U.S. patent application number 17/734345 was filed with the patent office on 2022-08-25 for combination therapy.
The applicant listed for this patent is MEI Pharma, Inc.. Invention is credited to Daniel P. GOLD.
Application Number | 20220265673 17/734345 |
Document ID | / |
Family ID | |
Filed Date | 2022-08-25 |
United States Patent
Application |
20220265673 |
Kind Code |
A1 |
GOLD; Daniel P. |
August 25, 2022 |
COMBINATION THERAPY
Abstract
Provided herein are methods of treating diseases, such as
cancer, using a combination therapy. In certain embodiments, the
methods comprise administering an effective amount of a
phosphoinositide-3-kinase (PI3K) inhibitor and an effective amount
of a CD20 inhibitor to a patient.
Inventors: |
GOLD; Daniel P.; (San Diego,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MEI Pharma, Inc. |
San Diego |
CA |
US |
|
|
Appl. No.: |
17/734345 |
Filed: |
May 2, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16639088 |
Feb 13, 2020 |
11351176 |
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PCT/US2018/046742 |
Aug 14, 2018 |
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17734345 |
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62545427 |
Aug 14, 2017 |
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International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61P 35/00 20060101 A61P035/00; C07K 16/28 20060101
C07K016/28 |
Claims
1. A method for treating or preventing cancer comprising
administering: (i) an effective amount of a compound of Formula
(i): ##STR00026## or an enantiomer, a mixture of enantiomers, a
mixture of two or more diastereomers, or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof; wherein: X, Y, and Z are each independently N
or CR.sup.X, with the proviso that at least two of X, Y, and Z are
nitrogen atoms; where R.sup.X is hydrogen or C.sub.1-6 alkyl;
R.sup.1 and R.sup.2 are each independently (a) hydrogen, cyano,
halo, or nitro; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-10 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(NR.sup.1a)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(.dbd.NR.sup.1a)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.aC(.dbd.NR.sup.1d)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, wherein each R.sup.1a, R.sup.1b,
R.sup.1c, and R.sup.1d is independently (i) hydrogen; (ii)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or
heterocyclyl; or (iii) R.sup.1b and R.sup.1c together with the N
atom to which they are attached form heterocyclyl; R.sup.3 and
R.sup.4 are each independently hydrogen or C.sub.1-6 alkyl; or
R.sup.3 and R.sup.4 are linked together to form a bond, C.sub.1-6
alkylene, C.sub.2-6 heteroalkylene, C.sub.2-6 alkenylene, or
C.sub.2-6 heteroalkenylene; R.sup.5a is (a) hydrogen or halo; (b)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
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(NR.sup.1a)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(.dbd.NR.sup.1a)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(.dbd.NR.sup.1d)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; R.sup.5b is (a) halo; (b) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 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(NR.sup.1a)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(.dbd.NR.sup.1a)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(.dbd.NR.sup.1d)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; R.sup.5c is
--(CR.sup.5fR.sup.5g).sub.n--(C.sub.6-14 aryl) or
--(CR.sup.5fR.sup.5g)-heteroaryl; R.sup.5d and R.sup.5e are each
independently (a) hydrogen or halo; (b) C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 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(NR.sup.1a)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(.dbd.NR.sup.1a)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(.dbd.NR.sup.1d)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)NR.sup.1bR.sup.1c; R.sup.5f and R.sup.5g are each
independently (a) hydrogen or halo; (b) C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 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(NR.sup.1a)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(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, --OS(O)R.sup.1d,
--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(.dbd.NR.sup.1d)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.aS(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; or (d) when one occurrence of
R.sup.5f and one occurrence of R.sup.5g are attached to the same
carbon atom, the R.sup.5f and R.sup.5g together with the carbon
atom to which they are attached form a C.sub.3-10 cycloalkyl or
heterocyclyl; R.sup.6 is hydrogen, C.sub.1-6 alkyl, --S--C.sub.1-6
alkyl, --S(O)--C.sub.1-6 alkyl, or --SO.sub.2--C.sub.1-6 alkyl; m
is 0 or 1; and n is 0, 1, 2, 3, or 4; wherein each alkyl, alkylene,
heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl,
cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl in R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.X, R.sup.1a, R.sup.1b,
R.sup.1c, R.sup.1d, R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d,
R.sup.5e, R.sup.5f, and R.sup.5g is optionally substituted with
one, two, three, four, or five substituents Q, wherein each
substituent Q is independently selected from (a) oxo, cyano, halo,
and nitro; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15
aralkyl, heteroaryl, and heterocyclyl, each of which is further
optionally substituted with 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(NR.sup.a)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(.dbd.NR.sup.a)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(.dbd.NR.sup.d)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; (ii) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl,
each of which is further optionally substituted with 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, which is further optionally substituted with one,
two, three, or four, substituents Q.sup.a; wherein each Q.sup.a is
independently selected from the group consisting of (a) oxo, cyano,
halo, and nitro; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-10 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(NR.sup.e)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(.dbd.NR.sup.e)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.h,
--NR.sup.eC(O)NR.sup.fR.sup.g,
--NR.sup.eC(.dbd.NR.sup.h)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; (ii) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6alkynyl, C.sub.3-10 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; wherein two substituents Q that are
adjacent to each other optionally form a C.sub.3-10 cycloalkenyl,
C.sub.6-14 aryl, heteroaryl, or heterocyclyl, each optionally
substituted with one, two, three, or four substituents Q.sup.a; and
(ii) an effective amount of a CD20 inhibitor.
2. The method of claim 1, wherein R.sup.5b is (a) halo; (b)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, or heteroaryl; or
(c) --C(O)R.sup.1a, --C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--C(NR.sup.1a)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(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, --OS(O)R.sup.1a,
--OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--S(O)NR.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(.dbd.NR.sup.1d)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.
3. The method of claim 1, wherein R.sup.5a and R.sup.5b are each
independently (a) halo; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-10 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(NR.sup.1a)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(.dbd.NR.sup.1a)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.1a,
--NR.sup.1aC(.dbd.NR.sup.1d)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.
4. The method of claim 3, wherein R.sup.5a and R.sup.5b are each
methyl, optionally substituted with one, two, or three halos.
5. The method of any one of claims 1-4, wherein n is 1.
6. The method of any one of claims 1-5, wherein R.sup.5f and
R.sup.5g are each hydrogen.
7. The method of any one of claims 1-4, wherein n is 0.
8. The method of any one of claims 1-7, wherein m is 0.
9. The method of any one of claims 1-8, wherein the compound of
Formula (I) is of Formula (XI): ##STR00027## or an enantiomer, a
mixture of enantiomers, a mixture of two or more diastereomers, or
an isotopic variant thereof; or a pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof, wherein: R.sup.7a, R.sup.7b,
R.sup.7c, R.sup.7d, and R.sup.7e are each independently (a)
hydrogen, cyano, halo, or nitro; (b) C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is
optionally substituted with one, two, three, or four substituents
Q.sup.a; or (c) --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.bR.sup.c, --C(NR.sup.a)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(.dbd.NR.sup.a)NR.sup.bR.sup.c, --OS(O)R.sup.a, --OS(O)R.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(.dbd.NR.sup.d)NR.sup.bR.sup.c, --NR.sup.aS(O)R.sup.d,
--NR.sup.cS(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, or
--S(O).sub.2NR.sup.bR.sup.c; or two of R.sup.7a, R.sup.7b,
R.sup.7c, R.sup.7d, and R.sup.7e that are adjacent to each other
form C.sub.3-10 cycloalkenyl, C.sub.6-14 aryl, heteroaryl, or
heterocyclyl, each optionally substituted with one, two, three, or
four substituents Q.sup.a.
10. The method of any one of claims 1-9, wherein the compound of
Formula (I) is Compound A35: ##STR00028## an isotopic variant
thereof, a pharmaceutically acceptable salt, solvate, hydrate, or
prodrug thereof.
11. The method of any one of claims 1-9, wherein the compound of
Formula (I) is Compound A36: ##STR00029## an isotopic variant
thereof, a pharmaceutically acceptable salt, solvate, hydrate, or
prodrug thereof.
12. The method of any one of claims 1-9, wherein the compound of
Formula (I) is Compound A68: ##STR00030## an isotopic variant
thereof, a pharmaceutically acceptable salt, solvate, hydrate, or
prodrug thereof.
13. The method of any one of claims 1-9, wherein the compound of
Formula (I) is Compound A70: ##STR00031## an isotopic variant
thereof, a pharmaceutically acceptable salt, solvate, hydrate, or
prodrug thereof.
14. The method of any one of claims 1-9, wherein the compound of
Formula (I) is Compound A37: ##STR00032## an isotopic variant
thereof, a pharmaceutically acceptable salt, solvate, hydrate, or
prodrug thereof.
15. The method of any one of claims 1-9, wherein the compound of
Formula (I) is Compound A38: ##STR00033## an isotopic variant
thereof, a pharmaceutically acceptable salt, solvate, hydrate, or
prodrug thereof.
16. The method of any one of claims 1-9, wherein the compound of
Formula (I) is Compound A41: ##STR00034## an isotopic variant
thereof, a pharmaceutically acceptable salt, solvate, hydrate, or
prodrug thereof.
17. The method of any one of claims 1-9, wherein the compound of
Formula (I) is Compound A42: ##STR00035## an isotopic variant
thereof, a pharmaceutically acceptable salt, solvate, hydrate, or
prodrug thereof.
18. The method of any one of claims 1-9, wherein the compound of
Formula (I) is Compound A43: ##STR00036## an isotopic variant
thereof, a pharmaceutically acceptable salt, solvate, hydrate, or
prodrug thereof.
19. The method of any one of claims 1-9, wherein the compound of
Formula (I) is Compound A44: ##STR00037## an isotopic variant
thereof, a pharmaceutically acceptable salt, solvate, hydrate, or
prodrug thereof.
20. The method of any one of claims 1-19, wherein the CD20
inhibitor is ofatumumab, obinutuzumab, rituximab, ocaratuzumab,
ocrelizumab, tositumomab, ibritumomab tiuxetan, tisotumab vedotin,
ublituximab, TRU-015, veltuzumab, BTCT4465A (RG7828), EDC9,
MT-3724, or a variant or biosimilar thereof, or combinations
thereof.
21. The method of claim 20, wherein the CD20 inhibitor is
ofatumumab or a variant or biosimilar thereof.
22. The method of claim 20, wherein the CD20 inhibitor is
obinutuzumab or a variant or biosimilar thereof.
23. The method of claim 20, wherein the CD20 inhibitor is rituximab
or a variant or biosimilar thereof.
24. The method of claim 20, wherein the CD20 inhibitor is
ocaratuzumab or a variant or biosimilar thereof.
25. The method of claim 20, wherein the CD20 inhibitor is
ocrelizumab or a variant or biosimilar thereof.
26. The method of claim 20, wherein the CD20 inhibitor is
tositumomab or a variant or biosimilar thereof.
27. The method of claim 20, wherein the CD20 inhibitor is
ibritumomab tiuxetan or a variant or biosimilar thereof.
28. The method of claim 20, wherein the CD20 inhibitor is tisotumab
vedotin or a variant or biosimilar thereof.
29. The method of claim 20, wherein the CD20 inhibitor is
ublituximab or a variant or biosimilar thereof.
30. The method of claim 20, wherein the CD20 inhibitor is TRU-015
or a variant or biosimilar thereof.
31. The method of claim 20, wherein the CD20 inhibitor is
veltuzumab or a variant or biosimilar thereof.
32. The method of claim 20, wherein the CD20 inhibitor is BTCT4465A
(RG7828) or a variant or biosimilar thereof.
33. The method of claim 20, wherein the CD20 inhibitor is EDC9 or a
variant or biosimilar thereof.
34. The method of claim 20, wherein the CD20 inhibitor is MT-3724
or a variant or biosimilar thereof.
35. The method of any one of claims 1-34, wherein the cancer is a
hematological malignancy.
36. The method of claim 35, wherein the hematological malignancy is
a B-cell malignancy.
37. The method of claim 36, wherein the B-cell malignancy is
selected from follicular lymphoma, large B cell lymphoma, and
chronic lymphocytic leukemia (CLL).
38. The method of claim 36, wherein the B-cell malignancy is
selected from chronic lymphocytic leukemia (CLL), small lymphocytic
lymphoma (SLL), follicular lymphoma (FL), marginal zone B cell
lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), and high
grade non-Hodgkin's lymphoma.
39. The method of claim 36, wherein the B-cell malignancy is
selected from chronic lymphocytic leukemia (CLL), follicular
lymphoma (FL), marginal zone B cell lymphoma (MZL), or diffuse
large B-cell lymphoma (DLBCL).
40. The method of any one of claims 1-34, wherein the cancer is
relapsed B-cell non-Hodgkin's lymphoma (NHL) or chronic lymphocytic
leukemia (CLL).
41. The method of any one of claims 1-40, wherein the
administration of compounds occurs in one or more cycles.
42. The method of any of claims 1-41, wherein the compound of
Formula (I), or an enantiomer, a mixture of enantiomers, a mixture
of two or more diastereomers, or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, and the CD20 inhibitor are administered
simultaneously.
43. The method of any of claim 1-41, wherein the compound of
Formula (I), or an enantiomer, a mixture of enantiomers, a mixture
of two or more diastereomers, or an isotopic variant thereof or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, and the CD20 inhibitor are administered sequentially.
44. The method of any of claims 1-43, wherein the compound of
Formula (I), or an enantiomer, a mixture of enantiomers, a mixture
of two or more diastereomers, or an isotopic variant thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, is administered orally and the CD20 inhibitor is
administered by injection.
45. The method of any of claims 1-44, wherein the compound of
Formula (I), or an enantiomer, a mixture of enantiomers, a mixture
of two or more diastereomers, or an isotopic variant thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, is administered orally and the CD20 inhibitor is
administered by intravenous infusion.
