiment 158 A compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • Embodiment 159 A compound according to any one of the preceding embodiments,
  • Embodiment 160 A compound according to any one of the preceding embodiments,
  • Embodiment 161 A compound according to any one of the preceding embodiments,
  • Embodiment 162 A compound according to any one of the preceding embodiments,
  • Embodiment 163 A compound according to any one of the preceding embodiments,
  • R 4 is vQ R" 6 .
  • Embodiment 164 A compound according to any one of the preceding embodiments,
  • Embodiment 165 A compound according to any one of the preceding embodiments, r a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • Embodiment 166 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • Embodiment 167 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is
  • Embodiment 168 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is
  • Embodiment 169 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is
  • Embodiment 170 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is
  • Embodiment 171 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is
  • Embodiment 172 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is
  • Embodiment 173 A compound according to any ceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is [00212] Embodiment 174. A compound according to any one of the preceding embodiments,
  • Embodiment 175. A compound according to any one of the preceding embodiments,
  • Embodiment 176 A compound according to any one of the preceding embodiments,
  • Embodiment 177 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is ⁇ C H
  • Embodiment 178 A compound according to any one of the preceding embodiments, ceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • Embodiment 179 A compound according to any one of the preceding embodiments,
  • Embodiment 180 A compound according to any one of the preceding embodiments,
  • Embodiment 18 A compound according to any one of the preceding embodiments,
  • Embodiment 183 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein
  • Embodiment 184 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R is
  • Embodiment 185 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R
  • Embodiment 186 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R is
  • Embodiment 187 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R is
  • Embodiment 188 A compound according to an one of the receding embodiments, or a pharmaceutically acceptable salt thereof, wherein R
  • Embodiment 89 A compound according to an ding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4
  • Embodiment 190 A compound according to any one of the preceding embodiments,
  • Embodiment 191 A compound according to any one of the preceding embodiments,
  • Embodiment 192 A compound according to any one of the preceding embodiments,
  • Embodiment 193 A compound according to any one of the preceding
  • R 4 is selected from a group consisting of:
  • Embodiment 194 A compound according to any one of the preceding embodiments,
  • Embodiment 195 A compound according to any one of the preceding embodiments,
  • Embodiment 196 A compound according to any one of the preceding embodiments,
  • Embodiment 197 A compound according to any one of the preceding embodiments, d from a group consisting of: is C 1-4 alkyl; and q is 0, 1 , 2, or 3.
  • Embodiment 198 A compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • R 9 is C 1-4 alkyl.
  • Embodiment 199 A compound according to any one of the preceding embodiments,
  • Embodiment 200 A compound according to any one of the preceding embodiments,
  • Embodiment 201 A compound according to any one of the preceding embodiments,
  • Embodiment 202 A compound according to any one of the preceding embodiments,
  • Embodiment 203 A compound according to any one of the preceding embodiments,
  • Embodiment 204 A compound according to any one of the preceding embodiments,
  • Embodiment 205 A compound according to any one of the preceding embodiments,
  • Embodiment 206 A compound according to any one of the preceding embodiments,
  • Embodiment 207 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of: ; and FT is C 1-4 alkyl.
  • Embodiment 208 A compound according to any one of the preceding embodiments,
  • Embodiment 2 A compound according to any one of the preceding embodiments,
  • Embodiment 210 A compound according to any one of the preceding embodiments,
  • R 4 is ; and R 9 is C -4 alkyl.
  • Embodiment 21 A compound according to any one of the preceding embodiments,
  • Embodiment 212 A compound according to any one of the preceding embodiments,
  • Embodiment 21 A compound according to any one of the preceding embodiments,
  • Embodiment 214 A compound according to any one of the preceding embodiments,
  • R 4 is R ; and R 9 is C 1-4 aikyl.
  • Embodiment 215. A compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of:
  • R 9 is C 1-4 alkyl.
  • Embodiment 216 A compound according to any one of the preceding embodiments,
  • Embodiment 217 A compound according to any one of the receding embodiments,
  • R 4 is ; and R is Ci. 4 alkyl.
  • Embodiment 218 A compound according to any one of the preceding embodiments,
  • R 9 is d. 4 alkyl.
  • Embodiment 219. A compound according to any one of the preceding embodiments,
  • Embodiment 220 A compound according to any one of the preceding embodiments,
  • Embodiment 22 A compound according to any one of the preceding embodiments,
  • R 4 is and R 9 is C -4 alkyl.
  • Embodiment 222 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6 is -(CH 2 ) m -(CO) n -(CH 2 )p-R 6a .
  • Embodiment 22 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6 is -0-R 6a .
  • Embodiment 224 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6a is H, -OH, -NR 7 R 8 , -CN, oxo, d_ 4 alkyl, C 1-4 hydroxyalkyl, -CH(NR 7 R 8 )-d- 3 haloalkyl, -C(CH 3 )(NR 7 R 8 )-C 1 . 3 alkyl, -S0 2 d- 4 alkyl, - S0 2 d. 4 hydroxyalkyl, or -S0 2 NR 7 R 8 .
  • Embodiment 225 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6a is H, -OH, -NR 7 R 8 , -CN, oxo, Ci_ 4 alkyl, -CH(NR 7 R 8 )-d. 3 haloalkyl, -S0 2 d. 4 alkyl, or -S0 2 NR 7 R 8 .
