6,6-fused bicyclic amides and compositions for use as 15-prostaglandin dehydrogenase modulators

Abstract

The present disclosure provides novel 15-hydroxy-prostaglandin dehydrogenase inhibitors, pharmaceutical compositions comprising such compounds, and methods of using such compounds and compositions in treating 15-hydroxy-prostaglandin dehydrogenase-mediated disease. Also provided are methods of making such compounds and intermediates thereof. The compounds have a structure of Formula (I): or a pharmaceutically acceptable salt thereof; wherein is Formula (i) or Formula (ii) Further, the disclosure provides intermediates useful in the synthesis of compounds of Formula (I).

Description

6,6-FUSED BICYCLIC AMIDES AND COMPOSITIONS FOR USE AS 15-PROSTAGLANDIN DEHYDROGENASE MODULATORS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 501,064, filed May 9, 2023, which is hereby incorporated by reference in its entirety for all purposes as if fully set forth herein. Field

[0002] Provided herein are novel compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds and compositions in treating 15-hydroxy- prostaglandin dehydrogenase-mediated disease. Also provided are methods of making such compounds and intermediates thereof. BACKGROUND

[0003] Short-chain dehydrogenases (SCDs) 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 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 levelsand treating diseases, disorders, or conditions that are related to 15-PGDH activity. In several embodiments, 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.

[0005] Several embodiments disclosed herein pertain to a compound of Formula (I): I); or a pharmaceutically acceptable salt thereo ; d f, or haloalkyl; wherein R1amay be unsubstituted or substituted with one or more substituents, each of which independently is halogen, –OH, -CN, alkoxy, -NH2, alkyl-amino, or dialkyl-amino; R1bis alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylene-cycloalkyl, alkylene-aryl, alkylene- heterocyclyl, or alkylene-heteroaryl; wherein R1bmay be unsubstituted or substituted with one or more substituents, each of which independently is halogen, –OH, -CN, C1-6alkoxy, -NH2, alkylamino, or dialkylamino; or, alternatively, R1aand R1btogether form a heterocyclyl or heteroaryl, each of which may be unsubstituted or substituted with one or more instances of R4; wherein each instance of R4independently is halogen, oxo, OH, -NH2, alkyl, heteroalkyl, alkoxy, alkylamino, dialkylamino, alkylene- OH, or haloalkyl; wherein each instance of R4may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, alkoxy, -NH2, alkylamino, or dialkylamino; R2is heteroaryl or heterocyclyl; wherein R2is unsubstituted or substituted with one or more instances of R5; wherein each instance of R5independently is halogen, oxo, -CN, -OH, alkyl, alkoxy, haloalkyl, heteroalkyl, cycloalkyl, amino, alkylamino, dialkylamino, -C(O)heterocyclyl, heterocyclyl, or heteroaryl; wherein each instance of R5may be unsubstituted or substituted one or more instances of R6; wherein each instance of R6independently is halogen, alkyl, -C(O)alkyl, -C(O)2alkyl, or alkylene-OH; each instance of R3independently is halogen, alkyl, alkenyl, alkoxy, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein R3may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, alkyl, alkoxy, haloalkyl, or heteroalkyl. In several embodiments, b and c are not both C-R3.

[0006] In several embodiments, R1ais H, C1-6alkyl, C1-6heteroalkyl, or C1-6haloalkyl. In several embodiments, R1ais C1-6alkyl, C1-6heteroalkyl, or C1-6haloalkyl. In several embodiments, R1ais -H, C1-6alkyl or C1-6haloalkyl. In several embodiments, R1ais -H. In several embodiments, R1ais C1-6alkyl. In several embodiments, R1ais C1-3alkyl. In several embodiments, R1ais C1-6haloalkyl. In several embodiments, R1ais C1-3haloalkyl.

[0007] In several embodiments, R1amay be unsubstituted or substituted with one or more substituents, each of which independently is halogen, –OH, -CN, C1-4alkoxy, -NH2, C1-4alkylamino, or diC1-4alkylamino. In several embodiments, each substituent of R1aindependently is halogen, –OH, or C1-4alkoxy. In several embodiments, each substituent of R1aindependently is halogen or C1-4alkoxy. In several embodiments, the R1ahalogen substituent is -F or -Cl. In several embodiments, the R1ahalogen substituent is -F. In several embodiments, when R1ais substituted, it is substituted with one substituent. In several embodiments, when R1ais substituted, it is substituted with two substituents. In several embodiments, when R1ais substituted, it is substituted with three substituents. In several embodiments, when R1ais substituted, it is substituted with four substituents. In several embodiments, when R1ais substituted, it is substituted with one to two substituents. In several embodiments, when R1ais substituted, it is substituted with one to three substituents. In several embodiments, when R1ais substituted, it is substituted with one to four substituents. In several embodiments, R1ais unsubstituted.

[0008] In several embodiments, R1bis C1-6alkyl, C1-6alkoxy, C1-6heteroalkyl, C3-7cycloalkyl, heterocyclyl with 3 to 10 ring members, C6-10aryl, heteroaryl having 5 to 10 ring members, C1-6alkylene- C3-7cycloalkyl, C1-6alkylene-C6-10aryl, C1-6alkylene-heterocyclyl with 3 to 7 ring members, or C1-6alkylene-heteroaryl with 5 to 10 ring members. In several embodiments, R1bis C1-3alkyl, C1-3alkoxy, C1-3heteroalkyl, C3-7cycloalkyl, heterocyclyl with 3 to 10 ring members, C6-10aryl, heteroaryl having 5 to 10 ring members, C1-6alkylene-C3-7cycloalkyl, C1-6alkylene-C6-10aryl, C1-6alkylene-heterocyclyl with 3 to 7 ring members, or C1-6alkylene-heteroaryl with 5 to 10 ring members. In several embodiments, R1bis C1-6alkyl, C1-6alkoxy, C1-6heteroalkyl, C3-7cycloalkyl, C6-10aryl, C1-6alkylene-C3-7cycloalkyl, C1-6alkylene-C6-10aryl, or C1-6alkylene-heterocyclyl with 3 to 7 ring members. In several embodiments, R1bis C1-6alkyl, C1-6alkoxy, C1-6heteroalkyl, C3-7cycloalkyl, C6-10aryl, C1-6alkylene-C3-7cycloalkyl, C1-6alkylene-C6-10aryl, or C1-6alkylene-heterocyclyl with 3 to 7 ring members. In several embodiments, R1bis C1-4alkyl. In several embodiments, R1bis C1-3alkoxy. In several embodiments, R1bis C1-4heteroalkyl. In several embodiments, R1bis C3-6cycloalkyl. In several embodiments, R1bis C6-10aryl. In several embodiments, R1bis C1-3alkylene-C3-6cycloalkyl. In several embodiments, R1bis C1-3alkylene-C6-10aryl. In several embodiments, R1bis C1-3alkylene-heterocyclyl with 3 to 6 ring members.

[0009] In several embodiments, R1bmay be unsubstituted or substituted with one or more substituents, each of which independently is halogen, –OH, -CN, C1-6alkoxy, -NH2, C1-4alkylamino, or di C1-4alkylamino. In several embodiments, R1bmay be unsubstituted or substituted with one or moresubstituents, each of which independently is halogen, -OH, -NH2, or C1-3 alkoxy. In several embodiments, when Rlbis substituted with a halogen, the halogen is -F. In several embodiments, when Rlbis substituted, it is substituted with one substituent. In several embodiments, when Rlbis substituted, it is substituted with two substituents. In several embodiments, when Rlbis substituted, it is substituted with three substituents. In several embodiments, when Rlbis substituted, it is substituted with four substituents. In several embodiments, when Rlbis substituted, it is substituted with one to two substituents. In several embodiments, when Rlbis substituted, it is substituted with one to three substituents. In several embodiments, when Rlbis substituted, it is substituted with one to four substituents. In several embodiments, Rlbis unsubstituted.

[0010] In several embodiments, alternatively, Rlaand Rlbtogether form a heterocyclyl with 3 to 20 ring members or heteroaryl with 5 to 20 ring members. In several embodiments, Rlaand Rlbtogether form a heterocyclyl with 3 to 10 ring members or heteroaryl with 5 to 10 ring members. In several embodiments, Rlaand Rlbtogether form a heterocyclyl with 3 to 10 ring members. In several embodiments, Rlaand Rlbtogether form a heterocyclyl with 10 ring members. In several embodiments, Rlaand Rlbtogether form a heterocyclyl with 9 ring members. In several embodiments, when Rlaand Rlbtogether form a heterocyclyl, it is substituted with one R4group. In several embodiments, when Rlaand Rlbtogether form a heterocyclyl, it is substituted with two R4groups. In several embodiments, when Rlaand Rlbtogether form a heterocyclyl, it is substituted with three R4groups. In several embodiments, when Rlaand Rlbtogether form a heterocyclyl, it is substituted with four R4groups. In several embodiments, when Rlaand Rlbtogether form a heterocyclyl, it is substituted with one to two R4groups. In several embodiments, when Rlaand Rlbtogether form a heterocyclyl, it is substituted with one to three R4groups. In several embodiments, when Rlaand Rlbtogether form a heterocyclyl, it is substituted with one to four R4groups. In several embodiments, when Rlaand Rlbtogether form a heterocyclyl, it is unsubstituted.

[0011] In several embodiments, each instance of R4independently 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. In several embodiments, each instance of R4independently is halogen, -OH, -NH2, CM alkyl, CM heteroalkyl, CM alkoxy, or Ci-ehaloalkyl. In several embodiments, each instance of R4independently is halogen, -OH, -NH2, CM alkyl, CM heteroalkyl, CM alkoxy, or CM haloalkyl. In several embodiments, R4is halogen. In several embodiments, R4is -F. In several embodiments, R4is -OH. In several embodiments, R4is -NH2. In several embodiments, R4is CM alkyl. In several embodiments, R4is CM heteroalkyl. In several embodiments, R4is CM alkoxy. In several embodiments, R4is C 1-3 haloalkyl.

[0012] In several embodiments, each instance of R4may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, CM alkoxy, -NH2, CM alkylamino, or di CMalkylamino. In several embodiments, each instance of R4may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, –OH, C1-3alkoxy, -NH2, C1-2alkylamino, or di C1-2alkylamino. In several embodiments, at least an instance of R4is halogen. In several embodiments, when R4is substituted with a halogen, the halogen is -F. In several embodiments, at least an instance of R4is –OH. In several embodiments, at least an instance of R4is C1-3alkoxy. In several embodiments, at least an instance of R4is -NH2. In several embodiments, at least an instance of R4is C1-2alkylamino. In several embodiments, at least an instance of R4is di C1-2alkylamino. In several embodiments, when R4is substituted, it is substituted with one substituent. In several embodiments, when R4is substituted, it is substituted with two substituents. In several embodiments, when R4is substituted, it is substituted with three substituents. In several embodiments, when R4is substituted, it is substituted with four substituents. In several embodiments, when R4is substituted, it is substituted with one to two substituents. In several embodiments, when R4is substituted, it is substituted with one to three substituents. In several embodiments, when R4is substituted, it is substituted with one to four substituents. In several embodiments, R4is unsubstituted.

[0013] In several embodiments, R2is heteroaryl having 5 to 20 ring members or heterocyclyl having 3 to 20 ring members. In several embodiments, R2is heteroaryl having 5 to 20 ring members or heterocyclyl having 5 to 20 ring members. In several embodiments, R2is heteroaryl having 5 to 10 ring members or heterocyclyl having 5 to 10 ring members. In several embodiments, R2is heteroaryl having 5 to 20 ring members. In several embodiments, R2is heterocyclyl having 5 to 20 ring members. In several embodiments, R2is heteroaryl having 5 to 10 ring members. In several embodiments, R2is heterocyclyl having 5 to 10 ring members. In several embodiments, R2is heterocyclyl having 5 to 10 ring members. In several embodiments, R2is unsubstituted or substituted with one or more instances of R5. In several embodiments, R2is substituted with 1 R5group. In several embodiments R2is substituted with 2 R5groups. In several embodiments, R2is substituted with 3 R5groups. In several embodiments, R2is substituted with 4 R5groups. In several embodiments, R2is substituted with 5 R5groups. In several embodiments, R2is substituted with 1 to 2 R5groups. In several embodiments, R2is substituted with 1 to 3 R5groups. In several embodiments, R2is substituted with 1 to 4 R5groups. In several embodiments, R2is substituted with 1 to 5 R5groups. In several embodiments, R2is unsubstituted.

[0014] In several embodiments, each instance of R5independently is halogen, oxo, -CN, OH, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6heteroalkyl, C3-6cycloalkyl, amino, C1-4alkylamino, di C1-4alkylamino, C(O)heterocyclyl having 3 to 6 ring members, heterocyclyl having 3 to 6 ring members, or heteroaryl having 5 to 10 ring members. In several embodiments, each instance of R5independently is halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, amino (-NH2), C(O)heterocyclyl having 3 to 6 ring members, orheterocyclyl having 3 to 6 ring members. In several embodiments, each instance of R5independently is halogen, oxo, C1-3alkyl, C1-3haloalkyl, amino (-NH2), C(O)heterocyclyl having 3 to 6 ring members, or heterocyclyl having 3 to 6 ring members. In several embodiments, at least an instance of R5is halogen. In several embodiments, the R5halogen is -F or -Cl. In several embodiments, the R5halogen (or halogens) is -F. In several embodiments, at least an instance of R5is -F. In several embodiments, at least an instance of R5is oxo. In several embodiments, at least an instance of R5is -CN. In several embodiments, at least an instance of R5is C1-6alkyl. In several embodiments, at least an instance of R5is C1-6haloalkyl. In several embodiments, at least an instance of R5is-NH2. In several embodiments, at least an instance of R5is C(O)heterocyclyl having 3 to 6 ring members. In several embodiments, at least an instance of R5is heterocyclyl having 3 to 6 ring members.

[0015] In several embodiments, each R5is unsubstituted or substituted with one or more instances of R6. In several embodiments, each R5is substituted with one R6group. In several embodiments, each R5is substituted with two R6groups. In several embodiments, each R5is substituted with three R6groups. In several embodiments, each R5is substituted with four R6groups. In several embodiments, each R6is substituted with one to two R6groups. In several embodiments, each R5is substituted with one to three R6groups. In several embodiments, each R5is substituted with one to four R6groups. In several embodiments, R5is unsubstituted.

[0016] In several embodiments, each instance of R6independently is halogen, C1-6alkyl, C(O)C1-6alkyl, C(O)2C1-6alkyl, or C1-6alkylene-OH. In several embodiments, when R6is halogen, it is -F. In several embodiments, each instance of R6independently is halogen, C1-3alkyl, C(O)C1-4alkyl, C(O)2C1-4alkyl, or C1-3alkylene-OH. In several embodiments, at least an instance of R6is halogen. In several embodiments, at least an instance of R6is -F.

[0017] In several embodiments, each instance of R3independently is halogen, C1-6alkyl, C1-6alkenyl, C1-6alkoxy, C1-6haloalkyl, C1-6heteroalkyl, C3-7cycloalkyl, heterocyclyl with 3 to 10 ring members, C6-10aryl, or heteroaryl having 5 to 10 ring members. In several embodiments, each instance of R3independently is halogen, C1-3alkyl, C1-3alkenyl, C1-3alkoxy, C1-3haloalkyl, C1-3heteroalkyl, C3-7cycloalkyl, heterocyclyl with 3 to 7 ring members, C6-10aryl, or heteroaryl having 5 to 10 ring members. In several embodiments, each instance of R3independently is halogen, C1-6alkyl, C1-6alkenyl, C3-7cycloalkyl, heterocyclyl with 3 to 10 ring members, C6-10aryl, or heteroaryl having 5 to 10 ring members. In several embodiments, b and c are not both C-R3. In several embodiments, R3is halogen. In several embodiments, R3is -F or -Cl. In several embodiments, R3is -Cl. In several embodiments, R3is C1-3alkyl. In several embodiments, R3is C1-3alkenyl. In several embodiments, R3is C1-3alkoxy. In several embodiments, R3is C1-3haloalkyl. In several embodiments, R3is C1-3heteroalkyl. In severalembodiments, R3is C3-7cycloalkyl. In several embodiments, R3is heterocyclyl with 3 to 7 ring members. In several embodiments, R3is C6-10aryl. In several embodiments, R3is heteroaryl having 5 to 10 ring members.

[0018] In several embodiments, R3may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, or C1-6heteroalkyl. In several embodiments, R3is substituted with halogen. In several embodiments, R3is substituted with -F or -Cl. In several embodiments, R3is substituted with -F. In several embodiments, R3is substituted with -OH. In several embodiments, R3is substituted with oxo. In several embodiments, R3is substituted with C1-6alkyl. In several embodiments, R3is substituted with C1-6alkoxy. In several embodiments, R3is substituted with C1-6haloalkyl. In several embodiments, R3is substituted with C1-6heteroalkyl. In several embodiments, when R3is substituted, it is substituted with one substituent. In several embodiments, when R3is substituted, it is substituted with two substituents. In several embodiments, when R3is substituted, it is substituted with three substituents. In several embodiments, when R3is substituted, it is substituted with four substituents. In several embodiments, when R3is substituted, it is substituted with one to two substituents. In several embodiments, when R3is substituted, it is substituted with one to three substituents. In several embodiments, when R3is substituted, it is substituted with one to four substituents. nts, ments, b is. , . , . ments, c is CH. In several embodiments, c is C-R3. In several embodiments, 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 Inseveral embodiments, the In several embodiments, tgroup is . In several embodiments, the group is . In several embodiments, the group .

[0022] In several embodiments, at lee 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.

[0025] 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 a 15-PGDH mediated disease or disorder.

[0026] 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 inflammatory bowel disease.

[0027] 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 ulcerative colitis.

[0028] 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.

[0029] 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 a fibrotic disease, disorder or condition.

[0030] 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).

[0031] Several embodiments pertain to a method of treating intestinal, gastrointestinal, or bowel disorders 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).

[0032] Further aspects and advantages will be apparent to those of ordinary skill in the art from a review of the following detailed description. The description hereafter includes specific cases, embodiments, and examples with the understanding that the disclosure is illustrative and is not intended to limit the embodiments of the present disclosure to the specific cases, embodiments, and examples described herein. To the contrary, reference to embodiments of the present disclosure is intended to cover alternatives, modifications, and equivalents as may be included within the spirit and scope of the embodiments of the present disclosure as defined by the appended claims. DETAILED DESCRIPTION

[0033] Several embodiments provide compounds and compositions, methods of use thereof, and methods of manufacture thereof. In several embodiments, the compounds disclosed herein are useful for inhibiting SCD and / or 15-PGDH and / or for treating SCD and / or 15-PGDH diseases, disorders, and conditions. In several embodiments, the compounds disclosed herein have an amido-6,6-fused bicyclic heteroaryl ring system core structure. In several embodiments, the compound comprises an amido moiety. Elsewhere herein, these compounds may be referred to as amido-6,6-fused-heteroaryl(s) for brevity. These compounds and any other compounds disclosed herein may be generally referred to as 15- PGDH inhibitors. The following description provides context and examples, but should not be interpreted to limit the scope of the inventions covered by the claims that follow in this specification or in any other application that claims priority to this specification. No single component or collection of components is essential or indispensable. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. Features disclosed under one heading (such as a composition or combination) can be combined with features disclosed under a different heading (a method of treating).Definitions

[0034] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0035] As used herein, “Ca-b” (or similar wording, such as, Cato Cb) 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. That is, 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. Thus, for example, a “C1-4alkyl” group (or C1to C4alkyl) refers to all alkyl groups having from 1 to 4 carbons (e.g., 1, 2, 3, or 4), that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CH3)3C-. A “C1-6alkyl” 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. As will be appreciated in view of the preceding disclosure, where a range is disclosed (for alkyl groups or other groups disclosed herein), each individual member within that disclosed range is also envisioned and disclosed. Thus, where a “C1-6alkyl” is disclosed, all alkyl groups having from 1 to 6 carbons and any alkyl groups containing 1 carbon, 2 carbons, 3 carbons, 4 carbons, 5 carbons, or 6 carbons, or combinations of the foregoing (e.g., 1, 2, 3, or 5 carbons; 2, 3, 4, or 6 carbons; etc.) are provided. Likewise, where a “C1-3alkyl” is disclosed, all alkyl groups having from 1 to 3 carbons and any alkyl groups containing 1 carbon, 2 carbons, or 3 carbons, or combinations of the foregoing (e.g., 1 or 3; 1 or 2; 2 or 3; etc.) are provided.

[0036] The term “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. Examples of 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 C1-5alkyl includes C5alkyls, C4alkyls, C3alkyls, C2alkyls and C1alkyl (i.e., methyl). A C1-6alkyl includes all moieties described above for C1-5alkyls but also includes C6alkyls. A C1-10alkyl includes all moieties described above for C1-5alkyls and C1-6alkyls, but also includes C7, C8, C9and C10alkyls. Similarly, a C1-12alkyl includes all the foregoing moieties, but also includes C11and C12alkyls. By way of example only, “C1-4alkyl” 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 C1-12alkyl include, but are in no way limited to, methyl (“Me” or -CH3), 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.

[0037] The term “alkylene” or “alkylene chain” refers to a fully saturated, straight or branched divalent hydrocarbon chain radical, and having from one to twelve carbon atoms. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene and octylene. A C1-12alkylene includes C12alkylenes, C11alkylenes, C10alkylenes, C9alkylenes, C8alkylenes, C7alkylenes, C6alkylenes, C5alkylenes, C4alkylenes, C3alkylenes, and C2alkylenes, and C1alkylene (i.e., methylene). An alkylene group may be a lower alkylene having 1 to 6 carbon atoms. A lower alkylene includes C6alkylenes, C5alkylenes, C4alkylenes, C3alkylenes, and C2alkylenes, and C1alkylene. It also is to be understood that certain 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. For example, a substituent identified as alkyl but that requires two points of attachment includes alkylene di-radicals such as –CH2–, –CH2CH2–, – CH2CH(CH3)CH2–, and the like.

[0038] As used herein, “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 C2-12alkenyl, an alkenyl comprising up to 10 carbon atoms is a C2-10alkenyl, an alkenyl group comprising up to 6 carbon atoms is a C2-6alkenyl and an alkenyl comprising up to 5 carbon atoms is a C2-5alkenyl. A C2-5alkenyl includes C5alkenyls, C4alkenyls, C3alkenyls, and C2alkenyls. A C2-6alkenyl includes all moieties described above for C2-5alkenyls but also includes C6alkenyls. A C2-10alkenyl includes all moieties described above for C2-5alkenyls and C2-6alkenyls, but also includes C7, C8, C9and C10alkenyls. A C2-12alkenyl includes all the foregoing moieties, but also includes C11and C12alkenyls. Non-limiting examples of C2-12alkenyl 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, 5- nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6- decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5- undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2- dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11-dodecenyl.

[0039] The term “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 C2-12alkynyl, an alkynyl comprising up to 10 carbon atoms is a C2-10alkynyl, an alkynyl group comprising up to 6 carbon atoms is a C2-6alkynyl and an alkynyl comprising up to 5 carbon atoms is a C2-5alkynyl. A C2-5alkynyl includes C5alkynyls, C4alkynyls, C3alkynyls, and C2alkynyls. A C2-6alkynyl includes all moieties described above for C2-5alkynyls but also includes C6alkynyls. A C2-10alkynyl includes all moieties described above for C2-5alkynyls and C2-6alkynyls, but also includes C7, C8, C9and C10alkynyls. A C2-12alkynyl includes all the foregoing moieties, but also includes C11and C12alkynyls. Non-limiting examples of C2-12alkynyl include ethynyl, propynyl, butynyl, pentynyl and the like.

[0040] The term “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).

[0041] The term “haloalkyl” refers to a straight- or branched-chain alkyl group, substituting one or more or all hydrogens with halogens. Examples of haloalkyl groups include, but are not limited to, -CF3, - CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2Cl, -CH2CF2CF3and 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).

[0042] The term “alkoxy” refers to the formula –OR wherein R is an alkyl group as defined elsewhere herein. For illustration, a “C1-9alkoxy” includes but is not limited to methoxy, ethoxy, n-propoxy, 1- methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.

[0043] As used herein, “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. In various embodiments, 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 “C1-4heteroalkyl” or similar designations. The heteroalkyl group may contain one or more heteroatoms. By way of example only, “C1-4heteroalkyl” 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. As will be understood from the above, in embodiments having one heteroatom, theheteroatom 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).

[0044] As used herein, “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. In some embodiments, the aryl group has 6 to 10 carbon atoms. The aryl group may be designated as “C6-10aryl,” “C6or C10aryl,” or similar designations. For example, the aryl group can be a C6-C14aryl group, a C6-C10aryl group, or a C6aryl group. For purposes of this invention, 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. Examples of 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.

[0045] The term “carbocyclyl,” “carbocyclic,” or “carbocycle” 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; C3-20). 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 “C3-6carbocyclyl” 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.

[0046] The term “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.

[0047] The term “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 includefused, 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.

[0048] The term “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.

[0049] The term “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”). Unless stated otherwise specifically in the specification, 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. Examples of such 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, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, succinimidyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, and the like. 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 3to 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.

[0050] The term “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. In various embodiments, 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. For example, in various embodiments, 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, isothiazolyl, imidazolyl, imidazo[1,2-a]pyridinyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolopyridinyl, pyridine-onyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl).

[0051] The term “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.

[0052] The term “hydroxy” (or “hydroxyl”) refers to a –OH group. 15

[0053] The term “cyano” refers to a “-CN” group.

[0054] The term “oxo” refers to the =O substituent.

[0055] The term “amino” refers to a NH2group.

[0056] The term “alkylamino” refers to a “-NRAH” group in which RAis alkyl.

[0057] The term “dialkylamino” refers to a “-NRARB” group in which RAand RBare each independently alkyl. RAand RBmay be taken together with the nitrogen to which they are attached to provide a heteroaryl or heterocyclyl.

[0058] The term “aminoalkyl” refers to an amino group connected via an alkylene group.

[0059] As used herein, any “R” group(s) such as, without limitation, R1, R2, R3, etc., represent substituents that can be attached to the indicated atom. An 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. For example, when the following substructure is present: and each instance of R is defined as being in ydrogen or alkyl, or each instance of R togetherwith the nitrogen to which they are attached form a heterocyclyl, it is meant that 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. As further illustration, without limitation, if RAand RBof an NRARBgroup are n ca e to be “taken together,” it means that they are covalently bonded to one another to form a ring: .

[0060] A cyclic structure may be shown u sing the following structure (or a similar structure with a different ring, heteroatoms,nds, etc.):. When a cyclic structure is depicted using this type of illustration, what is meant is that the R group may be attached to any position of the ring by replacing an –H of the ring with –R. For example, for the following ring: it is meant to include any of the following strucues: where “ ” indicates a bond toa e a g po o o e s ucue. ewise, for the following structure: where “ ” indicates a bond to a remainingstructure and n is 1 to 6, any of the following struct are envisioned or other variations (as would be readily appreciated by the one of skill in the art): . Addition ved from the nitrogen t. ,where indicates a bond to a remaining portion of the structure and n is 1 to 6, any of the following structures are envisioned or other variations (as would be readily appreciated by the one of skill in the art): . Where sp, . , structure: where “ ” indicates a bond to a remainingport on o t e structure and n is 1 to 6, any of the following struct are envisioned or other variations (as would be readily appreciated by the one of skill in the art): .

