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WO2024233563A1 - Amides bicycliques fusionnés en 6,6 et compositions destinées à être utilisées en tant que modulateurs de la 15-prostaglandine déshydrogénase - Google Patents

Amides bicycliques fusionnés en 6,6 et compositions destinées à être utilisées en tant que modulateurs de la 15-prostaglandine déshydrogénase Download PDF

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Publication number
WO2024233563A1
WO2024233563A1 PCT/US2024/028178 US2024028178W WO2024233563A1 WO 2024233563 A1 WO2024233563 A1 WO 2024233563A1 US 2024028178 W US2024028178 W US 2024028178W WO 2024233563 A1 WO2024233563 A1 WO 2024233563A1
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Prior art keywords
methyl
quinoxalinyl
piperidinyl
compound
several embodiments
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PCT/US2024/028178
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English (en)
Inventor
Kevin Lloyd Greenman
Hui-Ling Wang
Nicholas Anthony WEIRES
John G. Allen
Albert K. AMEGADZIE
Matthew P. Bourbeau
Kexue Li
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Amgen Inc
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Amgen Inc
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Priority to AU2024267728A priority Critical patent/AU2024267728A1/en
Publication of WO2024233563A1 publication Critical patent/WO2024233563A1/fr
Priority to MX2025013367A priority patent/MX2025013367A/es
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • 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

Definitions

  • Short-chain dehydrogenases are a family of dehydrogenases that are involved in synthesis and degradation of fatty acids, steroids, and some prostaglandins. They are therefore implicated in a variety of disorders such as lipid storage disease, myopathy, SCD deficiency, and certain genetic disorders.
  • the SCD 15-hydroxy-prostaglandin dehydrogenase (15-PGDH) (also identified as 15- prostaglandin dehydrogenase or hydroxyprostaglandin dehydrogenase 15-(nicotinamide adeninedinucleotide)), represents a key enzyme in the inactivation of a number of active prostaglandins, leukotrienes and hydroxyeicosatetraenoic acids (HETEs). Recent studies suggest that inhibitors of 15- PGDH and activators of 15-PGDH could be therapeutically valuable. 15-PGDH is responsible for the inactivation of prostaglandin E2 (PGE2), which is a downstream product of cyclooxygenase-2 (COX-2) metabolism.
  • PGE2 prostaglandin E2
  • COX-2 cyclooxygenase-2
  • PGE2 has been shown to be beneficial in a variety of biological processes, such as hair density, dermal wound healing, and bone formation.
  • SUMMARY [0004] Several embodiments disclosed herein provide novel compounds. In several embodiments, these compounds comprise an amido-6,6-fused bicyclic heteroaryl ring system as a core (see, e.g., Formula (I)). In several embodiments, the compounds disclosed herein are useful in modulating SCD and, more specifically, in modulating the activity of and/or in inhibiting the activity of 15-PDGH. In several embodiments, these 15-PGDH inhibiting compounds are useful in modulating tissue prostaglandin levels and treating diseases, disorders, or conditions that are related to 15-PGDH activity.
  • the compounds disclosed herein can be administered to a subject in an amount effective to inhibit the activity of a 15-PGDH and/or to treat a 15-PGDH mediated disease, disorder, or condition.
  • R 1a is H, C 1-6 alkyl, C 1-6 heteroalkyl, or C 1-6 haloalkyl. In several embodiments, R 1a is C 1-6 alkyl, C 1-6 heteroalkyl, or C 1-6 haloalkyl. In several embodiments, R 1a is -H, C 1-6 alkyl or C 1-6 haloalkyl. In several embodiments, R 1a is -H. In several embodiments, R 1a is C 1-6 alkyl. In several embodiments, R 1a is C 1-3 alkyl. In several embodiments, R 1a is C 1-6 haloalkyl.
  • R 1a is C 1-3 haloalkyl.
  • R 1a may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, –OH, -CN, C 1-4 alkoxy, -NH 2 , C 1-4 alkylamino, or diC 1- 4 alkylamino.
  • each substituent of R 1a independently is halogen, –OH, or C 1- 4 alkoxy.
  • each substituent of R 1a independently is halogen or C 1-4 alkoxy.
  • the R 1a halogen substituent is -F or -Cl.
  • the R 1a halogen substituent is -F. In several embodiments, when R 1a is substituted, it is substituted with one substituent. In several embodiments, when R 1a is substituted, it is substituted with two substituents. In several embodiments, when R 1a is substituted, it is substituted with three substituents. In several embodiments, when R 1a is substituted, it is substituted with four substituents. In several embodiments, when R 1a is substituted, it is substituted with one to two substituents. In several embodiments, when R 1a is substituted, it is substituted with one to three substituents. In several embodiments, when R 1a is substituted, it is substituted with one to four substituents.
  • R 1a is unsubstituted.
  • R 1b is C 1-6 alkyl, C 1-6 alkoxy, C 1-6 heteroalkyl, C 3-7 cycloalkyl, heterocyclyl with 3 to 10 ring members, C 6-10 aryl, heteroaryl having 5 to 10 ring members, C 1-6 alkylene- C 3-7 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heterocyclyl with 3 to 7 ring members, or C 1-6 alkylene-heteroaryl with 5 to 10 ring members.
  • R 1b is C 1-3 alkyl, C 1-3 alkoxy, C 1- 3 heteroalkyl, C 3-7 cycloalkyl, heterocyclyl with 3 to 10 ring members, C 6-10 aryl, heteroaryl having 5 to 10 ring members, C 1-6 alkylene-C 3-7 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, C 1-6 alkylene-heterocyclyl with 3 to 7 ring members, or C 1-6 alkylene-heteroaryl with 5 to 10 ring members.
  • R 1b is C 1-6 alkyl, C 1-6 alkoxy, C 1-6 heteroalkyl, C 3-7 cycloalkyl, C 6-10 aryl, C 1-6 alkylene-C 3-7 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, or C 1-6 alkylene-heterocyclyl with 3 to 7 ring members.
  • R 1b is C 1-6 alkyl, C 1-6 alkoxy, C 1-6 heteroalkyl, C 3-7 cycloalkyl, C 6-10 aryl, C 1-6 alkylene-C 3-7 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, or C 1-6 alkylene-heterocyclyl with 3 to 7 ring members.
  • R 1b is C 1-4 alkyl.
  • R 1b is C 1-3 alkoxy.
  • R 1b is C 1-4 heteroalkyl.
  • R 1b is C 3-6 cycloalkyl.
  • R 1b is C 6-10 aryl.
  • R 1b is C 1-3 alkylene-C 3-6 cycloalkyl. In several embodiments, R 1b is C 1-3 alkylene-C 6-10 aryl. In several embodiments, R 1b is C 1-3 alkylene-heterocyclyl with 3 to 6 ring members. [0009] In several embodiments, R 1b may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, –OH, -CN, C 1-6 alkoxy, -NH 2 , C 1-4 alkylamino, or di C 1-4 alkylamino.
  • R 1b may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, -NH 2 , or C1-3 alkoxy.
  • the halogen is -F.
  • R lb when R lb is substituted, it is substituted with one substituent.
  • R lb when R lb is substituted, it is substituted with two substituents.
  • R lb when R lb is substituted, it is substituted with three substituents.
  • R lb when R lb is substituted, it is substituted with four substituents.
  • R lb when R lb is substituted, it is substituted with one to two substituents. In several embodiments, when R lb is substituted, it is substituted with one to three substituents. In several embodiments, when R lb is substituted, it is substituted with one to four substituents. In several embodiments, R lb is unsubstituted.
  • R la and R lb together form a heterocyclyl with 3 to 20 ring members or heteroaryl with 5 to 20 ring members. In several embodiments, R la and R lb together form a heterocyclyl with 3 to 10 ring members or heteroaryl with 5 to 10 ring members. In several embodiments, R la and R lb together form a heterocyclyl with 3 to 10 ring members. In several embodiments, R la and R lb together form a heterocyclyl with 10 ring members. In several embodiments, R la and R lb together form a heterocyclyl with 9 ring members.
  • R la and R lb together form a heterocyclyl when R la and R lb together form a heterocyclyl, it is substituted with one R 4 group. In several embodiments, when R la and R lb together form a heterocyclyl, it is substituted with two R 4 groups. In several embodiments, when R la and R lb together form a heterocyclyl, it is substituted with three R 4 groups. In several embodiments, when R la and R lb together form a heterocyclyl, it is substituted with four R 4 groups. In several embodiments, when R la and R lb together form a heterocyclyl, it is substituted with one to two R 4 groups.
  • R la and R lb together form a heterocyclyl when R la and R lb together form a heterocyclyl, it is substituted with one to three R 4 groups. In several embodiments, when R la and R lb together form a heterocyclyl, it is substituted with one to four R 4 groups. In several embodiments, when R la and R lb together form a heterocyclyl, it is unsubstituted.
  • each instance of R 4 independently is halogen, oxo, OH, -NH2, CM alkyl, C 1.6 heteroalkyl, Ci-6 alkoxy, C1.4 alkylamino, di CM alkylamino, Ci-ealkylene-OH, or CM haloalkyl.
  • each instance of R 4 independently is halogen, -OH, -NH 2 , CM alkyl, CM heteroalkyl, CM alkoxy, or Ci-ehaloalkyl.
  • each instance of R 4 independently is halogen, -OH, -NH 2 , CM alkyl, CM heteroalkyl, CM alkoxy, or CM haloalkyl.
  • R 4 is halogen.
  • R 4 is -F.
  • R 4 is -OH.
  • R 4 is -NH 2 .
  • R 4 is CM alkyl.
  • R 4 is CM heteroalkyl.
  • R 4 is CM alkoxy.
  • R 4 is C 1-3 haloalkyl.
  • each instance of R 4 may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, CM alkoxy, -NH 2 , CM alkylamino, or di CM alkylamino. In several embodiments, each instance of R 4 may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, –OH, C 1-3 alkoxy, -NH 2 , C 1-2 alkylamino, or di C 1-2 alkylamino. In several embodiments, at least an instance of R 4 is halogen.
  • the halogen when R 4 is substituted with a halogen, the halogen is -F. In several embodiments, at least an instance of R 4 is –OH. In several embodiments, at least an instance of R 4 is C 1-3 alkoxy. In several embodiments, at least an instance of R 4 is -NH 2 . In several embodiments, at least an instance of R 4 is C 1-2 alkylamino. In several embodiments, at least an instance of R 4 is di C 1-2 alkylamino. In several embodiments, when R 4 is substituted, it is substituted with one substituent. In several embodiments, when R 4 is substituted, it is substituted with two substituents.
  • R 4 when R 4 is substituted, it is substituted with three substituents. In several embodiments, when R 4 is substituted, it is substituted with four substituents. In several embodiments, when R 4 is substituted, it is substituted with one to two substituents. In several embodiments, when R 4 is substituted, it is substituted with one to three substituents. In several embodiments, when R 4 is substituted, it is substituted with one to four substituents. In several embodiments, R 4 is unsubstituted. [0013] In several embodiments, R 2 is heteroaryl having 5 to 20 ring members or heterocyclyl having 3 to 20 ring members.
  • R 2 is heteroaryl having 5 to 20 ring members or heterocyclyl having 5 to 20 ring members. In several embodiments, R 2 is heteroaryl having 5 to 10 ring members or heterocyclyl having 5 to 10 ring members. In several embodiments, R 2 is heteroaryl having 5 to 20 ring members. In several embodiments, R 2 is heterocyclyl having 5 to 20 ring members. In several embodiments, R 2 is heteroaryl having 5 to 10 ring members. In several embodiments, R 2 is heterocyclyl having 5 to 10 ring members. In several embodiments, R 2 is heterocyclyl having 5 to 10 ring members. In several embodiments, R 2 is unsubstituted or substituted with one or more instances of R 5 .
  • R 2 is substituted with 1 R 5 group. In several embodiments R 2 is substituted with 2 R 5 groups. In several embodiments, R 2 is substituted with 3 R 5 groups. In several embodiments, R 2 is substituted with 4 R 5 groups. In several embodiments, R 2 is substituted with 5 R 5 groups. In several embodiments, R 2 is substituted with 1 to 2 R 5 groups. In several embodiments, R 2 is substituted with 1 to 3 R 5 groups. In several embodiments, R 2 is substituted with 1 to 4 R 5 groups. In several embodiments, R 2 is substituted with 1 to 5 R 5 groups. In several embodiments, R 2 is unsubstituted.
  • each instance of R 5 independently is halogen, oxo, -CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, amino, C 1-4 alkylamino, di C 1-4 alkylamino, C(O)heterocyclyl having 3 to 6 ring members, heterocyclyl having 3 to 6 ring members, or heteroaryl having 5 to 10 ring members.
  • each instance of R 5 independently is halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, amino (-NH 2 ), C(O)heterocyclyl having 3 to 6 ring members, or heterocyclyl having 3 to 6 ring members.
  • each instance of R 5 independently is halogen, oxo, C 1-3 alkyl, C 1-3 haloalkyl, amino (-NH 2 ), C(O)heterocyclyl having 3 to 6 ring members, or heterocyclyl having 3 to 6 ring members.
  • at least an instance of R 5 is halogen.
  • the R 5 halogen is -F or -Cl. In several embodiments, the R 5 halogen (or halogens) is -F. In several embodiments, at least an instance of R 5 is -F. In several embodiments, at least an instance of R 5 is oxo. In several embodiments, at least an instance of R 5 is -CN. In several embodiments, at least an instance of R 5 is C 1-6 alkyl. In several embodiments, at least an instance of R 5 is C 1-6 haloalkyl. In several embodiments, at least an instance of R 5 is-NH 2 . In several embodiments, at least an instance of R 5 is C(O)heterocyclyl having 3 to 6 ring members.
  • R 5 is heterocyclyl having 3 to 6 ring members.
  • each R 5 is unsubstituted or substituted with one or more instances of R 6 .
  • each R 5 is substituted with one R 6 group.
  • each R 5 is substituted with two R 6 groups.
  • each R 5 is substituted with three R 6 groups.
  • each R 5 is substituted with four R 6 groups.
  • each R 6 is substituted with one to two R 6 groups.
  • each R 5 is substituted with one to three R 6 groups.
  • each R 5 is substituted with one to four R 6 groups.
  • R 5 is unsubstituted.
  • each instance of R 6 independently is halogen, C 1-6 alkyl, C(O)C 1-6 alkyl, C(O) 2 C 1-6 alkyl, or C 1-6 alkylene-OH. In several embodiments, when R 6 is halogen, it is -F. In several embodiments, each instance of R 6 independently is halogen, C 1-3 alkyl, C(O)C 1-4 alkyl, C(O) 2 C 1-4 alkyl, or C 1-3 alkylene-OH. In several embodiments, at least an instance of R 6 is halogen. In several embodiments, at least an instance of R 6 is -F.
  • each instance of R 3 independently is halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1- 6 alkoxy, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-7 cycloalkyl, heterocyclyl with 3 to 10 ring members, C 6-10 aryl, or heteroaryl having 5 to 10 ring members.
  • each instance of R 3 independently is halogen, C 1-3 alkyl, C 1-3 alkenyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 heteroalkyl, C 3-7 cycloalkyl, heterocyclyl with 3 to 7 ring members, C 6-10 aryl, or heteroaryl having 5 to 10 ring members.
  • each instance of R 3 independently is halogen, C 1-6 alkyl, C 1-6 alkenyl, C 3-7 cycloalkyl, heterocyclyl with 3 to 10 ring members, C 6-10 aryl, or heteroaryl having 5 to 10 ring members.
  • b and c are not both C-R 3 .
  • R 3 is halogen. In several embodiments, R 3 is -F or -Cl. In several embodiments, R 3 is -Cl. In several embodiments, R 3 is C 1-3 alkyl. In several embodiments, R 3 is C 1-3 alkenyl. In several embodiments, R 3 is C 1-3 alkoxy. In several embodiments, R 3 is C 1-3 haloalkyl. In several embodiments, R 3 is C 1-3 heteroalkyl. In several embodiments, R 3 is C 3-7 cycloalkyl. In several embodiments, R 3 is heterocyclyl with 3 to 7 ring members. In several embodiments, R 3 is C 6-10 aryl.
  • R 3 is heteroaryl having 5 to 10 ring members.
  • R 3 may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 heteroalkyl.
  • R 3 is substituted with halogen.
  • R 3 is substituted with -F or -Cl.
  • R 3 is substituted with -F.
  • R 3 is substituted with -OH.
  • R 3 is substituted with oxo.
  • R 3 is substituted with C 1-6 alkyl. In several embodiments, R 3 is substituted with C 1-6 alkoxy. In several embodiments, R 3 is substituted with C 1-6 haloalkyl. In several embodiments, R 3 is substituted with C 1-6 heteroalkyl. In several embodiments, when R 3 is substituted, it is substituted with one substituent. In several embodiments, when R 3 is substituted, it is substituted with two substituents. In several embodiments, when R 3 is substituted, it is substituted with three substituents. In several embodiments, when R 3 is substituted, it is substituted with four substituents. In several embodiments, when R 3 is substituted, it is substituted with one to two substituents.
  • R 3 when R 3 is substituted, it is substituted with one to three substituents. In several embodiments, when R 3 is substituted, it is substituted with one to four substituents.
  • nts, ments, b is . , . , . ments, c is CH. In several embodiments, c is C-R 3 .
  • d is N. In several embodiments, d is CH. In several embodiments, e is N. In several embodiments, e is CH. In several embodiments, f is N. In several embodiments, f is CH. [0021] In several embodiments, th , n several embodiments, th In several embodiments, the In several embodiments, t group is .
  • the group is . In several embodiments, the group . [0022] In several embodiments, at le e and f is N. In several embodiments, no more than two of a, d, e, and f are N. In several embodiments, no more than one of e, d, and f is N. [0023] Several embodiments pertain to a pharmaceutical composition comprising a compound or salt of Formula (I) and a pharmaceutically acceptable excipient. [0024] Several embodiments pertain to a compound or salt of Formula (I) or a pharmaceutical composition comprising a compound of Formula (I) for use as a medicament.
  • a compound or salt of Formula (I) or a pharmaceutical composition comprising a compound of Formula (I) for use in treating a 15-PGDH mediated disease or disorder.
  • a compound or salt of Formula (I) or a pharmaceutical composition comprising a compound of Formula (I) for use in treating inflammatory bowel disease.
  • a compound or salt of Formula (I) or a pharmaceutical composition comprising a compound of Formula (I) for use in treating ulcerative colitis.
  • Several embodiments pertain to a compound or salt of Formula (I) or a pharmaceutical composition comprising a compound of Formula (I) for use in treating Crohn’s disease.
  • a compound or salt of Formula (I) or a pharmaceutical composition comprising a compound of Formula (I) for use in treating a fibrotic disease, disorder or condition.
  • Several embodiments pertain to a method of treating a 15-PGDH mediated disease, disorder, or condition in a subject in need thereof, the method comprising administering to the subject therapeutically an effective amount of a compound or salt of Formula (I) or a pharmaceutical composition comprising a compound of Formula (I).
  • C a-b (or similar wording, such as, C a to C b ) in which “a” and “b” are integers refer to the number of carbon atoms in an alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, haloalkyl, alkoxy, thioalkyl, heteroalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or other group.
  • the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, ring of the cycloalkynyl, ring of the aryl, or the ring of the heteroaryl can contain from “a” to “b”, inclusive, carbon atoms.
  • a “C 1-4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons (e.g., 1, 2, 3, or 4), that is, CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-.
  • a “C 1-6 alkyl” group refers to all alkyl groups having from 1 to 6 carbons (e.g., 1, 2, 3, 4, 5, or 6). If no “a” and “b” are designated with regard to a group, the ranges described in these definitions are envisioned.
  • alkyl refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). Examples of branched alkyl groups include, but are not limited to, iso-propyl, sec-butyl, t-butyl and the like.
  • straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and the like.
  • the alkyl group may have 1 to 12 carbon atoms.
  • the “alkyl” group could also be a lower alkyl having 1 to 6 carbon atoms.
  • a C 1-5 alkyl includes C 5 alkyls, C 4 alkyls, C 3 alkyls, C 2 alkyls and C 1 alkyl (i.e., methyl).
  • a C 1-6 alkyl includes all moieties described above for C 1-5 alkyls but also includes C 6 alkyls.
  • a C 1-10 alkyl includes all moieties described above for C 1-5 alkyls and C 1-6 alkyls, but also includes C 7 , C 8 , C 9 and C 10 alkyls.
  • a C 1-12 alkyl includes all the foregoing moieties, but also includes C 11 and C 12 alkyls.
  • “C 1-4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl.
  • Non-limiting examples of C 1-12 alkyl include, but are in no way limited to, methyl (“Me” or -CH 3 ), ethyl, n-propyl, i- propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, neo-pentyl, n-hexyl, n-heptyl, n-octyl, n- nonyl, n-decyl, n-undecyl, and n-dodecyl.
  • alkylene or “alkylene chain” refers to a fully saturated, straight or branched divalent hydrocarbon chain radical, and having from one to twelve carbon atoms.
  • alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene and octylene.
  • a C 1-12 alkylene includes C 12 alkylenes, C 11 alkylenes, C 10 alkylenes, C 9 alkylenes, C 8 alkylenes, C 7 alkylenes, C 6 alkylenes, C 5 alkylenes, C 4 alkylenes, C 3 alkylenes, and C 2 alkylenes, and C 1 alkylene (i.e., methylene).
  • An alkylene group may be a lower alkylene having 1 to 6 carbon atoms.
