N-heterocyclic phosphines

BACKGROUND

The N-heterocyclic phosphine (NHP), a five-membered nitrogen containing heterocycle with a unit of —N—P(X)—N— (two P—N bonds and one P—X bond) (Ansell and Wills (2002) Chem. Soc. Rev. 31: 259; Zijp et al. (2005) Dalton Trans. 512; Chelucci et al. (2003) Tetrahedron 59: 9471), has emerged as a powerful synthetic tool in chemical synthesis since its first observation in 1964 (Scherer and Schmidt (1964) Angew. Chem. 76, 787). Traditional NHP-mediated reactions have contributed to both C—C and C—P bond-forming techniques because the focus on NHP chemistry has so far been predominantly directed to phosphorus-donor nucleophiles (Ansell and Wills (2002) Chem. Soc. Rev. 31: 259) that assist NHP in coordinating to metal complexes or in forming covalent bonds to electrophiles as ligands or auxiliaries. For example, chiral and achiral NHP ligands have been utilized to create C—C bonds in various transition metal-catalyzed transformations such as hydroformylation (Breeden et al. (2000) Angew. Chem. Int. Ed. 39: 4106), Heck reactions (Wucher et al. (2011) PNAS 108: 8955), cross-coupling reactions (Ackermann et al. (2010) Org. Lett. 12: 1004), and allylic substitutions (Brunel et al. (1997) Tetrahedron Lett. 38: 5971).

In addition, chiral NHP-oxides of phosphorus-stabilized anions have been successfully employed as auxiliaries for stereoselective Pudovik-type reaction (De la Cruz et al. (1998) Tetrahedron 54: 10513; Blazis et al. (1995) J. Org. Chem. 60: 931) and Michael-type reaction (Hanessian et al. (2000) J. Org. Chem. 65: 5623; Hua et al. (1987) J. Am. Chem. Soc. 109: 5026; Denmark and Kim (1995) J. Org. Chem. 60: 7535) to form a C—P bond providing a stereogenic center to the NHP motifs. The widely known C—P bond forming Michaelis-Arbuzov reaction (Bhattacharya and Thyagarajan (1981) Chem. Rev. 81: 415; Arbuzov (1964) Pure Appl. Chem. 9: 307) utilizes a trialkyl phosphite P(III) and alkyl halide to access dialkyl alkylphosphonates P(V) via an elegant S_N²reaction sequence (Fernandez-Valle et al. (2015) J. Org. Chem. 80: 799; Buck and Yoke (1962) J. Org. Chem. 27: 3675). Since its discovery in 1898 (Michaelis and Kaehne (1898) Ber. Dtsch. Chem. Ges. 31: 1048), the Michaelis-Arbuzov reaction has served as a standard protocol for forming C—P bonds in versatile phosphonate derivatives such as phosphinate and phosphine oxide. Synthesis of such compounds, however, requires the use of aliphatic halides possessing good leaving groups and high temperature. Thus, for the search of more general and mild reaction conditions, attempts to expand the scope of the substrates within sp²carbon-containing electrophiles were demonstrated by Perkow (Borowitz et al. (1972) J. Am. Chem. Soc. 94: 1623) and Dougherty (Kedrowski and Dougherty (2010) Org. Lett. 12:3990). Alternatively, efforts of seeking mild reaction conditions resulted in the finding of Lewis acid-mediated reactions (Rajeshwaran et al. (2011) Org. Lett. 13: 1270; Renard et al. (2003) Angew. Chem. Int. Ed. 42: 2389).

Despite the widespread utility of NHPs, there remains limitations in terms of the substrate scope, only sp³- or sp²-carbon-containing electrophiles are tolerated, and reaction temperature, which increases the chance of side reaction (Fernandez et al. (2015) J. Org. Chem. 80: 799). These needs and others are met by the present invention.

SUMMARY

In accordance with the purpose(s) of the invention, as embodied and broadly described herein, the invention, in one aspect, relates to N-heterocyclic phosphines and methods of using these complexes for the preparation of, for example, vinylphosphonates.

Disclosed are compounds having a structure represented by a formula:

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wherein n is selected from 0 and 1; wherein p is selected from 0, 1, 2, 3, 4, and 5; wherein each of X^Aand X^Bis independently selected from NR¹, O, and S; wherein each occurrence of R¹, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each occurrence of R¹, when present, is independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein Y is selected from O, S, and NR²⁶; wherein R²⁶, when present, is selected from hydrogen and C1-C8 alkyl; wherein Z is selected from C═O, C═S, S═O, and SO₂; wherein each of R^Xand R^Yis independently selected from hydrogen, C1-C8 alkyl, C6-C10 aryl, and 4-10 membered heteroaryl, or wherein each of R^Xand R^Yare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 5- to 7-membered cycloalkyl or 5- to 6-membered aryl; wherein R²is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R²is substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein each of R^3aand R^3b, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each of R^3aand R^3bis independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein R⁴is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and —(C1-C3 alkyl)(C6-C10 aryl), and wherein R⁴is substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein each occurrence of R⁵, when present, is independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 haloalkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy, C1-C3 thioalkyl, C1-C3 alkyl(C1-C3 alkoxy), C1-C3 alkylamino, (C1-C3)(C1-C3) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —(C═O)(C1-C3 alkyl), —(S═O)(C1-C3 alkyl), —SO₂(C1-C3 alkyl), —CO₂R¹¹, —(C═O)NR^12aR^12b, —SO₂NR^12aR^12b, —O(C═O)NR^12aR^12b, —NHSO₂NR^12aR^12b, and —NH(C═O)NR^12aR^12b; wherein each occurrence of R¹¹, when present, is independently selected from hydrogen and C1-C4 alkyl; and wherein each occurrence of R^12aand R^12b, when present, is independently selected from hydrogen and C1-C3 alkyl, or a derivative thereof.

Also disclosed are methods of making a vinylphosphonate having a structure represented by a formula:

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wherein Q is selected from O, S, and NR²⁶; wherein R²⁶, when present, is selected from hydrogen and C1-C8 alkyl; wherein each of X^Aand X^Bis independently selected from NR¹, O, and S; wherein each occurrence of R¹, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each occurrence of R¹, when present, is independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein each of R^Xand R^Yis independently selected from hydrogen, C6-C10 aryl, and 4-10 membered heteroaryl, or wherein each of R^Xand R^Yare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 5- to 7-membered cycloalkyl or 5- to 7-membered aryl; wherein R^Ais an electron withdrawing group; wherein R^Bis selected from hydrogen, C1-C6 alkyl, C2-C6 alkylene, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R^Bis substituted with 0, 1, 2, 3, or 4 independently selected R⁶groups; and wherein each of R^Cand R^Dis independently selected from hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and wherein each of R^Cand R^Dis independently substituted with 0, 1, 2, 3, or 4 independently selected R⁶groups, or wherein each of R^Cand R^Dare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 3- to 10-membered cycloalkyl; wherein each occurrence of R⁵, when present, is independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 haloalkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy, C1-C3 thioalkyl, C1-C3 alkyl(C1-C3 alkoxy), C1-C3 alkylamino, (C1-C3)(C1-C3) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —(C═O)(C1-C3 alkyl), —(S═O)(C1-C3 alkyl), —SO₂(C1-C3 alkyl), —CO₂R¹¹, —(C═O)NR^12aR^12b, —SO₂NR^12aR^12b, —O(C═O)NR^12aR^12b, —NHSO₂NR^12aR^12b, and —NH(C═O)NR^12aR^12b; wherein each occurrence of R¹¹, when present, is independently selected from hydrogen and C1-C4 alkyl; wherein each occurrence of R^12aand R^12b, when present, is independently selected from hydrogen and C1-C3 alkyl; and wherein each occurrence of R⁶, when present, is independently selected from halogen, —NO₂, —CO₂(C1-C3 alkyl), C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 alkoxycarbonyl, C3-C7 cycloalkyl, and phenyl, or a derivative thereof, the method comprising the step of reacting an allene having a structure represented by a formula:

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or a derivative thereof, with a compound having a structure represented by a formula:

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wherein n is selected from 0 and 1; wherein p is selected from 0, 1, 2, 3, 4, and 5; wherein Y is selected from O, S, and NR²⁶; wherein R²⁶, when present, is selected from hydrogen and C1-C8 alkyl; wherein Z is selected from C═O, C═S, S═O, and SO₂; wherein each of R^Xand R^Yis independently selected from hydrogen, C6-C10 aryl, and 4-10 membered heteroaryl, or wherein each of R^Xand R^Yare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 5- to 7-membered cycloalkyl or 5- to 6-membered aryl; wherein R²is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R²is substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein each of R^3aand R^3b, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each of R^3aand R^3bis independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; and wherein R⁴is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and —(C1-C3 alkyl)(C6-C10 aryl), and wherein R⁴is substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups, or a derivative thereof.

Also disclosed are methods of making a compound having a structure represented by a formula:

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wherein n is selected from 0 and 1; wherein p is selected from 0, 1, 2, 3, 4, and 5; wherein each of X^Aand X^Bis independently selected from NR¹, O, and S; wherein each occurrence of R¹, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each occurrence of R¹, when present, is independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein Y is selected from O, S, and NR²⁶; wherein R²⁶, when present, is selected from hydrogen and C1-C8 alkyl; wherein Z is selected from C═O, C═S, S═O, and SO₂; wherein each of R^Xand R^Yis independently selected from hydrogen, C6-C10 aryl, and 4-10 membered heteroaryl, or wherein each of R^Xand R^Yare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 5- to 7-membered cycloalkyl or 5- to 6-membered aryl; wherein R²is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R²is substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein each of R^3aand R^3b, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each of R^3aand R^3bis independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein R⁴is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and —(C1-C3 alkyl)(C6-C10 aryl), and wherein R⁴is substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein each occurrence of R⁵, when present, is independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 haloalkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy, C1-C3 thioalkyl, C1-C3 alkyl(C1-C3 alkoxy), C1-C3 alkylamino, (C1-C3)(C1-C3) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —(C═O)(C1-C3 alkyl), —(S═O)(C1-C3 alkyl), —SO₂(C1-C3 alkyl), —CO₂R¹¹, —(C═O)NR^12aR^12b, —SO₂NR^12aR^12b, —O(C═O)NR^12aR^12b, —NHSO₂NR^12aR^12b, and —NH(C═O)NR^12aR^12b; wherein each occurrence of R¹¹, when present, is independently selected from hydrogen and C1-C4 alkyl; and wherein each occurrence of R^12aand R^12b, when present, is independently selected from hydrogen and C1-C3 alkyl, or a derivative thereof, the method comprising: (a) providing a first compound having a structure represented by a formula:

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wherein X¹is halogen, or a derivative thereof; and (b) reacting with a second compound having a structure represented by a formula:

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or a derivative thereof, in the presence of a base.

Also disclosed are compounds having a structure represented by a formula:

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wherein n is selected from 0 and 1; wherein p is selected from 0, 1, 2, 3, 4, and 5; wherein each of X^Aand X^Bis independently selected from NR¹, O, and S; wherein each occurrence of R¹, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each occurrence of R¹, when present, is independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein Y is selected from CH₂, O, and S; wherein Z is selected from C═O, C═S, S═O, and SO₂; wherein each of R^Xand R^Yis independently selected from hydrogen, C6-C10 aryl, and 4-10 membered heteroaryl, or wherein each of R^Xand R^Yare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 5- to 7-membered cycloalkyl or 5- to 6-membered aryl; wherein R²is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R²is substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein each of R^3aand R^3b, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each of R^3aand R^3bis independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein R⁴is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and —(C1-C3 alkyl)(C6-C10 aryl), and wherein R⁴is substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein each occurrence of R⁵, when present, is independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 haloalkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy, C1-C3 thioalkyl, C1-C3 alkyl(C1-C3 alkoxy), C1-C3 alkylamino, (C1-C3)(C1-C3) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —(C═O)(C1-C3 alkyl), —(S═O)(C1-C3 alkyl), —SO₂(C1-C3 alkyl), —CO₂R¹¹, —SO₂NR^12aR^12b, —O(C═O)NR^12aR^12b, —NHSO₂NR^12aR^12b, and —NH(C═O)NR^12aR^12b; wherein each occurrence of R¹¹, when present, is independently selected from hydrogen and C1-C4 alkyl; and wherein each occurrence of R^12aand R^12b, when present, is independently selected from hydrogen and C1-C3 alkyl, or a derivative thereof.

Also disclosed are methods of making a compound having a structure represented by a formula:

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wherein n is selected from 0 and 1; wherein p is selected from 0, 1, 2, 3, 4, and 5; wherein each of X^Aand X^Bis independently selected from NR¹, O, and S; wherein each occurrence of R¹, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each occurrence of R¹, when present, is independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein Y is selected from CH₂, O, and S; wherein Z is selected from C═O, C═S, S═O, and SO₂; wherein each of R^Xand R^Yis independently selected from hydrogen, C6-C10 aryl, and 4-10 membered heteroaryl, or wherein each of R^Xand R^Yare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 5- to 7-membered cycloalkyl or 5- to 6-membered aryl; wherein R²is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R²is substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein each of R^3aand R^3b, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each of R^3aand R^3bis independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein R⁴is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and —(C1-C3 alkyl)(C6-C10 aryl), and wherein R⁴is substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein each occurrence of R⁵, when present, is independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 haloalkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy, C1-C3 thioalkyl, C1-C3 alkyl(C1-C3 alkoxy), C1-C3 alkylamino, (C1-C3)(C1-C3) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —(C═O)(C1-C3 alkyl), —(S═O)(C1-C3 alkyl), —SO₂(C1-C3 alkyl), —CO₂R¹¹, —SO₂NR^12aR^12b, —O(C═O)NR^12aR^12b, NHSO₂NR^12aR^12b, and —NH(C═O)NR^12aR^12b; wherein each occurrence of R¹¹, when present, is independently selected from hydrogen and C1-C4 alkyl; and wherein each occurrence of R^12aand R^12b, when present, is independently selected from hydrogen and C1-C3 alkyl, or a derivative thereof, the method comprising: (a) providing a first compound having a structure represented by a formula:

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wherein X¹is halogen, or a derivative thereof; and reacting with a second compound having a structure represented by a formula:

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or a derivative thereof, in the presence of a base.

Also disclosed are methods of making a vinylphosphonate having a structure represented by a formula:

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wherein each of X^Aand X^Bis independently selected from NR¹, O, and S; wherein each occurrence of R¹, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each occurrence of R¹, when present, is independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein each of R^Xand R^Yis independently selected from hydrogen, C6-C10 aryl, and 4-10 membered heteroaryl, or wherein each of R^Xand R^Yare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 5- to 7-membered cycloalkyl or 5- to 7-membered aryl; wherein R^Ais an electron withdrawing group; wherein R^Bis selected from hydrogen, C1-C6 alkyl, C2-C6 alkylene, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R^Bis substituted with 0, 1, 2, 3, or 4 independently selected R⁶groups; and wherein each of R^Cand R^Dis independently selected from hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and wherein each of R^Cand R^Dis independently substituted with 0, 1, 2, 3, or 4 independently selected R⁶groups, or wherein each of R^Cand R^Dare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 3- to 10-membered cycloalkyl; wherein each occurrence of R⁵, when present, is independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 haloalkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy, C1-C3 thioalkyl, C1-C3 alkyl(C1-C3 alkoxy), C1-C3 alkylamino, (C1-C3)(C1-C3) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —(C═O)(C1-C3 alkyl), —(S═O)(C1-C3 alkyl), —SO₂(C1-C3 alkyl), —CO₂R¹¹, —SO₂NR^12aR^12b, —O(C═O)NR^{12 a}R^12b, —NHSO₂NR^12aR^12b, and —NH(C═O)NR^12aR^12b; wherein each occurrence of R¹¹, when present, is independently selected from hydrogen and C1-C4 alkyl; wherein each occurrence of R^12aand R^12b, when present, is independently selected from hydrogen and C1-C3 alkyl; and wherein each occurrence of R⁶, when present, is independently selected from halogen, —NO₂, —CO₂(C1-C3 alkyl), C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 alkoxycarbonyl, and phenyl, or a derivative thereof, the method comprising the step of reacting an allene having a structure represented by a formula:

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or a derivative thereof, with a compound having a structure represented by a formula:

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wherein n is selected from 0 and 1; wherein p is selected from 0, 1, 2, 3, 4, and 5; wherein Y is selected from CH₂, O, and S; wherein Z is selected from C═O, C═S, S═O, and SO₂; wherein each of R^Xand R^Yis independently selected from hydrogen, C6-C10 aryl, and 4-10 membered heteroaryl, or wherein each of R^Xand R^Yare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 5- to 7-membered cycloalkyl or 5- to 6-membered aryl; wherein R²is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R²is substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein each of R^3aand R^3b, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each of R^3aand R^3bis independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; and wherein R⁴is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and —(C1-C3 alkyl)(C6-C10 aryl), and wherein R⁴is substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups, or a derivative thereof.

Also disclosed are compounds of Formula (Ia):

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or a salt thereof, wherein: each X is independently selected from the group consisting of N, O, and S; Y is selected from the group consisting of CH₂, O, and S; Z is selected from the group consisting of C═O, C═S, S═O, and SO₂; R^Xis selected from the group consisting of H, C_6-10aryl, and 4-10 membered heteroaryl ring; R^Yis selected from the group consisting of H, C_6-10aryl, and 4-10 membered heteroaryl ring; or R^Xand R^Yin combination, together with the carbon atoms to which R^Xand R^Yare attached, form a 5, 6, or 7-membered cycloalkyl ring or a 5, 6, or 7-membered aryl ring; each R¹is independently selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; R²is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C2-6 alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; each R³is independently selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; R⁴is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; each R⁵is independently selected from the group consisting of OH, NO₂, CN, halo, C_1-3alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-3haloalkyl, cyano-C_1-3alkyl, HO—C_1-3alkyl, C_1-3alkoxy-C_1-3alkyl, C_3-7cycloalkyl, C_6-10aryl, C_1-3alkoxy, C_1-3haloalkoxy, amino, C_1-3alkylamino, di(C_1-3alkyl)amino, thio, C_1-3alkylthio, C_1-3alkylsulfinyl, C_1-3alkylsulfonyl, carbamyl, C_1-3alkylcarbamyl, di(C_1-3alkyl)carbamyl, carboxy, C_1-3alkylcarbonyl, C_1-4alkoxycarbonyl, C_1-3alkylcarbonylamino, C_1-3alkylsulfonylamino, aminosulfonyl, C_1-3alkylaminosulfonyl, di(C_1-3alkyl)aminosulfonyl, aminosulfonylamino, C_1-3alkylaminosulfonylamino, di(C_1-3alkyl)aminosulfonylamino, aminocarbonylamino, C_1-3alkylaminocarbonylamino, and di(C_1-3alkyl)aminocarbonylamino; n is 0 or 1; and p is 0, 1, 2, 3, 4, or 5.

