U.S. patent application number 16/968273 was filed with the patent office on 2020-12-10 for heteroaryl compounds, pharmaceutical compositions thereof, and their therapeutic use.
The applicant listed for this patent is Yissum Research Development Company of the Hebrew University of Jerusalem Ltd.. Invention is credited to Yinon Ben-Neriah, Irit Snir-Alkalay, Joseph P. Vacca.
Application Number | 20200383984 16/968273 |
Document ID | / |
Family ID | 1000005089493 |
Filed Date | 2020-12-10 |
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United States Patent
Application |
20200383984 |
Kind Code |
A1 |
Snir-Alkalay; Irit ; et
al. |
December 10, 2020 |
HETEROARYL COMPOUNDS, PHARMACEUTICAL COMPOSITIONS THEREOF, AND
THEIR THERAPEUTIC USE
Abstract
Provided herein are heteroaryl compounds, for example, a
compound of Formula I or IA, and pharmaceutical compositions
thereof. Also provided herein are methods of their use for
treating, ameliorating, or preventing one or more symptoms of a
disorder, disease, or condition mediated by a casein kinase 1
(CK1), an interleukin-1 receptor associated kinase (IRAK1), or a
cyclin-dependent kinase 9 (CDK9). Formula: (I),(IA)
##STR00001##
Inventors: |
Snir-Alkalay; Irit;
(Mevasseret Zion, IL) ; Vacca; Joseph P.;
(Telford, PA) ; Ben-Neriah; Yinon; (Mevasseret
Zion, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Yissum Research Development Company of the Hebrew University of
Jerusalem Ltd. |
Jerusalem |
|
IL |
|
|
Family ID: |
1000005089493 |
Appl. No.: |
16/968273 |
Filed: |
February 7, 2019 |
PCT Filed: |
February 7, 2019 |
PCT NO: |
PCT/IL2019/050151 |
371 Date: |
August 7, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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62627908 |
Feb 8, 2018 |
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62627921 |
Feb 8, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 405/14 20130101;
A61P 35/00 20180101; A61K 31/506 20130101; C07D 403/04 20130101;
C07D 495/04 20130101; C07D 413/04 20130101 |
International
Class: |
A61K 31/506 20060101
A61K031/506; A61P 35/00 20060101 A61P035/00; C07D 413/04 20060101
C07D413/04; C07D 403/04 20060101 C07D403/04; C07D 495/04 20060101
C07D495/04; C07D 405/14 20060101 C07D405/14 |
Claims
1. A compound of Formula I or IA: ##STR00144## or an enantiomer, a
mixture of enantiomers, a mixture of two or more diastereomers, a
tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein: U and V are each
independently --O-- and .dbd.C(R.sup.4)--; or U and V are each
independently .dbd.N-- and --N(R.sup.5)--; W, X, Y, and Z are each
independently .dbd.C(R.sup.6)-- or .dbd.N--, with the proviso that
at least one of W, X, Y, and Z is .dbd.N--; or W, X, and Z are each
independently .dbd.C(R.sup.6)--, --N(R.sup.7)--, .dbd.N--, --O--,
or --S--; and Y is a bond; R.sup.1 and R.sup.2 are each
independently (a) hydrogen or deuterium; (b) C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl;
or (c) --C(O)R.sup.1a, --C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--C(O)SR.sup.1a, --C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a,
--C(S)OR.sup.1a, --C(S)NR.sup.1bR.sup.1c, --OR.sup.1a,
--OC(O)R.sup.1a, --OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c,
--OC(O)SR.sup.1a, --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
--OC(S)R.sup.1a, --OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c,
--OS(O)R.sup.1a, --OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1d, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1aS(O)R.sup.1d,
--NR.sup.1aS(O).sub.2R.sup.1d, --NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.1a S(O).sub.2NR.sup.1bR.sup.1c, --S(O)R.sup.1a,
--S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c; or R.sup.1 and R.sup.2 together with
the N atom to which they are attached form heteroaryl or
heterocyclyl; each R.sup.3, R.sup.4, and R.sup.6 is independently
(a) hydrogen, deuterium, cyano, halo, or nitro; (b) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl;
or (c) --C(O)R.sup.1a, --C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--C(O)SR.sup.1a, --C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a,
--C(S)OR.sup.1a, --C(S)NR.sup.1bR.sup.1c, --OR.sup.1a,
--OC(O)R.sup.1a, --OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c,
--OC(O)SR.sup.1a, --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
--OC(S)R.sup.1a, --OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c,
--OS(O)R.sup.1a, --OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1d, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1aS(O)R.sup.1d,
--NR.sup.1a S(O).sub.2R.sup.1d, --NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.1a S(O).sub.2NR.sup.1bR.sup.1c, --SR.sup.1a,
--S(O)R.sup.1a, --S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c or
--S(O).sub.2NR.sup.1bR.sup.1c; R.sup.5 and R.sup.7 are each
independently (a) hydrogen or deuterium; (b) C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl;
or (c) --C(O)R.sup.1a, --C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--C(O)SR.sup.1a, --C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a,
--C(S)OR.sup.1a, --C(S)NR.sup.1bR.sup.1c, --OR.sup.1a,
--OC(O)R.sup.1a, --OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c,
--OC(O)SR.sup.1a, --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
--OC(S)R.sup.1a, --OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c,
--OS(O)R.sup.1a, --OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1d, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1aS(O)R.sup.1d,
--NR.sup.1aS(O).sub.2R.sup.1d, --NR.sup.1a S(O)NR.sup.1bR.sup.1c,
--NR.sup.1aS(O).sub.2NR.sup.1bR.sup.1c, --S(O)R.sup.1a,
--S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c; and R.sup.2a, R.sup.2b, R.sup.2c,
and R.sup.2d are (i) or (ii): (i) R.sup.2a and R.sup.2b are each
independently (a) hydrogen or deuterium; (b) C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl;
or (c) --C(O)R.sup.1a, --C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--C(O)SR.sup.1a, --C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a,
--C(S)OR.sup.1a, --C(S)NR.sup.1bR.sup.1c, --OR.sup.1a,
--OC(O)R.sup.1a, --OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c,
--OC(O)SR.sup.1a, --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
--OC(S)R.sup.1a, --OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c,
--OS(O)R.sup.1a, --OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1d, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1aS(O)R.sup.1d,
--NR.sup.1aS(O).sub.2R.sup.1d, --NR.sup.1a S(O)NR.sup.1bR.sup.1c,
--NR.sup.1aS(O).sub.2NR.sup.1bR.sup.1c, --S(O)R.sup.1a,
--S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c; or R.sup.2a and R.sup.2b together
with the N atom to which they are attached form heteroaryl or
heterocyclyl; and R.sup.2c and R.sup.2d are each independently (a)
hydrogen, deuterium, or cyano; or (b) C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or R.sup.2c and
R.sup.2d are linked together to form --O--, C.sub.1-6 alkylene,
C.sub.1-6 heteroalkylene, C.sub.2-6 alkenylene, or C.sub.2-6
alkynylene; or (ii) R.sup.2a and R.sup.2c together with the C and N
atoms to which they are attached form heterocyclyl; R.sup.2b is (a)
hydrogen or deuterium; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or (c)
--C(O)R.sup.1a, --C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--C(O)SR.sup.1a, --C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a,
--C(S)OR.sup.1a, --C(S)NR.sup.1bR.sup.1c, --OR.sup.1a,
--OC(O)R.sup.1a, --OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c,
--OC(O)SR.sup.1a, --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
--OC(S)R.sup.1a, --OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c,
--OS(O)R.sup.1a, --OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1d, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1aS(O)R.sup.1a,
--NR.sup.1aS(O).sub.2R.sup.1d, --NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.1a S(O).sub.2NR.sup.1bR.sup.1c, --S(O)R.sup.1a,
--S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c; R.sup.2d is (a) hydrogen, deuterium,
or cyano; or (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15
aralkyl, heteroaryl, or heterocyclyl; and each R.sup.1a, R.sup.1b,
R.sup.1c, and R.sup.1d is independently hydrogen, deuterium,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12
cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or
heterocyclyl; or R.sup.1a and R.sup.1c together with the C and N
atoms to which they are attached form heterocyclyl; or R.sup.1b and
R.sup.1c together with the N atom to which they are attached form
heterocyclyl; wherein each alkyl, alkylene, heteroalkylene,
alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl,
aralkyl, heteroaryl, and heterocyclyl is optionally substituted
with one or more, in one embodiment, one, two, three, or four,
substituents Q, where each Q is independently selected from (a)
deuterium, cyano, halo, and nitro; (b) C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is
further optionally substituted with one or more, in one embodiment,
one, two, three, or four, substituents Q.sup.a; and (c)
--C(O)R.sup.a, --C(O)OR.sup.a, --C(O)NR.sup.bR.sup.c,
--C(O)SR.sup.a, --C(NR.sup.a)NR.sup.bR.sup.c, --C(S)R.sup.a,
--C(S)OR.sup.a, --C(S)NR.sup.bR.sup.c, --OR.sup.a, --OC(O)R.sup.a,
--OC(O)OR.sup.a, --OC(O)NR.sup.bR.sup.c, --OC(O)SR.sup.a,
--OC(.dbd.NR.sup.a)NR.sup.bR.sup.c, --OC(S)R.sup.a,
--OC(S)OR.sup.a, --OC(S)NR.sup.bR.sup.c, --OS(O)R.sup.a,
--OS(O).sub.2R.sup.a, --OS(O)NR.sup.bR.sup.c,
--OS(O).sub.2NR.sup.bR.sup.c, --NR.sup.bR.sup.c,
--NR.sup.aC(O)R.sup.d, --NR.sup.aC(O)OR.sup.d,
--NR.sup.aC(O)NR.sup.bR.sup.c, --NR.sup.aC(O)SR.sup.d,
--NR.sup.aC(.dbd.NR.sup.d)NR.sup.bR.sup.c, --NR.sup.aC(S)R.sup.d,
--NR.sup.aC(S)OR.sup.d, --NR.sup.aC(S)NR.sup.bR.sup.c,
--NR.sup.aS(O)R.sup.d, --NR.sup.aS(O).sub.2R.sup.d,
--NR.sup.aS(O)NR.sup.1bR.sup.1c,
--NR.sup.aS(O).sub.2NR.sup.bR.sup.c, --SR.sup.a, --S(O)R.sup.a,
--S(O).sub.2R.sup.a, --S(O)NR.sup.bR.sup.c, and
--S(O).sub.2NR.sup.bR.sup.c, wherein each R.sup.a, R.sup.b,
R.sup.c, and R.sup.d is independently (i) hydrogen or deuterium;
(ii) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-12 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl,
heteroaryl, or heterocyclyl, each of which is optionally
substituted with one or more, in one embodiment, one, two, three,
or four, substituents Q.sup.a; or (iii) R.sup.b and R.sup.c
together with the N atom to which they are attached form
heterocyclyl, optionally substituted with one or more, in one
embodiment, one, two, three, or four, substituents Q.sup.a; wherein
each Q.sup.a is independently selected from the group consisting of
(a) deuterium, cyano, halo, and nitro; (b) C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, and heterocyclyl;
and (c) --C(O)R.sup.e, --C(O)OR.sup.e, --C(O)NR.sup.fR.sup.g,
--C(O)SR.sup.e, --C(NR.sup.e)NR.sup.fR.sup.g, --C(S)R.sup.e,
--C(S)OR.sup.e, --C(S)NR.sup.fR.sup.g, --OR.sup.e, --OC(O)R.sup.e,
--OC(O)OR.sup.e, --OC(O)NR.sup.fR.sup.g, --OC(O)SR.sup.e,
--OC(.dbd.NR.sup.e)NR.sup.fR.sup.g, --OC(S)R.sup.e,
--OC(S)OR.sup.e, --OC(S)NR.sup.fR.sup.g, --OS(O)R.sup.e,
--OS(O).sub.2R.sup.e, --OS(O)NR.sup.fR.sup.g,
--OS(O).sub.2NR.sup.fR.sup.g, --NR.sup.fR.sup.g,
--NR.sup.eC(O)R.sup.h, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.fR.sup.g, --NR.sup.eC(O)SR.sup.f,
--NR.sup.eC(.dbd.NR.sup.h)NR.sup.fR.sup.g, --NR.sup.eC(S)R.sup.h,
--NR.sup.eC(S)OR.sup.f, --NR.sup.eC(S)NR.sup.fR.sup.g,
--NR.sup.eS(O)R.sup.h, --NR.sup.eS(O).sub.2R.sup.h,
--NR.sup.eS(O)NR.sup.fR.sup.g, --NR.sup.eS(O).sub.2NR.sup.fR.sup.g,
--SR.sup.e, --S(O)R.sup.e, --S(O).sub.2R.sup.e,
--S(O)NR.sup.fR.sup.g, and --S(O).sub.2NR.sup.fR.sup.g; wherein
each R.sup.e, R.sup.f, R.sup.g, and R.sup.h is independently (i)
hydrogen or deuterium; (ii) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R.sup.f
and R.sup.g together with the N atom to which they are attached
form heterocyclyl.
2. The compound of claim 1, having the structure of Formula I:
##STR00145## or an enantiomer, a mixture of enantiomers, a mixture
of two or more diastereomers, a tautomer, a mixture of two or more
tautomers, or an isotopic variant thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof.
3. The compound of claim 2, wherein R.sup.2 is C.sub.3-12
cycloalkyl, optionally substituted with one or more substituents
Q.
4. The compound of claim 2, wherein R.sup.2 is cyclohexyl,
bicyclo[2.2.1]heptyl, or bicyclo[2.2.2]octyl, each optionally
substituted with one or more substituents Q.
5. The compound of any one of claims 2 to 4, having the structure
of Formula II: ##STR00146## or an enantiomer, a mixture of
enantiomers, a mixture of two or more diastereomers, a tautomer, a
mixture of two or more tautomers, or an isotopic variant thereof,
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, wherein: R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are
(i) or (ii): (i) R.sup.2a and R.sup.2b are each independently (a)
hydrogen or deuterium; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is
optionally substituted with one or more substituents Q; or (c)
--C(O)R.sup.1a, --C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--C(O)SR.sup.1a, --C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a,
--C(S)OR.sup.1a, --C(S)NR.sup.1bR.sup.1c, --OR.sup.1a,
--OC(O)R.sup.1a, --OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c,
--OC(O)SR.sup.1a, --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
--OC(S)R.sup.1a, --OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c,
--OS(O)R.sup.1a, --OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1a, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1aS(O)R.sup.1d,
--NR.sup.1aS(O).sub.2R.sup.1d, --NR.sup.1a S(O)NR.sup.1bR.sup.1c,
--NR.sup.1aS(O).sub.2NR.sup.1bR.sup.1c, --S(O)R.sup.1a,
--S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c; or R.sup.2a and R.sup.2b together
with the N atom to which they are attached form heteroaryl or
heterocyclyl, each of which is optionally substituted with one or
more substituents Q; and R.sup.2c and R.sup.2d are each
independently (a) hydrogen, deuterium, or cyano; or (b) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl,
each of which is optionally substituted with one or more
substituents Q; or R.sup.2c and R.sup.2d are linked together to
form --O--, C.sub.1-6 alkylene, C.sub.1-6 heteroalkylene, C.sub.2-6
alkenylene, or C.sub.2-6 alkynylene, wherein the alkylene,
heteroalkylene, alkenylene, and alkynylene are each optionally
substituted with one or more substituents Q; or (ii) R.sup.2a and
R.sup.2c together with the C and N atoms to which they are attached
form heterocyclyl, which is optionally substituted with one or more
substituents Q; R.sup.2b is (a) hydrogen or deuterium; (b)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12
cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or
heterocyclyl, each of which is optionally substituted with one or
more substituents Q; or (c) --C(O)R.sup.1a, --C(O)OR.sup.1a,
--C(O)NR.sup.1bR.sup.1c, --C(O)SR.sup.1a,
--C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a, --C(S)OR.sup.1a,
--C(S)NR.sup.1bR.sup.1c, --OR.sup.1a, --OC(O)R.sup.1a,
--OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c, --OC(O)SR.sup.1a,
--OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, --OC(S)R.sup.1a,
--OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c, --OS(O)R.sup.1a,
--OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1d, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1aS(O)R.sup.1a,
--NR.sup.1aS(O).sub.2R.sup.1d, --NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.1a S(O).sub.2NR.sup.1bR.sup.1c, --S(O)R.sup.1a,
--S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c; and R.sup.2d is (a) hydrogen,
deuterium, or cyano; or (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is
optionally substituted with one or more substituents Q.
6. The compound of claim 5, having the structure of Formula IIa:
##STR00147## or a tautomer, a mixture of two or more tautomers, or
an isotopic variant thereof, or a pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof.
7. The compound of claim 5, having the structure of Formula III:
##STR00148## or an enantiomer, a mixture of enantiomers, a mixture
of two or more diastereomers, a tautomer, a mixture of two or more
tautomers, or an isotopic variant thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof, wherein
R.sup.6a, R.sup.6b and R.sup.6c are each independently R.sup.6.
8. The compound of claim 5, having the structure of Formula VI:
##STR00149## or an enantiomer, a mixture of enantiomers, a mixture
of two or more diastereomers, a tautomer, a mixture of two or more
tautomers, or an isotopic variant thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof, wherein
R.sup.6b, R.sup.6c, and R.sup.6d are each independently
R.sup.6.
9. The compound of claim 5, having the structure of Formula VIII:
##STR00150## or an enantiomer, a mixture of enantiomers, a mixture
of two or more diastereomers, a tautomer, a mixture of two or more
tautomers, or an isotopic variant thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof, wherein
R.sup.6b and R.sup.6d are each independently R.sup.6.
10. The compound of claim 5, having the structure of Formula IX:
##STR00151## or an enantiomer, a mixture of enantiomers, a mixture
of two or more diastereomers, a tautomer, a mixture of two or more
tautomers, or an isotopic variant thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof, wherein
R.sup.6b and R.sup.6c are each independently R.sup.6.
11. The compound of claim 10, having the structure of Formula IXa:
##STR00152## or an enantiomer, a mixture of enantiomers, a mixture
of two or more diastereomers, a tautomer, a mixture of two or more
tautomers, or an isotopic variant thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof.
12. The compound of claim 10 or 11, wherein R.sup.6b is hydrogen,
--OR.sup.1a, or --NR.sup.1bR.sup.1c.
13. The compound of claim 12, wherein R.sup.6b is hydrogen,
hydroxyl, or amino.
14. The compound of any one of claims 10 to 13, wherein R.sup.6c is
hydrogen, halo, or C.sub.1-6 alkyl, where the alkyl is optionally
substituted with one or more substituents Q.
15. The compound of claim 14, wherein R.sup.6c is hydrogen, fluoro,
chloro, methyl, or trifluoromethyl.
16. The compound of any one of claims 5 to 15, wherein: R.sup.2a
and R.sup.2b are each independently (a) hydrogen or deuterium; (b)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12
cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or
heterocyclyl, each of which is optionally substituted with one or
more substituents Q; or (c) --C(O)R.sup.1a, --C(O)OR.sup.1a,
--C(O)NR.sup.1bR.sup.1c, --C(O)SR.sup.1a,
--C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a, --C(S)OR.sup.1a,
--C(S)NR.sup.1bR.sup.1c, --OR.sup.1a, --OC(O)R.sup.1a,
--OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c, --OC(O)SR.sup.1a,
--OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, --OC(S)R.sup.1a,
--OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c, --OS(O)R.sup.1a,
--OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1d, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1aS(O)R.sup.1d,
--NR.sup.1aS(O).sub.2R.sup.1d, --NR.sup.1a S(O)NR.sup.1bR.sup.1c,
--NR.sup.1aS(O).sub.2NR.sup.1bR.sup.1c, --S(O)R.sup.1a,
--S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c; or R.sup.2a and R.sup.2b together
with the N atom to which they are attached form heteroaryl or
heterocyclyl, each of which is optionally substituted with one or
more substituents Q; and R.sup.2c and R.sup.2d are each
independently (a) hydrogen, deuterium, or cyano; or (b) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl,
each of which is optionally substituted with one or more
substituents Q; or R.sup.2c and R.sup.2d are linked together to
form --O--, C.sub.1-6 alkylene, C.sub.1-6 heteroalkylene, C.sub.2-6
alkenylene, or C.sub.2-6 alkynylene, wherein the alkylene,
heteroalkylene, alkenylene, and alkynylene are each optionally
substituted with one or more substituents Q.
17. The compound of claim 16, wherein R.sup.2a is hydrogen, methyl,
trifluoroethyl, methoxyethyl, pentynyl, phenyl, benzyl,
(pyrazolyl)methyl, (methylpyrazolyl)methyl, (pyrazolyl)ethyl,
(pyridinyl)methyl, methoxyacetyl, butynylcarbonyl, or
(pyrazolyl)carbonyl.
18. The compound of claim 16, wherein R.sup.2a is hydrogen, methyl,
2,2,2-trifluoroethyl, 2-methoxyethyl, pent-4-ynyl, phenyl, benzyl,
(pyrazol-3-yl)methyl, (pyrazol-4-yl)methyl,
(1-methylpyrazol-4-yl)methyl, (3-methylpyrazol-4-yl)methyl,
1-(pyrazol-4-yl)ethyl, (pyridin-3-yl)methyl, 2-methoxyacetyl,
but-3-ynylcarbonyl, or (pyrazol-4-yl)carbonyl.
19. The compound of any one of claims 16 to 18, wherein R.sup.2b is
hydrogen, methyl, trifluoroethyl, methoxyethyl, phenyl, benzyl,
(pyrazolyl)methyl, (methylpyrazolyl)methyl, (pyrazolyl)ethyl,
(pyridinyl)methyl, methoxyacetyl, or (pyrazolyl)carbonyl.
20. The compound of claim 19, wherein R.sup.2b is hydrogen, methyl,
2,2,2-trifluoroethyl, 2-methoxyethyl, phenyl, benzyl,
(pyrazol-3-yl)methyl, (pyrazol-4-yl)methyl,
(1-methylpyrazol-4-yl)methyl, (3-methylpyrazol-4-yl)methyl,
1-(pyrazol-4-yl)ethyl, (pyridin-3-yl)methyl, 2-methoxyacetyl, or
(pyrazol-4-yl)carbonyl.
21. The compound of any one of claims 5 to 20, wherein R.sup.2c is
hydrogen.
22. The compound of any one of claims 5 to 21, wherein R.sup.2d is
hydrogen.
23. The compound of any one of claims 5 to 22, wherein R.sup.2c and
R.sup.2d are in a trans configuration in the cyclohexyl ring.
24. The compound of any one of claims 5 to 20, wherein R.sup.2c and
R.sup.2d are linked together to form C.sub.2-6 alkylene, optionally
substituted with one or more substituents Q.
25. The compound of claim 24, wherein R.sup.2c and R.sup.2d are
linked together to form methylene or eth-1,2-ylene.
26. The compound of any one of claims 2 to 25, wherein R.sup.1 is
hydrogen.
27. The compound of any one of claims 2 to 26, wherein R.sup.3 is
C.sub.1-6 alkyl, optionally substituted with one or more
substituents Q.
28. The compound of claim 27, wherein R.sup.3 is butylmethyl,
cyclopropylmethyl, cyclobutylmethyl, or cyclopentylmethyl; each of
which is independently and optionally substituted with one or more
substituents Q.
29. The compound of claim 27, wherein R.sup.3 is t-butylmethyl,
cyclopropylmethyl, 1-methylcyclopropylmethyl,
1-hydroxy(cyclopropylmethyl), cyclobutylmethyl, or
cyclopentylmethyl.
30. The compound of any one of claims 2 to 29, wherein U is
--O--.
31. The compound of any one of claims 2 to 30, wherein V is
.dbd.C(R.sup.4)--.
32. The compound of any one of claims 2 to 29, wherein U is
.dbd.C(R.sup.4)--.
33. The compound of any one of claims 2 to 29 and 32, wherein V is
--O--.
34. The compound of claim 31 or 32, wherein R.sup.4 is methyl,
isopropyl, cyclopentyl, oxetanyl, tetrahydrofuryl, or
tetrahydropyranyl.
35. The compound of claim 34, wherein R.sup.4 is methyl, isopropyl,
cyclopentyl, oxetan-3-yl, tetrahydrofur-3-yl, tetrahydropyran-4-yl,
or tetrahydropyran-3-yl.
36. The compound of any one of claims 2 to 29, wherein U is
.dbd.N--.
37. The compound of any one of claims 2 to 29 and 36, wherein V is
.dbd.N(R.sup.5)--.
38. The compound of claim 37, wherein R.sup.5 is methyl, isopropyl,
cyclopentyl, oxetanyl, tetrahydrofuryl, or tetrahydropyranyl.
39. The compound of claim 37, wherein R.sup.5 is methyl, isopropyl,
cyclopentyl, oxetan-3-yl, tetrahydrofur-3-yl, tetrahydropyran-4-yl,
or tetrahydropyran-3-yl.
40. The compound of any one of claims 2 to 29 and 36, wherein V is
.dbd.C(R.sup.4)--.
41. A compound of: ##STR00153## ##STR00154## ##STR00155## or a
tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof.
42. The compound of claim 1, having the structure of Formula IA:
##STR00156## or an enantiomer, a mixture of enantiomers, a mixture
of two or more diastereomers, a tautomer, a mixture of two or more
tautomers, or an isotopic variant thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof.
43. The compound of claim 42, having the structure of Formula IIA:
##STR00157## or an enantiomer, a mixture of enantiomers, a mixture
of two or more diastereomers, a tautomer, a mixture of two or more
tautomers, or an isotopic variant thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof, wherein
R.sup.6a, R.sup.6b and R.sup.6c are each independently R.sup.6.
44. The compound of claim 42, having the structure of Formula VA:
##STR00158## or an enantiomer, a mixture of enantiomers, a mixture
of two or more diastereomers, a tautomer, a mixture of two or more
tautomers, or an isotopic variant thereof; or a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof; wherein
R.sup.6b, R.sup.6c, and R.sup.6d are each independently
R.sup.6.
45. The compound of claim 42, having the structure of Formula VIIA:
##STR00159## or an enantiomer, a mixture of enantiomers, a mixture
of two or more diastereomers, a tautomer, a mixture of two or more
tautomers, or an isotopic variant thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof, wherein
R.sup.6b and R.sup.6d are each independently R.sup.6.
46. The compound of claim 42, having the structure of Formula
VIIIA: ##STR00160## or an enantiomer, a mixture of enantiomers, a
mixture of two or more diastereomers, a tautomer, a mixture of two
or more tautomers, or an isotopic variant thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, wherein R.sup.6b and R.sup.6c are each independently
R.sup.6.
47. The compound of claim 46, having the structure of Formula
VIIIAa: ##STR00161## or a tautomer, a mixture of two or more
tautomers, or an isotopic variant thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof.
48. The compound of claim 46, having the structure of Formula
VIIIAb: ##STR00162## or a tautomer, a mixture of two or more
tautomers, or an isotopic variant thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof.
49. The compound of claim 47 or 48, wherein R.sup.6b is hydrogen,
--OR.sup.1a, or --NR.sup.1bR.sup.1c.
50. The compound of claim 49, wherein R.sup.6b is hydrogen,
hydroxyl, or amino.
51. The compound of any one of claims 47 to 50, wherein R.sup.6c is
hydrogen, halo, or C.sub.1-6 alkyl, where the alkyl is optionally
substituted with one or more substituents Q.
52. The compound of claim 51, wherein R.sup.6c is hydrogen, fluoro,
chloro, methyl, or trifluoromethyl.
53. The compound of any one of claims 42 to 52, wherein: R.sup.2a
and R.sup.2b are each independently (a) hydrogen or deuterium; (b)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12
cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or
heterocyclyl, each of which is optionally substituted with one or
more substituents Q; or (c) --C(O)R.sup.1a, --C(O)OR.sup.1a,
--C(O)NR.sup.1bR.sup.1c, --C(O)SR.sup.1a,
--C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a, --C(S)OR.sup.1a,
--C(S)NR.sup.1bR.sup.1c, --OR.sup.1a, --OC(O)R.sup.1a,
--OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c, --OC(O)SR.sup.1a,
--OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, --OC(S)R.sup.1a,
--OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c, --OS(O)R.sup.1a,
--OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1d, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1a S(O)R.sup.1d,
--NR.sup.1aS(O).sub.2R.sup.1d, --NR.sup.1a S(O)NR.sup.1bR.sup.1c,
--NR.sup.1a S(O).sub.2NR.sup.1bR.sup.1c, --S(O)R.sup.1a,
--S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c; or R.sup.2a and R.sup.2b together
with the N atom to which they are attached form heteroaryl or
heterocyclyl, each of which is optionally substituted with one or
more substituents Q; and R.sup.2c and R.sup.2d are each
independently (a) hydrogen, deuterium, or cyano; or (b) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl,
each of which is optionally substituted with one or more
substituents Q; or R.sup.2c and R.sup.2d are linked together to
form --O--, C.sub.1-6 alkylene, C.sub.1-6 heteroalkylene, C.sub.2-6
alkenylene, or C.sub.2-6 alkynylene, wherein the alkylene,
heteroalkylene, alkenylene, and alkynylene are each optionally
substituted with one or more substituents Q.
54. The compound of any one of claims 42 to 53, wherein R.sup.2a
and R.sup.2b are each independently hydrogen, C.sub.1-6 alkyl,
C.sub.2-6 alkynyl, C.sub.7-14 aryl, C.sub.7-14 aralkyl, or
--C(O)R.sup.1a; or R.sup.2a and R.sup.2b together with the N atom
to which they are attached form heteroaryl or heterocyclyl; where
the alkyl, alkynyl, aryl, aralkyl, heteroaryl, and heterocyclyl is
each optionally substituted with one or more substituents Q.
55. The compound of claim 54, wherein R.sup.2a is hydrogen, methyl,
trifluoroethyl, methoxyethyl, pentynyl, phenyl, benzyl,
(pyrazolyl)methyl, (methylpyrazolyl)methyl, (pyrazolyl)ethyl,
(pyridinyl)methyl, methoxyacetyl, butynylcarbonyl, or
(pyrazolyl)carbonyl.
56. The compound of claim 54, wherein R.sup.2a is hydrogen, methyl,
2,2,2-trifluoroethyl, 2-methoxyethyl, pent-4-ynyl, phenyl, benzyl,
(pyrazol-3-yl)methyl, (pyrazol-4-yl)methyl,
(1-methylpyrazol-4-yl)methyl, (3-methylpyrazol-4-yl)methyl,
1-(pyrazol-4-yl)ethyl, (pyridin-3-yl)methyl, 2-methoxyacetyl,
but-3-ynylcarbonyl, or (pyrazol-4-yl)carbonyl.
57. The compound of any one of claims 42 to 56, wherein R.sup.2b is
hydrogen, C.sub.1-6 alkyl, C.sub.7-14 aryl, C.sub.7-14 aralkyl, or
--C(O)R.sup.1a; where the alkyl, aryl, and aralkyl are each
optionally substituted with one or more substituents Q.
58. The compound of claim 57, wherein R.sup.2b is hydrogen, methyl,
trifluoroethyl, methoxyethyl, phenyl, benzyl, (pyrazolyl)methyl,
(methylpyrazolyl)methyl, (pyrazolyl)ethyl, (pyridinyl)methyl,
methoxyacetyl, or (pyrazolyl)carbonyl.
59. The compound of claim 57, wherein R.sup.2b is hydrogen, methyl,
2,2,2-trifluoroethyl, 2-methoxyethyl, phenyl, benzyl,
(pyrazol-3-yl)methyl, (pyrazol-4-yl)methyl,
(1-methylpyrazol-4-yl)methyl, (3-methylpyrazol-4-yl)methyl,
1-(pyrazol-4-yl)ethyl, (pyridin-3-yl)methyl, 2-methoxyacetyl, or
(pyrazol-4-yl)carbonyl.
60. The compound of any one of claims 42 to 59, wherein R.sup.2c is
hydrogen.
61. The compound of any one of claims 42 to 60, wherein R.sup.2d is
hydrogen.
62. The compound of any one of claims 42 to 53, wherein R.sup.2c
and R.sup.2d are linked together to form C.sub.2-6 alkylene,
optionally substituted with one or more substituents Q.
63. The compound of claim 62, wherein R.sup.2c and R.sup.2d are
linked together to form methylene or eth-1,2-ylene.
64. The compound of any one of claims 42 to 63, wherein R.sup.1 is
hydrogen.
65. The compound of any one of claims 42 to 64, wherein R.sup.3 is
C.sub.1-6 alkyl, optionally substituted with one or more
substituents Q.
66. The compound of claim 65, wherein R.sup.3 is butylmethyl,
cyclopropylmethyl, cyclobutylmethyl, or cyclopentylmethyl; each of
which is independently and optionally substituted with one or more
substituents Q.
67. The compound of claim 65, wherein R.sup.3 is t-butylmethyl,
cyclopropylmethyl, 1-methylcyclopropylmethyl,
1-hydroxy(cyclopropylmethyl), cyclobutylmethyl, or
cyclopentylmethyl.
68. The compound of any one of claims 42 to 67, wherein R.sup.4 is
C.sub.1-6 alkyl, C.sub.3-12 cycloalkyl, or heterocyclyl, each of
which is independently and optionally substituted with one or more
substituents Q.
69. The compound of claim 68, wherein R.sup.4 is C.sub.1-6 alkyl,
C.sub.3-12 cycloalkyl, or 4- to 7-membered heterocyclyl, each of
which is independently and optionally substituted with one or more
substituents Q.
70. The compound of claim 69, wherein R.sup.4 is methyl, isopropyl,
cyclopentyl, oxetanyl, tetrahydrofuryl, or tetrahydropyranyl.
71. The compound of claim 69, wherein R.sup.4 is methyl, isopropyl,
cyclopentyl, oxetan-3-yl, tetrahydrofur-3-yl, tetrahydropyran-4-yl,
or tetrahydropyran-3-yl.
72. The compound of any one of claims 42 to 71, wherein R.sup.5 is
hydrogen.
73. A compound of: ##STR00163## ##STR00164## ##STR00165##
##STR00166## or a tautomer, a mixture of two or more tautomers, or
an isotopic variant thereof, or a pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof.
74. A compound of: ##STR00167## or a tautomer, a mixture of two or
more tautomers, or an isotopic variant thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof.
75. A pharmaceutical composition comprising a compound of any one
of claims 1 to 74, or an enantiomer, a mixture of enantiomers, a
mixture of two or more diastereomers, a tautomer, a mixture of two
or more tautomers, or an isotopic variant thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, and a pharmaceutically acceptable excipient.
76. The pharmaceutical composition of claim 75, wherein the
composition is in single dosage form.
77. The pharmaceutical composition of claim 75 or 76, wherein the
composition is in an oral, parenteral, or intravenous dosage
form.
78. The pharmaceutical composition of claim 77, wherein the oral
dosage form is a tablet, capsule, or solution.
79. The pharmaceutical composition of any one of claims 75 to 78,
further comprising a second therapeutic agent.
80. A method of treating, preventing, or ameliorating one or more
symptoms of a proliferative disease in a subject, comprising
administering to the subject a compound of any one of claims 1 to
74 or a pharmaceutical composition of any one of claims 75 to
79.
81. The method of claim 80, wherein the proliferative disease is
cancer.
82. The method of claim 81, wherein the cancer is bladder cancer,
breast cancer, cervical cancer, colon cancer, colorectal cancer,
esophageal cancer, glioma, glioblastoma multiforme, head and neck
cancer, leukemia, acute myelogenous leukemia, chronic myeloid
leukemia, liver cancer, lung cancer, small cell lung cancer,
non-small cell lung cancer, lymphoma, melanoma, myeloma,
neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer,
renal cancer, salivary gland cancer, sarcoma, osteosarcoma, skin
cancer, squamous cell carcinoma, stomach cancer, testicular cancer,
thyroid cancer, or uterine cancer.
83. A method of treating, preventing, or ameliorating one or more
symptoms of acquired immune deficiency syndrome (AIDS) in a
subject, comprising administering to the subject a compound of any
one of claims 1 to 74 or a pharmaceutical composition of any one of
claims 75 to 79.
84. A method of treating or preventing a virus infection in a
subject, comprising administering to the subject a compound of any
one of claims 1 to 74 or a pharmaceutical composition of any one of
claims 75 to 79.
85. The method of claim 84, wherein the virus infection is a human
immunodeficiency virus (HIV) infection.
86. A method of treating, ameliorating, or preventing a skin
disorder, disease, or condition in a subject, comprising
administering to the subject a compound of any one of claims 1 to
74 or a pharmaceutical composition of any one of claims 75 to
79.
87. A method of protecting a subject from ultraviolet radiation,
comprising administering to the subject a compound of any one of
claims 1 to 74 or a pharmaceutical composition of any one of claims
75 to 79.
88. A method of increasing skin pigmentation in a subject,
comprising administering to the subject a compound of any one of
claims 1 to 74 or a pharmaceutical composition of any one of claims
75 to 79.
89. A method of increasing eumelanin level in a subject, comprising
administering to the subject a compound of any one of claims 1 to
74 or a pharmaceutical composition of any one of claims 75 to
79.
90. A method of treating one or more symptoms of a disorder,
disease, or condition mediated by a casein kinase 1 (CK1) in a
subject, comprising administering to the subject a compound of any
one of claims 1 to 74 or a pharmaceutical composition of any one of
claims 75 to 79.
91. A method of treating one or more symptoms of a disorder,
disease, or condition mediated by an interleukin-1 receptor
associated kinase (IRAK1) in a subject, comprising administering to
the subject a compound of any one of claims 1 to 74 or a
pharmaceutical composition of any one of claims 75 to 79.
92. A method of treating one or more symptoms of a disorder,
disease, or condition mediated by a cyclin-dependent kinase 9
(CDK9) in a subject, comprising administering to the subject a
compound of any one of claims 1 to 74 or a pharmaceutical
composition of any one of claims 75 to 79.
93. A method of inhibiting the activity of a CK1 in a cell,
comprising contacting the cell with a compound of any one of claims
1 to 74 or a pharmaceutical composition of any one of claims 75 to
79.
94. A method of inhibiting the activity of an IRAK1 in a cell,
comprising contacting the cell with a compound of any one of claims
1 to 74 or a pharmaceutical composition of any one of claims 75 to
79.
95. A method of inhibiting the activity of a CDK9 in a cell,
comprising contacting the cell with a compound of any one of claims
1 to 74 or a pharmaceutical composition of any one of claims 75 to
79.
96. A method of inhibiting the growth of a cell, comprising
contacting the cell with a compound of any one of claims 1 to 74 or
a pharmaceutical composition of any one of claims 75 to 79.
97. A method of inhibiting replication of a virus in a host,
comprising contacting the host with a compound of any one of claims
1 to 74 or a pharmaceutical composition of any one of claims 75 to
79.
98. A method of increasing eumelanin level in a skin cell,
comprising contacting the cell with a compound of any one of claims
1 to 74 or a pharmaceutical composition of any one of claims 75 to
79.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of the priority of U.S.
Provisional Application Nos. 62/627,908 and 62/627,921, filed Feb.
8, 2018; the disclosure of each of which is incorporated herein by
reference in its entirety.
FIELD
[0002] Provided herein are heteroaryl compounds, and pharmaceutical
compositions thereof. Also provided herein are methods of their use
for treating, ameliorating, or preventing a disorder, disease, or
condition mediated by a casein kinase 1 (CK1), an interleukin-1
receptor associated kinase (IRAK1), or a cyclin-dependent kinase 9
(CDK9).
BACKGROUND
[0003] Casein kinase 1.alpha. (CK1.alpha.), encoded by the Csnk1a1
gene, is a component of the .beta.-catenin-degradation complex and
a critical regulator of the Wnt signaling pathway. Schittek and
Sinnberg, Mol. Cancer 2014, 13, 231; Cheong and Virshup, J.
Biochem. Cell Biol. 2011, 43, 465-469; Elyada et al., Nature 2011,
470, 409-413. CK1a phosphorylates 3-catenin at Ser45, which primes
it for subsequent phosphorylation by GSK-30. GSK-30 phosphorylates
.beta.-catenin at Ser33, Ser37, and Thr41, marking it for
ubiquitination and proteasomal degradation. This
CK1.alpha.-dependent phosphorylation functions as a molecular
switch for the Wnt pathway. Amit et al., Genes Dev. 2002, 16,
1066-1076. A homozygous deficiency of CK1a results in embryonic
lethality, suggesting a fundamental role for CK1a in embryogenesis.
In a study of murine intestine epithelium, a CK1a deficiency was
found to induce Wnt activation, and DNA damage response, with
robust p53 activation and cellular senescence; this was also seen
in other types of tissues such as in skin keratinocytes including
tissue stem cells. Elyada et al., Nature 2011, 470, 409-413;
Schneider et al., Cancer Cell 2014, 26, 509-520; Chang et al.,
Proc. Nat. Acad. Sci. U.S.A. 2017, 114, E8035-E8044. These facts
suggest that CK1a plays an important role in cellular processes in
various tissues, which is, at least, partly coordinated with p53.
The well-known tumor suppressor protein, p53, is a transcription
factor that plays a pivotal role in cellular responses to genotoxic
stress and DNA damage. Levine and Oren, Nat. Rev. Cancer 2009, 9,
749-758. In the skin, p53 also acts as a central player against UV
damage via the p53/POMC/.alpha.-MSH/MC1R/MITF skin tanning pathway
and through the DNA repair/cell cycle arrest/apoptotic pathway. Cui
et al., Cell 2007, 128, 853-864; Ogmundsdottir and Steingrimsson,
Pigment. Cell Melanoma Res. 2014, 27, 154-155.
[0004] An interleukin-1 receptor associated kinase (IRAK1) is a
serine/threonine kinase that mediates signals elicited from
Toll-like receptor (TLR) and interleukin-1 receptor (IL1R).
Janssens and Beyaert, Mol. Cell. 2003, 11, 293-302. Upon receptor
activation, IRAK1 becomes phosphorylated, leading to recruitment of
TRAF6 and activation of NF-.kappa.B and JNK pathways. IRAK1 has
been identified as a therapeutic target for many proliferative
diseases, including myelodysplastic syndrome (MDS), certain subsets
of acute myeloid leukemia (AML), triple negative breast cancer, and
head and neck cancer. Rhyasen et al., Cancer Cell. 2013, 24,
90-104; Rhyasen et al., Exp. Hematol. 2013, 41, 1005-1007; Wee et
al., Nat. Commun. 2015, 6, 8746; Adams et al., Oncotarget 2015, 6,
43395-43407. For example, it has been demonstrated that
IRAK-inhibition by a small molecule or the knockdown of IRAK1
impairs MDS cell proliferation, progenitor function, and viability
in vitro and in vivo. Rhyasen et al., Cancer Cell. 2013, 24,
90-104; Rhyasen et al., Exp. Hematol. 2013, 41, 1005-1007. It has
also been demonstrated that IRAK1 overexpression confers triple
negative breast cancer cells (TNBC) a growth advantage through
NF-.kappa.B-related cytokine secretion and metastatic TNBC cells
exhibit gain of IRAK1 dependency, resulting in high susceptibility
to genetic and pharmacologic inhibition of IRAK1. Wee et al., Nat.
Commun. 2015, 6, 8746. It has been demonstrated that IRAK1 is
essential for the cell survival of head and neck squamous cell
carcinomas. Adams et al., Oncotarget 2015, 6, 43395-43407.
[0005] Cyclin-dependent kinase 9 (CDK9) is a prominent member of
the transcriptional CDKs subfamily, a group of kinases whose
function is to control the primary steps of mRNA synthesis and
processing by eukaryotic RNA polymerase II. As a cyclin dependent
kinase, CDK9 activation in vivo depends upon its association with
T-type cyclins to assemble the positive transcription elongation
factor (P-TEFb). Several cases of CDK9 deregulation have been
linked to important human diseases, including various types of
cancer and AIDS due to its essential role in HIV replication. Many
human viruses including HIV have been shown to depend strongly on
CDK9 activity to be transcribed within host cells. Paparidis et
al., Mol. Biosyst. 2017, 13, 246-276.
[0006] Therefore, there is a need for a compound as an effective
therapy for treating a disorder, disease, or condition mediated by
a casein kinase 1, an interleukin-1 receptor associated kinase, or
a cyclin-dependent kinase 9.
SUMMARY OF THE DISCLOSURE
[0007] Provided herein is a compound of Formula I:
##STR00002##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein:
[0008] U and V are each independently --O-- and .dbd.C(R.sup.4)--;
or U and V are each independently .dbd.N-- and --N(R.sup.5)--;
[0009] W, X, Y, and Z are each independently .dbd.C(R.sup.6)-- or
.dbd.N--, with the proviso that at least one of W, X, Y, and Z is
.dbd.N--; or W, X, and Z are each independently .dbd.C(R.sup.6)--,
--N(R.sup.7)--, .dbd.N--, --O--, or --S--; and Y is a bond;
[0010] R.sup.1 and R.sup.2 are each independently (a) hydrogen or
deuterium; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-2 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl,
heteroaryl, or heterocyclyl; or (c) --C(O)R.sup.1a,
--C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c, --C(O)SR.sup.1a,
--C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a, --C(S)OR.sup.1a,
--C(S)NR.sup.1bR.sup.1c, --OR.sup.1a, --OC(O)R.sup.1a,
--OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c, --OC(O)SR.sup.1a,
--OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, --OC(S)R.sup.1a,
--OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c, --OS(O)R.sup.1a,
--OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1d, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1aS(O)R.sup.1a,
--NR.sup.1aS(O).sub.2R.sup.1d, --NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.1a S(O).sub.2NR.sup.1bR.sup.1c, --S(O)R.sup.1a,
--S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c; or R.sup.1 and R.sup.2 together with
the N atom to which they are attached form heteroaryl or
heterocyclyl;
[0011] each R.sup.3, R.sup.4, and R.sup.6 is independently (a)
hydrogen, deuterium, cyano, halo, or nitro; (b) C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl;
or (c) --C(O)R.sup.1a, --C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--C(O)SR.sup.1a, --C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a,
--C(S)OR.sup.1a, --C(S)NR.sup.1bR.sup.1c, --OR.sup.1a,
--OC(O)R.sup.1a, --OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c,
--OC(O)SR.sup.1a, --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
--OC(S)R.sup.1a, --OC(S)OR.sup.1a, --OC(S)NR.sup.bR.sup.c,
--OS(O)R.sup.1a, --OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1d, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1a S(O)R.sup.1d,
--NR.sup.1a S(O).sub.2R.sup.1d, --NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.1aS(O).sub.2NR.sup.1bR.sup.1c, --SR.sup.1a,
--S(O)R.sup.1a, --S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c;
[0012] R.sup.5 and R.sup.7 are each independently (a) hydrogen or
deuterium; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15
aralkyl, heteroaryl, or heterocyclyl; or (c) --C(O)R.sup.1a,
--C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c, --C(O)SR.sup.1a,
--C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a, --C(S)OR.sup.1a,
--C(S)NR.sup.1bR.sup.1c, --OR.sup.1a, --OC(O)R.sup.1a,
--OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c, --OC(O)SR.sup.1a,
--OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, --OC(S)R.sup.1a,
--OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c, --OS(O)R.sup.1a,
--OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1d, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1aS(O)R.sup.1d,
--NR.sup.1aS(O).sub.2R.sup.1d, --NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.1aS(O).sub.2NR.sup.1bR.sup.1c, --S(O)R.sup.1a,
--S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c; and
[0013] each R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d is
independently hydrogen, deuterium, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or R.sup.1a and
R.sup.1c together with the C and N atoms to which they are attached
form heterocyclyl; or R.sup.1b and R.sup.1c together with the N
atom to which they are attached form heterocyclyl;
[0014] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
aralkyl, heteroaryl, and heterocyclyl is optionally substituted
with one or more, in one embodiment, one, two, three, or four,
substituents Q, where each Q is independently selected from (a)
deuterium, cyano, halo, and nitro; (b) C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is
further optionally substituted with one or more, in one embodiment,
one, two, three, or four, substituents Q.sup.a; and (c)
--C(O)R.sup.a, --C(O)OR.sup.a, --C(O)NR.sup.bR.sup.c,
--C(O)SR.sup.a, --C(NR.sup.a)N.sup.bR.sup.c, --C(S)R.sup.a,
--C(S)OR.sup.a, --C(S)NR.sup.bR.sup.c, --OR.sup.a, --OC(O)R.sup.a,
--OC(O)OR.sup.a, --OC(O)NR.sup.bR.sup.c, --OC(O)SR.sup.a,
--OC(.dbd.NR.sup.a)NR.sup.bR.sup.c, --OC(S)R.sup.a,
--OC(S)OR.sup.a, --OC(S)NR.sup.bR.sup.c, --OS(O)R.sup.a,
--OS(O).sub.2R.sup.a, --OS(O)NR.sup.bR.sup.c,
--OS(O).sub.2NR.sup.bR.sup.c, --NR.sup.bR.sup.c,
--NR.sup.aC(O)R.sup.d, --NR.sup.aC(O)OR.sup.d,
--NR.sup.aC(O)NR.sup.bR.sup.c, --NR.sup.aC(O)SR.sup.d,
--NR.sup.aC(.dbd.NR.sup.d)NR.sup.bR.sup.c, --NR.sup.aC(S)R.sup.d,
--NR.sup.aC(S)OR.sup.d, --NR.sup.aC(S)NR.sup.bR.sup.c,
--NR.sup.aS(O)R.sup.d, --NR.sup.aS(O).sub.2R.sup.d,
--NR.sup.aS(O)NR.sup.bR.sup.c, --NR.sup.aS(O).sub.2NR.sup.bR.sup.c,
--SR.sup.a, --S(O)R.sup.a, --S(O).sub.2R.sup.a,
--S(O)NR.sup.bR.sup.c, and --S(O).sub.2NR.sup.bR.sup.c, wherein
each R.sup.a, R.sup.b, R.sup.c, and R.sup.d is independently (i)
hydrogen or deuterium; (ii) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is
optionally substituted with one or more, in one embodiment, one,
two, three, or four, substituents Q.sup.a; or (iii) R.sup.b and
R.sup.c together with the N atom to which they are attached form
heterocyclyl, optionally substituted with one or more, in one
embodiment, one, two, three, or four, substituents Q.sup.a;
[0015] wherein each Q.sup.a is independently selected from the
group consisting of (a) deuterium, cyano, halo, and nitro; (b)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12
cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, and
heterocyclyl; and (c) --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.fR.sup.g, --C(O)SR.sup.e,
--C(NR.sup.e)NR.sup.fR.sup.g, --C(S)R.sup.e, --C(S)OR.sup.e,
--C(S)NR.sup.fR.sup.g, --OR.sup.e, --OC(O)R.sup.e, --OC(O)OR.sup.e,
--OC(O)NR.sup.fR.sup.g, --OC(O)SR.sup.e,
--OC(.dbd.NR.sup.e)NR.sup.fR.sup.g, --OC(S)R.sup.e,
--OC(S)OR.sup.e, --OC(S)NR.sup.fR.sup.g, --OS(O)R.sup.e,
--OS(O).sub.2R.sup.e, --OS(O)NR.sup.fR.sup.g,
--OS(O).sub.2NR.sup.fR.sup.g, --NR.sup.fR.sup.g,
--NR.sup.eC(O)R.sup.h--, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.fR.sup.g, --NR.sup.eC(O)SR.sup.f,
--NR.sup.eC(.dbd.NR.sup.h)RR, --NR.sup.eC(S)R.sup.h,
--NR.sup.eC(S)OR.sup.f, --NR.sup.eC(S)NR.sup.fR.sup.g,
--NR.sup.eS(O)R.sup.h, --NR.sup.eS(O).sub.2R.sup.h,
--NR.sup.eS(O)NR.sup.fR.sup.g, --NR.sup.eS(O).sub.2NR.sup.fR.sup.g,
--SR.sup.e, --S(O)R.sup.e, --S(O).sub.2R.sup.e,
--S(O)NR.sup.fR.sup.g, and --S(O).sub.2NR.sup.fR.sup.g; wherein
each R.sup.e, R.sup.f, R.sup.g, and R.sup.h is independently (i)
hydrogen or deuterium; (ii) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R.sup.f
and R.sup.g together with the N atom to which they are attached
form heterocyclyl.
[0016] Also provided herein is a compound of Formula I:
##STR00003##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein:
[0017] U and V are each independently --O-- and .dbd.C(R.sup.4)--;
or U and V are each independently .dbd.N-- and --N(R.sup.5)--; or U
is .dbd.N-- and --N(R.sup.5)--; and V is .dbd.C(R.sup.4)--;
[0018] W, X, Y, and Z are each independently .dbd.C(R.sup.6)-- or
.dbd.N--, with the proviso that at least one of W, X, Y, and Z is
.dbd.N--; or W, X, and Z are each independently .dbd.C(R.sup.6)--,
--N(R.sup.7)--, .dbd.N--, --O--, or --S--; and Y is a bond;
[0019] R.sup.1 and R.sup.2 are each independently (a) hydrogen or
deuterium; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15
aralkyl, heteroaryl, or heterocyclyl; or (c) --C(O)R.sup.1a,
--C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c, --C(O)SR.sup.1a,
--C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a, --C(S)OR.sup.1a,
--C(S)NR.sup.1bR.sup.1c, --OR.sup.1a, --OC(O)R.sup.1a,
--OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c, --OC(O)SR.sup.1a,
--OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, --OC(S)R.sup.1a,
--OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c, --OS(O)R.sup.1a,
--OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1d, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1a S(O)R.sup.1d,
--NR.sup.1aS(O).sub.2R.sup.1d, --NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.1a S(O).sub.2NR.sup.1bR.sup.1c, --S(O)R.sup.1a,
--S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c; or R.sup.1 and R.sup.2 together with
the N atom to which they are attached form heteroaryl or
heterocyclyl;
[0020] each R.sup.3, R.sup.4, and R.sup.6 is independently (a)
hydrogen, deuterium, cyano, halo, or nitro; (b) C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl;
or (c) --C(O)R.sup.1a, --C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--C(O)SR.sup.1a, --C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a,
--C(S)OR.sup.1a, --C(S)NR.sup.1bR.sup.1c, --OR.sup.1a,
--OC(O)R.sup.1a, --OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c,
--OC(O)SR.sup.1a, --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
--OC(S)R.sup.1a, --OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c,
--OS(O)R.sup.1a, --OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c, --NR.sup.1c
(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--R.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1a,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1d, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1aS(O)R.sup.1d,
--NR.sup.1aS(O).sub.2R.sup.1d, --NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.1aS(O).sub.2NR.sup.1bR.sup.1c, --SR.sup.1a,
--S(O)R.sup.1a, --S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c or
--S(O).sub.2NR.sup.1bR.sup.1c;
[0021] R.sup.5 and R.sup.7 are each independently (a) hydrogen or
deuterium; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15
aralkyl, heteroaryl, or heterocyclyl; or (c) --C(O)R.sup.1a,
--C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c, --C(O)SR.sup.1a,
--C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a, --C(S)OR.sup.1a,
--C(S)NR.sup.1bR.sup.1c, --OR.sup.1a, --OC(O)R.sup.1a,
--OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c, --OC(O)SR.sup.1a,
--OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, --OC(S)R.sup.1a,
--OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c, --OS(O)R.sup.1a,
--OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1d, --NR.sup.1aC(S)OR.sup.1d,
--R.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1aS(O)R.sup.1d,
--NR.sup.1aS(O).sub.2R.sup.1d, --NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.1a S(O).sub.2NR.sup.1bR.sup.1c, --S(O)R.sup.1a,
--S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c; and
[0022] each R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d is
independently hydrogen, deuterium, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or R.sup.1a and
R.sup.1c together with the C and N atoms to which they are attached
form heterocyclyl; or R.sup.1b and R.sup.1c together with the N
atom to which they are attached form heterocyclyl;
[0023] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
aralkyl, heteroaryl, and heterocyclyl is optionally substituted
with one or more, in one embodiment, one, two, three, or four,
substituents Q, where each Q is independently selected from (a)
deuterium, cyano, halo, and nitro; (b) C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is
further optionally substituted with one or more, in one embodiment,
one, two, three, or four, substituents Q.sup.a; and (c)
--C(O)R.sup.a, --C(O)OR.sup.a, --C(O)NR.sup.bR.sup.c,
--C(O)SR.sup.a, --C(NR.sup.a)N.sup.bR.sup.c, --C(S)R.sup.a,
--C(S)OR.sup.a, --C(S)NR.sup.bR.sup.c, --OR.sup.a, --OC(O)R.sup.a,
--OC(O)OR.sup.a, --OC(O)NR.sup.bR.sup.c, --OC(O)SR.sup.a,
--OC(.dbd.NR.sup.a)NR.sup.bR.sup.c, --OC(S)R.sup.a,
--OC(S)OR.sup.a, --OC(S)NR.sup.bR.sup.c, --OS(O)R.sup.a,
--OS(O).sub.2R.sup.a, --OS(O)NR.sup.bR.sup.c,
--OS(O).sub.2NR.sup.bR.sup.c, --NR.sup.bR.sup.c,
--NR.sup.aC(O)R.sup.d, --NR.sup.aC(O)OR.sup.1d,
--NR.sup.aC(O)NR.sup.bR.sup.c, --NR.sup.aC(O)SR.sup.d,
--NR.sup.aC(.dbd.NR.sup.d)NR.sup.bR.sup.c, --NR.sup.aC(S)R.sup.d,
--NR.sup.aC(S)OR.sup.1d, --NR.sup.aC(S)NR.sup.bR.sup.c,
--NR.sup.aS(O)R.sup.d, --NR.sup.aS(O).sub.2R.sup.d,
--NR.sup.aS(O)NR.sup.bR.sup.c, --NR.sup.aS(O).sub.2NR.sup.bR.sup.c,
--SR.sup.a, --S(O)R.sup.a, --S(O).sub.2R.sup.a,
--S(O)NR.sup.bR.sup.c, and --S(O).sub.2NR.sup.bR.sup.c, wherein
each R.sup.a, R.sup.b, R.sup.c, and R.sup.d is independently (i)
hydrogen or deuterium; (ii) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is
optionally substituted with one or more, in one embodiment, one,
two, three, or four, substituents Q.sup.a; or (iii) R.sup.b and
R.sup.c together with the N atom to which they are attached form
heterocyclyl, optionally substituted with one or more, in one
embodiment, one, two, three, or four, substituents Q.sup.a;
[0024] wherein each Q.sup.a is independently selected from the
group consisting of (a) deuterium, cyano, halo, and nitro; (b)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12
cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, and
heterocyclyl; and (c) --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.fR.sup.g, --C(O)SR.sup.e,
--C(NR.sup.e)NR.sup.fR.sup.g, --C(S)R.sup.e, --C(S)OR.sup.e,
--C(S)NR.sup.fR.sup.g, --OR.sup.e, --OC(O)R.sup.e, --OC(O)OR.sup.e,
--OC(O)NR.sup.fR.sup.g, --OC(O)SR.sup.e,
--OC(.dbd.NR.sup.e)NR.sup.fR.sup.g, --OC(S)R.sup.e,
--OC(S)OR.sup.e, --OC(S)NR.sup.fR.sup.g, --OS(O)R.sup.e,
--OS(O).sub.2R.sup.e, --OS(O)NR.sup.fR.sup.g,
--OS(O).sub.2NR.sup.fR.sup.g, --NR.sup.fR.sup.g,
--NR.sup.eC(O)R.sup.h, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.fR.sup.g, --NR.sup.eC(O)SR.sup.f,
--NR.sup.eC(.dbd.NR.sup.h)NR.sup.fR.sup.g, --NR.sup.eC(S)R.sup.h,
--NR.sup.eC(S)OR.sup.f, --NR.sup.eC(S)NR.sup.fR.sup.g,
--NR.sup.eS(O)R.sup.h, --NR.sup.eS(O).sub.2R.sup.h,
--NR.sup.eS(O)NR.sup.fR.sup.g, --NR.sup.eS(O).sub.2NR.sup.fR.sup.g,
--SR.sup.e, --S(O)R.sup.e, --S(O).sub.2R.sup.e,
--S(O)NR.sup.fR.sup.g, and --S(O).sub.2NR.sup.fR.sup.g; wherein
each R.sup.e, R.sup.f, R.sup.g, and R.sup.h is independently (i)
hydrogen or deuterium; (ii) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R.sup.f
and R.sup.g together with the N atom to which they are attached
form heterocyclyl.
[0025] Additionally provided herein is a compound of Formula
IA:
##STR00004##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein:
[0026] W, X, Y, and Z are each independently .dbd.C(R.sup.6)-- or
.dbd.N--, with the proviso that at least one of W, X, Y, and Z is
.dbd.N--; or W, X, and Z are each independently .dbd.C(R.sup.6)--,
--N(R.sup.7)--, .dbd.N--, --O--, or --S--; and Y is a bond;
[0027] each R.sup.1, R.sup.4, and R.sup.7 is independently (a)
hydrogen or deuterium; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or (c)
--C(O)R.sup.1a, --C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--C(O)SR.sup.1a, --C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a,
--C(S)OR.sup.1a, --C(S)NR.sup.1bR.sup.1c, --OR.sup.1a,
--OC(O)R.sup.1a, --OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c,
--OC(O)SR.sup.1a, --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
--OC(S)R.sup.1a, --OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c,
--OS(O)R.sup.1a, --OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1vR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1a, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1aS(O)R.sup.1a,
--NR.sup.1aS(O).sub.2R.sup.1d, --NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.1a S(O).sub.2NR.sup.1bR.sup.1c, --S(O)R.sup.1a,
--S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c;
[0028] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0029] (i) R.sup.2a and R.sup.2b are each independently (a)
hydrogen or deuterium; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or (c)
--C(O)R.sup.1a, --C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--C(O)SR.sup.1a, --C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a,
--C(S)OR.sup.1a, --C(S)NR.sup.1bR.sup.1c, --OR.sup.1a,
--OC(O)R.sup.1a, --OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c,
--OC(O)SR.sup.1a, --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
--OC(S)R.sup.1a, --OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c,
--OS(O)R.sup.1a, --OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1a,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1a, --NR.sup.1aC(S)OR.sup.1d,
--R.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1aS(O)R.sup.1d,
--NR.sup.1aS(O).sub.2R.sup.1d, --NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.1a S(O).sub.2NR.sup.1bR.sup.1c, --S(O)R.sup.1a,
--S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c or
--S(O).sub.2NR.sup.1bR.sup.1c; or R.sup.2a and R.sup.2b together
with the N atom to which they are attached form heteroaryl or
heterocyclyl; and [0030] R.sup.2c and R.sup.2d are each
independently (a) hydrogen, deuterium, or cyano; or (b) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl;
or R.sup.2c and R.sup.2d are linked together to form --O--,
C.sub.1-6 alkylene, C.sub.1-6 heteroalkylene, C.sub.2-6 alkenylene,
or C.sub.2-6 alkynylene; or
[0031] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form heterocyclyl; [0032] R.sup.2b is
(a) hydrogen or deuterium; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or (c)
--C(O)R.sup.1a, --C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--C(O)SR.sup.1a, --C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a,
--C(S)OR.sup.1a, --C(S)NR.sup.1bR.sup.1c, --OR.sup.1a,
--OC(O)R.sup.1a, --OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c,
--OC(O)SR.sup.1a, --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
--OC(S)R.sup.1a, --OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c,
--OS(O)R.sup.1a, --OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --R.sup.1aC(O)OR.sup.1a,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1a, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1aS(O)R.sup.1a,
--NR.sup.1aS(O).sub.2R.sup.1d, --NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.1aS(O).sub.2NR.sup.1bR.sup.1c, --S(O)R.sup.1a,
--S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c; and [0033] R.sup.2d is (a) hydrogen,
deuterium, or cyano; or (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl;
[0034] each R.sup.3, R.sup.5, and R.sup.6 is independently (a)
hydrogen, deuterium, cyano, halo, or nitro; (b) C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl;
or (c) --C(O)R.sup.1a, --C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--C(O)SR.sup.1a, --C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a,
--C(S)OR.sup.1a, --C(S)NR.sup.1bR.sup.1c, --OR.sup.1a,
--OC(O)R.sup.1a, --OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c,
--OC(O)SR.sup.1a, --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
--OC(S)R.sup.1a, --OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c,
--OS(O)R.sup.1a, --OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1a,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1d, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1aS(O)R.sup.1d,
--NR.sup.1aS(O).sub.2R.sup.1d, --NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.1aS(O).sub.2NR.sup.1bR.sup.1c, --SR.sup.1a,
--S(O)R.sup.1a, --S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c or
--S(O).sub.2NR.sup.1bR.sup.1c; and
[0035] each R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d is
independently hydrogen, deuterium, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or R.sup.1a and
R.sup.1c together with the C and N atoms to which they are attached
form heterocyclyl; or R.sup.1b and R.sup.1c together with the N
atom to which they are attached form heterocyclyl;
[0036] wherein each alkyl, alkylene, heteroalkylene, alkenyl,
alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl,
heteroaryl, and heterocyclyl is optionally substituted with one or
more, in one embodiment, one, two, three, or four, substituents Q,
where each Q is independently selected from (a) deuterium, cyano,
halo, and nitro; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15
aralkyl, heteroaryl, and heterocyclyl, each of which is further
optionally substituted with one or more, in one embodiment, one,
two, three, or four, substituents Q.sup.a; and (c) --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)NR.sup.bR.sup.c, --C(O)SR.sup.a,
--C(NR.sup.a)NR.sup.bR.sup.c, --C(S)R.sup.a, --C(S)OR.sup.a,
--C(S)NR.sup.bR.sup.c, --OR.sup.a, --OC(O)R.sup.a, --OC(O)OR.sup.a,
--OC(O)NR.sup.bR.sup.c, --OC(O)SR.sup.a,
--OC(.dbd.NR.sup.a)NR.sup.bR.sup.c, --OC(S)R.sup.a,
--OC(S)OR.sup.a, --OC(S)NR.sup.bR.sup.c, --OS(O)R.sup.a,
--OS(O).sub.2R.sup.a, --OS(O)NR.sup.bR.sup.c,
--OS(O).sub.2NR.sup.bR.sup.c, --NR.sup.bR.sup.c,
--NR.sup.aC(O)R.sup.d, --NR.sup.aC(O)OR.sup.d,
--NR.sup.aC(O)NR.sup.bR.sup.c, --NR.sup.aC(O)SR.sup.d,
--NR.sup.aC(.dbd.NR.sup.d)NR.sup.bR.sup.c, --NR.sup.aC(S)R.sup.d,
--NR.sup.aC(S)OR.sup.d, --NR.sup.aC(S)NR.sup.bR.sup.c,
--NR.sup.aS(O)R.sup.d, --NR.sup.aS(O).sub.2R.sup.d,
--NR.sup.aS(O)NR.sup.bR.sup.c, --NR.sup.aS(O).sub.2NR.sup.bR.sup.c,
--SR.sup.a, --S(O)R.sup.a, --S(O).sub.2R.sup.a,
--S(O)NR.sup.bR.sup.c, and --S(O).sub.2NR.sup.bR.sup.c, wherein
each R.sup.a, R.sup.b, R.sup.c, and R.sup.d is independently (i)
hydrogen or deuterium; (ii) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is
optionally substituted with one or more, in one embodiment, one,
two, three, or four, substituents Q.sup.a; or (iii) R.sup.b and
R.sup.c together with the N atom to which they are attached form
heterocyclyl, optionally substituted with one or more, in one
embodiment, one, two, three, or four, substituents Q.sup.a;
[0037] wherein each Q.sup.a is independently selected from the
group consisting of (a) deuterium, cyano, halo, and nitro; (b)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12
cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, and
heterocyclyl; and (c) --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.fR.sup.g, --C(O)SR.sup.e,
--C(NR.sup.e)NR.sup.fR.sup.g, --C(S)R.sup.e, --C(S)OR.sup.e,
--C(S)NR.sup.fR.sup.g, --OR.sup.e, --OC(O)R.sup.e, --OC(O)OR.sup.e,
--OC(O)NR.sup.fR.sup.g, --OC(O)SR.sup.e,
--OC(.dbd.NR.sup.e)NR.sup.fR.sup.g, --OC(S)R.sup.e,
--OC(S)OR.sup.e, --OC(S)NR.sup.fR.sup.g, --OS(O)R.sup.e,
--OS(O).sub.2R.sup.e, --OS(O)NR.sup.fR.sup.g,
--OS(O).sub.2NR.sup.fR.sup.g, --NR.sup.fR.sup.g,
--NR.sup.eC(O)R.sup.h, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.fR.sup.g, --NR.sup.eC(O)SR.sup.f,
--NR.sup.eC(.dbd.NR.sup.h)NR.sup.fR.sup.g, --NR.sup.eC(S)R.sup.h,
--NR.sup.eC(S)OR.sup.f, --NR.sup.eC(S)NR.sup.fR.sup.g,
--NR.sup.eS(O)R.sup.h, --NR.sup.eS(O).sub.2R.sup.h,
--NR.sup.eS(O)NR.sup.fR.sup.g, --NR.sup.eS(O).sub.2NR.sup.fR.sup.g,
--SR.sup.e, --S(O)R.sup.e, --S(O).sub.2R.sup.e,
--S(O)NR.sup.fR.sup.g, and --S(O).sub.2NR.sup.fR.sup.g; wherein
each R.sup.e, R.sup.f, R.sup.g, and R.sup.h is independently (i)
hydrogen or deuterium; (ii) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R.sup.f
and R.sup.g together with the N atom to which they are attached
form heterocyclyl.