  • Embodiment 226 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6a is H.
  • Embodiment 227 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6a is -OH, -NR 7 R 8 , -CN, or oxo.
  • Embodiment 228 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6a is -OH.
  • Embodiment 229. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6a is -NR 7 R 8 .
  • Embodiment 230 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6a is -CN.
  • Embodiment 231. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6a is oxo.
  • Embodiment 232 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6a is C 1- alkyl or -CH(NR 7 R 8 )-Ci.
  • Embodiment 233 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6a is C -4 alkyl.
  • Embodiment 23 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6a is -CH(NR 7 R 8 )-C . 3 haloalkyl.
  • Embodiment 235 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6a is C 1-4 hydroxyalkyl.
  • Embodiment 236 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6a is -C(CH 3 )(NR 7 R 8 )-C 1 . 3 alkyl.
  • Embodiment 237 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6a is -S0 2 Ci. alkyl or -S0 2 NR 7 R 8 .
  • Embodiment 238 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6a is -S0 2 Ci. 4 alkyl.
  • Embodiment 239. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6a is -S0 2 Ci. 4 hydroxyalkyl.
  • Embodiment 240 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6a is -S0 2 NR 7 R 8 .
  • Embodiment 241. A compound according to any one of the preceding embodiments,
  • Embodiment 242 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6a is H, -OH, -NH 2 , -N(CH 3 ) 2 , - N(CH 2 CH 3 ) 2 , -NHCH 2 CH 2 OH, H , H , -CN, oxo, CH 3 , -CH(NH 2 )CF 3 , -S0 2 CH 3 , or -S0 2 N(CH 3 ) 2 .
  • Embodiment 243 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6 is -(CH 2 ) m -(CO) n -(CH 2 ) p -R 6 .
  • Embodiment 244 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6 is -0-R 6b .
  • Embodiment 245. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6b is a 4-10 membered heterocyclyl optionally substituted with 1 -2 substituents selected from a group consisting of halo, -OH, - NR 7 R 8 , C 1-4 a!kyl, -C ⁇ haloalkyl, -C ⁇ hydroxyaikyl, -C ⁇ alkyl-NR ⁇ 8 , -SOzd ⁇ alkyl, and 4-6 membered heterocyclyl.
  • R 6b is a 4-10 membered heterocyclyl optionally substituted with 1 -2 substituents selected from a group consisting of halo, -OH, - NR 7 R 8 , C 1-4 a!kyl, -C ⁇ haloalkyl, -C ⁇ hydroxyaikyl, -C ⁇ alkyl-NR ⁇ 8 , -SOzd ⁇ alkyl, and 4-6 membere
  • Embodiment 246 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6b is a 4-10 membered heterocyclyl optionally substituted with 1 substituent selected from a group consisting of -NR 7 R 8 , C 1-4 alkyl, - C ⁇ hydroxyalkyl, and -C 1 . alkyl-NR 7 R 8 .
  • R 6b is a 4-10 membered heterocyclyl optionally substituted with 1 -3 substituents independently selected from a group consisting of -NR 7 R 8 , C 1-4 alkyl, -C 1-4 hydroxyalkyl, and -C 1-4 alkyl-NR 7 R 8 .
  • R 4 is -C 6 H 4 -R 6 ;
  • R 6 is -(CH 2 ) m -(CO) n -(CH 2 ) p -R 6b ;
  • R 6b is a 4- 10 membered heterocyclyl optionally substituted with 1 -3 substituents independently selected from a group consisting of -NR 7 R 8 , Ci. 4 alkyl, -C 1 4 hydroxyalkyl, and -Ci. 4 alkyl-NR 7 R 8 .
  • Embodiment 247 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from a group consisting
  • r is 0 or 1 or 2.
  • Embodiment 248 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R ab is selected from a group consisting of:
  • R 0 is selected from a group consisting of -NR 7 R 8 , Ci. 4 alkyl, -C ⁇ hydroxyalkyl, and -d. alkyl- NR 7 R 8 ; and r is O oM .
  • Embodiment 249. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6b is selected from a group consisting of:
  • Embodiment 250 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6b is selected from a group consisting
  • R i o is se
  • Embodiment 251 A compound according to any ng embodiments,
  • R 6b is is selected from a group consisting of halo, -OH, -NR 7 R 8 , C ⁇ alkyl, -C 1-4 haloalkyl, -Ci. hydroxyalkyl, -C 1-4 alkyl- NR 7 R 8 , -S0 2 C 1 . 4 alkyl, and 4-6 membered heterocyclyl; and r is 0 or 1 or 2.
  • Embodiment 252 A compound according to any ng embodiments,
  • R 6b is is selected from a group consisting of -NR 7 R 8 , C 1-4 alkyl, -C ⁇ hydroxyalkyl, and -C . 4 alkyl-NR 7 R 8 ; and r is 0 or 1.
  • Embodiment 253 A compound according to any ne of the preceding embodiments,
  • R 6b is R 10 is selected from a group consisting of halo, -OH, -NR 7 R 8 , Ci. alkyl, -C 1-4 haloalkyl, -C 1-4 hydroxyalkyl, -C 1- alkyl- NR 7 R 8 , -S0 2 Ci_ 4 alkyl, and 4-6 membered heterocyclyl; and r is 0 or 1 or 2.