46. The method of any of claims 1-44, wherein the compound of
Formula (I), or an enantiomer, a mixture of enantiomers, a mixture
of two or more diastereomers, or an isotopic variant thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, is administered orally and the CD20 inhibitor is
administered by subcutaneous injection.
47. The method of any of claims 1-46, wherein about 60 mg, about
120 mg, about 150 mg, or about 180 mg of a compound of Formula (I)
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof is administered to the subject.
48. The method of claim 47, wherein about 60 mg of a compound of
Formula (I), or an enantiomer, a mixture of enantiomers, a mixture
of two or more diastereomers, or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof is administered to the subject.
49. The method of claim 47 or 48, wherein the compound of Formula
(I), or an enantiomer, a mixture of enantiomers, a mixture of two
or more diastereomers, or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof is administered to the subject daily.
50. The method of any one of claims 47-49, wherein the compound of
Formula (I), or an enantiomer, a mixture of enantiomers, a mixture
of two or more diastereomers, or an isotopic variant thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, is administered to the subject once per day, twice per
day, or three times per day.
51. The method of any one claims 47-50, wherein the compound of
Formula (I), or an enantiomer, a mixture of enantiomers, a mixture
of two or more diastereomers, or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, is administered to the subject once per day.
52. The method of any one of claims 47-51, wherein about 60 mg/day
of the compound of Formula (I), or an enantiomer, a mixture of
enantiomers, a mixture of two or more diastereomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof is administered to the subject.
53. The method of any one of the preceding claims, wherein the
compound of Formula (I), or an enantiomer, a mixture of
enantiomers, a mixture of two or more diastereomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, is administered to the subject on a
28-day cycle.
54. The method of any one of the preceding claims, wherein the
compound of Formula (I), or an enantiomer, a mixture of
enantiomers, a mixture of two or more diastereomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, is administered to the subject for at
least one 28-day cycle.
55. The method of any one of the preceding claims, wherein the
compound of Formula (I), or an enantiomer, a mixture of
enantiomers, a mixture of two or more diastereomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, is administered to the subject for at
least two 28-day cycles.
56. The method of any one of the preceding claims, wherein the
compound of Formula (I), or an enantiomer, a mixture of
enantiomers, a mixture of two or more diastereomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, is administered to the subject for a
period of up to about 7 days.
57. The method of claim 56, wherein the days over which the
compound of Formula (I), or an enantiomer, a mixture of
enantiomers, a mixture of two or more diastereomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof are intermittent.
58. The method of any one of claims 1-57, comprising administering
to subject the compound of Formula (I), or an enantiomer, a mixture
of enantiomers, a mixture of two or more diastereomers, or an
isotopic variant thereof; or a pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof for about 7 consecutive days
in a 28-day cycle.
59. The method any one of claims 1-58, wherein the method comprises
an intermittent dosing schedule (IS), comprising administering to
subject the compound of Formula (I), or an enantiomer, a mixture of
enantiomers, a mixture of two or more diastereomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof once daily for 7 consecutive days
followed by 21 days without treatment in a 28-day cycle.
60. The method of claim 59, wherein the compound of Formula (I), or
an enantiomer, a mixture of enantiomers, a mixture of two or more
diastereomers, or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, is administered to the subject for at least one 28-day
cycle.
61. The method of any one of claims 1-58, wherein the method
comprises a continuous daily dosing schedule (CS), comprising
administering to subject the compound of Formula (I), or an
enantiomer, a mixture of enantiomers, a mixture of two or more
diastereomers, or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof once daily for 28 consecutive days in a 28-day cycle.
62. The method of claim 61, wherein the compound of Formula (I), or
an enantiomer, a mixture of enantiomers, a mixture of two or more
diastereomers, or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, is administered to the subject for at least two CS 28-day
cycles.
63. The method of claim 62, further comprising an IS, comprising
administering to subject the compound of Formula (I), or an
enantiomer, a mixture of enantiomers, a mixture of two or more
diastereomers, or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof once daily for 7 consecutive days followed by 21 days
without treatment in a 28-day cycle after the at least two CS
28-day cycles.
64. The method of any one of the preceding claims, wherein the
compound of Formula (I), or an enantiomer, a mixture of
enantiomers, a mixture of two or more diastereomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof, is formulated as a tablet or
capsule.
65. The method of claim 23, wherein the rituximab is administered
at a dose of about 375 mg/m.sup.2.
66. The method of claim 23 or 65, wherein 8 doses of rituximab are
administered to the subject over a period of about 6 months
67. The method of any one of the preceding claims, wherein the
subject is treated for a period of about 6 months.
Description
CROSS-REFERENCE
[0001] This application is a continuation of U.S. application Ser.
No. 16/639,088, filed Feb. 13, 2020, which is a .sctn. 371 National
Stage Entry of International Application No. PCT/US2018/046742,
filed Aug. 14, 2018, which claims benefit of U.S. Provisional
Patent Application No. 62/545,427, filed on Aug. 14, 2017, which
are hereby incorporated by reference in their entirety.
BACKGROUND OF THE INVENTION
[0002] Phosphoinositide-3-kinases (PI3Ks) play a variety of roles
in normal tissue physiology, with p110.alpha. having a specific
role in cancer growth, p110.beta. in thrombus formation mediated by
integrin .alpha..sub..pi..beta..sub.3, and p110.gamma., in
inflammation, rheumatoid arthritis, and other chronic inflammation
states. Inhibitors of PI3K have therapeutic potential in the
treatment of various proliferative diseases, including cancer.
SUMMARY OF THE INVENTION
[0003] Disclosed herein is a method for treating or preventing a
disease comprising administering:
[0004] (i) an effective amount of a compound of Formula (I);
##STR00001## [0005] or an enantiomer, a mixture of enantiomers, a
mixture of two or more diastereomers, or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof; wherein: [0006] X, Y, and Z are each
independently N or CR.sup.X, with the proviso that at least two of
X, Y, and Z are nitrogen atoms; where R.sup.X is hydrogen or
C.sub.1-6 alkyl; [0007] R.sup.1 and R.sup.2 are each independently
(a) hydrogen, cyano, halo, or nitro; (b) C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6, alkynyl, C.sub.3-10 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(NR.sup.1a)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(.dbd.NR.sup.1a)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(.dbd.NR.sup.1d)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)NR.sup.1bR.sup.1c,
--SR.sup.1a, --S(O)R.sup.1a, --S(O)R.sup.1a,
--S(O)NR.sup.1bR.sup.1c, or --S(O).sub.2NR.sup.1bR.sup.1c; wherein
each R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d is independently
(i) hydrogen; (ii) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl. C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15
aralkyl, heteroaryl, or heterocyclyl; or (iii) R.sup.1b and
R.sup.1c together with the N atom to which they are attached form
heterocyclyl; [0008] R.sup.3 and R.sup.4 are each independently
hydrogen or C.sub.1-6 alkyl; or R.sup.3 and R.sup.4 are linked
together to forma bond. C.sub.1-6 alkylene, C.sub.1-6
heteroalkylene, C.sub.2-6 alkenylene, or C.sub.2-6
heteroalkenylene; [0009] R.sup.5a is (a) hydrogen or halo; (b)
C.sub.1-6 alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-10
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(NR.sup.1a)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(.dbd.NR.sup.1a)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(.dbd.NR.sup.1d)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; [0010] R.sup.5b is (a) halo; (b)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
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(NR.sup.1a)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(.dbd.NR.sup.1a)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(.dbd.NR.sup.1d)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; [0011] R.sup.5c is
--(CR.sup.5fR.sup.5g).sub.n--(C.sub.6-14 aryl) or
--(CR.sup.5fR.sup.5g).sub.n-heteroaryl; [0012] R.sup.5d and
R.sup.5e are each independently (a) hydrogen or halo; (b) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocycyl; or
(c) --C(O)R.sup.1a, --C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--C(NR.sup.1a)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(.dbd.NR.sup.1a)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(.dbd.NR.sup.1d)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)NR.sup.1bR.sup.1c,
--SR.sup.1a, --S(O)R.sup.1a, --S(O)R.sup.1a,
--S(O)NR.sup.1bR.sup.1c, or --S(O).sub.2NR.sup.1bR.sup.1c; [0013]
R.sup.5f and R.sup.5g are each independently (a) hydrogen or halo;
(b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 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(NR.sup.1a)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(.dbd.NR.sup.1a)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(.dbd.NR.sup.1d)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) R.sup.a, --S(O)NR.sup.1bR.sup.1c; or
--S(O).sub.2NR.sup.1bR.sup.1c; or (d) when one occurrence of
R.sup.5f and one occurrence of R.sup.5g are attached to the same
carbon atom, the R.sup.5f and R.sup.5g together with the carbon
atom to which they are attached form a C.sub.3-10 cycloalkyl or
heterocyclyl; [0014] R.sup.6 is hydrogen, C.sub.1-6 alkyl,
--S--C.sub.1-6 alkyl, --S(O)--C.sub.1-6alkyl, or
--SO.sub.2--C.sub.1-6 alkyl; [0015] m is 0 or 1; and [0016] n is 0,
1, 2, 3, or 4; [0017] wherein each alkyl, alkylene, heteroalkylene,
alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl,
aralkyl, heteroaryl, and heterocyclyl in R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.6, R.sup.X, R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d,
R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, R.sup.5e, R.sup.5f, and
R.sup.5g is optionally substituted with one, two, three, four, or
five substituents Q, wherein each substituent Q is independently
selected from (a) oxo, cyano, halo, and nitro; (b) C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, and heterocyclyl,
each of which is further optionally substituted with 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(NR.sup.a)NR.sup.bR.sup.c, --OR.sup.a, --OC(O)R.sup.a,
--OC(O)OR, --OC(O)NR.sup.bR.sup.c,
--OC(.dbd.NR.sup.a)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.2)NR.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(.dbd.NR.sup.d)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; (ii) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl,
each of which is further optionally substituted with 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, which is further optionally substituted with one,
two, three, or four, substituents Q.sup.a; [0018] wherein each
Q.sup.a is independently selected from the group consisting of (a)
oxo, cyano, halo, and nitro; (b) C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 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(NR.sup.e)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(.dbd.NR.sup.e)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.h,
--NR.sup.eC(O)NR.sup.fR.sup.g,
--NR.sup.eC(.dbd.NR.sup.h)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; (ii) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 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; [0019] wherein two substituents Q
that are adjacent to each other optionally form a C.sub.3-10
cycloalkenyl, C.sub.6-14 aryl, heteroaryl, or heterocyclyl, each
optionally substituted with one, two, three, or four substituents
Q.sup.a; and
[0020] (ii) an effective amount of a CD20 inhibitor to a patient in
need thereof.
[0021] In some embodiments, R.sup.5b is (a) halo; (b) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, or heteroaryl; or (c)
--C(O)R.sup.1a, --C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--C(NR.sup.1a)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(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, --OS(O)R.sup.1a,
--OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--S(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(.dbd.NR.sup.1d)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.a, --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.
[0022] In some embodiments, R.sup.5a and R.sup.5b are each
independently (a) halo; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-10 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(NR.sup.1a)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(.dbd.NR.sup.1a)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(.dbd.NR.sup.d)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.
[0023] In some embodiments, R.sup.5a and R.sup.5b are each methyl,
optionally substituted with one, two or three halos. In some
embodiments, n is 1. In some embodiments, n is 1 and R.sup.5f and
R.sup.5g are each hydrogen. In some embodiments, n is 0. In some
embodiments, m is 0.
[0024] In some embodiments, the compound of Formula (I) is of
Formula (XI):
##STR00002## [0025] or an enantiomer, a mixture of enantiomers, a
mixture of two or more diastereomers, or an isotopic variant
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof; wherein: [0026] R.sup.7a, R.sup.7b, R.sup.7c,
R.sup.7d, and R.sup.7e are each independently (a) hydrogen, cyano,
halo, or nitro; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15
aralkyl, heteroaryl, or heterocyclyl, each of which is optionally
substituted with one, two, three, or four substituents Q.sup.a; or
(c) --C(O)R.sup.a. --C(O)OR.sup.a, --C(O)NR.sup.bR.sup.c,
--C(NR.sup.a)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(.dbd.NR.sup.a)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(.dbd.NR.sup.d)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, or
--S(O).sub.2NR.sup.bR.sup.c; or [0027] two of R.sup.7a, R.sup.7b,
R.sup.7c, R.sup.7d and R.sup.7e that are adjacent to each other
form [0028] C.sub.3-10 cycloalkenyl, C.sub.6-14 aryl, heteroaryl,
or heterocyclyl, each optionally substituted with one, two, three,
or four substituents Q.sup.a.
[0029] In some embodiments, the compound of Formula (I) is Compound
A35:
##STR00003##
[0030] or an isotopic variant thereof, a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof.
[0031] In some embodiments, the compound of Formula (I) is Compound
A36:
##STR00004##
[0032] or an isotopic variant thereof, a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof.
[0033] In some embodiments, the compound of Formula (I) is Compound
A68:
##STR00005##
[0034] or an isotopic variant thereof, a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof.
[0035] In some embodiments, the compound of Formula (I) is Compound
A70:
##STR00006##
[0036] or an isotopic variant thereof, a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof.
[0037] In some embodiments, the compound of Formula (I) is Compound
A37:
##STR00007##
[0038] or an isotopic variant thereof, a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof.
[0039] In some embodiments, the compound of Formula (I) is Compound
A38:
##STR00008##
[0040] or an isotopic variant thereof, a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof.
[0041] In some embodiments, the compound of Formula (I) is Compound
A41:
##STR00009##
[0042] or an isotopic variant thereof, a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof.
[0043] In some embodiments, the compound of Formula (I) is Compound
A42:
##STR00010##
[0044] or an isotopic variant thereof, a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof.
[0045] In some embodiments, the compound of Formula (I) is Compound
A43:
##STR00011##
[0046] or an isotopic variant thereof, a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof.
