U.S. patent application number 16/144717 was filed with the patent office on 2019-01-31 for methods and compositions for substituted alpha-aminophosphonate analogues.
The applicant listed for this patent is The Board of Regents of the Nevada System of Higher Education on Behalf of the University of. Invention is credited to Jun Yong Kang, Karimulla Mulla.
Application Number | 20190031695 16/144717 |
Document ID | / |
Family ID | 59848238 |
Filed Date | 2019-01-31 |
View All Diagrams
United States Patent
Application |
20190031695 |
Kind Code |
A1 |
Kang; Jun Yong ; et
al. |
January 31, 2019 |
Methods and Compositions for Substituted Alpha-Aminophosphonate
Analogues
Abstract
Provided herein are .alpha.-aminophosphonates and methods for
making same. Also provided are N-heterocyclic phosphines (NHPs)
useful in metal-free phosphorus-carbon bond forming reactions such
as, for example, in the preparation of .alpha.-aminophosphonates.
This abstract is intended as a scanning tool for purposes of
searching in the particular art and is not intended to be limiting
of the present invention.
Inventors: |
Kang; Jun Yong; (Henderson,
NV) ; Mulla; Karimulla; (Las Vegas, NV) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
The Board of Regents of the Nevada System of Higher Education on
Behalf of the University of |
Las Vegas |
NV |
US |
|
|
Family ID: |
59848238 |
Appl. No.: |
16/144717 |
Filed: |
September 27, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15436608 |
Feb 17, 2017 |
10087204 |
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16144717 |
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62309674 |
Mar 17, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07F 9/65848
20130101 |
International
Class: |
C07F 9/6584 20060101
C07F009/6584 |
Claims
1. A compound having a structure represented by a formula:
##STR00176## wherein Q is selected from O, S, C.dbd.O, S.dbd.O,
SO.sub.2, and NR.sup.1; wherein each of X.sup.A and X.sup.B is
independently selected from NR.sup.1, O, and S; wherein each
occurrence of R.sup.1, 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.sup.1, when present, is
independently substituted with 0, 1, 2, 3, or 4 independently
selected R.sup.5 groups; wherein each occurrence of R.sup.5, when
present, is independently selected from halogen, --NO.sub.2, --CN,
--OH, --SH, --NH.sub.2, C1-C4 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, optionally substituted C6-C10 aryl, --(C.dbd.O)(C1-C3
alkyl), --(S.dbd.O)(C1-C3 alkyl), --SO.sub.2(C1-C3 alkyl),
--CO.sub.2R.sup.11, --(C.dbd.O)NR.sup.12aR.sup.12b,
--SO.sub.2NR.sup.12aR.sup.12b, --O(C.dbd.O)NR.sup.12aR.sup.12b,
NHSO.sub.2NR.sup.12aR.sup.12b, and
--NH(C.dbd.O)NR.sup.12aR.sup.12b; wherein each occurrence of
R.sup.11, when present, is independently selected from hydrogen and
C1-C4 alkyl; wherein each occurrence of R.sup.12a and R.sup.12b,
when present, is independently selected from hydrogen and C1-C3
alkyl; wherein each of Rx and R.sup.Y is independently selected
from hydrogen, C1-C8 alkyl, C6-C10 aryloxy, C6-C10 aryl, and 4-10
membered heteroaryl, or wherein each of Rx and R.sup.Y are
optionally covalently bonded together and, together with the
intermediate atoms, comprise a 5- to 7-membered cycloalkyl, a 5- to
7-membered heterocycloalkyl, a 5- to 7-membered aryl, or a 5- to
7-membered heteroaryl and are substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups; wherein R.sup.6 is 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 substituted with 0, 1, 2, 3, or 4 independently selected
R.sup.5 groups; and wherein each of R.sup.10a and R.sup.10b is
independently selected from hydrogen and C1-C4 alkyl, or a salt
thereof.
2. The compound of claim 1, wherein each of X.sup.A and X.sup.B is
NR.sup.1.
3. The compound of claim 1, wherein each of Rx and R.sup.Y is
hydrogen.
4. The compound of claim 1, wherein R.sup.5 is C6-C10 aryl
substituted with 0, 1, 2, or 3 groups independently selected from
halogen, --NO.sub.2, --CN, --OH, --SH, --NH.sub.2, and C1-C4
alkyl.
5. The compound of claim 1, wherein each of R.sup.10a and R.sup.10b
is hydrogen.
6. The compound of claim 1, wherein the compound has a structure
represented by a formula selected from: ##STR00177## or a salt
thereof.
7. The compound of claim 1, wherein the compound has a structure
represented by a formula selected from: ##STR00178## or a salt
thereof.
8. The compound of claim 1, wherein the compound has a structure
represented by a formula: ##STR00179## or a salt thereof.
9. The compound of claim 1, wherein the compound has a structure
represented by a formula: ##STR00180## or a salt thereof.
10. The compound of claim 1, wherein the compound is selected from:
##STR00181## ##STR00182## or a salt thereof.
11. The compound of claim 1, wherein the compound is selected from:
##STR00183## or a salt thereof.
12. A method of making a compound having a structure represented by
a formula: ##STR00184## wherein Q is selected from O, S, C.dbd.O,
S.dbd.O, SO.sub.2, and NR.sup.1; wherein each of X.sup.A and
X.sup.B is independently selected from NR.sup.1, O, and S; wherein
each occurrence of R.sup.1, 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.sup.1, when present, is
independently substituted with 0, 1, 2, 3, or 4 independently
selected R.sup.5 groups; wherein each occurrence of R.sup.5, when
present, is independently selected from halogen, --NO.sub.2, --CN,
--OH, --SH, --NH.sub.2, C1-C4 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, optionally substituted C6-C10 aryl, --(C.dbd.O)(C1-C3
alkyl), --(S.dbd.O)(C1-C3 alkyl), --SO.sub.2(C1-C3 alkyl),
--CO.sub.2R.sup.11, --(C.dbd.O)NR.sup.12aR.sup.12b,
--SO.sub.2NR.sup.12aR.sup.12b, --O(C.dbd.O)NR.sup.12aR.sup.12b,
NHSO.sub.2NR.sup.2aR.sup.12b, and --NH(C.dbd.O)NR.sup.2aR.sup.12b;
wherein each occurrence of R.sup.11, when present, is independently
selected from hydrogen and C1-C4 alkyl; wherein each occurrence of
R.sup.12a and R.sup.12b, when present, is independently selected
from hydrogen and C1-C3 alkyl; wherein each of Rx and R.sup.Y is
independently selected from hydrogen, C1-C8 alkyl, C6-C10 aryloxy,
C6-C10 aryl, and 4-10 membered heteroaryl, or wherein each of Rx
and R.sup.Y are optionally covalently bonded together and, together
with the intermediate atoms, comprise a 5- to 7-membered
cycloalkyl, a 5- to 7-membered heterocycloalkyl, a 5- to 7-membered
aryl, or a 5- to 7-membered heteroaryl and are substituted with 0,
1, 2, 3, or 4 independently selected R.sup.5 groups; wherein
R.sup.6 is 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 substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups; and wherein each of
R.sup.10a and R.sup.10b is independently selected from hydrogen and
C1-C4 alkyl, or a salt thereof, the method comprising the step of
reacting an aldehyde having a structure represented by a formula:
##STR00185## or a salt thereof, with a heterocycloalkane having a
structure represented by a formula: ##STR00186## or a salt thereof,
in the presence of a reagent having a structure represented by a
formula: ##STR00187## wherein m is selected from 0 and 1; wherein p
is selected from 0, 1, 2, 3, 4, and 5; wherein Z is selected from
C.dbd.O, C.dbd.S, S.dbd.O, SO.sub.2, and a structure represented by
a formula: ##STR00188## wherein each of R.sup.2a and R.sup.2b 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 substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups; wherein each of R.sup.3a and
R.sup.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.sup.3a and R.sup.3b is independently substituted with 0, 1, 2,
3, or 4 independently selected R.sup.5 groups; and wherein R.sup.4
is 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 substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups, or a salt thereof.
13. The method of claim 12, wherein the aldehyde, the
heterocycloalkane, and the reagent are simultaneously reacted.
14. The method of claim 12, wherein the aldehyde and the
heterocycloalkane react to form a reaction product and wherein the
reaction product reacts with the reagent.
15. The method of claim 12, wherein the aldehyde and the reagent
react to form a reaction product and wherein the reaction product
reacts with the heterocycloalkane.
16. The method of claim 12, wherein the heterocycloalkane and the
reagent react to form a reaction product and wherein the reaction
product reacts with the aldehyde.
17. A compound having a structure represented by a formula:
##STR00189## wherein m is selected from 0 and 1; wherein p is
selected from 0, 1, 2, 3, 4, and 5; wherein Y is selected from
CH.sub.2, CH(CH.sub.3), O, and S; wherein each of X.sup.A and
X.sup.B is independently selected from NR.sup.1, O, and S; wherein
each occurrence of R.sup.1, 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.sup.1, when present, is
independently substituted with 0, 1, 2, 3, or 4 independently
selected R.sup.5 groups; wherein each occurrence of R.sup.5, when
present, is independently selected from halogen, --NO.sub.2, --CN,
--OH, --SH, --NH.sub.2, 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.dbd.O)(C1-C3 alkyl),
--(S.dbd.O)(C1-C3 alkyl), --SO.sub.2(C1-C3 alkyl),
--CO.sub.2R.sup.11, --(C.dbd.O)NR.sup.12aR.sup.12b,
--SO.sub.2NR.sup.12aR.sup.12b, O(C.dbd.O)NR.sup.12aR.sup.12b,
--NHSO.sub.2NR.sup.12aR.sup.12b, and
--NH(C.dbd.O)NR.sup.12aR.sup.12b; wherein each occurrence of
R.sup.11, when present, is independently selected from hydrogen and
C1-C4 alkyl; wherein each occurrence of R.sup.12a and R.sup.12b,
when present, is independently selected from hydrogen and C1-C3
alkyl; wherein Z is selected from C.dbd.O, C.dbd.S, S.dbd.O,
SO.sub.2, and a structure represented by a formula: ##STR00190##
wherein each of R.sup.2a and R.sup.2b 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 substituted with 0, 1, 2, 3, or 4 independently selected
R.sup.5 groups; wherein each of R.sup.3a and R.sup.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.sup.3a
and R.sup.3b is independently substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups; and wherein R.sup.4 is
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 substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups, provided that Z is a
structure represented by a formula: ##STR00191## or provided that
each of R.sup.2a and R.sup.2b is not hydrogen, or a salt
thereof.
18. The compound of claim 17, wherein Z is a structure represented
by a formula: ##STR00192##
19. The compound of claim 17, wherein the compound has a structure
represented by a formula: ##STR00193## or a salt thereof.
20. The compound of claim 17, wherein the compound is selected
from: ##STR00194## or a salt thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Divisional Application of U.S.
application Ser. No. 15/436,608 filed Feb. 17, 2017, which claims
the benefit of U.S. Provisional Application No. 62/309,674, filed
on Mar. 17, 2016, each of which is incorporated herein fully by
reference in its' entirety.
BACKGROUND
[0002] Aminophosphonates have attracted great attention among
scientists including chemists, biochemists, and biologists due to
their broad spectrum of biomedical applications. They are well
known as pharmaceutically and biologically important compounds. Due
to intensive studies on aminophosphonate derivatives in medicinal
chemistry, various aminophosphonate derivatives including
.alpha.-aminophosphonates, .beta.-aminophosphonates, and
.gamma.-aminophosphonates have been synthesized over the past
several decades (Palacios et al. (2005) Chemical Reviews 105(3):
899-932; Bhagat et al. (2007) The Journal of Organic Chemistry
72(4): 1263-1270; Ordonez et al. (2009) Tetrahedron 65(1): 17-49;
Mucha et al. (2011) Journal of Medicinal Chemistry 54(17):
5955-5980; Naydenova et al. (2007) Amino Acids 33(4): 695-702;
Lavielle et al. (1991) Journal of Medicinal Chemistry 34(7):
1998-2003).
[0003] .alpha.-N-heterocyclic phosphonic acids and their
derivatives such as morpholine (Ghosh et al. (2004) J. Med. Chem.
47: 175-187; Yang et al. (2004) Bioorg. Med. Chem. Lett. 14:
3017-3025), piperazinyl (Yang et al. (2004) Bioorg. Med. Chem.
Lett. 14: 3017-3025; Chaudhary et al. (2006) Bioorg. Med. Chem. 14:
1819-1826; Younes (1994) J. Pharm. Belg. 49: 119-125), or
thiomorpholino-methyl phosphonates (Amar et al. (2008) Mater. Chem.
Phys. 110: 1-6) are an important class of amino phosphonate
compounds. They have received considerable interest from a number
of areas, ranging from medicinal chemistry to materials sciences.
Morpholino-methyl bisphosphonic acid has shown antimalarial
activity (Ghosh et al. (2004) J. Med. Chem. 47: 175-187) and the
morpholino-aryl-methyl phosphonate has been realized as an
effective agonist of endothelial target for acetylcholine (ETA)
(Yang et al. (2004) Bioorg. Med. Chem. Lett. 14: 3017-3025).
Piperazinyl-methyl phosphonate derivatives have proven to be potent
active pharmaceutical ingredients such as agonists of ETA (Yang et
al. (2004) Bioorg. Med. Chem. Lett. 14: 3017-3025), antibacterial
agents (Chaudhary et al. (2006) Bioorg. Med. Chem. 14: 1819-1826),
calcium antagonists (Younes (1994) J. Pharm. Belg. 49: 119-125),
and serotonin receptors (Lewkowski et al. (2015) Heteroat. Chem.
26: 290-298). These significant biological activities of
.alpha.-amino phosphonates are associated with the structural
analogues of the corresponding amino acids and mimics of the
transition state of peptide hydrolysis (Kafarski and Lejczak (1991)
Phosphorus, Sulfur Silicon Relat. Elem. 63: 193-215; Allen et al.
(1978) Nature 272: 56-58). In addition, thiomorpholino-methyl
phosphonic acid is known as an effective corrosion inhibitor for
carbon steel in seawater (Amar et al. (2008) Mater. Chem. Phys.
110: 1-6).
[0004] Since the pioneering early work by Kabachnick and Fields in
1952 (Fields (1952) J. Am. Chem. Soc. 74: 1528-1531; Kabachnik and
Medved (1952) Doklady Akademii Nauk SSSR 83: 689-692), the
multicomponent reaction involving amine, aldehyde, and dialkyl
phosphonate has emerged as a straightforward protocol towards
.alpha.-aminophosphonic acid esters. This transformation proceeds
via an in-situ imine formation, followed by phospha-Mannich
reaction (Pudovik reaction) (Pudovik and Konovalova (1979)
Synthesis 81-96) between phosphite nucleophile and imine
electrophile, constructing an N-C-P motif. This method offers
important advantages such as a simple one-pot process and a rapid
increase of molecular complexity using readily available starting
materials. Recently, with the surging interest in the application
of .alpha.-N-heterocyclic phosphonate derivatives to medicinal and
materials chemistry, a considerable emphasis has been placed on the
reaction system that utilizes cyclic secondary amines.
Phospha-Mannich reaction employing primary amine has been well
exploited (Ordonez et al. (2009) Tetrahedron 65: 17-49; Azizi et
al. (2014) Tet. Lett. 55: 7236-7239; Qian and Huang (1998) J. Org.
Chem. 63: 4125-4128; Kasthuraiah et al. (2007) Heteroat. Chem. 18:
2-8), however, secondary amine involved reactions are scarcely
developed. Dialkyl phosphonates stable towards hydrolysis and
oxidation due to the lack of lone pair electrons have been
extensively used for this phosphonylation to form a C--P bond
(Stawinski and Kraszewski (2002) Acc. Chem. Res. 35: 952-960; Doak
and Freedman (1961) Chem. Rev. 61: 31-44; Ma (2006) Chem. Soc. Rev.
35: 630-636; Kumar et al. (2014) Tetrahedron 70: 7044-7049; Suyama
et al. (2010) Angew. Chem. Int. Ed. 49: 797-799; Sobhani et al.
(2014) RSC Adv. 4: 15797-15806). They, however, are unreactive
phosphorus species. On the other hand, trialkyl phosphites are
highly reactive nucleophiles but they are susceptible to
spontaneous aerobic oxidation to form inactive phosphates
(Stawinski and Kraszewski (2002) Acc. Chem. Res. 35: 952-960; Doak
and Freedman (1961) Chem. Rev. 61: 31-44; Ma (2006) Chem. Soc. Rev.
35: 630-636). Thus, strategies for generating highly nucleophilic
phosphite species in-situ using dialkyl phosphonates for
phospha-Mannich reaction have been developed over the past decades.
The dialkyl phosphonates are activated by Lewis acids (Bhagat and
Chakraborti (2007) J. Org. Chem. 72: 1263-1270) or magnetic
nanoparticles (Reddy et al. (2015) New J. Chem. 39: 9605-9610;
Ma'mani et al. (2009) Curr. Org. Chem. 13: 758-762; Reddy et al.
(2011) Tetrahedron Lett. 52: 1359-1362; Nazish et al. (2014)
ChemPlusChem 79: 1753-1760; Sheykhan et al. (2011) J. Mol. Catal.
A: Chem. 335: 253-261) to generate the nucleophilic dialkyl
phosphites, which rapidly react with imminium intermediates to
ultimately construct the .alpha.-N-heterocyclic phosphonates.
Bronsted acid-catalyzed reaction with dialkyl phosphonates
(Malamiri et al. (2014) J. Chem. Sci. 126: 807; Prauda et al.
(2007) Synth. Commun. 37: 317-322; Zakharov et al. (2004) Russ. J.
Gen. Chem. 74: 873-881) and Lewis acid-mediated transformation
involving trialkyl phosphites (Makarov et al. (2015) Mendeleev
Commun. 25: 232-233; Azizi and Saidi (2003) Tetrahedron 59:
5329-5332; Malhiac et al. (1996) Phosphorus, Sulfur Silicon Relat.
Elem. 113: 299-301) are important alternative routes for the
synthesis of tertiary .alpha.-aminophosphonates.
[0005] Despite the great efforts devoted to the synthesis of
biologically significant .alpha.-N-heterocyclic phosphonates, there
remain limitations such as the use of toxic metals, low product
yields with especially secondary amines, and harsh reaction
conditions (elevated temperatures and basic conditions).
Consequently, the development of a general and direct method of
phosphonylation for accessing various .alpha.-aminophosphonates
under metal-free mild reaction conditions is highly desirable in
synthetic organic chemistry. These needs and others are met by the
present invention.
SUMMARY
[0006] 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.
[0007] Disclosed are compounds having a structure represented by a
formula:
##STR00001##
wherein Q is selected from O, S, C.dbd.O, S.dbd.O, SO.sub.2, and
NR.sup.1; wherein each of X.sup.A and X.sup.B is independently
selected from NR.sup.1, O, and S; wherein each occurrence of
R.sup.1, 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.sup.1, when present, is independently substituted
with 0, 1, 2, 3, or 4 independently selected R.sup.5 groups;
wherein each occurrence of R.sup.5, when present, is independently
selected from halogen, --NO.sub.2, --CN, --OH, --SH, --NH.sub.2,
C1-C4 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, optionally
substituted C6-C10 aryl, --(C.dbd.O)(C1-C3 alkyl),
--(S.dbd.O)(C1-C3 alkyl), --SO.sub.2(C1-C3 alkyl),
--CO.sub.2R.sup.11, --(C.dbd.O)NR.sup.2aR.sup.12b,
--SO.sub.2NR.sup.12aR.sup.12b, --O(C.dbd.O)NR.sup.12aR.sup.12b,
--NHSO.sub.2NR.sup.12aR.sup.12b, and
--NH(C.dbd.O)NR.sup.2aR.sup.12b; wherein each occurrence of
R.sup.11, when present, is independently selected from hydrogen and
C1-C4 alkyl; wherein each occurrence of R.sup.12a and R.sup.12b,
when present, is independently selected from hydrogen and C1-C3
alkyl; wherein each of Rx and R.sup.Y is independently selected
from hydrogen, C1-C8 alkyl, C6-C10 aryloxy, C6-C10 aryl, and 4-10
membered heteroaryl, or wherein each of Rx and R.sup.Y are
optionally covalently bonded together and, together with the
intermediate atoms, comprise a 5- to 7-membered cycloalkyl, a 5- to
7-membered heterocycloalkyl, a 5- to 7-membered aryl, or a 5- to
7-membered heteroaryl and are substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups; wherein R.sup.6 is 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 substituted with 0, 1, 2, 3, or 4 independently selected
R.sup.5 groups; and wherein each of R.sup.10a and R.sup.10b is
independently selected from hydrogen and C1-C4 alkyl, or a salt
thereof.
[0008] Also disclosed are compounds having a structure represented
by a formula:
##STR00002##
wherein m is selected from 0 and 1; wherein p is selected from 0,
1, 2, 3, 4, and 5; wherein Y is selected from CH.sub.2,
CH(CH.sub.3), O, and S; wherein each of X.sup.A and X.sup.B is
independently selected from NR.sup.1, O, and S; wherein each
occurrence of R.sup.1, 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.sup.1, when present, is
independently substituted with 0, 1, 2, 3, or 4 independently
selected R.sup.5 groups; wherein each occurrence of R.sup.5, when
present, is independently selected from halogen, --NO.sub.2, --CN,
--OH, --SH, --NH.sub.2, 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.dbd.O)(C1-C3 alkyl),
--(S.dbd.O)(C1-C3 alkyl), --SO.sub.2(C1-C3 alkyl),
--CO.sub.2R.sup.11, --(C.dbd.O)NR.sup.12aR.sup.12b,
--SO.sub.2NR.sup.12aR.sup.12b, --O(C.dbd.O)NR.sup.12aR.sup.12b,
--NHSO.sub.2NR.sup.12aR.sup.12b, and
--NH(C.dbd.O)NR.sup.12aR.sup.12b; wherein each occurrence of
R.sup.11, when present, is independently selected from hydrogen and
C1-C4 alkyl; wherein each occurrence of R.sup.12a and R.sup.12b,
when present, is independently selected from hydrogen and C1-C3
alkyl; wherein Z is selected from C.dbd.O, C.dbd.S, S.dbd.O,
SO.sub.2, and a structure represented by a formula:
##STR00003##
wherein each of R.sup.2a and R.sup.2b 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 substituted with 0, 1, 2, 3, or 4 independently selected
R.sup.5 groups; wherein each of R.sup.3a and R.sup.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.sup.3a
and R.sup.3b is independently substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups; and wherein R.sup.4 is
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 substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups, provided that Z is a
structure represented by a formula:
##STR00004##
or provided that each of R.sup.2a and R.sup.2b is not hydrogen, or
a salt thereof.