Also disclosed are compounds of Formula (Ib):

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or a salt thereof, wherein: each X is independently selected from the group consisting of N, O, and S; Y is selected from the group consisting of CH₂, O, and S; Z is selected from the group consisting of C═O, C═S, S═O, and SO₂; each R¹is independently selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; R²is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; each R³is independently selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C₁₃alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; R⁴is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; each R⁵is independently selected from the group consisting of OH, NO₂, CN, halo, C_1-3alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-3haloalkyl, cyano-C_1-3alkyl, HO—C_1-3alkyl, C_1-3alkoxy-C_1-3alkyl, C_3-7cycloalkyl, C_6-10aryl, C_1-3alkoxy, C_1-3haloalkoxy, amino, C_1-3alkylamino, di(C_1-3alkyl)amino, thio, C_1-3alkylthio, C_1-3alkylsulfinyl, C_1-3alkylsulfonyl, carbamyl, C_1-3alkylcarbamyl, di(C_1-3alkyl)carbamyl, carboxy, C_1-3alkylcarbonyl, C_1-4alkoxycarbonyl, C_1-3alkylcarbonylamino, C_1-3alkylsulfonylamino, aminosulfonyl, C_1-3alkylaminosulfonyl, di(C_1-3alkyl)aminosulfonyl, aminosulfonylamino, C_1-3alkylaminosulfonylamino, di(C_1-3alkyl)aminosulfonylamino, aminocarbonylamino, C_1-3alkylaminocarbonylamino, and di(C_1-3alkyl)aminocarbonylamino; n is 0 or 1; and p is 0, 1, 2, 3, 4, or 5.

Also disclosed are pharmaceutical compositions comprising a compound of Formula (Ia) or Formula (Ib), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

Also disclosed is a process of preparing a compound or salt of Formula (IIa):

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comprising reacting a compound or salt of Formula (III):

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with a compound or salt of Formula (Ia):

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wherein: each X is independently selected from the group consisting of N, O, and S; Y is selected from the group consisting of CH₂, O, and S; Z is selected from the group consisting of C═O, C═S, S═O, and SO₂; R^Xis selected from the group consisting of H, C_6-10aryl, and 4-10 membered heteroaryl ring; R^Yis selected from the group consisting of H, C_6-10aryl, and 4-10 membered heteroaryl ring; or R^Xand R^Yin combination, together with the carbon atoms to which R^Xand R^Yare attached, form a 5, 6, or 7-membered cycloalkyl ring or a 5, 6, or 7-membered aryl ring; each R¹is independently selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; R²is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; each R³is independently selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; R⁴is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; each R⁵is independently selected from the group consisting of OH, NO₂, CN, halo, C_1-3alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-3haloalkyl, cyano-C_1-3alkyl, HO—C_1-3alkyl, C_1-3alkoxy-C_1-3alkyl, C_3-7cycloalkyl, C_6-10aryl, C_1-3alkoxy, C_1-3haloalkoxy, amino, C_1-3alkylamino, di(C_1-3alkyl)amino, thio, C_1-3alkylthio, C_1-3alkylsulfinyl, C_1-3alkylsulfonyl, carbamyl, C_1-3alkylcarbamyl, di(C_1-3alkyl)carbamyl, carboxy, C_1-3alkylcarbonyl, C_1-4alkoxycarbonyl, C_1-3alkylcarbonylamino, C_1-3alkylsulfonylamino, aminosulfonyl, C_1-3alkylaminosulfonyl, di(C_1-3alkyl)aminosulfonyl, aminosulfonylamino, C_1-3alkylaminosulfonylamino, di(C_1-3alkyl)aminosulfonylamino, aminocarbonylamino, C_1-3alkylaminocarbonylamino, and di(C_1-3alkyl)aminocarbonylamino; R^Ais an electron withdrawing group; R^Bis selected from the group consisting of H, C_1-6alkyl, C_2-6alkylene, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁶groups; R^Cand R^Dare each independently selected from the group consisting of H, C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁶groups; or R^Cand R^Dtogether with the C atom to which they are attached form a C_3-10cycloalkyl group; each R^a1, R^b1, R^c1, R^d1, and R^e1is independently selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁶groups; or R^c1and R^d1together with the N atom to which they are attached form a 4-, 5-, 6-, or 7 membered heterocycloalkyl group, which is optionally substituted with C_1-3alkyl; each R⁶is independently selected from the group consisting of H, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3alkoxycarbonyl, and phenyl; n is 0 or 1; p is 0, 1, 2, 3, 4, or 5.

Also disclosed is a process of preparing a compound or salt of Formula (IIb):

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comprising reacting a compound or salt of Formula (III):

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with a compound or salt of Formula (Ib):

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wherein: each X is independently selected from the group consisting of N, O, and S; Y is selected from the group consisting of CH₂, O, and S; Z is selected from the group consisting of C═O, C═S, S═O, and SO₂; each R¹is independently selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; R²is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; each R³is independently selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; R⁴is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; each R⁵is independently selected from the group consisting of OH, NO₂, CN, halo, C_1-3alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-3haloalkyl, cyano-C_1-3alkyl, HO—C_1-3alkyl, C_1-3alkoxy-C_1-3alkyl, C_3-7cycloalkyl, C_6-10aryl, C_1-3alkoxy, C_1-3haloalkoxy, amino, C_1-3alkylamino, di(C_1-3alkyl)amino, thio, C_1-3alkylthio, C_1-3alkylsulfinyl, C_1-3alkylsulfonyl, carbamyl, C_1-3alkylcarbamyl, di(C_1-3alkyl)carbamyl, carboxy, C_1-3alkylcarbonyl, C_1-4alkoxycarbonyl, C_1-3alkylcarbonylamino, C_1-3alkylsulfonylamino, aminosulfonyl, C_1-3alkylaminosulfonyl, di(C_1-3alkyl)aminosulfonyl, aminosulfonylamino, C_1-3alkylaminosulfonylamino, di(C_1-3alkyl)aminosulfonylamino, aminocarbonylamino, C_1-3alkylaminocarbonylamino, and di(C_1-3alkyl)aminocarbonylamino; R^Ais an electron withdrawing group; R^Bis selected from the group consisting of H, C_1-6alkyl, C_2-6alkylene, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁶groups; R^Cand R^Dare each independently selected from the group consisting of H, C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁶groups; or R^Cand R^Dtogether with the C atom to which they are attached form a C_3-10cycloalkyl group; each R^a1, R^b1, R^c1, R^d1, and R^e1is independently selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁶groups; or R^c1and R^d1together with the N atom to which they are attached form a 4-, 5-, 6-, or 7 membered heterocycloalkyl group, which is optionally substituted with C_1-3alkyl; each R⁶is independently selected from the group consisting of H, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3alkoxycarbonyl, and phenyl; n is 0 or 1; p is 0, 1, 2, 3, 4, or 5.

Also disclosed are compounds having a structure represented by a formula:

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wherein each of X^Aand X^Bis independently selected from NR¹, 0, and S; wherein each occurrence of R¹, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each occurrence of R¹, when present, is independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein each of R^Xand R^Yis independently selected from hydrogen, C6-C10 aryl, and 4-10 membered heteroaryl, or wherein each of R^Xand R^Yare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 5- to 7-membered cycloalkyl or 5- to 7-membered aryl; wherein R^Ais an electron withdrawing group; wherein R^Bis selected from hydrogen, C1-C6 alkyl, C2-C6 alkylene, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R^Bis substituted with 0, 1, 2, 3, or 4 independently selected R⁶groups; and wherein each of R^Cand R^Dis independently selected from hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and wherein each of R^Cand R^Dis independently substituted with 0, 1, 2, 3, or 4 independently selected R⁶groups, or wherein each of R^Cand R^Dare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 3- to 10-membered cycloalkyl; wherein each occurrence of R⁵, when present, is independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 haloalkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy, C1-C3 thioalkyl, C1-C3 alkyl(C1-C3 alkoxy), C1-C3 alkylamino, (C1-C3)(C1-C3) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —(C═O)(C1-C3 alkyl), —(S═O)(C1-C3 alkyl), —SO₂(C1-C3 alkyl), —CO₂R¹¹, —SO₂NR^12aR^12b, —O(C═O)NR^12aR^12b, —NHSO₂NR^12aR^12b, and —NH(C═O)NR^12aR^12b; wherein each occurrence of R¹¹, when present, is independently selected from hydrogen and C1-C4 alkyl; wherein each occurrence of R^12aand R^12b, when present, is independently selected from hydrogen and C1-C3 alkyl; and wherein each occurrence of R⁶, when present, is independently selected from halogen, —NO₂, —CO₂(C1-C3 alkyl), C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 alkoxycarbonyl, and phenyl, or a derivative thereof.

While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects and together with the description serve to explain the principles of the invention.

FIG. 1 shows a representative image of an X-ray crystal structure of compound 1a.

FIG. 2 shows a representative image of an X-ray crystal structure of compound 3a.

Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION

The present invention can be understood more readily by reference to the following detailed description of the invention and the Examples included therein.

Before the present compounds, compositions, articles, systems, devices, and/or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein may be different from the actual publication dates, which can require independent confirmation.

A. Definitions

As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a functional group,” “an alkyl,” or “a residue” includes mixtures of two or more such functional groups, alkyls, or residues, and the like.

Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, a further aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

A weight percent (wt. %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.

As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate aspects, can also be provided in combination in a single aspect. Conversely, various features of the disclosure which are, for brevity, described in the context of a single aspect, can also be provided separately or in any suitable subcombination.

For the terms “for example” and “such as,” and grammatical equivalences thereof, the phrase “and without limitation” is understood to follow unless explicitly stated otherwise.

The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

All compounds, and salts thereof (e.g., pharmaceutically acceptable salts), can be found together with other substances such as water and solvents (e.g., hydrates and solvates).

Compounds provided herein also can include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers that are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone—enol pairs, amide—imidic acid pairs, lactam—lactim pairs, enamine—imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

Compounds provided herein can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include hydrogen, tritium, and deuterium.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

Also provided herein are pharmaceutically acceptable salts of the compounds described herein. As used herein, the term “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the compounds provided herein include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the compounds provided herein can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. In various aspects, a non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) can be used. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977). Conventional methods for preparing salt forms are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH, 2002.

In various aspects, the compounds provided herein, or salts thereof, are substantially isolated. By “substantially isolated” is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compounds provided herein. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds provided herein, or salt thereof. Methods for isolating compounds and their salts are routine in the art.

As used herein, chemical structures that contain one or more stereocenters depicted with dashed and bold bonds (i.e., custom character ) are meant to indicate absolute stereochemistry of the stereocenter(s) present in the chemical structure. As used herein, bonds symbolized by a simple line do not indicate a stereo-preference. Unless otherwise indicated to the contrary, chemical structures, which include one or more stereocenters, illustrated herein without indicating absolute or relative stereochemistry encompass all possible stereoisomeric forms of the compound (e.g., diastereomers and enantiomers) and mixtures thereof. Structures with a single bold or dashed line, and at least one additional simple line, encompass a single enantiomeric series of all possible diastereomers.

Resolution of racemic mixtures of compounds can be carried out using appropriate methods. An exemplary method includes fractional recrystallization using a chiral resolving acid that is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or the various optically active camphorsulfonic acids such as camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by one skilled in the art.

The expressions “ambient temperature” and “room temperature” as used herein are understood in the art and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20° C. to about 30° C.

At various places in the present specification, divalent linking substituents are described. It is specifically intended that each divalent linking substituent include both the forward and backward forms of the linking substituent. For example, —NR(CR′R″)_n— includes both —NR(CR′R″)_n— and —(CR′R″)_nNR—. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups.

The term “n-membered” where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

As used herein, the phrase “optionally substituted” means unsubstituted or substituted. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. It is to be understood that substitution at a given atom is limited by valency.

Throughout the definitions, the term “C_n-m” indicates a range that includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C_1-4, C_1-6, and the like.

As used herein, the term “C_n-malkyl,” employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. In various aspects, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

As used herein, “C_n-malkenyl” refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like. In various aspects, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, “C_n-malkynyl” refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In various aspects, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, the term “C_n-malkylene,” employed alone or in combination with other terms, refers to a divalent alkyl linking group having n to m carbons. Examples of alkylene groups include, but are not limited to, ethan-1,2-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl, and the like. In various aspects, the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms.

As used herein, the term “C_n-malkoxy,” employed alone or in combination with other terms, refers to a group of formula —O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, and the like. In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_n-malkylamino” refers to a group of formula —NH(alkyl), wherein the alkyl group has n to m carbon atoms. In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_n-malkoxycarbonyl” refers to a group of formula —C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms. In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_n-malkylcarbonyl” refers to a group of formula —C(O)— alkyl, wherein the alkyl group has n to m carbon atoms. In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_n-malkylcarbonylamino” refers to a group of formula —NHC(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_n-malkylsulfonylamino” refers to a group of formula —NHS(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms. In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminosulfonyl” refers to a group of formula —S(O)₂NH₂.

As used herein, the term “C_n-malkylaminosulfonyl” refers to a group of formula —S(O)₂NH(alkyl), wherein the alkyl group has n to m carbon atoms. In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_n-malkyl)aminosulfonyl” refers to a group of formula —S(O)₂N(alkyl)₂, wherein each alkyl group independently has n to m carbon atoms. In various aspects, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminosulfonylamino” refers to a group of formula —NHS(O)₂NH₂.

As used herein, the term “C_n-malkylaminosulfonylamino” refers to a group of formula —NHS(O)₂NH(alkyl), wherein the alkyl group has n to m carbon atoms. In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_n-malkyl)aminosulfonylamino” refers to a group of formula —NHS(O)₂N(alkyl)₂, wherein each alkyl group independently has n to m carbon atoms. In various aspects, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminocarbonylamino,” employed alone or in combination with other terms, refers to a group of formula —NHC(O)NH₂.

As used herein, the term “C_n-malkylaminocarbonylamino” refers to a group of formula —NHC(O)NH(alkyl), wherein the alkyl group has n to m carbon atoms. In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_n-malkyl)aminocarbonylamino” refers to a group of formula —NHC(O)N(alkyl)₂, wherein each alkyl group independently has n to m carbon atoms. In various aspects, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_n-malkylcarbamyl” refers to a group of formula —C(O)—NH(alkyl), wherein the alkyl group has n to m carbon atoms. In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “thio” refers to a group of formula —SH.

As used herein, the term “C_n-malkylthio” refers to a group of formula —S-alkyl, wherein the alkyl group has n to m carbon atoms. In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_n-malkylsulfinyl” refers to a group of formula —S(O)— alkyl, wherein the alkyl group has n to m carbon atoms. In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_n-malkylsulfonyl” refers to a group of formula —S(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms. In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “carbamyl” to a group of formula —C(O)NH₂.

As used herein, the term “carbonyl,” employed alone or in combination with other terms, refers to a —C(═O)— group, which may also be written as C(O).

As used herein, the term “cyano-C_1-3alkyl” refers to a group of formula —(C_1-3alkylene)-CN.

As used herein, the term “HO—C_1-3alkyl” refers to a group of formula —(C_1-3alkylene)-OH.

As used herein, the term “C_1-3alkoxy-C_1-3alkyl” refers to a group of formula —(C_1-3alkylene)-O(C_1-3alkyl).

As used herein, the term “carboxy” refers to a group of formula —C(O)OH.

As used herein, the term “di(C_n-m-alkyl)amino” refers to a group of formula —N(alkyl)₂, wherein the two alkyl groups each has, independently, n to m carbon atoms. In various aspects, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_n-m-alkyl)carbamyl” refers to a group of formula —C(O)N(alkyl)₂, wherein the two alkyl groups each has, independently, n to m carbon atoms. In various aspects, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, “halo” refers to F, C1, Br, or I. In various aspects, the halo group is F or Cl.

As used herein, “C_n-mhaloalkoxy” refers to a group of formula —O-haloalkyl having n to m carbon atoms. An example haloalkoxy group is OCF₃. In various aspects, the haloalkoxy group is fluorinated only. In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_n-mhaloalkyl,” employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+1 halogen atoms which may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In various aspects, the haloalkyl group is fluorinated only. In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “amine base” refers to a mono-substituted amine group (i.e., primary amine base), di-substituted amine group (i.e., secondary amine base), or a tri-substituted amine group (i.e., tertiary amine base). Example mono-substituted amine bases include methyl amine, ethyl amine, propyl amine, butyl amine, and the like. Example di-substituted amine bases include dimethylamine, diethylamine, dipropylamine, dibutylamine, pyrrolidine, piperidine, azepane, morpholine, and the like. In various aspects, the tertiary amine has the formula N(R′)₃, wherein each R′ is independently C_1-6alkyl, 3-10 member cycloalkyl, 4-10 membered heterocycloalkyl, 1-10 membered heteroaryl, and 5-10 membered aryl, wherein the 3-10 member cycloalkyl, 4-10 membered heterocycloalkyl, 1-10 membered heteroaryl, and 5-10 membered aryl are optionally substituted by 1, 2, 3, 4, 5, or 6 C_1-6alkyl groups. Example tertiary amine bases include trimethylamine, triethylamine, tripropylamine, triisopropylamine, tributylamine, tri-tert-butylamine, N,N-dimethylethanamine, N-ethyl-N-methylpropan-2-amine, N-ethyl-N-isopropylpropan-2-amine, morpholine, N-methylmorpholine, and the like. In various aspects, the term “tertiary amine base” refers to a group of formula N(R)₃, wherein each R is independently a linear or branched C_1-6alkyl group.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and/or alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (C_3-10). Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido (e.g., C(O) or C(S)). Cycloalkyl groups also include cycloalkylidenes. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcamyl, and the like. In various aspects, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, or adamantyl. In various aspects, the cycloalkyl has 6-10 ring-forming carbon atoms. In various aspects, cycloalkyl is cyclohexyl or adamantyl. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.

As used herein, “heterocycloalkyl” refers to non-aromatic monocyclic or polycyclic heterocycles having one or more ring-forming heteroatoms selected from O, N, or S. Included in heterocycloalkyl are monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles. Example heterocycloalkyl groups include pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or sulfido (e.g., C(O), S(O), C(S), or S(O)₂, etc.). The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In various aspects, the heterocycloalkyl group contains 0 to 3 double bonds. In various aspects, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. In various aspects, the heterocycloalkyl has 4-10, 4-7 or 4-6 ring atoms with 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members.

As used herein, the term “aryl,” employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term “C_n-maryl” refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In various aspects, aryl groups have from 6 to about 20 carbon atoms, from 6 to about 15 carbon atoms, or from 6 to about 10 carbon atoms. In various aspects, the aryl group is a substituted or unsubstituted phenyl.

As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In various aspects, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In various aspects, any ring-forming N in a heteroaryl moiety can be an N-oxide. In various aspects, the heteroaryl has 5-10 ring atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In various aspects, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In various aspects, the heteroaryl is a five-membered or six-membered heteroaryl ring. A five-membered heteroaryl ring is a heteroaryl with a ring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six-membered heteroaryl ring is a heteroaryl with a ring having six ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

At certain places, the definitions or aspects refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas an azetidin-3-yl ring is attached at the 3-position.