[0047] In some embodiments, the compound of Formula (I) is Compound
A44:
##STR00012##
[0048] or an isotopic variant thereof, a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof.
[0049] In some embodiments, the CD20 inhibitor is ofatumumab,
obinutuzumab, rituximab, ocaratuzumab, ocrelizumab, tositumomab,
ibritumomab tiuxetan, tisotumab vedotin, ublituximab, TRU-015,
veltuzumab, BTCT4465A (RG7828), EDC9, MT-3724, or a variant or
biosimilar thereof, or combinations thereof.
[0050] In some embodiments, the disease being treated is
cancer.
INCORPORATION BY REFERENCE
[0051] All publications, patents, and patent applications mentioned
in this specification are herein incorporated by reference to the
same extent as if each individual publication, patent, or patent
application was specifically and individually indicated to be
incorporated by reference.
DETAILED DESCRIPTION OF THE INVENTION
[0052] Described herein are pharmaceutical compositions comprising
a PI3K inhibitor and a CD20 inhibitor. In some instances, the
pharmaceutical compositions described herein may be used for
treating diseases or disorders associated with excessive cell
proliferation, such as cancer. Also described herein are methods of
treating the proliferative diseases and disorders with i) a PI3K
inhibitor; and ii) a CD20 inhibitor.
Definitions
[0053] To facilitate understanding of the disclosure set forth
herein, a number of terms are defined below.
[0054] Generally, the nomenclature used herein and the laboratory
procedures in organic chemistry, medicinal chemistry, 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. 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, a human.
[0055] 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.
[0056] 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.
[0057] The terms "therapeutically effective amount" or "effective
amount" are 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 terms "therapeutically
effective amount" or "effective amount" also refer to the amount of
a compound that is sufficient to elicit the 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.
[0058] 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
other ingredients of a pharmaceutical formulation, and suitable for
use in contact with the tissue or organ of humans and animals
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, 21st Edition, Lippincott Williams &
Wilkins: Philadelphia. Pa., 2005; Handbook of Pharmaceutical
Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical
Press and the American Pharmaceutical Association: 2005; and
Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash
Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation
and Formulation, 2nd Edition, Gibson Ed., CRC Press LLC: Boca
Raton, Fla., 2009.
[0059] 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.
[0060] 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.
[0061] 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.
[0062] The term "naturally occurring" or "native" when used in
connection with biological materials such as nucleic acid
molecules, polypeptides, host cells, and the like, refers to
materials which are found in nature and are not manipulated by man.
Similarly, "non-naturally occurring" or "non-native" refers to a
material that is not found in nature or that has been structurally
modified or synthesized by man.
[0063] The term "PI3K" refers to a phosphoinositide 3-kinase or
variant thereof, which is capable of phosphorylating the inositol
ring of PI in the D-3 position. The term "PI3K variant" is intended
to include proteins substantially homologous to a native PI3K,
i.e., proteins having one or more naturally or non-naturally
occurring amino acid deletions, insertions, or substitutions (e.g.,
PI3K derivatives, homologs, and fragments), as compared to the
amino acid sequence of a native PI3K. The amino acid sequence of a
PI3K variant is at least about 80% identical, at least about 90%
identical, or at least about 95% identical to a native PI3K.
Examples of PI3K include, but are not limited to, p110.alpha.,
p110.beta., p110.delta., p110.gamma., PI3K-C2.alpha.,
PI3K-C2.beta., PI3K-C2.gamma., Vps34, mTOR, ATM, ATR, and DNA-PK.
See, Fry, Biochem. Biophys. Acta 1994, 1226, 237-268;
Vanhaesebroeck and Waterfield, Exp. Cell. Res. 1999, 253, 239-254;
and Fry, Breast Cancer Res. 2001, 3, 304-312. PI3Ks are classified
into at least four classes. Class I includes p110.alpha.,
p110.beta., p110.delta., and p110.gamma.. Class II includes
PI3K-C2.alpha., PI3K-C2.beta., and PI3K-C2.gamma.. Class III
includes Vps34. Class IV includes mTOR, ATM, ATR, and DNA-PK. In
certain embodiments, the PI3K is a Class I kinase. In certain
embodiments, the PI3K is p110.alpha., p110.beta., p110.delta., or
p110.gamma.. In certain embodiments, the PI3K is a variant of a
Class I kinase. In certain embodiments, the PI3K is a p110.alpha.
mutant. Examples of p110.alpha. mutants include, but are not
limited to, R38H, G106V, K111N, K227E, N345K, C420R, P539R, E542K,
E545A, E545G, E545K, Q546K, Q546P, E453Q, H710P, I800L, T1025S,
M10431, M1043V, H1047L, H1047R, and H1047Y (Ikenoue et al., Cancer
Res. 2005, 65, 4562-4567; Gymnnopoulos et al., Proc. Natl. Acad
Sci., 2007, 104, 5569-5574). In certain embodiments, the PI3K is a
Class II kinase. In certain embodiments, the PI3K is
PI3K-C2.alpha., PI3K-C2.beta., or PI3K-C2.gamma.. In certain
embodiments, the PI3K is a Class III kinase. In certain
embodiments, the PI3K is Vps34. In certain embodiments, the PI3K is
a Class IV kinase. In certain embodiments, the PI3K is mTOR, ATM,
ATR, or DNA-PK.
[0064] The term "CD20" refers to an activated-glycosylated
phosphoprotein expressed on the surface of all B-cells beginning at
the pro-B phase (CD45R+. CD117+) and progressively increasing in
concentration until maturity. The CD20 in humans is encoded by the
MS4A1 gene. This gene encodes a member of the membrane-spanning 4A
gene family. Members of this nascent protein family are
characterized by common structural features and similar intron/exon
splice boundaries and display unique expression patterns among
hematopoietic cells and nonlymphoid tissues. This gene encodes a
B-lymphocyte surface molecule that plays a role in the development
and differentiation of B-cells into plasma cells. This family
member is localized to 11q12, among a cluster of family members.
Alternative splicing of this gene results in two transcript
variants that encode the same protein. The protein has no known
natural ligand and its function is to enable optimal B-cell immune
response, specifically against T-independent antigens. It is
suspected that it acts as a calcium channel in the cell membrane.
It has been shown that CD20 plays a role in the microenvironmental
interactions of B cells and are therefore used to treat some types
of cancer.
[0065] The term "antibody" refers to (a) immunoglobulin poly
peptides and immunologically active portions of immunoglobulin
polypeptides, i.e., polypeptides of the immunoglobulin family, or
fragments thereof, that contain an antigen binding site that
specifically binds to a specific antigen, or (b) conservatively
substituted derivatives of such immunoglobulin polypeptides or
fragments that specifically bind to the antigen. Examples of
antibody fragments include, but are not limited to, a Fab, Fab',
F(ab')2, Fd, Fv, scFv and scFv-Fc fragment, diabody, triabody,
tetrabody, linear anti body, single-chain antibody, and other
multispecific antibodies formed from antibody fragments. (See
Holliger and Hudson, 2005, Nat Biotechnol. 23: 1126-1136.) The
immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM,
IgD. IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and
IgA2) or subclass of immunoglobulin molecule. Included in the term
immunoglobulin are those immunoglobulin molecules that have
modifications in the constant region, including modification (e.g.,
substitutions, deletions or additions) in amino acid residues that
interact with Fey receptors. Antibodies are generally described in,
for example, Harlow & Lane, Antibodies: A Laboratory Manual
(Cold Spring Harbor Laboratory Press, 1988).
[0066] The term "monoclonal antibody" (mAb) refers to an antibody
obtained from a population of substantially homogeneous antibodies;
that is, the individual antibodies comprising the population are
identical except for naturally occurring mutations that may be
present in minor amounts. Monoclonal antibodies are highly
specific, being directed against a single antigenic determinant,
also referred to as an epitope. The modifier "monoclonal" is
indicative of a substantially homogeneous population of antibodies
directed to the identical epitope and is not to be construed as
requiring production of the antibody by any particular method.
Monoclonal antibodies can be made by any technique or methodology
known in the art; for example, the hybridoma method first described
by Kohler et al., 1975, Nature 256:495, or recombinant DNA methods
known in the art (see, e.g., U.S. Pat. No. 4,816,567). In another
example, monoclonal antibodies can also be isolated from phage
antibody libraries, using techniques described in Clackson et al.,
1991, Nature 352: 624-628, and Marks et al., 1991, J. Mol. Biol.
222:581-597. In contrast, the antibodies in a preparation of
polyclonal antibodies are typically a heterogeneous population of
immunoglobulin isotypes and/or classes and also exhibit a variety
of epitope specificity.
[0067] The term "biosimilar" or "follow-on biologic" or "subsequent
entry biologic" refers to a biologic medical product which is
almost an identical copy of an original product that is
manufactured by a different company. Biosimilars are officially
approved versions of original "innovator" products, and can be
manufactured when the original product's patent expires. Reference
to the innovator product is an integral component of the approval.
A biosimilar biological product is highly similar to the reference
product notwithstanding minor differences in clinically inactive
components, and there are no clinically meaningful differences
between the biological product and the reference product in terms
of the safety, purity, and potency of the product.
[0068] The term "variant" when referring to an antibody as
disclosed herein can include any antibody that retains at least
some of the activity, e.g., antigen-binding activity, of the
reference antibody, but which is structurally different. Variants
include fragments of antibodies (e.g., Fab. Fab' and F(ab')2, Fd,
Fvs, single-chain Fvs (scFv), single-chain antibodies,
disulfide-linked Fvs (sdFv) fragments) and also antibodies with
altered amino acid sequences, e.g., in the variable domains, due to
amino acid substitutions, deletions, or insertions. Variants can
occur spontaneously or be intentionally constructed. Intentionally
constructed variants can be produced using art-known mutagenesis
techniques. Variant antibodies can comprise conservative or
non-conservative amino acid substitutions, deletions or additions.
The variations are limited by the constraint that the antibody
maintains a function of the reference antibody, e.g., binding to
the same epitope as the reference antibody, or competitively
inhibiting the reference antibody.
[0069] The terms "synergy," "synergism," or "synergistic" as used
herein refer to a combination of therapies (e.g., use of a PI3K
inhibitor of Formula (I) and an anti-CD20 antibody) that is more
effective than the expected additive effects of any two or more
single therapies. For example, a synergistic effect of a
combination of therapies permits the use of lower dosages of one or
more of the therapies and/or less frequent administration of said
therapies to a subject. The ability to utilize lower dosages of
therapies and/or to administer the therapies less frequently
reduces the toxicity associated with the administration of the
therapies to a subject without reducing the efficacy of said
therapies in the prevention, management, treatment, or amelioration
of a given disease, such as a B cell malignancy. In addition, a
synergistic effect can result in improved efficacy of therapies in
the prevention, management, treatment, or amelioration of a given
disease, such as a B cell malignancy. Finally, synergistic effects
of a combination of therapies may avoid or reduce adverse or
unwanted side effects associated with the use of any single
therapy. The "synergy," "synergism," or "synergistic" effect of a
combination may be determined herein by the methods of Chou et al.,
and/or Clarke et al. See Ting-Chao Chou. Theoretical Basis,
Experimental Design, and Computerized Simulation of Synergism and
Antagonism in Drug Combination Studies, Pharmacol Rev 58:621-681
(2006), and Clarke et al., Issues in experimental design and
endpoint analysis in the study of experimental cytotoxic agents in
vivo in breast cancer and other models, Breast Cancer Research and
Treatment 46:255-278 (1997), which are both incorporated by
reference for the methods of determining the "synergy," synergism,"
or "synergistic" effect of a combination.
[0070] The term "isotopic variant" 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 "isotopic variant" of a compound contains unnatural proportions
of one or more isotopes, including, but not limited to, hydrogen
(.sup.1H), deuterium (.sup.2H), tritium (.sup.3H), carbon-11
(.sup.11C), carbon-12 (.sup.12C), carbon-13 (.sup.13C), carbon-14
(.sup.14C), nitrogen-13 (.sup.13N), nitrogen-14 (.sup.14N),
nitrogen-15 (.sup.15N), 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), phosphors-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 (.sup.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 isotopic variant" of a compound is in a stable
form, that is, non-radioactive. In certain embodiments, an
"isotopic variant" of a compound contains unnatural proportions of
one or more isotopes, including, but not limited to, hydrogen (H),
deuterium (.sup.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 "isotopic variant" of a compound is in an
unstable form, that is, radioactive. In certain embodiments, an
"isotopic variant" of a 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.33S), chlorine-36 (.sup.36Cl), iodine-123
(.sup.123I), iodine-125 (.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, for example, or
any carbon can be .sup.13C, for example, or any nitrogen can be
.sup.15N, for example, or any oxygen can be ISO, for example, where
feasible according to the judgment of one of skill. In certain
embodiments, an "isotopic variant" of a compound contains unnatural
proportions of deuterium (D).
[0071] The term "alkyl" refers to a linear or branched saturated
monovalent hydrocarbon radical, wherein the alkylene may optionally
be substituted with one or more substituents Q as described herein.
The term "alkyl" also encompasses both linear and branched alkyl,
unless otherwise specified. 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.3-15),
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). 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.
[0072] 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.
The term "alkylene" encompasses both linear and branched alkylene,
unless otherwise specified. 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.3-15) 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). 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.
[0073] 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.3-15),
3 to 10 (C.sub.1-10), 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.2O--,
--CH.sub.2NH--, --CH.sub.2NHCH.sub.2--, --CH.sub.2CH.sub.2NH--,
--CH.sub.2S--, --CH.sub.2SCH.sub.2--, and --CH.sub.2CH.sub.2S--. In
certain embodiments, heteroalkylene may also be optionally
substituted with one or more substituents Q as described
herein.
[0074] 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 may be optionally
substituted with one or more substituents Q as described herein.