[0061] hich they are attached,it is meant that the collective unit of the atoms, intervening bonds, and the two R groups are the recited ring. For example, when the following substructure is present:and RAand RBare each independently hydrogen or alkyl, or R1and R2together with the atoms to which they are attached form an aryl or carbocyclyl, it is meant that R1and R2can be selected from hydrogen or alkyl, or alternatively, the substructure has structure: where A is an aryl ring or a carbocyclyl containing the depicted double bond.

[0062] Wherever a substituent is depicted as a di-radical (i.e., has two points of attachment to the rest of the molecule), it is to be understood that the substituent can be attached in any directional configuration A unless otherwise indicated. Thus, for example, a substituent depicted as –AE– E includes the substituent being oriented such that the “A” is attached at the leftmoint of the molecule as well as the case in which “A” is attached at the rightmost attachment point of the molecule.

[0063] As noted in the definition for alkylene, it also is to be understood that 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. For example, a substituent identified as aminoalkyl that requires two points of attachment includes di-radicals such as –NHCH2–, –NHCH2CH2–, –NHCH2CH(CH3)CH2–, and the like. Other examples a substituent may require two points of attachment include alkoxy, aryl, heteroaryl, carbocyclyl, heterocyclyl, etc.

[0064] As used herein, a radical indicates species with a single, unpaired electron such that the species containing the radical can be covalently bonded to another species. Hence, in this context, a radical is not necessarily a free radical. Rather, a radical indicates a specific portion of a larger molecule.

[0065] Where a particular group (e.g., an R group) is indicated as being substituted, it is understood that such substitutions occur where valency allows. Thus, if the group is R and R is -H or alkyl with R is indicated as being substituted or unsubstituted, then it will be understood that the “-H” atom is not substituted because valency does not allow it to be. On the other hand, where R is alkyl, it may be unsubstituted or substituted.

[0066] The term “solvate” refers to the compound formed by the interaction of a solvent and a compound described herein, a metabolite, or salt thereof. 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 thecombination of one or more molecules of water with one of the substances in which the water retains its molecular state as H2O, 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. 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.

[0067] The term “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. In addition, various adjuvants such as are commonly used in the art may be included.

[0068] The term “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. In many cases, 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. Additionally, the salts of the compounds described herein, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules.

[0069] As used herein, “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.

[0070] 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. Accordingly, 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.

[0071] The term “mammal” is used in its usual biological sense. Thus, it specifically includes, but is not limited to, primates, including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rats and mice but also includes many other species.

[0072] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the standard deviation found in their respective testing measurements.

[0073] When referring to numerical values, the terms “or ranges including and / or spanning the aforementioned values” (and variations thereof) is meant to include any range that includes or spans the aforementioned values. For example, when the temperature of a reaction is expressed as “20oC, 30oC, 40oC, 50oC, or ranges including and / or spanning the aforementioned values,” this includes the particular temperature provided (e.g., 20oC, 30oC, 40oC, or 50oC) or temperature ranges extending between 20oC to 50oC, 20oC to 40oC, 20oC to 30oC, 30oC to 50oC, 30oC to 40oC, or 40oC to 50oC.Compounds

[0074] Provided herein as Embodiment 1 is a compound of Formula (I) or a pharmaceutically acceptable salt thereof; whereinb is C-H or C-R3; c is N, C-H, or C-R3; wherein b and c are not both C-R3; R1ais H, C1-6alkyl, C1-6heteroalkyl, or C1-6haloalkyl; wherein R1amay be unsubstituted or substituted with one or more substituents, each of which independently is halogen, –OH, -CN, C1-4alkoxy, -NH2, C1-4alkylamino, or diC1-4alkylamino; R1bis C1-6alkyl, C1-6alkoxy, C1-6heteroalkyl, C3-7cycloalkyl, heterocyclyl with 3 to 10 ring members, C6-10aryl, heteroaryl having 5 to 10 ring members, C1-6alkylene-C3-7cycloalkyl, C1-6alkylene- C6-10aryl, C1-6alkylene-heterocyclyl with 3 to 10 ring members, or C1-6alkylene-heteroaryl with 5 to 10 ring members; wherein R1bmay be unsubstituted or substituted with one or more substituents, each of which independently is halogen, –OH, -CN, C1-6alkoxy, -NH2, C1-4alkylamino, or di C1-4alkylamino; or, alternatively, R1aand R1btogether form a heterocyclyl with 3 to 20 ring members which may be unsubstituted or substituted with one or more instances of R4; wherein each instance of R4independently is halogen, oxo, OH, -NH2, C1-6alkyl, C1-6heteroalkyl, C1-6alkoxy, C1-4alkylamino, di C1-4alkylamino, C1-6alkylene-OH, or C1-6haloalkyl; wherein each instance of R4may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, –OH, C1-6alkoxy, -NH2, C1-4alkylamino, or di C1-4alkylamino; R2is heteroaryl having 5 to 20 ring members or heterocyclyl having 5 to 20 ring members; wherein R2is unsubstituted or substituted with one or more instances of R5; 22wherein each instance of R5independently is halogen, oxo, -CN, OH, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6heteroalkyl, C3-6cycloalkyl, amino, C1-4alkylamino, di C1-4alkylamino, C(O)heterocyclyl having 3 to 6 ring members, heterocyclyl having 3 to 6 ring members, or heteroaryl having 5 to 10 ring members; wherein each instance of R5may be unsubstituted or substituted one or more instances of R6; wherein each instance of R6independently is halogen, C1-6alkyl, C(O)C1-6alkyl, C(O)2C1-6alkyl, or C1-6alkylene-OH; R3, when present, is halogen, C1-6alkyl, C1-6alkenyl, C1-6alkoxy, C1-6haloalkyl, C1-6heteroalkyl, C3-7cycloalkyl, heterocyclyl with 3 to 10 ring members, C6-10aryl, or heteroaryl having 5 to 10 ring members; wherein R3may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, or C1-6heteroalkyl. In several embodiments, R1ais -H, C1-3alkyl, C1-3heteroalkyl, or C1-3haloalkyl. In several embodiments, R1ais C1-6alkyl, C1-6heteroalkyl, or C1-6haloalkyl. In several embodiments, R1ais C1-3alkyl, C1-3heteroalkyl, or C1-3haloalkyl. In several embodiments, R1ais C1-6alkyl or C1-6haloalkyl. In several embodiments, R1ais -H or C1-6alkyl. In several embodiments, R1ais -H or C1-6haloalkyl. In several embodiments, R1ais -H or C1-6heteroalkyl. In several embodiments, R1ais C1-6alkyl. In several embodiments, R1ais C1-6haloalkyl. In several embodiments, R1ais C1-6heteroalkyl. In several embodiments, R1ais -H. In several embodiments, R1bis C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6heteroalkyl, C3-7cycloalkyl, C6-10aryl, C1-6alkylene-C3-7cycloalkyl, C1-6alkylene-C6-10aryl, or C1-6alkylene-heterocyclyl with 3 to 7 ring members. In several embodiments, the R1balkylene (e.g., of C1-6alkylene-C3-7cycloalkyl, C1-6alkylene-C6-10aryl, or C1-6alkylene-heterocyclyl) is a C1-2alkylene. In several embodiments, the R1balkylene is a C1-3alkylene. In several embodiments, the R1balkylene is a C1-4alkylene. In several embodiments, the R1balkylene is a C1-5alkylene. In several embodiments, the cyclic group of R1b(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 R1b(e.g., the cycloalkyl group or the heterocyclyl group, including of the alkylene cycles) comprises 3, 4, 5, or 6 ring members. In several embodiments, R1bis C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C3-10cycloalkyl, or heterocyclyl having 3 to 10 ring members. In several embodiments, R1bis C1-6alkyl, C1-6haloalkyl, or C1-6heteroalkyl. In several embodiments, R1bis C3-10cycloalkyl or heterocyclyl having 3 to 10 ring members. In several embodiments, R1bis haloalkyl. In several embodiments, R1bis heterocyclyl having3 to 10 ring members. In several embodiments, R1aand R1btogether form a heterocyclyl having 5 to 12- ring members. In several embodiments, R1aand R1btogether form a heterocyclyl having 6 to 12-ring members. In several embodiments, R1aand R1btogether form a heterocyclyl having 5 to 12-ring members. In several embodiments, R1aand R1btogether form a heterocyclyl having 6 to 12-ring members. In several embodiments, R1aand R1btogether form a heterocyclyl having 3 to 10 ring members. In several embodiments, R1aand R1btogether form a heterocyclyl having 4 to 6 ring members. In several embodiments, R2is heteroaryl having 5 to 10 ring members or heterocyclyl having 3 to 10 ring members. In several embodiments, R2is heteroaryl having 5 to 10 ring members. In several embodiments, when present, R3is halogen, C1-6alkyl, C1-6alkenyl, C1-6alkoxy, C1-6haloalkyl, C1-6heteroalkyl, C3-7cycloalkyl, heterocyclyl with 3 to 10 ring members, C6-10aryl, or heteroaryl having 5 to 10 ring members. In several embodiments, R3is halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, heteroaryl having 5 to 10 ring members, or heterocyclyl having 5 to 10 ring members. In several embodiments, R3is C1-6alkyl, C1-6haloalkyl, C6-10aryl, heteroaryl having 5 to 10 ring members, or heterocyclyl having 5 to 10 ring members. In several embodiments, R3is C1-6alkyl, C1-6alkenyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, or heteroaryl having 5 to 10 ring members. In several embodiments, R3is C3-6cycloalkyl. In several embodiments, R3is heteroaryl having 5 to 10 ring members. In several embodiments, a haloalkyl as provided in a variable of Embodiment 1 (or any of the other embodiments provided herein) may be perhalogenated, where each -H has been exchanged with a halogen. In several embodiments, a haloalkyl as provided in a variable of Embodiment 1 (or any of the other embodiments provided herein) is not perhalogenated and one or more instances C-H occur (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or more). In several embodiments, C-H instances occurring within the haloalkyl may occur on the same carbon (e.g., providing CH2or CH3). In several embodiments, 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). In several embodiments, each halogen of the haloalkyl independently is -F, -Cl, -Br, or -I. In several embodiments, each halogen of the haloalkyl is -F or -Cl. In several embodiments, each halogen of the haloalkyl is -F. In several embodiments, a heteroalkyl as provided in a variable of Embodiment 1 (or any of the other embodiments provided herein) includes a heteroatom (or one or more heteroatoms) within the alkyl backbone. In several embodiments, each heteroatom of the heteroalkyl independently is nitrogen, oxygen, or sulfur (e.g., S, SO, or SO2). In several embodiments, each heteroatom of the heteroalkyl independently is nitrogen or oxygen. In several embodiments, each heteroatom of the heteroalkyl is nitrogen. In several embodiments, each heteroatom of the heteroalkyl is oxygen. In several embodiments, 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.

[0075] Provided herein as Embodiment 2 is the compound or salt of Embodiment 1, wherein, when R1ais H and R1bis C1-6alkylene-C3-7cycloalkyl or C1-6alkylene-heterocyclyl with 3 to 7 ring members, then R2is a heteroaryl or heterocyclyl with at least 6 ring members.

[0076] Provided herein as 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, R2is unsubstituted heteroaryl, and b is C- R3, then R3is not unsubstituted heteroaryl.

[0077] Provided herein as 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, R1aand R1btogether provide unsubstituted piperidinyl, R2is 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-R3, then R3is not unsubstituted phenyl.

[0078] Provided herein as 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, R1aand R1btogether provide 4-methyl piperazinyl, R2is heteroaryl, and b is C-R3where R3is -CF3, then R2is not heteroaryl having 5 members and substituted with a single methyl as its only substituent.

[0079] 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, R2is heteroaryl, and b is C-R3where R3is chloro, then R2is not heteroaryl having 5 members and substituted with a single methyl as its only substituent.

[0080] 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, R1aand R1btogether provide an unsubstituted piperidinyl, then R5is not amino or alkylamino.

[0081] Provided herein as 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, R1aand R1btogether provide an unsubstituted piperidinyl, and R2is a 10 membered heteroaryl with one R5substituent, then R5is not oxo.

[0082] Provided herein as 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 R1aand R1btogether provide an unsubstituted piperidinyl, then R2is 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 NH2as its only substitutents, pyridinyl substituted with a single instance of N(Me)2as its only substituent, pyridinyl substituted with a single instance of F as its only substituent, pyridinyl substituted with a single instance of morpholinyl as its onlysubstituent, unsubstituted heteroaryl with 10 ring members, heteroaryl with 10 ring members substituted with a single instance chloro as its only substituent, heteroaryl with 10 ring members substituted with a single methoxy as its only substituent, heteroaryl with 10 ring members substituted with a oxo and methyl as its only substituents, or heteroaryl with 10 ring members substituted with a single instance of CN as its only substituent.

[0083] Provided herein as Embodiment 10 is the compound or salt of any one of Embodiments 1 to 9, wherein R2is not morpholinyl.

[0084] Provided herein as Embodiment 11 is the compound or salt of any one of Embodiments 1 to 10, wherein R2and R3are different.

[0085] Provided herein as Embodiment 12 is the compound or salt of any one of Embodiments 1 to 11, wherein b and c are not both C-R3.

[0086] Provided herein as Embodiment 13 is the compound or salt of any one of Embodiments 1 to 12, wherein R5is not heteroaryl.

[0087] Provided herein as Embodiment 14 is the compound or salt of any one of Embodiments 1 to 13, wherein, when R2is heterocyclyl having 6 to 10 ring members, the heterocyclyl group includes at least one unsaturation.

[0088] Provided herein as 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, Rais methyl, Rbis methyl, and R2is 5 membered heterocyclyl, then R5is not a 6 membered heterocyclyl.

[0089] Provided herein as 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, R1aand R1btogether provide an unsubstituted piperidinyl, R2is a 9 membered heterocyclyl or 9 membered heteroaryl with one instance of R5, and R5is amino, then R2does not include a ring heteroatom that is S.

[0090] Provided herein as 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, R1aand R1btogether provide an unsubstituted morpholinyl, R2is a 9 membered heterocyclyl or 9 membered heteroaryl with one instance of R5, and R5is amino, then R2does not include a ring heteroatom that is O.

[0091] 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 R1aand R1btogether provide an unsubstituted piperidinyl, then R2is not benzoxazolyl substituted with NH2.

[0092] 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-R3, each of b, d, e, and f is CH, R1ais H, and R2is unsubstituted orsubstituted heteroaryl having 5 to 6 ring members or unsubstituted or substituted heterocyclyl having 6 ring members, then R1bis not C1-3alkylene-heteroaryl with 5 ring members.

[0093] Provided herein as Embodiment 20 is the compound or salt of any one of Embodiments 1 to 19, wherein, when a is N, c is C-R3, each of b, d, e, and f is CH, and R1ais H, then R3is not alkoxy.

[0094] Provided herein as Embodiment 21 is the compound or salt of any one of Embodiments 1 to 20, wherein, when a is N, c is C-R3, R3is alkoxyl, each of b, d, e, and f is CH, R1ais H, and R2is unsubstituted or substituted heteroaryl having 5 to 6 ring members or unsubstituted or substituted heterocyclyl having 6 ring members, then R1bis not C1-3alkylene-heteroaryl with 5 to 9 ring members.

[0095] Provided herein as Embodiment 22 is the compound or salt of any one of Embodiments 1 to 21, wherein, when a is N, c is C-R3, each of b, d, e, and f is CH, and R2is unsubstituted or substituted heteroaryl having 5 to 6 ring members or unsubstituted or substituted heterocyclyl having 6 ring members, then R1ais not H.

[0096] 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-R3, each of b, d, e, and f is CH, R1aand R1btogether form an unsubstituted or substituted heterocyclyl with 6 ring members, and R2is unsubstituted or substituted heteroaryl having 5 ring members, then R3is not Cl.

[0097] Provided herein as 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, R1ais methyl, and R2is substituted or unsubstituted heteroaryl having 9 ring members, then R1bis not -CH2CH2N(CH2CH3)2.

[0098] Provided herein as 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 R2is heteroaryl having 9 ring members and substituted with oxo, then R1aand R1bdo not together form 4-methyl piperazinyl.

[0099] Provided herein as 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 R2is unsubstituted or substituted heterocyclyl having 6 ring members, then R1ais not H.

[0100] Provided herein as 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, R2is unsubstituted or substituted heterocyclyl having 6 ring members, and R1ais H, then R1bis not C4-6cycloalkyl, C4-5alkyl, or C1-3alkylene-heterocyclyl with 6 ring members.

[0101] Provided herein as 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 R2is unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted thiazolyl, or unsubstituted or substituted pyrazolyl, then R1aand R1bdo not together form unsubstituted piperidinyl.

[0102] Provided herein as 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 R2is unsubstituted or substituted heteroaryl having 10 ring members or unsubstituted or substituted heterocyclyl having 10 ring members, then R1aand R1bdo not together form unsubstituted piperidinyl.

[0103] Provided herein as 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 R2is unsubstituted or substituted indazolyl, then R1aand R1bdo not together form unsubstituted piperidinyl.

[0104] Provided herein as 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 R2is unsubstituted or substituted piperazinyl, then R1aand R1bare not both unsubstituted propyl.

[0105] Provided herein as 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 R2is unsubstituted or substituted piperazinyl, then R1aand R1bare not both unsubstituted C1-3alkyl.

[0106] Provided herein as 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 R2is unsubstituted or substituted piperazinyl, then R1aand R1bdo not together provide unsubstituted or substituted piperidinyl.

[0107] Provided herein as 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, R1ais H, and R2is unsubstituted or substituted heteroaryl having 5 ring members, then R1bis not unsubstituted or substituted C1-6alkylene-C6aryl.

[0108] Provided herein as 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, R1ais H, and R2is heteroaryl having 8 ring members substituted with a unsubstituted or substituted pyridinyl, then R1bis not unsubstituted C1-3alkyl or C1-3alkyl substituted with amino.

[0109] Provided herein as 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 R2is unsubstituted or substituted benzoxazolyl, then R1aand R1bdo not together form an unsubstituted morpholinyl.

[0110] Provided herein as Embodiment 37 is the compound or salt of any one of Embodiments 1 to 36, wherein R1bis not unsubstituted or substituted pyridinyl.

[0111] Provided herein as 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 R1aand R1bare both ethyl, then R2is not piperazinyl.

[0112] Provided herein as 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 R1aand R1btogether provide an unsubstituted piperadinyl group, then R2is not pyridinyl, pyrimidinyl, or quinolinyl.

[0113] Provided herein as 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, R1ais H, and R1bis C1-6alkyl or cyclohexyl, then R2is not piperazinyl.

[0114] Provided herein as 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 R1aand R1btogether do not provide unsubstituted piperadinyl.

[0115] Provided herein as 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, R1aand R1btogether provide an unsubstituted piperidinyl, and R2is a 10 membered heteroaryl with one R5substituent, then R5is not oxo.

[0116] Provided herein as 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).

[0118] the compound or salt of any one of Embodiments 1 to 44, whereina is N.

[0119] Provided herein as Embodiment 46 is the compound or salt of any one of Embodiments 1 to 44, wherein a is CH.

[0120] Provided herein as Embodiment 47 is the compound or salt of any one of Embodiments 1 to 46, wherein b is CH.

[0121] Provided herein as Embodiment 48 is the compound or salt of any one of Embodiments 1 to 46, wherein b is C-R3.

[0122] Provided herein as Embodiment 49 is the compound or salt of any one of Embodiments 1 to 48, wherein c is N.

[0123] Provided herein as Embodiment 50 is the compound or salt of any one of Embodiments 1 to 48, wherein c is CH.

[0124] Provided herein as Embodiment 51 is the compound or salt of any one of Embodiments 1 to 48, wherein c is C-R3.

[0125] Provided herein as Embodiment 52 is the compound or salt of any one of Embodiments 1 to 51, wherein d is N.

[0126] Provided herein as Embodiment 53 is the compound or salt of any one of Embodiments 1 to 51, wherein d is CH.

[0127] Provided herein as Embodiment 54 is the compound or salt of any one of Embodiments 1 to 53, wherein e is N.

[0128] Provided herein as Embodiment 55 is the compound or salt of any one of Embodiments 1 to 53, wherein e is CH.

[0129] Provided herein as Embodiment 56 is the compound or salt of any one of Embodiments 1 to 55, wherein f is N.

[0130] Provided herein as Embodiment 57 is the compound or salt of any one of Embodiments 1 to 55, wherein f is CH.

[0131] Provided herein as Embodiment 58 is the compound or salt of any one of Embodiments 1 to 57,ralembodiments, the Inseveral embodiments, the Inseveral embodiments, the .

[0132] Provided herein ane of Embodiments 1 to 44, 47, 51, and 52 to 57, wherein th grou .

[0133] Provided herein as Embs the ct of any one of Embodiments 1 to 45, 47, 49, and 52 to 58, wherein th .

[0134] Provided herein as Emb o lt of any one of Embodiments 1 to 44,46, 47, 50, and 52 to 58, wherein th .

[0135] Provided herein as Embodi any one of Embodiments 1 to 45,48, 49, and 52 to 58, wherein the group .

[0136] Provided herein as Emb s the co t of any one of Embodiments 1 to 45,47, 50, and 52 to 58, wherein the grou .

[0137] 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.

[0138] Provided herein as 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.

[0139] Provided herein as 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.

[0140] Provided herein as Embodiment 67 is the compound or salt of any one of Embodiments 1 to 66, wherein R1ais -H, C1-3alkyl, or C1-3haloalkyl. For example, in several embodiments, R1ais -H or C1-3haloalkyl. In several embodiments, R1ais C1-3alkyl or C1-3haloalkyl. In several embodiments, R1ais -H or C1-3alkyl. In several embodiments, R1ais C1-2alkyl. In several embodiments, R1ais methyl. In several embodiments, R1ais C2alkyl. In several embodiments, R1ais C3alkyl. In several embodiments, R1ais C1-2haloalkyl. In several embodiments, R1ais C1haloalkyl. In several embodiments, R1ais C2haloalkyl. In several embodiments, R1ais C3haloalkyl.

[0141] Provided herein as Embodiment 68 is the compound or salt of any one of Embodiments 1 to 67, wherein R1ais alkyl. For example, in several embodiments, R1ais C1-6alkyl. In several embodiments, R1ais C1-5alkyl. In several embodiments, R1ais C1-4alkyl. In several embodiments, R1ais C1-3alkyl. In several embodiments, R1ais C1-2alkyl. In several embodiments, R1ais C2-3alkyl. In several embodiments, R1ais C1alkyl. In several embodiments, R1ais C2alkyl. In several embodiments, R1ais C3alkyl.

[0142] Provided herein as Embodiment 69 is the compound or salt of any one of Embodiments 1 to 67, wherein R1ais haloalkyl. For example, in several embodiments, R1ais C1-6haloalkyl. In several embodiments, R1ais C1-5haloalkyl. In several embodiments, R1ais C1-4haloalkyl. In several embodiments, R1ais C1-3haloalkyl. In several embodiments, R1ais C1-2haloalkyl. In several embodiments, R1ais C2-3haloalkyl. In several embodiments, R1ais C1haloalkyl. In several embodiments, R1ais C2haloalkyl. In several embodiments, R1ais C3haloalkyl.

[0143] Provided herein as Embodiment 70 is the compound or salt of any one of Embodiments 1 to 69, wherein R1ais substituted with 1, 2, 3, or 4 substituents. For example, in several embodiments, R1ais substituted with 1 to 4 substituents. In several embodiments, R1ais substituted with 1 to 3 substituents. In several embodiments, R1ais substituted with 1 to 2 substituents. In several embodiments, R1ais substituted with 2 to 4 substituents. In several embodiments, R1ais substituted with 3 to 4 substituents. In several embodiments, R1ais substituted with 2 to 3 substituents.

[0144] Provided herein as Embodiment 71 is the compound or salt of any one of Embodiments 1 to 70, wherein R1ais substituted with 1, 2, or 3 substituents.

[0145] Provided herein as Embodiment 72 is the compound or salt of any one of Embodiments 1 to 71, wherein R1ais substituted with 1 or 2 substituents.

[0146] Provided herein as Embodiment 73 is the compound or salt of any one of Embodiments 1 to 72, wherein R1ais substituted with 1 substituent.

[0147] Provided herein as Embodiment 74 is the compound or salt of any one of Embodiments 1 to 73, wherein, when R1ais substituted, each R1asubstituent independently is halogen, -OH, C1-3alkyl, or C1-3alkoxy. For example, in several embodiments, R1ais substituted with -F or -OH. In several embodiments, R1ais substituted with -OH or C1-3alkoxy. In several embodiments, R1ais substituted with -F or C1-3alkoxy. In several embodiments, R1ais substituted with -F, -OH, C1alkyl, C2alkyl, C3alkyl, C1alkoxy, C2alkoxy, and / or C3alkoxy. In several embodiments, R1ais substituted with methyl, C2alkyl, and / or C3alkyl. In several embodiments, R1ais substituted with -C1alkoxy, C2alkoxy, or C3alkoxy. In several embodiments, R1ais substituted with -C1alkoxy. In several embodiments, R1ais substituted with C2alkoxy. In several embodiments, R1ais substituted with C3alkoxy. In several embodiments, R1ais substituted with -F. In several embodiments, R1ais substituted with -OH. In several embodiments, R1ais substituted with methyl.

[0148] Provided herein as Embodiment 75 is the compound or salt of any one of Embodiments 1 to 74, wherein, when R1ais substituted, each R1asubstituent independently is -F, -OH, or C1-3alkoxy.

[0149] Provided herein as Embodiment 76 is the compound or salt of any one of Embodiments 1 to 69, wherein R1ais unsubstituted.

[0150] Provided herein as Embodiment 77 is the compound or salt of any one of Embodiments 1 to 67, wherein R1ais -H (-H) or . For example, in several embodiments, R1ais -H. In several embodiments, bodiments, R1ais ethyl. In several embodiments, R1ais isopropyl.

[0151] Provided herein as Embodiment 78 is the compound or salt of any one of Embodiments 1 to 67, wherein R1ais -H.

[0152] Provided herein as Embodiment 79 is the compound or salt of any one of Embodiments 1 to 67, wherein R1ais ethyl.

[0153] Provided herein as Embodiment 80 is the compound or salt of any one of Embodiments 1 to 67, wherein R1ais isopropyl.

[0154] Provided herein as Embodiment 81 is the compound or salt of any one of Embodiments 1 to 67, wherein R1ais -CH3.