[0009] Also disclosed are methods of making a disclosed
compound.
[0010] Also disclosed are pharmaceutical compositions comprising
the disclosed compounds.
[0011] 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
[0012] 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.
[0013] FIG. 1A-C show a representative image of the tautomeric
equilibria of H-phosphonates without (1A) and with (1B) additive
and a NHP-thiourea reagent (1C).
[0014] FIG. 2 shows a representative schematic of a proposed
reaction sequence.
[0015] 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
[0016] The present invention can be understood more readily by
reference to the following detailed description of the invention
and the Examples included therein.
[0017] 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.
[0018] 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.
[0019] 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
[0020] 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.
[0021] 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.
[0022] 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.
[0023] 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.
[0024] 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.
[0025] 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.
[0026] 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.
[0027] 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.
[0028] 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).
[0029] 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.
[0030] 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.
[0031] 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.
[0032] 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.
[0033] 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.
[0034] As used herein, chemical structures that contain one or more
stereocenters depicted with dashed and bold bonds (i.e., ) 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.
[0035] 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.
[0036] 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.
[0037] 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.degree. C. to about 30.degree.
C.
[0038] 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'').sub.n-- includes both --NR(CR'R'').sub.n-- and
--(CR'R'').sub.nNR--. Where the structure clearly requires a
linking group, the Markush variables listed for that group are
understood to be linking groups.
[0039] 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.
[0040] 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.
[0041] Throughout the definitions, the term "C.sub.n-m" indicates a
range that includes the endpoints, wherein n and m are integers and
indicate the number of carbons. Examples include C.sub.1-4,
C.sub.1-6, and the like.
[0042] As used herein, the term "C.sub.n-m alkyl," 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.
[0043] As used herein, "C.sub.n-m alkenyl" 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.
[0044] As used herein, "C.sub.n-m alkynyl" 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.
[0045] As used herein, the term "C.sub.n-m alkylene," 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.
[0046] As used herein, the term "C.sub.n-m alkoxy," 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.
[0047] As used herein, the term "C.sub.n-m alkylamino" 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.
[0048] As used herein, the term "C.sub.n-m alkoxycarbonyl" 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.
[0049] As used herein, the term "C.sub.n-m alkylcarbonyl" 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.
[0050] As used herein, the term "C.sub.n-m alkylcarbonylamino"
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.
[0051] As used herein, the term "C.sub.n-m alkylsulfonylamino"
refers to a group of formula --NHS(O).sub.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.
[0052] As used herein, the term "aminosulfonyl" refers to a group
of formula --S(O).sub.2NH.sub.2.
[0053] As used herein, the term "C.sub.n-m alkylaminosulfonyl"
refers to a group of formula --S(O).sub.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.
[0054] As used herein, the term "di(C.sub.n-m alkyl)aminosulfonyl"
refers to a group of formula --S(O).sub.2N(alkyl).sub.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.
[0055] As used herein, the term "aminosulfonylamino" refers to a
group of formula --NHS(O).sub.2NH.sub.2.
[0056] As used herein, the term "C.sub.n-m alkylaminosulfonylamino"
refers to a group of formula --NHS(O).sub.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.
[0057] As used herein, the term "di(C.sub.n-m
alkyl)aminosulfonylamino" refers to a group of formula
--NHS(O).sub.2N(alkyl).sub.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.
[0058] As used herein, the term "aminocarbonylamino," employed
alone or in combination with other terms, refers to a group of
formula --NHC(O)NH.sub.2.
[0059] As used herein, the term "C.sub.n-m alkylaminocarbonylamino"
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.
[0060] As used herein, the term "di(C.sub.n-m
alkyl)aminocarbonylamino" refers to a group of formula
--NHC(O)N(alkyl).sub.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.
[0061] As used herein, the term "C-m alkylcarbamyl" 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.
[0062] As used herein, the term "thio" refers to a group of formula
--SH.
[0063] As used herein, the term "C.sub.n-m alkylthio" 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.
[0064] As used herein, the term "C.sub.n-m alkylsulfinyl" 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.
[0065] As used herein, the term "C.sub.n-m alkylsulfonyl" refers to
a group of formula --S(O).sub.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.
[0066] As used herein, the term "amino" refers to a group of
formula --NH.sub.2.
[0067] As used herein, the term "carbamyl" to a group of formula
--C(O)NH.sub.2.
[0068] As used herein, the term "carbonyl," employed alone or in
combination with other terms, refers to a --C(.dbd.O)-- group,
which may also be written as C(O).
[0069] As used herein, the term "cyano-C.sub.1-3 alkyl" refers to a
group of formula --(C.sub.1-3 alkylene)-CN.
[0070] As used herein, the term "HO--C.sub.1-3 alkyl" refers to a
group of formula --(C.sub.1-3 alkylene)-OH.
[0071] As used herein, the term "C.sub.1-3 alkoxy-C.sub.1-3 alkyl"
refers to a group of formula --(C.sub.1-3 alkylene)-O(C.sub.1-3
alkyl).
[0072] As used herein, the term "carboxy" refers to a group of
formula --C(O)OH.
[0073] As used herein, the term "di(C.sub.n-m-alkyl)amino" refers
to a group of formula --N(alkyl).sub.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.
[0074] As used herein, the term "di(C.sub.n-m-alkyl)carbamyl"
refers to a group of formula --C(O)N(alkyl).sub.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.
[0075] As used herein, "halo" refers to F, C.sub.1, Br, or I. In
various aspects, the halo group is F or C.sub.1.
[0076] As used herein, "C.sub.n-m haloalkoxy" refers to a group of
formula --O-haloalkyl having n to m carbon atoms. An example
haloalkoxy group is OCF.sub.3. 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.
[0077] As used herein, the term "C.sub.n-m haloalkyl," 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.
[0078] 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').sub.3, wherein each R' is independently C.sub.1-6 alkyl, 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.sub.1-6 alkyl 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).sub.3, wherein each R is
independently a linear or branched C.sub.1-6 alkyl group.
[0079] 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.sub.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, norbomyl, 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.
[0080] 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).sub.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.
[0081] 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.sub.n-m aryl" 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.
[0082] 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.
[0083] 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.
[0084] 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 it-system (e.g.,
substituted onto an aryl or heteroaryl ring) that draws electron
density away from the it-system through induction (e.g.,
withdrawing electron density about a G-bond) or resonance (e.g.,
withdrawing electron density about a .pi.-bond or .pi.-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.,
--NO.sub.2), haloalkyl groups (e.g., --CH.sub.2F, --CHF.sub.2,
--CF.sub.3, and the like), alkenyl groups (e.g., vinyl), alkynyl
groups (e.g., ethynyl), sulfonyl groups (e.g., S(O)R, S(O).sub.2R),
sulfonate groups (e.g., --SO.sub.3H), and sulfonamide groups (e.g.,
S(O)N(R).sub.2, S(O).sub.2N(R).sub.2). In various aspects, the
electron withdrawing group is selected from the group consisting of
halo, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-3 haloalkyl,
CN, NO.sub.2, C(.dbd.O)OR.sup.a1, C(.dbd.O)R.sup.b1,
C(.dbd.O)NR.sup.c1R.sup.d1, C(.dbd.O)SR.sup.e1,
--NR.sup.c1S(O)R.sup.e1, --NR.sup.c1S(O).sub.2R.sup.e1,
S(.dbd.O)R.sup.e1, S(.dbd.O).sub.2R.sup.e1,
S(.dbd.O)NR.sup.c1R.sup.d1, S(.dbd.O).sub.2NR.sup.c1R.sup.d1, and
P(O)(OR.sup.a1).sub.2. In various aspects, the electron withdrawing
group is selected from the group consisting of C(.dbd.O)OR.sup.a1,
C(.dbd.O)R.sup.b1, C(.dbd.O)NR.sup.c1R.sup.d1, C(.dbd.O)SR.sup.e1,
S(.dbd.O)R.sup.e1, S(.dbd.O).sub.2R.sup.e1,
S(.dbd.O)NR.sup.c1R.sup.d1, and S(.dbd.O).sub.2NR.sup.c1R.sup.d1.
In various aspects, the electron withdrawing group is
C(.dbd.O)OR.sup.a1. In various aspects, the electron withdrawing
group is C(.dbd.O)OR.sup.a1, wherein R.sup.a1 is C.sub.1-6 alkyl or
(C.sub.6-10 aryl)-C.sub.1-3 alkylene. In various aspects, the
electron withdrawing group is an ester.
[0085] 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).
[0086] The following abbreviations may be used herein: AcOH (acetic
acid); aq. (aqueous); atm. (atmosphere(s)); Br.sub.2 (bromine); Bn
(benzyl); calc. (calculated); d (doublet); dd (doublet of
doublets); DCM (dichloromethane); DMF (N,N-dimethylformamide); Et
(ethyl); Et.sub.2O (diethyl ether); EtOAc (ethyl acetate); EtOH
(ethanol); EWG (electron withdrawing group); g (gram(s)); h
(hour(s)); H.sub.2 (hydrogen gas); HCl (hydrochloric acid/hydrogen
choride); HPLC (high performance liquid chromatography);
H.sub.2SO.sub.4 (sulfuric acid); Hz (hertz); 12 (iodine); IPA
(isopropyl alcohol); J (coupling constant); KOH (potassium
hydroxide); K.sub.3PO.sub.4 (potassium phosphate); LCMS (liquid
chromatography--mass spectrometry); LiICA (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); NaBH.sub.3CN (sodium cyanoborohydride);
NHP (N-heterocyclic phosphine); NHP-C.sub.1 (N-heterocyclic
phosphine chloride); Na.sub.2CO.sub.3 (sodium carbonate);
NaHCO.sub.3 (sodium bicarbonate); NaOH (sodium hydroxide);
Na.sub.2SO.sub.4 (sodium sulfate); nM (nanomolar); NMR (nuclear
magnetic resonance spectroscopy); PCl.sub.3 (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); .mu.g
(microgram(s)); .mu.L (microliter(s)); .mu.M (micromolar); wt %
(weight percent).
B. .alpha.-AMINOPHOSPHONATES
[0087] In one aspect, the invention relates to
.alpha.-aminophosphonates useful as intermediates in, for example,
the synthesis of cinnarizine and flunarizine, known antihistamine
and antivertiginous pharmaceuticals, respectively. The use of the
disclosed .alpha.-aminophosphonates as intermediates in the
synthesis of other pharmaceutically active compounds is also
envisioned.
[0088] 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.
[0089] 1. Structure
[0090] In one aspect, disclosed are compounds having a structure
represented by a formula:
##STR00005##
wherein Q is selected from O, S, C.dbd.O, S.dbd.O, SO.sub.2, and
NR.sup.1; wherein each of X.sup.A and X.sup.B is independently
selected from NR.sup.1, O, and S; wherein each occurrence of
R.sup.1, 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.sup.1, when present, is independently substituted
with 0, 1, 2, 3, or 4 independently selected R.sup.5 groups;
wherein each occurrence of R.sup.5, when present, is independently
selected from halogen, --NO.sub.2, --CN, --OH, --SH, --NH.sub.2,
C1-C4 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, optionally
substituted C6-C10 aryl, --(C.dbd.O)(C1-C3 alkyl),
--(S.dbd.O)(C1-C3 alkyl), --SO.sub.2(C1-C3 alkyl),
--CO.sub.2R.sup.11, (C.dbd.O)NR.sup.12aR.sup.12b,
--SO.sub.2NR.sup.12aR.sup.12b, --O(C.dbd.O)NR.sup.12aR.sup.12b,
--NHSO.sub.2NR.sup.12aR.sup.12b, and
--NH(C.dbd.O)NR.sup.12aR.sup.12b; wherein each occurrence of
R.sup.11, when present, is independently selected from hydrogen and
C1-C4 alkyl; wherein each occurrence of R.sup.12a and R.sup.12b,
when present, is independently selected from hydrogen and C1-C3
alkyl; wherein each of Rx and R.sup.Y is independently selected
from hydrogen, C1-C8 alkyl, C6-C10 aryloxy, C6-C10 aryl, and 4-10
membered heteroaryl, or wherein each of Rx and R.sup.Y are
optionally covalently bonded together and, together with the
intermediate atoms, comprise a 5- to 7-membered cycloalkyl, a 5- to
7-membered heterocycloalkyl, a 5- to 7-membered aryl, or a 5- to
7-membered heteroaryl and are substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups; wherein R.sup.6 is 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 substituted with 0, 1, 2, 3, or 4 independently selected
R.sup.5 groups; and wherein each of R.sup.10a and R.sup.10b is
independently selected from hydrogen and C1-C4 alkyl, or a salt
thereof.
[0091] In a further aspect, the compound has a structure
represented by a formula selected from:
##STR00006##
or a salt thereof.
[0092] In a further aspect, the compound has a structure
represented by a formula selected from:
##STR00007##
or a salt thereof.
[0093] In a further aspect, the compound has a structure
represented by a formula:
##STR00008##
or a salt thereof.
[0094] In a further aspect, the compound has a structure
represented by a formula:
##STR00009##
or a salt thereof.
[0095] In a further aspect, the compound has a structure
represented by a formula:
##STR00010##
or a salt thereof.
[0096] In a further aspect, the compound has a structure
represented by a formula:
##STR00011##
or a salt thereof.
[0097] In a further aspect, the compound has a structure
represented by a formula:
##STR00012##
or a salt thereof.
[0098] In a further aspect, the compound has a structure
represented by a formula:
##STR00013##
or a salt thereof.
[0099] In a further aspect, the compound has a structure
represented by a formula selected from:
##STR00014##
or a salt thereof.
[0100] In a further aspect, the compound has a structure
represented by a formula:
##STR00015##
or a salt thereof.
[0101] In a further aspect, the compound has a structure
represented by a formula:
##STR00016##
or a salt thereof.
[0102] In a further aspect, the compound has a structure
represented by a formula:
##STR00017##
or a salt thereof.
[0103] In a further aspect, the compound has a structure
represented by a formula selected from:
##STR00018##
or a salt thereof.
[0104] In a further aspect, the compound has a structure
represented by a formula:
##STR00019##
or a salt thereof.
[0105] In a further aspect, the compound has a structure
represented by a formula:
##STR00020##
or a salt thereof.
[0106] In a further aspect, the compound has a structure
represented by a formula:
##STR00021##
or a salt thereof.
[0107] In a further aspect, the compound has a structure
represented by a formula:
##STR00022##
or a salt thereof.
[0108] In a further aspect, the compound has a structure
represented by a formula:
##STR00023##
or a salt thereof.
[0109] a. Q Groups
[0110] In one aspect, Q is selected from O, S, C.dbd.O, S.dbd.O,
SO.sub.2, and NR.sup.1. In a further aspect, Q is selected from O,
S, C.dbd.O, S.dbd.O, and SO.sub.2. In a still further aspect, Q is
selected from O, S, C.dbd.O, and S.dbd.O. In yet a further aspect,
Q is selected from O, S, and C.dbd.O. In an even further aspect, Q
is selected from O and S. In a still further aspect, Q is NR.sup.1.
In yet a further aspect, Q is SO.sub.2. In an even further aspect,
Q is S.dbd.O. In a still further aspect, Q is C.dbd.O. In yet a
further aspect, Q is S. In an even further aspect, Q is O.
[0111] b. X.sup.A and X.sup.B Groups
[0112] In one aspect, each of X.sup.A and X.sup.B is independently
selected from NR.sup.1, O, and S. In a further aspect, each of
X.sup.A and X.sup.B is independently selected from NR.sup.1 and O.
In a still further aspect, each of X.sup.A and X.sup.B is
independently selected from NR.sup.1 and S. In yet a further
aspect, each of X.sup.A and X.sup.B is independently selected from
O and S. In an even further aspect, each of X.sup.A and X.sup.B is
NR.sup.1. In a still further aspect, each of X.sup.A and X.sup.B is
O. In yet a further aspect, each of X.sup.A and X.sup.B is S.
[0113] c. R.sup.1 Groups
[0114] In one aspect, each occurrence of R.sup.1, when present,
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.sup.1,
when present, is independently substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups. In a further aspect, each
occurrence of R.sup.1, 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 R.sup.1, when present, is independently
substituted with 0, 1, 2, 3, or 4 independently selected R.sup.5
groups. In a still further aspect, each occurrence of R.sup.1 is
H.
[0115] In a further aspect, each occurrence of R.sup.1, 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.sup.1, when present, is independently substituted with 0, 1, 2,
or 3 independently selected R.sup.5 groups. In a still further
aspect, each occurrence of R.sup.1, 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.sup.1,
when present, is independently substituted with 0, 1, or 2
independently selected R.sup.5 groups. In yet a further aspect,
each occurrence of R.sup.1, 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.sup.1, when present, is
independently substituted with 0 or 1 R.sup.5 group. In an even
further aspect, each occurrence of R.sup.1, 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.sup.1,
when present, is independently monosubstituted with a R.sup.5
group. In a still further aspect, each occurrence of R.sup.1, 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.sup.1, when present, is unsubstituted.
[0116] In a further aspect, each occurrence of R.sup.1, when
present, is C6-C10 aryl substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups. In a still further aspect,
each occurrence of R.sup.1, when present, is C6-C10 aryl
substituted with 0, 1, 2, or 3 independently selected R.sup.5
groups. In yet a further aspect, each occurrence of R.sup.1, when
present, is C6-C10 aryl substituted with 0, 1, or 2 independently
selected R.sup.5 groups. In an even further aspect, each occurrence
of R.sup.1, when present, is C6-C10 aryl substituted with 0 or 1
R.sup.5 groups. In a still further aspect, each occurrence of
R.sup.1, when present, is C6-C10 aryl monosubstituted with a
R.sup.5 groups. In yet a further aspect, each occurrence of
R.sup.1, when present, is unsubstituted C6-C10 aryl.
[0117] In a further aspect, each occurrence of R.sup.1, when
present, is phenyl substituted with 0, 1, 2, 3, or 4 independently
selected R.sup.5 groups. In a still further aspect, each occurrence
of R.sup.1, when present, is phenyl substituted with 0, 1, 2, or 3
independently selected R.sup.5 groups. In yet a further aspect,
each occurrence of R.sup.1, when present, is phenyl substituted
with 0, 1, or 2 independently selected R.sup.5 groups. In an even
further aspect, each occurrence of R.sup.1, when present, is phenyl
substituted with 0 or 1 R.sup.5 groups. In a still further aspect,
each occurrence of R.sup.1, when present, is phenyl monosubstituted
with a R.sup.5 groups. In yet a further aspect, each occurrence of
R.sup.1, when present, is unsubstituted phenyl.
[0118] In a further aspect, each occurrence of R.sup.1, 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 R.sup.1, 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 R.sup.1, when present, is independently selected
from methyl, ethyl, n-propyl, i-propyl, cyclohexyl, phenyl, and
benzyl. In a still further aspect, each occurrence of R.sup.1, when
present, is independently selected from methyl, ethyl, cyclohexyl,
phenyl and benzyl. In yet a further aspect, each occurrence of
R.sup.1, when present, is independently selected from methyl,
cyclohexyl, phenyl, and benzyl. In an even further aspect, each
occurrence of R.sup.1, when present, is independently selected from
cyclohexyl, phenyl, and benzyl. In a still further aspect, each
occurrence of R.sup.1, when present, is cyclohexyl. In yet a
further aspect, each occurrence of R.sup.1, when present, is
phenyl. In an even further aspect, each occurrence of R.sup.1, when
present, is benzyl.
[0119] In a further aspect, each occurrence of R.sup.1, when
present, is independently selected from hydrogen, C1-C6 alkyl, and
C6-C10 aryl. In a still further aspect, each occurrence of R.sup.1,
when present, is independently selected from hydrogen, C1-C4 alkyl,
and C6-C8 aryl. In yet a further aspect, each occurrence of
R.sup.1, when present, is independently selected from hydrogen,
methyl, ethyl, n-propyl, i-propyl, and phenyl. In an even further
aspect, each occurrence of R.sup.1, when present, is independently
selected from hydrogen, methyl, ethyl, and phenyl. In a still
further aspect, each occurrence of R.sup.1, when present, is
independently selected from hydrogen, methyl and phenyl.
[0120] In a further aspect, each occurrence of R.sup.1, when
present, is independently selected from C1-C6 alkyl and C6-C10
aryl. In a still further aspect, each occurrence of R.sup.1, when
present, is independently selected from C1-C4 alkyl and C6-C8 aryl.
In yet a further aspect, each occurrence of R.sup.1, when present,
is independently selected from methyl, ethyl, n-propyl, i-propyl,
and phenyl. In an even further aspect, each occurrence of R.sup.1,
when present, is independently selected from methyl, ethyl, and
phenyl. In a still further aspect, each occurrence of R.sup.1, when
present, is independently selected from ethyl and phenyl. In yet a
further aspect, each occurrence of R.sup.1, when present, is
independently selected from methyl and phenyl.