The term "alkenyl" also embraces radicals having "cis" and "trans"
configurations, or alternatively. "Z" and "E" configurations, as
appreciated by those of ordinary skill in the art. As used herein,
the term "alkenyl" encompasses both linear and branched alkenyl,
unless otherwise specified. 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.3-15), 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.
[0075] The term "alkenylene" 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, carbon-carbon double bond(s). The alkenylene may be optionally
substituted with one or more substituents Q as described herein.
Similarly, the term "alkenylene" also embraces radicals having
"cis" and "trans" configurations, or alternatively, "E" and "Z"
configurations. As used herein, the term "alkenylene" encompasses
both linear and branched alkenylene, unless otherwise specified.
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.3-15), 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.
[0076] The term "heteroalkenylene" 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, carbon-carbon double bond(s), and which contains one or more
heteroatoms each independently selected from O, S, and N in the
hydrocarbon chain. The heteroalkenylene may be optionally
substituted with one or more substituents Q as described herein.
The term "heteroalkenylene" 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
heteroalkenylene 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 heteroalkenylene 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 atom or a
branched divalent hydrocarbon radical of 3 to 20 (C.sub.3-20), 3 to
15 (C.sub.3-15), 3 to 10 (C.sub.3-10), or 3 to 6 (C.sub.1-6) carbon
atoms. Examples of heteroalkenylene groups include, but are not
limited to, --CH.dbd.CHO--, --CH.dbd.CHOCH.sub.2--,
--CH.dbd.CHCH.sub.2O--, --CH.dbd.CHS--, --CH.dbd.CHSCH.sub.2--,
--CH.dbd.CHCH.sub.2S--, or --CH.dbd.CHCH.sub.2NH--.
[0077] 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 may be optionally
substituted with one or more substituents Q as described herein.
The term "alkynyl" also encompasses both linear and branched
alkynyl, unless otherwise specified. 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 3 to 20 (C.sub.3-20), 3 to 15 (C.sub.3-15), 3 to 10
(C.sub.3-10), or 3 to 6 (C.sub.3-6) carbon atoms. Examples of
alkynyl groups include, but are not limited to, ethynyl
(--C.ident.CH) and propargyl (--CH.sub.2C.ident.CH). 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 3 to 6 carbon
atoms.
[0078] The term "cycloalkyl" refers to a cyclic saturated bridged
and/or non-bridged monovalent hydrocarbon radical, which may be
optionally substituted with one or more substituents Q as described
herein. In certain embodiments, the cycloalkyl has from 3 to 20
(C.sub.3-20), from 3 to 15 (C.sub.3-15), from 3 to 10 (C.sub.3-10),
or from 3 to 7 (C.sub.3-7) carbon atoms. Examples of cycloalkyl
groups include, but are not limited to, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.1.1]hexyl,
bicyclo[2.2.1]heptyl, decalinyl, and adamantyl.
[0079] The term "cycloalkenyl" refers to a cyclic unsaturated,
nonaromatic bridged and/or non-bridged monovalent hydrocarbon
radical, which may be optionally substituted with one or more
substituents Q as described herein. In certain embodiments, the
cycloalkenyl has from 3 to 20 (C.sub.3-20), from 3 to 15
(C.sub.3-15), from 3 to 10 (C.sub.3-10), or from 3 to 7 (C.sub.3-7)
carbon atoms. Examples of cycloalkyl groups include, but are not
limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, or
cycloheptenyl,
[0080] The term "aryl" refers to a monocyclic aromatic group and/or
multicyclic monovalent aromatic group that contain at least one
aromatic hydrocarbon ring. In certain embodiments, the aryl has
from 6 to 20 (C.sub.6-20), from 6 to 15 (C.sub.6-5), or from 6 to
10 (C.sub.6-10) ring atoms. Examples of aryl groups include, but
are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl,
phenanthryl, pyrenyl, biphenyl, and terphenyl. 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 certain
embodiments, aryl may be optionally substituted with one or more
substituents Q as described herein.
[0081] 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 are optionally substituted with one or more substituents Q
as described herein.
[0082] 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 independently selected from O, S,
N, and P in the ring. A heteroaryl group is bonded to the rest of a
molecule through its aromatic ring. Each ring of a heteroaryl group
can contain one or two O atoms, one or two S atoms, one to four N
atoms, and/or one or two P 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. 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. 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, thiadiazolopytimidyl, and
thienopyridyl. 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 may also be
optionally substituted with one or more substituents Q as described
herein as described herein.
[0083] 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 independently selected from O, S. N, and P; 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.
A heterocyclyl group is bonded to the rest of a molecule through
its non-aromatic ring. In certain embodiments, the heterocyclyl is
a monocyclic, bicyclic, tricyclic, or tetracyclic ring system,
which may be spiro, 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 such heterocyclic
groups include, but are not limited to, azepinyl, benzodioxanyl,
benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl,
benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl,
benzoxazinyl, .beta.-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 may also be optionally
substituted with one or more substituents Q as described
herein.
[0084] The term "halogen", "halide" or "halo" refers to fluorine,
chlorine, bromine, and/or iodine.
[0085] The term "optionally substituted" is intended to mean that a
group or substituent, such as an alkyl, alkylene, heteroalkylene,
alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl,
cycloalkenyl, aryl, aralkyl, heteroaryl, heteroaryl-C.sub.1-6
alkyl, and heterocyclyl group, may be substituted with one or more
substituents Q, each of which is independently selected from, e.g.,
(a) oxo (.dbd.O), halo, cyano (--CN), and nitro (--NO.sub.2); (b)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
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, four, or five,
substituents Q.sup.a; and (c) --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)NR.sup.bR.sup.c, --C(NR.sup.a)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(.dbd.NR.sup.a)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(.dbd.NR.sup.d)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, --P(O)R.sup.aR.sup.d,
--P(O)(OR.sup.a)R.sup.d, --P(O)(OR.sup.a)(OR.sup.d), --SR.sup.a,
--S(O)R.sup.a, --S(O)--R.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; (ii) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 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 heteroaryl or heterocyclyl, optionally
substituted with one or more, in one embodiment, one, two, three,
or four, substituents Q. As used herein, all groups that can be
substituted are "optionally substituted," unless otherwise
specified.
[0086] In one embodiment, each substituent Q.sup.a is independently
selected from the group consisting of (a) oxo, cyano, halo, and
nitro; and (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6alkynyl, C.sub.3-10cycloalkyl, 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(NR.sup.a)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(.dbd.NR)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.aC(O)R.sup.h, --NR.sup.eC(O)OR.sup.h,
--NR.sup.aC(O)NR.sup.fR.sup.g,
--NR.sup.eC(.dbd.NR.sup.h)NR.sup.fR.sup.g, --NR.sup.eS(O)R.sup.h,
--NR.sup.eS(O)R.sup.h, --NR.sup.eS(O)NR.sup.fR.sup.g,
--NR.sup.eS(O).sub.2NR.sup.fR.sup.g, --P(O)R.sup.eR.sup.h,
--P(O)(OR.sup.e)R.sup.h, --P(O)(OR.sup.e)(OR.sup.h), --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, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl;
or (ii) R.sup.f and R.sup.g together with the N atom to which they
are attached form heteroaryl or heterocyclyl.
[0087] 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 %%,
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, the compound comprises about 95% or more of
the desired enantiomer and about 5% or less of the less preferred
enantiomer based on the total weight of the racemate in
question.
[0088] In describing an optically active compound, the prefixes R
and S are used to denote the absolute configuration of the molecule
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 molecule, R and S.
[0089] The phrase "an enantiomer, a mixture of enantiomers, a
mixture of two or more diastereomers, or an isotopic variant
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof" has the same meaning as the phrase "an
enantiomer, a mixture of enantiomers, a mixture of two or more
diastereomers, or an isotopic variant of the compound referenced
therein; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug of the compound referenced therein; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug of
an enantiomer, a mixture of enantiomers, a mixture of two or more
diastereomers, or an isotopic variant of the compound referenced
therein."
[0090] 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 a
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.
[0091] The terms "resistant," "elapsed," or "refractory" refer to a
cancer that has a reduced responsiveness to a treatment, e.g., the
point at which the cancer does not respond to attempted forms of
treatment. The cancer can be resistant at the beginning of
treatment or it may become resistant during treatment. The term
"refractory" can refer to a cancer for which treatment (e.g.,
chemotherapy drugs, biological agents, and/or radiation therapy)
has proven to be ineffective. A refractory cancer tumor may shrink,
but not to the point where the treatment is determined to be
effective. Typically however, the tumor stays the same size as it
was before treatment (stable disease), or it grows (progressive
disease).
[0092] "Responsiveness" or to "respond" to treatment, and other
forms of this term, as used herein, refer to the reaction of a
subject to treatment with a therapeutic. e.g., a PI3K inhibitor,
alone or in combination, e.g., monotherapy or combination therapy.
Responsiveness to a therapy, e.g., treatment with a PI3K inhibitor
alone or in combination, can be evaluated by comparing a subject's
response to the therapy using one or more clinical criteria, such
as IWCLL 2008 (for CLL) described in, e.g., Hallek, M. et al.
(2008) Blood 111 (12). 5446-5456; the Lugano Classification
described in, e.g., Cheson, B. D. et al. Journal of Clinical
Oncology, 32(27): 3059-3067; and the like. Additional
classifications of responsiveness are provided by. These criteria
provide a set of published rules that define when cancer patients
improve ("respond"), stay the same ("stable") or worsen
("progression") during treatments.
[0093] For example, a subject having CLL can be determined to be
incomplete remission (CR) or partial remission (PR). For example,
according to IWCLL 2008, a subject is considered to be in CR if at
least all of the following criteria as assessed after completion of
therapy are met: (i) Peripheral blood lymphocytes (evaluated by
blood and different count) below 4.times.10.sup.9/L (4000 .mu.i):
(ii) no hepatomegaly or splenomegaly by physical examination; (iii)
absence of constitutional symptoms; and (iv) blood counts (e.g.,
neutrophils, platelets, hemoglobin) above the values set forth in
Hallek, M. et al. Partial remission (PR) for CLL is defined
according to IWCLL 2008 as including one of: (i) a decrease in
number of blood lymphocytes by 50% or more from the value before
therapy; (ii) a reduction in lymphadenopathy, as detected by CT
scan or palpation; or (iii) a reduction in pretreatment enlargement
of spleen or liver by 50% or more, as detected by CT scan or
palpation; and blood counts (e.g., neutrophils, platelets,
hemoglobin) according to the values set forth in Hallek, M. et al.
In other embodiments, a subject having CLL is determined to have
progressive disease (PD) or stable disease (SD). For example,
according to IWCLL 2008, a subject is considered to be in PD during
therapy or after therapy if at least one of the following criteria
is met: (i) progression on lymphadenopathy; (ii) an increase in
pretreatment enlargement of spleen or liver by 50% or more, or de
novo appearance of hepatomegaly or splenomegaly; (iii) an increase
in the number of blood lymphocytes by 50% or more with at least
5000 B lymphocytes per microliter; (iv) transformation to a more
aggressive histology (e.g., Richter syndrome); or (v) occurrence of
cytopenia (neutropenia, anemia or thrombocytopenia) attributable to
CLL. Stable disease (SD) for CLL is defined according to IWCLL 2008
as a patient who has not achieved CR or a PR, and who has not
exhibited progressive disease.
[0094] For example, in some embodiments, a subject with CLL
responds to treatment with a PI3K inhibitor, alone or in
combination, if at least one of the criteria for disease
progression according to IWCLL is retarded or reduced, e.g., by
about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more. In
another example, a subject responds to treatment with a PI3K
inhibitor, alone or in combination, if the subject experiences a
life expectancy extension, e.g., extended by about 5%, 10%, 20%,
30%, 40%, 50% or more beyond the life expectancy predicted if no
treatment is administered. In another example, a subject responds
to treatment with a PI3K inhibitor, alone or in combination, if the
subject has one or more of: an increased progression-free survival,
overall survival or increased time to progression (TTP), e.g., as
described in Hallek, M. et al.