[0155] Provided herein as Embodiment 82 is the compound or salt of any one of Embodiments 1 to 81, wherein R1bis C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6heteroalkyl, C3-7cycloalkyl, heterocyclyl with 3 to 7 ring members, C6-10aryl, C1-6alkylene-C3-7cycloalkyl, C1-6alkylene-C6-10aryl, or C1-6alkylene- heterocyclyl with 3 to 7 ring members. For example, in several embodiments, R1bis C1-3alkyl, C1-3haloalkyl, C3-6cycloalkyl, or heterocyclyl having 3- to 6-ring members. In several embodiments, R1bis C1-3haloalkyl, C3-6cycloalkyl, or heterocyclyl having 3- to 6-ring members. In several embodiments, R1bis C1-3alkyl, C3-6cycloalkyl, or heterocyclyl having 3- to 6-ring members. In several embodiments, R1bis C1-3alkyl, C1-3haloalkyl, or C3-6cycloalkyl. In several embodiments, R1bis C1-3alkyl or C3-6cycloalkyl. In several embodiments, R1bis C1-3alkyl or C1-3haloalkyl. In several embodiments, R1bis C3-6cycloalkyl or heterocyclyl having 3- to 6-ring members. In several embodiments, R1bis C1-3haloalkyl or heterocyclyl having 3- to 6-ring members. In several embodiments, R1bis C1-3haloalkyl or C3-6cycloalkyl. In several embodiments, R1bis alkyl. In several embodiments, where R1bis alkyl, R1bis C1-2alkyl. In several embodiments, where R1bis alkyl, R1bis C2-3alkyl. In several embodiments, where R1bis alkyl, R1bis methyl. In several embodiments, where R1bis alkyl, R1bis C2alkyl (e.g., ethyl). In several embodiments, where R1bis alkyl, R1bis C3alkyl. In several embodiments, R1bis alkoxy. In several embodiments, where R1bis alkoxy, R1bis C1-2alkoxy. In several embodiments, where R1bis alkoxy, R1bis C2-3alkoxy. In several embodiments, where R1bis alkoxy, R1bis methoxy. In several embodiments, where R1bis alkoxy, R1bis C2alkoxy (e.g., ethoxy). In several embodiments, where R1bis alkoxy, R1bis C3alkoxy. In several embodiments, R1bis haloalkyl. In several embodiments, where R1bis haloalkyl, R1bis C1-2haloalkyl. In several embodiments, where R1bis haloalkyl, R1bis C2-3haloalkyl. In several embodiments, where R1bis haloalkyl, R1bis C1haloalkyl. In several embodiments, where R1bis haloalkyl, R1bis C2haloalkyl (e.g., -CH2CHF2, -CH2CH2F, -CH2CF3, -CF2CF3, etc.). In several embodiments, where R1bis haloalkyl, R1bis C3haloalkyl (e.g., -CH2CH2CHF2, -CH2CH2CH2F, - CH2CH2CF3, -CH2CF2CF3, -CF2CF2CF3, etc.). In several embodiments, R1bis cycloalkyl. In several embodiments, where R1bis cycloalkyl, R1bis C4-6cycloalkyl. In several embodiments, where R1bis cycloalkyl, R1bis C3-5cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl). In several embodiments, where R1bis cycloalkyl, R1bis C3cycloalkyl. In several embodiments, where R1bis cycloalkyl, R1bis C4cycloalkyl. In several embodiments, where R1bis cycloalkyl, R1bis C5cycloalkyl. In several embodiments, where R1bis cycloalkyl, R1bis C6cycloalkyl. In several embodiments, where R1bis cycloalkyl (or comprises a cycloalkyl in the case of an alkylene- cycloalkyl), the cycloalkyl includes 4 to 6-ring members. In several embodiments, where R1bis cycloalkyl (or comprises a cycloalkyl in the case of an alkylene- cycloalkyl), the cycloalkyl includes 3 to 5-ring members. In several embodiments, where R1bis cycloalkyl (or comprises a cycloalkyl in the case of an alkylene- cycloalkyl), the cycloalkylincludes 3-ring members. In several embodiments, where R1bis cycloalkyl (or comprises a cycloalkyl in the case of an alkylene- cycloalkyl), the cycloalkyl includes 4-ring members. In several embodiments, where R1bis cycloalkyl (or comprises a cycloalkyl in the case of an alkylene- cycloalkyl), the cycloalkyl includes 5-ring members. In several embodiments, where R1bis cycloalkyl (or comprises a cycloalkyl in the case of an alkylene- cycloalkyl), the cycloalkyl includes 6-ring members. In several embodiments, R1bis heterocyclyl. In several embodiments, R1bis alkylene-heterocyclyl. In several embodiments, where R1bis heterocyclyl (or comprises a heterocyclyl in the case of an alkylene-heterocyclyl), the heterocyclyl includes 4 to 6-ring members. In several embodiments, where R1bis heterocyclyl (or comprises a heterocyclyl in the case of an alkylene-heterocyclyl), the heterocyclyl includes 3 to 5-ring members. In several embodiments, where R1bis heterocyclyl (or comprises a heterocyclyl in the case of an alkylene-heterocyclyl), the heterocyclyl includes 3-ring members. In several embodiments, where R1bis heterocyclyl (or comprises a heterocyclyl in the case of an alkylene-heterocyclyl), the heterocyclyl includes 4-ring members. In several embodiments, where R1bis heterocyclyl (or comprises a heterocyclyl in the case of an alkylene-heterocyclyl), the heterocyclyl includes 5-ring members. In several embodiments, where R1bis heterocyclyl (or comprises a heterocyclyl in the case of an alkylene- heterocyclyl), the heterocyclyl includes 6-ring members.

[0156] Provided herein as Embodiment 83 is the compound or salt of any one of Embodiments 1 to 81, wherein R1bis C1-6alkyl, C1-6alkoxy, C3-7cycloalkyl, C1-3alkylene-C6aryl, heterocyclyl with 3 to 7 ring members, C6aryl, C1-3alkylene-C3-7cycloalkyl, or C1-3alkylene-heterocyclyl with 3 to 7 ring members.

[0157] Provided herein as Embodiment 84 is the compound or salt of any one of Embodiments 1 to 83, wherein R1bis heterocyclyl with 3 to 7 ring members.

[0158] Provided herein as Embodiment 85 is the compound or salt of any one of Embodiments 1 to 83, wherein R1bis C1-3alkylene-heterocyclyl with 3 to 7 ring members.

[0159] Provided herein as Embodiment 86 is the compound or salt of any one of Embodiments 1 to 85, wherein, when R1bcomprises or is a heterocyclyl, the R1bheterocyclyl 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. For example, in several embodiments, when R1bis heterocyclyl, the R1bheterocyclyl includes 1 or 3 heteroatom ring members. In several embodiments, when R1bis heterocyclyl, the R1bheterocyclyl includes 2 or 3 heteroatom ring members. In several embodiments, x is 0. In several embodiments, x is 1. In several embodiments, x is 2 (e.g., S(O)2).

[0160] Provided herein as Embodiment 87 is the compound or salt of any one of Embodiments 1 to 86, wherein, when R1bcomprises or is a heterocyclyl, the R1bheterocyclyl has 1, 2, or 3 heteroatom ring members.

[0161] Provided herein as Embodiment 88 is the compound or salt of any one of Embodiments 1 to 87, wherein, when R1bcomprises or is a heterocyclyl, the R1bheterocyclyl has 1 or 2 heteroatom ring members.

[0162] Provided herein as Embodiment 89 is the compound or salt of any one of Embodiments 1 to 88, wherein, when R1bcomprises or is a heterocyclyl, the R1bheterocyclyl has 1 heteroatom ring member.

[0163] Provided herein as Embodiment 90 is the compound or salt of any one of Embodiments 1 to 89, wherein, when R1bcomprises or is a heterocyclyl, the R1bheterocyclyl includes a heteroatom ring member or ring members that comprise or consist of nitrogen.

[0164] Provided herein as Embodiment 91 is the compound or salt of any one of Embodiments 1 to 90, wherein, when R1bcomprises a heterocyclyl, the R1bheterocyclyl includes a heteroatom ring member or ring members that comprise or consist of oxygen.

[0165] Provided herein as Embodiment 92 is the compound or salt of any one of Embodiments 1 to 83, wherein R1bis alkyl.

[0166] Provided herein as Embodiment 93 is the compound or salt of any one of Embodiments 1 to 83, wherein R1bis alkoxy.

[0167] Provided herein as Embodiment 94 is the compound or salt of any one of Embodiments 1 to 83, wherein R1bis heteroalkyl.

[0168] Provided herein as Embodiment 95 is the compound or salt of any one of Embodiments 1 to 83, wherein R1bis haloalkyl.

[0169] Provided herein as Embodiment 96 is the compound or salt of any one of Embodiments 1 to 83, wherein R1bis cycloalkyl.

[0170] Provided herein as Embodiment 97 is the compound or salt of any one of Embodiments 1 to 91, wherein R1bcomprises a 3- to 6-ring member heterocyclyl.

[0171] Provided herein as Embodiment 98 is the compound or salt of any one of Embodiments 1 to 97, wherein R1bis substituted with 1, 2, 3, or 4 substituents. For example, in several embodiments, R1bis substituted with 1 to 4 substituents. In several embodiments, R1bis substituted with 1 to 3 substituents. In several embodiments, R1bis substituted with 1 to 2 substituents. In several embodiments, R1bis substituted with 2 to 4 substituents. In several embodiments, R1bis substituted with 3 to 4 substituents. In several embodiments, R1bis substituted with 2 to 3 substituents.

[0172] Provided herein as Embodiment 99 is the compound or salt of any one of Embodiments 1 to 98, wherein R1bis substituted with 1, 2, or 3 substituents.

[0173] Provided herein as Embodiment 100 is the compound or salt of any one of Embodiments 1 to 99, wherein R1bis substituted with 1 or 2 substituents.

[0174] Provided herein as Embodiment 101 is the compound or salt of any one of Embodiments 1 to 100, wherein R1bis substituted with 1 substituent.

[0175] Provided herein as Embodiment 102 is the compound or salt of any one of Embodiments 1 to 101, wherein, when R1bis substituted, each R1bsubstituent independently is halogen, C1-3alkyl, or C1-3alkoxy. For example, in several embodiments, when R1bis substituted, each R1bsubstituent independently is halogen or C1-3alkoxy. In several embodiments, when R1bis substituted, each R1bsubstituent independently is halogen or C1-3alkyl. In several embodiments, when R1bis substituted, each R1bsubstituent independently is C1-3alkyl or C1-3alkoxy. In several embodiments, 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 C1-2alkyl. In several embodiments, the substituent is C2-3alkyl. In several embodiments, the substituent is Methyl. In several embodiments, the substituent is C2alkyl. In several embodiments, the substituent is C3alkyl. In several embodiments, the substituent is C1-2alkoxy. In several embodiments, the substituent is C2-3alkoxy. In several embodiments, the substituent is C1alkoxy. In several embodiments, the substituent is C2alkoxy. In several embodiments, the substituent is C3alkoxy.

[0176] Provided herein as Embodiment 103 is the compound or salt of any one of Embodiments 1 to 101, wherein each substituent of R1bindependently is -F, -OH, methyl, or -OMe. For example, in several embodiments, the substituent is -OH, methyl, or OMe. In several embodiments, the substituent is -F, methyl, or OMe. In several embodiments, the substituent is -F, -OH, or OMe. In several embodiments, the substituent is -F, -OH, or methyl. In several embodiments, the substituent is -F or -OH. In several embodiments, 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.

[0177] Provided herein as Embodiment 104 is the compound or salt of any one of Embodiments 1 to 103, wherein R1bis substituted with -F.

[0178] Provided herein as Embodiment 105 is the compound or salt of any one of Embodiments 1 to 104, wherein R1bis substituted with -OH.

[0179] Provided herein as Embodiment 106 is the compound or salt of any one of Embodiments 1 to 105, wherein R1bis substituted with -OMe.

[0180] Provided herein as Embodiment 107 is the compound or salt of any one of Embodiments 1 to 97, wherein R1bis unsubstituted.

[0181] Provided herein as Embodiment 108 is the compound or salt of any one of Embodiments 1 to 107, wherein R1bis:, ,1 to 66, wherein R1aand R1btogether form a 3 to 10 membered heterocyclyl. For example, in several embodiments, R1aand R1btogether form a heterocyclyl having 4 to 6-ring members. In several embodiments, R1aand R1btogether form a heterocyclyl having 5 to 6-ring members. In several embodiments, R1aand R1btogether form a heterocyclyl having 3 to 5-ring members. In several embodiments, R1aand R1btogether form a heterocyclyl having 3 to 4-ring members. In several embodiments, R1aand R1btogether form a heterocyclyl having 4 to 5-ring members. In several embodiments, R1aand R1btogether form a heterocyclyl having 5 to 10-ring members. In several embodiments, R1aand R1btogether form a heterocyclyl having 6 to 10-ring members. In several embodiments, R1aand R1btogether form a heterocyclyl having 5 to 9-ring members. In several embodiments, R1aand R1btogether form a heterocyclyl having 6 to 9-ring members. In several embodiments, R1aand R1btogether form a heterocyclyl having 3-ring members. In several embodiments, R1aand R1btogether form a heterocyclyl having 4-ring members. In several embodiments, R1aand R1btogether form a heterocyclyl having 5-ring members. In several embodiments, R1aand R1btogether form a heterocyclyl having 6-ring members. In several embodiments, R1aand R1btogether form a heterocyclyl having 7-ring members. In several embodiments, R1aand R1btogether form a spirocyclic heterocyclyl. In several embodiments, R1aand R1btogether form a heterocyclyl having a fused ring system. In several embodiments, R1aand R1btogether form a heterocyclyl having a bridged ring system. In several embodiments, R1aand R1btogether 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 R1aand R1btogether form a 3 to 9 membered heterocyclyl.

[0184] Provided herein as Embodiment 111 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 110, wherein R1aand R1btogether form a heterocyclyl that is fully saturated.

[0185] Provided herein as Embodiment 112 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 111, wherein R1aand R1btogether form a heterocyclyl and each heteroatom ring member of the R1aand R1bheterocyclyl independently is nitrogen, oxygen, or -S(O)x-, where x is 0, 1, or 2. For example, in several embodiments, R1aand R1btogether form a heterocyclyl having 1 or 3 heteroatom ring members. In several embodiments, R1aand R1btogether form a heterocyclyl having 2 or 3 heteroatom ring members. In several embodiments, x is 0. In several embodiments, x is 1. In several embodiments, x is 2 (e.g., S(O)2).

[0186] Provided herein as Embodiment 113 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 112, wherein R1aand R1btogether form a heterocyclyl having 1, 2, or 3 heteroatom ring members.

[0187] Provided herein as Embodiment 114 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 113, wherein R1aand R1btogether form a heterocyclyl having 1 or 2 heteroatom ring members.

[0188] Provided herein as Embodiment 115 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 114, wherein R1aand R1btogether form a heterocyclyl having 1 heteroatom ring member.

[0189] Provided herein as Embodiment 116 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 115, wherein R1aand R1btogether form a heterocyclyl and the heteroatom or heteroatoms of the R1aand R1bheterocyclyl comprise or consist of nitrogen.

[0190] Provided herein as Embodiment 117 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 116, wherein R1aand R1btogether form a heterocyclyl and the heteroatom or heteroatoms of the R1aand R1bheterocyclyl comprise oxygen.

[0191] Provided herein as Embodiment 118 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 117, wherein R1aand R1btogether form a multicyclic heterocyclyl.

[0192] Provided herein as Embodiment 119 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 118, wherein R1aand R1btogether form a tricyclic heterocyclyl.

[0193] Provided herein as Embodiment 120 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 118, wherein R1aand R1btogether form a bicyclic heterocyclyl.

[0194] Provided herein as Embodiment 121 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 120, wherein R1aand R1btogether form a bridged heterocyclyl ring system.

[0195] Provided herein as Embodiment 122 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 121, wherein R1aand R1btogether form a fused heterocyclyl ring system.

[0196] Provided herein as Embodiment 123 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 122, wherein R1aand R1btogether form a spirocyclic heterocyclyl.

[0197] Provided herein as Embodiment 124 is the compound or salt of any one of Embodiments 120 to 123, wherein the R1aand R1bheterocyclyl ring system comprises at least a first and a second ring, the first ring comprising at least 7 ring members.

[0198] Provided herein as Embodiment 125 is the compound or salt of any one of Embodiments 120 to 123, wherein the R1aand R1bheterocyclyl ring system comprises at least a first and a second ring, the first ring comprising at least 6 ring members.

[0199] Provided herein as Embodiment 126 is the compound or salt of any one of Embodiments 120 to 123, wherein the R1aand R1bheterocyclyl ring system comprises at least a first and a second ring, the first ring comprising at least 5 ring members.

[0200] Provided herein as Embodiment 127 is the compound or salt of any one of Embodiments 120 to 123, wherein the R1aand R1bheterocyclyl ring system comprises at least a first and a second ring, the first ring comprising at least 4 ring members.

[0201] Provided herein as Embodiment 128 is the compound or salt of any one of Embodiments 124 to 127, wherein the second ring of the R1aand R1bheterocyclyl ring system comprises 6 ring members.

[0202] Provided herein as Embodiment 129 is the compound or salt of any one of Embodiments 124 to 127, wherein the second ring of the R1aand R1bheterocyclyl ring system comprises 5 ring members.

[0203] Provided herein as Embodiment 130 is the compound or salt of any one of Embodiments 124 to 127, wherein the second ring of the R1aand R1bheterocyclyl ring system comprises 4 ring members.

[0204] Provided herein as Embodiment 131 is the compound or salt of any one of Embodiments 124 to 127, wherein the second ring of the R1aand R1bheterocyclyl ring system comprises 3 ring members.

[0205] Provided herein as Embodiment 132 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 131, wherein the R1aand R1bheterocyclyl comprises a carbocyclyl ring.

[0206] Provided herein as Embodiment 133 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 131, wherein the R1aand R1bheterocyclyl comprises at least two heterocyclic rings.

[0207] Provided herein as Embodiment 134 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 133, wherein R1aand R1btogether form a heterocyclyl that is substituted with 1, 2, 3, 4, or 5 instances of R4. For example, in several embodiments, the R1aand R1bheterocyclyl is substituted with 2 to 5 R4substituents. In several embodiments, the R1aand R1bheterocyclyl is substituted with 3 to 4 R4substituents. In several embodiments, the R1aand R1bheterocyclyl is substituted with 3 to 5 R4substituents. In several embodiments, the R1aand R1bheterocyclyl is substituted with 4 to 5 R4substituents. In several embodiments, the R1aand R1bheterocyclyl is substituted with 2, 3, 4, or 5 R4substituents. In several embodiments, the R1aand R1bheterocyclyl is substituted with 1, 2, or 4 R4substituents. In several embodiments, the R1aand R1bheterocyclyl is substituted with 1 or 3 R4substituents.

[0208] Provided herein as Embodiment 135 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 134, wherein R1aand R1btogether form a heterocyclyl that is substituted with 1, 2, 3, or 4 instances of R4.

[0209] Provided herein as Embodiment 136 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 135, wherein R1aand R1btogether form a heterocyclyl that is substituted with 1, 2, or 3 instances of R4.

[0210] Provided herein as Embodiment 137 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 136, wherein R1aand R1btogether form a heterocyclyl that is substituted with 1 or 2 instances of R4.

[0211] Provided herein as Embodiment 138 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 137, wherein R1aand R1btogether form a heterocyclyl that is substituted with 1 instance of R4.

[0212] Provided herein as Embodiment 139 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 138, wherein each instance of R4independently is halogen, OH, -NH2, C1-6alkyl, C1-6heteroalkyl, C1-6alkoxy, C1-4alkylamino, di C1-4alkylamino, C1-6alkylene-OH, C1-6haloalkyl. For example, in several embodiments, each instance of R4independently is halogen, OH, -NH2, C1-6alkyl, C1-6heteroalkyl, C1-6alkoxy, or C1-6haloalkyl. In several embodiments, an instance of R4is -OH. In several embodiments, an instance of R4is C1-6alkylene-OH. In several embodiments, an instance of R4is -NH2. In several embodiments, an instance of R4is halogen. In several embodiments, an instance of R4is -F, - Cl, or -Br. In several embodiments, an instance of R4is -F or -Cl. In several embodiments, an instance of R4is -F. In several embodiments, an instance of R4is C1-3alkyl. In several embodiments, an instance of R4is C1-2alkyl. In several embodiments, an instance of R4is C2-3alkyl. In several embodiments, an instance of R4is methyl. In several embodiments, an instance of R4is C2alkyl. In several embodiments, an instance of R4is C3alkyl. In several embodiments, an instance of R4is C1-3haloalkyl. In several embodiments, an instance of R4is C1-2haloalkyl. In several embodiments, an instance of R4is C2-3haloalkyl. In several embodiments, an instance of R4is C1haloalkyl. In several embodiments, an instance of R4is C2haloalkyl. In several embodiments, an instance of R4is C3haloalkyl. In several embodiments, an instance of R4is C1-3heteroalkyl. In several embodiments, an instance of R4is C1-2heteroalkyl. In several embodiments, an instance of R4is C2-3heteroalkyl. In several embodiments, an instance of R4is C1heteroalkyl. In several embodiments, an instance of R4is C2heteroalkyl. In several embodiments, an instance of R4is C3heteroalkyl. In several embodiments, an instance of R4is C1-2alkoxy. In several embodiments, an instance of R4is C2-3alkoxy. In several embodiments, an instance of R4is methoxy. In several embodiments, an instance of R4is C2alkoxy. In several embodiments, an instance of R4is C3alkoxy.

[0213] Provided herein as Embodiment 140 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 139, wherein each instance of R4independently is halogen, OH, -NH2, C1-3alkyl, C1-3alkoxy, or C1-3haloalkyl.

[0214] Provided herein as Embodiment 141 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 138, wherein each instance of R4independently is -F, -OH, -NH2, -CH3, -CF3, -CH2OH, - OCH3, -OCH2CH3, or -OCHF2,.

[0215] Provided herein as Embodiment 142 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 138, wherein each instance of R4independently is -CF3, -CF2CF3, or -CF2CF2CF3,

[0216] Provided herein as Embodiment 143 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 140, wherein each instance of R4may be substituted with 1, 2, or 3 substituents.

[0217] Provided herein as Embodiment 144 is the compound or salt of any one of Embodiments 1 to 66, 109 to 140, and 143, wherein each instance of R4may be substituted with 1 or 2 substituents.

[0218] Provided herein as 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 R4may be substituted with 1 substituent.

[0219] Provided herein as 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 R4is substituted with a substituent that independently is halogen, –OH, C1-3alkoxy, -NH2, C1-2alkylamino, or di C1-2alkylamino. For example, in several embodiments, each substituent of R4independently is halogen, OH, -NH2, or C1-3alkoxy. In several embodiments, an instance of a R4substituent is -F, -Cl, or -Br. In several embodiments, an instance of a R4substituent is -F or -Cl. In several embodiments, an instance of a R4substituent is -F. In several embodiments, an instance of a R4substituent is C1-2alkoxy. In several embodiments, an instance of a R4substituent is C2-3alkoxy. In several embodiments, an instance of a R4substituent is methoxy. In several embodiments, an instance of a R4substituent is C2alkoxy. In several embodiments an instance of a R4substituent is C3alkoxy. In several embodiments, an instance of a R4substituent is NH2. In several embodiments, an instance of a R4substituent is C1-2alkylamino. In several embodiments, an instance of a R4substituent is C1-2dialkylamino.

[0220] Provided herein as Embodiment 147 is the compound or salt of any one of Embodiments 1 to 66, 109 to 140, wherein each instance of R4is unsubstituted.

[0221] Provided herein as Embodiment 148 is the compound or salt of any one of Embodiments 1 to 66 and 109 to 133, wherein R1aand R1btogether form a heterocyclyl that is unsubstituted.

[0222] Provided herein as Embodiment 149 is the compound or salt of any one of Embodiments 1 to 66,wherein, is represented by: ; whereinh is 1, 2, 3, 4, 5, or 6; and g is 0, 1, 2, 3, 4, 5, or 6.

[0223] Provided herein as Embodiment 150 is the compound or salt of Embodiment 149, wherein h is 1, 2, 3, 4, or 5.

[0224] Provided herein as Embodiment 151 is the compound or salt of Embodiment 149 or 150, wherein h is 1, 2, 3, or 4.

[0225] Provided herein as Embodiment 152 is the compound or salt of any one of Embodiments 149 to 151, wherein h is 1, 2, or 3.

[0226] Provided herein as 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.

[0227] Provided herein as Embodiment 154 is the compound or salt of any one of Embodiments 149 to 153, wherein g is 0, 1, 2, 3, or 4.

[0228] Provided herein as Embodiment 155 is the compound or salt of any one of Embodiments 149 to 154, wherein g is 0, 1, 2, or 3.

[0229] Provided herein as Embodiment 156 is the compound or salt of any one of Embodiments 149 to 155, wherein g is 0, 1, or 2.

[0230] Provided herein as Embodiment 157 is the compound or salt of any one of Embodiments 149 to 156, wherein g is 0 or 1.

[0231] Provided herein as Embodiment 158 is the compound or salt of any one of Embodiments 149 to 157, wherein g is 0.

[0232] Provided herein as 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, isrepresented n several embodiments, is represented by . Inseveral embodiments, In several embodiments,is represented byeralembodiments, . In several embodimen isrepresented by . In several embodiment .In several embodiments,R1a N is represented by . In several embodimentsis represented .R1a N In several embodiments,R1a N is represented by . In several embodimentsR1bis represent .R1aIn several embodimentsis represented by . In several embodiments, is represented .In several embodiments, is represented by . In several embodiments,is represented by . In several embodiments . Inseveral embodiments,is represented by . In several embodiments, is represented b . In1aR1a several embodiments,isrepresented by . In several embodiment is represented . InR1a several embodiments, isrepresented by . Inseveral embodiments, isrepresented b . Inseveral embodiments, is represented by I l b di t isrepresented by . In several embodiment . In R1aNseveral embodiments,R1bis represented In several embodiments, isrepresented by . In several embodime s, s represented by .

[0233] Provided herein as Embodiment 160 is the compound or salt of any one of Embodiments 1 to 66,wherein, is represented by: .

[0234] Provided herein as Embodiment 161 is the compound or salt of any one of Embodiments 1 to 66,161, wherein R is heterocyclyl.

[0236] Provided herein as Embodiment 163 is the compound or salt of any one of Embodiments 1 to 161, wherein R2is heteroaryl.

[0237] Provided herein as Embodiment 164 is the compound or salt of any one of Embodiments 1 to 163, wherein the R2has 1, 2, 3, 4, or 5 heteroatom ring members. For example, in several embodiments, R2includes 5 heteroatom ring members. In several embodiments, R2includes 4 heteroatom ring members. In several embodiments, R2includes 3 heteroatom ring members. In several embodiments, R2includes 2 heteroatom ring members. In several embodiments, R2includes 1 heteroatom ring member. Inseveral embodiments, R2comprises 1 to 5 heteroatom ring members. In several embodiments, R2comprises 1 to 4 heteroatom ring members. In several embodiments, R2comprises 1 to 3 heteroatom ring members. In several embodiments, R2comprises 1 or 2 heteroatom ring members. In several embodiments, R2comprises 2 to 5 heteroatom ring members. In several embodiments, R2comprises 3 to 5 heteroatom ring members. In several embodiments, R2comprises 3 to 4 heteroatom ring members. In several embodiments, R2comprises nitrogen atoms as the only ring heteroatoms. In several embodiments, R2comprises one nitrogen atom as a ring heteroatom. In several embodiments, R2comprises two nitrogen atoms as a ring heteroatoms. In several embodiments, R2comprises three nitrogen atoms as a ring heteroatoms. In several embodiments, R2comprises four nitrogen atoms as a ring heteroatoms. In several embodiments, R2comprises five nitrogen atoms as a ring heteroatoms. In several embodiments, R2comprises one oxygen ring heteroatom and the remaining ring heteroatoms are nitrogen atoms. In several embodiments, R2comprises oxygen atoms as the only ring heteroatoms.

[0238] Provided herein as Embodiment 165 is the compound or salt of any one of Embodiments 1 to 164, wherein R2has 1, 2, 3, or 4 heteroatom ring members.