[0038] Furthermore provided herein is a pharmaceutical composition,
comprising a compound of Formula I or IA, or an enantiomer, a
mixture of enantiomers, a mixture of two or more diastereomers, a
tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, and a pharmaceutically acceptable
excipient.
[0039] Provided herein is a method of treating, preventing, or
ameliorating one or more symptoms of a proliferative disease in a
subject, comprising administering to the subject a therapeutically
effective amount of a compound of Formula I or IA, or an
enantiomer, a mixture of enantiomers, a mixture of two or more
diastereomers, a tautomer, a mixture of two or more tautomers, or
an isotopic variant thereof; or a pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof.
[0040] Provided herein is a method of treating, preventing, or
ameliorating one or more symptoms of acquired immune deficiency
syndrome (AIDS) in a subject, comprising administering to the
subject a therapeutically effective amount of a compound of Formula
I or IA, or an enantiomer, a mixture of enantiomers, a mixture of
two or more diastereomers, a tautomer, a mixture of two or more
tautomers, or an isotopic variant thereof; or a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof.
[0041] Provided herein is a method of treating or preventing a
viral infection in a subject, comprising administering to the
subject a therapeutically effective amount of a compound of Formula
I or IA, or an enantiomer, a mixture of enantiomers, a mixture of
two or more diastereomers, a tautomer, a mixture of two or more
tautomers, or an isotopic variant thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof.
[0042] Provided herein is a method of treating, ameliorating, or
preventing a skin disorder, disease, or condition in a subject,
comprising administering to the subject a therapeutically effective
amount of a compound of Formula I or IA, or an enantiomer, a
mixture of enantiomers, a mixture of two or more diastereomers, a
tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof.
[0043] Provided herein is a method of protecting a subject from
ultraviolet radiation, comprising administering to the subject a
therapeutically effective amount of a compound of Formula I or IA,
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof, or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof.
[0044] Provided herein is a method of increasing skin pigmentation
in a subject, comprising administering to the subject a
therapeutically effective amount of a compound of Formula I or IA,
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof, or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof.
[0045] Provided herein is a method of increasing eumelanin level in
a subject, comprising administering to the subject a
therapeutically effective amount of a compound of Formula I or IA,
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof, or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof.
[0046] Provided herein is a method of treating one or more symptoms
of a disorder, disease, or condition mediated by a casein kinase 1
(CK1) in a subject, comprising administering to the subject a
therapeutically effective amount of a compound of Formula I or IA,
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof.
[0047] Provided herein is a method of treating one or more symptoms
of a disorder, disease, or condition mediated by an interleukin-1
receptor associated kinase (RAK1) in a subject, comprising
administering to the subject a therapeutically effective amount of
a compound of Formula I or IA, or an enantiomer, a mixture of
enantiomers, a mixture of two or more diastereomers, a tautomer, a
mixture of two or more tautomers, or an isotopic variant thereof,
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof.
[0048] Provided herein is a method of treating one or more symptoms
of a disorder, disease, or condition mediated by a cyclin-dependent
kinase 9 (CDK9) in a subject, comprising administering to the
subject a therapeutically effective amount of a compound of Formula
I or IA, or an enantiomer, a mixture of enantiomers, a mixture of
two or more diastereomers, a tautomer, a mixture of two or more
tautomers, or an isotopic variant thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof.
[0049] Provided herein is a method of inhibiting the activity of a
CK1 in a cell, comprising contacting the cell with an effective
amount of a compound of Formula I or IA, or an enantiomer, a
mixture of enantiomers, a mixture of two or more diastereomers, a
tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof.
[0050] Provided herein is a method of inhibiting the activity of an
IRAK1 in a cell, comprising contacting the cell with an effective
amount of a compound of Formula I or IA, or an enantiomer, a
mixture of enantiomers, a mixture of two or more diastereomers, a
tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof.
[0051] Provided herein is a method of inhibiting the activity of a
CDK9 in a cell, comprising contacting the cell with an effective
amount of a compound of Formula I or IA, or an enantiomer, a
mixture of enantiomers, a mixture of two or more diastereomers, a
tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof.
[0052] Provided herein is a method of inhibiting the growth of a
cell, comprising contacting the cell with an effective amount of a
compound of Formula I or IA, or an enantiomer, a mixture of
enantiomers, a mixture of two or more diastereomers, a tautomer, a
mixture of two or more tautomers, or an isotopic variant thereof;
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof.
[0053] Provided herein is a method for inhibiting replication of a
virus in a host, comprising administering to the host a
therapeutically effective amount of a compound of Formula I or IA,
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof, or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof.
[0054] Provided herein is a method of increasing eumelanin level in
a skin cell, comprising contacting the cell with an effective
amount of a compound of Formula I or IA, or an enantiomer, a
mixture of enantiomers, a mixture of two or more diastereomers, a
tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0055] FIG. 1 shows the effects of compounds A1, A2, B1, and B2 on
the protein expression levels of .beta.-catenin, MDM2, MCL-1, MYC,
and p53; and on the phosphorylation of RNA POL2-CTD (pCTD) and H2AX
(.gamma.H2AX), following 16 h-treatment of RKO cells, where PP2Ac
was used as a loading control.
DETAILED DESCRIPTION
[0056] To facilitate understanding of the disclosure set forth
herein, a number of terms are defined below.
[0057] Generally, the nomenclature used herein and the laboratory
procedures in organic chemistry, medicinal chemistry, biochemistry,
biology, and pharmacology described herein are those well known and
commonly employed in the art. Unless defined otherwise, all
technical and scientific terms used herein generally have the same
meaning as commonly understood by one of ordinary skill in the art
to which this disclosure belongs.
[0058] The term "subject" refers to an animal, including, but not
limited to, a primate (e.g., human), cow, pig, sheep, goat, horse,
dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient"
are used interchangeably herein in reference, for example, to a
mammalian subject, such as a human subject. In one embodiment, the
subject is a human.
[0059] The term "host" refers to a unicellular or multicellular
organism in which a virus can replicate, including, but not limited
to, a cell, cell line, and animal, such as a human.
[0060] The terms "treat," "treating," and "treatment" are meant to
include alleviating or abrogating a disorder, disease, or
condition, or one or more of the symptoms associated with the
disorder, disease, or condition; or alleviating or eradicating the
cause(s) of the disorder, disease, or condition itself.
[0061] The terms "prevent," "preventing," and "prevention" are
meant to include a method of delaying and/or precluding the onset
of a disorder, disease, or condition, and/or its attendant
symptoms; barring a subject from acquiring a disorder, disease, or
condition; or reducing a subject's risk of acquiring a disorder,
disease, or condition.
[0062] The terms "alleviate" and "alleviating" refer to easing or
reducing one or more symptoms (e.g., pain) of a disorder, disease,
or condition. The terms can also refer to reducing adverse effects
associated with an active ingredient. Sometimes, the beneficial
effects that a subject derives from a prophylactic or therapeutic
agent do not result in a cure of the disorder, disease, or
condition.
[0063] The term "contacting" or "contact" is meant to refer to
bringing together of a therapeutic agent and cell or tissue such
that a physiological and/or chemical effect takes place as a result
of such contact. Contacting can take place in vitro, ex vivo, or in
vivo. In one embodiment, a therapeutic agent is contacted with a
cell in cell culture (in vitro) to determine the effect of the
therapeutic agent on the cell. In another embodiment, the
contacting of a therapeutic agent with a cell or tissue includes
the administration of a therapeutic agent to a subject having the
cell or tissue to be contacted.
[0064] The term "therapeutically effective amount" or "effective
amount" is meant to include the amount of a compound that, when
administered, is sufficient to prevent development of, or alleviate
to some extent, one or more of the symptoms of the disorder,
disease, or condition being treated. The term "therapeutically
effective amount" or "effective amount" also refers to the amount
of a compound that is sufficient to elicit a biological or medical
response of a biological molecule (e.g., a protein, enzyme, RNA, or
DNA), cell, tissue, system, animal, or human, which is being sought
by a researcher, veterinarian, medical doctor, or clinician.
[0065] The term "pharmaceutically acceptable carrier,"
"pharmaceutically acceptable excipient," "physiologically
acceptable carrier," or "physiologically acceptable excipient"
refers to a pharmaceutically acceptable material, composition, or
vehicle, such as a liquid or solid filler, diluent, solvent, or
encapsulating material. In one embodiment, each component is
"pharmaceutically acceptable" in the sense of being compatible with
the other ingredients of a pharmaceutical formulation, and suitable
for use in contact with the tissue or organ of a subject (e.g., a
human or an animal) without excessive toxicity, irritation,
allergic response, immunogenicity, or other problems or
complications, commensurate with a reasonable benefit/risk ratio.
See, Remington: The Science and Practice of Pharmacy, 22nd ed.;
Allen Ed.: Philadelphia, Pa., 2012; Handbook of Pharmaceutical
Excipients, 8th ed.; Sheskey et al., Eds.; The Pharmaceutical Press
and the American Pharmacists Association: 2017; Handbook of
Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower
Publishing Company: 2007; Pharmaceutical Preformulation and
Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla.,
2009.
[0066] The term "about" or "approximately" means an acceptable
error for a particular value as determined by one of ordinary skill
in the art, which depends in part on how the value is measured or
determined. In certain embodiments, the term "about" or
"approximately" means within 1, 2, 3, or 4 standard deviations. In
certain embodiments, the term "about" or "approximately" means
within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%,
0.5%, or 0.05% of a given value or range.
[0067] The terms "active ingredient" and "active substance" refer
to a compound, which is administered, alone or in combination with
one or more pharmaceutically acceptable excipients, to a subject
for treating, preventing, or ameliorating one or more symptoms of a
disorder, disease, or condition. As used herein, "active
ingredient" and "active substance" may be an optically active
isomer of a compound described herein.
[0068] The terms "drug," "therapeutic agent," and "chemotherapeutic
agent" refer to a compound or a pharmaceutical composition thereof,
which is administered to a subject for treating, preventing, or
ameliorating one or more symptoms of a disorder, disease, or
condition.
[0069] The term "alkyl" refers to a linear or branched saturated
monovalent hydrocarbon radical, wherein the alkyl is optionally
substituted with one or more substituents Q as described herein.
For example, C.sub.1-6 alkyl refers to a linear saturated
monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched
saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In
certain embodiments, the alkyl is a linear saturated monovalent
hydrocarbon radical that has 1 to 20 (C.sub.1-20), 1 to 15
(C.sub.1-15), 1 to 10 (C.sub.1-10), or 1 to 6 (C.sub.1-6) carbon
atoms, or branched saturated monovalent hydrocarbon radical of 3 to
20 (C.sub.3-20), 3 to 15 (C.sub.3-5), 3 to 10 (C.sub.3-10), or 3 to
6 (C.sub.3-6) carbon atoms. As used herein, linear C.sub.1-6 and
branched C.sub.3-6 alkyl groups are also referred as "lower alkyl."
Examples of alkyl groups include, but are not limited to, methyl,
ethyl, propyl (including all isomeric forms), n-propyl, isopropyl,
butyl (including all isomeric forms), n-butyl, isobutyl, sec-butyl,
t-butyl, pentyl (including all isomeric forms), and hexyl
(including all isomeric forms).
[0070] The term "alkylene" refers to a linear or branched saturated
divalent hydrocarbon radical, wherein the alkylene may optionally
be substituted with one or more substituents Q as described herein.
For example, C.sub.1-6 alkylene refers to a linear saturated
divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched
saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In
certain embodiments, the alkylene is a linear saturated divalent
hydrocarbon radical that has 1 to 20 (C.sub.1-20), 1 to 15
(C.sub.1-15), 1 to 10 (C.sub.1-10), or 1 to 6 (C.sub.1-6) carbon
atoms, or branched saturated divalent hydrocarbon radical of 3 to
20 (C.sub.3-20), 3 to 15 (C.sub.3-5), 3 to 10 (C.sub.3-10), or 3 to
6 (C.sub.3-6) carbon atoms. As used herein, linear C.sub.1-6 and
branched C.sub.3-6 alkylene groups are also referred as "lower
alkylene." Examples of alkylene groups include, but are not limited
to, methylene, ethylene, propylene (including all isomeric forms),
n-propylene, isopropylene, butylene (including all isomeric forms),
n-butylene, isobutylene, t-butylene, pentylene (including all
isomeric forms), and hexylene (including all isomeric forms).
[0071] The term "heteroalkylene" refers to a linear or branched
saturated divalent hydrocarbon radical that contains one or more
heteroatoms each independently selected from O, S, and N in the
hydrocarbon chain. For example, C.sub.1-6 heteroalkylene refers to
a linear saturated divalent hydrocarbon radical of 1 to 6 carbon
atoms or a branched saturated divalent hydrocarbon radical of 3 to
6 carbon atoms. In certain embodiments, the heteroalkylene is a
linear saturated divalent hydrocarbon radical that has 1 to 20
(C.sub.1-20), 1 to 15 (C.sub.1-15), 1 to 10 (C.sub.1-10), or 1 to 6
(C.sub.1-6) carbon atoms, or branched saturated divalent
hydrocarbon radical of 3 to 20 (C.sub.3-20), 3 to 15 (C.sub.3-5), 3
to 10 (C.sub.3-10), or 3 to 6 (C.sub.3-6) carbon atoms. As used
herein, linear C.sub.1-6 and branched C.sub.3-6 heteroalkylene
groups are also referred as "lower heteroalkylene." Examples of
heteroalkylene groups include, but are not limited to,
--CH.sub.2O--, --CH.sub.2OCH.sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2NH--, --CH.sub.2NHCH.sub.2--, --CH.sub.2CH.sub.2NH--,
--C(O)NH--, --C(O)NHCH.sub.2--, --CH.sub.2C(O)NH--, --CH.sub.2S--,
--CH.sub.2SCH.sub.2--, --CH.sub.2CH.sub.2S--,
--CH.sub.2S(O).sub.2NH--, --CH.sub.2S(O).sub.2NHCH.sub.2--, and
--CH.sub.2CH.sub.2S(O).sub.2NH--. In certain embodiments,
heteroalkylene may also be optionally substituted with one or more
substituents Q as described herein.
[0072] The term "alkenyl" refers to a linear or branched monovalent
hydrocarbon radical, which contains one or more, in one embodiment,
one, two, three, four, or five, in another embodiment, one,
carbon-carbon double bond(s). The alkenyl is optionally substituted
with one or more substituents Q as described herein. The term
"alkenyl" embraces radicals having a "cis" or "trans" configuration
or a mixture thereof, or alternatively, a "Z" or "E" configuration
or a mixture thereof, as appreciated by those of ordinary skill in
the art. For example, C.sub.2-6 alkenyl refers to a linear
unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms
or a branched unsaturated monovalent hydrocarbon radical of 3 to 6
carbon atoms. In certain embodiments, the alkenyl is a linear
monovalent hydrocarbon radical of 2 to 20 (C.sub.2-20), 2 to 15
(C.sub.2-15), 2 to 10 (C.sub.2-10), or 2 to 6 (C.sub.2-6) carbon
atoms, or a branched monovalent hydrocarbon radical of 3 to 20
(C.sub.3-20), 3 to 15 (C.sub.3-5), 3 to 10 (C.sub.3-10), or 3 to 6
(C.sub.3-6) carbon atoms. Examples of alkenyl groups include, but
are not limited to, ethenyl, propen-1-yl, propen-2-yl, allyl,
butenyl, and 4-methylbutenyl.
[0073] The term "alkenylene" refers to a linear or branched
divalent hydrocarbon radical, which contains one or more
carbon-carbon double bond(s), in one embodiment, one to five
carbon-carbon double bond(s), in another embodiment, one
carbon-carbon double bond. The alkenylene may be optionally
substituted with one or more substituents Q as described herein.
The term "alkenylene" embraces radicals having a "cis" or "trans"
configuration or a mixture thereof, or alternatively, a "Z" or "E"
configuration or a mixture thereof, as appreciated by those of
ordinary skill in the art. For example, C.sub.2-6 alkenylene refers
to a linear unsaturated divalent hydrocarbon radical of 2 to 6
carbon atoms or a branched unsaturated divalent hydrocarbon radical
of 3 to 6 carbon atoms. In certain embodiments, the alkenylene is a
linear divalent hydrocarbon radical of 2 to 20 (C.sub.2-20), 2 to
15 (C.sub.2-15), 2 to 10 (C.sub.2-10), or 2 to 6 (C.sub.2-6) carbon
atoms, or a branched divalent hydrocarbon radical of 3 to 20
(C.sub.3-20), 3 to 15 (C.sub.3-5), 3 to 10 (C.sub.3-10), or 3 to 6
(C.sub.3-6) carbon atoms. Examples of alkenylene groups include,
but are not limited to, ethenylene, allylene, propenylene,
butenylene, and 4-methylbutenylene.
[0074] The term "alkynyl" refers to a linear or branched monovalent
hydrocarbon radical, which contains one or more, in one embodiment,
one, two, three, four, or five, in another embodiment, one,
carbon-carbon triple bond(s). The alkynyl is optionally substituted
with one or more substituents Q as described herein. For example,
C.sub.2-6 alkynyl refers to a linear unsaturated monovalent
hydrocarbon radical of 2 to 6 carbon atoms or a branched
unsaturated monovalent hydrocarbon radical of 4 to 6 carbon atoms.
In certain embodiments, the alkynyl is a linear monovalent
hydrocarbon radical of 2 to 20 (C.sub.2-20), 2 to 15 (C.sub.2-15),
2 to 10 (C.sub.2-10), or 2 to 6 (C.sub.2-6) carbon atoms, or a
branched monovalent hydrocarbon radical of 4 to 20 (C.sub.4-20), 4
to 15 (C.sub.4-15), 4 to 10 (C.sub.4-10), or 4 to 6 (C.sub.4-6)
carbon atoms. Examples of alkynyl groups include, but are not
limited to, ethynyl (--C.ident.CH), propynyl (including all
isomeric forms, e.g., 1-propynyl (--C.ident.CCH.sub.3) and
propargyl (--CH.sub.2C.ident.CH)), butynyl (including all isomeric
forms, e.g., 1-butyn-1-yl and 2-butyn-1-yl), pentynyl (including
all isomeric forms, e.g., 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl),
and hexynyl (including all isomeric forms, e.g., 1-hexyn-1-yl).
[0075] The term "alkynylene" refers to a linear or branched
divalent hydrocarbon radical, which contains one or more, in one
embodiment, one, two, three, four, or five, in another embodiment,
one or two, carbon-carbon triple bond(s). The alkynylene may be
optionally substituted with one or more substituents Q as described
herein. For example, C.sub.2-6 alkynylene refers to a linear
unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or
a branched unsaturated divalent hydrocarbon radical of 4 to 6
carbon atoms. In certain embodiments, the alkynylene is a linear
divalent hydrocarbon radical of 2 to 20 (C.sub.2-20), 2 to 15
(C.sub.2-15), 2 to 10 (C.sub.2-10), or 2 to 6 (C.sub.2-6) carbon
atoms, or a branched divalent hydrocarbon radical of 4 to 20
(C.sub.4-20), 4 to 15 (C.sub.4-15), 4 to 10 (C.sub.4-10), or 4 to 6
(C.sub.4-6) carbon atoms. Examples of alkynylene groups include,
but are not limited to, ethynylene, propynylene (including all
isomeric forms, e.g., 1-propynylene and propargylene), butynylene
(including all isomeric forms, e.g., 1-butyn-1-ylene and
2-butyn-1-ylene), pentynylene (including all isomeric forms, e.g.,
1-pentyn-1-ylene and 1-methyl-2-butyn-1-ylene), and hexynylene
(including all isomeric forms, e.g., 1-hexyn-1-ylene).
[0076] The term "cycloalkyl" refers to a cyclic monovalent
hydrocarbon radical, which is optionally substituted with one or
more substituents Q as described herein. In one embodiment, the
cycloalkyl is a saturated or unsaturated but non-aromatic, and/or
bridged or non-bridged, and/or fused bicyclic group. In certain
embodiments, the cycloalkyl has from 3 to 20 (C.sub.3-20), from 3
to 15 (C.sub.3-5), from 3 to 12 (C.sub.3-12), from 3 to 10
(C.sub.3-10), or from 3 to 7 (C.sub.3-7)carbon atoms. In one
embodiment, the cycloalkyl is monocyclic. In another embodiment,
the cycloalkyl is bicyclic. In yet another embodiment, the
cycloalkyl is polycyclic. Examples of cycloalkyl groups include,
but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl,
cycloheptyl, cycloheptenyl, bicyclo[2.1.1]hexyl,
bicyclo[2.2.1]heptyl, decalinyl, and adamantyl.
[0077] The term "aryl" refers to a monovalent monocyclic aromatic
hydrocarbon radical and/or monovalent polycyclic aromatic
hydrocarbon radical that contain at least one aromatic carbon ring.
In certain embodiments, the aryl has from 6 to 20 (C.sub.6-20),
from 6 to 15 (C.sub.6-15), or from 6 to 10 (C.sub.6-10) ring carbon
atoms. Examples of aryl groups include, but are not limited to,
phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl,
pyrenyl, biphenyl, and terphenyl. The aryl also refers to bicyclic
or tricyclic carbon rings, where one of the rings is aromatic and
the others of which may be saturated, partially unsaturated, or
aromatic, for example, dihydronaphthyl, indenyl, indanyl, or
tetrahydronaphthyl (tetralinyl). In one embodiment, the aryl is
monocyclic. In another embodiment, the aryl is polycyclic. In yet
another embodiment, the aryl is bicyclic. In still another
embodiment, the aryl is tricyclic. In certain embodiments, the aryl
is optionally substituted with one or more substituents Q as
described herein.
[0078] The term "aralkyl" or "arylalkyl" refers to a monovalent
alkyl group substituted with one or more aryl groups. In certain
embodiments, the aralkyl has from 7 to 30 (C.sub.7-30), from 7 to
20 (C.sub.7-20), or from 7 to 16 (C.sub.7-16) carbon atoms.
Examples of aralkyl groups include, but are not limited to, benzyl,
2-phenylethyl, and 3-phenylpropyl. In certain embodiments, the
aralkyl is optionally substituted with one or more substituents Q
as described herein.
[0079] The term "heteroaryl" refers to a monovalent monocyclic
aromatic group or monovalent polycyclic aromatic group that contain
at least one aromatic ring, wherein at least one aromatic ring
contains one or more heteroatoms, each independently selected from
O, S, and N, in the ring. The heteroaryl is bonded to the rest of a
molecule through the aromatic ring. Each ring of a heteroaryl group
can contain one or two O atoms, one or two S atoms, and/or one to
four N atoms; provided that the total number of heteroatoms in each
ring is four or less and each ring contains at least one carbon
atom. In certain embodiments, the heteroaryl has from 5 to 20, from
5 to 15, or from 5 to 10 ring atoms. In one embodiment, the
heteroaryl is monocyclic. Examples of monocyclic heteroaryl groups
include, but are not limited to, furanyl, imidazolyl, isothiazolyl,
isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl,
thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and
triazolyl. In another embodiment, the heteroaryl is bicyclic.
Examples of bicyclic heteroaryl groups include, but are not limited
to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl,
benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl,
benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl,
indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl,
isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl,
oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl,
pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl,
thiadiazolopyrimidyl, and thienopyridyl. In yet another embodiment,
the heteroaryl is tricyclic. Examples of tricyclic heteroaryl
groups include, but are not limited to, acridinyl, benzindolyl,
carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl,
phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl,
phenoxazinyl, and xanthenyl. In certain embodiments, the heteroaryl
is optionally substituted with one or more substituents Q as
described herein.
[0080] The term "heterocyclyl" or "heterocyclic" refers to a
monovalent monocyclic non-aromatic ring system or monovalent
polycyclic ring system that contains at least one non-aromatic
ring, wherein one or more of the non-aromatic ring atoms are
heteroatoms, each independently selected from O, S, and N; and the
remaining ring atoms are carbon atoms. In certain embodiments, the
heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15,
from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms.
The heterocyclyl is bonded to the rest of a molecule through the
non-aromatic ring. In certain embodiments, the heterocyclyl is a
monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which
may be fused or bridged, and in which nitrogen or sulfur atoms may
be optionally oxidized, nitrogen atoms may be optionally
quaternized, and some rings may be partially or fully saturated, or
aromatic. The heterocyclyl may be attached to the main structure at
any heteroatom or carbon atom which results in the creation of a
stable compound. Examples of heterocyclyls and heterocyclic groups
include, but are not limited to, azepinyl, benzodioxanyl,
benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl,
benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl,
benzoxazinyl, 3-carbolinyl, chromanyl, chromonyl, cinnolinyl,
coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl,
dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl,
dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl,
dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl,
1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl,
isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl,
isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl,
morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl,
oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl,
pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl,
quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl,
tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl,
thiazolidinyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In
certain embodiments, the heterocyclyl is optionally substituted
with one or more substituents Q as described herein.
[0081] The term "halogen", "halide," or "halo" refers to fluorine,
chlorine, bromine, and/or iodine.
[0082] The term "optionally substituted" is intended to mean that a
group or substituent, such as an alkyl, alkylene, heteroalkylene,
alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl,
aralkyl, heteroaryl, or heterocyclyl group, may be substituted with
one or more, one, two, three, or four, substituents Q, each of
which is independently selected from, e.g., (a) deuterium (-D),
cyano (--CN), halo, and nitro (--NO.sub.2); (b) C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, and heterocyclyl,
each of which is further optionally substituted with one or more,
in one embodiment, one, two, three, or four, substituents Q.sup.a;
and (c) --C(O)R.sup.a, --C(O)OR.sup.a, --C(O)NR.sup.bR.sup.c,
--C(O)SR.sup.a, --C(NR.sup.a)NR.sup.bR.sup.c, --C(S)R.sup.a,
--C(S)OR.sup.a, --C(S)NR.sup.bR.sup.c, --OR.sup.a, --OC(O)R.sup.a,
--OC(O)OR.sup.a, --OC(O)NR.sup.bR.sup.c, --OC(O)SR.sup.a,
--OC(.dbd.NR.sup.a)NR.sup.bR.sup.c, --OC(S)R.sup.a,
--OC(S)OR.sup.a, --OC(S)NR.sup.bR.sup.c, --OS(O)R.sup.a,
--OS(O).sub.2R.sup.a, --OS(O)NR.sup.bR.sup.c,
--OS(O).sub.2NR.sup.bR.sup.c, --NR.sup.bR.sup.c,
--NR.sup.aC(O)R.sup.d, --NR.sup.aC(O)OR.sup.d,
--NR.sup.aC(O)NR.sup.bR.sup.c, --NR.sup.aC(O)SR.sup.d,
--NR.sup.aC(.dbd.NR.sup.d)NR.sup.bR.sup.c, --NR.sup.aC(S)R.sup.d,
--NR.sup.aC(S)OR.sup.d, --NR.sup.aC(S)NR.sup.bR.sup.c,
--NR.sup.aS(O)R.sup.d, --NR.sup.aS(O).sub.2R.sup.d,
--NR.sup.aS(O)NR.sup.bR.sup.c, --NR.sup.aS(O).sub.2NR.sup.bR.sup.c,
--SR.sup.a, --S(O)R.sup.a, --S(O).sub.2R.sup.a,
--S(O)NR.sup.bR.sup.c, and --S(O).sub.2NR.sup.bR.sup.c, wherein
each R.sup.a, R.sup.b, R.sup.c, and R.sup.d is independently (i)
hydrogen or deuterium; (ii) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is
optionally substituted with one or more, in one embodiment, one,
two, three, or four, substituents Q.sup.a; or (iii) R.sup.b and
R.sup.c together with the N atom to which they are attached form
heterocyclyl, optionally substituted with one or more, in one
embodiment, one, two, three, or four, substituents Q.sup.a. As used
herein, all groups that can be substituted are "optionally
substituted," unless otherwise specified.
[0083] In one embodiment, each Q.sup.a is independently selected
from the group consisting of (a) deuterium, cyano, halo, and nitro;
(b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-12 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl,
heteroaryl, and heterocyclyl; and (c) --C(O)R.sup.e,
--C(O)OR.sup.d, --C(O)NR.sup.fR.sup.g, --C(O)SR.sup.e,
--C(NR.sup.e)NR.sup.fR.sup.g, --C(S)R.sup.e, --C(S)OR.sup.e,
--C(S)NR.sup.fR.sup.g, --OR.sup.e, --OC(O)R.sup.e, --OC(O)OR.sup.d,
--OC(O)NR.sup.fR.sup.g, --OC(O)SR.sup.d,
--OC(.dbd.NR.sup.e)NR.sup.fR.sup.g, --OC(S)R.sup.e,
--OC(S)OR.sup.e, --OC(S)NR.sup.fR.sup.g, --OS(O)R.sup.e,
--OS(O).sub.2R.sup.e, --OS(O)NR.sup.fR.sup.g,
--OS(O).sub.2NR.sup.fR.sup.g, --NR.sup.fR.sup.g,
--NR.sup.eC(O)R.sup.h, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.fR.sup.g, --NR.sup.eC(O)SR.sup.f,
--NR.sup.eC(.dbd.NR.sup.h)NR.sup.fR.sup.g, --NR.sup.eC(S)R.sup.h,
--NR.sup.eC(S)OR.sup.f, --NR.sup.eC(S)NR.sup.fR.sup.g,
--NR.sup.eS(O)R.sup.h, --NR.sup.eS(O).sub.2R.sup.h,
--NR.sup.eS(O)NR.sup.fR.sup.g, --NR.sup.eS(O).sub.2NR.sup.fR.sup.g,
--SR.sup.e, --S(O)R.sup.e, --S(O).sub.2R.sup.e,
--S(O)NR.sup.fR.sup.g, and --S(O).sub.2NR.sup.fR.sup.g; wherein
each R.sup.e, R.sup.f, R.sup.g, and R.sup.h is independently (i)
hydrogen or deuterium; (ii) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R.sup.f
and R.sup.g together with the N atom to which they are attached
form heterocyclyl.
[0084] In certain embodiments, "optically active" and
"enantiomerically active" refer to a collection of molecules, which
has an enantiomeric excess of no less than about 50%, no less than
about 70%, no less than about 80%, no less than about 90%, no less
than about 91%, no less than about 92%, no less than about 93%, no
less than about 94%, no less than about 95%, no less than about
96%, no less than about 97%, no less than about 98%, no less than
about 99%, no less than about 99.5%, or no less than about 99.8%.
In certain embodiments, an optically active compound comprises
about 95% or more of one enantiomer and about 5% or less of the
other enantiomer based on the total weight of the enantiomeric
mixture in question.
[0085] In describing an optically active compound, the prefixes R
and S are used to denote the absolute configuration of the compound
about its chiral center(s). The (+) and (-) are used to denote the
optical rotation of the compound, that is, the direction in which a
plane of polarized light is rotated by the optically active
compound. The (-) prefix indicates that the compound is
levorotatory, that is, the compound rotates the plane of polarized
light to the left or counterclockwise. The (+) prefix indicates
that the compound is dextrorotatory, that is, the compound rotates
the plane of polarized light to the right or clockwise. However,
the sign of optical rotation, (+) and (-), is not related to the
absolute configuration of the compound, R and S.
[0086] The term "isotopically enriched" refers to a compound that
contains an unnatural proportion of an isotope at one or more of
the atoms that constitute such a compound. In certain embodiments,
an isotopically enriched compound contains unnatural proportions of
one or more isotopes, including, but not limited to, hydrogen (H),
deuterium (2H), tritium (H), carbon-11 (.sup.11C), carbon-12
(.sup.12C), carbon-13 (.sup.13C), carbon-14 (.sup.14C), nitrogen-13
(13N), nitrogen-14 (14N), nitrogen-15 (.sup.1N), oxygen-14
(.sup.14O), oxygen-15 (.sup.15O), oxygen-16 (.sup.16O), oxygen-17
(.sup.17O), oxygen-18 (.sup.18O), fluorine-17 (.sup.17F),
fluorine-18 (.sup.18F), phosphorus-31 (.sup.31P), phosphorus-32
(.sup.32P), phosphorus-33 (.sup.33P), sulfur-32 (.sup.32S),
sulfur-33 (.sup.33S), sulfur-34 (.sup.34S), sulfur-35 (.sup.35S),
sulfur-36 (.sup.36S), chlorine-35 (.sup.35Cl), chlorine-36
(.sup.36Cl), chlorine-37 (37Cl), bromine-79 (.sup.79Br), bromine-81
(.sup.81Br), iodine-123 (.sup.123I), iodine-125 (.sup.125I),
iodine-127 (.sup.127I), iodine-129 (.sup.129I), and iodine-131
(.sup.131I). In certain embodiments, an isotopically enriched
compound is in a stable form, that is, non-radioactive. In certain
embodiments, an isotopically enriched compound contains unnatural
proportions of one or more isotopes, including, but not limited to,
hydrogen (H), deuterium (2H), carbon-12 (.sup.12C), carbon-13
(.sup.13C), nitrogen-14 (.sup.14N), nitrogen-15 (.sup.15N),
oxygen-16 (.sup.16O), oxygen-17 (.sup.17O), oxygen-18 (.sup.18O),
fluorine-17 (.sup.17F), phosphorus-31 (.sup.31P), sulfur-32
(.sup.32S), sulfur-33 (.sup.33S), sulfur-34 (.sup.34S), sulfur-36
(.sup.36S), chlorine-35 (.sup.35Cl), chlorine-37 (.sup.37Cl),
bromine-79 (.sup.79Br), bromine-81 (.sup.81Br), and iodine-127
(.sup.127I). In certain embodiments, an isotopically enriched
compound is in an unstable form, that is, radioactive. In certain
embodiments, an isotopically enriched compound contains unnatural
proportions of one or more isotopes, including, but not limited to,
tritium (.sup.3H), carbon-11 (.sup.11C), carbon-14 (.sup.14C),
nitrogen-13 (.sup.13N), oxygen-14 (.sup.14O), oxygen-15 (.sup.15O),
fluorine-18 (.sup.18F), phosphorus-32 (.sup.32P), phosphorus-33
(.sup.33P), sulfur-35 (.sup.35S), chlorine-36 (.sup.36Cl),
iodine-123 (.sup.123I), iodine-25 (.sup.125I), iodine-129
(.sup.129I), and iodine-131 (.sup.131I). It will be understood
that, in a compound as provided herein, any hydrogen can be
.sup.2H, as example, or any carbon can be .sup.13C, as example, or
any nitrogen can be .sup.15N, as example, or any oxygen can be
.sup.18O, as example, where feasible according to the judgment of
one of ordinary skill in the art.
[0087] The term "isotopic enrichment" refers to the percentage of
incorporation of a less prevalent isotope (e.g., D for deuterium or
hydrogen-2) of an element at a given position in a molecule in the
place of a more prevalent isotope (e.g., .sup.1H for protium or
hydrogen-1) of the element. As used herein, when an atom at a
particular position in a molecule is designated as a particular
less prevalent isotope, it is understood that the abundance of that
isotope at that position is substantially greater than its natural
abundance.
[0088] The term "isotopic enrichment factor" refers the ratio
between the isotopic abundance in an isotopically enriched compound
and the natural abundance of a specific isotope.
[0089] The term "hydrogen" or the symbol "H" refers to the
composition of naturally occurring hydrogen isotopes, which include
protium (H), deuterium (2H or D), and tritium (.sup.3H), in their
natural abundances. Protium is the most common hydrogen isotope
having a natural abundance of more than 99.98%. Deuterium is a less
prevalent hydrogen isotope having a natural abundance of about
0.0156%.
[0090] The term "deuterium enrichment" refers to the percentage of
incorporation of deuterium at a given position in a molecule in the
place of hydrogen. For example, deuterium enrichment of 1% at a
given position means that 1% of molecules in a given sample contain
deuterium at the specified position. Because the naturally
occurring distribution of deuterium is about 0.0156% on average,
deuterium enrichment at any position in a compound synthesized
using non-enriched starting materials is about 0.0156% on average.
As used herein, when a particular position in an isotopically
enriched compound is designated as having deuterium, it is
understood that the abundance of deuterium at that position in the
compound is substantially greater than its natural abundance
(0.0156%).
[0091] The term "carbon" or the symbol "C" refers to the
composition of naturally occurring carbon isotopes, which include
carbon-12 (.sup.12C) and carbon-13 (.sup.13C) in their natural
abundances. Carbon-12 is the most common carbon isotope having a
natural abundance of more than 98.89%. Carbon-13 is a less
prevalent carbon isotope having a natural abundance of about
1.11%.
[0092] The term "carbon-13 enrichment" or ".sup.13C enrichment"
refers to the percentage of incorporation of carbon-13 at a given
position in a molecule in the place of carbon. For example,
carbon-13 enrichment of 10% at a given position means that 10% of
molecules in a given sample contain carbon-13 at the specified
position. Because the naturally occurring distribution of carbon-13
is about 1.11% on average, carbon-13 enrichment at any position in
a compound synthesized using non-enriched starting materials is
about 1.11% on average. As used herein, when a particular position
in an isotopically enriched compound is designated as having
carbon-13, it is understood that the abundance of carbon-13 at that
position in the compound is substantially greater than its natural
abundance (1.11%).
[0093] The terms "substantially pure" and "substantially
homogeneous" mean sufficiently homogeneous to appear free of
readily detectable impurities as determined by standard analytical
methods used by one of ordinary skill in the art, including, but
not limited to, thin layer chromatography (TLC), gel
electrophoresis, high performance liquid chromatography (HPLC), gas
chromatography (GC), nuclear magnetic resonance (NMR), and mass
spectrometry (MS); or sufficiently pure such that further
purification would not detectably alter the physical, chemical,
biological, and/or pharmacological properties, such as enzymatic
and biological activities, of the substance. In certain
embodiments, "substantially pure" or "substantially homogeneous"
refers to a collection of molecules, wherein at least about 50%, at
least about 70%, at least about 80%, at least about 90%, at least
about 95%, at least about 98%, at least about 99%, or at least
about 99.5% by weight of the molecules are a single compound,
including a single enantiomer, a racemic mixture, or a mixture of
enantiomers, as determined by standard analytical methods. As used
herein, when an atom at a particular position in an isotopically
enriched molecule is designated as a particular less prevalent
isotope, a molecule that contains other than the designated isotope
at the specified position is an impurity with respect to the
isotopically enriched compound. Thus, for a deuterated compound
that has an atom at a particular position designated as deuterium,
a compound that contains a protium at the same position is an
impurity.
[0094] The term "solvate" refers to a complex or aggregate formed
by one or more molecules of a solute, e.g., a compound provided
herein, and one or more molecules of a solvent, which present in
stoichiometric or non-stoichiometric amount. Suitable solvents
include, but are not limited to, water, methanol, ethanol,
n-propanol, isopropanol, and acetic acid. In certain embodiments,
the solvent is pharmaceutically acceptable. In one embodiment, the
complex or aggregate is in a crystalline form. In another
embodiment, the complex or aggregate is in a noncrystalline form.
Where the solvent is water, the solvate is a hydrate. Examples of
hydrates include, but are not limited to, a hemihydrate,
monohydrate, dihydrate, trihydrate, tetrahydrate, and
pentahydrate.
[0095] The phrase "an enantiomer, a mixture of enantiomers, a
mixture of two or more diastereomers, a tautomer, a mixture of two
or more tautomers, or an isotopic variant thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof" has the same meaning as the phrase "(i) an enantiomer, a
mixture of enantiomers, a mixture of two or more diastereomers, a
tautomer, a mixture of two or more tautomers, or an isotopic
variant of the compound referenced therein; or (ii) a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug of
the compound referenced therein; or (iii) a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug of an enantiomer, a
mixture of enantiomers, a mixture of two or more diastereomers, a
tautomer, a mixture of two or more tautomers, or an isotopic
variant of the compound referenced therein."
Compounds
[0096] In one embodiment, provided herein is a compound of Formula
I:
##STR00005##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein:
[0097] U and V are each independently --O-- and .dbd.C(R.sup.4)--;
or U and V are each independently .dbd.N-- and --N(R.sup.5)--;
[0098] W, X, Y, and Z are each independently .dbd.C(R.sup.6)-- or
.dbd.N--, with the proviso that at least one of W, X, Y, and Z is
.dbd.N--; or W, X, and Z are each independently .dbd.C(R.sup.6)--,
--N(R.sup.7)--, .dbd.N--, --O--, or --S--; and Y is a bond;
[0099] R.sup.1 and R.sup.2 are each independently (a) hydrogen or
deuterium; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15
aralkyl, heteroaryl, or heterocyclyl; or (c) --C(O)R.sup.1a,
--C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c, --C(O)SR.sup.1a,
--C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a, --C(S)OR.sup.1a,
--C(S)NR.sup.1bR.sup.1c, --OR.sup.1a, --OC(O)R.sup.1a,
--OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c, --OC(O)SR.sup.1a,
--OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, --OC(S)R.sup.1a,
--OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c, --OS(O)R.sup.1a,
--OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1a, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1a S(O)R.sup.1a,
--NR.sup.1aS(O).sub.2R.sup.1d, --NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.1a S(O).sub.2NR.sup.1bR.sup.1c, --S(O)R.sup.1a,
--S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c; or R.sup.1 and R.sup.2 together with
the N atom to which they are attached form heteroaryl or
heterocyclyl;
[0100] each R.sup.3, R.sup.4, and R.sup.6 is independently (a)
hydrogen, deuterium, cyano, halo, or nitro; (b) C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl;
or (c) --C(O)R.sup.1a, --C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--C(O)SR.sup.1a, --C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a,
--C(S)OR.sup.1a, --C(S)NR.sup.1bR.sup.1c, --OR.sup.1a,
--OC(O)R.sup.1a, --OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c,
--OC(O)SR.sup.1a, --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
--OC(S)R.sup.1a, --OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c,
--OS(O)R.sup.1a, --OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1a,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1d, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1aS(O)R.sup.1d,
--NR.sup.1aS(O).sub.2R.sup.1d, --NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.1aS(O).sub.2NR.sup.1bR.sup.1c, --SR.sup.1a,
--S(O)R.sup.1a, --S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c or
--S(O).sub.2NR.sup.1bR.sup.1c;
[0101] R.sup.5 and R.sup.7 are each independently (a) hydrogen or
deuterium; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15
aralkyl, heteroaryl, or heterocyclyl; or (c) --C(O)R.sup.1a,
--C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c, --C(O)SR.sup.1a,
--C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a, --C(S)OR.sup.1a,
--C(S)NR.sup.1bR.sup.1c, --OR.sup.1a, --OC(O)R.sup.1a,
--OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c, --OC(O)SR.sup.1a,
--OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, --OC(S)R.sup.1a,
--OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c, --OS(O)R.sup.1a,
--OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1a,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1a, --NR.sup.1aC(S)OR.sup.1d,
--R.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1aS(O)R.sup.1d,
--NR.sup.aS(O).sub.2R.sup.1d, --NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.1a S(O).sub.2NR.sup.1bR.sup.1c, --S(O)R.sup.1a,
--S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c; and
[0102] each R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d is
independently hydrogen, deuterium, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or R.sup.1a and
R.sup.1c together with the C and N atoms to which they are attached
form heterocyclyl; or R.sup.1b and R.sup.1c together with the N
atom to which they are attached form heterocyclyl;
[0103] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
aralkyl, heteroaryl, and heterocyclyl is optionally substituted
with one or more, in one embodiment, one, two, three, or four,
substituents Q, where each Q is independently selected from (a)
deuterium, cyano, halo, and nitro; (b) C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is
further optionally substituted with one or more, in one embodiment,
one, two, three, or four, substituents Q.sup.a; and (c)
--C(O)R.sup.a, --C(O)OR.sup.a, --C(O)NR.sup.bR.sup.c,
--C(O)SR.sup.a, --C(NR.sup.a)N.sup.bR.sup.c, --C(S)R.sup.a,
--C(S)OR.sup.a, --C(S)NR.sup.bR.sup.c, --OR.sup.a, --OC(O)R.sup.a,
--OC(O)OR.sup.a, --OC(O)NR.sup.bR.sup.c, --OC(O)SR.sup.a,
--OC(.dbd.NR.sup.a)NR.sup.bR.sup.c, --OC(S)R.sup.a,
--OC(S)OR.sup.a, --OC(S)NR.sup.bR.sup.c, --OS(O)R.sup.a,
--OS(O).sub.2R.sup.a, --OS(O)NR.sup.bR.sup.c,
--OS(O).sub.2NR.sup.bR.sup.c, --NR.sup.bR.sup.c,
--NR.sup.aC(O)R.sup.d, --NR.sup.aC(O)OR.sup.d,
--NR.sup.aC(O)NR.sup.bR.sup.c, --NR.sup.aC(O)SR.sup.d,
--NR.sup.aC(.dbd.NR.sup.d)NR.sup.bR.sup.c, --NR.sup.aC(S)R.sup.d,
--NR.sup.aC(S)OR.sup.d, --NR.sup.aC(S)NR.sup.bR.sup.c,
--NR.sup.aS(O)R.sup.d, --NR.sup.aS(O).sub.2R.sup.d,
--NR.sup.aS(O)NR.sup.bR.sup.c, --NR.sup.aS(O).sub.2NR.sup.bR.sup.c,
--SR.sup.a, --S(O)R.sup.a, --S(O).sub.2R.sup.a,
--S(O)NR.sup.bR.sup.c, and --S(O).sub.2NR.sup.bR.sup.c, wherein
each R.sup.a, R.sup.b, R.sup.c, and R.sup.d is independently (i)
hydrogen or deuterium; (ii) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is
optionally substituted with one or more, in one embodiment, one,
two, three, or four, substituents Q.sup.a; or (iii) R.sup.b and
R.sup.c together with the N atom to which they are attached form
heterocyclyl, optionally substituted with one or more, in one
embodiment, one, two, three, or four, substituents Q.sup.a;
[0104] wherein each Q.sup.a is independently selected from the
group consisting of (a) deuterium, cyano, halo, and nitro; (b)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12
cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, and
heterocyclyl; and (c) --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.fR.sup.g, --C(O)SR.sup.e,
--C(NR.sup.e)NR.sup.fR.sup.g, --C(S)R.sup.e, --C(S)OR.sup.e,
--C(S)NR.sup.fR.sup.g, --OR.sup.e, --OC(O)R.sup.e, --OC(O)OR.sup.e,
--OC(O)NR.sup.fR.sup.g, --OC(O)SR.sup.e,
--OC(.dbd.NR.sup.e)NR.sup.fR.sup.g, --OC(S)R.sup.e,
--OC(S)OR.sup.e, --OC(S)NR.sup.fR.sup.g, --OS(O)R.sup.e,
--OS(O).sub.2R.sup.e, --OS(O)NR.sup.fR.sup.g,
--OS(O).sub.2NR.sup.fR.sup.g, --NR.sup.fR.sup.g,
--NR.sup.eC(O)R.sup.h, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.fR.sup.g, --NR.sup.eC(O)SR.sup.f,
--NR.sup.eC(.dbd.NR.sup.h)NR.sup.fR.sup.g, --NR.sup.eC(S)R.sup.h,
--NR.sup.eC(S)OR.sup.f, --NR.sup.eC(S)NR.sup.fR.sup.g,
--NR.sup.eS(O)R.sup.h, --NR.sup.eS(O).sub.2R.sup.h,
--NR.sup.eS(O)NR.sup.fR.sup.g, --NR.sup.eS(O).sub.2NR.sup.fR.sup.g,
--SR.sup.e, --S(O)R.sup.e, --S(O).sub.2R.sup.e,
--S(O)NR.sup.fR.sup.g, and --S(O).sub.2NR.sup.fR.sup.g; wherein
each R.sup.e, R.sup.f, R.sup.g, and R.sup.h is independently (i)
hydrogen or deuterium; (ii) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R.sup.f
and R.sup.g together with the N atom to which they are attached
form heterocyclyl.
[0105] In another embodiment, provided herein is a compound of
Formula I:
##STR00006##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein:
[0106] U and V are each independently --O-- and .dbd.C(R.sup.4)--;
or U and V are each independently .dbd.N-- and --N(R.sup.5)--; or U
is .dbd.N-- and --N(R.sup.5)--; and V is .dbd.C(R.sup.4)--;
[0107] W, X, Y, and Z are each independently .dbd.C(R.sup.6)-- or
.dbd.N--, with the proviso that at least one of W, X, Y, and Z is
.dbd.N--; or W, X, and Z are each independently .dbd.C(R.sup.6)--,
--N(R.sup.7)--, .dbd.N--, --O--, or --S--; and Y is a bond;
[0108] R.sup.1 and R.sup.2 are each independently (a) hydrogen or
deuterium; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15
aralkyl, heteroaryl, or heterocyclyl; or (c) --C(O)R.sup.1a,
--C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c, --C(O)SR.sup.1a,
--C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a, --C(S)OR.sup.1a,
--C(S)NR.sup.1bR.sup.1c, --OR.sup.1a, --OC(O)R.sup.1a,
--OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c, --OC(O)SR.sup.1a,
--OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, --OC(S)R.sup.1a,
--OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c, --OS(O)R.sup.1a,
--OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1a, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1a S(O)R.sup.1a,
--NR.sup.1aS(O).sub.2R.sup.1d, --NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.1a S(O).sub.2NR.sup.1bR.sup.1c, --S(O)R.sup.1a,
--S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c; or R.sup.1 and R.sup.2 together with
the N atom to which they are attached form heteroaryl or
heterocyclyl;
[0109] each R.sup.3, R.sup.4, and R.sup.6 is independently (a)
hydrogen, deuterium, cyano, halo, or nitro; (b) C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl;
or (c) --C(O)R.sup.1a, --C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--C(O)SR.sup.1a, --C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a,
--C(S)OR.sup.1a, --C(S)NR.sup.1bR.sup.1c, --OR.sup.1a,
--OC(O)R.sup.1a, --OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c,
--OC(O)SR.sup.1a, --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
--OC(S)R.sup.1a, --OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c,
--OS(O)R.sup.1a, --OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1a,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1d, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1aS(O)R.sup.1d,
--NR.sup.1aS(O).sub.2R.sup.1d, --NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.1aS(O).sub.2NR.sup.1bR.sup.1c, --SR.sup.1a,
--S(O)R.sup.1a, --S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c or
--S(O).sub.2NR.sup.1bR.sup.1c;
[0110] R.sup.5 and R.sup.7 are each independently (a) hydrogen or
deuterium; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15
aralkyl, heteroaryl, or heterocyclyl; or (c) --C(O)R.sup.1a,
--C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c, --C(O)SR.sup.1a,
--C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a, --C(S)OR.sup.1a,
--C(S)NR.sup.1bR.sup.1c, --OR.sup.1a, --OC(O)R.sup.1a,
--OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c, --OC(O)SR.sup.1a,
--OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, --OC(S)R.sup.1a,
--OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c, --OS(O)R.sup.1a,
--OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1a, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1a S(O)R.sup.1a,
--NR.sup.1aS(O).sub.2R.sup.1d, --NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.1aS(O).sub.2NR.sup.1bR.sup.1c, --S(O)R.sup.1a,
--S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c; and
[0111] each R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d is
independently hydrogen, deuterium, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or R.sup.1a and
R.sup.1c together with the C and N atoms to which they are attached
form heterocyclyl; or R.sup.1b and R.sup.1c together with the N
atom to which they are attached form heterocyclyl;
[0112] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
aralkyl, heteroaryl, and heterocyclyl is optionally substituted
with one or more, in one embodiment, one, two, three, or four,
substituents Q, where each Q is independently selected from (a)
deuterium, cyano, halo, and nitro; (b) C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is
further optionally substituted with one or more, in one embodiment,
one, two, three, or four, substituents Q.sup.a; and (c)
--C(O)R.sup.a, --C(O)OR.sup.a, --C(O)NR.sup.bR.sup.c,
--C(O)SR.sup.a, --C(NR.sup.a)NR.sup.bR.sup.c, --C(S)R.sup.a,
--C(S)OR.sup.a, --C(S)NR.sup.bR.sup.c, --OR.sup.a, --OC(O)R.sup.a,
--OC(O)OR.sup.a, --OC(O)NR.sup.fR.sup.g, --OC(O)SR.sup.a,
--OC(.dbd.NR.sup.a)NR.sup.bR.sup.c, --OC(S)R.sup.a,
--OC(S)OR.sup.a, --OC(S)NR.sup.bR.sup.c, --OS(O)R.sup.a,
--OS(O).sub.2R.sup.a, --OS(O)NR.sup.bR.sup.c,
--OS(O).sub.2NR.sup.bR.sup.c, --NR.sup.bR.sup.c,
--NR.sup.aC(O)R.sup.d, --NR.sup.aC(O)OR.sup.d,
--NR.sup.aC(O)NR.sup.bR.sup.c, --NR.sup.aC(O)SR.sup.d,
--NR.sup.aC(.dbd.NR.sup.d)NR.sup.bR.sup.c, --NR.sup.aC(S)R.sup.d,
--NR.sup.aC(S)OR.sup.d, --NR.sup.aC(S)NR.sup.bR.sup.c,
--NR.sup.aS(O)R.sup.d, --NR.sup.aS(O).sub.2R.sup.d,
--NR.sup.aS(O)NR.sup.bR.sup.c, --NR.sup.aS(O).sub.2NR.sup.bR.sup.c,
--SR.sup.a, --S(O)R.sup.a, --S(O).sub.2R.sup.a,
--S(O)NR.sup.bR.sup.c, and --S(O).sub.2NR.sup.bR.sup.c, wherein
each R.sup.a, R.sup.b, R.sup.c, and R.sup.d is independently (i)
hydrogen or deuterium; (ii) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is
optionally substituted with one or more, in one embodiment, one,
two, three, or four, substituents Q.sup.a; or (iii) R.sup.b and
R.sup.c together with the N atom to which they are attached form
heterocyclyl, optionally substituted with one or more, in one
embodiment, one, two, three, or four, substituents Q.sup.a;
[0113] wherein each Q.sup.a is independently selected from the
group consisting of (a) deuterium, cyano, halo, and nitro; (b)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12
cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, and
heterocyclyl; and (c) --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.fR.sup.g, --C(O)SR.sup.e,
--C(NR.sup.e)NR.sup.fR.sup.g, --C(S)R.sup.e, --C(S)OR.sup.e,
--C(S)NR.sup.fR.sup.g, --OR.sup.e, --OC(O)R.sup.e, --OC(O)OR.sup.e,
--OC(O)NR.sup.fR.sup.g, --OC(O)SR.sup.e,
--OC(.dbd.NR.sup.e)NR.sup.fR.sup.g, --OC(S)R.sup.e,
--OC(S)OR.sup.e, --OC(S)NR.sup.fR.sup.g, --OS(O)R.sup.e,
--OS(O).sub.2R.sup.e, --OS(O)NR.sup.fR.sup.g,
--OS(O).sub.2NR.sup.fR.sup.g, --NR.sup.fR.sup.g,
--NR.sup.eC(O)R.sup.h, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.fR.sup.g, --NR.sup.eC(O)SR.sup.f,
--NR.sup.eC(.dbd.NR.sup.h)NR.sup.fR.sup.g, --NR.sup.eC(S)R.sup.h,
--NR.sup.eC(S)OR.sup.f, --NR.sup.eC(S)NR.sup.fR.sup.g,
--NR.sup.eS(O)R.sup.h, --NR.sup.eS(O).sub.2R.sup.h,
--NR.sup.eS(O)NR.sup.fR.sup.g, --NR.sup.eS(O).sub.2NR.sup.fR.sup.g,
--SR.sup.e, --S(O)R.sup.e, --S(O).sub.2R.sup.e,
--S(O)NR.sup.fR.sup.g, and --S(O).sub.2NR.sup.fR.sup.g; wherein
each R.sup.e, R.sup.f, R.sup.g, and R.sup.h is independently (i)
hydrogen or deuterium; (ii) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R.sup.f
and R.sup.g together with the N atom to which they are attached
form heterocyclyl.
[0114] In one embodiment, in Formula I, R.sup.1 is hydrogen or
C.sub.1-6 alkyl; and R.sup.2 is C.sub.3-12 cycloalkyl or
heterocyclyl; wherein each alkyl, cycloalkyl, and heterocyclyl is
optionally substituted with one or more substituents Q as defined
herein.
[0115] In another embodiment, in Formula I, R.sup.1 is hydrogen or
C.sub.1-6 alkyl; and R.sup.2 is monocyclic C.sub.3-12 cycloalkyl,
bicyclic C.sub.3-12 cycloalkyl, or bicyclic heterocyclyl; wherein
each alkyl, cycloalkyl, and heterocyclyl is optionally substituted
with one or more substituents Q as defined herein.
[0116] In yet another embodiment, in Formula I, R.sup.1 is hydrogen
or C.sub.1-6 alkyl; and R.sup.2 is monocyclic C.sub.3-12
cycloalkyl, bridged C.sub.3-12 cycloalkyl, or spiro heterocyclyl,
wherein each alkyl, cycloalkyl, and heterocyclyl is optionally
substituted with one or more substituents Q as defined herein.
[0117] In still another embodiment, in Formula I, R.sup.1 is
hydrogen or methyl; and R.sup.2 is cyclohexyl,
bicyclo[2.2.1]heptyl, or bicyclo[2.2.2]octyl, each of which is
substituted with one or two substituents, wherein each substituent
is independently C.sub.1-6 alkyl or --NR.sup.1bR.sup.1c, where the
alkyl is optionally substituted with one or more substituents Q as
defined herein and R.sup.1b and R.sup.1c are each as defined
herein.
[0118] In yet another embodiment, provided herein is a compound of
Formula II
##STR00007##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein:
[0119] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0120] (i) R.sup.2a and R.sup.2b are each independently (a)
hydrogen or deuterium; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is
optionally substituted with one or more substituents Q; or (c)
--C(O)R.sup.1a, --C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--C(O)SR.sup.1a, --C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a,
--C(S)OR.sup.1a, --C(S)NR.sup.1bR.sup.1c, --OR.sup.1a,
--OC(O)R.sup.1a, --OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c,
--OC(O)SR.sup.1a, --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
--OC(S)R.sup.1a, --OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c,
--OS(O)R.sup.1a, --OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1a, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1aS(O)R.sup.1a,
--NR.sup.1a S(O).sub.2R.sup.1d, --NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.1aS(O).sub.2NR.sup.1bR.sup.1c, --S(O)R.sup.1a,
--S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c; or R.sup.2a and R.sup.2b together
with the N atom to which they are attached form heteroaryl or
heterocyclyl, each of which is optionally substituted with one or
more substituents Q; and [0121] R.sup.2c and R.sup.2d are each
independently (a) hydrogen, deuterium, or cyano; or (b) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl,
each of which is optionally substituted with one or more
substituents Q; or R.sup.2c and R.sup.2d are linked together to
form --O--, C.sub.1-6 alkylene, C.sub.1-6 heteroalkylene, C.sub.2-6
alkenylene, or C.sub.2-6 alkynylene, wherein the alkylene,
heteroalkylene, alkenylene, and alkynylene are each optionally
substituted with one or more substituents Q; or
[0122] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form heterocyclyl, which is optionally
substituted with one or more substituents Q; [0123] R.sup.2b is (a)
hydrogen or deuterium; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is
optionally substituted with one or more substituents Q; or (c)
--C(O)R.sup.1a, --C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--C(O)SR.sup.1a, --C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a,
--C(S)OR.sup.1a, --C(S)NR.sup.1bR.sup.1c, --OR.sup.1a,
--OC(O)R.sup.1a, --OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c,
--OC(O)SR.sup.1a, --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
--OC(S)R.sup.1a, --OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c,
--OS(O)R.sup.1a, --OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1d, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1aS(O)R.sup.1d,
--NR.sup.1a S(O).sub.2R.sup.1d, --NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.1a S(O).sub.2NR.sup.1bR.sup.1c, --S(O)R.sup.1a,
--S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c or
--S(O).sub.2NR.sup.1bR.sup.1c; and [0124] R.sup.2d is (a) hydrogen,
deuterium, or cyano; or (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is
optionally substituted with one or more substituents Q; and
[0125] R.sup.1, R.sup.3, R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, Q,
U, V, W, X, Y, and Z are each as defined herein.
[0126] In one embodiment, in Formula II,
[0127] U is --O-- and V is .dbd.C(R.sup.4)--; or U is .dbd.N-- and
V is --N(R.sup.5)--;
[0128] W, X, Y, and Z are each independently .dbd.C(R.sup.6)-- or
.dbd.N--;
[0129] R.sup.1 is hydrogen or C.sub.1-6 alkyl;
[0130] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0131] (i) R.sup.2a and R.sup.2b are each independently hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkynyl, C.sub.6-14 aryl, C.sub.6-14
aralkyl, or --C(O)R.sup.1a; or R.sup.2a and R.sup.2b together with
the N atom to which they are attached form heteroaryl or
heterocyclyl; and [0132] R.sup.2c and R.sup.2d are each
independently hydrogen or C.sub.1-6 alkyl; or R.sup.2c and R.sup.2d
are linked together to form --O--, C.sub.1-6 alkylene, or C.sub.1-6
heteroalkylene; or
[0133] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form heteroaryl or heterocyclyl; and
[0134] R.sup.2b and R.sup.2d are each hydrogen;
[0135] R.sup.3 is C.sub.1-6 alkyl;
[0136] R.sup.4 and R.sup.5 are each independently C.sub.1-6 alkyl,
C.sub.3-12 cycloalkyl, or heterocyclyl;
[0137] each R.sup.6 is independently hydrogen, halo, C.sub.1-6
alkyl, --OR.sup.1a, or --NR.sup.1bR.sup.1c; and
[0138] each R.sup.1a, R.sup.1b, and R.sup.1c is as defined
herein;
[0139] wherein each alkyl, alkylene, heteroalkylene, alkynyl,
cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is
optionally substituted with one or more, in one embodiment, one,
two, three, or four, substituents Q.