Compounds
[0095] Disclosed herein are PI3K inhibitors of Formula (I):
##STR00013## [0096] or an enantiomer, a mixture of enantiomers, a
mixture of two or more diastereomers, or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof; wherein: [0097] X, Y, and Z are each
independently N or CR.sup.X, with the proviso that at least two of
X, Y, and Z are nitrogen atoms; where R.sup.X is hydrogen or
C.sub.1-6 alkyl; [0098] R.sup.1 and R.sup.2 are each independently
(a) hydrogen, cyano, halo, or nitro; (b) C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 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(NR.sup.1a)NR.sup.1bR.sup.1c, --OR.sup.1b, --OC(O)R.sup.1a,
--OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c,
--OC(.dbd.NR.sup.1a)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(.dbd.NR.sup.1d)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)R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c; wherein each R.sup.1a, R.sup.1b,
R.sup.1c, and R.sup.1d is independently (i) hydrogen; (ii)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or
heterocyclyl; or (iii) R.sup.1b and R.sup.1c together with the N
atom to which they are attached form heterocyclyl; [0099] R.sup.3
and R.sup.4 are each independently hydrogen or C.sub.1-6 alkyl; or
R.sup.3 and R.sup.4 are linked together to form a bond, C.sub.1-6
alkylene, C.sub.1-6 heteroalkylene, C.sub.2-6 alkenylene, or
C.sub.2-6 heteroalkenylene; [0100] R.sup.5a is (a) hydrogen or
halo; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 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(NR.sup.1a)NR.sup.1bR.sup.1c, --OR.sup.1a, --OC(O)R.sup.1a,
--OC(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--OC(.dbd.NR.sup.a)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.aC(O)NR.sup.1bR.sup.1c,
--NR.sup.1aC(.dbd.NR.sup.1d)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.aS(O)NR.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.5b is (a) halo; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or (c)
--C(O)R.sup.a, --C(O)OR.sup.a, --C(O)NR.sup.1bR.sup.1c,
--C(NR.sup.1a)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(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, --OS(O)R.sup.a,
--OS(O).sub.2R.sup.a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.aS(O)R.sup.1d, --NR'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.a, --S(O)NR.sup.1bR.sup.1c, or
--S(O)NR.sup.1bR.sup.1c; [0102] R.sup.5c is
--(CR.sup.5fR.sup.5g).sub.n--(C.sub.6-14 aryl) or
--(CR.sup.5fR.sup.5g).sub.n-heteroaryl; [0103] R.sup.5d and
R.sup.5e are each independently (a) hydrogen or halo; (b) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 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(NR.sup.1a)NR.sup.1bR.sup.1c, --OR.sup.1a, --OC(O)R.sup.1a,
--OC(O)OR.sup.a, --OC(O)NR.sup.1bR.sup.1c,
--OC(.dbd.NR.sup.1a)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(.dbd.NR.sup.1d)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.aS(O)NR.sup.1bR.sup.1c,
--SR.sup.1a, --S(O)R.sup.1a, --S(OR.sup.a, --S(O)NR.sup.1bR.sup.1c,
or --S(O).sub.2NR.sup.1bR.sup.1c; [0104] R.sup.5f and R.sup.5g are
each independently (a) hydrogen or halo; (b) C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 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(NR.sup.1a)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(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, --OS(O)R.sup.a,
--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(.dbd.NR.sup.1d)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)NR.sup.1bR.sup.1c,
--SR.sup.1a, --S(O)R.sup.1a, --S(O)R.sup.1a,
--S(O)NR.sup.1bR.sup.1c; or --S(O).sub.2NR.sup.1bR.sup.1c; or (d)
when one occurrence of R.sup.5f and one occurrence of R.sup.5g are
attached to the same carbon atom, the R.sup.5f and R.sup.5g
together with the carbon atom to which they are attached form a
C.sub.3-10 cycloalkyl or heterocyclyl; [0105] R.sup.6 is hydrogen,
C.sub.1-6 alkyl, --S--C.sub.1-6 alkyl, --S(O)--C.sub.1-6 alkyl, or
--SO.sub.2--C.sub.1-6 alkyl; [0106] m is 0 or 1; and [0107] n is 0,
1, 2, 3, or 4; [0108] wherein each alkyl, alkylene, heteroalkylene,
alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl,
aralkyl, heteroaryl, and heterocyclyl in R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.6, R.sup.X, R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d,
R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, R.sup.5e, R.sup.5f, and
R.sup.5g is optionally substituted with one or more, in one
embodiment, one, two, three, four, or five substituents Q, wherein
each substituent Q is independently selected from (a) oxo, cyano,
halo, and nitro; (b) C.sub.1-4 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-10 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(NR.sup.a)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(.dbd.NR.sup.a)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.a(O)R.sup.d, --NR.sup.eC(O)OR.sup.d,
--NR.sup.aC(O)NR.sup.bR.sup.c,
--NR.sup.aC(.dbd.NR.sup.d)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; (ii) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl,
each of which is further 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, which is further optionally
substituted with one or more, in one embodiment, one, two, three,
or four, substituents Q.sup.a; [0109] wherein each Q.sup.a is
independently selected from the group consisting of (a) oxo, cyano,
halo, and nitro; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-10 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(NR)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(.dbd.NR.sup.e)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.h,
--NR.sup.eC(O)NR.sup.fR.sup.g,
--NR.sup.eC(.dbd.NR.sup.h)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)NR.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; (ii) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocycyl; or
(iii) R.sup.f and RR together with the N atom to which they are
attached form heterocyclyl; or [0110] wherein two substituents Q
that are adjacent to each other optionally form a [0111] C.sub.3-10
cycloalkenyl, C.sub.6-14 aryl, heteroaryl, or heterocyclyl, each
optionally substituted with one, two, three, or four substituents
Q.sup.a. In one embodiment of a compound of Formula (I), [0112] X,
Y, and Z are each independently N or CR.sup.X, with the proviso
that at least two of X, Y, and Z are nitrogen atoms; where R.sup.X
is hydrogen or C.sub.1-6 alkyl; [0113] R.sup.1 and R.sup.2 are each
independently (a) hydrogen, cyano, halo, or nitro; (b) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 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(NR.sup.1a)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(.dbd.NR.sup.1a)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(.dbd.NR.sup.1d)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; wherein each R.sup.1a, R.sup.1b,
R.sup.1c, and R.sup.1d is independently (i) hydrogen; (ii)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or
heterocyclyl; or (iii) R.sup.1b and R.sup.1c together with the N
atom to which they are attached form heterocyclyl; [0114] R.sup.3
and R.sup.4 are each independently hydrogen or C.sub.1-6 alkyl; or
R.sup.3 and R.sup.4 are linked together to form a bond, C.sub.1-6
alkylene, C.sub.1-6 heteroalkylene, C.sub.2-6 alkenylene, or
C.sub.2-6 heteroalkenylene; [0115] R.sup.5a is (a) hydrogen or
halo; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 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(NR.sup.1a)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(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, --OS(O)R.sup.1a,
--OS(O).sub.2R.sup.a, --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(.dbd.NR.sup.1d)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)--R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c; [0116] R.sup.5b is (a) halo; (b)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
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(NR.sup.1a)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(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
--OS(O)R.sup.h, --OS(O).sub.2R.sup.a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.aC(O)R.sup.1d, --NR.sup.aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.aS(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; [0117] R.sup.5c is
--(CR.sup.5fR.sup.5g).sub.n--(C.sub.6-14 aryl) or
--(CR.sup.5fR.sup.5g).sub.n-heteroaryl; [0118] R.sup.5d and
R.sup.5e are each independently (a) hydrogen or halo; (b) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl;
or (c) --C(O)R, --C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--C(NR.sup.1a)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(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, --OS(O)R.sup.1a,
--OS(O).sub.2R.sup.a, --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.aC(O)NR.sup.1bR.sup.1c,
--NR.sup.1aC(.dbd.NR.sup.1d)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.aS(O).sub.2NR.sup.1bR.sup.1c, --SR.sup.1a, --S(O)R.sup.a,
--S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c; [0119] R.sup.5f and R.sup.5g are
each independently (a) hydrogen or halo; (b) C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 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(NR.sup.1a)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(.dbd.NR.sup.1a)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.bR.sup.c,
--NR.sup.1aC(.dbd.NR.sup.1d)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)NR.sup.1bR.sup.1c,
--SR.sup.1a, --S(O)R.sup.1a, --S(O)R.sup.1a,
--S(O)NR.sup.1bR.sup.1c; or --S(O).sub.2NR.sup.1bR.sup.1c; or (d),
when one occurrence of R.sup.5f and one occurrence of R
.sup.5g are attached to the same carbon atom, the R.sup.5f and
R.sup.5g together with the carbon atom to which they are attached
form a C.sub.3-10 cycloalkyl or heterocyclyl; [0120] R.sup.6 is
hydrogen, C.sub.1-6 alkyl, --S--C.sub.1-6 alkyl, --S(O)--C.sub.1-6
alkyl, or --SO.sub.2--C.sub.1-6 alkyl; [0121] m is 0 or 1; and
[0122] n is 0, 1, 2, 3, or 4; [0123] wherein each alkyl, alkylene,
heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl,
cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is
optionally substituted with one or more, in one embodiment, one,
two, three, four, or five substituents Q as defined herein.
[0124] In another embodiment of a compound of Formula (I), [0125]
X, Y, and Z are each independently N or CR.sup.X, with the proviso
that at least two of X, Y, and Z are nitrogen atoms; where R.sup.X
is hydrogen or C.sub.1-6 alkyl; [0126] R.sup.1 and R.sup.2 are each
independently (a) hydrogen, cyano, halo, or nitro; (b) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 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(NR.sup.1a)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(.dbd.NR.sup.1a)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.aC(O)NR.sup.1bR.sup.1c,
--NR.sup.1aC(.dbd.NR.sup.1d)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.aS(O).sub.2NR.sup.1bR.sup.1c, --SR.sup.1a, --S(O)R.sup.1a,
--S(O)R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c; wherein each R.sup.1a, R.sup.1b,
R.sup.1c, and R.sup.1d is independently (i) hydrogen; (ii)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or
heterocyclyl; or (iii) R.sup.1b and R.sup.1c together with the N
atom to which they are attached form heterocyclyl; [0127] R.sup.3
and R.sup.4 are each independently hydrogen or C.sub.1-6 alkyl; or
R.sup.3 and R.sup.4 are linked together to form a bond, C.sub.1-6
alkylene, C.sub.1-6 heteroalkylene, C.sub.2-6 alkenylene, or
C.sub.2-6 heteroalkenylene; [0128] R.sup.5a is (a) hydrogen or
halo; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 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(NR.sup.1a)NR.sup.1bR.sup.1c, --OR.sup.1a, --OC(O)R.sup.1a,
--OC(O)OR.sup.a, --OC(O)NR.sup.1bR.sup.1c,
--OC(.dbd.NR.sup.1a)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(.dbd.NR.sup.1d)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)R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c; [0129] R.sup.5b is (a) halo; (b)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl. C.sub.3-10
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(NR.sup.1a)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(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c,
--OS(O)R.sup.a, --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(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.aS(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)R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O)NR.sup.1bR.sup.1c; [0130] R.sup.5c is
--(CR.sup.5fR.sup.5g).sub.n--(C.sub.6-14 aryl) or
--(CR.sup.5fR.sup.5g).sub.n-heteroaryl; [0131] R.sup.5d and
R.sup.5e are each independently (a) hydrogen or halo; (b) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 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(NR.sup.1a)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(.dbd.NR.sup.1a)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(.dbd.NR.sup.1d)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)NR.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; [0132]
R.sup.5f and R.sup.5g are each independently (a) hydrogen or halo;
(b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 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(NR.sup.1a)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(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, --OS(O)R.sup.a,
--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.d,
--NR.sup.aC(O)NR.sup.1bR.sup.1c,
--NR.sup.1aC(.dbd.NR.sup.1d)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; or (d) when one occurrence of
R.sup.5f and one occurrence of R.sup.5g are attached to the same
carbon atom, the R.sup.5f and R.sup.5g together with the carbon
atom to which they are attached form a C.sub.3-10 cycloalkyl or
heterocyclyl; [0133] R.sup.6 is hydrogen, C.sub.1-6 alkyl,
--S--C.sub.1-6alkyl, --S(O)--C.sub.1-6alkyl, or
--SO.sub.2--C.sub.1-6 alkyl; [0134] m is 0 or 1; and [0135] n is 0,
1, 2, 3, or 4; [0136] wherein each alkyl, alkylene, heteroalkylene,
alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl,
aralkyl, heteroaryl, and heterocyclyl is optionally substituted
with one or more, in one embodiment, one, two, three, four, or five
substituents Q as defined herein.
[0137] In yet another embodiment of a compound of Formula (I),
[0138] X, Y, and Z are each independently N or CR.sup.X, with the
proviso that at least two of X, Y, and Z are nitrogen atoms; where
R.sup.X is hydrogen or C.sub.1-6 alkyl; [0139] R.sup.1 and R.sup.2
are each independently (a) hydrogen, cyano, halo, or nitro; (b)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
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(NR.sup.1a)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(.dbd.NR.sup.1a)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(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c,
--NR.sup.aS(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; wherein each R.sup.1a, R.sup.1b,
R.sup.1c, and R.sup.1d is independently (i) hydrogen; (ii)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl. C.sub.3-10
cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or
heterocyclyl; or (iii) R.sup.1b and R.sup.1c together with the N
atom to which they are attached form heterocyclyl; [0140] R.sup.3
and R.sup.4 are each independently hydrogen or C.sub.1-6 alkyl; or
R.sup.3 and R.sup.4 are linked together to form a bond, C.sub.1-6
alkylene, C.sub.1-6 heteroalkylene, C.sub.2-6 alkenylene, or
C.sub.2-6 heteroalkenylene; [0141] R.sup.5a is (a) halo; (b)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
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(NR.sup.1a)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(.dbd.NR.sup.1a)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.aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c,
--NR.sup.1aC(.dbd.NR.sup.1d)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.aS(O)NR.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; [0142]
R.sup.5b is (a) halo; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-10 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(NR.sup.1a)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(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, --OS(O)R,
--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.1C(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.bR.sup.c,
--NR.sup.1aC(.dbd.NR.sup.1d)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.aS(O).sub.2NR.sup.bR.sup.c, --SR.sup.1a, --S(O)R.sup.1a,
--S(O)R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or
--S(O)NR.sup.1bR.sup.1c; [0143] R.sup.5c is
--(CR.sup.5fR.sup.5g).sub.n--(C.sub.6-14 aryl) or
--(CR.sup.5fR.sup.5g).sub.n-heteroaryl; [0144] R.sup.5d and
R.sup.5e are each independently (a) hydrogen or halo; (b) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 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(NR.sup.1a)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(.dbd.NR.sup.1a)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.aC(O)NR.sup.1bR.sup.1c,
--NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.bR.sup.c,
--NR.sup.aS(O)R.sup.1d, --NR.sup.1aS(O).sub.2R.sup.1d,
--NR.sup.1aS(O)NR.sup.1bR.sup.1c,
--NR.sup.aS(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; [0145] R.sup.5f and R.sup.5g are
each independently (a) hydrogen or halo; (b) C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 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(NR.sup.1a)NR.sup.1bR.sup.1c, --OR.sup.1a, --OC(O)R.sup.1a,
--OC(O)OR.sup.1a, --OC(O)NR.sup.bR.sup.c,
--OC(.dbd.NR.sup.1a)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(.dbd.NR.sup.1d)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)R.sup.1bR.sup.1c, --S(O)NR.sup.1bR.sup.1c; or
--S(O).sub.2NR.sup.1bR.sup.1c; or (d) when one occurrence of
R.sup.5f and one occurrence of R.sup.5g are attached to the same
carbon atom, the R.sup.5f and R.sup.5g together with the carbon
atom to which they are attached form a C.sub.3-10 cycloalkyl or
heterocyclyl; [0146] R.sup.6 is hydrogen, C.sub.1-6 alkyl,
--S--C.sub.1-6 alkyl, --S(O)--C.sub.1-6 alkyl, or
--SO.sub.2--C.sub.1-6 alkyl; [0147] m is 0 or 1; and [0148] n is 0,
1, 2, 3, or 4; [0149] wherein each alkyl, alkylene, heteroalkylene,
alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl,
aralkyl, heteroaryl, and heterocyclyl is optionally substituted
with one or more, in one embodiment, one, two, three, four, or five
substituents Q as defined herein.