  • a lower alkylene includes C 6 alkylenes, C 5 alkylenes, C 4 alkylenes, C 3 alkylenes, and C 2 alkylenes, and C 1 alkylene.
  • diradical naming conventions can include either mono- radical or di-radical naming conventions, depending on the context. For example, where a position of a substituent within a molecule requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di-radical.
  • a substituent identified as alkyl but that requires two points of attachment includes alkylene di-radicals such as –CH 2 –, –CH 2 CH 2 –, – CH 2 CH(CH 3 )CH 2 –, and the like.
  • alkenyl or “alkenyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms and having one or more carbon-carbon double bonds.
  • An alkenyl group comprising up to 12 carbon atoms is a C 2-12 alkenyl
  • an alkenyl comprising up to 10 carbon atoms is a C 2-10 alkenyl
  • an alkenyl group comprising up to 6 carbon atoms is a C 2-6 alkenyl
  • an alkenyl comprising up to 5 carbon atoms is a C 2-5 alkenyl.
  • a C 2-5 alkenyl includes C 5 alkenyls, C 4 alkenyls, C 3 alkenyls, and C 2 alkenyls.
  • a C 2-6 alkenyl includes all moieties described above for C 2-5 alkenyls but also includes C 6 alkenyls.
  • a C 2-10 alkenyl includes all moieties described above for C 2-5 alkenyls and C 2-6 alkenyls, but also includes C 7 , C 8 , C 9 and C 10 alkenyls.
  • a C 2-12 alkenyl includes all the foregoing moieties, but also includes C 11 and C 12 alkenyls.
  • Non-limiting examples of C 2-12 alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3- butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5- hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3- octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl
  • alkynyl or “alkynyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms and having one or more carbon-carbon triple bonds.
  • An alkynyl group comprising up to 12 carbon atoms is a C 2-12 alkynyl
  • an alkynyl comprising up to 10 carbon atoms is a C 2-10 alkynyl
  • an alkynyl group comprising up to 6 carbon atoms is a C 2-6 alkynyl
  • an alkynyl comprising up to 5 carbon atoms is a C 2-5 alkynyl.
  • a C 2-5 alkynyl includes C 5 alkynyls, C 4 alkynyls, C 3 alkynyls, and C 2 alkynyls.
  • a C 2-6 alkynyl includes all moieties described above for C 2-5 alkynyls but also includes C 6 alkynyls.
  • a C 2-10 alkynyl includes all moieties described above for C 2-5 alkynyls and C 2-6 alkynyls, but also includes C 7 , C 8 , C 9 and C 10 alkynyls.
  • a C 2-12 alkynyl includes all the foregoing moieties, but also includes C 11 and C 12 alkynyls.
  • Non-limiting examples of C 2-12 alkynyl include ethynyl, propynyl, butynyl, pentynyl and the like.
  • halogen or “halo,” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, e.g., fluorine (-F), chlorine (-Cl), bromine (-Br), or iodine (-I).
  • haloalkyl refers to a straight- or branched-chain alkyl group, substituting one or more or all hydrogens with halogens.
  • haloalkyl groups include, but are not limited to, -CF 3 , - CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CF 2 CF 3 and other groups that in light of the ordinary skill in the art and the teachings provided herein, would be considered equivalent to any one of the foregoing examples.
  • the haloalkyl may be a lower haloalkyl.
  • the haloalkyl may be perhalogenated (e.g., perfluorinated).
  • alkoxy refers to the formula –OR wherein R is an alkyl group as defined elsewhere herein.
  • R is an alkyl group as defined elsewhere herein.
  • a “C 1-9 alkoxy” includes but is not limited to methoxy, ethoxy, n-propoxy, 1- methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.
  • heteroalkyl refers to a straight or branched hydrocarbon chain (e.g., alkyl) containing one or more heteroatoms.
  • a heteroatom is given its plain and ordinary meaning in organic chemistry, which includes an element other than carbon, including but not limited to, nitrogen (e.g., amino, etc.), oxygen (e.g., alkoxy, ether, hydroxyl, etc.), sulfur, and halogens.
  • the heteroalkyl group may have 1 to 12 carbon atoms although the present definition also covers the occurrence of the term “heteroalkyl” where no numerical range is designated.
  • the heteroalkyl group could also be a lower heteroalkyl having 1 to 6 carbon atoms.
  • the heteroalkyl may have from 1 to 4 heteroatoms, from 1 to 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom.
  • the heteroalkyl group of the compounds may be designated as “C 1-4 heteroalkyl” or similar designations.
  • the heteroalkyl group may contain one or more heteroatoms.
  • C 1-4 heteroalkyl indicates that there are one to four carbon atoms in the heteroalkyl chain and additionally one or more heteroatoms in the backbone of the chain.
  • the heteroatom may be found anywhere along the alkyl portion of the heteroalkyl group, including in the first position (e.g., the heteroatom of the heteroalkyl may serve as the atom that directly attaches the alkyl to the rest of the molecule).
  • aryl refers to a hydrocarbon ring system radical comprising hydrogen and at least one aromatic ring.
  • the aryl group may have 6 to 18 carbon atoms, although the present definition also covers the occurrence of the term “aryl” where no numerical range is designated.
  • the aryl group has 6 to 10 carbon atoms.
  • the aryl group may be designated as “C 6-10 aryl,” “C 6 or C 10 aryl,” or similar designations.
  • the aryl group can be a C 6 -C 14 aryl group, a C 6 -C 10 aryl group, or a C 6 aryl group.
  • the aryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems, wherein at least one ring in the system is aromatic.
  • aryl groups include, but are not limited to, phenyl, aceanthrylenyl, acenaphthylenyl, acephenanthrylenyl, anthracenyl, azulenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacene-yl, s-indacene-yl, indanyl, indenyl, naphthalenyl, phenalenyl, phenanthrenyl, pleiadenyl, pyrenyl, and triphenylenyl.
  • Carbocyclyl means a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone and comprising 3 to 20 ring members (3 to 20 carbon atom ring members; C 3-20 ). When the carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged or spiro-connected fashion.
  • Carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls.
  • the carbocyclyl group may be a medium size carbocyclyl having 3 to 10 carbon atoms.
  • the carbocyclyl group could have 3 to 6 carbon atoms.
  • the carbocyclyl group may be designated as “C 3-6 carbocyclyl” or similar designations.
  • Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.
  • cycloalkyl refers to a non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, which can include fused, bridged, or spiral ring systems, having from 3 to 20 carbon atom ring members (e.g., having from 3 to 10 ring atoms, 3 to 8 ring atoms, etc.), and which is attached to the rest of the molecule by a single bond. No ring in a cycloalkyl ring or ring system is aromatic.
  • Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
  • cycloalkenyl refers to a monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, which can include fused, bridged, or spiral (e.g., spiro) ring systems, having from 3 to 20 carbon atoms, preferably having from 3 to 10 or 4 to 10 carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • No ring in a cycloalkenyl ring or ring system is aromatic.
  • An example is cyclohexenyl.
  • cycloalkenyl groups can contain 4 to 10 atoms in the ring(s).
  • Monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, and the like.
  • Polycyclic cycloalkenyl radicals include, for example, bicyclo[2.2.1]hept-2-enyl and the like.
  • cycloalkynyl refers to a monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, which can include fused, bridged, or spiral (e.g., spiro) ring systems, having from 8 to 20 ring members (e.g., having from 8 to 10 ring atoms, etc.). No ring in a cycloalkynyl ring or ring system is aromatic.
  • Monocyclic cycloalkynyl radicals include, for example, cycloheptynyl, cyclooctynyl, and the like.
  • heterocyclyl refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 20- membered monocyclic, bicyclic, and tricyclic ring systems wherein carbon atoms together with from 1 to 5 heteroatoms (each of which independently is nitrogen (e.g., N, NH, N-R, etc.), oxygen, or sulfur) constitute said ring system.
  • Heterocyclyl or heterocyclic rings include non-heteroaryl ring systems (e.g., those cycles comprising heteroatoms as ring members that do not fall within the definition of a “heteroaryl”).
  • the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, and spiral (e.g., spiro) ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl radical can be partially or fully saturated.
  • heterocyclyl radicals include, but are not limited to, azetidinyl, aziridinyl, 1,3-dioxin-yl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,3-oxathiolanyl, 1,3- dithiolyl, 1,3-dithiolanyl, 1,4-oxathianyl, tetrahydro-1,4-thiazinyl, dioxolanyl, decahydroisoquinolyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, maleimidyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxetanyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, o
  • the point of attachment of the heterocyclyl, heterocyclic ring, or heterocycle to the rest of the molecule by a single bond is through a ring member atom, which can be carbon or nitrogen.
  • a heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur in any ring of the ring system.
  • the heterocyclyl group may be a medium size heterocyclyl having 3 to 10 ring members.
  • the heterocyclyl group could also be a heterocyclyl having 3 to 6 ring members.
  • the heterocyclyl group may be designated as “3-6 membered heterocyclyl” or similar designations.
  • heteroaryl refers to a 5- to 20-membered ring system radical with 1 to 19 carbon atoms and 1 to 6 heteroatoms (each of which independently is nitrogen (e.g., N, NH, N-R, etc.), oxygen, or sulfur) as the ring members.
  • the heteroaryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems, wherein at least one ring is aromatic.
  • the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized and the nitrogen atom can be optionally quaternized.
  • the heteroaryl group can contain 5 to 14 ring members (atoms in the ring(s)), 5 to 10 ring members (atoms in the ring(s)), 5 to 9 ring members (atoms in the ring(s)), 5 to 7 ring members (atoms in the ring(s)), 5 to 6 ring members (atoms in the ring(s)).
  • the heteroaryl group may be a medium size heteroaryl having 5 to 10 ring members.
  • the heteroaryl group could also be a heteroaryl having 5 to 6 ring members.
  • the heteroaryl group could also be a heteroaryl having 6 to 9 ring members.
  • the heteroaryl group could also have 6 ring members.
  • the heteroaryl group could also have 9 ring members.
  • a heteroaryl contains from 1 to 6 heteroatoms, from 1 to 5 heteroatoms, from 1 to 4 heteroatoms, from 1 to 3 heteroatoms, from 1 to 2 heteroatoms, or 1 heteroatom.
  • a heteroaryl contains 1 to 5 nitrogen atoms, 1 to 4 nitrogen atoms, 1 to 3 nitrogen atoms, 1 to 2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, 1 sulfur or oxygen atom, etc.
  • Examples include, but are not limited to, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophene-yl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophene-yl, furanyl, iso
  • multicyclic refers to a ring system having more than one ring (e.g., bicyclic, tricyclic or tetracyclic), which can include fused, bridged, and spiral (e.g., spiro) ring systems.
  • hydroxy (or “hydroxyl”) refers to a –OH group. 15
  • cyano refers to a “-CN” group.
  • amino refers to a NH 2 group.
  • alkylamino refers to a “-NR A H” group in which R A is alkyl.
  • dialkylamino refers to a “-NR A R B ” group in which R A and R B are each independently alkyl. R A and R B may be taken together with the nitrogen to which they are attached to provide a heteroaryl or heterocyclyl.
  • aminoalkyl refers to an amino group connected via an alkylene group.
  • any “R” group(s) such as, without limitation, R 1 , R 2 , R 3 , etc., represent substituents that can be attached to the indicated atom.
  • R group may be substituted or unsubstituted. If two “R” groups are described as being “taken together” (or similar language), the R groups and the atoms they are attached to can form a cycle (e.g., cycloalkyl, aryl, heteroaryl, heterocycle). When two R groups are said to form a ring (e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring) “together with the atom to which they are attached,” it is meant that the collective unit of the atom and the two R groups are the recited ring. The ring is not otherwise limited by the definition of each R group when taken individually.
  • each instance of R is defined as being in ydrogen or alkyl, or each instance of R together with the nitrogen to which they are attached form a heterocyclyl
  • each instance of R can be independently hydrogen or alkyl, or alternatively, the substructure has structure: where ring A is a heterocyclyl ring co d nitrogen.
  • R A and R B of an NR A R B g roup are n ca e to be “taken together,” it means that they are covalently bonded to one another to form a ring: .
  • a cyclic structure may be shown u sing the following structure (or a similar structure with a different ring, heteroatoms, nds, etc.): .
  • R group may be attached to any position of the ring by replacing an –H of the ring with –R.
  • struc ues where “ ” indicates a bond to a e a g po o o e s ucue.
  • R A and R B are each independently hydrogen or alkyl, or R 1 and R 2 together with the atoms to which they are attached form an aryl or carbocyclyl
  • R 1 and R 2 can be selected from hydrogen or alkyl, or alternatively, the substructure has structure: where A is an aryl ring or a carbocyclyl con taining the depicted double bond.
  • A is an aryl ring or a carbocyclyl con taining the depicted double bond.
  • a substituent depicted as –AE– E includes the substituent being oriented such that the “A” is attached at the leftm oint of the molecule as well as the case in which “A” is attached at the rightmost attachment point of the molecule.
  • certain radical naming conventions can include either a mono-radical or a di-radical, depending on the context. For example, where a substituent (e.g., in a genus structure) requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di-radical.
  • a substituent identified as aminoalkyl that requires two points of attachment includes di-radicals such as –NHCH 2 –, –NHCH 2 CH 2 –, –NHCH 2 CH(CH 3 )CH 2 –, and the like.
  • a substituent may require two points of attachment include alkoxy, aryl, heteroaryl, carbocyclyl, heterocyclyl, etc.
  • a radical indicates species with a single, unpaired electron such that the species containing the radical can be covalently bonded to another species.
  • a radical is not necessarily a free radical. Rather, a radical indicates a specific portion of a larger molecule.
  • a solvate means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H 2 O, such combination being able to form one or more hydrate. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.
  • various adjuvants such as are commonly used in the art may be included.
  • pharmaceutically acceptable salt refers to salts that retain the biological effectiveness and properties of a compound, which are not biologically or otherwise undesirable for use in a pharmaceutical.
  • the compounds herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be prepared using and/or formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, camphorsulfonic acid, maleic acid, malonic acid, succinic acid, fumaric acid, formic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, carbonic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be prepared using and/or formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • Organic bases from which salts can be derived also include, for example, ethylenediamine, N-methyl- glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, ethylamine, basic amino acids, and the like.
  • intermediate compounds includes structures produced from the synthetic procedures described, whether isolated or generated in-situ and not isolated, prior to obtaining the finally desired compound. These intermediates are included in the scope of this disclosure. Exemplary embodiments of such intermediate compounds are set forth elsewhere herein.
  • the compounds of the present disclosure may contain, for example, double bonds, one or more asymmetric carbon atoms, and bonds with a hindered rotation, and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers (E/Z)), enantiomers, diastereomers, and atropoisomers.
  • stereoisomers such as double-bond isomers (i.e., geometric isomers (E/Z)), enantiomers, diastereomers, and atropoisomers.
  • the scope of the instant disclosure is to be understood to encompass all possible stereoisomers of the illustrated compounds, including the stereoisomerically pure form (for example, geometrically pure, enantiomerically pure (e.g., (R), (S), (R)(R), (S)(S), etc.), diastereomerically pure, and atropoisomerically pure) and stereoisomeric mixtures (e.g., both (R) and (S), etc., diastereomers, and atropoisomers, or mixture of any of the foregoing) of any chemical structures disclosed herein (in whole or in part), unless the stereochemistry is specifically identified.
  • stereoisomerically pure form for example, geometrically pure, enantiomerically pure (e.g., (R), (S), (R)(R), (S)(S), etc.), diastereomerically pure, and atropoisomerically pure) and stereoisomeric mixtures (e.g., both (R) and (S), etc.
  • the terms “or ranges including and/or spanning the aforementioned values” is meant to include any range that includes or spans the aforementioned values.
  • the temperature of a reaction is expressed as “20 o C, 30 o C, 40 o C, 50 o C, or ranges including and/or spanning the aforementioned values,” this includes the particular temperature provided (e.g., 20 o C, 30 o C, 40 o C, or 50 o C) or temperature ranges extending between 20 o C to 50 o C, 20 o C to 40 o C, 20 o C to 30 o C, 30 o C to 50 o C, 30 o C to 40 o C, or 40 o C to 50 o C.
  • Embodiment 1 is a compound of Formula (I) or a pharmaceutically accepta ble salt thereof; wherein b is C-H or C-R 3 ; c is N, C-H, or C-R 3 ; wherein b and c are not both C-R 3 ; R 1a is H, C 1-6 alkyl, C 1-6 heteroalkyl, or C 1-6 haloalkyl; wherein R 1a may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, –OH, -CN, C 1-4 alkoxy, -NH 2 , C 1-4 alkylamino, or diC 1- 4 alkylamino; R 1b is C 1-6 alkyl, C 1-6 alkoxy, C 1-6 heteroalkyl, C 3-7 cycloalkyl, heterocyclyl with 3 to 10 ring members, C 6-10 aryl, heteroaryl having 5 to 10 ring
  • R 1a is -H, C 1-3 alkyl, C 1-3 heteroalkyl, or C 1-3 haloalkyl. In several embodiments, R 1a is C 1-6 alkyl, C 1-6 heteroalkyl, or C 1-6 haloalkyl. In several embodiments, R 1a is C 1-3 alkyl, C 1-3 heteroalkyl, or C 1-3 haloalkyl. In several embodiments, R 1a is C 1-6 alkyl or C 1-6 haloalkyl. In several embodiments, R 1a is -H or C 1-6 alkyl. In several embodiments, R 1a is -H or C 1-6 haloalkyl.
  • R 1a is -H or C 1-6 heteroalkyl. In several embodiments, R 1a is C 1-6 alkyl. In several embodiments, R 1a is C 1-6 haloalkyl. In several embodiments, R 1a is C 1-6 heteroalkyl. In several embodiments, R 1a is -H.
  • R 1b is C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-7 cycloalkyl, C 6-10 aryl, C 1-6 alkylene-C 3-7 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, or C 1-6 alkylene-heterocyclyl with 3 to 7 ring members.
  • the R 1b alkylene e.g., of C 1-6 alkylene-C 3-7 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, or C 1-6 alkylene-heterocyclyl
  • the R 1b alkylene is a C 1-3 alkylene. In several embodiments, the R 1b alkylene is a C 1-4 alkylene. In several embodiments, the R 1b alkylene is a C 1-5 alkylene. In several embodiments, the cyclic group of R 1b (e.g., the cycloalkyl group, the aryl group, the heterocyclyl group, or the heteroaryl group) comprises 5 or 6 ring members. In several embodiments, the cyclic group of R 1b (e.g., the cycloalkyl group or the heterocyclyl group, including of the alkylene cycles) comprises 3, 4, 5, or 6 ring members.
  • R 1b is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-10 cycloalkyl, or heterocyclyl having 3 to 10 ring members. In several embodiments, R 1b is C 1-6 alkyl, C 1-6 haloalkyl, or C 1- 6 heteroalkyl. In several embodiments, R 1b is C 3-10 cycloalkyl or heterocyclyl having 3 to 10 ring members. In several embodiments, R 1b is haloalkyl. In several embodiments, R 1b is heterocyclyl having 3 to 10 ring members. In several embodiments, R 1a and R 1b together form a heterocyclyl having 5 to 12- ring members.
  • R 1a and R 1b together form a heterocyclyl having 6 to 12-ring members. In several embodiments, R 1a and R 1b together form a heterocyclyl having 5 to 12-ring members. In several embodiments, R 1a and R 1b together form a heterocyclyl having 6 to 12-ring members. In several embodiments, R 1a and R 1b together form a heterocyclyl having 3 to 10 ring members. In several embodiments, R 1a and R 1b together form a heterocyclyl having 4 to 6 ring members. In several embodiments, R 2 is heteroaryl having 5 to 10 ring members or heterocyclyl having 3 to 10 ring members. In several embodiments, R 2 is heteroaryl having 5 to 10 ring members.
  • R 3 is halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-7 cycloalkyl, heterocyclyl with 3 to 10 ring members, C 6-10 aryl, or heteroaryl having 5 to 10 ring members.
  • R 3 is halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, heteroaryl having 5 to 10 ring members, or heterocyclyl having 5 to 10 ring members.
  • R 3 is C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, heteroaryl having 5 to 10 ring members, or heterocyclyl having 5 to 10 ring members.
  • R 3 is C 1-6 alkyl, C 1-6 alkenyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, or heteroaryl having 5 to 10 ring members.
  • R 3 is C 3-6 cycloalkyl.
  • R 3 is heteroaryl having 5 to 10 ring members.
  • a haloalkyl as provided in a variable of Embodiment 1 may be perhalogenated, where each -H has been exchanged with a halogen.
  • a haloalkyl as provided in a variable of Embodiment 1 is not perhalogenated and one or more instances C-H occur (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or more).
  • C-H instances occurring within the haloalkyl may occur on the same carbon (e.g., providing CH 2 or CH 3 ).
  • the haloalkyl includes at least one and optionally more instances of a halogen (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, more instances, or perhalo).
  • each halogen of the haloalkyl independently is -F, -Cl, -Br, or -I.
  • each halogen of the haloalkyl is -F or -Cl.
  • each halogen of the haloalkyl is -F.
  • a heteroalkyl as provided in a variable of Embodiment 1 includes a heteroatom (or one or more heteroatoms) within the alkyl backbone.
  • each heteroatom of the heteroalkyl independently is nitrogen, oxygen, or sulfur (e.g., S, SO, or SO 2 ).
  • each heteroatom of the heteroalkyl independently is nitrogen or oxygen.
  • each heteroatom of the heteroalkyl is nitrogen.