[0140] In another embodiment, in Formula II,
[0141] U is --O-- and V is .dbd.C(R.sup.4)--; or U is .dbd.N-- and
V is --N(R.sup.5)--;
[0142] W, X, Y, and Z are each independently .dbd.C(R.sup.6)-- or
.dbd.N--;
[0143] R.sup.1 is hydrogen or C.sub.1-6 alkyl;
[0144] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0145] (i) R.sup.2a and R.sup.2b are each independently hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkynyl, 5- or 6-membered
heteroaryl-C.sub.1-6 alkyl, C.sub.6-14 aryl, C.sub.6-14 aralkyl,
--C(O)--C.sub.1-6 alkyl, --C(O)--C.sub.2-6 alkynyl, or
--C(O)-5-membered heteroaryl; or R.sup.2a and R.sup.2b together
with the N atom to which they are attached form 5-membered
heteroaryl or 4- to 6-membered heterocyclyl; and [0146] R.sup.2c is
hydrogen or C.sub.1-6 alkyl; and R.sup.2d is hydrogen; or R.sup.2c
and R.sup.d are linked together to form C.sub.2-6 alkylene; or
[0147] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form 5-membered heteroaryl or 5-membered
heterocyclyl; and [0148] R.sup.2b and R.sup.2d are each
hydrogen;
[0149] R.sup.3 is C.sub.1-6 alkyl or C.sub.3-12
cycloalkyl-C.sub.1-6 alkyl;
[0150] R.sup.4 and R.sup.5 are each independently C.sub.1-6 alkyl,
C.sub.3-12 cycloalkyl, or 4- to 6-membered heterocyclyl; and
[0151] each R.sup.6 is independently hydrogen, fluoro, chloro,
C.sub.1-6 alkyl, hydroxyl, or amino;
[0152] wherein each alkyl, alkylene, alkynyl, cycloalkyl, aryl,
aralkyl, heteroaryl, and heterocyclyl is optionally substituted
with one or more, in one embodiment, one, two, three, or four,
substituents Q.
[0153] In yet another embodiment, in Formula II,
[0154] U is --O-- and V is .dbd.C(R.sup.4)--; or U is .dbd.N-- and
V is --N(R.sup.5)--;
[0155] W, X, Y, and Z are each independently .dbd.C(R.sup.6)-- or
.dbd.N--;
[0156] R.sup.1 is hydrogen or methyl;
[0157] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0158] (i) R.sup.2a is hydrogen, methyl, trifluoroethyl,
methoxyethyl, pentynyl, phenyl, benzyl, (pyrazolyl)methyl,
(methylpyrazolyl)methyl, (pyrazolyl)ethyl, (pyridinyl)methyl,
pentanoyl, methoxyacetyl, butynylcarbonyl, or (pyrazolyl)carbonyl;
and R.sup.2b is hydrogen, methyl, trifluoroethyl, or
(pyrazolyl)methyl; or R.sup.2a and R.sup.2b together with the N
atom to which they are attached form azetidinyl, pyrrolidinyl,
piperidinyl, morpholinyl, pyrazolyl, methylpyrazolyl, or
imidazolyl; and [0159] R.sup.2c is hydrogen, methyl, or
hydroxymethyl; and R.sup.2d is hydrogen; or R.sup.2c and R.sup.2d
are linked together to form methylene or ethylene; or
[0160] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form pyrrolidinylene-one,
imidazolidinylene-dione, or oxazolidinylene-one; and [0161]
R.sup.2b and R.sup.2d are each hydrogen;
[0162] R.sup.3 is butylmethyl, cyclopropylmethyl,
methylcyclopropylmethyl, hydroxy(cyclopropylmethyl),
cyclobutylmethyl, or cyclopentylmethyl;
[0163] R.sup.4 and R.sup.5 are each independently methyl,
isopropyl, cyclopentyl, oxetanyl, tetrahydrofuryl, or
tetrahydropyranyl; and
[0164] each R.sup.6 is independently hydrogen, fluoro, chloro,
methyl, trifluoromethyl, hydroxyl, or amino.
[0165] In yet another embodiment, in Formula II,
[0166] U is --O-- and V is .dbd.C(R.sup.4)--; or U is .dbd.N-- and
V is --N(R.sup.5)--;
[0167] W, X, Y, and Z are each independently .dbd.C(H)--,
.dbd.C(F)--, .dbd.C(Cl)--, .dbd.C(CH.sub.3)--, .dbd.C(CF.sub.3)--,
.dbd.C(OH)--, .dbd.C(NH.sub.2)--, or .dbd.N--;
[0168] R.sup.1 is hydrogen;
[0169] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0170] (i) R.sup.2a is hydrogen, methyl, 2,2,2-trifluoroethyl,
2-methoxyethyl, pent-4-ynyl, phenyl, benzyl, (pyrazol-3-yl)methyl,
(pyrazol-4-yl)methyl, (1-methylpyrazol-4-yl)methyl,
(3-methylpyrazol-4-yl)methyl, 1-(pyrazol-4-yl)ethyl,
(pyridin-3-yl)methyl, pentanoyl, 2-methoxyacetyl,
but-3-ynylcarbonyl, or (pyrazol-4-yl)carbonyl; and R.sup.2b is
hydrogen, methyl, 2,2,2-trifluoroethyl, or (pyrazol-4-yl)methyl; or
R.sup.2a and R.sup.2b together with the N atom to which they are
attached form azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl,
morpholin-4-yl, pyrazol-1-yl, 3-methylpyrazol-1-yl,
4-methylpyrazol-1-yl, 5-methylpyrazol-1-yl, or imidazol-1-yl; and
[0171] R.sup.2c is hydrogen, methyl, or hydroxymethyl; and R.sup.2d
is hydrogen; or R.sup.2c and R.sup.2d are linked together to form
methylene or eth-1,2-ylene; or
[0172] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form pyrrolidin-5,5-ylene-2-one,
imidazolidin-5,5-ylene-2,4-dione, or oxazolidin-4,4-ylene-2-one;
and [0173] R.sup.2b and R.sup.2d are each hydrogen;
[0174] R.sup.3 is t-butylmethyl, cyclopropylmethyl,
1-methylcyclopropylmethyl, 1-hydroxy(cyclopropylmethyl),
cyclobutylmethyl, or cyclopentylmethyl; and
[0175] R.sup.4 and R.sup.5 are each independently methyl,
isopropyl, cyclopentyl, oxetan-3-yl, tetrahydrofur-3-yl,
tetrahydropyran-4-yl, or tetrahydropyran-3-yl.
[0176] In yet another embodiment, in Formula II,
[0177] U is --O-- and V is .dbd.C(R.sup.4)--; or U is .dbd.N-- and
V is --N(R.sup.5)--;
[0178] W and Z are each independently .dbd.C(H)-- or .dbd.N--;
[0179] X is .dbd.C(H)--, .dbd.C(OH)--, or .dbd.C(NH.sub.2)--;
[0180] Y is .dbd.C(H)--, .dbd.C(F)--, .dbd.C(Cl)--,
.dbd.C(CH.sub.3)--, .dbd.C(CF.sub.3)--, or .dbd.N--;
[0181] R.sup.1 is hydrogen;
[0182] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0183] (i) R.sup.2a is hydrogen, methyl, 2,2,2-trifluoroethyl,
2-methoxyethyl, pent-4-ynyl, phenyl, benzyl, (pyrazol-3-yl)methyl,
(pyrazol-4-yl)methyl, (1-methylpyrazol-4-yl)methyl,
(3-methylpyrazol-4-yl)methyl, 1-(pyrazol-4-yl)ethyl,
(pyridin-3-yl)methyl, pentanoyl, 2-methoxyacetyl,
but-3-ynylcarbonyl, or (pyrazol-4-yl)carbonyl; and R.sup.2b is
hydrogen, methyl, 2,2,2-trifluoroethyl, or (pyrazol-4-yl)methyl; or
R.sup.2a and R.sup.2b together with the N atom to which they are
attached form azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl,
morpholin-4-yl, pyrazol-1-yl, 3-methylpyrazol-1-yl,
4-methylpyrazol-1-yl, 5-methylpyrazol-1-yl, or imidazol-1-yl; and
[0184] R.sup.2c is hydrogen, methyl, or hydroxymethyl; and R.sup.2d
is hydrogen; or R.sup.2c and R.sup.2d are linked together to form
methylene or 1,2-ethylene; or
[0185] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form pyrrolidin-5,5-ylene-2-one,
imidazolidin-5,5-ylene-2,4-dione, or oxazolidin-4,4-ylene-2-one;
and [0186] R.sup.2b and R.sup.2d are each hydrogen;
[0187] R.sup.3 is t-butylmethyl, cyclopropylmethyl,
1-methylcyclopropylmethyl, 1-hydroxy(cyclopropylmethyl),
cyclobutylmethyl, or cyclopentylmethyl; and
[0188] R.sup.4 and R.sup.5 are each independently methyl,
isopropyl, cyclopentyl, oxetan-3-yl, tetrahydrofur-3-yl,
tetrahydropyran-4-yl, or tetrahydropyran-3-yl.
[0189] In still another embodiment, in Formula II,
[0190] U is --O-- and V is .dbd.C(CH.sub.3)--; or U is .dbd.N-- and
V is --N(CH.sub.3)--;
[0191] W and Z are each independently .dbd.C(H)-- or .dbd.N--;
[0192] X is .dbd.C(H)--;
[0193] Y is .dbd.C(H)--, .dbd.C(F)--, or .dbd.C(Cl)--;
[0194] R.sup.1 is hydrogen;
[0195] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0196] (i) R.sup.2a is hydrogen, methyl, 2,2,2-trifluoroethyl,
2-methoxyethyl, pent-4-ynyl, pentanoyl, 2-methoxyacetyl, or
but-3-ynylcarbonyl; and R.sup.2b is hydrogen or methyl; or R.sup.2a
and R.sup.2b together with the N atom to which they are attached
form azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl,
morpholin-4-yl, pyrazol-1-yl, 3-methylpyrazol-1-yl,
4-methylpyrazol-1-yl, 5-methylpyrazol-1-yl, or imidazol-1-yl; and
[0197] R.sup.2c and R.sup.2d are each hydrogen; or R.sup.2c and
R.sup.2d are linked together to form methylene or eth-1,2-ylene;
or
[0198] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form pyrrolidin-5,5-ylene-2-one,
imidazolidin-5,5-ylene-2,4-dione, or oxazolidin-4,4-ylene-2-one;
and [0199] R.sup.2b and R.sup.2d are each hydrogen; and
[0200] R.sup.3 is cyclopropylmethyl.
[0201] In yet another embodiment, provided herein is a compound of
Formula IIa:
##STR00008##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3,
R.sup.2aR.sup.2b, R.sup.2c, R.sup.2d, U, V, W, X, Y, and Z are each
as defined herein.
[0202] In one embodiment, in Formula IIa,
[0203] U is --O-- and V is .dbd.C(R.sup.4)--; or U is .dbd.N-- and
V is --N(R.sup.5)--;
[0204] W, X, Y, and Z are each independently .dbd.C(R.sup.6)-- or
.dbd.N--;
[0205] R.sup.1 is hydrogen or C.sub.1-6 alkyl;
[0206] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0207] (i) R.sup.2a and R.sup.2b are each independently hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkynyl, C.sub.6-14 aryl, C.sub.6-14
aralkyl, or --C(O)R.sup.1a; or R.sup.2a and R.sup.2b together with
the N atom to which they are attached form heteroaryl or
heterocyclyl; and [0208] R.sup.2c and R.sup.2d are each
independently hydrogen or C.sub.1-6 alkyl; or
[0209] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form heteroaryl or heterocyclyl; and
[0210] R.sup.2b and R.sup.2d are each hydrogen;
[0211] R.sup.3 is C.sub.1-6 alkyl;
[0212] R.sup.4 and R.sup.5 are each independently C.sub.1-6 alkyl,
C.sub.3-12 cycloalkyl, or heterocyclyl;
[0213] each R.sup.6 is independently hydrogen, halo, C.sub.1-6
alkyl, --OR.sup.a, or --NR.sup.1bR.sup.1c; and
[0214] each R.sup.1a, R.sup.1b, and R.sup.1c is as defined
herein;
[0215] wherein each alkyl, alkynyl, cycloalkyl, aryl, aralkyl,
heteroaryl, and heterocyclyl is optionally substituted with one or
more, in one embodiment, one, two, three, or four, substituents
Q.
[0216] In another embodiment, in Formula IIa,
[0217] U is --O-- and V is .dbd.C(R.sup.4)--; or U is .dbd.N-- and
V is --N(R.sup.5)--;
[0218] W, X, Y, and Z are each independently .dbd.C(R.sup.6)-- or
.dbd.N--;
[0219] R.sup.1 is hydrogen or C.sub.1-6 alkyl;
[0220] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0221] (i) R.sup.2a and R.sup.2b are each independently hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkynyl, 5- or 6-membered
heteroaryl-C.sub.1-6 alkyl, C.sub.6-14 aryl, C.sub.6-14 aralkyl,
--C(O)--C.sub.1-6 alkyl, --C(O)--C.sub.2-6 alkynyl, or
--C(O)-5-membered heteroaryl; or R.sup.2a and R.sup.2b together
with the N atom to which they are attached form 5-membered
heteroaryl or 4- to 6-membered heterocyclyl; [0222] R.sup.2c is
hydrogen or C.sub.1-6 alkyl; and [0223] R.sup.2d is hydrogen;
or
[0224] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form 5-membered heteroaryl or 5-membered
heterocyclyl; and [0225] R.sup.2b and R.sup.2d are each
hydrogen;
[0226] R.sup.3 is C.sub.1-6 alkyl or C.sub.3-12
cycloalkyl-C.sub.1-6 alkyl;
[0227] R.sup.4 and R.sup.5 are each independently C.sub.1-6 alkyl,
C.sub.3-12 cycloalkyl, or 4- to 6-membered heterocyclyl; and
[0228] each R.sup.6 is independently hydrogen, fluoro, chloro,
C.sub.1-6 alkyl, hydroxyl, or amino;
[0229] wherein each alkyl, alkynyl, cycloalkyl, aryl, aralkyl,
heteroaryl, and heterocyclyl is optionally substituted with one or
more, in one embodiment, one, two, three, or four, substituents
Q.
[0230] In yet another embodiment, in Formula IIa,
[0231] U is --O-- and V is .dbd.C(R.sup.4)--; or U is .dbd.N-- and
V is --N(R.sup.5)--;
[0232] W, X, Y, and Z are each independently .dbd.C(R.sup.6)-- or
.dbd.N--;
[0233] R.sup.1 is hydrogen or methyl;
[0234] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0235] (i) R.sup.2a is hydrogen, methyl, trifluoroethyl,
methoxyethyl, pentynyl, phenyl, benzyl, (pyrazolyl)methyl,
(methylpyrazolyl)methyl, (pyrazolyl)ethyl, (pyridinyl)methyl,
pentanoyl, methoxyacetyl, butynylcarbonyl, or (pyrazolyl)carbonyl;
and R.sup.2b is hydrogen, methyl, trifluoroethyl, or
(pyrazolyl)methyl; or R.sup.2a and R.sup.2b together with the N
atom to which they are attached form azetidinyl, pyrrolidinyl,
piperidinyl, morpholinyl, pyrazolyl, methylpyrazolyl, or
imidazolyl; [0236] R.sup.2c is hydrogen, methyl, or hydroxymethyl;
and [0237] R.sup.2d is hydrogen; or
[0238] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form pyrrolidinylene-one,
imidazolidinylene-dione, or oxazolidinylene-one; and [0239]
R.sup.2b and R.sup.2d are each hydrogen;
[0240] R.sup.3 is butylmethyl, cyclopropylmethyl,
methylcyclopropylmethyl, hydroxy(cyclopropylmethyl),
cyclobutylmethyl, or cyclopentylmethyl;
[0241] R.sup.4 and R.sup.5 are each independently methyl,
isopropyl, cyclopentyl, oxetanyl, tetrahydrofuryl, or
tetrahydropyranyl; and
[0242] each R.sup.6 is independently hydrogen, fluoro, chloro,
methyl, trifluoromethyl, hydroxyl, or amino.
[0243] In yet another embodiment, in Formula IIa,
[0244] U is --O-- and V is .dbd.C(R.sup.4)--; or U is .dbd.N-- and
V is --N(R.sup.5)--;
[0245] W, X, Y, and Z are each independently .dbd.C(H)--,
.dbd.C(F)--, .dbd.C(Cl)--, .dbd.C(CH.sub.3)--, .dbd.C(CF.sub.3)--,
.dbd.C(OH)--, .dbd.C(NH.sub.2)--, or .dbd.N--;
[0246] R.sup.1 is hydrogen;
[0247] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0248] (i) R.sup.2a is hydrogen, methyl, 2,2,2-trifluoroethyl,
2-methoxyethyl, pent-4-ynyl, phenyl, benzyl, (pyrazol-3-yl)methyl,
(pyrazol-4-yl)methyl, (1-methylpyrazol-4-yl)methyl,
(3-methylpyrazol-4-yl)methyl, 1-(pyrazol-4-yl)ethyl,
(pyridin-3-yl)methyl, pentanoyl, 2-methoxyacetyl,
but-3-ynylcarbonyl, or (pyrazol-4-yl)carbonyl; and R.sup.2b is
hydrogen, methyl, 2,2,2-trifluoroethyl, or (pyrazol-4-yl)methyl; or
R.sup.2a and R.sup.2b together with the N atom to which they are
attached form azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl,
morpholin-4-yl, pyrazol-1-yl, 3-methylpyrazol-1-yl,
4-methylpyrazol-1-yl, 5-methylpyrazol-1-yl, or imidazol-1-yl;
[0249] R.sup.2c is hydrogen, methyl, or hydroxymethyl; and [0250]
R.sup.2d is hydrogen; or
[0251] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form pyrrolidin-5,5-ylene-2-one,
imidazolidin-5,5-ylene-2,4-dione, or oxazolidin-4,4-ylene-2-one;
and [0252] R.sup.2b and R.sup.2d are each hydrogen;
[0253] R.sup.3 is t-butylmethyl, cyclopropylmethyl,
1-methylcyclopropylmethyl, 1-hydroxy(cyclopropylmethyl),
cyclobutylmethyl, or cyclopentylmethyl; and
[0254] R.sup.4 and R.sup.5 are each independently methyl,
isopropyl, cyclopentyl, oxetan-3-yl, tetrahydrofur-3-yl,
tetrahydropyran-4-yl, or tetrahydropyran-3-yl.
[0255] In yet another embodiment, in Formula IIa,
[0256] U is --O-- and V is .dbd.C(R.sup.4)--; or U is .dbd.N-- and
V is --N(R.sup.5)--;
[0257] W and Z are each independently .dbd.C(H)-- or .dbd.N--;
[0258] X is .dbd.C(H)--, .dbd.C(OH)--, or .dbd.C(NH.sub.2)--;
[0259] Y is .dbd.C(H)--, .dbd.C(F)--, .dbd.C(Cl)--,
.dbd.C(CH.sub.3)--, .dbd.C(CF.sub.3)--, or .dbd.N--;
[0260] R.sup.1 is hydrogen;
[0261] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0262] (i) R.sup.2a is hydrogen, methyl, 2,2,2-trifluoroethyl,
2-methoxyethyl, pent-4-ynyl, phenyl, benzyl, (pyrazol-3-yl)methyl,
(pyrazol-4-yl)methyl, (1-methylpyrazol-4-yl)methyl,
(3-methylpyrazol-4-yl)methyl, 1-(pyrazol-4-yl)ethyl,
(pyridin-3-yl)methyl, pentanoyl, 2-methoxyacetyl,
but-3-ynylcarbonyl, or (pyrazol-4-yl)carbonyl; and R.sup.2b is
hydrogen, methyl, 2,2,2-trifluoroethyl, or (pyrazol-4-yl)methyl; or
R.sup.2a and R.sup.2b together with the N atom to which they are
attached form azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl,
morpholin-4-yl, pyrazol-1-yl, 3-methylpyrazol-1-yl,
4-methylpyrazol-1-yl, 5-methylpyrazol-1-yl, or imidazol-1-yl;
[0263] R.sup.2c is hydrogen, methyl, or hydroxymethyl; and [0264]
R.sup.2d is hydrogen; or
[0265] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form pyrrolidin-5,5-ylene-2-one,
imidazolidin-5,5-ylene-2,4-dione, or oxazolidin-4,4-ylene-2-one;
and [0266] R.sup.2b and R.sup.2d are each hydrogen;
[0267] R.sup.3 is t-butylmethyl, cyclopropylmethyl,
1-methylcyclopropylmethyl, 1-hydroxy(cyclopropylmethyl),
cyclobutylmethyl, or cyclopentylmethyl; and
[0268] R.sup.4 and R.sup.5 are each independently methyl,
isopropyl, cyclopentyl, oxetan-3-yl, tetrahydrofur-3-yl,
tetrahydropyran-4-yl, or tetrahydropyran-3-yl.
[0269] In still another embodiment, in Formula IIa,
[0270] U is --O-- and V is .dbd.C(CH.sub.3)--; or U is .dbd.N-- and
V is --N(CH.sub.3)--;
[0271] W and Z are each independently .dbd.C(H)-- or .dbd.N--;
[0272] X is .dbd.C(H)--;
[0273] Y is .dbd.C(H)--, .dbd.C(F)--, or .dbd.C(Cl)--;
[0274] R.sup.1 is hydrogen;
[0275] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0276] (i) R.sup.2a is hydrogen, methyl, 2,2,2-trifluoroethyl,
2-methoxyethyl, pent-4-ynyl, pentanoyl, 2-methoxyacetyl, or
but-3-ynylcarbonyl; and R.sup.2b is hydrogen or methyl; or R.sup.2a
and R.sup.2b together with the N atom to which they are attached
form azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl,
morpholin-4-yl, pyrazol-1-yl, 3-methylpyrazol-1-yl,
4-methylpyrazol-1-yl, 5-methylpyrazol-1-yl, or imidazol-1-yl; and
[0277] R.sup.2c and R.sup.2d are each hydrogen; or
[0278] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form pyrrolidin-5,5-ylene-2-one,
imidazolidin-5,5-ylene-2,4-dione, or oxazolidin-4,4-ylene-2-one;
and [0279] R.sup.2b and R.sup.2d are each hydrogen; and
[0280] R.sup.3 is cyclopropylmethyl.
[0281] In Formula I, II, or IIa, in one embodiment, W and X are
.dbd.N--; in another embodiment, W and Y are .dbd.N--; in yet
another embodiment, W and Z are .dbd.N--; in yet another
embodiment, X and Y are .dbd.N--; in yet another embodiment, X and
Z are .dbd.N--; and in still another embodiment, Y and Z are
.dbd.N--.
[0282] In yet another embodiment, provided herein is a compound of
Formula III:
##STR00009##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein R.sup.6a,
R.sup.6b, and R.sup.6c are each independently R.sup.6; and R.sup.1,
R.sup.3, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6, U, and V
are each as defined herein. In Formula III, in one embodiment, U is
--O-- and V is .dbd.C(R.sup.4)--, in another embodiment, U is
.dbd.N-- and V is --N(R.sup.5)--, wherein R.sup.4 and R.sup.5 are
each as defined herein.
[0283] In yet another embodiment, provided herein is a compound of
Formula IIIa:
##STR00010##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.2a,
R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6a, R.sup.6b, R.sup.6c, U, and
V are each as defined herein. In Formula IIIa, in one embodiment, U
is --O-- and V is .dbd.C(R.sup.4)--, in another embodiment, U is
.dbd.N-- and V is --N(R.sup.5)--, wherein R.sup.4 and R.sup.5 are
each as defined herein.
[0284] In yet another embodiment, provided herein is a compound of
Formula IV:
##STR00011##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein R.sup.6d is
R.sup.6; and R.sup.1, R.sup.3, R.sup.6, R.sup.2a, R.sup.2b,
R.sup.2c, R.sup.2d, R.sup.6a, R.sup.6b, U and V are each as defined
herein. In Formula IV, in one embodiment, U is --O-- and V is
.dbd.C(R.sup.4)--, in another embodiment, U is .dbd.N-- and V is
--N(R.sup.5)--, wherein R.sup.4 and R.sup.5 are each as defined
herein.
[0285] In yet another embodiment, provided herein is a compound of
Formula IVa:
##STR00012##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof; wherein R.sup.1, R.sup.3, R.sup.2a,
R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6a, R.sup.6b, R.sup.6d, U, and
V are each as defined herein. In Formula IVa, in one embodiment, U
is --O-- and V is .dbd.C(R.sup.4)--, in another embodiment, U is
.dbd.N-- and V is --N(R.sup.5)--, wherein R.sup.4 and R.sup.5 are
each as defined herein.
[0286] In yet another embodiment, provided herein is a compound of
Formula V:
##STR00013##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof; wherein R.sup.1,
R.sup.3, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6a,
R.sup.6c, R.sup.6d U, and V are each as defined herein. In Formula
V, in one embodiment, U is --O-- and V is .dbd.C(R.sup.4)--, in
another embodiment, U is .dbd.N-- and V is --N(R.sup.5)--, wherein
R.sup.4 and R.sup.5 are each as defined herein.
[0287] In yet another embodiment provided herein is a compound of
Formula Va:
##STR00014##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof; wherein R.sup.1, R.sup.3, R.sup.2a,
R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6a, R.sup.6c, R.sup.6d, U, and
V are each as defined herein. In Formula Va, in one embodiment, U
is --O-- and V is .dbd.C(R.sup.4)--, in another embodiment, U is
.dbd.N-- and V is --N(R.sup.5)--, wherein R.sup.4 and R.sup.5 are
each as defined herein.
[0288] In yet another embodiment, provided herein is a compound of
Formula VI:
##STR00015##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein R.sup.1,
R.sup.3, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6b,
R.sup.6c, R.sup.6d U, and V are each as defined herein. In Formula
VI, in one embodiment, U is --O-- and V is .dbd.C(R.sup.4)--, in
another embodiment, U is .dbd.N-- and V is --N(R.sup.5)--, wherein
R.sup.4 and R.sup.5 are each as defined herein.
[0289] In yet another embodiment, provided herein is a compound of
Formula VIa:
##STR00016##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.2a,
R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6b, R.sup.6c, R.sup.6d U, and V
are each as defined herein. In Formula VIa, in one embodiment, U is
--O-- and V is .dbd.C(R.sup.4)--, in another embodiment, U is
.dbd.N-- and V is --N(R.sup.5)--, wherein R.sup.4 and R.sup.5 are
each as defined herein.
[0290] In yet another embodiment, provided herein is a compound of
Formula VII:
##STR00017##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein R.sup.1,
R.sup.3, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6c,
R.sup.6d, U, and V are each as defined herein. In Formula VII, in
one embodiment, U is --O-- and V is .dbd.C(R.sup.4)--, in another
embodiment, U is .dbd.N-- and V is --N(R.sup.5)--, wherein R.sup.4
and R.sup.5 are each as defined herein.
[0291] In yet another embodiment, provided herein is a compound of
Formula VIIa:
##STR00018##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.2a,
R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6c, R.sup.6d, U, and V are each
as defined herein. In Formula VIIa, in one embodiment, U is --O--
and V is .dbd.C(R.sup.4)--, in another embodiment, U is .dbd.N--
and V is --N(R.sup.5)--, wherein R.sup.4 and R.sup.5 are each as
defined herein.
[0292] In yet another embodiment, provided herein is a compound of
Formula VIII:
##STR00019##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein R.sup.1,
R.sup.3, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6b,
R.sup.6d, U, and V are each as defined herein. In Formula VIII, in
one embodiment, U is --O-- and V is .dbd.C(R.sup.4)--, in another
embodiment, U is .dbd.N-- and V is --N(R.sup.5)--, wherein R.sup.4
and R.sup.5 are each as defined herein.
[0293] In yet another embodiment, provided herein is a compound of
Formula VIIIa:
##STR00020##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.2a,
R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6b, R.sup.6d, U, and V are each
as defined herein. In Formula VIIIa, in one embodiment, U is --O--
and V is .dbd.C(R.sup.4)--, in another embodiment, U is .dbd.N--
and V is --N(R.sup.5)--, wherein R.sup.4 and R.sup.5 are each as
defined herein.
[0294] In yet another embodiment, provided herein is a compound of
Formula IX:
##STR00021##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein R.sup.1,
R.sup.3, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6b,
R.sup.6c, U, and V are each as defined herein. In Formula IX, in
one embodiment, U is --O-- and V is .dbd.C(R.sup.4)--, in another
embodiment, U is .dbd.N-- and V is --N(R.sup.5)--, wherein R.sup.4
and R.sup.5 are each as defined herein.
[0295] In yet another embodiment, provided herein is a compound of
Formula IXa:
##STR00022##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.2a,
R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6b, R.sup.6c, U, and V are each
as defined herein. In Formula IXa, in one embodiment, U is --O--
and V is .dbd.C(R.sup.4)--, in another embodiment, U is .dbd.N--
and V is --N(R.sup.5)--, wherein R.sup.4 and R.sup.5 are each as
defined herein.
[0296] In yet another embodiment, provided herein is a compound of
Formula X:
##STR00023##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein R.sup.1, R,
R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.a, R, U, and V are
each as defined herein. In Formula X, in one embodiment, U is --O--
and V is .dbd.C(R.sup.4)--, in another embodiment, U is .dbd.N--
and V is --N(R.sup.5)--, wherein R.sup.4 and R.sup.5 are each as
defined herein.
[0297] In yet another embodiment, provided herein is a compound of
Formula Xa:
##STR00024##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.2a,
R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6a, R.sup.6d, U, and V are each
as defined herein. In Formula Xa, in one embodiment, U is --O-- and
V is .dbd.C(R.sup.4)--, in another embodiment, U is .dbd.N-- and V
is --N(R.sup.5)--, wherein R.sup.4 and R.sup.5 are each as defined
herein.
[0298] In yet another embodiment, provided herein is a compound of
Formula XI:
##STR00025##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein R.sup.1,
R.sup.3, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6b,
R.sup.6c, U, and V are each as defined herein. In Formula XI, in
one embodiment, U is --O-- and V is .dbd.C(R.sup.4)--, in another
embodiment, U is .dbd.N-- and V is --N(R.sup.5)--, wherein R.sup.4
and R.sup.5 are each as defined herein.
[0299] In yet another embodiment, provided herein is a compound of
Formula XIa:
##STR00026##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.2a,
R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6a, R.sup.6c, U, and V are each
as defined herein. In Formula XIa, in one embodiment, U is --O--
and V is .dbd.C(R.sup.4)--, in another embodiment, U is .dbd.N--
and V is --N(R.sup.5)--, wherein R.sup.4 and R.sup.5 are each as
defined herein.
[0300] In yet another embodiment, provided herein is a compound of
Formula XII:
##STR00027##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein R.sup.1,
R.sup.3, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6a,
R.sup.6b, U, and V are each as defined herein. In Formula XII, in
one embodiment, U is --O-- and V is .dbd.C(R.sup.4)--, in another
embodiment, U is .dbd.N-- and V is --N(R.sup.5)--, wherein R.sup.4
and R.sup.5 are each as defined herein.
[0301] In yet another embodiment, provided herein is a compound of
Formula XIIa:
##STR00028##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.2a,
R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6a, R.sup.6b, U, and V are each
as defined herein. In Formula XIIa, in one embodiment, U is --O--
and V is .dbd.C(R.sup.4)--, in another embodiment, U is .dbd.N--
and V is --N(R.sup.5)--, wherein R.sup.4 and R.sup.5 are each as
defined herein.
[0302] In yet another embodiment, provided herein is a compound of
Formula XIII:
##STR00029##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein R.sup.1,
R.sup.3, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6c, U, and V
are each as defined herein. In Formula XIII, in one embodiment, U
is --O-- and V is .dbd.C(R.sup.4)--, in another embodiment, U is
.dbd.N-- and V is --N(R.sup.5)--, wherein R.sup.4 and R.sup.5 are
each as defined herein.
[0303] In yet another embodiment, provided herein is a compound of
Formula XIIIa:
##STR00030##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3,
R.sup.2aR.sup.2b, R.sup.2c, R.sup.2d, R.sup.6c, U, and V are each
as defined herein. In Formula XIIIa, in one embodiment, U is --O--
and V is .dbd.C(R.sup.4)--, in another embodiment, U is .dbd.N--
and V is --N(R.sup.5)--, wherein R.sup.4 and R.sup.5 are each as
defined herein.
[0304] In yet another embodiment, provided herein is a compound of
Formula XIV:
##STR00031##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein R.sup.1,
R.sup.3, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6b, U, and V
are each as defined herein. In Formula XIV, in one embodiment, U is
--O-- and V is .dbd.C(R.sup.4)--, in another embodiment, U is
.dbd.N-- and V is --N(R.sup.5)--, wherein R.sup.4 and R.sup.5 are
each as defined herein.
[0305] In yet another embodiment, provided herein is a compound of
Formula XIVa:
##STR00032##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.2a,
R.sup.2b, R.sup.2c, R.sup.2a, R.sup.6b, U, and V are each as
defined herein. In Formula XIVa, in one embodiment, U is --O-- and
V is .dbd.C(R.sup.4)--, in another embodiment, U is .dbd.N-- and V
is --N(R.sup.5)--, wherein R.sup.4 and R.sup.5 are each as defined
herein.
[0306] In yet another embodiment, provided herein is a compound of
Formula XV:
##STR00033##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein R.sup.1,
R.sup.3, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6a, U, and V
are each as defined herein. In Formula XV, in one embodiment, U is
--O-- and V is .dbd.C(R.sup.4)--, in another embodiment, U is
.dbd.N-- and V is --N(R.sup.5)--, wherein R.sup.4 and R.sup.5 are
each as defined herein.
[0307] In yet another embodiment, provided herein is a compound of
Formula XVa:
##STR00034##
or tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.2a,
R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6a, U, and V are each as
defined herein. In Formula XVa, in one embodiment, U is --O-- and V
is .dbd.C(R.sup.4)--, in another embodiment, U is .dbd.N-- and V is
--N(R.sup.5)--, wherein R.sup.4 and R.sup.5 are each as defined
herein.
[0308] In yet another embodiment, provided herein is a compound of
Formula XVI:
##STR00035##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein R.sup.1,
R.sup.3, R.sup.2aR.sup.2b, R.sup.2c, R.sup.2d, U, V, W, X, and Z
are each as defined herein. In Formula XVI, in one embodiment, U is
--O-- and V is .dbd.C(R.sup.4)--, in another embodiment, U is
.dbd.N-- and V is --N(R.sup.5)--, wherein R.sup.4 and R.sup.5 are
each as defined herein.
[0309] In yet another embodiment, provided herein is a compound of
Formula XVIa:
##STR00036##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.2a,
R.sup.2b, R.sup.2c, R.sup.2d, U, V, W, X, and Z are each as defined
herein. In Formula XVIa, in one embodiment, U is --O-- and V is
.dbd.C(R.sup.4)--, in another embodiment, U is .dbd.N-- and V is
--N(R.sup.5)--, wherein R.sup.4 and R.sup.5 are each as defined
herein.
[0310] In yet another embodiment, provided herein is a compound of
Formula XVII:
##STR00037##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein R.sup.1,
R.sup.3, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6c, U, and V
are each as defined herein. In Formula XVII, in one embodiment, U
is --O-- and V is .dbd.C(R.sup.4)--, in another embodiment, U is
.dbd.N-- and V is --N(R.sup.5)--, wherein R.sup.4 and R.sup.5 are
each as defined herein.
[0311] In yet another embodiment, provided herein is a compound of
Formula XVIIa:
##STR00038##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.2a,
R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6c, U, and V are each as
defined herein. In Formula XVIIa, in one embodiment, U is --O-- and
V is .dbd.C(R.sup.4)--, in another embodiment, U is .dbd.N-- and V
is --N(R.sup.5)--, wherein R.sup.4 and R.sup.5 are each as defined
herein.
[0312] In yet another embodiment, provided herein is a compound of
Formula XVIII:
##STR00039##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein R.sup.1,
R.sup.3, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6c, U, and V
are each as defined herein. In Formula XVIII, in one embodiment, U
is --O-- and V is .dbd.C(R.sup.4)--, in another embodiment, U is
.dbd.N-- and V is --N(R.sup.5)--, wherein R.sup.4 and R.sup.5 are
each as defined herein.
[0313] In yet another embodiment, provided herein is a compound of
Formula XVIIIa:
##STR00040##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.2a,
R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6c, U, and V are each as
defined herein. In Formula XVIIIa, in one embodiment, U is --O--
and V is .dbd.C(R.sup.4)--, in another embodiment, U is .dbd.N--
and V is --N(R.sup.5)--, wherein R.sup.4 and R.sup.5 are each as
defined herein.
[0314] In yet another embodiment, provided herein is a compound of
Formula XIX:
##STR00041##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein R.sup.1,
R.sup.3, R.sup.7, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6c,
U, and V are each as defined herein. In Formula XIX, in one
embodiment, U is --O-- and V is .dbd.C(R.sup.4)--, in another
embodiment, U is .dbd.N-- and V is --N(R.sup.5)--, wherein R.sup.4
and R.sup.5 are each as defined herein.
[0315] In still another embodiment, provided herein is a compound
of Formula XIXa:
##STR00042##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.7,
R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6c, U, and V are each
as defined herein. In Formula XIXa, in one embodiment, U is --O--
and V is .dbd.C(R.sup.4)--, in another embodiment, U is .dbd.N--
and V is --N(R.sup.5)--, wherein R.sup.4 and R.sup.5 are each as
defined herein.
[0316] In one embodiment, in any one of Formulae III to XIX,
[0317] U is --O-- and V is .dbd.C(R.sup.4)--; or U is .dbd.N-- and
V is --N(R.sup.5)--;
[0318] R.sup.1 is hydrogen or C.sub.1-6 alkyl;
[0319] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0320] (i) R.sup.2a and R.sup.2b are each independently hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkynyl, C.sub.6-14 aryl, C.sub.6-14
aralkyl, or --C(O)R.sup.1a; or R.sup.2a and R.sup.2b together with
the N atom to which they are attached form heteroaryl or
heterocyclyl; and [0321] R.sup.2c and R.sup.2d are each
independently hydrogen or C.sub.1-6 alkyl; or R.sup.2c and R.sup.2d
are linked together to form --O--, C.sub.1-6 alkylene, or C.sub.1-6
heteroalkylene; or
[0322] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form heteroaryl or heterocyclyl; and
[0323] R.sup.2b and R.sup.2d are each hydrogen;
[0324] R.sup.3 is C.sub.1-6 alkyl;
[0325] R.sup.4 and R.sup.5 are each independently C.sub.1-6 alkyl,
C.sub.3-12 cycloalkyl, or heterocyclyl;
[0326] R.sup.6a, R.sup.6b, R.sup.6c, and R.sup.6d, if present, are
each independently hydrogen, halo, C.sub.1-6 alkyl, --OR.sup.1a, or
--NR.sup.1bR.sup.1c;
[0327] R.sup.7, if present, is hydrogen or C.sub.1-6 alkyl; and
[0328] each R.sup.1a, R.sup.1b, and R.sup.1c is as defined
herein;
[0329] wherein each alkyl, alkylene, heteroalkylene, alkynyl,
cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is
optionally substituted with one or more, in one embodiment, one,
two, three, or four, substituents Q.
[0330] In another embodiment, in any one of Formulae III to
XIX,
[0331] U is --O-- and V is .dbd.C(R.sup.4)--; or U is .dbd.N-- and
V is --N(R.sup.5)--;
[0332] R.sup.1 is hydrogen or C.sub.1-6 alkyl;
[0333] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0334] (i) R.sup.2a and R.sup.2b are each independently hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkynyl, 5- or 6-membered
heteroaryl-C.sub.1-6 alkyl, C.sub.6-14 aryl, C.sub.6-14 aralkyl,
--C(O)--C.sub.1-6 alkyl, --C(O)--C.sub.2-6 alkynyl, or
--C(O)-5-membered heteroaryl; or R.sup.2a and R.sup.2b together
with the N atom to which they are attached form 5-membered
heteroaryl or 4- to 6-membered heterocyclyl; and [0335] R.sup.2c is
hydrogen or C.sub.1-6 alkyl; and R.sup.2d is hydrogen; or R.sup.2c
and R.sup.2de linked together to form C.sub.2-6 alkylene; or
[0336] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form 5-membered heteroaryl or 5-membered
heterocyclyl; and [0337] R.sup.2b and R.sup.2d are each
hydrogen;
[0338] R.sup.3 is C.sub.1-6 alkyl or C.sub.3-12
cycloalkyl-C.sub.1-6 alkyl;
[0339] R.sup.4 and R.sup.5 are each independently C.sub.1-6 alkyl,
C.sub.3-12 cycloalkyl, or 4- to 6-membered heterocyclyl;
[0340] R.sup.6a, R.sup.6b, R.sup.6c, and R.sup.6d, if present, are
each independently hydrogen, fluoro, chloro, C.sub.1-6 alkyl,
hydroxyl, or amino; and
[0341] R.sup.7, if present, is hydrogen or methyl;
[0342] wherein each alkyl, alkylene, alkynyl, cycloalkyl, aryl,
aralkyl, heteroaryl, and heterocyclyl is optionally substituted
with one or more, in one embodiment, one, two, three, or four,
substituents Q.
[0343] In yet another embodiment, in any one of Formulae III to
XIX,
[0344] U is --O-- and V is .dbd.C(R.sup.4)--; or U is .dbd.N-- and
V is --N(R.sup.5)--;
[0345] R.sup.1 is hydrogen;
[0346] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0347] (i) R.sup.2a is hydrogen, methyl, 2,2,2-trifluoroethyl,
2-methoxyethyl, pent-4-ynyl, phenyl, benzyl, (pyrazol-3-yl)methyl,
(pyrazol-4-yl)methyl, (1-methylpyrazol-4-yl)methyl,
(3-methylpyrazol-4-yl)methyl, 1-(pyrazol-4-yl)ethyl,
(pyridin-3-yl)methyl, pentanoyl, 2-methoxyacetyl,
but-3-ynylcarbonyl, or (pyrazol-4-yl)carbonyl; and R.sup.2b is
hydrogen, methyl, 2,2,2-trifluoroethyl, or (pyrazol-4-yl)methyl; or
R.sup.2a and R.sup.2b together with the N atom to which they are
attached form azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl,
morpholin-4-yl, pyrazol-1-yl, 3-methylpyrazol-1-yl,
4-methylpyrazol-1-yl, 5-methylpyrazol-1-yl, or imidazol-1-yl; and
[0348] R.sup.2c is hydrogen, methyl, or hydroxymethyl; and R.sup.2d
is hydrogen; or R.sup.2c and R.sup.2d are linked together to form
methylene or 1,2-ethylene; or
[0349] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form pyrrolidin-5,5-ylene-2-one,
imidazolidin-5,5-ylene-2,4-dione, or oxazolidin-4,4-ylene-2-one;
and [0350] R.sup.2b and R.sup.2d are each hydrogen;
[0351] R.sup.3 is t-butylmethyl, cyclopropylmethyl,
1-methylcyclopropylmethyl, 1-hydroxy(cyclopropylmethyl),
cyclobutylmethyl, or cyclopentylmethyl;
[0352] R.sup.4 and R.sup.5 are each independently methyl,
isopropyl, cyclopentyl, oxetan-3-yl, tetrahydrofur-3-yl,
tetrahydropyran-4-yl, or tetrahydropyran-3-yl;
[0353] R.sup.6a, R.sup.6b, and R.sup.6d, if present, are each
independently hydrogen;
[0354] R.sup.6c, if present, is hydrogen, fluoro, chloro, methyl,
or trifluoromethyl; and
[0355] R.sup.7, if present, is hydrogen or methyl.
[0356] In still another embodiment, in any one of Formulae III to
XIX,
[0357] U is --O-- and V is .dbd.C(CH.sub.3)--; or U is .dbd.N-- and
V is --N(CH.sub.3)--;
[0358] R.sup.1 is hydrogen;
[0359] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0360] (i) R.sup.2a is hydrogen, methyl, 2,2,2-trifluoroethyl,
2-methoxyethyl, pent-4-ynyl, pentanoyl, 2-methoxyacetyl, or
but-3-ynylcarbonyl; and R.sup.2b is hydrogen or methyl; or R.sup.2a
and R.sup.2b together with the N atom to which they are attached
form azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl,
morpholin-4-yl, pyrazol-1-yl, 3-methylpyrazol-1-yl,
4-methylpyrazol-1-yl, 5-methylpyrazol-1-yl, or imidazol-1-yl; and
[0361] R.sup.2c and R.sup.2d are each hydrogen; or R.sup.2c and
R.sup.2d are linked together to form methylene or eth-1,2-ylene;
or
[0362] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form pyrrolidin-5,5-ylene-2-one,
imidazolidin-5,5-ylene-2,4-dione, or oxazolidin-4,4-ylene-2-one;
and [0363] R.sup.2b and R.sup.2d are each hydrogen;
[0364] R.sup.3 is cyclopropylmethyl;
[0365] R.sup.6a, R.sup.6b, and R.sup.6d, if present, are each
independently hydrogen;
[0366] R.sup.6c, if present, is hydrogen, fluoro, or chloro;
and
[0367] R.sup.7, if present, is hydrogen or methyl.
[0368] In one embodiment, in any one of Formulae IIIa to XIXa,
[0369] U is --O-- and V is .dbd.C(R.sup.4)--; or U is .dbd.N-- and
V is --N(R.sup.5)--;
[0370] R.sup.1 is hydrogen or C.sub.1-6 alkyl;
[0371] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0372] (i) R.sup.2a and R.sup.2b are each independently hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkynyl, C.sub.6-14 aryl, C.sub.6-14
aralkyl, or --C(O)R.sup.1a; or R.sup.2a and R.sup.2b together with
the N atom to which they are attached form heteroaryl or
heterocyclyl; and [0373] R.sup.2c and R.sup.2d are each
independently hydrogen or C.sub.1-6 alkyl; or
[0374] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form heteroaryl or heterocyclyl; and
[0375] R.sup.2b and R.sup.2d are each hydrogen;
[0376] R.sup.3 is C.sub.1-6 alkyl;
[0377] R.sup.4 and R.sup.5 are each independently C.sub.1-6 alkyl,
C.sub.3-12 cycloalkyl, or heterocyclyl;
[0378] R.sup.6a, R.sup.6b, R.sup.6c, and R.sup.6d, if present, are
each independently hydrogen, halo, C.sub.1-6 alkyl, --OR.sup.1a, or
--NR.sup.1bR.sup.1c;
[0379] R.sup.7, if present, is hydrogen or C.sub.1-6 alkyl; and
[0380] each R.sup.1a, R.sup.1b, and R.sup.1c is as defined
herein;
[0381] wherein each alkyl, alkynyl, cycloalkyl, aryl, aralkyl,
heteroaryl, and heterocyclyl is optionally substituted with one or
more, in one embodiment, one, two, three, or four, substituents
Q.
[0382] In another embodiment, in any one of Formulae IIIa to
XIXa,
[0383] U is --O-- and V is .dbd.C(R.sup.4)--; or U is .dbd.N-- and
V is --N(R.sup.5)--;
[0384] R.sup.1 is hydrogen or C.sub.1-6 alkyl;
[0385] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0386] (i) R.sup.2a and R.sup.2b are each independently hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkynyl, 5- or 6-membered
heteroaryl-C.sub.1-6 alkyl, C.sub.6-14 aryl, C.sub.6-14 aralkyl,
--C(O)--C.sub.1-6 alkyl, --C(O)--C.sub.2-6 alkynyl, or
--C(O)-5-membered heteroaryl; or R.sup.2a and R.sup.2b together
with the N atom to which they are attached form 5-membered
heteroaryl or 4- to 6-membered heterocyclyl; [0387] R.sup.2c is
hydrogen or C.sub.1-6 alkyl; and [0388] R.sup.2d is hydrogen;
or
[0389] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form 5-membered heteroaryl or 5-membered
heterocyclyl; and [0390] R.sup.2b and R.sup.2d are each
hydrogen;
[0391] R.sup.3 is C.sub.1-6 alkyl or C.sub.3-12
cycloalkyl-C.sub.1-6 alkyl;
[0392] R.sup.4 and R.sup.5 are each independently C.sub.1-6 alkyl,
C.sub.3-12 cycloalkyl, or 4- to 6-membered heterocyclyl;
[0393] R.sup.6a, R.sup.6b, R.sup.6c, and R.sup.6d, if present, are
each independently hydrogen, fluoro, chloro, C.sub.1-6 alkyl,
hydroxyl, or amino; and
[0394] R.sup.7, if present, is hydrogen or methyl;
[0395] wherein each alkyl, alkynyl, cycloalkyl, aryl, aralkyl,
heteroaryl, and heterocyclyl is optionally substituted with one or
more, in one embodiment, one, two, three, or four, substituents
Q.
[0396] In yet another embodiment, in any one of Formulae IIIa to
XIXa,
[0397] U is --O-- and V is .dbd.C(R.sup.4)--; or U is .dbd.N-- and
V is --N(R.sup.5)--;
[0398] R.sup.1 is hydrogen;
[0399] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0400] (i) R.sup.2a is hydrogen, methyl, 2,2,2-trifluoroethyl,
2-methoxyethyl, pent-4-ynyl, phenyl, benzyl, (pyrazol-3-yl)methyl,
(pyrazol-4-yl)methyl, (1-methylpyrazol-4-yl)methyl,
(3-methylpyrazol-4-yl)methyl, 1-(pyrazol-4-yl)ethyl,
(pyridin-3-yl)methyl, pentanoyl, 2-methoxyacetyl,
but-3-ynylcarbonyl, or (pyrazol-4-yl)carbonyl; and R.sup.2b is
hydrogen, methyl, 2,2,2-trifluoroethyl, or (pyrazol-4-yl)methyl; or
R.sup.2a and R.sup.2b together with the N atom to which they are
attached form azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl,
morpholin-4-yl, pyrazol-1-yl, 3-methylpyrazol-1-yl,
4-methylpyrazol-1-yl, 5-methylpyrazol-1-yl, or imidazol-1-yl;
[0401] R.sup.2c is hydrogen, methyl, or hydroxymethyl; and [0402]
R.sup.2d is hydrogen; or
[0403] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form pyrrolidin-5,5-ylene-2-one,
imidazolidin-5,5-ylene-2,4-dione, or oxazolidin-4,4-ylene-2-one;
and [0404] R.sup.2b and R.sup.2d are each hydrogen;
[0405] R.sup.3 is t-butylmethyl, cyclopropylmethyl,
1-methylcyclopropylmethyl, 1-hydroxy(cyclopropylmethyl),
cyclobutylmethyl, or cyclopentylmethyl;
[0406] R.sup.4 and R.sup.5 are each independently methyl,
isopropyl, cyclopentyl, oxetan-3-yl, tetrahydrofur-3-yl,
tetrahydropyran-4-yl, or tetrahydropyran-3-yl;
[0407] R.sup.6a, R.sup.6b, and R.sup.6d, if present, are each
independently hydrogen;
[0408] R.sup.6c, if present, is hydrogen, fluoro, chloro, methyl,
or trifluoromethyl; and
[0409] R.sup.7, if present, is hydrogen or methyl.
[0410] In still another embodiment, in any one of Formulae IIIa to
XIXa,
[0411] U is --O-- and V is .dbd.C(CH.sub.3)--; or U is .dbd.N-- and
V is --N(CH.sub.3)--;
[0412] R.sup.1 is hydrogen;
[0413] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0414] (i) R.sup.2a is hydrogen, methyl, 2,2,2-trifluoroethyl,
2-methoxyethyl, pent-4-ynyl, pentanoyl, 2-methoxyacetyl, or
but-3-ynylcarbonyl; and R.sup.2b is hydrogen or methyl; or R.sup.2a
and R.sup.2b together with the N atom to which they are attached
form azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl,
morpholin-4-yl, pyrazol-1-yl, 3-methylpyrazol-1-yl,
4-methylpyrazol-1-yl, 5-methylpyrazol-1-yl, or imidazol-1-yl; and
[0415] R.sup.2c and R.sup.2d are each hydrogen; or
[0416] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form pyrrolidin-5,5-ylene-2-one,
imidazolidin-5,5-ylene-2,4-dione, or oxazolidin-4,4-ylene-2-one;
and [0417] R.sup.2b and R.sup.2d are each hydrogen;
[0418] R.sup.3 is cyclopropylmethyl;
[0419] R.sup.6a, R.sup.6b, and R.sup.6d, if present, are each
independently hydrogen;
[0420] R.sup.6c, if present, is hydrogen, fluoro, or chloro;
and
[0421] R.sup.7, if present, is hydrogen or methyl.
[0422] In one embodiment, provided herein is a compound of:
##STR00043##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or a prodrug thereof.
[0423] In another embodiment, provided herein is a compound of:
##STR00044##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or a prodrug thereof.
[0424] In yet another embodiment, provided herein is a compound
of:
##STR00045##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or a prodrug thereof.
[0425] In yet another embodiment, provided herein is a compound
of:
##STR00046##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or a prodrug thereof.
[0426] In yet another embodiment, provided herein is a compound
of:
##STR00047##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or a prodrug thereof.
[0427] In still another embodiment, provided herein is a compound
of:
##STR00048##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or a prodrug thereof.
[0428] In one embodiment, provided herein is an isolated compound
C17. In another embodiment, provided herein is a purified compound
C17.
[0429] In one embodiment, provided herein is a compound of Formula
IA:
##STR00049##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein:
[0430] W, X, Y, and Z are each independently .dbd.C(R.sup.6)-- or
.dbd.N--, with the proviso that at least one of W, X, Y, and Z is
.dbd.N--; or W, X, and Z are each independently .dbd.C(R.sup.6)--,
--N(R.sup.7)--, .dbd.N--, --O--, or --S--; and Y is a bond;
[0431] each R.sup.1, R.sup.4, and R.sup.7 is independently (a)
hydrogen or deuterium; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or (c)
--C(O)R.sup.1a, --C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--C(O)SR.sup.1a, --C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a,
--C(S)OR.sup.1a, --C(S)NR.sup.1bR.sup.1c, --OR.sup.1a,
--OC(O)R.sup.1a, --OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c,
--OC(O)SR.sup.1a, --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
--OC(S)R.sup.1a, --OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c,
--OS(O)R.sup.1a, --OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1aR.sup.1b, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1d, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1a S(O)R.sup.1a,
--NR.sup.1a S(O).sub.2R.sup.1d, --NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.1a S(O).sub.2NR.sup.1bR.sup.1c, --S(O)R.sup.1a,
--S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c;
[0432] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0433] (i) R.sup.2a and R.sup.2b are each independently (a)
hydrogen or deuterium; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or (c)
--C(O)R.sup.1a, --C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--C(O)SR.sup.1a, --C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a,
--C(S)OR.sup.1a, --C(S)NR.sup.1bR.sup.1c, --OR.sup.1a,
--OC(O)R.sup.1a, --OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c,
--OC(O)SR.sup.1a, --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
--OC(S)R.sup.1a, --OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c,
--OS(O)R.sup.1a, --OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1a,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1d, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1aS(O)R.sup.1d,
--NR.sup.1aS(O).sub.2R.sup.1d, --NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.1aS(O).sub.2NR.sup.1bR.sup.1c, --S(O)R.sup.1a,
--S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c; or R.sup.2a and R.sup.2b together
with the N atom to which they are attached form heteroaryl or
heterocyclyl; and [0434] R.sup.2c and R.sup.2d are each
independently (a) hydrogen, deuterium, or cyano; or (b) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl;
or R.sup.2c and R.sup.2d are linked together to form --O--,
C.sub.1-6 alkylene, C.sub.1-6 heteroalkylene, C.sub.2-6 alkenylene,
or C.sub.2-6 alkynylene; or
[0435] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form heterocyclyl; [0436] R.sup.2b is
(a) hydrogen or deuterium; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or (c)
--C(O)R.sup.1a, --C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--C(O)SR.sup.1a, --C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a,
--C(S)OR.sup.1a, --C(S)NR.sup.1bR.sup.1c, --OR.sup.1a,
--OC(O)R.sup.1a, --OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c,
--OC(O)SR.sup.1a, --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
--OC(S)R.sup.1a, --OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c,
--OS(O)R.sup.1a, --OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --R.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)R.sup.1d, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1aS(O)R.sup.1d,
--NR.sup.1aS(O).sub.2R.sup.1d, --NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.1aS(O).sub.2NR.sup.1bR.sup.1c, --S(O)R.sup.1a,
--S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c; and [0437] R.sup.2d is (a) hydrogen,
deuterium, or cyano; or (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl;
[0438] each R.sup.3, R.sup.5, and R.sup.6 is independently (a)
hydrogen, deuterium, cyano, halo, or nitro; (b) C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl;
or (c) --C(O)R.sup.1a, --C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--C(O)SR.sup.1a, --C(NR.sup.1a)NR.sup.1bR.sup.1c, --C(S)R.sup.1a,
--C(S)OR.sup.1a, --C(S)NR.sup.1bR.sup.1c, --OR.sup.1a,
--OC(O)R.sup.1a, --OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c,
--OC(O)SR.sup.1a, --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
--OC(S)R.sup.1a, --OC(S)OR.sup.1a, --OC(S)NR.sup.1bR.sup.1c,
--OS(O)R.sup.1a, --OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.1d,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.1aC(S)OR.sup.1d, --NR.sup.1aC(S)OR.sup.1d,
--NR.sup.1aC(S)NR.sup.1bR.sup.1c, --NR.sup.1aS(O)R.sup.1d,
--NR.sup.1a S(O).sub.2NR.sup.1bR.sup.1c,
--NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.1aS(O).sub.2NR.sup.1bR.sup.1c, --SR.sup.1a,
--S(O)R.sup.1a, --S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c or
--S(O).sub.2NR.sup.1bR.sup.1c; and
[0439] each R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d is
independently hydrogen, deuterium, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or R.sup.1a and
R.sup.1c together with the C and N atoms to which they are attached
form heterocyclyl; or R.sup.1b and R.sup.1c together with the N
atom to which they are attached form heterocyclyl;
[0440] wherein each alkyl, alkylene, heteroalkylene, alkenyl,
alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl,
heteroaryl, and heterocyclyl is optionally substituted with one or
more, in one embodiment, one, two, three, or four, substituents Q,
where each Q is independently selected from (a) deuterium, cyano,
halo, and nitro; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15
aralkyl, heteroaryl, and heterocyclyl, each of which is further
optionally substituted with one or more, in one embodiment, one,
two, three, or four, substituents Q.sup.a; and (c) --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)NR.sup.1bR.sup.1c, --C(O)SR.sup.a,
--C(NR.sup.a)NR.sup.fR.sup.g, --C(S)R.sup.1a, --C(S)OR.sup.a,
--C(S)NR.sup.bR.sup.c, --OR.sup.a, --OC(O)R.sup.1a,
--OC(O)OR.sup.a, --OC(O)NR.sup.bR.sup.c, --OC(O)SR.sup.a,
--OC(.dbd.NR.sup.a)NR.sup.1bR.sup.1c, --OC(S)R.sup.a,
--OC(S)OR.sup.a, --OC(S)NR.sup.1bR.sup.1c, --OS(O)R.sup.1a,
--OS(O).sub.2R.sup.1a, --OS(O)NR.sup.bR.sup.c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.fR.sup.g,
--NR.sup.1aC(O)R.sup.d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(O)SR.sup.d,
--NR.sup.1aC(.dbd.NR.sup.d)NR.sup.fR.sup.g, --NR.sup.1aC(S)R.sup.d,
--NR.sup.1aC(S)OR.sup.1d, --NR.sup.1aC(S)NR.sup.fR.sup.g,
--NR.sup.aS(O)R.sup.d, --NR.sup.1aS(O).sub.2R.sup.d,
--NR.sup.1aS(O)NR.sup.bR.sup.c,
--NR.sup.1aS(O).sub.2NR.sup.1bR.sup.1c, --SR.sup.a, --S(O)R.sup.1a,
--S(O).sub.2R.sup.1a, --S(O)NR.sup.bR.sup.c, and
--S(O).sub.2NR.sup.1bR.sup.1c, wherein each R.sup.a, R, R, and
R.sup.d is independently (i) hydrogen or deuterium; (ii) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2. 6 alkynyl, C.sub.312 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl,
each of which is optionally substituted with one or more, in one
embodiment, one, two, three, or four, substituents Q.sup.a; or
(iii) R.sup.b and R.sup.c together with the N atom to which they
are attached form heterocyclyl, optionally substituted with one or
more, in one embodiment, one, two, three, or four, substituents
Q.sup.a;
[0441] wherein each Q.sup.a is independently selected from the
group consisting of (a) deuterium, cyano, halo, and nitro; (b)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12
cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, and
heterocyclyl; and (c) --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.fR.sup.g, --C(O)SR.sup.e,
--C(NR.sup.e)NR.sup.fR.sup.g, --C(S)R.sup.e, --C(S)OR.sup.e,
--C(S)NR.sup.fR.sup.g, --OR.sup.e, --OC(O)R.sup.e, --OC(O)OR.sup.e,
--OC(O)NR.sup.fR.sup.g, --OC(O)SR.sup.1d,
--OC(.dbd.NR.sup.e)NR.sup.fR.sup.g, --OC(S)R.sup.e, --OC(S)OR,
--OC(S)NR.sup.fR.sup.g, --OS(O)R.sup.e, --OS(O).sub.2R.sup.e,
--OS(O)NR.sup.fR.sup.g, --OS(O).sub.2NR.sup.fR.sup.g,
--NR.sup.fR.sup.g, --NR.sup.eC(O)R.sup.h, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.fR.sup.g, --NR.sup.eC(O)SR.sup.1d,
--NR.sup.eC(.dbd.NR.sup.h)NR.sup.fR.sup.g, --NR.sup.eC(S)R.sup.h,
--NR.sup.eC(S)OR.sup.f, --NR.sup.eC(S)NR.sup.fR.sup.g,
--NR.sup.eS(O)R.sup.h, --NR.sup.eS(O).sub.2R.sup.h,
--NR.sup.eS(O)NR.sup.fR.sup.g, --NR.sup.eS(O).sub.2NR.sup.fR.sup.g,
--SR.sup.e, --S(O)R.sup.e, --S(O).sub.2R.sup.e,
--S(O)NR.sup.fR.sup.g, and --S(O).sub.2NR.sup.fR.sup.g; wherein
each R.sup.e, R.sup.f, R.sup.g, and R.sup.h is independently (i)
hydrogen or deuterium; (ii) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R.sup.f
and R.sup.g together with the N atom to which they are attached
form heterocyclyl.
[0442] In another embodiment, provided herein is a compound of
Formula IAa:
##STR00050##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, W, X, Y, and Z are
each as defined herein.
[0443] In yet another embodiment, provided herein is a compound of
Formula IAb:
##STR00051##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, W, X, Y, and Z are
each as defined herein.
[0444] In one embodiment, in Formula IA, IAa, or IAb,
[0445] W, X, Y, and Z are each independently .dbd.C(R.sup.6)-- or
.dbd.N--;
[0446] R.sup.1 and R.sup.5 are each independently hydrogen or
C.sub.1-6 alkyl;
[0447] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0448] (i) R.sup.2a and R.sup.2b are each independently hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkynyl, C.sub.6-14 aryl, C.sub.6-14
aralkyl, or --C(O)R.sup.1a; or R.sup.2a and R.sup.2b together with
the N atom to which they are attached form heteroaryl or
heterocyclyl; and [0449] R.sup.2c and R.sup.2d are each
independently hydrogen or C.sub.1-6 alkyl; or R.sup.2c and R.sup.2d
in Formula I or Ib are linked together to form --O--, C.sub.1-6
alkylene, or C.sub.1-6 heteroalkylene; or
[0450] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form heteroaryl or heterocyclyl; and
[0451] R.sup.2b and R.sup.2d are each hydrogen;
[0452] R.sup.3 is C.sub.1-6 alkyl;
[0453] R.sup.4 is C.sub.1-6 alkyl, C.sub.3-12 cycloalkyl, or
heterocyclyl;
[0454] each R.sup.6 is independently hydrogen, halo, C.sub.1-6
alkyl, --OR.sup.1a, or --NR.sup.1bR.sup.1c; and
[0455] each R.sup.1a, R.sup.1b, and R.sup.1c is as defined
herein;
[0456] wherein each alkyl, alkylene, heteroalkylene, alkynyl,
cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is
optionally substituted with one or more, in one embodiment, one,
two, three, or four, substituents Q.
[0457] In another embodiment, in Formula IA, IAa, or IAb,
[0458] W, X, Y, and Z are each independently .dbd.C(R.sup.6)-- or
.dbd.N--;
[0459] R and R.sup.5 are each independently hydrogen or C.sub.1-6
alkyl;
[0460] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0461] (i) R.sup.2a and R.sup.2b are each independently hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkynyl, 5- or 6-membered
heteroaryl-C.sub.1-6 alkyl, C.sub.6-14 aryl, C.sub.6-14 aralkyl,
--C(O)--C.sub.1-6 alkyl, --C(O)--C.sub.2-6 alkyl, --C(O)--C.sub.2-6
alkynyl, or --C(O)-5-membered heteroaryl; or R.sup.2a and R.sup.2b
together with the N atom to which they are attached form 5-membered
heteroaryl or 4- to 6-membered heterocyclyl; and [0462] R.sup.2c is
hydrogen or C.sub.1-6 alkyl; and R.sup.2d is hydrogen; or R.sup.2c
and R.sup.2d in Formula I or Ib are linked together to form
C.sub.2-6 alkylene; or
[0463] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form 5-membered heteroaryl or 5-membered
heterocyclyl; and [0464] R.sup.2b and R.sup.2d are each
hydrogen;
[0465] R.sup.3 is C.sub.1-6 alkyl or C.sub.3-12
cycloalkyl-C.sub.1-6 alkyl;
[0466] R.sup.4 is C.sub.1-6 alkyl, C.sub.3-12 cycloalkyl, or 4- to
6-membered heterocyclyl; and
[0467] each R.sup.6 is independently hydrogen, fluoro, chloro,
C.sub.1-6 alkyl, hydroxyl, or amino;
[0468] wherein each alkyl, alkylene, alkynyl, cycloalkyl, aryl,
aralkyl, heteroaryl, and heterocyclyl is optionally substituted
with one or more, in one embodiment, one, two, three, or four,
substituents Q.