[0150] In still another embodiment of a compound of Formula (I),
[0151] X, Y, and Z are N; [0152] R.sup.1 and R.sup.2 are each
independently (a) hydrogen, cyano, halo, or nitro (b) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 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(NR.sup.1a)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(.dbd.NR.sup.1a)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(.dbd.NR.sup.1d)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.bR.sup.c, --SR.sup.1a, --S(O)R.sup.1a,
--S(O).sub.2R.sup.a, --S(O)NR.sup.1bR.sup.1c, or
--S(O).sub.2NR.sup.1bR.sup.1c; wherein each R.sup.1a, R.sup.1b,
R.sup.1c, and R.sup.1d is independently (i) hydrogen; (ii)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or
heterocyclyl; or (iii) R.sup.1b and R.sup.1c together with the N
atom to which they are attached form heterocyclyl; [0153] R.sup.3
and R.sup.4 are each independently hydrogen or C.sub.1-6 alkyl; or
R.sup.3 and R.sup.4 are linked together to form a bond, C.sub.1-6
alkylene, C.sub.1-6 heteroalkylene, C.sub.2-6 alkenylene, or
C.sub.2-6 heteroalkenylene; [0154] R.sup.5a is (a) hydrogen or
halo; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 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.ta, --C(O)NR.sup.1bR.sup.1c,
--C(NR.sup.1a)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(.dbd.NR.sup.1a)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.bR.sup.c, --NR.sup.1bR.sup.1c, --NR.sup.1a,
--C(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c,
--NR.sup.1aC(.dbd.NR.sup.1d)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; [0155] R.sup.5b is (a) halo; (b)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, or heteroaryl; or
(c) --C(O)R.sup.1a, --C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--C(NR.sup.1a)NR.sup.1bR.sup.1c, --OR.sup.1a, --OC(O)R.sup.1a,
--OC(O)OR.sup.a, --OC(O)NR.sup.1bR.sup.1c,
--OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, --OS(O)R.sup.1a,
--OS(O)R.sup.1a, --OS(O)NR.sup.1bR.sup.1c,
--OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c,
--NR.sup.aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c,
--NR.sup.1aC(.dbd.NR.sup.1d)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.bR.sup.c, --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; [0156] R.sup.5c is
--(CR.sup.5fR.sup.5g).sub.n--(C.sub.6-14 aryl) or
--(CR.sup.5fR.sup.5g).sub.n-heteroaryl; [0157] R.sup.5d and
R.sup.5e are each independently (a) hydrogen or halo; (b) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 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.1a,
--C(NR.sup.1a)NR.sup.1bR.sup.1c, --OR.sup.1a, --OC(O)R.sup.a,
--OC(O)OR.sup.1a, --OC(O)NR.sup.bR.sup.c,
--OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, --OS(O)R.sup.a,
--OS(O).sub.2R.sup.1a, --OS(O)NR.sup.bR.sup.c,
--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(.dbd.NR.sup.1d)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)NR.sup.1bR.sup.1c,
--SR.sup.1a, --S(O)R.sup.a, --S(O)R.sup.1a,
--S(O)NR.sup.1bR.sup.1c, or --S(O).sub.2NR.sup.1bR.sup.1c; [0158]
R.sup.5f and R.sup.5g are each independently (a) hydrogen or halo;
(b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 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(NR.sup.1a)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(.dbd.NR.sup.1a)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(.dbd.NR.sup.1d)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)NR.sup.1bR.sup.1c,
--SR.sup.1a, --S(O)R.sup.1a, --S(O)R.sup.1a,
--S(O)NR.sup.1bR.sup.1c; or --S(O).sub.2NR.sup.1bR.sup.1c; or (d)
when one occurrence of R and one occurrence of R.sup.3g are
attached to the same carbon atom, the R.sup.5f and R.sup.5g
together with the carbon atom to which they are attached form a
C.sub.3-10 cycloalkyl or heterocyclyl; [0159] R.sup.6 is hydrogen,
C.sub.1-6 alkyl, --S--C.sub.1-6alkyl, --S(O)--C.sub.1-6 alkyl, or
--SO.sub.2--C.sub.1-6 alkyl; [0160] m is 0 or 1; and [0161] n is 0,
1, 2, 3, or 4; [0162] wherein each alkyl, alkylene, heteroalkylene,
alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl,
aralkyl, heteroaryl, and heterocyclyl is optionally substituted
with one or more, in one embodiment, one, two, three, four, or five
substituents Q as defined herein.
[0163] In some embodiments of compounds of structural Formula (I):
[0164] X, Y, and Z are each N; [0165] R.sup.1 and R.sup.2 are each
hydrogen; [0166] R.sup.3 and R.sup.4 are each hydrogen; [0167]
R.sup.5 is C.sub.1-6 alkyl; [0168] R.sup.5b is C.sub.1-6 alkyl;
[0169] R.sup.5c is --(CH.sub.2)-phenyl, wherein R.sup.5c is
optionally substituted with one, two, three, or four, substituents
Q.sup.a; [0170] R.sup.5d and R.sup.5e are each hydrogen; [0171]
R.sup.6 is CHF.sub.2; and [0172] m is 0;
[0173] wherein each alkyl is optionally substituted with one, two,
three, or four, substituents Q, wherein each substituent Q is
independently selected from C.sub.6-14 aryl, heteroaryl, and
heterocyclyl, each of which is further optionally substituted with
one, two, three, or four, substituents Q.sup.a, wherein the
heteroaryl has from 5 to 10 ring atoms and one or more heteroatoms
independently selected from O, S, and N, and the heterocyclyl has
from 3 to 15 ring atoms and one or more heteroatoms independently
selected from O, S, and N;
wherein each Q.sup.a is independently selected from the group
consisting of halo, C.sub.1-6 alkyl, C.sub.1-6 alkylsulfonyl and
--OR.sup.e, wherein R.sup.e is hydrogen or C.sub.1-6 alkyl.
[0174] Also provided herein is a compound of Formula (IX):
##STR00014## [0175] or an enantiomer, a mixture of enantiomers, a
mixture of two or more diastereomers, or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof; wherein: R.sup.7a, R.sup.7b, R.sup.7c,
R.sup.7d, and R.sup.7e are each independently (a) hydrogen, cyano,
halo, or nitro; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15
aralkyl, heteroaryl, or heterocyclyl, each of which is optionally
substituted with one, two, three, or four substituents Q.sup.a; or
(c) --C(O)R.sup.a, --C(O)OR.sup.a, --C(O)NR.sup.bR.sup.c,
--C(NR.sup.a)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(.dbd.NR.sup.a)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(.dbd.NR.sup.d)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.eS(O).sub.2NR.sup.bR.sup.c, --SR.sup.a, --S(O)R.sup.a,
--S(O).sub.2R, --S(O)NR.sup.bR.sup.c or
--S(O).sub.2NR.sup.bR.sup.c; or two of R.sup.7a, R.sup.7b,
R.sup.7c, R.sup.7d, and R.sup.7e that are adjacent to each other
form C.sub.3-10 cycloalkenyl, C.sub.6-14 aryl, heteroaryl, or
heterocyclyl, each optionally substituted with one, two, three, or
four substituents Q.sup.a; and R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.6, R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, R.sup.5a,
R.sup.5b, R.sup.5d, R.sup.5e, X, Y, and Z are each as defined
herein.
[0176] In certain embodiments of compounds of Formula (IX), one of
R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e is C.sub.6-14
aryl, heteroaryl, or heterocyclyl, each of which is optionally
substituted with one, two, three, or four substituents Q.sup.a; in
certain embodiments, one of R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d,
and R.sup.7e is C.sub.6-14 aryl, e.g., phenyl, optionally
substituted with one, two, three, or four substituents Q.sup.a; in
certain embodiments, one of R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d,
and R.sup.7e is heteroaryl, e.g., 5-membered or 6-membered
heteroaryl, optionally substituted with one, two, three, or four
substituents Q.sup.a; in certain embodiments, one of R.sup.7a,
R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e is heterocyclyl, e.g.,
5-membered or 6-membered heterocyclyl, optionally substituted with
one, two, three, or four substituents Q.sup.a; in certain
embodiments, one of R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and
R.sup.7e is phenyl, imidazolyl, pyrazolyl, pyridinyl, piperidinyl,
or piperazinyl, each optionally substituted with one, two, three,
or four substituents Q.sup.a; in certain embodiments, one of
R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e is phenyl,
imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl,
piperidinyl, or piperazinyl, each optionally substituted with one,
two, three, or four substituents Q.sup.a; in certain embodiments,
one of R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e is
phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl,
2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl,
3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl,
4-methoxyphenyl, imidazol-1-yl, pyrazol-4-yl,
1-methyl-pyrozol-4-yl, 2-methylpyrazol-3-yl, pyridin-2-yl,
pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl,
2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or
4-methylpiperazin-1-yl; and in certain embodiments, one of
R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e is phenyl,
2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,
2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,
3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl,
4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,
2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl 3-methoxyphenyl,
4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl imidazol-1-yl,
pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrazol-3-v,
pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl,
2-methylpyridin-4-yl, 2-(4-methylpiperazin-1-yl)pyridin-4-yl,
2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl,
1-methylpyrrolidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl,
1-ethylpiperidin-4-yl, 1-isopropylpiperidin-4-yl,
1-acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl, or
4-methylpiperazin-1-yl.
[0177] In certain embodiments of compounds of Formula (IX),
R.sup.1a is C.sub.6-14 aryl, heteroaryl, or heterocyclyl, each of
which is optionally substituted with one, two, three, or four
substituents Q.sup.a; in certain embodiments, R.sup.7a is
C.sub.6-14 aryl, e.g., phenyl, optionally substituted with one,
two, three, or four substituents Q.sup.a; in certain embodiments,
R.sup.1a is heteroaryl, e.g., 5-membered or 6-membered heteroaryl,
optionally substituted with one, two, three, or four substituents
Q.sup.a; in certain embodiments, R.sup.7a is heterocyclyl, e.g.,
5-membered or 6-membered heterocyclyl, optionally substituted with
one, two, three, or four substituents Q.sup.a; in certain
embodiments. R.sup.7a is phenyl, imidazolyl, pyrozolyl, pyridinyl,
piperidinyl, or piperazinyl, each optionally substituted with one,
two, three, or four substituents Q.sup.a; in certain embodiments,
R.sup.7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,
pyrrolidinyl, piperidinyl, or piperazinyl, each optionally
substituted with one, two, three, or four substituents Q.sup.a; in
certain embodiments, R.sup.7a is phenyl, 2-fluorophenyl,
2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl,
3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl,
4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl,
pyrozol-4-yl, 1-methyl-pyrozol-4-yl 2-methylpyrazol-3-yl,
pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl,
2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or
4-methylpiperazin-1-yl; and in certain embodiments, R.sup.a is
phenyl, 2-fluorophenyl. 2-chlorophenyl, 2-bromophenyl,
2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl,
3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl,
4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,
2,4-difluorophenyl. 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl,
3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl,
imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,
2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,
2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,
2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,
pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,
piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,
1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,
1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.
[0178] In certain embodiments of compounds of Formula (IX),
R.sup.1 is hydrogen or --OR.sup.1a, where R.sup.1a is C.sub.1-6
alkyl, optionally substituted with one, two, three, four, or five
substituents Q.sup.a; R.sup.2 is hydrogen; R.sup.3 and R.sup.4 are
hydrogen; R.sup.6 is C.sub.1-6 alkyl, optionally substituted with
one, two, three, four, or five substituents Q.sup.a; R.sup.5a and
R.sup.5b are each independently hydrogen, halo, C.sub.1-6 alkyl,
optionally substituted with one, two, three, four, or five
substituents Q.sup.a; R.sup.5d and R.sup.5e are each independently
C.sub.1-6 alkyl, optionally substituted with one, two, three, four,
or five substituents Q.sup.a; R.sup.7a is C.sub.6-14 aryl,
heteroaryl, or heterocyclyl, each of which is optionally
substituted with one, two, three, or four substituents Q.sup.a;
R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e are hydrogen; and X, Y,
and Z are each independently N or CR.sup.X, with the proviso that
at least two of X, Y, and Z are N; where R.sup.X is a hydrogen or
C.sub.1-6 alkyl, optionally substituted with one, two, three, or
four substituents Q.sup.a.
[0179] In certain embodiments of compounds of Formula (IX),
R.sup.1 is hydrogen or methoxy; R.sup.2 is hydrogen; R.sup.3 and
R.sup.4 are hydrogen; R.sup.6 is C.sub.1-6 alkyl, optionally
substituted with one or more halo; R.sup.5a and R.sup.5b are
hydrogen; R.sup.5d and R.sup.5e are each independently C.sub.1-6
alkyl; R.sup.7a is C.sub.6-14 aryl, heteroaryl, or heterocyclyl,
each of which is optionally substituted with one, two, three, or
four substituents Q.sup.a; R.sup.7b, R.sup.7c, R.sup.7d, and
R.sup.7e are hydrogen; and X, Y, and Z are each independently N or
CH.