[0239] Provided herein as Embodiment 166 is the compound or salt of any one of Embodiments 1 to 165, wherein R2has 1, 2, or 3 heteroatom ring members.

[0240] Provided herein as Embodiment 167 is the compound or salt of any one of Embodiments 1 to 166, wherein R2has 1 or 2 heteroatom ring members.

[0241] Provided herein as Embodiment 168 is the compound or salt of any one of Embodiments 1 to 167, wherein R2has 1 heteroatom ring member.

[0242] Provided herein as Embodiment 169 is the compound or salt of any one of Embodiments 1 to 168, wherein each heteroatom ring member of R2independently is nitrogen, oxygen, or -S(O)y-, where y is 0, 1, or 2.

[0243] Provided herein as Embodiment 170 is the compound or salt of any one of Embodiments 1 to 169, wherein each heteroatom of the R2ring independently is nitrogen or oxygen.

[0244] Provided herein as Embodiment 171 is the compound or salt of any one of Embodiments 1 to 170, wherein each ring heteroatom of the R2is nitrogen.

[0245] Provided herein as Embodiment 172 is the compound or salt of any one of Embodiments 1 to 170, wherein each ring heteroatom of R2is oxygen.

[0246] Provided herein as Embodiment 173 is the compound or salt of any one of Embodiments 1 to 172, wherein R2is a fused bicyclic group. In several embodiments, the fused bicyclic R2comprises a 6- membered ring. In several embodiments, the fused bicyclic R2comprises a 5-membered ring. In severalembodiments, the fused bicyclic R2is a 5,6-member fused ring. In several embodiments, the fused bicyclic R2is a 6,6-member fused ring.

[0247] Provided herein as Embodiment 174 is the compound or salt of any one of Embodiments 1 to 173, wherein R2comprises 5 to 10 ring-members.

[0248] Provided herein as Embodiment 175 is the compound or salt of any one of Embodiments 1 to 174, wherein R2comprises 5 to 9 ring-members.

[0249] Provided herein as Embodiment 176 is the compound or salt of any one of Embodiments 1 to 174, wherein R2has 10 ring members.

[0250] Provided herein as Embodiment 177 is the compound or salt of any one of Embodiments 1 to 175, wherein R2has 9 ring members.

[0251] Provided herein as Embodiment 178 is the compound or salt of any one of Embodiments 1 to 172, wherein R2has 6 ring members.

[0252] Provided herein as Embodiment 179 is the compound or salt of any one of Embodiments 1 to 163 and 165 to 172, wherein R2has 5 ring members.

[0253] Provided herein as Embodiment 180 is the compound or salt of any one of Embodiments 1 to 179, wherein R2is substituted with 1, 2, 3, 4, or 5 instances of R5. For example, in several embodiments, R2is substituted with 2 to 5 R5substituents. In several embodiments, R2is substituted with 3 to 4 R5substituents. In several embodiments, R5is substituted with 3 to 5 R5substituents. In several embodiments, R2is substituted with 4 to 5 R5substituents. In several embodiments, R2is substituted with 2, 3, 4, or 5 R5substituents. In several embodiments R2is substituted with 1, 2, or 4 R5substituents. In several embodiments, R2is substituted 1 or 3 R5substituents.

[0254] Provided herein as Embodiment 181 is the compound or salt of any one of Embodiments 1 to 180, wherein R2is substituted with 1, 2, 3, or 4 instances of R5.

[0255] Provided herein as Embodiment 182 is the compound or salt of any one of Embodiments 1 to 181, wherein R2is substituted with 1, 2, or 3 instances of R5.

[0256] Provided herein as Embodiment 183 is the compound or salt of any one of Embodiments 1 to 182, wherein R2is substituted with 1 or 2 instances of R5.

[0257] Provided herein as Embodiment 184 is the compound or salt of any one of Embodiments 1 to 183, wherein R2is substituted with 1 instance of R5.

[0258] Provided herein as Embodiment 185 is the compound or salt of any one of Embodiments 1 to 184, wherein each instance of R5is substituted with 1, 2, or 3 instances of R6.

[0259] Provided herein as Embodiment 186 is the compound or salt of any one of Embodiments 1 to 185, wherein each instance of R5is substituted with 1 or 2 instances of R6.

[0260] Provided herein as Embodiment 187 is the compound or salt of any one of Embodiments 1 to 186, wherein each instance of R5is substituted with 1 instance of R6.

[0261] Provided herein as Embodiment 188 is the compound or salt of any one of Embodiments 1 to 187, wherein, each instance of R5independently is halogen, oxo, -CN, OH, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C3-6cycloalkyl, amino, C1-4alkylamino, di C1-4alkylamino, C(O)heterocyclyl having 3 to 6 ring members, or heterocyclyl having 3 to 6 ring members. For example, in several embodiments, each R5independently is halogen, -OH, oxo, or C1-3alkyl. In several embodiments, each R5independently is halogen, -OH, oxo, C1-3alkyl, or C1-3alkoxy. In several embodiments, each R5independently is halogen, - OH, oxo, or C1-3alkoxy. In several embodiments, each R5independently is halogen, -OH, C1-3alkyl, or C1-3alkoxy. In several embodiments, each R5independently is halogen, oxo, C1-3alkyl, or C1-3alkoxy. In several embodiments, each R5independently is -OH, oxo, C1-3alkyl, or C1-3alkoxy. In several embodiments, each R5independently is oxo, C1-3alkyl, or C1-3alkoxy. In several embodiments, each R5independently is halogen, C1-3alkyl, or C1-3alkoxy. In several embodiments, each R5independently is halogen, -OH, or C1-3alkoxy. In several embodiments, each R5independently is halogen, -OH, or oxo. In several embodiments, each R5independently is halogen, -OH, oxo, C1-3alkyl, or C1-3alkoxy. In several embodiments, each R5independently is halogen, -OH, oxo, C1-3alkyl, or C1-3haloalkyl. In several embodiments, each R5independently is halogen, oxo, or C1-3alkyl. In several embodiments, each R5independently is halogen or C1-3alkyl. In several embodiments, each R5independently is oxo or C1-3alkyl. In several embodiments, each R5independently is halogen or oxo. In several embodiments, an instance of R5is halogen. In several embodiments, a halogen R5substituent (or one or more substituents independently) is -F, -Cl, or -Br. In several embodiments, a halogen R5substituent (or one or more substituents independently) is -F or -Cl. In several embodiments, a halogen R5substituent (or one or more substituents) is -F. In several embodiments, an R5independently is C1-3alkyl. In several embodiments, an R5alkyl is C1-2alkyl. In several embodiments, an R5alkyl is C2-3alkyl. In several embodiments, an R5alkyl is methyl. In several embodiments, an R5alkyl is C2alkyl. In several embodiments, an R5alkyl is C3alkyl. In several embodiments, an R5alkoxy is C1-2alkoxy. In several embodiments, an R5alkoxy is C2-3alkoxy. In several embodiments, an R5alkoxy is methoxy. In several embodiments, an R5alkoxy is C2alkoxy. In several embodiments, an R5alkoxy is C3alkoxy.

[0262] Provided herein as Embodiment 189 is the compound or salt of any one of Embodiments 1 to 188, wherein, each instance of R5independently is halogen, oxo, OH, C1-6alkyl, C1-6haloalkyl, amino, - NH(C1-2alkyl), -N(C1-2alkyl)2, C(O)heterocyclyl having 3 to 6 ring members, or heterocyclyl having 3 to 6 ring members.

[0263] Provided herein as Embodiment 190 is the compound or salt of any one of Embodiments 1 to 189, wherein, each instance of R5independently is oxo, C1-3alkyl, C1-3haloalkyl, or C1-3alkoxy.

[0264] Provided herein as Embodiment 191 is the compound or salt of any one of Embodiments 1 to 189, wherein, each instance of R5independently is -F, oxo, -Me, -CF3, -C(O)piperidinyl, or - C(O)piperizinyl.

[0265] Provided herein as Embodiment 192 is the compound or salt of any one of Embodiments 1 to 189, wherein, each instance of R5independently is -C(O)piperidinyl or -C(O)piperizinyl.

[0266] Provided herein as Embodiment 193 is the compound or salt of any one of Embodiments 1 to 189, wherein each instance of R5independently is -F, oxo, methyl, ethyl, or isopropyl.

[0267] Provided herein as Embodiment 194 is the compound or salt of any one of Embodiments 1 to 193, wherein at least one instance of R5is -F.

[0268] Provided herein as Embodiment 195 is the compound or salt of any one of Embodiments 1 to 194, wherein at least one instance of R5is methyl.

[0269] Provided herein as Embodiment 196 is the compound or salt of any one of Embodiments 1 to 195, wherein at least one instance of R5is oxo.

[0270] Provided herein as Embodiment 197 is the compound or salt of any one of Embodiments 1 to 196, wherein, each instance of R6independently is halogen, -C1-6alkyl, -C(O)2C1-6alkyl.

[0271] Provided herein as Embodiment 198 is the compound or salt of any one of Embodiments 1 to 197, wherein each instance of R6independently is -F, -Me, -C(O)OtBu.

[0272] Provided herein as Embodiment 199 is the compound or salt of any one of Embodiments 1 to 198, wherein at least one instance of R6is -F.

[0273] Provided herein as Embodiment 200 is the compound or salt of any one of Embodiments 1 to 199, wherein at least one instance of R6is methyl.

[0274] Provided herein as Embodiment 201 is the compound or salt of any one of Embodiments 1 to 200, wherein at least one instance of R6is -C(O)OtBu.

[0275] Provided herein as Embodiment 202 is the compound or salt of any one of Embodiments 1 to 179, wherein R2is unsubstituted.

[0276] Provided herein as Embodiment 203 is the compound or salt of any one of Embodiments 1 to 184 and 188 to 196, wherein R5is unsubstituted.

[0277] Provided herein as Embodiment 204 is the compound or salt of any one of Embodiments 1 to 203, wherein R2is, where“ ” indicates a double bond or single bond may be present; each instance of Xaindependently is nitrogen, oxygen, or carbon;each instance of n, where present, is an integer selected from 1, 2, 3, 4, or 5; each instance of n’, where present, is an integer selected from 0, 1, 2, 3, 4, or 5; each instance of p, where present, is an integer selected from 0, 1, 2, 3, or 4; 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 R2group, the total of both r values combined does not exceed 5; and wherein a –N= ring nitrogen can be bonded to an R5to provide a cation.

[0278] Provided herein as Embodiment 205 is the compound or salt of any one of Embodiments 1 to 204, wherein R2is;where “ ” indicates a double bond or single bond may be present; each instance of Xaindependently is nitrogen, oxygen, or carbon; n is an integer selected from 1, 2, 3, 4, or 5; n’ is an integer selected from 0, 1, 2, 3, 4, or 5; s is an integer selected from 0, 1, 2, or 3; and wherein a –N= ring nitrogen can be bonded to an R5to provide a cation.

[0279] Provided herein as Embodiment 206 is the compound or salt of any one of Embodiments 1 to 204, wherein R2is ; where“ ” indicates a double bond or single bond may be present; each instance of Xaindependently is nitrogen, oxygen, or carbon; p is an integer selected from 0, 1, 2, 3, or 4; s is an integer selected from 0, 1, 2, or 3; and wherein a –N= ring nitrogen can be bonded to an R5to provide a cation.

[0280] Provided herein as Embodiment 207 is the compound or salt of any one of Embodiments 1 to 204, wherein R2is ; where “ ” indicates a double bonpresent;each instance of Xaindependently is nitrogen, oxygen, or carbon; s is an integer selected from 0, 1, 2, or 3; r is an integer selected from 0, 1, 2, 3, 4, or 5; and wherein a –N= ring nitrogen can be bonded to an R5to provide a cation.

[0281] Provided herein as Embodiment 208 is the compound or salt of any one of Embodiments 1 to 204, wherein R2is ; where“ ” indicates a double bond or single bond may be present; each instance of Xaindependently is nitrogen, oxygen, or carbon; each instance of s is an integer selected from 0, 1, 2, or 3; each instance of r independently is an integer selected from 0, 1, 2, 3, 4, or 5, wherein the total of both r values combined does not exceed 5; and wherein a –N= ring nitrogen can be bonded to an R5to provide a cation.

[0282] Provided herein as Embodiment 209 is the compound or salt of any one of Embodiments 1 to 204, wherein R2is ; where “ ” indicates a double bsent; each instance of Xaindependently is nitrogen, oxygen, or carbon; each instance of s is an integer selected from 0, 1, 2, or 3;each instance of r independently is an integer selected from 0, 1, 2, 3, 4, or 5, wherein the total of both r values combined does not exceed 5; and wherein a –N= ring nitrogen can be bonded to an R5to provide a cation.

[0283] Provided herein as Embodiment 210 is the compound or salt of any one of Embodiments 1 to 204, wherein R2is ; where“ ” indicates a double bond or single bond may be present; each instance of Xaindependently 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 R2group, the total of both r values combined does not exceed 5; and wherein a –N= ring nitrogen can be bonded to an R5to provide a cation.

[0284] Provided herein as Embodiment 211 is the compound or salt of any one of Embodiments 1 to 171 and 173 to 203, wherein R2is , ,,wherein R may be unsubstituted or substituted by replacing any ring -H with an R group.

[0285] Provided herein as Embodiment 212 is the compound or salt of any one of Embodiments 1 to 163, wherein R2together with its substituents is , ,,p y Embodiments 1 to 161, wherein R2is .

[0287] Provided herein as Embodiment 214ound or salt of any one of Embodiments 1 to 213, wherein R3is C1-6alkyl, C1-6alkenyl, C1-6alkoxy, C3-7cycloalkyl, heterocyclyl with 3 to 7 ring members, C6-10aryl, or heteroaryl having 5 to 10 ring members. For example, in several embodiments, R3is C1-6alkyl, C3-6cycloalkyl, C6-10aryl, heteroaryl having 5 to 10 ring members, or heterocyclyl having 5 to 10 ring members. In several embodiments, R3is C1-6alkyl, heteroaryl having 5 to 10 ring members, or heterocyclyl having 5 to 10 ring members. In several embodiments, R3is C1-6alkyl, C1-6alkenyl, C3-6cycloalkyl, or heteroaryl having 5 to 10 ring members. In several embodiments, R3is 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 R3is C3-6cycloalkyl, C6-10aryl, heteroaryl having 5 to 10 ring members, or heterocyclyl having 3 to 10 ring members.

[0289] Provided herein as Embodiment 216 is the compound or salt of any one of Embodiments 1 to 215, wherein R3is heteroaryl or heterocyclyl and the R3heteroaryl or heterocyclyl includes 1, 2, 3, or 4 heteroatom ring members. For example, in several embodiments, R3includes 4 heteroatom ring members. In several embodiments, R3includes 3 heteroatom ring members. In several embodiments, R3includes 2 heteroatom ring members. In several embodiments, R3includes 1 heteroatom ring member. In several embodiments, R3comprises 1 to 4 heteroatom ring members. In several embodiments, R3comprises 1 to 3 heteroatom ring members. In several embodiments, R3comprises 1 or 2 heteroatom ring members. In several embodiments, R3comprises 3 to 4 heteroatom ring members. In several embodiments, R3comprises nitrogen atoms as the only ring heteroatoms. In several embodiments, R3comprises onenitrogen atom as a ring heteroatom. In several embodiments, R3comprises two nitrogen atoms as a ring heteroatoms. In several embodiments, R3comprises three nitrogen atoms as a ring heteroatoms. In several embodiments, R3comprises four nitrogen atoms as a ring heteroatoms. In several embodiments, R3comprises one oxygen ring heteroatom and the remaining ring heteroatoms are nitrogen atoms. In several embodiments, R3comprises oxygen atoms as the only ring heteroatoms.

[0290] Provided herein as Embodiment 217 is the compound or salt of any one of Embodiments 1 to 216, wherein R3is heteroaryl or heterocyclyl and the R3heteroaryl or heterocyclyl includes 1, 2, or 3 heteroatom ring members.

[0291] Provided herein as Embodiment 218 is the compound or salt of any one of Embodiments 1 to 217, wherein R3is heteroaryl or heterocyclyl and the R3heteroaryl or heterocyclyl includes 1 or 2 heteroatom ring members.

[0292] Provided herein as Embodiment 219 is the compound or salt of any one of Embodiments 1 to 218, wherein R3is heteroaryl or heterocyclyl and the R3heteroaryl or heterocyclyl includes 1 heteroatom ring member.

[0293] Provided herein as Embodiment 220 is the compound or salt of any one of Embodiments 1 to 219, wherein R3is heteroaryl or heterocyclyl and each heteroatom of the R3ring independently is nitrogen, oxygen, or -S(O)z-, where z is 0, 1, or 2.

[0294] Provided herein as Embodiment 221 is the compound or salt of any one of Embodiments 1 to 220, wherein R3is heteroaryl or heterocyclyl and each heteroatom of the R3ring independently is nitrogen or oxygen.

[0295] Provided herein as Embodiment 222 is the compound or salt of any one of Embodiments 1 to 221, wherein R3is heteroaryl or heterocyclyl and each heteroatom of the R3ring is nitrogen.

[0296] Provided herein as Embodiment 223 is the compound or salt of any one of Embodiments 1 to 215 and 217 to 221, wherein R3is heteroaryl or heterocyclyl and each heteroatom of the R3ring is oxygen.

[0297] Provided herein as Embodiment 224 is the compound or salt of any one of Embodiments 1 to 223, wherein R3is fused bicyclic heteroaryl or fused bicyclic heterocyclic.

[0298] Provided herein as Embodiment 225 is the compound or salt of any one of Embodiments 1 to 224, wherein R3is heteroaryl.

[0299] Provided herein as Embodiment 226 is the compound or salt of any one of Embodiments 1 to 224, wherein R3is heterocyclyl.

[0300] Provided herein as Embodiment 227 is the compound or salt of any one of Embodiments 1 to 226, wherein R3comprises 5 to 10 ring-members.

[0301] Provided herein as Embodiment 228 is the compound or salt of any one of Embodiments 1 to 227, wherein R3comprises 5 to 9 ring-members.

[0302] Provided herein as Embodiment 229 is the compound or salt of any one of Embodiments 1 to 228, wherein R3has 9-ring members.

[0303] Provided herein as Embodiment 230 is the compound or salt of any one of Embodiments 1 to 215 and 217 to 223 and 225 to 228, wherein R3has 6-ring members.

[0304] Provided herein as Embodiment 231 is the compound or salt of any one of Embodiments 1 to 223 and 225 to 228, wherein R3has 5-ring members.

[0305] Provided herein as Embodiment 232 is the compound or salt of any one of Embodiments 1 to 214, wherein R3is C3-4cycloalkyl.

[0306] Provided herein as Embodiment 233 is the compound or salt of any one of Embodiments 1 to 214, wherein R3is C1-6alkyl.

[0307] Provided herein as Embodiment 234 is the compound or salt of any one of Embodiments 1 to 214, wherein R3is C6-10aryl.

[0308] Provided herein as Embodiment 235 is the compound or salt of any one of Embodiments 1 to 214, wherein R3is C6aryl. In several embodiments, when R3is C6aryl (e.g., phenyl), then R2is 9 membered heteroaryl. In several embodiments, when R3is C6aryl (e.g., phenyl), then R2is 9 membered heteroaryl comprising 1, 2, or 3 N atoms as the only ring heteroatoms. In several embodiments, when R3is C6aryl (e.g., phenyl), then R2is pyrazolo[3,4-b]pyridinyl. In several embodiments, when R3is C6aryl (e.g., phenyl), then R2is 2-methyl-2H-pyrazolo[3,4-b]pyridinyl.

[0309] Provided herein as Embodiment 236 is the compound or salt of any one of Embodiments 1 to 235, wherein R3is substituted with 1, 2, 3, 4, or 5 substituents. For example, in several embodiments, R3is substituted with 2 to 5 substituents. In several embodiments, R3is substituted with 3 to 4 substituents. In several embodiments, R3is substituted with 3 to 5 substituents. In several embodiments, R3is substituted with 4 to 5 substituents. In several embodiments, R3is substituted with 2, 3, 4, or 5 substituents. In several embodiments R3is substituted with 1, 2, or 4 substituents. In several embodiments, R3is substituted 1 or 3 substituents.

[0310] Provided herein as Embodiment 237 is the compound or salt of any one of Embodiments 1 to 236, wherein R3is substituted with 1, 2, 3, or 4 substituents.

[0311] Provided herein as Embodiment 238 is the compound or salt of any one of Embodiments 1 to 237, wherein R3is substituted with 1, 2, or 3 substituents.

[0312] Provided herein as Embodiment 239 is the compound or salt of any one of Embodiments 1 to 238, wherein R3is substituted with 1 or 2 substituents.

[0313] Provided herein as Embodiment 240 is the compound or salt of any one of Embodiments 1 to 239, wherein R3is substituted with 1 substituent.

[0314] Provided herein as Embodiment 241 is the compound or salt of any one of Embodiments 1 to 240, wherein each substituent of R3independently is halogen, OH, C1-3alkyl, C1-3alkoxy, or C1-3alkylene- C1-3alkoxy. For example, in several embodiments, each substituent of R3independently is C1-3alkyl, C1-3alkoxy, or C1-3alkylene-C1-3alkoxy. In several embodiments, R3is substituted with -F or -OH. In several embodiments, R3is substituted with -OH or C1-3alkoxy. In several embodiments, R3is substituted with -F or C1-3alkoxy. In several embodiments, R3is substituted with -F, -OH, C1alkyl, C2alkyl, C3alkyl, C1alkoxy, C2alkoxy, and / or C3alkoxy. In several embodiments, R3is substituted with methyl, C2alkyl, and / or C3alkyl. In several embodiments, R3is substituted with -C1alkoxy, C2alkoxy, or C3alkoxy. In several embodiments, R3is substituted with -C1alkoxy. In several embodiments, R3is substituted with C2alkoxy. In several embodiments, R3is substituted with C3alkoxy. In several embodiments, R3is substituted with -F. In several embodiments, R3is substituted with -OH. In several embodiments, R3is substituted with methyl.

[0315] Provided herein as Embodiment 242 is the compound or salt of any one of Embodiments 1 to 241, wherein each substituent of R3substituent independently is methyl, ethyl, or isopropyl.

[0316] Provided herein as Embodiment 243 is the compound or salt of any one of Embodiments 1 to 214 and 236 to 242, wherein R3is , where“ ” indicates a double bond or single bond may be present;each instance of Xbindependently 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 R3group, the total of both v values combined does not exceed 5; each instance of R13, when present and attached to an N ring member, independently is C1-3alkyl, C1-3haloalkyl, or C1-3alkylene-C1-3alkoxy; and each instance of R13, when present and attached to a C ring member, independently is halogen, - OH, oxo, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, or C1-3alkylene-O-C1-3alkyl; wherein a –N= ring nitrogen can be bonded to an R13to provide a cation.

[0317] Provided herein as Embodiment 244 is the compound or salt of any one of Embodiments 1 to 214 and 236 to 243, wherein R3is: ; whereeach 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 R3group, the total of both v values combined does not exceed 5; each instance of R13, when present and attached to an N ring member, independently is C1-3alkyl, C1-3haloalkyl, or C1-3alkylene-C1-3alkoxy; and each instance of R13, when present and attached to a C ring member, independently is halogen, - OH, oxo, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, or C1-3alkylene-O-C1-3alkyl; and wherein a –N= ring nitrogen can be bonded to an R13to provide a cation.

[0318] Provided herein as Embodiment 245 is the compound or salt of any one of Embodiments 1 to 214, wherein R3is halogen.

[0319] Provided herein as Embodiment 246 is the compound or salt of any one of Embodiments 1 to 214, wherein R3is -Cl.

[0320] Provided herein as Embodiment 248 is the compound or salt of any one of Embodiments 1 to 214, wherein R3is: .

[0321] Provided herein as Embodiment 249 is the compound or salt of any one of Embodiments 1 to 214, wherein R3is: .

[0322] Provided herein as Embodiment 250 is the compound or salt of any one of Embodiments 1 to 214, wherein R3is: .

[0323] Provided herein as Embodiment 251 is tmpound or salt of any one of Embodiments 1 to 214, wherein R3is: .

[0324] Provided herein as Embodiment 252 is tmpound or salt of any one of Embodiments 1 to 214, wherein R3is: .

[0325] Provided herein as Embodiment 253 is t mpound or salt of any one of Embodiments 1 to 3214, wherein R is: .

[0326] 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, where n he compound of Formula (I) is further represented by Formula (Ia): 62a).

[0327] 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).

[0328] Provided herein as Embodit 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).

[0329] Provided herein as 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).

[0330] Provided herein as Embodi lt of any one of Embodiments 1 to 43, 45, 48, 49, 53, 54, 57, 58, 62, and 64o , w e e e co pou d of Formula (I) is further represented by Formula (Id): d).

[0331] Provided herein as Embodi lt of any one of Embodiments 1 to 42, 44, 45, 47, 49, 53, 54, 57, 58, 60, anund of Formula (I) is further represented by Formula (Ie):e).

[0332] Provided herein as 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).

[0333] Provided herein as Embodilt of any one of Embodiments 1 to 43, 45, 47, 50, 53, 54, 57, 58, 63 to 213, wherein the compound of Formula (I) is further represented by Formula (Ig): g).

[0334] Provided herein as Embodi lt of any one of Embodiments 1 to 43,46, 47, 50, 52, 55, 57, 58, 61, and 64 to 213, wherein the compound of Formula (I) is further represented by Formula (Ih): h).

[0335] Provided herein as Embodi lt of any one of Embodiments 1 to 43, 46, 47, 50, 53, 55, 56, 58, 61, and 64o , w ere n e compound of Formula (I) is further represented by Formula (Ij): i).

[0336] In several embodiments, the (I) (e.g., as provided in Embodiment 1) may be further represented by a commulae (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), and / or (Ii). For example, in several embodiments, the compound or salt of Formula (I) (e.g., as provided in Embodiment 1) 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). For example, in several embodiments, 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 (Ih) (e.g., excluding Formula (Ii)). In several embodiments, 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)). In several embodiments, 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), (Ih), and / or (Ii) (e.g., excluding Formula (Ig)). In several embodiments, 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)). In several embodiments, 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), (If), (Ig), (Ih), and / or (Ii) (e.g., excluding Formula (Ie)). In several embodiments, 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)). In several embodiments, the compound or salt of Formula (I) (e.g., as provided in Embodiment 1) may be further represented by Formulae (Ia), (Ia.i), (Ib), (Id), (Ie), (If), (Ig), (Ih), and / or (Ii) (e.g., excluding Formula (Ic)). In several embodiments, the compound or salt of Formula (I) (e.g., as provided in Embodiment 1) may be further represented by Formulae (Ia), (Ia.i), (Ic), (Id), (Ie), (If), (Ig), (Ih), and / or (Ii) (e.g., excluding Formula (Ib)). In several embodiments, the compound or salt of Formula (I) (e.g., as provided in Embodiment 1) may be further represented by Formulae (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), and / or (Ii) (e.g., excluding Formula (Ia.i)). In several embodiments, 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)). In several embodiments, 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 (Ig) (e.g., excluding Formulae (Ih) and (Ii)). In several embodiments, 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)). In several embodiments, 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), (Ih), and / or (Ii) (e.g., excluding Formulae (If) and (Ig)). In several embodiments, 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)). In several embodiments, 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), (If), (Ig), (Ih), and / or (Ii) (e.g., excludingFormulae (Id) and (Ie)). In several embodiments, 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)). In several embodiments, the compound or salt of Formula (I) (e.g., as provided in Embodiment 1) may be further represented by Formulae (Ia), (Ia.i), (Id), (Ie), (If), (Ig), (Ih), and / or (Ii) (e.g., excluding Formulae (Ib) and (Ic)). In several embodiments, 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)). In several embodiments, the compound or salt of Formula (I) (e.g., as provided in Embodiment 1) may be further represented by Formulae (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), and / or (Ii) (e.g., excluding Formulae (Ia) and (Ia.i)). In several embodiments, 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). In several embodiments, the compound or salt of Formula (I) (e.g., as provided in Embodiment 1) may be further represented by Formulae (Ic), (Id), and / or (Ie). In several embodiments, the compound or salt of Formula (I) (e.g., as provided in Embodiment 1) may be further represented by Formulae (If), (Ig), (Ih), and / or (Ii). As will be appreciated, any other combinations of formulae are also envisioned. In several embodiments, 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.