  • each heteroatom of the heteroalkyl is oxygen.
  • the heteroalkyl may have from 1 to 4 heteroatoms (e.g., 1, 2, 3, or 4), from 1 to 3 heteroatoms (e.g., 1, 2, or 3), 1 or 2 heteroatoms, or 1 heteroatom.
  • Embodiment 2 Provided herein as Embodiment 2, is the compound or salt of Embodiment 1, wherein, when R 1a is H and R 1b is C 1-6 alkylene-C 3-7 cycloalkyl or C 1-6 alkylene-heterocyclyl with 3 to 7 ring members, then R 2 is a heteroaryl or heterocyclyl with at least 6 ring members.
  • Embodiment 3 is the compound or salt of any one of Embodiments 1 or 2, wherein, when each of a and c is N, each of d, e, and f is CH, R 2 is unsubstituted heteroaryl, and b is C- R 3 , then R 3 is not unsubstituted heteroaryl.
  • Embodiment 4 is the compound or salt of any one of Embodiments 1 to 3, wherein, when each of a and c is N, each of d, e, and f is CH, R 1a and R 1b together provide unsubstituted piperidinyl, R 2 is methyl pyrazolyl, unsubstituted pyridinyl, pyridinyl substituted with a single methyl as its only substituent, pyridinyl substituted with a single chloro as its only substituent, pyridinyl substituted with a single fluoro as its only substituent, or unsubstituted pyrimidinyl, and b is C-R 3 , then R 3 is not unsubstituted phenyl.
  • Embodiment 5 is the compound or salt of any one of Embodiments 1 to 4, wherein, when each of a and c is N, each of d, e, and f is CH, R 1a and R 1b together provide 4-methyl piperazinyl, R 2 is heteroaryl, and b is C-R 3 where R 3 is -CF 3 , then R 2 is not heteroaryl having 5 members and substituted with a single methyl as its only substituent.
  • Embodiment 6 Provided herein as Embodiment 6 is the compound or salt of any one of Embodiments 1 to 5, wherein, when each of a and c is N, each of d, e, and f is CH, R 2 is heteroaryl, and b is C-R 3 where R 3 is chloro, then R 2 is not heteroaryl having 5 members and substituted with a single methyl as its only substituent.
  • Embodiment 7 Provided herein as Embodiment 7 is the compound or salt of any one of Embodiments 1 to 6, wherein, when each of a and c is N, each of b, d, e, and f is CH, R 1a and R 1b together provide an unsubstituted piperidinyl, then R 5 is not amino or alkylamino.
  • Embodiment 8 is the compound or salt of any one of Embodiments 1 to 7, wherein, when each of a and c is N, each of b, d, e, and f is CH, R 1a and R 1b together provide an unsubstituted piperidinyl, and R 2 is a 10 membered heteroaryl with one R 5 substituent, then R 5 is not oxo.
  • Embodiment 9 is the compound or salt of any one of Embodiments 1 to 8, wherein, when each of a and c is N, each of b, d, e, and f is CH, and R 1a and R 1b together provide an unsubstituted piperidinyl, then R 2 is not dimethyl pyrazolyl, unsubstituted pyridinyl, unsubstituted pyrimidinyl, unsubstituted thiazolyl, unsubstituted indazolyl, pyridinyl substituted with a single methoxy as its only substituent, pyridinyl substituted with Cl and NH 2 as its only substitutents, pyridinyl substituted with a single instance of N(Me) 2 as its only substituent, pyridinyl substituted with a single instance of F as its only substituent, pyridinyl substituted with a single instance of morpholiny
  • Embodiment 10 is the compound or salt of any one of Embodiments 1 to 9, wherein R 2 is not morpholinyl.
  • Embodiment 11 is the compound or salt of any one of Embodiments 1 to 10, wherein R 2 and R 3 are different.
  • Embodiment 12 is the compound or salt of any one of Embodiments 1 to 11, wherein b and c are not both C-R 3 .
  • Embodiment 13 is the compound or salt of any one of Embodiments 1 to 12, wherein R 5 is not heteroaryl.
  • Embodiment 14 is the compound or salt of any one of Embodiments 1 to 13, wherein, when R 2 is heterocyclyl having 6 to 10 ring members, the heterocyclyl group includes at least one unsaturation.
  • Embodiment 15 is the compound or salt of any one of Embodiments 1 to 14, wherein, when each of a and d are N, each of b, c, e, and f is CH, R a is methyl, R b is methyl, and R 2 is 5 membered heterocyclyl, then R 5 is not a 6 membered heterocyclyl.
  • Embodiment 16 is the compound or salt of any one of Embodiments 1 to 15, wherein, when each of a and c is N, each of b, d, e, and f is CH, R 1a and R 1b together provide an unsubstituted piperidinyl, R 2 is a 9 membered heterocyclyl or 9 membered heteroaryl with one instance of R 5 , and R 5 is amino, then R 2 does not include a ring heteroatom that is S.
  • Embodiment 17 is the compound or salt of any one of Embodiments 1 to 16, wherein, when each of a and c is N, each of b, d, e, and f is CH, R 1a and R 1b together provide an unsubstituted morpholinyl, R 2 is a 9 membered heterocyclyl or 9 membered heteroaryl with one instance of R 5 , and R 5 is amino, then R 2 does not include a ring heteroatom that is O.
  • Embodiment 18 Provided herein as Embodiment 18 is the compound or salt of any one of Embodiments 1 to 17, wherein, when each of a, b, c, e, and f is CH, d is N, and R 1a and R 1b together provide an unsubstituted piperidinyl, then R 2 is not benzoxazolyl substituted with NH 2 .
  • Embodiment 19 Provided herein as Embodiment 19 is the compound or salt of any one of Embodiments 1 to 18, wherein, when a is N, c is C-R 3 , each of b, d, e, and f is CH, R 1a is H, and R 2 is unsubstituted or substituted heteroaryl having 5 to 6 ring members or unsubstituted or substituted heterocyclyl having 6 ring members, then R 1b is not C 1-3 alkylene-heteroaryl with 5 ring members.
  • Embodiment 20 is the compound or salt of any one of Embodiments 1 to 19, wherein, when a is N, c is C-R 3 , each of b, d, e, and f is CH, and R 1a is H, then R 3 is not alkoxy.
  • Embodiment 21 is the compound or salt of any one of Embodiments 1 to 20, wherein, when a is N, c is C-R 3 , R 3 is alkoxyl, each of b, d, e, and f is CH, R 1a is H, and R 2 is unsubstituted or substituted heteroaryl having 5 to 6 ring members or unsubstituted or substituted heterocyclyl having 6 ring members, then R 1b is not C 1-3 alkylene-heteroaryl with 5 to 9 ring members.
  • Embodiment 22 is the compound or salt of any one of Embodiments 1 to 21, wherein, when a is N, c is C-R 3 , each of b, d, e, and f is CH, and R 2 is unsubstituted or substituted heteroaryl having 5 to 6 ring members or unsubstituted or substituted heterocyclyl having 6 ring members, then R 1a is not H.
  • Embodiment 23 Provided herein as Embodiment 23 is the compound or salt of any one of Embodiments 1 to 22, wherein, when a is N, c is C-R 3 , each of b, d, e, and f is CH, R 1a and R 1b together form an unsubstituted or substituted heterocyclyl with 6 ring members, and R 2 is unsubstituted or substituted heteroaryl having 5 ring members, then R 3 is not Cl.
  • Embodiment 24 is the compound or salt of any one of Embodiments 1 to 23, wherein, when a is N, each of b, c, d, e, and f is CH, R 1a is methyl, and R 2 is substituted or unsubstituted heteroaryl having 9 ring members, then R 1b is not -CH 2 CH 2 N(CH 2 CH 3 ) 2 .
  • Embodiment 25 is the compound or salt of any one of Embodiments 1 to 24, wherein, when a is N, each of b, c, d, e, and f is CH, and R 2 is heteroaryl having 9 ring members and substituted with oxo, then R 1a and R 1b do not together form 4-methyl piperazinyl.
  • Embodiment 26 is the compound or salt of any one of Embodiments 1 to 25, wherein, when each of a and c is N, each of b, d, e, and f is CH, and R 2 is unsubstituted or substituted heterocyclyl having 6 ring members, then R 1a is not H.
  • Embodiment 27 is the compound or salt of any one of Embodiments 1 to 26, wherein, when each of a and c is N, each of b, d, e, and f is CH, R 2 is unsubstituted or substituted heterocyclyl having 6 ring members, and R 1a is H, then R 1b is not C 4-6 cycloalkyl, C 4-5 alkyl, or C 1-3 alkylene-heterocyclyl with 6 ring members.
  • Embodiment 28 is the compound or salt of any one of Embodiments 1 to 27, wherein, when each of a and c is N, each of b, d, e, and f is CH, and R 2 is unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted thiazolyl, or unsubstituted or substituted pyrazolyl, then R 1a and R 1b do not together form unsubstituted piperidinyl.
  • Embodiment 29 is the compound or salt of any one of Embodiments 1 to 28, wherein, when each of a and c is N, each of b, d, e, and f is CH, and R 2 is unsubstituted or substituted heteroaryl having 10 ring members or unsubstituted or substituted heterocyclyl having 10 ring members, then R 1a and R 1b do not together form unsubstituted piperidinyl.
  • Embodiment 30 is the compound or salt of any one of Embodiments 1 to 29, wherein, when each of a and c is N, each of b, d, e, and f is CH, and R 2 is unsubstituted or substituted indazolyl, then R 1a and R 1b do not together form unsubstituted piperidinyl.
  • Embodiment 31 is the compound or salt of any one of Embodiments 1 to 30, wherein, when each of a and c is N, each of b, d, e, and f is CH, and R 2 is unsubstituted or substituted piperazinyl, then R 1a and R 1b are not both unsubstituted propyl.
  • Embodiment 32 is the compound or salt of any one of Embodiments 1 to 31, wherein, when each of a and c is N, each of b, d, e, and f is CH, and R 2 is unsubstituted or substituted piperazinyl, then R 1a and R 1b are not both unsubstituted C 1-3 alkyl.
  • Embodiment 33 is the compound or salt of any one of Embodiments 1 to 32, wherein, when each of a and c is N, each of b, d, e, and f is CH, and R 2 is unsubstituted or substituted piperazinyl, then R 1a and R 1b do not together provide unsubstituted or substituted piperidinyl.
  • Embodiment 34 is the compound or salt of any one of Embodiments 1 to 33, wherein, when d is N, each of a, b, c, d, and f is CH, R 1a is H, and R 2 is unsubstituted or substituted heteroaryl having 5 ring members, then R 1b is not unsubstituted or substituted C 1-6 alkylene-C 6 aryl.
  • Embodiment 35 is the compound or salt of any one of Embodiments 1 to 34, wherein, when d is N, each of a, b, c, d, and f is CH, R 1a is H, and R 2 is heteroaryl having 8 ring members substituted with a unsubstituted or substituted pyridinyl, then R 1b is not unsubstituted C 1-3 alkyl or C 1-3 alkyl substituted with amino.
  • Embodiment 36 is the compound or salt of any one of Embodiments 1 to 35, wherein, when d is N, each of a, b, c, d, and f is CH, and R 2 is unsubstituted or substituted benzoxazolyl, then R 1a and R 1b do not together form an unsubstituted morpholinyl.
  • Embodiment 37 is the compound or salt of any one of Embodiments 1 to 36, wherein R 1b is not unsubstituted or substituted pyridinyl.
  • Embodiment 38 is the compound or salt of any one of Embodiments 1 to 18, wherein, when each of a and c is N, each of b, d, e, and f is CH, and R 1a and R 1b are both ethyl, then R 2 is not piperazinyl.
  • Embodiment 39 is the compound or salt of any one of Embodiments 1 to 38, wherein, when each of a and c is N, each of b, d, e, and f is CH, and R 1a and R 1b together provide an unsubstituted piperadinyl group, then R 2 is not pyridinyl, pyrimidinyl, or quinolinyl.
  • Embodiment 40 is the compound or salt of any one of Embodiments 1 to 39, wherein, when each of a and c is N, each of b, d, e, and f is CH, R 1a is H, and R 1b is C 1-6 alkyl or cyclohexyl, then R 2 is not piperazinyl.
  • Embodiment 41 is the compound or salt of any one of Embodiments 1 to 40, wherein, when each of a and c is N, and each of b, d, e, and f is CH, then R 1a and R 1b together do not provide unsubstituted piperadinyl.
  • Embodiment 42 is the compound or salt of any one of Embodiments 1 to 41, wherein, when each of a and b is N, each of c, d, e, and f is CH, R 1a and R 1b together provide an unsubstituted piperidinyl, and R 2 is a 10 membered heteroaryl with one R 5 substituent, then R 5 is not oxo.
  • Embodiment 43 is the compound or salt of any one of Embodiments 1 to 42, i). the compound or salt of any one of Embodiments 1 to 42, wherein i).
  • Embodiment 46 is the compound or salt of any one of Embodiments 1 to 44, wherein a is CH.
  • Embodiment 47 is the compound or salt of any one of Embodiments 1 to 46, wherein b is CH.
  • Embodiment 48 is the compound or salt of any one of Embodiments 1 to 46, wherein b is C-R 3 .
  • Embodiment 49 is the compound or salt of any one of Embodiments 1 to 48, wherein c is N.
  • Embodiment 50 is the compound or salt of any one of Embodiments 1 to 48, wherein c is CH.
  • Embodiment 51 is the compound or salt of any one of Embodiments 1 to 48, wherein c is C-R 3 .
  • Embodiment 52 is the compound or salt of any one of Embodiments 1 to 51, wherein d is N.
  • Embodiment 53 is the compound or salt of any one of Embodiments 1 to 51, wherein d is CH.
  • Embodiment 54 is the compound or salt of any one of Embodiments 1 to 53, wherein e is N.
  • Embodiment 55 is the compound or salt of any one of Embodiments 1 to 53, wherein e is CH.
  • Embodiment 56 is the compound or salt of any one of Embodiments 1 to 55, wherein f is N.
  • Embodiment 57 is the compound or salt of any one of Embodiments 1 to 55, wherein f is CH.
  • Embodiment 58 is the compound or salt of any one of Embodiments 1 to 57, ral embodiments, the In several embodiments, the In several embodiments, the .
  • Emb s Provided herein as Emb s the c t of any one of Embodiments 1 to 45, 47, 49, and 52 to 58, wherein th .
  • Embodi any one of Embodiments 1 to 45, 48, 49, and 52 to 58 wherein the group .
  • Provided herein as Embodiment 64 is the compound or salt of any one of Embodiments 1 to 63, wherein at least one of a, d, e and f is N.
  • Embodiment 65 is the compound or salt of any one of Embodiments 1 to 64, wherein no more than two of a, d, e, and f are N.
  • Embodiment 66 is the compound or salt of any one of Embodiments 1 to 65, wherein no more than one of e, d, and f is N.
  • Embodiment 67 is the compound or salt of any one of Embodiments 1 to 66, wherein R 1a is -H, C 1-3 alkyl, or C 1-3 haloalkyl.
  • R 1a is -H or C 1- 3 haloalkyl.
  • R 1a is C 1-3 alkyl or C 1-3 haloalkyl.
  • R 1a is -H or C 1-3 alkyl.
  • R 1a is C 1-2 alkyl. In several embodiments, R 1a is methyl. In several embodiments, R 1a is C 2 alkyl. In several embodiments, R 1a is C 3 alkyl. In several embodiments, R 1a is C 1- 2 haloalkyl. In several embodiments, R 1a is C 1 haloalkyl. In several embodiments, R 1a is C 2 haloalkyl. In several embodiments, R 1a is C 3 haloalkyl. [0141] Provided herein as Embodiment 68 is the compound or salt of any one of Embodiments 1 to 67, wherein R 1a is alkyl.
  • R 1a is C 1-6 alkyl. In several embodiments, R 1a is C 1-5 alkyl. In several embodiments, R 1a is C 1-4 alkyl. In several embodiments, R 1a is C 1-3 alkyl. In several embodiments, R 1a is C 1-2 alkyl. In several embodiments, R 1a is C 2-3 alkyl. In several embodiments, R 1a is C 1 alkyl. In several embodiments, R 1a is C 2 alkyl. In several embodiments, R 1a is C 3 alkyl. [0142] Provided herein as Embodiment 69 is the compound or salt of any one of Embodiments 1 to 67, wherein R 1a is haloalkyl.
  • R 1a is C 1-6 haloalkyl. In several embodiments, R 1a is C 1-5 haloalkyl. In several embodiments, R 1a is C 1-4 haloalkyl. In several embodiments, R 1a is C 1-3 haloalkyl. In several embodiments, R 1a is C 1-2 haloalkyl. In several embodiments, R 1a is C 2-3 haloalkyl. In several embodiments, R 1a is C 1 haloalkyl. In several embodiments, R 1a is C 2 haloalkyl. In several embodiments, R 1a is C 3 haloalkyl.
  • Embodiment 70 is the compound or salt of any one of Embodiments 1 to 69, wherein R 1a is substituted with 1, 2, 3, or 4 substituents.
  • R 1a is substituted with 1 to 4 substituents.
  • R 1a is substituted with 1 to 3 substituents.
  • R 1a is substituted with 1 to 2 substituents.
  • R 1a is substituted with 2 to 4 substituents.
  • R 1a is substituted with 3 to 4 substituents.
  • R 1a is substituted with 2 to 3 substituents.
  • Embodiment 71 is the compound or salt of any one of Embodiments 1 to 70, wherein R 1a is substituted with 1, 2, or 3 substituents.
  • Embodiment 72 is the compound or salt of any one of Embodiments 1 to 71, wherein R 1a is substituted with 1 or 2 substituents.
  • Embodiment 73 is the compound or salt of any one of Embodiments 1 to 72, wherein R 1a is substituted with 1 substituent.
  • Embodiment 74 is the compound or salt of any one of Embodiments 1 to 73, wherein, when R 1a is substituted, each R 1a substituent independently is halogen, -OH, C 1-3 alkyl, or C 1-3 alkoxy.
  • R 1a is substituted with -F or -OH.
  • R 1a is substituted with -OH or C 1-3 alkoxy.
  • R 1a is substituted with -F or C 1-3 alkoxy.
  • R 1a is substituted with -F, -OH, C 1 alkyl, C 2 alkyl, C 3 alkyl, C 1 alkoxy, C 2 alkoxy, and/or C 3 alkoxy. In several embodiments, R 1a is substituted with methyl, C 2 alkyl, and/or C 3 alkyl. In several embodiments, R 1a is substituted with -C 1 alkoxy, C 2 alkoxy, or C 3 alkoxy. In several embodiments, R 1a is substituted with -C 1 alkoxy. In several embodiments, R 1a is substituted with C 2 alkoxy. In several embodiments, R 1a is substituted with C 3 alkoxy.
  • R 1a is substituted with -F. In several embodiments, R 1a is substituted with -OH. In several embodiments, R 1a is substituted with methyl.
  • Embodiment 75 is the compound or salt of any one of Embodiments 1 to 74, wherein, when R 1a is substituted, each R 1a substituent independently is -F, -OH, or C 1-3 alkoxy.
  • Embodiment 76 is the compound or salt of any one of Embodiments 1 to 69, wherein R 1a is unsubstituted.
  • Embodiment 77 is the compound or salt of any one of Embodiments 1 to 67, wherein R 1a is -H (-H) or .
  • R 1a is -H.
  • bodiments R 1a is ethyl.
  • R 1a is isopropyl.
  • Embodiment 78 is the compound or salt of any one of Embodiments 1 to 67, wherein R 1a is -H.
  • Embodiment 79 is the compound or salt of any one of Embodiments 1 to 67, wherein R 1a is ethyl.
  • Embodiment 80 is the compound or salt of any one of Embodiments 1 to 67, wherein R 1a is isopropyl.
  • Embodiment 81 is the compound or salt of any one of Embodiments 1 to 67, wherein R 1a is -CH 3 .
  • Embodiment 82 is the compound or salt of any one of Embodiments 1 to 81, wherein R 1b is C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-7 cycloalkyl, heterocyclyl with 3 to 7 ring members, C 6-10 aryl, C 1-6 alkylene-C 3-7 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, or C 1-6 alkylene- heterocyclyl with 3 to 7 ring members.
  • R 1b is C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-7 cycloalkyl, heterocyclyl with 3 to 7 ring members, C 6-10 aryl, C 1-6 alkylene-C 3-7 cycloalkyl, C 1-6 alkylene-C 6-10 aryl, or C 1-6 alkylene- heterocyclyl with 3
  • R 1b is C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, or heterocyclyl having 3- to 6-ring members.
  • R 1b is C 1-3 haloalkyl, C 3-6 cycloalkyl, or heterocyclyl having 3- to 6-ring members.
  • R 1b is C 1-3 alkyl, C 3-6 cycloalkyl, or heterocyclyl having 3- to 6-ring members.
  • R 1b is C 1-3 alkyl, C 1-3 haloalkyl, or C 3-6 cycloalkyl.
  • R 1b is C 1-3 alkyl or C 3-6 cycloalkyl. In several embodiments, R 1b is C 1-3 alkyl or C 1-3 haloalkyl. In several embodiments, R 1b is C 3-6 cycloalkyl or heterocyclyl having 3- to 6-ring members. In several embodiments, R 1b is C 1-3 haloalkyl or heterocyclyl having 3- to 6-ring members. In several embodiments, R 1b is C 1-3 haloalkyl or C 3-6 cycloalkyl. In several embodiments, R 1b is alkyl. In several embodiments, where R 1b is alkyl, R 1b is C 1-2 alkyl.