  • Embodiment 254 A compound according to any one of the preceding
  • R 6b is R 10 is selected from a group consisting of halo, -OH, -NR 7 R 8 , C 1-4 alkyl, -C - haloalkyl, -Ci.
  • Embodiment 255 A compound according to any eding embodiments,
  • R 6b is R is selected from a group consisting of -NR 7 R 8 , C 1-4 alkyi, -Ci. hydroxyalkyl, and -C 1-4 alkyl-NR 7 R 8 ; and r is 0 or 1.
  • Embodiment 256 A compound according to any one of the preceding embodiments,
  • Embodiment 257 A compound according to any one of the receding embodiments,
  • R 6b is R is selected from a group consisting of -NR 7 R 8 , C 1-4 alkyl, -C ⁇ hydroxyalkyl, and -C 1-4 alkyl-NR 7 R 8 ; and r is 0 or 1.
  • Embodiment 258 A compound according to any on of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6b is R 10 is selected from a group consisting of halo, -OH, -NR 7 R 8 , C 1-4 alkyl, -C ⁇ haloalkyl, -C 1-4 hydroxyalkyi, -C 1-4 alkyl- NR 7 R a , -S0 2 Ci- 4 alkyl, and 4-6 membered heterocyclyl; and r is 0 or 1 or 2.
  • Embodiment 259. A compound according to any one f the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6b is R 0 is selected from a group consisting of -NR 7 R 8 , C 1-4 alkyl, -C 1-4 hydroxyalkyl, and -C 1 . alkyl-NR 7 R 8 ; and r is 0 or 1 .
  • Embodiment 260 A compound according to any one of the preceding embodiments,
  • R 6b is and R 10 is selected from a group consisting of -NR 7 R 8 , C 1-4 alkyl, -C 1-4 hydroxyalkyl, and -C 1- alkyl-NR 7 R 8 .
  • Embodiment 26 A compound according to any one of the r ceding embodiments,
  • R 6b is R 10 is selected from a group consisting of -NR 7 R 8 , C 1-4 alkyl, -C V4 hydroxyalkyl, and -C 1-4 alkyl-NR 7 R 8 ; and r is 0 or 1.
  • Embodiment 262 A compound according to any one of the preceding embodiments,
  • R 6 is ( Rl0 )r ;
  • R 10 is selected from a group consisting of halo, -OH, -NR 7 R 8 , -C 1-4 haloalkyl, -C 1-4 hydroxyalkyl, -Ci -4 alkyl- NR 7 R 8 , -S0 2 Ci. 4 alkyl, and 4-6 membered heterocyclyl; and r is 0 or 1 or 2.
  • Embodiment 264 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6b is ⁇ - ⁇ ; R 10 is selected from a group consisting of halo, -OH, -NR 7 R 8 , C 1-4 alkyl, -C 1-4 haloalkyl, -C ⁇
  • Embodiment 265. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6b is is selected from a group consisting of -NR 7 R 8 , C 1-4 alkyl, -Ci. 4 hydroxyalkyl, and -C 1-4 alkyl-NR 7 R 8 ; and r is 0 or 1 .
  • Embodiment 266 A compound according to any ing embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6b is is selected from a group consisting of halo, -OH, -NR 7 R 8 , C 1-4 alkyl, -C ⁇ haloalkyl, -C 1-4 hydroxyalkyl, -C 1- alkyl- NR 7 R 8 , -S0 2 C 1 . 4 alkyl, and 4-6 membered heterocyclyl; and r is 0 or 1 or 2.
  • Embodiment 267 A compound according to any one of the preceding embodiments,
  • R 6b is >--0 ;
  • R 10 is selected from a group consisting of -NR 7 R 8 , C 1-4 alkyl, -C ⁇ hydroxyalkyl, and -C 1-4 alkyl-NR 7 R 8 ; and r is 0 or 1 .
  • Embodiment 268 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6b is and R 10 is selected from a group consisting of halo, -OH, -NR 7 R 8 , Ci. 4 alkyl, -Ci -4 haloalkyl, -C ⁇ hydroxya!kyl, -Ci. 4 alkyl- NR 7 R 8 , -S0 2 C 1 . 4 alkyl, and 4-6 membered heterocyclyl.
  • R 6b is and R 10 is selected from a group consisting of -NR 7 R 8 , C 1-4 aSkyl, -C 1-4 hydroxyalkyl, and -C 1-4 alkyl-NR 7 R 8 .
  • Embodiment 270 A compound according to any one of the preceding embodiments,
  • R 6b is v-NH .
  • R io ig se j ec ec j from a group consisting of -NR 7 R 8 , C 1-4 alkyl, -C ⁇ hydroxyalkyl, and -C 1 . 4 alkyl-NR 7 R 8 ; and r is 0 or 1.
  • Embodiment 27 A compound according to any ing embodiments,
  • R 6 is ; and R 10 is selected from a group consisting of -NR 7 R 8 , C 1- alkyl, -C 1-4 hydroxyalkyl, and -C 1-4 alkyl-NR 7 R 8 .
  • Embodiment 272 A compound according to any g embodiments,
  • R 6B is 0 is selected from a group consisting of halo, -OH, -NR 7 R 8 , C 1-4 alkyl, -C 1 . 4 haloalkyl, -Ci. 4 hydroxyalkyl, -d. 4 alkyl-NR 7 R 8 , -S0 2 C 1 4 alkyl, and 4-6 membered heterocyclyl; and r is 0 or 1 or 2.