[0469] In yet another embodiment, in Formula IA, IAa, or IAb,
[0470] W, X, Y, and Z are each independently .dbd.C(R.sup.6)-- or
.dbd.N--;
[0471] R and R.sup.5 are each independently hydrogen or methyl;
[0472] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0473] (i) R.sup.2a is hydrogen, methyl, trifluoroethyl,
methoxyethyl, pentynyl, phenyl, benzyl, (pyrazolyl)methyl,
(methylpyrazolyl)methyl, (pyrazolyl)ethyl, (pyridinyl)methyl,
pentanoyl, methoxyacetyl, butynylcarbonyl, or (pyrazolyl)carbonyl;
and R.sup.2b is hydrogen, methyl, trifluoroethyl, or
(pyrazolyl)methyl; or R.sup.2a and R.sup.2b together with the N
atom to which they are attached form azetidinyl, pyrrolidinyl,
piperidinyl, morpholinyl, pyrazolyl, methylpyrazolyl, or
imidazolyl; and [0474] R.sup.2c is hydrogen, methyl, or
hydroxymethyl; and R.sup.2d is hydrogen; or R.sup.2c and R.sup.2d
in Formula I or Ib are linked together to form methylene or
ethylene; or
[0475] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form pyrrolidinylene-one,
imidazolidinylene-dione, or oxazolidinylene-one; and [0476]
R.sup.2b and R.sup.2d are each hydrogen;
[0477] R.sup.3 is butylmethyl, cyclopropylmethyl,
methylcyclopropylmethyl, hydroxy(cyclopropylmethyl),
cyclobutylmethyl, or cyclopentylmethyl;
[0478] R.sup.4 is methyl, isopropyl, cyclopentyl, oxetanyl,
tetrahydrofuryl, or tetrahydropyranyl; and
[0479] each R.sup.6 is independently hydrogen, fluoro, chloro,
methyl, trifluoromethyl, hydroxyl, or amino.
[0480] In yet another embodiment, in Formula IA, IAa, or IAb,
[0481] W, X, Y, and Z are each independently .dbd.C(H)--,
.dbd.C(F)--, .dbd.C(Cl)--, .dbd.C(CH.sub.3)--, .dbd.C(CF.sub.3)--,
.dbd.C(OH)--, .dbd.C(NH.sub.2)--, or .dbd.N--;
[0482] R and R.sup.5 are each hydrogen;
[0483] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0484] (i) R.sup.2a is hydrogen, methyl, 2,2,2-trifluoroethyl,
2-methoxyethyl, pent-4-ynyl, phenyl, benzyl, (pyrazol-3-yl)methyl,
(pyrazol-4-yl)methyl, (1-methylpyrazol-4-yl)methyl,
(3-methylpyrazol-4-yl)methyl, 1-(pyrazol-4-yl)ethyl,
(pyridin-3-yl)methyl, pentanoyl, 2-methoxyacetyl,
but-3-ynylcarbonyl, or (pyrazol-4-yl)carbonyl; and R.sup.2b is
hydrogen, methyl, 2,2,2-trifluoroethyl, or (pyrazol-4-yl)methyl; or
R.sup.2a and R.sup.2b together with the N atom to which they are
attached form azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl,
morpholin-4-yl, pyrazol-1-yl, 3-methylpyrazol-1-yl,
4-methylpyrazol-1-yl, 5-methylpyrazol-1-yl, or imidazol-1-yl; and
[0485] R.sup.2c is hydrogen, methyl, or hydroxymethyl; and R.sup.2d
is hydrogen; or R.sup.2c and R.sup.2d in Formula I or Ib are linked
together to form methylene or eth-1,2-ylene; or
[0486] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form pyrrolidin-5,5-ylene-2-one,
imidazolidin-5,5-ylene-2,4-dione, or oxazolidin-4,4-ylene-2-one;
and [0487] R.sup.2b and R.sup.2d are each hydrogen;
[0488] R.sup.3 is t-butylmethyl, cyclopropylmethyl,
1-methylcyclopropylmethyl, 1-hydroxy(cyclopropylmethyl),
cyclobutylmethyl, or cyclopentylmethyl; and
[0489] R.sup.4 is methyl, isopropyl, cyclopentyl, oxetan-3-yl,
tetrahydrofur-3-yl, tetrahydropyran-4-yl, or
tetrahydropyran-3-yl.
[0490] In yet another embodiment, in Formula IA,
[0491] W and Z are each independently .dbd.C(H)-- or .dbd.N--;
[0492] X is .dbd.C(H)--, .dbd.C(OH)--, or .dbd.C(NH.sub.2)--;
[0493] Y is .dbd.C(H)--, .dbd.C(F)--, .dbd.C(Cl)--,
.dbd.C(CH.sub.3)--, .dbd.C(CF.sub.3)--, or .dbd.N--;
[0494] R and R.sup.5 are each hydrogen;
[0495] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0496] (i) R.sup.2a is hydrogen, methyl, 2,2,2-trifluoroethyl,
2-methoxyethyl, pent-4-ynyl, phenyl, benzyl, (pyrazol-3-yl)methyl,
(pyrazol-4-yl)methyl, (1-methylpyrazol-4-yl)methyl,
(3-methylpyrazol-4-yl)methyl, 1-(pyrazol-4-yl)ethyl,
(pyridin-3-yl)methyl, pentanoyl, 2-methoxyacetyl,
but-3-ynylcarbonyl, or (pyrazol-4-yl)carbonyl; and R.sup.2b is
hydrogen, methyl, 2,2,2-trifluoroethyl, or (pyrazol-4-yl)methyl; or
R.sup.2a and R.sup.2b together with the N atom to which they are
attached form azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl,
morpholin-4-yl, pyrazol-1-yl, 3-methylpyrazol-1-yl,
4-methylpyrazol-1-yl, 5-methylpyrazol-1-yl, or imidazol-1-yl; and
[0497] R.sup.2c is hydrogen, methyl, or hydroxymethyl; and R.sup.2d
is hydrogen; or R.sup.2c and R.sup.2d in Formula I or Ib are linked
together to form methylene or 1,2-ethylene; or
[0498] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form pyrrolidin-5,5-ylene-2-one,
imidazolidin-5,5-ylene-2,4-dione, or oxazolidin-4,4-ylene-2-one;
and [0499] R.sup.2b and R.sup.2d are each hydrogen;
[0500] R.sup.3 is t-butylmethyl, cyclopropylmethyl,
1-methylcyclopropylmethyl, 1-hydroxy(cyclopropylmethyl),
cyclobutylmethyl, or cyclopentylmethyl; and
[0501] R.sup.4 is methyl, isopropyl, cyclopentyl, oxetan-3-yl,
tetrahydrofur-3-yl, tetrahydropyran-4-yl, or
tetrahydropyran-3-yl.
[0502] In still another embodiment, in Formula IA,
[0503] W and Z are each independently .dbd.C(H)-- or .dbd.N--;
[0504] X is .dbd.C(H)--;
[0505] Y is .dbd.C(H)--, .dbd.C(F)--, or .dbd.C(Cl)--;
[0506] R and R.sup.5 are each hydrogen;
[0507] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0508] (i) R.sup.2a is hydrogen, methyl, 2,2,2-trifluoroethyl,
2-methoxyethyl, pent-4-ynyl, pentanoyl, 2-methoxyacetyl, or
but-3-ynylcarbonyl; and R.sup.2b is hydrogen or methyl; or R.sup.2a
and R.sup.2b together with the N atom to which they are attached
form azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl,
morpholin-4-yl, pyrazol-1-yl, 3-methylpyrazol-1-yl,
4-methylpyrazol-1-yl, 5-methylpyrazol-1-yl, or imidazol-1-yl; and
[0509] R.sup.2c and R.sup.2d are each hydrogen; or R.sup.2c and
R.sup.2d in Formula I or Ib are linked together to form methylene
or eth-1,2-ylene; or
[0510] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form pyrrolidin-5,5-ylene-2-one,
imidazolidin-5,5-ylene-2,4-dione, or oxazolidin-4,4-ylene-2-one;
and [0511] R.sup.2b and R.sup.2d are each hydrogen;
[0512] R.sup.3 is cyclopropylmethyl; and
[0513] R.sup.4 is methyl.
[0514] In one embodiment, in Formula IA, IAa, or IAb,
[0515] W, X, Y, and Z are each independently .dbd.C(R.sup.6)-- or
.dbd.N--;
[0516] R and R.sup.5 are each independently hydrogen or C.sub.1-6
alkyl;
[0517] R.sup.2a and R.sup.2b are each independently hydrogen,
C.sub.2-6 alkynyl, or --C(O)R.sup.1a;
[0518] R.sup.2c and R.sup.2d are each independently hydrogen or
C.sub.1-6 alkyl;
[0519] R.sup.3 is C.sub.1-6 alkyl;
[0520] R.sup.4 is C.sub.1-6 alkyl, C.sub.3-12 cycloalkyl, or
heterocyclyl;
[0521] each R.sup.6 is independently hydrogen, halo, C.sub.1-6
alkyl, --OR.sup.a, or --NR.sup.1bR.sup.1c; and
[0522] each R.sup.1a, R.sup.1b, and R.sup.1c is as defined
herein;
[0523] wherein each alkyl, alkynyl, cycloalkyl, and heterocyclyl is
optionally substituted with one or more, in one embodiment, one,
two, three, or four, substituents Q.
[0524] In another embodiment, in Formula IA, IAa, or IAb,
[0525] W, X, Y, and Z are each independently .dbd.C(R.sup.6)-- or
.dbd.N--;
[0526] R and R.sup.5 are each independently hydrogen or C.sub.1-6
alkyl;
[0527] R.sup.2a and R.sup.2b are each independently hydrogen,
C.sub.2-6 alkynyl, --C(O)--C.sub.2-6 alkyl, or --C(O)--C.sub.2-6
alkynyl;
[0528] R.sup.2c is hydrogen or C.sub.1-6 alkyl;
[0529] R.sup.2d is hydrogen;
[0530] R.sup.3 is C.sub.1-6 alkyl or C.sub.3-12
cycloalkyl-C.sub.1-6 alkyl;
[0531] R.sup.4 is C.sub.1-6 alkyl, C.sub.3-12 cycloalkyl, or 4- to
6-membered heterocyclyl; and
[0532] each R.sup.6 is independently hydrogen, fluoro, chloro,
C.sub.1-6 alkyl, hydroxyl, or amino;
[0533] wherein each alkyl, alkynyl, cycloalkyl, and heterocyclyl is
optionally substituted with one or more, in one embodiment, one,
two, three, or four, substituents Q.
[0534] In yet another embodiment, in Formula IA, IAa, or IAb,
[0535] W, X, Y, and Z are each independently .dbd.C(R.sup.6)-- or
.dbd.N--;
[0536] R and R.sup.5 are each independently hydrogen or methyl;
[0537] R.sup.2a is pentynyl, pentanoyl, or butynylcarbonyl;
[0538] R.sup.2b is hydrogen, methyl, trifluoroethyl, or
(pyrazolyl)methyl;
[0539] R.sup.2c is hydrogen, methyl, or hydroxymethyl;
[0540] R.sup.2d is hydrogen;
[0541] R.sup.3 is butylmethyl, cyclopropylmethyl,
methylcyclopropylmethyl, hydroxy(cyclopropylmethyl),
cyclobutylmethyl, or cyclopentylmethyl;
[0542] R.sup.4 is methyl, isopropyl, cyclopentyl, oxetanyl,
tetrahydrofuryl, or tetrahydropyranyl; and
[0543] each R.sup.6 is independently hydrogen, fluoro, chloro,
methyl, trifluoromethyl, hydroxyl, or amino.
[0544] In still another embodiment, in Formula IA, IAa, or IAb,
[0545] W and Z are each independently .dbd.C(H)-- or .dbd.N--;
[0546] X is .dbd.C(H)--;
[0547] Y is .dbd.C(H)--, .dbd.C(F)--, or .dbd.C(Cl)--;
[0548] R and R.sup.5 are each hydrogen;
[0549] R.sup.2a is pent-4-ynyl, pentanoyl, or
but-3-ynylcarbonyl;
[0550] R.sup.2b is hydrogen or methyl;
[0551] R.sup.2c and R.sup.2d are each hydrogen;
[0552] R.sup.3 is cyclopropylmethyl; and
[0553] R.sup.4 is methyl.
[0554] In one embodiment, in Formula IA or IAb,
[0555] W, X, Y, and Z are each independently .dbd.C(R.sup.6)-- or
.dbd.N--;
[0556] R and R.sup.5 are each independently hydrogen or C.sub.1-6
alkyl;
[0557] R.sup.2a and R.sup.2b are each independently hydrogen,
C.sub.1-6 alkyl, C.sub.3-6 alkynyl, C.sub.6-14 aryl, C.sub.6-14
aralkyl, or --C(O)R.sup.1a; or R.sup.2a and R.sup.2b together with
the N atom to which they are attached form heteroaryl or
heterocyclyl;
[0558] R.sup.2c and R.sup.2d are linked together to form --O--,
C.sub.1-6 alkylene, or C.sub.1-6 heteroalkylene;
[0559] R.sup.3 is C.sub.1-6 alkyl;
[0560] R.sup.4 is C.sub.1-6 alkyl, C.sub.3-12 cycloalkyl, or
heterocyclyl;
[0561] each R.sup.6 is independently hydrogen, halo, C.sub.1-6
alkyl, --OR.sup.1a, or --NR.sup.1bR.sup.1c; and
[0562] each R.sup.1a, R.sup.1b, and R.sup.1c is as defined
herein;
[0563] wherein each alkyl, alkylene, heteroalkylene, alkynyl,
cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is
optionally substituted with one or more, in one embodiment, one,
two, three, or four, substituents Q.
[0564] In another embodiment, in Formula IA or IAb,
[0565] W, X, Y, and Z are each independently .dbd.C(R.sup.6)-- or
.dbd.N--;
[0566] R and R.sup.5 are each independently hydrogen or C.sub.1-6
alkyl;
[0567] R.sup.2a and R.sup.2b are each independently hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkynyl, 5- or 6-membered
heteroaryl-C.sub.1-6 alkyl, C.sub.6-14 aryl, C.sub.6-14 aralkyl,
--C(O)--C.sub.1-6 alkyl, --C(O)--C.sub.2-6 alkynyl, or
--C(O)-5-membered heteroaryl; or R.sup.2a and R.sup.2b together
with the N atom to which they are attached form 5-membered
heteroaryl or 4- to 6-membered heterocyclyl;
[0568] R.sup.2c and R.sup.2d are linked together to form C.sub.2-6
alkylene;
[0569] R.sup.3 is C.sub.1-6 alkyl or C.sub.3-12
cycloalkyl-C.sub.1-6 alkyl;
[0570] R.sup.4 is C.sub.1-6 alkyl, C.sub.3-12 cycloalkyl, or 4- to
6-membered heterocyclyl; and
[0571] each R.sup.6 is independently hydrogen, fluoro, chloro,
C.sub.1-6 alkyl, hydroxyl, or amino;
[0572] wherein each alkyl, alkylene, alkynyl, cycloalkyl, aryl,
aralkyl, heteroaryl, and heterocyclyl is optionally substituted
with one or more, in one embodiment, one, two, three, or four,
substituents Q.
[0573] In yet another embodiment, in Formula IA or IAb,
[0574] W, X, Y, and Z are each independently .dbd.C(R.sup.6)-- or
.dbd.N--;
[0575] R and R.sup.5 are each independently hydrogen or methyl;
[0576] R.sup.2a is hydrogen, methyl, trifluoroethyl, methoxyethyl,
pentynyl, phenyl, benzyl, (pyrazolyl)methyl,
(methylpyrazolyl)methyl, (pyrazolyl)ethyl, (pyridinyl)methyl,
pentanoyl, methoxyacetyl, butynylcarbonyl, or (pyrazolyl)carbonyl;
and R.sup.2b is hydrogen, methyl, trifluoroethyl, or
(pyrazolyl)methyl; or R.sup.2a and R.sup.2b together with the N
atom to which they are attached form azetidinyl, pyrrolidinyl,
piperidinyl, morpholinyl, pyrazolyl, methylpyrazolyl, or
imidazolyl;
[0577] R.sup.2c and R.sup.2d are linked together to form methylene
or ethylene;
[0578] R.sup.3 is butylmethyl, cyclopropylmethyl,
methylcyclopropylmethyl, hydroxy(cyclopropylmethyl),
cyclobutylmethyl, or cyclopentylmethyl;
[0579] R.sup.4 is methyl, isopropyl, cyclopentyl, oxetanyl,
tetrahydrofuryl, or tetrahydropyranyl; and
[0580] each R.sup.6 is independently hydrogen, fluoro, chloro,
methyl, trifluoromethyl, hydroxyl, or amino.
[0581] In yet another embodiment, in Formula IA or IAb,
[0582] W, X, Y, and Z are each independently .dbd.C(H)--,
.dbd.C(F)--, .dbd.C(Cl)--, .dbd.C(CH.sub.3)--, .dbd.C(CF.sub.3)--,
.dbd.C(OH)--, .dbd.C(NH.sub.2)--, or .dbd.N--;
[0583] R and R.sup.5 are each hydrogen;
[0584] R.sup.2a is hydrogen, methyl, trifluoroethyl, methoxyethyl,
pentynyl, phenyl, benzyl, (pyrazolyl)methyl,
(1-methylpyrazolyl)methyl, (3-methylpyrazolyl)methyl,
(pyrazol-yl)ethyl, (pyridinyl)methyl, pentanoyl, methoxyacetyl,
butynylcarbonyl, or (pyrazolyl)carbonyl; and R.sup.2b is hydrogen,
methyl, trifluoroethyl, or (pyrazolyl)methyl; or R.sup.2a and
R.sup.2b together with the N atom to which they are attached form
azetidinyl, pyrrolidinyl, piperidineyl, morpholinyl, pyrazolyl,
methylpyrazolyl, or imidazolyl;
[0585] R.sup.2c and R.sup.2d are linked together to form methylene
or ethylene;
[0586] R.sup.3 is t-butylmethyl, cyclopropylmethyl,
methylcyclopropylmethyl, hydroxy(cyclopropylmethyl),
cyclobutylmethyl, or cyclopentylmethyl; and
[0587] R.sup.4 is methyl, isopropyl, cyclopentyl, oxetanyl,
tetrahydrofuryl, tetrahydropyranyl, or tetrahydropyranyl.
[0588] In yet another embodiment, in Formula IA or IAb,
[0589] W and Z are each independently .dbd.C(H)-- or .dbd.N--;
[0590] X is .dbd.C(H)--, .dbd.C(OH)--, or .dbd.C(NH.sub.2)--;
[0591] Y is .dbd.C(H)--, .dbd.C(F)--, .dbd.C(Cl)--,
.dbd.C(CH.sub.3)--, .dbd.C(CF.sub.3)--, or .dbd.N--;
[0592] R and R.sup.5 are each hydrogen;
[0593] R.sup.2a is hydrogen, methyl, 2,2,2-trifluoroethyl,
2-methoxyethyl, pent-4-ynyl, phenyl, benzyl, (pyrazol-3-yl)methyl,
(pyrazol-4-yl)methyl, (1-methylpyrazol-4-yl)methyl,
(3-methylpyrazol-4-yl)methyl, 1-(pyrazol-4-yl)ethyl,
(pyridin-3-yl)methyl, pentanoyl, 2-methoxyacetyl,
but-3-ynylcarbonyl, or (pyrazol-4-yl)carbonyl; and R.sup.2b is
hydrogen, methyl, 2,2,2-trifluoroethyl, or (pyrazol-4-yl)methyl; or
R.sup.2a and R together with the N atom to which they are attached
form azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl,
morpholin-4-yl, pyrazol-1-yl, 3-methylpyrazol-1-yl,
4-methylpyrazol-1-yl, 5-methylpyrazol-1-yl, or imidazol-1-yl;
[0594] R.sup.2c and R.sup.2d are linked together to form methylene
or 1,2-ethylene;
[0595] R.sup.3 is t-butylmethyl, cyclopropylmethyl,
1-methylcyclopropylmethyl, 1-hydroxy(cyclopropylmethyl),
cyclobutylmethyl, or cyclopentylmethyl; and
[0596] R.sup.4 is methyl, isopropyl, cyclopentyl, oxetan-3-yl,
tetrahydrofur-3-yl, tetrahydropyran-4-yl, or
tetrahydropyran-3-yl.
[0597] In still another embodiment, in Formula IA or IAb,
[0598] W and Z are each independently .dbd.C(H)-- or .dbd.N--;
[0599] X is .dbd.C(H)--;
[0600] Y is .dbd.C(H)--, .dbd.C(F)--, or .dbd.C(Cl)--;
[0601] R and R.sup.5 are each hydrogen;
[0602] R.sup.2a is hydrogen, methyl, 2,2,2-trifluoroethyl,
2-methoxyethyl, pent-4-ynyl, pentanoyl, 2-methoxyacetyl, or
but-3-ynylcarbonyl; and R.sup.2b is hydrogen or methyl; or R.sup.2a
and R.sup.2b together with the N atom to which they are attached
form azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl,
morpholin-4-yl, pyrazol-1-yl, 3-methylpyrazol-1-yl,
4-methylpyrazol-1-yl, 5-methylpyrazol-1-yl, or imidazol-1-yl;
[0603] R.sup.2c and R.sup.2d are linked together to form methylene
or eth-1,2-ylene;
[0604] R.sup.3 is cyclopropylmethyl; and
[0605] R.sup.4 is methyl.
[0606] In Formula IA, IAa, or IAb, in one embodiment, W and X are
.dbd.N--; in another embodiment, W and Y are .dbd.N--; in yet
another embodiment, W and Z are .dbd.N--; in yet another
embodiment, X and Y are .dbd.N--; in yet another embodiment, X and
Z are .dbd.N--; and in still another embodiment, Y and Z are
.dbd.N--.
[0607] In yet another embodiment, provided herein is a compound of
Formula IIA:
##STR00052##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein R.sup.6a,
R.sup.6b, and R.sup.6c are each independently R.sup.6; and R.sup.1,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.2a, R.sup.2b, R.sup.2c,
and R.sup.2d are each as defined herein.
[0608] In yet another embodiment, provided herein is a compound of
Formula IIAa:
##STR00053##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6a, R.sup.6b
and R.sup.6c are each as defined herein.
[0609] In yet another embodiment, provided herein is a compound of
Formula IIAb:
##STR00054##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof; wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6a, R.sup.6b
and R.sup.6c are each as defined herein.
[0610] In yet another embodiment, provided herein is a compound of
Formula IIIA:
##STR00055##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof; wherein R.sup.6d is
R.sup.6; and R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.2a,
R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6a, and R.sup.6b are each as
defined herein.
[0611] In yet another embodiment, provided herein is a compound of
Formula IIIAa:
##STR00056##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof; wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6a, R.sup.6b
and R.sup.6d are each as defined herein.
[0612] In yet another embodiment, provided herein is a compound of
Formula IIIAb:
##STR00057##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6a, R.sup.6b
and R.sup.6d are each as defined herein.
[0613] In yet another embodiment, provided herein is a compound of
Formula IVA:
##STR00058##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein R.sup.1,
R.sup.3, R.sup.4, R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d,
R.sup.6a, R.sup.6c and R.sup.6d are each as defined herein.
[0614] In yet another embodiment, provided herein is a compound of
Formula IVAa:
##STR00059##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6a, R.sup.6c
and R.sup.6d are each as defined herein.
[0615] In yet another embodiment, provided herein is a compound of
Formula IVAb:
##STR00060##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof; wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6a, R.sup.6c
and R.sup.6d are each as defined herein.
[0616] In yet another embodiment, provided herein is a compound of
Formula VA:
##STR00061##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof; wherein R.sup.1,
R.sup.3, R.sup.4, R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d,
R.sup.6b, R.sup.6c, and R.sup.6d are each as defined herein.
[0617] In yet another embodiment, provided herein is a compound of
Formula VAa:
##STR00062##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof; wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6b,
R.sup.6c, and R.sup.6d are each as defined herein.
[0618] In yet another embodiment, provided herein is a compound of
Formula VAb:
##STR00063##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6b,
R.sup.6c, and R.sup.6d are each as defined herein.
[0619] In yet another embodiment, provided herein is a compound of
Formula VIA:
##STR00064##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein R.sup.1,
R.sup.3, R.sup.4, R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d,
R.sup.6c, and R.sup.6d are each as defined herein.
[0620] In yet another embodiment, provided herein is a compound of
Formula VIAa:
##STR00065##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6c, and
R.sup.6d are each as defined herein.
[0621] In yet another embodiment, provided herein is a compound of
Formula VIAb:
##STR00066##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6c, and
R.sup.6d are each as defined herein.
[0622] In yet another embodiment, provided herein is a compound of
Formula VIIA:
##STR00067##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein R.sup.1,
R.sup.3, R.sup.4, R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d,
R.sup.6b, and R.sup.6d are each as defined herein.
[0623] In yet another embodiment, provided herein is a compound of
Formula VIIAa:
##STR00068##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6b, and
R.sup.6d are each as defined herein.
[0624] In yet another embodiment, provided herein is a compound of
Formula VIIAb:
##STR00069##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof; wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6b, and
R.sup.6d are each as defined herein.
[0625] In yet another embodiment, provided herein is a compound of
Formula VIIIA:
##STR00070##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof; wherein R.sup.1,
R.sup.3, R.sup.4, R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d,
R.sup.6b, and R.sup.6c are each as defined herein.
[0626] In yet another embodiment, provided herein is a compound of
Formula VIIIAa:
##STR00071##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof; wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6b, and
R.sup.6c are each as defined herein.
[0627] In yet another embodiment, provided herein is a compound of
Formula VIIIAb:
##STR00072##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6b, and
R.sup.6c are each as defined herein.
[0628] In yet another embodiment, provided herein is a compound of
Formula IXA:
##STR00073##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein R.sup.1,
R.sup.3, R.sup.4, R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d,
R.sup.6b, and R.sup.6d are each as defined herein.
[0629] In yet another embodiment, provided herein is a compound of
Formula IXAa:
##STR00074##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6b, and
R.sup.6d are each as defined herein.
[0630] In yet another embodiment, provided herein is a compound of
Formula IXAb:
##STR00075##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof; wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6b, and
R.sup.6d are each as defined herein.
[0631] In yet another embodiment, provided herein is a compound of
Formula XA:
##STR00076##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof; wherein R.sup.1,
R.sup.3, R.sup.4, R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d,
R.sup.6b, and R.sup.6c are each as defined herein.
[0632] In yet another embodiment, provided herein is a compound of
Formula XAa:
##STR00077##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof; wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6b, and
R.sup.6c are each as defined herein.
[0633] In yet another embodiment, provided herein is a compound of
Formula XAb:
##STR00078##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof; wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6b, and
R.sup.6c are each as defined herein.
[0634] In yet another embodiment, provided herein is a compound of
Formula XIA:
##STR00079##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof; wherein R.sup.1,
R.sup.3, R.sup.4, R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d,
R.sup.6b, and R.sup.6b are each as defined herein.
[0635] In yet another embodiment, provided herein is a compound of
Formula XIAa:
##STR00080##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof; wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6b, and
R.sup.6b are each as defined herein.
[0636] In yet another embodiment, provided herein is a compound of
Formula XIAb:
##STR00081##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof; wherein R.sup.1, R.sup.3, R.sup.4, R,
R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6a, and R.sup.6b are
each as defined herein.
[0637] In yet another embodiment, provided herein is a compound of
Formula XIIA:
##STR00082##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof; wherein R.sup.1,
R.sup.3, R.sup.4, R, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, and
R.sup.6c are each as defined herein.
[0638] In yet another embodiment, provided herein is a compound of
Formula XIIAa:
##STR00083##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof; wherein R.sup.1, R.sup.3, R.sup.4, R,
R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, and R.sup.6c are each as
defined herein.
[0639] In yet another embodiment, provided herein is a compound of
Formula XIIAb:
##STR00084##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, and R.sup.6c are
each as defined herein.
[0640] In yet another embodiment, provided herein is a compound of
Formula XIIIA:
##STR00085##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein R.sup.1,
R.sup.3, R.sup.4, R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d,
and R.sup.6b are each as defined herein.
[0641] In yet another embodiment, provided herein is a compound of
Formula XIIIAa:
##STR00086##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof; wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, and R.sup.6b are
each as defined herein.
[0642] In yet another embodiment, provided herein is a compound of
Formula XIIIAb:
##STR00087##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof; wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, and R.sup.6b are
each as defined herein.
[0643] In yet another embodiment, provided herein is a compound of
Formula XIVA:
##STR00088##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof; wherein R.sup.1,
R.sup.3, R.sup.4, R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d,
and R.sup.6a are each as defined herein.
[0644] In yet another embodiment, provided herein is a compound of
Formula XIVAa:
##STR00089##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof; wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, and R.sup.6a are
each as defined herein.
[0645] In yet another embodiment, provided herein is a compound of
Formula XIVAb:
##STR00090##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof; wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, and R.sup.6a are
each as defined herein.
[0646] In yet another embodiment, provided herein is a compound of
Formula XVA:
##STR00091##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof; wherein R.sup.1,
R.sup.3, R.sup.4, R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d,
W, X, and Z are each as defined herein.
[0647] In yet another embodiment, provided herein is a compound of
Formula XVAa:
##STR00092##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof; wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, W, X, and Z are
each as defined herein.
[0648] In yet another embodiment, provided herein is a compound of
Formula XVAb:
##STR00093##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, W, X, and Z are
each as defined herein.
[0649] In yet another embodiment, provided herein is a compound of
Formula XVIA:
##STR00094##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein R.sup.1,
R.sup.3, R.sup.4, R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d,
and R.sup.6c are each as defined herein.
[0650] In yet another embodiment, provided herein is a compound of
Formula XVIAa:
##STR00095##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, and R.sup.6c are
each as defined herein.
[0651] In yet another embodiment, provided herein is a compound of
Formula XVIAb:
##STR00096##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, and R.sup.6c are
each as defined herein.
[0652] In yet another embodiment, provided herein is a compound of
Formula XVIIA:
##STR00097##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein R.sup.1,
R.sup.3, R.sup.4, R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d,
and R.sup.6c are each as defined herein.
[0653] In yet another embodiment, provided herein is a compound of
Formula XVIIAa:
##STR00098##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, and R.sup.6c are
each as defined herein.
[0654] In yet another embodiment, provided herein is a compound of
Formula XVIIAb:
##STR00099##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, and R.sup.6c are
each as defined herein.
[0655] In yet another embodiment, provided herein is a compound of
Formula XVIIIA:
##STR00100##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, wherein R.sup.1,
R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.2a, R.sup.2b, R.sup.2c,
R.sup.2d, and R.sup.6d are each as defined herein.
[0656] In yet another embodiment, provided herein is a compound of
Formula XVIIIAa:
##STR00101##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.7, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, and
R.sup.6d are each as defined herein.
[0657] In yet another embodiment, provided herein is a compound of
Formula XVIIIAb:
##STR00102##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, wherein R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.7, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, and
R.sup.6d are each as defined herein.
[0658] In one embodiment, in any one of Formulae IIA to XVIIIA,
IIAa to XVIIIAa, and IIAb to XVIIIAb,
[0659] R.sup.1 and R.sup.5 are each independently hydrogen or
C.sub.1-6 alkyl;
[0660] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0661] (i) R.sup.2a and R.sup.2b are each independently hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkynyl, C.sub.6-14 aryl, C.sub.6-14
aralkyl, or --C(O)R.sup.1a; or R.sup.2a and R.sup.2b together with
the N atom to which they are attached form heteroaryl or
heterocyclyl; and [0662] R.sup.2c and R.sup.2d are each
independently hydrogen or C.sub.1-6 alkyl; or R.sup.2c and R.sup.2d
in any one of Formulae IIA to XVIIIA and IIAb to XVIIIAb are linked
together to form --O--, C.sub.1-6 alkylene, or C.sub.1-6
heteroalkylene; or
[0663] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form heteroaryl or heterocyclyl; and
[0664] R.sup.2b and R.sup.2d are each hydrogen;
[0665] R.sup.3 is C.sub.1-6 alkyl;
[0666] R.sup.4 is C.sub.1-6 alkyl, C.sub.3-12 cycloalkyl, or
heterocyclyl;
[0667] R.sup.6a, R.sup.6b, R.sup.6c, and R.sup.6d, if present, are
each independently hydrogen, halo, C.sub.1-6 alkyl, --OR.sup.1a, or
--NR.sup.1bR.sup.1c;
[0668] R.sup.7, if present, is hydrogen or C.sub.1-6 alkyl; and
[0669] each R.sup.1a, R.sup.1b, and R.sup.1c is as defined
herein;
[0670] wherein each alkyl, alkylene, heteroalkylene, alkynyl,
cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is
optionally substituted with one or more, in one embodiment, one,
two, three, or four, substituents Q.
[0671] In another embodiment, in any one of Formulae IIA to XVIIIA,
IIAa to XVIIIAa, and IIAb to XVIIIAb,
[0672] R and R.sup.5 are each independently hydrogen or C.sub.1-6
alkyl;
[0673] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0674] (i) R.sup.2a and R.sup.2b are each independently hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkynyl, 5- or 6-membered
heteroaryl-C.sub.1-6 alkyl, C.sub.6-14 aryl, C.sub.6-14 aralkyl,
--C(O)--C.sub.1-6 alkyl, --C(O)--C.sub.2-6 alkyl, --C(O)--C.sub.2-6
alkynyl, or --C(O)-5-membered heteroaryl; or R.sup.2a and R.sup.2b
together with the N atom to which they are attached form 5-membered
heteroaryl or 4- to 6-membered heterocyclyl; and [0675] R.sup.2c is
hydrogen or C.sub.1-6 alkyl; and R.sup.2d is hydrogen; or R.sup.2c
and R.sup.2d in any one of Formulae IIA to XVIIIA and IIAb to
XVIIIAb are linked together to form C.sub.2-6 alkylene; or
[0676] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form 5-membered heteroaryl or 5-membered
heterocyclyl; and [0677] R.sup.2b and R.sup.2d are each
hydrogen;
[0678] R.sup.3 is C.sub.1-6 alkyl or C.sub.3-12
cycloalkyl-C.sub.1-6 alkyl;
[0679] R.sup.4 is C.sub.1-6 alkyl, C.sub.3-12 cycloalkyl, or 4- to
6-membered heterocyclyl;
[0680] R.sup.6a, R.sup.6b, R.sup.6c, and R.sup.6d, if present, are
each independently hydrogen, fluoro, chloro, C.sub.1-6 alkyl,
hydroxyl, or amino; and
[0681] R.sup.7, if present, is hydrogen or methyl;
[0682] wherein each alkyl, alkylene, alkynyl, cycloalkyl, aryl,
aralkyl, heteroaryl, and heterocyclyl is optionally substituted
with one or more, in one embodiment, one, two, three, or four,
substituents Q.
[0683] In yet another embodiment, in any one of Formulae IIA to
XVIIIA, IIAa to XVIIIAa, and IIAb to XVIIIAb,
[0684] R and R.sup.5 are each hydrogen;
[0685] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0686] (i) R.sup.2a is hydrogen, methyl, 2,2,2-trifluoroethyl,
2-methoxyethyl, pent-4-ynyl, phenyl, benzyl, (pyrazol-3-yl)methyl,
(pyrazol-4-yl)methyl, (1-methylpyrazol-4-yl)methyl,
(3-methylpyrazol-4-yl)methyl, 1-(pyrazol-4-yl)ethyl,
(pyridin-3-yl)methyl, pentanoyl, 2-methoxyacetyl,
but-3-ynylcarbonyl, or (pyrazol-4-yl)carbonyl; and R.sup.2b is
hydrogen, methyl, 2,2,2-trifluoroethyl, or (pyrazol-4-yl)methyl; or
R.sup.2a and R.sup.2b together with the N atom to which they are
attached form azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl,
morpholin-4-yl, pyrazol-1-yl, 3-methylpyrazol-1-yl,
4-methylpyrazol-1-yl, 5-methylpyrazol-1-yl, or imidazol-1-yl; and
[0687] R.sup.2c is hydrogen, methyl, or hydroxymethyl; and R.sup.2d
is hydrogen; or R.sup.2c and R.sup.2d in any one of Formulae IIA to
XVIIIA and IIAb to XVIIIAb are linked together to form methylene or
1,2-ethylene; or
[0688] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form pyrrolidin-5,5-ylene-2-one,
imidazolidin-5,5-ylene-2,4-dione, or oxazolidin-4,4-ylene-2-one;
and [0689] R.sup.2b and R.sup.2d are each hydrogen;
[0690] R.sup.3 is t-butylmethyl, cyclopropylmethyl,
1-methylcyclopropylmethyl, 1-hydroxy(cyclopropylmethyl),
cyclobutylmethyl, or cyclopentylmethyl;
[0691] R.sup.4 is methyl, isopropyl, cyclopentyl, oxetan-3-yl,
tetrahydrofur-3-yl, tetrahydropyran-4-yl, or
tetrahydropyran-3-yl;
[0692] R.sup.6a, R.sup.6b, and R.sup.6d, if present, are each
independently hydrogen;
[0693] R.sup.6c, if present, is hydrogen, fluoro, chloro, methyl,
or trifluoromethyl; and
[0694] R.sup.7, if present, is hydrogen or methyl.
[0695] In still another embodiment, in any one of Formulae IIA to
XVIIIA, IIAa to XVIIIAa, and IIAb to XVIIIAb,
[0696] R and R.sup.5 are each hydrogen;
[0697] R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d are (i) or
(ii):
[0698] (i) R.sup.2a is hydrogen, methyl, 2,2,2-trifluoroethyl,
2-methoxyethyl, pent-4-ynyl, pentanoyl, 2-methoxyacetyl, or
but-3-ynylcarbonyl; and R.sup.2b is hydrogen or methyl; or R.sup.2a
and R.sup.2b together with the N atom to which they are attached
form azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl,
morpholin-4-yl, pyrazol-1-yl, 3-methylpyrazol-1-yl,
4-methylpyrazol-1-yl, 5-methylpyrazol-1-yl, or imidazol-1-yl; and
[0699] R.sup.2c and R.sup.2d are each hydrogen; or R.sup.2c and
R.sup.2d in any one of Formulae IIA to XVIIIA and IIAb to XVIIIAb
are linked together to form methylene or eth-1,2-ylene; or
[0700] (ii) R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form pyrrolidin-5,5-ylene-2-one,
imidazolidin-5,5-ylene-2,4-dione, or oxazolidin-4,4-ylene-2-one;
and [0701] R.sup.2b and R.sup.2d are each hydrogen;
[0702] R.sup.3 is cyclopropylmethyl;
[0703] R.sup.4 is methyl;
[0704] R.sup.6a, R.sup.6b, and R.sup.6d, if present, are each
independently hydrogen;
[0705] R.sup.6c, if present, is hydrogen, fluoro, or chloro;
and
[0706] R.sup.7, if present, is hydrogen or methyl.
[0707] In one embodiment, in any one of Formulae IIA to XVIIIA and
IIAb to XVIIIAb,
[0708] R and R.sup.5 are each independently hydrogen or C.sub.1-6
alkyl;
[0709] R.sup.2a and R.sup.2b are each independently hydrogen,
C.sub.1-6 alkyl, C.sub.3-6 alkynyl, C.sub.6-14 aryl, C.sub.6-14
aralkyl, or --C(O)R.sup.1a; or R.sup.2a and R.sup.2b together with
the N atom to which they are attached form heteroaryl or
heterocyclyl;
[0710] R.sup.2c and R.sup.2d are linked together to form --O--,
C.sub.1-6 alkylene, or C.sub.1-6 heteroalkylene;
[0711] R.sup.3 is C.sub.1-6 alkyl;
[0712] R.sup.4 is C.sub.1-6 alkyl, C.sub.3-12 cycloalkyl, or
heterocyclyl;
[0713] R.sup.6a, R.sup.6b, R.sup.6c, and R.sup.6d, if present, are
each independently hydrogen, halo, C.sub.1-6 alkyl, --OR.sup.1a, or
--NR.sup.1bR.sup.1c;
[0714] R.sup.7, if present, is hydrogen or C.sub.1-6 alkyl; and
[0715] each R.sup.1a, R.sup.1b, and R.sup.1c is as defined
herein;
[0716] wherein each alkyl, alkylene, heteroalkylene, alkynyl,
cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is
optionally substituted with one or more, in one embodiment, one,
two, three, or four, substituents Q.
[0717] In another embodiment, in any one of Formulae IIA to XVIIIA
and IIAb to XVIIIAb,
[0718] R and R.sup.5 are each independently hydrogen or C.sub.1-6
alkyl;
[0719] R.sup.2a and R.sup.2b are each independently hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkynyl, 5- or 6-membered
heteroaryl-C.sub.1-6 alkyl, C.sub.6-14 aryl, C.sub.6-14 aralkyl,
--C(O)--C.sub.1-6 alkyl, --C(O)--C.sub.2-6 alkynyl, or
--C(O)-5-membered heteroaryl; or R.sup.2a and R.sup.2b together
with the N atom to which they are attached form 5-membered
heteroaryl or 4- to 6-membered heterocyclyl;
[0720] R.sup.2c and R.sup.2d are linked together to form C.sub.2-6
alkylene;
[0721] R.sup.3 is C.sub.1-6 alkyl or C.sub.3-12
cycloalkyl-C.sub.1-6 alkyl;
[0722] R.sup.4 is C.sub.1-6 alkyl, C.sub.3-12 cycloalkyl, or 4- to
6-membered heterocyclyl;
[0723] R.sup.6a, R.sup.6b, R.sup.6c, and R.sup.6d, if present, are
each independently hydrogen, fluoro, chloro, C.sub.1-6 alkyl,
hydroxyl, or amino; and
[0724] R.sup.7, if present, is hydrogen or methyl;
[0725] wherein each alkyl, alkylene, alkynyl, cycloalkyl, aryl,
aralkyl, heteroaryl, and heterocyclyl is optionally substituted
with one or more, in one embodiment, one, two, three, or four,
substituents Q.
[0726] In yet another embodiment, in any one of Formulae IIA to
XVIIIA and IIAb to XVIIIAb,
[0727] R and R.sup.5 are each independently hydrogen or methyl;
[0728] R.sup.2a is hydrogen, methyl, trifluoroethyl, methoxyethyl,
pentynyl, phenyl, benzyl, (pyrazolyl)methyl,
(methylpyrazolyl)methyl, (pyrazolyl)ethyl, (pyridinyl)methyl,
pentanoyl, methoxyacetyl, butynylcarbonyl, or (pyrazolyl)carbonyl;
and R.sup.2b is hydrogen, methyl, trifluoroethyl, or
(pyrazolyl)methyl; or R.sup.2a and R.sup.2b together with the N
atom to which they are attached form azetidinyl, pyrrolidinyl,
piperidinyl, morpholinyl, pyrazolyl, methylpyrazolyl, or
imidazolyl;
[0729] R.sup.2c and R.sup.2d are linked together to form methylene
or ethylene;
[0730] R.sup.3 is butylmethyl, cyclopropylmethyl,
methylcyclopropylmethyl, hydroxy(cyclopropylmethyl),
cyclobutylmethyl, or cyclopentylmethyl;
[0731] R.sup.4 is methyl, isopropyl, cyclopentyl, oxetanyl,
tetrahydrofuryl, or tetrahydropyranyl;
[0732] R.sup.6a, R.sup.6b, and R.sup.6d, if present, are each
independently hydrogen;
[0733] R.sup.6c, if present, is hydrogen, fluoro, chloro, methyl,
or trifluoromethyl; and
[0734] R.sup.7, if present, is hydrogen or methyl.
[0735] In yet another embodiment, in any one of Formulae IIA to
XVIIIA and IIAb to XVIIIAb,
[0736] R and R.sup.5 are each hydrogen;
[0737] R.sup.2a is hydrogen, methyl, trifluoroethyl, methoxyethyl,
pentynyl, phenyl, benzyl, (pyrazolyl)methyl,
(1-methylpyrazolyl)methyl, (3-methylpyrazolyl)methyl,
(pyrazol-yl)ethyl, (pyridinyl)methyl, pentanoyl, methoxyacetyl,
butynylcarbonyl, or (pyrazolyl)carbonyl; and R.sup.2b is hydrogen,
methyl, trifluoroethyl, or (pyrazolyl)methyl; or R.sup.2a and
R.sup.2b together with the N atom to which they are attached form
azetidinyl, pyrrolidinyl, piperidineyl, morpholinyl, pyrazolyl,
methylpyrazolyl, or imidazolyl;
[0738] R.sup.2c and R.sup.2d are linked together to form methylene
or ethylene;
[0739] R.sup.3 is t-butylmethyl, cyclopropylmethyl,
methylcyclopropylmethyl, hydroxy(cyclopropylmethyl),
cyclobutylmethyl, or cyclopentylmethyl; and
[0740] R.sup.4 is methyl, isopropyl, cyclopentyl, oxetanyl,
tetrahydrofuryl, tetrahydropyranyl, or tetrahydropyranyl.
[0741] In yet another embodiment, in any one of Formulae IIA to
XVIIIA and IIAb to XVIIIAb,
[0742] W and Z are each independently .dbd.C(H)-- or .dbd.N--;
[0743] X is .dbd.C(H)--, .dbd.C(OH)--, or .dbd.C(NH.sub.2)--;
[0744] Y is .dbd.C(H)--, .dbd.C(F)--, .dbd.C(Cl)--,
.dbd.C(CH.sub.3)--, .dbd.C(CF.sub.3)--, or .dbd.N--;
[0745] R and R.sup.5 are each hydrogen;
[0746] R.sup.2a is hydrogen, methyl, 2,2,2-trifluoroethyl,
2-methoxyethyl, pent-4-ynyl, phenyl, benzyl, (pyrazol-3-yl)methyl,
(pyrazol-4-yl)methyl, (1-methylpyrazol-4-yl)methyl,
(3-methylpyrazol-4-yl)methyl, 1-(pyrazol-4-yl)ethyl,
(pyridin-3-yl)methyl, pentanoyl, 2-methoxyacetyl,
but-3-ynylcarbonyl, or (pyrazol-4-yl)carbonyl; and R.sup.2b is
hydrogen, methyl, 2,2,2-trifluoroethyl, or (pyrazol-4-yl)methyl; or
R.sup.2a and R.sup.2b together with the N atom to which they are
attached form azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl,
morpholin-4-yl, pyrazol-1-yl, 3-methylpyrazol-1-yl,
4-methylpyrazol-1-yl, 5-methylpyrazol-1-yl, or imidazol-1-yl;
[0747] R.sup.2c and R.sup.2d are linked together to form methylene
or 1,2-ethylene;
[0748] R.sup.3 is t-butylmethyl, cyclopropylmethyl,
1-methylcyclopropylmethyl, 1-hydroxy(cyclopropylmethyl),
cyclobutylmethyl, or cyclopentylmethyl;
[0749] R.sup.4 is methyl, isopropyl, cyclopentyl, oxetan-3-yl,
tetrahydrofur-3-yl, tetrahydropyran-4-yl, or
tetrahydropyran-3-yl;
[0750] R.sup.6a, R.sup.6b, and R.sup.6d, if present, are each
independently hydrogen;
[0751] R.sup.6c, if present, is hydrogen, fluoro, chloro, methyl,
or trifluoromethyl; and
[0752] R.sup.7, if present, is hydrogen or methyl.
[0753] In still another embodiment, in any one of Formulae IIA to
XVIIIA and IIAb to XVIIIAb,
[0754] R and R.sup.5 are each hydrogen;
[0755] R.sup.2a is hydrogen, methyl, 2,2,2-trifluoroethyl,
2-methoxyethyl, pent-4-ynyl, pentanoyl, 2-methoxyacetyl, or
but-3-ynylcarbonyl; and R.sup.2b is hydrogen or methyl; or R.sup.2a
and R.sup.2b together with the N atom to which they are attached
form azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl,
morpholin-4-yl, pyrazol-1-yl, 3-methylpyrazol-1-yl,
4-methylpyrazol-1-yl, 5-methylpyrazol-1-yl, or imidazol-1-yl;
[0756] R.sup.2c and R.sup.2d are linked together to form methylene
or eth-1,2-ylene;
[0757] R.sup.3 is cyclopropylmethyl;
[0758] R.sup.4 is methyl;
[0759] R.sup.6a, R.sup.6b, and R.sup.6d, if present, are each
independently hydrogen;
[0760] R.sup.6c, if present, is hydrogen, fluoro, or chloro;
and
[0761] R.sup.7, if present, is hydrogen or methyl.
[0762] In one embodiment, provided herein is a compound of:
##STR00103##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or a prodrug thereof.
[0763] In another embodiment, provided herein is a compound of:
##STR00104##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or a prodrug thereof.
[0764] In yet another embodiment, provided herein is a compound
of:
##STR00105## ##STR00106## ##STR00107##
or a tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or a prodrug thereof.
[0765] The groups, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.6a,
R.sup.6b, R.sup.6a, R.sup.6d, U, V, W, X, Y, and Z, in formulae
described herein, including Formulae I to XIX, Formulae IIa to
XIXa, Formulae IA to XVIIIA, Formulae IAa to XVIIIAa, and Formulae
IAb to XVIIIAb, are further defined in the embodiments described
herein. All combinations of the embodiments provided herein for
such groups are within the scope of this disclosure.
[0766] In certain embodiments, R.sup.1 is hydrogen. In certain
embodiments, R.sup.1 is deuterium. In certain embodiments, R.sup.1
is C.sub.1-6 alkyl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.1 is methyl,
optionally substituted with one or more substituents Q. In certain
embodiments, R.sup.1 is C.sub.2-6 alkenyl, optionally substituted
with one or more substituents Q. In certain embodiments, R.sup.1 is
C.sub.2-6 alkynyl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.1 is C.sub.3-12
cycloalkyl, optionally substituted with one or more substituents Q.
In certain embodiments, R.sup.1 is C.sub.6-14 aryl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.1 is C.sub.7-15 aralkyl, optionally substituted
with one or more substituents Q. In certain embodiments, R.sup.1 is
heteroaryl, optionally substituted with one or more substituents Q.
In certain embodiments, R.sup.1 is heterocyclyl, optionally
substituted with one or more substituents Q.
[0767] In certain embodiments, R.sup.1 is --C(O)R.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.1 is
--C(O)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.1 is --C(O)NR.sup.1bR.sup.1c, wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.1 is --C(O)SR.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.1 is --C(NR.sup.1a)NR.sup.1bR.sup.1c,
wherein R.sup.1a, R.sup.1b, and R.sup.1c are each as defined
herein. In certain embodiments, R.sup.1 is --C(S)R.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.1 is
--C(S)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.1 is --C(S)NR.sup.1bR.sup.1c wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.1 is --OR.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.1 is --OC(O)R.sup.1awherein R.sup.1a is
as defined herein. In certain embodiments, R.sup.1 is
--OC(O)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.1 is --OC(O)NR.sup.1bR.sup.1c, wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.1 is --OC(O)SR.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.1 is
--OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, wherein R.sup.1a, R.sup.1b,
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.1 is --OC(S)R.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.1 is --OC(S)OR.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.1 is
--OC(S)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.1 is --OS(O)R.sup.1a,
wherein R.sup.1a is as defined herein. In certain embodiments,
R.sup.1 is --OS(O).sub.2R.sup.1a, wherein R.sup.1a is as defined
herein. In certain embodiments, R.sup.1 is
--OS(O)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.1 is
--OS(O).sub.2NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are
each as defined herein. In certain embodiments, R.sup.1 is
--NR.sup.1bR.sup.1c, wherein R band R.sup.1c are each as defined
herein. In certain embodiments, R.sup.1 is --NR.sup.1aC(O)R.sup.1d,
wherein R.sup.1a and R.sup.1d are each as defined herein. In
certain embodiments, R.sup.1 is --NR.sup.1aC(O)OR.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.1 is --NR.sup.1aC(O)NR.sup.1bR.sup.1c, wherein
R.sup.1a, R.sup.1b and R.sup.1c are each as defined herein. In
certain embodiments, R.sup.1 is --NR.sup.1aC(O)SR.sup.1d, wherein
R.sup.1a and R.sup.d are each as defined herein. In certain
embodiments, R.sup.1 is
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c, wherein R.sup.1a,
R.sup.1b, R.sup.1c, and R.sup.1d are each as defined herein. In
certain embodiments, R.sup.1 is --NR.sup.1aC(S)R.sup.1a wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.1 is --NR.sup.1aC(S)OR.sup.1d, wherein R.sup.1a
and R.sup.1d are each as defined herein. In certain embodiments,
R.sup.1 is --NR.sup.1aC(S)NR.sup.1bR.sup.1c, wherein R.sup.1a,
R.sup.1b, and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.1 is --NR.sup.1a S(O)R.sup.1d, wherein R.sup.1a
and R.sup.1d are each as defined herein. In certain embodiments,
R.sup.1 is --NR.sup.1aS(O).sub.2R.sup.1d, wherein R.sup.1a and
R.sup.1d are each as defined herein. In certain embodiments,
R.sup.1 is --NR.sup.1a S(O)NR.sup.1bR.sup.1c, wherein R.sup.1a,
R.sup.1b, and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.1 is NR.sup.1aS(O).sub.2NR.sup.1bR.sup.1c
wherein R.sup.1a, R.sup.1b, and R.sup.1c are each as defined
herein. In certain embodiments, R.sup.1 is --S(O)R.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.1 is
--S(O).sub.2R.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.1 is --S(O)NR.sup.1bR.sup.1c, wherein
R.sup.1b and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.1 is --S(O).sub.2NR.sup.1bR.sup.1c, wherein
R.sup.1b and R.sup.1c are each as defined herein.
[0768] In certain embodiments, R.sup.2 is hydrogen. In certain
embodiments, R.sup.2 is deuterium. In certain embodiments, R.sup.2
is C.sub.1-6 alkyl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.2 is methyl,
optionally substituted with one or more substituents Q. In certain
embodiments, R.sup.2 is C.sub.2-6 alkenyl, optionally substituted
with one or more substituents Q. In certain embodiments, R.sup.2 is
C.sub.2-6 alkynyl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.2 is C.sub.3-12
cycloalkyl, optionally substituted with one or more substituents Q.
In certain embodiments, R.sup.2 is C.sub.3-12 cycloalkyl,
optionally substituted with one or more substituents Q. In certain
embodiments, R.sup.2 is monocyclic C.sub.3-12 cycloalkyl,
optionally substituted with one or more substituents Q. In certain
embodiments, R.sup.2 is cyclobutyl, cyclopentyl, cyclohexyl, or
cycloheptyl, each optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.2 is cyclopentyl or
cyclohexyl, each optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.2 is cyclohexyl,
optionally substituted with one or more substituents Q. In certain
embodiments, R.sup.2 is bicyclic C.sub.3-12 cycloalkyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.2 is bicyclic C.sub.3-12 cycloalkyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.2 is bridged C.sub.3-12 cycloalkyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.2 is bicyclo[2.2.1]heptyl or
bicyclo[2.2.2]octyl, each optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.2 is cyclohexyl,
bicyclo[2.2.1]heptyl, or bicyclo[2.2.2]octyl, each of which is
substituted with one or two substituents, wherein each substituent
is independently C.sub.1-6 alkyl or NR.sup.1bR.sup.1c, where the
alkyl is optionally substituted with one or more substituents Q as
defined herein and R.sup.1b and R.sup.1c are each as defined
herein. In certain embodiments, R.sup.2 is C.sub.6-14 aryl,
optionally substituted with one or more substituents Q. In certain
embodiments, R.sup.2 is C.sub.7-15 aralkyl, optionally substituted
with one or more substituents Q. In certain embodiments, R.sup.2 is
heteroaryl, optionally substituted with one or more substituents Q.
In certain embodiments, R.sup.2 is heterocyclyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.2 is bicyclic heterocyclyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.2 is spiro heterocyclyl, optionally substituted
with one or more substituents Q. In certain embodiments, R.sup.2 is
4- to 6-membered heterocyclyl, optionally substituted with one or
more substituents Q.
[0769] In certain embodiments, R.sup.2 is --C(O)R.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.2 is
--C(O)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.2 is --C(O)NR.sup.1bR.sup.1c, wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.2 is --C(O)SR.sup.a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.2 is --C(NR.sup.1a)NR.sup.1bR.sup.1c,
wherein R.sup.1a, R.sup.1b and R.sup.1c are each as defined herein.
In certain embodiments, R.sup.2 is --C(S)R.sup.1a, wherein R.sup.1a
is as defined herein. In certain embodiments, R.sup.2 is
--C(S)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.2 is --C(S)NR.sup.1bR.sup.1c, wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.2 is --OR.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.2 is --OC(O)R.sup.1a, wherein R.sup.1a
is as defined herein. In certain embodiments, R.sup.2 is
--OC(O)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.2 is --OC(O)NR.sup.1bR.sup.1c, wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.2 is --OC(O)SR.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.2 is
--OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, wherein R.sup.1a, R.sup.1b,
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.2 is --OC(S)R.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.2 is --OC(S)OR.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.2 is
--OC(S)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.2 is --OS(O)R.sup.1a,
wherein R.sup.1a is as defined herein. In certain embodiments,
R.sup.2 is --OS(O).sub.2R.sup.1a, wherein R.sup.1a is as defined
herein. In certain embodiments, R.sup.2 is
--OS(O)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.2 is
--OS(O).sub.2NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are
each as defined herein. In certain embodiments, R.sup.2 is
--NR.sup.1bR.sup.1c, wherein R band R.sup.1c are each as defined
herein. In certain embodiments, R.sup.2 is --NR.sup.1aC(O)R.sup.1d,
wherein R.sup.1a and R.sup.1d are each as defined herein. In
certain embodiments, R.sup.2 is --NR.sup.1aC(O)OR.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.2 is --NR.sup.1aC(O)NR.sup.1bR.sup.1c, wherein
R.sup.1a, R.sup.1b and R.sup.1c are each as defined herein. In
certain embodiments, R.sup.2 is --NR.sup.1aC(O)SR.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.2 is
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c, wherein R.sup.1a,
R.sup.1b, R.sup.1c, and R.sup.1d are each as defined herein. In
certain embodiments, R.sup.2 is --NR.sup.1aC(S)R.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.2 is --NR.sup.1aC(S)OR.sup.1d wherein R.sup.1a
and R.sup.1d are each as defined herein. In certain embodiments,
R.sup.2 is --NR.sup.1aC(S)NR.sup.1bR.sup.1c, wherein R.sup.1a,
R.sup.1b, and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.2 is --NR.sup.1a S(O)R.sup.1d, wherein R.sup.1a
and R.sup.1d are each as defined herein. In certain embodiments,
R.sup.2 is --NR.sup.1aS(O).sub.2R.sup.1d, wherein R.sup.1a and
R.sup.1d are each as defined herein. In certain embodiments,
R.sup.2 is --NR.sup.1a S(O)NR.sup.1bR.sup.1c, wherein R.sup.1a,
R.sup.1b, and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.2 is NR.sup.1a S(O).sub.2NR.sup.1bR.sup.1c
wherein R.sup.1a, R.sup.1b, and R.sup.1c are each as defined
herein. In certain embodiments, R.sup.2 is --S(O)R.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.2 is
--S(O).sub.2R.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.2 is --S(O)NR.sup.1bR.sup.1c, wherein
R.sup.1b and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.2 is --S(O).sub.2N.sup.1bR.sup.1c wherein
R.sup.1b and R.sup.1c are each as defined herein.
[0770] In certain embodiments, R.sup.3 is hydrogen. In certain
embodiments, R.sup.3 is deuterium. In certain embodiments, R.sup.3
is cyano. In certain embodiments, R.sup.3 is halo. In certain
embodiments, R.sup.3 is fluoro. In certain embodiments, R.sup.3 is
chloro. In certain embodiments, R.sup.3 is nitro. In certain
embodiments, R.sup.3 is C.sub.1-6 alkyl, optionally substituted
with one or more substituents Q. In certain embodiments, R.sup.3 is
C.sub.3-12 cycloalkyl-C.sub.1-6 alkyl, where the alkyl and
cycloalkyl are each independently and optionally substituted with
one or more substituents Q. In certain embodiments, R.sup.3 is
t-butylmethyl, cyclopropylmethyl, 1-methylcyclopropylmethyl,
1-hydroxy(cyclopropylmethyl), cyclobutylmethyl, or
cyclopentylmethyl. In certain embodiments, R.sup.3 is
cyclopropylmethyl. In certain embodiments, R.sup.3 is C.sub.2-6
alkenyl, optionally substituted with one or more substituents Q. In
certain embodiments, R.sup.3 is C.sub.2-6 alkynyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.3 is C.sub.3-12 cycloalkyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.3 is cyclopentyl, optionally substituted with
one or more substituents Q. In certain embodiments, R.sup.3 is
C.sub.6-14 aryl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.3 is C.sub.7-15
aralkyl, optionally substituted with one or more substituents Q. In
certain embodiments, R.sup.3 is heteroaryl, optionally substituted
with one or more substituents Q. In certain embodiments, R.sup.3 is
heterocyclyl, optionally substituted with one or more substituents
Q.
[0771] In certain embodiments, R.sup.3 is --C(O)R.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.3 is
--C(O)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.3 is --C(O)NR.sup.1bR.sup.1c, wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.3 is --C(O)SR.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.3 is --C(NR.sup.1a)NR.sup.1bR.sup.1c,
wherein R.sup.1a, R.sup.1b and R.sup.1c are each as defined herein.
In certain embodiments, R.sup.3 is --C(S)R.sup.1a, wherein R.sup.1a
is as defined herein. In certain embodiments, R.sup.3 is
--C(S)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.3 is --C(S)NR.sup.1bR.sup.1c wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.3 is --OR.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.3 is --OC(O)R.sup.1a, wherein R.sup.1a
is as defined herein. In certain embodiments, R.sup.3 is
--OC(O)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.3 is --OC(O)NR.sup.1bR.sup.1c wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.3 is --OC(O)SR.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.3 is
--OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, wherein R.sup.1a, R.sup.1b,
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.3 is --OC(S)R.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.3 is --OC(S)OR.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.3 is
--OC(S)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.3 is --OS(O)R.sup.1a,
wherein R.sup.1a is as defined herein. In certain embodiments,
R.sup.3 is --OS(O).sub.2R.sup.1a, wherein R.sup.1a is as defined
herein. In certain embodiments, R.sup.3 is
--OS(O)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.3 is
--OS(O).sub.2NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are
each as defined herein. In certain embodiments, R.sup.3 is
--NR.sup.1bR.sup.1c, wherein R band R.sup.1c are each as defined
herein. In certain embodiments, R.sup.3 is --NR.sup.1aC(O)R.sup.1d,
wherein R.sup.1a and R.sup.1d are each as defined herein. In
certain embodiments, R.sup.3 is --NR.sup.1aC(O)OR.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.3 is --NR.sup.1aC(O)NR.sup.1bR.sup.1c, wherein
R.sup.1a, R.sup.1b and R.sup.1c are each as defined herein. In
certain embodiments, R.sup.3 is --NR.sup.1aC(O)SR.sup.1d, wherein
R.sup.1a and R.sup.d are each as defined herein. In certain
embodiments, R.sup.3 is
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c, wherein R.sup.1a,
R.sup.1b, R.sup.1c, and R.sup.1d are each as defined herein. In
certain embodiments, R.sup.3 is --NR.sup.1aC(S)R.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.3 is --NR.sup.1aC(S)OR.sup.1d, wherein R.sup.1a
and R.sup.1d are each as defined herein. In certain embodiments,
R.sup.3 is --NR.sup.1aC(S)NR.sup.1bR.sup.1c, wherein R.sup.1a,
R.sup.1b, and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.3 is --NR.sup.1a S(O)R.sup.1d, wherein R.sup.1a
and R.sup.1d are each as defined herein. In certain embodiments,
R.sup.3 is --NR.sup.1aS(O).sub.2R.sup.1d, wherein R.sup.1a and
R.sup.1d are each as defined herein. In certain embodiments,
R.sup.3 is --NR.sup.1a S(O)NR.sup.1bR.sup.1c, wherein R.sup.1a,
R.sup.1b, and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.3 is NR.sup.1aS(O).sub.2NR.sup.1bR.sup.1c
wherein R.sup.1a, R.sup.1b, and R.sup.1c are each as defined
herein. In certain embodiments, R.sup.3 is --SR.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.3 is
--S(O)R.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.3 is --S(O).sub.2R.sup.1a, wherein R.sup.1a is
as defined herein. In certain embodiments, R.sup.3 is
--S(O)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.3 is
--S(O).sub.2NR.sup.1bR.sup.1c, wherein R band R.sup.1c are each as
defined herein.