As used herein, the term “electron withdrawing group” (EWG), employed alone or in combination with other terms, refers to an atom or group of atoms substituted onto a π-system (e.g., substituted onto an aryl or heteroaryl ring) that draws electron density away from the n-system through induction (e.g., withdrawing electron density about a σ-bond) or resonance (e.g., withdrawing electron density about a n-bond or n-system). Example electron withdrawing groups include, but are not limited to, halo groups (e.g., fluoro, chloro, bromo, iodo), nitriles (e.g., —CN), carbonyl groups (e.g., aldehydes, ketones, carboxylic acids, acid chlorides, esters, and the like), nitro groups (e.g., —NO₂), haloalkyl groups (e.g., —CH₂F, —CHF₂, —CF₃, and the like), alkenyl groups (e.g., vinyl), alkynyl groups (e.g., ethynyl), sulfonyl groups (e.g., S(O)R, S(O)₂R), sulfonate groups (e.g., —SO₃H), and sulfonamide groups (e.g., S(O)N(R)₂, S(O)₂N(R)₂). In various aspects, the electron withdrawing group is selected from the group consisting of halo, C_2-6alkenyl, C_2-6alkynyl, C_1-3haloalkyl, CN, NO₂, C(═O)OR^a1, C(═O)R^b1, C(═O)NR^c1R^d1, C(═O)SR^e1, —NR^c1S(O)R^e1, —NR^c1S(O)₂R^e1, S(═O)R^e1, S(═O)₂R^e1, S(═O)NR^c1R^d1, S(═O)₂NR^c1R^d1, and P(O)(OR^a1)₂. In various aspects, the electron withdrawing group is selected from the group consisting of C(═O)OR^a1, C(═O)R^b1, C(═O)NR^c1R^d1, C(═O)SR^e1, S(═O)R^e1, S(═O)₂R^e1, S(═O)NR^c1R^d1, and S(═O)₂NR^c1R^d1. In various aspects, the electron withdrawing group is C(═O)OR^a1. In various aspects, the electron withdrawing group is C(═O)OR^a1, wherein R^a1is C_1-6alkyl or (C_6-10aryl)-C_1-3alkylene. In various aspects, the electron withdrawing group is an ester.

Preparation of the compounds described herein can involve a reaction in the presence of an acid or a base. Example acids can be inorganic or organic acids and include, but are not limited to, strong and weak acids. Example acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, 4-nitrobenzoic acid, methanesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, and nitric acid. Example weak acids include, but are not limited to, acetic acid, propionic acid, butanoic acid, benzoic acid, tartaric acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, and decanoic acid. Example bases include, without limitation, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, and amine bases. Example strong bases include, but are not limited to, hydroxide, alkoxides, metal amides, metal hydrides, metal dialkylamides and arylamines, wherein; alkoxides include lithium, sodium and potassium salts of methyl, ethyl and t-butyl oxides; metal amides include sodium amide, potassium amide and lithium amide; metal hydrides include sodium hydride, potassium hydride and lithium hydride; and metal dialkylamides include lithium, sodium, and potassium salts of methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, trimethylsilyl and cyclohexyl substituted amides (e.g., lithium N-isopropylcyclohexylamide).

The following abbreviations may be used herein: AcOH (acetic acid); aq. (aqueous); atm. (atmosphere(s)); Br₂(bromine); Bn (benzyl); calc. (calculated); d (doublet); dd (doublet of doublets); DCM (dichloromethane); DMF (N,N-dimethylformamide); Et (ethyl); Et₂O (diethyl ether); EtOAc (ethyl acetate); EtOH (ethanol); EWG (electron withdrawing group); g (gram(s)); h (hour(s)); H₂(hydrogen gas); HCl (hydrochloric acid/hydrogen choride); HPLC (high performance liquid chromatography); H₂SO₄(sulfuric acid); Hz (hertz); I₂(iodine); IPA (isopropyl alcohol); J (coupling constant); KOH (potassium hydroxide); K₃PO₄(potassium phosphate); LCMS (liquid chromatography—mass spectrometry); LilCA (lithium N-isopropylcyclohexylamide); m (multiplet); M (molar); MS (Mass spectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg (milligram(s)); min. (minutes(s)); mL (milliliter(s)); mmol (millimole(s)); N (normal); NaBH₃CN (sodium cyanoborohydride); NHP (N-heterocyclic phosphine); NHP—C₁(N-heterocyclic phosphine chloride); Na₂CO₃(sodium carbonate); NaHCO₃(sodium bicarbonate); NaOH (sodium hydroxide); Na₂SO₄(sodium sulfate); nM (nanomolar); NMR (nuclear magnetic resonance spectroscopy); PCl₃(trichlorophosphine); PMP (4-methoxyphenyl); RP-HPLC (reverse phase high performance liquid chromatography); t (triplet or tertiary); t-Bu (tert-butyl); TEA (triethylamine); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TLC (thin layer chromatography); g (microgram(s)); L (microliter(s)); M (micromolar); wt % (weight percent).

B. N-Heterocyclic Phosphines

In one aspect, the invention relates to compounds useful in C—C and C—P bond-forming techniques. More specifically, in one aspect, the present invention relates to compounds useful in chemical reactions including, but not limited to, hydroformylations, Heck reactions, cross-coupling reactions, allylic substitutions, Pudovik-type reactions, Michael-type reactions, and Michaelis-Arbuzov reaction. The present invention further relates to compounds useful in the preparation of vinylphosphonates.

The disclosed N-heterocyclic phosphines (NHPs) are useful in, for example, generating phosphorus-carbon bonds under metal-free reaction conditions. As provided herein, one application of NHPs in organic synthesis is the formation of vinylphosphonates. In various aspects, the reaction of an appropriately substituted allene and NHP compound can promote a tandem Michael addition/Arbuzov reaction to generate vinylphosphonates. This process can deliver a regio- and stereoselective (e.g., E/Z ratio of about 6:1 to about 20:1) reaction via dual activation of the allene by a bi-functional NHP-thiourea scaffold which functions as Lewis base and Brønsted acid. Forming phosphorus-carbon bonds under metal-free reaction conditions is also useful in, for example, polymer synthesis, where metal impurities may impart undesirable material or thermal properties. Organophosphorus compounds (i.e., compounds having a P—C bond) are also useful, for example, as fire retardants and insecticides, and the production of these compounds via metal-free reactions is desirable.

It is contemplated that each disclosed derivative can be optionally further substituted. It is also contemplated that any one or more derivative can be optionally omitted from the invention. It is understood that a disclosed compound can be provided by the disclosed methods. It is also understood that the disclosed compounds can be employed in the disclosed methods of using.

1. Structure

In one aspect, compounds of Formula (Ia):

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or a salt thereof, wherein: each X is independently selected from the group consisting of N, O, and S; Y is selected from the group consisting of CH₂, O, and S; Z is selected from the group consisting of C═O, C═S, S═O, and SO₂; R^Xis selected from the group consisting of H, C_6-10aryl, and 4-10 membered heteroaryl ring; R^Yis selected from the group consisting of H, C_6-10aryl, and 4-10 membered heteroaryl ring; or R^Xand R^Yin combination, together with the carbon atoms to which R^Xand R^Yare attached, form a 5, 6, or 7-membered cycloalkyl ring or a 5, 6, or 7-membered aryl ring; each R¹is independently selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; R²is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; each R³is independently selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; R⁴is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; each R⁵is independently selected from the group consisting of OH, NO₂, CN, halo, C_1-3alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-3haloalkyl, cyano-C_1-3alkyl, HO—C_1-3alkyl, C_1-3alkoxy-C_1-3alkyl, C_3-7cycloalkyl, C_6-10aryl, C_1-3alkoxy, C_1-3haloalkoxy, amino, C_1-3alkylamino, di(C_1-3alkyl)amino, thio, C_1-3alkylthio, C_1-3alkylsulfinyl, C_1-3alkylsulfonyl, carbamyl, C_1-3alkylcarbamyl, di(C_1-3alkyl)carbamyl, carboxy, C_1-3alkylcarbonyl, C_1-4alkoxycarbonyl, C_1-3alkylcarbonylamino, C_1-3alkylsulfonylamino, aminosulfonyl, C_1-3alkylaminosulfonyl, di(C_1-3alkyl)aminosulfonyl, aminosulfonylamino, C_1-3alkylaminosulfonylamino, di(C_1-3alkyl)aminosulfonylamino, aminocarbonylamino, C_1-3alkylaminocarbonylamino, and di(C_1-3alkyl)aminocarbonylamino; n is 0 or 1; and p is 0, 1, 2, 3, 4, or 5 are disclosed. In a further aspect, the salt is a pharmaceutically acceptable salt.

In one aspect, compounds of Formula (Ib):

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or a salt thereof, wherein: each X is independently selected from the group consisting of N, O, and S; Y is selected from the group consisting of CH₂, O, and S; Z is selected from the group consisting of C═O, C═S, S═O, and SO₂; each R¹is independently selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; R²is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; each R³is independently selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; R⁴is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; each R⁵is independently selected from the group consisting of OH, NO₂, CN, halo, C_1-3alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-3haloalkyl, cyano-C_1-3alkyl, HO—C_1-3alkyl, C_1-3alkoxy-C_1-3alkyl, C_3-7cycloalkyl, C_6-10aryl, C_1-3alkoxy, C_1-3haloalkoxy, amino, C_1-3alkylamino, di(C_1-3alkyl)amino, thio, C_1-3alkylthio, C_1-3alkylsulfinyl, C_1-3alkylsulfonyl, carbamyl, C_1-3alkylcarbamyl, di(C_1-3alkyl)carbamyl, carboxy, C_1-3alkylcarbonyl, C_1-4alkoxycarbonyl, C_1-3alkylcarbonylamino, C_1-3alkylsulfonylamino, aminosulfonyl, C_1-3alkylaminosulfonyl, di(C_1-3alkyl)aminosulfonyl, aminosulfonylamino, C_1-3alkylaminosulfonylamino, di(C_1-3alkyl)aminosulfonylamino, aminocarbonylamino, C_1-3alkylaminocarbonylamino, and di(C_1-3alkyl)aminocarbonylamino; n is 0 or 1; and p is 0, 1, 2, 3, 4, or 5 are disclosed. In a further aspect, the salt is a pharmaceutically acceptable salt.

In one aspect, compounds having a structure represented by a formula:

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wherein n is selected from 0 and 1; wherein p is selected from 0, 1, 2, 3, 4, and 5; wherein each of X^Aand X^Bis independently selected from NR¹, O, and S; wherein each occurrence of R¹, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each occurrence of R¹, when present, is independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein Y is selected from O and S; wherein Z is selected from C═O, C═S, S═O, and SO₂; wherein each of R^Xand R^Yis independently selected from hydrogen, C1-C8 alkyl, C6-C10 aryl, and 4-10 membered heteroaryl, or wherein each of R^Xand R^Yare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 5- to 7-membered cycloalkyl or 5- to 6-membered aryl; wherein R²is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R²is substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein each of R^3aand R^3b, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each of R^3aand R^3bis independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein R⁴is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and —(C1-C3 alkyl)(C6-C10 aryl), and wherein R⁴is substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein each occurrence of R⁵, when present, is independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 haloalkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy, C1-C3 thioalkyl, C1-C3 alkyl(C1-C3 alkoxy), C1-C3 alkylamino, (C1-C3)(C1-C3) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —(C═O)(C1-C3 alkyl), —(S═O)(C1-C3 alkyl), —SO₂(C1-C3 alkyl), —CO₂R¹¹, (C═O)NR^12aR^12b, —SO₂NR^12aR^12b, —O(C═O)NR^12aR^12b, —NHSO₂NR^12aR^12b, and —NH(C═O)NR^12aR^12b; wherein each occurrence of R¹¹, when present, is independently selected from hydrogen and C1-C4 alkyl; and wherein each occurrence of R^12aand R^12b, when present, is independently selected from hydrogen and C1-C3 alkyl, or a derivative thereof.

In one aspect, compounds having a structure represented by a formula:

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wherein n is selected from 0 and 1; wherein p is selected from 0, 1, 2, 3, 4, and 5; wherein each of X^Aand X^Bis independently selected from NR¹, O, and S; wherein each occurrence of R¹, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each occurrence of R¹, when present, is independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein Y is selected from CH₂, O, and S; wherein Z is selected from C═O, C═S, S═O, and SO₂; wherein each of R^Xand R^Yis independently selected from hydrogen, C6-C10 aryl, and 4-10 membered heteroaryl, or wherein each of R^Xand R^Yare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 5- to 7-membered cycloalkyl or 5- to 6-membered aryl; wherein R²is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R²is substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein each of R^3aand R^3b, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each of R^3aand R^3bis independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein R⁴is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and —(C1-C3 alkyl)(C6-C10 aryl), and wherein R⁴is substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein each occurrence of R⁵, when present, is independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 haloalkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy, C1-C3 thioalkyl, C1-C3 alkyl(C1-C3 alkoxy), C1-C3 alkylamino, (C1-C3)(C1-C3) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —(C═O)(C1-C3 alkyl), —(S═O)(C1-C3 alkyl), —SO₂(C1-C3 alkyl), —CO₂R¹¹, —SO₂NR^12aR^12b, —O(C═O)NR^12aR^12b, —NHSO₂NR^12aR^12b, and —NH(C═O)NR^12aR^12b; wherein each occurrence of R¹¹, when present, is independently selected from hydrogen and C1-C4 alkyl; and wherein each occurrence of R^12aand R^12b, when present, is independently selected from hydrogen and C1-C3 alkyl, or a derivative thereof.

In a further aspect, each X is N; Y is O; Z is selected from the group consisting of C═O, C═S, and SO₂; each R¹is C_6-10aryl, wherein each C_6-10aryl is optionally substituted by 1 or 2 independently selected R⁵groups; R²is H or C_1-6alkyl; each R³is independently selected from H and C_1-6alkyl; R⁴is C_6-10aryl or (C_6-10aryl)-C_1-3alkylene-, wherein the C_6-10aryl and (C_6-10aryl)-C_1-3alkylene- are each optionally substituted by 1 or 2 independently selected R⁵groups; each R⁵is independently selected from the group consisting of NO₂, halo, C_1-3alkyl, C_1-3alkoxy, C_1-3haloalkyl; and p is 1 or 2.

In a further aspect, each X is N; Y is S; Z is selected from the group consisting of C═O, C═S, and SO₂; each R¹is C_6-10aryl, wherein each C_6-10aryl is optionally substituted by 1 or 2 independently selected R⁵groups; R²is H or C_1-6alkyl; each R³is independently selected from H and C_1-6alkyl; R⁴is C_6-10aryl or (C_6-10aryl)-C_1-3alkylene-, wherein the C_6-10aryl and (C_6-10aryl)-C_1-3alkylene- are each optionally substituted by 1 or 2 independently selected R⁵groups; each R⁵is independently selected from the group consisting of NO₂, halo, C_1-3alkyl, C_1-3alkoxy, C_1-3haloalkyl; and p is 1 or 2.

In a further aspect, the compound of Formula (Ia) or Formula (Ib) is not:

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In a further aspect, the compound of Formula (Ia) or Formula (Ib) is a compound of Formula (Ic):

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or a salt thereof. In a still further aspect, each X is independently selected from the group consisting of N, O, and S; Y is selected from the group consisting of CH₂, O, and S; Z is selected from the group consisting of C═O, C═S, S═O, and SO₂; each R¹is independently selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C₁₃alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; R²is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; R³is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; R⁴is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; and each R⁵is independently selected from the group consisting of OH, NO₂, CN, halo, C_1-3alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-3haloalkyl, cyano-C_1-3alkyl, HO—C_1-3alkyl, C_1-3alkoxy-C_1-3alkyl, C_3-7cycloalkyl, C_6-10aryl, C_1-3alkoxy, C_1-3haloalkoxy, amino, C_1-3alkylamino, di(C_1-3alkyl)amino, thio, C_1-3alkylthio, C_1-3alkylsulfinyl, C_1-3alkylsulfonyl, carbamyl, C_1-3alkylcarbamyl, di(C_1-3alkyl)carbamyl, carboxy, C_1-3alkylcarbonyl, C_1-4alkoxycarbonyl, C_1-3alkylcarbonylamino, C_1-3alkylsulfonylamino, aminosulfonyl, C_1-3alkylaminosulfonyl, di(C_1-3alkyl)aminosulfonyl, aminosulfonylamino, C_1-3alkylaminosulfonylamino, di(C_1-3alkyl)aminosulfonylamino, aminocarbonylamino, C_1-3alkylaminocarbonylamino, and di(C_1-3alkyl)aminocarbonylamino. In a still further aspect, the salt is a pharmaceutically acceptable salt.

In a further aspect, the compound of Formula (Ia) or Formula (Ib) is a compound of Formula (Id):

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or a salt thereof. In a still further aspect, Y is selected from the group consisting of CH₂, O, and S; Z is selected from the group consisting of C═O, C═S, S═O, and SO₂; each R¹is independently selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; R²is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; R³is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; R⁴is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; and each R⁵is independently selected from the group consisting of OH, NO₂, CN, halo, C_1-3alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-3haloalkyl, cyano-C_1-3alkyl, HO—C_1-3alkyl, C_1-3alkoxy-C_1-3alkyl, C_3-7cycloalkyl, C_6-10aryl, C_1-3alkoxy, C_1-3haloalkoxy, amino, C_1-3alkylamino, di(C_1-3alkyl)amino, thio, C_1-3alkylthio, C_1-3alkylsulfinyl, C_1-3alkylsulfonyl, carbamyl, C_1-3alkylcarbamyl, di(C_1-3alkyl)carbamyl, carboxy, C_1-3alkylcarbonyl, C_1-4alkoxycarbonyl, C_1-3alkylcarbonylamino, C_1-3alkylsulfonylamino, aminosulfonyl, C_1-3alkylaminosulfonyl, di(C_1-3alkyl)aminosulfonyl, aminosulfonylamino, C_1-3alkylaminosulfonylamino, di(C_1-3alkyl)aminosulfonylamino, aminocarbonylamino, C_1-3alkylaminocarbonylamino, and di(C_1-3alkyl)aminocarbonylamino. In a still further aspect, the salt is a pharmaceutically acceptable salt.

In a further aspect, the compound of Formula (Ia) or Formula (Ib) is a compound of Formula (Ie):

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or a salt thereof. In a still further aspect, each X is independently selected from the group consisting of N, O, and S; Y is selected from the group consisting of CH₂, O, and S; Z is selected from the group consisting of C═O, C═S, S═O, and SO₂; each R¹is independently selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; R²is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; R³is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C₁₃alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; R⁴is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; and each R⁵is independently selected from the group consisting of OH, NO₂, CN, halo, C_1-3alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-3haloalkyl, cyano-C_1-3alkyl, HO—C_1-3alkyl, C_1-3alkoxy-C_1-3alkyl, C_3-7cycloalkyl, C_6-10aryl, C_1-3alkoxy, C_1-3haloalkoxy, amino, C_1-3alkylamino, di(C_1-3alkyl)amino, thio, C_1-3alkylthio, C_1-3alkylsulfinyl, C_1-3alkylsulfonyl, carbamyl, C_1-3alkylcarbamyl, di(C_1-3alkyl)carbamyl, carboxy, C_1-3alkylcarbonyl, C_1-4alkoxycarbonyl, C_1-3alkylcarbonylamino, C_1-3alkylsulfonylamino, aminosulfonyl, C_1-3alkylaminosulfonyl, di(C_1-3alkyl)aminosulfonyl, aminosulfonylamino, C_1-3alkylaminosulfonylamino, di(C_1-3alkyl)aminosulfonylamino, aminocarbonylamino, C_1-3alkylaminocarbonylamino, and di(C_1-3alkyl)aminocarbonylamino. In a still further aspect, the salt is a pharmaceutically acceptable salt.