  • Embodiment 273. A compound according to any ng embodiments,
  • R 6b iiss is selected from a group consisting of halo, -OH, -NR 7 R 8 , C 1- alkyl, -C ⁇ haloalkyl, -C 1-4 hydroxyalkyl, -C 1-4 aikyl- NR 7 R 8 , -S0 2 C 1-4 alkyl, and 4-6 membered heterocyclyl; and r is 0 or 1 or 2.
  • Embodiment 274 A compound according to any ng embodiments,
  • R 6b is R 10 is selected from a group consisting of halo, -OH, -NR 7 R 8 , C 1 . 4 alkyl, -d. 4 haloalkyl, -d. 4 hydroxyalkyl, -d-
  • Embodiment 275 A compound according to any one of the preceding embodiments,
  • R 6b is -0 ;
  • R 10 j s selected from a group consisting of halo, -OH, -NR 7 R 8 , C 1-4 alkyi, -d- 4 haloalkyl, -C 1-4 hydroxyalkyl, -Ci -4 aSkyl- NR 7 R 8 , -S0 2 C 1 . 4 alkyl, and 4-6 membered heterocyclyl; and r is 0 or 1 or 2.
  • Embodiment 276 A compound according to any one of the preceding embodiments,
  • R 6 is R 10 is selected from a group consisting of halo, -OH, -NR 7 R 8 , C 1-4 alkyl, -C 1-4 haloalkyl, -C 1 . 4 hydroxyalkyl, -Ci. 4 alkyl-NR 7 R 8 , -S0 2 C 1 . 4 alkyl, and 4-6 membered heterocyclyl; and r is 0 or 1 or 2.
  • Embodiment 277 A compound according to any eding embodiments,
  • R 6b is R 10 is selected from a group consisting of halo, -OH, -NR 7 R 8 , C -4 alkyl, -d- haloalkyl, -C 1- hydroxyalkyl, -d- alkyl- NR 7 R 8 , -S0 2 C 1-4 alkyl, and 4-6 membered heterocyclyl; and r is 0 or 1 or 2.
  • Embodiment 278 A compound according to any one of the preceding embodiments,
  • R 6 is R 10 is selected from a group consisting of halo, -OH, -NR 7 R 8 , C 1-4 alkyl, -C 1-4 haloalkyl, -C ⁇ hydroxyalkyl, -d- 4 alkyl-NR 7 R 8 , and 4-6 membered heterocyclyl; and r is 0 or 1 or 2.
  • Embodiment 279. A compound according to any one of the receding embodiments,
  • Embodiment 280 A compound according to any one of the r ceding embodiments,
  • R 6b is R 10 is selected from a group consisting of halo, -OH, -NR 7 R 8 , Ci_ alkyl, -C 1-4 haloalkyl, -d ⁇ hydroxyalkyl, -d. 4 alkyl-NR 7 R 8 , -S0 2 C 1 . alkyl, and 4-6 membered heterocyclyl; and r is 0 or 1 or 2.
  • Embodiment 28 A compound according to any ne of the preceding embodiments,
  • R 6b is R 10 is selected from a group consisting of halo, -OH , -NR 7 R 8 , d- 4 alkyl, -C 1-4 haloalkyl, -d. 4 hydroxyalkyl, -d- alkyl-NR 7 R 8 , -S0 2 C 1-4 alkyl, and 4-6 membered heterocyclyl; and r is 0 or 1 or 2.
  • Embodiment 282. A compound according to any one of the preceding embodiments,
  • R 6b is v-NH .
  • p i o is se !ected from a group consisting of halo, -OH, -NR 7 R 8 , d. 4 alkyl, -C 1-4 haloalkyl, -d ⁇ hydroxyalkyl, -d- 4 alkyl-NR 7 R 8 , -S0 2 C 1 . 4 alkyl, and 4-6 membered heterocyclyl; and r is 0 or 1 or 2.
  • Embodiment 283. A compound according to any one of the receding embodiments,
  • R 6b is ;
  • R 10 is selected from a group consisting of halo, -OH, -NR 7 R 8 , Ci. 4 alkyl, -C 1-4 haloalkyl, -C -4 hydroxyalkyl, -C 1- alkyl- NR 7 R 8 , -S0 2 Cv alkyl, and 4-6 membered heterocyclyl; and r is 0 or 1 or 2.
  • Embodiment 284 A compound according to any ing embodiments,
  • R 6B is 0 j S selected from a group consisting of halo, -OH, -NR 7 R 8 , C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 hydroxyalkyl, -CL 4 alkyl-NR 7 R 8 , -S0 2 C 1 . 4 alkyl, and 4-6 membered heterocyclyl; and r is 0 or 1 or 2.
  • NR 7 R 8 -S0 2 C 1 . 4 alkyl, and 4-6 membered heterocyclyl; and r is 0 or 1 or 2.
  • Embodiment 286 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6b is selected from a group consisting
  • Embodiment 287 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6b is selected from a group consisting
  • Embodiment 288 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6b is selected from a group consisting
  • Embodiment 289. A compound according to any ding embodiments,
  • Embodiment 290 A compound according to any ing embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6b is
  • Embodiment 29 A compound according to any ding embodiments,
  • Embodiment 292. A compound according to any one of the preceding embodiments,
  • Embodiment 293. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6 is -(CH 2 ) m -(CO) n -(CH 2 )p-R 6c .