[0121] In a further aspect, each occurrence of R.sup.1, when
present, is independently selected from hydrogen and C1-C6 alkyl.
In a still further aspect, each occurrence of R.sup.1, 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 R.sup.1, when present, is
independently selected from hydrogen, methyl, ethyl, n-propyl, and
i-propyl. In an even further aspect, each occurrence of R.sup.1,
when present, is independently selected from hydrogen, methyl, and
ethyl. In a still further aspect, each occurrence of R.sup.1, when
present, is independently selected from hydrogen and ethyl. In yet
a further aspect, each occurrence of R.sup.1, when present, is
independently selected from hydrogen and methyl.
[0122] In a further aspect, each occurrence of R.sup.1, when
present, is independently C1-C6 alkyl. In a still further aspect,
each occurrence of R.sup.1, 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 R.sup.1,
when present, is independently selected from methyl, ethyl,
n-propyl, and i-propyl. In an even further aspect, each occurrence
of R.sup.1, when present, is independently selected from methyl and
ethyl. In a still further aspect, each occurrence of R.sup.1, when
present, is ethyl. In yet a further aspect, each occurrence of
R.sup.1, when present, is methyl.
[0123] d. R.sup.5 Groups
[0124] In one aspect, each occurrence of R.sup.5, when present, is
independently selected from halogen, --NO.sub.2, --CN, --OH, --SH,
--NH.sub.2, C1-C4 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,
optionally substituted C6-C10 aryl, --(C.dbd.O)(C1-C3 alkyl),
--(S.dbd.O)(C1-C3 alkyl), --SO.sub.2(C1-C3 alkyl),
--CO.sub.2R.sup.11, --(C.dbd.O)NR.sup.12aR.sup.12b,
--SO.sub.2NR.sup.12aR.sup.12b, O(C.dbd.O)NR.sup.12aR.sup.12b,
--NHSO.sub.2NR.sup.12aR.sup.12b, and
--NH(C.dbd.O)NR.sup.12aR.sup.12b.
[0125] In a further aspect, each occurrence of R.sup.5, when
present, is independently selected from --F, --Cl, --NO.sub.2,
--CN, --OH, --SH, --NH.sub.2, methyl, ethyl, propyl, ethenyl,
propenyl, ethynyl, propynyl, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--CH.sub.2CH.sub.2F, --CH.sub.2Cl, --CHCl.sub.2, --CHCl.sub.3,
--CH.sub.2CH.sub.2Cl, --CH.sub.2CN, --CH.sub.2CH.sub.2CN,
--CH.sub.2OH, --CH.sub.2CH.sub.2OH, --OCH.sub.2F, --OCHF.sub.2,
--OCF.sub.3, --OCH.sub.3, --OCH.sub.2CH.sub.3, --SCH.sub.3,
--SCH.sub.2CH.sub.3, --CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2OCH.sub.2CH.sub.3, --NHCH.sub.3,
--NHCH.sub.2CH.sub.3, --N(CH.sub.3).sub.2,
--NH(CH.sub.2CH.sub.3).sub.2, cyclopropyl, cyclobutyl, cyclopentyl,
optionally substituted phenyl, --(C.dbd.O)CH.sub.3,
--(C.dbd.O)CH.sub.2CH.sub.3, --(S.dbd.O)CH.sub.3,
--(S.dbd.O)CH.sub.2CH.sub.3, --SO.sub.2CH.sub.3,
--SO.sub.2CH.sub.2CH.sub.3, --CO.sub.2CH.sub.3,
--CO.sub.2CH.sub.2CH.sub.3, --(C.dbd.O)NH.sub.2,
--(C.dbd.O)NHCH.sub.3, --(C.dbd.O)N(CH.sub.3).sub.2,
--SO.sub.2NH.sub.2, --SO.sub.2NHCH.sub.3,
--SO.sub.2N(CH.sub.3).sub.2, --O(C.dbd.O)NH.sub.2,
--O(C.dbd.O)NHCH.sub.3, --O(C.dbd.O)N(CH.sub.3).sub.2,
--NHSO.sub.2NH.sub.2, --NHSO.sub.2NHCH.sub.3,
--NHSO.sub.2N(CH.sub.3).sub.2, --NH(C.dbd.O)NH.sub.2,
--NH(C.dbd.O)NHCH.sub.3, and --NH(C.dbd.O)N(CH.sub.3).sub.2. In a
still further aspect, each occurrence of R.sup.5, when present, is
independently selected from --F, --Cl, --NO.sub.2, --CN, --OH,
--SH, --NH.sub.2, methyl, ethyl, ethenyl, ethynyl, --CH.sub.2F,
--CHF.sub.2, --CF.sub.3, --CH.sub.2Cl, --CHCl.sub.2, --CCl.sub.3,
--CH.sub.2CN, --CH.sub.2OH, --OCH.sub.2F, --OCHF.sub.2,
--OCF.sub.3, --OCH.sub.3, --SCH.sub.3, --CH.sub.2OCH.sub.3,
--NHCH.sub.3, --N(CH.sub.3).sub.2, cyclopropyl, cyclobutyl,
optionally substituted phenyl, --(C.dbd.O)CH.sub.3,
--(S.dbd.O)CH.sub.3, --SO.sub.2CH.sub.3, --CO.sub.2CH.sub.3,
--(C.dbd.O)NH.sub.2, --(C.dbd.O)NHCH.sub.3,
--(C.dbd.O)N(CH.sub.3).sub.2, --SO.sub.2NH.sub.2,
--SO.sub.2NHCH.sub.3, --SO.sub.2N(CH.sub.3).sub.2,
--O(C.dbd.O)NH.sub.2, --O(C.dbd.O)NHCH.sub.3,
--O(C.dbd.O)N(CH.sub.3).sub.2, --NHSO.sub.2NH.sub.2,
--NHSO.sub.2NHCH.sub.3, --NHSO.sub.2N(CH.sub.3).sub.2,
--NH(C.dbd.O)NH.sub.2, --NH(C.dbd.O)NHCH.sub.3, and
--NH(C.dbd.O)N(CH.sub.3).sub.2. In yet a further aspect, each
occurrence of R.sup.5, when present, is independently selected from
--F, --Cl, --NO.sub.2, --CN, --OH, --SH, --NH.sub.2, methyl,
--CH.sub.2F, --CHF.sub.2, --CF.sub.3, --CH.sub.2Cl, --CHCl.sub.2,
--CCl.sub.3, --CH.sub.2CN, --CH.sub.2OH, --OCH.sub.2F,
--OCHF.sub.2, --OCF.sub.3, --OCH.sub.3, --SCH.sub.3,
--CH.sub.2OCH.sub.3, --NHCH.sub.3, --N(CH.sub.3).sub.2,
cyclopropyl, optionally substituted phenyl, --(C.dbd.O)CH.sub.3,
--(S.dbd.O)CH.sub.3, --SO.sub.2CH.sub.3, --CO.sub.2CH.sub.3,
--(C.dbd.O)NH.sub.2, --(C.dbd.O)NHCH.sub.3,
--(C.dbd.O)N(CH.sub.3).sub.2, --SO.sub.2NH.sub.2,
--SO.sub.2NHCH.sub.3, --SO.sub.2N(CH.sub.3).sub.2,
--O(C.dbd.O)NH.sub.2, --O(C.dbd.O)NHCH.sub.3,
--O(C.dbd.O)N(CH.sub.3).sub.2, --NHSO.sub.2NH.sub.2,
--NHSO.sub.2NHCH.sub.3, --NHSO.sub.2N(CH.sub.3).sub.2,
--NH(C.dbd.O)NH.sub.2, --NH(C.dbd.O)NHCH.sub.3, and
--NH(C.dbd.O)N(CH.sub.3).sub.2.
[0126] In a further aspect, each occurrence of R.sup.5, when
present, is optionally substituted C6-C10 aryl. In a still further
aspect, each occurrence of R.sup.5, when present, is C6-C10 aryl
substituted with 0, 1, 2, or 3 groups independently selected from
halogen, --NO.sub.2, --CN, --OH, --SH, --NH.sub.2, and C1-C4 alkyl.
In yet a further aspect, each occurrence of R.sup.5, when present,
is C6-C10 aryl substituted with 0, 1, or 2 groups independently
selected from halogen, --NO.sub.2, --CN, --OH, --SH, --NH.sub.2,
and C1-C4 alkyl. In a still further aspect, each occurrence of
R.sup.5, when present, is C6-C10 aryl substituted with 0 or 1 group
selected from halogen, --NO.sub.2, --CN, --OH, --SH, --NH.sub.2,
and C1-C4 alkyl. In yet a further aspect, each occurrence of
R.sup.5, when present, is C6-C10 aryl monosubstituted with a group
selected from halogen, --NO.sub.2, --CN, --OH, --SH, --NH.sub.2,
and C1-C4 alkyl. In an even further aspect, each occurrence of
R.sup.5, when present, is unsubstituted C6-C10 aryl.
[0127] In a further aspect, each occurrence of R.sup.5, when
present, is optionally substituted phenyl. In a still further
aspect, each occurrence of R.sup.5, when present, is phenyl
substituted with 0, 1, 2, or 3 groups independently selected from
halogen, --NO.sub.2, --CN, --OH, --SH, --NH.sub.2, and C1-C4 alkyl.
In yet a further aspect, each occurrence of R.sup.5, when present,
is phenyl substituted with 0, 1, or 2 groups independently selected
from halogen, --NO.sub.2, --CN, --OH, --SH, --NH.sub.2, and C1-C4
alkyl. In a still further aspect, each occurrence of R.sup.5, when
present, is phenyl substituted with 0 or 1 group selected from
halogen, --NO.sub.2, --CN, --OH, --SH, --NH.sub.2, and C1-C4 alkyl.
In yet a further aspect, each occurrence of R.sup.5, when present,
is phenyl monosubstituted with a group selected from halogen,
--NO.sub.2, --CN, --OH, --SH, --NH.sub.2, and C1-C4 alkyl. In an
even further aspect, each occurrence of R.sup.5, when present, is
unsubstituted phenyl.
[0128] In a further aspect, each occurrence of R.sup.5, when
present, is independently selected from halogen, --NO.sub.2, --CN,
--OH, --SH, --NH.sub.2, C1-C4 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, each occurrence
of R.sup.5, when present, is independently selected from --F, --Cl,
--NO.sub.2, --CN, --OH, --SH, --NH.sub.2, methyl, ethyl, propyl,
--CH.sub.2F, --CHF.sub.2, --CF.sub.3, --CH.sub.2CH.sub.2F,
--CH.sub.2Cl, --CHCl.sub.2, --CCl.sub.3, --CH.sub.2CH.sub.2Cl,
--OCH.sub.3, --OCH.sub.2CH.sub.3, --SCH.sub.3, --SCH.sub.2CH.sub.3,
--CH.sub.2OCH.sub.3, --CH.sub.2CH.sub.2OCH.sub.2CH.sub.3,
--NHCH.sub.3, --NHCH.sub.2CH.sub.3, --N(CH.sub.3).sub.2, and
--NH(CH.sub.2CH.sub.3).sub.2. In a still further aspect, each
occurrence of R.sup.5, when present, is independently selected from
--F, --Cl, --NO.sub.2, --CN, --OH, --SH, --NH.sub.2, methyl, ethyl,
--CH.sub.2F, --CHF.sub.2, --CF.sub.3, --CH.sub.2Cl, --CHCl.sub.2,
--CCl.sub.3, --OCH.sub.3, --SCH.sub.3, --CH.sub.2OCH.sub.3,
--NHCH.sub.3, and --N(CH.sub.3).sub.2. In yet a further aspect,
each occurrence of R.sup.5, when present, is independently selected
from --F, --Cl, --NO.sub.2, --CN, --OH, --SH, --NH.sub.2, methyl,
--CH.sub.2F, --CHF.sub.2, --CF.sub.3, --CH.sub.2Cl, --CHCl.sub.2,
--CCl.sub.3, --OCH.sub.3, --SCH.sub.3, --CH.sub.2OCH.sub.3,
--NHCH.sub.3, and --N(CH.sub.3).sub.2.
[0129] In a further aspect, each occurrence of R.sup.5, when
present, is independently selected from halogen, --NO.sub.2, --CN,
--OH, --SH, --NH.sub.2, C1-C4 alkyl, C1-C3 haloalkyl, and C1-C3
alkoxy. In a further aspect, each occurrence of R.sup.5, when
present, is independently selected from --F, --Cl, --NO.sub.2,
--CN, --OH, --SH, --NH.sub.2, methyl, ethyl, propyl, --CH.sub.2F,
--CHF.sub.2, --CF.sub.3, --CH.sub.2CH.sub.2F, --CH.sub.2Cl,
--CHCl.sub.2, --CCl.sub.3, --CH.sub.2CH.sub.2Cl, --OCH.sub.3, and
--OCH.sub.2CH.sub.3. In a still further aspect, each occurrence of
R.sup.5, when present, is independently selected from --F, --Cl,
--NO.sub.2, --CN, --OH, --SH, --NH.sub.2, methyl, ethyl,
--CH.sub.2F, --CHF.sub.2, --CF.sub.3, --CH.sub.2Cl, --CHCl.sub.2,
--CCl.sub.3, and --OCH.sub.3. In yet a further aspect, each
occurrence of R.sup.5, when present, is independently selected from
--F, --Cl, --NO.sub.2, --CN, --OH, --SH, --NH.sub.2, methyl,
--CH.sub.2F, --CHF.sub.2, --CF.sub.3, --CH.sub.2Cl, --CHCl.sub.2,
--CCl.sub.3, and --OCH.sub.3.
[0130] In a further aspect, each occurrence of R.sup.5, when
present, is independently selected from C1-C4 alkyl, C1-C3
haloalkyl, and C1-C3 alkoxy. In a further aspect, each occurrence
of R.sup.5, when present, is independently selected from methyl,
ethyl, propyl, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--CH.sub.2CH.sub.2F, --CH.sub.2Cl, --CHCl.sub.2, --CCl.sub.3,
--CH.sub.2CH.sub.2Cl, --OCH.sub.3, and --OCH.sub.2CH.sub.3. In a
still further aspect, each occurrence of R.sup.5, when present, is
independently selected from methyl, ethyl, --CH.sub.2F,
--CHF.sub.2, --CF.sub.3, --CH.sub.2Cl, --CHCl.sub.2, --CCl.sub.3,
and --OCH.sub.3. In yet a further aspect, each occurrence of
R.sup.5, when present, is independently selected from methyl,
--CH.sub.2F, --CHF.sub.2, --CF.sub.3, --CH.sub.2Cl, --CHCl.sub.2,
--CCl.sub.3, and --OCH.sub.3.
[0131] In a further aspect, each occurrence of R.sup.5, when
present, is independently selected from C1-C4 alkyl and C1-C3
alkoxy. In a further aspect, each occurrence of R.sup.5, when
present, is independently selected from methyl, ethyl, propyl,
--OCH.sub.3, and --OCH.sub.2CH.sub.3. In a still further aspect,
each occurrence of R.sup.5, when present, is independently selected
from methyl, ethyl, and --OCH.sub.3. In yet a further aspect, each
occurrence of R.sup.5, when present, is independently selected from
methyl and --OCH.sub.3.
[0132] In a further aspect, each occurrence of R.sup.5, when
present, is C1-C3 haloalkyl. In a further aspect, each occurrence
of R.sup.5, when present, is independently selected from
--CH.sub.2F, --CHF.sub.2, --CF.sub.3, --CH.sub.2CH.sub.2F,
--CH.sub.2Cl, --CHCl.sub.2, --CCl.sub.3, and --CH.sub.2CH.sub.2C1.
In a still further aspect, each occurrence of R.sup.5, when
present, is independently selected from --CH.sub.2F, --CHF.sub.2,
--CF.sub.3, --CH.sub.2Cl, --CHCl.sub.2, and --CCl.sub.3. In yet a
further aspect, each occurrence of R.sup.5, when present, is
independently selected from --CHF.sub.2, --CF.sub.3, --CHCl.sub.2,
and --CCl.sub.3. In an even further aspect, each occurrence of
R.sup.5, when present, is independently selected from --CF.sub.3
and --CCl.sub.3. In a still further aspect, each occurrence of
R.sup.5, when present, is --CF.sub.3. In yet a further aspect, each
occurrence of R.sup.5, when present, is --CCl.sub.3.
[0133] In a further aspect, each occurrence of R.sup.5, when
present, is independently selected from --OCH.sub.3,
--OCH.sub.2CH.sub.3, --OCH.sub.2CH.sub.2CH.sub.3, and
--OCH(CH.sub.3).sub.2. In a still further aspect, each occurrence
of R.sup.5, when present, is independently selected from
--OCH.sub.3 and --OCH.sub.2CH.sub.3. In yet a further aspect, each
occurrence of R.sup.5, when present, is
--OCH.sub.2CH.sub.2CH.sub.3. In an even further aspect, each
occurrence of R.sup.5, when present, is --OCH(CH.sub.3).sub.2. In a
still further aspect, each occurrence of R.sup.5, when present, is
--OCH.sub.2CH.sub.3. In yet a further aspect, each occurrence of
R.sup.5, when present, is --OCH.sub.3.
[0134] In a further aspect, each occurrence of R.sup.5, when
present, is independently selected from methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl. In a still
further aspect, each occurrence of R.sup.5, when present, is
independently selected from methyl, ethyl, n-propyl, and i-propyl.
In yet a further aspect, R.sup.5, when present, is independently
selected from methyl and ethyl. In an even further aspect, each
occurrence of R.sup.5, when present, is ethyl. In a still further
aspect, each occurrence of R.sup.5, when present, is methyl.
[0135] e. R.sup.11 Groups
[0136] In one aspect, each occurrence of R.sup.11, when present, is
independently selected from hydrogen and C1-C4 alkyl. In a further
aspect, each occurrence of R.sup.11, when present, is independently
selected from hydrogen, methyl, ethyl, n-propyl, and i-propyl. In a
still further aspect, each occurrence of R.sup.11, when present, is
independently selected from hydrogen, methyl, and ethyl. In yet a
further aspect, each occurrence of R.sup.11, when present, is
independently selected from hydrogen and ethyl. In an even further
aspect, each occurrence of R.sup.11, when present, is independently
selected from hydrogen and methyl. In a still further aspect, each
occurrence of R.sup.11, when present, is ethyl. In yet a further
aspect, each occurrence of R.sup.11, when present, is methyl. In an
even further aspect, each occurrence of R.sup.1, when present, is
hydrogen.
[0137] f. R.sup.12A and R.sup.12B Groups
[0138] In one aspect, each occurrence of R.sup.12a and R.sup.12b,
when present, is independently selected from hydrogen and C1-C3
alkyl. In a further aspect, each occurrence of R.sup.12a and
R.sup.12b, when present, is independently selected from hydrogen,
methyl, and ethyl. In a still further aspect, each occurrence of
R.sup.12a and R.sup.12b, when present, is independently selected
from hydrogen and ethyl. In yet a further aspect, each occurrence
of R.sup.12a and R.sup.12b, when present, is independently selected
from hydrogen and methyl. In an even further aspect, each
occurrence of R.sup.12a and R.sup.12b, when present, is ethyl. In a
still further aspect, each occurrence of R.sup.12a and R.sup.12b,
when present, is methyl. In yet a further aspect, each occurrence
of R.sup.12a and R.sup.12b, when present, is hydrogen.
[0139] g. R.sup.X and R.sup.Y Groups
[0140] In one aspect, each of Rx and R.sup.Y is independently
selected from hydrogen, C1-C8 alkyl, C6-C10 aryloxy, C6-C10 aryl,
and 4-10 membered heteroaryl, or wherein each of Rx and R.sup.Y are
optionally covalently bonded together and, together with the
intermediate atoms, comprise a 5- to 7-membered cycloalkyl, a 5- to
7-membered heterocycloalkyl, a 5- to 7-membered aryl, or a 5- to
7-membered heteroaryl and are substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups. In a further aspect, each of
Rx and R.sup.Y is hydrogen.
[0141] In a further aspect, each of Rx and R.sup.Y are optionally
covalently bonded together and, together with the intermediate
atoms, comprise a 5- to 7-membered cycloalkyl, a 5- to 7-membered
heterocycloalkyl, a 5- to 7-membered aryl, or a 5- to 7-membered
heteroaryl and are substituted with 0, 1, 2, 3, or 4 independently
selected R.sup.5 groups. In a still further aspect, each of Rx and
R.sup.Y are optionally covalently bonded together and, together
with the intermediate atoms, comprise a 5- to 7-membered
cycloalkyl, a 5- to 7-membered heterocycloalkyl, a 5- to 7-membered
aryl, or a 5- to 7-membered heteroaryl and are substituted with 0,
1, 2, or 3 independently selected R.sup.5 groups. In yet a further
aspect, each of Rx and R.sup.Y are optionally covalently bonded
together and, together with the intermediate atoms, comprise a 5-
to 7-membered cycloalkyl, a 5- to 7-membered heterocycloalkyl, a 5-
to 7-membered aryl, or a 5- to 7-membered heteroaryl and are
substituted with 0, 1, or 2 independently selected R.sup.5 groups.
In an even further aspect, each of Rx and R.sup.Y are optionally
covalently bonded together and, together with the intermediate
atoms, comprise a 5- to 7-membered cycloalkyl, a 5- to 7-membered
heterocycloalkyl, a 5- to 7-membered aryl, or a 5- to 7-membered
heteroaryl and are substituted with 0 or 1 R.sup.5 groups. In a
still further aspect, each of Rx and R.sup.Y are optionally
covalently bonded together and, together with the intermediate
atoms, comprise a 5- to 7-membered cycloalkyl, a 5- to 7-membered
heterocycloalkyl, a 5- to 7-membered aryl, or a 5- to 7-membered
heteroaryl and are monosubstituted with a R.sup.5 group. In yet a
further aspect, each of Rx and R.sup.Y are optionally covalently
bonded together and, together with the intermediate atoms, comprise
a 5- to 7-membered cycloalkyl, a 5- to 7-membered heterocycloalkyl,
a 5- to 7-membered aryl, or a 5- to 7-membered heteroaryl and are
unsubstituted.