In a further aspect, the compound of Formula (Ia) or Formula (Ib) is a compound of Formula (If):

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or a salt thereof. In a still further aspect, each X is independently selected from the group consisting of N, O, and S; Y is selected from the group consisting of CH₂, O, and S; Z is selected from the group consisting of C═O, C═S, S═O, and SO₂; each R¹is independently selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; R²is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; R³is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; R⁴is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; and each R⁵is independently selected from the group consisting of OH, NO₂, CN, halo, C_1-3alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-3haloalkyl, cyano-C_1-3alkyl, HO—C_1-3alkyl, C_1-3alkoxy-C_1-3alkyl, C_3-7cycloalkyl, C_6-10aryl, C_1-3alkoxy, C_1-3haloalkoxy, amino, C_1-3alkylamino, di(C_1-3alkyl)amino, thio, C_1-3alkylthio, C_1-3alkylsulfinyl, C_1-3alkylsulfonyl, carbamyl, C_1-3alkylcarbamyl, di(C_1-3alkyl)carbamyl, carboxy, C_1-3alkylcarbonyl, C_1-4alkoxycarbonyl, C_1-3alkylcarbonylamino, C_1-3alkylsulfonylamino, aminosulfonyl, C_1-3alkylaminosulfonyl, di(C_1-3alkyl)aminosulfonyl, aminosulfonylamino, C_1-3alkylaminosulfonylamino, di(C_1-3alkyl)aminosulfonylamino, aminocarbonylamino, C_1-3alkylaminocarbonylamino, and di(C_1-3alkyl)aminocarbonylamino. In a still further aspect, the salt is a pharmaceutically acceptable salt.

In a further aspect, the compound of Formula (Ia) or Formula (Ib) is a compound of Formula (Ig):

In a further aspect, the compound of Formula (Ia) or Formula (Ib) is a compound of Formula (Ih):

In a further aspect, the compound has a structure represented by a formula:

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wherein n is selected from 0 and 1; wherein p is selected from 0, 1, 2, 3, 4, and 5; wherein each occurrence of R¹, when present, is independently selected from hydrogen, C1-C6 alkyl, and C6-C10 aryl, and wherein each occurrence of R¹, when present, is independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein Y is selected from O, S, and NR²⁶; wherein R²⁶, when present, is selected from hydrogen and C1-C8 alkyl; wherein Z is selected from C═O, C═S, S═O, and SO₂; wherein R²is selected from hydrogen and C1-C6 alkyl substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein each of R^3aand R^3b, when present, is independently selected from hydrogen and C1-C6 alkyl substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein R⁴is selected from C3-C10 cycloalkyl, C6-C10 aryl, and —(C1-C3 alkyl)(C6-C10 aryl), and wherein R⁴is substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein each occurrence of R⁵, when present, is independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 thioalkyl, C1-C3 alkylamino, and (C1-C3)(C1-C3) dialkylamino; or a derivative thereof.

In a further aspect, the compound has a structure represented by a formula:

In a further aspect, the compound has a structure represented by a formula selected from:

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or a derivative thereof.

In a further aspect, the compound has a structure represented by a formula selected from:

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or a derivative thereof.

In a further aspect, the compound has a structure represented by a formula:

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or a derivative thereof.

In a further aspect, the compound has a structure represented by a formula selected from:

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or a derivative thereof.

In a further aspect, the compound has a structure represented by a formula:

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or a derivative thereof.

In a further aspect, the compound has a structure represented by a formula selected from:

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or a derivative thereof.

In a further aspect, the compound has a structure represented by a formula:

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or a derivative thereof.

In a further aspect, the compound has a structure represented by a formula:

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or a derivative thereof.

In a further aspect, the compound has a structure represented by a formula:

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or a derivative thereof.

In a further aspect, the compound has a structure represented by a formula:

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or a derivative thereof.

In a further aspect, the compound has a structure represented by a formula:

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or a derivative thereof.

Non-limiting examples of a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), and/or (Ig) include:

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or a salt thereof. In a further aspect, the salt is a pharmaceutically acceptable salt.

In one aspect, n is selected from 0 and 1. In a further aspect, n is 1. In a still further aspect, n is 0.

In one aspect, p is selected from 0, 1, 2, 3, 4, and 5. In a further aspect, p is selected from 0, 1, 2, 3, and 4. In a still further aspect, p is selected from 0, 1, 2, and 3. In yet a further aspect, p is selected from 0, 1, and 2. In an even further aspect, p is selected from 0 and 1. In a still further aspect, p is selected from 1 and 2. In yet a further aspect, p is 5. In an even further aspect, p is 4. In a still further aspect, p is 3. In yet a further aspect, p is 2. In an even further aspect, p is 1. In a still further aspect, p is 0.

a. Q Groups

In one aspect, Q is selected from O, S, and NR²⁶. In a further aspect, Q is selected from O and S. In a still further aspect, Q is selected from O and NR²⁶. In yet a further aspect, Q is selected from S and NR²⁶. In an even further aspect, Q is S. In a still further aspect, Q is NR²⁶. In yet a further aspect, Q is O.

b. X, X^A, and X^BGroups

In one aspect, each X is independently selected from N, O, and S. In various aspects, each X is N. In a further aspect, each X is independently selected from N and O. In a still further aspect, each X is independently selected from O and S. In yet a further aspect, each X is independently selected from N and S. In an even further aspect, each X is N. In a still further aspect, each X is O. In yet a further aspect, each X is S.

In one aspect, each of X^Aand X^Bis independently selected from NR¹, O, and S. In a further aspect, each of X^Aand X^Bis independently selected from NR¹and O. In a still further aspect, each of X^Aand X^Bis independently selected from NR¹and S. In yet a further aspect, each of X^Aand X^Bis independently selected from O and S. In an even further aspect, each of X^Aand X^Bis NR¹. In a still further aspect, each of X^Aand X^Bis O. In yet a further aspect, each of X^Aand X^Bis S.

c. X¹Groups

In one aspect, X¹is halogen. In a further aspect, X¹is selected from —Br, —Cl, and —F. In a still further aspect, X¹is selected from —Cl and —F. In yet a further aspect, X¹is —I. In an even further aspect, X¹is —Br. In a still further aspect, X¹is —Cl. In yet a further aspect, X¹is —F.

d. X²Groups

In one aspect, each X²is independently selected from the group consisting of —NH—, —O—, and —S—. In a further aspect, each X²is independently selected from the group consisting of —NH— and —O—. In a still further aspect, each X²is independently selected from the group consisting of —NH— and —S—. In yet a further aspect, each X²is independently selected from the group consisting of —O— and —S—. In an even further aspect, each X²is —NH. In a still further aspect, each X²is —O—. In yet a further aspect, each X²is —S—.

e. X³Groups

In one aspect, X³is selected from halogen, tosyl, and mesyl. In a further aspect, X³is selected from —Cl, —F, tosyl, and mesyl. In a still further aspect, X³is selected from —Cl, tosyl, and mesyl. In yet a further aspect, X³is tosyl. In an even further aspect, X³is mesyl. In a still further aspect, X³is —Cl. In yet a further aspect, X³is —F.

f. Y Groups

In one aspect, Y is selected from CH₂, O, and S. In a further aspect, Y is selected from O and S. In a still further aspect, Y is selected from CH₂and S. In yet a further aspect, Y is selected from CH₂and O. In an even further aspect, Y is O. In a still further aspect, Y is S. In yet a further aspect, Y is CH₂.

In one aspect, Y is selected from O, S, and NR²⁶. In a further aspect, Y is selected from O and S. In a still further aspect, Y is selected from O and NR²⁶. In yet a further aspect, Y is selected from S and NR²⁶. In an even further aspect, Y is S. In a still further aspect, Y is NR²⁶. In yet a further aspect, Y is O.

g. Y¹Groups

In one aspect, Y¹is OH, SH, or —CH₃. In a further aspect, Y¹is OH. In a still further aspect, Y¹is SH. In yet a further aspect, Y¹is —CH₃.

h. Z Groups

In one aspect, Z is selected from C═O, C═S, S═O, and SO₂. In a further aspect, Z is selected from C═O, C═S and SO₂. In a still further aspect, Z is selected from C═O, C═S and S═O. In yet a further aspect, Z is selected from C═O and C═S. In an even further aspect, Z is selected from C═O and S═O. In a still further aspect, Z is selected from C═O and SO₂. In yet a further aspect, Z is selected from C═S and S═O. In an even further aspect, Z is selected from C═S and SO₂. In a still further aspect, Z is selected from S═O and SO₂. In yet a further aspect, Z is C═O. In an even further aspect, Z is C═S. In a still further aspect, Z is S═O. In yet a further aspect, Z is SO₂.

i. R¹Groups

In one aspect, each R¹is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups. In a further aspect, each R¹is independently selected from the group consisting of H, C_1-3alkyl, C_1-3haloalkyl, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 4-8 membered heterocycloalkyl, C_6-8aryl, (C_6-8aryl)-C_1-3alkylene-, and 4-8 membered heteroaryl, wherein the C_1-3alkyl, C_3--8 cycloalkyl, 4-8 membered heterocycloalkyl, C_6-8aryl, (C_6-8aryl)-C_1-3alkylene-, and 4-8 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups.

In one aspect, each occurrence of R¹, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each occurrence of R¹, when present, is independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups. In a further aspect, each occurrence of R¹, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl, C6-C8 aryl, —(C1-C3 alkyl)(C6-C8 aryl), and 4-8 membered heteroaryl, and wherein each occurrence of R¹, when present, is independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups. In a still further aspect, each occurrence of R¹is H.

In a further aspect, each R¹is independently selected from the group consisting of H, C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl. In a still further aspect, each R¹is independently selected from C_1-6alkyl, (C_6-10aryl)-C_1-3alkylene, and C_6-10aryl. In yet a further aspect, each R¹is independently C_1-6alkyl, optionally substituted by 1 R⁵group. In an even further aspect, each R¹is methyl.

In a further aspect, each R¹is ethyl, substituted by 1 R⁵; and R⁵is phenyl.

In a further aspect, each R¹is independently C_6-10aryl optionally substituted by 1 or 2 independently selected R⁵groups; and R⁵is NO₂, halo, C_1-3alkyl or C_1-3alkoxy. In a still further aspect, each R¹is phenyl, optionally substituted by 1 or 2 independently selected R⁵groups; and R⁵is NO₂, halo, C_1-3alkyl or C_1-3alkoxy. In yet a further aspect, each R¹is phenyl, optionally substituted by 1 or 2 independently selected R⁵groups; and R⁵is selected from the group consisting of NO₂, bromo, methyl, isopropyl, and methoxy.

In a further aspect, each occurrence of R¹, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each occurrence of R¹, when present, is independently substituted with 0, 1, 2, or 3 independently selected R⁵groups. In a still further aspect, each occurrence of R¹, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each occurrence of R¹, when present, is independently substituted with 0, 1, or 2 independently selected R⁵groups. In yet a further aspect, each occurrence of R¹, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each occurrence of R¹, when present, is independently substituted with 0 or 1 R⁵group. In an even further aspect, each occurrence of R¹, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each occurrence of R¹, when present, is independently monosubstituted with a R⁵group. In a still further aspect, each occurrence of R¹, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each occurrence of R¹, when present, is unsubstituted.

In a further aspect, each occurrence of R¹, when present, is independently selected from C1-C6 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, and —(C1-C3 alkyl)(C6-C10 aryl). In a still further aspect, each occurrence of R¹, when present, is independently selected from C1-C4 alkyl, C3-C8 cycloalkyl, C6-C8 aryl, and —(C1-C3 alkyl)(C6-C8 aryl). In yet a further aspect, each occurrence of R¹, when present, is independently selected from methyl, ethyl, n-propyl, i-propyl, cyclohexyl, phenyl, and benzyl. In a still further aspect, each occurrence of R¹, when present, is independently selected from methyl, ethyl, cyclohexyl, phenyl and benzyl. In yet a further aspect, each occurrence of R¹, when present, is independently selected from methyl, cyclohexyl, phenyl, and benzyl. In an even further aspect, each occurrence of R¹, when present, is independently selected from cyclohexyl, phenyl, and benzyl. In a still further aspect, each occurrence of R¹, when present, is cyclohexyl. In yet a further aspect, each occurrence of R¹, when present, is phenyl. In an even further aspect, each occurrence of R¹, when present, is benzyl.

In a further aspect, each occurrence of R¹, when present, is independently selected from C1-C6 alkyl and C6-C10 aryl. In a still further aspect, each occurrence of R¹, when present, is independently selected from C1-C4 alkyl and C6-C8 aryl. In yet a further aspect, each occurrence of R¹, when present, is independently selected from methyl, ethyl, n-propyl, i-propyl, and phenyl. In an even further aspect, each occurrence of R¹, when present, is independently selected from methyl, ethyl, and phenyl. In a still further aspect, each occurrence of R¹, when present, is independently selected from ethyl and phenyl. In yet a further aspect, each occurrence of R¹, when present, is independently selected from methyl and phenyl.

In a further aspect, each occurrence of R¹, when present, is independently selected from hydrogen and C1-C6 alkyl. In a still further aspect, each occurrence of R¹, when present, is independently selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl. In yet a further aspect, each occurrence of R¹, when present, is independently selected from hydrogen, methyl, ethyl, n-propyl, and i-propyl. In an even further aspect, each occurrence of R¹, when present, is independently selected from hydrogen, methyl, and ethyl. In a still further aspect, each occurrence of R¹, when present, is independently selected from hydrogen and ethyl. In yet a further aspect, each occurrence of R¹, when present, is independently selected from hydrogen and methyl.

In a further aspect, each occurrence of R¹, when present, is independently C1-C6 alkyl. In a still further aspect, each occurrence of R¹, when present, is independently selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl. In yet a further aspect, each occurrence of R¹, when present, is independently selected from methyl, ethyl, n-propyl, and i-propyl. In an even further aspect, each occurrence of R¹, when present, is independently selected from methyl and ethyl. In a still further aspect, each occurrence of R¹, when present, is ethyl. In yet a further aspect, each occurrence of R¹, when present, is methyl.

j. R²Groups

In one aspect, R²is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups. In a further aspect, R²is selected from the group consisting of H, C_1-3alkyl, C_1-3haloalkyl, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 4-8 membered heterocycloalkyl, C_6-8aryl, (C_6-8aryl)-C_1-3alkylene, and 4-8 membered heteroaryl, wherein the C_1-3alkyl, C_3-8cycloalkyl, 4-8 membered heterocycloalkyl, C_6-8aryl, (C_6-8aryl)-C_1-3alkylene-, and 4-8 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups. In a still further aspect, R²is H.

In one aspect, R²is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R²is substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups. In a further aspect, R²is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl, C6-C8 aryl, —(C1-C3 alkyl)(C6-C8 aryl), and 4-8 membered heteroaryl, and wherein R²is substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups.

In a further aspect, R²is selected from the group consisting of H, C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl. In a still further aspect, R²is H or C_1-6alkyl. In yet a further aspect, R²is C_1-6alkyl. In an even further aspect, R²is methyl.

In a further aspect, R²is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R²is substituted with 0, 1, 2, or 3 independently selected R⁵groups. In a still further aspect, R²is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R²is substituted with 0, 1, or 2 independently selected R⁵groups. In yet a further aspect, R²is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R²is substituted with 0 or 1 R⁵group. In an even further aspect, R²is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R²is monosubstituted with a R⁵group. In a still further aspect, R²is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R²is unsubstituted.

In a further aspect, R²is selected from hydrogen and C1-C6 alkyl. In a still further aspect, R²is selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl. In yet a further aspect, R²is selected from hydrogen, methyl, ethyl, n-propyl, and i-propyl. In an even further aspect, R²is selected from hydrogen, methyl and ethyl. In a still further aspect, R²is selected from hydrogen and ethyl. In yet a further aspect, R²is selected from hydrogen and methyl.

In a further aspect, R²is C1-C6 alkyl. In a still further aspect, R²is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl. In yet a further aspect, R²is selected from methyl, ethyl, n-propyl, and i-propyl. In an even further aspect, R²is selected from methyl and ethyl. In a still further aspect, R²is ethyl. In yet a further aspect, R²is methyl.

k. R³, R^3A, and R^3BGroups

In one aspect, each R³is independently selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups. In a further aspect, each R³is independently selected from the group consisting of H, C_1-3alkyl, C_1-3haloalkyl, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 4-8 membered heterocycloalkyl, C_6-8aryl, (C_6-8aryl)-C_1-3alkylene-, and 4-8 membered heteroaryl, wherein the C_1-3alkyl, C_3-8cycloalkyl, 4-8 membered heterocycloalkyl, C_6-8aryl, (C_6-8aryl)-C_1-3alkylene-, and 4-8 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups. In a still further aspect, each R³is H.

In one aspect, each of R^3aand R^3b, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each of R^3aand R^3bis independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups. In a further aspect, each of R^3aand R^3b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl, C6-C8 aryl, —(C1-C3 alkyl)(C6-C8 aryl), and 4-8 membered heteroaryl, and wherein each of R^3aand R^3bis independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups. In a still further aspect, each of R^3aand R^3b, when present, is hydrogen.

In a further aspect, each R³is independently selected from the group consisting of H, C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl. In a still further aspect, each R³is independently selected from H and C_1-6alkyl. In yet a further aspect, each R³is independently selected from H and methyl. In an even further aspect, each R³is H.

In a further aspect, each of R^3aand R^3b, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each of R^3aand R^3bis independently substituted with 0, 1, 2, or 3 independently selected R⁵groups. In a still further aspect, each of R^3aand R^3b, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each of R^3aand R^3bis independently substituted with 0, 1, or 2 independently selected R⁵groups. In yet a further aspect, each of R^3aand R^3b, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each of R^3aand R^3bis independently substituted with 0 or 1 R⁵group. In an even further aspect, each of R^3aand R^3b, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each of R^3aand R^3bis independently monosubstituted with a R⁵group. In a still further aspect, each of R^3aand R^3b, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each of R^3aand R^3bis unsubstituted.

In a further aspect, each of R^3aand R^3b, when present, is independently selected from hydrogen and C1-C6 alkyl. In a still further aspect, each of R^3aand R^3b, when present, is independently selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl. In yet a further aspect, each of R^3aand R^3b, when present, is independently selected from hydrogen, methyl, ethyl, n-propyl, and i-propyl. In an even further aspect, each R³is independently selected from H, methyl, and ethyl. In a still further aspect, each of R^3aand R^3b, when present, is independently selected from hydrogen and ethyl. In yet a further aspect, each of R^3aand R^3b, when present, is independently selected from hydrogen and methyl.