[0772] In certain embodiments, R.sup.4 is hydrogen. In certain
embodiments, R.sup.4 is deuterium. In certain embodiments, R.sup.4
is cyano. In certain embodiments, R.sup.4 is halo. In certain
embodiments, R.sup.4 is fluoro. In certain embodiments, R.sup.4 is
chloro. In certain embodiments, R.sup.4 is nitro. In certain
embodiments, R.sup.4 is C.sub.1-6 alkyl, optionally substituted
with one or more substituents Q. In certain embodiments, R.sup.4 is
methyl, ethyl, or propyl, each optionally substituted with one or
more substituents Q. In certain embodiments, R.sup.4 is methyl or
isopropyl, each optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.4 is C.sub.2-6
alkenyl, optionally substituted with one or more substituents Q. In
certain embodiments, R.sup.4 is C.sub.2-6 alkynyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.4 is C.sub.3-12 cycloalkyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.4 is C.sub.6-14 aryl, optionally substituted
with one or more substituents Q. In certain embodiments, R.sup.4 is
C.sub.7-15 aralkyl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.4 is heteroaryl,
optionally substituted with one or more substituents Q. In certain
embodiments, R.sup.4 is heterocyclyl, optionally substituted with
one or more substituents Q. In certain embodiments, R.sup.4 is 4-
to 6-membered heterocyclyl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.4 is oxetanyl,
tetrahydrofuryl, or tetrahydropyranyl, each optionally substituted
with one or more substituents Q.
[0773] In certain embodiments, R.sup.4 is --C(O)R.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.4 is
--C(O)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.4 is --C(O)NR.sup.fR.sup.g, wherein R.sup.1b and
R.sup.1c are each as defined herein. In certain embodiments,
R.sup.4 is --C(O)SR.sup.a, wherein R.sup.1 is as defined herein. In
certain embodiments, R.sup.4 is --C(NR.sup.1a)NR.sup.1bR.sup.1c,
wherein R.sup.1a, R.sup.1b and R.sup.1c are each as defined herein.
In certain embodiments, R.sup.4 is --C(S)R.sup.1a, wherein R.sup.1a
is as defined herein. In certain embodiments, R.sup.4 is
--C(S)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.4 is --C(S)NR.sup.1bR.sup.1c wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.4 is --OR.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.4 is --OH. In certain embodiments,
R.sup.4 is --OC(O)R.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.4 is --OC(O)OR.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.4 is
--OC(O)NR.sup.1bR.sup.1c wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.4 is
--OC(O)SR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.4 is --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
wherein R.sup.1a, R.sup.1b, R.sup.1c are each as defined herein. In
certain embodiments, R.sup.4 is --OC(S)R.sup.1a, wherein R.sup.1a
is as defined herein. In certain embodiments, R.sup.4 is
--OC(S)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.4 is --OC(S)NR.sup.1bR.sup.1c, wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.4 is --OS(O)R.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.4 is --OS(O).sub.2R.sup.1a wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.4 is
--OS(O)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.4 is
--OS(O).sub.2NR.sup.1bR.sup.1c wherein R.sup.1b and R.sup.1c are
each as defined herein. In certain embodiments, R.sup.4 is
--NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.4 is --NH.sub.2. In
certain embodiments, R.sup.4 is --NR.sup.1aC(O)R.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.4 is --NR.sup.1aC(O)OR.sup.1d, wherein R.sup.1a
and R.sup.1d are each as defined herein. In certain embodiments,
R.sup.4 is --NR.sup.1aC(O)NR.sup.1bR.sup.1c, wherein R.sup.1a,
R.sup.1b and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.4 is --NR.sup.1aC(O)SR.sup.1d, wherein R.sup.1a
and R.sup.1d are each as defined herein. In certain embodiments,
R.sup.4 is --NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c, wherein
R.sup.1a, R.sup.1bR.sup.1c, and R.sup.1d are each as defined
herein. In certain embodiments, R.sup.4 is --NR.sup.1aC(S)R.sup.1d,
wherein R.sup.1a and R.sup.1d are each as defined herein. In
certain embodiments, R.sup.4 is --NR.sup.1aC(S)OR.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.4 is --NR.sup.1aC(S)NR.sup.1bR.sup.1c, wherein
R.sup.1a, R.sup.1b, and R.sup.1c are each as defined herein. In
certain embodiments, R.sup.4 is --NR.sup.1a S(O)R.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.4 is --NR.sup.1aS(O).sub.2R.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.4 is --NR.sup.1a S(O)NR.sup.1bR.sup.1c, wherein
R.sup.1a, R.sup.1b, and R.sup.1c are each as defined herein. In
certain embodiments, R.sup.4 is NR.sup.1a
S(O).sub.2NR.sup.1bR.sup.1c wherein R.sup.1a, R.sup.1b, and
R.sup.1c are each as defined herein. In certain embodiments,
R.sup.4 is --SR.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.4 is --S(O)R.sup.1a, wherein R.sup.1a is
as defined herein. In certain embodiments, R.sup.4 is
--S(O).sub.2R.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.4 is --S(O)NR.sup.1bR.sup.1c, wherein
R.sup.1b and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.4 is --S(O).sub.2NR.sup.1bR.sup.1c, wherein
R.sup.1b and R.sup.1c are each as defined herein.
[0774] In certain embodiments, R.sup.5 is hydrogen. In certain
embodiments, R.sup.5 is deuterium. In certain embodiments, R.sup.5
is C.sub.1-6 alkyl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.5 is methyl, ethyl,
or propyl, each optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.5 is methyl or
isopropyl, each optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.5 is C.sub.2-6
alkenyl, optionally substituted with one or more substituents Q. In
certain embodiments, R.sup.5 is C.sub.2-6 alkynyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.5 is C.sub.3-12 cycloalkyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.5 is cyclopentyl, optionally substituted with
one or more substituents Q. In certain embodiments, R.sup.5 is
C.sub.6-14 aryl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.5 is C.sub.7-15
aralkyl, optionally substituted with one or more substituents Q. In
certain embodiments, R.sup.5 is heteroaryl, optionally substituted
with one or more substituents Q. In certain embodiments, R.sup.5 is
heterocyclyl, optionally substituted with one or more substituents
Q. In certain embodiments, R.sup.5 is 4- to 6-membered
heterocyclyl, optionally substituted with one or more substituents
Q. In certain embodiments, R.sup.5 is oxetanyl, tetrahydrofuryl, or
tetrahydropyranyl, each optionally substituted with one or more
substituents Q.
[0775] In certain embodiments, R.sup.5 is --C(O)R.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.5 is
--C(O)OR.sup.1a, wherein R.sup.1 is as defined herein. In certain
embodiments, R.sup.5 is --C(O)NR.sup.fR.sup.g, wherein R.sup.1b and
R.sup.1c are each as defined herein. In certain embodiments,
R.sup.5 is --C(O)SR.sup.a, wherein R.sup.1 is as defined herein. In
certain embodiments, R.sup.5 is --C(NR.sup.a)NR.sup.1bR.sup.1c,
wherein R.sup.1a, R.sup.1b and R.sup.1c are each as defined herein.
In certain embodiments, R.sup.5 is --C(S)R.sup.1a, wherein R.sup.1a
is as defined herein. In certain embodiments, R.sup.5 is
--C(S)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.5 is --C(S)NR.sup.1bR.sup.1c wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.5 is --OR.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.5 is --OC(O)R.sup.1a wherein R.sup.1a is
as defined herein. In certain embodiments, R.sup.5 is
--OC(O)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.5 is --OC(O)NR.sup.1bR.sup.1c wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.5 is --OC(O)SR.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.5 is
--OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, wherein R.sup.1a, R.sup.1b,
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.5 is --OC(S)R.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.5 is --OC(S)OR.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.5 is
--OC(S)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.5 is --OS(O)R.sup.1a,
wherein R.sup.1a is as defined herein. In certain embodiments,
R.sup.5 is --OS(O).sub.2R.sup.1a, wherein R.sup.1a is as defined
herein. In certain embodiments, R.sup.5 is
--OS(O)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.5 is
--OS(O).sub.2NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are
each as defined herein. In certain embodiments, R.sup.5 is
--NR.sup.1bR.sup.1c, wherein R band R.sup.1c are each as defined
herein. In certain embodiments, R.sup.5 is --NR.sup.1aC(O)R.sup.1d,
wherein R.sup.1a and R.sup.1d are each as defined herein. In
certain embodiments, R.sup.5 is --NR.sup.1aC(O)OR.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.5 is --NR.sup.1aC(O)NR.sup.1bR.sup.1c, wherein
R.sup.1a, R.sup.1b and R.sup.1c are each as defined herein. In
certain embodiments, R.sup.5 is --NR.sup.1aC(O)SR.sup.1d, wherein
R.sup.1a and R.sup.d are each as defined herein. In certain
embodiments, R.sup.5 is
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c, wherein R.sup.1a,
R.sup.1b, R.sup.1c, and R.sup.1d are each as defined herein. In
certain embodiments, R.sup.5 is --NR.sup.1aC(S)R.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.5 is --NR.sup.1aC(S)OR.sup.1d, wherein R.sup.1a
and R.sup.1d are each as defined herein. In certain embodiments, R
is --NR.sup.1aC(S)NR.sup.1bR.sup.1c, wherein R.sup.1a, R.sup.1b,
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.5 is --NR.sup.1a S(O)R.sup.1d, wherein R.sup.1a and R.sup.1d
are each as defined herein. In certain embodiments, R.sup.5 is
--NR.sup.1a S(O).sub.2R.sup.1d, wherein R.sup.1a and R.sup.1d are
each as defined herein. In certain embodiments, R.sup.5 is
--NR.sup.1a S(O)NR.sup.1bR.sup.1c, wherein R.sup.1a, R.sup.1b, and
R.sup.1c are each as defined herein. In certain embodiments,
R.sup.5 is NR.sup.1aS(O).sub.2NR.sup.1bR.sup.1c, wherein R.sup.1a,
R.sup.1b, and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.5 is --S(O)R.sup.1a, wherein R.sup.1a is as
defined herein. In certain embodiments, R.sup.5 is
--S(O).sub.2R.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.5 is --S(O)NR.sup.1bR.sup.1c, wherein
R.sup.1b and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.5 is --S(O).sub.2N.sup.1bR.sup.1c wherein
R.sup.1b and R.sup.1c are each as defined herein.
[0776] In certain embodiments, R.sup.6 is hydrogen. In certain
embodiments, R.sup.6 is deuterium. In certain embodiments, R.sup.6
is cyano. In certain embodiments, R.sup.6 is halo. In certain
embodiments, R.sup.6 is fluoro. In certain embodiments, R.sup.6 is
chloro. In certain embodiments, R.sup.6 is nitro. In certain
embodiments, R.sup.6 is C.sub.1-6 alkyl, optionally substituted
with one or more substituents Q. In certain embodiments, R.sup.6 is
methyl, optionally substituted with one or more substituents Q. In
certain embodiments, R.sup.6 is methyl or trifluoromethyl. In
certain embodiments, R.sup.6 is C.sub.2-6 alkenyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.6 is C.sub.2-6 alkynyl, optionally substituted
with one or more substituents Q. In certain embodiments, R.sup.6 is
C.sub.3-12 cycloalkyl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.6 is C.sub.6-14 aryl,
optionally substituted with one or more substituents Q. In certain
embodiments, R.sup.6 is C.sub.7-15 aralkyl, optionally substitute
with one or more substituents Q. In certain embodiments, R.sup.6 is
heteroaryl, optionally substituted with one or more substituents Q.
In certain embodiments, R.sup.6 is heterocyclyl substituted with
one or more substituents Q. In certain embodiments, R.sup.6 is 4-
to 6-membered heterocyclyl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.6 is oxetanyl,
tetrahydrofuryl, or tetrahydropyranyl, each optionally substituted
with one or more substituents Q.
[0777] In certain embodiments, R.sup.6 is --C(O)R.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.6 is
--C(O)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.6 is --C(O)NR.sup.1bR.sup.1c, wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.6 is --C(O)SR.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.6 is --C(NR.sup.1a)NR.sup.1bR.sup.1c,
wherein R.sup.1a, R.sup.1b, and R.sup.1c are each as defined
herein. In certain embodiments, R.sup.6 is --C(S)R.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.6 is
--C(S)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.6 is --C(S)NR.sup.1bR.sup.1c, wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.6 is --OR.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.6 is --OH. In certain embodiments,
R.sup.6 is --OC(O)R.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.6 is --OC(O)OR.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.6 is
--OC(O)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.6 is
--OC(O)SR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.6 is --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
wherein R.sup.1a, R.sup.1b and R.sup.1c are each as defined herein.
In certain embodiments, R.sup.6 is --OC(S)R.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.6 is
--OC(S)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.6 is --OC(S)NR.sup.1bR.sup.1c wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.6 is --OS(O)R.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.6 is --OS(O).sub.2R.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.6 is
--OS(O)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.6 is
--OS(O).sub.2NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are
each as defined herein. In certain embodiments, R.sup.6 is
--NR.sup.1bR.sup.1c wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.6 is --NH.sub.2. In
certain embodiments, R.sup.6 is --NR.sup.1aC(O)R.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.6 is --NR.sup.1aC(O)OR.sup.1d, wherein R.sup.1a
and R.sup.1d are each as defined herein. In certain embodiments,
R.sup.6 is --NR.sup.1aC(O)NR.sup.1bR.sup.1c, wherein R.sup.1a,
R.sup.1b and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.6 is --NR.sup.1aC(O)SR.sup.1d, wherein R.sup.1a
and R.sup.1d are each as defined herein. In certain embodiments,
R.sup.6 is --NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c, wherein
R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d are each as defined
herein. In certain embodiments, R.sup.6 is --NR.sup.1aC(S)R.sup.1a,
wherein R.sup.1a and R.sup.1d are each as defined herein. In
certain embodiments, R.sup.6 is --NR.sup.1aC(S)OR.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.6 is --NR.sup.1aC(S)NR.sup.1bR.sup.1c, wherein
R.sup.1a, R.sup.1b, and R.sup.1c are each as defined herein. In
certain embodiments, R.sup.6 is --NR.sup.1a S(O)R.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.1 is --NR.sup.1a S(O).sub.2R.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.6 is --NR.sup.1aS(O)NR.sup.1bR.sup.1c, wherein
R.sup.1a, R.sup.1b, and R.sup.1c are each as defined herein. In
certain embodiments, R.sup.6 is --NR.sup.1a
S(O).sub.2NR.sup.1bR.sup.1c, wherein R.sup.1a, R and R are each as
defined herein. In certain embodiments, R.sup.6 is --SR.sup.1a,
wherein R.sup.1a is as defined herein. In certain embodiments,
R.sup.1 is --S(O)R.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.6 is --S(O).sub.2R.sup.1a, wherein
R.sup.6 is as defined herein. In certain embodiments, R is
--S(O)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.6 is
--S(O).sub.2NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are
each as defined herein.
[0778] In certain embodiments, R.sup.7 is hydrogen. In certain
embodiments, R.sup.7 is deuterium. In certain embodiments, R.sup.7
is C.sub.1-6 alkyl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.7 is methyl,
optionally substituted with one or more substituents Q. In certain
embodiments, R.sup.7 is C.sub.2-6 alkenyl, optionally substituted
with one or more substituents Q. In certain embodiments, R.sup.7 is
C.sub.2-6 alkynyl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.7 is C.sub.3-12
cycloalkyl, optionally substituted with one or more substituents Q.
In certain embodiments, R.sup.7 is cyclopentyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.7 is C.sub.6-14 aryl, optionally substituted
with one or more substituents Q. In certain embodiments, R.sup.7 is
C.sub.7-15 aralkyl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.7 is heteroaryl,
optionally substituted with one or more substituents Q. In certain
embodiments, R.sup.7 is heterocyclyl, optionally substituted with
one or more substituents Q. In certain embodiments, R.sup.7 is 4-
to 6-membered heterocyclyl, optionally substituted with one or more
substituents Q.
[0779] In certain embodiments, R.sup.7 is --C(O)R.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.7 is
--C(O)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.7 is --C(O)NR.sup.fR.sup.g, wherein R.sup.1b and
R.sup.1c are each as defined herein. In certain embodiments,
R.sup.7 is --C(O)SR.sup.1a, wherein R.sup.1 is as defined herein.
In certain embodiments, R.sup.7 is --C(NR.sup.1a)NR.sup.1bR.sup.1c,
wherein R.sup.1a, R.sup.1b and R.sup.1c are each as defined herein.
In certain embodiments, R.sup.7 is --C(S)R.sup.1a, wherein R.sup.1a
is as defined herein. In certain embodiments, R.sup.7 is
--C(S)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.7 is --C(S)NR.sup.1bR.sup.1c wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.7 is --OR.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.7 is --OC(O)R.sup.1a, wherein R.sup.1a
is as defined herein. In certain embodiments, R.sup.7 is
--OC(O)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.7 is --OC(O)NR.sup.1bR.sup.1c, wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.7 is --OC(O)SR.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.7 is
--OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, wherein R.sup.1a, R.sup.1b,
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.7 is --OC(S)R.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.7 is --OC(S)OR.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.7 is
--OC(S)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.7 is --OS(O)R.sup.1a,
wherein R.sup.1a is as defined herein. In certain embodiments,
R.sup.7 is --OS(O).sub.2R.sup.1a, wherein R.sup.1a is as defined
herein. In certain embodiments, R.sup.7 is
--OS(O)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.7 is
--OS(O).sub.2NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are
each as defined herein. In certain embodiments, R.sup.7 is
--NR.sup.1bR.sup.1c, wherein R band R.sup.1c are each as defined
herein. In certain embodiments, R.sup.7 is --NR.sup.1aC(O)R.sup.1d,
wherein R.sup.1a and R.sup.1d are each as defined herein. In
certain embodiments, R.sup.7 is --NR.sup.1aC(O)OR.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.7 is --NR.sup.1aC(O)NR.sup.1bR.sup.1c, wherein
R.sup.1a, R.sup.1b and R.sup.1c are each as defined herein. In
certain embodiments, R.sup.7 is --NR.sup.1c (O)SR.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.7 is
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c wherein R.sup.1a,
R.sup.1b, R.sup.1c, and R.sup.1d are each as defined herein. In
certain embodiments, R.sup.7 is --NR.sup.1aC(S)R.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.7 is --NR.sup.1aC(S)OR.sup.1d, wherein R.sup.1a
and R.sup.1d are each as defined herein. In certain embodiments,
R.sup.7 is --NR.sup.1aC(S)NR.sup.1bR.sup.1c, wherein R.sup.1a,
R.sup.1b, and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.7 is --NR.sup.1a S(O)R.sup.1d, wherein R.sup.1a
and R.sup.1d are each as defined herein. In certain embodiments,
R.sup.7 is --NR.sup.1a S(O).sub.2R.sup.1d, wherein R.sup.1a and
R.sup.1d are each as defined herein. In certain embodiments,
R.sup.7 is --NR.sup.1a S(O)NR.sup.1bR.sup.1c, wherein R.sup.1a,
R.sup.1b, and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.7 is NR.sup.1a S(O).sub.2NR.sup.1bR.sup.1c
wherein R.sup.1a, R.sup.1b, and R.sup.1c are each as defined
herein. In certain embodiments, R.sup.7 is --S(O)R.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.7 is
--S(O).sub.2R.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.7 is --S(O)NR.sup.1bR.sup.1c, wherein
R.sup.1b and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.7 is --S(O).sub.2NR.sup.1bR.sup.1c wherein
R.sup.1b and R.sup.1c are each as defined herein.
[0780] In certain embodiments, R.sup.2a is hydrogen. In certain
embodiments, R.sup.2a is deuterium. In certain embodiments,
R.sup.2a is C.sub.1-6 alkyl, optionally substituted with one or
more substituents Q. In certain embodiments, R.sup.2a is methyl or
ethyl, each optionally substituted with one or more substituents Q.
In certain embodiments, R.sup.2a is methyl, 2,2,2-trifluoroethyl,
or 2-methoxyethyl. In certain embodiments, R.sup.2a is
heteroaryl-C.sub.1-6 alkyl, where the alkyl and heteroaryl are each
optionally substituted with one or more substituents Q. In certain
embodiments, R.sup.2a is 5-membered heteroaryl-C.sub.1-6 alkyl,
where the alkyl and heteroaryl are each optionally substituted with
one or more substituents Q. In certain embodiments, R.sup.2a is
6-membered heteroaryl-C.sub.1-6 alkyl, where the alkyl and
heteroaryl are each optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.2a is
(pyrazol-3-yl)methyl, (pyrazol-4-yl)methyl,
(1-methylpyrazol-4-yl)methyl, (3-methylpyrazol-4-yl)methyl,
1-(pyrazol-4-yl)ethyl, or (pyridin-3-yl)methyl. In certain
embodiments, R.sup.2a is C.sub.2-6 alkenyl, optionally substituted
with one or more substituents Q. In certain embodiments, R.sup.2a
is C.sub.2-6 alkynyl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.2a is pent-4-ynyl. In
certain embodiments, R.sup.2a is C.sub.3-12 cycloalkyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.2a is C.sub.6-14 aryl, optionally substituted
with one or more substituents Q. In certain embodiments, R.sup.2a
is phenyl, optionally substituted with one or more substituents Q.
In certain embodiments, R.sup.2a is C.sub.7-15 aralkyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.2a is benzyl, optionally substituted with one or
more substituents Q. In certain embodiments, R.sup.2a is
heteroaryl, optionally substituted with one or more substituents Q.
In certain embodiments, R.sup.2a is heterocyclyl, optionally
substituted with one or more substituents Q.
[0781] In certain embodiments, R.sup.2a is --C(O)R.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.2a is
--C(O)R.sup.1a, wherein R.sup.1a is C.sub.1-6 alkyl, C.sub.2-6
alkyl, C.sub.2-6 alkynyl, or heteroaryl, each of which is
optionally substituted with one or more substituents Q. In certain
embodiments, R.sup.2a is 2-methoxyacetyl, pentanoyl,
but-3-ynylcarbonyl, or (pyrazol-4-yl)carbonyl. In certain
embodiments, R.sup.2a is --C(O)OR.sup.1a, wherein R.sup.1a is as
defined herein. In certain embodiments, R.sup.2a is
--C(O)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.2a is
--C(O)SR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.2a is --C(NR.sup.1a)NR.sup.1bR.sup.1c, wherein
R.sup.1a, R.sup.1b, and R.sup.1c are each as defined herein. In
certain embodiments, R.sup.2a is --C(S)R.sup.1a, wherein R.sup.1a
is as defined herein. In certain embodiments, R.sup.2a is
--C(S)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.2a is --C(S)NR.sup.1bR.sup.1c, wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.2a is --OR.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.2a is --OC(O)R.sup.1a wherein R.sup.1a
is as defined herein. In certain embodiments, R.sup.2a is
--OC(O)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.2a is --OC(O)NR.sup.1bR.sup.1c, wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.2a is --OC(O)SR.sup.1a, wherein R.sup.1a is as defined
herein. In certain embodiments, R.sup.2a is
--OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, wherein R.sup.1a, R.sup.1b,
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.2a is --OC(S)R.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.2a is --OC(S)OR.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.2a is
--OC(S)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.2a is
--OS(O)R.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.2a is --OS(O).sub.2R.sup.1a, wherein R.sup.1a is
as defined herein. In certain embodiments, R.sup.2a is
--OS(O)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.2a is
--OS(O).sub.2NR.sup.1bR.sup.1c wherein R.sup.1b and R.sup.1c are
each as defined herein. In certain embodiments, R.sup.2a is
--NR.sup.1bR.sup.1c wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.2a is
--NR.sup.1aC(O)R.sup.1d, wherein R.sup.1a and R.sup.1d are each as
defined herein. In certain embodiments, R.sup.2a is
--NR.sup.1aC(O)OR.sup.1d, wherein R.sup.1a and R.sup.1d are each as
defined herein. In certain embodiments, R.sup.2a is
--NR.sup.1aC(O)NR.sup.1bR.sup.1c wherein R.sup.1a, R.sup.1b, and
R.sup.1c are each as defined herein. In certain embodiments,
R.sup.2a is --NR.sup.1aC(O)SR.sup.1d, wherein R.sup.1a and R.sup.1d
are each as defined herein. In certain embodiments, R.sup.2a is
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c, wherein R.sup.1a,
R.sup.1b, R.sup.1c, and R.sup.1d are each as defined herein. In
certain embodiments, R.sup.2a is --NR.sup.1aC(S)R.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.2a is --NR.sup.1aC(S)OR.sup.1d, wherein R.sup.1a
and R.sup.1d are each as defined herein. In certain embodiments,
R.sup.2a is --NR.sup.1aC(S)NR.sup.1bR.sup.1c, wherein R.sup.1a,
R.sup.1b and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.2a is --NR.sup.1a S(O)R.sup.1d, wherein R.sup.1a
and R.sup.1d are each as defined herein. In certain embodiments,
R.sup.2a is --NR.sup.1a S(O).sub.2R.sup.1d, wherein R.sup.1a and
R.sup.1d are each as defined herein. In certain embodiments,
R.sup.2a is --NR.sup.1a S(O)NR.sup.1bR.sup.1c, wherein R.sup.1a,
R.sup.1b, and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.2a is --NR.sup.1a S(O).sub.2NR.sup.1bR.sup.1c,
wherein R.sup.1a, R.sup.1b, and R.sup.1c are each as defined
herein. In certain embodiments, R.sup.2a is --S(O)R.sup.1a, wherein
R.sup.1a is as defined herein embodiments, R.sup.2a is
--S(O).sub.2R.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.2a is --S(O)NR.sup.1bR.sup.1c, wherein
R.sup.1b and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.2a is --S(O).sub.2NR.sup.1bR.sup.1c, wherein
R.sup.1b and R.sup.1c are each as defined herein.
[0782] In certain embodiments, R.sup.2b is hydrogen. In certain
embodiments, R.sup.2b is deuterium. In certain embodiments,
R.sup.2b is C.sub.1-6 alkyl, optionally substituted with one or
more substituents Q. In certain embodiments, R.sup.2b is methyl or
ethyl, each optionally substituted with one or more substituents Q.
In certain embodiments, R.sup.2b is methyl, 2,2,2-trifluoroethyl,
or 2-methoxyethyl. In certain embodiments, R.sup.2b is
heteroaryl-C.sub.1-6 alkyl, where the alkyl and heteroaryl are each
optionally substituted with one or more substituents Q. In certain
embodiments, R.sup.2b is 5-membered heteroaryl-C.sub.1-6 alkyl,
where the alkyl and heteroaryl are each optionally substituted with
one or more substituents Q. In certain embodiments, R.sup.2b is
6-membered heteroaryl-C.sub.1-6 alkyl, where the alkyl and
heteroaryl are each optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.2b is
(pyrazol-3-yl)methyl, (pyrazol-4-yl)methyl,
(1-methylpyrazol-4-yl)methyl, (3-methylpyrazol-4-yl)methyl,
1-(pyrazol-4-yl)ethyl, or (pyridin-3-yl)methyl. In certain
embodiments, R.sup.2b is C.sub.2-6 alkenyl, optionally substituted
with one or more substituents Q. In certain embodiments, R.sup.2b
is C.sub.2-6 alkynyl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.2b is pent-4-ynyl. In
certain embodiments, R.sup.2b is C.sub.3-12 cycloalkyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.2b is C.sub.6-14 aryl, optionally substituted
with one or more substituents Q. In certain embodiments, R.sup.2b
is phenyl, optionally substituted with one or more substituents Q.
In certain embodiments, R.sup.2b is C.sub.7-15 aralkyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.2b is benzyl, optionally substituted with one or
more substituents Q. In certain embodiments, R.sup.2b is
heteroaryl, optionally substituted with one or more substituents Q.
In certain embodiments, R.sup.2b is heterocyclyl, optionally
substituted with one or more substituents Q.
[0783] In certain embodiments, R.sup.2b is --C(O)R.sup.1a, wherein
R.sup.6 is as defined herein. In certain embodiments, R.sup.2b is
--C(O)R.sup.1a, wherein R.sup.1a is C.sub.1-6 alkyl, C.sub.2-6
alkyl, C.sub.2-6 alkynyl, or heteroaryl, each of which is
optionally substituted with one or more substituents Q. In certain
embodiments, R.sup.2b is 2-methoxyacetyl, pentanoyl,
but-3-ynylcarbonyl, or (pyrazol-4-yl)carbonyl. In certain
embodiments, R.sup.2b is --C(O)OR.sup.1a, wherein R.sup.1a is as
defined herein. In certain embodiments, R.sup.2b is
--C(O)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.2b is
--C(O)SR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.2b is --C(NR.sup.1a)NR.sup.1bR.sup.1c, wherein
R.sup.1a, R.sup.1b and R.sup.1c are each as defined herein. In
certain embodiments, R.sup.2b is --C(S)R.sup.1a, wherein R.sup.1a
is as defined herein. In certain embodiments, R.sup.2b is
--C(S)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.2b is --C(S)NR.sup.1bR.sup.1c, wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.2b is --OR.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.2b is --OC(O)R.sup.1a wherein R.sup.1a
is as defined herein. In certain embodiments, R.sup.2b is
--OC(O)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.2b is --OC(O)NR.sup.1bR.sup.1c, wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.2b is --OC(O)SR.sup.1a, wherein R.sup.1a is as defined
herein. In certain embodiments, R.sup.2b is
--OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, wherein R.sup.1a, R.sup.1b,
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.2b is --OC(S)R.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.2b is --OC(S)OR.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.2b is
--OC(S)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.2b is
--OS(O)R.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.2b is --OS(O).sub.2R.sup.1a, wherein R.sup.1a is
as defined herein. In certain embodiments, R.sup.2b is
--OS(O)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.2b is
--OS(O).sub.2NR.sup.1bR.sup.1c wherein R.sup.1b and R.sup.1c are
each as defined herein. In certain embodiments, R.sup.2b is
--NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.2b is
--NR.sup.1aC(O)R.sup.1d, wherein R.sup.1a and R.sup.1d are each as
defined herein. In certain embodiments, R.sup.2b is
--NR.sup.1aC(O)OR.sup.1d, wherein R.sup.1a and R.sup.1d are each as
defined herein. In certain embodiments, R.sup.2b is
--NR.sup.1aC(O)NR.sup.1bR.sup.1c, wherein R.sup.1a, R.sup.1b, and
R.sup.1c are each as defined herein. In certain embodiments,
R.sup.2b is --NR.sup.1aC(O)SR.sup.1d, wherein R.sup.1a and R.sup.1d
are each as defined herein. In certain embodiments, R.sup.2b is
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bNR.sup.1c, wherein R.sup.1a,
R.sup.1b, R.sup.1c and R.sup.1d are each as defined herein. In
certain embodiments, R.sup.2b is --NR.sup.1aC(S)R.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.2b is --NR.sup.1aC(S)OR.sup.1d, wherein R.sup.1a
and R.sup.1d are each as defined herein. In certain embodiments,
R.sup.2b is --NR.sup.1aC(S)NR.sup.1bR.sup.1c wherein R.sup.1a,
R.sup.1b, and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.2b is --NR.sup.1aS(O)R.sup.1d, wherein R.sup.1a
and R.sup.1d are each as defined herein. In certain embodiments,
R.sup.2b is --NR.sup.1a S(O).sub.2R.sup.1d, wherein R.sup.1a and
R.sup.1d are each as defined herein. In certain embodiments,
R.sup.2b is --NR.sup.1a S(O)NR.sup.1bR.sup.1c, wherein R.sup.1a,
R.sup.1b, and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.2b is NR.sup.1a S(O).sub.2NR.sup.1bR.sup.1c,
wherein R.sup.1a, R.sup.1b, and R.sup.1c are each as defined
herein. In certain embodiments, R.sup.2b is --S(O)R.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.2b is
--S(O).sub.2R.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.2b is --S(O)NR.sup.1bR.sup.1c wherein
R.sup.1b and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.2b is --S(O).sub.2NR.sup.1bR.sup.1c, wherein
R.sup.1b and R.sup.1c are each as defined herein.
[0784] In certain embodiments, R.sup.2a and R.sup.2b together with
the N atom to which they are attached form heteroaryl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.2a and R.sup.2b together with the N atom to
which they are attached form 5-membered heteroaryl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.2a and R.sup.2b together with the N atom to
which they are attached form heterocyclyl, optionally substituted
with one or more substituents Q. In certain embodiments, R.sup.2a
and R.sup.2b together with the N atom to which they are attached
form 5-membered heterocyclyl, optionally substituted with one or
more substituents Q. In certain embodiments, R.sup.2a and R.sup.2b
together with the N atom to which they are attached form
azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrazolyl, or
imidazolyl, each of which is independently and optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.2a and R.sup.2b together with the N atom to
which they are attached form azetidin-1-yl, pyrrolidin-1-yl,
piperidine-1-yl, morpholin-4-yl, pyrazol-1-yl,
3-methylpyrazol-1-yl, 4-methylpyrazol-1-yl, 5-methylpyrazol-1-yl,
or imidazol-1-yl.
[0785] In certain embodiments, R.sup.2c is hydrogen. In certain
embodiments, R.sup.2c is deuterium. In certain embodiments,
R.sup.2c is cyano. In certain embodiments, R.sup.2c is C.sub.1-6
alkyl, optionally substituted with one or more substituents Q. In
certain embodiments, R.sup.2c is methyl, optionally substituted
with one or more substituents Q. In certain embodiments, R.sup.2c
is methyl or hydroxymethyl. In certain embodiments, R.sup.2c is
C.sub.2-6 alkenyl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.2c is C.sub.2-6
alkynyl, optionally substituted with one or more substituents Q. In
certain embodiments, R.sup.2c is C.sub.3-12 cycloalkyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.2c is C.sub.6-14 aryl, optionally substituted
with one or more substituents Q. In certain embodiments, R.sup.2c
is C.sub.7-15 aralkyl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.2c is heteroaryl,
optionally substituted with one or more substituents Q. In certain
embodiments, R.sup.2c is heterocyclyl, optionally substituted with
one or more substituents Q.
[0786] In certain embodiments, R.sup.2a and R.sup.2c together with
the C and N atoms to which they are attached form heterocyclyl,
optionally substituted with one or more substituents Q. In certain
embodiments, R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form 5-membered heterocyclyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.2a and R.sup.2c together with the C and N atoms
to which they are attached form pyrrolidin-5,5-ylene-2-one,
imidazolidin-5,5-ylene-2,4-dione, or
oxazolidin-4,4-ylene-2-one.
[0787] In certain embodiments, R.sup.2d is hydrogen. In certain
embodiments, R.sup.2d is deuterium. In certain embodiments,
R.sup.2d is cyano. In certain embodiments, R.sup.2d is C.sub.1-6
alkyl, optionally substituted with one or more substituents Q. In
certain embodiments, R.sup.2d is C.sub.2-6 alkenyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.2d is C.sub.2-6 alkynyl, optionally substituted
with one or more substituents Q. In certain embodiments, R.sup.2d
is C.sub.3-12 cycloalkyl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.2d is C.sub.6-14
aryl, optionally substituted with one or more substituents Q. In
certain embodiments, R.sup.2d is C.sub.7-15 aralkyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.2d is heteroaryl, optionally substituted with
one or more substituents Q. In certain embodiments, R.sup.2d is
heterocyclyl, optionally substituted with one or more substituents
Q.
[0788] In certain embodiments, R.sup.2c and R.sup.2d are linked
together to form --O--. In certain embodiments, R.sup.2c and
R.sup.2d are linked together to form C.sub.1-6 alkylene, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.2c and R.sup.2d are linked together to form
methylene or ethylene, each optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.2c and R.sup.2d are
linked together to form methylene or eth-1,2-ylene, each optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.2c and R.sup.2d are linked together to form
C.sub.1-6 heteroalkylene, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.2c and R.sup.2d are
linked together to form C.sub.2-6 alkenylene, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.2c and R.sup.2d are linked together to form
C.sub.2-6 alkynylene, optionally substituted with one or more
substituents Q.
[0789] In certain embodiments, R.sup.6a is hydrogen. In certain
embodiments, R.sup.6a is deuterium. In certain embodiments,
R.sup.6a is cyano. In certain embodiments, R.sup.6a is halo. In
certain embodiments, R.sup.6a is fluoro. In certain embodiments,
R.sup.6a is chloro. In certain embodiments, R.sup.6a is nitro. In
certain embodiments, R.sup.6a is C.sub.1-6 alkyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.6a is methyl, optionally substituted with one or
more substituents Q. In certain embodiments, R.sup.6a is C.sub.2-6
alkenyl, optionally substituted with one or more substituents Q. In
certain embodiments, R.sup.6a is C.sub.2-6 alkynyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.6a is C.sub.3-12 cycloalkyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.6a is C.sub.6-14 aryl, optionally substituted
with one or more substituents Q. In certain embodiments, R.sup.6a
is C.sub.7-15 aralkyl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.6a is heteroaryl,
optionally substituted with one or more substituents Q. In certain
embodiments, R.sup.6a is heterocyclyl, optionally substituted with
one or more substituents Q. In certain embodiments, R.sup.6a is 4-
to 6-membered heterocyclyl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.6a is oxetanyl,
tetrahydrofuryl, or tetrahydropyranyl, each optionally substituted
with one or more substituents Q.
[0790] In certain embodiments, R.sup.6a is --C(O)R.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.6a is
--C(O)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.6a is --C(O)NR.sup.1bR.sup.1c wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.6a is --C(O)SR.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.6a is
--C(NR.sup.1a)NR.sup.1bR.sup.1c, wherein R.sup.1a, R.sup.1b, and
R.sup.1c are each as defined herein. In certain embodiments,
R.sup.6a is --C(S)R.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.6a is --C(S)OR.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.6a is
--C(S)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.6a is --OR.sup.1a,
wherein R.sup.1a is as defined herein. In certain embodiments,
R.sup.6a is --OH. In certain embodiments, R.sup.6a is
--OC(O)R.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.6a is --OC(O)OR.sup.1a, wherein R.sup.1a is as
defined herein. In certain embodiments, R.sup.6a is
--OC(O)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.6a is
--OC(O)SR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.6a is --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
wherein R.sup.1a, R.sup.1b, and R.sup.1c are each as defined
herein. In certain embodiments, R.sup.6a is --OC(S)R.sup.1a,
wherein R.sup.1a is as defined herein. In certain embodiments,
R.sup.6a is --OC(S)OR.sup.1a, wherein R.sup.1a is as defined
herein. In certain embodiments, R.sup.6a is
--OC(S)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.6a is
--OS(O)R.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.6a is --OS(O).sub.2R.sup.1a, wherein R.sup.1a is
as defined herein. In certain embodiments, R.sup.6a is
--OS(O)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.6a is
--OS(O).sub.2NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are
each as defined herein. In certain embodiments, R.sup.6a is
--NR.sup.1bR.sup.1c wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.6a is --NH.sub.2. In
certain embodiments, R.sup.6a is --NR.sup.1aC(O)R.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.6a is --NR.sup.1aC(O)OR.sup.1d, wherein
R.sup.1a, and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.6a is --NR.sup.1aC(O)NR.sup.1bR.sup.1c wherein
R.sup.1a, R.sup.1b, and R.sup.1c are each as defined herein. In
certain embodiments, R.sup.6a is --NR.sup.1aC(O)SR.sup.1d wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.6a is
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c wherein R.sup.1a,
R.sup.1b, R.sup.1c, and R.sup.1d are each as defined herein. In
certain embodiments, R.sup.6a is --NR.sup.1aC(S)R.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.6a is --NR.sup.1aC(S)OR.sup.1d, wherein R.sup.1a
and R.sup.1d are each as defined herein. In certain embodiments,
R.sup.6a is --NR.sup.1aC(S)NR.sup.1bR.sup.1c, wherein R.sup.1a,
R.sup.1b and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.6a is --NR.sup.1a S(O)R.sup.1d, wherein R.sup.1a
and R area each as defined herein. In certain embodiments, R.sup.6a
is --NR.sup.1a S(O).sub.2R.sup.1d wherein R.sup.1a and R.sup.1d are
each as defined herein. In certain embodiments, R.sup.6a is
--NR.sup.1a S(O)NR.sup.1bR.sup.1c, wherein R.sup.1a, R.sup.1b, and
R.sup.1c are each as defined herein. In certain embodiments,
R.sup.6a is --NR.sup.1a S(O).sub.2NR.sup.1bR.sup.1c, wherein
R.sup.1a, R.sup.1b, and R.sup.1c are each as defined herein. In
certain embodiments, R.sup.6a is --SR.sup.1a wherein R.sup.1a is as
defined herein. In certain embodiments, R.sup.6a is --S(O)R.sup.1a,
wherein R.sup.1a is as defined herein. In certain embodiments,
R.sup.6a is --S(O).sub.2R.sup.1a, wherein R.sup.1a is as defined
herein. In certain embodiments, R.sup.6a is
--S(O)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.6a is
--S(O).sub.2NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are
each as defined herein.
[0791] In certain embodiments, R.sup.6b is hydrogen. In certain
embodiments, R.sup.6b is deuterium. In certain embodiments,
R.sup.6b is cyano. In certain embodiments, R.sup.6b is halo. In
certain embodiments, R.sup.6b is fluoro. In certain embodiments,
R.sup.6b is chloro. In certain embodiments, R.sup.6b is nitro. In
certain embodiments, R.sup.6b is C.sub.1-6 alkyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.6b is methyl, optionally substituted with one or
more substituents Q. In certain embodiments, R.sup.6b is C.sub.2-6
alkenyl, optionally substituted with one or more substituents Q. In
certain embodiments, R.sup.6b is C.sub.2-6 alkynyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.6b is C.sub.3-12 cycloalkyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.6b is C.sub.6-14 aryl, optionally substituted
with one or more substituents Q. In certain embodiments, R.sup.6b
is C.sub.7-15 aralkyl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.6b is heteroaryl,
optionally substituted with one or more substituents Q. In certain
embodiments, R.sup.6b is heterocyclyl, optionally substituted with
one or more substituents Q. In certain embodiments, R.sup.6b is 4-
to 6-membered heterocyclyl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.6b is oxetanyl,
tetrahydrofuryl, or tetrahydropyranyl, each optionally substituted
with one or more substituents Q.
[0792] In certain embodiments, R.sup.6b is --C(O)R.sup.1a, wherein
R.sup.6 is as defined herein. In certain embodiments, R.sup.6b is
--C(O)OR.sup.a, wherein R.sup.6 is as defined herein. In certain
embodiments, R.sup.1 is --C(O)NR.sup.1bR.sup.1c, wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.6b is --C(O)SR.sup.a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.6b is
--C(NR.sup.1a)NR.sup.1bR.sup.1c, wherein R.sup.1a, R.sup.1b and
R.sup.1c are each as defined herein. In certain embodiments,
R.sup.6b is --C(S)R.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.6b is --C(S)OR.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.6b is
--C(S)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.6b is --OR.sup.1a,
wherein R.sup.1a is as defined herein. In certain embodiments,
R.sup.6b is --OH. In certain embodiments, R.sup.6b is
--OC(O)R.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.6b is --OC(O)OR.sup.1a, wherein R.sup.1a is as
defined herein. In certain embodiments, R.sup.6b is
--OC(O)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.6b is
--OC(O)SR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.6b is --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
wherein R.sup.1a, R.sup.1b, and R.sup.1c are each as defined
herein. In certain embodiments, R.sup.6b is --OC(S)R.sup.1a,
wherein R.sup.1a is as defined herein. In certain embodiments,
R.sup.6b is --OC(S)OR.sup.1a, wherein R.sup.1a is as defined
herein. In certain embodiments, R.sup.6b is
--OC(S)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.6b is
--OS(O)R.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.1 is --OS(O).sub.2R.sup.1a, wherein R.sup.1a is
as defined herein. In certain embodiments, R.sup.6b is
--OS(O)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.6b is
--OS(O).sub.2NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are
each as defined herein. In certain embodiments, R.sup.6b is
--NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.6b is --NH.sub.2. In
certain embodiments, R.sup.6b is --NR.sup.1c (O)R.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.6b is --NR.sup.1aC(O)OR.sup.1d, wherein
R.sup.1a, and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.6b is --NR.sup.1aC(O)NR.sup.1bR.sup.1c wherein
R.sup.1a, R.sup.1b, and R.sup.1c are each as defined herein. In
certain embodiments, R.sup.6b is --NR.sup.1aC(O)SR.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.6b is
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c, wherein R.sup.1a,
R.sup.1b, R.sup.1c, and R.sup.1d are each as defined herein. In
certain embodiments, R.sup.6b is --NR.sup.1aC(S)R.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.6b is --NR.sup.1aC(S)OR.sup.1d, wherein R.sup.1a
and R.sup.1d are each as defined herein. In certain embodiments,
R.sup.6b is --NR.sup.1aC(S)NR.sup.1bR.sup.1c, wherein R.sup.1a,
R.sup.1b, and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.1 is --NR.sup.1a S(O)R.sup.1d, wherein R.sup.1a
and R.sup.1d area each as defined herein. In certain embodiments,
R.sup.6b is --NR.sup.1a S(O).sub.2R.sup.1d, wherein R.sup.1a and
R.sup.d are each as defined herein. In certain embodiments,
R.sup.6b is --NR.sup.1a S(O)NR.sup.1bR.sup.1c, wherein R.sup.1a,
R.sup.1b, and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.6b is --NR.sup.1a S(O).sub.2NR.sup.1bR.sup.1c,
wherein R.sup.1a, R.sup.1b, and R.sup.1c are each as defined
herein. In certain embodiments, R.sup.6b is --SR.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.6b is
--S(O)R.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.6b is --S(O).sub.2R.sup.1a, wherein R.sup.1a is
as defined herein. In certain embodiments, R.sup.6b is
--S(O)NR.sup.1bR.sup.1c wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.6b is
--S(O).sub.2NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are
each as defined herein.
[0793] In certain embodiments, R.sup.6c is hydrogen. In certain
embodiments, R.sup.6c is deuterium. In certain embodiments,
R.sup.6c is cyano. In certain embodiments, R.sup.6c is halo. In
certain embodiments, R.sup.6c is fluoro. In certain embodiments,
R.sup.6c is chloro. In certain embodiments, R.sup.6c is nitro. In
certain embodiments, R.sup.6c is C.sub.1-6 alkyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.6c is methyl, optionally substituted with one or
more substituents Q. In certain embodiments, R.sup.6c is methyl or
trifluoromethyl. In certain embodiments, R.sup.6c is C.sub.2-6
alkenyl, optionally substituted with one or more substituents Q. In
certain embodiments, R.sup.6c is C.sub.2-6 alkynyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.6c is C.sub.3-12 cycloalkyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.6c is C.sub.6-14 aryl, optionally substituted
with one or more substituents Q. In certain embodiments, R.sup.6c
is C.sub.7-15 aralkyl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.6 is heteroaryl,
optionally substituted with one or more substituents Q. In certain
embodiments, R.sup.6c is heterocyclyl, optionally substituted with
one or more substituents Q. In certain embodiments, R.sup.6, is 4-
to 6-membered heterocyclyl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.6, is oxetanyl,
tetrahydrofuryl, or tetrahydropyranyl, each optionally substituted
with one or more substituents Q.
[0794] In certain embodiments, R.sup.6c is --C(O)R.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.6c is
--C(O)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.6c is --C(O)NR.sup.1bR.sup.1c wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.6c is --C(O)SR.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.6c is
--C(NR.sup.1a)NR.sup.1bR.sup.1c, wherein R.sup.1a, R.sup.1b, and
R.sup.1c are each as defined herein. In certain embodiments,
R.sup.6c is --C(S)R.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.6 is --C(S)OR.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.6c is
--C(S)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.6c is --OR.sup.1a,
wherein R.sup.1a is as defined herein. In certain embodiments,
R.sup.6c is --OH. In certain embodiments, R.sup.6c is
--OC(O)R.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.6 is --OC(O)OR.sup.1a, wherein R.sup.1a is as
defined herein. In certain embodiments, R.sup.6c is
--OC(O)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.6 is
--OC(O)SR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.6c is --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
wherein R.sup.1a, R.sup.1b, and R.sup.1c are each as defined
herein. In certain embodiments, R.sup.6 is --OC(S)R.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.6c is
--OC(S)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.6c is --OC(S)NR.sup.1bR.sup.1c, wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.6c is --OS(O)R.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.6c is --OS(O).sub.2R.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.6c is
--OS(O)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.6c is
--OS(O).sub.2NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are
each as defined herein. In certain embodiments, R.sup.6c is
--NR.sup.1bR.sup.1c wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.6c is --NH.sub.2. In
certain embodiments, R.sup.6c is --NR.sup.1aC(O)R.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.6c is --NR.sup.1aC(O)OR.sup.1d, wherein
R.sup.1a, and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.6c is --NR.sup.1aC(O)NR.sup.1bR.sup.1c wherein
R.sup.1a, R.sup.1b, and R.sup.1c are each as defined herein. In
certain embodiments, R.sup.6c is --NR.sup.1aC(O)SR.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.6c is
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c wherein R.sup.1a,
R.sup.1b, R.sup.1c, and R.sup.1d are each as defined herein. In
certain embodiments, R.sup.6c is --NR.sup.1aC(S)R.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.6c is --NR.sup.1aC(S)OR.sup.1d, wherein R.sup.1a
and R.sup.1d are each as defined herein. In certain embodiments,
R.sup.6, is --NR.sup.1aC(S)NR.sup.1bR.sup.1c, wherein R.sup.1a,
R.sup.1b, and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.6, is --NR.sup.1a S(O)R.sup.1d, wherein R.sup.1a
and R.sup.1d are each as defined herein. In certain embodiments,
R.sup.6c is --NR.sup.1aS(O).sub.2R.sup.1d, wherein R.sup.1a and
R.sup.d are each as defined herein. In certain embodiments,
R.sup.6, is --NR.sup.1a S(O)NR.sup.1bR.sup.1c, wherein R.sup.1a,
R.sup.1b, and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.6c is --NR.sup.1aS(O).sub.2NR.sup.1bR.sup.1c
wherein R.sup.1a, R.sup.1b and R.sup.1c are each as defined herein.
In certain embodiments, R.sup.6c is --SR.sup.1a wherein R.sup.1a is
as defined herein. In certain embodiments, R.sup.6c is
--S(O)R.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.6c is --S(O).sub.2R.sup.1a, wherein R.sup.1a is
as defined herein. In certain embodiments, R.sup.6c is
--S(O)NR.sup.1bR.sup.1c wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.6c is
--S(O).sub.2NR.sup.1bR.sup.1c wherein R.sup.1b and R.sup.1c are
each as defined herein.
[0795] In certain embodiments, R.sup.6d is hydrogen. In certain
embodiments, R.sup.6d is deuterium. In certain embodiments,
R.sup.6d is cyano. In certain embodiments, R.sup.6d is halo. In
certain embodiments, R.sup.6d is fluoro. In certain embodiments,
R.sup.6d is chloro. In certain embodiments, R.sup.6d is nitro. In
certain embodiments, R.sup.6d is C.sub.1-6 alkyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.6d is methyl, optionally substituted with one or
more substituents Q. In certain embodiments, R.sup.6d is C.sub.2-6
alkenyl, optionally substituted with one or more substituents Q. In
certain embodiments, R.sup.6d is C.sub.2-6 alkynyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.6d is C.sub.3-12 cycloalkyl, optionally
substituted with one or more substituents Q. In certain
embodiments, R.sup.6d is C.sub.6-14 aryl, optionally substituted
with one or more substituents Q. In certain embodiments, R.sup.6d
is C.sub.7-15 aralkyl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.6d is heteroaryl,
optionally substituted with one or more substituents Q. In certain
embodiments, R.sup.6d is heterocyclyl, optionally substituted with
one or more substituents Q. In certain embodiments, R.sup.6d is 4-
to 6-membered heterocyclyl, optionally substituted with one or more
substituents Q. In certain embodiments, R.sup.6d is oxetanyl,
tetrahydrofuryl, or tetrahydropyranyl, each optionally substituted
with one or more substituents Q.
[0796] In certain embodiments, R.sup.6d is --C(O)R.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.6d is
--C(O)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.6d is --C(O)NR.sup.1bR.sup.1c wherein R.sup.1b
and R.sup.1c are each as defined herein. In certain embodiments,
R.sup.6d is --C(O)SR.sup.a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.6d is
--C(NR.sup.1a)NR.sup.1bR.sup.1c, wherein R.sup.1a, R.sup.1b and
R.sup.1c are each as defined herein. In certain embodiments,
R.sup.6d is --C(S)R.sup.1a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.6d is --C(S)OR.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.6d is
--C(S)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.6d is --OR.sup.1a,
wherein R.sup.1a is as defined herein. In certain embodiments,
R.sup.6d is --OH. In certain embodiments, R.sup.6d is
--OC(O)R.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.6d is --OC(O)OR.sup.1a, wherein R.sup.1a is as
defined herein. In certain embodiments, R.sup.6d is
--OC(O)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.6d is
--OC(O)SR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.6d is --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
wherein R.sup.1a, R.sup.1b, and R.sup.1c are each as defined
herein. In certain embodiments, R.sup.6d is --OC(S)R.sup.1a,
wherein R.sup.1a is as defined herein. In certain embodiments,
R.sup.6d is --OC(S)OR.sup.1a, wherein R.sup.1a is as defined
herein. In certain embodiments, R.sup.6d is
--OC(S)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.6d is
--OS(O)R.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.6d is --OS(O).sub.2R.sup.1a, wherein R.sup.1a is
as defined herein. In certain embodiments, R.sup.6d is
--OS(O)NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.6d is
--OS(O).sub.2NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are
each as defined herein. In certain embodiments, R.sup.6d is
--NR.sup.1R.sup.1c wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.6d is --NH.sub.2. In
certain embodiments, R.sup.6d is --NR.sup.1aC(O)R.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.6d is --NR.sup.1aC(O)OR.sup.1d, wherein
R.sup.1a, and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.6d is --NR.sup.1aC(O)NR.sup.1bR.sup.1c wherein
R.sup.1a, R.sup.1b, and R.sup.1c are each as defined herein. In
certain embodiments, R.sup.6d is --NR.sup.1aC(O)SR.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.6d is
--NR.sup.1aC(.dbd.NR.sup.d)NR.sup.1bR.sup.1c wherein R.sup.1a,
R.sup.1b, R.sup.1c, and R.sup.1d are each as defined herein. In
certain embodiments, R.sup.6d is --NR.sup.1aC(S)R.sup.1d, wherein
R.sup.1a and R.sup.1d are each as defined herein. In certain
embodiments, R.sup.6d is --NR.sup.1aC(S)OR.sup.1d, wherein R.sup.1a
and R.sup.1d are each as defined herein. In certain embodiments,
R.sup.6d is --NR.sup.1aC(S)NR.sup.1bR.sup.1c, wherein R.sup.1a,
R.sup.1b and R.sup.1c are each as defined herein. In certain
embodiments, R.sup.6d is --NR.sup.1a S(O)R.sup.1d, wherein R.sup.1a
and R area each as defined herein. In certain embodiments, R.sup.6d
is --NR.sup.1a S(O).sub.2R.sup.1d, wherein R.sup.1a and R.sup.1d
are each as defined herein. In certain embodiments, R.sup.6d is
--NR.sup.1a S(O)NR.sup.1bR.sup.1c, wherein R.sup.1a, R.sup.1b, and
R.sup.1c are each as defined herein. In certain embodiments,
R.sup.6d is --NR.sup.1a S(O).sub.2NR.sup.1bR.sup.1c wherein
R.sup.1a, R.sup.1b, and R.sup.1c are each as defined herein. In
certain embodiments, R.sup.6d is --SR.sup.1a wherein R.sup.1a is as
defined herein. In certain embodiments, R.sup.6d is --S(O)R.sup.1a,
wherein R.sup.1a is as defined herein. In certain embodiments,
R.sup.6d is --S(O).sub.2R.sup.1a, wherein R.sup.1a is as defined
herein. In certain embodiments, R.sup.6d is --S(O)NR.sup.1bR.sup.1c
wherein R.sup.1b and R.sup.1c are each as defined herein. In
certain embodiments, R.sup.6d is --S(O).sub.2NR.sup.1bR.sup.1c,
wherein R.sup.1b and R.sup.1c are each as defined herein.
[0797] In certain embodiments, U is --O--. In certain embodiments,
U is .dbd.C(R.sup.4)--, wherein R.sup.4 is as defined herein. In
certain embodiments, U is .dbd.C(H)--. In certain embodiments, U is
.dbd.C(CH.sub.3)--. In certain embodiments, U is .dbd.N--. In
certain embodiments, U is --N(R.sup.5)--, wherein R.sup.5 is as
defined herein. In certain embodiments, U is --N(H)--. In certain
embodiments, U is --N(CH.sub.3)--.
[0798] In certain embodiments, V is --O--. In certain embodiments,
V is .dbd.C(R.sup.4)--, wherein R.sup.4 is as defined herein. In
certain embodiments, V is .dbd.C(H)--. In certain embodiments, V is
.dbd.C(CH.sub.3)--. In certain embodiments, V is .dbd.N--. In
certain embodiments, V is --N(R.sup.5)--, wherein R.sup.5 is as
defined herein. In certain embodiments, V is --N(H)--. In certain
embodiments, V is --N(CH.sub.3)--.
[0799] In certain embodiments, W is .dbd.C(R.sup.6)--, wherein
R.sup.6 is as defined herein. In certain embodiments, W is
.dbd.C(H)--, .dbd.C(F)--, .dbd.C(Cl)--, .dbd.C(CH.sub.3)--,
.dbd.C(CF.sub.3)--, .dbd.C(OH)--, or .dbd.C(NH.sub.2)--. In certain
embodiments, W is .dbd.N--. In certain embodiments, W is
--NR.sup.7--, wherein R.sup.7 is as defined herein. In certain
embodiments, W is --NH--. In certain embodiments, W is --O--. In
certain embodiments, W is --S--.
[0800] In certain embodiments, X is .dbd.C(R.sup.6)--, wherein
R.sup.6 is as defined herein. In certain embodiments, X is
.dbd.C(H)--, .dbd.C(F)--, .dbd.C(Cl)--, .dbd.C(CH.sub.3)--,
.dbd.C(CF.sub.3)--, .dbd.C(OH)--, or .dbd.C(NH.sub.2)--. In certain
embodiments, X is .dbd.N--. In certain embodiments, X is
--NR.sup.7--, wherein R.sup.7 is as defined herein. In certain
embodiments, X is --NH--. In certain embodiments, X is --O--. In
certain embodiments, X is --S--.
[0801] In certain embodiments, Y is .dbd.C(R.sup.6)--, wherein
R.sup.6 is as defined herein. In certain embodiments, Y is
.dbd.C(H)--, .dbd.C(F)--, .dbd.C(Cl)--, .dbd.C(CH.sub.3)--,
.dbd.C(CF.sub.3)--, .dbd.C(OH)--, or .dbd.C(NH.sub.2)--. In certain
embodiments, Y is .dbd.N--. In certain embodiments, Y is a
bond.
[0802] In certain embodiments, Z is .dbd.C(R.sup.6)--, wherein
R.sup.6 is as defined herein. In certain embodiments, Z is
.dbd.C(H)--, .dbd.C(F)--, .dbd.C(Cl)--, .dbd.C(CH.sub.3)--,
.dbd.C(CF.sub.3)--, .dbd.C(OH)--, or .dbd.C(NH.sub.2)--. In certain
embodiments, Z is .dbd.N--. In certain embodiments, Z is
--NR.sup.7--, wherein R.sup.7 is as defined herein. In certain
embodiments, Z is --NH--. In certain embodiments, Z is --O--. In
certain embodiments, Z is --S--.
[0803] In certain embodiments, a compound provided herein is
deuterium-enriched. In certain embodiments, a compound provided
herein is carbon-13 enriched. In certain embodiments, a compound
provided herein is carbon-14 enriched. In certain embodiments, a
compound provided herein contains one or more less prevalent
isotopes for other elements, including, but not limited to,
.sup.16N for nitrogen; .sup.17O or .sup.18O for oxygen, and
.sup.33S, .sup.34S, or .sup.37S for sulfur.
[0804] In certain embodiments, a compound provided herein has an
isotopic enrichment factor of no less than about 6, no less than
about 10, no less than about 20, no less than about 30, no less
than about 40, no less than about 60, no less than about 70, no
less than about 70, no less than about 80, no less than about 90,
no less than about 100, no less than about 200, no less than about
600, no less than about 1,000, no less than about 2,000, no less
than about 6,000, or no less than about 10,000. In any events,
however, an isotopic enrichment factor for a specified isotope is
no greater than the maximum isotopic enrichment factor for the
specified isotope, which is the isotopic enrichment factor when a
compound at a given position is 100% enriched with the specified
isotope. Thus, the maximum isotopic enrichment factor is different
for different isotopes. The maximum isotopic enrichment factor is
7410 for deuterium and 90 for carbon-13.
[0805] In certain embodiments, a compound provided herein has a
deuterium enrichment factor of no less than about 74 (about 1%
deuterium enrichment), no less than about 130 (about 2% deuterium
enrichment), no less than about 320 (about 6% deuterium
enrichment), no less than about 740 (about 10% deuterium
enrichment), no less than about 1,300 (about 20% deuterium
enrichment), no less than about 3,200 (about 60% deuterium
enrichment), no less than about 4,800 (about 76% deuterium
enrichment), no less than about 6,130 (about 80% deuterium
enrichment), no less than about 6,460 (about 86% deuterium
enrichment), no less than about 6,770 (about 90% deuterium
enrichment), no less than about 7,090 (about 96% deuterium
enrichment), no less than about 7,220 (about 97% deuterium
enrichment), no less than about 7,280 (about 98% deuterium
enrichment), no less than about 7,360 (about 99% deuterium
enrichment), or no less than about 7,380 (about 99.6% deuterium
enrichment). The deuterium enrichment can be determined using
conventional analytical methods known to one of ordinary skill in
the art, including mass spectrometry and nuclear magnetic resonance
spectroscopy.
[0806] In certain embodiments, a compound provided herein has a
carbon-13 enrichment factor of no less than about 1.8 (about 2%
carbon-13 enrichment), no less than about 4.6 (about 6% carbon-13
enrichment), no less than about 9 (about 10% carbon-13 enrichment),
no less than about 18 (about 20% carbon-13 enrichment), no less
than about 46 (about 60% carbon-13 enrichment), no less than about
78 (about 76% carbon-13 enrichment), no less than about 72 (about
80% carbon-13 enrichment), no less than about 77 (about 86%
carbon-13 enrichment), no less than about 81 (about 90% carbon-13
enrichment), no less than about 87 (about 96% carbon-13
enrichment), no less than about 87 (about 97% carbon-13
enrichment), no less than about 88 (about 98% carbon-13
enrichment), no less than about 89 (about 99% carbon-13
enrichment), or no less than about 90 (about 99.6% carbon-13
enrichment). The carbon-13 enrichment can be determined using
conventional analytical methods known to one of ordinary skill in
the art, including mass spectrometry and nuclear magnetic resonance
spectroscopy.
[0807] In certain embodiments, at least one of the atoms of a
compound provided herein, as specified as isotopically enriched,
has isotopic enrichment of no less than about 1%, no less than
about 2%, no less than about 6%, no less than about 10%, no less
than about 20%, no less than about 60%, no less than about 70%, no
less than about 80%, no less than about 90%, or no less than about
98%. In certain embodiments, the atoms of a compound provided
herein, as specified as isotopically enriched, have isotopic
enrichment of no less than about 1%, no less than about 2%, no less
than about 6%, no less than about 10%, no less than about 20%, no
less than about 60%, no less than about 70%, no less than about
80%, no less than about 90%, or no less than about 98%. In any
events, the isotopic enrichment of the isotopically enriched atom
of a compound provided herein is no less than the natural abundance
of the isotope specified.
[0808] In certain embodiments, at least one of the atoms of a
compound provided herein, as specified as deuterium-enriched, has
deuterium enrichment of no less than about 1%, no less than about
2%, no less than about 6%, no less than about 10%, no less than
about 20%, no less than about 60%, no less than about 70%, no less
than about 80%, no less than about 90%, or no less than about 98%.
In certain embodiments, the atoms of a compound provided herein, as
specified as deuterium-enriched, have deuterium enrichment of no
less than about 1%, no less than about 2%, no less than about 6%,
no less than about 10%, no less than about 20%, no less than about
60%, no less than about 70%, no less than about 80%, no less than
about 90%, or no less than about 98%.
[0809] In certain embodiments, at least one of the atoms of a
compound provided herein, as specified as .sup.13C-enriched, has
carbon-13 enrichment of no less than about 2%, no less than about
6%, no less than about 10%, no less than about 20%, no less than
about 60%, no less than about 70%, no less than about 80%, no less
than about 90%, or no less than about 98%. In certain embodiments,
the atoms of a compound provided herein, as specified as
13C-enriched, have carbon-13 enrichment of no less than about 1%,
no less than about 2%, no less than about 6%, no less than about
10%, no less than about 20%, no less than about 60%, no less than
about 70%, no less than about 80%, no less than about 90%, or no
less than about 98%.
[0810] In certain embodiments, a compound provided herein is
isolated or purified. In certain embodiments, a compound provided
herein has a purity of at least about 60%, at least about 70%, at
least about 80%, at least about 90%, at least about 96%, at least
about 98%, at least about 99%, or at least about 99.6% by
weight.
[0811] The compounds provided herein are intended to encompass all
possible stereoisomers, unless a particular stereochemistry is
specified. Where a compound provided herein contains an alkenyl
group, the compound may exist as one or mixture of geometric
cis/trans (or Z/E) isomers. Where structural isomers are
interconvertible, the compound may exist as a single tautomer or a
mixture of tautomers. This can take the form of proton tautomerism
in the compound that contains, for example, an imino, keto, or
oxime group; or so-called valence tautomerism in the compound that
contain an aromatic moiety. It follows that a single compound may
exhibit more than one type of isomerism.