[0142] In a further aspect, each of Rx and R.sup.Y are optionally
covalently bonded together and, together with the intermediate
atoms, comprise a 5- to 7-membered cycloalkyl or a 5- to 7-membered
heterocycloalkyl and are substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups. In a still further aspect,
each of Rx and R.sup.Y are optionally covalently bonded together
and, together with the intermediate atoms, comprise a 5- to
7-membered cycloalkyl or a 5- to 7-membered heterocycloalkyl and
are substituted with 0, 1, 2, or 3 independently selected R.sup.5
groups. In yet a further aspect, each of Rx and R.sup.Y are
optionally covalently bonded together and, together with the
intermediate atoms, comprise a 5- to 7-membered cycloalkyl or a 5-
to 7-membered heterocycloalkyl and are substituted with 0, 1, or 2
independently selected R.sup.5 groups. In an even further aspect,
each of Rx and R.sup.Y are optionally covalently bonded together
and, together with the intermediate atoms, comprise a 5- to
7-membered cycloalkyl or a 5- to 7-membered heterocycloalkyl and
are substituted with 0 or 1 R.sup.5 groups. In a still further
aspect, each of Rx and R.sup.Y are optionally covalently bonded
together and, together with the intermediate atoms, comprise a 5-
to 7-membered cycloalkyl or a 5- to 7-membered heterocycloalkyl and
are monosubstituted with a R.sup.5 group. In yet a further aspect,
each of Rx and R.sup.Y are optionally covalently bonded together
and, together with the intermediate atoms, comprise a 5- to
7-membered cycloalkyl or a 5- to 7-membered heterocycloalkyl and
are unsubstituted.
[0143] In a further aspect, each of Rx and R.sup.Y are optionally
covalently bonded together and, together with the intermediate
atoms, comprise a 5- to 7-membered cycloalkyl substituted with 0,
1, 2, 3, or 4 independently selected R.sup.5 groups. In a still
further aspect, each of Rx and R.sup.Y are optionally covalently
bonded together and, together with the intermediate atoms, comprise
a 5- to 7-membered cycloalkyl substituted with 0, 1, 2, or 3
independently selected R.sup.5 groups. In yet a further aspect,
each of Rx and R.sup.Y are optionally covalently bonded together
and, together with the intermediate atoms, comprise a 5- to
7-membered cycloalkyl substituted with 0, 1, or 2 independently
selected R.sup.5 groups. In an even further aspect, each of Rx and
R.sup.Y are optionally covalently bonded together and, together
with the intermediate atoms, comprise a 5- to 7-membered cycloalkyl
substituted with 0 or 1 R.sup.5 groups. In a still further aspect,
each of Rx and R.sup.Y are optionally covalently bonded together
and, together with the intermediate atoms, comprise a 5- to
7-membered cycloalkyl monosubstituted with a R.sup.5 group. In yet
a further aspect, each of Rx and R.sup.Y are optionally covalently
bonded together and, together with the intermediate atoms, comprise
an unsubstituted 5- to 7-membered cycloalkyl.
[0144] In a further aspect, each of Rx and R.sup.Y are optionally
covalently bonded together and, together with the intermediate
atoms, comprise a cyclohexyl substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups. In a still further aspect,
each of Rx and R.sup.Y are optionally covalently bonded together
and, together with the intermediate atoms, comprise a cyclohexyl
substituted with 0, 1, 2, or 3 independently selected R.sup.5
groups. In yet a further aspect, each of Rx and R.sup.Y are
optionally covalently bonded together and, together with the
intermediate atoms, comprise a cyclohexyl substituted with 0, 1, or
2 independently selected R.sup.5 groups. In an even further aspect,
each of Rx and R.sup.Y are optionally covalently bonded together
and, together with the intermediate atoms, comprise a cyclohexyl
substituted with 0 or 1 R.sup.5 groups. In a still further aspect,
each of Rx and R.sup.Y are optionally covalently bonded together
and, together with the intermediate atoms, comprise a cyclohexyl
monosubstituted with a R.sup.5 group. In yet a further aspect, each
of Rx and R.sup.Y are optionally covalently bonded together and,
together with the intermediate atoms, comprise an unsubstituted
cyclohexyl.
[0145] In a further aspect, each of Rx and R.sup.Y are optionally
covalently bonded together and, together with the intermediate
atoms, comprise a 5- to 7-membered aryl or a 5- to 7-membered
heteroaryl and are substituted with 0, 1, 2, 3, or 4 independently
selected R.sup.5 groups. In a still further aspect, each of Rx and
R.sup.Y are optionally covalently bonded together and, together
with the intermediate atoms, comprise a 5- to 7-membered aryl or a
5- to 7-membered heteroaryl and are substituted with 0, 1, 2, or 3
independently selected R.sup.5 groups. In yet a further aspect,
each of Rx and R.sup.Y are optionally covalently bonded together
and, together with the intermediate atoms, comprise a 5- to
7-membered aryl or a 5- to 7-membered heteroaryl and are
substituted with 0, 1, or 2 independently selected R.sup.5 groups.
In an even further aspect, each of Rx and R.sup.Y are optionally
covalently bonded together and, together with the intermediate
atoms, comprise a 5- to 7-membered aryl or a 5- to 7-membered
heteroaryl and are substituted with 0 or 1 R.sup.5 groups. In a
still further aspect, each of Rx and R.sup.Y are optionally
covalently bonded together and, together with the intermediate
atoms, comprise a 5- to 7-membered aryl or a 5- to 7-membered
heteroaryl and are monosubstituted with a R.sup.5 group. In yet a
further aspect, each of Rx and R.sup.Y are optionally covalently
bonded together and, together with the intermediate atoms, comprise
a 5- to 7-membered aryl or a 5- to 7-membered heteroaryl and are
unsubstituted.
[0146] In a further aspect, each of Rx and R.sup.Y are optionally
covalently bonded together and, together with the intermediate
atoms, comprise a 5- to 7-membered aryl substituted with 0, 1, 2,
3, or 4 independently selected R.sup.5 groups. In a still further
aspect, each of Rx and R.sup.Y are optionally covalently bonded
together and, together with the intermediate atoms, comprise a 5-
to 7-membered aryl substituted with 0, 1, 2, or 3 independently
selected R.sup.5 groups. In yet a further aspect, each of Rx and
R.sup.Y are optionally covalently bonded together and, together
with the intermediate atoms, comprise a 5- to 7-membered aryl
substituted with 0, 1, or 2 independently selected R.sup.5 groups.
In an even further aspect, each of Rx and R.sup.Y are optionally
covalently bonded together and, together with the intermediate
atoms, comprise a 5- to 7-membered aryl substituted with 0 or 1
R.sup.5 groups. In a still further aspect, each of Rx and R.sup.Y
are optionally covalently bonded together and, together with the
intermediate atoms, comprise a 5- to 7-membered aryl
monosubstituted with a R.sup.5 group. In yet a further aspect, each
of Rx and R.sup.Y are optionally covalently bonded together and,
together with the intermediate atoms, comprise an unsubstituted 5-
to 7-membered aryl.
[0147] In a further aspect, each of Rx and R.sup.Y is independently
selected from hydrogen, C1-C8 alkyl, C6-C10 aryloxy, C6-C10 aryl,
and 4-10 membered heteroaryl. In a still further aspect, each of Rx
and R.sup.Y is independently selected from hydrogen, C1-C4 alkyl,
C6-C8 aryloxy, C6-C8 aryl, and 4-8 membered heteroaryl. In yet a
further aspect, each of Rx and R.sup.Y is independently selected
from hydrogen, --OPh, phenyl, and cyclohexyl. In an even further
aspect, each of Rx and R.sup.Y is hydrogen. In a still further
aspect, each of Rx and R.sup.Y is phenyl. In yet a further aspect,
each of Rx and R.sup.Y is cyclohexyl. In an even further aspect,
each of Rx and R.sup.Y is phenyl. In yet a further aspect, each of
Rx and R.sup.Y is --OPh.
[0148] In a further aspect, each of Rx and R.sup.Y is independently
C1-C8 alkyl. In a still further aspect, each of Rx and R.sup.Y is
independently C1-C4 alkyl. In yet a further aspect, each of Rx and
R.sup.Y is independently selected from methyl, ethyl, n-propyl, and
i-propyl. In an even further aspect, each of Rx and R.sup.Y is
independently selected from methyl and ethyl. In a still further
aspect, each of Rx and R.sup.Y is ethyl. In yet a further aspect,
each of Rx and R.sup.Y is methyl.
[0149] h. R.sup.6 Groups
[0150] In one aspect, R.sup.6 is 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 substituted
with 0, 1, 2, 3, or 4 independently selected R.sup.5 groups. In a
further aspect, each occurrence of R.sup.1, 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 substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups. In a still further aspect,
R.sup.6 is H.
[0151] In a further aspect, R.sup.6 is 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 substituted
with 0, 1, 2, or 3 independently selected R.sup.5 groups. In a
still further aspect, R.sup.6 is 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 substituted
with 0, 1, or 2 independently selected R.sup.5 groups. In yet a
further aspect, R.sup.6 is 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 substituted with 0 or 1
R.sup.5 group. In an even further aspect, R.sup.6 is 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 monosubstituted with a R.sup.5 group. In a still further
aspect, R.sup.6 is 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 unsubstituted.
[0152] In a further aspect, R.sup.6 is selected from C6-C10 aryl
and 4-10 membered heteroaryl and substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups. In a still further aspect,
R.sup.6 is selected from C6-C10 aryl and 4-10 membered heteroaryl
and substituted with 0, 1, 2, or 3 independently selected R.sup.5
groups. In yet a further aspect, R.sup.6 is selected from C6-C10
aryl and 4-10 membered heteroaryl and substituted with 0, 1, or 2
independently selected R.sup.5 groups. In an even further aspect,
R.sup.6 is selected from C6-C10 aryl and 4-10 membered heteroaryl
and substituted with 0 or 1 R.sup.5 group. In a still further
aspect, R.sup.6 is selected from C6-C10 aryl and 4-10 membered
heteroaryl and unsubstituted.
[0153] In a further aspect, R.sup.6 is C6-C10 aryl substituted with
0, 1, 2, 3, or 4 independently selected R.sup.5 groups. In a still
further aspect, R.sup.6 is C6-C10 aryl substituted with 0, 1, 2, or
3 independently selected R.sup.5 groups. In yet a further aspect,
R.sup.6 is C6-C10 aryl substituted with 0, 1, or 2 independently
selected R.sup.5 groups. In an even further aspect, R.sup.6 is
C6-C10 aryl substituted with 0 or 1 R.sup.5 groups. In a still
further aspect, R.sup.6 is C6-C10 aryl monosubstituted with a
R.sup.5 groups. In yet a further aspect, R.sup.6 is unsubstituted
C6-C10 aryl.
[0154] In a further aspect, R.sup.6 is phenyl substituted with 0,
1, 2, 3, or 4 independently selected R.sup.5 groups. In a still
further aspect, R.sup.6 is phenyl substituted with 0, 1, 2, or 3
independently selected R.sup.5 groups. In yet a further aspect,
R.sup.6 is phenyl substituted with 0, 1, or 2 independently
selected R.sup.5 groups. In an even further aspect, R.sup.6 is
phenyl substituted with 0 or 1 R.sup.5 groups. In a still further
aspect, R.sup.6 is phenyl monosubstituted with a R.sup.5 groups. In
yet a further aspect, R.sup.6 is unsubstituted phenyl.
[0155] In a further aspect, R.sup.6 is selected from C1-C6 alkyl,
C3-C10 cycloalkyl, C6-C10 aryl, and --(C1-C3 alkyl)(C6-C10 aryl).
In a still further aspect, R.sup.6 is selected from C1-C4 alkyl,
C3-C8 cycloalkyl, C6-C8 aryl, and --(C1-C3 alkyl)(C6-C8 aryl). In
yet a further aspect, R.sup.6 is selected from methyl, ethyl,
n-propyl, i-propyl, cyclohexyl, phenyl, and benzyl. In a still
further aspect, R.sup.6 is selected from methyl, ethyl, cyclohexyl,
phenyl and benzyl. In yet a further aspect, R.sup.6 is selected
from methyl, cyclohexyl, phenyl, and benzyl. In an even further
aspect, R.sup.6 is selected from cyclohexyl, phenyl, and benzyl. In
a still further aspect, R.sup.6 is cyclohexyl. In yet a further
aspect, R.sup.6 is phenyl. In an even further aspect, R.sup.6 is
benzyl.
[0156] In a further aspect, R.sup.6 is selected from hydrogen,
C1-C6 alkyl, and C6-C10 aryl. In a still further aspect, R.sup.6 is
selected from hydrogen, C1-C4 alkyl, and C6-C8 aryl. In yet a
further aspect, R.sup.6 is selected from hydrogen, methyl, ethyl,
n-propyl, i-propyl, and phenyl. In an even further aspect, R.sup.6
is selected from hydrogen, methyl, ethyl, and phenyl. In a still
further aspect, R.sup.6 is selected from hydrogen, methyl and
phenyl.
[0157] In a further aspect, R.sup.6 is selected from C1-C6 alkyl
and C6-C10 aryl. In a still further aspect, R.sup.6 is selected
from C1-C4 alkyl and C6-C8 aryl. In yet a further aspect, R.sup.6
is selected from methyl, ethyl, n-propyl, i-propyl, and phenyl. In
an even further aspect, R.sup.6 is selected from methyl, ethyl, and
phenyl. In a still further aspect, R.sup.6 is selected from ethyl
and phenyl. In yet a further aspect, R.sup.6 is selected from
methyl and phenyl.
[0158] In a further aspect, R.sup.6 is selected from hydrogen and
C1-C6 alkyl. In a still further aspect, R.sup.6 is selected from
hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,
s-butyl, and t-butyl. In yet a further aspect, R.sup.6 is selected
from hydrogen, methyl, ethyl, n-propyl, and i-propyl. In an even
further aspect, R.sup.6 is selected from hydrogen, methyl, and
ethyl. In a still further aspect, R.sup.6 is selected from hydrogen
and ethyl. In yet a further aspect, R.sup.6 is selected from
hydrogen and methyl.
[0159] In a further aspect, R.sup.6 is C1-C6 alkyl. In a still
further aspect, R.sup.6 is selected from methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl. In yet a further
aspect, R.sup.6 is selected from methyl, ethyl, n-propyl, and
i-propyl. In an even further aspect, R.sup.6 is selected from
methyl and ethyl. In a still further aspect, R.sup.6 is ethyl. In
yet a further aspect, R.sup.6 is methyl.
[0160] i. R.sup.10A and R.sup.10B Groups
[0161] In one aspect, each of R.sup.10a and R.sup.10b is
independently selected from hydrogen and C1-C4 alkyl. In a further
aspect, each of R.sup.10a and R.sup.10b is hydrogen.
[0162] In a further aspect, each of R.sup.10a and R.sup.10b is
independently selected from hydrogen, methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl. In a still
further aspect, each of R.sup.10a and R.sup.10b is independently
selected from hydrogen, methyl, ethyl, n-propyl, and i-propyl. In
yet a further aspect, each of R.sup.10a and R.sup.10b is
independently selected from hydrogen, methyl, and ethyl. In an even
further aspect, each of R.sup.10a and R.sup.10b is independently
selected from hydrogen and ethyl. In a still further aspect, each
of R.sup.10a and R.sup.10b is independently selected from hydrogen
and methyl.
[0163] In a further aspect, each of R.sup.10a and R.sup.10b is
independently selected from methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, s-butyl, and t-butyl. In a still further aspect,
each of R.sup.10a and R.sup.10b is independently selected from
methyl, ethyl, n-propyl, and i-propyl. In yet a further aspect,
each of R.sup.10a and R.sup.10b is independently selected from
methyl, and ethyl. In an even further aspect, each of R.sup.10a and
R.sup.10b is ethyl. In a still further aspect, each of R.sup.10a
and R.sup.10b is methyl.
[0164] 2. .alpha.-Aminophosphonates Examples
[0165] In one aspect, a compound is selected from:
##STR00024## ##STR00025## ##STR00026##
or a salt thereof.
[0166] In one aspect, a compound is selected from:
##STR00027##
or a salt thereof.
[0167] 3. Prophetic Compound Examples
[0168] 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. Thus, in one aspect, a compound can be selected from:
##STR00028## ##STR00029##
or a derivative thereof.
[0169] In one aspect, a compound can be selected from:
##STR00030## ##STR00031##
or a derivative thereof.
[0170] In one aspect, a compound can be selected from:
##STR00032## ##STR00033##
or a derivative thereof.
[0171] In one aspect, a compound can be selected from:
##STR00034##
or a derivative thereof.
C. N-HETEROCYCLIC PHOSPHINE REAGENTS
[0172] 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, Michaelis-Arbuzov reactions, and Mannich-Arbuzov
reactions. The present invention further relates to compounds
useful in the preparation of vinylphosphonates.
[0173] 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
.alpha.-aminophosphonates. In various aspects, the reaction of an
appropriately substituted aldehyde, an appropriately substituted
amine, and an NHP compound can promote a Manich Arbuzov cascade
reaction to generate .alpha.-aminophosphonates. A further
application of NHPs in organic synthesis is the formation of
.beta.-aminophosphonates. In various aspects, the reaction of an
appropriately substituted heterocycloalkane and an NHP compound can
promote a ring-opening reaction to generate
.beta.-aminophosphonates. 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.
[0174] 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.
[0175] 1. Structure
[0176] In one aspect, disclosed are compounds having a structure
represented by a formula:
##STR00035##
wherein m is selected from 0 and 1; wherein p is selected from 0,
1, 2, 3, 4, and 5; wherein Y is selected from CH.sub.2,
CH(CH.sub.3), O, and S; wherein each of X.sup.A and X.sup.B is
independently selected from NR.sup.1, O, and S; wherein each
occurrence of R.sup.1, 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.sup.1, when present, is
independently substituted with 0, 1, 2, 3, or 4 independently
selected R.sup.5 groups; wherein each occurrence of R.sup.5, when
present, is independently selected from halogen, --NO.sub.2, --CN,
--OH, --SH, --NH.sub.2, 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.dbd.O)(C1-C3 alkyl),
--(S.dbd.O)(C1-C3 alkyl), --SO.sub.2(C1-C3 alkyl),
--CO.sub.2R.sup.11, --(C.dbd.O)NR.sup.2aR.sup.12b,
--SO.sub.2NR.sup.12aR.sup.12b, --O(C.dbd.O)NR.sup.12aR.sup.12b,
--NHSO.sub.2NR.sup.12aR.sup.12b, and
--NH(C.dbd.O)NR.sup.12aR.sup.12b; wherein each occurrence of
R.sup.11, when present, is independently selected from hydrogen and
C1-C4 alkyl; wherein each occurrence of R.sup.12a and R.sup.12b,
when present, is independently selected from hydrogen and C1-C3
alkyl; wherein Z is selected from C.dbd.O, C.dbd.S, S.dbd.O,
SO.sub.2, and a structure represented by a formula:
##STR00036##
wherein each of R.sup.2a and R.sup.2b 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 substituted with 0, 1, 2, 3, or 4 independently selected
R.sup.5 groups; wherein each of R.sup.3a and R.sup.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.sup.3a
and R.sup.3b is independently substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups; and wherein R.sup.4 is
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 substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups, provided that Z is a
structure represented by a formula:
##STR00037##
or provided that each of R.sup.2a and R.sup.2b is not hydrogen, or
a salt thereof.
[0177] In one aspect, disclosed are compounds having a structure
represented by a formula:
##STR00038##
wherein q is selected from 1 and 2; wherein each of X.sup.A and
X.sup.B is independently selected from NR.sup.1, O, and S; wherein
each occurrence of R.sup.1, 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.sup.1, when present, is
independently substituted with 0, 1, 2, 3, or 4 independently
selected R.sup.5 groups; wherein each occurrence of R.sup.5, when
present, is independently selected from halogen, --NO.sub.2, --CN,
--OH, --SH, --NH.sub.2, 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, optionally substituted C6-C10 aryl, --(C.dbd.O)(C1-C3
alkyl), --(S.dbd.O)(C1-C3 alkyl), --SO.sub.2(C1-C3 alkyl),
--CO.sub.2R.sup.11, --(C.dbd.O)NR.sup.12aR.sup.12b,
--SO.sub.2NR.sup.12aR.sup.12b, --O(C.dbd.O)NR.sup.12aR.sup.12b,
--NHSO.sub.2NR.sup.12aR.sup.12b, and
--NH(C.dbd.O)NR.sup.2aR.sup.12b; wherein each occurrence of
R.sup.11, when present, is independently selected from hydrogen and
C1-C4 alkyl; wherein each occurrence of R.sup.12.sup.a and
R.sup.12b, when present, is independently selected from hydrogen
and C1-C3 alkyl; wherein each of Rx and R.sup.Y is independently
selected from hydrogen, C1-C8 alkyl, C6-C10 aryloxy, C6-C10 aryl,
and 4-10 membered heteroaryl, or wherein each of Rx and R.sup.Y are
optionally covalently bonded together and, together with the
intermediate carbon atoms, comprise a 5- to 7-membered cycloalkyl,
a 5- to 7-membered heterocycloalkyl, a 5- to 7-membered aryl, or a
5- to 7-membered heteroaryl and are substituted with 0, 1, 2, 3, or
4 independently selected R.sup.5 groups; wherein each of R.sup.7a
and R.sup.7b 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.sup.7a
and R.sup.7b is independently substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups; wherein each of R.sup.8a and
R.sup.8b 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.sup.8a
and R.sup.8b is independently substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups; wherein R.sup.9 is selected
from --CN, --SOR.sup.20, --SO.sub.2R.sup.20, --SO.sub.3R.sup.20,
--COR.sup.20, --CO.sub.2R.sup.20, --CONHR.sup.20, --CSNHR.sup.20,
--PO(OR.sup.21a)(OR.sup.21b), --PO(R.sup.21a)(R.sup.21b), and a
compound having a structure represented by a formula:
##STR00039##
wherein R.sup.20, when present, is selected from C1-C8 alkyl, C1-C8
alkylamine, (C1-C8)(C1-C8) dialkylamine, C6-C10 arylamine,
(C6-C10)(C6-C10) diarylamino, (C6-C10)(C1-C8) aryalkylamine, and
C6-C10 aryl and substituted with 0, 1, 2, or 3 groups independently
selected from halogen, --NO.sub.2, --CN, --OH, --SH, --NH.sub.2,
and C1-C4 alkyl; and wherein each of R.sup.21a and R.sup.21b, when
present, is independently selected from C1-C8 alkyl and C6-C10 aryl
and substituted with 0, 1, 2, or 3 groups independently selected
from halogen, --NO.sub.2, --CN, --OH, --SH, --NH.sub.2, and C1-C4
alkyl, or a salt thereof.