[0337] Provided herein as Embodiment 264 is the compound or salt of Embodiment 1, wherein the compound is: ,, , , , ,O , , ,, , , , , ,, , , , , ,, , , , ,71,D59 D60 , D61 , , ,72, , , ,, , ,, , ,, , , , , ,, ,, , , , , ,N N , , ,,, ,, , , , .

[03] rov e eren as m o men s e compoun or sa o m o men , w eren e compound is: ,, , , , , ,, , , , ,, , or

[0339] 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; 2-methyl-6-(7-(1-piperidinylcarbonyl)-4-(2-propanyl)-2-quinolinyl)-1(2H)-isoquinolinone; 2-methyl-6-(7-(1-piperidinylcarbonyl)-4-(1-propen-2-yl)-2-quinolinyl)-1(2H)-isoquinolinone; 6-(4-cyclobutyl-7-(1-piperidinylcarbonyl)-2-quinolinyl)-2-methyl-1(2H)-isoquinolinone; 6-(7-(2-azaspiro[3.3]heptan-2-ylcarbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; 2-methyl-6-(7-((3-methyl-1-pyrrolidinyl)carbonyl)-2-quinoxalinyl)-1(2H)-isoquinolinone; 6-(7-(5-azaspiro[2.5]octan-5-ylcarbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; N,N-diethyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6-quinoxalinecarboxamide; 2-methyl-6-(7-((3-(trifluoromethyl)-1-piperidinyl)carbonyl)-2-quinoxalinyl)-1(2H)- isoquinolinone; 6-(7-((3-fluoro-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; 6-(7-((4,4-difluoro-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; (3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6-quinoxalinyl)(4-morpholinyl)methanone;(4,4-difluoro-1-piperidinyl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinyl)methanone; (3,3-difluoro-1-piperidinyl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinyl)methanone; N-methoxy-N-methyl-3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6-quinoxalinecarboxamide; 2-methyl-6-(7-(4-morpholinylcarbonyl)-2-quinoxalinyl)-1(2H)-isoquinolinone; 6-(7-((4-methoxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; 6-(7-((4-fluoro-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; N-(cyclopropylmethyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; 2-methyl-6-(7-(2-oxa-6-azaspiro[3.5]nonan-6-ylcarbonyl)-2-quinoxalinyl)-1(2H)-isoquinolinone; 6-(7-((4-hydroxy-6-azaspiro[2.5]octan-6-yl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-phenyl-6-quinoxalinecarboxamide; N-benzyl-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6-quinoxalinecarboxamide; 6-(7-((3,4-dihydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; 6-(7-((3-hydroxy-4-(hydroxymethyl)-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(2,2,2-trifluoroethyl)-6- quinoxalinecarboxamide; 6-(7-((4-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; 6-(7-((3,3-difluoro-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; 6-(7-((3,4-dihydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; N-(2-hydroxypropyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-(2-methoxyethyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; 6-(7-((3-methoxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(3-oxetanylmethyl)-6- quinoxalinecarboxamide; N-(2-hydroxy-2-methylpropyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide;N-(3-methoxypropyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; 6-(7-((3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; 6-(7-((3-(difluoromethoxy)-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-((3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; 3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(3-oxetanylmethyl)-6- quinoxalinecarboxamide; 3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(2-oxetanylmethyl)-6- quinoxalinecarboxamide; N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(2-oxetanylmethyl)-6- quinoxalinecarboxamide; N-(2,2-difluoroethyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-(3,3-difluoropropyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-(2-cyclopropylethyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-(3-hydroxybutyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-(2-fluoroethyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-(cyclobutylmethyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; 6-(7-(1,4-dioxa-7-azaspiro[4.5]decan-7-ylcarbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-((3-ethoxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; N-(2-cyclobutylethyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; 6-(7-((5-hydroxy-2-methyl-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-((4,4-difluoro-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone;6-(7-((4-amino-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-((3-hydroxy-4-methoxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(3,3,3-trifluoropropyl)-6- quinoxalinecarboxamide; 6-(7-((4-amino-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-((3-hydroxy-3-methyl-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-((4-amino-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 2-methyl-6-(7-(1-oxa-6-azaspiro[3.5]nonan-6-ylcarbonyl)-2-quinoxalinyl)-1(2H)-isoquinolinone; 2-methyl-6-(7-(1-oxa-6-azaspiro[3.5]nonan-6-ylcarbonyl)-2-quinoxalinyl)-1(2H)-isoquinolinone; 6-(7-((4-amino-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-((3-hydroxy-3-methyl-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; N-(3-hydroxy-3-methylbutyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; (1,1-dioxido-4-thiomorpholinyl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinyl)methanone; 6-(7-((3-methoxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(2-(2-oxetanyl)ethyl)-6- quinoxalinecarboxamide; 6-(7-((3-amino-5-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-((3-methoxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; N-(3-fluoropropyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(2-(3-oxetanyl)ethyl)-6- quinoxalinecarboxamide;(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6-quinoxalinyl)(3,3,4,4-tetrafluoro-1- pyrrolidinyl)methanone; (6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinyl)methanone; (6,6-difluoro-3-azabicyclo[3.1.1]heptan-3-yl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinyl)methanone; (9,9-difluoro-3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)-6-quinoxalinyl)methanone; (3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6-quinoxalinyl)(6-oxa-3-azabicyclo[3.1.1]heptan- 3-yl)methanone; (6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinyl)methanone; (6,6-difluoro-1,4-oxazepan-4-yl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinyl)methanone; (7,7-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)-6-quinoxalinyl)methanone; 2-methyl-2-propanyl 4-(5-(7-(1-piperidinylcarbonyl)-2-quinoxalinyl)-2-pyrimidinyl)-1- piperazinecarboxylate; (3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6-quinoxalinyl)(1,4-oxazepan-4-yl)methanone; (3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6-quinoxalinyl)(1-piperidinyl)methanone; (7,7-difluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinyl)methanone; (5,5-difluoro-2-azaspiro[3.3]heptan-2-yl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinyl)methanone; (3-(2-(1-piperazinyl)-5-pyrimidinyl)-6-quinoxalinyl)(1-piperidinyl)methanone; (3,3-difluoro-1-pyrrolidinyl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinyl)methanone; (3,3-difluoro-1-azetidinyl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinyl)methanone; (3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6-quinoxalinyl)(1-pyrrolidinyl)methanone; 6-(7-((3-hydroxy-4-(hydroxymethyl)-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone;2-methyl-2-propanyl 4-(5-(7-((4,4-difluoro-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2- pyrimidinyl)-1-piperazinecarboxylate; (4,4-difluoro-1-piperidinyl)(3-(2-(1-piperazinyl)-5-pyrimidinyl)-6-quinoxalinyl)methanone; N-cyclobutyl-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-cyclopentyl-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-cyclopropyl-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-cyclohexyl-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-(cyclopentylmethyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-(cyclohexylmethyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-cyclopropyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(2-propanyl)-6- quinoxalinecarboxamide; N-(cyclopropylmethyl)-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(2-propanyl)-6- quinoxalinecarboxamide; 5-(7-((4,4-difluoro-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2(1H)-pyridinone; N-(cyclopropylmethyl)-3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-N-(2-propanyl)-6- quinoxalinecarboxamide; N-(cyclopropylmethyl)-N-methyl-3-(2-methyl-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-6- quinoxalinecarboxamide; N-(cyclobutylmethyl)-N-methyl-3-(2-methyl-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-6- quinoxalinecarboxamide; 5-(7-((4,4-difluoro-1-piperidinyl)carbonyl)-2-quinoxalinyl)-1-methyl-2(1H)-pyridinone; 4-(7-((4,4-difluoro-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2(1H)-pyridinone; 4-(7-((4,4-difluoro-1-piperidinyl)carbonyl)-2-quinoxalinyl)-1-methyl-2(1H)-pyridinone; N-(cyclopropylmethyl)-N-methyl-3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinecarboxamide; N-(cyclobutylmethyl)-N-methyl-3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinecarboxamide;N-(cyclopentylmethyl)-N-methyl-3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinecarboxamide; N-(cyclohexylmethyl)-N-methyl-3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinecarboxamide; (4,4-difluoro-1-piperidinyl)(3-(2-methyl-2H-indazol-6-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(2-(trifluoromethyl)-3-pyridinyl)-6-quinoxalinyl)methanone; (3-(2-amino-5-pyrimidinyl)-6-quinoxalinyl)(4,4-difluoro-1-piperidinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(imidazo[1,2-a]pyridin-6-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(imidazo[1,2-a]pyridin-7-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(pyrazolo[1,5-a]pyridin-5-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(imidazo[1,2-a]pyrimidin-6-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(1-methyl-1H-benzotriazol-5-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(1-methyl-1H-benzimidazol-5-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6- quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-6- quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(1H-pyrazolo[4,3-b]pyridin-5-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinyl)methanone; N-cyclobutyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(2-propanyl)-6- quinoxalinecarboxamide; (4,4-difluoro-1-piperidinyl)(3-(imidazo[1,2-a]pyrazin-6-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(3-methyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-6- quinoxalinyl)methanone; 6-(7-((4,4-difluoro-1-piperidinyl)carbonyl)-2-quinoxalinyl)-1-methyl-2(1H)-pyridinone; (4,4-difluoro-1-piperidinyl)(3-(3-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-6- quinoxalinyl)methanone;N-(cyclobutylmethyl)-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(2-propanyl)-6- quinoxalinecarboxamide; (4,4-difluoro-1-piperidinyl)(3-([1,2,4]triazolo[4,3-a]pyridin-7-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(2-methyl-2H-indazol-5-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(1-methyl-1H-indazol-5-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-6- quinoxalinyl)methanone; N-(cyclobutylmethyl)-3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-N-(2-propanyl)-6- quinoxalinecarboxamide; N-(cyclopentylmethyl)-3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-N-(2-propanyl)-6- quinoxalinecarboxamide; (4,4-difluoro-1-piperidinyl)(3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(2-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6- quinoxalinyl)methanone; N-(cyclohexylmethyl)-3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-N-(2-propanyl)-6- quinoxalinecarboxamide; (4,4-difluoro-1-piperidinyl)(3-(pyrazolo[1,5-a]pyridin-6-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(2-methyl-2H-benzotriazol-5-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(2-methyl-2H-pyrazolo[3,4-c]pyridin-5-yl)-6- quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(3-methyl[1,2,4]triazolo[4,3-a]pyridin-7-yl)-6- quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(1,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-6- quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(2-methyl-2H-pyrazolo[4,3-b]pyridin-5-yl)-6- quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-([1,2,3]triazolo[1,5-a]pyridin-6-yl)-6-quinoxalinyl)methanone; 5-(7-((4,4-difluoro-1-piperidinyl)carbonyl)-2-quinoxalinyl)-1-methyl-2(1H)-pyrimidinone; 4-(7-((4,4-difluoro-1-piperidinyl)carbonyl)-2-quinoxalinyl)-1-methyl-2(1H)-pyrimidinone; (4,4-difluoro-1-piperidinyl)(3-(tetrazolo[1,5-a]pyridin-6-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)-6- quinoxalinyl)methanone;[2,2'-biquinoxaline]-7,7'-diylbis((4,4-difluoro-1-piperidinyl)methanone); (6-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-3-isoquinolinyl)(1-piperidinyl)methanone; 2-methyl-2-propanyl 4-(5-(3-(1-piperidinylcarbonyl)-6-isoquinolinyl)-2-pyrimidinyl)-1- piperazinecarboxylate; 2-methyl-3'-(1-piperidinylcarbonyl)[6,6'-biisoquinolin]-1(2H)-one; (4,4-difluoro-1-piperidinyl)(2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-3-phenylpyrido[3,4- b]pyrazin-7-yl)methanone; (2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-3-phenylpyrido[3,4-b]pyrazin-7-yl)(1- piperidinyl)methanone; (3,3-difluoro-1-piperidinyl)(2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-3-phenylpyrido[3,4- b]pyrazin-7-yl)methanone; (4,4-difluoro-1-piperidinyl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrido[3,4-b]pyrazin-7- yl)methanone; (3,3-difluoro-1-piperidinyl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrido[3,4-b]pyrazin-7- yl)methanone; (3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrido[3,4-b]pyrazin-7-yl)(1- piperidinyl)methanone; (4,4-difluoro-1-piperidinyl)(6-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-3- isoquinolinyl)methanone; (3,3-difluoro-1-piperidinyl)(6-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-3- isoquinolinyl)methanone; (2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrido[3,4-b]pyrazin-7-yl)(1- piperidinyl)methanone; (4,4-difluoro-1-piperidinyl)(2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrido[3,4-b]pyrazin-7- yl)methanone; (3,3-difluoro-1-piperidinyl)(2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrido[3,4-b]pyrazin-7- yl)methanone; (4,4-difluoro-1-piperidinyl)(2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-1,6-naphthyridin-7- yl)methanone; (3,3-difluoro-1-piperidinyl)(2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-1,6-naphthyridin-7- yl)methanone; (2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-1,6-naphthyridin-7-yl)(1-piperidinyl)methanone;(4,4-difluoro-1-piperidinyl)(6-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-3- quinolinyl)methanone; or (4,4-difluoro-1-piperidinyl)(7-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-2- quinolinyl)methanone.

[0340] Provided herein as 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-(7-(((3S)-3-fluoro-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; 6-(7-(((3R)-3-fluoro-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; 6-(7-(((3S,4S)-4-fluoro-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((4R)-4-hydroxy-6-azaspiro[2.5]octan-6-yl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((4S)-4-hydroxy-6-azaspiro[2.5]octan-6-yl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3S,4S)-3,4-dihydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinlinone; 6-(7-(((3R,4R)-3-hydroxy-4-(hydroxymethyl)-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl- 1(2H)-isoquinolinone; 6-(7-(((3R,4S)-3,4-dihydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; N-((2R)-2-hydroxypropyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-((2S)-2-hydroxypropyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; 6-(7-(((3R)-3-methoxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; 6-(7-(((3R)-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone;6-(7-(((3R)-3-(difluoromethoxy)-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3S)-3-(difluoromethoxy)-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3S)-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; 3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-((2R)-2-oxetanylmethyl)-6- quinoxalinecarboxamide; 3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-((2S)-2-oxetanylmethyl)-6- quinoxalinecarboxamide; N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-((2R)-2-oxetanylmethyl)-6- quinoxalinecarboxamide; N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-((2S)-2-oxetanylmethyl)-6- quinoxalinecarboxamide; N-((3R)-3-hydroxybutyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-((3S)-3-hydroxybutyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; 6-(7-(((3R)-3-ethoxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; 6-(7-(((3S)-3-ethoxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; 6-(7-(((2R,5S)-5-hydroxy-2-methyl-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3R)-4,4-difluoro-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3S)-4,4-difluoro-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3R,4S)-4-amino-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3S,4S)-3-hydroxy-4-methoxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3S,4R)-4-amino-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3R)-3-hydroxy-3-methyl-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone;6-(7-(((3R,4R)-4-amino-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 2-methyl-6-(7-((4S)-1-oxa-6-azaspiro[3.5]nonan-6-ylcarbonyl)-2-quinoxalinyl)-1(2H)- isoquinolinone; 2-methyl-6-(7-((4R)-1-oxa-6-azaspiro[3.5]nonan-6-ylcarbonyl)-2-quinoxalinyl)-1(2H)- isoquinolinone; 6-(7-(((3S,4S)-4-amino-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3S)-3-hydroxy-3-methyl-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3S)-3-methoxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(2-((2R)-2-oxetanyl)ethyl)-6- quinoxalinecarboxamide; N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(2-((2S)-2-oxetanyl)ethyl)-6- quinoxalinecarboxamide; 6-(7-(((3R,5R)-3-amino-5-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3R,5S)-3-amino-5-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3S,5R)-3-amino-5-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3S,5S)-3-amino-5-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3R)-3-methoxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; 6-(7-(((3S)-3-methoxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; ((1R,5S)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)-6-quinoxalinyl)methanone; ((1R,5S)-6,6-difluoro-3-azabicyclo[3.1.1]heptan-3-yl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)-6-quinoxalinyl)methanone; ((1S,5S)-9,9-difluoro-3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)(3-(2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)-6-quinoxalinyl)methanone; (3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6-quinoxalinyl)((1R,5S)-6-oxa-3- azabicyclo[3.1.1]heptan-3-yl)methanone;((1S,5S)-7,7-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)(3-(2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)-6-quinoxalinyl)methanone; or 6-(7-(((3R,4S)-3-hydroxy-4-(hydroxymethyl)-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl- 1(2H)-isoquinolinone.

[0341] Provided herein as Embodiment 268 is the compound or salt of Embodiment 1, wherein the compound is: .5

[0342] Provided herein as Embodiment 269 is the compound or salt of Embodiment 1, wherein the compound is: .

[0343] Provided herein as Embodiment 270 is the compound or salt of Embodiment 1, wherein the compound is: .

[0344] Provided herein as Em Embodiment 1, wherein the compound is:.

[0345] Provided herein as EEmbodiment 1, wherein the compound is:.D121

[0346] Provided herein as Embodiment 273 is the compound or salt of Embodiment 1, wherein the compound is: .

[0347] Provided herein as Embodiment 274 is the compound or salt of any one of Embodiments 1 to 273, wherein the compound is not: N ,, , , ,, 5 ,of the foregoing.

[0348] Several embodiments pertain to the compound of any one of Embodiments 1 to 274.

[0349] The compounds or salts disclosed in Embodiments 1 to 274 may be stereoisomerically pure or stereoisomerically enriched.

[0350] If 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.

[0351] The term “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. For example, 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.

[0352] 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 stereoisomers of the compound, greater than about 99% by weight of one stereoisomer of the compound and equal or less than about 1% by weight of other stereoisomers of the compound, or greater than about 99.9% by weight of one stereoisomer of the compound and equal or less than about 0. 1% by weight of other stereoisomers of the compound.

[0353] 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. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen etal., Tetrahedron 33:2725; Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, page 268 (Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN, 1972).

[0354] As known by those skilled in the art, certain compounds disclosed herein may exist in one or more tautomeric forms. Because one chemical structure may only be used to represent one tautomeric form, it will be understood that for convenience, referral to a compound of a given structural formula includes other tautomers of said structural formula. Accordingly, the scope of the instant disclosure is to be understood to encompass all tautomeric forms of the compounds disclosed herein. Exemplary tautomers include enol and imine forms, the keto and enamine forms, and geometric isomers and mixtures thereof A tautomer is one of two or more structural isomers that exist in equilibrium and are readilyconverted from one isomeric form to another. This reaction results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds.

[0355] As discussed elsewhere herein, the compounds disclosed herein and the stereoisomers, tautomers, and isotopically-labelled forms thereof or a pharmaceutically acceptable salt of any of the foregoing may exist in solvated or unsolvated forms.

[0356] In several embodiments, 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. In several embodiments, the assay is a cellular assay or a cell-free binding assay. In several embodiments, 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) inhibits the enzymatic activity of 15-PGDH in the assay at an IC50of less than or equal to about: 1 μM, 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. In several embodiments, 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) inhibits the enzymatic activity of recombinant 15-PGDH at an IC50ranging 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 0.1 nM, or from about 5 nM to about 1 nM.

[0357] In several embodiments, the IC50is measured using an assay as disclosed in the Examples. In several embodiments, the IC50for 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 µL volume of reaction buffer containing 50 mM Tris, pH 7.5, 0.01% Tween-20 and 100 µM 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. In several embodiments, thereafter, PGE2 and ß-NAD+ are added to initiate the 15-PGDH reaction. After 60 minutes at room temperature, the reaction is quenched and NADH signal was measured using a microtiter plate reader.

[0358] In several embodiments, 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). In several embodiments, inhibition of ACHE may be measured using the method described in Ellman G. L., et al., A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol. 1961;7:88-95. In several embodiments, ACHE inhibition is measured by colorimetric detection of conversion of acetylthiocholine to thiocholine using a compound concentration of 10 µM under the Ellman conditions. In several embodiments, the substrate (acetylthiocholine; ATch) is provided at a concentration of 400 µM. In several embodiments, the ACHE enzyme is provided at a concentration of 1 mU. In several embodiments, dithiobisnotrobenzoate (DTNB) is provided at a concentration of 500 µM. In several embodiments, the reaction is carried out in a buffer of 8 mM NaH2PO4 / Na2HPO4, 20 mM NaCl, 0.06% Triton and 0.8 mM EDTA and about 1 mU enzyme (ACHE). In several embodiments, the test compound is added to the buffer comprising enzyme. In several embodiments, the enzymatic reaction is initiated by addition of 400 μM of the substrate ATch and 500 μM 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. In several embodiments, the absorbance is measured immediately (t=0) at λ = 405 nm using a microplate reader. In several embodiments, the plate reader is an Envision, Perkin Elmer plate reader. In several embodiments, the this measurement allows to verify compound interference with the spectrophotometric detection at this wavelength. After 30 min incubation, a second measurement of the absorbance is made. The enzyme activity is determined by subtracting the signal measured at t=0 from that measured at t=30. In several embodiments, water is used as a control (substituted for the experimental compound). In several embodiments, 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 µM test compound concentration. In several embodiments, 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 µM test compound concentration. In several embodiments, 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 µM test compound concentration. In several embodiments, 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 µM test compound concentration. In several embodiments, at a concentration of test compound of 10 µM, 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.Isotopically-Labelled Compounds

[0359] Further, 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. Examples of isotopes suitable for inclusion in the compounds disclosed herein include isotopes of hydrogen, such as2H (deuterium) and3H (tritium), carbon, such as11C,13C and14C, chlorine, such as36CI, fluorine, such as18F, iodine, such as123I and125I, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulphur, such as35S. Certain isotopically- labelled compounds of Formula (I), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium (3H) and carbon-14 (14C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with isotopes such as deuterium (2H 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. In several embodiments, 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). Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies, for example, for examining target occupancy. 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. The term “solvate” as used herein 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 beunderstood 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. Thus, in several embodiments, provided herein is 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. In several embodiments, a pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein.

[0362] 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. The compounds and 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.

[0363] 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.

[0364] 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.

[0365] Further, 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. Accordingly, the scope of the methods and uses provided in the instant disclosure is tobe understood to encompass also methods and uses employing all such forms. Besides being useful for human treatment, the compounds provided herein may be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. For example, animals including horses, dogs, and cats may be treated with compounds provided herein.

[0367] In several embodiments, as disclosed elsewhere herein, a method of treating a patient is provided. In several embodiments, 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.

[0368] In several embodiments, the method comprises selecting a patient. In several embodiments, the patient is one suffering from a 15-PGDH mediated disease, disorder, or condition.

[0369] In several embodiments, after administration of a 15-PGDH inhibitor to the patient, the patient’s response is measured. In several embodiments, 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. In several embodiments, the inflammatory biomarker may comprise or consist of one or more of cytokines or inflammatory cytokines (e.g., those associated with fibrosis). Such cytokines can include, for example, ΉHb, 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. In several embodiments, 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 F2α PGF2α, 6-keto prostaglandin F1α (6-keto-PGF1α), 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- dihydroxy-9Z-octadecenoic acid (12, 13-DiHOME), 9,10-dihydroxy-9Z-octadecenoic acid 9,10- DiHOME, 14,15-dihydroxyeicosatrienoic acid (14,15-DHET), 11,12-dihydroxyeicosatrienoic acid (11,12-DHET), or combinations of the foregoing. 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 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 thesubject 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.

[0370] In several embodiments, as disclosed elsewhere herein, the patient is one suffering from a 15- PGDH mediated disease or disorder. In several embodiments, the 15-PGDH mediated disease or disorder is inflammatory bowel disease, ulcerative colitis, Crohn’s disease, fibrotic disease disorder or condition. In several embodiments, the 15-PGDH mediated disease or disorder is atherosclerosis. In several embodiments, the 15-PGDH mediated disease or disorder is autoimmune disease. In several embodiments, 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 fibrosis, or organ specific fibrosis. In several embodiments, 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.

[0371] Provided herein as Embodiment 276 is the compound or salt of any one of Embodiments 1 to 274 or the pharmaceutical composition of Embodiment 275 for use as a medicament.

[0372] Provided herein as 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.

[0373] Provided herein as 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.

[0374] Provided herein as 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.

[0375] Provided herein as 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.

[0376] Provided herein as 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.

[0377] 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.

[0378] 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 cirrhosis, chronic renal failure; myelofibrosis, bone marrow fibrosis, acute fibrosis, or organ specific fibrosis.

[0379] Provided herein as Embodiment 284 is the compound, salt, or composition of Embodiment 281 or 282, wherein the fibrotic disease, disorder, or condition is idiopathic pulmonary fibrosis.

[0380] Provided herein as Embodiment 285 is the compound, salt, or composition of Embodiment 281 or 282, wherein the fibrotic disease, disorder, or condition is kidney fibrosis.

[0381] Provided herein as Embodiment 286 is the compound, salt, or composition of Embodiment 281 or 282, wherein the fibrotic disease, disorder, or condition is liver fibrosis.

[0382] Provided herein as 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.

[0383] Provided herein as 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.

[0384] Provided herein as 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.

[0385] 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. Combinations

[0386] In several embodiments, 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) can be provided in combination with other therapeutic agents.

[0387] In several embodiments, a 15-PGDH inhibitor as disclosed herein is used in combination with a tumor necrosis factor (TNF) inhibitor (e.g., TNF-α inhibitor). In several embodiments, 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.

[0388] In several embodiments, a 15-PGDH inhibitor as disclosed herein is used in combination with a corticosteroid. In several embodiments, 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, cortisol sodium succinate, cortisone, cortisone acetate, cortodoxone, cyclocort, deflazacort, defluprednate, descinolone, desonide, desowen, desoximetasone, desoxycorticosterone acetate, desoxycorticosterone pivalate, 11-desoxycortisol, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, dichlorisone, diflorasone diacetate, dihydroxycortisone, diprolen, diprolene, diprosone, esters of betamethasone, florone, flucetonide, flucloronide, flucortolone, fludrocortisone, fludrocortisone acetate, flumethalone, flumethasone, flumethasone pivalate, flunisolide, fluocinolone acetonide, fluocinolone acetonide acetate, fluocinonide, fluorametholone, fluorocortisone,fluperolone, fluprednisolone, flurandrenolide, fluroandrenolone acetonide, fluticasone propionate, fuprednisolone, halcinonide, halobetasol propionate, halog, hydrocortamate, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone valerate, hydrocortisone-17- valera111yridinalog, lidex, locold, locorten, maxiflor, medrysone, meprednisone, methylprednisolone, 6α-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, methylprednisone, mometasone furoate, paramethasone, paramethasone acetate, prednidone, prednisone, prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisolone sodium succinate, prednisolone tebutate, prednisone, psorcon, synalar, temovate, tetrahydrocortisol, topicort, topicort LP, triamcinolone, triamcinolone acetonide, triamcinolone diacetate, triamcinolone hexacotonide, tridesilone, valisone, westcort, or a combination of the foregoing.