  • R 1b is alkyl
  • R 1b is C 2-3 alkyl. In several embodiments, where R 1b is alkyl, R 1b is methyl. In several embodiments, where R 1b is alkyl, R 1b is C 2 alkyl (e.g., ethyl). In several embodiments, where R 1b is alkyl, R 1b is C 3 alkyl. In several embodiments, R 1b is alkoxy. In several embodiments, where R 1b is alkoxy, R 1b is C 1-2 alkoxy. In several embodiments, where R 1b is alkoxy, R 1b is C 2-3 alkoxy. In several embodiments, where R 1b is alkoxy, R 1b is methoxy.
  • R 1b is alkoxy
  • R 1b is C 2 alkoxy (e.g., ethoxy). In several embodiments, where R 1b is alkoxy, R 1b is C 3 alkoxy.
  • R 1b is haloalkyl. In several embodiments, where R 1b is haloalkyl, R 1b is C 1-2 haloalkyl. In several embodiments, where R 1b is haloalkyl, R 1b is C 2-3 haloalkyl. In several embodiments, where R 1b is haloalkyl, R 1b is C 1 haloalkyl.
  • R 1b is C 2 haloalkyl (e.g., -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CF 3 , -CF 2 CF 3 , etc.). In several embodiments, where R 1b is haloalkyl, R 1b is C 3 haloalkyl (e.g., -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CH 2 F, - CH 2 CH 2 CF 3 , -CH 2 CF 2 CF 3 , -CF 2 CF 2 CF 3 , etc.). In several embodiments, R 1b is cycloalkyl.
  • R 1b is cycloalkyl
  • R 1b is C 4-6 cycloalkyl.
  • R 1b is C 3-5 cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl).
  • R 1b is C 3 cycloalkyl.
  • R 1b is C 4 cycloalkyl.
  • R 1b is C 5 cycloalkyl.
  • R 1b is cycloalkyl
  • R 1b is C 6 cycloalkyl.
  • the cycloalkyl includes 4 to 6-ring members.
  • the cycloalkyl includes 3 to 5-ring members.
  • R 1b is cycloalkyl (or comprises a cycloalkyl in the case of an alkylene- cycloalkyl)
  • the cycloalkyl includes 3-ring members.
  • the cycloalkyl includes 4-ring members.
  • the cycloalkyl includes 5-ring members.
  • R 1b is cycloalkyl (or comprises a cycloalkyl in the case of an alkylene- cycloalkyl)
  • the cycloalkyl includes 6-ring members.
  • R 1b is heterocyclyl.
  • R 1b is alkylene-heterocyclyl.
  • the heterocyclyl includes 4 to 6-ring members.
  • the heterocyclyl includes 3 to 5-ring members.
  • the heterocyclyl includes 3-ring members. In several embodiments, where R 1b is heterocyclyl (or comprises a heterocyclyl in the case of an alkylene-heterocyclyl), the heterocyclyl includes 4-ring members. In several embodiments, where R 1b is heterocyclyl (or comprises a heterocyclyl in the case of an alkylene-heterocyclyl), the heterocyclyl includes 5-ring members.
  • R 1b is heterocyclyl (or comprises a heterocyclyl in the case of an alkylene- heterocyclyl)
  • the heterocyclyl includes 6-ring members.
  • Embodiment 83 is the compound or salt of any one of Embodiments 1 to 81, wherein R 1b is C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, C 1-3 alkylene-C 6 aryl, heterocyclyl with 3 to 7 ring members, C 6 aryl, C 1-3 alkylene-C 3-7 cycloalkyl, or C 1-3 alkylene-heterocyclyl with 3 to 7 ring members.
  • Embodiment 84 is the compound or salt of any one of Embodiments 1 to 83, wherein R 1b is heterocyclyl with 3 to 7 ring members.
  • Embodiment 85 is the compound or salt of any one of Embodiments 1 to 83, wherein R 1b is C 1-3 alkylene-heterocyclyl with 3 to 7 ring members.
  • Embodiment 86 is the compound or salt of any one of Embodiments 1 to 85, wherein, when R 1b comprises or is a heterocyclyl, the R 1b heterocyclyl has 1, 2, 3, or 4 heteroatom ring members each of which independently is nitrogen, oxygen, or -S(O) x -, where x is 0, 1, or 2.
  • the R 1b heterocyclyl when R 1b is heterocyclyl, the R 1b heterocyclyl includes 1 or 3 heteroatom ring members.
  • R 1b heterocyclyl when R 1b is heterocyclyl, the R 1b heterocyclyl includes 2 or 3 heteroatom ring members.
  • x is 0. In several embodiments, x is 1.
  • x is 2 (e.g., S(O) 2 ).
  • Embodiment 87 is the compound or salt of any one of Embodiments 1 to 86, wherein, when R 1b comprises or is a heterocyclyl, the R 1b heterocyclyl has 1, 2, or 3 heteroatom ring members.
  • Embodiment 88 is the compound or salt of any one of Embodiments 1 to 87, wherein, when R 1b comprises or is a heterocyclyl, the R 1b heterocyclyl has 1 or 2 heteroatom ring members.
  • Embodiment 89 is the compound or salt of any one of Embodiments 1 to 88, wherein, when R 1b comprises or is a heterocyclyl, the R 1b heterocyclyl has 1 heteroatom ring member.
  • Embodiment 90 is the compound or salt of any one of Embodiments 1 to 89, wherein, when R 1b comprises or is a heterocyclyl, the R 1b heterocyclyl includes a heteroatom ring member or ring members that comprise or consist of nitrogen.
  • Embodiment 91 is the compound or salt of any one of Embodiments 1 to 90, wherein, when R 1b comprises a heterocyclyl, the R 1b heterocyclyl includes a heteroatom ring member or ring members that comprise or consist of oxygen.
  • Embodiment 92 is the compound or salt of any one of Embodiments 1 to 83, wherein R 1b is alkyl.
  • Embodiment 93 is the compound or salt of any one of Embodiments 1 to 83, wherein R 1b is alkoxy.
  • Embodiment 94 is the compound or salt of any one of Embodiments 1 to 83, wherein R 1b is heteroalkyl.
  • Embodiment 95 is the compound or salt of any one of Embodiments 1 to 83, wherein R 1b is haloalkyl.
  • Embodiment 96 is the compound or salt of any one of Embodiments 1 to 83, wherein R 1b is cycloalkyl.
  • Embodiment 97 is the compound or salt of any one of Embodiments 1 to 91, wherein R 1b comprises a 3- to 6-ring member heterocyclyl.
  • Embodiment 98 is the compound or salt of any one of Embodiments 1 to 97, wherein R 1b is substituted with 1, 2, 3, or 4 substituents.
  • R 1b is substituted with 1 to 4 substituents.
  • R 1b is substituted with 1 to 3 substituents.
  • R 1b is substituted with 1 to 2 substituents.
  • R 1b is substituted with 2 to 4 substituents.
  • R 1b is substituted with 3 to 4 substituents.
  • R 1b is substituted with 2 to 3 substituents.
  • Embodiment 99 is the compound or salt of any one of Embodiments 1 to 98, wherein R 1b is substituted with 1, 2, or 3 substituents.
  • Embodiment 100 is the compound or salt of any one of Embodiments 1 to 99, wherein R 1b is substituted with 1 or 2 substituents.
  • Embodiment 101 is the compound or salt of any one of Embodiments 1 to 100, wherein R 1b is substituted with 1 substituent.
  • Embodiment 102 is the compound or salt of any one of Embodiments 1 to 101, wherein, when R 1b is substituted, each R 1b substituent independently is halogen, C 1-3 alkyl, or C 1- 3 alkoxy. For example, in several embodiments, when R 1b is substituted, each R 1b substituent independently is halogen or C 1-3 alkoxy. In several embodiments, when R 1b is substituted, each R 1b substituent independently is halogen or C 1-3 alkyl. In several embodiments, when R 1b is substituted, each R 1b substituent independently is C 1-3 alkyl or C 1-3 alkoxy.
  • the substituent is -F, - Cl, or -Br. In several embodiments, the substituent is -F or -Cl. In several embodiments, the substituent is -F. In several embodiments, the substituent is C 1-2 alkyl. In several embodiments, the substituent is C 2-3 alkyl. In several embodiments, the substituent is Methyl. In several embodiments, the substituent is C 2 alkyl. In several embodiments, the substituent is C 3 alkyl. In several embodiments, the substituent is C 1-2 alkoxy. In several embodiments, the substituent is C 2-3 alkoxy. In several embodiments, the substituent is C 1 alkoxy. In several embodiments, the substituent is C 2 alkoxy.
  • the substituent is C 3 alkoxy.
  • Embodiment 103 is the compound or salt of any one of Embodiments 1 to 101, wherein each substituent of R 1b independently is -F, -OH, methyl, or -OMe.
  • the substituent is -OH, methyl, or OMe.
  • the substituent is -F, methyl, or OMe.
  • the substituent is -F, -OH, or OMe.
  • the substituent is -F, -OH, or methyl.
  • the substituent is -F or -OH.
  • the substituent is -F or methyl. In several embodiments, the substituent is -F or OMe. In several embodiments, the substituent is -OH or methyl. In several embodiments, the substituent is -OH or OMe. In several embodiments, the substituent is methyl or OMe.
  • Embodiment 104 is the compound or salt of any one of Embodiments 1 to 103, wherein R 1b is substituted with -F.
  • Embodiment 105 is the compound or salt of any one of Embodiments 1 to 104, wherein R 1b is substituted with -OH.
  • Embodiment 106 is the compound or salt of any one of Embodiments 1 to 105, wherein R 1b is substituted with -OMe.
  • Embodiment 107 is the compound or salt of any one of Embodiments 1 to 97, wherein R 1b is unsubstituted.
  • Embodiment 108 is the compound or salt of any one of Embodiments 1 to 107, wherein R 1b is: , , 1 to 66, wherein R 1a and R 1b together form a 3 to 10 membered heterocyclyl.
  • R 1a and R 1b together form a heterocyclyl having 4 to 6-ring members.
  • R 1a and R 1b together form a heterocyclyl having 5 to 6-ring members.
  • R 1a and R 1b together form a heterocyclyl having 3 to 5-ring members.
  • R 1a and R 1b together form a heterocyclyl having 3 to 4-ring members.
  • R 1a and R 1b together form a heterocyclyl having 4 to 5-ring members.
  • R 1a and R 1b together form a heterocyclyl having 5 to 10-ring members.
  • R 1a and R 1b together form a heterocyclyl having 6 to 10-ring members.
  • R 1a and R 1b together form a heterocyclyl having 5 to 9-ring members. In several embodiments, R 1a and R 1b together form a heterocyclyl having 6 to 9-ring members. In several embodiments, R 1a and R 1b together form a heterocyclyl having 3-ring members. In several embodiments, R 1a and R 1b together form a heterocyclyl having 4-ring members. In several embodiments, R 1a and R 1b together form a heterocyclyl having 5-ring members. In several embodiments, R 1a and R 1b together form a heterocyclyl having 6-ring members. In several embodiments, R 1a and R 1b together form a heterocyclyl having 7-ring members.
  • R 1a and R 1b together form a spirocyclic heterocyclyl. In several embodiments, R 1a and R 1b together form a heterocyclyl having a fused ring system. In several embodiments, R 1a and R 1b together form a heterocyclyl having a bridged ring system. In several embodiments, R 1a and R 1b together form a heterocyclyl having two rings in a ring system. [0183] Provided herein as Embodiment 110 is the compound or salt of any one of Embodiments 1 to 66 and 109, wherein R 1a and R 1b together form a 3 to 9 membered heterocyclyl.
  • Embodiment 111 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 110, wherein R 1a and R 1b together form a heterocyclyl that is fully saturated.
  • Embodiment 112 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 111, wherein R 1a and R 1b together form a heterocyclyl and each heteroatom ring member of the R 1a and R 1b heterocyclyl independently is nitrogen, oxygen, or -S(O) x -, where x is 0, 1, or 2.
  • R 1a and R 1b together form a heterocyclyl having 1 or 3 heteroatom ring members.
  • R 1a and R 1b together form a heterocyclyl having 2 or 3 heteroatom ring members.
  • x is 0.
  • x is 1.
  • x is 2 (e.g., S(O) 2 ).
  • Embodiment 113 Provided herein as Embodiment 113 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 112, wherein R 1a and R 1b together form a heterocyclyl having 1, 2, or 3 heteroatom ring members.
  • Embodiment 114 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 113, wherein R 1a and R 1b together form a heterocyclyl having 1 or 2 heteroatom ring members.
  • Embodiment 115 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 114, wherein R 1a and R 1b together form a heterocyclyl having 1 heteroatom ring member.
  • Embodiment 116 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 115, wherein R 1a and R 1b together form a heterocyclyl and the heteroatom or heteroatoms of the R 1a and R 1b heterocyclyl comprise or consist of nitrogen.
  • Embodiment 117 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 116, wherein R 1a and R 1b together form a heterocyclyl and the heteroatom or heteroatoms of the R 1a and R 1b heterocyclyl comprise oxygen.
  • Embodiment 118 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 117, wherein R 1a and R 1b together form a multicyclic heterocyclyl.
  • Embodiment 119 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 118, wherein R 1a and R 1b together form a tricyclic heterocyclyl.
  • Embodiment 120 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 118, wherein R 1a and R 1b together form a bicyclic heterocyclyl.
  • Embodiment 121 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 120, wherein R 1a and R 1b together form a bridged heterocyclyl ring system.
  • Embodiment 122 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 121, wherein R 1a and R 1b together form a fused heterocyclyl ring system.
  • Embodiment 123 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 122, wherein R 1a and R 1b together form a spirocyclic heterocyclyl.
  • Embodiment 124 is the compound or salt of any one of Embodiments 120 to 123, wherein the R 1a and R 1b heterocyclyl ring system comprises at least a first and a second ring, the first ring comprising at least 7 ring members.
  • Embodiment 125 is the compound or salt of any one of Embodiments 120 to 123, wherein the R 1a and R 1b heterocyclyl ring system comprises at least a first and a second ring, the first ring comprising at least 6 ring members.
  • Embodiment 126 is the compound or salt of any one of Embodiments 120 to 123, wherein the R 1a and R 1b heterocyclyl ring system comprises at least a first and a second ring, the first ring comprising at least 5 ring members.
  • Embodiment 127 is the compound or salt of any one of Embodiments 120 to 123, wherein the R 1a and R 1b heterocyclyl ring system comprises at least a first and a second ring, the first ring comprising at least 4 ring members.
  • Embodiment 128 is the compound or salt of any one of Embodiments 124 to 127, wherein the second ring of the R 1a and R 1b heterocyclyl ring system comprises 6 ring members.
  • Embodiment 129 is the compound or salt of any one of Embodiments 124 to 127, wherein the second ring of the R 1a and R 1b heterocyclyl ring system comprises 5 ring members.
  • Embodiment 130 Provided herein as Embodiment 130 is the compound or salt of any one of Embodiments 124 to 127, wherein the second ring of the R 1a and R 1b heterocyclyl ring system comprises 4 ring members.
  • Embodiment 131 is the compound or salt of any one of Embodiments 124 to 127, wherein the second ring of the R 1a and R 1b heterocyclyl ring system comprises 3 ring members.
  • Embodiment 132 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 131, wherein the R 1a and R 1b heterocyclyl comprises a carbocyclyl ring.
  • Embodiment 133 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 131, wherein the R 1a and R 1b heterocyclyl comprises at least two heterocyclic rings.
  • Embodiment 134 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 133, wherein R 1a and R 1b together form a heterocyclyl that is substituted with 1, 2, 3, 4, or 5 instances of R 4 .
  • R 1a and R 1b heterocyclyl is substituted with 2 to 5 R 4 substituents.
  • the R 1a and R 1b heterocyclyl is substituted with 3 to 4 R 4 substituents.
  • the R 1a and R 1b heterocyclyl is substituted with 3 to 5 R 4 substituents.
  • the R 1a and R 1b heterocyclyl is substituted with 4 to 5 R 4 substituents. In several embodiments, the R 1a and R 1b heterocyclyl is substituted with 2, 3, 4, or 5 R 4 substituents. In several embodiments, the R 1a and R 1b heterocyclyl is substituted with 1, 2, or 4 R 4 substituents. In several embodiments, the R 1a and R 1b heterocyclyl is substituted with 1 or 3 R 4 substituents.
  • Embodiment 135 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 134, wherein R 1a and R 1b together form a heterocyclyl that is substituted with 1, 2, 3, or 4 instances of R 4 .
  • Embodiment 136 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 135, wherein R 1a and R 1b together form a heterocyclyl that is substituted with 1, 2, or 3 instances of R 4 .
  • Embodiment 137 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 136, wherein R 1a and R 1b together form a heterocyclyl that is substituted with 1 or 2 instances of R 4 .
  • Embodiment 138 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 137, wherein R 1a and R 1b together form a heterocyclyl that is substituted with 1 instance of R 4 .
  • Embodiment 139 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 138, wherein each instance of R 4 independently is halogen, OH, -NH 2 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-4 alkylamino, di C 1-4 alkylamino, C 1-6 alkylene-OH, C 1-6 haloalkyl.
  • each instance of R 4 independently is halogen, OH, -NH 2 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, or C 1-6 haloalkyl.
  • an instance of R 4 is -OH. In several embodiments, an instance of R 4 is C 1-6 alkylene-OH. In several embodiments, an instance of R 4 is -NH 2 . In several embodiments, an instance of R 4 is halogen. In several embodiments, an instance of R 4 is -F, - Cl, or -Br. In several embodiments, an instance of R 4 is -F or -Cl. In several embodiments, an instance of R 4 is -F. In several embodiments, an instance of R 4 is C 1-3 alkyl. In several embodiments, an instance of R 4 is C 1-2 alkyl. In several embodiments, an instance of R 4 is C 2-3 alkyl.
  • an instance of R 4 is methyl. In several embodiments, an instance of R 4 is C 2 alkyl. In several embodiments, an instance of R 4 is C 3 alkyl. In several embodiments, an instance of R 4 is C 1-3 haloalkyl. In several embodiments, an instance of R 4 is C 1-2 haloalkyl. In several embodiments, an instance of R 4 is C 2-3 haloalkyl. In several embodiments, an instance of R 4 is C 1 haloalkyl. In several embodiments, an instance of R 4 is C 2 haloalkyl. In several embodiments, an instance of R 4 is C 3 haloalkyl. In several embodiments, an instance of R 4 is C 1-3 heteroalkyl.
  • an instance of R 4 is C 1-2 heteroalkyl. In several embodiments, an instance of R 4 is C 2-3 heteroalkyl. In several embodiments, an instance of R 4 is C 1 heteroalkyl. In several embodiments, an instance of R 4 is C 2 heteroalkyl. In several embodiments, an instance of R 4 is C 3 heteroalkyl. In several embodiments, an instance of R 4 is C 1-2 alkoxy. In several embodiments, an instance of R 4 is C 2-3 alkoxy. In several embodiments, an instance of R 4 is methoxy. In several embodiments, an instance of R 4 is C 2 alkoxy. In several embodiments, an instance of R 4 is C 3 alkoxy.
  • Embodiment 140 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 139, wherein each instance of R 4 independently is halogen, OH, -NH 2 , C 1-3 alkyl, C 1-3 alkoxy, or C 1-3 haloalkyl.
  • Embodiment 141 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 138, wherein each instance of R 4 independently is -F, -OH, -NH 2 , -CH 3 , -CF 3 , -CH 2 OH, - OCH 3 , -OCH 2 CH 3 , or -OCHF 2 ,.
  • Embodiment 142 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 138, wherein each instance of R 4 independently is -CF 3 , -CF 2 CF 3 , or -CF 2 CF 2 CF 3 ,
  • Embodiment 143 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 140, wherein each instance of R 4 may be substituted with 1, 2, or 3 substituents.
  • Embodiment 144 is the compound or salt of any one of Embodiments 1 to 66, 109 to 140, and 143, wherein each instance of R 4 may be substituted with 1 or 2 substituents.
  • Embodiment 145 is the compound or salt of any one of Embodiments 1 to 66, 109 to 140, 143, and 144, wherein each instance of R 4 may be substituted with 1 substituent.
  • Embodiment 146 is the compound or salt of any one of Embodiments 1 to 66, 109 to 140, 143, and 144, wherein at least one instance of R 4 is substituted with a substituent that independently is halogen, –OH, C 1-3 alkoxy, -NH 2 , C 1-2 alkylamino, or di C 1-2 alkylamino.
  • a substituent that independently is halogen, –OH, C 1-3 alkoxy, -NH 2 , C 1-2 alkylamino, or di C 1-2 alkylamino.
  • each substituent of R 4 independently is halogen, OH, -NH 2 , or C 1-3 alkoxy.
  • an instance of a R 4 substituent is -F, -Cl, or -Br.
  • an instance of a R 4 substituent is -F or -Cl. In several embodiments, an instance of a R 4 substituent is -F. In several embodiments, an instance of a R 4 substituent is C 1-2 alkoxy. In several embodiments, an instance of a R 4 substituent is C 2-3 alkoxy. In several embodiments, an instance of a R 4 substituent is methoxy. In several embodiments, an instance of a R 4 substituent is C 2 alkoxy. In several embodiments an instance of a R 4 substituent is C 3 alkoxy. In several embodiments, an instance of a R 4 substituent is NH 2 . In several embodiments, an instance of a R 4 substituent is C 1-2 alkylamino.
  • an instance of a R 4 substituent is C 1-2 dialkylamino.