[0812] A compound provided herein can be enantiomerically pure,
such as a single enantiomer or a single diastereomer, or be
stereoisomeric mixtures, such as a mixture of enantiomers, e.g., a
racemic mixture of two enantiomers; or a mixture of two or more
diastereomers. As such, one of ordinary skill in the art will
recognize that administration of a compound in its (R) form is
equivalent, for compounds that undergo epimerization in vivo, to
administration of the compound in its (S) form. Conventional
techniques for the preparation/isolation of individual enantiomers
include synthesis from a suitable optically pure precursor,
asymmetric synthesis from achiral starting materials, or resolution
of an enantiomeric mixture, for example, chiral chromatography,
recrystallization, resolution, diastereomeric salt formation, or
derivatization into diastereomeric adducts followed by
separation.
[0813] In certain embodiments, the compounds provided herein are
inhibitors of a casein kinase 1. In certain embodiments, the
compounds provided herein are inhibitors of casein kinase 1.alpha.
(CK1.alpha.). In certain embodiments, the compounds provided herein
are selective inhibitors of casein kinase 1.alpha. (CK1.alpha.). In
certain embodiments, the compounds provided herein are inhibitors
of human casein kinase 1.alpha. (CK1.alpha.). In certain
embodiments, the compounds provided herein are selective inhibitors
of human casein kinase 1.alpha. (CK1.alpha.). The CK1a inhibitory
activity of the compounds provided herein are determined according
to the procedures described in International Publication No. WO
2017/021970, the disclosure of which is incorporated herein by
reference in its entirety.
[0814] When a compound provided herein contains an acidic or basic
moiety, it can also be provided as a pharmaceutically acceptable
salt (See, Berge et al., J. Pharm. Sci. 1977, 77, 1-19; and
"Handbook of Pharmaceutical Salts, Properties, and Use," Stahl and
Wermuth, Ed.; Wiley-VCH and VHCA, Zurich, 2011).
[0815] Suitable acids for use in the preparation of
pharmaceutically acceptable salts include, but are not limited to,
acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic
acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic
acid, benzoic acid, 4-acetamidobenzoic acid, boric acid,
(+)-camphoric acid, camphorsulfonic acid,
(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid,
caprylic acid, cinnamic acid, citric acid, cyclamic acid,
cyclohexanesulfamic acid, dodecylsulfuric acid,
ethane-1,2-disulfonic acid, ethanesulfonic acid,
2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,
galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic
acid, D-glucuronic acid, L-glutamic acid, .alpha.-oxoglutaric acid,
glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid,
hydroiodic acid, (+)-L-lactic acid, (.+-.)-DL-lactic acid,
lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid,
malonic acid, (.+-.)-DL-mandelic acid, methanesulfonic acid,
naphthalene-2-sulfonic acid, naphthalene-1,6-disulfonic acid,
1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic
acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,
perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic
acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic
acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric
acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid,
and valeric acid. In certain embodiments, the compounds provided
herein are hydrochloride salts.
[0816] Suitable bases for use in the preparation of
pharmaceutically acceptable salts, including, but not limited to,
inorganic bases, such as magnesium hydroxide, calcium hydroxide,
potassium hydroxide, zinc hydroxide, or sodium hydroxide; and
organic bases, such as primary, secondary, tertiary, and
quaternary, aliphatic and aromatic amines, including L-arginine,
benethamine, benzathine, choline, deanol, diethanolamine,
diethylamine, dimethylamine, dipropylamine, diisopropylamine,
2-(diethylamino)-ethanol, ethanolamine, ethylamine,
ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine,
1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine,
methylamine, piperidine, piperazine, propylamine, pyrrolidine,
1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline,
isoquinoline, triethanolamine, trimethylamine, triethylamine,
N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol,
and tromethamine.
[0817] The compound provided herein may also be provided as a
prodrug, which is a functional derivative of a compound, for
example, of Formula I and is readily convertible into the parent
compound in vivo. Prodrugs are often useful because, in some
situations, they may be easier to administer than the parent
compound. They may, for instance, be bioavailable by oral
administration whereas the parent compound is not. The prodrug may
also have enhanced solubility in pharmaceutical compositions over
the parent compound. A prodrug may be converted into the parent
drug by various mechanisms, including enzymatic processes and
metabolic hydrolysis. See Harper, Progress in Drug Research 1972,
4, 221-294; Morozowich et al. in "Design of Biopharmaceutical
Properties through Prodrugs and Analogs," Roche Ed., APHA Acad.
Pharm. Sci. 1977; "Bioreversible Carriers in Drug in Drug Design,
Theory and Application," Roche Ed., APHA Acad. Pharm. Sci. 1987;
"Design of Prodrugs," Bundgaard, Elsevier, 1986; Wang et al., Curr.
Pharm. Design 1999, 6, 276-287; Pauletti et al., Adv. Drug.
Delivery Rev. 1997, 27, 236-267; Mizen et al., Pharm. Biotech.
1998, 11, 346-376; Gaignault et al., Pract. Med. Chem. 1997,
771-797; Asgharnejad in "Transport Processes in Pharmaceutical
Systems," Amidon et al., Ed., Marcell Dekker, 186-218, 2000; Balant
et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 16, 143-63;
Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209;
Browne, Clin. Neuropharmacol. 1997, 20, 1-12; Bundgaard, Arch.
Pharm. Chem. 1979, 87, 1-39; Bundgaard, Controlled Drug Delivery
1987, 17, 179-97; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38;
Fleisher et al., Adv. Drug Delivery Rev. 1997, 19, 116-130;
Fleisher et al., Methods Enzymol. 1986, 112, 370-381; Farquhar et
al., J. Pharm. Sci. 1983, 72, 324-326; Freeman et al., J. Chem.
Soc., Chem. Commun. 1991, 876-877; Friis and Bundgaard, Eur. J.
Pharm. Sci. 1997, 4, 49-69; Gangwar et al., Des. Biopharm. Prop.
Prodrugs Analogs, 1977, 409-421; Nathwani and Wood, Drugs 1993, 46,
877-94; Sinhababu and Thakker, Adv. Drug Delivery Rev. 1997, 19,
241-273; Stella et al., Drugs 1986, 29, 466-73; Tan et al., Adv.
Drug Delivery Rev. 1999, 39, 117-161; Taylor, Adv. Drug Delivery
Rev. 1997, 19, 131-148; Valentino and Borchardt, Drug Discovery
Today 1997, 2, 148-166; Wiebe and Knaus, Adv. Drug Delivery Rev.
1999, 39, 73-80; and Waller et al., Br. J. Clin. Pharmac. 1989, 28,
497-607.
Methods of Synthesis
[0818] The compounds provided herein can be prepared, isolated, or
obtained by any method known to one of ordinary skill in the art.
In certain embodiments, a compound of Formula II is synthesized as
shown in Scheme I, wherein L is chloro, bromo, iodo, or
--OSO.sup.2R.sup.1a; and R.sup.1, R.sup.3, R.sup.1a, R.sup.2a,
R.sup.2b, R.sup.2c, R.sup.2d, U, V, W, X, Y, and Z are each as
defined herein. Compound I-1 is coupled with compound I-2, for
example, under the Suzuki coupling conditions, to form a compound
of Formula II.
##STR00108##
[0819] In certain embodiments, a compound of Formula II is
synthesized as shown in Scheme II, wherein R.sup.1, R.sup.3,
R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, L, U, V, W, X, Y, and Z are
each as defined herein. Compound I-3 is coupled with compound I-4,
for example, under the Suzuki coupling conditions, to form a
compound of Formula II.
##STR00109##
[0820] In certain embodiments, a compound of Formula IA is
synthesized as shown in Scheme III, wherein L is chloro, bromo,
iodo, or --OSO.sup.2R.sup.1a; and R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.1a, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, W, X, Y,
and Z are each as defined herein. Compound IA-1 is coupled with
compound IA-2, for example, under the Suzuki coupling conditions,
to form a compound of Formula IA.
##STR00110##
[0821] In certain embodiments, a compound of Formula IA is
synthesized as shown in Scheme IV, wherein R.sup.1, R.sup.3,
R.sup.4, R.sup.5, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, L, W, X,
Y, and Z are each as defined herein. Compound IA-3 is coupled with
compound IA-4, for example, under the Suzuki coupling conditions,
to form a compound of Formula IA.
##STR00111##
[0822] Additional synthetic procedures for the synthesis of a
compound provided herein include those described in International
Publication No. WO 2017/021969, the disclosure of which is
incorporated herein by reference in its entirety.
Pharmaceutical Compositions
[0823] In one embodiment, provided herein is a pharmaceutical
composition comprising a compound provided herein, e.g., a compound
of Formula I or IA, or an enantiomer, a mixture of enantiomers, a
mixture of two or more diastereomers, a tautomer, a mixture of two
or more tautomers, or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, and a pharmaceutically acceptable excipient.
[0824] In one embodiment, a pharmaceutical composition provided
herein is formulated in a dosage form for oral administration,
which comprises a compound provided herein, e.g., a compound of
Formula I or IA, or an enantiomer, a mixture of enantiomers, a
mixture of two or more diastereomers, a tautomer, a mixture of two
or more tautomers, or an isotopic variant thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, and a pharmaceutically acceptable excipient.
[0825] In another embodiment, a pharmaceutical composition provided
herein is formulated in a dosage form for parenteral
administration, which comprises a compound provided herein, e.g., a
compound of Formula I or IA, or an enantiomer, a mixture of
enantiomers, a mixture of two or more diastereomers, a tautomer, a
mixture of two or more tautomers, or an isotopic variant thereof,
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, and a pharmaceutically acceptable excipient. In one
embodiment, a pharmaceutical composition provided herein is
formulated in a dosage form for intravenous administration. In
another embodiment, a pharmaceutical composition provided herein is
formulated in a dosage form for intramuscular administration. In
yet another embodiment, a pharmaceutical composition provided
herein is formulated in a dosage form for subcutaneous
administration.
[0826] In yet another embodiment, a pharmaceutical composition
provided herein is formulated in a dosage form for topical
administration, which comprise a compound provided herein, e.g., a
compound of Formula I or IA, or an enantiomer, a mixture of
enantiomers, a mixture of two or more diastereomers, a tautomer, a
mixture of two or more tautomers, or an isotopic variant thereof,
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, and a pharmaceutically acceptable excipient.
[0827] In one embodiment, a pharmaceutical composition provided
herein is formulated as a cream for topical administration, which
comprises a compound provided herein, e.g., a compound of Formula I
or IA, or an enantiomer, a mixture of enantiomers, a mixture of two
or more diastereomers, a tautomer, a mixture of two or more
tautomers, or an isotopic variant thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof, and a
pharmaceutically acceptable excipient. In one embodiment, the cream
provided herein comprises a compound provided herein, e.g., a
compound of Formula I or IA, or an enantiomer, a mixture of
enantiomers, a mixture of two or more diastereomers, a tautomer, a
mixture of two or more tautomers, or an isotopic variant thereof;
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, and one or more pharmaceutically acceptable excipients
selected from the group consisting of water, octyldodecanol,
mineral oil, stearyl alcohol, cocamide DEA, polysorbate 70,
myristyl alcohol, sorbitan monostearate, lactic acid, and benzyl
alcohol. In another embodiment, the cream provided herein comprises
a compound provided herein, e.g., a compound of Formula I or IA, or
an enantiomer, a mixture of enantiomers, a mixture of two or more
diastereomers, a tautomer, a mixture of two or more tautomers, or
an isotopic variant thereof, or a pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof, and water, octyldodecanol,
mineral oil, stearyl alcohol, cocamide DEA, polysorbate 70,
myristyl alcohol, sorbitan monostearate, lactic acid, and benzyl
alcohol.
[0828] In another embodiment, a pharmaceutical composition provided
herein is formulated as a gel for topical administration, which
comprises a compound provided herein, e.g., a compound of Formula I
or IA, or an enantiomer, a mixture of enantiomers, a mixture of two
or more diastereomers, a tautomer, a mixture of two or more
tautomers, or an isotopic variant thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof; and a
pharmaceutically acceptable excipient. In one embodiment, the gel
provided herein comprises a compound provided herein, e.g., a
compound of Formula I or IA, or an enantiomer, a mixture of
enantiomers, a mixture of two or more diastereomers, a tautomer, a
mixture of two or more tautomers, or an isotopic variant thereof;
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, and one or more pharmaceutically acceptable excipients
selected from the group consisting of water, isopropyl alcohol,
octyldodecanol, dimethicone copolyol 190, carbomer 980, sodium
hydroxide, and docusate sodium. In another embodiment, the gel
provided herein comprises a compound provided herein, e.g., a
compound of Formula I or IA, or an enantiomer, a mixture of
enantiomers, a mixture of two or more diastereomers, a tautomer, a
mixture of two or more tautomers, or an isotopic variant thereof,
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, and water, isopropyl alcohol, octyldodecanol, dimethicone
copolyol 190, carbomer 980, sodium hydroxide, and docusate
sodium.
[0829] In yet another embodiment, a pharmaceutical composition
provided herein is formulated as a lacquer for topical
administration, which comprises a compound provided herein, e.g., a
compound of Formula I or IA, or an enantiomer, a mixture of
enantiomers, a mixture of two or more diastereomers, a tautomer, a
mixture of two or more tautomers, or an isotopic variant thereof,
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, and a pharmaceutically acceptable excipient. In one
embodiment, the lacquer provided herein comprises a compound
provided herein, e.g., a compound of Formula I or IA, or an
enantiomer, a mixture of enantiomers, a mixture of two or more
diastereomers, a tautomer, a mixture of two or more tautomers, or
an isotopic variant thereof; or a pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof, and one or more
pharmaceutically acceptable excipients selected from the group
consisting of ethyl acetate, isopropyl alcohol, and butyl monoester
of poly(methylvinyl ether/maleic acid) in isopropyl alcohol.
[0830] The compound provided herein may be administered alone, or
in combination with one or more other compounds provided herein.
The pharmaceutical compositions that comprise a compound provided
herein, e.g., a compound of Formula I or IA, can be formulated in
various dosage forms for oral, parenteral, and topical
administration. The pharmaceutical compositions can also be
formulated as modified release dosage forms, including delayed-,
extended-, prolonged-, sustained-, pulsatile-, controlled-,
accelerated-, fast-, targeted-, programmed-release, and gastric
retention dosage forms. These dosage forms can be prepared
according to conventional methods and techniques known to those
skilled in the art (see, Remington: The Science and Practice of
Pharmacy, supra; Modified-Release Drug Delivery Technology, 2nd
Edition, Rathbone et al., Eds., Marcel Dekker, Inc.: New York,
N.Y., 2008).
[0831] The pharmaceutical compositions provided herein can be
provided in a unit-dosage form or multiple-dosage form. A
unit-dosage form, as used herein, refers to physically discrete a
unit suitable for administration to a human and animal subject, and
packaged individually as is known in the art. Each unit-dose
contains a predetermined quantity of an active ingredient(s)
sufficient to produce the desired therapeutic effect, in
association with the required pharmaceutical carriers or
excipients. Examples of a unit-dosage form include an ampoule,
syringe, and individually packaged tablet and capsule. A
unit-dosage form may be administered in fractions or multiples
thereof. A multiple-dosage form is a plurality of identical
unit-dosage forms packaged in a single container to be administered
in segregated unit-dosage form. Examples of a multiple-dosage form
include a vial, bottle of tablets or capsules, or bottle of pints
or gallons.
[0832] The pharmaceutical compositions provided herein can be
administered at once, or multiple times at intervals of time. It is
understood that the precise dosage and duration of treatment may
vary with the age, weight, and condition of the patient being
treated, and may be determined empirically using known testing
protocols or by extrapolation from in vivo or in vitro test or
diagnostic data. It is further understood that for any particular
individual, specific dosage regimens should be adjusted over time
according to the individual need and the professional judgment of
the person administering or supervising the administration of the
formulations.
A. Oral Administration
[0833] The pharmaceutical compositions provided herein for oral
administration can be provided in solid, semisolid, or liquid
dosage forms for oral administration. As used herein, oral
administration also includes buccal, lingual, and sublingual
administration. Suitable oral dosage forms include, but are not
limited to, tablets, fastmelts, chewable tablets, capsules, pills,
strips, troches, lozenges, pastilles, cachets, pellets, medicated
chewing gum, bulk powders, effervescent or non-effervescent powders
or granules, oral mists, solutions, emulsions, suspensions, wafers,
sprinkles, elixirs, and syrups. In addition to the active
ingredient(s), the pharmaceutical compositions can contain one or
more pharmaceutically acceptable carriers or excipients, including,
but not limited to, binders, fillers, diluents, disintegrants,
wetting agents, lubricants, glidants, coloring agents,
dye-migration inhibitors, sweetening agents, flavoring agents,
emulsifying agents, suspending and dispersing agents,
preservatives, solvents, non-aqueous liquids, organic acids, and
sources of carbon dioxide.
[0834] Binders or granulators impart cohesiveness to a tablet to
ensure the tablet remaining intact after compression. Suitable
binders or granulators include, but are not limited to, starches,
such as corn starch, potato starch, and pre-gelatinized starch
(e.g., STARCH 1600); gelatin; sugars, such as sucrose, glucose,
dextrose, molasses, and lactose; natural and synthetic gums, such
as acacia, alginic acid, alginates, extract of Irish moss, panwar
gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose,
methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch
arabogalactan, powdered tragacanth, and guar gum; celluloses, such
as ethyl cellulose, cellulose acetate, carboxymethyl cellulose
calcium, sodium carboxymethyl cellulose, methyl cellulose,
hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC),
hydroxypropyl methyl cellulose (HPMC); microcrystalline celluloses,
such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC1-681, AVICEL-PH-106
(FMC Corp., Marcus Hook, Pa.); and mixtures thereof. Suitable
fillers include, but are not limited to, talc, calcium carbonate,
microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch,
and mixtures thereof. The amount of a binder or filler in the
pharmaceutical compositions provided herein varies upon the type of
formulation, and is readily discernible to those of ordinary skill
in the art. The binder or filler may be present from about 60 to
about 99% by weight in the pharmaceutical compositions provided
herein.
[0835] Suitable diluents include, but are not limited to, dicalcium
phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol,
cellulose, kaolin, mannitol, sodium chloride, dry starch, and
powdered sugar. Certain diluents, such as mannitol, lactose,
sorbitol, sucrose, and inositol, when present in sufficient
quantity, can impart properties to some compressed tablets that
permit disintegration in the mouth by chewing. Such compressed
tablets can be used as chewable tablets. The amount of a diluent in
the pharmaceutical compositions provided herein varies upon the
type of formulation, and is readily discernible to those of
ordinary skill in the art.
[0836] Suitable disintegrants include, but are not limited to,
agar; bentonite; celluloses, such as methylcellulose and
carboxymethylcellulose; wood products; natural sponge;
cation-exchange resins; alginic acid; gums, such as guar gum and
Veegum HV; citrus pulp; cross-linked celluloses, such as
croscarmellose; cross-linked polymers, such as crospovidone;
cross-linked starches; calcium carbonate; microcrystalline
cellulose, such as sodium starch glycolate; polacrilin potassium;
starches, such as corn starch, potato starch, tapioca starch, and
pre-gelatinized starch; clays; aligns; and mixtures thereof. The
amount of a disintegrant in the pharmaceutical compositions
provided herein varies upon the type of formulation, and is readily
discernible to those of ordinary skill in the art. The amount of a
disintegrant in the pharmaceutical compositions provided herein
varies upon the type of formulation, and is readily discernible to
those of ordinary skill in the art. The pharmaceutical compositions
provided herein may contain from about 0.6 to about 16% or from
about 1 to about 6% by weight of a disintegrant.
[0837] Suitable lubricants include, but are not limited to, calcium
stearate; magnesium stearate; mineral oil; light mineral oil;
glycerin; sorbitol; mannitol; glycols, such as glycerol behenate
and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate;
talc; hydrogenated vegetable oil, including peanut oil, cottonseed
oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean
oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch;
lycopodium; silica or silica gels, such as AEROSIL.RTM. 200 (W.R.
Grace Co., Baltimore, Md.) and CAB-O-SIL.RTM. (Cabot Co. of Boston,
Mass.); and mixtures thereof. The pharmaceutical compositions
provided herein may contain about 0.1 to about 6% by weight of a
lubricant.
[0838] Suitable glidants include, but are not limited to, colloidal
silicon dioxide, CAB-O-SIL.RTM. (Cabot Co. of Boston, Mass.), and
asbestos-free talc. Suitable coloring agents include, but are not
limited to, any of the approved, certified, water soluble FD&C
dyes, and water insoluble FD&C dyes suspended on alumina
hydrate, and color lakes and mixtures thereof. A color lake is the
combination by adsorption of a water-soluble dye to a hydrous oxide
of a heavy metal, resulting in an insoluble form of the dye.
Suitable flavoring agents include, but are not limited to, natural
flavors extracted from plants, such as fruits, and synthetic blends
of compounds which produce a pleasant taste sensation, such as
peppermint and methyl salicylate. Suitable sweetening agents
include, but are not limited to, sucrose, lactose, mannitol,
syrups, glycerin, and artificial sweeteners, such as saccharin and
aspartame. Suitable emulsifying agents include, but are not limited
to, gelatin, acacia, tragacanth, bentonite, and surfactants, such
as polyoxyethylene sorbitan monooleate (TWEEN.RTM. 20),
polyoxyethylene sorbitan monooleate 80 (TWEEN.RTM. 80), and
triethanolamine oleate. Suitable suspending and dispersing agents
include, but are not limited to, sodium carboxymethylcellulose,
pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose,
hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable
preservatives include, but are not limited to, glycerin, methyl and
propylparaben, benzoic add, sodium benzoate and alcohol. Suitable
wetting agents include, but are not limited to, propylene glycol
monostearate, sorbitan monooleate, diethylene glycol monolaurate,
and polyoxyethylene lauryl ether. Suitable solvents include, but
are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup.
Suitable non-aqueous liquids utilized in emulsions include, but are
not limited to, mineral oil and cottonseed oil. Suitable organic
acids include, but are not limited to, citric and tartaric acid.
Suitable sources of carbon dioxide include, but are not limited to,
sodium bicarbonate and sodium carbonate.
[0839] It should be understood that many carriers and excipients
may serve several functions, even within the same formulation.
[0840] The pharmaceutical compositions provided herein for oral
administration can be provided as compressed tablets, tablet
triturates, chewable lozenges, rapidly dissolving tablets, multiple
compressed tablets, or enteric-coating tablets, sugar-coated, or
film-coated tablets. Enteric-coated tablets are compressed tablets
coated with substances that resist the action of stomach acid but
dissolve or disintegrate in the intestine, thus protecting the
active ingredients from the acidic environment of the stomach.
Enteric-coatings include, but are not limited to, fatty acids,
fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and
cellulose acetate phthalates. Sugar-coated tablets are compressed
tablets surrounded by a sugar coating, which may be beneficial in
covering up objectionable tastes or odors and in protecting the
tablets from oxidation. Film-coated tablets are compressed tablets
that are covered with a thin layer or film of a water-soluble
material. Film coatings include, but are not limited to,
hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene
glycol 4000, and cellulose acetate phthalate. Film coating imparts
the same general characteristics as sugar coating. Multiple
compressed tablets are compressed tablets made by more than one
compression cycle, including layered tablets, and press-coated or
dry-coated tablets.
[0841] The tablet dosage forms can be prepared from the active
ingredient in powdered, crystalline, or granular forms, alone or in
combination with one or more carriers or excipients described
herein, including binders, disintegrants, controlled-release
polymers, lubricants, diluents, and/or colorants. Flavoring and
sweetening agents are especially useful in the formation of
chewable tablets and lozenges.
[0842] The pharmaceutical compositions provided herein for oral
administration can be provided as soft or hard capsules, which can
be made from gelatin, methylcellulose, starch, or calcium alginate.
The hard gelatin capsule, also known as the dry-filled capsule
(DFC), consists of two sections, one slipping over the other, thus
completely enclosing the active ingredient. The soft elastic
capsule (SEC) is a soft, globular shell, such as a gelatin shell,
which is plasticized by the addition of glycerin, sorbitol, or a
similar polyol. The soft gelatin shells may contain a preservative
to prevent the growth of microorganisms. Suitable preservatives are
those as described herein, including methyl- and propyl-parabens,
and sorbic acid. The liquid, semisolid, and solid dosage forms
provided herein may be encapsulated in a capsule. Suitable liquid
and semisolid dosage forms include solutions and suspensions in
propylene carbonate, vegetable oils, or triglycerides. Capsules
containing such solutions can be prepared as described in U.S. Pat.
Nos. 4,328,246; 4,409,239; and 4,410,646. The capsules may also be
coated as known by those of skill in the art in order to modify or
sustain dissolution of the active ingredient.
[0843] The pharmaceutical compositions provided herein for oral
administration can be provided in liquid and semisolid dosage
forms, including emulsions, solutions, suspensions, elixirs, and
syrups. An emulsion is a two-phase system, in which one liquid is
dispersed in the form of small globules throughout another liquid,
which can be oil-in-water or water-in-oil. Emulsions may include a
pharmaceutically acceptable non-aqueous liquid or solvent,
emulsifying agent, and preservative. Suspensions may include a
pharmaceutically acceptable suspending agent and preservative.
Aqueous alcoholic solutions may include a pharmaceutically
acceptable acetal, such as a di(lower alkyl) acetal of a lower
alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and a
water-miscible solvent having one or more hydroxyl groups, such as
propylene glycol and ethanol. Elixirs are clear, sweetened, and
hydroalcoholic solutions. Syrups are concentrated aqueous solutions
of a sugar, for example, sucrose, and may also contain a
preservative. For a liquid dosage form, for example, a solution in
a polyethylene glycol may be diluted with a sufficient quantity of
a pharmaceutically acceptable liquid carrier, e.g., water, to be
measured conveniently for administration.
[0844] Other useful liquid and semisolid dosage forms include, but
are not limited to, those containing the active ingredient(s)
provided herein, and a dialkylated mono- or poly-alkylene glycol,
including, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme,
polyethylene glycol-360-dimethyl ether, polyethylene
glycol-660-dimethyl ether, polyethylene glycol-760-dimethyl ether,
wherein 360, 660, and 760 refer to the approximate average
molecular weight of the polyethylene glycol. These formulations can
further comprise one or more antioxidants, such as butylated
hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl
gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,
lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric
acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its
esters, and dithiocarbamates.
[0845] The pharmaceutical compositions provided herein for oral
administration can be also provided in the forms of liposomes,
micelles, microspheres, or nanosystems. Micellar dosage forms can
be prepared as described in U.S. Pat. No. 7,360,468.
[0846] The pharmaceutical compositions provided herein for oral
administration can be provided as non-effervescent or effervescent,
granules and powders, to be reconstituted into a liquid dosage
form. Pharmaceutically acceptable carriers and excipients used in
the non-effervescent granules or powders may include diluents,
sweeteners, and wetting agents. Pharmaceutically acceptable
carriers and excipients used in the effervescent granules or
powders may include organic acids and a source of carbon
dioxide.
[0847] Coloring and flavoring agents can be used in all of the
above dosage forms.
[0848] The pharmaceutical compositions provided herein for oral
administration can be formulated as immediate or modified release
dosage forms, including delayed-, sustained, pulsed-, controlled,
targeted-, and programmed-release forms.
B. Parenteral Administration
[0849] The pharmaceutical compositions provided herein can be
administered parenterally by injection, infusion, or implantation,
for local or systemic administration. Parenteral administration, as
used herein, include intravenous, intraarterial, intraperitoneal,
intrathecal, intraventricular, intraurethral, intrasternal,
intracranial, intramuscular, intrasynovial, intravesical, and
subcutaneous administration.
[0850] The pharmaceutical compositions provided herein for
parenteral administration can be formulated in any dosage forms
that are suitable for parenteral administration, including
solutions, suspensions, emulsions, micelles, liposomes,
microspheres, nanosystems, and solid forms suitable for solutions
or suspensions in liquid prior to injection. Such dosage forms can
be prepared according to conventional methods known to those
skilled in the art of pharmaceutical science (see, Remington: The
Science and Practice of Pharmacy, supra).
[0851] The pharmaceutical compositions intended for parenteral
administration can include one or more pharmaceutically acceptable
carriers and excipients, including, but not limited to, aqueous
vehicles, water-miscible vehicles, non-aqueous vehicles,
antimicrobial agents or preservatives against the growth of
microorganisms, stabilizers, solubility enhancers, isotonic agents,
buffering agents, antioxidants, local anesthetics, suspending and
dispersing agents, wetting or emulsifying agents, complexing
agents, sequestering or chelating agents, cryoprotectants,
lyoprotectants, thickening agents, pH adjusting agents, and inert
gases.
[0852] Suitable aqueous vehicles include, but are not limited to,
water, saline, physiological saline or phosphate buffered saline
(PBS), sodium chloride injection, Ringers injection, isotonic
dextrose injection, sterile water injection, dextrose and lactated
Ringers injection. Suitable non-aqueous vehicles include, but are
not limited to, fixed oils of vegetable origin, castor oil, corn
oil, cottonseed oil, olive oil, peanut oil, peppermint oil,
safflower oil, sesame oil, soybean oil, hydrogenated vegetable
oils, hydrogenated soybean oil, and medium-chain triglycerides of
coconut oil, and palm seed oil. Suitable water-miscible vehicles
include, but are not limited to, ethanol, 1,3-butanediol, liquid
polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene
glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone,
N,N-dimethylacetamide, and dimethyl sulfoxide.
[0853] Suitable antimicrobial agents or preservatives include, but
are not limited to, phenols, cresols, mercurials, benzyl alcohol,
chlorobutanol, methyl and propyl p-hydroxybenzoates, thimerosal,
benzalkonium chloride (e.g., benzethonium chloride), methyl- and
propyl-parabens, and sorbic acid. Suitable isotonic agents include,
but are not limited to, sodium chloride, glycerin, and dextrose.
Suitable buffering agents include, but are not limited to,
phosphate and citrate. Suitable antioxidants are those as described
herein, including bisulfite and sodium metabisulfite. Suitable
local anesthetics include, but are not limited to, procaine
hydrochloride. Suitable suspending and dispersing agents are those
as described herein, including sodium carboxymethylcelluose,
hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable
emulsifying agents are those described herein, including
polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan
monooleate 80, and triethanolamine oleate. Suitable sequestering or
chelating agents include, but are not limited to EDTA. Suitable pH
adjusting agents include, but are not limited to, sodium hydroxide,
hydrochloric acid, citric acid, and lactic acid. Suitable
complexing agents include, but are not limited to, cyclodextrins,
including .alpha.-cyclodextrin, .beta.-cyclodextrin,
hydroxypropyl-.beta.-cyclodextrin,
sulfobutylether-.beta.-cyclodextrin, and sulfobutylether
7-.beta.-cyclodextrin (CAPTISOL.RTM., CyDex, Lenexa, Kans.).
[0854] When the pharmaceutical compositions provided herein are
formulated for multiple dosage administration, the multiple dosage
parenteral formulations must contain an antimicrobial agent at
bacteriostatic or fungistatic concentrations. All parenteral
formulations must be sterile, as known and practiced in the
art.
[0855] In one embodiment, the pharmaceutical compositions for
parenteral administration are provided as ready-to-use sterile
solutions. In another embodiment, the pharmaceutical compositions
are provided as sterile dry soluble products, including lyophilized
powders and hypodermic tablets, to be reconstituted with a vehicle
prior to use. In yet another embodiment, the pharmaceutical
compositions are provided as ready-to-use sterile suspensions. In
yet another embodiment, the pharmaceutical compositions are
provided as sterile dry insoluble products to be reconstituted with
a vehicle prior to use. In still another embodiment, the
pharmaceutical compositions are provided as ready-to-use sterile
emulsions.
[0856] The pharmaceutical compositions provided herein for
parenteral administration can be formulated as immediate or
modified release dosage forms, including delayed-, sustained,
pulsed-, controlled, targeted-, and programmed-release forms.
[0857] The pharmaceutical compositions provided herein for
parenteral administration can be formulated as a suspension, solid,
semi-solid, or thixotropic liquid, for administration as an
implanted depot. In one embodiment, the pharmaceutical compositions
provided herein are dispersed in a solid inner matrix, which is
surrounded by an outer polymeric membrane that is insoluble in body
fluids but allows the active ingredient in the pharmaceutical
compositions diffuse through.
[0858] Suitable inner matrixes include, but are not limited to,
polymethylmethacrylate, polybutyl-methacrylate, plasticized or
unplasticized polyvinylchloride, plasticized nylon, plasticized
polyethylene terephthalate, natural rubber, polyisoprene,
polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl
acetate copolymers, silicone rubbers, polydimethylsiloxanes,
silicone carbonate copolymers, hydrophilic polymers, such as
hydrogels of esters of acrylic and methacrylic acid, collagen,
cross-linked polyvinyl alcohol, and cross-linked partially
hydrolyzed polyvinyl acetate.
[0859] Suitable outer polymeric membranes include but are not
limited to, polyethylene, polypropylene, ethylene/propylene
copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl
acetate copolymers, silicone rubbers, polydimethyl siloxanes,
neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl
chloride copolymers with vinyl acetate, vinylidene chloride,
ethylene and propylene, ionomer polyethylene terephthalate, butyl
rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,
ethylene/vinyl acetate/vinyl alcohol terpolymer, and
ethylene/vinyloxyethanol copolymer.
C. Topical Administration
[0860] The pharmaceutical compositions provided herein can be
administered topically to the skin, orifices, or mucosa. The
topical administration, as used herein, includes (intra)dermal,
conjunctival, intracorneal, intraocular, ophthalmic, auricular,
transdermal, nasal, vaginal, urethral, respiratory, and rectal
administration.
[0861] The pharmaceutical compositions provided herein can be
formulated in any dosage forms that are suitable for topical
administration for local or systemic effect, including emulsions,
solutions, suspensions, creams, gels, hydrogels, ointments, dusting
powders, dressings, elixirs, lotions, suspensions, tinctures,
pastes, foams, films, aerosols, irrigations, sprays, suppositories,
bandages, and dermal patches. The topical formulation of the
pharmaceutical compositions provided herein can also comprise
liposomes, micelles, microspheres, nanosystems, and mixtures
thereof.
[0862] Pharmaceutically acceptable carriers and excipients suitable
for use in the topical formulations provided herein include, but
are not limited to, aqueous vehicles, water-miscible vehicles,
non-aqueous vehicles, antimicrobial agents or preservatives against
the growth of microorganisms, stabilizers, solubility enhancers,
isotonic agents, buffering agents, antioxidants, local anesthetics,
suspending and dispersing agents, wetting or emulsifying agents,
complexing agents, sequestering or chelating agents, penetration
enhancers, cryoprotectants, lyoprotectants, thickening agents, and
inert gases.
[0863] The pharmaceutical compositions can also be administered
topically by electroporation, iontophoresis, phonophoresis,
sonophoresis, or microneedle or needle-free injection, such as
POWDERJECT.TM. (Chiron Corp., Emeryville, Calif.), and BIOJECT.TM.
(Bioject Medical Technologies Inc., Tualatin, Oreg.).
[0864] The pharmaceutical compositions provided herein can be
provided in the forms of ointments, creams, and gels. Suitable
ointment vehicles include oleaginous or hydrocarbon vehicles,
including lard, benzoinated lard, olive oil, cottonseed oil, and
other oils, white petrolatum; emulsifiable or absorption vehicles,
such as hydrophilic petrolatum, hydroxystearin sulfate, and
anhydrous lanolin; water-removable vehicles, such as hydrophilic
ointment; water-soluble ointment vehicles, including polyethylene
glycols of varying molecular weight; emulsion vehicles, either
water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions,
including cetyl alcohol, glyceryl monostearate, lanolin, and
stearic acid (see, Remington: The Science and Practice of Pharmacy,
supra). These vehicles are emollient but generally require addition
of antioxidants and preservatives.
[0865] Suitable cream base can be oil-in-water or water-in-oil.
Suitable cream vehicles may be water-washable, and contain an oil
phase, an emulsifier, and an aqueous phase. The oil phase is also
called the "internal" phase, which is generally comprised of
petrolatum and a fatty alcohol such as cetyl or stearyl alcohol.
The aqueous phase usually, although not necessarily, exceeds the
oil phase in volume, and generally contains a humectant. The
emulsifier in a cream formulation may be a nonionic, anionic,
cationic, or amphoteric surfactant.
[0866] Gels are semisolid, suspension-type systems. Single-phase
gels contain organic macromolecules distributed substantially
uniformly throughout the liquid carrier. Suitable gelling agents
include, but are not limited to, crosslinked acrylic acid polymers,
such as carbomers, carboxypolyalkylenes, and CARBOPOL.RTM.;
hydrophilic polymers, such as polyethylene oxides,
polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol;
cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethyl
cellulose, hydroxypropyl methylcellulose, hydroxypropyl
methylcellulose phthalate, and methylcellulose; gums, such as
tragacanth and xanthan gum; sodium alginate; and gelatin. In order
to prepare a uniform gel, dispersing agents such as alcohol or
glycerin can be added, or the gelling agent can be dispersed by
trituration, mechanical mixing, and/or stirring.
[0867] The pharmaceutical compositions provided herein can be
administered rectally, urethrally, vaginally, or perivaginally in
the forms of suppositories, pessaries, bougies, poultices or
cataplasm, pastes, powders, dressings, creams, plasters,
contraceptives, ointments, solutions, emulsions, suspensions,
tampons, gels, foams, sprays, or enemas. These dosage forms can be
manufactured using conventional processes as described in
Remington: The Science and Practice of Pharmacy, supra.
[0868] Rectal, urethral, and vaginal suppositories are solid bodies
for insertion into body orifices, which are solid at ordinary
temperatures but melt or soften at body temperature to release the
active ingredient(s) inside the orifices. Pharmaceutically
acceptable carriers utilized in rectal and vaginal suppositories
include bases or vehicles, such as stiffening agents, which produce
a melting point in the proximity of body temperature, when
formulated with the pharmaceutical compositions provided herein;
and antioxidants as described herein, including bisulfite and
sodium metabisulfite. Suitable vehicles include, but are not
limited to, cocoa butter (theobroma oil), glycerin-gelatin,
carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and
yellow wax, and appropriate mixtures of mono-, di- and
triglycerides of fatty acids, and hydrogels, such as polyvinyl
alcohol, hydroxyethyl methacrylate, and polyacrylic acid.
Combinations of the various vehicles can also be used. Rectal and
vaginal suppositories may be prepared by compressing or molding.
The typical weight of a rectal and vaginal suppository is about 2
to about 3 g.
[0869] The pharmaceutical compositions provided herein can be
administered ophthalmically in the forms of solutions, suspensions,
ointments, emulsions, gel-forming solutions, powders for solutions,
gels, ocular inserts, and implants.
[0870] The pharmaceutical compositions provided herein can be
administered intranasally or by inhalation to the respiratory
tract. The pharmaceutical compositions can be provided in the form
of an aerosol or solution for delivery using a pressurized
container, pump, spray, atomizer, such as an atomizer using
electrohydrodynamics to produce a fine mist, or nebulizer, alone or
in combination with a suitable propellant, such as
1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. The
pharmaceutical compositions can also be provided as a dry powder
for insufflation, alone or in combination with an inert carrier
such as lactose or phospholipids; and nasal drops. For intranasal
use, the powder can comprise a bioadhesive agent, including
chitosan or cyclodextrin.
[0871] Solutions or suspensions for use in a pressurized container,
pump, spray, atomizer, or nebulizer can be formulated to contain
ethanol, aqueous ethanol, or a suitable alternative agent for
dispersing, solubilizing, or extending release of the active
ingredient provided herein; a propellant as solvent; and/or a
surfactant, such as sorbitan trioleate, oleic acid, or an
oligolactic acid.
[0872] The pharmaceutical compositions provided herein can be
micronized to a size suitable for delivery by inhalation, such as
about 60 micrometers or less, or about 10 micrometers or less.
Particles of such sizes can be prepared using a comminuting method
known to those skilled in the art, such as spiral jet milling,
fluid bed jet milling, supercritical fluid processing to form
nanoparticles, high pressure homogenization, or spray drying.
[0873] Capsules, blisters, and cartridges for use in an inhaler or
insufflator can be formulated to contain a powder mix of the
pharmaceutical compositions provided herein; a suitable powder
base, such as lactose or starch; and a performance modifier, such
as l-leucine, mannitol, or magnesium stearate. The lactose may be
anhydrous or in the form of the monohydrate. Other suitable
excipients or carriers include, but are not limited to, dextran,
glucose, maltose, sorbitol, xylitol, fructose, sucrose, and
trehalose. The pharmaceutical compositions provided herein for
inhaled/intranasal administration can further comprise a suitable
flavor, such as menthol and levomenthol; and/or sweeteners, such as
saccharin and saccharin sodium.
[0874] The pharmaceutical compositions provided herein for topical
administration can be formulated to be immediate release or
modified release, including delayed-, sustained-, pulsed-,
controlled-, targeted, and programmed release.
D. Modified Release
[0875] The pharmaceutical compositions provided herein can be
formulated as a modified release dosage form. As used herein, the
term "modified release" refers to a dosage form in which the rate
or place of release of the active ingredient(s) is different from
that of an immediate dosage form when administered by the same
route. Modified release dosage forms include, but are not limited
to, delayed-, extended-, prolonged-, sustained-, pulsatile-,
controlled-, accelerated- and fast-, targeted-, programmed-release,
and gastric retention dosage forms. The pharmaceutical compositions
in modified release dosage forms can be prepared using a variety of
modified release devices and methods known to those skilled in the
art, including, but not limited to, matrix controlled release
devices, osmotic controlled release devices, multiparticulate
controlled release devices, ion-exchange resins, enteric coatings,
multilayered coatings, microspheres, liposomes, and combinations
thereof. The release rate of the active ingredient(s) can also be
modified by varying the particle sizes and polymorphorism of the
active ingredient(s).
[0876] Examples of modified release include, but are not limited
to, those described in U.S. Pat. Nos. 3,846,770; 3,917,899;
3,637,809; 3,698,123; 4,008,719; 6,774,633; 6,069,696; 6,691,777;
6,120,648; 6,073,643; 6,739,477; 6,364,667; 6,739,480; 6,733,677;
6,739,108; 6,891,474; 6,922,367; 6,972,891; 6,980,946; 6,993,866;
7,046,830; 7,087,324; 7,113,943; 7,197,360; 7,248,373; 7,274,970;
7,277,981; 7,377,471; 7,419,971; 7,689,648; 7,713,368; and
7,799,600.
1. Matrix Controlled Release Devices
[0877] The pharmaceutical compositions provided herein in a
modified release dosage form can be fabricated using a matrix
controlled release device known to those skilled in the art (see,
Takada et al. in "Encyclopedia of Controlled Drug Delivery," Vol.
2, Mathiowitz Ed., Wiley, 1999).
[0878] In certain embodiments, the pharmaceutical compositions
provided herein in a modified release dosage form is formulated
using an erodible matrix device, which is water-swellable,
erodible, or soluble polymers, including, but not limited to,
synthetic polymers, and naturally occurring polymers and
derivatives, such as polysaccharides and proteins.
[0879] Materials useful in forming an erodible matrix include, but
are not limited to, chitin, chitosan, dextran, and pullulan; gum
agar, gum arabic, gum karaya, locust bean gum, gum tragacanth,
carrageenans, gum ghatti, guar gum, xanthan gum, and scleroglucan;
starches, such as dextrin and maltodextrin; hydrophilic colloids,
such as pectin; phosphatides, such as lecithin; alginates;
propylene glycol alginate; gelatin; collagen; cellulosics, such as
ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl
cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl
cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP),
cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP,
CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS,
hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and
ethyl hydroxyethyl cellulose (EHEC); polyvinyl pyrrolidone;
polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters;
polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or
methacrylic acid (EUDRAGIT.RTM., Rohm America, Inc., Piscataway,
N.J.); poly(2-hydroxyethyl-methacrylate); polylactides; copolymers
of L-glutamic acid and ethyl-L-glutamate; degradable lactic
acid-glycolic acid copolymers; poly-D-(-)-3-hydroxybutyric acid;
and other acrylic acid derivatives, such as homopolymers and
copolymers of butylmethacrylate, methyl methacrylate, ethyl
methacrylate, ethylacrylate, (2-dimethylaminoethyl)methacrylate,
and (trimethylaminoethyl)methacrylate chloride.
[0880] In certain embodiments, the pharmaceutical compositions
provided herein are formulated with a non-erodible matrix device.
The active ingredient(s) is dissolved or dispersed in an inert
matrix and is released primarily by diffusion through the inert
matrix once administered. Materials suitable for use as a
non-erodible matrix device include, but are not limited to,
insoluble plastics, such as polyethylene, polypropylene,
polyisoprene, polyisobutylene, polybutadiene,
polymethylmethacrylate, polybutylmethacrylate, chlorinated
polyethylene, polyvinylchloride, methyl acrylate-methyl
methacrylate copolymers, ethylene-vinyl acetate copolymers,
ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,
vinyl chloride copolymers with vinyl acetate, vinylidene chloride,
ethylene and propylene, ionomer polyethylene terephthalate, butyl
rubbers, epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,
ethylene/vinyl acetate/vinyl alcohol terpolymer,
ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticized
nylon, plasticized polyethylene terephthalate, natural rubber,
silicone rubbers, polydimethylsiloxanes, and silicone carbonate
copolymers; hydrophilic polymers, such as ethyl cellulose,
cellulose acetate, crospovidone, and cross-linked partially
hydrolyzed polyvinyl acetate; and fatty compounds, such as carnauba
wax, microcrystalline wax, and triglycerides.
[0881] In a matrix controlled release system, the desired release
kinetics can be controlled, for example, via the polymer type
employed, the polymer viscosity, the particle sizes of the polymer
and/or the active ingredient(s), the ratio of the active
ingredient(s) versus the polymer, and other excipients or carriers
in the compositions.
[0882] The pharmaceutical compositions provided herein in a
modified release dosage form can be prepared by methods known to
those skilled in the art, including direct compression, dry or wet
granulation followed by compression, and melt-granulation followed
by compression.
2. Osmotic Controlled Release Devices
[0883] The pharmaceutical compositions provided herein in a
modified release dosage form can be fabricated using an osmotic
controlled release device, including, but not limited to,
one-chamber system, two-chamber system, asymmetric membrane
technology (AMT), and extruding core system (ECS). In general, such
devices have at least two components: (a) a core that contains an
active ingredient; and (b) a semipermeable membrane with at least
one delivery port, which encapsulates the core. The semipermeable
membrane controls the influx of water to the core from an aqueous
environment of use so as to cause drug release by extrusion through
the delivery port(s).
[0884] In addition to the active ingredient(s), the core of the
osmotic device optionally includes an osmotic agent, which creates
a driving force for transport of water from the environment of use
into the core of the device. One class of osmotic agents is
water-swellable hydrophilic polymers, which are also referred to as
"osmopolymers" and "hydrogels." Suitable water-swellable
hydrophilic polymers as osmotic agents include, but are not limited
to, hydrophilic vinyl and acrylic polymers, polysaccharides such as
calcium alginate, polyethylene oxide (PEO), polyethylene glycol
(PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl
methacrylate), poly(acrylic) acid, poly(methacrylic) acid,
polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol
(PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic
monomers such as methyl methacrylate and vinyl acetate, hydrophilic
polyurethanes containing large PEO blocks, sodium croscarmellose,
carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose
(HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl
cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate,
polycarbophil, gelatin, xanthan gum, and sodium starch
glycolate.
[0885] The other class of osmotic agents is osmogens, which are
capable of imbibing water to affect an osmotic pressure gradient
across the barrier of the surrounding coating. Suitable osmogens
include, but are not limited to, inorganic salts, such as magnesium
sulfate, magnesium chloride, calcium chloride, sodium chloride,
lithium chloride, potassium sulfate, potassium phosphates, sodium
carbonate, sodium sulfite, lithium sulfate, potassium chloride, and
sodium sulfate; sugars, such as dextrose, fructose, glucose,
inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose,
trehalose, and xylitol; organic acids, such as ascorbic acid,
benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid,
sorbic acid, adipic acid, edetic acid, glutamic acid,
p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and
mixtures thereof.
[0886] Osmotic agents of different dissolution rates can be
employed to influence how rapidly the active ingredient(s) is
initially delivered from the dosage form. For example, amorphous
sugars, such as MANNOGEM.TM. EZ (SPI Pharma, Lewes, Del.) can be
used to provide faster delivery during the first couple of hours to
promptly produce the desired therapeutic effect, and gradually and
continually release of the remaining amount to maintain the desired
level of therapeutic or prophylactic effect over an extended period
of time. In this case, the active ingredient(s) is released at such
a rate to replace the amount of the active ingredient metabolized
and excreted.
[0887] The core can also include a wide variety of other excipients
and carriers as described herein to enhance the performance of the
dosage form or to promote stability or processing.
[0888] Materials useful in forming the semipermeable membrane
include various grades of acrylics, vinyls, ethers, polyamides,
polyesters, and cellulosic derivatives that are water-permeable and
water-insoluble at physiologically relevant pHs, or are susceptible
to being rendered water-insoluble by chemical alteration, such as
crosslinking. Examples of suitable polymers useful in forming the
coating, include plasticized, unplasticized, and reinforced
cellulose acetate (CA), cellulose diacetate, cellulose triacetate,
CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB),
CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate,
cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA
ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl
sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar
acetate, amylose triacetate, beta glucan acetate, beta glucan
triacetate, acetaldehyde dimethyl acetate, triacetate of locust
bean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG
copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT,
poly(acrylic) acids and esters and poly-(methacrylic) acids and
esters and copolymers thereof, starch, dextran, dextrin, chitosan,
collagen, gelatin, polyalkenes, polyethers, polysulfones,
polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl
esters and ethers, natural waxes, and synthetic waxes.
[0889] Semipermeable membrane can also be a hydrophobic microporous
membrane, wherein the pores are substantially filled with a gas and
are not wetted by the aqueous medium but are permeable to water
vapor, as disclosed in U.S. Pat. No. 6,798,119. Such hydrophobic
but water-vapor permeable membrane are typically composed of
hydrophobic polymers such as polyalkenes, polyethylene,
polypropylene, polytetrafluoroethylene, polyacrylic acid
derivatives, polyethers, polysulfones, polyethersulfones,
polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl
esters and ethers, natural waxes, and synthetic waxes.
[0890] The delivery port(s) on the semipermeable membrane can be
formed post-coating by mechanical or laser drilling. Delivery
port(s) can also be formed in situ by erosion of a plug of
water-soluble material or by rupture of a thinner portion of the
membrane over an indentation in the core. In addition, delivery
ports can be formed during coating process, as in the case of
asymmetric membrane coatings of the type disclosed in U.S. Pat.
Nos. 6,712,069 and 6,798,220.
[0891] The total amount of the active ingredient(s) released and
the release rate can substantially by modulated via the thickness
and porosity of the semipermeable membrane, the composition of the
core, and the number, size, and position of the delivery ports.
[0892] The pharmaceutical compositions in an osmotic
controlled-release dosage form can further comprise additional
conventional excipients or carriers as described herein to promote
performance or processing of the formulation.
[0893] The osmotic controlled-release dosage forms can be prepared
according to conventional methods and techniques known to those
skilled in the art (see, Remington: The Science and Practice of
Pharmacy, supra; Santus and Baker, J. Controlled Release 1996, 36,
1-21; Verma et al., Drug Development and Industrial Pharmacy 2000,
27, 796-708; Verma et al., J. Controlled Release 2002, 79,
7-27).
[0894] In certain embodiments, the pharmaceutical compositions
provided herein are formulated as AMT controlled-release dosage
form, which comprises an asymmetric osmotic membrane that coats a
core comprising the active ingredient(s) and other pharmaceutically
acceptable excipients or carriers. See, U.S. Pat. No. 6,712,069 and
WO 2002/17918. The AMT controlled-release dosage forms can be
prepared according to conventional methods and techniques known to
those skilled in the art, including direct compression, dry
granulation, wet granulation, and a dip-coating method.
[0895] In certain embodiments, the pharmaceutical compositions
provided herein are formulated as ESC controlled-release dosage
form, which comprises an osmotic membrane that coats a core
comprising the active ingredient(s), a hydroxylethyl cellulose, and
other pharmaceutically acceptable excipients or carriers.
3. Multiparticulate Controlled Release Devices
[0896] The pharmaceutical compositions provided herein in a
modified release dosage form can be fabricated as a
multiparticulate controlled release device, which comprises a
multiplicity of particles, granules, or pellets, ranging from about
10 .mu.m to about 3 mm, about 60 .mu.m to about 2.6 mm, or from
about 100 .mu.m to about 1 mm in diameter. Such multiparticulates
can be made by the processes known to those skilled in the art,
including wet- and dry-granulation, extrusion/spheronization,
roller-compaction, melt-congealing, and by spray-coating seed
cores. See, for example, Multiparticulate Oral Drug Delivery;
Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology;
Marcel Dekker: 1989.
[0897] Other excipients or carriers as described herein can be
blended with the pharmaceutical compositions to aid in processing
and forming the multiparticulates. The resulting particles can
themselves constitute the multiparticulate device or can be coated
by various film-forming materials, such as enteric polymers,
water-swellable, and water-soluble polymers. The multiparticulates
can be further processed as a capsule or a tablet.
4. Targeted Delivery
[0898] The pharmaceutical compositions provided herein can also be
formulated to be targeted to a particular tissue, receptor, or
other area of the body of the subject to be treated, including
liposome-, resealed erythrocyte-, and antibody-based delivery
systems. Examples include, but are not limited to, those disclosed
in U.S. Pat. Nos. 7,317,762; 7,274,662; 7,271,369; 7,263,872;
7,139,876; 7,131,670; 7,120,761; 7,071,496; 7,070,082; 7,048,737;
7,039,976; 7,004,634; 6,986,307; 6,972,377; 6,900,262; 6,840,774;
6,769,642; and 6,709,874.
Methods of Use
[0899] In one embodiment, provided herein is a method of treating,
ameliorating, or preventing a proliferative disease in a subject,
comprising administering to the subject a compound provided herein,
e.g., a compound of Formula I or IA, including an enantiomer, a
mixture of enantiomers, or a mixture of diastereomers thereof, or a
pharmaceutically acceptable salt, solvate, or prodrug thereof.
[0900] In certain embodiments, the proliferative disease is cancer.
In certain embodiments, the cancer is bladder cancer, breast
cancer, cervical cancer, colon cancer (e.g., colorectal cancer),
esophageal cancer, glioma, glioblastoma multiforme, head and neck
cancer, leukemia (e.g., acute myelogenous leukemia (AML) or chronic
myeloid leukemia (CML)), liver cancer, lung cancer (e.g., small
cell and non-small cell lung cancer), lymphoma, melanoma, myeloma,
neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer,
renal cancer, salivary gland cancer, sarcoma (e.g., osteosarcoma),
skin cancer (e.g., squamous cell carcinoma), stomach cancer,
testicular cancer, thyroid cancer, or uterine cancer. In certain
embodiments, the cancer is leukemia, melanoma, breast cancer,
prostate cancer, or colorectal cancer.
[0901] In certain embodiments, the cancer is metastatic. In certain
embodiments, the cancer is refractory. In certain embodiments, the
cancer is relapsed. In certain embodiments, the cancer is
drug-resistant.
[0902] In certain embodiments, the subject to be treated with one
of the methods provided herein has not been treated with anticancer
therapy for the proliferative disease to be treated prior to the
administration of a compound provided herein, e.g., a compound of
Formula I or IA, including an enantiomer, a mixture of enantiomers,
a mixture of two or more diastereomers, a tautomer, a mixture of
two or more tautomers, or an isotopic variant thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof.
[0903] In certain embodiments, the subject to be treated with one
of the methods provided herein has been treated with anticancer
therapy for the proliferative disease to be treated prior to the
administration of a compound provided herein, e.g., a compound of
Formula I or IA, including an enantiomer, a mixture of enantiomers,
a mixture of two or more diastereomers, a tautomer, a mixture of
two or more tautomers, or an isotopic variant thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof.
[0904] In certain embodiments, provided herein is a method for
treating a subject who has undergone surgery in an attempt to treat
the disease or condition at issue, as well as the one who have not.
Because the subjects with cancer have heterogeneous clinical
manifestations and varying clinical outcomes, the treatment given
to a particular subject may vary, depending on his/her prognosis.
The skilled clinician will be able to readily determine without
undue experimentation, specific secondary agents, types of surgery,
and types of non-drug based standard therapy that can be
effectively used to treat an individual subject with cancer.
[0905] In certain embodiments, the proliferative disease is an
inflammatory disease or disorder related to immune dysfunction,
immunodeficiency, or immunomodulation, including, but not limited
to, autoimmune diseases, tissue transplant rejection,
graft-versus-host disease, wound healing, kidney disease, multiple
sclerosis, thyroiditis, type 1 diabetes, sarcoidosis, allergic
rhinitis, inflammatory bowel diseases (including Crohn's disease
and ulcerative colitis (UC)), systemic lupus erythematosis (SLE),
arthritis, osteoarthritis, rheumatoid arthritis, osteoporosis,
asthma, and chronic obstructive pulmonary disease (COPD).
[0906] In another embodiment, provided herein is a method of
treating, preventing, or ameliorating one or more symptoms of
acquired immune deficiency syndrome (AIDS) in a subject, comprising
administering to the subject a compound of Formula I or IA, or an
enantiomer, a mixture of enantiomers, a mixture of two or more
diastereomers, a tautomer, a mixture of two or more tautomers, or
an isotopic variant thereof; or a pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof.
[0907] In yet another embodiment, provided herein is a method of
treating or preventing a virus infection in a subject, comprising
administering to the subject a compound of Formula I or IA, or an
enantiomer, a mixture of enantiomers, a mixture of two or more
diastereomers, a tautomer, a mixture of two or more tautomers, or
an isotopic variant thereof, or a pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof. In one embodiment, the virus
infection is a human immunodeficiency virus (HIV) infection.
[0908] In yet another embodiment, provided herein is a method of
treating, ameliorating, or preventing a skin disorder, disease, or
condition in a subject, comprising administering to the subject a
compound of Formula I or IA, or an enantiomer, a mixture of
enantiomers, a mixture of two or more diastereomers, a tautomer, a
mixture of two or more tautomers, or an isotopic variant thereof,
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof.
[0909] In one embodiment, the skin disorder, disease, or condition
is caused by UV overexposure. In another embodiment, the skin
disorder, disease, or condition is solar erythema, solar allergy,
solar urticaria, solar elastosis, photoaging, or a sunburn. In yet
another embodiment, the skin disorder, disease, or condition is a
sunburn. In yet another embodiment, the skin disorder, disease, or
condition is an acute sunburn. In yet another embodiment, the skin
disorder, disease, or condition is hypopigmentation. In yet another
embodiment, the skin disorder, disease, or condition is
hypomelanosis, idiopathic guttate hypomelanosis, lichen sclerosus,
leprosy, piebaldism, pityriasis alba, pityriasis versicolor,
progressive macular hypomelanosis, vitiligo, or Waardenburg
syndrome. In yet another embodiment, the skin disorder, disease, or
condition is vitiligo. In yet another embodiment, the skin
disorder, disease, or condition is a skin cancer. In still another
embodiment, the skin disorder, disease, or condition is actinic
keratosis, atypical mole, basel cell carcinoma (BCC), melanoma,
Merkel cell carcinoma (MCC), squamous cell carcinoma (SCC), or
cutaneous malignant melanoma.
[0910] In yet another embodiment, provided herein is a method of
protecting a subject from ultraviolet radiation, comprising
administering to the subject a compound of Formula I or IA, or an
enantiomer, a mixture of enantiomers, a mixture of two or more
diastereomers, a tautomer, a mixture of two or more tautomers, or
an isotopic variant thereof, or a pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof.
[0911] In yet another embodiment, provided herein is a method of
increasing skin pigmentation in a subject, comprising administering
to the subject a compound of Formula I or IA, or an enantiomer, a
mixture of enantiomers, a mixture of two or more diastereomers, a
tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof.
[0912] In yet another embodiment, provided herein is a method of
increasing eumelanin level in a subject, comprising administering
to the subject a compound of Formula I or IA, or an enantiomer, a
mixture of enantiomers, a mixture of two or more diastereomers, a
tautomer, a mixture of two or more tautomers, or an isotopic
variant thereof, or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof. In one embodiment, the method provided
herein for increasing eumelanin level is to increase the eumelanin
level selectively over the pheomelanin level. In another
embodiment, the method provided herein for increasing eumelanin
level is to increase the eumelanin level at least ten or more times
more than the pheomelanin level.
[0913] In yet another embodiment, provided herein is a method of
treating one or more symptoms of a disorder, disease, or condition
mediated by a CK1 in a subject, comprising administering to the
subject a compound of Formula I or IA, or an enantiomer, a mixture
of enantiomers, a mixture of two or more diastereomers, a tautomer,
a mixture of two or more tautomers, or an isotopic variant thereof,
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof.
[0914] In certain embodiments, the disorder, disease, or condition
mediated by a CK1 is a proliferative disease. In certain
embodiments, the disorder, disease, or condition mediated by a CK1
is a skin disorder, disease, or condition.
[0915] In yet another embodiment, provided herein is a method of
treating one or more symptoms of a disorder, disease, or condition
mediated by an IRAK1 in a subject, comprising administering to the
subject a compound of Formula I or IA, or an enantiomer, a mixture
of enantiomers, a mixture of two or more diastereomers, a tautomer,
a mixture of two or more tautomers, or an isotopic variant thereof;
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof.
[0916] In certain embodiments, the disorder, disease, or condition
mediated by an IRAK1 is a proliferative disease. In certain
embodiments, the disorder, disease, or condition mediated by an
IRAK1 is a skin disorder, disease, or condition.
[0917] In still another embodiment, provided herein is a method of
treating one or more symptoms of a disorder, disease, or condition
mediated by a CDK9 in a subject, comprising administering to the
subject a compound of Formula I or IA, or an enantiomer, a mixture
of enantiomers, a mixture of two or more diastereomers, a tautomer,
a mixture of two or more tautomers, or an isotopic variant thereof;
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof.
[0918] In certain embodiments, the disorder, disease, or condition
mediated by a CDK9 is an infectious disease. In certain
embodiments, the disorder, disease, or condition mediated by a CDK9
is a viral infection. In certain embodiments, the disorder,
disease, or condition mediated by a CDK9 is AIDS. In certain
embodiments, the disorder, disease, or condition mediated by a CDK9
is an HIV infection. In certain embodiments, the disorder, disease,
or condition mediated by a CDK9 is a proliferative disease.
[0919] The methods provided herein encompass treating a subject
regardless of patient's age, although some diseases or disorders
are more common in certain age groups.
[0920] Depending on the disease to be treated and the subject's
condition, a compound provided herein, e.g., a compound of Formula
I or IA, including an enantiomer, a mixture of enantiomers, a
mixture of two or more diastereomers, a tautomer, a mixture of two
or more tautomers, or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, may be administered by oral, parenteral (e.g.,
intramuscular, intraperitoneal, intravenous, CIV, intracistemal
injection or infusion, subcutaneous injection, or implant),
inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g.,
transdermal or local) routes of administration. A compound provided
herein, e.g., an enantiomer, a mixture of enantiomers, a mixture of
two or more diastereomers, a tautomer, a mixture of two or more
tautomers, or an isotopic variant thereof; or a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof, may be
formulated, alone or together, in suitable dosage unit with
pharmaceutically acceptable excipients, carriers, adjuvants and
vehicles, appropriate for each route of administration.
[0921] In one embodiment, a compound provided herein, e.g., a
compound of Formula I or IA, including an enantiomer, a mixture of
enantiomers, a mixture of two or more diastereomers, a tautomer, a
mixture of two or more tautomers, or an isotopic variant thereof,
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, is administered orally. In another embodiment, a compound
provided herein, e.g., a compound of Formula I or IA, including an
enantiomer, a mixture of enantiomers, a mixture of two or more
diastereomers, a tautomer, a mixture of two or more tautomers, or
an isotopic variant thereof, or a pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof, is administered parenterally.
In yet another embodiment, a compound provided herein, e.g., a
compound of Formula I or IA, including an enantiomer, a mixture of
enantiomers, a mixture of two or more diastereomers, a tautomer, a
mixture of two or more tautomers, or an isotopic variant thereof,
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, is administered intravenously. In yet another embodiment,
a compound provided herein, e.g., a compound of Formula I or IA,
including an enantiomer, a mixture of enantiomers, a mixture of two
or more diastereomers, a tautomer, a mixture of two or more
tautomers, or an isotopic variant thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof, is
administered intramuscularly. In yet another embodiment, a compound
provided herein, e.g., a compound of Formula I or IA, including an
enantiomer, a mixture of enantiomers, a mixture of two or more
diastereomers, a tautomer, a mixture of two or more tautomers, or
an isotopic variant thereof, or a pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof, is administered
subcutaneously. In still another embodiment, a compound provided
herein, e.g., a compound of Formula I or IA, including an
enantiomer, a mixture of enantiomers, a mixture of two or more
diastereomers, a tautomer, a mixture of two or more tautomers, or
an isotopic variant thereof, or a pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof, is administered
topically.