[0389] In several embodiments, each constituent of the therapeutic combination can be administered in using the same route or a different route. For example, as disclosed elsewhere herein, 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.

[0390] 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.

[0391] It will be appreciated that, for a particular biologic (e.g., antibody or protein-based therapeutic), those therapeutic agents may be more suitably for administered by injection. Alternatively, 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) may be suitable for 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 synthetic methods described herein are merely exemplary, and the compounds disclosed herein may also be synthesized by alternate routes utilizing alternative synthetic strategies, as appreciated by persons of ordinary skill in the art, in view of the teachings of the present disclosure. It should be appreciated that the general synthetic procedures and specific examples provided herein are illustrative only and should not be construed as limiting the scope of the present disclosure in any manner. See, e.g., W. Friedrichsen, Furans, Thiophenes and Selenophenes with Fused Six-membered Heterocyclic Rings, in Comprehensive Heterocyclic Chemistry, 1984.

[0393] Generally, the compounds of Formula (I) (e.g., or 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) 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. Thus, for example, where R2(or R1a, R1b, or any other variable) is defined in one manner for Formula (I) and in another way for Formula (Ia), the definition for R2(or R1a, R1b, or any other variable) in Formula (I) may be substituted for the definition of R2(or R1a, R1b, or any other variable) in Formula (Ia) and vice versa. Likewise, 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.

[0394] 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 (Ba-R2):2); whereXHis a halogen; Ri1is C1-6alkoxy; Bais 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 Xaindependently 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 R2group, the total of both r values combined does not exceed 5; and wherein a –N= ring nitrogen can be bonded to an R5to provide a cation.

[0395] 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 (Ba-R2): 2); whereXHis a halogen; Bais a boronic acid group or a boronic ester group; “ ” indicates a double bond or single bond may be present; each instance of Xaindependently 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 R2group, the total of both r values combined does not exceed 5; and

[0397] wherein a –N= ring nitrogen can be bonded to an R5to provide a cation. Intermediates

[0398] Several embodiments pertain to intermediates useful for synthesizing a compound 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. Formula (I-int-a.i) Several embodiments pertain to a compound of Formula (I-int-a.i) or a salt thereof:where XHrepresents a suitable group for cross-coupling, Ri1is C1-6alkoxy, and the remaining variables are as disclosed elsewhere herein. In several embodiments, a, d, e, and f are independently N or CH. In several embodiments, b is C-H or C-R3. In several embodiments, c is N, C-H, or C-R3. In several embodiments, each instance of R3independently is halogen, C1-6alkyl, C1-6alkenyl, C1-6alkoxy, C1-6haloalkyl, C3-7cycloalkyl, heterocyclyl with 3 to 7 ring members, C6-10aryl, or heteroaryl having 5 to 10 ring members. In several embodiments, only one instance of R3may be present. In several embodiments, R3may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, or C1-6alkylene-C1-6alkoxy. In several embodiments, Ri1is C1-6alkoxy. In several embodiments, XHrepresents a suitable group for cross- coupling. In several embodiments, XHrepresents a suitable halogen atom (e.g., Cl, Br, etc.) or a similar reactive group (e.g., -OTf, -OTs, or -OMs). In several embodiments, XHis a halogen. In several embodiments, XHis Cl. In several embodiments, XHis Br. In several embodiments, Ri1is ethoxy. Inseveral embodiments, Ri1is 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 Ri1is C1-6alkoxy and the remaining variables are as disclosed elsewhere herein. In several embodiments, a, d, e, and f are independently N or CH. In several embodiments, b is C-H or C-R3. In several embodiments, c is N, C-H, or C-R3. In several embodiments, each instance of R3independently is halogen, C1-6alkyl, C1-6alkenyl, C1-6alkoxy, C1-6haloalkyl, C3-7cycloalkyl, heterocyclyl with 3 to 7 ring members, C6-10aryl, or heteroaryl having 5 to 10 ring members. In several embodiments, only one instance of R3may be present. In several embodiments, R3may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, or C1-6alkylene-C1-6alkoxy. In several embodiments, Ri1is ethoxy. In several embodiments, Ri1is 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.i)

[0400] Several embodiments pertain to a compound of Formula (I-int-c.i) or a salt thereof: where the variables are as disclosed elsewhere herein. In several embodiments, a, d, e, and f are independently N or CH. In several embodiments, b is C-H or C-R3. In several embodiments, c is N, C-H, or C-R3. In several embodiments, R2is heteroaryl having 6 to 10 ring members or heterocyclyl having 6 to 10 ring members. In several embodiments, when R2is heterocyclyl having 6 to 10 ring members, the heterocyclyl group includes at least one unsaturation. In several embodiments, wherein, when R2is which is heteroaryl having 6 to 10 ring members or heterocyclyl having 6 to 10 ring members, then R2is unsubstituted or substituted with one or more instances of R5. In several embodiments, each instance of R5independently is halogen, oxo, -CN, OH, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C3-6cycloalkyl, amino,C1-4alkylamino, di C1-4alkylamino, C(O)heterocyclyl having 3 to 6 ring members, heterocyclyl having 3 to 6 ring members, or heteroaryl having 5 to 10 ring members. In several embodiments, each instance of R5may be unsubstituted or substituted one or more instances of R6. In several embodiments, each instance of R6independently is halogen, C1-6alkyl, C(O)C1-6alkyl, C(O)2C1-6alkyl, or C1-6alkylene-OH. In several embodiments, each instance of R3independently is halogen, C1-6alkyl, C1-6alkenyl, C1-6alkoxy, C1-6haloalkyl, C3-7cycloalkyl, heterocyclyl with 3 to 7 ring members, C6-10aryl, or heteroaryl having 5 to 10 ring members. In several embodiments, R3may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, or C1-6alkylene-C1-6alkoxy. 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-a.ii)

[0401] Several embodiments pertain to a compound of Formula (I-int-a.ii) or a salt thereof: where XHrepresents a suitable group forcross-coupling, R is C1-6alkoxy, and the remaining variables are as disclosed elsewhere herein. In several embodiments, a, d, e, and f are independently N or CH. In several embodiments, b is C-H or C-R3. In several embodiments, c is N, C-H, or C-R3. In several embodiments, each instance of R3independently is halogen, C1-6alkyl, C1-6alkenyl, C1-6alkoxy, C1-6haloalkyl, C3-7cycloalkyl, heterocyclyl with 3 to 7 ring members, C6-10aryl, or heteroaryl having 5 to 10 ring members. In several embodiments, only one instance of R3may be present. In several embodiments, R3may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, or C1-6alkylene-C1-6alkoxy. In several embodiments, Ri1is C1-6alkoxy. In several embodiments, XHrepresents a suitable group for cross- coupling. In several embodiments, XHrepresents a suitable halogen atom (e.g., Cl, Br, etc.) or a similar reactive group (e.g., -OTf, -OTs, or -OMs). In several embodiments, XHis a halogen. In several embodiments, XHis Cl. In several embodiments, XHis Br. In several embodiments, Ri1is ethoxy. In several embodiments, Ri1is 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.ii)

[0402] Several embodiments pertain to a compound of Formula (I-int-b.ii) or a salt thereof:where Ri1is C1-6alkoxy and the remaining variables are as disclosed elsewhere herein. In several embodiments, a, d, e, and f are independently N or CH. In several embodiments, b is C-H or C-R3. In several embodiments, c is N, C-H, or C-R3. In several embodiments, each instance of R3independently is halogen, C1-6alkyl, C1-6alkenyl, C1-6alkoxy, C1-6haloalkyl, C3-7cycloalkyl, heterocyclyl with 3 to 7 ring members, C6-10aryl, or heteroaryl having 5 to 10 ring members. In several embodiments, only one instance of R3may be present. In several embodiments, R3may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, or C1-6alkylene-C1-6alkoxy. In several embodiments, Ri1is ethoxy. In several embodiments, Ri1is 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 elseral embodiments, a, d, e, and f are independently N or CH. In several embodiments, b is C-H or C-R3. In several embodiments, c is N, C-H, or C-R3. In several embodiments, R2is heteroaryl having 6 to 10 ring members or heterocyclyl having 6 to 10 ring members. In several embodiments, when R2is heterocyclyl having 6 to 10 ring members, the heterocyclyl group includes at least one unsaturation. In several embodiments, wherein, when R2is which is heteroaryl having 6 to 10 ring members or heterocyclyl having 6 to 10 ring members, then R2is unsubstituted or substituted with one or more instances of R5. In several embodiments, each instance of R5independently is halogen, oxo, -CN, OH, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C3-6cycloalkyl, amino, C1-4alkylamino, di C1-4alkylamino, C(O)heterocyclyl having 3 to 6 ring members, heterocyclyl having 3 to 6 ring members, or heteroaryl having 5 to 10 ring members. In several embodiments, each instance of R5may be unsubstituted or substituted one or more instances of R6. In several embodiments, each instance of R6independently is halogen, C1-6alkyl, C(O)C1-6alkyl, C(O)2C1-6alkyl, or C1-6alkylene-OH. In several embodiments, each instance of R3independently is halogen, C1-6alkyl, C1-6alkenyl, C1-6alkoxy, C1-6haloalkyl, C3-7cycloalkyl, heterocyclyl with 3 to 7 ring members, C6-10aryl, or heteroaryl having 5 to 10 ring members. In several embodiments, R3may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, or C1-6alkylene-C1-6alkoxy. 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-2a.i)

[0404] Several embodiments pertain to a compound of Formula (I-int-2a.i) or a salt thereof:where XHrepresents a suitable group for cross-coupling and the remaining variables are as disclosed elsewhere herein. In several embodiments, a, d, e, and f are independently N or CH. In several embodiments, b is C-H or C-R3. In several embodiments, c is N, C-H, or C-R3. In several embodiments, each instance of R3independently is halogen, C1-6alkyl, C1-6alkenyl, C1-6alkoxy, C1-6haloalkyl, C3-7cycloalkyl, heterocyclyl with 3 to 7 ring members, C6-10aryl, or heteroaryl having 5 to 10 ring members. In several embodiments, only one instance of R3may be present. In several embodiments, R3may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, or C1-6alkylene-C1-6alkoxy. In several embodiments, Ri1is C1-6alkoxy. In several embodiments, XHrepresents a suitable group for cross-coupling. In several embodiments, XHrepresents a suitable halogen atom (e.g., Cl, Br, etc.) or a similar reactive group (e.g., - OTf, -OTs, or -OMs). In several embodiments, XHis a halogen. In several embodiments, XHis Cl. In several embodiments, XHis Br. 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-2a.ii)

[0405] Several embodiments pertain to a compound of Formula (I-int-2a.ii) or a salt thereof: where XHrepresents a suitable group fo e remaining variables are as disclosed elsewhere herein. In several embodiments, a, d, e, and f are independently N or CH. In severalembodiments, b is C-H or C-R3. In several embodiments, c is N, C-H, or C-R3. In several embodiments, each instance of R3independently is halogen, C1-6alkyl, C1-6alkenyl, C1-6alkoxy, C1-6haloalkyl, C3-7cycloalkyl, heterocyclyl with 3 to 7 ring members, C6-10aryl, or heteroaryl having 5 to 10 ring members. In several embodiments, only one instance of R3may be present. In several embodiments, R3may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, or C1-6alkylene-C1-6alkoxy. In several embodiments, Ri1is C1-6alkoxy. In several embodiments, XHrepresents a suitable group for cross-coupling. In several embodiments, XHrepresents a suitable halogen atom (e.g., Cl, Br, etc.) or a similar reactive group (e.g., - OTf, -OTs, or -OMs). In several embodiments, XHis a halogen. In several embodiments, XHis Cl. In several embodiments, XHis Br. 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). Preparation of Formula (I) Compounds

[0406] As illustrated in the schemes below and in the Examples, compounds of Formula (I) can be prepared using intermediate compounds as disclosed herein.

[0407] 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.i or 1.2.i. In several embodiments, 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) Scheme 1.1.a.i: R2Coupling to Compound of Formula (I-int-b.i)

[0408] In se, . oupling R2to the compound of Formula (I-int-a.i). In several embodiments, XHrepresents a suitable halogen atom (e.g.,Cl, Br, etc.) or a similar reactive group (e.g., -OTf, -OTs, or -OMs). In several embodiments, the compound of Formula (I-int-a.i) is reacted with an intermediate of Ba-R2. In several embodiments, R2is as defined elsewhere herein (e.g., as in Formula (I), (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), etc.). 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). In several embodiments, Barepresents a suitable reactive moiety for cross-coupling reactions including, for example, Suzuki or Stille cross- coupling. In several embodiments, Bais a boronic acid or a boronic acid ester (e.g., boronic pinacol ester) or a tributyl stannyl group. In several embodiments, 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)

[0409] In several embodiments, 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.

[0410] In several embodiments, 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)). Scheme 1.1.c.i: Amide Formation to Provide a Compound of Formula (I.i)

[0411] In several embodiments, 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.

[0412] As illust by the reaction of an intermediate of Fl embodiments, theamide of Formula (I.i) is prepared in the presence of a coupling reagent (e.g., TBTU, DCC, DIC, EDC HCl, etc.). In several embodiments, the amide of Formula (I.i) is prepared in the presence of a base. In several embodiments, the base is an organic base. In several embodiments the base is TEA, DIPEA, etc. Scheme 1.1.ii (Scheme 1.1.a.ii-1.1.c.ii) Scheme 1.1.a.ii: R2Coupling to Compound of Formula (I-int-b.ii)

[0413] In several embodiments, a compound of Formula (I-int-b.ii) can be prepared by coupling R2to the compound of Formula (I-int-a.ii). In several embodiments, XHrepresents a suitable halogen atom (e.g., Cl, Br, etc.) or a similar reactive group (e.g., -OTf, -OTs, or -OMs). In several embodiments, the compound of Formula (I-int-a.ii) is reacted with an intermediate of Ba-R2. In several embodiments, R2is as defined elsewhere herein (e.g., as in Formula (I), (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), etc.). 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). In several embodiments, Barepresents a suitable reactive moiety for cross-coupling reactions including, for example, Suzuki or Stille cross- coupling. In several embodiments, Bais a boronic acid or a boronic acid ester (e.g., boronic pinacol ester) or a tributyl stannyl group. In several embodiments, 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.ii: Saponification to Provide Formula (I-int-c.ii)

[0414] In several embodiments, 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.

[0415] In several e d using base (e.g.,LiOH, NaOH, etc.). In several embodiments, the compound of Formula (I-int-b.ii) 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.ii) is provided. In several embodiments, thecompound 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)). Scheme 1.1.c.ii: Amide Formation to Provide a Compound of Formula (I.ii)

[0416] In several embodiments, 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. R2a d Base R2a d1bR1a

[0417] As illusra e n c eme . .c. , 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(R1a)(R1b). In several embodiments, the amide of Formula (I.ii) is prepared in the presence of a coupling reagent (e.g., TBTU, DCC, DIC, EDC HCl, etc.). In several embodiments, the amide of Formula (I.ii) is prepared in the presence of a base. In several embodiments, the base is an organic base. In several embodiments the base is TEA, DIPEA, etc. Scheme 1.2.i (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: R2Coupling to Compound of Formula (I-int-c.i)

[0419] In se oupling R2to the compound ofgen atom (e.g.,Cl, Br, etc.) or a similar reactive group (e.g., -OTf, -OTs, or -OMs). In several embodiments, XHis Br. In several embodiments, the compound of Formula (I-int-2a.i) is reacted with an intermediate of Ba-R2. In several embodiments, R2is as defined elsewhere herein (e.g., as in Formula (I), (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), etc.). 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). In several embodiments, Barepresents a suitable reactive moiety for cross-coupling reactions including, for example, Suzuki or Stille cross-coupling. In several embodiments, Bais a boronic acid or a boronic acid ester (e.g., boronic pinacol ester) or a tributyl stannyl group. In several embodiments, 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)

[0420] In several embodiments, 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.

[0421] As illustrated in Scheme 1.2.b.i (and 1.c.1.i), 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(R1a)(R1b). In several embodiments, the amide of Formula (I.i) is prepared in the presence of a coupling reagent (e.g., TBTU, DCC, DIC, EDC HCl, etc.). In several embodiments, the amide of Formula (I.i) is prepared in the presence of a base. In several embodiments, the base is an organic base. In several embodiments the base is TEA, DIPEA, etc. Scheme 1.2.ii (Scheme 1.2.a.ii-1.2.b.ii) Scheme 1.2.a.ii: R2Coupling to Compound of Formula (I-int-c.ii)

[0422] In severa by coupling R2to the compound of Forhalogen atom (e.g., Cl, Br, etc.) or a similar reactive group (e.g., -OTf, -OTs, or -OMs). In several embodiments, XHis Br.In several embodiments, the compound of Formula (I-int-2a.ii) is reacted with an intermediate of Ba-R2. In several embodiments, R2is as defined elsewhere herein (e.g., as in Formula (I), (Ia), (Ia.i), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), etc.). 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). In several embodiments, Barepresents a suitable reactive moiety for cross-coupling reactions including, for example, Suzuki or Stille cross-coupling. In several embodiments, Bais a boronic acid or a boronic acid ester (e.g., boronic pinacol ester) or a tributyl stannyl group. In several embodiments, 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.c.ii: Amide Formation to Provide a Compound of Formula (I.ii)

[0423] In several embodiments, 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.

[0424] As illusn be prepared by the reaction of an intermediate of Formula (I-int-c.ii) with an amine of formula H-N(R1a)(R1b). In several embodiments, the amide of Formula (I.ii) is prepared in the presence of a coupling reagent (e.g., TBTU, DCC, DIC, EDC HCl, etc.). In several embodiments, the amide of Formula (I.ii) is prepared in the presence of a base. In several embodiments, the base is an organic base. In several embodiments the base is TEA, DIPEA, etc. EXAMPLES

[0425] This section provides specific examples of compounds of Formula I and methods of making the same. Table A: List of Abbreviations Ac acetyl MeCN or ACN acetonitrile’ ’SECTIO

[0426] Provided in this section is the synthesis of various intermediates used to prepare compounds of Formula (I). All starting materials are either commercially available from Fisher Scientific or similar vendors, unless otherwise noted, or known in the art and may be synthesized by employing known procedures using ordinary skill.Intermediate 1: 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-pyrazolo[3,4- b]pyridine.

[0427] Step 1: 5-bromo-2-methyl-2H-pyrazolo[3,4-b]pyridine. To a mixture of 5-bromo-2H- pyrazolo[3,4-b]pyridine (50.0 g, 252 mmol) in THF (1600 mL) was added NaHMDS (379 mL, 379 mmol) at 0 °C, After stirring for 0.5 h., MeI (47.4 mL, 757 mmol) was added at 0 °C. The mixture was warmed to 25 °C and stirred for 4 h. The reaction mixture was quenched with H2O (300 mL) at 0 °C, then diluted with H2O (200 mL), extracted with EtOAc (3 × 150 mL), washed with brine (150 mL), dried over Na2SO4, 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. ether, to provide 5-bromo-2-methyl-2H- pyrazolo[3,4-b]pyridine (8.00 g, 37.7 mmol, 74.7% yield) as a yellow solid. m / z (ESI): 212.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 2.38 Hz, 1 H), 8.42 (s, 1 H) 8.51 (d, J = 2.38 Hz, 1 H), 4.21 (s, 3 H)

[0428] Step 2: 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-pyrazolo[3,4- b]pyridine. To a solution of 5-bromo-2-methyl-2H-pyrazolo[3,4-b]pyridine (20.0 g, 94 mmol) in 1,4- dioxane (300 mL) was added KOAc (13.9 g, 141 mmol), B2pin2(28.7 g, 113 mmol) and Pd(dppf)Cl2- DCM adduct (3.85 g, 4.72 mmol). The mixture was stirred at 100 °C for 12 h under an atmosphere of N2. The mixture was filtered through a celite plug and the filtrate was concentrated in vacuo. The reaction mixture was diluted with EtOAc (50 mL) / pet. ether (300 mL) and stirred at 20 °C for 15 min. The mixture was filtered and the filter cake was washed with pet. ether (3 × 300 mL). The filtrate was concentrated in vacuo and the solid was further dried under vacuum, to provide Intermediate 1 (24.0 g, 93 mmol, 98% yield) as a black solid. m / z (ESI): 178.1 (M-pinacol+2OH)+.1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 1.75 Hz, 1 H), 8.53 (d, J = 1.75 Hz, 1 H), 8.47 (s, 1 H) , 4.21 (s, 3 H), 1.32 (s, 12 H).Intermediate 2: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-[1,2,3]triazolo[4,5-b]pyridine

[0429] Step 1: 6-bromo-2H-[1,2,3]triazolo[4,5-b]pyridine. To a solution of 1N H2SO4(150 mL) in H2O (500 mL) was added 5-bromopyridine-2,3-diamine (10.0 g, 53.2 mmol). The mixture was cooled to 0 °C and NaNO2(4.25 g, 61.6 mmol) in H2O (120 mL) was added. Then, the mixture was stirred at 25°C for 12 h under an atmosphere of N2. The reaction mixture was poured into H2O (80 mL), extracted with 2Me-THF (3 × 60 mL), washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the residue. The resulting residue was stirred with MTBE (50 mL) at 25 °C for 0.5 h. The suspension was filtered and the filter cake was dried under reduced pressure, to provide 6-bromo-2H- [1,2,3]triazolo[4,5-b]pyridine (8.00 g, 40.2 mmol, 76% yield) as a brown solid. m / z (ESI): 198.9 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 8.78–8.79 (m, 2H).

[0430] Step 2: 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-[1,2,3]triazolo[4,5-b]pyridine. To a solution of 6-bromo-1H-[1,2,3]triazolo[4,5-b]pyridine (1.00 g, 5.02 mmol) in THF (10 mL) at 0 °C was added NaH (0.181 g, 7.54 mmol).The mixture was stirred at 0 °C for 30 min. Then, (2- ethoxyethyl)trimethylsilyl chloride (1.10 g, 6.62 mmol) was added dropwise at 0 °C and stirring was continued for 1 h. The reaction mixture was diluted with H2O (40 mL) and sat. NH4Cl solution (30 mL), extracted with EtOAc (3 × 30 mL), washed with brine (30 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The crude material was absorbed onto a plug of silica gel and purified by column chromatography through a SepaFlash® pre-packed silica gel column (40 g), eluting with a gradient of 0% to 55% EtOAc in pet ether, to provide 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- [1,2,3]triazolo[4,5-b]pyridine (650 mg, 1.97 mmol, 39% yield) as an oil. m / z (ESI): 328.9 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 2.0 Hz, 1H), 8.92 (d, J = 2.0 Hz, 1H), 6.04 (s, 2H), 3.67 (t, J = 8.0 Hz, 2H), 0.84 (t, J = 8.0 Hz, 2H), -0.11 (s, 9H).

[0431] Step 3: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-[1,2,3]triazolo[4,5-b]pyridine. To a solution of B2pin2(93.0 mg, 0.364 mmol) and 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-[1,2,3]triazolo[4,5-b]pyridine (100 mg, 0.304 mmol) in 1,4-dioxane (1 mL) was added KOAc (44.7 mg, 0.456 mmol) and Pd(dppf)Cl2-DCM adduct (12.6 mg, 0.015 mmol). The mixture was degassed with N2, then stirred at 80 °C for 12 h. The solvent was removed in vacuo and the resulting crude boronate ester was used without further purification. m / z (ESI): 377.1 (M+H)+. Intermediate 3: 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-[1,2,3]triazolo[4,5- b]pyridine

[0432] Step 1: 6-bromo-2-methyl-2H-[1,2,3]triazolo[4,5-b]pyridine.6-bromo-2-methyl-2H- [1,2,3]triazolo[4,5-b]pyridine was prepared according to the literature procedure (Journal of Organic Chemistry (2018), 83(12), 6334-6353).

[0433] 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. To a solution of 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 B2Pin2(3.580 g, 14.08 mmol), KOAc (1.175 g, 11.97 mmol), and Pd(dppf)Cl2^DCM (0.575 g, 0.704 mmol).The mixture was stirred at 110 °C for 12 hr. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Pet ether / EtOAc= 5 / 1 to 3 / 1) to afford Intermediate 3 as a yellow solid (1.60 g, 6.15 mmol, 87% yield) . m / z (ESI): 261.0 (M+H)+SECTION 2 – GENERAL PROCEDURES Group 1 Example 1-1: 2-methyl-6-(4-phenyl-7-(piperidine-1-carbonyl)quinolin-2-yl)isoquinolin-1(2H)-one D3quinoline- 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 N2. The mixture was diluted with EtOAc (50 mL), then washed with water (30 mL), LiCl solution (3% w / v, 2 ^ 30 mL) and brine (30 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0–25% Ethylacetate / Petroleum ether gradient). (2,4-Dichloro-7-quinolyl)-(1-piperidyl)methanone was obtained as a white solid (1.50 g, 4.66 mmol, 98% yield).1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J=8.4 Hz, 1H), 8.05 (s, 1H), 7.98 (s, 1H), 7.75-7.80 (m, 1H), 3.55-3.7 (m, 2H), 3.20-3.30 (m, 2H), 1.40- 1.70 (m, 6H).

[0435] Step 2: 6-[4-chloro-7-(piperidine-1-carbonyl)-2-quinolyl]-2-methyl-isoquinolin-1-one. A mixture of (2,4-dichloro-7-quinolyl)-(1-piperidyl)methanone (1.50 g, 4.85 mmol) , 2-methyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one (1.38 g, 4.85 mmol), Pd(dppf)Cl2.CH2Cl2(396 mg, 0.485 mmol) and aq. K3PO4(2 M, 7.27 mL, 14.54 mmol) in dioxane (15 mL) was degassed with N2. The mixture was stirred at 100 °C for 1 hr under an atmosphere of N2. The 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 Na2SO4, 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. m / z (ESI): 466.0 (M+H)+;1H NMR (400 MHz, DMSO-d6) δ 8.64-8.60 (m, 2H), 8.47-8.38 (m, 2H), 8.31 (d, J = 8.4 Hz, 1H), 8.13 (s, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 3.68 (s, 2H), 3.55 (s, 3H), 3.32 (s, 2H), 1.65 (s, 4H), 1.48 (s, 2H).

[0436] Step 3: 2-methyl-6-(4-phenyl-7-(piperidine-1-carbonyl)quinolin-2-yl)isoquinolin-1(2H)-one. A mixture of 6-[4-chloro-7-(piperidine-1-carbonyl)-2-quinolyl]-2-methyl-isoquinolin-1-one (100 mg, 0.232 mmol), phenylboronic acid (28.2 mg, 0.232 mmol) , Pd(dppf)Cl2.CH2Cl2(18.91 mg, 0.023 mmol) and K2CO3(86.7 mg, 0.627 mmol) in dioxane (1 mL) and H2O (0.1 mL) was degassed with N2. The mixture was stirred at 100 °C for 1 hr under an atmosphere of N2. The mixture was concentrated under reduce pressure. The resultant residue was triturated with MeOH (1 mL). The product was collected by filtration.2-Methyl-6-[4-phenyl-7-(piperidine-1-carbonyl)-2-quinolyl]isoquinolin-1-one was obtained as a white solid (29 mg, 0.06 mmol, 26% yield). m / z (ESI): 474.1 (M+H)+;1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H),8.50 (d, J=8.4Hz, 1H), 8.38 (d, J=8.4Hz, 1H), 8.26 (s, 1H), 8.14 (s, 1H),7.95-7.89 (m, 1H), 7.7-7.5 (m, 7H), 6.77 (d, J=7.2Hz, 1H), 3.75-3.57 (m, 2H), 3.55 (s, 3H),3.4-3.35 (m, 2H), 1.69-1.4 (m, 6H).