  • Embodiment 294 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6 is -0-R 6c .
  • Embodiment 295. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6c is a 5 membered heteroaryl optionally substituted with 1 substituent selected from a group consisting of -NR 7 R 8 , C 1-4 alkyl, -d.
  • Embodiment 296 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6c is selected from a group consisting
  • s is 0 or 1.
  • Embodiment 297 A compound according to any ceding embodiments,
  • R 6c is ;
  • R 11 is selected from a group consisting of -NR 7 R 8 , C 1-4 alkyl, -Ci. 4 hydroxyalkyl, and -Ci. alkyl-NR 7 R 8 .
  • Embodiment 298 A compound according to any receding embodiments,
  • Embodiment 299. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6 is -(CH 2 ) m -(CO) n -(CH 2 ) p -R 6d .
  • Embodiment 300 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6 is -0-R 6d .
  • R 6d is R 14 is selected from a group consisting of halo, -OH, -NR 7 R 8 , C 1-4 alkyl, -C -4 haloalkyl, -C . 4 hydroxyalkyl, -C 1-4 aikyl- NR 7 R 8 , -S0 2 C 1 . alkyl, and 4-6 membered heterocyclyl; and t is 0 or 1 or 2.
  • Embodiment 301 A compound according to any one of the preceding
  • R 4 is selected from a group consisting of:
  • Embodiment 303 A compound according to any one of the preceding embodiments, of:
  • Embodiment 304 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a group consisting of: embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a
  • Embodiment 305 A compound according to any one of the preceding embodiments,
  • Embodiment 306. A compound according to any bodiments,
  • Embodiment 307. A compound according to any one of the preceding embodiments,
  • Embodiment 308 A compound according to any one of the preceding embodiments,
  • Embodiment 309 A compound according to any bodiments,
  • Embodiment 310 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 5 is H.
  • Embodiment 31 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 together with the carbon atoms to which they are attached form a 5-12 membered carbocyclic, heterocyclic, aryl, heteroaryl, fused heterocyclyl-aryl, fused heterocyclyl-heteroaryl , fused carbocyclyl-aryl, or fused carbocyclyl-heteroaryl ring, wherein said carbocyclic, heterocyclic, aryl, heteroaryl, fused heterocyclyl-aryl, fused heterocyclyl-heteroaryl, fused carbocyclyl-aryl, or fused carbocyclyl- heteroaryl ring is optionally substituted with 1 -3 C . 4 alkyl groups.
  • Embodiment 312 A compound according to any one of the preceding
  • R 4 and R 5 together with the carbon atoms to which they are attached form a 5-12 membered carbocyclic ring, wherein said carbocyclic ring is optionally substituted with 1 -3 C 1- alkyl groups.
  • Embodiment 31 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 together with the carbon atoms to which they are attached form a 5-12 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with 1 -3 C 1-4 alkyl groups.
  • Embodiment 31 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 together with the carbon atoms to which they are attached form a 5-12 membered aryl ring, wherein said aryl ring is optionally substituted with 1 -3 C 1-4 alkyl groups.
  • Embodiment 315 A compound according to any one of the preceding
  • R 4 and R 5 together with the carbon atoms to which they are attached form a 5-12 membered heteroaryl ring, wherein said heteroaryl ring is optionally substituted with 1-3 Ci_ 4 alkyl groups.
  • Embodiment 316 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 together with the carbon atoms to which they are attached form a 5-12 membered fused heterocyclyl-aryl ring, wherein said fused heterocyclyl-aryl ring is optionally substituted with 1-3 C 1-4 alkyl groups.
  • Embodiment 317 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 together with the carbon atoms to which they are attached form a 5-12 membered fused heterocyclyl-heteroaryl ring, wherein said fused heterocyclyl-heteroaryl ring is optionally substituted with 1 -3 d. alkyl groups.
  • Embodiment 318 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 together with the carbon atoms to which they are attached form a 5-12 membered fused carbocyclyl-aryl ring, wherein said fused carbocyclyl-aryl ring is optionally substituted with 1-3 C h alky I groups.
  • Embodiment 319 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 together with the carbon atoms to which they are attached form a 5-12 membered fused carbocyclyl-heteroaryl ring, wherein said fused carbocyclyl-heteroaryl ring is optionally substituted with 1 -3 C 1 alkyl groups.
  • Embodiment 320 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 together with the carbon
  • Embodiment 32 A compound according to any one of the preceding
  • Embodiment 32 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 together with the carbon
  • Embodiment 32 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 together with the carbon
  • Embodiment 324 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 together with the carbon
  • * is the carbon atom bearing R 4 , and the carbon atom designated ** is the carbon atom bearing R 5 ; wherein Y is CH 2 , O, NR 13 , or S; R 12 is C 1-4 alkyS; and R 13 is H or C 1-4 aSkyl.
  • Embodiment 325 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 together with the carbon
  • Embodiment 326 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 together with the carbon
  • Embodiment 327 A compound according to any one of the preceding
  • Embodiment 328 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 together with the carbon
  • Embodiment 329 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 together with the carbon * is the carbon atom bearing R 4 , and the carbon atom designated ** is the carbon atom bearing R 5 ; wherein R 12 is C 1-4 alkyl.