[0922] A compound provided herein, e.g., a compound of Formula I or
IA, including an enantiomer, a mixture of enantiomers, a mixture of
two or more diastereomers, a tautomer, a mixture of two or more
tautomers, or an isotopic variant thereof; or a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof, can be
delivered as a single dose such as, e.g., a single bolus injection,
or oral tablets or pills; or overtime such as, e.g., continuous
infusion over time or divided bolus doses over time. The compound
provided herein can be administered repetitively if necessary, for
example, until the patient experiences stable disease or
regression, or until the patient experiences disease progression or
unacceptable toxicity. Stable disease or lack thereof is determined
by methods known in the art such as evaluation of patient symptoms,
physical examination, visualization of the tumor that has been
imaged using X-ray, CAT, PET, or MRI scan and other commonly
accepted evaluation modalities.
[0923] A compound provided herein, e.g., a compound of Formula I or
IA, including an enantiomer, a mixture of enantiomers, a mixture of
two or more diastereomers, a tautomer, a mixture of two or more
tautomers, or an isotopic variant thereof; or a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof, can be
administered once daily (QD), or divided into multiple daily doses
such as twice daily (BID), and three times daily (TID). In
addition, the administration can be continuous, i.e., every day, or
intermittently. The term "intermittent" or "intermittently" as used
herein is intended to mean stopping and starting at either regular
or irregular intervals. For example, intermittent administration of
a compound provided herein, e.g., a compound of Formula I or IA,
including an enantiomer, a mixture of enantiomers, a mixture of two
or more diastereomers, a tautomer, a mixture of two or more
tautomers, or an isotopic variant thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof, is
administration for one to six days per week, administration in
cycles (e.g., daily administration for two to eight consecutive
weeks, then a rest period with no administration for up to one
week), or administration on alternate days.
[0924] In certain embodiments, the therapeutically effective amount
is ranging from about 0.001 to 100 mg per kg subject body weight
per day (mg/kg per day), from about 0.01 to about 76 mg/kg per day,
from about 0.1 to about 60 mg/kg per day, from about 0.6 to about
26 mg/kg per day, or from about 1 to about 20 mg/kg per day, which
can be administered in single or multiple doses. Within this range,
the dosage can be ranging from about 0.006 to about 0.06, from
about 0.06 to about 0.6, from about 0.6 to about 6.0, from about 1
to about 16, from about 1 to about 20, or from about 1 to about 60
mg/kg per day.
[0925] It will be understood, however, that the specific dose level
and frequency of dosage for any particular subject can be varied
and will depend upon a variety of factors including the activity of
the specific compound employed, the metabolic stability and length
of action of that compound, the age, body weight, general health,
sex, diet, mode and time of administration, rate of excretion, drug
combination, the severity of the particular condition, and the host
undergoing therapy.
[0926] In certain embodiments, the subject is a mammal. In certain
embodiments, the subject is a human.
[0927] A compound provided herein, e.g., a compound of Formula I or
IA, or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, a tautomer, a mixture of two or more tautomers,
or an isotopic variant thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof, can also be combined or
used in combination with other therapeutic agents useful in the
treatment and/or prevention of a disorder, disease, or condition
described herein.
[0928] As used herein, the term "in combination" includes the use
of more than one therapy (e.g., one or more prophylactic and/or
therapeutic agents). However, the use of the term "in combination"
does not restrict the order in which therapies (e.g., prophylactic
and/or therapeutic agents) are administered to a subject with a
disease or disorder. A first therapy (e.g., a prophylactic or
therapeutic agent such as a compound provided herein) can be
administered prior to (e.g., 6 minutes, 16 minutes, 30 minutes, 46
minutes, 1 hour, 2 hours, 4 hours, 7 hours, 12 hours, 24 hours, 48
hours, 72 hours, 97 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 6
weeks, 7 weeks, 8 weeks, or 12 weeks before), concomitantly with,
or subsequent to (e.g., 6 minutes, 16 minutes, 30 minutes, 46
minutes, 1 hour, 2 hours, 4 hours, 7 hours, 12 hours, 24 hours, 48
hours, 72 hours, 97 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 6
weeks, 7 weeks, 8 weeks, or 12 weeks after) the administration of a
second therapy (e.g., a prophylactic or therapeutic agent) to the
subject. Triple therapy is also contemplated herein.
[0929] The route of administration of a compound provided herein,
e.g., a compound of Formula I or IA, or an enantiomer, a mixture of
enantiomers, or a mixture of diastereomers thereof, or a
pharmaceutically acceptable salt, solvate, or prodrug thereof, is
independent of the route of administration of a second therapy. In
one embodiment, a compound provided herein, e.g., a compound of
Formula I or IA, or an enantiomer, a mixture of enantiomers, or a
mixture of diastereomers thereof, or a pharmaceutically acceptable
salt, solvate, or prodrug thereof, is administered orally. In
another embodiment, a compound provided herein, e.g., a compound of
Formula I or IA, or an enantiomer, a mixture of enantiomers, or a
mixture of diastereomers thereof, or a pharmaceutically acceptable
salt, solvate, or prodrug thereof, is administered intravenously.
Thus, in accordance with these embodiments, a compound provided
herein, e.g., a compound of Formula I or IA, or an enantiomer, a
mixture of enantiomers, or a mixture of diastereomers thereof, or a
pharmaceutically acceptable salt, solvate, or prodrug thereof, is
administered orally or intravenously, and the second therapy can be
administered orally, parenterally, intraperitoneally,
intravenously, intraarterially, transdermally, sublingually,
intramuscularly, rectally, transbuccally, intranasally,
liposomally, via inhalation, vaginally, intraoccularly, via local
delivery by catheter or stent, subcutaneously, intraadiposally,
intraarticularly, intrathecally, or in a slow release dosage form.
In one embodiment, a compound provided herein, e.g., a compound of
Formula I or IA, or an enantiomer, a mixture of enantiomers, or a
mixture of diastereomers thereof; or a pharmaceutically acceptable
salt, solvate, or prodrug thereof, and a second therapy are
administered by the same mode of administration, orally or by IV.
In another embodiment, a compound provided herein, e.g., a compound
of Formula I or IA, including an enantiomer, a mixture of
enantiomers, or a mixture of diastereomers thereof, or a
pharmaceutically acceptable salt, solvate, or prodrug thereof, is
administered by one mode of administration, e.g., by IV, whereas
the second agent (an anticancer agent) is administered by another
mode of administration, e.g., orally.
[0930] In certain embodiments, each method provided herein may
independently, further comprise the step of administering a second
therapeutic agent.
[0931] The compounds provided herein can also be provided as an
article of manufacture using packaging materials well known to
those of skill in the art. See, e.g., U.S. Pat. Nos. 6,323,907;
6,062,668; and 6,033,262. Examples of pharmaceutical packaging
materials include, but are not limited to, blister packs, bottles,
tubes, inhalers, pumps, bags, vials, containers, syringes, and any
packaging material suitable for a selected formulation and intended
mode of administration and treatment.
[0932] In certain embodiments, provided herein also are kits which,
when used by the medical practitioner, can simplify the
administration of appropriate amounts of active ingredients to a
subject. In certain embodiments, the kit provided herein includes a
container and a dosage form of a compound provided herein,
including a single enantiomer or a mixture of diastereomers
thereof, or a pharmaceutically acceptable salt, solvate, or prodrug
thereof.
[0933] In certain embodiments, the kit includes a container
comprising a dosage form of the compound provided herein, including
a single enantiomer or a mixture of diastereomers thereof, or a
pharmaceutically acceptable salt, solvate, or prodrug thereof, in a
container comprising one or more other therapeutic agent(s)
described herein.
[0934] Kits provided herein can further include devices that are
used to administer the active ingredients. Examples of such devices
include, but are not limited to, syringes, needle-less injectors
drip bags, patches, and inhalers. The kits provided herein can also
include condoms for administration of the active ingredients.
[0935] Kits provided herein can further include pharmaceutically
acceptable vehicles that can be used to administer one or more
active ingredients. For example, if an active ingredient is
provided in a solid form that must be reconstituted for parenteral
administration, the kit can comprise a sealed container of a
suitable vehicle in which the active ingredient can be dissolved to
form a particulate-free sterile solution that is suitable for
parenteral administration. Examples of pharmaceutically acceptable
vehicles include, but are not limited to: aqueous vehicles,
including, but not limited to, Water for Injection USP, Sodium
Chloride Injection, Ringer's Injection, Dextrose Injection,
Dextrose and Sodium Chloride Injection, and Lactated Ringer's
Injection; water-miscible vehicles, including, but not limited to,
ethyl alcohol, polyethylene glycol, and polypropylene glycol; and
non-aqueous vehicles, including, but not limited to, corn oil,
cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl
myristate, and benzyl benzoate.
[0936] In one embodiment, provided herein is a method of inhibiting
the activity of a casein kinase 1 in a cell, comprising contacting
the cell with a compound provided herein, e.g., a compound of
Formula I or IA, including an enantiomer, a mixture of enantiomers,
or a mixture of diastereomers thereof, or a pharmaceutically
acceptable salt, solvate, or prodrug thereof. In one embodiment,
the casein kinase 1 is a human casein kinase 1. In another
embodiment, the casein kinase 1 is a casein kinase 1a. In another
embodiment, the casein kinase 1 is a human casein kinase 1a.
[0937] In another embodiment, provided herein is a method of
inhibiting the activity of an interleukin-1 receptor-associated
kinase 1 in a cell, comprising contacting the cell with a compound
provided herein, e.g., a compound of Formula I or IA, including an
enantiomer, a mixture of enantiomers, or a mixture of diastereomers
thereof, or a pharmaceutically acceptable salt, solvate, or prodrug
thereof. In one embodiment, the interleukin-1 receptor-associated
kinase 1 is a human interleukin-1 receptor-associated kinase 1.
[0938] In yet another embodiment, provided herein is a method of
inhibiting the activity of a cyclin-dependent kinase 9 in a cell,
comprising contacting the cell with a compound provided herein,
e.g., a compound of Formula I or IA, including an enantiomer, a
mixture of enantiomers, or a mixture of diastereomers thereof, or a
pharmaceutically acceptable salt, solvate, or prodrug thereof. In
one embodiment, the cyclin-dependent kinase 9 is a human
cyclin-dependent kinase 9.
[0939] In yet another embodiment, provided herein is a method of
inhibiting the growth of a cell, comprising contacting the cell
with a compound provided herein, e.g., a compound of Formula I or
IA, including an enantiomer, a mixture of enantiomers, or a mixture
of diastereomers thereof, or a pharmaceutically acceptable salt,
solvate, or prodrug thereof. In one embodiment, the cell is a
cancerous cell. In another embodiment, the cell is a virus-infected
cell. In another embodiment, the cell is an HIV-infected cell.
[0940] In yet another embodiment, provided herein is a method of
inhibiting replication of a virus in a host, comprising contacting
the host with a compound provided herein, e.g., a compound of
Formula I or IA, including an enantiomer, a mixture of enantiomers,
or a mixture of diastereomers thereof, or a pharmaceutically
acceptable salt, solvate, or prodrug thereof. In one embodiment,
the virus is an HIV.
[0941] In yet another embodiment, provided herein is a method of
increasing eumelanin level in a skin cell, comprising contacting
the skin cell with an effective amount of a compound provided
herein, e.g., a compound of Formula I or IA, including an
enantiomer, a mixture of enantiomers, or a mixture of diastereomers
thereof, or a pharmaceutically acceptable salt, solvate, or prodrug
thereof. In one embodiment, the method of increasing eumelanin
level in the skin cell is UV-independent. In one embodiment, the
skin cell is a human skin cell. In another embodiment, the skin
cell is an epidermal cell. In yet another embodiment, the skin cell
is a keratinocyte. In yet another embodiment, the skin cell is a
melanocyte. In still another embodiment, the skin cell is an
epidermal melanocyte.
[0942] In certain embodiment, the effective amount of a compound
provided herein ranges from about 1 pM to about 1 mM, from about 10
pM to about 10 .mu.M, from about 100 pM to about 2 .mu.M, or from
about 1 nM to about 1 .mu.M.
[0943] The disclosure will be further understood by the following
non-limiting examples.
EXAMPLES
[0944] As used herein, the symbols and conventions used in these
processes, schemes and examples, regardless of whether a particular
abbreviation is specifically defined, are consistent with those
used in the contemporary scientific literature, for example, the
Journal of the American Chemical Society, the Journal of Medicinal
Chemistry, or the Journal of Biological Chemistry.
Example 1
CK1.alpha. Inhibition
[0945] The CK1.alpha. inhibitory activity of a test compound was
evaluated in RKO colorectal cells by measuring the protein
expression levels of .beta.-catenin, p53, and MDM2; and the
phosphorylation level of H2AX. See, e.g., Elyada et al., Nature
2011, 470, 409-413; Pribluda et al., Cancer Cell 2013, 24, 242-56.
RKO cells were incubated with predetermined concentrations of the
test compound for 16 h at 37.degree. C. The cells were washed with
PBS. The cell pellets were incubated with an ice cold protein lysis
buffer containing a protease inhibitor cocktail (Calibiochem) and
phosphatase inhibitors (20 mM p-nitrophenyl phosphate (PNPP), 20 mM
.beta.-glycerophosphate, and 300 nM okadaic acid). Western blot
analysis was performed to determine the protein expression levels
of .beta.-catenin, MCL-1, MYC, p53, MDM2, and PP2A; and the
phosphorylation levels of H2AX and POL2-CTD using antibodies
specific to the indicated proteins. Secondary antibodies were
HRP-linked goat anti-mouse, goat anti-rabbit, and rabbit anti-goat
antibodies. Blots were developed using enhanced chemiluminescent
(ECL).
Example 2
Mouse Model of CML Blast Crisis
[0946] To generate a BCR-ABL-inducible chronic myeloid leukemia
(CML) mouse model, bone marrow (BM) cells from a 10-week old wild
type mouse were extracted and enriched for cKit expressing cells.
The cells were incubated overnight at 37.degree. C. in a RPMI
(Roswell Park Memorial Institute) growth medium supplemented with
15% fetal calf serum (FCS), L-glutamine, penicillin/streptomycin,
and stem cell factor (SCF), IL-3, IL-6, and thrombopoietin (TPO).
The cells were then infected with a p210BCR-ABL-IRES-GFP retrovirus
construct in the supernatant medium for 4 h, followed by addition
of a growth medium. After incubated at 37.degree. C. for additional
24 h, the infected cells were injected intravenously into
sublethally irradiated (500 rad) mice. Upon observing a fast steady
increase in GFP-expressing cells in the peripheral blood of the
inoculated mice by FACS and in the numbers of leukocyte and
immature cells by Wright-Giemsa stained blood films, the mice were
sacrificed and their BM cells were transferred to new sublethally
irradiated mouse hosts. By the fourth transfer, new mouse hosts
were no longer sublethally irradiated prior to the BM cells
transfer. Blast crisis development was readily detectable by a
highly abnormal number of blast cells, more than 30% of white blood
cells (WBC) in the peripheral blood (PB), and short time intervals
between transfers. CK1 inhibition studies are performed on the late
generation diseases, in which PB blasts are easily detectable, with
no host irradiation and a short generation time (up to 12 days).
Mice were monitored daily for cachexia, weight loss, lethargy, and
ruff coats, and moribund mice are sacrificed upon moribund.
[0947] To evaluate CK1.alpha. inhibition effect on CML in the mouse
model, a test compound is dissolved in 1% methylcellulose with 0.1%
tween 80 and 0.2% polyethylene glycol. The test compound is then
administered by oral gavage once a day at a dose of 10 mg/kg,
starting from 24 h after BM transplantation (BMT). Control mice are
treated with a mixture of 1% methylcellulose, 0.1% tween 80, and
0.2% polyethylene glycol (vehicle) only.
Example 3
AML Mouse Model
[0948] To generate an MLL-AF9 acute myeloid leukemia (AML) mouse
model, bone marrow (BM) cells from 10-week old wild type mouse were
extracted and enriched for cKit expressing cells and incubated
overnight in a RPMI medium supplemented with 15% FCS L-glutamine,
penicillin/streptomycin, stem cell factor (SCF), IL-3, IL-6, and
TPO. The cells were infected with a MSCV-MLL-AF9-IRES-GFP
retrovirus construct in the supernatant medium for 4 h, followed by
addition of the growth medium. After incubated at 37.degree. C. for
additional 24 h, the infected cells were then injected
intravenously into sublethally irradiated (500 rad) mice. Upon
observing a detectable steady increase in GFP expressing cells in
the mice peripheral blood by FACS and a rise in leukocyte numbers
and immature cells by Wright-Giemsa stained blood films, the mice
were sacrificed and their BM was transferred (1.sup.st BMT) to new
sublethally irradiated host mice. Upon emergence of AML disease,
the mice were sacrificed and 50,000 BM cells were transplanted (2nd
BMT) into new host mice. GFP expressing cells were monitored in the
peripheral blood and upon detecting >10% GFP.sup.+ in PB (day 11
after BMT) mice are treated with a test compound. The test compound
is dissolved in 1% methylcellulose with 0.1% tween 80, and 0.2%
polyethylene glycol. The test compound is administered by oral
gavage once a day at a dose of 20 mg/kg for 3 days, followed by 10
mg/kg/day for 6 more days. Control mice are treated with a mixture
of 1% methylcellulose, 0.1% tween 80, and 0.2% polyethylene glycol
(vehicle) only. The mice are monitored daily for cachexia,
lethargy, and ruff coats, and moribund mice were sacrificed. For a
single dose experiment, a test compound is administered by oral
gavage at a single dose of 20 mg/kg and mice are sacrificed 16 h
following treatment.
Example 4
Ex Vivo Inhibition
[0949] Freshly isolated BM from AML or CML blast crisis carrying
mice are grown in a RPMI medium supplemented with 15% FCS,
L-glutamine, penicillin/streptomycin, hepes, sodium pyruvate, and
nonessential amino acids. A test compound is dissolved in DMSO and
added to the tissue culture medium at predetermined concentrations;
control cultures are treated with DMSO only. Several hours
following treatment, cells are harvested and counted manually using
a camera and standard inverted light microscope. Dead cells are
excluded using trypan blue. AnnexinV-PE, 7AAD, and PD-L1 staining
are evaluated by FACS.
Example 5
IRAK1 Inhibition
[0950] RKO cells are incubated for 16 h at 37.degree. C. with
predetermined concentrations of a test compound. At predetermined
time points, RKO are treated with TNF.alpha. (100 units/mL). The
cells are harvested and analyzed by Western blot. Blots are
incubated with the following antibodies: phospho-IRAK (Thr209),
phospho-IKK.alpha./.beta. (Serl76/180), IKK.alpha., IKK .beta.,
Phospho-c-Jun (Ser 63), p53, CK1.alpha., and phospho-H2AX.
Secondary antibodies are HRP-linked goat anti-mouse, goat
anti-rabbit and rabbit anti-goat antibodies. Blots are developed
using ECL.
Example 6
Synthesis of 2-(Methylsulfonyl)-4-(trimethylstannyl)pyrimidine
3
[0951] Compound 3 was prepared as shown in Scheme 1 below.
##STR00112##
[0952] Compound 2. A mixture of compound 1 (3 g, 19 mmol, 2.2 mL, 1
eq.), trimethyl(trimethylstannyl)stannane (11 g, 34 mmol, 7.0 mL,
1.8 eq.), Pd(PPh.sub.3).sub.4 (2.2 g, 1.9 mmol, 0.1 eq.) in dioxane
(15 mL) was degassed and purged with N.sub.2 3 times. After stirred
at 80.degree. C. for 2 h under N.sub.2, the reaction mixture was
quenched with saturated aq. KF (50 mL) and extracted with EtOAc
(2.times.30 mL). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, concentrated, and purified by column
chromatography (Al.sub.2O.sub.3, petroleum ether/ethyl acetate
(100:1 to 50:1)) to afford compound 2 (2.5 g, 8.7 mmol, 46% yield)
as a colourless oil. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.29
(d, J=4.52 Hz, 1H), 7.11 (d, J=4.52 Hz, 1H), 2.56 (s, 3H),
0.22-0.52 (m, 9H).
[0953] Compound 3. To a solution of compound 2 (2 g, 6.9 mmol, 1
eq.) in DCM (30 mL) was added mCPBA (3.5 g, 17 mmol, 2.5 eq.).
After the reaction mixture was stirred at 0.degree. C. for 0.5 h,
TLC indicated that compound 2 was consumed completely and one new
spot was formed. The reaction mixture was poured into saturated aq.
NaCl (30 mL) at 0.degree. C. and extracted with EtOAc (3.times.10
mL). The combined organic layers were dried over Na.sub.2SO.sub.4,
filtered, concentrated, and purified by column chromatography
(Al.sub.2O.sub.3, petroleum ether/ethyl acetate (10:1 to 4:1)) to
afford compound 3 (1.5 g, 4.7 mmol, 68% yield) as a colourless oil.
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.68 (d, J=4.63 Hz, 1H),
7.69 (d, J=4.85 Hz, 1H), 3.38 (s, 3H), 0.30-0.56 (m, 9H).
Example 7
Synthesis of
4-Bromo-5-(cyclopropylmethyl)-1-methyl-1H-1,2,3-triazole 9
[0954] Compound 9 was prepared as shown in Scheme 2 below.
##STR00113##
[0955] Compound 6. To a solution of compound 4 (5 g, 60 mmol, 1
eq.) in THE (120 mL) was added LDA (2M in THF, 45 mL, 1.5 eq.)
dropwise at -78.degree. C. under N.sub.2. After the mixture was
stirred at -78.degree. C. for 1 h, compound 5 (6.33 g, 90.3 mmol,
6.7 mL, 1.5 eq.) was added dropwise at -78.degree. C. The mixture
was stirred at -78.degree. C. for additional 2 h under N.sub.2. The
reaction mixture was then poured into ice sat. NH.sub.4Cl (100 mL)
and extracted with DCM (150 mL.times.5). The combined organics were
washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered,
concentrated, and purified by column chromatography (SiO.sub.2,
petroleum ether/ethyl acetate (1:1 to 0:1)) to afford compound 6 as
a yellow solid. .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 7.61 (s,
1H), 4.16-4.12 (m, 1H), 4.11 (s, 3H), 2.82 (d, J=5.1 Hz, 1H), 1.37
(tq, J=4.9, 8.2 Hz, 1H), 0.78-0.66 (m, 2H), 0.57-0.48 (m, 1H),
0.42-0.30 (m, 1H).
[0956] Compound 7. To a solution of compound 6 (4.0 g, 26 mmol, 1
eq.) in DCM (20 mL) was added SOCl.sub.2 (4.66 g, 39.2 mmol, 2.84
mL, 1.5 eq.) dropwise at 0.degree. C. After stirred at 0.degree. C.
for 1 h under N.sub.2, the reaction mixture was poured into ice
water (80 mL) and extrated with DCM (60 mL.times.3). The combined
organics were washed with brine (100 mL.times.3), dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to afford
compound 7 (4.0 g, 23 mmol, 89% yield) as a yellow oil. .sup.1H-NMR
(CDCl.sub.3, 400 MHz) .delta. 7.65 (s, 1H), 4.33 (br d, J=9.2 Hz,
1H), 4.01-3.97 (m, 3H), 1.61-1.49 (m, 1H), 0.82-0.72 (m, 2H),
0.60-0.49 (m, 1H), 0.47-0.35 (m, 1H).
[0957] Compound 8. To a solution of compound 7 (4.0 g, 23 mmol, 1
eq.) in THE (150 mL) was added Pd/C (23 mmol, 10% purity, 1 eq.) in
one portion at 25.degree. C. The mixture was stirred at 25.degree.
C. for 5 h under H.sub.2 (15 psi). The reaction mixture was
filtered through a pad of celite. The filter cake was washed with
THE (20 mL.times.3). The filtrate was concentrated in vacuo. The
residue was diluted in DCM (60 mL) and washed with sat. aq.
NaHCO.sub.3 (40 mL). The organic phase was washed with brine (50
mL), dried over Na.sub.2SO.sub.4, filtered, and purified by
prep-HPLC (HCl) to give compound 8 (1.2 g, 8.8 mmol, 38% yield) as
a yellow oil. .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 7.96 (s,
1H), 4.19 (s, 3H), 2.73 (d, J=7.1 Hz, 2H), 1.09 (br d, J=4.0 Hz,
1H), 0.78-0.64 (m, 2H), 0.32 (q, J=5.0 Hz, 2H).
[0958] Compound 9. To a solution of compound 8 (1.0 g, 7.3 mmol, 1
eq.) in MeCN (10 mL) was added NBS (1.56 g, 8.75 mmol, 1.2 eq.) in
portions at 0.degree. C. The mixture was stirred at 25.degree. C.
for 10 h under N.sub.2. The reaction mixture was partitioned
between H.sub.2O (10 mL) and DCM (30 mL). The organic phase was
washed with brine (10 mL.times.2), dried over Na.sub.2SO.sub.4,
filtered, and purified by column chromatography (SiO.sub.2,
petroleum ether/ethyl acetate (10:1 to 5:1)) to afford compound 9
(1.3 g, 6.0 mmol, 83% yield) as a yellow oil. .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 4.05 (s, 3H), 2.65 (d, J=6.84 Hz, 2H),
0.98-0.95 (m, 1H), 0.60-0.55 (m, 2H), 0.30-0.26 (m, 2H).
Example 8
Synthesis of
(1r,4r)-N.sup.1-(4-(4-(Cyclopropylmethyl)-3-methylisoxazol-5-yl)pyrimidin-
-2-yl)cyclohexane-1,4-diamine A1
[0959] Compound A1 was prepared as shown in Scheme 3 below.
##STR00114##
[0960] Compound 12. To a solution of methyl 3-oxobutanoate 11 (20
g, 172 mmol, 18.5 mL, 1 eq.) in THE (50 mL) was added NaH (8.27 g,
207 mmol, 60% purity, 1.2 eq.) at 0.degree. C. After the mixture
was stirred at 0.degree. C. for 30 min, bromomethylcyclopropane
(18.6 g, 137 mmol, 13.2 mL, 0.8 eq.) was added dropwise at
25.degree. C. After stirred at 65.degree. C. for 5 h, the reaction
mixture was quenched with saturated aq. NH.sub.4Cl (300 mL) and
then extracted with EtOAc (3.times.100 mL). The organic phase was
separated, dried over Na.sub.2SO.sub.4, filtered, concentrated, and
purified by column chromatography (SiO.sub.2, petroleum ether/ethyl
acetate (20:1 to 15:1)) to afford compound 12 (3 g, 18 mmol, 10%
yield) as a colorless oil. .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 3.74 (s, 3H), 3.57 (t, J=7.39 Hz, 1H), 2.25 (s, 3H), 1.76
(t, J=7.17 Hz, 2H), 0.61-0.76 (m, 1H), 0.37-0.51 (m, 2H), 0.00-0.15
(m, 2H).
[0961] Compounds 13 and 14. A mixture of compound 12 (3 g, 18 mmol,
1 eq.), hydroxylamine (1.16 g, 18 mmol, 1 eq.) in EtOH (10 mL) was
degassed and purged with N.sub.2 3 times. After stirred at
85.degree. C. for 10 h under N.sub.2, the reaction mixture was
concentrated under reduced pressure and purified by column
chromatography (SiO.sub.2, petroleum ether/ethyl acetate (5:1 to
1:1)) to afford compounds 13 and 14 (2 g, 13 mmol, 74% yield) as a
colorless oil. The crude product was directly used in the next step
without further purification.
[0962] Compound 15. To a solution of compounds 13 and 14 (1.8 g, 12
mmol, 1 eq.) in toulene (6 mL) was added phosphorus oxybromide
(1.68 g, 5.88 mmol, 597 .mu.L, 0.5 eq.). After stirred at
60.degree. C. for 10 h, the reaction mixture was concentrated under
reduced pressure to remove solvent. The residue was diluted with
H.sub.2O (50 mL) and extracted with EtOAc (3.times.20 mL). The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered,
concentrated, and purified by column chromatography (SiO.sub.2,
petroleum ether/ethyl acetate (20:1 to 10:1)) to afford compound 15
(0.7 g, 3.24 mmol, 28% yield) as a colorless oil. .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. 2.16-2.41 (m, 5H), 0.78-1.00 (m, 1H),
0.40-0.61 (m, 2H), 0.19 (q, J=5.02 Hz, 2H).
[0963] Compound 16. A mixture of compound 3 (0.1 g, 463 .mu.mol, 1
eq.), compound 15 (149 mg, 463 .mu.mol, 1 eq.), Pd(PPh.sub.3).sub.4
(54 mg, 46 .mu.mol, 0.1 eq.) in toluene (2 mL) was degassed and
purged with N.sub.2 3 times. After stirred at 100.degree. C. for 10
hr under N.sub.2, the reaction mixture was concentrated and
purified by prep-TLC (SiO.sub.2, petroleum ether/ethyl acetate
(1:1)) to afford compound 16 (35 mg, 119 .mu.mol, 26% yield) as a
colorless oil. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 9.03 (d,
J=5.52 Hz, 1H), 8.01 (d, J=5.52 Hz, 1H), 3.37-3.46 (m, 3H), 2.94
(d, J=6.53 Hz, 2H), 2.40 (s, 3H), 0.83-0.92 (m, 1H), 0.47-0.52 (m,
2H), 0.25-0.35 (m, 2H).
[0964] Compound 18. A mixture of compound 16 (35 mg, 119 .mu.mol, 1
eq.), tert-butyl N-(4-aminocyclohexyl)carbamate 17 (38 mg, 178
.mu.mol, 1.5 eq.) in 1-butanol (2 mL) was degassed and purged with
N.sub.2 3 times. After stirred at 140.degree. C. for 10 h under
N.sub.2, the reaction mixture was concentrated and purified by
prep-TLC (SiO.sub.2, petroleum ether/ethyl acetate (3:1)) to afford
compound 18 (20 mg, 47 .mu.mol, 39% yield) as a white solid. H-NMR
(400 MHz, CDCl.sub.3) .delta. 8.35 (d, J=5.02 Hz, 1H), 7.06 (d,
J=5.52 Hz, 1H), 5.07-5.41 (m, 1H), 4.42 (br s, 1H), 3.74-3.89 (m,
1H), 3.49 (br s, 1H), 2.87 (d, J=6.53 Hz, 2H), 2.35 (s, 3H),
2.15-2.22 (m, 2H), 2.07-2.14 (m, 2H), 1.46 (s, 9H), 1.25-1.28 (m,
4H), 1.03-1.13 (m, 1H), 0.44-0.50 (m, 2H), 0.17-0.26 (m, 2H).
[0965] Compound A1. To a solution of compound 18 (10 mg, 23
.mu.mol, 1 eq.) in EtOAc (1 mL) was added HCl/EtOAc (4M, 1 mL).
After stirred at 25.degree. C. for 0.5 h, the reaction mixture was
concentrated and purified by prep-HPLC (HCl condition) to afford
compound A1 (3 mg, 9.2 .mu.mol, 39% yield) as a colorless oil. MS
(ESI) m/z: [M+H].sup.+ Calcd for C.sub.18H.sub.26N.sub.5O 328.2;
Found 328.4; .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.43 (d,
J=6.39 Hz, 1H), 7.38 (d, J=6.39 Hz, 1H), 4.05 (br s, 1H), 3.21 (br
s, 1H), 2.95 (d, J=6.61 Hz, 2H), 2.39 (s, 3H), 2.15-2.29 (m, 4H),
1.52-1.67 (m, 4H), 1.12 (br s, 1H), 0.54 (br d, J=7.28 Hz, 2H),
0.29 (q, J=4.85 Hz, 2H).
Example 9
Synthesis of
(1r,4r)-N.sup.1-(5-Chloro-4-(4-(cyclopropylmethyl)-3-methylisoxazol-5-yl)-
pyrimidin-2-yl)cyclohexane-1,4-diamine A2
[0966] Compound A2 was prepared as shown in Scheme 4 below.
##STR00115##
[0967] Compound 19. A mixture of compound 18 (20 mg, 47 .mu.mol, 1
eq.), NCS (7.5 mg, 56 .mu.mol, 1.2 eq.) in acetonitrile (2 mL) was
degassed and purged with N.sub.2 3 times. After stirred at
85.degree. C. for 1 h under N.sub.2, the reaction mixture was
concentrated and purified by prep-TLC (SiO.sub.2, petroleum
ether/ethyl acetate (3:1)) to afford compound 19 (15 mg, 32
.mu.mol, 69% yield) as a white solid. The product was directly used
in the next step without further purification.
[0968] Compound A2. To a solution of compound 19 (15 mg, 32
.mu.mol, 1 eq.) in EtOAc (1 mL) was added HCl/EtOAc (4M, 1 mL).
After stirred at 25.degree. C. for 0.5 h, the reaction mixture was
concentrated and purified by prep-HPLC (HCl condition) to afford
compound A2 (2.4 mg, 6.6 .mu.mol, 20% yield) as a colorless oil. MS
(ESI) m/z: [M+H].sup.+ Calcd for C.sub.18H.sub.25ClN.sub.5O 362.2;
Found 362.4; .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.40 (s,
1H), 3.76-3.87 (m, 1H), 3.08-3.18 (m, 1H), 2.66 (br d, J=6.62 Hz,
2H), 2.36 (s, 3H), 2.05-2.21 (m, 4H), 1.38-1.64 (m, 4H), 0.97 (br
s, 1H), 0.34-0.56 (m, 2H), 0.15 (br d, J=4.63 Hz, 2H).
Example 10
Synthesis of
(1r,4r)-N.sup.1-(4-(5-(Cyclopropylmethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-
pyrimidin-2-yl)cyclohexane-1,4-diamine B1
[0969] Compound B1 was prepared as shown in Scheme 5 below.
##STR00116##
[0970] Compound 21. A mixture of 34 9 (202 mg, 935 .mu.mol, 1 eq.),
compound 3 (360 mg, 1.12 mmol, 1.2 eq.), Pd(PPh.sub.3).sub.4 (108
mg, 93.5 .mu.mol, 0.1 eq.) in toluene (5 mL) was degassed and
purged with N.sub.2 3 times. After stirred at 120.degree. C. for 10
h under N.sub.2, the reaction mixture was concentrated and purified
by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate
(5:1 to 3:1)) to afford compound 4 (200 mg, 682 .mu.mol, 73% yield)
as a yellow solid. The crude product was used directly in the next
step without further purification.
[0971] Compound 22. A mixture of compound 21 (200 mg, 682 .mu.mol,
1 eq.) and tert-butyl N-(4-aminocyclohexyl)carbamate 17 (438 mg,
2.05 mmol, 3 eq.) in 1-butanol (5 mL) was degassed and purged with
N.sub.2 3 times. After stirred at 140.degree. C. for 10 hr under
N.sub.2, the reaction mixture was concentrated and purified by
column chromatography (SiO.sub.2, petroleum ether/ethyl acetate
(5:1 to 3:1)) to afford compound 22 (140 mg, 328 .mu.mol, 48%
yield) as a white solid. H-NMR (400 MHz, CDCl.sub.3) .delta. 8.28
(d, J=5.07 Hz, 1H), 7.40 (d, J=5.07 Hz, 1H), 5.06 (br s, 1H), 4.49
(br s, 1H), 3.98-4.12 (m, 3H), 3.71-3.88 (m, 1H), 3.47 (br s, 1H),
3.20 (d, J=6.62 Hz, 2H), 2.04-2.21 (m, 4H), 1.40-1.48 (m, 9H),
1.21-1.37 (m, 4H), 1.04-1.17 (m, 1H), 0.45-0.56 (m, 2H), 0.22-0.33
(m, 2H).
[0972] Compound B1. To a solution of compound 22 (50 mg, 117
.mu.mol, 1 eq.) in EtOAc (1 mL) was added HCl/EtOAc (4M, 1 mL).
After stirred at 25.degree. C. for 0.5 h, the reaction mixture was
concentrated and purified by prep-HPLC (HCl condition) to give
desired compound B1 (6.6 mg, yield 17%, purity 95%) as a colorless
oil. MS (ESI) m/z: [M+H].sup.+ Calcd for C.sub.17H2.sub.6N.sub.7
328.2; Found 328.4; H-NMR (400 MHz, CDCl.sub.3) .delta. 8.29 (br d,
J=6.84 Hz, 1H), 7.73 (d, J=6.84 Hz, 1H), 4.15 (s, 4H), 3.29 (br d,
J=6.62 Hz, 2H), 3.22 (br s, 1H), 2.23 (br d, J=15.21 Hz, 4H),
1.56-1.72 (m, 4H), 1.20 (br s, 1H), 0.58 (br s, 2H), 0.38 (q,
J=5.00 Hz, 2H).
Example 11
Synthesis of
(1r,4r)-N.sub.1-(5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-1,2,3-tria-
zol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine B2
[0973] Compound B2 was prepared as shown in Scheme 6 below.
##STR00117##
[0974] Compound 23. A mixture of compound 22 (50 mg, 117 .mu.mol, 1
eq.), NCS (19 mg, 140 .mu.mol, 1.2 eq.) in CH.sub.3CN (2 mL) was
degassed and purged with N.sub.2 for 3 times. After stirred at
85.degree. C. for 4 h under N.sub.2, the reaction mixture was
concentrated under reduced pressure to remove solvent. The residue
was diluted with EtOAc (10 mL). The organic layers were washed with
H.sub.2O (5 mL), dried over Na.sub.2SO.sub.4, filtered, and
concentrated to afford compound 23 (30 mg, 65 .mu.mol, 56% yield)
as a white solid, which was used directly in the next step without
further purification.
[0975] Compound B2. To a solution of compound 23 (30 mg, 65
.mu.mol, 1 eq.) in EtOAc (1 mL) was added HCl/EtOAc (4M, 1 mL).
After stirred at 25.degree. C. for 0.5 h, the reaction mixture was
concentrated under reduced pressure. The residue was purified by
prep-HPLC (neutral condition) to give compound B2 (13 mg, yield
56%, purity 95%) as a colourless oil. MS (ESI) m/z: [M+H].sup.+
Calcd for C.sub.17H.sub.25N.sub.7 362.2; Found 362.4; .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta. 8.32 (s, 1H), 4.06-4.17 (m, 3H),
3.66-3.86 (m, 1H), 3.00 (br d, J=7.03 Hz, 2H), 2.71-2.81 (m, 1H),
2.07 (br d, J=11.54 Hz, 2H), 1.96 (br d, J=12.55 Hz, 2H), 1.24-1.45
(m, 4H), 1.02 (br s, 1H), 0.49 (br d, J=7.53 Hz, 2H), 0.19 (br d,
J=4.52 Hz, 2H).
Example 12
Synthesis of
(1r,4r)-N.sup.1-(5-Chloro-4-(3-(cyclopropylmethyl)isoxazol-4-yl)pyrimidin-
-2-yl)cyclohexane-1,4-diamine C.sub.1
[0976] Compound C1 was prepared as shown in Scheme 7 below.
##STR00118##
[0977] Compound 25. To a solution of compound 24 (10 g, 116 mmol, 1
eq.) in DCM (50 mL) was added PCC (32.53 g, 151 mmol, 1.3 eq.) at
0.degree. C. in portions. The mixture was stirred at 15.degree. C.
for 2 h. The reaction mixture was filtered through celite. The
filtrate was used directly in the next step without further
purification. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.73 (s,
1H), 2.31-2.29 (m, 2H), 1.02-0.99 (m, 1H), 0.63-0.57 (m, 2H),
0.55-0.17 (m, 2H).
[0978] Compound 26. To a solution of compound 25 (.about.9.7 g, 115
mmol, 1 eq.) in DCM (50 mL) was added NH.sub.2OH.HCl (9.62 g, 138
mmol, 1.2 eq.) and TEA (11.67 g, 115 mmol, 16.05 mL, 1 eq.) in
portions at 15.degree. C. After stirred at 15.degree. C. for 1 h,
the reaction mixture was concentrated in vacuo. The residue was
diluted with PE (50 mL) and stirred for 10 min. The mixture was
filtered through celite and concentrated in vacuo to afford
compound 26 (11 g, 111 mmol, 96% yield) as a yellow oil, which was
used directly in the next step without further purification.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.47 (t, J=6.1 Hz, 1H),
6.82 (t, J=5.1 Hz, 1H), 2.22 (d, J=7.2 Hz, 2H), 0.98-0.96 (m, 1H),
0.58-0.52 (m, 2H), 0.19-0.13 (m, 2H).
[0979] Compound 27. To a solution of compound 26 (11 g, 111 mmol, 1
eq.) in DMF (20 mL) was added NCS (17.78 g, 133 mmol, 1.2 eq.) in
portions at 15.degree. C. The mixture was degassed and purged with
N.sub.2 for 3 times and then stirred at 50.degree. C. for 2 h under
N.sub.2. The reaction mixture was then partitioned between H.sub.2O
(50 mL) and EtOAc (50 mL.times.2). The organic phase was separated,
washed with brine (5 mL.times.2), dried over Na.sub.2SO.sub.4,
filtered, and concentrated under reduced pressure to afford
compound 27 (12 g, 90 mmol, 81% yield) as a yellow oil, which was
used directly in the next step without further purification.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.68 (s, 1H), 3.86 (m,
3H), 2.82 (d, J=6.8 Hz, 2H), 1.30 (m, 12H), 1.03-0.85 (m, 1H),
0.51-0.39 (m, 2H), 0.32-0.17 (m, 2H).
[0980] Compound 28. To a solution of compound 27 (10 g, 75 mmol, 1
eq.) and ethynyl(trimethyl)silane (7.35 g, 75 mmol, 10.37 mL, 1
eq.) in DCM (20 mL) was added TEA (7.58 g, 75 mmol, 10.42 mL, 1
eq.) in one portion at 0.degree. C. After stirred at 0-15.degree.
C. for 10 h, the mixture was concentrated in vacuo. The residue was
diluted with EtOAc (50 mL), washed with brine (30 mL), dried over
Na.sub.2SO.sub.4, and concentrated in vacuo. The crude product was
purified by column chromatography (SiO.sub.2, PE/EtOAc: 30/1 to
20/1) to afford compound 28 (6 g, 31 mmol, 41% yield) as a yellow
oil. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 6.35 (s, 1H), 2.61
(d, J=6.5 Hz, 2H), 1.06-1.07 (m, 1H), 2.54-0.52 (m, 2H), 0.51-0.40
(m, 2H), 0.34 (s, 9H), 0.25-0.22 (m, 2H).
[0981] Compound 29. To a solution of compound 28 (6 g, 31 mmol, 1
eq.) in AcOH (15 mL) was added NBS (5.47 g, 31 mmol, 1 eq.) in
portions at 25.degree. C. After stirred at 80.degree. C. for 3 h
under N.sub.2, the reaction mixture was concentrated in vacuo. The
mixture was poured into ice sat. NaHCO.sub.3(50 mL) and extracted
with EtOAc (50 mL.times.3). The combined organics were washed with
brine (50 mL), dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo. The crude produce was purified by column
chromatography (SiO.sub.2, PE/EtOAc: 30/1 to 10:1) to afford
compound 29 (4.5 g, 16 mmol, 53% yield) as a yellow oil.
.sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 2.53 (br d, J=6.5 Hz,
2H), 1.10-1.05 (m, 1H), 0.50-0.49 (m, 2H), 0.35 (S, 9H), 0.33-0.19
(m, 2H).
[0982] Compound 30. To a mixture of compound 29 (2.7 g, 9.9 mmol, 1
eq.) in MeCN (1.5 mL) and EtOH (0.5 mL) was added CsF (2.99 g, 20
mmol, 726 .mu.L, 2 eq.) in one portion at 15.degree. C. After
stirred at 15.degree. C. for 1 h, the reaction mixture was
concentrated in vacuo. The residue was diluted with EtOAc (20 mL),
washed with brine (10 mL.times.2), dried over Na.sub.2SO.sub.4,
filtered, and concentrated in vacuo. The crude product was purified
by column chromatography (SiO.sub.2, PE/EtOAc: 30/1 to 20/1) to
afford compound 30 (1.7 g, 8.4 mmol, 85% yield) as a colorless oil.
.sup.1H NMR (CDCl.sub.3, 400 MHz,) .delta. 8.40-8.29 (m, 1H), 2.62
(d, J=7.1 Hz, 2H), 1.01-0.90 (m, 1H), 0.63-0.51 (m, 2H), 0.32-0.22
(m, 2H).
[0983] Compound 31. To a mixture of compound 30 (1.5 g, 7.42 mmol,
1 eq.) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(1.66 g, 8.91 mmol, 1.82 mL, 1.2 eq.) in THF (20 mL) was added
n-BuLi (2.5 M, 3.56 mL, 1.2 eq.) dropwise at -78.degree. C. under
N.sub.2. After stirred at -78.degree. C. for 1 h, the reaction
mixture was poured into ice sat. NH.sub.4Cl (30 mL) and extracted
with EtOAc (30 mL.times.2). The combined organics were washed with
brine (50 mL), dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo. The residue was purified by column
chromatography (SiO.sub.2, PE/EtOAc: 50/1 to 40:1) to afford
compound 31 (1.2 g, 4.82 mmol, 65% yield). .sup.1H NMR (CDCl.sub.3,
400 MHz) .delta. 8.62-8.48 (m, 1H), 2.73 (d, J=7.0 Hz, 2H), 1.32
(s, 12H), 1.19-1.11 (m, 1H), 0.55-0.46 (m, 2H), 0.29-0.20 (m,
2H).
[0984] Compound 32. A mixture of 2,4,5-trichloropyrimidine (491 mg,
2.68 mmol, 1 eq.), compound 31 (0.8 g, 3.21 mmol, 1.2 eq.), aq.
Na.sub.2CO.sub.3 (2 M, 4.01 mL, 3 eq.), and
4-di(tert-butyl)phosphanyl-N,N-dimethyl-aniline dichloropalladium
(189.49 mg, 268 .mu.mol, 189 .mu.L, 0.1 eq.) in DME (8 mL) was
degassed and purged with N.sub.2 for 3 times and then stirred at
85.degree. C. for 2 h under N.sub.2. The reaction mixture was
concentrated in vacuo. The mixture was diluted H.sub.2O (20 mL) and
then extracted with EtOAc (30 mL.times.3). The combined organic
layers were washed with brine (20 mL), dried over Na.sub.2SO.sub.4,
filtered, and concentrated under reduced pressure. The residue was
purified by column chromatography (SiO.sub.2, PE/EtOAc: 4/1 to 2:1)
to afford compound 32 (0.5 g, 1.85 mmol, 69% yield). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 9.15 (s, 1H), 8.53-8.45 (m, 1H), 2.84
(d, J=6.8 Hz, 2H), 1.05-0.99 (m, 1H), 0.40-0.31 (m, 2H), 0.17-0.05
(m, 2H).
[0985] Compound C.sub.1. A mixture of trans-cyclohexane-1,4-diamine
(507 mg, 4.44 mmol, 4 eq.), compound 32 (0.3 g, 1.11 mmol, 1 eq.)
in n-BuOH (5 mL) was degassed and purged with N.sub.2 for 3 times.
After stirred at 160.degree. C. for 2 h under N.sub.2, the reaction
mixture was partitioned between H.sub.2O (10 mL) and EtOAc (15 mL).
The organic phase was separated, washed with brine (10 mL.times.2),
dried over Na.sub.2SO.sub.4, filtered, and concentrated under
reduced pressure. The residue was purified by prep-HPLC (HCl
condition) to afford compound C1 (0.147 g, 0.421 mmol, 38% yield,
100% purity). .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.63 (s,
1H), 8.47 (s, 1H), 3.94 (br s, 1H), 3.19 (br s, 1H), 3.01 (d, J=6.9
Hz, 2H), 3.05-2.91 (m, 1H), 2.22-2.11 (m, 4H), 1.65-1.50 (m, 4H),
1.19-1.05 (m, 1H), 0.62-0.47 (m, 2H), 0.23 (q, J=4.9 Hz, 2H).
Example 13
Synthesis of
(1r,4r)-4-((5-Chloro-4-(3-(cyclopropylmethyl)isoxazol-4-yl)pyrimidin-2-yl-
)amino)cyclohexan-1-ol C2
[0986] Compound C2 was prepared as shown in Scheme 8 below.
##STR00119##
[0987] Compound C2. A mixture of trans-4-aminocyclohexanol (21.32
mg, 185 .mu.mol, 2.5 eq.) and compound 32 (0.02 g, 74 .mu.mol, 1
eq.) in n-BuOH (5 mL) was degassed and purged with N.sub.2 for 3
times and then stirred at 160.degree. C. for 2 h under N.sub.2. The
reaction mixture was concentrated under reduced pressure. The
residue was purified by prep-HPLC (HCl condition) to afford
compound C2 (6.7 mg, 19 .mu.mol, 26% yield). .sup.1H NMR
(CD.sub.3OD, 400 MHz) .delta. 9.62 (s, 1H), 8.41 (s, 1H), 3.86 (br
s, 1H), 3.68-3.48 (m, 1H), 3.01 (d, J=6.9 Hz, 2H), 2.17-1.98 (m,
4H), 1.54-1.36 (m, 4H), 1.28-1.08 (m, 1H), 1.21-1.07 (m, 1H),
0.71-0.35 (m, 2H), 0.24 (q, J=4.8 Hz, 2H).
Example 14
Synthesis of
(1r,4r)-4-((4-(4-(Cyclopropylmethyl)-3-methylisoxazol-5-yl)pyrimidin-2-yl-
)amino)cyclohexan-1-ol C.sub.3 and
(1r,4r)-4-((5-Chloro-4-(4-(cyclopropylmethyl)-3-methylisoxazol-5-yl)pyrim-
idin-2-yl)amino)cyclohexan-1-ol C4
[0988] Compounds C3 and C4 were prepared as shown in Scheme 9
below.
##STR00120##
[0989] Compound C3. A mixture of compound 16 (59 mg, 511 .mu.mol,
2.5 eq.) and compound 33 (60 mg, 204 .mu.mol, 1 eq.) in t-BuOH (5
mL) was stirred at 140.degree. C. for 2 h. The reaction mixture was
concentrated in vacuo. The residue was partitioned between H.sub.2O
(5 mL) and DCM (10 mL). The organic phase was separated, washed
with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo. The crude product was purified by orep-TLC
(EtOAc) to afford compound C3 (40 mg, 122 .mu.mol, 60% yield).
.sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 8.39 (d, J=6.5 Hz, 1H),
7.39 (d, J=6.5 Hz, 1H), 4.07 (br s, 1H), 3.70-3.55 (m, 1H), 2.95
(d, J=6.7 Hz, 2H), 2.39 (s, 3H), 2.17-2.00 (m, 4H), 1.63-1.35 (m,
4H), 1.12 (br s, 1H), 0.54 (br d, J=7.0 Hz, 2H), 0.30 (q, J=5.1 Hz,
2H).
[0990] Compound C.sub.4. To a solution of compound C.sub.3 (20.0
mg, 61 .mu.mol, 1 eq.) in MeCN (5 mL) was added NCS (8.1 mg, 61
.mu.mol, 1.0 eq.) in portions at 25.degree. C. The mixture was
degassed and purged with N.sub.2 for 3 times. Then the mixture was
warmed to 80.degree. C. and stirred for 12 h under N.sub.2. The
reaction mixture was concentrated in vacuo. The residue was
purified by prep-HPLC (neutral condition) to afford compound C4
(10.5 mg, 29 .mu.mol, 47% yield). .sup.1H NMR (CD.sub.3OD, 400 MHz)
.delta. 8.36 (s, 1H), 3.78 (br s, 1H), 3.58 (br s, 1H), 2.69 (br s,
2H), 2.35 (s, 3H), 2.11-1.91 (m, 4H), 1.45-1.31 (m, 4H), 1.00 (br
s, 1H), 0.47 (br d, J=7.2 Hz, 2H), 0.24-0.09 (m, 2H).
Example 15
Synthesis of
(1r,4r)-4-((4-(5-(Cyclopropylmethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyrim-
idin-2-yl)amino)cyclohexan-1-ol C.sub.5 and
(1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-1,2,3-triazol-4-
-yl)pyrimidin-2-yl)amino)cyclohexan-1-ol C6
[0991] Compounds C5 and C6 were prepared as shown in Scheme 10
below.
##STR00121##
[0992] Compound C5. A mixture of compound 33 (0.2 g, 1.70 mmol, 2.5
eq.) and compound 21 (0.2 g, 682 .mu.mol, 1 eq.) in t-BuOH (5 mL)
was stirred at 140.degree. C. for 2 h under N.sub.2. The reaction
mixture was cooled down to 25.degree. C. and concentrated in vacuo.
The residue was purified by prep-HPLC (neural condition) to afford
compound C5 (0.11 g, 335 .mu.mol, 49% yield). .sup.1H NMR
(CD.sub.3OD, 400 MHz) .delta. 8.25 (d, J=5.3 Hz, 1H), 7.26 (d,
J=5.3 Hz, 1H), 4.10 (s, 3H), 3.86 (br s, 1H), 3.68-3.56 (m, 1H),
3.33-3.32 (m, 2H), 2.12-1.98 (m, 4H), 1.50-1.36 (m, 4H), 1.17 (br
s, 1H), 0.58-0.50 (m, 2H), 0.39-0.32 (m, 2H).
[0993] Compound C.sub.6. To a solution of compound C5 (50 mg, 152
.mu.mol, 1 eq.) in MeCN (5 mL) was added NCS (24 mg, 183 .mu.mol,
1.2 eq.) in one portion at 25.degree. C. The mixture was warmed to
80.degree. C. and stirred for 0.5 hr under N.sub.2. The reaction
mixture was concentrated in vacuo. The residue was purified by
prep-HPLC (HCl condition) to afford compound C6 (24 mg, 67 .mu.mol,
44% yield). .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 8.31 (s, 1H),
4.12 (s, 3H), 3.77 (br s, 1H), 3.58 (br s, 1H), 3.01 (br d, J=6.7
Hz, 2H), 2.12-1.89 (m, 4H), 1.47-1.28 (m, 4H), 1.04 (br s, 1H),
0.50 (br d, J=7.7 Hz, 2H), 0.21 (br d, J=4.5 Hz, 2H).
Example 16
Synthesis of
(1r,4r)-N.sup.1-(4-(5-(Cyclopropylmethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-
-5-ethylpyrimidin-2-yl)cyclohexane-1,4-diamine C.sub.7
[0994] Compound C7 was prepared as shown in Scheme 11 below.
##STR00122##
[0995] Compound 34. To a solution of compound 9 (0.5 g, 2.31 mmol,
1 eq.) and TMEDA (323 mg, 2.78 mmol, 419 .mu.L, 1.2 eq.) in THF (20
mL) was added dropwise n-BuLi (2.5 M, 1.11 mL, 1.2 eq.) at
-78.degree. C. under N.sub.2. After addition, the mixture was
stirred at this temperature for 15 min. Bu.sub.3SnCl (1.13 g, 3.47
mmol, 934 .mu.L, 1.5 eq.) was added dropwise at -78.degree. C. The
mixture was stirred at -78.degree. C. for 25 mins. The reaction
mixture was poured into sat. NH.sub.4Cl (20 mL) and extracted with
EtOAc (30 mL.times.3). The combined organics were washed with sat.
KF (30 mL), brine (30 mL), dried over Na.sub.2SO.sub.4, and
concentrated in vacuo. The residue was purified by column
chromatography (Al.sub.2O.sub.3, PE/EtOAc: 7/1 to 6/1) to afford
compound 34 (0.6 g, 1.41 mmol, 61% yield) as a colorless oil.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 3.85 (s, 3H), 2.46 (d,
J=6.3 Hz, 2H), 1.41-1.31 (m, 6H), 1.19-1.10 (m, 6H), 1.00-0.89 (m,
6H), 0.71 (t, J=7.2 Hz, 9H), 0.52-0.50 (m. 1H), 0.42-0.33 (m, 2H),
0.04-0.03 (m, 2H).
[0996] Compound 36. A mixture of compound 34 (100 mg, 234 .mu.mol,
1 eq.), compound 35 (62 mg, 352 .mu.mol, 1.5 eq.),
Pd(PPh.sub.3).sub.4 (27 mg, 23 .mu.mol, 0.1 eq.), and LiCl (20 mg,
469 .mu.mol, 2 eq.) in toluene (1 mL) was degassed and purged with
N.sub.2 for 3 times. Then the mixture was stirred at 100.degree. C.
for 5 h under N.sub.2. The reaction mixture was cooled down to
25.degree. C. and poured into sat. KF (10 mL) and stirred for 20
min. Then the mixture was extracted with EtOAc (10 mL.times.2). The
combined organics were washed with brine (20 mL), dried over
Na.sub.2SO.sub.4, and concentrated in vacuo to afford crude
compound 36 (40 mg) as a yellow solid, which was used directly in
the next step without further purification.
[0997] Compound C.sub.7. A mixture of compound 36 (30 mg, 108
.mu.mol, 1 eq.) and compound 37 (31 mg, 270 .mu.mol, 2.5 eq.) in
n-BuOH (0.5 mL) was stirred at 140.degree. C. for 3 h. The mixture
was cooled down to 25.degree. C. and concentrated in vacuo. The
residue was purified by prep-HPLC (HCl condition) to afford
compound C7 (7.5 mg, 21 .mu.mol, 20% yield) as a brown oil. .sup.1H
NMR (CD.sub.3OD, 400 MHz) .delta. 8.19 (s, 1H), 4.15 (s, 3H),
4.11-3.96 (m, 1H), 3.22 (s, 2H), 3.21-3.18 (m, 1H), 3.15 (q, J=7.4
Hz, 2H), 2.25-2.16 (m, 4H), 1.68-1.56 (m, 4H), 1.22 (t, J=7.4 Hz,
3H), 1.11 (br s, 1H), 0.56 (br d, J=7.4 Hz, 2H), 0.30 (br d, J=4.5
Hz, 2H).
Example 17
Synthesis of
(1r,4r)-N.sup.1-(4-(5-(Cyclopropylmethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-
-5-fluoropyrimidin-2-yl)cyclohexane-1,4-diamine C.sub.8
[0998] Compound C8 was prepared as shown in Scheme 12 below.
##STR00123##
[0999] Compound 39. A mixture of compound 34 (150 mg, 352 .mu.mol,
1 eq.), compound 38 (588 mg, 3.52 mmol, 10 eq.), BINAP (88 mg, 141
.mu.mol, 0.4 eq.), and Pd.sub.2(dba).sub.3 (65 mg, 70 .mu.mol, 0.2
eq.) in toluene (10 mL) was degassed and purged with N.sub.2 for 3
times. Then the mixture was stirred at 100.degree. C. for 8 h under
N.sub.2. The mixture was cooled down to 25.degree. C. and
partitioned between sat. KF (20 mL) and EtOAc (20 mL). The organic
phase was separated, washed with brine (15 mL), dried over
Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was
purified by column chromatography (PE/EtOAc: 10/1 to 3/1) to afford
compound 39 (80 mg, 299 .mu.mol, 85% yield). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 8.56 (d, J=2.6 Hz, 1H), 4.14 (s, 3H),
3.16 (d, J=6.8 Hz, 2H), 1.15-0.93 (m, 1H), 0.60-0.44 (m, 2H),
0.42-0.21 (m, 2H).
[1000] Compound C.sub.8. To a solution of compound 39 (30 mg, 112
.mu.mol, 1 eq.) and compound 38 (38 mg, 336 .mu.mol, 3 eq.) in
n-BuOH (0.5 mL) was stirred at 140.degree. C. for 3 h. The mixture
was cooled down to 25.degree. C. and concentrated in vacuo. The
residue was purified by prep-HPLC (neutral condition) to compound
C8 (13 mg, 38 .mu.mol, 34% yield). .sup.1H NMR (CD.sub.3OD, 400
MHz) .delta. 8.27 (d, J=3.4 Hz, 1H), 4.13 (s, 3H), 3.82-3.69 (m,
1H), 3.20 (d, J=6.7 Hz, 2H), 2.79-2.66 (m, 1H), 2.16-2.03 (m, 2H),
1.98-1.89 (m, 2H), 1.43-1.25 (m, 4H), 1.10 (br d, J=6.5 Hz, 1H),
0.58-0.48 (m, 2H), 0.34-0.25 (m, 2H).
Example 18
Synthesis of
(1r,4r)-4-((4-(5-(Cyclopropylmethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-5-fl-
uoropyrimidin-2-yl)amino)cyclohexan-1-ol C9
[1001] Compound C9 was prepared as shown in Scheme 13 below.
##STR00124##
[1002] Compound C9. To a solution of compound 39 (10 mg, 37
.mu.mol, 1 eq.) and compound 33 (13 mg, 112 .mu.mol, 3 eq.) in
n-BuOH (0.5 mL) was stirred at 140.degree. C. for 11 h. The mixture
was cooled down to 25.degree. C. and concentrated in vacuo. The
residue was purified by prep-HPLC (HCl condition) to afford
compound C9 (2.0 mg, 5.8 .mu.mol, 15% yield) as a yellow oil.
.sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 8.43 (d, J=4.3 Hz, 1H),
4.16 (s, 3H), 3.96-3.82 (m, 1H), 3.67-3.54 (m, 1H), 3.24 (d, J=6.8
Hz, 2H), 2.13-2.07 (m, 2H), 2.03 (br d, J=9.4 Hz, 2H), 1.54-1.42
(m, 4H), 1.21-1.09 (m, 1H), 0.61-0.51 (m, 2H), 0.40-0.28 (m,
2H).
Example 19
Synthesis of
(1r,4r)-N.sup.1-(4-(5-(Cyclopropylmethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-
-5-(trifluoromethyl)pyrimidin-2-yl)cyclohexane-1,4-diamine
C.sub.10
[1003] Compound C10 was prepared as shown in Scheme 14 below.
##STR00125##
[1004] Compound 41. A mixture of compound 34 (0.1 g, 235 .mu.mol, 1
eq.), compound 40 (102 mg, 469 .mu.mol, 2 eq.), CsF (71 mg, 469
.mu.mol, 2 eq.), and Pd(dppf)Cl.sub.2 (17 mg, 23 .mu.mol, 0.1 eq.)
in dioxane (3 mL) was degassed and purged with N.sub.2 for 3 times.
Then the mixture was stirred at 100.degree. C. for 5 h under
N.sub.2. The reaction mixture was cooled down to 25.degree. C. and
partitioned between sat. KF (20 mL) and EtOAc (10 mL.times.3). The
organic phase was separated, washed with brine (20 mL), dried over
Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was
purified by prep-TLC (PE/EtOAc: 3:1) to afford compound 41 (10 mg,
20 .mu.mol, 9% yield, 65% purity) as a yellow oil. LCMS
(M+H+)=318.
[1005] Compound C10. A mixture of compound 41 (5 mg, 16 .mu.mol, 1
eq.) and compound 37 (5 mg, 47 .mu.mol, 3 eq.) in n-BuOH (0.5 mL)
was stirred at 140.degree. C. for 11 h. The mixture was cooled down
to 25.degree. C. and concentrated in vacuo. The residue was
purified by prep-HPLC (HCl condition) to afford compound C10 (1.2
mg, 3 .mu.mol, 19% yield) as a yellow oil. .sup.1H NMR (CD.sub.3OD,
400 MHz) .delta. 8.52 (s, 1H), 4.93-4.92 (m, 1H), 4.56 (s, 1H),
4.16 (s, 3H), 3.29-3.28 (m, 2H), 2.16 (br s, 4H), 1.74-1.58 (m,
4H), 1.20 (s, 1H), 0.57 (br d, J=8.3 Hz, 2H), 0.37 (br d, J=4.8 Hz,
2H).
Example 20
Synthesis of
(1r,4r)-N.sub.1-(4-(5-(Cyclopropylmethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-
-5-vinylpyrimidin-2-yl)cyclohexane-1,4-diamine C11
[1006] Compound C11 was prepared as shown in Scheme 15 below.
##STR00126##
[1007] Compound 44. A mixture of compound 42 (1.0 g, 4.22 mmol, 1.5
eq.), compound 43 (1.2 g, 2.82 mmol, 1 eq.), Pd(PPh.sub.3).sub.4
(325 mg, 282 .mu.mol, 0.1 eq.), and LiCl (239 mg, 5.63 mmol, 2 eq.)
in toluene (10 mL) was degassed and purged with N.sub.2 for 3
times. Then the mixture was stirred at 100.degree. C. for 8 h under
N.sub.2. The reaction mixture was cooled down to 25.degree. C. and
partitioned between sat. KF (30 mL) and EtOAc (40 mL). The organic
phase was separated, washed with brine (20 mL), dried over
Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was
purified by column chromatography (PE/EtOAc: 10/1 to 3/1) to afford
compound 44 (400 mg, 1.18 mmol, 42% yield). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 8.72 (s, 1H), 4.11 (s, 3H), 3.00 (d,
J=6.7 Hz, 2H), 2.57 (s, 3H), 1.07-0.92 (m, 1H), 0.57-0.46 (m, 2H),
0.32-0.17 (m, 2H).
[1008] Compound 45. To a solution of compound 44 (70 mg, 206
.mu.mol, 1 eq.) in DCM (10 mL) was added m-CPBA (111 mg, 514
.mu.mol, 80% purity, 2.5 eq.) in portions at 0.degree. C. The
mixture was stirred at 0-15.degree. C. for 1 h under N.sub.2. The
reaction mixture was poured into sat. NaHCO.sub.3 (20 mL) and
extracted with DCM (20 mL.times.2). The combined organics were
poured into sat. Na.sub.2SO.sub.3 (20 mL) and stirred for 5 min.
The organic phase was separated and washed with brine (40 mL),
dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue
was purified by column chromatography (PE/EtOAc: 10:1 to 3:1) to
afford compound 45 (70 mg, 188 .mu.mol, 91% yield). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 9.07 (s, 1H), 4.15 (s, 3H), 3.36 (s,
3H), 3.15 (d, J=6.7 Hz, 2H), 1.14-1.02 (m, 1H), 0.61-0.50 (m, 2H),
0.34 (q, J=4.9 Hz, 2H).