[0437] The compounds of Table 1-1 were prepared following the procedure described in Group 1. Table 1-1 Ex. # Chemical Structure & NLCMS: (ESI + ve ion) m / z; NMR- - ,- - ), , , - - 5Group 2 Example 2-1: N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(2-oxetanylmethyl)-6- quinoxalinecarboxamide D43

[0438] Step: methyl 3-( -methyl- -oxo- , -d hydro soqu nol n-6-yl)qu noxal ne-6-carboxylate. A mixture of methyl 3-chloroquinoxaline-6-carboxylate (46.00 g, 206.6 mmol), 2-methyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one (58.92 g, 206.6 mmol), K3PO4(131.58 g, 619.9 mmol) and Pd(dppf)Cl2.CH2Cl2(16.87 g, 20.7 mmol) in dioxane (460 mL) and H2O (160 mL) was degassed with N2. The mixture was stirred at 100 °C for 1 h under an atmosphere of N2. The mixture was filtered, and the solid was collected. The yellow solid was washed with MeOH, and then the mixture was filtered. The resulting white solid was collected. The crude product was used in the next step without further purification. Compound methyl 3-(2-methyl-1-oxo-6-isoquinolyl)quinoxaline-6-carboxylate (140 g, crude) was obtained as a white solid. m / z (ESI): 346.1 (M+H)+;1H NMR (400 MHz, CDCl3) δ 9.51 (s, 1H), 8.94 (d, J=2.0 Hz, 1H), 8.65 (d, J=8.8 Hz, 1H), 8.27-8.45 (m, 3H), 8.22 (d, J=8.8 Hz, 1H), 7.19 (d, J= 7.6 Hz, 1H), 6.67 (d, J=7.2 Hz, 1H), 4.05 (s, 3H), 3.67 (s, 3H).

[0439] Step 2: 3-(2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl)quinoxaline-6-carboxylic acid. To a solution of methyl 3-(2-methyl-1-oxo-6-isoquinolyl)quinoxaline-6-carboxylate (140.0 g, 405.4 mmol) in THF (300 mL) was added aq. LiOH•H2O (2 M, 304.0 mL, 608.0 mmol). The mixture was stirred at 20 °C for 2 h. The mixture was adjusted to pH 2 with 1N HCl, and the mixture was filtered. The gray solid was collected. The residue was triturated with acetone (500 mL). The mixture was filtered, the gray solid was collected and dried.3-(2-Methyl-1-oxo-6-isoquinolyl)quinoxaline-6-carboxylic acid was obtained as a gray solid (20.00 g, 59.76 mmol, 15% yield over two steps). m / z (ESI): 332.1 [M+H]+;1H NMR (400MHz, DMSO-d6) δ 9.78 (s, 1H), 8.65-8.75 (m, 2H), 8.35-8.48 (m, 2H), 8.16-8.34 (m, 2H), 7.57 (d, J=7.2 Hz, 1H), 6.78 (d, J=7.2 Hz, 1H), 3.55 (s, 3H).

[0440] Step 3: 3-(2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl)quinoxaline-6-carbonyl chloride. To a solution of 3-(2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl)quinoxaline-6-carboxylic acid (600 mg, 1.81 mmol) in dichloromethane (10 mL) was added oxalyl chloride (240 µL, 2.80 mmol) followed by DMF (14 µL, 0.181 mmol) at 0 °C. The reaction mixture was stirred under an atmosphere of N2at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford the acid chloride as a yellow solid 3-(2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl)quinoxaline-6-carbonyl chloride (600 mg, 1.715 mmol, 95 % yield), which was used directly in the next step without further purification.

[0441] Step 4: N-methyl-3-(2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl)-N-(oxetan-2- ylmethyl)quinoxaline-6-carboxamide. To a stirred mixture of 3-(2-methyl-1-oxo-1,2- dihydroisoquinolin-6-yl)quinoxaline-6-carbonyl chloride (110 mg, 0.314 mmol) and N-methyl-1-(oxetan- 2-yl)methanamine (31.8 mg, 0.314 mmol) in ACN (1 mL) was added anhydrous K2CO3(87 mg, 0.629 mmol) at 25 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column:Phenomenex C1875*30mm*3um; mobile phase: H2O (NH4HCO3)-ACN;B%: 30%-50%, 8 min) to provide Compound D43 as yellow solid (37.1 mg, 0.090 mmol, 29% yield). m / z (ESI): 415.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1 H), 8.66 (s, 1 H), 8.38 - 8.51 (m, 2 H), 8.16 - 8.29 (m, 2 H), 7.88 (br dd, J=8.44, 1.69 Hz, 1 H), 7.58 (d, J=7.25 Hz, 1 H), 6.79 (d, J=7.25 Hz, 1 H), 4.85 - 5.14 (m, 1 H), 4.22 - 4.67 (m, 2 H), 3.71 - 3.92 (m, 1.4 H), 3.55 (s, 3 H), 3.37 - 3.47 (m, 0.6 H), 3.09 (s, 3 H), 2.55 - 2.77 (m, 1.6 H), 2.08 - 2.25 (m, 0.4 H) Alternate Conditions for Group 3-1:

[0442] (1) To a mixture of the product of Step 3 (0.858 mmol) and TEA (120 µL, 0.858 mmol) in DCM (2 mL) was added the appropriate amine (0.858 mmol) at 25 °C and the mixture was stirred for 1 h at 25 °C. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was triturated with H2O (10 mL) at 20 °C for 30 min, and the solid collected by filtration. Then, the filter cake was triturated with MTBE (10 mL) at 20 °C for 30 min. and the solid collected by filtration.

[0443] (2) To a mixture of the product of Step 4 (1 equiv.) in EtOAc (1.5 mL / equiv) was added HCl in dioxane (20 equiv.) at 0°C .Then the mixture was stirred at 20°C for 2 h under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875*30mm*3um;mobile phase: [H2O (10mM NH4HCO3)-ACN];B%: 1%-25%,8 min) to obtain the product.

[0444] (3) Deprotection: Following Step 4, the product was dissolved in DCM (2.5 mL) and TFA (0.25 mL, 3.3 mmol) and stirred at 20 °C for 4 h. The reaction mixture was concentrated in vacuo. The crude material 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 80% EtOAc in pet ether, to provide the product.

[0445] (4) To a solution of the chloroquinoxaline (1 equiv.) and the appropriate pinacol boronic ester (1.5 equiv.) in THF (2.4 mL) and H2O (0.6 mL) was added K3PO4(204 mg, 0.962 mmol) and Pd(dppf)Cl2(0.05 equiv.). The mixture was stirred at 80 °C for 3 h under N2.

[0446] The compounds of Table 2-1 were prepared following the procedure described in Group 2. Table 2-1 Reaction3, , : m, w 3, , : m, w1, %) te k ; : te1k ; : % a, % ) te , % ) te13, m; : te , % ) te1rr r r rr rr r r r r rr r r r r1r r r r1r r r r rr r rr r r rGroup 3 Example 3-1: (6,6-difluoro-1,4-oxazepan-4-yl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinyl)methanone D78

[0447] Step : methyl 3-( -methyl- H-pyrazolo[3, -b]pyr d n-5-yl)qu noxal ne-6-carboxylate. A mixture of methyl 3-chloroquinoxaline-6-carboxylate (1.500 g, 6.74 mmol), (2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)boronic acid (1.908 g, 10.78 mmol), Pd(dppf)Cl2(0.740 g, 1.01 mmol), and K2CO3(2.79 g, 20.2 mmol) in 1,4-dioxane (14 mL) and H2O (2 mL) in a 20-mL microwave vial was purged with N2for 10 min. The vial was capped and subjected to microwave irradiation (2 h min at 105 °C). The crude mixture was directly loaded onto a silica gel precolumn (25 g) and subjected to combi-flash column chromatography on a 80-g ISCO RediSep® Gold® column eluting with MeOH / DCM (4 min at 0 and 25 min from 0 to 16%) to give, methyl 3-(2-methyl- 2H-pyrazolo[3,4-b]pyridin-5-yl)quinoxaline-6- carboxylate (2.15 g, 6.74 mmol, Yield: 100%) as a light yellow film. m / z (ESI): 320.1(M+H)+.1H NMR (chloroform-d, 400 MHz) δ 9.61 (d, J=2.1 Hz, 1H), 9.48 (s, 1H), 8.90 (d, J=2.1 Hz, 2H), 8.36 (dd, J=1.9, 8.8 Hz, 1H), 8.19 (d, J=8.8 Hz, 1H), 8.11 (s, 1H), 4.34 (s, 3H), 4.05 (s, 3H).

[0448] Step 2: 3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)quinoxaline-6-carboxylic acid. A mixture of methyl 3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)quinoxaline-6-carboxylate (2.160 g, 6.76 mmol) and LiOH•H2O (0.341 g, 8.12 mmol) in MeOH (60 mL) and H2O (10 mL) in a 500-mL single-necked RBF was stirred at 50oC for 12 h. The volatiles were removed and the residue was dried in a 40 °C oven to give crude 3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)quinoxaline-6-carboxylic acid (2.5 g, 7.64 mmol, crude yield: 113 %) as a red solid which was used directly in the next step. m / z (ESI): 306.20 (M+H)+.1H NMR (DMSO-d6, 400 MHz) δ 9.50-9.70 (m, 2H), 9.15 (br s, 1H), 8.50-8.70 (m, 2H), 8.32 (br d, J=8.4 Hz, 1H), 7.97 (br d, J=8.2 Hz, 1H), 7.4-7.6 (m, 1H), 4.27 (s, 3H).

[0449] 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. To a stirred ice-cooled mixture of sodium 3-(2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)quinoxaline-6-carboxylate (50 mg, 0.130 mmol) and HATU (59.3 mg, 0.156 mmol) in DMF (1 mL) and DCM (1 mL) was added 6,6-difluoro-1,4-oxazepane (33.8 mg, 0.195 mmol) followed by DIPEA (888 mg, 1.20 mL, 6.87 mmol). The resulting mixture was stirred at ambient temperature for 1 h. 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. The solid was dissolved in DMSO and MeOH and subjected to preparative reverse-phase HPLC (Gemini™ Prep C1810 µm column; Phenomenex, Torrance, CA; gradient elution of 15 to 95% MeCN in H2O, where both solvents contain 0.1% TFA 15 min in a 24-min method) to give, after lyophilization, Compound D78 (46 mg, 0.108 mmol, Yield: 83%) as a white solid as the TFA salt. m / z (ESI): 425.00 (M+H)+.1H NMR (chloroform-d, 400 MHz) δ 9.74 (d, J=1.5 Hz, 1H), 9.49 (s, 1H), 9.06 (d, J=2.1 Hz, 1H), 8.2-8.3 (m, 3H), 7.82 (dd, J=1.7, 8.5 Hz, 1H), 4.3-4.5 (m, 6H), 4.02 (br d, J=3.1 Hz, 5H).19F NMR (chloroform-d, 377 MHz) δ -76.55 (s, 3F, TFA), -101.37 (br s, 2F). Alternate Conditions for Group 3:

[0450] (1) A mixture of the product of step 1 and HATU (47.4 mg, 0.125 mmol) in DMA (1 mL) was stirred at rt for 10 min.7,7-Difluoro-5-oxa-2-azaspiro[3.4]octane-trifluoroacetate (27.3 mg, 0.104 mmol) was added as a solid followed by DIPEA (148 mg, 0.2 mL, 1.145 mmol). The resulting mixture was stirred at ambient temperature for 0.5 h. The crude mixture was taken up in MeOH and subjected to preparative reverse-phase HPLC (Gemini™ Prep C1810 µm column; Phenomenex, Torrance, CA; gradient elution of 15 to 100% MeCN in H2O, where both solvents contain 0.1% TFA 15 min in a 24-min method) to give the product.

[0451] (2) Base was omitted for Step 3.

[0452] (3) Deprotection: Following Step 2, the product was dissolved in DCM (2.5 mL) and TFA (0.25 mL, 3.3 mmol) and stirred at 20 °C for 4 h. The reaction mixture was concentrated in vacuo. The crude material 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 80% EtOAc in pet ether, to provide the product.

[0453] The compounds of Table 3-1 were prepared following the procedure described in Group 3. Table 3-1 Chemical Structure & LCMS:Reaction Ex. #Name(ESI + ve ion) m / z; NMRComments))) ) ) ) )19) ) ) ) )Group 4 Example 4-1: (4,4-difluoro-1-piperidinyl)(6-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-3- isoquinolinyl)methanone D165

[0454] Step 1: (6-bromoisoquinolin-3-yl)(4,4-difluoropiperidin-1-yl)methanone. To a stirred mixture of 6-bromoisoquinoline-3-carboxylic acid (600 mg, 2.38 mmol)), TBTU (1.146 g, 3.57 mmol), and N,N- dimethylacetamide (1 mL). The resulting solution was cooled to 0 °C.4,4-Difluoropiperidine (288 mg, 2.38 mmol)) and DIPEA (2.08 mL, 11.90 mmol) were added, and the resulting mixture was stirred at 0 °C for 1 hr. The reaction mixture was poured into brine (30 mL). Then the mixture was extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to obtain a residue. MTBE (30 mL) was added to the residue and the resulting solution stirred at 25 °C for 0.5 h, then filtered. The filter cake was dried under reduced pressure to afford (6-bromoisoquinolin-3-yl)(4,4-difluoropiperidin-1-yl)methanone (719 mg, 2.38 mmol, 85% yield). m / z (ESI): 355.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.41 (d, J=1.6Hz, 1H), 8.17 (d, J=4.8Hz, 1H), 8.13 (s, 1H), 7.93 – 7.90 (m, 1H), 3.80 (br s, 2H), 3.54 (br s, 2H) 2.1 – 1.99 (m, 4H).

[0455] Step 2: (4,4-difluoropiperidin-1-yl)(6-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)isoquinolin- 3-yl)methanone. To a solution of (6-bromoisoquinolin-3-yl)(4,4-difluoropiperidin-1-yl)methanone (200 mg, 0.563 mmol) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-pyrazolo[3,4- b]pyridine (438 mg, 1.689 mmol) in DMF (2mL) and H2O (0.4mL) was added Na2CO3(149 mg, 1.408 mmol) and Pd(PPh3)4(32.5 mg, 0.028 mmol). The mixture was stirred at 120 °C for 1 h. The reaction mixture was poured into H2O (20 mL). Then the mixture was extracted with EtOAc (3 × 40 mL). The combined organic layer was washed with brine (40 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (12 g SiO2, Eluent of 0–95% EtOAc / Pet Ether with a flow rate of 80 mL / min) andnormal phase-HPLC to obtain Compound D165 (15.3mg, 0.038 mmol, 6.7 % yield) was obtained as white solid. m / z (ESI): 408.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 9.10 (d, J=2.0Hz, 1H), 8.68 (d, J=2.0Hz, 1H), 8.57 (s, 1H), 8.51 (s, 1H), 8.33 (s=d, J=4.8Hz, 1H), 8.23 (s, 1H), 8.20 (d, J=3.6Hz, 2H), 4.26 (s, 3H), 3.83 (br s, 2H), 3.60 (br s, 2H), 2.16 -2.08 (m, 4H), 1.24 (m, 1H), 0.85 (d, J=7.2Hz, 1H). Alternate Conditions for Group 4

[0456] (1) HATU was used instead of TBTU.

[0457] (2) TEA and PyBOP used instead of DIPEA and TBTU.

[0458] (3) In Step 1, the corresponding methyl ester was used in place of the carboxylic acid, FeCl3was used instead of TBTU.

[0459] (4) K2CO3, and Pd(dppf)Cl2^was used as the base and catalyst, instead of Na2CO3and Pd(PPh3)4.

[0460] The compounds of Table 4-1 were prepared following the procedure described in Group 4. Table 4-1 Chemical Structure & Reaction s s s' nn ss n nExample 5-1: (4,4-difluoro-1-piperidinyl)(3-(3-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-6- quinoxalinyl)methanone D132

[0461] To a stirred mixture of (3-chloroquinoxalin-6-yl)(4,4-difluoropiperidin-1-yl)methanone (360 mg, 1.155 mmol) in 1,4-dioxane (4 mL) was added 3-methyl-5-(trimethylstannyl)-1H-pyrazolo[4,3-b]pyridine (342 mg, 1.155 mmol) and Pd(PPh3)4(66.7 mg, 0.058 mmol) at 25 °C. The mixture was degassed with N2. The solution was stirred at 100 °C for 12 h under an atmosphere of N2. 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: [H2O (NH4HCO3)-ACN; B%: 30%-55%,8min). Compound D132 (55 mg, 0.13 mmol, 12% yield) was obtained as light red solid. m / z (ESI): 409.0(M+H)+.1H NMR (400 MHz, DMSO-d6) δ 13.21 (br s, 1 H), 10.08 (s, 1 H), 8.59 (d, J=8.88 Hz, 1 H), 8.21 - 8.28 (m, 2H), 8.18 (d, J=8.88 Hz, 1 H), 7.91 (dd, J=8.50, 1.75 Hz, 1 H), 3.82 (br s, 2 H), 3.51 (br s, 2 H), 2.68 (s, 3 H), 2.11 (br d, J=2.00 Hz, 4 H);19F NMR (377 MHz, DMSO-d6) δ -95.77 (s, 2 F) Alternate Conditions for Group 5:

[0462] (1) 1,1,1,2,2,2-hexamethyldistannane and 5-bromo-1-methyl-1H-pyrazolo[4,3-b]pyridine (or an equivalent aryl halide) was used, instead of 3-methyl-5-(trimethylstannyl)-1H-pyrazolo[4,3-b]pyridine.

[0463] (2) XPhos Pd G2 was used, instead of Pd(PPh3)4

[0464] (3) To a stirred mixture of (4,4-difluoropiperidin-1-yl)(3-(tributylstannyl)quinoxalin-6- yl)methanone (85mg, 0.150 mmol) (or an equivalent aryl halide) in DMF (1 mL) in a microwave reactor vial was added 5-bromo-1-methylpyrimidin-2(1H)-one (34.0 mg, 0.180 mmol) and XPhos Pd G2 (11.80 mg, 0.015 mmol). The mixture was degassed with N2. The vial was capped and subjected to microwave irradiation (110 °C for 1 h). The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (Column: Waters Xbridge BEH C18100*30mm*10um; H2O (10mM NH4HCO3)- ACN;B%: 10%-40%,8min. to obtain the product.

[0465] The compounds of Table 5-1 were prepared following the procedure described in Group 5. Table 5-1 Ex. # Chemical Structure & NameLCMS: (ESI + ve ion) m / z; NMR Reagents19s s s ss sGroup 6 Example 6-1: (4,4-difluoro-1-piperidinyl)(6-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-3- quinolinyl)methanone D173mixture of 6-bromoquinoline-3-carboxylic acid (150 mg, 0.595 mmol), TBTU (287 mg, 0.893 mmol), 4,4-difluoropiperidine (144 mg, 0.144 mL, 1.19 mmol) and TEA (301 mg, 0.418 mL, 2.98 mmol) in DMF (2 mL) was stirred at 25°C for 18 h. The reaction mixture was diluted with H2O (5 mL). The resulting precipitate was collected by filtration, washed with H2O and dried to give (6-bromoquinolin-3-yl)(4,4- difluoropiperidin-1-yl)methanone (181.2 mg, 0.510 mmol, Yield: 86%) as a tan solid. m / z (ESI): 354.9 / 356.9 (1:1) (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J=2.1 Hz, 1 H), 8.50 (d, J=1.9 Hz, 1H), 8.38 (d, J=2.1 Hz, 1 H),7.95 - 8.05 (m, 2 H), 3.71 - 3.89 (m, 2 H), 3.38 - 3.60 (m, 2 H), 2.11 (br s, 4 H)19F NMR (376 MHz, DMSO-d6) δ -95.74 (s, 2 F).

[0467] Step 2: (4,4-difluoropiperidin-1-yl)(6-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)quinolin-3- yl)methanone. In a 20 mL vial, 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 K2CO3(117 mg, 0.845 mmol) and Pd(dppf)Cl2(20.60 mg, 0.028 mmol ) in 1,4- dioxane (1.2 mL) and H2O (0.3 mL) was stirred at 90°C for 18 h. The reaction mixture was concentrated under reduced pressure, absorbed onto silica gel and purified by chromatography through a RediSep® pre-packed silica gel column (12 g), eluting with a gradient of 0 % to 10% MeOH in DCM, to obtain Compound D173 (66.4 mg, 0.163 mmol, Yield: 58%) as a tan solid. m / z (ESI): 408.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J=2.3 Hz, 1 H), 8.98 (d, J=2.1 Hz, 1 H), 8.65 (d, J=2.3 Hz, 1 H), 8.54 - 8.59 (m, 2 H), 8.49 (d, J=1.9 Hz, 1 H), 8.29 (dd, J=8.7, 2.1 Hz, 1 H), 8.19 (d, J=8.7 Hz, 1 H), 4.26 (s, 3 H), 3.82 (br s, 2 H), 3.56 (br s, 2 H), 2.13 (br s, 4 H)19F NMR (376 MHz, DMSO-d6) δ -95.70 (br s, 2 F)

[0468] The compound of Table 6-1 was prepared following the procedure described in Group J.3. Table 6-1 Ex. # Chemical Structure & LCMS: (ESI + ve ion) m / z; NMR- d, - SECTIOExample 7: Inhibition Study The compound dose-response of its inhibition of 15-PGDH activity was determined in human, mouse, rat and dog recombinant 15-PGDH enzymatical assays. These assays measured 15-PGDH enzymatic activity by quantifying the amount of NADH produced during a 60-minute reaction initiated by the addition of PGE2 and NAD+. Under the conditions of these experiments, the increase of NADH signal upon oxidation of PGE2 and reduction of NAD+ was linearly proportional to 15-PGDH enzymatic activity. The recombinant human, mouse, rat and dog 15-PGDH enzymatic assays were performed in a25 µL volume of reaction buffer containing 50 mM Tris, pH 7.5, 0.01% Tween-20 and 100 µM DTT in a 384-well microtiter plate. In 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.

[0469] The following data (Table 7-1) provides the IC50 of each compound for inhibiting enzymatic activity of recombinant 15-PGDH in the assay described above. Table 7-1 ID PGDH-Lumi IC50Example 8: Cellula

[0470] This assay was used for the quantification of IL-1β induced Native Prostaglandin E2 (PGE2) produced by A549 cells (epithelial cells from lung carcinoma) in cell culture supernatants. Inhibition of 15-PGDH blocks PGE2 degradation and resulted in PGE2 accumulation over basal level. Briefly, A549 cells were treated with 2.5ng / mL IL-1β (EC80) and a 15-PGDH inhibitor for 24 hrs. 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 twoHTRF 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] The following data (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

Claims

What is claimed is:

1. A compound of Formula (I): I); or a pharmaceutically acceptable salt thereof; ii);, , , b is C-H or C-R3; c is N, C-H, or C-R3; wherein b and c are not both C-R3; R1ais H, C1-6alkyl, C1-6heteroalkyl, or C1-6haloalkyl; wherein R1amay be unsubstituted or substituted with one or more substituents, each of which independently is halogen, –OH, -CN, C1-4alkoxy, -NH2, C1-4alkylamino, or diC1-4alkylamino; R1bis C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6heteroalkyl, C3-7cycloalkyl, heterocyclyl with 3 to 10 ring members, C6-10aryl, heteroaryl having 5 to 10 ring members, C1-6alkylene-C3-7cycloalkyl, C1-6alkylene-C6-10aryl, C1-6alkylene-heterocyclyl with 3 to 7 ring members, or C1-6alkylene-heteroaryl with 5 to 10 ring members; wherein R1bmay be unsubstituted or substituted with one or more substituents, each of which independently is halogen, –OH, -CN, C1-6alkoxy, -NH2, C1-4alkylamino, or di C1-4alkylamino; or, alternatively, R1aand R1btogether form a heterocyclyl with 3 to 20 ring members which may be unsubstituted or substituted with one or more instances of R4; wherein each instance of R4independently is halogen, oxo, OH, -NH2, C1-6alkyl, C1-6heteroalkyl, C1-6alkoxy, C1-4alkylamino, di C1-4alkylamino, C1-6alkylene-OH, or C1-6haloalkyl; wherein each instance of R4may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, –OH, C1-6alkoxy, -NH2, C1-4alkylamino, or di C1-4alkylamino; R2is heteroaryl having 5 to 20 ring members or heterocyclyl having 5 to 20 ring members;wherein R2is unsubstituted or substituted with one or more instances of R5; wherein each instance of R5independently is halogen, oxo, -CN, OH, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6heteroalkyl, C3-6cycloalkyl, amino, C1-4alkylamino, di C1-4alkylamino, -C(O)heterocyclyl having 3 to 6 ring members, heterocyclyl having 3 to 6 ring members, or heteroaryl having 5 to 10 ring members; wherein each instance of R5may be unsubstituted or substituted one or more instances of R6; wherein each instance of R6independently is halogen, C1-6alkyl, C(O)C1-6alkyl, C(O)2C1-6alkyl, or C1-6alkylene-OH; R3, when present, is -H, halogen, C1-6alkyl, C1-6alkenyl, C1-6alkoxy, C1-6haloalkyl, C1-6heteroalkyl, C3-7cycloalkyl, heterocyclyl with 3 to 10 ring members, C6-10aryl, or heteroaryl having 5 to 10 ring members; wherein R3may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, or C1-6heteroalkyl; provided that: when R1ais H and R1bis C1-6alkylene-C3-7cycloalkyl or C1-6alkylene- heterocyclyl with 3 to 7 ring members, then R2is a heteroaryl or heterocyclyl with at least 6 ring members; when each of a and c is N, each of d, e, and f is CH, R2is unsubstituted heteroaryl, and b is C-R3, then R3is not unsubstituted heteroaryl; when each of a and c is N, each of d, e, and f is CH, R1aand R1btogether provide unsubstituted piperidinyl, R2is 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-R3, then R3is not unsubstituted phenyl; when each of a and c is N, each of d, e, and f is CH, R1aand R1btogether provide 4-methyl piperazinyl, R2is heteroaryl, and b is C-R3where R3is -CF3, then R2is not heteroaryl having 5 members and substituted with a single methyl as its only substituent; when each of a and c is N, each of d, e, and f is CH, R2is heteroaryl, and b is C- R3where R3is chloro, then R2is not heteroaryl having 5 members and substituted with a single methyl as its only substituent;when each of a and c is N, each of b, d, e, and f is CH, R1aand R1btogether provide an unsubstituted piperidinyl, then R5is not amino or alkylamino; when each of a and c is N, each of b, d, e, and f is CH, R1aand R1btogether provide an unsubstituted piperidinyl, and R2is a 10 membered heteroaryl with one R5substituent, then R5is not oxo; and when each of a and c is N, each of b, d, e, and f is CH, and R1aand R1btogether provide an unsubstituted piperidinyl, then R2is 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 NH2as its only substitutents, pyridinyl substituted with a single instance of N(Me)2as its only substituent, pyridinyl substituted with a single instance of F as its only substituent, pyridinyl substituted with a single instance of morpholinyl as its only substituent, unsubstituted heteroaryl with 10 ring members, heteroaryl with 10 ring members substituted with a single instance chloro as its only substituent, heteroaryl with 10 ring members substituted with a single methoxy as its only substituent, heteroaryl with 10 ring members substituted with a oxo and methyl as its only substituents, or heteroaryl with 10 ring members substituted with a single instance of CN as its only substituent. ii). s5. The compound or salt of any one of claims 1 to 4, wherein R1ais -H, C1-3alkyl, or C1-3haloalkyl.