  • Embodiment 330 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 together with the carbon
  • Embodiment 331 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 together with the carbon
  • Embodiment 332 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from a group consisting of H, C 1-4 alkyl, C 1-4 hydroxyalkyl, a 4-6 membered heterocyclyl, and a 4-6 membered cycloalkyl.
  • Embodiment 333 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from a group consisting of H, d ⁇ alkyl, C ⁇ hydroxya!kyl, 2-oxetanyl, 3-oxetanyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2- tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-azetidinyl, 3-azetidinyl, 2- pyrrolidinyl, 3-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-morpholinyl, 3-morpholinyl, 2-piperazinyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • R 7 is selected from a group consisting of H, d ⁇ alkyl, C ⁇ hydroxya!kyl, 2-
  • Embodiment 334 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from a group consisting of H, Ci -4 alkyl, C ⁇ hydroxyalkyl, 3-oxetanyl, and cyclobutyl.
  • Embodiment 335 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 7 is H.
  • Embodiment 336 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 7 is Ci. 4 alkyl.
  • Embodiment 337 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 7 is CH 3 .
  • Embodiment 338 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 7 is CH 2 CH 3 .
  • Embodiment 339 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 7 is Ci_ 4 hydroxyalkyl.
  • Embodiment 340 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 7 is CH 2 CH 2 OH.
  • Embodiment 34 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 7 is CH 2 C(CH 3 ) 2 OH.
  • Embodiment 342 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 7 is a 4-6 membered heterocyclyl.
  • Embodiment 343 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 7 is 2-oxetanyl, 3-oxetanyl, 2- tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4- tetrahydropyranyl, 2-azetidinyl, 3-azetidinyl, 2- pyrrolidinyl, 3-pyrrolidinyl, 2-piperidinyl, 3- piperidinyl, 4-piperidinyl, 2-morpholinyl, 3-morpholinyl, or 2-piperazinyl.
  • Embodiment 344 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 7 is 3-oxetanyl.
  • Embodiment 345 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 7 is 3-azetidinyl.
  • Embodiment 346 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 7 is a 4-6 membered cycloalkyl.
  • Embodiment 347 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 7 is cyclobutyl, cyclopentyl, or cyclohexyl.
  • Embodiment 348 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 7 is cyclobutyl.
  • Embodiment 349 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from a group consisting of H, C 1 . 4 alkyl, Ci_ 4 hydroxyalkyl, a 4-6 membered heterocyclyl, and a 4-6 membered cycloalkyl.
  • Embodiment 350 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from a group consisting of H, Ci_ 4 alkyl, C -4 hydroxyalkyl, 2-oxetanyl, 3-oxetanyl, 2-tetra hyd rof u ra nyl , 3-tetrahydrofuranyl, 2- tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-azetidinyl, 3-azetidinyl, 2- pyrrolidinyl, 3-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-morpholinyl, 3-morpholinyl, 2-piperazinyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • R 8 is selected from a group consisting of H, Ci_ 4 al
  • Embodiment 35 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from a group consisting of H, C 1-4 alkyl, C 1-4 hydroxyalkyl, 3-oxetanyl, and cyclobutyl.
  • Embodiment 352 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 8 is H.
  • Embodiment 353 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 8 is C ⁇ alkyl.
  • Embodiment 354 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 8 is CH 3 .
  • Embodiment 355. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 8 is CH 2 CH 3 .
  • Embodiment 356 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 8 is C ⁇ hydroxyalkyl.
  • Embodiment 357 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 8 is CH 2 CH 2 OH.
  • Embodiment 358 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 8 is CH 2 C(CH 3 )20H.
  • Embodiment 359. A compound according to any one of the preceding
  • R 8 is a 4-6 membered heterocyclyl
  • Embodiment 360 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 8 is 2-oxetanyl, 3-oxetanyl, 2- tetrahydrofuranyl, 3-tetrahydrofuranyl, 2 -tetrahydropyranyl, 3-tetra hyd ropyra ny 1 , 4- tetrahydropyranyl, 2-azetidinyl, 3-azetidinyl, 2- pyrrolidinyl, 3-pyrrolidinyl, 2-piperidinyl, 3- piperidinyl, 4-piperidinyl, 2-morpholinyl, 3-morpholinyl, or 2-pipera7inyl.
  • Embodiment 36 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 8 is 3-oxetanyl.
  • Embodiment A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 8 is 3-azetidinyl.
  • Embodiment 362. A compound according to any one of the preceding
  • R 8 is a 4-6 membered cycloalkyl.
  • Embodiment 363 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 8 is cyclobutyl, cyclopentyl, or cyclohexyl.
  • Embodiment 364 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 8 is cyclobutyl.
  • Embodiment 365 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 9 is CH 3 .
  • Embodiment 366 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from a group consisting of F, -OH, -NR 7 R 8 , CH 3 , C(CH 3 ) 3 , CF 3 , -CH 2 OH, -CH 2 CH 2 OH, -C(CH 3 ) 2 OH, -CH 2 NR 7 R 8 , -S0 2 CH 3 , and 3-oxetanyl.