[0178] In a further aspect, the compound has a structure
represented by a formula selected from:
##STR00040##
or a salt thereof.
[0179] In a further aspect, the compound has a structure
represented by a formula:
##STR00041##
or a salt thereof.
[0180] In a further aspect, the compound has a structure
represented by a formula:
##STR00042##
or a salt thereof.
[0181] In a further aspect, the compound has a structure
represented by a formula:
##STR00043##
or a salt thereof.
[0182] In a further aspect, the compound has a structure
represented by a formula:
##STR00044##
or a salt thereof.
[0183] In a further aspect, the compound has a structure
represented by a formula:
##STR00045##
or a salt thereof.
[0184] In a further aspect, the compound has a structure
represented by a formula:
##STR00046##
or a salt thereof.
[0185] In a further aspect, the compound has a structure
represented by a formula:
##STR00047##
or a salt thereof.
[0186] In a further aspect, the compound is selected from:
##STR00048##
or a salt thereof.
[0187] In a further aspect, the compound is:
##STR00049##
or a salt thereof.
[0188] In a further aspect, the compound is:
##STR00050##
or a salt thereof.
[0189] In a further aspect, the compound has a structure
represented by a formula:
##STR00051##
or a salt thereof.
[0190] In a further aspect, the compound has a structure
represented by a formula:
##STR00052##
or a salt thereof.
[0191] In a further aspect, the compound has a structure
represented by a formula:
##STR00053##
or a salt thereof.
[0192] In a further aspect, the compound has a structure
represented by a formula:
##STR00054##
or a salt thereof.
[0193] In a further aspect, the compound is:
##STR00055##
or a salt thereof.
[0194] In a further aspect, m is selected from 0 and 1. In a still
further aspect, m is 0. In yet a further aspect, m is 1.
[0195] In a further aspect, p is selected from 0, 1, 2, 3, 4, and
5. In a still further aspect, p is selected from 0, 1, 2, 3, and 4.
In yet a further aspect, p is selected from 0, 1, 2, and 3. In an
even further aspect, p is selected from 0, 1, and 2. In a still
further aspect, p is selected from 0 and 1. In yet a further
aspect, p is selected from 1 and 2. In an even further aspect, p is
5. In a still further aspect, p is 4. In yet a further aspect, p is
3. In an even further aspect, p is 2. In a still further aspect, p
is 1. In yet a further aspect, p is 3. In an even further aspect, p
is 2. In still further aspect, p is 1. In yet a further aspect, p
is 0.
[0196] a. Y Groups
[0197] In one aspect, Y is selected from CH.sub.2, CH(CH.sub.3), O,
and S. In a further aspect, Y is selected from CH.sub.2, O, and S.
In a still further aspect, Y is selected from O and S. In yet a
further aspect, Y is CH.sub.2. In an even further aspect, Y is
CH(CH.sub.3). In a still further aspect, Y is O. In yet a further
aspect, Y is S.
[0198] b. Z Groups
[0199] In one aspect, Z is selected from C.dbd.O, C.dbd.S, S.dbd.O,
SO.sub.2, and a structure represented by a formula:
##STR00056##
[0200] In one aspect, Z is selected from C.dbd.O, C.dbd.S, S.dbd.O,
and SO.sub.2. In a further aspect, Z is selected from C.dbd.O,
C.dbd.S and SO.sub.2. In a still further aspect, Z is selected from
C.dbd.O, C.dbd.S and S.dbd.O. In yet a further aspect, Z is
selected from C.dbd.O and C.dbd.S. In an even further aspect, Z is
selected from C.dbd.O and S.dbd.O. In a still further aspect, Z is
selected from C.dbd.O and SO.sub.2. In yet a further aspect, Z is
selected from C.dbd.S and S.dbd.O. In an even further aspect, Z is
selected from C.dbd.S and SO.sub.2. In a still further aspect, Z is
selected from S.dbd.O and SO.sub.2. In yet a further aspect, Z is
C.dbd.O. In an even further aspect, Z is C.dbd.S. In a still
further aspect, Z is S.dbd.O. In yet a further aspect, Z is
SO.sub.2.
[0201] In a further aspect, Z is a structure represented by a
formula:
##STR00057##
[0202] c. R.sup.2A and R.sup.2B Groups
[0203] In one aspect, each of R.sup.2a and R.sup.2b 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 substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups. In a further aspect, each of
R.sup.2a and R.sup.2b 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 substituted
with 0, 1, 2, 3, or 4 independently selected R.sup.5 groups. In a
still further aspect, each of R.sup.2a and R.sup.2b is
hydrogen.
[0204] In a further aspect, each of R.sup.2a and R.sup.2b 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 substituted with 0, 1, 2, or 3
independently selected R.sup.5 groups. In a still further aspect,
each of R.sup.2a and R.sup.2b 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 substituted with 0, 1, or 2 independently selected R.sup.5
groups. In yet a further aspect, each of R.sup.2a and R.sup.2b 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 substituted with 0 or 1 R.sup.5 group.
In an even further aspect, each of R.sup.2a and R.sup.2b 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 monosubstituted with a R.sup.5 group.
In a still further aspect, each of R.sup.2a and R.sup.2b 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 unsubstituted.
[0205] In a further aspect, each of R.sup.2a and R.sup.2b is
independently selected from 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 substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups. In a still further aspect,
each of R.sup.2a and R.sup.2b is independently selected from 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. In yet a further
aspect, each of R.sup.2a and R.sup.2b is independently selected
from 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. In an
even further aspect, each of R.sup.2a and R.sup.2b is independently
selected from methyl, ethyl, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--CH.sub.2CH.sub.2F, --CH.sub.2Cl, --CHCl.sub.2, --CCl.sub.3,
--CH.sub.2CH.sub.2Cl, ethenyl, propenyl, ethynyl, propynyl, C3-C8
cycloalkyl, 4-8 membered heterocycloalkyl, C6-C8 aryl, --(C1-C3
alkyl)(C6-C8 aryl), and 4-8 membered heteroaryl. In a still further
aspect, each of R.sup.2a and R.sup.2b is independently selected
from methyl, ethyl, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--CH.sub.2CH.sub.2F, --CH.sub.2Cl, --CHCl.sub.2, --CCl.sub.3,
--CH.sub.2CH.sub.2Cl, ethenyl, ethynyl, C3-C8 cycloalkyl, 4-8
membered heterocycloalkyl, C6-C8 aryl, --(C1-C3 alkyl)(C6-C8 aryl),
and 4-8 membered heteroaryl. In yet a further aspect, each of
R.sup.2a and R.sup.2b is independently selected from methyl,
--CH.sub.2F, --CHF.sub.2, --CF.sub.3, --CH.sub.2Cl, --CHCl.sub.2,
--CCl.sub.3, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl, C6-C8
aryl, --(C1-C3 alkyl)(C6-C8 aryl), and 4-8 membered heteroaryl.
[0206] In a further aspect, each of R.sup.2a and R.sup.2b is
independently selected from hydrogen and C1-C6 alkyl. In a still
further aspect, each of R.sup.2a and R.sup.2b 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.sup.2a and R.sup.2b is independently selected from hydrogen,
methyl, ethyl, n-propyl, and i-propyl. In an even further aspect,
each of R.sup.2a and R.sup.2b is independently selected from
hydrogen, methyl and ethyl. In a still further aspect, each of
R.sup.2a and R.sup.2b is independently selected from hydrogen and
ethyl. In yet a further aspect each of R.sup.2a and R.sup.2b is
independently selected from hydrogen and methyl.
[0207] In a further aspect, each of R.sup.2a and R.sup.2b is C1-C6
alkyl. In a still further aspect, each of R.sup.2a and R.sup.2b 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.sup.2a and R.sup.2b is independently selected from
methyl, ethyl, n-propyl, and i-propyl. In an even further aspect,
each of R.sup.2a and R.sup.2b is independently selected from methyl
and ethyl. In a still further aspect, each of R.sup.2a and R.sup.2b
is ethyl. In yet a further aspect, each of R.sup.2a and R.sup.2b is
methyl.
[0208] d. R.sup.3A and R.sup.3B Groups
[0209] In one aspect, each of R.sup.3a and R.sup.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.sup.3a
and R.sup.3b is independently substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups. In a further aspect, each of
R.sup.3a and R.sup.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.sup.3a and R.sup.3b is independently substituted
with 0, 1, 2, 3, or 4 independently selected R.sup.5 groups. In a
still further aspect, each of R.sup.3a and R.sup.3b, when present,
is hydrogen.
[0210] In a further aspect, each of R.sup.3a and R.sup.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.sup.3a
and R.sup.3b is independently substituted with 0, 1, 2, or 3
independently selected R.sup.5 groups. In a still further aspect,
each of R.sup.3a and R.sup.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.sup.3a and R.sup.3b
is independently substituted with 0, 1, or 2 independently selected
R.sup.5 groups. In yet a further aspect, each of R.sup.3a and
R.sup.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.sup.3a and R.sup.3b is independently substituted with 0 or 1
R.sup.5 group. In an even further aspect, each of R.sup.3a and
R.sup.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.sup.3a and R.sup.3b is independently monosubstituted with a
R.sup.5 group. In a still further aspect, each of R.sup.3a and
R.sup.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.sup.3a and R.sup.3b is unsubstituted.
[0211] In a further aspect, each of R.sup.3a and R.sup.3b, when
present, is independently selected from hydrogen and C1-C6 alkyl.
In a still further aspect, each of R.sup.3a and R.sup.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.sup.3a and R.sup.3b, when present, is
independently selected from hydrogen, methyl, ethyl, n-propyl, and
i-propyl. In an even further aspect, each R.sup.3 is independently
selected from H, methyl, and ethyl. In a still further aspect, each
of R.sup.3a and R.sup.3b, when present, is independently selected
from hydrogen and ethyl. In yet a further aspect, each of R.sup.3a
and R.sup.3b, when present, is independently selected from hydrogen
and methyl.
[0212] In a further aspect, each of R.sup.3a and R.sup.3b, when
present, is independently C1-C6 alkyl. In a still further aspect,
each of R.sup.3a and R.sup.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.sup.3a and
R.sup.3b, when present, is independently selected from methyl,
ethyl, n-propyl, and i-propyl. In an even further aspect, each of
R.sup.3a and R.sup.3b, when present, is independently selected from
methyl and ethyl. In a still further aspect, each of R.sup.3a and
R.sup.3b when present, is ethyl. In yet a further aspect, each of
R.sup.3a and R.sup.3b, when present, is methyl.
[0213] e. R.sup.4 Groups
[0214] In one aspect, R.sup.4 is 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, 4-10
membered heteroaryl, and --(C1-C3 alkyl)(C6-C10 aryl), and
substituted with 0, 1, 2, 3, or 4 independently selected R.sup.5
groups. In a further aspect, R.sup.4 is 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
R.sup.4 is substituted with 0, 1, 2, 3, or 4 independently selected
R.sup.5 groups.
[0215] In a further aspect, R.sup.4 is 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, 4-10
membered heteroaryl, and --(C1-C3 alkyl)(C6-C10 aryl), and
substituted with 0, 1, 2, or 3 independently selected R.sup.5
groups. In a still further aspect, R.sup.4 is 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, 4-10 membered heteroaryl, and --(C1-C3 alkyl)(C6-C10 aryl),
and substituted with 0, 1, or 2 independently selected R.sup.5
groups. In yet a further aspect, R.sup.4 is 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, 4-10
membered heteroaryl, and --(C1-C3 alkyl)(C6-C10 aryl), and
substituted with 0 or 1 R.sup.5 group. In an even further aspect,
R.sup.4 is 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, 4-10 membered heteroaryl, and
--(C1-C3 alkyl)(C6-C10 aryl), and monosubstituted with a R.sup.5
group. In a still further aspect, R.sup.4 is 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, 4-10 membered heteroaryl, and --(C1-C3 alkyl)(C6-C10 aryl),
and unsubstituted.
[0216] In a further aspect, R.sup.4 is selected from C3-C10
cycloalkyl, C6-C10 aryl, and --(C1-C3 alkyl)(C6-C10 aryl). In a
still further aspect, R.sup.4 is selected from C3-C8 cycloalkyl,
C6-C8 aryl, and --(C1-C3 alkyl)(C6-C8 aryl). In yet a further
aspect, R.sup.4 is selected from cyclohexyl, phenyl, and benzyl. In
an even further aspect, R.sup.4 is selected from cyclohexyl and
phenyl. In a still further aspect, R.sup.4 is selected from
cyclohexyl and benzyl. In yet a further aspect, R.sup.4 is selected
from phenyl and benzyl. In an even further aspect, R.sup.4 is
cyclohexyl. In a still further aspect, R.sup.4 is phenyl. In an
even further aspect, R.sup.4 is benzyl.
[0217] 2. Prophetic Compound Examples
[0218] 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.
[0219] In one aspect, a compound can be selected from:
##STR00058##
or a derivative thereof.
[0220] In one aspect, a compound can be selected from:
##STR00059##
or a derivative thereof.
[0221] In one aspect, a compound can be selected from:
##STR00060## ##STR00061##
or a derivative thereof.
[0222] In one aspect, a compound can be selected from:
##STR00062## ##STR00063##
or a derivative thereof.
[0223] In one aspect, a compound can be selected from:
##STR00064##
or a derivative thereof.
[0224] In one aspect, a compound can be selected from:
##STR00065## ##STR00066## ##STR00067##
or a derivative thereof.
D. METHODS OF MAKING .alpha.-AMINOPHOSPHONATES
[0225] In one aspect, the invention relates to methods of making
N-heterocyclic phosphines useful in the preparation of
.alpha.-aminophosphonates. The .alpha.-aminophosphonates 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.
[0226] Thus, in one aspect, disclosed are methods of making a
compound having a structure represented by a formula:
##STR00068##
wherein Q is selected from O, S, C.dbd.O, S.dbd.O, SO.sub.2, and
NR.sup.1; wherein each of X.sup.A and X.sup.B is independently
selected from NR.sup.1, O, and S; wherein each occurrence of
R.sup.1, 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.sup.1, when present, is independently substituted
with 0, 1, 2, 3, or 4 independently selected R.sup.5 groups;
wherein each occurrence of R.sup.5, when present, is independently
selected from halogen, --NO.sub.2, --CN, --OH, --SH, --NH.sub.2,
C1-C4 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, optionally
substituted C6-C10 aryl, --(C.dbd.O)(C1-C3 alkyl),
--(S.dbd.O)(C1-C3 alkyl), --SO.sub.2(C1-C3 alkyl), --CO.sub.2R,
--(C.dbd.O)NR.sup.12aR.sup.12b, --SO.sub.2NR.sup.12aR.sup.12b,
--O(C.dbd.O)NR.sup.12aR.sup.12b, --NHSO.sub.2NR.sup.12aR.sup.12b,
and --NH(C.dbd.O)NR.sup.12aR.sup.12b; wherein each occurrence of
R.sup.11, when present, is independently selected from hydrogen and
C1-C4 alkyl; wherein each occurrence of R.sup.12a and R.sup.12b,
when present, is independently selected from hydrogen and C1-C3
alkyl; wherein each of Rx and R.sup.Y is independently selected
from hydrogen, C1-C8 alkyl, C6-C10 aryloxy, C6-C10 aryl, and 4-10
membered heteroaryl, or wherein each of Rx and R.sup.Y are
optionally covalently bonded together and, together with the
intermediate atoms, comprise a 5- to 7-membered cycloalkyl, a 5- to
7-membered heterocycloalkyl, a 5- to 7-membered aryl, or a 5- to
7-membered heteroaryl and are substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups; wherein R.sup.6 is 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 substituted with 0, 1, 2, 3, or 4 independently selected
R.sup.5 groups; and wherein each of R.sup.10a and R.sup.10b is
independently selected from hydrogen and C1-C4 alkyl, or a salt
thereof, the method comprising the step of reacting an aldehyde
having a structure represented by a formula:
##STR00069##
or a salt thereof, with a heterocycloalkane having a structure
represented by a formula:
##STR00070##
or a salt thereof, in the presence of a reagent having a structure
represented by a formula:
##STR00071##
wherein m is selected from 0 and 1; wherein p is selected from 0,
1, 2, 3, 4, and 5; wherein Z is selected from C.dbd.O, C.dbd.S,
S.dbd.O, SO.sub.2, and a structure represented by a formula:
##STR00072##
wherein each of R.sup.2a and R.sup.2b 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 substituted with 0, 1, 2, 3, or 4 independently selected
R.sup.5 groups; wherein each of R.sup.3a and R.sup.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.sup.3a
and R.sup.3b is independently substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups; and wherein R.sup.4 is
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 substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups, or a salt thereof.
[0227] In a further aspect, the aldehyde, the heterocycloalkane,
and the reagent are simultaneously reacted. In a still further
aspect, the aldehyde and the heterocycloalkane react to form a
reaction product and wherein the reaction product reacts with the
reagent. In yet a further aspect, the aldehyde and the reagent
react to form a reaction product and wherein the reaction product
reacts with the heterocycloalkane. In an even further aspect, the
heterocycloalkane and the reagent react to form a reaction product
and wherein the reaction product reacts with the aldehyde.
[0228] 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, antibiotics (e.g., dehydrophos; see PNAS,
2010, 107, 17557-17562).
[0229] 1. Route I
[0230] In one aspect, .alpha.-aminophosphonates can be prepared as
shown below.
##STR00073##
[0231] Compounds are represented in generic form, with substituents
as noted in compound descriptions elsewhere herein. A more specific
example is set forth below.
##STR00074##
[0232] In one aspect, the synthesis of .alpha.-aminophosphonates
can begin with an aldehyde. Aldehydes are commercially available or
readily prepared by one skilled in the art. Thus, compounds of type
1.3, and similar compounds, can be prepared according to reaction
Scheme 1B above. Compounds of type 1.8 can be prepared by a Mannich
Arbuzov cascade reaction of an appropriate aldehyde derivative,
e.g., 1.5 as shown above, and an appropriate N-heterocyclic
phosphine, e.g., 1.7 as shown above. The Mannich Arbuzov cascade
reaction is carried out in the presence of an appropriate amine,
e.g., 1.6 as shown above, in an appropriate solvent, e.g.,
1,2-dichloroethane, at an appropriate temperature, e.g., 85.degree.
C., for an appropriate period of time, e.g., 14 hours. 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, 1.2, and 1.3), can be substituted in the
reaction to provide substituted .alpha.-aminophosphonates similar
to Formula 1.4.
E. METHODS OF MAKING N-HETEROCYCLIC PHOSPHINES
[0233] In one aspect, disclosed are methods of making a compound
having a structure represented by a formula:
##STR00075##
wherein m is selected from 0 and 1; wherein p is selected from 0,
1, 2, 3, 4, and 5; wherein Y is selected from CH.sub.2,
CH(CH.sub.3), O, and S; wherein each of X.sup.A and X.sup.B is
independently selected from NR.sup.1, O, and S; wherein each
occurrence of R.sup.1, 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.sup.1, when present, is
independently substituted with 0, 1, 2, 3, or 4 independently
selected R.sup.5 groups; wherein each occurrence of R.sup.5, when
present, is independently selected from halogen, --NO.sub.2, --CN,
--OH, --SH, --NH.sub.2, 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.dbd.O)(C1-C3 alkyl),
--(S.dbd.O)(C1-C3 alkyl), --SO.sub.2(C1-C3 alkyl),
--CO.sub.2R.sup.11, --(C.dbd.O)NR.sup.12aR.sup.12b,
--SO.sub.2NR.sup.12aR.sup.12b, --O(C.dbd.O)NR.sup.12aR.sup.12b,
--NHSO.sub.2NR.sup.12aR.sup.12b, and
--NH(C.dbd.O)NR.sup.12aR.sup.12b; wherein each occurrence of
R.sup.11, when present, is independently selected from hydrogen and
C1-C4 alkyl; wherein each occurrence of R.sup.12a and R.sup.12b,
when present, is independently selected from hydrogen and C1-C3
alkyl; wherein Z is selected from C.dbd.O, C.dbd.S, S.dbd.O,
SO.sub.2, and a structure represented by a formula:
##STR00076##
wherein each of R.sup.2a and R.sup.2b 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 substituted with 0, 1, 2, 3, or 4 independently selected
R.sup.5 groups; wherein each of R.sup.3a and R.sup.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.sup.3a
and R.sup.3b is independently substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups; and wherein R.sup.4 is
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 substituted with 0, 1, 2, 3, or 4
independently selected R.sup.5 groups, provided that Z is a
structure represented by a formula:
##STR00077##
or provided that each of R.sup.2a and R.sup.2b is not hydrogen, or
a salt thereof, the method comprising: (a) providing a first
compound having a structure represented by a formula:
##STR00078##
wherein X.sup.1 is halogen, or a derivative thereof; and (b)
reacting with a second compound having a structure represented by a
formula:
##STR00079##
or a derivative thereof, in the presence of a base.