  • Embodiment 147 is the compound or salt of any one of Embodiments 1 to 66, 109 to 140, wherein each instance of R 4 is unsubstituted.
  • Embodiment 148 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 133, wherein R 1a and R 1b together form a heterocyclyl that is unsubstituted.
  • Embodiment 149 is the compound or salt of any one of Embodiments 1 to 66, wherein, is represented by: ; wherein h is 1, 2, 3, 4, 5, or 6; and g is 0, 1, 2, 3, 4, 5, or 6.
  • Embodiment 150 is the compound or salt of Embodiment 149, wherein h is 1, 2, 3, 4, or 5.
  • Embodiment 151 is the compound or salt of Embodiment 149 or 150, wherein h is 1, 2, 3, or 4.
  • Embodiment 152 is the compound or salt of any one of Embodiments 149 to 151, wherein h is 1, 2, or 3.
  • Embodiment 153 is the compound or salt of any one of Embodiments 149 to 152, wherein g is 0, 1, 2, 3, 4, or 5.
  • Embodiment 154 is the compound or salt of any one of Embodiments 149 to 153, wherein g is 0, 1, 2, 3, or 4.
  • Embodiment 155 is the compound or salt of any one of Embodiments 149 to 154, wherein g is 0, 1, 2, or 3.
  • Embodiment 156 is the compound or salt of any one of Embodiments 149 to 155, wherein g is 0, 1, or 2.
  • Embodiment 157 is the compound or salt of any one of Embodiments 149 to 156, wherein g is 0 or 1.
  • Embodiment 158 is the compound or salt of any one of Embodiments 149 to 157, wherein g is 0.
  • Embodiment 159 is the compound or salt of any one of Embodiments 1 to 66, wherein, is represented by: , . In several embodiments, is represented by . In several embodiments, is represented by . In several embodiments, is represented n several embodiments, is represented by . In several embodiments, In several embodiments, is represented by eral embodiments, . In several embodimen is represented by . In several embodiment .
  • R1a N is represented by . In several embodiments is represented . R1a N In several embodiments, R1a N is represented by . In several embodiments R1b is represent . R 1a In several embodiments is represented by . In several embodiments, is represented by . In several embodiments, is represented by . In several embodiments. In several embodiments, is represented by . In several embodiments , is represented by b . In 1a R 1a several embodiments, is represented by . In several embodiment is represented . In R1a several embodiments, is represented by . In several embodiments, is represented b . In several embodiments, is represented by I l b di t is represented by . In several embodiment .
  • R1a N several embodiments, R1b is represented In several embodiments, is represented by . In several embodime s, s represented by .
  • Embodiment 160 is the compound or salt of any one of Embodiments 1 to 66, wherein, is represented by: .
  • Embodiment 161 is the compound or salt of any one of Embodiments 1 to 66, 161, wherein R is heterocyclyl.
  • Embodiment 163 is the compound or salt of any one of Embodiments 1 to 161, wherein R 2 is heteroaryl.
  • Embodiment 164 is the compound or salt of any one of Embodiments 1 to 163, wherein the R 2 has 1, 2, 3, 4, or 5 heteroatom ring members.
  • R 2 includes 5 heteroatom ring members.
  • R 2 includes 4 heteroatom ring members.
  • R 2 includes 3 heteroatom ring members.
  • R 2 includes 2 heteroatom ring members.
  • R 2 includes 1 heteroatom ring member.
  • R 2 comprises 1 to 5 heteroatom ring members.
  • R 2 comprises 1 to 4 heteroatom ring members.
  • R 2 comprises 1 to 3 heteroatom ring members.
  • R 2 comprises 1 or 2 heteroatom ring members. In several embodiments, R 2 comprises 2 to 5 heteroatom ring members. In several embodiments, R 2 comprises 3 to 5 heteroatom ring members. In several embodiments, R 2 comprises 3 to 4 heteroatom ring members. In several embodiments, R 2 comprises nitrogen atoms as the only ring heteroatoms. In several embodiments, R 2 comprises one nitrogen atom as a ring heteroatom. In several embodiments, R 2 comprises two nitrogen atoms as a ring heteroatoms. In several embodiments, R 2 comprises three nitrogen atoms as a ring heteroatoms. In several embodiments, R 2 comprises four nitrogen atoms as a ring heteroatoms.
  • R 2 comprises five nitrogen atoms as a ring heteroatoms. In several embodiments, R 2 comprises one oxygen ring heteroatom and the remaining ring heteroatoms are nitrogen atoms. In several embodiments, R 2 comprises oxygen atoms as the only ring heteroatoms.
  • Embodiment 165 is the compound or salt of any one of Embodiments 1 to 164, wherein R 2 has 1, 2, 3, or 4 heteroatom ring members.
  • Embodiment 166 is the compound or salt of any one of Embodiments 1 to 165, wherein R 2 has 1, 2, or 3 heteroatom ring members.
  • Embodiment 167 is the compound or salt of any one of Embodiments 1 to 166, wherein R 2 has 1 or 2 heteroatom ring members.
  • Embodiment 168 is the compound or salt of any one of Embodiments 1 to 167, wherein R 2 has 1 heteroatom ring member.
  • Embodiment 169 is the compound or salt of any one of Embodiments 1 to 168, wherein each heteroatom ring member of R 2 independently is nitrogen, oxygen, or -S(O) y -, where y is 0, 1, or 2.
  • Embodiment 170 is the compound or salt of any one of Embodiments 1 to 169, wherein each heteroatom of the R 2 ring independently is nitrogen or oxygen.
  • Embodiment 171 is the compound or salt of any one of Embodiments 1 to 170, wherein each ring heteroatom of the R 2 is nitrogen.
  • Embodiment 172 is the compound or salt of any one of Embodiments 1 to 170, wherein each ring heteroatom of R 2 is oxygen.
  • Embodiment 173 is the compound or salt of any one of Embodiments 1 to 172, wherein R 2 is a fused bicyclic group.
  • the fused bicyclic R 2 comprises a 6- membered ring. In several embodiments, the fused bicyclic R 2 comprises a 5-membered ring. In several embodiments, the fused bicyclic R 2 is a 5,6-member fused ring. In several embodiments, the fused bicyclic R 2 is a 6,6-member fused ring.
  • Embodiment 174 is the compound or salt of any one of Embodiments 1 to 173, wherein R 2 comprises 5 to 10 ring-members.
  • Embodiment 175 is the compound or salt of any one of Embodiments 1 to 174, wherein R 2 comprises 5 to 9 ring-members.
  • Embodiment 176 is the compound or salt of any one of Embodiments 1 to 174, wherein R 2 has 10 ring members.
  • Embodiment 177 is the compound or salt of any one of Embodiments 1 to 175, wherein R 2 has 9 ring members.
  • Embodiment 178 is the compound or salt of any one of Embodiments 1 to 172, wherein R 2 has 6 ring members.
  • Embodiment 179 Provided herein as Embodiment 179 is the compound or salt of any one of Embodiments 1 to 163 and 165 to 172, wherein R 2 has 5 ring members.
  • Embodiment 180 is the compound or salt of any one of Embodiments 1 to 179, wherein R 2 is substituted with 1, 2, 3, 4, or 5 instances of R 5 .
  • R 2 is substituted with 2 to 5 R 5 substituents.
  • R 2 is substituted with 3 to 4 R 5 substituents.
  • R 5 is substituted with 3 to 5 R 5 substituents.
  • R 2 is substituted with 4 to 5 R 5 substituents.
  • R 2 is substituted with 2, 3, 4, or 5 R 5 substituents.
  • R 2 is substituted with 1, 2, or 4 R 5 substituents.
  • R 2 is substituted 1 or 3 R 5 substituents.
  • Embodiment 181 Provided herein as Embodiment 181 is the compound or salt of any one of Embodiments 1 to 180, wherein R 2 is substituted with 1, 2, 3, or 4 instances of R 5 .
  • Embodiment 182 Provided herein as Embodiment 182 is the compound or salt of any one of Embodiments 1 to 181, wherein R 2 is substituted with 1, 2, or 3 instances of R 5 .
  • Embodiment 183 Provided herein as Embodiment 183 is the compound or salt of any one of Embodiments 1 to 182, wherein R 2 is substituted with 1 or 2 instances of R 5 .
  • Embodiment 184 is the compound or salt of any one of Embodiments 1 to 183, wherein R 2 is substituted with 1 instance of R 5 .
  • Embodiment 185 is the compound or salt of any one of Embodiments 1 to 184, wherein each instance of R 5 is substituted with 1, 2, or 3 instances of R 6 .
  • Embodiment 186 is the compound or salt of any one of Embodiments 1 to 185, wherein each instance of R 5 is substituted with 1 or 2 instances of R 6 .
  • Embodiment 187 is the compound or salt of any one of Embodiments 1 to 186, wherein each instance of R 5 is substituted with 1 instance of R 6 .
  • Embodiment 188 is the compound or salt of any one of Embodiments 1 to 187, wherein, each instance of R 5 independently is halogen, oxo, -CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl, amino, C 1-4 alkylamino, di C 1-4 alkylamino, C(O)heterocyclyl having 3 to 6 ring members, or heterocyclyl having 3 to 6 ring members.
  • each R 5 independently is halogen, -OH, oxo, or C 1-3 alkyl. In several embodiments, each R 5 independently is halogen, -OH, oxo, C 1-3 alkyl, or C 1-3 alkoxy. In several embodiments, each R 5 independently is halogen, - OH, oxo, or C 1-3 alkoxy. In several embodiments, each R 5 independently is halogen, -OH, C 1-3 alkyl, or C 1- 3 alkoxy. In several embodiments, each R 5 independently is halogen, oxo, C 1-3 alkyl, or C 1-3 alkoxy.
  • each R 5 independently is -OH, oxo, C 1-3 alkyl, or C 1-3 alkoxy. In several embodiments, each R 5 independently is oxo, C 1-3 alkyl, or C 1-3 alkoxy. In several embodiments, each R 5 independently is halogen, C 1-3 alkyl, or C 1-3 alkoxy. In several embodiments, each R 5 independently is halogen, -OH, or C 1-3 alkoxy. In several embodiments, each R 5 independently is halogen, -OH, or oxo. In several embodiments, each R 5 independently is halogen, -OH, oxo, C 1-3 alkyl, or C 1-3 alkoxy.
  • each R 5 independently is halogen, -OH, oxo, C 1-3 alkyl, or C 1-3 haloalkyl. In several embodiments, each R 5 independently is halogen, oxo, or C 1-3 alkyl. In several embodiments, each R 5 independently is halogen or C 1-3 alkyl. In several embodiments, each R 5 independently is oxo or C 1-3 alkyl. In several embodiments, each R 5 independently is halogen or oxo. In several embodiments, an instance of R 5 is halogen. In several embodiments, a halogen R 5 substituent (or one or more substituents independently) is -F, -Cl, or -Br.
  • a halogen R 5 substituent (or one or more substituents independently) is -F or -Cl. In several embodiments, a halogen R 5 substituent (or one or more substituents) is -F. In several embodiments, an R 5 independently is C 1-3 alkyl. In several embodiments, an R 5 alkyl is C 1-2 alkyl. In several embodiments, an R 5 alkyl is C 2-3 alkyl. In several embodiments, an R 5 alkyl is methyl. In several embodiments, an R 5 alkyl is C 2 alkyl. In several embodiments, an R 5 alkyl is C 3 alkyl. In several embodiments, an R 5 alkoxy is C 1-2 alkoxy.
  • an R 5 alkoxy is C 2-3 alkoxy. In several embodiments, an R 5 alkoxy is methoxy. In several embodiments, an R 5 alkoxy is C 2 alkoxy. In several embodiments, an R 5 alkoxy is C 3 alkoxy.
  • Embodiment 189 is the compound or salt of any one of Embodiments 1 to 188, wherein, each instance of R 5 independently is halogen, oxo, OH, C 1-6 alkyl, C 1-6 haloalkyl, amino, - NH(C 1-2 alkyl), -N(C 1-2 alkyl) 2 , C(O)heterocyclyl having 3 to 6 ring members, or heterocyclyl having 3 to 6 ring members.
  • Embodiment 190 is the compound or salt of any one of Embodiments 1 to 189, wherein, each instance of R 5 independently is oxo, C 1-3 alkyl, C 1-3 haloalkyl, or C 1-3 alkoxy.
  • Embodiment 191 is the compound or salt of any one of Embodiments 1 to 189, wherein, each instance of R 5 independently is -F, oxo, -Me, -CF 3 , -C(O)piperidinyl, or - C(O)piperizinyl.
  • Embodiment 192 is the compound or salt of any one of Embodiments 1 to 189, wherein, each instance of R 5 independently is -C(O)piperidinyl or -C(O)piperizinyl.
  • Embodiment 193 is the compound or salt of any one of Embodiments 1 to 189, wherein each instance of R 5 independently is -F, oxo, methyl, ethyl, or isopropyl.
  • Embodiment 194 is the compound or salt of any one of Embodiments 1 to 193, wherein at least one instance of R 5 is -F.
  • Embodiment 195 is the compound or salt of any one of Embodiments 1 to 194, wherein at least one instance of R 5 is methyl.
  • Embodiment 196 is the compound or salt of any one of Embodiments 1 to 195, wherein at least one instance of R 5 is oxo.
  • Embodiment 197 is the compound or salt of any one of Embodiments 1 to 196, wherein, each instance of R 6 independently is halogen, -C 1-6 alkyl, -C(O) 2 C 1-6 alkyl.
  • Embodiment 198 is the compound or salt of any one of Embodiments 1 to 197, wherein each instance of R 6 independently is -F, -Me, -C(O)OtBu.
  • Embodiment 199 is the compound or salt of any one of Embodiments 1 to 198, wherein at least one instance of R 6 is -F.
  • Embodiment 200 is the compound or salt of any one of Embodiments 1 to 199, wherein at least one instance of R 6 is methyl.
  • Embodiment 201 is the compound or salt of any one of Embodiments 1 to 200, wherein at least one instance of R 6 is -C(O)OtBu.
  • Embodiment 202 is the compound or salt of any one of Embodiments 1 to 179, wherein R 2 is unsubstituted.
  • Embodiment 203 is the compound or salt of any one of Embodiments 1 to 184 and 188 to 196, wherein R 5 is unsubstituted.
  • R 2 is ; where “ ” indicates a double bond or single bond may be present; each instance of X a independently is nitrogen, oxygen, or carbon; each instance of s, where present, is an integer selected from 0, 1, 2, or 3; each instance of r, where present, independently is an integer selected from 0, 1, 2, 3, 4, or 5, wherein where two instances of r occur on the
  • Embodiment 211 is the compound or salt of any one of Embodiments 1 to 171 and 173 to 203, wherein R 2 is , , , wherein R may be unsubstituted or substituted by replacing any ring -H with an R group.
  • Embodiment 212 is the compound or salt of any one of Embodiments 1 to 163, wherein R 2 together with its substituents is , , , p y Embodiments 1 to 161, wherein R 2 is .
  • Embodiment 214 ound or salt of any one of Embodiments 1 to 213, wherein R 3 is C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkoxy, C 3-7 cycloalkyl, heterocyclyl with 3 to 7 ring members, C 6-10 aryl, or heteroaryl having 5 to 10 ring members.
  • R 3 is C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, heteroaryl having 5 to 10 ring members, or heterocyclyl having 5 to 10 ring members.
  • R 3 is C 1-6 alkyl, heteroaryl having 5 to 10 ring members, or heterocyclyl having 5 to 10 ring members. In several embodiments, R 3 is C 1-6 alkyl, C 1-6 alkenyl, C 3-6 cycloalkyl, or heteroaryl having 5 to 10 ring members. In several embodiments, R 3 is heteroaryl having 5 to 9 ring members. [0288] Provided herein as Embodiment 215 is the compound or salt of any one of Embodiments 1 to 214, wherein R 3 is C 3-6 cycloalkyl, C 6-10 aryl, heteroaryl having 5 to 10 ring members, or heterocyclyl having 3 to 10 ring members.
  • Embodiment 216 is the compound or salt of any one of Embodiments 1 to 215, wherein R 3 is heteroaryl or heterocyclyl and the R 3 heteroaryl or heterocyclyl includes 1, 2, 3, or 4 heteroatom ring members.
  • R 3 includes 4 heteroatom ring members.
  • R 3 includes 3 heteroatom ring members.
  • R 3 includes 2 heteroatom ring members.
  • R 3 includes 1 heteroatom ring member.
  • R 3 comprises 1 to 4 heteroatom ring members.
  • R 3 comprises 1 to 3 heteroatom ring members.
  • R 3 comprises 1 or 2 heteroatom ring members.
  • R 3 comprises 3 to 4 heteroatom ring members. In several embodiments, R 3 comprises nitrogen atoms as the only ring heteroatoms. In several embodiments, R 3 comprises one nitrogen atom as a ring heteroatom. In several embodiments, R 3 comprises two nitrogen atoms as a ring heteroatoms. In several embodiments, R 3 comprises three nitrogen atoms as a ring heteroatoms. In several embodiments, R 3 comprises four nitrogen atoms as a ring heteroatoms. In several embodiments, R 3 comprises one oxygen ring heteroatom and the remaining ring heteroatoms are nitrogen atoms. In several embodiments, R 3 comprises oxygen atoms as the only ring heteroatoms.
  • Embodiment 217 is the compound or salt of any one of Embodiments 1 to 216, wherein R 3 is heteroaryl or heterocyclyl and the R 3 heteroaryl or heterocyclyl includes 1, 2, or 3 heteroatom ring members.
  • Embodiment 218 is the compound or salt of any one of Embodiments 1 to 217, wherein R 3 is heteroaryl or heterocyclyl and the R 3 heteroaryl or heterocyclyl includes 1 or 2 heteroatom ring members.
  • Embodiment 219 is the compound or salt of any one of Embodiments 1 to 218, wherein R 3 is heteroaryl or heterocyclyl and the R 3 heteroaryl or heterocyclyl includes 1 heteroatom ring member.
  • Embodiment 220 is the compound or salt of any one of Embodiments 1 to 219, wherein R 3 is heteroaryl or heterocyclyl and each heteroatom of the R 3 ring independently is nitrogen, oxygen, or -S(O) z -, where z is 0, 1, or 2.
  • Embodiment 221 is the compound or salt of any one of Embodiments 1 to 220, wherein R 3 is heteroaryl or heterocyclyl and each heteroatom of the R 3 ring independently is nitrogen or oxygen.
  • Embodiment 222 is the compound or salt of any one of Embodiments 1 to 221, wherein R 3 is heteroaryl or heterocyclyl and each heteroatom of the R 3 ring is nitrogen.
  • Embodiment 223 is the compound or salt of any one of Embodiments 1 to 215 and 217 to 221, wherein R 3 is heteroaryl or heterocyclyl and each heteroatom of the R 3 ring is oxygen.
  • Embodiment 224 is the compound or salt of any one of Embodiments 1 to 223, wherein R 3 is fused bicyclic heteroaryl or fused bicyclic heterocyclic.
  • Embodiment 225 is the compound or salt of any one of Embodiments 1 to 224, wherein R 3 is heteroaryl.
  • Embodiment 226 is the compound or salt of any one of Embodiments 1 to 224, wherein R 3 is heterocyclyl.
  • Embodiment 227 is the compound or salt of any one of Embodiments 1 to 226, wherein R 3 comprises 5 to 10 ring-members.
  • Embodiment 228 is the compound or salt of any one of Embodiments 1 to 227, wherein R 3 comprises 5 to 9 ring-members.
  • Embodiment 229 is the compound or salt of any one of Embodiments 1 to 228, wherein R 3 has 9-ring members.
  • Embodiment 230 is the compound or salt of any one of Embodiments 1 to 215 and 217 to 223 and 225 to 228, wherein R 3 has 6-ring members.
  • Embodiment 231 is the compound or salt of any one of Embodiments 1 to 223 and 225 to 228, wherein R 3 has 5-ring members.
  • Embodiment 232 is the compound or salt of any one of Embodiments 1 to 214, wherein R 3 is C 3-4 cycloalkyl.
  • Embodiment 233 is the compound or salt of any one of Embodiments 1 to 214, wherein R 3 is C 1-6 alkyl.
  • Embodiment 234 is the compound or salt of any one of Embodiments 1 to 214, wherein R 3 is C 6-10 aryl.
  • Embodiment 235 is the compound or salt of any one of Embodiments 1 to 214, wherein R 3 is C 6 aryl.
  • R 3 when R 3 is C 6 aryl (e.g., phenyl), then R 2 is 9 membered heteroaryl. In several embodiments, when R 3 is C 6 aryl (e.g., phenyl), then R 2 is 9 membered heteroaryl comprising 1, 2, or 3 N atoms as the only ring heteroatoms. In several embodiments, when R 3 is C 6 aryl (e.g., phenyl), then R 2 is pyrazolo[3,4-b]pyridinyl. In several embodiments, when R 3 is C 6 aryl (e.g., phenyl), then R 2 is 2-methyl-2H-pyrazolo[3,4-b]pyridinyl.
  • Embodiment 236 is the compound or salt of any one of Embodiments 1 to 235, wherein R 3 is substituted with 1, 2, 3, 4, or 5 substituents.
  • R 3 is substituted with 2 to 5 substituents.
  • R 3 is substituted with 3 to 4 substituents.
  • R 3 is substituted with 3 to 5 substituents.
  • R 3 is substituted with 4 to 5 substituents.
  • R 3 is substituted with 2, 3, 4, or 5 substituents.