6. The compound or salt of any one of claims 1 to 5, wherein R1ais substituted with 1 substituent.

7. The compound or salt of any one of claims 1 to 6, wherein, when R1ais substituted, each R1asubstituent independently is halogen, -OH, C1-3alkyl, or C1-3alkoxy.

8. The compound or salt of any one of claims 1 to 5, wherein R1ais unsubstituted.

9. The compound or salt of any one of claims 1 to 4, wherein R1ais -, or .

10. The compound or salt of any one of claims 1 to 9, wherein R1bis C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6heteroalkyl, C3-7cycloalkyl, heterocyclyl with 3 to 7 ring members, C6-10aryl, C1-6alkylene-C3-7cycloalkyl, C1-6alkylene-C6-10aryl, or C1-6alkylene-heterocyclyl with 3 to 7 ring members.

11. The compound or salt of any one of claims 1 to 10, wherein R1bcomprises is a heterocyclyl having 1 or 2 heteroatom ring members each of which independently is nitrogen, oxygen, or -S(O)x-, where x is 0, 1, or 2.

12. The compound or salt of any one of claims 1 to 4, wherein R1aand R1btogether form a 3 to 10 membered heterocyclyl.

13. The compound or salt of any one of claims 1 to 4 and 12, wherein R1aand R1btogether form a 3 to 9 membered heterocyclyl.

14. The compound or salt of any one of claims 1 to 4 and 12 to 13, wherein R1aand R1btogether form a heterocyclyl and each heteroatom ring member of the R1aand R1bheterocyclyl independently is nitrogen, oxygen, or -S(O)x-, where x is 0, 1, or 2.

15. The compound or salt of any one of claims 1 to 4 and 12 to 14, wherein R1aand R1btogether form a heterocyclyl having 1 or 2 heteroatom ring members.

16. The compound or salt of any one of claims 1 to 4 and 12 to 15, wherein R1aand R1btogether form a bicyclic heterocyclyl.

17. The compound or salt of any one of claims 1 to 4 and 12 to 16, wherein R1aand R1btogether form a heterocyclyl that is substituted with 1 or 2 instances of R4.

18. The compound or salt of any one of claims 1 to 4 and 12 to 17, wherein each instance of R4independently is halogen, OH, -NH2, C1-6alkyl, C1-6heteroalkyl, C1-6alkoxy, C1-4alkylamino, di C1-4alkylamino, C1-6alkylene-OH, C1-6haloalkyl.

19. The compound or salt of any one of claims 1 to 4 and 12 to 18, wherein each instance of R4independently is halogen, OH, -NH2, C1-3alkyl, C1-3alkoxy, or C1-3haloalkyl.

20. The compound or salt of any one of claims 1 to 4 and 12 to 19, wherein each instance of R4may be substituted with 1 or 2 substituents.

21. The compound or salt of any one of claims 1 to 4 and 12 to 20, wherein at least one instance of R4is substituted with a substituent that independently is halogen, –OH, C1-3alkoxy, -NH2, C1-2alkylamino, or di C1-2alkylamino.

22. The compound or salt of any one of claims 1 to 4 and 12 to 19, wherein each instance of R4is unsubstituted. 23 Th m nd r lt f n n f l im 1 t 4 h r in i r r nt d by:,24. The compound or salt of any one of claims 1 to 23, wherein R2is heterocyclyl or heteroaryl.

25. The compound or salt of claim 24, wherein R2has 1, 2, 3, or 4 heteroatom ring members.

26. The compound or salt of claim 24 or 25, wherein each heteroatom ring member of R2independently is nitrogen, oxygen, or -S(O)y-, where y is 0, 1, or 2.

27. The compound or salt of any one of claims 1 to 26, wherein R2is a fused bicyclic group.

28. The compound or salt of any one of claims 1 to 27, wherein R2has 9 or 10 ring members.

29. The compound or salt of any one of claims 1 to 28, wherein R2is substituted with 1 or 2 instances of R5.

30. The compound or salt of any one of claims 1 to 29, wherein at least one instance of R5is substituted with at least one instance of R6.

31. The compound or salt of any one of claims 1 to 30, wherein, each instance of R5independently is halogen, oxo, -CN, OH, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C3-6cycloalkyl, amino, C1-4alkylamino, di C1-4alkylamino, C(O)heterocyclyl having 3 to 6 ring members, or heterocyclyl having 3 to 6 ring members.

32. The compound or salt of any one of claims 1 to 31, wherein, each instance of R6independently is halogen, -C1-6alkyl, -C(O)2C1-6alkyl.

33. The compound or salt of any one of claims 1 to 28, wherein R2is unsubstituted.

34. The compound or salt of any one of claims 1 to 29 and 31, wherein R5is unsubstituted.

35. The compound or salt of any one of claims 1 to 29, wherein R2is , ,36. The compound or salt of any one of claims 1 to 29, wherein R2together with its substituents is ,, ,, C1-6alkenyl, C1-6alkoxy, C3-7cycloalkyl, heterocyclyl with 3 to 7 ring members, C6-10aryl, or heteroaryl having 5 to 10 ring members.

38. The compound or salt of any one of claims 1 to 37, wherein R3is heteroaryl or heterocyclyl and the R3heteroaryl or heterocyclyl includes 1, 2, or 3 heteroatom ring members.

39. The compound or salt of any one of claims 1 to 38, wherein R3is heteroaryl or heterocyclyl and each heteroatom of the R3cycle independently is nitrogen, oxygen, or -S(O)z-, where z is 0, 1, or 2.

40. The compound or salt of any one of claims 1 to 39, wherein R3is substituted with 1 or 2 substituents.

41. The compound or salt of any one of claims 1 to 40, wherein each substituent of R3independently is C1-3alkyl, C1-3alkoxy, or C1-3alkylene-C1-3alkoxy.

42. The compound or salt of any one of claims 1 to 36, wherein R3is: .

43. The compound or salt of claim 1, wherein the compound is: , ,, , , , ,, , , , ,,D174D173The compound or salt of claim 1, wherein the compound is :D34R D38RD60RR D60SSD90RS45. The compound or salt of claim 1 , wherein the compound is:6-(4-chloro-7-(l-piperidinylcarbonyl)-2-quinolinyl)-2-methyl-l(2H)-isoquinolinone;2-methyl-6-(4-( 1 -methyl-7H-pyrazol-5-yl)-7-( 1 -piperidinylcarbonyl)-2-quinolinyl)- 1 (2H)- isoquinolinone; 2-methyl-6-(4-phenyl-7 -( 1 -piperidinylcarbonyl)-2-quinolinyl)- 1 (2H)-isoquinolinone;2-methyl-6-(7-(l-piperidinylcarbonyl)-4-(2-propanyl)-2-quinolinyl)-l(2H)-isoquinolinone;2-methyl-6-(7-( 1 -piperidinylcarbonyl)-4-( 1 -propen-2 -yl)-2-quinolinyl)- 1 (2H)-isoquinolinone ;6-(4-cyclobutyl-7-(l-piperidinylcarbonyl)-2-quinolinyl)-2 -methyl- l(2H)-isoquinolinone;6-(7-(2-azaspiro[3.3]heptan-2-ylcarbonyl)-2-quinoxalinyl)-2-methyl-l(2H)-isoquinolinone;2-methyl-6-(7-((3 -methyl- l-pyrrolidinyl)carbonyl)-2-quinoxalmyl)-l(2H)-isoquinolinone;6-(7-(5-azaspiro[2.5]octan-5-ylcarbonyl)-2-quinoxalinyl)-2-methyl-l(2H)-isoquinolinone;N, 7V-dicthyl-3-(2 -methyl- 1-oxo- l,2-dihydro-6-isoquinolinyl)-6-quinoxalinecarboxamide;2-methyl-6-(7-((3-(trifluoromethyl)-l-piperidinyl)carbonyl)-2-quinoxalinyl)-l(2H)- isoquinolinone;6-(7-((3-fluoro-l-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-l(2H)-isoquinohnone;6-(7-((4,4-difluoro-l-piperidinyl)carbonyl)-2-quinoxalmyl)-2-methyl-l(2H)-isoquinolinone;(3 -(2-mcthyl-2H-pyrazolo [3 ,4-h |pyridin-5 -yl)-6-quinoxalinyl)(4-morpholinyl)methanone;(4,4-difluoro-l-piperidmyl)(3-(2-methyl-2J7-pyrazolo[3,4-h]pyridin-5-yl)-6- quinoxalinyl)methanone ;(3,3-difluoro-l-piperidmyl)(3-(2-methyl-2J7-pyrazolo[3,4-h]pyridin-5-yl)-6- quinoxalinyl)methanone ;A-mcthoxy-A-mcthy 1 -3 -(2-methy 1-277-py razolo [3 ,4-h]pyridin-5 -yl)-6-quinoxalinecarboxamide;2-methyl-6-(7-(4-morpholinylcarbonyl)-2-quinoxalinyl)-l(2H)-isoquinolinone;6-(7-((4-methoxy-l-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-l(2H)-isoquinolinone;6-(7-((4-fluoro-3-hydroxy-l-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-l(2H)- isoquinolinone;A'-(cyclopropy Imcthy I )-A'-mcthy I -3 -(2 -methyl- 1 -oxo- 1 ,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide ;2-methyl-6-(7-(2-oxa-6-azaspiro[3.5]nonan-6-ylcarbonyl)-2-quinoxalinyl)-l(2H)-isoquinolinone;6-(7-((4-hydroxy-6-azaspiro[2.5]octan-6-yl)carbonyl)-2-quinoxalinyl)-2 -methyl- 1(2H)- isoquinolinone;A'-mcthyl -3-(2 -methyl- 1 -oxo- 1 ,2-dihydro-6-isoquinol inyl )-A-phcny l-6-quinoxal inccarboxamidc ;A'-bcnzyl-A'-mcthyl-3 -(2 -methyl- 1 -oxo- 1 ,2-dihydro-6-isoquinolinyl)-6-quinoxalinecarboxamide ;6-(7-((3,4-dihydroxy- 1 -piperidinyl)carbonyl)-2-qumoxalinyl)-2 -methyl- 1 (2H)-isoquinolmone;6-(7-((3-hydroxy-4-(hydroxymethyl)-l-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-l(2H)- isoquinolinone;ALmethyl-3-(2-methyl-l-oxo-l,2-dihydro-6-isoquinolinyl)-JV-(2,2,2-trifluoroethyl)-6- quinoxalinecarboxamide ;6-(7-((4-hydroxy-l-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-l(2H)-isoquinolinone;6-(7-((3,3-difluoro-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; 6-(7-((3,4-dihydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; N-(2-hydroxypropyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-(2-methoxyethyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; 6-(7-((3-methoxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(3-oxetanylmethyl)-6- quinoxalinecarboxamide; N-(2-hydroxy-2-methylpropyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-(3-methoxypropyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; 6-(7-((3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; 6-(7-((3-(difluoromethoxy)-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-((3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; 3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(3-oxetanylmethyl)-6- quinoxalinecarboxamide; 3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(2-oxetanylmethyl)-6- quinoxalinecarboxamide; N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(2-oxetanylmethyl)-6- quinoxalinecarboxamide; N-(2,2-difluoroethyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-(3,3-difluoropropyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-(2-cyclopropylethyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-(3-hydroxybutyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-(2-fluoroethyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide;N-(cyclobutylmethyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; 6-(7-(1,4-dioxa-7-azaspiro[4.5]decan-7-ylcarbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-((3-ethoxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; N-(2-cyclobutylethyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; 6-(7-((5-hydroxy-2-methyl-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-((4,4-difluoro-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-((4-amino-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-((3-hydroxy-4-methoxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(3,3,3-trifluoropropyl)-6- quinoxalinecarboxamide; 6-(7-((4-amino-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-((3-hydroxy-3-methyl-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-((4-amino-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 2-methyl-6-(7-(1-oxa-6-azaspiro[3.5]nonan-6-ylcarbonyl)-2-quinoxalinyl)-1(2H)-isoquinolinone; 2-methyl-6-(7-(1-oxa-6-azaspiro[3.5]nonan-6-ylcarbonyl)-2-quinoxalinyl)-1(2H)-isoquinolinone; 6-(7-((4-amino-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-((3-hydroxy-3-methyl-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; N-(3-hydroxy-3-methylbutyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; (1,1-dioxido-4-thiomorpholinyl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinyl)methanone;6-(7-((3-methoxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(2-(2-oxetanyl)ethyl)-6- quinoxalinecarboxamide; 6-(7-((3-amino-5-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-((3-methoxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; N-(3-fluoropropyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(2-(3-oxetanyl)ethyl)-6- quinoxalinecarboxamide; (3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6-quinoxalinyl)(3,3,4,4-tetrafluoro-1- pyrrolidinyl)methanone; (6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinyl)methanone; (6,6-difluoro-3-azabicyclo[3.1.1]heptan-3-yl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinyl)methanone; (9,9-difluoro-3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)-6-quinoxalinyl)methanone; (3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6-quinoxalinyl)(6-oxa-3-azabicyclo[3.1.1]heptan- 3-yl)methanone; (6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinyl)methanone; (6,6-difluoro-1,4-oxazepan-4-yl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinyl)methanone; (7,7-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)-6-quinoxalinyl)methanone; 2-methyl-2-propanyl 4-(5-(7-(1-piperidinylcarbonyl)-2-quinoxalinyl)-2-pyrimidinyl)-1- piperazinecarboxylate; (3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6-quinoxalinyl)(1,4-oxazepan-4-yl)methanone; (3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6-quinoxalinyl)(1-piperidinyl)methanone; (7,7-difluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinyl)methanone;(5,5-difluoro-2-azaspiro[3.3]heptan-2-yl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinyl)methanone; (3-(2-(1-piperazinyl)-5-pyrimidinyl)-6-quinoxalinyl)(1-piperidinyl)methanone; (3,3-difluoro-1-pyrrolidinyl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinyl)methanone; (3,3-difluoro-1-azetidinyl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinyl)methanone; (3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6-quinoxalinyl)(1-pyrrolidinyl)methanone; 6-(7-((3-hydroxy-4-(hydroxymethyl)-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 2-methyl-2-propanyl 4-(5-(7-((4,4-difluoro-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2- pyrimidinyl)-1-piperazinecarboxylate; (4,4-difluoro-1-piperidinyl)(3-(2-(1-piperazinyl)-5-pyrimidinyl)-6-quinoxalinyl)methanone; N-cyclobutyl-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-cyclopentyl-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-cyclopropyl-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-cyclohexyl-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-(cyclopentylmethyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-(cyclohexylmethyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-cyclopropyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(2-propanyl)-6- quinoxalinecarboxamide; N-(cyclopropylmethyl)-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(2-propanyl)-6- quinoxalinecarboxamide; 5-(7-((4,4-difluoro-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2(1H)-pyridinone; N-(cyclopropylmethyl)-3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-N-(2-propanyl)-6- quinoxalinecarboxamide;N-(cyclopropylmethyl)-N-methyl-3-(2-methyl-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-6- quinoxalinecarboxamide; N-(cyclobutylmethyl)-N-methyl-3-(2-methyl-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-6- quinoxalinecarboxamide; 5-(7-((4,4-difluoro-1-piperidinyl)carbonyl)-2-quinoxalinyl)-1-methyl-2(1H)-pyridinone; 4-(7-((4,4-difluoro-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2(1H)-pyridinone; 4-(7-((4,4-difluoro-1-piperidinyl)carbonyl)-2-quinoxalinyl)-1-methyl-2(1H)-pyridinone; N-(cyclopropylmethyl)-N-methyl-3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinecarboxamide; N-(cyclobutylmethyl)-N-methyl-3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinecarboxamide; N-(cyclopentylmethyl)-N-methyl-3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinecarboxamide; N-(cyclohexylmethyl)-N-methyl-3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinecarboxamide; (4,4-difluoro-1-piperidinyl)(3-(2-methyl-2H-indazol-6-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(2-(trifluoromethyl)-3-pyridinyl)-6-quinoxalinyl)methanone; (3-(2-amino-5-pyrimidinyl)-6-quinoxalinyl)(4,4-difluoro-1-piperidinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(imidazo[1,2-a]pyridin-6-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(imidazo[1,2-a]pyridin-7-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(pyrazolo[1,5-a]pyridin-5-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(imidazo[1,2-a]pyrimidin-6-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(1-methyl-1H-benzotriazol-5-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(1-methyl-1H-benzimidazol-5-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6- quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-6- quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(1H-pyrazolo[4,3-b]pyridin-5-yl)-6-quinoxalinyl)methanone;(4,4-difluoro-1-piperidinyl)(3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-6- quinoxalinyl)methanone; N-cyclobutyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(2-propanyl)-6- quinoxalinecarboxamide; (4,4-difluoro-1-piperidinyl)(3-(imidazo[1,2-a]pyrazin-6-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(3-methyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-6- quinoxalinyl)methanone; 6-(7-((4,4-difluoro-1-piperidinyl)carbonyl)-2-quinoxalinyl)-1-methyl-2(1H)-pyridinone; (4,4-difluoro-1-piperidinyl)(3-(3-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-6- quinoxalinyl)methanone; N-(cyclobutylmethyl)-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(2-propanyl)-6- quinoxalinecarboxamide; (4,4-difluoro-1-piperidinyl)(3-([1,2,4]triazolo[4,3-a]pyridin-7-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(2-methyl-2H-indazol-5-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(1-methyl-1H-indazol-5-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-6- quinoxalinyl)methanone; N-(cyclobutylmethyl)-3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-N-(2-propanyl)-6- quinoxalinecarboxamide; N-(cyclopentylmethyl)-3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-N-(2-propanyl)-6- quinoxalinecarboxamide; (4,4-difluoro-1-piperidinyl)(3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(2-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6- quinoxalinyl)methanone; N-(cyclohexylmethyl)-3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-N-(2-propanyl)-6- quinoxalinecarboxamide; (4,4-difluoro-1-piperidinyl)(3-(pyrazolo[1,5-a]pyridin-6-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(2-methyl-2H-benzotriazol-5-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(2-methyl-2H-pyrazolo[3,4-c]pyridin-5-yl)-6- quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(3-methyl[1,2,4]triazolo[4,3-a]pyridin-7-yl)-6- quinoxalinyl)methanone;(4,4-difluoro-1-piperidinyl)(3-(1,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-6- quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(2-methyl-2H-pyrazolo[4,3-b]pyridin-5-yl)-6- quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-([1,2,3]triazolo[1,5-a]pyridin-6-yl)-6-quinoxalinyl)methanone; 5-(7-((4,4-difluoro-1-piperidinyl)carbonyl)-2-quinoxalinyl)-1-methyl-2(1H)-pyrimidinone; 4-(7-((4,4-difluoro-1-piperidinyl)carbonyl)-2-quinoxalinyl)-1-methyl-2(1H)-pyrimidinone; (4,4-difluoro-1-piperidinyl)(3-(tetrazolo[1,5-a]pyridin-6-yl)-6-quinoxalinyl)methanone; (4,4-difluoro-1-piperidinyl)(3-(1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)-6- quinoxalinyl)methanone; [2,2'-biquinoxaline]-7,7'-diylbis((4,4-difluoro-1-piperidinyl)methanone); (6-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-3-isoquinolinyl)(1-piperidinyl)methanone; 2-methyl-2-propanyl 4-(5-(3-(1-piperidinylcarbonyl)-6-isoquinolinyl)-2-pyrimidinyl)-1- piperazinecarboxylate; 2-methyl-3'-(1-piperidinylcarbonyl)[6,6'-biisoquinolin]-1(2H)-one; (4,4-difluoro-1-piperidinyl)(2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-3-phenylpyrido[3,4- b]pyrazin-7-yl)methanone; (2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-3-phenylpyrido[3,4-b]pyrazin-7-yl)(1- piperidinyl)methanone; (3,3-difluoro-1-piperidinyl)(2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-3-phenylpyrido[3,4- b]pyrazin-7-yl)methanone; (4,4-difluoro-1-piperidinyl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrido[3,4-b]pyrazin-7- yl)methanone; (3,3-difluoro-1-piperidinyl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrido[3,4-b]pyrazin-7- yl)methanone; (3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrido[3,4-b]pyrazin-7-yl)(1- piperidinyl)methanone; (4,4-difluoro-1-piperidinyl)(6-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-3- isoquinolinyl)methanone; (3,3-difluoro-1-piperidinyl)(6-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-3- isoquinolinyl)methanone; (2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrido[3,4-b]pyrazin-7-yl)(1- piperidinyl)methanone;(4,4-difluoro-1-piperidinyl)(2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrido[3,4-b]pyrazin-7- yl)methanone; (3,3-difluoro-1-piperidinyl)(2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)pyrido[3,4-b]pyrazin-7- yl)methanone; (4,4-difluoro-1-piperidinyl)(2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-1,6-naphthyridin-7- yl)methanone; (3,3-difluoro-1-piperidinyl)(2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-1,6-naphthyridin-7- yl)methanone; (2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-1,6-naphthyridin-7-yl)(1-piperidinyl)methanone; (4,4-difluoro-1-piperidinyl)(6-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-3- quinolinyl)methanone; or (4,4-difluoro-1-piperidinyl)(7-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-2- quinolinyl)methanone.

46. The compound or salt of claim 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-(7-(((3S)-3-fluoro-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; 6-(7-(((3R)-3-fluoro-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; 6-(7-(((3S,4S)-4-fluoro-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((4R)-4-hydroxy-6-azaspiro[2.5]octan-6-yl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((4S)-4-hydroxy-6-azaspiro[2.5]octan-6-yl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3S,4S)-3,4-dihydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinlinone; 6-(7-(((3R,4R)-3-hydroxy-4-(hydroxymethyl)-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl- 1(2H)-isoquinolinone;6-(7-(((3R,4S)-3,4-dihydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; N-((2R)-2-hydroxypropyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-((2S)-2-hydroxypropyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; 6-(7-(((3R)-3-methoxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; 6-(7-(((3R)-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; 6-(7-(((3R)-3-(difluoromethoxy)-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3S)-3-(difluoromethoxy)-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3S)-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; 3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-((2R)-2-oxetanylmethyl)-6- quinoxalinecarboxamide; 3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-((2S)-2-oxetanylmethyl)-6- quinoxalinecarboxamide; N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-((2R)-2-oxetanylmethyl)-6- quinoxalinecarboxamide; N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-((2S)-2-oxetanylmethyl)-6- quinoxalinecarboxamide; N-((3R)-3-hydroxybutyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; N-((3S)-3-hydroxybutyl)-N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-6- quinoxalinecarboxamide; 6-(7-(((3R)-3-ethoxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; 6-(7-(((3S)-3-ethoxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; 6-(7-(((2R,5S)-5-hydroxy-2-methyl-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3R)-4,4-difluoro-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3S)-4,4-difluoro-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone;6-(7-(((3R,4S)-4-amino-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3S,4S)-3-hydroxy-4-methoxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3S,4R)-4-amino-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3R)-3-hydroxy-3-methyl-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3R,4R)-4-amino-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 2-methyl-6-(7-((4S)-1-oxa-6-azaspiro[3.5]nonan-6-ylcarbonyl)-2-quinoxalinyl)-1(2H)- isoquinolinone; 2-methyl-6-(7-((4R)-1-oxa-6-azaspiro[3.5]nonan-6-ylcarbonyl)-2-quinoxalinyl)-1(2H)- isoquinolinone; 6-(7-(((3S,4S)-4-amino-3-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3S)-3-hydroxy-3-methyl-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3S)-3-methoxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(2-((2R)-2-oxetanyl)ethyl)-6- quinoxalinecarboxamide; N-methyl-3-(2-methyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-N-(2-((2S)-2-oxetanyl)ethyl)-6- quinoxalinecarboxamide; 6-(7-(((3R,5R)-3-amino-5-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3R,5S)-3-amino-5-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3S,5R)-3-amino-5-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3S,5S)-3-amino-5-hydroxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)- isoquinolinone; 6-(7-(((3R)-3-methoxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone; 6-(7-(((3S)-3-methoxy-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl-1(2H)-isoquinolinone;((1R,5S)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)-6-quinoxalinyl)methanone; ((1R,5S)-6,6-difluoro-3-azabicyclo[3.1.1]heptan-3-yl)(3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)-6-quinoxalinyl)methanone; ((1S,5S)-9,9-difluoro-3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)(3-(2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)-6-quinoxalinyl)methanone; (3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-6-quinoxalinyl)((1R,5S)-6-oxa-3- azabicyclo[3.1.1]heptan-3-yl)methanone; ((1S,5S)-7,7-difluoro-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)(3-(2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)-6-quinoxalinyl)methanone; or 6-(7-(((3R,4S)-3-hydroxy-4-(hydroxymethyl)-1-piperidinyl)carbonyl)-2-quinoxalinyl)-2-methyl- 1(2H)-isoquinolinone.

47. The compound or salt of any one of claims 1 to 43, wherein the compound is not: N ,, , ,, 5 ,, or48. The compound of any one of claims 1 to 47.

49. A pharmaceutical composition comprising the compound or salt of any one of claims 1 to 48 and a pharmaceutically acceptable excipient.

50. The compound or salt of any one of claims 1 to 48 or the pharmaceutical composition of claim 49 for use in treating a 15-PGDH mediated disease or disorder.

51. The compound or salt of any one of claims 1 to 48 or the pharmaceutical composition of claim 49 for use in treating inflammatory bowel disease.

52. The compound or salt of any one of claims 1 to 48 or the pharmaceutical composition of claim 49 for use in treating ulcerative colitis.

53. The compound or salt of any one of claims 1 to 48 or the pharmaceutical composition of claim 49 for use in treating Crohn’s disease.

54. The compound or salt of any one of claims 1 to 48 or the pharmaceutical composition of claim 49 for use in treating a fibrotic disease.

55. A method of manufacturing the compound or salt of claim 1, 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 (Ba-R2): 2); whereXHis a halogen; Ri1is C1-6alkoxy; Bais a boronic acid group or a boronic ester group; “ ” indicates a double bond or single bond may be present; each instance of Xaindependently 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 R2group, the total of both r values combined does not exceed 5; and wherein a –N= ring nitrogen can be bonded to an R5to provide a cation.

56. A method of manufacturing the compound or salt of claim 1, the method comprising: performing a Suzuki coupling between a compound of Formula (I-int-2a.i) (I-int-2a.i) with a compound of Formu a - :2); whereXHis a halogen; Bais a boronic acid group or a boronic ester group; “ ” indicates a double bond or single bond may be present; each instance of Xaindependently 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 R2group, the total of both r values combined does not exceed 5; and wherein a –N= ring nitrogen can be bonded to an R5to provide a cation.

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