  • R 10 is selected from a group consisting of F, -OH, -NR 7 R 8 , CH 3 , C(CH 3 ) 3 , CF 3 , -CH 2 OH, -CH 2 CH 2 OH, -C(CH 3 ) 2 OH, -CH 2 NR 7 R 8 , -S0 2 CH 3 , and 3-oxetanyl.
  • Embodiment 367 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from a group consisting of -NR 7 R 8 , CH 3 , -CH 2 OH, and -CH 2 NR 7 R 8 .
  • Embodiment 368 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 10 is halo.
  • Embodiment 369 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 10 is F.
  • Embodiment 370 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 10 is -OH.
  • Embodiment 371. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 10 is -NR 7 R 8 .
  • Embodiment 372 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 10 is Ci -4 alkyl.
  • Embodiment 373 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 10 is CH 3 .
  • Embodiment 374 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 10 is C(CH 3 ) 3 .
  • Embodiment 375 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 10 is C 1-4 haloalkyl.
  • Embodiment 376 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 10 is CF 3 .
  • Embodiment 377 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 10 is C ⁇ hydroxyalk l.
  • Embodiment 378 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 10 is CH 2 OH.
  • Embodiment 379 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 10 is -CH 2 CH 2 OH.
  • Embodiment 380 A compound according to any one of the preceding
  • Embodiment 381 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 10 is -Ci. 4 alkyl-NR 7 R 8 .
  • Embodiment 382 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 10 is -CH 2 NR 7 R 8 .
  • Embodiment 383 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 11 is C 1-4 alkyl.
  • Embodiment 384 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 10 is -S0 2 C 1 . alkyl.
  • Embodiment 385 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 10 is -S0 2 CH 3 .
  • Embodiment 386 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 10 is 4-6 membered heterocyclyl.
  • Embodiment 387 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 10 is 3-oxetanyl.
  • Embodiment 388 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 11 is CH 3 .
  • Embodiment 389 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 14 is OH.
  • Embodiment 390 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein m is 0.
  • Embodiment 391 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein m is 1.
  • Embodiment 392 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein n is 0.
  • Embodiment 393 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein n is 1.
  • Embodiment 394 A compound according to any one of the preceding
  • Embodiment 395 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein p is 1 .
  • Embodiment 396 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein q is 0.
  • Embodiment 397 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein q is 1 .
  • Embodiment 398 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein q is 2.
  • Embodiment 399 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein q is 3.
  • Embodiment 400 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein r is 0.
  • Embodiment 401 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein r is 1.
  • Embodiment 402. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein r is 2.
  • Embodiment 403. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein s is 0.
  • Embodiment 404 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein s is 1 .
  • Embodiment 405. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein f is 0.
  • Embodiment 406 A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein t is 1.
  • Embodiment 407. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein t is 2.
  • Embodiment 408 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from a group consisting of:
  • [00551] 1 -(4-((4'-((2-oxa-6-azaspiro[3.3]heptan-6-yl)meihyl)-[1 ,1 '-biphenyl]-4- yl)methyl)phenyl)-5-methyl-1 H-1 ,2,4-triazole-3-carboxamide; [00552] 1-(4-((4 , -((2-(hydroxymethyl)pyrrolidin-1-yl)methyl)-[1,r-biphenyl]-4- yl)methyl)phenyl)-5-methyl-1 H-1 ,2,4-triazole-3-carboxamide;
  • [00615] 1 -(4-(4-(4-(4-(2-hydroxypropan-2-yl)piperidin-1 -yl)benzyl)phenyl)-5-methyl-1 H-1 ,2,4- triazole-3-carboxamide; [00616] 1-(4-((4 N-(2-hydroxy-2-meihylpropyl)sulfamoylH1 ,1'-biphenyl]-4-yi)methyl)phenyl)- 5-methyl-1 H-1 ,2,4-triazole-3-carboxamide;
  • Embodiment 409 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from a group consisting of.
  • [00666] 1 -(4-(2-(4-(2-aminopyridin-4-yl)phenyl)propan-2-yl)phenyl)-5-methy!-1 H-pyrazole-3- carboxamide; [00667] 5-methyl-1 -(4-(2-(4'-(5-methyl-1 ,3,4-oxadiazol-2-yl)-[1 ,1 '-biphenyl]-4-yl)propan-2- yl)phenyl)-1 H-pyrazole-3-carboxamide;
  • Embodiment 410 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 1 -(4-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5- methyl-1 H-1 ,2,4-triazole-3-carboxamide.
  • Embodiment 41 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 1 -(4-((6H-benzo[c]chromen-3- yl)methyl)phenyl)-5-methyl-1 H-pyrazole-3-carboxamide.
  • Embodiment 412 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 5-methyl-1 -(4-((4'-(pyrrolidin-1 -ylmethyl)-[1 ,1 '- biphenyl]-4-yl)methyl)phenyl)-1 H-pyrazole-3-carboxamide.
  • Embodiment 413 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 1 -(4-((4'-((diethylamino)methyl)-[1 ,1 '- biphenyl]-4-yl)methyl)phenyl)-5-methyl-1 H-pyrazole-3-carboxamide.
  • Embodiment 414 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 5-methyl-1 -(4-(4-(2-methyl-1 ,2,3,4- tetrahydroisoquinolin-6-yl)benzyl)phenyl)-1 H-pyrazole-3-carboxamide.