  • R 3 is substituted with 1, 2, or 4 substituents.
  • R 3 is substituted 1 or 3 substituents.
  • Embodiment 237 is the compound or salt of any one of Embodiments 1 to 236, wherein R 3 is substituted with 1, 2, 3, or 4 substituents.
  • Embodiment 238 is the compound or salt of any one of Embodiments 1 to 237, wherein R 3 is substituted with 1, 2, or 3 substituents.
  • Embodiment 239 is the compound or salt of any one of Embodiments 1 to 238, wherein R 3 is substituted with 1 or 2 substituents.
  • Embodiment 240 is the compound or salt of any one of Embodiments 1 to 239, wherein R 3 is substituted with 1 substituent.
  • Embodiment 241 is the compound or salt of any one of Embodiments 1 to 240, wherein each substituent of R 3 independently is halogen, OH, C 1-3 alkyl, C 1-3 alkoxy, or C 1-3 alkylene- C 1-3 alkoxy.
  • each substituent of R 3 independently is C 1-3 alkyl, C 1- 3 alkoxy, or C 1-3 alkylene-C 1-3 alkoxy.
  • R 3 is substituted with -F or -OH.
  • R 3 is substituted with -OH or C 1-3 alkoxy.
  • R 3 is substituted with -F or C 1-3 alkoxy.
  • R 3 is substituted with -F, -OH, C 1 alkyl, C 2 alkyl, C 3 alkyl, C 1 alkoxy, C 2 alkoxy, and/or C 3 alkoxy. In several embodiments, R 3 is substituted with methyl, C 2 alkyl, and/or C 3 alkyl. In several embodiments, R 3 is substituted with -C 1 alkoxy, C 2 alkoxy, or C 3 alkoxy. In several embodiments, R 3 is substituted with -C 1 alkoxy. In several embodiments, R 3 is substituted with C 2 alkoxy. In several embodiments, R 3 is substituted with C 3 alkoxy. In several embodiments, R 3 is substituted with -F.
  • Embodiment 242 is the compound or salt of any one of Embodiments 1 to 241, wherein each substituent of R 3 substituent independently is methyl, ethyl, or isopropyl.
  • Embodiment 243 is the compound or salt of any one of Embodiments 1 to 214 and 236 to 242, wherein R 3 is , where “ ” indicates a double bond or single bond may be present; each instance of X b independently is nitrogen, oxygen, or carbon; each instance of t, where present, is an integer selected from 1, 2, 3, 4, or 5; each instance of t’, where present, is an integer selected from 0, 1, 2, 3, 4, or 5; each instance of u, where present, is an integer selected from 0, 1, 2, 3, 4, or 5; each instance of v, where present, is an integer selected from 0, 1, 2, 3, 4, or 5, wherein where two instances of v occur on the same R 3 group, the total of both v values combined does not exceed 5; each instance of R 13 , when present and attached to an N ring member, independently is C 1-3 alkyl, C 1-3 haloalkyl, or C 1-3 alkylene-C 1-3 alkoxy; and each instance of R 13 , when present
  • Embodiment 244 is the compound or salt of any one of Embodiments 1 to 214 and 236 to 243, wherein R 3 is: ; where each instance of t, where present, is an integer selected from 1, 2, 3, 4, or 5; each instance of t’, where present, is an integer selected from 0, 1, 2, 3, 4, or 5; each instance of u, where present, is an integer selected from 0, 1, 2, or 3; each instance of v, where present, is an integer selected from 0, 1, 2, or 3, wherein where two instances of v occur on the same R 3 group, the total of both v values combined does not exceed 5; each instance of R 13 , when present and attached to an N ring member, independently is C 1-3 alkyl, C 1-3 haloalkyl, or C 1-3 alkylene-C 1-3 alkoxy; and each instance of R 13 , when present and attached to a C ring member, independently is halogen, - OH, oxo, C 1-3 alkyl,
  • Embodiment 245 is the compound or salt of any one of Embodiments 1 to 214, wherein R 3 is halogen.
  • Embodiment 246 is the compound or salt of any one of Embodiments 1 to 214, wherein R 3 is -Cl.
  • Embodiment 248 is the compound or salt of any one of Embodiments 1 to 214, wherein R 3 is: .
  • Embodiment 249 is the compound or salt of any one of Embodiments 1 to 214, wherein R 3 is: .
  • Embodiment 250 is th e compound or salt of any one of Embodiments 1 to 214, wherein R 3 is: .
  • Embodiment 251 is t mpound or salt of any one of Embodiments 1 to 214, wherein R 3 is: .
  • Embodiment 252 is t mpound or salt of any one of Embodiments 1 to 214, wherein R 3 is: .
  • Embodiment 253 Provided herein as Embodiment 253 is t mpound or salt of any one of Embodiments 1 to 3 214, wherein R is: .
  • Embodiment 254 Provided herein as Embodiment 254 is pound or salt of any one of Embodiments 1 to 43, 45, 47, 51, 53, 55, 57, 58, 59, and 64 to 253, wh ere n he compound of Formula (I) is further represented by Formula (Ia): 62 a).
  • Embodiment 255 Provided herein as Embodiment 255 is the compound or salt of any one of Embodiments 1 to 43, 45, 47, 51, 53, 55, 57, 58, 59, 64 to 213, and 254, wherein the compound of Formula (I) is further represented by Formula (Ia.i): i).
  • Embodi t of any one of Embodiments 1 to 43, 45, 47, 49, 53, 55, 57, 58, 60, and 64 to 213, wherein the compound of Formula (I) is further represented by Formula (Ib): b).
  • Embodi lt of any one of Embodiments 1 to 43, 46, 47, 50, 53, 54, 57, 58, 61, and 64 to 213, wherein the compound of Formula (I) is further represented by Formula (Ic): c).
  • an und of Formula (I) is further represented by Formula (Ie): e).
  • Embodiment 260 is the compound or salt of any one of Embodiments 1 to 43, 45, 47, 49, 53, 54, 57, 58, 60, and 64 to 213, wherein the compound of Formula (I) is further represented by Formula (If): f).
  • Embodi lt of any one of Embodiments 1 to 43, 46, 47, 50, 53, 55, 56, 58, 61, and 64 o w ere n e compound of Formula (I) is further represented by Formula (Ij): i).
  • the (I) may be further represented by a com mulae (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), and/or (Ii).
  • the compound or salt of Formula (I) may be further represented by all of, or any sub-combination of, Formulae (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), and/or (Ii).
  • the compound or salt of Formula (I) may be further represented by Formulae (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ig), and/or (Ih) (e.g., excluding Formula (Ii)).
  • the compound or salt of Formula (I) e.g., as provided in Embodiment 1) may be further represented by Formulae (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ig), and/or (Ii) (e.g., excluding Formula (Ih)).
  • the compound or salt of Formula (I) may be further represented by Formulae (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ih), and/or (Ii) (e.g., excluding Formula (Ig)).
  • the compound or salt of Formula (I) e.g., as provided in Embodiment 1) may be further represented by Formulae (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (Ig), (Ih), and/or (Ii) (e.g., excluding Formula (If)).
  • the compound or salt of Formula (I) may be further represented by Formulae (Ia), (Ia.i), (Ib), (Ic), (Id), (If), (Ig), (Ih), and/or (Ii) (e.g., excluding Formula (Ie)).
  • the compound or salt of Formula (I) e.g., as provided in Embodiment 1) may be further represented by Formulae (Ia), (Ia.i), (Ib), (Ic), (Ie), (If), (Ig), (Ih), and/or (Ii) (e.g., excluding Formula (Id)).
  • the compound or salt of Formula (I) may be further represented by Formulae (Ia), (Ia.i), (Ib), (Id), (Ie), (If), (Ig), (Ih), and/or (Ii) (e.g., excluding Formula (Ic)).
  • the compound or salt of Formula (I) may be further represented by Formulae (Ia), (Ia.i), (Ic), (Id), (Ie), (If), (Ig), (Ih), and/or (Ii) (e.g., excluding Formula (Ib)).
  • the compound or salt of Formula (I) may be further represented by Formulae (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), and/or (Ii) (e.g., excluding Formula (Ia.i)).
  • the compound or salt of Formula (I) e.g., as provided in Embodiment 1) may be further represented by Formulae (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), and/or (Ii) (e.g., excluding Formula (Ia)).
  • the compound or salt of Formula (I) may be further represented by Formulae (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), and/or (Ig) (e.g., excluding Formulae (Ih) and (Ii)).
  • the compound or salt of Formula (I) e.g., as provided in Embodiment 1) may be further represented by Formulae (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), and/or (Ii) (e.g., excluding Formulae (Ig) and (Ih)).
  • the compound or salt of Formula (I) may be further represented by Formulae (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (Ih), and/or (Ii) (e.g., excluding Formulae (If) and (Ig)).
  • the compound or salt of Formula (I) e.g., as provided in Embodiment 1) may be further represented by Formulae (Ia), (Ia.i), (Ib), (Ic), (Id), (Ig), (Ih), and/or (Ii) (e.g., excluding Formulae (Ie) and (If)).
  • the compound or salt of Formula (I) may be further represented by Formulae (Ia), (Ia.i), (Ib), (Ic), (If), (Ig), (Ih), and/or (Ii) (e.g., excluding Formulae (Id) and (Ie)).
  • the compound or salt of Formula (I) e.g., as provided in Embodiment 1) may be further represented by Formulae (Ia), (Ia.i), (Ib), (Ie), (If), (Ig), (Ih), and/or (Ii) (e.g., excluding Formulae (Ic) and (Id)).
  • the compound or salt of Formula (I) may be further represented by Formulae (Ia), (Ia.i), (Id), (Ie), (If), (Ig), (Ih), and/or (Ii) (e.g., excluding Formulae (Ib) and (Ic)).
  • the compound or salt of Formula (I) e.g., as provided in Embodiment 1) may be further represented by Formulae (Ia), (Ic), (Id), (Ie), (If), (Ig), (Ih), and/or (Ii) (e.g., excluding Formulae (Ia.i) and (Ib)).
  • the compound or salt of Formula (I) may be further represented by Formulae (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), and/or (Ii) (e.g., excluding Formulae (Ia) and (Ia.i)).
  • the compound or salt of Formula (I) e.g., as provided in Embodiment 1) may be further represented by Formulae (Ia), (Ia.i), and/or (Ib).
  • the compound or salt of Formula (I) may be further represented by Formulae (Ic), (Id), and/or (Ie).
  • the compound or salt of Formula (I) may be further represented by Formulae (If), (Ig), (Ih), and/or (Ii).
  • any other combinations of formulae are also envisioned.
  • provided herein is a compound or salt of any one or more of Embodiments 254 to 263 (including any sub-combination of Embodiments 254 to 263) as further defined in any one or more of Embodiments 1 to 253.
  • Embodiment 264 is the compound or salt of Embodiment 1, wherein the compound is: , , , , , , O , , , , , , , , , , , , , , , , , , , , , , , , 71 , D59 D60 , D61 , , , 72 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , N N , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
  • Embodiment 266 Provided herein as Embodiment 266 is the compound or salt of Embodiment 1, wherein the compound is: 6-(4-chloro-7-(1-piperidinylcarbonyl)-2-quinolinyl)-2-methyl-1(2H)-isoquinolinone; 2-methyl-6-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1-piperidinylcarbonyl)-2-quinolinyl)-1(2H)- isoquinolinone; 2-methyl-6-(4-phenyl-7-(1-piperidinylcarbonyl)-2-quinolinyl)-1(2H)-isoquinolinone;
  • Embodiment 267 is the compound or salt of Embodiment 1, wherein the compound is: 2-methyl-6-(7-(((3R)-3-methyl-1-pyrrolidinyl)carbonyl)-2-quinoxalinyl)-1(2H)-isoquinolinone; 2-methyl-6-(7-(((3S)-3-methyl-1-pyrrolidinyl)carbonyl)-2-quinoxalinyl)-1(2H)-isoquinolinone; 2-methyl-6-(7-(((3S)-3-(trifluoromethyl)-1-piperidinyl)carbonyl)-2-quinoxalinyl)-1(2H)- isoquinolinone; 2-methyl-6-(7-(((3R)-3-(trifluoromethyl)-1-piperidinyl)carbonyl)-2-quinoxalinyl)-1(2H)- isoquinolinone; 6-methyl-6-(7-(((3R)-3-(tri
  • Embodiment 268 is the compound or salt of Embodiment 1, wherein the compound is: . 5
  • Embodiment 269 is the compound or salt of Embodiment 1, wherein the compound is: .
  • Embodiment 270 is the compound or salt of Embodiment 1, wherein the compound is: .
  • Embodiment 270 is the compound or salt of Embodiment 1, wherein the compound is: .
  • Embodiment 1 Provided herein as Em Embodiment 1, wherein the compound is: .
  • Embodiment 1 Provided herein as E Embodiment 1, wherein the compound is: . D121
  • Embodiment 273 is the compound or salt of Embodiment 1, wherein the compound is: .
  • Embodiment 274 is the compound or salt of any one of Embodiments 1 to 273, wherein the compound is not: N , , , , , 5 ,
  • the compounds or salts disclosed in Embodiments 1 to 274 may be stereoisomerically pure or stereoisomerically enriched.
  • the stereochemistry of a structure or a portion of a structure disclosed herein is not explicitly shown (e g., such as with dashed or bold lines), then the structure or portion of structure is either achiral or interpreted as being any of the possible stereoisomers of the structure or portion of the structure. If the stereochemistry of a structure or portion of a structure is explicitly shown, a single stereoisomer of the structure or portion of the structure is represented, with the understanding that the stereochemistry of the structure or portion of the structure may have been arbitrarily assigned.
  • stereoisomer or “stereoisomerically pure” compound as used herein refers to one stereoisomer (for example, geometric isomer, enantiomer, diastereomer and atropoisomer) of a compound that is substantially free of other stereoisomers of that compound.
  • a stereoisomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of the compound and a stereoisomerically pure compound having two chiral centers will be substantially free of other enantiomers or diastereomers of the compound.
  • a typical stereoisomerically enriched compound comprises greater than about 50% by weight of one stereoisomer of the compound and equal or less than about 50% by weight of other stereoisomers of the compound, greater than about 60% by weight of one stereoisomer of the compound and equal or less than about 40% by weight of other stereoisomers of the compound, greater than about 70% by weight of one stereoisomer of the compound and equal or less than about 30% by weight of other stereoisomers of the compound, greater than about 80% by weight of one stereoisomer of the compound and equal or less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and equal or less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and equal or less than about 5% by weight of the other stereoisomers of the compound, greater than about 97% by weight of one stereoisomer of the compound and equal or less than about 3% by weight of other stereoiso
  • This disclosure also encompasses the pharmaceutical compositions comprising stereoisomerically pure forms (or enriched forms) and the use of stereoisomerically pure forms (or enriched forms) of any compounds disclosed herein. Further, this disclosure also encompasses pharmaceutical compositions comprising mixtures of stereoisomers of any compounds disclosed herein and the use of said pharmaceutical compositions or mixtures of stereoisomers. These stereoisomers or mixtures thereof may be synthesized in accordance with methods well known in the art and methods disclosed herein. Mixtures of stereoisomers may be resolved using standard techniques, such as chiral columns or chiral resolving agents.
  • the compound of Formula (I) (and/or any of Formulae (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), an amido-6,6-fused-heteroaryl, or any other compound disclosed herein) can be characterized by its ability to inhibit the enzymatic activity of 15-PGDH (e.g., recombinant 15- PGDH) in an assay.
  • the assay is a cellular assay or a cell-free binding assay.
  • the compound of Formula (I) inhibits the enzymatic activity of 15-PGDH in the assay at an IC 50 of less than or equal to about: 1 ⁇ M, 250 nM, 50 nM, 20 nM, 10 nM, 5 nM, 2.5 nM 1 nM, 0.1 nM, 0.01 nM, 1 pM, or ranges including and/or spanning the aforementioned values.
  • the compound of Formula (I) inhibits the enzymatic activity of recombinant 15-PGDH at an IC 50 ranging from about 20 nM to about 0.01 pM, from about 20 nM to about 0.01 nM, from about 20 nM to about 0.1 nM, from about 20 nM to about 1 nM, from about 10 nM to about 0.01 pM, from about 10 nM to about 0.01 nM, from about 10 nM to about 0.1 nM, from about 10 nM to about 1 nM, from about 5 nM to about 0.01 pM, from about 5 nM to about 0.01 nM, from about 5 nM to about 0.01 nM, from about 5 nM to about 5 nM to about 5 nM, from about 5 nM to about 0.01 nM, from about 5 nM to about 5 nM to about 5 nM to about 5 nM, from about 5 nM to about 0.01 n
  • the IC 50 is measured using an assay as disclosed in the Examples. In several embodiments, the IC 50 for inhibition of 15-PGDH is measured using a cell-free binding assay. In several embodiments, recombinant 15-PGDH enzymatic assays are performed in a 25 ⁇ L volume of reaction buffer containing 50 mM Tris, pH 7.5, 0.01% Tween-20 and 100 ⁇ M DTT in a 384-well microtiter plate. In several embodiments, concentration-response experiments with test compounds are performed at 22 concentrations from 2-fold serial dilutions in DMSO. In several embodiments, the test compounds are pre-incubated with 15-PGDH for 15 minutes at room temperature.
  • the compound of Formula (I) (and/or any of Formulae (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), an amido-6,6-fused-heteroaryl, or any other compound disclosed herein) can be characterized by its low inhibition of acetylcholinesterase (ACHE).
  • ACHE acetylcholinesterase
  • inhibition of ACHE may be measured using the method described in Ellman G.
  • ACHE inhibition is measured by colorimetric detection of conversion of acetylthiocholine to thiocholine using a compound concentration of 10 ⁇ M under the Ellman conditions.
  • the substrate acetylthiocholine; ATch
  • the ACHE enzyme is provided at a concentration of 1 mU.
  • dithiobisnotrobenzoate (DTNB) is provided at a concentration of 500 ⁇ M.
  • the reaction is carried out in a buffer of 8 mM NaH 2 PO 4 /Na 2 HPO 4 , 20 mM NaCl, 0.06% Triton and 0.8 mM EDTA and about 1 mU enzyme (ACHE).
  • the test compound is added to the buffer comprising enzyme.
  • the enzymatic reaction is initiated by addition of 400 ⁇ M of the substrate ATch and 500 ⁇ M DTNB. In this reaction ATch is transformed in thiocholine that will react with DTNB and forms an anion, 5-thio-2-nitrobenzoate that is yellow.
  • the plate reader is an Envision, Perkin Elmer plate reader.
  • a compound of Formula (I) (and/or any of Formulae (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), an amido-6,6-fused-heteroaryl, or any other compound disclosed herein) resulted in no detectable inhibition of ACHE at a 10 ⁇ M test compound concentration.
  • a compound of Formula (I) (and/or any of Formulae (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), an amido-6,6-fused-heteroaryl, or any other compound disclosed herein) resulted in no detectable inhibition of ACHE at a 5 ⁇ M test compound concentration.
  • a compound of Formula (I) (and/or any of Formulae (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), an amido-6,6-fused-heteroaryl, or any other compound disclosed herein) resulted in no detectable inhibition of ACHE at a 2.5 ⁇ M test compound concentration.
  • a compound of Formula (I) (and/or any of Formulae (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), an amido-6,6-fused-heteroaryl, or any other compound disclosed herein) resulted in no detectable inhibition of ACHE at a 1.0 ⁇ M test compound concentration.
  • the % inhibition of the enzyme is less than or equal to about 0% (undetectable), 0.05%, 0.1%, 0.5%, 0.75%, 1.0%, 2.0%, 5.0%, or ranges including and/or spanning the aforementioned values.
  • the scope of the present disclosure includes all pharmaceutically acceptable isotopically-labelled compounds of the compounds disclosed herein, such as the compounds of Formula (I) (and/or any of Formulae (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), an amido-6,6-fused-heteroaryl, or any other compound disclosed herein) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • Formula (I) and/or any of Formulae (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), an amido-6,6-fused-heteroaryl, or any other compound disclosed herein
  • isotopes suitable for inclusion in the compounds disclosed herein include isotopes of hydrogen, such as 2 H (deuterium) and 3 H (tritium), carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopically- labelled compounds of Formula (I) for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • radioactive isotopes tritium ( 3 H) and carbon-14 ( 14 C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with isotopes such as deuterium ( 2 H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be advantageous in some circumstances.
  • the compounds herein are deuterated at metabolic hot spots (e.g., where certain hydrogen atoms of a structure are more metabolically labile than other hydrogens present on the molecule).
  • Isotopically-labelled compounds of the compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying General Synthetic Schemes and Examples using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.
  • Solvates [0360] As discussed above, the compounds disclosed herein and the stereoisomers and isotopically- labelled forms thereof or a pharmaceutically acceptable salt of any of the foregoing may exist in solvated or unsolvated forms.
  • solvate refers to a molecular complex comprising a compound or a pharmaceutically acceptable salt thereof as described herein and a stoichiometric or non- stoichiometric amount of one or more pharmaceutically acceptable solvent molecules. If the solvent is water, the solvate is referred to as a “hydrate.” Accordingly, the scope of the instant disclosure is to be understood to encompass all solvents of the compounds disclosed herein and the stereoisomers, tautomers and isotopically-labelled forms thereof or a pharmaceutically acceptable salt of any of the foregoing.
  • Formulation and Route of Administration [0361] While it may be possible to administer a compound disclosed herein alone in the uses described, the compound administered normally will be present as an active ingredient in a pharmaceutical composition.