In a further aspect, each of R^3aand R^3b, when present, is independently C1-C6 alkyl. In a still further aspect, each of R^3aand R^3b, when present, is independently selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl. In yet a further aspect, each of R^3aand R^3b, when present, is independently selected from methyl, ethyl, n-propyl, and i-propyl. In an even further aspect, each of R^3aand R^3b, when present, is independently selected from methyl and ethyl. In a still further aspect, each of R^3aand R^3b, when present, is ethyl. In yet a further aspect, each of R^3aand R^3b, when present, is methyl.

l. R⁴Groups

In one aspect, R⁴is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups. In a further aspect, R⁴is selected from the group consisting of H, C_1-3alkyl, C_1-3haloalkyl, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 4-8 membered heterocycloalkyl, C_6-8aryl, (C_6-8aryl)-C_1-3alkylene-, and 4-8 membered heteroaryl, wherein the C_1-8alkyl, C_3-8cycloalkyl, 4-8 membered heterocycloalkyl, C_6-8aryl, (C_6-8aryl)-C_1-3alkylene-, and 4-8 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups. In a still further aspect, R⁴is H.

In one aspect, R⁴is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and —(C1-C3 alkyl)(C6-C10 aryl), and wherein R⁴is substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups. In a further aspect, R⁴is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl, C6-C8 aryl, and 4-8 membered heteroaryl, and —(C1-C3 alkyl)(C6-C8 aryl), and wherein R⁴is substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups.

In a further aspect, R⁴is selected from the group consisting of H, C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl. In a still further aspect, R⁴is C_6-10aryl or (C_6-10aryl)-C_1-6alkylene-. In yet a further aspect, R⁴is (C_6-10aryl)-C_1-6alkylene-. In an even further aspect, R⁴is benzyl.

In a further aspect, R⁴is C_6-10aryl, optionally substituted by 1 or 2 independently selected R⁵groups; and R⁵is selected from the group consisting of C_1-3alkyl, C_1-3alkoxy, and C_1-3haloalkyl. In a still further aspect, R⁴is phenyl, optionally substituted by 1 or 2 independently selected R⁵groups; and R⁵is selected from the group consisting of C_1-3alkyl, C_1-3alkoxy, and C_1-3haloalkyl. In yet a further aspect, R⁴is phenyl, optionally substituted by 1 or 2 independently selected R⁵groups; and R⁵is selected from the group consisting of methyl, trifluoromethyl, and methoxy.

In a further aspect, R⁴is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and —(C1-C3 alkyl)(C6-C10 aryl), and wherein R⁴is substituted with 0, 1, 2, or 3 independently selected R⁵groups. In a still further aspect, R⁴is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and —(C1-C3 alkyl)(C6-C10 aryl), and wherein R⁴is substituted with 0, 1, or 2 independently selected R⁵groups. In yet a further aspect, R⁴is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and —(C1-C3 alkyl)(C6-C10 aryl), and wherein R⁴is substituted with 0 or 1 R⁵group. In an even further aspect, R⁴is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and —(C1-C3 alkyl)(C6-C10 aryl), and wherein R⁴is monosubstituted with a R⁵group. In a still further aspect, R⁴is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and —(C1-C3 alkyl)(C6-C10 aryl), and wherein R⁴is unsubstituted.

In a further aspect, R⁴is selected from C3-C10 cycloalkyl, C6-C10 aryl, and —(C1-C3 alkyl)(C6-C10 aryl). In a still further aspect, R⁴is selected from C3-C8 cycloalkyl, C6-C8 aryl, and —(C1-C3 alkyl)(C6-C8 aryl). In yet a further aspect, R⁴is selected from cyclohexyl, phenyl, and benzyl. In an even further aspect, R⁴is selected from cyclohexyl and phenyl. In a still further aspect, R⁴is selected from cyclohexyl and benzyl. In yet a further aspect, R⁴is selected from phenyl and benzyl. In an even further aspect, R⁴is cyclohexyl. In a still further aspect, R⁴is phenyl. In an even further aspect, R⁴is benzyl.

m. R⁵Groups

In one aspect, each R⁵is independently selected from the group consisting of OH, NO₂, CN, halo, C_1-3alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-3haloalkyl, cyano-C_1-3alkyl, HO—C_1-3alkyl, C_1-3alkoxy-C_1-3alkyl, C_3-7cycloalkyl, C_6-10aryl, C_1-3alkoxy, C_1-3haloalkoxy, amino, C_1-3alkylamino, di(C_1-3alkyl)amino, thio, C_1-3alkylthio, C_1-3alkylsulfinyl, C_1-3alkylsulfonyl, carbamyl, C_1-3alkylcarbamyl, di(C_1-3alkyl)carbamyl, carboxy, C_1-3alkylcarbonyl, C_1-4alkoxycarbonyl, C_1-3alkylcarbonylamino, C_1-3alkylsulfonylamino, aminosulfonyl, C_1-3alkylaminosulfonyl, di(C_1-3alkyl)aminosulfonyl, aminosulfonylamino, C_1-3alkylaminosulfonylamino, di(C_1-3alkyl)aminosulfonylamino, aminocarbonylamino, C_1-3alkylaminocarbonylamino, and di(C_1-3alkyl)aminocarbonylamino.

In one aspect, R⁵, when present, is independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 haloalkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy, C1-C3 thioalkyl, C1-C3 alkyl(C1-C3 alkoxy), C1-C3 alkylamino, (C1-C3)(C1-C3) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —(C═O)(C1-C3 alkyl), —(S═O)(C1-C3 alkyl), —SO₂(C1-C3 alkyl), —CO₂R¹¹, —(C═O)NR^12aR^12b, —SO₂NR^12aR^12b, —O(C═O)NR^12aR^12b, —NHSO₂NR^12aR^12b, and —NH(C═O)NR^12aR^12b. In a further aspect, R⁵, when present, is independently selected from —F, —Cl, —NO₂, —CN, —OH, —SH, —NH₂, methyl, ethyl, ethenyl, propenyl, ethynyl, propynyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂Cl, —CH₂CN, —CH₂CH₂CN, —CH₂OH, —CH₂CH₂OH, —OCH₂F, —OCHF₂, —OCF₃, —OCH₃, —OCH₂CH₃, —SCH₃, —SCH₂CH₃, —CH₂OCH₃, —CH₂CH₂OCH₂CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —NH(CH₂CH₃)₂, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, —(C═O)CH₃, —(C═O)CH₂CH₃, —(S═O)CH₃, —(S═O)CH₂CH₃, —SO₂CH₃, —SO₂CH₂CH₃, —CO₂CH₃, —CO₂CH₂CH₃, —(C═O)NH₂, —(C═O)NHCH₃, —(C═O)N(CH₃)₂, —SO₂NH₂, —SO₂NHCH₃, —SO₂N(CH₃)₂, —O(C═O)NH₂, —O(C═O)NHCH₃, —O(C═O)N(CH₃)₂, —NHSO₂NH₂, —NHSO₂NHCH₃, —NHSO₂N(CH₃)₂, —NH(C═O)NH₂, —NH(C═O)NHCH₃, and —NH(C═O)N(CH₃)₂. In a still further aspect, R⁵, when present, is independently selected from —F, —Cl, —NO₂, —CN, —OH, —SH, —NH₂, methyl, ethenyl, ethynyl, —CH₂F, —CHF₂, —CF₃, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CN, —CH₂OH, —OCH₂F, —OCHF₂, —OCF₃, —OCH₃, —SCH₃, —CH₂OCH₃, —NHCH₃, —N(CH₃)₂, cyclopropyl, cyclobutyl, phenyl, —(C═O)CH₃, —(S═O)CH₃, —SO₂CH₃, —CO₂CH₃, —(C═O)NH₂, —(C═O)NHCH₃, —(C═O)N(CH₃)₂, —SO₂NH₂, —SO₂NHCH₃, —SO₂N(CH₃)₂, —O(C═O)NH₂, —O(C═O)NHCH₃, —O(C═O)N(CH₃)₂, —NHSO₂NH₂, —NHSO₂NHCH₃, —NHSO₂N(CH₃)₂, —NH(C═O)NH₂, —NH(C═O)NHCH₃, and —NH(C═O)N(CH₃)₂.

In a further aspect, R⁵, when present, is independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 thioalkyl, C1-C3 alkyl(C1-C3 alkoxy), C1-C3 alkylamino, and (C1-C3)(C1-C3) dialkylamino. In a further aspect, R⁵, when present, is independently selected from —F, —Cl, —NO₂, —CN, —OH, —SH, —NH₂, methyl, ethyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂Cl, —OCH₃, —OCH₂CH₃, —SCH₃, —SCH₂CH₃, —CH₂OCH₃, —CH₂CH₂OCH₂CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, and —NH(CH₂CH₃)₂. In a still further aspect, R⁵, when present, is independently selected from —F, —Cl, —NO₂, —CN, —OH, —SH, —NH₂, methyl, —CH₂F, —CHF₂, —CF₃, —CH₂Cl, —CHCl₂, —CCl₃, —OCH₃, —SCH₃, —CH₂OCH₃, —NHCH₃, and —N(CH₃)₂.

In a further aspect, R⁵, when present, is independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy. In a further aspect, R⁵, when present, is independently selected from —F, —Cl, —NO₂, —CN, —OH, —SH, —NH₂, methyl, ethyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂C1, —CHCl₂, —CCl₃, —CH₂CH₂C1, —OCH₃, and —OCH₂CH₃. In a still further aspect, R⁵, when present, is independently selected from —F, —Cl, —NO₂, —CN, —OH, —SH, —NH₂, methyl, —CH₂F, —CHF₂, —CF₃, —CH₂Cl, —CHCl₂, —CCl₃, and —OCH₃.

In a further aspect, R⁵, when present, is independently selected from C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy. In a further aspect, R⁵, when present, is independently selected from methyl, ethyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂Cl, —OCH₃, and —OCH₂CH₃. In a still further aspect, R⁵, when present, is independently selected from methyl, —CH₂F, —CHF₂, —CF₃, —CH₂Cl, —CHCl₂, —CCl₃, and —OCH₃.

In a further aspect, R⁵, when present, is independently selected from C1-C3 alkyl and C1-C3 alkoxy. In a further aspect, R⁵, when present, is independently selected from methyl, ethyl, —OCH₃, and —OCH₂CH₃. In a still further aspect, R⁵, when present, is independently selected from methyl and —OCH₃.

In a further aspect, R⁵, when present, is C1-C3 haloalkyl. In a further aspect, R⁵, when present, is independently selected from —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂C1, —CHCl₂, —CCl₃, and —CH₂CH₂Cl. In a still further aspect, R⁵, when present, is independently selected from —CH₂F, —CHF₂, —CF₃, —CH₂C1, —CHCl₂, and —CCl₃. In yet a further aspect, R⁵, when present, is independently selected from —CHF₂, —CF₃, —CHCl₂, and —CCl₃. In an even further aspect, R⁵, when present, is independently selected from —CF₃and —CCl₃. In a still further aspect, R⁵, when present, is —CF₃. In yet a further aspect, R⁵, when present, is —CCl₃.

In a further aspect, R⁵, when present, is independently selected from —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, and —OCH(CH₃)₂. In a still further aspect, R⁵, when present, is independently selected from —OCH₃and —OCH₂CH₃. In yet a further aspect, R⁵, when present, is —OCH₂CH₂CH₃. In an even further aspect, R⁵, when present, is —OCH(CH₃)₂. In a still further aspect, R⁵, when present, is —OCH₂CH₃. In yet a further aspect, R⁵, when present, is —OCH₃.

In a further aspect, R⁵, when present, is independently selected from methyl, ethyl, n-propyl, and i-propyl. In a still further aspect, R⁵, when present, is independently selected from methyl and ethyl. In yet a further aspect, R⁵, when present, is n-propyl. In an even further aspect, R⁵, when present, is i-propyl. In a still further aspect, R⁵, when present, is ethyl. In yet a further aspect, R⁵, when present, is methyl.

n. R⁶Groups

In one aspect, each R⁶is independently selected from the group consisting of H, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3alkoxycarbonyl, C3-C7 cycloalkyl, and phenyl.

In one aspect, each occurrence of R⁶, when present, is independently selected from halogen, —NO₂, —CO₂(C1-C3 alkyl), C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 alkoxycarbonyl, C3-C7 cycloalkyl, and phenyl. In a further aspect, each occurrence of R⁶, when present, is independently selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 alkoxycarbonyl, C3-C7 cycloalkyl, and phenyl.

In a further aspect, each occurrence of R⁶, when present, is independently selected from —F, —Cl, —NO₂, —CO₂CH₃, —CO₂CH₂, CH₃, methyl, ethyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂Cl, —OCH₃, —OCH₂CH₃, —O(C═O)CH₃, —O(C═O)CH₂CH₃, cyclopropyl, cyclobutyl, and phenyl. In a still further aspect, each occurrence of R⁶, when present, is independently selected from —F, —Cl, —NO₂, —CO₂CH₃, methyl, —CH₂F, —CHF₂, —CF₃, —CH₂Cl, —CHCl₂, —CCl₃, —OCH₃, —O(C═O)CH₃, cyclopropyl, and phenyl.

In a further aspect, each occurrence of R⁶, when present, is independently selected from methyl, ethyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂C1, —OCH₃, —OCH₂CH₃, —O(C═O)CH₃, —O(C═O)CH₂CH₃, and phenyl. In a still further aspect, each occurrence of R⁶, when present, is independently selected from methyl, —CH₂F, —CHF₂, —CF₃, —CH₂Cl, —CHCl₂, —CCl₃, —OCH₃, —O(C═O)CH₃, and phenyl.

o. R¹¹Groups

In one aspect, each occurrence of R¹¹, when present, is independently selected from hydrogen and C1-C4 alkyl. In a further aspect, each occurrence of R¹¹, when present, is independently selected from hydrogen, methyl, ethyl, n-propyl, and i-propyl. In a still further aspect, each occurrence of R¹¹, when present, is independently selected from hydrogen, methyl, and ethyl. In yet a further aspect, each occurrence of R¹¹, when present, is independently selected from hydrogen and ethyl. In an even further aspect, each occurrence of R¹¹, when present, is independently selected from hydrogen and methyl. In a still further aspect, each occurrence of R¹¹, when present, is ethyl. In yet a further aspect, each occurrence of R¹¹, when present, is methyl. In an even further aspect, each occurrence of R¹¹, when present, is hydrogen.

p. R^12Aand R^12BGroups

In one aspect, each occurrence of R^12aand R^12b, when present, is independently selected from hydrogen and C1-C3 alkyl. In a further aspect, each occurrence of R^12aand R^12b, when present, is independently selected from hydrogen, methyl, and ethyl. In a still further aspect, each occurrence of R^12aand R^12b, when present, is independently selected from hydrogen and ethyl. In yet a further aspect, each occurrence of R^12aand R^12b, when present, is independently selected from hydrogen and methyl. In an even further aspect, each occurrence of R^12aand R^12b, when present, is ethyl. In a still further aspect, each occurrence of R^12aand R^12b, when present, is methyl. In yet a further aspect, each occurrence of R^12aand R^12b, when present, is hydrogen.

q. R²⁰Groups

In one aspect, R²⁰is selected from C1-C8 alkyl and C6-C10 aryl and substituted with 0, 1, 2, or 3 independently selected R⁵groups. In a further aspect, R²⁰is selected from C1-C4 alkyl and C6-C8 aryl and substituted with 0, 1, 2, or 3 independently selected R⁵groups.

In a further aspect, R²⁰is selected from C1-C8 alkyl and C6-C10 aryl and substituted with 0, 1, or 2 independently selected R⁵groups. In a still further aspect, R²⁰is selected from C1-C8 alkyl and C6-C10 aryl and substituted with 0 or 1 R⁵groups. In yet a further aspect, R²⁰is selected from C1-C8 alkyl and C6-C10 aryl and monosubstituted with a R⁵group. In an even further aspect, R²⁰is selected from C1-C8 alkyl and C6-C10 aryl and unsubstituted.

In a further aspect, R²⁰is C6-C10 aryl substituted with 0, 1, 2, or 3 independently selected R⁵groups. In a still further aspect, R²⁰is C6-C8 aryl substituted with 0, 1, 2, or 3 independently selected R⁵groups. In yet a further aspect, R²⁰is phenyl substituted with 0, 1, 2, or 3 independently selected R⁵groups.

In a further aspect, R²⁰is C1-C4 alkyl substituted with 0, 1, 2, or 3 independently selected R⁵groups. In a still further aspect, R²⁰is selected from methyl, ethyl, n-propyl, and i-propyl and substituted with 0, 1, 2, or 3 independently selected R⁵groups. In yet a further aspect, R²⁰is selected from methyl and ethyl and substituted with 0, 1, 2, or 3 independently selected R⁵groups. In an even further aspect, R²⁰is ethyl substituted with 0, 1, 2, or 3 independently selected R⁵groups. In a still further aspect, R²⁰is methyl substituted with 0, 1, 2, or 3 independently selected R⁵groups.

In a further aspect, R²⁰is C1-C8 alkyl substituted with 0, 1, or 2 independently selected R⁵groups. In a still further aspect, R²⁰is C1-C8 alkyl substituted with 0 or 1 R⁵group. In yet a further aspect, R²⁰is C1-C8 alkyl monosubstituted with a R⁵group. In an even further aspect, R²⁰is unsubstituted C1-C8 alkyl.

r. R^21Aand R^21BGroups

In one aspect, each of R^21aand R^21bis independently C1-C8 alkyl substituted with 0, 1, 2, or 3 independently selected R⁵groups. In a further aspect, each of R^21aand R^21bis independently C1-C4 alkyl substituted with 0, 1, 2, or 3 independently selected R⁵groups. In a still further aspect, each of R^21aand R^21bis independently selected from methyl, ethyl, n-propyl, and i-propyl and substituted with 0, 1, 2, or 3 independently selected R⁵groups. In yet a further aspect, each of R^21aand R^21bis independently selected from methyl and ethyl and substituted with 0, 1, 2, or 3 independently selected R⁵groups. In an even further aspect, each of R^21aand R^21bis ethyl substituted with 0, 1, 2, or 3 independently selected R⁵groups. In a still further aspect, each of R^21aand R^21bis methyl substituted with 0, 1, 2, or 3 independently selected R⁵groups.

In a further aspect, each of R^21aand R^21bis independently C1-C8 alkyl substituted with 0, 1, or 2 independently selected R⁵groups. In a still further aspect, each of R^21aand R^21bis independently C1-C8 alkyl substituted with 0 or 1 R⁵group. In yet a further aspect, each of R^21aand R^21bis independently C1-C8 alkyl monosubstituted with a R⁵group. In an even further aspect, each of R^21aand R^21bis independently C1-C8 alkyl and unsubstituted.

s. R^22Aand R^22BGroups

In one aspect, each of R^22aand R^22bis independently selected from C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl and wherein each of R^22aand R^22bis independently substituted with 0, 1, 2, or 3 independently selected R⁵groups. In a further aspect, each of R^22aand R^22bis independently selected from C1-C4 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl, C6-C8 aryl, and 4-8 membered heteroaryl and wherein each of R^22aand R^22bis independently substituted with 0, 1, 2, or 3 independently selected R⁵groups. In a still further aspect, each of R^22aand R^22bis independently selected from methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and pyridinyl and wherein each of R^22aand R^22bis independently substituted with 0, 1, 2, or 3 independently selected R⁵groups.