  • Embodiment 415 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 1 -(4-(4-(isoindolin-5-yl)benzyl)phenyl)-5- methyl-1 H-pyrazole-3-carboxamide.
  • Embodiment 416 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 5-methyl-1-(4-(4-(pyridin-4-yl)benzyl)phenyl)- 1 H-pyrazole-3-carboxamide.
  • Embodiment 417 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 5-methyl-1 -(4-((4'-(methylsulfonyl)-[1 , 1 '- biphenyl]-4-yl)methyl)phenyl)-1 H-pyrazole-3-carboxamide.
  • Embodiment 418 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 5-methyl-1-(4-((3'-(5-methyl-1 ,3,4-oxadiazol-2- y!)-[1 ,1'-biphenyl]-4-y!methyl)phenyl)-1 H-pyrazole-3-carboxamide.
  • Embodiment 419 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 1-(4-([1 ,1 '-biphenyl]-4-ylmethyl)phenyl)-5- methyl-1 H-pyrazole-3-carboxamide.
  • Embodiment 420 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 5-methyl-1 -(4-((4'-(5-methyl-1 ,3,4-oxadiazol-2- yl)-[1 ,1'-biphenyl]-4-yl)methyl)phenyl)-1 H-pyrazole-3-carboxamide.
  • Fmbodiment 4?1 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 5-methyl-1-(4-(4-(pyridin-3-yl)benzyl)phenyl)- 1 H-pyrazole-3-carboxamide.
  • Embodiment 422. A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 1 -(4-(4-(1 -(dimethylglycyl)-l ,2,3,6- tetrahydropyridin-4-yl)benzyl)phenyl)-5-methyl-1 H-pyrazole-3-carboxamide.
  • Embodiment 423 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 5-methyl-1 -(4-((4'-((4-methylpiperazin-1 - yl)methyl)-[1 , 1 '-biphenyl]-4-yl)methyl)phenyl)-1 H-pyrazole-3-carboxamide.
  • Embodiment 424 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 5-methyl-1-(4-(4-(2-methylisoindolin-5- yl)benzyl)phenyl)-1 H-pyrazole-3-carboxamide.
  • Embodiment 425 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 5-methyl-1 -(4-(4-(1 ,2,3,4- tetrahydroisoquinolin-6-yl)benzyl)phenyl)-1 H-pyrazole-3-carboxamide.
  • Embodiment 426 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 5-methyl-1 -(4-(4-(1-methyl-1 ,2,3,6- tetrahydropyridin-4-yl)benzyl)phenyl)-1 H-pyrazole-3-carboxamide.
  • Embodiment 427 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 5-methyl-1 -(4-(4-(1-methylpiperidin-4- yl)benzyl)phenyl)-1 H-pyrazole-3-carboxamide.
  • Embodiment 428 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 5-methyl-1-(4-(4-(1 -methylpyrrolidin-3- yl)benzyl)phenyl)-1 H-pyrazole-3-carboxamide.
  • Embodiment 429 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is (R)-5-methyl-1 -(4-(4-(1 -methylpyrrolidin-3- yl)benzyl)phenyl)-1 H-pyrazole-3-carboxamide.
  • Embodiment 430 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is (S)-5-methyl-1-(4-(4-(1 -methylpyrrolidin-3- yl)benzyl)phenyl)-1 H-pyrazole-3-carboxamide.
  • Embodiment 431 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 1 -(4-(4-(6-((dimethylamino)methyl)pyridin-3- yl)benzyl)phenyl)-5-methyl-1 H-pyrazole-3-carboxamide.
  • Embodiment 432 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 1 -(4-(4-(2-((dimethylamino)methyl)pyridin-4- yl)benzyl)phenyl)-5-methyl-1 H-pyrazole-3-carboxamide.
  • Embodiment 433 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 5-methyl-1 -(4-(4-(6-(pyrrolidin-1 - ylmethyl)pyridin-3-yl)benzyl)phenyl)-1 H-pyrazole-3-carboxamide.
  • Embodiment 434 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 1 -(4-(4-(5-((dimethylamino)methyl)pyridin-3- yl)benzyl)phenyl)-5-methyl-1 H-pyrazole-3-carboxamide.
  • Embodiment 435 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 5-methyl-1 -(4-(4-(1-methyl-2,3,6,7-tetrahydro-
  • Embodiment 436 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 5-methyl-1-(4-((4'-(1-methylpyrrolidin-2-yl)- [1 ,1 '-biphenyl]-4-yl)methyl)phenyl)-1 H-pyrazole-3-carboxamide.
  • Embodiment 437 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is (R)-5-methyl-1-(4-((4'-(1 -methylpyrrolidin-2- yl)-[1 , 1 '-biphenyl]-4-yl)methyl)phenyl)-1 H-pyrazole-3-carboxamide.
  • Embodiment 438 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is (S)-5-methyl-1 -(4-((4'-(1 -methylpyrrolidin-2-yl)- [1 ,1 '-biphenyl]-4-yl)methyl)phenyl)-1 H-pyrazole-3-carboxamide.
  • Embodiment 439 A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 5-methyl-1 -(4-(2-(4'-(pyrrolidin-1-ylmethyl)- [1 ,1 '-biphenyl]-4-yl)propan-2-yl)phenyl)-1 H-pyrazole-3-carboxamide.

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