  • a pharmaceutical composition comprising a compound disclosed herein in combination with one or more pharmaceutically acceptable excipients, such as diluents, carriers, adjuvants and the like, and, if desired, other active ingredients.
  • a pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein.
  • the compound(s) disclosed herein may be administered by any suitable route in the form of a pharmaceutical composition adapted to such a route and in a dose effective for the treatment intended.
  • compositions presented herein may, for example, be administered orally, mucosally, topically, transdermally, rectally, pulmonarily, parentally, intranasally, intravascularly, intravenously, intraarterial, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, vaginally or by infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable excipients.
  • the pharmaceutical composition may be in the form of, for example, a tablet, chewable tablet, minitablet, caplet, pill, bead, hard capsule, soft capsule, gelatin capsule, granule, powder, lozenge, patch, cream, gel, sachet, microneedle array, syrup, flavored syrup, juice, drop, injectable solution, emulsion, microemulsion, ointment, aerosol, aqueous suspension, or oily suspension.
  • the pharmaceutical composition is typically made in the form of a dosage unit containing a particular amount of the active ingredient.
  • Embodiment 275 Provided herein as Embodiment 275 is a pharmaceutical composition comprising the compound or salt of any one of Embodiments 1 to 274, and a pharmaceutically acceptable excipient.
  • this disclosure encompasses pharmaceutical compositions comprising mixtures of any of the compounds disclosed herein and one or more other active agents disclosed herein.
  • Use of Compounds and Compositions, Medicaments for Use, and Methods of Treatment [0366] As discussed herein, the compounds described herein are to be understood to include all stereoisomers, tautomers, or pharmaceutically acceptable salts of any of the foregoing or solvates of any of the foregoing.
  • the scope of the methods and uses provided in the instant disclosure is to be understood to encompass also methods and uses employing all such forms.
  • the compounds provided herein may be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like.
  • animals including horses, dogs, and cats may be treated with compounds provided herein.
  • a method of treating a patient is provided.
  • the method comprises administering a therapeutic amount of a 15-PGDH inhibitor compound (e.g., of any one of Formulae (I), (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), an amido-6,6-fused-heteroaryl, or any other compound disclosed herein) to a patient.
  • a 15-PGDH inhibitor compound e.g., of any one of Formulae (I), (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), an amido-6,6-fused-heteroaryl, or any other compound disclosed herein
  • the method comprises selecting a patient.
  • the patient is one suffering from a 15-PGDH mediated disease, disorder, or condition.
  • the patient after administration of a 15-PGDH inhibitor to the patient, the patient’s response is measured.
  • a beneficial effect of the 15-PGDH inhibitors may be assessed by a reduction in one or more inflammatory biomarkers in a relevant sample from the subject.
  • the inflammatory biomarker may comprise or consist of one or more of cytokines or inflammatory cytokines (e.g., those associated with fibrosis).
  • cytokines can include, for example, ⁇ Hb, MIP2 (e.g., CCL3 or CCL4), IFN5, TGFP, TNFa, IL-6, MCP-1, IL2, and IL-10 in BAL fluid.
  • Methods for measuring the amount of such biomarkers include but are not limited to ELISAs.
  • the biomarker is an eicosanoid or a PGE2 metabolite, such as, prostaglandin E2 (PGE2), prostaglandin E metabolite (PGE-M; tetranor-PGEM), 15-keto prostaglandin E 2 (15-keto-PGE2), prostaglandin F2 ⁇ PGF2 ⁇ , 6-keto prostaglandin F1 ⁇ (6-keto-PGF1 ⁇ ), prostaglandin D2 (PGD2), prostaglandin J2 (PGJ2), tetranor-PGE1 (TN-E), thromboxane B2 (TXB2), leukotriene B4 (LTB4), 15- hydroxyeicosatetraenoic acid (15-HETE), 12-hydroxyeicosatetraenoic acid (12-HETE), 8- hydroxyeicosatetraenoic acid (8-HETE), 5-hydroxyeicosatetraenoic acid (5-HETE), 17-I, 12,13-
  • the methods disclosed herein may comprise reducing an amount of one or more biomarkers in a sample from the subject compared to control. In several embodiments, the methods disclosed herein may comprise reducing an amount of one or more biomarkers in a sample from the subject compared to the patient prior to treatment. In several embodiments, the methods disclosed herein may comprise increasing an amount of one or more biomarkers in a sample from the subject compared to control. In several embodiments, the methods disclosed herein may comprise increasing an amount of one or more biomarkers in a sample from the subject compared to the patient prior to treatment. Thus, the levels of these biomarkers may be measured before or after treatment with a 15-PDGH inhibitor as disclosed herein.
  • the patient is one suffering from a 15- PGDH mediated disease or disorder.
  • the 15-PGDH mediated disease or disorder is inflammatory bowel disease, ulcerative colitis, Crohn’s disease, fibrotic disease disorder or condition.
  • the 15-PGDH mediated disease or disorder is atherosclerosis.
  • the 15-PGDH mediated disease or disorder is autoimmune disease.
  • the 15-PGDH mediated disease, disorder, or condition is systemic sclerosis, multifocal fibrosclerosis, nephrogenic systemic fibrosis, kidney fibrosis, glomerular sclerosis, renal tubulointerstitial fibrosis, progressive renal disease or diabetic nephropathy, cardiac fibrosis, pulmonary fibrosis, glomerulosclerosis pulmonary fibrosis, idiopathic pulmonary fibrosis, silicosis, asbestosis, interstitial lung disease, interstitial fibrotic lung disease, chemotherapy/radiation induced pulmonary fibrosis, endomyocardial fibrosis, deltoid fibrosis, pancreatitis, general fibrosis syndrome characterized by replacement of normal muscle tissue by fibrous tissue in varying degrees, retroperitoneal fibrosis, liver fibrosis, liver cirrhosis, chronic renal failure, myelofibrosis, bone marrow fibrosis, acute fibros
  • the 15-PGDH mediated disease, disorder, or condition is intestinal ischemia, ischemia, ischemic brain disease, ischemic heart diseasI, ischemic peripheral vascular disease, ischemic placenta, ischemic renal disease, ischemic vascular disease, ischemic-reperfusion injury, limb ischemia, lower extremity ischemia, myocardial ischemia, organ ischemia, peripheral ischemia, tissue ischemia, transient ischemic attack (TIA), and wounds to tissues or organs.
  • TIA transient ischemic attack
  • Embodiment 277 is the compound or salt of any one of Embodiments 1 to 274 or the pharmaceutical composition of Embodiment 275 for use in treating a 15-PGDH mediated disease or disorder.
  • Embodiment 278 is the compound or salt of any one of Embodiments 1 to 274 or the pharmaceutical composition of Embodiment 275 for use in treating inflammatory bowel disease.
  • Embodiment 279 is the compound or salt of any one of Embodiments 1 to 274 or the pharmaceutical composition of Embodiment 275 for use in treating ulcerative colitis.
  • Embodiment 280 is the compound or salt of any one of Embodiments 1 to 274 or the pharmaceutical composition of Embodiment 275 for use in treating Crohn’s disease.
  • Embodiment 281 is the compound or salt of any one of Embodiments 1 to 274 or the pharmaceutical composition of Embodiment 275 for use in treating a fibrotic disease, disorder or condition.
  • Embodiment 282 Provided herein as Embodiment 282 is the compound, salt, or composition of Embodiment 281, wherein the fibrotic disease, disorder, or condition is characterized, in whole or in part, by the excess production of fibrous material, including excess production of fibrotic material within the extracellular matrix, or the replacement of normal tissue elements by abnormal, non-functional, and/or excessive accumulation of matrix-associated components.
  • Embodiment 283 Provided herein as Embodiment 283 is the compound, salt, or composition of Embodiment 281 or 282, wherein the fibrotic disease, disorder, or condition is systemic sclerosis, multifocal fibrosclerosis, nephrogenic systemic fibrosis, kidney fibrosis, glomerular sclerosis, renal tubulointerstitial fibrosis, progressive renal disease or diabetic nephropathy, cardiac fibrosis, pulmonary fibrosis, glomerulosclerosis pulmonary fibrosis, idiopathic pulmonary fibrosis, silicosis, asbestosis, interstitial lung disease, interstitial fibrotic lung disease, chemotherapy/radiation induced pulmonary fibrosis, endomyocardial fibrosis, deltoid fibrosis, pancreatitis, general fibrosis syndrome characterized by replacement of normal muscle tissue by fibrous tissue in varying degrees, retroperitoneal fibrosis, liver fibrosis, liver
  • Embodiment 284 is the compound, salt, or composition of Embodiment 281 or 282, wherein the fibrotic disease, disorder, or condition is idiopathic pulmonary fibrosis.
  • Embodiment 285 is the compound, salt, or composition of Embodiment 281 or 282, wherein the fibrotic disease, disorder, or condition is kidney fibrosis.
  • Embodiment 286 is the compound, salt, or composition of Embodiment 281 or 282, wherein the fibrotic disease, disorder, or condition is liver fibrosis.
  • Embodiment 287 is the compound or salt of any one of Embodiments 1 to 274 or the pharmaceutical composition of Embodiment 275 for use in treating one or more of atherosclerotic cardiovascular disease, autoimmune disease, intestinal ischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic renal disease, ischemic vascular disease, ischemic-reperfusion injury, limb ischemia, lower extremity ischemia, myocardial ischemia, organ ischemia, peripheral ischemia, tissue ischemia, transient ischemic attack (TIA), and wounds to tissues or organs.
  • atherosclerotic cardiovascular disease autoimmune disease, intestinal ischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic renal disease, ischemic vascular disease, ischemic-reperfusion injury, limb ischemia, lower extremity ischemia
  • Embodiment 288 is a method of treating a 15-PGDH mediated disease, disorder, or condition in a subject in need thereof, the method comprising: administering to the subject therapeutically an effective amount of the compound or salt of any one of Embodiments 1 to 274 or the pharmaceutical composition of Embodiment 275.
  • Embodiment 289 is a method of treating intestinal, gastrointestinal, or bowel disorders in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of the compound or salt of any one of Embodiments 1 to 274 or the pharmaceutical composition of Embodiment 275.
  • Embodiment 290 Provided herein as Embodiment 290 is the method of Embodiment 288 or 289, wherein the disease or disorder comprises at least one of ulcerative colitis, inflammatory bowel disease, and Crohn’s disease.
  • the 15-PGDH inhibitor compounds disclosed herein e.g., of any one of Formulae (I), (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), an amido-6,6-fused-heteroaryl, or any other compound disclosed herein
  • the 15-PGDH inhibitor compounds disclosed herein can be provided in combination with other therapeutic agents.
  • a 15-PGDH inhibitor as disclosed herein is used in combination with a tumor necrosis factor (TNF) inhibitor (e.g., TNF- ⁇ inhibitor).
  • TNF tumor necrosis factor
  • the TNF inhibitors can include, but are not limited to, anti-TNF alpha antibodies (e.g., infliximab, adalimumab, certolizumab pegol, and golimumab), receptor-construct fusion proteins (such as etanercept), or small molecules, such as, but not limited to, pomalidomide, thalidomide, lenalidomide and bupropion.
  • a 15-PGDH inhibitor as disclosed herein is used in combination with a corticosteroid.
  • the corticosteroid is aclovate, alclometasone dipropionate, amcinafel, amcinafide, amcinonide, aristocort A, augmented betamethasone dipropiona110yridine110110e110nesone, beclopmethasone dipropionate, betamethasone, betamethasone benzoate, betamethasone-17-benzoate, betamethasone dipropionate, betamethasone sodium phosphate and acetate, betamethasone valerate, betamethasone-17-valerate, chloroprednisone, clobetasol propionate, clobetasone propionate, clocortelone, cordran, corticosterone, cortisol, cortisol acetate, cortisol cypionate, cortisol sodium phosphate, cor
  • each constituent of the therapeutic combination can be administered in using the same route or a different route.
  • the 15-PGDH inhibitors compounds disclosed herein may be administered by any suitable route in the form of a pharmaceutical composition adapted to such a route and in a dose effective for the treatment intended.
  • Each constituent of the therapeutic combination can, for example, be administered orally, mucosally, topically, transdermally, rectally, pulmonarily, parentally, intranasally, intravascularly, intravenously, intraarterial, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, vaginally or by infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable excipients.
  • the individual therapeut111yridinerising the combination can be administered substantially simultaneously using any of the disclosed routes for any of the disclosed methods of treatment (e.g., methods of treating IBD, etc.).
  • the individual therapeutics comprising the combination can be administered in a sequential manner using any of the disclosed routes for any of the disclosed methods of treatment (e.g., methods of treating IBD, etc.).
  • the individual therapeutics comprising the combination may be administered together as part of the same composition or as different compositions.
  • those therapeutic agents may be more suitably for administered by injection.
  • small molecules e.g., of any one of Formulae (I), (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), an amido- 6,6-fused-heteroaryl, or any other compound disclosed herein
  • injection or other administration methods e.g., through other routes, including orally.
  • Methods of Manufacture [0392]
  • the compounds provided herein can be synthesized according to the procedures described in this and the following sections.
  • the compounds of Formula (I) can be synthesized using one or more steps according to the following schemes and/or using one or more of the following intermediates. Any variables used in the following schemes in intermediates may be as defined elsewhere herein, unless otherwise noted.
  • R 2 (or R 1a , R 1b , or any other variable) is defined in one manner for Formula (I) and in another way for Formula (Ia)
  • the definition for R 2 (or R 1a , R 1b , or any other variable) in Formula (I) may be substituted for the definition of R 2 (or R 1a , R 1b , or any other variable) in Formula (Ia) and vice versa.
  • the definitions for like variables in two different intermediates may be used interchangeably. Suitable reaction conditions, such as, solvent, reaction temperature, and reagents, for the Schemes discussed in this section, may be found in the examples provided herein.
  • Embodiment 291 Provided herein as Embodiment 291 is a method of manufacturing the compound or salt of any one of Embodiments 1 to 168, 180 to 258, and 259 to 263, the method comprising: performing a Suzuki coupling between a compound of Formula (I-int-a.i) (I-int-a.i) with a compound of Formula (B a -R 2 ): 2 ); where X H is a halogen; R i1 is C 1-6 alkoxy; B a is a boronic acid group or a boronic ester group (e.g., a pinacol ester); “ ” indicates a double bond or single bond may be present; each instance of X a independently is nitrogen, oxygen, or carbon; each instance of s, where present, is an integer selected from 0, 1, 2, or 3; each instance of r, where present, independently is an integer selected from 0, 1, 2, 3, 4, or 5, wherein where two instances of r occur on the same R 2 group, the
  • Embodiment 292 Provided herein as Embodiment 292 is a method of manufacturing the compound or salt of any one of Embodiments 1 to 168, 180 to 258, and 259 to 263, the method comprising: performing a Suzuki coupling between a compound of Formula (I-int-2a.i) (I-int-2a.i) with a compound of Formula (B a -R 2 ): 2); where X H is a halogen; B a is a boronic acid group or a boronic ester group; “ ” indicates a double bond or single bond may be present; each instance of X a independently is nitrogen, oxygen, or carbon; each instance of s, where present, is an integer selected from 0, 1, 2, or 3; [0396] each instance of r, where present, independently is an integer selected from 0, 1, 2, 3, 4, or 5, wherein where two instances of r occur on the same R 2 group, the total of both r values combined does not exceed 5; and [0397] wherein a
  • a, d, e, and f are independently N or CH.
  • b is C-H or C-R 3 .
  • c is N, C-H, or C-R 3 .
  • each instance of R 3 independently is halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-7 cycloalkyl, heterocyclyl with 3 to 7 ring members, C 6-10 aryl, or heteroaryl having 5 to 10 ring members. In several embodiments, only one instance of R 3 may be present.
  • R 3 may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 alkylene-C 1-6 alkoxy.
  • R i1 is C 1-6 alkoxy.
  • X H represents a suitable group for cross- coupling.
  • X H represents a suitable halogen atom (e.g., Cl, Br, etc.) or a similar reactive group (e.g., -OTf, -OTs, or -OMs).
  • X H is a halogen.
  • X H is Cl. In several embodiments, X H is Br. In several embodiments, R i1 is ethoxy. In several embodiments, R i1 is methoxy. In several embodiments, each of a, b, c, d, e, and f independently is as disclosed elsewhere herein (e.g., including as defined in any one of Embodiments 45 to 66).
  • Formula (I-int-b.i) [0399] Several embodiments pertain to a compound of Formula (I-int-b.i) or a salt thereof: where R i1 is C 1-6 alkoxy and the remaining variables are as disclosed elsewhere herein.
  • a, d, e, and f are independently N or CH.
  • b is C-H or C-R 3 .
  • c is N, C-H, or C-R 3 .
  • each instance of R 3 independently is halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-7 cycloalkyl, heterocyclyl with 3 to 7 ring members, C 6-10 aryl, or heteroaryl having 5 to 10 ring members. In several embodiments, only one instance of R 3 may be present.
  • R 3 may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 alkylene-C 1-6 alkoxy.
  • R i1 is ethoxy.
  • R i1 is methoxy.
  • each of a, b, c, d, e, and f independently is as disclosed elsewhere herein (e.g., including as defined in any one of Embodiments 45 to 66).
  • Formula (I-int-c.i) [0400] Several embodiments pertain to a compound of Formula (I-int-c.i) or a salt thereof: where the variables are as disclosed else where herein.
  • a, d, e, and f are independently N or CH.
  • b is C-H or C-R 3 .
  • c is N, C-H, or C-R 3 .
  • R 2 is heteroaryl having 6 to 10 ring members or heterocyclyl having 6 to 10 ring members. In several embodiments, when R 2 is heterocyclyl having 6 to 10 ring members, the heterocyclyl group includes at least one unsaturation.
  • R 2 when R 2 is which is heteroaryl having 6 to 10 ring members or heterocyclyl having 6 to 10 ring members, then R 2 is unsubstituted or substituted with one or more instances of R 5 .
  • each instance of R 5 independently is halogen, oxo, -CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl, amino, C 1-4 alkylamino, di C 1-4 alkylamino, C(O)heterocyclyl having 3 to 6 ring members, heterocyclyl having 3 to 6 ring members, or heteroaryl having 5 to 10 ring members.
  • each instance of R 5 may be unsubstituted or substituted one or more instances of R 6 .
  • each instance of R 6 independently is halogen, C 1-6 alkyl, C(O)C 1-6 alkyl, C(O) 2 C 1-6 alkyl, or C 1-6 alkylene-OH.
  • each instance of R 3 independently is halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-7 cycloalkyl, heterocyclyl with 3 to 7 ring members, C 6-10 aryl, or heteroaryl having 5 to 10 ring members.
  • R 3 may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 alkylene-C 1-6 alkoxy.
  • substituents each of which independently is halogen, -OH, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 alkylene-C 1-6 alkoxy.
  • each of a, b, c, d, e, and f independently is as disclosed elsewhere herein (e.g., including as defined in any one of Embodiments 45 to 66).
  • Formula (I-int-a.ii) [0401] Several embodiments pertain to a compound of Formula (I-int-a.ii) or a salt thereof: where X H represents a suitable group for cross-coupling, R is C 1-6 alkoxy, and the remaining variables are as disclosed elsewhere herein.
  • a, d, e, and f are independently N or CH.
  • b is C-H or C-R 3 .
  • c is N, C-H, or C-R 3 .
  • each instance of R 3 independently is halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-7 cycloalkyl, heterocyclyl with 3 to 7 ring members, C 6-10 aryl, or heteroaryl having 5 to 10 ring members. In several embodiments, only one instance of R 3 may be present. In several embodiments, R 3 may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 alkylene-C 1-6 alkoxy.
  • R i1 is C 1-6 alkoxy.
  • X H represents a suitable group for cross- coupling.
  • X H represents a suitable halogen atom (e.g., Cl, Br, etc.) or a similar reactive group (e.g., -OTf, -OTs, or -OMs).
  • X H is a halogen.
  • X H is Cl.
  • X H is Br.
  • R i1 is ethoxy. In several embodiments, R i1 is methoxy.
  • each of a, b, c, d, e, and f independently is as disclosed elsewhere herein (e.g., including as defined in any one of Embodiments 45 to 66).
  • Formula (I-int-b.ii) [0402] Several embodiments pertain to a compound of Formula (I-int-b.ii) or a salt thereof: where R i1 is C 1-6 alkoxy and the remaining variables are as disclosed elsewhere herein.
  • a, d, e, and f are independently N or CH.
  • b is C-H or C-R 3 .
  • c is N, C-H, or C-R 3 .
  • each instance of R 3 independently is halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-7 cycloalkyl, heterocyclyl with 3 to 7 ring members, C 6-10 aryl, or heteroaryl having 5 to 10 ring members. In several embodiments, only one instance of R 3 may be present. In several embodiments, R 3 may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 alkylene-C 1-6 alkoxy.
  • R i1 is ethoxy. In several embodiments, R i1 is methoxy. In several embodiments, each of a, b, c, d, e, and f independently is as disclosed elsewhere herein (e.g., including as defined in any one of Embodiments 45 to 66).
  • Formula (I-int-c.ii) [0403] Several embodiments pertain to a compound of Formula (I-int-c.ii) or a salt thereof: where the variables are as disclosed else ral embodiments, a, d, e, and f are independently N or CH. In several embodiments, b is C-H or C-R 3 .
  • c is N, C-H, or C-R 3 .
  • R 2 is heteroaryl having 6 to 10 ring members or heterocyclyl having 6 to 10 ring members.
  • the heterocyclyl group includes at least one unsaturation.