[0234] 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.
[0235] In a further aspect, providing comprises reacting a compound
having a structure represented by a formula:
##STR00080##
with a phosphine in the presence of a base.
[0236] 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.
[0237] 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.
[0238] 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.
[0239] 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.
[0240] 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, 1st Ed., Oxford University Press, 2000;
March's Advanced Organic Chemistry: Reactions, Mechanisms, and
Structure, 5.sup.th Ed., Wiley-Interscience Publication, 2001; and
Peturssion, S. et al., "Protecting Groups in Carbohydrate
Chemistry," J. Chem. Educ., 74(11), 1297 (1997).
[0241] 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., .sup.1H or
.sup.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.
[0242] 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.sup.nd Edition, 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.sup.th Ed.
(Wiley, 2007); Trost et al. (Ed.), Comprehensive Organic Synthesis
(Pergamon Press, 1991).
[0243] 1. Route I
[0244] In one aspect, substituted N-heterocyclic phosphine halide
intermediates can be prepared as shown below.
##STR00081##
[0245] Compounds are represented in generic form, with substituents
as noted in compound descriptions elsewhere herein and wherein
X.sup.1 is halogen. A more specific example is set forth below.
##STR00082##
[0246] 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 2.6, and similar
compounds, can be prepared according to reaction Scheme 2B above.
Compounds of type 2.6 can be prepared by a cyclization reaction of
an appropriate ethylene derivative, e.g., 2.4 as shown above. The
cyclization reaction is carried out in the presence of an
appropriate phosphorous trihalide, e.g., 2.5 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 2.1 and
2.2), can be substituted in the reaction to provide substituted
N-heterocyclic phosphine halide intermediates similar to Formula
2.3.
[0247] 2. Route II
[0248] In one aspect, substituted N-heterocyclic phosphine analogs
can be prepared as shown below.
##STR00083##
[0249] Compounds are represented in generic form, with substituents
as noted in compound descriptions elsewhere herein, wherein X.sup.1
is halogen. A more specific example is set forth below.
##STR00084##
[0250] 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
1.7, and similar compounds, can be prepared according to reaction
Scheme 3B above. Compounds of type 1.7 can be prepared by a
substitution reaction of an appropriate N-heterocyclic phosphine
halide, e.g., 3.3 as shown above. The substitution reaction is
carried out in the presence of an appropriate urea, thiourea,
sulfonyl, or sulfonyl derivative, e.g., 3.4 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 2.3 and
3.1), can be substituted in the reaction to provide substituted
N-heterocyclic phosphine analogs similar to Formula 1.3.
[0251] 3. Route III
[0252] In one aspect, substituted N-heterocyclic phosphine analogs
can be prepared as shown below.
##STR00085##
[0253] Compounds are represented in generic form, with substituents
as noted in compound descriptions elsewhere herein. A more specific
example is set forth below.
##STR00086##
[0254] In one aspect, the synthesis of N-heterocyclic phosphine
analogs can begin with a substituted diazaphospholidine.
Substituted diazaphospholidines are commercially available or
readily prepared by one skilled in the art. Thus, compounds of type
4.6, and similar compounds, can be prepared according to reaction
Scheme 4B above. Compounds of type 4.6 can be prepared by an
alkylation reaction of an appropriate diazaphospholidine, e.g., 4.4
as shown above. The alkylation reaction is carried out in the
presence of an appropriate alkyl halide, e.g., 4.5 as shown above,
and an appropriate base, e.g., potassium tert-butoxide, in an
appropriate solvent, e.g., tetrahydrofuran. 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 and 5.2), can be substituted in the reaction to provide
substituted N-heterocyclic phosphine analogs similar to Formula
4.3.
[0255] 4. Route IV
[0256] In one aspect, substituted N-heterocyclic phosphine analogs
can be prepared as shown below.
##STR00087##
[0257] Compounds are represented in generic form, with substituents
as noted in compound descriptions elsewhere herein. A more specific
example is set forth below.
##STR00088##
[0258] In one aspect, the synthesis of N-heterocyclic phosphine
analogs can begin with an amine. Amines are commercially available
or readily prepared by one skilled in the art. Thus, compounds of
type 5.4, and similar compounds, can be prepared according to
reaction Scheme 5B above. Compounds of type 5.4 can be prepared by
nucleophilic addition of an appropriate amine, e.g., 4.6 as shown
above, to an appropriate isothiocyanate, e.g., 5.3 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 4.3 and 5.1), can be substituted in
the reaction to provide substituted N-heterocyclic phosphine
analogs similar to Formula 5.2.
F. METHODS OF MAKING CHIRAL N-HETEROCYCLIC PHOSPHINES
[0259] In one aspect, disclosed are methods of making chiral
N-heterocyclic phosphines. 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.
[0260] 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.
[0261] 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.sup.st Ed., Oxford University Press,
2000; March's Advanced Organic Chemistry: Reactions, Mechanisms,
and Structure, 5.sup.th Ed., Wiley-Interscience Publication, 2001;
and Peturssion, S. et al., "Protecting Groups in Carbohydrate
Chemistry," J Chem. Educ., 74(11), 1297 (1997).
[0262] 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., .sup.1H or
.sup.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.
[0263] 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.sup.nd Edition, 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.sup.th Ed.
(Wiley, 2007); Trost et al. (Ed.), Comprehensive Organic Synthesis
(Pergamon Press, 1991).
[0264] 1. Route I
[0265] In one aspect, substituted chiral N-heterocyclic phosphine
reagents can be prepared as shown below.
##STR00089##
##STR00090##
##STR00091##
##STR00092##
[0266] 2. Route II
[0267] In one aspect, substituted chiral N-heterocyclic phosphine
reagents can be prepared as shown below.
##STR00093##
##STR00094##
[0268] 3. Route III
[0269] In one aspect, substituted chiral N-heterocyclic phosphine
reagents can be prepared as shown below.
##STR00095##
[0270] 4. Route IV
[0271] In one aspect, substituted chiral N-heterocyclic phosphine
reagents can be prepared as shown below.
##STR00096##
##STR00097##
##STR00098##
##STR00099##
##STR00100##
[0272] 5. Route V
[0273] In one aspect, substituted chiral N-heterocyclic phosphine
reagents can be prepared as shown below.
##STR00101##
##STR00102##
##STR00103##
##STR00104##
##STR00105##
##STR00106##
[0274] 6. Route VI
[0275] In one aspect, substituted chiral N-heterocyclic phosphine
reagents can be prepared as shown below.
##STR00107##
##STR00108##
##STR00109##
##STR00110##
##STR00111##
[0276] 7. Route VII
[0277] In one aspect, substituted chiral N-heterocyclic phosphine
reagents can be prepared as shown below.
##STR00112##
##STR00113##
##STR00114##
##STR00115##
G. REPRESENTATIVE EXAMPLE OF THE UTILITY OF
.alpha.-AMINOPHOSPHONATES: SYNTHESIS OF CINNARIZINE AND
FLUNARIZINE
[0278] Cinnarizine is an antihistamine pharmaceutical used to treat
seasickness, cerebral arteriosclerosis, and cerebral apoplexy
(Towse, G. (1980) The Journal ofLaryngology & Otology 94(9):
1009-1015; Singh, B. N. (1986) British Journal of Clinical
Pharmacology 21(52): 109S-121S; Shupak et al. (1994) Clinical
Pharmacology & Therapeutics 55(6): 670-680). Flunarizine is one
of the most popular antivertiginous drugs (Rascol et al. (1989)
Fundamental & Clinical Pharmacology 3(S1): 79s-87s;
Wilder-Smith et al. (1991) Acta Oncologica 30(6): 731-734) and a
class IV calcium antagonist for a treatment of migraine (Todd and
Benfield (1989) Drugs 38(4): 481-499). Many synthetic approaches
toward the synthesis of Cinnarizine have been reported over the
past decades. These synthetic methods utilized metal reagents such
as Pd (Xie et al. (2012) Journal of the American Chemical Society
134(51): 20613-20616; Beck et al. (2013) RSC Advances 3(43):
20708-20718) and Fe (Shakhmaev et al. (2015) Russ. J Org. Chem.
51(1): 95-97). In pharmaceutical industries, the removal of
impurities such as toxic metal catalysts is a challenging task and
significantly related to the cost of drugs. In this context,
transition metal-free synthetic methods are highly desirable. The
synthetic method disclosed herein below for Cinnarizine and
Flunarizine avoids the use of metal reagents. Without wishing to be
bound by theory, this transformation can demonstrate the continued
importance of NHP's in the production of pharmaceutically
interesting precursors. Preliminary data for the synthesis of
.alpha.-aminophosphonates provided the desired products in 78-87%
yield (see Scheme 8). The Homer-Wadsworth-Emmons (HWE)-type
olefination (Wadsworth, W. S. (1977) Organic Reactions 73-253) and
the base-promoted isomerization reaction (Bartrum et al. (2013)
Tetrahedron 69(10): 2276-2282) would complete the synthesis of
Cinnarizine and Flunarizine (Scheme 15).
##STR00116##
H. PHARMACEUTICAL COMPOSITIONS AND FORMULATIONS
[0279] When employed as pharmaceuticals, the compounds provided
herein can be administered in the form of pharmaceutical
compositions. These compositions can be prepared as described
herein or elsewhere, and can be administered by a variety of
routes, depending upon whether local or systemic treatment is
desired and upon the area to be treated. Administration may be
topical (including, for example, transdermal, epidermal, ophthalmic
and to mucous membranes including, for example, intranasal, vaginal
and rectal delivery), pulmonary (e.g, by inhalation or insufflation
of powders or aerosols, including by nebulizer; intratracheal or
intranasal), oral or parenteral. Parenteral administration includes
intravenous, intraarterial, subcutaneous, intraperitoneal
intramuscular or injection or infusion; or intracranial (e.g.,
intrathecal or intraventricular, administration). Parenteral
administration can be in the form of a single bolus dose, or may
be, for example, by a continuous perfusion pump. Pharmaceutical
compositions and formulations for topical administration may
include transdermal patches, ointments, lotions, creams, gels,
drops, suppositories, sprays, liquids, and powders. Conventional
pharmaceutical carriers, aqueous, powder or oily bases, thickeners,
and the like may be necessary or desirable.
[0280] Also provided are pharmaceutical compositions that contain,
as the active ingredient, a compound provided herein (e.g., a
compound of Formula (IIa) or Formula (IIb)) or a pharmaceutically
acceptable salt thereof, in combination with one or more
pharmaceutically acceptable carriers (excipients). In making the
compositions provided herein, the active ingredient is typically
mixed with an excipient, diluted by an excipient or enclosed within
such a carrier in the form of, for example, a capsule, sachet,
paper, or other container. When the excipient serves as a diluent,
it can be a solid, semi-solid, or liquid material, which acts as a
vehicle, carrier or medium for the active ingredient. Thus, the
compositions can be in the form of tablets, pills, powders,
lozenges, sachets, cachets, elixirs, suspensions, emulsions,
solutions, syrups, aerosols (as a solid or in a liquid medium),
ointments, soft and hard gelatin capsules, suppositories, sterile
injectable solutions, and sterile packaged powders.
[0281] Some examples of suitable excipients include, without
limitation, lactose, dextrose, sucrose, sorbitol, mannitol,
starches, gum acacia, calcium phosphate, alginates, tragacanth,
gelatin, calcium silicate, microcrystalline cellulose,
polyvinylpyrrolidone, cellulose, water, syrup, and methyl
cellulose. The formulations can additionally include, without
limitation, lubricating agents such as talc, magnesium stearate,
and mineral oil; wetting agents; emulsifying and suspending agents;
preserving agents such as methyl- and propylhydroxy-benzoates;
sweetening agents; flavoring agents, or combinations thereof.
[0282] The active compound can be effective over a wide dosage
range and is generally administered in a pharmaceutically effective
amount. It will be understood, however, that the amount of the
compound actually administered will usually be determined by a
physician, according to the relevant circumstances, including the
condition to be treated, the chosen route of administration, the
actual compound administered, the age, weight, and response of the
individual patient, the severity of the patient's symptoms, and the
like.
I. EXAMPLES
[0283] The following examples are put forth so as to provide those
of ordinary skill in the art with a complete disclosure and
description of how the compounds, and/or methods disclosed herein
are made and evaluated, and are intended to be purely exemplary of
the invention and are not intended to limit the scope of what the
inventors regard as their invention. Efforts have been made to
ensure accuracy with respect to numbers (e.g., amounts,
temperature, etc.), but some errors and deviations should be
accounted for. Unless indicated otherwise, parts are parts by
weight, temperature is in .degree. C. or is at ambient temperature,
and pressure is at or near atmospheric.
[0284] The Examples are provided herein to illustrate the
invention, and should not be construed as limiting the invention in
any way. Examples are provided herein to illustrate the invention
and should not be construed as limiting the invention in any
way.
1. General Procedure for the Synthesis of
.alpha.-Aminophosphonates
##STR00117##
[0286] To a solution NHP-thiourea (0.1 mmol, 1.0 equiv) and
aldehyde (0.2 mmol, 2.0 equiv) in 1,2-dichloroethane (0.43 mL) was
added secondary amine (0.2 mmol, 2 equiv) followed by 4 A molecular
sieves and the mixture was stirred at 85.degree. C. for about 14 h.
The solvent was removed under vacuo to obtain crude product which
was purified by column chromatography over silica gel, eluting with
25-35% EtOAc/hexanes to yield the corresponding aminophosphonates
as solids.
a. Synthesis of
(S)-2-(Morpholino(Phenyl)Methyl)-1,3-Diphenyl-1,3,2-Diazaphospholidine
2-Oxide
##STR00118##
[0288] Colorless solid (39.1 mg. 0.090 mmol, 90%). mp:
209-210.degree. C. IR (Neat, cm.sup.-1): 3059, 2962, 2852, 1599,
1498, 1273, 1129, 1033; .sup.1H NMR (400 MHz CDCI.sub.3): .delta.
7.54 (d, J=8.6 Hz, 2H), 7.36 (q, J 7.4 Hz, 4H), 7.25-7.16 (m, 5H),
7.07 (q, J 7.6 Hz, 2H), 6.90 (d, J 7.4 Hz, 2H), 4.07 (d, J 9.2 Hz,
1H), 3.69-3.59 (m, 5H), 3.27 (dq, J 8.6, 2.5 Hz, 1H), 3.03-2.95 (m,
3H), 2.49-2.44 (m, 2H), 2.19 (dq, J 8.4, 2.1 Hz, 1H); .sup.13C NMR
(100 MHz, CDCI.sub.3): .delta. 142.1 (dd, J 38.1, 7.5 Hz), 134.3
(d, J 5.9 Hz), 130.3 (d, J 7.5 Hz), 129.4 (d, J 30.7 Hz), 128.3 (d,
J 3.0 Hz), 128.1 (d, J 2.2 Hz), 122.3 (d, J 47.6 Hz), 117.8 (dd, J
198.9, 3.7 Hz), 72.1 (d, J 129.0 Hz), 67.4, 53.9 (d, J 8.2 Hz),
43.4 (dd, J 57.6, 6.7 Hz); .sup.31P NMR (162 MHz CDCI.sub.3):
.delta. 25.03 ppm; HRMS (ESI) calcd for C25H.sub.28N.sub.3O.sub.2P
[M+Na].sup.+: 456.1811; found: 456.1810.
b. Synthesis of
(S)-2-(Morpholino(4-(Trifluoromethyl)Phenyl)Methyl)-1,3-Diphenyl-1,3,2-Di-
azaphospholidine 2-Oxide
##STR00119##
[0290] Colorless solid (41.7 mg, 0.083 mmol, 83%). mp:
202-204.degree. C. IR (Neat, cm-1): 3059, 2960, 2858, 1599, 1504,
1269, 1166, 1033; .sup.1H NMR (400 MHz, CDCI.sub.3): .delta.
7.50-7.43 (m, 4H), 7.39-7.34 (m, 4H), 7.24 (d, J=8.2 Hz, 2H),
7.12-7.06 (m, 4H), 4.15 (d, J=10.9, Hz, 1H), 3.72-3.57 (m, 5H),
3.36 (dq, J=8.8, 3.1 Hz, 1H), 1H), 3.12-2.94 (m, 3H), 2.47-2.42 (m,
2H), 2.36 (dq, J=8.4, 3.1 Hz, 1H); .sup.13C NMR (100 MHz,
CDCI.sub.3): .delta. 141.8 (dd, J=45.6, 7.5 Hz), 138.6 (d, J=4.5
Hz), 130.6 (d, J=6.7 Hz), 130.3 (d, J=3.0 Hz), 129.5 (d, J=34.4
Hz), 125.3, 124.9 (t, J=3.7 Hz), 122.8 (d, J=55.3 Hz), 118.1 (dd,
J=219, 4.5 Hz), 71.8 (d, J 128.6 Hz), 67.2, 53.8 (d, J=8.2 Hz),
43.9 (dd, J=56.8, 7.5 Hz); .sup.31P NMR (162 MHz, CDCI.sub.3):
.delta. 24.86 ppm (d, J=1.9 Hz); HRMS (ESI) calcd for
C26H.sub.27F3N.sub.3O.sub.2P [M+Na].sup.+: 524.1685; found
524.1702.
c. Synthesis of
(S)-2-((4-Chlorophenyl)(Morpholino)Methyl)-1,3-Diphenyl-1,3,2-Diazaphosph-
olidine 2-Oxide
##STR00120##
[0292] Off-white solid (40.2, 0.086 mmol, 86%). mp: 185-186.degree.
C. IR (Neat, cm.sup.-1): 3057, 2958, 2852, 1599, 1494, 1269, 1116,
1033, .sup.1H NMR (400 MHz, CDCI.sub.3): .delta. 7.51 (app d, J=8.6
Hz 2H) 6.87-6.83 (m, 2H), 7.39-7.33 (m, 4H), 7.23 (d, J=8.2 Hz,
2H), 7.16 (d, J=8.4 Hz, 2H) 7.09 (q, J=7.4 Hz, 2H), 4.05 (d, J=9.9
Hz, 1H), 3.73-3.57 (m, 5H), 3.35 (dq, J=9.0, 2.3 Hz, 1H), 3.12-2.94
(m, 3H), 2.46-2.40 (m, 2H), 2.35 (dq, J=8.4, 2.7 Hz, 1H); .sup.13C
NMR (100 MHz, CDCI.sub.3): .delta. 141.8 (dd, J=41.9, 7.5 Hz),
134.1 (d, J=3.7 Hz), 132.9 (d, J=5.2 Hz), 131.5 (d, J=6.2 Hz),
129.4 (d, J=31.7 Hz), 128.3 (d, J=2.2 Hz), 122.4 (d, J=47.1 Hz),
117.9 (dd, J=207.1, 3.7 Hz), 71.4 (d, J=128.6 Hz), 67.3, 53.9 (d,
J=8.2 Hz), 43.7 (dd, J=47.9, 7.5 Hz); .sup.31P NMR (162 MHz,
CDCI.sub.3): .delta. 25.80 ppm; HRMS (ESI) calcd for
C.sub.26H.sub.27CIN.sub.3O.sub.2P [M+Na].sup.+: 490.1422; found:
490.1424.
d. Synthesis of
(S)-2-((4-Bromophenyl)(Morpholino)Methyl)-1,3-Diphenyl-1,3,2-Diazaphospho-
lidine 2-Oxide
##STR00121##
[0294] Pale brown solid (46.4, 0.091 mmol, 91%). mp:
169-172.degree. C. IR (Neat, cm.sup.-1): 3057, 2852, 1599, 1504,
1269, 1163, 1008; .sup.1H NMR (400 MHz, CDCI.sub.3): .delta. 7.50
(d, J=8.0 Hz, 2H), 7.38-7.31 (m, 6H), 7.22 (d, J=8.0 Hz, 2H), 7.08
(q, J=7.8 Hz, 2H), 6.79 (d, J=8.2 Hz, 2H), 4.04 (d, J=9.9 Hz, 1H),
3.72-3.57 (m, 5H), 3.34 (q, J=11.1, 2.5 Hz, 1H), 3.11-2.99 (m, 3H),
2.44-2.32 (m, 3H): .sup.13C NMR (100 MHz, CDCI.sub.3): .delta.
141.8 (dd, J=41.4, 7.5 Hz), 133.4 (d, J=5.4 Hz), 133.4 (d, J=5.4
Hz), 131.8 (d, J=6.7 Hz), 131.2 (d, J=2.2 Hz), 129.4 (d, J=32.2
Hz), 122.6 (d, J=46.4 Hz), 122.3 (d, J=4.5 Hz), 117.9 (dd, J=206.4,
3.7 Hz), 71.4 (d, J=128.6 Hz), 67.2, 53.8 (d, J=7.5 Hz), 43.6 (dd,
J=46.4, 6.7 Hz); .sup.31P NMR (162 MHz, CDCI.sub.3): .delta. 25.64
ppm; HRMS (ESI) calcd for C26H.sub.27BRN.sub.3N.sub.3O.sub.2P
[M+Na].sup.+: 534.0916; found: 534.0925.
e. Synthesis of
(S)-2-((2,4-Dichlorophenyl)(Morpholino)Methyl)-1,3-Diphenyl-1,3,2-Diazaph-
ospholidine 2-Oxide
##STR00122##
[0296] Colorless solid (43.8 mg, 0.087 mmol, 87%). mp:
168-170.degree. C. IR (Neat, cm.sup.-1): 3072, 2968, 2852, 1599,
1502, 1269, 1114, 1033; .sup.1H NMR (400 MHz, CDCI.sub.3): .delta.