[1009] Compound 46. A mixture of compound 45 (38 mg, 62 .mu.mol, 1
eq.), trifluoro(vinyl)-?-borane, potassium salt (8 mg, 62 .mu.mol,
1 eq.), Na.sub.2CO.sub.3 (20 mg, 185 .mu.mol, 3 eq.), and
Pd(PPh.sub.3).sub.4 (7 mg, 6.2 .mu.mol, 0.1 eq.) in dioxane (1.5
mL) and H.sub.2O (0.3 mL) was degassed and purged with N.sub.2 for
3 times. Then the mixture was stirred at 80.degree. C. for 2 h
under N.sub.2. The mixture was cooled down to 25.degree. C. and
filtered through celite. The filtrate was concentrated in vacuo.
The residue was purified by prep-TLC (PE/EtOAc: 1/1) to afford
compound 46 (18 mg, 56 .mu.mol, 91% yield) as a yellow oil. .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 9.02 (s, 1H), 7.85 (dd, J=11.1,
17.6 Hz, 1H), 5.91 (d, J=17.6 Hz, 1H), 5.67 (d, J=11.4 Hz, 1H),
4.14 (s, 3H), 3.37 (s, 3H), 3.24 (d, J=6.8 Hz, 2H), 1.12-1.10 (br
s, 1H), 0.56-0.50 (m, 2H), 0.36 (q, J=5.1 Hz, 2H).
[1010] Compound C.sub.11. A mixture of compound 46 (18 mg, 56
.mu.mol, 1 eq.) and compound 37 (10 mg, 85 .mu.mol, 1.5 eq.) in
t-BuOH (0.5 mL) was stirred at 100.degree. C. for 3 h. The mixture
was cooled down to 25.degree. C. and concentrated in vacuo. The
residue was purified by prep-HPLC (HCl) to afford compound C11 (2.6
mg, 7.4 .mu.mol, 13% yield) as a brown oil. H NMR (CD.sub.3OD, 400
MHz) .delta. 8.47 (s, 1H), 7.45 (br s, 1H), 5.69 (d, J=17.6 Hz,
1H), 5.38 (d, J=11.0 Hz, 1H), 4.84-4.79 (m, 1H), 4.15 (s, 3H),
4.12-3.95 (m, 1H), 3.19 (br d, J=6.5 Hz, 2H), 2.20 (br d, J=15.3
Hz, 4H), 1.69-1.53 (m, 4H), 1.19-1.07 (m, 1H), 0.56 (br d, J=7.2
Hz, 2H), 0.32 (br s, 2H).
Example 21
Synthesis of
(1r,4r)-N.sup.1-(5-Cyclopropyl-4-(5-(cyclopropylmethyl)-1-methyl-1H-1,2,3-
-triazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine C12
[1011] Compound C12 was prepared as shown in Scheme 16 below.
##STR00127##
[1012] Compound 47. A mixture of cyclopropylboronic acid (16 mg,
188 .mu.mol, 1 eq.), compound 45 (70 mg, 188 .mu.mol, 1 eq.),
K.sub.2CO.sub.3 (51.98 mg, 376 .mu.mol, 2 eq.), and
Pd(PPh.sub.3).sub.4 (21.73 mg, 19 .mu.mol, 0.1 eq.) in toluene (5
mL) was stirred at 80.degree. C. for 2 h under N.sub.2. The mixture
was cooled down to 25.degree. C. and concentrated in vacuo. The
residue was purified by prep-TLC (PE/EtOAc: 1/1) to afford compound
47 (10 mg, 30 .mu.mol, 16% yield). LCMS(M+H+)=334.
[1013] Compound C12. To a solution of compound 37 (6.8 mg, 60
.mu.mol, 2 eq.) and compound 47 (10 mg, 30 .mu.mol, 1 eq.) in
t-BuOH (0.5 mL) was stirred at 160.degree. C. for 10 h. The mixture
was cooled down to 25.degree. C. and concentrated in vacuo. The
residue was purified by prep-HPLC (neutral condition and HCl
condition) to afford compound C12 (1.0 mg, 2.4 .mu.mol, 8% yield,
97% purity). .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 8.06 (s,
1H), 4.15 (s, 3H), 3.72 (s, 1H), 3.16 (br d, J=5.3 Hz, 2H), 2.54
(br s, 1H), 2.22-2.12 (m, 4H), 1.58 (br t, J=9.3 Hz, 4H), 1.10 (br
s, 1H), 0.96 (br d, J=8.3 Hz, 2H), 0.56 (br d, J=5.4 Hz, 5H), 0.27
(br s, 2H).
Example 22
Synthesis of
(1r,4r)-N.sup.1-(5-Chloro-4-(5-(cyclopropylmethyl)-2H-1,2,3-triazol-4-yl)-
pyrimidin-2-yl)cyclohexane-1,4-diamine C13
[1014] Compound C13 was prepared as shown in Scheme 17 below.
##STR00128##
[1015] Compound 49. To a solution of ethynyl(trimethyl)silane (15
g, 153 mmol, 21.16 mL, 1 eq.) in THE (100 mL) was added n-BuLi (2.5
M, 73.31 mL, 1.2 eq.) dropwise at -78.degree. C. under N.sub.2. The
mixture was stirred at 0.degree. C. for 10 min. Then HMPA (41.05 g,
229 mmol, 40.25 mL, 1.5 eq.) was added dropwise at -78.degree. C.
The mixture was stirred at -78.degree. C. for 20 min under N.sub.2.
Then compound 48 (20.62 g, 153 mmol, 14.62 mL, 1 eq.) was added
dropwise at -78.degree. C. Then the mixture was stirred
-78.about.25.degree. C. for 9.5 h. The reaction mixture was poured
into ice sat. NH.sub.4Cl (100 mL) and extracted with MTBE (150 mL).
The organic phase was washed with brine (200 mL), dried over
Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was
purified by column chromatography (SiO.sub.2, hexane) to afford
compound 49 (21 g, 138 mmol, 90% yield) as a yellow liquid. .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 2.31 (d, J=5.6 Hz, 2H), 0.95-0.91
(m, 1H), 0.50-0.39 (m, 2H), 0.28-0.22 (m, 2H), 0.17-0.14 (m,
9H).
[1016] Compound 51. To a mixture of compound 49 (976 mg, 5.13 mmol,
2 eq.), compound 50 (0.5 g, 2.56 mmol, 1 eq.),
Pd(PPh.sub.3).sub.2Cl.sub.2 (360 mg, 512 .mu.mol, 0.2 eq.), and CuI
(244 mg, 1.28 mmol, 0.5 eq.) in THE (10 mL) was added TBAF (1 M,
2.56 mL, 1 eq.) in one portion at 0.degree. C. under N.sub.2. The
reaction mixture was stirred at 60.degree. C. under N.sub.2 for 10
h. The mixture was partitioned between H.sub.2O(100 mL) and
EtOAc(200 mL). The combined organic phase were washed with brine
(200 mL), dried over Na.sub.2SO.sub.4, and concentrated in vacuo.
The residue was purified by column chromatography (SiO.sub.2,
PE/EtOAc: 1/0 to 50/1) and prep-TLC (PE/EtOAc: 20:1) to afford
compound 51 (0.3 g, 1.26 mmol, 49% yield) as a brown oil. H NMR
(CDCl.sub.3, 400 MHz) .delta. 8.47 (s, 1H), 2.61 (d, J=5.9 Hz, 2H),
2.56 (s, 3H), 1.13-1.03 (m, 1H), 0.61-0.52 (m, 2H), 0.36 (q, J=4.9
Hz, 2H).
[1017] Compound 52. A mixture of NaN.sub.3 (123 mg, 1.88 mmol, 1.5
eq., compound 51 (300 mg, 1.26 mmol, 1 eq.), CuSO.sub.4.5H.sub.2O
(376.51 mg, 1.51 mmol, 1.2 eq.), and sodium
(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate
(299 mg, 1.51 mmol, 1.2 eq.) in DMF (5 mL) was stirred at
20.degree. C. for 12 h. The reaction mixture was partitioned
between H.sub.2O(10 mL) and EtOAc(20 mL.times.2). The organic phase
was separated and dried over Na.sub.2SO.sub.4 and concentrated in
vacuo. The residue was purified by column chromatography
(SiO.sub.2, PE/EtOAc: 10/1 to 5:1) to afford compound 52 (20 mg, 71
.mu.mol, 6% yield) as a yellow oil. .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 11.82 (br s, 1H), 8.60 (s, 1H), 3.01 (d, J=7.0 Hz,
2H), 2.60 (s, 3H), 1.17-0.97 (m, 1H), 0.59 (br d, J=7.4 Hz, 2H),
0.38-0.13 (m, 2H).
[1018] Compound 53. To a solution of compound 52 (15 mg, 53
.mu.mol, 1 eq.) in DCM (10 mL) was added m-CPBA (29 mg, 133
.mu.mol, 80% purity, 2.5 eq.) in portions at -78.degree. C. The
mixture was stirred at -78 to 0.degree. C. for 1 h under N.sub.2.
The reaction mixture was poured into sat. Na.sub.2SO.sub.3 (10 mL)
and stirred for 5 min. Then the mixture was extracted with DCM (20
mL.times.2). The combined organic layers were poured into sat.
NaHCO.sub.3(10 mL). The organic layer was washed with brine (20
mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated in
vacuo to give compound 53 (16 mg, 51 .mu.mol, 96% yield) as a
yellow solid. H NMR (CDCl.sub.3, 400 MHz) .delta. 8.96 (s, 1H),
3.39 (s, 3H), 3.12 (d, J=7.2 Hz, 2H), 0.97 (br t, J=7.5 Hz, 1H),
0.70-0.60 (m, 2H), 0.34 (q, J=5.0 Hz, 2H).
[1019] Compound C.sub.13. A mixture of compound 53 (0.015 g, 48
.mu.mol, 1 eq.) and compound 37 (10.92 mg, 96 .mu.mol, 2 eq.) in
t-BuOH (0.5 mL) was stirred at 140.degree. C. for 2 h. The mixture
was concentrated in vacuo. The residue was purified by prep-HPLC
(HCl condition) to afford compound C13 (1.7 mg, 4.9 .mu.mol, 10%
yield). .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 8.40 (s, 1H),
3.93-3.75 (m, 1H), 3.15 (br s, 1H), 2.93 (d, J=7.0 Hz, 2H), 2.19
(br d, J=10.8 Hz, 2H), 2.12 (br d, J=11.2 Hz, 2H), 1.57-1.46 (m,
4H), 1.11 (s, 1H), 0.61-0.47 (m, 2H), 0.23 (q, J=5.1 Hz, 2H).
Example 23
Synthesis of
(1r,4r)-N.sup.1-(5-Chloro-4-(4-(cyclopropylmethyl)-1H-pyrazol-5-yl)pyrimi-
din-2-yl)cyclohexane-1,4-diamine C.sub.14
[1020] Compound C14 was prepared as shown in Scheme 18 below.
##STR00129##
[1021] Compound 55. To a solution of compound 54 (7.58 g, 108 mmol,
8.09 mL, 2 eq.) in THE (200 mL) was added n-BuLi (2.5 M, 26 mL, 1.2
eq.) dropwise at -78.degree. C. under N.sub.2. The mixture was
stirred at -78.degree. C. for 0.5 h. Then cyclopropyl aldehydre (15
g, 54 mmol, 1 eq.) was added dropwise at -78.degree. C. The mixture
was stirred at -78.degree. C. for 0.5 h under N.sub.2. The reaction
mixture was poured into ice NH.sub.4Cl (100 mL) and extracted with
EtOAc (150 mL.times.2). The combined organic layers were washed
with brine (150 mL), dried over Na.sub.2SO.sub.4, and concentrated
in vacuo. The residue was purified by column chromatography
(SiO.sub.2, PE/EtOAc: 10/1 to 2/1) to afford compound 55 (4.69 g,
17 mmol, 32% yield) as a yellow oil. H NMR (CDCl.sub.3, 400 MHz)
.delta. 7.38 (d, J=1.7 Hz, 1H), 6.35 (d, J=1.6 Hz, 1H), 5.60-5.41
(m, 2H), 4.23-4.12 (m, 1H), 3.51 (t, J=8.4 Hz, 2H), 3.31 (br d,
J=3.3 Hz, 1H), 1.41-1.29 (m, 1H), 0.89-0.78 (m, 2H), 0.68-0.43 (m,
3H), 0.30 (qd, J=4.8, 9.7 Hz, 1H), 0.03-0.25 (m, 9H).
[1022] Compound 56. To a solution of compound 55 (4.6 g, 17 mmol, 1
eq.) in DCM (17 mL) was added TFA (39 g, 343 mmol, 25.38 mL, 20
eq.) and triethylsilane (9.96 g, 86 mmol, 13.69 mL, 5 eq.) in one
portion at 25.degree. C. The mixture was stirred at 60.degree. C.
for 12 h. The reaction mixture was concentrated in vacuo. The
mixture was poured into ice NaHCO.sub.3 (100 mL) and extracted with
EtOAc (50 mL.times.3). The combined organic layers were washed with
brine (50 mL), dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo. The residue was purified by column
chromatography (SiO.sub.2, PE/EtOAc: 10/1 to 2/1) to afford
compound 56 (2.0 g, 16 mmol, 96% yield) as a yellow oil. .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 12.76 (br s, 1H), 7.64 (s, 1H),
6.39-6.04 (m, 1H), 2.67 (d, J=7.0 Hz, 2H), 1.18-0.95 (m, 1H),
0.72-0.49 (m, 2H), 0.34-0.07 (m, 2H).
[1023] Compound 57. To solution of compound 56 (2 g, 16 mmol, 1
eq.) in THE (50 mL) was added NaH (786 mg, 30 mmol, 60% purity, 1.2
eq.) in portions at 0.degree. C. under N.sub.2. Then the mixture
was stirred at 0.degree. C. for 30 min. SEM-Cl (4.09 g, 25 mmol,
4.35 mL, 1.5 eq.) was added dropwise at 0.degree. C. The mixture
was stirred at 0-30.degree. C. for 2 h under N.sub.2. The reaction
mixture was poured into ice sat. NH.sub.4Cl (100 mL) and extracted
with EtOAc (50 mL.times.2). The combined organic layers were washed
with brine (50 mL), dried over Na.sub.2SO.sub.4, and concentrated
in vacuo. The residue was purified by column chromatography
(SiO.sub.2, PE/EtOAc: 20/1 to 1/1) to afford compound 57 (4 g, 16
mmol, 97% yield) as a yellow oil. .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 7.45 (dd, J=2.0, 15.8 Hz, 1H), 5.39 (d, J=17.6 Hz, 2H),
3.60-3.42 (m, 2H), 2.60 (dd, J=6.8, 19.0 Hz, 2H), 1.10-0.94 (m,
1H), 0.94-0.81 (m, 2H), 0.61-0.41 (m, 2H), 0.27-0.14 (m, 2H), -0.03
(d, J=3.3 Hz, 9H).
[1024] Compound 58. To solution of compound 57 (4 g, 15.85 mmol, 1
eq.) in MeCN (0.5 mL) was added NBS (2.82 g, 15.85 mmol, 1 eq.) in
portions at 0.degree. C. Then the mixture was stirred at
0-30.degree. C. for 2.5 h. The reaction mixture was poured into
H.sub.2O (30 mL) and concentrated in vacuo. Then the mixture was
partitioned between H.sub.2O (20 mL) and EtOAc (50 mL). The organic
phase was separated, washed with brine (30 mL), dried over
Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was
purified by column chromatography (SiO.sub.2, PE/EtOAc: 20/1 to
1/1) to afford compound 58 (2.1 g, 3 mmol, 38% yield) as a yellow
oil. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.59-7.40 (m, 2H),
5.55-5.24 (m, 4H), 3.60-3.52 (m, 4H), 2.74-2.51 (m, 4H), 1.17-1.02
(m, 2H), 0.96-0.85 (m, 4H), 0.54-0.44 (m, 4H), 0.34-0.18 (m, 4H),
-0.02 (d, J=2.3 Hz, 18H).
[1025] Compound 60. To a mixture of compound 58 (2.0 g, 3.02 mmol,
1 eq.) and compound 59 (1.68 g, 9.05 mmol, 1.85 mL, 3 eq.) in THE
(30 mL) was added n-BuLi (2.5 M, 2.90 mL, 2.4 eq.) dropwise at
-78.degree. C. under N.sub.2. The mixture was stirred at
-78.degree. C. for 0.5 h. The mixture was poured into ice
NH.sub.4Cl (50 mL) and extracted with EtOAc (50 mL.times.2). The
combined organics were washed with brine (50 mL), dried over
Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was
purified by column chromatography (SiO.sub.2, PE/EtOAc: 10/1 to
3/1) to afford compound 60 (0.8 g, 2 mmol, 70% yield) as a yellow
oil. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.79-7.69 (m, 2H),
5.50-5.36 (m, 4H), 3.62-3.51 (m, 4H), 2.92-2.67 (m, 4H), 1.31 (s,
24H), 1.11-1.01 (m, 2H), 0.93-0.88 (m, 4H), 0.48-0.37 (m, 4H),
0.34-0.21 (m, 4H), -0.02 (s, 18H).
[1026] Compound 62. A mixture of compound 61 (242 mg, 1.32 mmol, 1
eq.), compound 60 (1 g, 1.32 mmol, 1 eq.), Pd(dppf)C.sub.12 (97 mg,
132 .mu.mol, 0.1 eq.), and K.sub.2CO.sub.3 (365 mg, 2.64 mmol, 2
eq.) in dioxane:MeCN:H.sub.2O (2:2:1; 5 mL) was degassed and purged
with N.sub.2 for 3 times. Then the mixture was stirred at
80.degree. C. for 2 h under N.sub.2. The reaction mixture was
partitioned between H.sub.2O (20 mL) and EtOAc(30 mL). The organic
phase was separated, washed with brine (10 mL), dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue
was purified by column chromatography (SiO.sub.2, PE/EtOAc: 20/1 to
3/1) to afford compound 62 (0.5 g, 626 .mu.mol, 47% yield) as a
yellow oil. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.58-8.53 (m,
2H), 8.34-8.25 (m, 2H), 5.58-5.53 (m, 3H), 3.69-3.58 (m, 4H),
3.20-3.07 (m, 4H), 0.96-0.84 (m, 6H), 0.50-0.39 (m, 4H), 0.34-0.22
(m, 4H), 0.01-(-0.04) (m, 18H). 2.7 Preparation of Compound
11--Notebook Page: ET18031-630
[1027] Compound 63. A mixture of compound 37 (143 mg, 1.25 mmol, 5
eq), compound 62 (100 mg, 250 .mu.mol, 1 eq.) in n-BuOH (1 mL) was
stirred at 140.degree. C. for 4 h. The reaction mixture was
partitioned between H.sub.2O (20 mL) and EtOAc (30 mL). The organic
phase was separated, washed with brine (10 mL), dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give
compound 63 (0.230 g, 96% yield) as a yellow oil. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 8.36 (br s, 1H), 8.25-8.19 (m, 2H),
8.14 (br s, 1H), 5.53 (s, 2H), 5.44 (s, 2H), 4.91 (br d, J=5.3 Hz,
2H), 3.81 (br s, 2H), 3.66-3.58 (m, 4H), 3.12 (br d, J=5.6 Hz, 2H),
2.98 (br s, 2H), 2.74 (br s, 1H), 2.29-2.09 (m, 4H), 1.52-1.26 (m,
16H), 1.14-1.02 (m, 2H), 0.94-0.90 (m, 4H), 0.43 (br s, 4H), 0.19
(br t, J=5.0 Hz, 3H), 0.00 (s, 16H).
[1028] Compound C.sub.14. To a mixture of compound 63 (0.23 g, 241
.mu.mol, 1 eq.) in DCM (2 mL) was added TFA (27 mg, 241 .mu.mol,
17.85 .mu.L, 1 eq.) dropwise at 0.degree. C. The mixture was
stirred at 0-30.degree. C. for 2 h. The reaction mixture was poured
into NaHCO.sub.3 (10 mL) and DCM (15 mL.times.2). The organic phase
was separated and washed with brine (15 mL), dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue
was purified by prep-HPLC(basic condition) to afford compound C14
(13 mg, 38 .mu.mol, 16% yield). .sup.1H NMR (CD.sub.3OD, 400 MHz)
.delta. 8.27 (br s, 1H), 8.19 (s, 1H), 3.81 (br s, 1H), 3.00 (br d,
J=6.9 Hz, 2H), 2.86 (br s, 1H), 2.10 (br s, 2H), 2.01 (br s, 2H),
1.46-1.34 (m, 4H), 1.11 (br s, 1H), 0.49 (br d, J=7.4 Hz, 2H), 0.21
(br d, J=4.5 Hz, 2H).
Example 24
Synthesis of
(1r,4r)-4-((5-Chloro-4-(4-(cyclopropylmethyl)-1H-pyrazol-5-yl)pyrimidin-2-
-yl)amino)cyclohexan-1-ol C15
[1029] Compound C15 was prepared as shown in Scheme 19 below.
##STR00130##
[1030] Compound 64. A mixture of compound 62 (200 mg, 250 .mu.mol,
1 eq.) and compound 33 (72 mg, 626 .mu.mol, 2.5 eq.) in n-BuOH (1
mL) was stirred at 140.degree. C. for 4 h. The reaction mixture was
partitioned between H.sub.2O (20 mL) and EtOAc (30 mL). The organic
phase was separated, washed with brine (10 mL), dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to afford
compound 64 (0.15 g, 63% yield) as a yellow oil. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 8.28-8.06 (m, 4H), 5.54 (s, 4H), 4.98
(br s, 2H), 3.82 (br s, 2H), 3.11 (br d, J=6.0 Hz, 4H), 2.15 (br d,
J=10.5 Hz, 4H), 2.02 (br s, 4H), 1.44-1.40 (m, 4H), 1.36-1.22 (m,
8H), 1.06 (br s, 2H), 0.49-0.36 (m, 4H), 0.23-0.13 (m, 4H), 0.00
(s, 18H).
[1031] Compound C.sub.15. To a solution of compound 64 (0.14 g, 146
.mu.mol, 1 eq.) in DCM (1.5 mL) was added TFA (1.08 g, 9.45 mmol,
700 .mu.L, 65 eq.) at 0.degree. C. The mixture was stirred at
0-30.degree. C. for 0.5 h. The reaction mixture was poured into
NaHCO.sub.3 (10 mL) and extracted with EtOAc (15 mL.times.2). The
organic phase was separated and washed with brine (15 mL), dried
over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was
purified by prep-HPLC (basic condition) to afford compound C15
(18.5 mg, 36% yield). .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta.
8.26 (br s, 1H), 8.18 (s, 1H), 4.60 (br s, 1H), 3.81 (br s, 1H),
3.68-3.54 (m, 1H), 3.01 (br d, J=6.3 Hz, 2H), 2.10-1.96 (m, 4H),
1.45-1.32 (m, 4H), 1.13 (br s, 1H), 0.51 (br s, 2H), 0.23 (br s,
2H).
Example 25
Synthesis of
(1r,4r)-N.sup.1-(5-Fluoro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4--
yl)pyrimidin-2-yl)-N.sup.4-(pent-4-yn-1-yl)cyclohexane-1,4-diamine
AA1
[1032] Compound AA1 was prepared as shown in Scheme A1 below.
##STR00131##
[1033] Compound 3A. A mixture of compound 1A (0.25 g, 954 .mu.mol,
1 eq.), compound 2A (159 mg, 954 .mu.mol, 1 eq.), Pd(dppf)Cl.sub.2
(70 mg, 96 .mu.mol, 0.1 eq.), and K.sub.2CO.sub.3 (264 mg, 1.91
mmol, 2 eq.) in dioxane:MeCN:H.sub.2O (2:2:1) (3 mL) was degassed
and purged with N.sub.2 for 3 times at 25.degree. C. After stirred
at 90.degree. C. for 10 h, the reaction mixture was cooled to
25.degree. C. and partitioned between H.sub.2O (10 mL) and EtOAc
(10 mL). The organic phase was separated, washed with brine (10
mL), dried over Na.sub.2SO.sub.4, and concentrated in vacuo to give
a residue. The residue was purified by prep-TLC (PE:EtOAc (3:1)) to
give compound 3A (0.2 g, 750 .mu.mol, 79% yield). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 8.37 (d, J=3.1 Hz, 1H), 8.07 (d,
J=4.3 Hz, 1H), 3.95 (s, 3H), 3.22 (d, J=6.7 Hz, 2H), 1.14-0.96 (m,
1H), 0.54-0.44 (m, 2H), 0.38 (q, J=4.9 Hz, 2H).
[1034] Compound 5A. A mixture of compound 3A (0.17 g, 637 .mu.mol,
1 eq.) and compound 4A (364 mg, 3.19 mmol, 5 eq.) in n-BuOH (5 mL)
was degassed and purged with N.sub.2 for 3 times at 25.degree. C.
After stirred at 160.degree. C. for 5 h, the reaction mixture was
cooled to 25.degree. C. and partitioned between H.sub.2O (10 mL)
and EtOAc (15 mL). The organic phase was separated, washed with
brine (10 mL), dried over Na.sub.2SO.sub.4, and concentrated in
vacuo to give a residue. The residue was purified by prep-HPLC
(neutral condition) to give compound 5A (0.12 g, 55% yield).
.sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 8.09 (d, J=3.5 Hz, 1H),
8.02 (d, J=4.2 Hz, 1H), 4.85 (br d, J=8.2 Hz, 1H), 3.91 (s, 3H),
3.84-3.72 (m, 1H), 3.22 (d, J=6.4 Hz, 2H), 2.87-2.77 (m, 1H), 2.17
(br d, J=11.5 Hz, 2H), 1.99 (br d, J=11.9 Hz, 2H), 1.40-1.24 (m,
4H), 1.16-1.04 (m, 1H), 0.53-0.46 (m, 2H), 0.28-0.22 (m, 2H).
[1035] 5-Iodopent-1-yne. A mixture of 5-chloropent-1-yne (0.5 g,
4.9 mmol, 1 eq.) and NaI (2.2 g, 15 mmol, 3 eq.) in acetone (5 mL)
was stirred at 80.degree. C. for 12 h. The mixture was filtered and
the filtrate was concentrated in vacuo to give 5-iodopent-1-yne
(0.4 g), which was used directly in the next step without further
purification. .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 3.31 (t,
J=6.7 Hz, 2H), 2.35-2.29 (m, 2H), 2.02-1.95 (m, 3H).
[1036] Compound AA1. A mixture of compound 5A (0.1 g, 290 .mu.mol,
1 eq.), 5-iodopent-1-yne (45 mg, 232 .mu.mol, 0.8 eq.), and
K.sub.2CO.sub.3 (48 mg, 348 .mu.mol, 143 .mu.L, 1.2 eq.) in DMF
(1.5 mL) was stirred at 25.degree. C. for 12 h under N.sub.2. The
reaction mixture was partitioned between H.sub.2O (10 mL) and EtOAc
(10 mL). The organic phase was separated, washed with brine (10
mL), dried over Na.sub.2SO.sub.4, and concentrated in vacuo to give
a residue. The residue was purified by prep-HPLC (HCl condition) to
give AA1 (30 mg, 23% yield) as a HCl salt. .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. 8.36 (d, J=5.7 Hz, 1H), 8.21 (d, J=4.9 Hz, 1H),
4.15-4.00 (m, 1H), 3.96 (s, 3H), 3.34-3.32 (m, 2H), 3.28-3.23 (m,
1H), 3.23-3.16 (m, 2H), 2.43-2.39 (m, 2H), 2.39-2.36 (m, 1H), 2.28
(br dd, J=9.8, 20.0 Hz, 4H), 2.02-1.90 (m, 2H), 1.76-1.54 (m, 4H),
1.26-1.12 (m, 1H), 0.60-0.51 (m, 2H), 0.42-0.29 (m, 2H).
Example 26
Synthesis of
N-((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl-
)pyrimidin-2-yl)amino)cyclohexyl)pent-4-ynamide AA2
[1037] Compound AA2 was prepared as shown in Scheme 2A below.
##STR00132##
[1038] Compound 7A. A mixture of compound 6A (2.5 g, 8.83 mmol, 1
eq.) and compound 4A (5.04 g, 44 mmol, 5 eq.) in n-BuOH (5 mL) was
degassed and purged with N.sub.2 for 3 times at 25.degree. C. After
stirred at 160.degree. C. for 2 h, the reaction mixture was cooled
to 25.degree. C. and partitioned between H.sub.2O (10 mL) and EtOAc
(15 mL). The organic phase was separated, washed with brine (10
mL.times.2), dried over Na.sub.2SO.sub.4, and concentrated in vacuo
to give a residue. The residue was purified by prep-HPLC (neutral
condition) to give compound 7A (2.7 g, 85% yield). .sup.1H-NMR (400
MHz, CD.sub.3OD) .delta. 8.19 (s, 1H), 8.06 (br s, 1H), 3.90 (s,
3H), 3.85-3.69 (m, 1H), 3.13 (br d, J=6.5 Hz, 2H), 2.90-2.73 (m,
1H), 2.14-1.90 (m, 4H), 1.45-1.25 (m, 4H), 1.07-0.92 (m, 1H),
0.51-0.40 (m, 2H), 0.16 (br d, J=4.8 Hz, 2H).
[1039] Compound AA2. A mixture of compound 7A (500 mg, 1.39 mmol, 1
eq.), pent-4-ynoic acid (143 mg, 1.45 mmol, 1.05 eq.), HATU (579
mg, 1.52 mmol, 1.1 eq.), and TEA (280 mg, 2.77 mmol, 386 .mu.L, 2
eq.) in DMF (5 mL) was stirred at 25.degree. C. for 2 h under
N.sub.2. The reaction mixture was partitioned between H.sub.2O (10
mL) and EtOAc (10 mL). The organic phase was separated, washed with
brine (10 mL), dried over Na.sub.2SO.sub.4, and concentrated in
vacuo to give a residue. The residue was purified by prep-HPLC (HCl
condition) to give compound AA2 (0.375 g, 57% yield) as a HCl salt.
.sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 8.36-7.97 (m, 2H), 3.93
(s, 3H), 3.90-3.84 (m, 1H), 3.75-3.65 (m, 1H), 3.17 (d, J=6.4 Hz,
2H), 2.52-2.33 (m, 4H), 2.26 (t, J=2.6 Hz, 1H), 2.15-1.92 (m, 4H),
1.56-1.30 (m, 4H), 1.13-0.98 (m, 1H), 0.51 (br d, J=7.7 Hz, 2H),
0.23 (br d, J=4.5 Hz, 2H).
Example 27
Synthesis of
(1r,4r)-N.sup.1-(5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4--
yl)pyrimidin-2-yl)-N.sup.4-(pent-4-yn-1-yl)cyclohexane-1,4-diamine
AA3
[1040] Compound AA3 was prepared as shown in Scheme 3A below.
##STR00133##
[1041] Compound AA3. To a solution of compound 7A (100 mg, 277
.mu.mol, 1 eq.) in DMF (5 mL) was added K.sub.2CO.sub.3 (57 mg, 416
.mu.mol, 1.5 eq.) at 25.degree. C. After the mixture was stirred at
25.degree. C. for 30 mins, 5-iodopent-1-yne (54 mg, 277 .mu.mol, 1
eq.) in DMF (5 mL) was added. The mixture was stirred at 25.degree.
C. for 2 h. The reaction mixture was then filtered, concentrated,
and purified by prep-HPLC (neutral condition) to give compound AA3
(13 mg, 11% yield). .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 8.19
(s, 1H), 7.96-8.14 (m, 1H), 3.87-3.98 (m, 3H), 3.71-3.86 (m, 1H),
3.03-3.26 (m, 2H), 2.69-2.87 (m, 2H), 2.49-2.68 (m, 1H), 2.15-2.36
(m, 3H), 1.96-2.15 (m, 4H), 1.74 (quin, J=7.18 Hz, 2H), 1.22-1.45
(m, 4H), 1.01 (br d, J=6.40 Hz, 1H), 0.47 (br d, J=7.53 Hz, 2H),
0.17 (br d, J=4.64 Hz, 2H).
Example 28
Synthesis of
N-((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl-
)pyrimidin-2-yl)amino)cyclohexyl)pentanamide AA4
[1042] Compound AA4 was prepared as shown in Scheme 4A below.
##STR00134##
[1043] Pentanoyl chloride. To a solution of pentanoic acid (500 mg,
4.9 mmol, 532 .mu.L, 1 eq.) in DCM (3 mL) was added oxalyl chloride
(684 mg, 5.4 mmol, 471.39 .mu.L, 1.1 eq.) at 0.degree. C., followed
by two drops of DMF at 0.degree. C. After stirred at 25.degree. C.
for 1 h, the reaction mixture was concentrated in vacuo to yield
pentanoyl chloride (600 mg), which was directly in the next step
without further purification.
[1044] Compound AA4. To a solution of compound 7A (50 mg, 139
.mu.mol, 1 eq.) in DCM (2 mL) was added TEA (21 mg, 208 .mu.mol,
28.93 .mu.L, 1.5 eq.) at 0.degree. C. After stirred at 0.degree. C.
for 10 min, pentanoyl chloride (17 mg, 139 .mu.mol, 17 .mu.L, 1
eq.) in DCM (0.5 mL) was added dropwise at 0.degree. C. After
stirred at 25.degree. C. for 1 h, the reaction mixture was then
partitioned between H.sub.2O (10 mL) and EtOAc (20 mL). The organic
phase was separated, dried over Na.sub.2SO.sub.4, and concentrated
in vacuo to give a residue. The residue was purified by prep-HPLC
(HCl condition) to give compound AA4 (13 mg, yield 32%, purity
95%). .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 8.20-8.49 (m, 2H),
3.94 (s, 4H), 3.68 (tt, J=11.33, 3.89 Hz, 1H), 3.20 (d, J=6.39 Hz,
2H), 2.06-2.24 (m, 4H), 1.93-2.03 (m, 2H), 1.26-1.67 (m, 8H),
1.02-1.15 (m, 1H), 0.94 (t, J=7.39 Hz, 3H), 0.46-0.60 (m, 2H), 0.27
(br d, J=4.63 Hz, 2H).
Example 29
Synthesis of
N-(5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-
-yl)bicyclo[2.2.1]heptane-1,4-diamine AB1
[1045] Compound AB1 was prepared as shown in Scheme 5A below.
##STR00135##
[1046] Compound AB1. A mixture of compound 6A (75 mg, 265 .mu.mol,
1 eq.), bicyclo[2.2.1]heptane-1,4-diamine (47 mg, 371 .mu.mol, 1.4
eq.), and DIPEA (103 mg, 795 .mu.mol, 138 .mu.L, 3 eq.) in DMSO (1
mL) was degassed and purged with N.sub.2 for three times at
25.degree. C. After stirred at 140.degree. C. for 10 h under
N.sub.2, the reaction mixture was purified by prep-HPLC (HCl) to
give compound AB1 (21 mg, yield 21%, purity 95%). .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 8.46 (s, 1H), 8.15 (s, 1H), 3.98 (s, 3H),
3.05-3.24 (m, 1H), 3.15 (d, J=6.53 Hz, 2H), 1.87-2.32 (m, 10H),
0.95 (br t, J=5.02 Hz, 1H), 0.48 (br d, J=7.53 Hz, 2H), 0.14 (d,
J=5.52 Hz, 2H).
Example 30
Synthesis of
N-(5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-
-yl)bicyclo[2.2.2]octane-1,4-diamine AB2
[1047] Compound AB2 was prepared as shown in Scheme 6A below.
##STR00136##
[1048] Compound 8A. A mixture of compound 6A (60 mg, 212 .mu.mol, 1
eq.), tert-butyl N-(1-amino-4-bicyclo[2.2.2]octanyl)carbamate (51
mg, 212 .mu.mol, 1 eq.), and DIPEA (41 mg, 318 .mu.mol, 55 .mu.L,
1.5 eq.) in DMSO (2 mL) was degassed and purged with N.sub.2 for
three times at 25.degree. C. After stirred at 140.degree. C. for 10
h under N.sub.2, the reaction mixture was partitioned between
H.sub.2O (5 mL) and EtOAc (10 mL). The organic phase was separated,
dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give
compound 8A (60 mg), which was used directly in the next step
without further purification.
[1049] Compound AB2. To a solution of compound 8A (60 mg, 123
.mu.mol, 1 eq.) in EtOAc (3 mL) was added HCl/EtOAc (4 M, 31 .mu.L,
1 eq.) at 25.degree. C. After stirred at 25.degree. C. for 0.5 h,
the reaction mixture was concentrated in vacuo to give a residue.
The residue was then purified by prep-HPLC (neutral condition) to
give compound AB2 (9.6 mg, yield 20%, purity 95%). .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 8.20 (s, 1H), 7.90 (s, 1H), 3.91 (s, 3H),
3.09 (d, J=6.62 Hz, 2H), 2.04-2.17 (m, 6H), 1.64-1.76 (m, 6H),
0.86-1.01 (m, 1H), 0.34-0.51 (m, 2H), 0.00-0.14 (m, 2H).
Example 31
Synthesis of
(1r,4r)-N.sup.1-(5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4--
yl)pyrimidin-2-yl)-M-pentylcyclohexane-1,4-diamine AA5 and
(1r,4r)-N.sup.1-(5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4--
yl)pyrimidin-2-yl)-N.sup.4,N.sup.4-dipentylcyclohexane-1,4-diamine
AA6
[1050] Compounds AA5 and AA6 were prepared as shown in Scheme 7A
below.
##STR00137##
[1051] Compounds AA5 and AA6. To a solution of compound 7A (40 mg,
111 .mu.mol, 1 eq.) in DMF (3 mL) was added K.sub.2CO.sub.3 (18.38
mg, 133 .mu.mol, 1.2 eq.) at 25.degree. C. After addition, the
mixture was stirred at this temperature for 30 min and then
1-iodopentane (21.95 mg, 111 .mu.mol, 1 eq.) in DMF (3 mL) was
added. The mixture was stirred at 25.degree. C. for 2 h. The
reaction mixture was filtered and concentrated. The residue was
purified by prep-HPLC (HCl condition) to afford compound AA5 (12
mg, 28 .mu.mol, 25% yield) as a colorless oil and compound AA6 (7
mg, 14 .mu.mol, 13% yield) as a colorless oil.
[1052] Compound AA5: MS (ESI) m/z: [M+H].sup.+ Calcd for
C.sub.23H.sub.36ClN.sub.6 431.3; Found 431.5; .sup.1H NMR
(CD.sub.3OD, 400 MHz) .delta. 8.32-8.55 (m, 2H), 3.87-4.15 (m, 4H),
3.13-3.25 (m, 3H), 3.00-3.09 (m, 2H), 2.15-2.35 (m, 4H), 1.68-1.78
(m, 2H), 1.52-1.67 (m, 4H), 1.33-1.48 (m, 4H), 1.03-1.14 (m, 1H),
1.02-1.16 (m, 1H), 0.91-1.02 (m, 3H), 0.45-0.64 (m, 2H), 0.24-0.32
(m, 2H). 431.5
[1053] Compound AA6: MS (ESI) m/z: [M+H].sup.+ Calcd for
C.sub.28H.sub.46ClN.sub.6 501.2; Found 501.6; .sup.1H NMR
(CD.sub.3OD, 400 MHz) .delta. 8.14-8.41 (m, 2H), 3.84-4.06 (m, 4H),
3.43 (t, J=11.91 Hz, 1H), 3.06-3.28 (m, 6H), 2.12-2.33 (m, 4H),
1.69-1.84 (m, 6H), 1.50-1.65 (m, 2H), 1.37-1.46 (m, 8H), 1.01-1.14
(m, 1H), 0.97 (t, J=6.84 Hz, 6H), 0.45-0.55 (m, 2H), 0.15-0.30 (m,
2H). 501.6
Example 32
Synthesis of
(1r,4r)-N.sup.1-(3-Aminopropyl)-N.sup.4-(5-chloro-4-(5-(cyclopropylmethyl-
)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine
AA7 and (Z)-Cyclooct-4-en-1-yl
(3-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4--
yl)pyrimidin-2-yl)amino)cyclohexyl)amino)propyl)carbamate AA8
[1054] Compounds AA7 and AA8 were prepared as shown in Scheme 8A
below.
[1055] Compound 9A. A mixture of compound 7A (27.25 mg, 76 .mu.mol,
1 eq.), tert-butyl (3-bromopropyl)carbamate (21.57 mg, 91 .mu.mol,
1.2 eq.) and K.sub.2CO.sub.3 (31.31 mg, 227 .mu.mol, 3 eq.) in DMF
(2 mL) was degassed and purged with N.sub.2 for 3 times and then
stirred at 50.degree. C. for 6 h under N.sub.2 atmosphere. The
reaction mixture was partitioned between H.sub.2O(10 mL) and
EtOAc(10 mL). The organic phase was separated, washed with brine
(10 mL.times.3), dried over Na.sub.2SO.sub.4, filtered, and
concentrated under reduced pressure. The residue was purified by
prep-HPLC (HCl condition) to afford compound 9A (8.1 mg, 16
.mu.mol, 21% yield) as a yellow oil. .sup.1H NMR (CD.sub.3OD, 400
MHz) .delta. 8.19 (s, 1H), 8.14-7.98 (m, 1H), 3.91 (s, 3H), 3.80
(br t, J=10.8 Hz, 1H), 3.16-3.03 (m, 4H), 2.67 (t, J=7.3 Hz, 2H),
2.55 (br t, J=10.8 Hz, 1H), 2.12-2.02 (m, 4H), 1.68 (quin, J=6.9
Hz, 2H), 1.44 (s, 9H), 1.37-1.23 (m, 4H), 1.07-0.94 (m, 1H),
0.54-0.41 (m, 2H), 0.17 (q, J=5.0 Hz, 2H).
##STR00138##
[1056] Compound AA7. A mixture of compound A9 (200 mg, 386 .mu.mol,
1 eq.) in EtOAc (5 mL) was added HCl/EtOAc (4 M, 965 .mu.L, 10 eq.)
in one portion. After stirred at 25.degree. C. for 0.5 h, the
reaction mixture was filtered and the filter cake was washed with
EtOAc (5 mL.times.3). The filter cake was dried in vacuo to afford
crude compound AA7 (150 mg), which was used directly in the next
step without further purification. Some of the crude product (15
mg) was purified by preo-HPLC (HCl condition) to afford compound
AA7 (4.5 mg). .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 8.51 (br s,
1H), 8.44 (s, 1H), 4.18-4.02 (m, 1H), 3.98 (s, 3H), 3.28-3.16 (m,
5H), 3.12 (br t, J=7.6 Hz, 2H), 2.40-2.22 (m, 4H), 2.19-2.09 (m,
2H), 1.80-1.48 (m, 4H), 1.12 (br s, 1H), 0.56 (br d, J=7.5 Hz, 2H),
0.31 (br d, J=4.5 Hz, 2H).
[1057] Compound AA8. A mixture of (Z)-cyclooct-4-en-1-ol (42 mg,
330 .mu.mol, 1.5 eq.), N,N'-disuccinimidyl carbonate (DSC) (101 mg,
396 .mu.mol, 1.8 eq.), and TEA (40 mg, 396 .mu.mol, 1.8 eq.) in
MeCN (0.5 mL) was degassed and purged with N.sub.2 for 3 times.
After stirred at 25.degree. C. for 4 h under N.sub.2, the mixture
was added into a mixture of compound AA7 (91.98 mg, 220 .mu.mol, 1
eq.) and TEA (40 mg, 396 .mu.mol, 1.8 eq.) in DMF (0.5 mL) dropwise
at 25.degree. C. under N.sup.2. After stirred at 25.degree. C. for
0.5 h under N.sub.2, the reaction mixture was filtered and the
filtrate was concentrated in vacuo. The mixture was purificated by
prep-HPLC (HCl) to afford compound AA8 (8.9 mg, 16 .mu.mol, 7%
yield) as a yellow oil. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta.
8.47 (br s, 1H), 8.42 (s, 1H), 5.75-5.50 (m, 2H), 4.70 (br s, 1H),
4.15-4.00 (m, 1H), 3.96 (s, 3H), 3.29-3.18 (m, 4H), 3.14-2.97 (m,
2H), 2.62-2.49 (m, 2H), 2.44-2.32 (m, 1H), 2.25 (br d, J=13.2 Hz,
2H), 2.21-2.13 (m, 2H), 2.10-2.00 (m, 1H), 1.95-1.81 (m, 4H), 1.73
(br dd, J=4.6, 9.9 Hz, 1H), 1.68-1.34 (m, 7H), 1.10 (br s, 1H),
0.54 (br d, J=7.3 Hz, 2H), 0.30 (br s, 1H).
Example 33
Synthesis of Cyclooctyl
(3-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4--
yl)pyrimidin-2-yl)amino)cyclohexyl)amino)propyl)carbamate AA9
[1058] Compound AA9 was prepared as shown in Scheme 9A below.
##STR00139##
[1059] Compound AA9. A mixture of cyclooctanol (15.52 mg, 121
.mu.mol, 1.1 eq.), DSC (33.82 mg, 132 .mu.mol, 1.2 eq.), and TEA
(15.59 mg, 154 .mu.mol, 21.44 .mu.L, 1.4 eq.) in MeCN (0.5 mL) was
degassed and purged with N.sub.2 for 3 times and stirred at
25.degree. C. for 4 h under N.sub.2. The mixture was added into a
mixture of compound AA7 (0.05 g, 110 .mu.mol, 1 eq.) and TEA (15.59
mg, 154 .mu.mol, 21.44 .mu.L, 1.4 eq.) in DMF (0.5 mL) dropwise at
25.degree. C. under N.sub.2. The mixture was stirred at 25.degree.
C. for 0.5 h under N.sub.2. The reaction mixture was then
concentrated under reduced pressure. The residue was filtered. The
filtrate was purified by prep-HPLC (HCl) to afford compound AA9
(6.6 mg, 11 .mu.mol, 10% yield) as a yellow oil. .sup.1H NMR
(CD.sub.3OD, 400 MHz) .delta. 8.52-8.32 (m, 2H), 4.17-3.85 (m, 4H),
3.25-3.18 (m, 4H), 3.08 (br t, J=7.5 Hz, 2H), 2.66-2.48 (m, 1H),
2.26 (br d, J=10.3 Hz, 4H), 1.94-1.75 (m, 6H), 1.71-1.43 (m, 14H),
1.10 (br s, 1H), 0.54 (br d, J=7.5 Hz, 2H), 0.29 (br s, 2H).
Example 34
Synthesis of (E)-Cyclooct-4-en-1-yl
(3-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4--
yl)pyrimidin-2-yl)amino)cyclohexyl)amino)propyl)carbamate AA10
[1060] Compound AA10 was prepared as shown in Scheme 10A below.
##STR00140##
[1061] Compound AA10. A mixture of compound 7A (0.28 g, 616
.mu.mol, 1 eq.), TEA (125 mg, 1.23 mmol, 172 .mu.L, 2 eq.) in DCM
(1 mL) was degassed and purged with N.sub.2 for 3 times. A solution
of compound 10A (165 mg, 616 .mu.mol, 1 eq.) in DCM (1 mL) was
added dropwise at 0.degree. C. under N.sub.2. The mixture was
stirred at 0-25.degree. C. for 0.5 h under N.sub.2. The reaction
mixture was filtered and the filtrate was concentrated in vacuo.
The mixture was purificated by prep-HPLC (HCl condition) to afford
compound AA10 (131 mg, 217 .mu.mol, 35% yield). .sup.1H NMR (CD3OD,
400 MHz) .delta. 8.66-8.35 (m, 2H), 5.81-5.28 (m, 2H), 4.83-4.28
(m, 1H), 4.09 (br s, 1H), 3.98 (s, 3H), 3.26 (br d, J=5.3 Hz, 5H),
3.10 (br s, 2H), 2.46-2.15 (m, 7H), 2.03-1.88 (m, 5H), 1.80-1.34
(m, 8H), 1.13 (br s, 1H), 0.57 (br d, J=6.3 Hz, 2H), 0.32 (br s,
2H).
Example 35
Synthesis of
N-(2-(2-(2-(2-(((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-
-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethoxy)ethoxy)ethoxy)e-
thyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentana-
mide AA11
[1062] Compound AA11 was prepared as shown in Scheme 11A below.
##STR00141##
[1063] Compound 12A. A mixture of compound 11A (0.22 g, 1.41 mmol,
2 eq.) and compound 6A (0.2 g, 706 .mu.mol, 1 eq.) in n-BuOH (5 mL)
was degassed and purged with N.sub.2 for 3 times. After stirred at
160.degree. C. for 5 h, the reaction mixture was partitioned
between H.sub.2O (10 mL) and DCM (15 mL). The organic phase was
separated, washed with brine (10 mL.times.2), dried over
Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was
purified by prep-TLC (PE/EtOAc: 1:1) to afford compound 12A (0.24
g, 594 .mu.mol, 84% yield). .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 8.26-8.05 (m, 2H), 4.95 (br d, J=7.4 Hz, 1H), 3.97 (s, 4H),
3.92 (s, 3H), 3.06 (br d, J=6.5 Hz, 2H), 2.06 (br dd, J=4.0, 12.4
Hz, 2H), 1.88-1.76 (m, 2H), 1.74-1.58 (m, 4H), 1.09-0.97 (m, 1H),
0.54-0.42 (m, 2H), 0.23-0.14 (m, 2H).
[1064] Compound 13A. A mixture of compound 12A (0.22 g, 545
.mu.mol, 1 eq.) in aq. HCl (4 M, 2.72 mL, 20 eq.) was stirred at
15.degree. C. for 2 h under N.sub.2. The reaction mixture was
concentrated in vacuo. The residue was purified by prep-HPLC (HCl
condition) to afford compound 13A (0.20 g, 505 .mu.mol, 92.65%
yield). .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.30 (br s, 1H),
8.17 (s, 1H), 4.46-4.31 (m, 1H), 3.95 (s, 3H), 3.10 (d, J=6.1 Hz,
2H), 2.69-2.54 (m, 2H), 2.45 (ddd, J=5.7, 9.7, 15.1 Hz, 2H),
2.35-2.25 (m, 2H), 2.07-1.95 (m, 2H), 1.10-0.95 (m, 1H), 0.58-0.49
(m, 2H), 0.30-0.17 (m, 2H).
[1065] Compound AA11. A mixture of compound 13A (92 mg, 255
.mu.mol, 1 eq.) and compound 14A (160 mg, 382 .mu.mol, 1.5 eq.) in
MeOH (2 mL) stirred at 15.degree. C. for 5 h. To the mixture was
added CH.sub.3COOH (31 mg, 510 .mu.mol, 29 .mu.L, 2 eq.) and
NaBH(OAc).sub.3 (162 mg, 765 .mu.mol, 3 eq.) in one portion. The
reaction mixture was then stirred at 15-50.degree. C. for 24 h
under N.sub.2. The reaction mixture was cooled to 25.degree. C. and
partitioned between H.sub.2O (10 mL) and EtOAc (15 mL). The organic
phase was separated and washed with brine (10 mL), dried over
Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was
purified by prep-HPLC (HCl condition) to afford compound AA11 (20
mg, 25 .mu.mol, 10% yield). .sup.1H NMR (CD.sub.3OD, 400 MHz)
.delta. 8.42-8.21 (m, 2H), 4.60-4.47 (m, 1H), 4.38-4.25 (m, 1H),
3.90 (br s, 1H), 3.81 (s, 3H), 3.64 (br s, 2H), 3.54 (s, 4H), 3.50
(br s, 2H), 3.42 (br t, J=5.2 Hz, 2H), 3.26 (br t, J=5.2 Hz, 2H),
3.15 (br s, 6H), 3.08 (br d, J=6.5 Hz, 2H), 2.85 (br dd, J=4.3,
13.1 Hz, 1H), 2.64 (br d, J=13.3 Hz, 1H), 2.15 (br t, J=6.8 Hz,
4H), 2.09 (br s, 2H), 1.68-1.38 (m, 8H), 1.36-1.21 (m, 2H), 0.94
(br s, 1H), 0.38 (br d, J=7.2 Hz, 2H), 0.14 (br s, 2H).
Example 36
Synthesis of
(1r,4r)-N.sup.1-(4-(1-Methyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl-
)pyrimidin-2-yl)cyclohexane-1,4-diamine AA12
[1066] Compound AA12 was prepared as shown in Scheme 12A below.
[1067] Compound 16A. To a solution of compound 15A (5.0 g, 31 mmol,
1 eq.) in THE (50 mL) was added LDA (2 M in THF, 17 mL, 1.1 eq.)
dropwise at -78.degree. C. under N.sub.2. The mixture was stirred
at -78.degree. C. for 1 h. TMSCl (3.9 g, 36 mmol, 4.5 mL, 1.15 eq.)
was added at -78.degree. C. dropwise. After stirred at -78.degree.
C. for 30 mins, the mixture was poured into sat. NH.sub.4Cl (50 mL)
and extracted with EtOAc (50 mL.times.2). The combined organics
were washed with brine (20 mL.times.3), dried over
Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was
purified by column chromatography (PE/EtOAc: 5/1 to 1/1) to afford
compound 16A (7.0 g, 30 mmol, 97% yield) as a yellow oil. .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 7.43 (s, 1H), 3.98-3.91 (m, 3H),
0.51-0.39 (m, 9H).
[1068] Compound 17A. To a solution of compound 16A (6.2 g, 27 mmol,
1 eq.) in THE (50 mL) was added LDA (2 M, 19.9 mL, 1.5 eq.) in THE
dropwise at -78.degree. C. under N.sub.2. The mixture was stirred
at -78.degree. C. for 1 h. Tetrahydro-4H-pyran-4-one (4.0 g, 40
mmol, 3.66 mL, 1.5 eq.) was added dropwise at -78.degree. C. The
mixture was stirred at -78.degree. C. for 30 mins. The mixture was
poured into ice water (50 mL) and extracted with EtOAc (100
mL.times.2). The combined organics were washed with brine (100
mL.times.3), dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo to give compound 17A (8.0 g, 24 mmol, 90%
yield) as a yellow oil. H NMR (CD.sub.3OD, 400 MHz) .delta. 4.00
(s, 6H), 3.79-3.60 (m, 4H), 2.67-2.52 (m, 1H), 1.98-1.72 (m, 4H),
0.50-0.40 (m, 9H).
##STR00142##
[1069] Compound 18A. To a mixture of compound 17A (8.0 g, 24 mmol,
1 eq.) and TFA (54.7 g, 480 mmol, 35.54 mL, 20 eq.) in DCM (50 mL)
was added triethylsilane (13.96 g, 120 mmol, 19 mL, 5 eq.) at
15.degree. C. The mixture was stirred at 15-50.degree. C. for 12 h
under N.sub.2. The mixture was concentrated in vacuo. The residue
was purified by column chromatography (PE/EtOAc: 20/1 to 10/1) to
afford compound 18A (6.0 g, 19 mmol, 79% yield) as a yellow oil.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 4.06 (br dd, J=2.4, 11.3
Hz, 2H), 3.95-3.86 (m, 3H), 3.45 (s, 1H), 3.54 (dt, J=2.1, 11.7 Hz,
1H), 2.93 (tt, J=3.9, 11.7 Hz, 1H), 2.01-1.79 (m, 4H), 0.49-0.39
(m, 9H).
[1070] Compound 19A. To a mixture of compound 18A (5.0 g, 16 mmol,
1 eq.) in EtOH (5 mL) and MeCN (15 mL) was added CsF (4.8 g, 32
mmol, 2 eq.) in one portion at 15.degree. C. The mixture was
stirred at 15.degree. C. for 4 h. The reaction mixture was filtered
through celite. The filtrate was concentrated in vacuo. The residue
was purified by column chromatography (PE/EtOAc: 10/1 to 5/1) to
afford compound 19A (3.6 g, 15 mmol, 93% yield) as a yellow oil.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.32 (s, 1H), 4.06 (br
dd, J=2.3, 11.5 Hz, 2H), 3.53 (dt, J=2.1, 11.7 Hz, 2H), 2.93 (tt,
J=3.9, 11.7 Hz, 1H), 2.01-1.86 (m, 2H), 1.86-1.76 (m, 2H).
[1071] Compound 20A. To a mixture of compound 19A (1.0 g, 4.08
mmol, 1 eq.) and
2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.9 g, 4.90
mmol, 1.2 eq.) in THE (30 mL) was added n-BuLi (2.5 M, 2.0 mL, 1.2
eq.) dropwise at -78.degree. C. under N.sub.2. The mixture was
stirred at -78.degree. C. for 0.5 h. The mixture was poured into
sat. NH.sub.4Cl (50 mL) and extracted with EtOAc (30 mL.times.3).
The combined organics were washed with brine (30 mL), dried over
Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was
purified by column chromatography (PE/EtOAc: 20/1 to 5:1) to afford
compound 20A (0.5 g, 1.71 mmol, 42% yield) as a yellow oil. .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 7.56 (s, 1H), 4.03 (br dd, J=3.5,
10.4 Hz, 2H), 3.82 (s, 3H), 3.51 (dt, J=2.1, 11.7 Hz, 2H),
3.26-2.77 (m, 1H), 1.99-1.88 (m, 2H), 1.83-1.75 (m, 2H), 1.28 (s,
12H).
[1072] Compound 21A. A mixture of compound 20A (0.5 g, 1.71 mmol,
1.2 eq.), 2,4-dichloropyrimidine (0.21 g, 1.43 mmol, 1 eq.), aq.
Na.sub.2CO.sub.3 (2 M, 2.1 mL, 3 eq.), and PdCl.sub.2(Amphos).sub.2
(0.1 g, 143 .mu.mol, 0.1 eq.) in DME (3 mL) was degassed and purged
with N.sub.2 for 3 times. Then the mixture was stirred at
85.degree. C. for 2 h under N.sub.2. The reaction mixture was
cooled down to 25.degree. C. and partitioned between H.sub.2O (20
mL) and EtOAc (20 mL.times.2). The organic phase was separated,
washed with brine (50 mL), dried over Na.sub.2SO.sub.4, and
concentrated in vacuo. The residue was purified by prep-TLC
(PE/EtOAc: 1:1) to afford compound 21A (90 mg, 323 .mu.mol, 23%
yield) as a yellow oil. LCMS (M+H+): 279.
[1073] Compound AA12. A mixture of compound 21A (90 mg, 323
.mu.mol, 1 eq.) and compound 4A (111 mg, 969 .mu.mol, 3 eq.) in
n-BuOH (5 mL) was degassed and purged with N.sub.2 for 3 times.
Then the mixture was stirred at 160.degree. C. for 2 h under
N.sub.2. The reaction mixture was cooled down to 25.degree. C. and
concentrated in vacue. The residue was purified by prep-HPLC
(neutral condition) to afford compound AA12 (8 mg, 22 .mu.mol, 7%
yield). .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 8.09 (br d, J=5.3
Hz, 1H), 8.06 (s, 1H), 6.73 (br d, J=5.4 Hz, 1H), 4.04 (br d,
J=10.9 Hz, 2H), 3.88 (s, 3H), 3.86-3.76 (m, 2H), 3.61 (dt, J=2.3,
11.2 Hz, 2H), 2.83 (br s, 1H), 2.15-1.98 (m, 4H), 1.89 (br s, 4H),
1.40 (br s, 4H).
Example 37
Synthesis of
(1r,4r)-N.sup.1-(4-(5-Ethyl-1-methyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyra-
zol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine AA13
[1074] Compound AA13 was prepared as shown in Scheme 13A below.
##STR00143##
[1075] Compound 22A. To a solution of compound 15A (20.0 g, 124
mmol, 1 eq.) in THE (50 mL) was added LDA (2 M, 74.5 mL, 1.2 eq.)
dropwise at -78.degree. C. under N.sub.2. The mixture was stirred
at -78.degree. C. for 1 h. Iodoethane (25.2 g, 161 mmol, 12.92 mL,
1.3 eq.) was added dropwise at -78.degree. C. The mixture was
stirred at -78.degree. C. for 30 mins. The mixture was poured into
ice sat. NH.sub.4Cl (50 mL) and extracted with EtOAc (100
mL.times.2). The combined organics were washed with brine (100 mL),
dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo.
The residue was purified by column chromatography (PE/EtOAc: 5/1 to
1/1) to afford compound 22A (20 g, 106 mmol, 85% yield) as a yellow
oil. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.37 (s, 1H), 3.83
(s, 3H), 2.69 (q, J=7.6 Hz, 2H), 1.18 (t, J=7.6 Hz, 3H).
[1076] Compound 23A. To a solution of compound 22A (10.0 g, 53
mmol, 1 eq.) in THE (50 mL) was added LDA (2 M, 26.5 mL, 1 eq.)
dropwise at -78.degree. C. under N.sub.2. The mixture was stirred
at -78.degree. C. for 1 h. Tetrahydro-4H-pyran-4-one (7.9 g, 79
mmol, 7.29 mL, 1.5 eq.) was added dropwise at -78.degree. C. The
mixture was stirred at -78.degree. C. for 30 mins. The mixture was
poured into ice sat.NH.sub.4Cl (50 mL) and extracted with EtOAc
(100 mL.times.2). The combined organics were washed with brine (100
mL), dried over Na.sub.2SO.sub.4, and concentrated in vacuo to
afford compound 23A (15 g, 52 mmol) as a yellow oil, which was used
directly in the next step without further purification. .sup.1H NMR
(CD.sub.3OD, 400 MHz) .delta. 3.90 (dd, J=2.5, 10.8 Hz, 2H), 3.82
(s, 3H), 3.77-3.73 (m, 2H), 2.73 (d, J=7.7 Hz, 2H), 2.40-2.30 (m,
2H), 1.92-1.87 (m, 2H), 1.18 (d, J=7.0 Hz, 3H).
[1077] Compound 24A. To a mixture of compound 23A (15.0 g, 52 mmol,
1 eq.) and TFA (118.3 g, 1.04 mol, 76.81 mL, 20 eq.) in DCM (50 mL)
was added triethylsilane (30.16 g, 259.36 mmol, 41.43 mL, 5 eq.) in
one portion at 15.degree. C. The mixture was stirred at
15-50.degree. C. for 12 h under N.sub.2. The mixture was cooled
down to 25.degree. C. and concentrated in vacuo. The residue was
purified by column chromatography (PE/EtOAc: 20/1 to 10/1) to
afford compound 24A (14 g, 51 mmol, 99% yield) as a yellow oil.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 4.12-4.00 (m, 2H), 3.79
(s, 3H), 3.53 (dt, J=2.0, 11.7 Hz, 2H), 2.89 (tt, J=3.9, 11.7 Hz,
1H), 2.66 (q, J=7.7 Hz, 2H), 2.02-1.88 (m, 2H), 1.86-1.76 (m, 2H),
1.17 (t, J=7.6 Hz, 3H).
[1078] Compound 25A. A mixture of compound 23A (0.50 g, 1.83 mmol,
1 eq.), compound 3 (0.65 g, 2.01 mmol, 1.1 eq.) and
Pd(PPh.sub.3).sub.4 (0.21 g, 183 .mu.mol, 0.1 eq.) in toluene (5
mL) was degassed and purged with N.sub.2 for 3 times. The mixture
was stirred at 90.degree. C. for 12 h under N.sub.2. The reaction
mixture was cooled down to 25.degree. C. and concentrated in vacuo.
The residue was purified by column chromatography (PE/EtOAc: 10/1
to 8/1) to afford compound 25A (80 mg, 228 .mu.mol, 12% yield) as a
yellow oil. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.87-8.73 (m,
1H), 7.37-7.30 (m, 1H), 4.07 (br d, J=10.8 Hz, 2H), 3.86 (d, J=1.6
Hz, 3H), 3.55 (br t, J=11.7 Hz, 2H), 3.37 (d, J=1.6 Hz, 3H), 3.27
(br d, J=11.0 Hz, 1H), 3.00-2.87 (m, 2H), 2.02-1.92 (m, 2H), 1.84
(br d, J=11.2 Hz, 2H), 1.35-1.29 (m, 3H).
[1079] Compound AA13. A mixture of compound 25A (50 mg, 143
.mu.mol, 1 eq.) and compound 4A (49 mg, 428 .mu.mol, 3 eq.) in
t-BuOH (5 mL) was degassed and purged with N.sub.2 for 3 times.
Then the mixture was stirred at 140.degree. C. for 2 h under
N.sub.2. The reaction mixture was cooled down to 25.degree. C. and
concentrated in vacuo. The residue was purified by prep-HPLC
(neutral condition) to afford compound AA13 (17.5 mg, 46 .mu.mol,
32% yield). .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 8.19 (d,
J=5.1 Hz, 1H), 6.59 (d, J=5.3 Hz, 1H), 4.06-3.95 (m, 2H), 3.82 (s,
4H), 3.49 (br d, J=1.6 Hz, 2H), 3.32 (br s, 2H), 2.86 (d, J=7.4 Hz,
2H), 2.81-2.71 (m, 1H), 2.09 (br d, J=13.5 Hz, 2H), 1.99-1.84 (m,
4H), 1.80-1.70 (m, 2H), 1.37 (br d, J=9.2 Hz, 4H), 1.22 (t, J=7.5
Hz, 3H).
[1080] The examples set forth above are provided to give those of
ordinary skill in the art with a complete disclosure and
description of how to make and use the claimed embodiments, and are
not intended to limit the scope of what is disclosed herein.
Modifications that are obvious to persons of skill in the art are
intended to be within the scope of the following claims. All
publications, patents, and patent applications cited in this
specification are incorporated herein by reference as if each such
publication, patent or patent application were specifically and
individually indicated to be incorporated herein by reference.
* * * * *