  • R 2 is unsubstituted or substituted with one or more instances of R 5 .
  • each instance of R 5 independently is halogen, oxo, -CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl, amino, C 1-4 alkylamino, di C 1-4 alkylamino, C(O)heterocyclyl having 3 to 6 ring members, heterocyclyl having 3 to 6 ring members, or heteroaryl having 5 to 10 ring members.
  • each instance of R 5 may be unsubstituted or substituted one or more instances of R 6 .
  • each instance of R 6 independently is halogen, C 1-6 alkyl, C(O)C 1-6 alkyl, C(O) 2 C 1-6 alkyl, or C 1-6 alkylene-OH.
  • each instance of R 3 independently is halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-7 cycloalkyl, heterocyclyl with 3 to 7 ring members, C 6-10 aryl, or heteroaryl having 5 to 10 ring members.
  • R 3 may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 alkylene-C 1-6 alkoxy.
  • substituents each of which independently is halogen, -OH, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 alkylene-C 1-6 alkoxy.
  • each of a, b, c, d, e, and f independently is as disclosed elsewhere herein (e.g., including as defined in any one of Embodiments 45 to 66).
  • Formula (I-int-2a.i) [0404] Several embodiments pertain to a compound of Formula (I-int-2a.i) or a salt thereof: where X H represents a suitable group for cross-coupling and the remaining variables are as disclosed elsewhere herein.
  • a, d, e, and f are independently N or CH.
  • b is C-H or C-R 3 .
  • c is N, C-H, or C-R 3 .
  • each instance of R 3 independently is halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-7 cycloalkyl, heterocyclyl with 3 to 7 ring members, C 6-10 aryl, or heteroaryl having 5 to 10 ring members. In several embodiments, only one instance of R 3 may be present. In several embodiments, R 3 may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 alkylene-C 1-6 alkoxy.
  • R i1 is C 1-6 alkoxy.
  • X H represents a suitable group for cross-coupling.
  • X H represents a suitable halogen atom (e.g., Cl, Br, etc.) or a similar reactive group (e.g., - OTf, -OTs, or -OMs).
  • X H is a halogen.
  • X H is Cl.
  • X H is Br.
  • each of a, b, c, d, e, and f independently is as disclosed elsewhere herein (e.g., including as defined in any one of Embodiments 45 to 66).
  • Formula (I-int-2a.ii) [0405] Several embodiments pertain to a compound of Formula (I-int-2a.ii) or a salt thereof: where X H represents a suitable group fo e remaining variables are as disclosed elsewhere herein.
  • a, d, e, and f are independently N or CH.
  • b is C-H or C-R 3 .
  • c is N, C-H, or C-R 3 .
  • each instance of R 3 independently is halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-7 cycloalkyl, heterocyclyl with 3 to 7 ring members, C 6-10 aryl, or heteroaryl having 5 to 10 ring members. In several embodiments, only one instance of R 3 may be present. In several embodiments, R 3 may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 alkylene-C 1-6 alkoxy.
  • R i1 is C 1-6 alkoxy.
  • X H represents a suitable group for cross-coupling.
  • X H represents a suitable halogen atom (e.g., Cl, Br, etc.) or a similar reactive group (e.g., - OTf, -OTs, or -OMs).
  • X H is a halogen.
  • X H is Cl.
  • X H is Br.
  • each of a, b, c, d, e, and f independently is as disclosed elsewhere herein (e.g., including as defined in any one of Embodiments 45 to 66).
  • compounds of Formula (I) can be prepared using intermediate compounds as disclosed herein.
  • compounds of Formula (I) e.g., a compound of Formula (I.i) ing.
  • a compound of Formula (I.i) is prepared using the method disclosed in Scheme 1.1.i or 1.2.i.
  • a compound of Formula (I.ii) is prepared using the method disclosed in Scheme 1.1.ii or 1.2.ii.
  • Scheme 1.1.i Scheme 1.1.a.i-1.1.c.i
  • X H represents a suitable halogen atom (e.g., Cl, Br, etc.) or a similar reactive group (e.g., -OTf, -OTs, or -OMs).
  • the compound of Formula (I-int-a.i) is reacted with an intermediate of B a -R 2 .
  • R 2 is as defined elsewhere herein (e.g., as in Formula (I), (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), etc.).
  • each of a, b, c, d, e, and f independently is as disclosed elsewhere herein (e.g., including as defined in any one of Embodiments 45 to 66).
  • B a represents a suitable reactive moiety for cross-coupling reactions including, for example, Suzuki or Stille cross- coupling.
  • B a is a boronic acid or a boronic acid ester (e.g., boronic pinacol ester) or a tributyl stannyl group.
  • a Suzuki coupling is performed using a palladium or similar transition metal catalyst together with appropriate ligands according to methods described in the literature and known to those skilled in the art.
  • Scheme 1.1.b.i Saponification to Provide Formula (I-int-c.i)
  • a compound of Formula (I-int-c.i) can be prepared by saponification of the compound of Formula (I-int-b.i) in the presence of base.
  • the compound of Formula (I-int-b.i) is saponified using base (e.g., LiOH, NaOH, etc.). In several embodiments, the compound of Formula (I-int-b.i) is saponified using LiOH. In several embodiments, the reaction is performed in the presence of an appropriate solvent. In several embodiments, a compound of Formula (I-int-c.i) is provided. In several embodiments, the compound of Formula (I-int-c.i) is then subject to coupling conditions to provide a compound of Formula (I), as shown in the scheme below (as Formula (I.i)).
  • base e.g., LiOH, NaOH, etc.
  • the compound of Formula (I-int-b.i) is saponified using LiOH.
  • the reaction is performed in the presence of an appropriate solvent.
  • a compound of Formula (I-int-c.i) is provided.
  • the compound of Formula (I-int-c.i) is then subject to coupling conditions to provide
  • a compound of Formula (I) (e.g., Formula (I.i)) can be prepared by coupling an amine with the compound of Formula (I-int-c.i) in the presence of a coupling reagent.
  • a coupling reagent e.g., TBTU, DCC, DIC, EDC HCl, etc.
  • the amide of Formula (I.i) is prepared in the presence of a base.
  • the base is an organic base.
  • the base is TEA, DIPEA, etc.
  • Scheme 1.1.ii Scheme 1.1.a.ii-1.1.c.ii
  • a compound of Formula (I-int-b.ii) can be prepared by coupling R 2 to the compound of Formula (I-int-a.ii).
  • X H represents a suitable halogen atom (e.g., Cl, Br, etc.) or a similar reactive group (e.g., -OTf, -OTs, or -OMs).
  • the compound of Formula (I-int-a.ii) is reacted with an intermediate of B a -R 2 .
  • R 2 is as defined elsewhere herein (e.g., as in Formula (I), (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), etc.).
  • each of a, b, c, d, e, and f independently is as disclosed elsewhere herein (e.g., including as defined in any one of Embodiments 45 to 66).
  • B a represents a suitable reactive moiety for cross-coupling reactions including, for example, Suzuki or Stille cross- coupling.
  • B a is a boronic acid or a boronic acid ester (e.g., boronic pinacol ester) or a tributyl stannyl group.
  • a Suzuki coupling is performed using a palladium or similar transition metal catalyst together with appropriate ligands according to methods described in the literature and known to those skilled in the art.
  • a compound of Formula (I-int-c.ii) can be prepared by saponification of the compound of Formula (I-int-b.ii) in the presence of base.
  • base e.g., LiOH, NaOH, etc.
  • the compound of Formula (I-int-b.ii) is saponified using LiOH.
  • the reaction is performed in the presence of an appropriate solvent.
  • a compound of Formula (I-int-c.ii) is provided.
  • the compound of Formula (I-int-c.ii) is then subject to coupling conditions to provide a compound of Formula (I), as shown in the scheme below (as Formula (I.ii)).
  • a compound of Formula (I) e.g., Formula (I.ii)
  • R 2 a d Base R 2 a d 1b R 1a
  • compoun s o ormu a can e prepare by the reaction of an intermediate of Formula (I-int-c.ii) with an amine of formula H-N(R 1a )(R 1b ).
  • the amide of Formula (I.ii) is prepared in the presence of a coupling reagent (e.g., TBTU, DCC, DIC, EDC HCl, etc.).
  • the amide of Formula (I.ii) is prepared in the presence of a base.
  • the base is an organic base.
  • the base is TEA, DIPEA, etc.
  • Scheme 1.2.i Scheme 1.2.a (Scheme 1.2.a.i-1.2.b.i) [0418] As illustrated in the schemes below, compounds of Formula (I) (e.g., a compound of Formula (I.i) ing. In several embodiments, a compound of Formula (I.i) is prepared using the method disclosed in Scheme 1.1.1.i. In several embodiments, a compound of Formula (I.i) is prepared using the method disclosed in Scheme 1.1.1.ii.
  • Scheme 1.2.a.i R 2 Coupling to Compound of Formula (I-int-c.i) [0419] In se oupling R 2 to the compound of gen atom (e.g., Cl, Br, etc.) or a similar reactive group (e.g., -OTf, -OTs, or -OMs). In several embodiments, X H is Br. In several embodiments, the compound of Formula (I-int-2a.i) is reacted with an intermediate of B a -R 2 .
  • the compound of Formula (I-int-2a.i) is reacted with an intermediate of B a -R 2 .
  • R 2 is as defined elsewhere herein (e.g., as in Formula (I), (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), etc.).
  • each of a, b, c, d, e, and f independently is as disclosed elsewhere herein (e.g., including as defined in any one of Embodiments 45 to 66).
  • B a represents a suitable reactive moiety for cross-coupling reactions including, for example, Suzuki or Stille cross-coupling.
  • B a is a boronic acid or a boronic acid ester (e.g., boronic pinacol ester) or a tributyl stannyl group.
  • a Suzuki coupling is performed using a palladium or similar transition metal catalyst together with appropriate ligands according to methods described in the literature and known to those skilled in the art.
  • Scheme 1.2.b.i Amide Formation to Provide a Compound of Formula (I.i)
  • a compound of Formula (I) (e.g., Formula (I.i)) can be prepared by coupling an amine with the compound of Formula (I-int-c.i) in the presence of a coupling reagent.
  • compounds of Formula (I.i) can be prepared by the reaction of an intermediate of Formula (I-int-c.i) with an amine of formula H-N(R 1a )(R 1b ).
  • the amide of Formula (I.i) is prepared in the presence of a coupling reagent (e.g., TBTU, DCC, DIC, EDC HCl, etc.).
  • the amide of Formula (I.i) is prepared in the presence of a base.
  • the base is an organic base.
  • the base is TEA, DIPEA, etc.
  • Scheme 1.2.ii Scheme 1.2.a.ii-1.2.b.ii
  • Scheme 1.2.a.ii R 2 Coupling to Compound of Formula (I-int-c.ii)
  • R 2 Coupling to Compound of Formula (I-int-c.ii)
  • R 2 Coupling to Compound of Formula (I-int-c.ii)
  • R 2 Coupling to Compound of Formula (I-int-c.ii)
  • X H is Br.
  • the compound of Formula (I-int-2a.ii) is reacted with an intermediate of B a -R 2 .
  • R 2 is as defined elsewhere herein (e.g., as in Formula (I), (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), etc.).
  • each of a, b, c, d, e, and f independently is as disclosed elsewhere herein (e.g., including as defined in any one of Embodiments 45 to 66).
  • B a represents a suitable reactive moiety for cross-coupling reactions including, for example, Suzuki or Stille cross-coupling.
  • B a is a boronic acid or a boronic acid ester (e.g., boronic pinacol ester) or a tributyl stannyl group.
  • a Suzuki coupling is performed using a palladium or similar transition metal catalyst together with appropriate ligands according to methods described in the literature and known to those skilled in the art.
  • a compound of Formula (I) (e.g., Formula (I.ii)) can be prepared by coupling an amine with the compound of Formula (I-int-c.ii) in the presence of a coupling reagent.
  • a coupling reagent e.g., As illus n be prepared by the reaction of an intermediate of Formula (I-int-c.ii) with an amine of formula H-N(R 1a )(R 1b ).
  • the amide of Formula (I.ii) is prepared in the presence of a coupling reagent (e.g., TBTU, DCC, DIC, EDC HCl, etc.).
  • a coupling reagent e.g., TBTU, DCC, DIC, EDC HCl, etc.
  • the amide of Formula (I.ii) is prepared in the presence of a base.
  • the base is an organic base.
  • the base is TEA, DIPEA, etc.
  • the reaction mixture was quenched with H 2 O (300 mL) at 0 °C, then diluted with H 2 O (200 mL), extracted with EtOAc (3 ⁇ 150 mL), washed with brine (150 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • the crude mixture of isomers was absorbed onto a plug of silica gel and purified by column chromatography through a RediSep® pre-packed silica gel column (12 g), eluting with a gradient of 0% to 70% EtOAc in pet.
  • Step 1 6-bromo-2H-[1,2,3]triazolo[4,5-b]pyridine.
  • Step 2 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-[1,2,3]triazolo[4,5-b]pyridine.
  • THF 10 mL
  • NaH 0.181 g, 7.54 mmol
  • Step 2 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-[1,2,3]triazolo[4,5- b]pyridine.
  • 6-bromo-2-methyl-2H-[1,2,3]triazolo[4,5-b]pyridine (1.50g, 7.04 mmol) in 1,4-dioxane (5 mL) was added B 2 Pin 2 (3.580 g, 14.08 mmol), KOAc (1.175 g, 11.97 mmol), and Pd(dppf)Cl 2 ⁇ DCM (0.575 g, 0.704 mmol). The mixture was stirred at 110 °C for 12 hr.
  • Example 1-1 2-methyl-6-(4-phenyl-7-(piperidine-1-carbonyl)quinolin-2-yl)isoquinolin-1(2H)-one D3 quinoline- 7-carboxylic acid (1.15 g, 4.75 mmol), HATU (1.81 g, 4.75 mmol), and DIPEA (2.46 g, 19.0 mmol, 3.31 mL) in DMF (11 mL) was stirred at 20 °C for 30 min. Piperidine (404.5 mg, 4.75 mmol, 0.469 mL) was added. The mixture was stirred at 20 °C for 1h under an atmosphere of N 2 .
  • Step 2 6-[4-chloro-7-(piperidine-1-carbonyl)-2-quinolyl]-2-methyl-isoquinolin-1-one.
  • reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 ⁇ 30mL). The combined organic layers were washed with brine (90 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0–50% ethyl acetate/petroleum ether gradient).6-[4-Chloro-7-(piperidine-1-carbonyl)-2- quinolyl]-2-methyl-isoquinolin-1-one (900 mg, 1.15 mmol, 24% yield) was obtained as a white solid.
  • Step 3 2-methyl-6-(4-phenyl-7-(piperidine-1-carbonyl)quinolin-2-yl)isoquinolin-1(2H)-one.
  • Step 3 3-(2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl)quinoxaline-6-carbonyl chloride.
  • dichloromethane 10 mL
  • oxalyl chloride 240 ⁇ L, 2.80 mmol
  • DMF 14 ⁇ L, 0.181 mmol
  • Step 4 N-methyl-3-(2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl)-N-(oxetan-2- ylmethyl)quinoxaline-6-carboxamide.
  • Step 3 (6,6-difluoro-1,4-oxazepan-4-yl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)quinoxalin-6-yl)methanone.
  • the crude mixture was directly loaded onto a silica gel precolumn (25 g) and subjected to combi-flash column chromatography on a 24-g ISCO RediSep Gold® column eluting with MeOH/DCM (16 min from 0 to 13%) to give impure product as a light brown solid.
  • Step 2 (4,4-difluoropiperidin-1-yl)(6-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)isoquinolin- 3-yl)methanone.
  • the mixture was degassed with N 2 .
  • the solution was stirred at 100 °C for 12 h under an atmosphere of N 2 .
  • the reaction mixture was concentrated under reduced pressure.
  • the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0–80% EtOAc /Pet ether gradient with a flow rate of 80 mL/min) and then purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [H 2 O (NH 4 HCO 3 )-ACN; B%: 30%-55%,8min).
  • Example 6-1 (4,4-difluoro-1-piperidinyl)(6-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-3- quinolinyl)methanone
  • Step 2 (4,4-difluoropiperidin-1-yl)(6-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)quinolin-3- yl)methanone.
  • a mixture of (6-bromoquinolin-3-yl)(4,4-difluoropiperidin-1- yl)methanone (100 mg, 0.282 mmol), (2-methyl-2h-pyrazolo[3,4-b]pyridin-5-yl)boronic acid (74.7 mg, 0.422 mmol), anhydrous K 2 CO 3 (117 mg, 0.845 mmol) and Pd(dppf)Cl 2 (20.60 mg, 0.028 mmol ) in 1,4- dioxane (1.2 mL) and H 2 O (0.3 mL) was stirred at 90°C for 18 h.
  • the recombinant human, mouse, rat and dog 15-PGDH enzymatic assays were performed in a 25 ⁇ L volume of reaction buffer containing 50 mM Tris, pH 7.5, 0.01% Tween-20 and 100 ⁇ M DTT in a 384-well microtiter plate.
  • concentration-response experiments with tested compounds 22 concentrations from 2-fold serial dilutions in DMSO were pre-incubated with 15-PGDH for 15 minutes at room temperature. Then, PGE2 and ß-NAD+ were added to initiate the 15-PGDH reaction. After 60 minutes at room temperature, the reaction was quenched and NADH signal was measured using a microtiter plate reader.
  • PGE2 was detected in a competitive HTRF assay by using anti PGE2 antibody labeled with Europium cryptate, and PGE2 labeled with deuterium.
  • the PGE2 present in the sample competes with the binding between the two HTRF detection solutions (reagents) and thereby prevents FRET from occurring.
  • the specific signal is inversely proportional to the PGE2 concentration. From this binding data, IC50 values were calculated. [0471]
  • Table 8-1 provides the IC50 of each compound for inhibiting enzymatic activity in the assay described above. Table 8-1 ID A549 Cell Assay IC50

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Abstract

La présente invention concerne de nouveaux inhibiteurs de la 15-hydroxy-prostaglandine déshydrogénase, des compositions pharmaceutiques comprenant de tels composés, et des méthodes d'utilisation de tels composés et compositions dans le traitement d'une maladie médiée par la 15-hydroxy-prostaglandine déshydrogénase. L'invention concerne également des procédés de fabrication de tels composés et des intermédiaires de ceux-ci. Les composés, ou un sel pharmaceutiquement acceptable de ceux-ci, ont une structure représentés par la formule (I) : où désigne formule (i) ou formule (ii). L'invention concerne en outre des intermédiaires utiles dans la synthèse de composés représentés par la formule (I).
PCT/US2024/028178 2023-05-09 2024-05-07 Amides bicycliques fusionnés en 6,6 et compositions destinées à être utilisées en tant que modulateurs de la 15-prostaglandine déshydrogénase Pending WO2024233563A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015161142A1 (fr) * 2014-04-18 2015-10-22 Millennium Pharmaceuticals, Inc. Composés à base de quinoxaline et leurs utilisations
WO2016118565A1 (fr) * 2015-01-20 2016-07-28 Millennium Pharmaceuticals, Inc. Composés quinazoline et quinoléine, et utilisations de ceux-ci
WO2018145080A1 (fr) * 2017-02-06 2018-08-09 Case Western Reserve University Compositions et procédés de modulation de l'activité de la déshydrogénase à chaîne courte
WO2020160151A1 (fr) * 2019-01-31 2020-08-06 Kyorin Pharmaceutical Co., Ltd. Inhibiteurs de 15-pgdh
WO2022109311A1 (fr) * 2020-11-20 2022-05-27 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Procédés et matériaux pour augmenter l'activité nicotinamide phosphoribosyltransférase

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015161142A1 (fr) * 2014-04-18 2015-10-22 Millennium Pharmaceuticals, Inc. Composés à base de quinoxaline et leurs utilisations
WO2016118565A1 (fr) * 2015-01-20 2016-07-28 Millennium Pharmaceuticals, Inc. Composés quinazoline et quinoléine, et utilisations de ceux-ci
WO2018145080A1 (fr) * 2017-02-06 2018-08-09 Case Western Reserve University Compositions et procédés de modulation de l'activité de la déshydrogénase à chaîne courte
WO2020160151A1 (fr) * 2019-01-31 2020-08-06 Kyorin Pharmaceutical Co., Ltd. Inhibiteurs de 15-pgdh
WO2022109311A1 (fr) * 2020-11-20 2022-05-27 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Procédés et matériaux pour augmenter l'activité nicotinamide phosphoribosyltransférase

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY [online] Chemical Abstract Service, Columbus, Ohio, US; 2 September 2020 (2020-09-02), XP093187719, retrieved from https://stn.org/stn/# Database accession no. 2469194-00-9 *
ELIEL: "Stereochemistry of Carbon Compounds", 1962, MCGRAW-HILL
ELLMAN G. L. ET AL.: "A new and rapid colorimetric determination of acetylcholinesterase activity", BIOCHEM PHARMACOL, vol. 7, 1961, pages 88 - 95, XP023765099, DOI: 10.1016/0006-2952(61)90145-9
JACQUES ET AL.: "Enantiomers, Racemates and Resolutions", 1981, WILEY-INTERSCIENCE
JOURNAL OF ORGANIC CHEMISTRY, vol. 83, no. 12, 2018, pages 6334 - 6353
WILEN ET AL., TETRAHEDRON, vol. 33, pages 2725
WILEN: "Tables of Resolving Agents and Optical Resolutions", 1972, UNIV. OF NOTRE DAME PRESS, pages: 268

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