In a further aspect, each of R^22aand R^22bis independently selected from C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl and wherein each of R^22aand R^22bis independently substituted with 0, 1, or 2 independently selected R⁵groups. In a still further aspect, each of R^22aand R^22bis independently selected from C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl and wherein each of R^22aand R^22bis independently substituted with 0 or 1 R⁵group. In yet a further aspect, each of R^22aand R^22bis independently selected from C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl and wherein each of R^22aand R^22bis independently monosubstituted with a R⁵group. In an even further aspect, each of R^22aand R^22bis independently selected from C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl and unsubstituted.

t. R²³Groups

In one aspect, R²³, when present, is C1-C8 alkyl. In a further aspect, R²³, when present, is C1-C4 alkyl. In a still further aspect, R²³, when present, is selected from methyl, ethyl, n-propyl, and i-propyl. In yet a further aspect, R²³, when present, is selected from methyl and ethyl. In an even further aspect, R²³, when present, is ethyl. In a still further aspect, R²³, when present, is methyl.

u. R^24Aand R^24BGroups

In one aspect, each of R^24aand R^24bis independently selected from C1-C4 alkyl. In a further aspect, each of R^24aand R^24bis independently selected from methyl, ethyl, n-propyl, and i-propyl. In a still further aspect, each of R^24aand R^24bis independently selected from methyl and ethyl. In yet a further aspect, each of R^24aand R^24bis ethyl. In an even further aspect, each of R^24aand R^24bis methyl.

v. R²⁵Groups

In one aspect, R²⁵is selected from C1-C4 alkyl and C1-C4 alkoxy. In a further aspect, R²⁵is selected from methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, n-propoxy, and i-propoxy. In a still further aspect, R²⁵is selected from methyl, ethyl, methoxy, and ethoxy. In yet a further aspect, R²⁵is selected from methyl and methoxy.

In a further aspect, R²⁵is C1-C4 alkyl. In a still further aspect, R²⁵is selected from methyl, ethyl, n-propyl, and i-propyl. In yet a further aspect, R²⁵is selected from methyl and ethyl. In an even further aspect, R²⁵is ethyl. In a still further aspect, R²⁵is methyl.

In a further aspect, R²⁵is C1-C4 alkoxy. In a still further aspect, R²⁵is selected from methoxy, ethoxy, n-propoxy, and i-propoxy. In yet a further aspect, R²⁵is selected from methoxy and ethoxy. In an even further aspect, R²⁵is ethoxy. In a still further aspect, R²⁵is methoxy.

w. R²⁶Groups

In one aspect, R²⁶is selected from hydrogen and C1-C8 alkyl. In a further aspect, R²⁶is selected from hydrogen and C1-C4 alkyl. In a still further aspect, R²⁶is selected from hydrogen, methyl, ethyl, n-propyl, and i-propyl. In yet a further aspect, R²⁶is selected from hydrogen, methyl, and ethyl. In an even further aspect, R²⁶is selected from hydrogen and ethyl. In a still further aspect, R²⁶is selected from hydrogen and methyl. In yet a further aspect, R²⁶is ethyl. In an even further aspect, R²⁶is methyl. In a still further aspect, R²⁶is hydrogen.

x. R^AGroups

In one aspect, R^Ais an electron withdrawing group.

In a further aspect, the electron withdrawing group is selected from the group consisting of halo, C_2-6alkenyl, C_2-6alkynyl, C_1-3haloalkyl, CN, NO₂, C(═O)OR^a1, C(═O)R^b1, C(═O)NR^c1R^d1, C(═O)SR^e1, —NR^c1S(O)R^e1, —NR^c1S(O)₂R^e1, S(═O)R^e1, S(═O)₂R^e1, S(═O)NR^c1R^d1, S(═O)₂NR^c1R^d1, and P(O)(OR^a1)₂. In a still further aspect, the electron withdrawing group is selected from the group consisting of C(═O)OR^a1, C(═O)R^b1, C(═O)NR^c1R^d1, C(═O)SR^e1, S(═O)R^e1, S(═O)₂R^e1, S(═O)NR^c1R^d1, and S(═O)₂NR^c1R^d1. In yet a further aspect, the electron withdrawing group is C(═O)OR^a1.

In a further aspect, the electron withdrawing group is selected from halogen, —CN, —NO₂, C2-C6 alkenyl, C2-C6 alkynyl, C1-C3 haloalkyl, —CO₂R^a1, —(C═O)R^b1, (C═O)NR^c1R^d1, —(C═O)SR^e1, —NR^c1(S═O)R^e1, —NR^c1SO₂R^e1, —(S═O)R^e1, —SO₂R^e1, —(S═O)NR^c1R^d1, —SO₂NR^c1R^d1, —(P═O)(R^a1)₂, and —(P═O)(OR^a1)₂. In a still further aspect, the electron withdrawing group is selected from halogen, —CN, —NO₂, C2-C6 alkenyl, C2-C6 alkynyl, C1-C3 haloalkyl, —CO₂R^a1, —(C═O)R^b1, —(C═O)NR^c1R^d1, —(C═O)SR^e1, —NR^c1(S═O)R^e1, —NR^c1SO₂R^e1, —(S═O)R^e1, —SO₂R^e1, —(S═O)NR^c1R^d1, —SO₂NR^c1R^d1, and —(P═O)(OR^a1)₂. In yet a further aspect, the electron withdrawing group is —CO₂R^a1.

In a further aspect, the electron withdrawing group is C(═O)OR^a1, wherein R^a1is C_1-6alkyl or (C_6-10aryl)-C_1-3alkylene.

y. R^BGroups

In one aspect, R^Bis selected from the group consisting of H, C_1-6alkyl, C_2-6alkylene, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁶groups.

In one aspect, R^Bis selected from hydrogen, C1-C6 alkyl, C2-C6 alkylene, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R^Bis substituted with 0, 1, 2, 3, or 4 independently selected R⁶groups.

In a further aspect, R^Bis selected from the group consisting of H, C_1-6alkyl, C_2-6alkylene, C_6-10aryl, and (C_6-10aryl)-C_1-3alkylene-. In a still further aspect, R^Bis selected from the group consisting of H, C_1-6alkyl, C_2-6alkylene, C_6-10aryl, and (C_6-10aryl)-C_1-3alkylene-, wherein the C_1-6alkyl, C_6-10aryl, and (C_6-10aryl)-C_1-3alkylene- are each optionally substituted by 1 or 2 independently selected R⁶groups. In yet a further aspect, R^Bis selected from the group consisting of H, C_1-6alkyl, C_2-6alkylene, C_6-10aryl, and (C_6-10aryl)-C_1-3alkylene-, wherein the C_1-6alkyl, C_6-10aryl, and (C_6-10aryl)-C_1-3alkylene- are each optionally substituted by 1 or 2 independently selected R⁶groups.

In a further aspect, R^Bis selected from hydrogen, C1-C6 alkyl, C2-C6 alkylene, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R^Bis substituted with 0, 1, 2, or 3 independently selected R⁶groups. In a still further aspect, R^Bis selected from hydrogen, C1-C6 alkyl, C2-C6 alkylene, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R^Bis substituted with 0, 1, or 2 independently selected R⁶groups. In yet a further aspect, R^Bis selected from hydrogen, C1-C6 alkyl, C2-C6 alkylene, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R^Bis substituted with 0 or 1 R⁶group. In an even further aspect, R^Bis selected from hydrogen, C1-C6 alkyl, C2-C6 alkylene, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R^Bis monosubstituted with a R⁶group. In a still further aspect, R^Bis selected from hydrogen, C1-C6 alkyl, C2-C6 alkylene, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R^Bis unsubstituted.

In a further aspect, R^Bis selected from hydrogen and C1-C6 alkyl. In a still further aspect, R^Bis selected from hydrogen and C1-C3 alkyl. In yet a further aspect, R^Bis selected from hydrogen, methyl, and ethyl. In an even further aspect, R^Bis selected from hydrogen and ethyl. In a still further aspect, R^Bis selected from hydrogen and methyl. In yet a further aspect, R^Bis hydrogen.

In a further aspect, R^Bis selected from C1-C6 alkyl and C2-C6 alkylene. In a still further aspect, R^Bis selected from C1-C3 alkyl and C2-C4 alkylene. In yet a further aspect, R^Bis selected from methyl, ethyl, ethylene, and propylene. In an even further aspect, R^Bis selected from methyl and ethylene. In a still further aspect, R^Bis methyl. In yet a further aspect, R^Bis ethyl. In an even further aspect, R^Bis ethylene. In a still further aspect, R^Bis propylene.

In a further aspect, R^Bis C6-C10 aryl substituted with 0, 1, 2, 3, or 4 independently selected R⁶groups. In a still further aspect, R^Bis C6-C10 aryl substituted with 0, 1, 2, or 3 independently selected R⁶groups. In yet a further aspect, R^Bis C6-C10 aryl substituted with 0, 1, or 2 independently selected R⁶groups. In an even further aspect, R^Bis C6-C10 aryl substituted with 0 or 1 R⁶group. In a still further aspect, R^Bis C6-C10 aryl monosubstituted with a R⁶group. In yet a further aspect, R^Bis unsubstituted C6-C10 aryl.

In a further aspect, R^Bis phenyl substituted with 0, 1, 2, 3, or 4 independently selected R⁶groups. In a still further aspect, R^Bis phenyl substituted with 0, 1, 2, or 3 independently selected R⁶groups. In yet a further aspect, R^Bis phenyl substituted with 0, 1, or 2 independently selected R⁶groups. In an even further aspect, R^Bis phenyl substituted with 0 or 1 R⁶group. In a still further aspect, R^Bis phenyl monosubstituted with a R⁶group. In yet a further aspect, R^Bis unsubstituted phenyl.

In a further aspect, R^Bis —(C1-C3 alkyl)(C6-C10 aryl) substituted with 0, 1, 2, 3, or 4 independently selected R⁶groups. In a still further aspect, R^Bis —(C1-C3 alkyl)(C6-C10 aryl) substituted with 0, 1, 2, or 3 independently selected R⁶groups. In yet a further aspect, R^Bis —(C1-C3 alkyl)(C6-C10 aryl) substituted with 0, 1, or 2 independently selected R⁶groups. In an even further aspect, R^Bis —(C1-C3 alkyl)(C6-C10 aryl) substituted with 0 or 1 R⁶group. In a still further aspect, R^Bis —(C1-C3 alkyl)(C6-C10 aryl) monosubstituted with a R⁶group. In yet a further aspect, R^Bis unsubstituted —(C1-C3 alkyl)(C6-C10 aryl).

In a further aspect, R^Bis benzyl substituted with 0, 1, 2, 3, or 4 independently selected R⁶groups. In a still further aspect, R^Bis benzyl substituted with 0, 1, 2, or 3 independently selected R⁶groups. In yet a further aspect, R^Bis benzyl substituted with 0, 1, or 2 independently selected R⁶groups. In an even further aspect, R^Bis benzyl substituted with 0 or 1 R⁶group. In a still further aspect, R^Bis benzyl monosubstituted with a R⁶group. In yet a further aspect, R^Bis unsubstituted benzyl.

z. R^CAND R^DGroups

In one aspect, R^Cand R^Dare each independently selected from the group consisting of H, C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁶groups; or R^Cand R^Dtogether with the C atom to which they are attached form a C_3-10cycloalkyl group.

In one aspect, each of R^Cand R^Dis independently selected from hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and wherein each of R^Cand R^Dis independently substituted with 0, 1, 2, 3, or 4 independently selected R⁶groups, or wherein each of R^Cand R^Dare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 3- to 10-membered cycloalkyl.

In a further aspect, each of R^Cand R^Dis independently selected from hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and wherein each of R^Cand R^Dis independently substituted with 0, 1, 2, 3, or 4 independently selected R⁶groups. In a still further aspect, each of R^Cand R^Dis independently selected from hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and wherein each of R^Cand R^Dis independently substituted with 0, 1, 2, or 3 independently selected R⁶groups. In yet a further aspect, each of R^Cand R^Dis independently selected from hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and wherein each of R^Cand R^Dis independently substituted with 0, 1, or 2 independently selected R⁶groups. In an even further aspect, each of R^Cand R^Dis independently selected from hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and wherein each of R^Cand R^Dis substituted with 0 or 1 R⁶group. In a still further aspect, each of R^Cand R^Dis independently selected from hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and wherein each of R^Cand R^Dis monosubstituted with a R⁶group. In yet a further aspect, each of R^Cand R^Dis independently selected from hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and wherein each of R^Cand R^Dis unsubstituted.

In a further aspect, each of R^Cand R^Dis independently selected from hydrogen and C1-C6 alkyl. In a still further aspect, each of R^Cand R^Dis independently selected from hydrogen, methyl, ethyl, n-propyl, and i-propyl. In yet a further aspect, each of R^Cand R^Dis independently selected from hydrogen, methyl, and ethyl. In an even further aspect, each of R^Cand R^Dis independently selected from hydrogen and ethyl. In a still further aspect, each of R^Cand R^Dis independently selected from hydrogen and methyl. In yet a further aspect, each of R^Cand R^Dis hydrogen.

In a further aspect, each of R^Cand R^Dare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 3- to 10-membered cycloalkyl. In a still further aspect, each of R^Cand R^Dare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 3- to 8-membered cycloalkyl. In yet a further aspect, each of R^Cand R^Dare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 3- to 6-membered cycloalkyl. In an even further aspect, each of R^Cand R^Dare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a cyclopropyl. In a still further aspect, each of R^Cand R^Dare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a cyclobutyl. In yet a further aspect, each of R^Cand R^Dare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a cyclopentyl. In an even further aspect, each of R^Cand R^Dare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a cyclohexyl.

In a further aspect, R^Cand R^Dare each independently selected from the group consisting of H, C_1-6alkyl, and C_6-10aryl. In a still further aspect, R^Cand R^Dtogether with the C atom to which they are attached form a C_3-10cycloalkyl group.

aa. R^A1, R^B1, R^C1, R^D1, and R^e1Groups

In one aspect, each R^a1, R^b1, R^c1, R^d1, and R^e1is independently selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁶groups; or R^c1and R^d1together with the N atom to which they are attached form a 4-, 5-, 6-, or 7 membered heterocycloalkyl group, which is optionally substituted with C_1-3alkyl.

In one aspect, wherein each occurrence of R^a1, R^b1, R^e1, R^d1, and R^e1, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each occurrence of R^a1, R^b1, R^e1, R^d1, R^e1, when present, is independently substituted with 0, 1, 2, 3, or 4 independently selected R⁶groups; or wherein each of R^c1and R^d1are optionally covalently bonded together and, together with the intermediate atoms, comprises a 4- to 7-membered heterocycloalkyl optionally substituted with a C1-C3 alkyl. In a further aspect, wherein each occurrence of R^a1, R^b1, R^c1, R^d1, and R^e1, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each occurrence of R^a1, R^b1, R^c1, R^d1, R^e1, when present, is independently substituted with 0, 1, 2, 3, or 4 independently selected R⁶groups; or wherein each of R^c1and R^d1are optionally covalently bonded together and, together with the intermediate atoms, comprises a 4- to 7-membered heterocycloalkyl optionally substituted with a C1-C3 alkyl.

bb. R^XAND R^YGroups

In one aspect, R^Xis selected from the group consisting of H, C_6-10aryl, and 4-10 membered heteroaryl ring; R^Yis selected from the group consisting of H, C_6-10aryl, and 4-10 membered heteroaryl ring; or R^Xand R^Yin combination, together with the carbon atoms to which R^Xand R^Yare attached, form a 5, 6, or 7-membered cycloalkyl ring or a 5, 6, or 7-membered aryl ring.

In one aspect, each of R^Xand R^Yis independently selected from hydrogen, C1-C8 alkyl, C6-C10 aryl, and 4-10 membered heteroaryl, or wherein each of R^Xand R^Yare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 5- to 7-membered cycloalkyl or 5- to 6-membered aryl.

In a further aspect, R^Xis selected from the group consisting of H and C_6-10aryl. In a still further aspect, R^Xis phenyl. In yet a further aspect, R^Xis H.

In a further aspect, R^Yis selected from the group consisting of H and C_6-10aryl. In a still further aspect, R^Yis phenyl. In yet a further aspect, R^Yis H.

In a further aspect, R^Xand R^Yare each H. In a still further aspect, R^Xand R^Yare each phenyl.

In a further aspect, R^Xand R^Yin combination, together with the carbon atoms to which R^Xand R^Yare attached, form a 5, 6, or 7-member cycloalkyl ring or a 5, 6, or 7-member aryl ring. In a still further aspect, R^Xand R^Yin combination, together with the carbon atoms to which R^Xand R^Yare attached, form a 5, 6, or 7-member cycloalkyl ring. In yet a further aspect, R^Xand R^Yin combination, together with the carbon atoms to which R^Xand R^Yare attached, form a cyclohexyl ring. In an even further aspect, R^Xand R^Yin combination, together with the carbon atoms to which R^Xand R^Yare attached, form a 5, 6, or 7-member aryl ring. In a still further aspect, R^Xand R^Yin combination, together with the carbon atoms to which R^Xand R^Yare attached, form a phenyl ring.

In a further aspect, each of R^Xand R^Yis independently selected from hydrogen, C1-C8 alkyl, C6-C10 aryl, and 4-10 membered heteroaryl. In a still further aspect, each of R^Xand R^Yis independently selected from hydrogen, C1-C4 alkyl, C6-C8 aryl, and 4-8 membered heteroaryl. In yet a further aspect, each of R^Xand R^Yis independently selected from hydrogen, phenyl, and cyclohexyl. In an even further aspect, each of R^Xand R^Yis hydrogen. In a still further aspect, each of R^Xand R^Yis phenyl. In yet a further aspect, each of R^Xand R^Yis cyclohexyl.

In a further aspect, each of R^Xand R^Yis independently C1-C8 alkyl. In a still further aspect, each of R^Xand R^Yis independently C1-C4 alkyl. In yet a further aspect, each of R^Xand R^Yis independently selected from methyl, ethyl, n-propyl, and i-propyl. In an even further aspect, each of R^Xand R^Yis independently selected from methyl and ethyl. In a still further aspect, each of R^Xand R^Yis ethyl. In yet a further aspect, each of R^Xand R^Yis methyl.

In a further aspect, each of R^Xand R^Yare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 5- to 7-membered cycloalkyl or 5- to 6-membered aryl. In a still further aspect, each of R^Xand R^Yare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 5- to 7-membered cycloalkyl. In yet a further aspect, each of R^Xand R^Yare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a cyclohexyl ring. In an even further aspect, each of R^Xand R^Yare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 5- to 6-membered aryl. In a still further aspect, each of R^Xand R^Yare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a phenyl.