7.42-7.31 (m, 5H), 7.26-7.16 (m, 5H), 7.07 (t, J=7.2 Hz, 1H),
7.00-6.95 (m, 2H), 4.78 (d, J=17.8, Hz, 1H), 3.72-3.58 (m, 3H),
3.47-3.38 (m, 5H), 2.66-2.57 (m, 4H); .sup.13C NMR (100 MHz,
CDCI.sub.3): .delta. 142.1 (dd, J=101.7, 6.7 Hz), 136.4 (d, J=11.9
Hz), 134.5 (d, J=3.0 Hz), 133.5 (d, J=4.5 Hz), 129.4, 129.2 (d,
J=28.4 Hz), 129.0 (d, J=3.0 Hz), 126.4 (d, J=1.5 Hz), 122.9 (d,
J=6.0 Hz), 118.9 (dd, J=52.4, 3.7 Hz), 67.1, 65.7 (d, J=136.1 Hz),
52.4 (d, J=8.2 Hz), 44.2 (dd, J=13.5, 8.2 HZ); .sup.31P NMR (162
MHz, CDCI.sub.3): .delta. 23.80 ppm; HRMS (ESI) calcd for
C.sub.25H.sub.26CI.sub.2N.sub.3O.sub.2P [M+Na].sup.+: 524.1032;
found: 524.1032.
f. Synthesis of
(S)-2-((2-Bromo-4-Methylphenyl)(Morpholino)Methyl)-1,3-Diphenyl-1,3,2-Dia-
zaphospholidine 2-Oxide
##STR00123##
[0298] Colorless solid (48.9 mg, 0.093 mmol, 93%). mp:
169-171.degree. C. IR (Neat, cm.sup.-1): 3059, 2957, 2854, 1599,
1494, 1269, 1116, 1037; .sup.1H NMR (400 MHz, CDCI.sub.3): .delta.
7.39 (d, J=7.8 Hz, 2H), 7.34-7.25 (m, 5H), 7.21-7.16 (m, 3H), 7.05
(t, J=8.2 Hz, 1H), 6.94 (t, J=7.2 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H),
4.85 (d, J=18.1 Hz, 1H), 3.71-3.54 (m, 3H), 3.48 (t, J=8.8, Hz,
4H), 3.47-3.27 (m, 1H), 2.65 (bs, 4H), 2.20 (s, 3H); .sup.13C NMR
(100 MHz, CDCI.sub.3): .delta. 142.3 (dd, J=95.7, 6.7 Hz), 139.8
(d, J=2.2 Hz), 133.5, 132.5 (d, J=4.5 Hz), 129.1 (d, J=32.9 Hz),
128.8 (d, J=3.0 Hz), 127.5 (d, J=2.0 Hz), 126.9 (d, J=11.9 Hz),
122.5 (d, J=13.5 Hz), 118.59 (dd, J=50.1, 3.7 Hz), 69.2 (d, J=216.0
Hz), 67.2, 52.4 (d, J=8.9 Hz), 44.0 (dd, J=21.7, 8.2 Hz), 20.7;
.sup.31P NMR (162 MHz CDCI.sub.3): .delta. 25.00 ppm; HRMS (ESI)
calcd for C.sub.26H.sub.29BrN.sub.3O.sub.2P [M+Na].sup.+: found:
548.1070.
g. Synthesis of
(S)-2-(Morpholino(Thiophen-2-Yl)Methyl)-1,3-Diphenyl-1,3,2-Diazaphospholi-
dine 2-Oxide
##STR00124##
[0300] Colorless solid (30.3 mg, 0.069 mmol, 69%. mp:
207-209.degree. C. IR (Neat, cm.sup.-1): 3059, 2918, 2848, 1599,
1496, 1273, 1112, 1033; .sup.1H NMR (400 MHz CDCI.sub.3): .delta.
7.50 (d, J=7.6 Hz, 2H), 7.36-7.26 (m, 6H), 7.19 (d, J=5.1 Hz, 1H),
7.07 (t, J=7.2 Hz, 2H), 6.86 (d, J=4.5 Hz, 1H), 6.58 (bs, 1H), 4.38
(d, J=15.1 Hz, 1H), 3.79 (m, 1H), 3.59-3.43 (m, 6H), 2.91-2.84 (m,
1H), 2.70 (bs, 2H) 2.54-2.49 (m. 2H): .sup.13C NMR (100 MHz,
CDCI.sub.3): .delta. 142.0 (dd, J=62.1, 7.5 Hz), 135.3 (d, J=1.5
Hz), 129.3 (d, J=26.2 Hz), 128.9 (d, J=8.2 Hz), 126.6 (d, J=2.2
Hz), 126.2 (d, J=3.0 Hz), 122.8 (d, J=57.6 Hz), 118.7 (dd, J=223.6,
3.6 Hz), 67.2, 66.1 (d, J=136.1 Hz), 52.9 (d, J=7.5 Hz), 44.4 (dd,
J=94.2, 6.7 Hz), .sup.31P NMR (162 MHz, CDCI.sub.3): .delta. 24.71
ppm; HRMS (ESI) calcd for C.sub.23H.sub.26N.sub.3O.sub.2PS
[M+Na].sup.+: 462.1376; found: 462.1378.
h. Synthesis of
(S)-2-(1-Morpholinobutyl)-1,3-Diphenyl-1,3,2-Diazaphospholidine
2-Oxide
##STR00125##
[0302] Off-white solid (25.0 mg, 0.063 mmol, 63%), mp:
165-167.degree. C. IR (Neat, cm.sup.-1): 3059, 2957, 2870, 1599,
1502, 1271, 1116, 1033; .sup.1H NMR (400 MHz, CDCI.sub.3): .delta.
7.34-7.29 (m, 8H), 7.03-7.00 (m, 2H), 4.10-4.03 (m, 1H), 3.84-3.80
(m, 3H), 3.53-3.46 (m, 4H), 3.25-2.17 (m, 1H), 2.54-2.52 (m, 2H),
2.19-2.17 (m, 2H), 2.02-1.93 (m, 1H), 1.85-1.71 (m, 1H), 1.56-1.26
(m, 2H), 0.88 (t, J=6.1 Hz, 3H); .sup.13C NMR (100 MHz,
CDCI.sub.3): .delta. 142.8 (dd, J=34.4, 8.2 Hz), 129.5 (d, J=3.0
Hz), 122.1 (d, J=12.7 Hz), 117.0 (dd, J=29.9, 4.5 Hz), 67.7, 63.6
(d, J=129.0 Hz), 51.0, 44.3 (dd, J=83.8, 5.9 Hz), 28.9 (d, J=5.9
Hz), 23.2 (d, J=17.2 Hz), 13.9 (d, J=1.5 Hz); .sup.31P NMR (162
MHz, CDCI.sub.3): .delta. 32.52 ppm; HRMS (ESI) calcd for
C.sub.22H.sub.30N.sub.3O.sub.2P [M+Na].sup.+: found 422.1975.
i. Synthesis of
(S)-2-((2-Fluorophenyl)(Morpholino)Methyl)-1,3-Diphenyl-1,3,2-Diazaphosph-
olidine 2-Oxide
##STR00126##
[0304] Colorless solid (39.8 mg, 0.088 mmol, 88%). mp:
178-179.degree. C. IR (Neat, cm.sup.-1): 3055, 2966, 2854, 1600,
1494, 1269, 1114, 1033; .sup.1H NMR (400 MHz, CDCI.sub.3): .delta.
7.37-7.23 (m, 9H), 7.19-7.13 (m, 1H), 7.09-7.05 (m, 1H), 7.00 (t,
J=7.2 Hz, 1H), 6.94-6.87 (m, 2H), 4.57 (d, J=16.0 Hz, 1H) 3.71
(quint, J=8.0 Hz, 1H), 3.58-3.41 (m, 6H), 3.15-3.08 (m, 1H),
2.62-2.53 (m, 4H); .sup.13C NMR (100 MHz, CDCI.sub.3): .delta.
161.3 (dd, J=247.6, 9.7 Hz), 142.4 (dd, J 68.8, 7.5 Hz), 132.4 (dd,
J=4.5, 3.0 Hz), 129.8 (dd, J=8.2, 2.2 Hz), 129.2 (d, J=17.9 Hz),
123.5 (dd, J=3.7, 2.2 Hz), 122.7 (d, J=10.5 Hz), 120.0 (d, J=14.9
Hz), 118.5 (dd, J=84.5, 3.7 Hz), 115.4 (d, J=23.2 Hz), 67.2, 62.5
(d, J=136.9 Hz), 52.8 (d, J=7.5 Hz), 44.1 (dd, J=17.2, 7.5 Hz);
.sup.31P NMR (162 MHz, CDCI.sub.3): .delta. 25.14 ppm (d, J=7.1
Hz); HRMS (ESI) calcd for C.sub.25H.sub.27FN.sub.3N.sub.3O.sub.2P
[M+Na].sup.+: found: 474.1720.
j. Synthesis of
(S)-2-((4-Fluorophenyl)(Morpholino)Methyl)-1,3-Diphenyl-1,3,2-Diazaphosph-
olidine 2-Oxide
##STR00127##
[0306] Colorless solid (39.1 mg, 0.087 mmol, 87%). mp:
194-196.degree. C. IR (Neat, cm.sup.-1): 3059, 2976, 2854, 1600,
1504, 1273, 1114, 1033; .sup.1H NMR (400 MHz, CDCI.sub.3): .delta.
7.51 (d, J=8.0 Hz, 2H), 7.38-7.33 (m, 4H), 7.22 (d, J=8.0 Hz, 2H),
7.08 (q, J=7.2 Hz, 2H), 6.88 (d, J=7.2 Hz, 4H), 4.05 (d, J=9.8 Hz,
1H), 3.72-3.58 (m, 5H), 3.33 (q, J=8.6 Hz, 1H), 3.11-2.98 (m, 3H),
2.46-2.30 (m, 3H); .sup.13C NMR (100 MHz, CDCI.sub.3): .delta.
162.5 (dd, J=248.3, 3.0 Hz), 142.4 (dd, J=42.6, 7.5 Hz), 131.8 (t,
J=7.5 Hz), 130.1 (t, J=3.0 Hz), 129.3 (d, J=30.7 Hz), 122.5 (d,
J=44.9 Hz), 117.9 (dd, J=203.4, 3.7 Hz), 115.1 (dd, J=21.7, 2.2
Hz), 71.2 (d, J=129.4 Hz), 67.3, 53.8 (d, J=8.2 Hz), 43.6 (dd,
J=51.6, 7.5 Hz); .sup.31P NMR (162 MHz, CDCI.sub.3): .delta. 26.33
ppm (d, J=4.9 Hz); HRMS (ESI) calcd for
C.sub.25H.sub.27FN.sub.3O.sub.2P [M+Na].sup.+: 474.1717; found:
474.1718.
k. Synthesis of
(S)-2-(Morpholino(P-Tolyl)Methyl)-1,3-Diphenyl-1,3,2-Diazaphospholidine
2-Oxide
##STR00128##
[0308] Off-white solid (37.2 mg, 0.083 mmol, 83%). mp:
189-190.degree. C. IR (Neat, cm.sup.-1): 3055, 2957, 2850, 1599,
1496, 1271, 1116, 1033; .sup.1H NMR (400 MHz, CDCI.sub.3): .delta.
7.54 (d, J=8.0 Hz, 2H), 7.36 (q, J=7.4 Hz, 4H), 7.22 (d, J=8.0 Hz,
2H), 7.08 (q, J=7.2 Hz, 2H), 6.98 (d, J=7.8 Hz, 2H), 6.78 (d, J=6.3
Hz, 2H), 4.03 (d, J=9.2 Hz, 1H), 3.69-3.60 (m, 5H), 3.27 (q, J=10.8
Hz, 1H), 3.05-2.96 (m, 3H), 2.48-2.42 (m, 2H), 2.29 (s, 3H), 2.21
(q, J=7.2 Hz, 1H); .sup.13C NMR (100 MHz, CDCI.sub.3): .delta.
142.1 (dd, J=38.1, 7.5 Hz), 138.1 (d, J=3.7 Hz), 131.1 (d, J=5.2
Hz), 130.2 (d, J=7.5 Hz), 129.3 (d, J=29.9 Hz), 128.8 (d, J=3.0
Hz), 122.2 (d, J=31.4 Hz), 117.7 (dd, J=178.0, 4.5 Hz), 72.2 (d,
J=129.4 Hz), 67.4, 53.9 (d, J=8.2 Hz), 43.4 (dd, J=41.4, 6.7 Hz),
21.3; .sup.31P NMR (162 MHz, CDCI.sub.3): .delta. 27.14 ppm; HRMS
(ESI) calcd for C.sub.26H.sub.30N.sub.3O.sub.2P [M+Na].sup.+:
470.1968; found: 470.1964.
l. Synthesis of
(S)-2-(Morpholino(O-Tolyl)Methyl)-1,3-Diphenyl-1,3,2-Diazaphospholidine
2-Oxide
##STR00129##
[0310] Off-white solid (35.3 mg, 0.079 mmol, 79%). mp:
199-201.degree. C. IR (Neat, cm.sup.-1): 3057, 2957, 2850, 1599,
1494, 1271, 1116, 1033; .sup.1H NMR (400 MHz, CDCI.sub.3): .delta.
7.57 (d, J=8.2 Hz, 2H), 7.39-7.28 (m, 5H), 7.19 (d, J=8.2 Hz, 2H),
7.14-7.01 (m, 5H), 4.44 (d, J=10.6 Hz, 1H), 3.75-3.55 (m, 5H),
3.34-3.01 (m, 4H), 2.48-2.44 (m, 2H), 2.31 (q, J=8.2 Hz, 1H), 1.59
(s, 3H); .sup.13C NMR (100 MHz, CDCI.sub.3): .delta. 142.3 (dd,
J=58.3, 7.5 Hz), 138.4 (d, J=8.9 Hz), 132.0 (d, J=3.7 Hz), 130.8
(d, J=1.5 Hz), 130.7, 128.7 (d, J=36.6 Hz), 127.8 (d, J=2.2 Hz),
125.3 (d, J=3.0 Hz), 122.3 (d, J=36.6 Hz), 117.8 (dd, J=205.7, 3.7
Hz), 67.4, 53.7 (d, J=8.9 Hz), 43.9 (d, J=7.5 Hz), 43.2 (d, J=6.7
Hz), 19.6; .sup.31P NMR (162 MHz, CDCI.sub.3): .delta. 27.72 ppm;
HRMS (ESI) calcd for C.sub.26H.sub.30N.sub.3O.sub.2P [M+Na:
470.1968; found: 470.1973.
m. Synthesis of
(S)-2-((4-Methoxyphenyl)(Morpholino)Methyl)-1,3-Diphenyl-1,3,2-Diazaphosp-
holidine 2-Oxide
##STR00130##
[0312] Off-white solid (34.1 mg, 0.074 mmol, 74%). mp:
178-180.degree. C. IR (Neat, cm.sup.-1): 3059, 2960, 2854, 1600,
1504, 1271, 1116, 1033; .sup.1H NMR (400 MHz, CDCI.sub.3): .delta.
7.54 (d, J=7.8 Hz, 2H), 7.39-7.33 (m, 4H), 7.22 (d, J=8.4 Hz, 2H),
7.08 (q, J=7.2 Hz, 2H), 6.83-6.79 (m, 2H), 6.71 (d, J=2.7 Hz, 2H),
4.02 (d, J=8.8 Hz, 1H), 3.77 (s, 3H), 3.73-3.61 (m, 5H), 3.31 (dq,
J=8.6, 2.5 Hz, 1H), 3.09-3.02 (m, 3H), 2.47-2.42 (m, 2H), 2.30 (dq,
J=8.6, 2.5 Hz, 1H); .sup.13C NMR (100 MHz, CDCI.sub.3): .delta.
159.5 (d, J=2.2 Hz), 142.2 (dd, J=40.4, 7.5 Hz), 131.5 (d, J=6.7
Hz), 129.3 (d, J=29.9 Hz), 126.2 (d, J=5.2 Hz), 122.3 (d, J=32.9
Hz), 117.8 (dd, J=180.3, 4.5 Hz), 113.5 (d, J=2.2 Hz), 71.3 (d,
J=130.1 Hz), 67.4, 55.4, 53.8 (d, J=8.2 Hz), 43.6 (dd, J=37.4, 6.7
Hz); .sup.31P NMR (162 MHz, CDCI.sub.3): .delta. 27.40 ppm; HRMS
(ESI) calcd for C.sub.26H.sub.30N.sub.3O.sub.3P
[M+Na].sup.+486.1917; found: 486.1925.
n. Synthesis of
(S)-2-((2-Bromo-4-Chlorophenyl)(Morpholino)Methyl)-1,3-Diphenyl-1,3,2-Dia-
zaphospholidine 2-Oxide
##STR00131##
[0314] Off-white solid (45.4 mg, 0.083 mmol, 83%). mp:
176-178.degree. C. IR (Neat, cm.sup.-1): 3061, 2962, 2854, 1599,
1504, 1267, 1116, 1035; .sup.1H NMR (400 MHz, CDCI.sub.3): .delta.
7.43-7.31 (m, 6H), 7.22 (d, J=7.8 Hz, 2H), 7.16 (t, J=8.6 Hz, 2H),
7.07 (t, J=6.3 Hz, 1H), 7.02-6.93 (m, 2H), 4.80 (d, J=18.2 Hz, 1H),
3.72-3.62 (m, 3H), 3.48-3.41 (m, 5H), 2.69-2.56 (m, 4H); .sup.13C
NMR (100 MHz, CDCI.sub.3): .delta. 142.4 (dd, J=108.4, 6.7 Hz),
134.6 (d, J=2.2 Hz), 133.5 (d, J=3.7 Hz), 132.5, 130.6 (d, J=3.7
Hz), 129.2 (d, J=29.9 Hz), 127.2 (d, J=11.9 Hz), 126.9 (d, J=2.2
Hz), 122.9, 118.9 (dd, J=40.4, 3.7 Hz), 68.5 (d, J=135.4 Hz), 67.1,
52.2 (d, J=7.5 Hz), 44.2 (dd, J=17.2, 9.0 Hz); .sup.31P NMR (162
MHz, CDCI.sub.3): .delta. 23.68 ppm; HRMS (ESI) calcd for
C.sub.25H.sub.26BrCIN.sub.3O.sub.2P [M+Na].sup.+: 568.0527; found:
568.0534.
o. Synthesis of
(S)-2-(Furan-2-Yl(Morpholino)Methyl)-1,3-Diphenyl-1,3,2-Diazaphospholidin-
e 2-Oxide
##STR00132##
[0316] Pale brown solid (14.1 mg, 0.033 mmol, 33o/o). mp:
180-183.degree. C. IR (Neat, cm.sup.-1): 3059, 2958, 2854, 1599,
1496, 1273, 1112, 1033; .sup.1H NMR (400 MHz, CDCI.sub.3): .delta.
7.44-7.41 (m, 2H), 7.37-7.30 (m, 6H), 7.24-7.23 (m, 1H), 7.09-7.03
(m, 2H), 6.24 (q, J=1.4 Hz, 1H), 6.06 (q, J=1.4 Hz, 1H), 4.23 (d,
J=20.5 Hz, 1H), 3.82-3.66 (m, 3H), 3.56-3.47 (m, 5H), 2.57-2.52 (m,
2H), 2.34-2.29 (m, 2H); .sup.13C NMR (100 MHz, CDCI.sub.3): .delta.
147.6 (d, J=2.2 Hz), 142.7 (d, J=2.2 Hz), 142.2 (dd, J=7.5 Hz),
129.3 (d, J=3.0 Hz), 122.7 (d, J=8.9 Hz), 118.5 (dd, J=13.5, 4.5
Hz), 122.9, 111.9 (d, J=7.5 Hz), 110.6 (d, J=135.4 Hz), 67.3, 63.3
(d, J=139.1 Hz), 52.4 (d, J=6.7 Hz), 44.1 (d, J=7.5 Hz); .sup.31P
NMR (162 MHz, CDCI.sub.3): .delta. 24.29 ppm; HRMS (ESI) calcd for
C.sub.23H.sub.26N.sub.3O.sub.3P [M+Na].sup.+: 446.1604; found:
446.1603.
p. Synthesis of
(S)-2-((4-Methylpiperazin-1-Yl)(Phenyl)Methyl)-1,3-Diphenyl-1,3,2-Diazaph-
ospholidine 2-Oxide
##STR00133##
[0318] Off-white solid (25.9 mg, 0.059 mmol, 59%). mp:
175-177.degree. C. IR (Neat, cm.sup.-1): 3059, 2933, 2839, 1599,
1494, 1269, 1126, 1035; .sup.1H NMR (400 MHz, CDCI.sub.3): .delta.