[0180] In certain embodiments of compounds of Formula (IX),
[0181] R.sup.1 is hydrogen or methoxy;
[0182] R.sup.2 is hydrogen;
[0183] R.sup.3 and R.sup.4 are hydrogen;
[0184] R.sup.6 is difluoromethyl;
[0185] R.sup.5a and R.sup.5b are hydrogen;
[0186] R.sup.5d and R.sup.5e are methyl;
[0187] R.sup.7a is C.sub.6-14 aryl, monocyclic heteroaryl, or
monocyclic heterocyclyl, each of which is optionally substituted
with one, two, three, or four substituents Q.sup.a;
[0188] R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e are hydrogen;
and
[0189] X, Y, and Z are each independently N or CH.
[0190] In certain embodiments of compounds of Formula (IX),
[0191] R.sup.1 is hydrogen or methoxy;
[0192] R.sup.2 is hydrogen.
[0193] R.sup.3 and R.sup.4 are hydrogen;
[0194] R.sup.6 is difluoromethyl;
[0195] R.sup.5a and R.sup.5b are hydrogen;
[0196] R.sup.5d and R.sup.5e are methyl;
[0197] R.sup.7 is phenyl, 5- or 6-membered heteroaryl, or 5- or
6-membered heterocyclyl, each of which is optionally substituted
with one, two, three, or four substituents Q.sup.a;
[0198] R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e are hydrogen;
and
[0199] X, Y, and Z are each independently N or CH.
[0200] In certain embodiments of compounds of Formula (IX),
[0201] R.sup.1 is hydrogen or methoxy;
[0202] R.sup.2 is hydrogen;
[0203] R.sup.3 and R.sup.4 are hydrogen;
[0204] R.sup.6 is difluoromethyl;
[0205] R.sup.5a and R.sup.5b are hydrogen;
[0206] R.sup.5d and R.sup.5e are methyl;
[0207] R.sup.7a is phenyl, imidazolyl, pyrozolyl, pyridinyl,
pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of
which is optionally substituted with one, two, three, or four
substituents Q.sup.a;
[0208] R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e are hydrogen;
and
[0209] X, Y, and Z are each independently N or CH.
[0210] In certain embodiments of compounds of Formula (IX),
[0211] R.sup.1 is hydrogen or methoxy;
[0212] R.sup.2 is hydrogen;
[0213] R.sup.3 and R.sup.4 are hydrogen;
[0214] R.sup.6 is difluoromethyl;
[0215] R.sup.5a and R.sup.5b are hydrogen;
[0216] R.sup.5d and R.sup.5e are methyl;
[0217] R.sup.7a is phenyl, imidazolyl, pyrozolyl, pyridinyl,
piperidinyl, or piperazinyl, each of which is optionally
substituted with one, two, three, or four substituents Q.sup.a;
[0218] R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e are hydrogen;
and
[0219] X, Y, and Z are each independently N or CH.
[0220] Also provided herein is a compound of Formula (X):
##STR00015##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof; wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6,
R.sup.5a, R.sup.5b, R.sup.5d, R.sup.5e, R.sup.7a, R.sup.7b,
R.sup.7c, R.sup.7d, and R.sup.7e are each as defined herein.
[0221] In certain embodiments of compounds of Formula (X), one of
R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e is C.sub.6-14
aryl, heteroaryl, or heterocyclyl, each of which is optionally
substituted with one, two, three, or four substituents Q.sup.a; in
certain embodiments, one of R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d,
and R.sup.7e is C.sub.6-14 aryl, e.g., phenyl, optionally
substituted with one, two, three, or four substituents Q.sup.a; in
certain embodiments, one of R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d,
and R.sup.7e is heteroaryl, e.g., 5-membered or 6-membered
heteroaryl, optionally substituted with one, two, three, or four
substituents Q.sup.a; in certain embodiments, one of R.sup.7a,
R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e is heterocyclyl, e.g.,
5-membered or 6-membered heterocyclyl, optionally substituted with
one, two, three, or four substituents Q.sup.a; in certain
embodiments, one of R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and
R.sup.7e is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl,
or piperazinyl, each optionally substituted with one, two, three,
or four substituents Q.sup.a; in certain embodiments, one of
R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e is phenyl,
imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl,
piperidinyl, or piperazinyl, each optionally substituted with one,
two, three, or four substituents Q.sup.a; in certain embodiments,
one of R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e is
phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl,
2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl,
3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl,
4-methoxyphenyl, imidazol-1-yl, pyrozol-4-yl,
1-methyl-pyrozol-4-yl, 2-methylpyrazol-3-yl, pyridin-2-yl,
pyridin-3-yl pyridin-4-yl, 2-methylpyridin-4-yl,
2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or
4-methylpiperazin-1-yl; and in certain embodiments, one of
R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e is phenyl,
2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,
2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,
3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl,
4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,
2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,
4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,
pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrazol-3-yl,
pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl,
2-methylpyridin-4-yl, 2-(4-methylpiperazin-1-yl)pyridin-4-yl,
2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl,
1-methylpyrrolidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-1,
l-ethylpiperidin-4-yl, 1-isopropylpiperidin-4-yl,
1-acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl, or
4-methylpiperazin-1-yl.
[0222] In certain embodiments of compounds of Formula (X), R.sup.1a
is C.sub.6-14 aryl, heteroaryl, or heterocyclyl, each of which is
optionally substituted with one, two, three, or four substituents
Q.sup.a; in certain embodiments, R.sup.7a is C.sub.6-14 aryl, e.g.,
phenyl, optionally substituted with one, two, three, or four
substituents Q.sup.a; in certain embodiments, R.sup.1a is
heteroaryl, e.g., 5-membered or 6-membered heteroaryl, optionally
substituted with one, two, three, or four substituents Q.sup.a; in
certain embodiments, R.sup.7a is heterocyclyl, e.g., 5-membered or
6-membered heterocyclyl, optionally substituted with one, two,
three, or four substituents Q.sup.a; in certain embodiments.
R.sup.7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl,
or piperazinyl, each optionally substituted with one, two, three,
or four substituents Q.sup.a; in certain embodiments, R.sup.7a is
phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,
pyrrolidinyl, piperidinyl, or piperazinyl, each optionally
substituted with one, two, three, or four substituents Q.sup.a; in
certain embodiments, R.sup.7a is phenyl, 2-fluorophenyl,
2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl,
3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl,
4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl,
pyrozol-4-yl, 1-methyl-pyrozol-4-yl 2-methylpyrazol-3-yl,
pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl,
2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or
4-methylpiperazin-1-yl; and in certain embodiments, R.sup.7a is
phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl,
2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl,
3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl. 3-methoxyphenyl,
4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,
2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl,
3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl,
imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,
2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,
2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,
2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,
pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,
piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,
1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,
1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.
[0223] In certain embodiments of compounds of Formula (X),
[0224] R.sup.1 is hydrogen or --OR.sup.1a, where R.sup.1a is
C.sub.1-6 alkyl, optionally substituted with one, two, three, four,
or five substituents Q.sup.a;
[0225] R.sup.2 is hydrogen;
[0226] R.sup.3 and R.sup.4 are hydrogen;
[0227] R.sup.6 is C.sub.1-6 alkyl, optionally substituted with one,
two, three, four, or five substituents Q.sup.a;
[0228] R.sup.5a and R.sup.5b are each independently hydrogen, halo,
C.sub.1-6 alkyl, optionally substituted with one, two, three, four,
or five substituents Q.sup.a;
[0229] R.sup.5d and R.sup.5e are each independently C.sub.1-6
alkyl, optionally substituted with one, two, three, four, or five
substituents Q.sup.a;
[0230] R.sup.7a is C.sub.6-14 aryl, heteroaryl, heterocyclyl, each
of which is optionally substituted with one, two, three, or four
substituents Q.sup.a; and
[0231] R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e are hydrogen.
[0232] In certain embodiments of compounds of Formula (X),
[0233] R.sup.1 is hydrogen or methoxy;
[0234] R.sup.2 is hydrogen;
[0235] R.sup.3 and R.sup.4 are hydrogen;
[0236] R.sup.6 is C.sub.1-6 alkyl, optionally substituted with one
or more halo;
[0237] R.sup.5a and R.sup.5b are hydrogen;
[0238] R.sup.5d and R.sup.5e are each independently C.sub.1-6
alkyl;
[0239] R.sup.7a is C.sub.6-14 aryl, heteroaryl, or heterocyclyl,
each of which is optionally substituted with one, two, three, or
four substituents Q.sup.a; and
[0240] R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e are hydrogen.
[0241] In certain embodiments of compounds of Formula (X),
[0242] R.sup.1 is hydrogen or methoxy;
[0243] R.sup.2 is hydrogen;
[0244] R.sup.3 and R.sup.4 are hydrogen;
[0245] R.sup.6 is difluoromethyl;
[0246] R.sup.5a and R.sup.5b are hydrogen;
[0247] R.sup.5d and R.sup.5e are methyl;
[0248] R.sup.7a is C.sub.6-14 aryl, monocyclic heteroaryl, or
monocyclic heterocyclyl, each of which is optionally substituted
with one, two, three, or four substituents Q.sup.a; and
[0249] R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e are hydrogen.
[0250] In certain embodiments of compounds of Formula (X),
[0251] R.sup.1 is hydrogen or methoxy;
[0252] R.sup.2 is hydrogen;
[0253] R.sup.3 and R.sup.4 are hydrogen;
[0254] R.sup.6 is difluoromethyl;
[0255] R.sup.5a and R.sup.5b are hydrogen;
[0256] R.sup.5d and R.sup.e are methyl;
[0257] R.sup.7a is phenyl, 5- or 6-membered heteroaryl, or 5- or
6-membered heterocyclyl, each of which is optionally substituted
with one, two, three, or four substituents Q.sup.a; and
[0258] R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e are hydrogen.
[0259] In certain embodiments of compounds of Formula (X),
[0260] R.sup.1 is hydrogen or methoxy;
[0261] R.sup.2 is hydrogen;
[0262] R.sup.3 and R.sup.4 are hydrogen;
[0263] R.sup.6 is difluoromethyl;
[0264] R.sup.5a and R.sup.5b are hydrogen;
[0265] R.sup.5d and R.sup.5e are methyl;
[0266] R.sup.7a is phenyl, imidazolyl, pyrozolyl, pyridinyl,
pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of
which is optionally substituted with one, two, three, or four
substituents Q.sup.a; and
[0267] R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e are hydrogen.
[0268] In certain embodiments of compounds of Formula (X),
[0269] R.sup.1 is hydrogen or methoxy;
[0270] R.sup.2 is hydrogen;
[0271] R.sup.3 and R.sup.4 are hydrogen;
[0272] R.sup.6 is difluoromethyl;
[0273] R.sup.5a and R.sup.5b are hydrogen;
[0274] R.sup.5d and R.sup.5e are methyl;
[0275] R.sup.7a is phenyl, imidazolyl, pyrozolyl, pyridinyl,
piperidinyl, or piperazinyl, each of which is optionally
substituted with one, two, three, or four substituents Q.sup.a;
and
[0276] R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e are hydrogen.
[0277] Provide herein is a compound of Formula (XI):
##STR00016##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof; wherein: [0278] R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d,
and R.sup.7e are each independently (a) hydrogen, cyano, halo, or
nitro; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl,
heteroaryl, or heterocyclyl, each of which is optionally
substituted with one, two, three, or four substituents Q.sup.a; or
(c) --C(O)R.sup.a, --C(O)OR.sup.a, --C(O)NR.sup.bR.sup.c,
--C(NR.sup.a)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(.dbd.NR.sup.a)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(.dbd.NR.sup.d)NR.sup.bR.sup.c, --NR.sup.aS(O)R.sup.d,
--NR.sup.aS(O).sub.2R.sup.d, --NR.sup.eS(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, or
--S(O).sub.2NR.sup.bR.sup.c; or two of R.sup.7a, R.sup.7b,
R.sup.7c, R.sup.7d, and R.sup.7e that are adjacent to each other
form C.sub.3-10 cycloalkenyl, C.sub.6-14 aryl, heteroaryl, or
heterocyclyl, each optionally substituted with one, two, three, or
four substituents Q.sup.a; and [0279] R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.6, R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, R.sup.5a,
R.sup.5b, R.sup.5f, R.sup.5g, X, Y, and Z are each as defined
herein.
[0280] In certain embodiments of compounds of Formula (XI),
R.sup.5a and R.sup.5b are each independently (a) halo; (b)
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
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(NR.sup.1a)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(.dbd.NR.sup.1a)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(.dbd.NR.sup.1d)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 R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.3, R.sup.4, R.sup.5f, R.sup.5g, R.sup.6, R.sup.7a,
R.sup.7b, R.sup.7c, R.sup.7d, R.sup.7e, X, Y, Z, R.sup.1a,
R.sup.1b, R.sup.1c, and R.sup.1d are defined herein elsewhere.
[0281] In certain embodiments of compounds of Formula (XI), one of
R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e is C.sub.6-14
aryl, heteroaryl, or heterocyclyl, each of which is optionally
substituted with one, two, three, or four substituents Q.sup.a; in
certain embodiments, one of R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d,
and R.sup.7e is C.sub.6-14 aryl, e.g., phenyl, optionally
substituted with one, two, three, or four substituents Q.sup.a; in
certain embodiments, one of R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d,
and R.sup.7e is heteroaryl, e.g., 5-membered or 6-membered
heteroaryl, optionally substituted with one, two, three, or four
substituents Q.sup.a; in certain embodiments, one of R.sup.7a,
R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e is heterocyclyl, e.g.,
5-membered or 6-membered heterocyclyl, optionally substituted with
one, two, three, or four substituents Q.sup.a; in certain
embodiments, one of R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and
R.sup.7e is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl,
or piperazinyl, each optionally substituted with one, two, three,
or four substituents Q.sup.a; in certain embodiments, one of
R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e is phenyl,
imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl,
piperidinyl, or piperazinyl, each optionally substituted with one,
two, three, or four substituents Q.sup.a; in certain embodiments,
one of R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e is
phenyl, 2-fluorophenyl. 2-chlorophenyl, 2-bromophenyl,
2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl,
3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl,
4-methoxyphenyl, imidazol-1-yl, pyrozol-4-yl,
1-methyl-pyrozol-4-yl, 2-methylpyrazol-3-yl, pyridin-2-yl,
pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl,
2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or
4-methylpiperazin-1-yl; and in certain embodiments, one of
R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e is phenyl,
2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,
2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,
3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl,
4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,
2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,
4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,
pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrazol-3-yl,
pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl,
2-methylpyridin-4-yl, 2-(4-methylpiperazin-1-yl)pyridin-4-yl,
2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl,
1-methylpyrrolidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl,
1-ethylpiperidin-4-yl, 1-isopropylpiperidin-4-yl,
1-acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl, or
4-methylpiperazin-1-yl.