2. N-Heterocyclic Phosphine Examples

In one aspect, a compound is selected from:

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or a derivative thereof.

In one aspect, a compound can be present as:

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or a derivative thereof.

3. Prophetic Compound Examples

The following compound examples are prophetic, and can be prepared using the synthesis methods described herein above and other general methods as needed as would be known to one skilled in the art. It is anticipated that the prophetic compounds would be useful in the preparation of vinylphosphonates, and such utility can be determined using the synthetic methods described herein below.

In one aspect, a compound can be selected from:

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In one aspect, a compound can be present as:

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In one aspect, a compound can be present as:

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In one aspect, a compound can be present as:

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C. Methods of Making N-Heterocyclic Phosphines

In one aspect, the invention relates to methods of making a compound having a structure represented by a formula:

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wherein n is selected from 0 and 1; wherein p is selected from 0, 1, 2, 3, 4, and 5; wherein each of X^Aand X^Bis independently selected from NR¹, O, and S; wherein each occurrence of R¹, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each occurrence of R¹, when present, is independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein Y is selected from O, S, and NR²⁶; wherein R²⁶, when present, is selected from hydrogen and C1-C8 alkyl; wherein Z is selected from C═O, C═S, S═O, and SO₂; wherein each of R^Xand R^Yis independently selected from hydrogen, C6-C10 aryl, and 4-10 membered heteroaryl, or wherein each of R^Xand R^Yare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 5- to 7-membered cycloalkyl or 5- to 6-membered aryl; wherein R²is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R²is substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein each of R^3aand R^3b, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each of R^3aand R^3bis independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein R⁴is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and —(C1-C3 alkyl)(C6-C10 aryl), and wherein R⁴is substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein each occurrence of R⁵, when present, is independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 haloalkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy, C1-C3 thioalkyl, C1-C3 alkyl(C1-C3 alkoxy), C1-C3 alkylamino, (C1-C3)(C1-C3) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —(C═O)(C1-C3 alkyl), —(S═O)(C1-C3 alkyl), —SO₂(C1-C3 alkyl), —CO₂R¹¹, —(C═O)NR^12aR^12b, —SO₂NR^12aR^12b, —O(C═O)NR^12aR^12b, —NHSO₂NR^12aR^12b, and —NH(C═O)NR^12aR^12b; wherein each occurrence of R¹¹, when present, is independently selected from hydrogen and C1-C4 alkyl; and wherein each occurrence of R^12aand R^12b, when present, is independently selected from hydrogen and C1-C3 alkyl, or a derivative thereof, the method comprising: (a) providing a first compound having a structure represented by a formula:

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wherein X¹is halogen, or a derivative thereof; and (b) reacting with a second compound having a structure represented by a formula:

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or a derivative thereof, in the presence of a base.

In one aspect, the invention relates to methods of making a compound having a structure represented by a formula:

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wherein n is selected from 0 and 1; wherein p is selected from 0, 1, 2, 3, 4, and 5; wherein each of X^Aand X^Bis independently selected from NR¹, O, and S; wherein each occurrence of R¹, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each occurrence of R¹, when present, is independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein Y is selected from CH₂, O, and S; wherein Z is selected from C═O, C═S, S═O, and SO₂; wherein each of R^Xand R^Yis independently selected from hydrogen, C6-C10 aryl, and 4-10 membered heteroaryl, or wherein each of R^Xand R^Yare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 5- to 7-membered cycloalkyl or 5- to 6-membered aryl; wherein R²is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R²is substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein each of R^3aand R^3b, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each of R^3aand R^3bis independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein R⁴is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and —(C1-C3 alkyl)(C6-C10 aryl), and wherein R⁴is substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein each occurrence of R⁵, when present, is independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 haloalkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy, C1-C3 thioalkyl, C1-C3 alkyl(C1-C3 alkoxy), C1-C3 alkylamino, (C1-C3)(C1-C3) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —(C═O)(C1-C3 alkyl), —(S═O)(C1-C3 alkyl), —SO₂(C1-C3 alkyl), —CO₂R¹¹, —SO₂NR^12aR^12b, —O(C═O)NR^12aR^12b, —NHSO₂NR^12aR^12b, and —NH(C═O)NR^12aR^12b; wherein each occurrence of R¹¹, when present, is independently selected from hydrogen and C1-C4 alkyl; and wherein each occurrence of R^12aand R^12b, when present, is independently selected from hydrogen and C1-C3 alkyl, or a derivative thereof, the method comprising: (a) providing a first compound having a structure represented by a formula:

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wherein X¹is halogen, or a derivative thereof; and (b) reacting with a second compound having a structure represented by a formula:

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or a derivative thereof, in the presence of a base.

In a further aspect, the base is an amine base. In a still further aspect, the base is selected from trimethylamine, tripropylamine, triisopropylamine, tri-tert-butylamine, N,N-dimethylethanamine, N-ethyl-N-methylpropan-2-amine, N-ethyl-N-isopropylpropan-2-amine, morpholine, N-methylmorpholine, diisopropylethylamine, DABCO, triphenylamine, quinuclidine, trimethylamine, tripropylamine, triisopropylamine, tri-tert-butylamine, pyrrolidine, pyridine, 2,6-lutidine, 1,8-diazabicyclo[5.4.0]undec-7-ene, tributylamine, and triethylamine. In yet a further aspect, the base is triethylamine.

In a further aspect, providing comprises reacting a compound having a structure represented by a formula:

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with a phosphine in the presence of a base.

In a further aspect, the phosphine is a trihalophosphine. In a still further aspect, the phosphine is selected from tribromophosphine and trichlorophosphine. In yet a further aspect, the phosphine is trichlorophosphine.

In a further aspect, the base is an amine base. In a still further aspect, the base is selected from diisopropylethylamine, DABCO, triphenylamine, quinuclidine, pyrrolidine, pyridine, 2,6-lutidine, 1,8-diazabicyclo[5.4.0]undec-7-ene, Hunig's base, tributylamine, and triethylamine. In yet a further aspect, the base is triethylamine.

The compounds provided herein, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes.

The reactions for preparing the compounds provided herein can be carried out in suitable solvents that can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.

Preparation of the compounds provided herein can involve the protection and deprotection of various chemical groups. The chemistry of protecting groups can be found, for example, in Protecting Group Chemistry, 1^stEd., Oxford University Press, 2000; March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5^thEd., Wiley-Interscience Publication, 2001; and Peturssion, S. et al., “Protecting Groups in Carbohydrate Chemistry,” J. Chem. Educ., 74(11), 1297 (1997).

Reactions can be monitored using an appropriate method. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or ¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC). Compounds can be purified using appropriate methods such as high performance liquid chromatography (HPLC) (“Preparative LC-MS Purification: Improved Compound Specific Method Optimization” K. F. Blom, et al., J. Combi. Chem. 6(6), 874 (2004)) and normal phase silica chromatography.

Thus, in various aspects, a process of preparing a compound of Formula (I) is provided, comprising reacting a compound or salt of Formula (IV):

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with a compound or a salt of Formula (V):

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in the presence of a base, wherein: variables R¹, X, R^X, and R^Yof Formula (IV) and variables R², R³, Z, R⁴, n, and p are defined according to the definitions described herein for compounds of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), and/or (Ih)); X¹is halo; and Y¹is OH, SH, or —CH₃.

In various aspects, the salt of the compound of Formula (IV) is a pharmaceutically acceptable salt. In various aspects, the salt of the compound of Formula (V) is a pharmaceutically acceptable salt.

In various aspects, each X is N. In various aspects, each X is O. In various aspects, each X is S.

In various aspects, X¹is chloro.

In various aspects, Y¹is OH. In various aspects, Y¹is SH.

In various aspects, the base is a strong base, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, or an amine base. In various aspects, the base is an amine base, for example, diisopropylethylamine, DABCO, triphenylamine, quinuclidine, trimethylamine, triethylamine, tripropylamine, triisopropylamine, tributylamine, tri-tert-butylamine, N,N-dimethylethanamine, N-ethyl-N-methylpropan-2-amine, N-ethyl-N-isopropylpropan-2-amine, morpholine, or N-methylmorpholine. In various aspects, the base is a tertiary amine base, for example, trimethylamine, triethylamine, tripropylamine, triisopropylamine, tributylamine, or tri-tert-butylamine. In various aspects, the base is triethylamine.

In various aspects, the reaction is run at a temperature at from about −10° C. to about 10° C., for example, from about −10° C. to about −5° C., from about −10° C. to about 0° C., from about −10° C. to about 5° C., from about −10° C. to about 10° C., from about −5° C. to about 0° C., from about −5° C. to about 5° C., from about −5° C. to about 10° C., from about 0° C. to about 5° C., from about 0° C. to about 10° C., or from about 5° C. to about 10° C. In various aspects, the reacting is run at a temperature at about 0° C.

In various aspects, about 1 to about 1.5 equivalents of the compound or salt of Formula (IV) is used based on 1 equivalent of the compound or salt of Formula (V), for example, about 1 equivalent, about 1.1 equivalents, about 1.15 equivalents, about 1.2 equivalents, about 1.25 equivalents, about 1.3 equivalents, about 1.35 equivalents, about 1.4 equivalents, about 1.45 equivalents, or about 1.5 equivalents. In various aspects, about 1 equivalent of the compound or salt of Formula (IV) is used based on 1 equivalent of the compound or salt of Formula (V).

In various aspects, about 1 to about 1.5 equivalents of base is used based on 1 equivalent of the compound or salt of Formula (V), for example, about 1 equivalent, about 1.1 equivalents, about 1.15 equivalents, about 1.2 equivalents, about 1.25 equivalents, about 1.3 equivalents, about 1.35 equivalents, about 1.4 equivalents, about 1.45 equivalents, or about 1.5 equivalents. In various aspects, about 1.25 equivalents of base is used based on 1 equivalent of the compound or salt of Formula (V).

In various aspects, the process comprises a solvent component. In various aspects, the solvent component comprises dichloromethane. In various aspects, the solvent component comprises toluene.

In various aspects, a process of preparing a compound or salt of Formula (IV) is provided, comprising reacting a compound or salt of Formula (VI):

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with a phosphine in the presence of a base, wherein: variables R¹, R^X, and R^Yof Formula (VI) are defined according to the definitions described herein for compounds of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), and/or (Ih)); and each X²is independently selected from the group consisting of —NH—, —O—, and —S—.

In various aspects, the salt of the compound of Formula (IV) is a pharmaceutically acceptable salt. In various aspects, the salt of the compound of Formula (VI) is a pharmaceutically acceptable salt.

In various aspects, each X²is —NH—.

In various aspects, the phosphine is a trihalophosphine, for example, triiodophosphine, tribromophosphine, or trichlorophosphine. In various aspects, the phosphine is trichlorophosphine.

In various aspects, about 0.5 to about 2 equivalents of phosphine is used based on 1 equivalent of the compound or salt of Formula (VI), for example, about 0.5 equivalents, about 0.6 equivalents, about 0.7 equivalents, about 0.8 equivalents, about 0.9 equivalents, about 1 equivalent, about 1.1 equivalents, about 1.2 equivalents, about 1.3 equivalents, about 1.4 equivalents, about 1.5 equivalents, about 1.6 equivalents, about 1.7 equivalents, about 1.8 equivalents, about 1.9 equivalents, about 2.0 equivalents, about 2.1 equivalents, about 2.2 equivalents, about 2.3 equivalents, about 2.4 equivalents, or about 2.5 equivalents. In various aspects, about 1 equivalent of phosphine is used based on 1 equivalent of the compound or salt of Formula (VI).

In various aspects, about 1.5 to about 2.5 equivalents of base is used based on 1 equivalent of the compound or salt of Formula (VI), for example, about 1 equivalent, about 1.1 equivalents, about 1.2 equivalents, about 1.3 equivalents, about 1.4 equivalents, about 1.5 equivalents, about 1.6 equivalents, about 1.7 equivalents, about 1.8 equivalents, about 1.9 equivalents, about 2.0 equivalents, about 2.1 equivalents, about 2.2 equivalents, about 2.3 equivalents, about 2.4 equivalents, or about 2.5 equivalents. In various aspects, about 2.0 equivalents of base is used based on 1 equivalent of the compound or salt of Formula (VI).

In various aspects, the reacting is run at a temperature from about −100° C. to about 10° C., for example, from about −100° C. to about −90° C., from about −100° C. to about −80° C., from about −100° C. to about −70° C., from about −100° C. to about −60° C., from about −100° C. to about −50° C., from about −100° C. to about −40° C., from about −100° C. to about −30° C., from about −100° C. to about −20° C., from about −100° C. to about −10° C., from about −100° C. to about 0° C., from about −100° C. to about 5° C., from about −100° C. to about 10° C., from about −80° C. to about −70° C., from about −80° C. to about −60° C., from about −80° C. to about −50° C., from about −80° C. to about −40° C., from about −80° C. to about −30° C., from about −80° C. to about −20° C., from about −80° C. to about −10° C., from about −80° C. to about 0° C., from about −80° C. to about 5° C., from about −80° C. to about 10° C., from about −50° C. to about −40° C., from about −50° C. to about −30° C., from about −50° C. to about −20° C., from about −50° C. to about −10° C., from about −50° C. to about 0° C., from about −50° C. to about 5° C., from about −50° C. to about 10° C., from about −20° C. to about −10° C., from about −20° C. to about 0° C., from about −20° C. to about 5° C., from about −20° C. to about 10° C., or from about 0° C. to about 10° C. In various aspects, the reacting is run at a temperature from about −78° C. to about 0° C. In various aspects, the reacting is run at a temperature that is about −78° C. In various aspects, the reacting is run at a temperature that is about 0° C.

In various aspects, the process further comprises heating the reaction to room temperature.

In various aspects, the process further comprises a solvent component. In various aspects, the solvent component comprises dichloromethane.

It will be appreciated by one skilled in the art that the processes described are not the exclusive means by which compounds of the invention may be synthesized and that a broad repertoire of synthetic organic reactions is available to be potentially employed in synthesizing compounds of the invention. The person skilled in the art knows how to select and implement appropriate synthetic routes. Suitable synthetic methods of starting materials, intermediates and products may be identified by reference to the literature, including reference sources such as: Advances in Heterocyclic Chemistry, Vols. 1-107 (Elsevier, 1963-2012); Journal of Heterocyclic Chemistry Vols. 1-49 (Journal of Heterocyclic Chemistry, 1964-2012); Carreira, et al. (Ed.) Science of Synthesis, Vols. 1-48 (2001-2010) and Knowledge Updates KU2010/1-4; 2011/1-4; 2012/1-2 (Thieme, 2001-2012); Katritzky, et al. (Ed.) Comprehensive Organic Functional Group Transformations, (Pergamon Press, 1996); Katritzky et al. (Ed.); Comprehensive Organic Functional Group Transformations II (Elsevier, 2^ndEdition, 2004); Katritzky et al. (Ed.), Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984); Katritzky et al., Comprehensive Heterocyclic Chemistry II, (Pergamon Press, 1996); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6^thEd. (Wiley, 2007); Trost et al. (Ed.), Comprehensive Organic Synthesis (Pergamon Press, 1991).

1. Route I

In one aspect, substituted N-heterocyclic phosphine halide intermediates can be prepared as shown below.

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Compounds are represented in generic form, with substituents as noted in compound descriptions elsewhere herein and wherein X¹is halogen. A more specific example is set forth below.

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In one aspect, the synthesis of N-heterocyclic phosphine halide intermediates can begin with an ethylene derivative. Ethylene derivatives are commercially available or readily prepared by one skilled in the art. Thus, compounds of type 1.6, and similar compounds, can be prepared according to reaction Scheme 1B above. Compounds of type 1.6 can be prepared by a cyclization reaction of an appropriate ethylene derivative, e.g., 1.4 as shown above. The cyclization reaction is carried out in the presence of an appropriate phosphorous trihalide, e.g., 1.5 as shown above, and an appropriate base, e.g., triethylamine, in an appropriate solvent, e.g., dichloromethane. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 1.1 and 1.2), can be substituted in the reaction to provide substituted N-heterocyclic phosphine halide intermediates similar to Formula 1.3.

2. Route II

In one aspect, substituted N-heterocyclic phosphine analogs can be prepared as shown below.

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Compounds are represented in generic form, with substituents as noted in compound descriptions elsewhere herein, wherein X¹is halogen, and wherein Y is selected from O, S, and NR²⁶. A more specific example is set forth below.

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In one aspect, the synthesis of N-heterocyclic phosphine analogs can begin with an N-heterocyclic phosphine halide. N-heterocyclic phosphine halides are commercially available or readily prepared by one skilled in the art. Thus, compounds of type 2.5, and similar compounds, can be prepared according to reaction Scheme 2B above. Compounds of type 2.5 can be prepared by a substitution reaction of an appropriate N-heterocyclic phosphine halide, e.g., 2.3 as shown above. The substitution reaction is carried out in the presence of an appropriate urea, thiourea, sulfonyl, or sulfonyl derivative, e.g., 2.4 as shown above, and an appropriate base, e.g., triethylamine, in an appropriate solvent, e.g., dichloromethane. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 1.3 and 2.1), can be substituted in the reaction to provide substituted N-heterocyclic phosphine analogs similar to Formula 2.3.

D. Vinylphosphonates

In one aspect, the invention relates to vinylphosphonates useful as intermediates in, for example, the synthesis of Doxapram, a known respiratory stimulant. The use of the disclosed vinylphosphonates as intermediates in the synthesis of other pharmaceutically active compounds is also envisioned.

1. Structure

In one aspect, compounds having a structure represented by a formula:

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wherein Q is selected from O, S, and NR²⁶; wherein R²⁶, when present, is selected from hydrogen and C1-C8 alkyl; wherein each of X^Aand X^Bis independently selected from NR¹, O, and S; wherein each occurrence of R¹, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each occurrence of R¹, when present, is independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein each of R^Xand R^Yis independently selected from hydrogen, C6-C10 aryl, and 4-10 membered heteroaryl, or wherein each of R^Xand R^Yare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 5- to 7-membered cycloalkyl or 5- to 7-membered aryl; wherein R^Ais an electron withdrawing group; wherein R^Bis selected from hydrogen, C1-C6 alkyl, C2-C6 alkylene, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R^Bis substituted with 0, 1, 2, 3, or 4 independently selected R⁶groups; and wherein each of R^Cand R^Dis independently selected from hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and wherein each of R^Cand R^Dis independently substituted with 0, 1, 2, 3, or 4 independently selected R⁶groups, or wherein each of R^Cand R^Dare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 3- to 10-membered cycloalkyl; wherein each occurrence of R⁵, when present, is independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 haloalkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy, C1-C3 thioalkyl, C1-C3 alkyl(C1-C3 alkoxy), C1-C3 alkylamino, (C1-C3)(C1-C3) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —(C═O)(C1-C3 alkyl), —(S═O)(C1-C3 alkyl), —SO₂(C1-C3 alkyl), —CO₂R¹¹, —(C═O)NR^12aR^12b, —SO₂NR^12aR^12b, —O(C═O)NR^12aR^12b, —NHSO₂NR^12aR^12b, and —NH(C═O)NR^12aR^12b; wherein each occurrence of R¹¹, when present, is independently selected from hydrogen and C1-C4 alkyl; wherein each occurrence of R^12aand R^12b, when present, is independently selected from hydrogen and C1-C3 alkyl; and wherein each occurrence of R⁶, when present, is independently selected from halogen, —NO₂, —CO₂(C1-C3 alkyl), C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 alkoxycarbonyl, C3-C7 cycloalkyl, and phenyl, or a derivative thereof.