7.52-7.49 (m, 2H), 7.38-7.33 (m, 4H), 7.24-7.16 (m, 5H), 7.10-7.05
(m, 2H), 6.90-6.88 (m, 2H), 4.10 (d, J=9.8 Hz, 1H), 3.65 (dq,
J=8.2, 2.7 Hz, 1H), 3.29 (dq, J=8.6, 2.7 Hz, 1H), 3.01 (dq, J=8.4,
2.7 Hz, 1H), 2.58-2.56 (m, 7H), 2.35 (s, 3H), 2.23 (dq, J=8.4, 2.5
Hz, 2H); .sup.13C NMR (100 MHz, CDCI.sub.3): .delta. 142.1 (dd,
J=24.7, 7.5 Hz), 134.4 (dl J=4.5 Hz), 130.2 (d, J=6.7 Hz), 129.4
(d, J=34.4 Hz), 128.4 (d, J=3.0 Hz), 128.1 (d, J=2.2 Hz), 122.3 (d,
J=27.7 Hz), 117.8 (dd, J=185.5, 4.5 Hz), 72.0 (d, J=129.4 Hz),
55.2, 52.1, 45.3, 43.4 (dd, J=57.8, 6.7 Hz); .sup.31P NMR (162 MHz,
CDCI.sub.3): .delta. 25.11 ppm; HRMS (ESI) calcd for
C.sub.26H.sub.31N.sub.4OP [M+Na].sup.+: 469.2128; found:
469.2126.
q. Synthesis of
(S)-2-((4-Cyclohexylpiperazin-1-Yl)(Phenyl)Methyl)-1,3-Diphenyl-1,3,2-Dia-
zaphospholidine 2-Oxide
##STR00134##
[0320] Off-white solid (35.2 mg, 0.068 mmol, 68%). mp:
180-182.degree. C. IR (Neat, cm.sup.-1): 3059, 2931, 2856, 1599,
1494, 1269, 1124, 1035; .sup.1H NMR (400 MHz, CDCI.sub.3): .delta.
7.48 (d, J=8.4 Hz, 2H), 7.37-7.31 (m, 4H), 7.25-7.16 (m, 5H), 7.08
(t, J=7.4 Hz, 2H), 6.86 (d, J=7.6 Hz, 2H), 4.16 (d, J=9.4 Hz, 1H),
3.62 (dq, J=7.8, 2.7 Hz, 1H), 3.30 (dq, J=8.6, 2.7 Hz, 1H),
3.03-2.66 (m, 8H), 2.27 (dq, J=8.4, 2.5 Hz, 1H), 2.05 (d, J=10.4
Hz, 2H), 1.85 (d, J=12.9 Hz, 2H), 1.67 (d, J=12.7 Hz, 2H),
1.39-1.08 (m, 6H); .sup.13C NMR (100 MHz, CDCI.sub.3): .delta.
142.0 (dd, J=11.9, 8.2 Hz), 133.8 (d, J=5.2 Hz), 130.1 (d, J=6.7
Hz), 129.4 (d, J=48.6 Hz), 128.5 (d, J=3.0 Hz), 128.2 (d, J=2.2
Hz), 122.4 (d, J=11.9 Hz), 117.7 (dd, J=189.9, 3.7 Hz), 70.9 (d,
J=130.2 Hz), 64.7, 50.8, 49.0, 43.5 (dd, J=72.5, 6.7 Hz), 27.6,
25.4, 25.3; .sup.31P NMR (162 MHz, CDCI.sub.3): .delta. 26.29 ppm;
HRMS (ESI) calcd for C.sub.31H.sub.39N4OP [M+Na].sup.+: 515.2934;
found: 515.2951.
r. Synthesis of
(S)-2-((4-Benzhydrylpiperazin-1-Yl)(Phenyl)Methyl)-1,3-Diphenyl-1,3,2-Dia-
zaphospholidine 2-Oxide
##STR00135##
[0322] Colorless solid (52.1 mg, 0.052 mmol, 87%). mp:
176-178.degree. C. IR (Neat, cm.sup.-1): 3059, 2962, 2808, 1599,
1494, 1269, 1128, 1033; .sup.1H NMR (400 MHz, CDCI.sub.3): .delta.
7.47 (d, J=7.8 Hz, 2H), 7.38 (d, J=7.8 Hz, 2H), 7.37-7.29 (m, 6H),
7.24-7.02 (m, 13H), 6.87 (d, J=6.3 Hz, 2H), 4.14 (s, 1H), 4.10 (d,
J=11.3 Hz, 1H), 3.64 (dq, J=7.8, 2.9 Hz, 1H), 3.28 (dq, J=8.6, 2.7
Hz, 1H), 3.07 (dq, J=8.7, 3.0 Hz, 1H), 2.51-2.31 (m, 9H); .sup.13C
NMR (100 MHz, CDCI.sub.3): .delta. 142.8 (d, J=3.7 Hz), 142.2 (dd,
J=53.1, 7.5 Hz), 134.4 (d, J=3.7 Hz), 130.4 (d, J=7.5 Hz), 129.3
(d, J=23.2 Hz), 128.5 (d, J=6.7 Hz), 128.1 (d, J=3.0 Hz), 128.0,
127.9 (d, J=3.0 Hz, 1H), 122.1 (d, J=19.5 Hz), 117.8 (dd, J=137.6,
3.7 Hz), 76.2, 71.8 (d, J=129.4 Hz), 53.3, 52.3, 43.5 (dd, J=24.7,
6.7 Hz); .sup.31P NMR (162 MHz, CDCI.sub.3): .delta. 27.21 ppm;
HRMS (ESI) calcd for C.sub.38H.sub.39N.sub.4OP [M+Na].sup.+:
621.2754; found: 621.2763.
s. Synthesis of
(S)-1,3-Diphenyl-2-(Phenyl(Thiomorpholino)Methyl)-1,3,2-Diazaphospholidin-
e 2-Oxide
##STR00136##
[0324] Off-white solid (22.1 mg, 0.049 mmol, 49%). mp:
191-193.degree. C. IR (Neat, cm.sup.-1): 3057, 2951, 2883, 1599,
1494, 1271, 1114, 1033; .sup.1H NMR (400 MHz, CDCI.sub.3): .delta.
7.45 (d, J=7.8 Hz, 2H), 7.35 (q, J=6.4 Hz, 4H), 7.28-7.16 (m, 5H),
7.08 (qt, J=7.4, 1.2 Hz, 2H), 6.93 (d, J=6.8 Hz, 2H), 4.18 (d,
J=7.3 Hz, 1H), 3.70-3.63 (m, 1H), 3.38 (dq, J=8.2, 2.7 Hz, 1H),
3.23 (dq, J=8.6, 2.7 Hz, 1H), 3.08-3.03 (m, 2H), 2.86-2.80 (m, 2H),
2.61-2.51 (m, 5H); .sup.13C NMR (100 MHz, CDCI.sub.3): .delta.
142.0 (dd, J=43.4, 7.5 Hz), 133.7 (d, J=2.2 Hz), 130.3 (d, J=7.5
Hz), 129.2 (d, J=23.2 Hz), 128.1 (d, J=3.0 Hz), 127.9 (d, J=1.5
Hz), 122.4 (d, J=38.1 Hz), 118.1 (dd, J=158.6, 3.7 Hz), 72.1 (d,
J=130.1 Hz), 54.6 (d, J=8.2 Hz), 43.7 (dd, J=73.3, 6.7 Hz), 27.9;
.sup.31P NMR (162 MHz, CDCI.sub.3): .delta. 26.51 ppm; HRMS (ESI)
calcd for C.sub.25H.sub.28N.sub.3OPS [M+Na].sup.+: 472.1583; found:
472.1589.
t. Synthesis of
2-((1S)-(3,5-Dimethylmorpholino)(Phenyl)Methyl)-1,3-Diphenyl-1,3,2-Diazap-
hospholidine 2-Oxide
##STR00137##
[0326] Off-white solid (40.4 mg, 0.087 mmol, 87%). mp:
188-189.degree. C. IR (Neat, cm.sup.-1): 3061, 2972, 2874, 1599,
1494, 1269, 1126, 1035; .sup.1H NMR (400 MHz, CDCI.sub.3): .delta.
7.52 (d, J=8.6 Hz, 2H), 7.34 (t, J=8.2 Hz, 4H), 7.25-7.16 (m, 5H),
7.06 (q, J=7.2 Hz, 2H), 6.91-6.89 (m, 2H), 4.09-4.05 (m, 2H),
3.70-3.62 (m, 2H), 3.56-3.50 (m, 1H), 3.29 (dq, J=8.8, 2.7 Hz, 1H),
3.07 (dq, J=8.4, 2.7 Hz, 1H), 2.50 (d, J=11.3 Hz, 1H), 2.24 (dq,
J=8.4, 2.5 Hz, 1H), 2.00 (t, J=10.7 Hz, 1H), 1.39 (t, J=10.7 Hz,
1H), 1.18 (d, J=6.3 Hz, 3H), 0.93 (t, J=6.3 Hz, 3H); .sup.13C NMR
(100 MHz, CDCI.sub.3): .delta. 142.1 (dd, J=39.6, 7.5 Hz), 134.3
(d, J=4.5 Hz), 130.3 (d, J=7.5 Hz), 129.3 (d, J=29.2 Hz), 128.2 (d,
J=3.0 Hz), 128.1 (d, J=2.2 Hz), 122.4 (d, J=52.3 Hz), 117.9 (dd,
J=216.9, 3.7 Hz), 71.9 (d, J=6.7 Hz), 71.8 (d, J=128.6 Hz), 60.1
(d, J=2.2 Hz), 58.2 (d, J=13.5 Hz), 43.6 (dd, J=74.8, 6.7 Hz), 19.3
(d, J=14.9 Hz); .sup.31P NMR (162 MHz, CDCI.sub.3): .delta. 26.66
ppm; HRMS (ESI) calcd for C.sub.27H.sub.32N.sub.3O.sub.2P
[M+Nat].sup.+: 484.2124; found: 484.2126.
u. Synthesis of
(S)-1-((2-Oxido-1,3-Diphenyl-1,3,2-Diazaphospholidin-2-Yl)(Phenyl)Methyl)-
Piperidin-4-One
##STR00138##
[0328] Off-white solid (19.3 mg, 0.043 mmol, 43%). mp:
151-154.degree. C. IR (Neat, cm.sup.-1): 3059, 2970, 2887, 1716,
1599, 1504, 1271, 1118, 1035; .sup.1H NMR (400 MHz, CDCI.sub.3):
.delta. 7.50 (d, J=8.4 Hz, 2H), 7.37-7.15 (m, 9H), 7.10-6.96 (m,
4H), 4.23 (d, J=11.3 Hz, 1H), 3.66 (dq, J=8.0, 3.1 Hz, 1H), 3.34
(dq, J=8.8, 3.2 Hz, 1H), 3.22 (quint, J=5.6 Hz, 2H), 3.15 (dq,
J=8.4, 4.7 Hz, 1H), 2.86 (quint, J=7.0 Hz, 2H), 2.42-2.24 (m, 5H);
.sup.13C NMR (100 MHz, CDCI.sub.3): .delta. 209.2, 142.1 (dd,
J=27.7, 7.5 Hz), 134.7 (d, J=3.7 Hz), 130.0 (d, J=6.7 Hz), 129.3
(d, J=27.7 Hz), 128.5 (d, J=2.2 Hz), 128.3 (d, J=2.2 Hz), 122.5 (d,
J=59.8 Hz), 118.1 (dd, J=214.7, 5.3 Hz), 70.8 (d, J=129.4 Hz), 52.6
(d, J=8.2 Hz), 43.8 (dd, J=106.2, 7.5 Hz), 41.4; .sup.31P NMR (162
MHz, CDCI.sub.3): .delta. 26.03 ppm; HRMS (ESI) calcd for
C.sub.26H.sub.28N.sub.3O.sub.2P [M+Nat].sup.+: 468.1811; found:
468.1814.
v. Synthesis of
2-(Morpholinomethyl)-1,3-Diphenyl-1,3,2-Diazaphospholidine
2-Oxide
##STR00139##
[0330] Off-white solid (25.5 mg, 0.071 mmol, 71%). mp:
170-172.degree. C. IR (Neat, cm.sup.-1): 3061, 2957, 2850, 1599,
1494, 1271, 1116, 1033; .sup.1H NMR (400 MHz, CDCI.sub.3): .delta.
7.36-7.27 (m, 8H), 7.03 (app t, J=5.9 Hz, 2H), 3.92-3.86 (m, 4H),
3.48-3.46 (m, 4H), 3.12 (d, J=8.0 Hz, 2H), 2.18-2.16 (m, 4H);
.sup.13C NMR (100 MHz, CDCI.sub.3): .delta. 142.0 (d, J=8.2 Hz),
129.7, 122.1, 116.5 (d, J=4.5 Hz), 67.3, 54.9 (d, J=8.2 Hz), 54.2
(d, J=137.6 Hz), 44.0 (d, J=6.0 Hz); .sup.31P NMR (162 MHz,
CDCI.sub.3): .delta. 29.86 ppm; HRMS (ESI) calcd for
C.sub.19H.sub.24N.sub.3O.sub.2P [M+Nat].sup.+: 380.1498; found:
380.1492.
2. Synthesis of
1-(2-((1,3-Diphenyl-1,3,2-Diazaphospholidin-2-Yl)Oxy)-2-Methylpropyl)-3-P-
henylthiourea
##STR00140##
[0332] .sup.1H (CDCI.sub.3, 400 MHZ): .delta. 7.91 (bs, 1H),
7.46-6.88 (m, 15H), 6.24 (bs, 1H), 3.51-3.40 (m, 6H), 1.24 (s, 6H);
.sup.13C (CDCI.sub.3, 100.5 MHZ): .delta. 180.3, 144.6 (d, J=17.1
Hz), 130.3, 129.9, 129.3, 126.9, 125.0, 120.1, 115.9 (d, J=14.1
Hz), 56.3, 46.2 (d, J=8.6 Hz), 26.7 (d, J=9.7 Hz).
3. Optimization of Reaction Conditions
[0333] A highly reactive phosphorus nucleophile is key to achieving
mild and efficient phosphonylation of .alpha.-aminophosphonates
employing amines and aldehydes. To generate the active phosphite
species in-situ, additives are typically required to facilitate
phosphonate-phosphite tautomerization because non-nucleophilic
phosphonates are the predominant form under neutral conditions
(FIG. 1A and FIG. 1B) (Suyama et al. (2010) Angew. Chem. Int. Ed.
49: 797-799; Mastryukova et al. (1980) Pure Appl. Chem. 52:
945-957; Hammond (1962) J. Chem. Soc. 1365-1369). Hence, the design
and synthesis of highly nucleophilic phosphite derivatives is
desirable (FIG. 1C).
[0334] A recent study on a previously unknown N-heterocyclic
phosphine (NHP)-thiourea has demonstrated a strong nucleophilicity
toward allene electrophiles affording vinyldiazaphosphonates via
phospha-Michael/intramolecular nucleophilic displacement under mild
reaction conditions (Mulla et al. (2015) J. Org. Chem.). Without
wishing to be bound by theory, it is therefore hypothesized that an
effective phosphonylation reagent for tertiary
.alpha.-aminophosphonates would contain: (a) an N-heterocyclic
phosphine (NHP) as a strong phosphorus nucleophile in favor of
phospha-Mannich process and (b) a Bronsted acid motif to accelerate
the intramolecular nucleophilic displacement in the absence of
additives.
[0335] To test this hypothesis, a one-pot multicomponent reaction
among benzaldehyde 1a, morpholine 2a, and NHP-thiourea 3a without
base or metal additives was explored (Table 1). An initial reaction
in THF provided a moderate yield of the .alpha.-N-heterocyclic
phosphonates (entry 1, 48%). Sequential screening of polar solvents
such as CH3CN and EtOH generated the desired product in high yields
at elevated temperatures (entries 2-3, 69-83%). Further increase in
reaction temperature using high boiling point solvents such as
toluene and xylene (entries 4, 5) was found to cause significant
decomposition of NHP to ethylenedianiline, resulting in lowered
yields (41-69%). Next, halogenated solvents such as CHCl3 and
1,2-DCE were investigated (entries 6, 7). Exploring the chlorinated
solvents provided an optimum solvent of 1,2-DCE for this
transformation, yielding the desired product in 90% (entry 7).
TABLE-US-00001 TABLE 1 ##STR00141## ##STR00142## entry solvent t
(.degree. C..quadrature.) product/yield (%).sup.[b] 1 THF 66 4a/48
2 CH.sub.3CN 69 4a/69 3 EtOH 82 4a/83 4 toluene 110 4a/69 5 xylene
140 4a/41 6 CHCl.sub.3 65 4a/84 7 1,2-DCE 85 4a/90 8.sup.[c]
1,2-DCE 85 4a/75
4. Screening of N-Heterocyclic Phosphines
[0336] The effect of the Bronsted acid motif on this transformation
was then explored (Table 2). First, variations of the pKa values of
Bronsted acids were screened. The parent NHP-phenyl-thiourea
provided .alpha.-N-heterocyclic phosphonate 4a in excellent yield
(entry 1, 90%). Replacement of the phenyl-thiourea moiety with a
lower pKa valued group, 3,5-bis(trifluoromethyl)phenyl-thiourea,
led to a significant reduction in the yield of 4a (entry 1 vs 2).
The less acidic 4-methoxylphenyl-thioure, on the other hand, did
not show any better performance than the parent thiourea (entry 3,
72%). Further variation of the Bronsted acid with a methyl
substitution on the nitrogen atom significantly lowered their
reactivity (entries 4, 5), presumably preventing the intramolecular
nucleophilic substitution reaction sequence. Without wishing to be
bound by theory, these low-yielding reactions may be attributed to
the slower intermolecular substitution reaction compared with the
intramolecular nucleophilic displacement, which can be
experimentally supported by a comparison of NHP-thiourea and
NHP-N-methylated thiourea reactions (entry 1, 90% vs 4, 48%).
Moreover, the NHP-ethanol-mediated reaction, which provided a
significantly reduced yield (entry 6, 31%), proved the Bronsted
acid motif as an accelerator for this substitution reaction.
Lastly, it should be noted that the use of triethyl phosphite
P(OEt)3 gave a relatively lower yield of 79%, although it has been
widely applied in the additive-mediated synthesis of
.alpha.-aminophosphonates.
TABLE-US-00002 TABLE 2 ##STR00143## ##STR00144## entry NHP
product/yield (%).sup.[b] 1 ##STR00145## 4a/90 2 ##STR00146## 4a/40
3 ##STR00147## 4a/72 4 ##STR00148## 4a/48 5 ##STR00149## 4a/31 6
##STR00150## 4a/31
5. Aldehyde Scope of One-Pot Synthesis of .alpha.-N-Heterocyclic
Phosphonate
[0337] With the optimized reaction conditions established, the
scope of the reaction was explored in terms of aldehyde substrates
(Table 3). A wide range of aldehydes with different substituents
underwent clean reactions to afford .alpha.-N-heterocyclic
phosphonates in moderate to excellent yields (33-93% yields). Ortho
and/or para-halogenated benzaldehydes were transformed into the
corresponding products (4b-4h) in high to excellent yields,
attesting to a high steric tolerance. In particular, a sterically
hindered 3,5-dimethylmorpholine was well tolerated under the
reaction conditions and afforded the desired product in high yield
(4i, 87%). The electronic effects of the aldehyde electrophiles
were also explored. Attachment of electron-donating groups to
aldehydes (4j-4l) had a negligible influence on this reaction;
however, a sharp decrease in product yields was observed when
electron-deficient groups were present in the aldehydes such as
nitro-benzaldehydes (4n, 43%), presumably due to the instability of
in-situ generated transient iminium intermediates. In addition,
heteroaromatic aldehydes provided the target compounds in moderate
to high yields (4o, 33% and 4p, 69%). Finally, the aliphatic
aldehydes such as butyraldehyde and formaldehyde were found to
undergo effective transformation (4q, 63% and 4r, 71%).
TABLE-US-00003 TABLE 3 ##STR00151## ##STR00152## ##STR00153##
##STR00154## ##STR00155## ##STR00156## ##STR00157## ##STR00158##
##STR00159## ##STR00160## ##STR00161## ##STR00162## ##STR00163##
##STR00164## ##STR00165## ##STR00166## ##STR00167## ##STR00168##
##STR00169## ##STR00170## ##STR00171## ##STR00172## ##STR00173##
##STR00174## ##STR00175##
[0338] Next, the scope of the N-heterocyclic amines that would be
tolerated in this transformation was explored (Table 3). Piperazine
derivatives with various substituents at the nitrogen atom were
similarly tolerated in this protocol (entries 4s-4u). Similarly,
thiopiperazine, a sulfur analogue of piperazine, has proven
effective under the standard reaction conditions (4v). In addition,
4-piperidinone turned out to be a viable amine for this
transformation (4w), which showed a high tolerance to a wide range
of cyclic secondary amines, found in numerous biologically active
molecules (FIG. 2).
6. Proposed Reaction Sequence
[0339] Based on the experiment results and previous report (Mulla
et al. (2016) J. Org. Chem.), a proposed reaction sequence is
illustrated in FIG. 2. The treatment of aldehyde 1a with amine 2a
generated a transient iminium intermediate, which rapidly underwent
phospha-Mannich reaction with the NHP-thiourea 3a to generate a
diazaphosphonium intermediate I. A sequential
deprotonation/intramolecular nucleophilic substitution reaction
ultimately furnished the .alpha.-N-heterocyclic phosphonate 4a and
the thiazolidine byproduct, which contributed critically to the
mechanism analysis.
[0340] Accordingly, a novel N-heterocyclic phosphine-mediated
phospha-Mannich/intramolecular nucleophilic substitution reaction
as a general method for making tertiary .alpha.-aminophosphonates
has been developed. This transformation provides a rapid access to
.alpha.-N-heterocyclic phosphonates, having the advantages of
moderate to excellent yields for various substrates (33-93%) and
metal-free mild reaction conditions. This method would be a useful
alternative to the classical metal-mediated synthesis of
.alpha.-N-heterocyclic phosphonates, which is typically challenging
and low-yielding. Moreover, this study, for the first time,
demonstrated the critical role of Bronsted acid motif as an
accelerator of the sequential intramolecular nucleophilic
substitution process in the phosphonylation such as the Kabachnick
and Fields reaction.
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[0377] It will be apparent to those skilled in the art that various
modifications and variations can be made in the present invention
without departing from the scope or spirit of the invention. Other
aspects of the invention will be apparent to those skilled in the
art from consideration of the specification and practice of the
invention disclosed herein. It is intended that the specification
and examples be considered as exemplary only, with a true scope and
spirit of the invention being indicated by the following
claims.
* * * * *