In one aspect, compounds having a structure represented by a formula:

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wherein each of X^Aand X^Bis independently selected from NR¹, O, and S; wherein each occurrence of R¹, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each occurrence of R¹, when present, is independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein each of R^Xand R^Yis independently selected from hydrogen, C6-C10 aryl, and 4-10 membered heteroaryl, or wherein each of R^Xand R^Yare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 5- to 7-membered cycloalkyl or 5- to 7-membered aryl; wherein R^Ais an electron withdrawing group; wherein R^Bis selected from hydrogen, C1-C6 alkyl, C2-C6 alkylene, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R^Bis substituted with 0, 1, 2, 3, or 4 independently selected R⁶groups; and wherein each of R^Cand R^Dis independently selected from hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and wherein each of R^Cand R^Dis independently substituted with 0, 1, 2, 3, or 4 independently selected R⁶groups, or wherein each of R^Cand R^Dare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 3- to 10-membered cycloalkyl; wherein each occurrence of R⁵, when present, is independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 haloalkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy, C1-C3 thioalkyl, C1-C3 alkyl(C1-C3 alkoxy), C1-C3 alkylamino, (C1-C3)(C1-C3) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —(C═O)(C1-C3 alkyl), —(S═O)(C1-C3 alkyl), —SO₂(C1-C3 alkyl), —CO₂R¹¹, —SO₂NR^12aR^12b, —O(C═O)NR^12aR^12b, —NHSO₂NR^12aR^12b, and —NH(C═O)NR^12aR^12b; wherein each occurrence of R¹¹, when present, is independently selected from hydrogen and C1-C4 alkyl; wherein each occurrence of R^12aand R^12b, when present, is independently selected from hydrogen and C1-C3 alkyl; and wherein each occurrence of R⁶, when present, is independently selected from halogen, —NO₂, —CO₂(C1-C3 alkyl), C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 alkoxycarbonyl, and phenyl, or a derivative thereof are disclosed.

In a further aspect, the compound has a structure represented by a formula:

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In a further aspect, the compound has a structure represented by a formula selected from:

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In a further aspect, the compound has a structure represented by a formula:

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In a further aspect, the compound has a structure represented by a formula:

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In a further aspect, the compound has a structure represented by a formula:

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2. Vinylphosphonate Examples

In one aspect, a compound is selected from:

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3. Prophetic Compound Examples

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In one aspect, a compound can be selected from:

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In one aspect, a compound can be selected from:

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In one aspect, a compound can be selected from:

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E. Methods of Making Vinylphosphonates

In one aspect, the invention relates to methods of making N-heterocyclic phosphines useful in the preparation of vinylphosphonates. The vinylphosphonates of this invention can be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature, exemplified in the experimental sections or clear to one skilled in the art. For clarity, examples having a single substituent are shown where multiple substituents are allowed under the definitions disclosed herein.

Thus, in one aspect, the invention relates to a process of preparing a compound or salt of Formula (II):

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is provided, comprising reacting a compound or salt of Formula (III):

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with a compound or salt of Formula (I):

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wherein the compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), and/or (Ih)) is defined as described herein; variables R¹, X, R^X, and R^Yof Formula (II) are defined according to the definitions described herein for compounds of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), and/or (Ih)); R^Ais an electron withdrawing group; R^Bis selected from the group consisting of H, C_1-6alkyl, C_2-6alkylene, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁶groups; R^Cand R^Dre each independently selected from the group consisting of H, C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁶groups; or R^Cand R^Dtogether with the C atom to which they are attached form a C_3-10cycloalkyl group; each R^a1, R^b1, R^c1, R^d1, and R^e1is independently selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁶groups; or R^c1and R^d1together with the N atom to which they are attached form a 4-, 5-, 6-, or 7 membered heterocycloalkyl group, which is optionally substituted with C_1-3alkyl; and each R⁶is independently selected from the group consisting of H, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3alkoxycarbonyl, and phenyl.

In one aspect, the invention relates to a process of preparing a compound or salt of Formula (IIb):

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comprising reacting a compound or salt of Formula (III):

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with a compound or salt of Formula (Ib):

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wherein: each X is independently selected from the group consisting of N, O, and S; Y is selected from the group consisting of CH₂, O, and S; Z is selected from the group consisting of C═O, C═S, S═O, and SO₂; each R¹is independently selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; R²is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; each R³is independently selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; R⁴is selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁵groups; each R⁵is independently selected from the group consisting of OH, NO₂, CN, halo, C_1-3alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-3haloalkyl, cyano-C_1-3alkyl, HO—C_1-3alkyl, C_1-3alkoxy-C_1-3alkyl, C_3-7cycloalkyl, C_6-10aryl, C_1-3alkoxy, C_1-3haloalkoxy, amino, C_1-3alkylamino, di(C_1-3alkyl)amino, thio, C_1-3alkylthio, C_1-3alkylsulfinyl, C_1-3alkylsulfonyl, carbamyl, C_1-3alkylcarbamyl, di(C_1-3alkyl)carbamyl, carboxy, C_1-3alkylcarbonyl, C_1-4alkoxycarbonyl, C_1-3alkylcarbonylamino, C_1-3alkylsulfonylamino, aminosulfonyl, C_1-3alkylaminosulfonyl, di(C_1-3alkyl)aminosulfonyl, aminosulfonylamino, C_1-3alkylaminosulfonylamino, di(C_1-3alkyl)aminosulfonylamino, aminocarbonylamino, C_1-3alkylaminocarbonylamino, and di(C_1-3alkyl)aminocarbonylamino; R^Ais an electron withdrawing group; R^Bis selected from the group consisting of H, C_1-6alkyl, C_2-6alkylene, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁶groups; R^Cand R^Dare each independently selected from the group consisting of H, C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁶groups; or R^Cand R^Dtogether with the C atom to which they are attached form a C_3-10cycloalkyl group; each R^a1, R^b1, R^c1, R^d1, and R^e1is independently selected from the group consisting of H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, (C_6-10aryl)-C_1-3alkylene-, and 4-10 membered heteroaryl, wherein the C_1-6alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, and 4-10 membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R⁶groups; or R^c1and R^d1together with the N atom to which they are attached form a 4-, 5-, 6-, or 7 membered heterocycloalkyl group, which is optionally substituted with C_1-3alkyl; each R⁶is independently selected from the group consisting of H, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3alkoxycarbonyl, and phenyl; n is 0 or 1; p is 0, 1, 2, 3, 4, or 5.

In one aspect, the invention relates to methods of making a vinylphosphonate having a structure represented by a formula:

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or a derivative thereof, with a compound having a structure represented by a formula:

In one aspect, the invention relates to methods of making a vinylphosphonate having a structure represented by a formula:

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wherein each of X^Aand X^Bis independently selected from NR¹, O, and S; wherein each occurrence of R¹, when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein each occurrence of R¹, when present, is independently substituted with 0, 1, 2, 3, or 4 independently selected R⁵groups; wherein each of R^Xand R^Yis independently selected from hydrogen, C6-C10 aryl, and 4-10 membered heteroaryl, or wherein each of R^Xand R^Yare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 5- to 7-membered cycloalkyl or 5- to 7-membered aryl; wherein R^Ais an electron withdrawing group; wherein R^Bis selected from hydrogen, C1-C6 alkyl, C2-C6 alkylene, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, —(C1-C3 alkyl)(C6-C10 aryl), and 4-10 membered heteroaryl, and wherein R^Bis substituted with 0, 1, 2, 3, or 4 independently selected R⁶groups; and wherein each of R^Cand R^Dis independently selected from hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, and 4-10 membered heteroaryl, and wherein each of R^Cand R^Dis independently substituted with 0, 1, 2, 3, or 4 independently selected R⁶groups, or wherein each of R^Cand R^Dare optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 3- to 10-membered cycloalkyl; wherein each occurrence of R⁵, when present, is independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 haloalkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy, C1-C3 thioalkyl, C1-C3 alkyl(C1-C3 alkoxy), C1-C3 alkylamino, (C1-C3)(C1-C3) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —(C═O)(C1-C3 alkyl), —(S═O)(C1-C3 alkyl), —SO₂(C1-C3 alkyl), —CO₂R¹¹, —SO₂NR^12aR^12b, —O(C═O)NR^12aR^12b, —NHSO₂NR^12aR^12b, and —NH(C═O)NR^12aR^12b; wherein each occurrence of R¹, when present, is independently selected from hydrogen and C1-C4 alkyl; wherein each occurrence of R^12aand R^12b, when present, is independently selected from hydrogen and C1-C3 alkyl; and wherein each occurrence of R⁶, when present, is independently selected from halogen, —NO₂, —CO₂(C1-C3 alkyl), C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 alkoxycarbonyl, and phenyl, or a derivative thereof, the method comprising the step of reacting an allene having a structure represented by a formula:

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or a derivative thereof, with a compound having a structure represented by a formula:

In various aspects, the salt of the compound of Formula (I) is a pharmaceutically acceptable salt. In various aspects, the salt of the compound of Formula (II) is a pharmaceutically acceptable salt. In various aspects, the salt of the compound of Formula (III) is a pharmaceutically acceptable salt.

Non-limiting examples of compounds of Formula (III) include:

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or a salt thereof.

In various aspects, the salt is a pharmaceutically acceptable salt.

Non-limiting examples of compounds of Formula (IIa) or (IIb) include:

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or a salt thereof.

In various aspects, the salt is a pharmaceutically acceptable salt.

In various aspects, the compound of Formula (IIa) or (IIb) is:

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or a salt thereof.

In various aspects, the salt is a pharmaceutically acceptable salt.

In various aspects, the process provided herein can be used to prepare bioactive compounds having a phosphorus-carbon bond. A non-limiting list of bioactive compounds that can be prepared includes, for example, tamiphoshor (see Angew. Chem. Int. Ed. 2008, 47, 5788-5791); phosphorus chromones (see Tetrahedron 2014, 70, 417-426); inhibitors of Farnesyl Protein Transferase (see Bioorg. Med. Chem., 1998, 6, 687-694); anti-inflammatory compounds (e.g., (E)-diethyl (2-(3-hydroxy-3-phenylpropyl)hex-1-en-1-yl)phosphonate; see Eur. J. Pharmacol. 2007, 556, 9-13); and antibiotics (e.g., dehydrophos and fosfomycin; see PNAS, 2010, 107, 17557-17562).

In various aspects, the process can be run at a temperature from about 0° C. to about 40° C., for example, from about 0° C. to about 35° C., from about 0° C. to about 30° C., from about 0° C. to about 25° C., from about 0° C. to about 20° C., from about 0° C. to about 15° C., from about 0° C. to about 10° C., from about 0° C. to about 5° C., from about 10° C. to about 40° C., from about 10° C. to about 35° C., from about 10° C. to about 30° C., from about 10° C. to about 25° C., from about 10° C. to about 20° C., from about 10° C. to about 15° C., from about 20° C. to about 40° C., from about 20° C. to about 35° C., from about 20° C. to about 30° C., from about 20° C. to about 25° C., from about 25° C. to about 40° C., from about 20° C. to about 35° C., from about 20° C. to about 30° C., or from about 20° C. to about 25° C. In various aspects, the process is run at a temperature that is about room temperature.

In various aspects, the process comprises a solvent component. In various aspects, the solvent component comprises dichloromethane.

In various aspects, the process is a regioselective process.

In various aspects, the process is a stereoselective process. In various aspects, the stereoselective process forms a compound of Formula (IIa) or (IIb) having an E:Z ratio of from about 2:1 to about 99:1, for example, about 2:1, about 4:3, about 3:2, about 3:1, about 5:1, about 10:1, about 15:1, about 20:1, about 25:1, about 30:1, about 35:1, about 40:1, about 45:1, about 50:1, about 55:1, about 60:1, about 65:1, about 70:1, about 75:1, about 80:1, about 85:1, about 90:1, about 95:1, about 99:1. In various aspects, the stereoselective process forms a compound of Formula (II) having an E:Z ratio of from about 5:1 to about 20:1. In a further aspect, the process of preparing a compound of Formula (IIa) or Formula (IIb) is a stereoselective process, wherein the compound of Formula (IIa) or Formula (IIb) has an E:Z ratio of from about 2:1 to about 50:1. In a still further aspect, the process of preparing a compound of Formula (IIa) or Formula (IIb) is a stereoselective process, wherein the compound of Formula (IIa) or Formula (IIb) has an E:Z ratio of from about 2:1 to about 30:1. In yet a further aspect, the process of preparing a compound of Formula (IIa) or Formula (IIb) is a stereoselective process, wherein the compound of Formula (IIa) or Formula (IIb) has an E:Z ratio of from about 5:1 to about 20:1.

In a further aspect, the compound is prepared by reacting a first compound having a structure represented by a formula:

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wherein X¹is halogen, or a derivative thereof, with a compound having a structure represented by a formula:

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or a derivative thereof, in the presence of a base. In a still further aspect, the first compound is prepared by reacting a second compound having a structure represented by a formula:

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with a phosphine in the presence of a base.

In a further aspect, the compound of Formula (Ia) or Formula (Ib) is prepared by a process comprising reacting a compound or salt of Formula (IV):

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with a compound or salt of Formula (V):

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in the presence of a base, wherein: X¹is halo; and Y¹is OH, SH, or —CH₃.

In a further aspect, the base is an amine base. In a still further aspect, the base is selected from diisopropylethylamine, DABCO, triphenylamine, quinuclidine, trimethylamine, tripropylamine, triisopropylamine, tri-tert-butylamine, N,N-dimethylethanamine, N-ethyl-N-methylpropan-2-amine, N-ethyl-N-isopropylpropan-2-amine, morpholine, N-methylmorpholine, trimethylamine, tripropylamine, triisopropylamine, tri-tert-butylamine, pyrrolidine, pyridine, 2,6-lutidine, 1,8-diazabicyclo[5.4.0]undec-7-ene, tributylamine, and triethylamine. In yet a further aspect, the base is triethylamine.

In a further aspect, the reaction is run at a temperature at from about −10° C. to about 10° C. In a still further aspect, the reaction is run at a temperature at from about −5° C. to about 10° C. In yet a further aspect, the reaction is run at a temperature at from about 0° C. to about 10° C. In an even further aspect, the reaction is run at a temperature at from about 5° C. to about 10° C. In a still further aspect, the reaction is run at a temperature at from about −10° C. to about 5° C. In yet a further aspect, the reaction is run at a temperature at from about −10° C. to about 0° C. In an even further aspect, the reaction is run at a temperature at from about −10° C. to about −5° C. In a still further aspect, the reaction is run at a temperature at about 0° C.

In a further aspect, the compound or salt of Formula (IV) is prepared by a process comprising reacting a compound or salt of Formula (VI):

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with a phosphine in the presence of a base, wherein: each X²is independently selected from the group consisting of —NH—, —O—, and —S—.

In a further aspect, the process further comprises heating the reaction to room temperature.

1. Route I

In one aspect, allene intermediates can be prepared as shown below.

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Compounds are represented in generic form, with substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below.

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In one aspect, the synthesis of allene intermediates can begin with an allene. Allenes are commercially available or readily prepared by one skilled in the art. Thus, compounds of type 3.6, and similar compounds, can be prepared according to reaction Scheme 3B above. Compounds of type 3.6 can be prepared by a Wittig-like reaction of an appropriate triphenylphosphine derivative, e.g., 3.4 as shown above. The Wittig-like reaction is carried out in the presence of an appropriate acyl halide, e.g., 3.5 as shown above, in an appropriate solvent, e.g., dichloromethane. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 3.1 and 3.2), can be substituted in the reaction to provide substituted allene intermediates similar to Formula 3.3.

2. Route II

In one aspect, allene intermediates can be prepared as shown below.

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Compounds are represented in generic form, with substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below.

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In one aspect, the synthesis of allene intermediates can begin with a triphenylphosphine derivative. Triphenylphosphine derivatives are commercially available or readily prepared by one skilled in the art. Thus, compounds of type 4.10, and similar compounds, can be prepared according to reaction Scheme 4B above. Compounds of type 4.8 can be prepared by an alkylation reaction of an appropriate triphenylphosphine derivative, e.g., 4.6 as shown above. The alkylation reaction is carried out in the presence of an appropriate alkyl halide, e.g., 4.5 as shown above, in the presence of an appropriate base, e.g., triethylamine as shown above. Compounds of type 4.10 can be prepared by a Wittig-like reaction of an appropriate triphenylphosphine derivative, e.g., 4.8 as shown above. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 4.1, 4.2, 4.3, and 4.4), can be substituted in the reaction to provide substituted allene intermediates similar to Formula 4.5.

3. Route III

The compounds of provided herein may be useful in, for example, phosphorus-carbon bond forming reactions (e.g., the synthesis of vinylphosphonates), as shown below. Thus, in one aspect, vinylphosphonate analogs can be prepared as shown below.

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Compounds are represented in generic form, with substituents as noted in compound descriptions elsewhere herein and wherein each of Y and Q is selected from O, S, and NR²⁶. A more specific example is set forth below.

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In one aspect, the synthesis of vinylphosphonate analogs can begin with an allene. Allenes are commercially available or readily prepared by one skilled in the art. Thus, compounds of type 5.3, and similar compounds, can be prepared according to reaction Scheme 5B above. Compounds of type 5.3 can be prepared by oxidation of an appropriate N-heterocyclic phosphine, e.g., 2.5 as shown above. The oxidation is carried out in the presence of an appropriate allene, e.g., 5.2 as shown above, in an appropriate solvent, e.g., dichloromethane. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 2.2 and 4.4), can be substituted in the reaction to provide substituted vinylphosphonate analogs similar to Formula 5.1.

4. Route IV

Once prepared, vinyldiazaphosphonates may be further functionalized using a variety of methods known in the art. Thus, in one aspect, substituted vinylphosphonate analogs can be prepared as shown below.

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Compounds are represented in generic form, with substituents as note in compound descriptions elsewhere herein and wherein R²⁰is selected from C1-C8 alkyl and C6-C10 aryl and substituted with 0, 1, 2, or 3 independently selected R⁵groups and wherein Q is selected from O, S, and NR²⁶. A more specific example is set forth below.

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In one aspect, compounds of type 6.6, and similar compounds, can be prepared according to reaction Scheme 6B above. Compounds of type 6.6 can be prepared by dehydration of an appropriate vinylphosphonate, e.g., 6.4 as shown above. The dehydration is carried out in the presence of an appropriate aldehyde, e.g., 6.5 as shown above, in the presence of an appropriate base, e.g., pyrrolidine. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 6.1 and 6.2), can be substituted in the reaction to provide substituted vinylphosphonate analogs similar to Formula 6.3.

5. Route V