[0282] In certain embodiments of compounds of Formula (XI),
R.sup.7a is C.sub.6-14 aryl, heteroaryl, or heterocyclyl, each of
which is optionally substituted with one, two, three, or four
substituents Q.sup.a; in certain embodiments, R.sup.7a is
C.sub.6-14 aryl, e.g., phenyl, optionally substituted with one,
two, three, or four substituents Q.sup.a; in certain embodiments,
R.sup.7a is heteroaryl, e.g., 5-membered or 6-membered heteroaryl,
optionally substituted with one, two, three, or four substituents
Q.sup.a; in certain embodiments, R.sup.7a is heterocyclyl, e.g.,
5-membered or 6-membered heterocyclyl, optionally substituted with
one, two, three, or four substituents Q.sup.a; in certain
embodiments, R.sup.7a is phenyl, imidazolyl, pyrozolyl, pyridinyl,
piperidinyl, or piperazinyl, each optionally substituted with one,
two, three, or four substituents Q.sup.a, in certain embodiments,
R.sup.7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,
pyrrolidinyl, piperidinyl, or piperazinyl, each optionally
substituted with one, two, three, or four substituents Q.sup.a; in
certain embodiments, R.sup.7a is phenyl, 2-fluorophenyl,
2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl,
3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl,
4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl,
pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrazol-3-yl,
pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl,
2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or
4-methylpiperazin-1-yl; and in certain embodiments, R.sup.1a is
phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl,
2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl,
3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl,
4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,
2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl,
3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl,
imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,
2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,
2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,
2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,
pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,
piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,
1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,
1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.
[0283] In certain embodiments of compounds of Formula (XI),
[0284] R.sup.1 is hydrogen or --OR.sup.1a, where R.sup.1a is
C.sub.1-6 alkyl, optionally substituted with one, two, three, four,
or five substituents Q.sup.a;
[0285] R.sup.2 is hydrogen;
[0286] R.sup.3 and R.sup.4 are hydrogen;
[0287] R.sup.6 is C.sub.1-6 alkyl, optionally substituted with one,
two, three, four, or five substituents Q.sup.a;
[0288] R.sup.5a and R.sup.5b are each independently C.sub.1-6
alkyl, optionally substituted with one, two, three, four, or five
substituents Q.sup.a;
[0289] R.sup.5f and R.sup.5g are each independently hydrogen, halo,
C.sub.1-6 alkyl, optionally substituted with one, two, three, four,
or five substituents Q.sup.a; or R.sup.5f and R.sup.5g together
with the carbon atom to which they are attached form C.sub.1-10
cycloalkyl or heterocyclyl, each of which is optionally substituted
with one, two, three, four, or five substituents Q.sup.a;
[0290] R.sup.7a is C.sub.6-14 aryl, heteroaryl, or heterocyclyl,
each of which is optionally substituted with one, two, three, or
four substituents Q.sup.a;
[0291] R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e are hydrogen;
and
[0292] X, Y, and Z are each independently N or CR.sup.X, with the
proviso that at least two of X, Y, and Z are N; where R.sup.X is a
hydrogen or C.sub.1-6 alkyl, optionally substituted with one, two,
three, or four substituents Q.sup.a.
[0293] In certain embodiments of compounds of Formula (XI),
[0294] R.sup.1 is hydrogen or methoxy;
[0295] R.sup.2 is hydrogen;
[0296] R.sup.3 and R.sup.4 are hydrogen;
[0297] R.sup.6 is C.sub.1-6 alkyl, optionally substituted with one
or more halo;
[0298] R.sup.5a and R.sup.5b are each independently C.sub.1-6
alkyl;
[0299] R.sup.5f and R.sup.5g are each independently hydrogen or
C.sub.1-6 alkyl; or R.sup.5f and R.sup.5g together with the carbon
atom to which they are attached form C.sub.1-10 cycloalkyl;
[0300] R.sup.7a is C.sub.6-14 aryl, heteroaryl, or heterocyclyl,
each of which is optionally substituted with one, two, three, or
four substituents Q.sup.a;
[0301] R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e are hydrogen;
and
[0302] X, Y, and Z are each independently N or CH.
[0303] In certain embodiments of compounds of Formula (XI),
[0304] R.sup.1 is hydrogen or methoxy;
[0305] R.sup.2 is hydrogen;
[0306] R.sup.3 and R.sup.4 are hydrogen;
[0307] R.sup.6 is difluoromethyl;
[0308] R.sup.5a and R.sup.5b are methyl;
[0309] R.sup.5f and R.sup.5g are hydrogen; or R.sup.5f and R.sup.5g
together with the carbon atom to which they are attached form
cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
[0310] R.sup.7a is C.sub.6-14 aryl, monocyclic heteroaryl, or
monocyclic heterocyclyl, each of which is optionally substituted
with one, two, three, or four substituents Q.sup.a;
[0311] R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e are hydrogen;
and
[0312] X, Y, and Z are each independently N or CH.
[0313] In certain embodiments of compounds of Formula (XI),
[0314] R.sup.1 is hydrogen or methoxy;
[0315] R.sup.2 is hydrogen;
[0316] R.sup.3 and R.sup.4 are hydrogen;
[0317] R.sup.6 is difluoromethyl;
[0318] R.sup.5a and R.sup.5b are methyl;
[0319] R.sup.5f and R.sup.5g are hydrogen; or R.sup.5f and R.sup.5g
together with the carbon atom to which they are attached form
cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
[0320] R.sup.7a is phenyl, 5- or 6-membered heteroaryl, or 5- or
6-membered heterocyclyl, each of which is optionally substituted
with one, two, three, or four substituents Q.sup.a;
[0321] R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e are hydrogen;
and
[0322] X, Y, and Z are each independently N or CH.
[0323] In certain embodiments of compounds of Formula (XI),
[0324] R.sup.1 is hydrogen or methoxy;
[0325] R.sup.2 is hydrogen;
[0326] R.sup.3 and R.sup.4 are hydrogen;
[0327] R.sup.6 is difluoromethyl;
[0328] R.sup.5a and R.sup.5b are methyl;
[0329] R.sup.5f and R.sup.5g are hydrogen; or R.sup.5f and R.sup.5g
together with the carbon atom to which they are attached form
cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R.sup.7a is
phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,
pyrrolidinyl, piperidinyl, or piperazinyl, each of which is
optionally substituted with one, two, three, or four substituents
Q.sup.a;
[0330] R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e are hydrogen;
and
[0331] X, Y, and Z are each independently N or CH.
[0332] In certain embodiments of compounds of Formula (XI),
[0333] R.sup.1 is hydrogen or methoxy;
[0334] R.sup.2 is hydrogen;
[0335] R.sup.3 and R.sup.4 are hydrogen;
[0336] R.sup.6 is difluoromethyl;
[0337] R.sup.5a and R.sup.5b are methyl;
[0338] R.sup.5f and R.sup.5g are hydrogen; or R.sup.5f and R.sup.5g
together with the carbon atom to which they are attached form
cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
[0339] R.sup.7a is phenyl, imidazolyl, pyrozolyl, pyridinyl,
piperidinyl, or piperazinyl, each of which is optionally
substituted with one, two, three, or four substituents Q.sup.a;
[0340] R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e are hydrogen;
and
[0341] X, Y, and Z are each independently N or CH.
[0342] Provided herein is a compound of Formula (XVI):
##STR00017##
or an enantiomer, a mixture of enantiomers, a mixture of two or
more diastereomers, or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof; wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6,
R.sup.5a, R.sup.5b, R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and
R.sup.7e are each as defined herein.
[0343] In one embodiment of a compound of Formula (XVI), one of
R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e is C.sub.6-14
aryl, heteroaryl, or heterocyclyl, each of which is optionally
substituted with one, two, three, or four substituents Q.sup.a; and
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.5a, R.sup.5b,
the remaining of R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and
R.sup.7e, X, Y, and Z are each as defined herein.
[0344] In another embodiment of a compound of Formula (XVI), one of
R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e is C.sub.6-14
aryl, which is optionally substituted with one, two, three, or four
substituents Q.sup.a; and R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.6, R.sup.5a, R.sup.5b, the remaining of R.sup.7a, R.sup.7b,
R.sup.7c, R.sup.7d, and R.sup.7e, X, Y, and Z are each as defined
herein.
[0345] In yet another embodiment of a compound of Formula (XVI),
one of R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e is
heteroaryl, which is optionally substituted with one, two, three,
or four substituents Q.sup.a; and R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.6, R.sup.5a, R.sup.5b, the remaining of R.sup.7a,
R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e, X, Y, and Z are each as
defined herein.
[0346] In yet another embodiment of a compound of Formula (XVI),
one of R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e is
5-membered or 6-membered heteroaryl which is optionally substituted
with one, two, three, or four substituents Q.sup.a; and R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.5a, R.sup.5b, the
remaining of R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e,
X, Y, and Z are each as defined herein.
[0347] In yet another embodiment of a compound of Formula (XVI),
one of R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e is
heterocyclyl, which is optionally substituted with one, two, three,
or four substituents Q.sup.a; and R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.6, R.sup.5a, R.sup.5b, the remaining of R.sup.7a,
R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e, X, Y, and Z are each as
defined herein.
[0348] In yet another embodiment of a compound of Formula (XVI),
one of R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e is
5-membered or 6-membered heterocyclyl, which is optionally
substituted with one, two, three, or four substituents Q.sup.a; and
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.5a, R.sup.5b,
the remaining of R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and
R.sup.7e, X, Y, and Z are each as defined herein.
[0349] In yet another embodiment of a compound of Formula (XVI),
one of R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e is
phenyl, imidazolyl, pyrozolyl, pyridyl, piperidinyl, or
piperazinyl, each optionally substituted with one, two, three, or
four substituents Q.sup.a; and R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.6, R.sup.5a, R.sup.5b, the remaining of R.sup.7a, R.sup.7b,
R.sup.7c, R.sup.7d, and R.sup.7e, X, Y, and Z are each as defined
herein.
[0350] In yet another embodiment of a compound of Formula (XVI),
one of R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e is
phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,
pyrrolidinyl, piperidinyl, or piperazinyl, each optionally
substituted with one, two, three, or four substituents Q.sup.a, and
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.5a, R.sup.5b,
the remaining of R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and
R.sup.7e, X, Y, and Z are each as defined herein.
[0351] In yet another embodiment of a compound of Formula (XVI),
one of R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e is
phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl,
2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl,
3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl,
4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,
2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl,
3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl,
imidazol-1-yl, pyrozol-4-yl,
1-methyl-pyrozol-4-yl-2-methylpyrazol-3-yl, pyridin-2-yl,
pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl,
2-methylpyridin-4-yl, 2-(4-methylpiperazin-1-yl)pyridin-4-yl,
2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl,
1-methylpyrrolidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl,
1-ethylpiperidin-4-yl,
1-isopropylpiperidin-4-yl-1-acetylpiperidin-4-yl,
1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.
[0352] In still another embodiment of a compound of Formula (XVI),
one of R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e is
phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl,
2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl. 3-chlorophenyl,
3-methoxyphenyl, 4-fluorophenyl. 4-chlorophenyl, 4-bromophenyl,
4-methoxyphenyl, imidazol-1-yl, pyrozol-4-yl,
1-methyl-pyrozol-4-yl, 2-methylpyrazol-3-yl, pyridin-2-yl,
pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl,
2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or
4-methylpiperazin-1-yl; and R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.6, R.sup.5a, R.sup.5b, the remaining of R.sup.7a, R.sup.7b,
R.sup.7c, R.sup.7d, and R.sup.7e, X, Y, and Z are each as defined
herein.
[0353] In one embodiment of a compound of Formula (XVI), R.sup.1a
is C.sub.6-14 aryl, heteroaryl, or heterocyclyl, each of which is
optionally substituted with one, two, three, or four substituents
Q.sup.a; and R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.5a,
R.sup.5b, R.sup.7b, R.sup.7c, R.sup.7d, R.sup.7e, X, Y, and Z are
each as defined herein.
[0354] In another embodiment of a compound of Formula (XVI),
R.sup.7a is C.sub.6-14 aryl, which is optionally substituted with
one, two, three, or four substituents Q.sup.a; and R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.5a, R.sup.5b, R.sup.7b,
R.sup.7c, R.sup.7d, R.sup.7e, X, Y, and Z are each as defined
herein.
[0355] In yet another embodiment of a compound of Formula (XVI),
R.sup.7a is heteroaryl, which is optionally substituted with one,
two, three, or four substituents Q.sup.a; and R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.6, R.sup.5a, R.sup.5b, R.sup.7bR.sup.7c,
R.sup.7d, R.sup.7e, X, Y, and Z are each as defined herein.
[0356] In yet another embodiment of a compound of Formula (XVI),
R.sup.7a is 5-membered or 6-membered heteroaryl, which is
optionally substituted with one, two, three, or four substituents
Q.sup.a; and R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.5a,
R.sup.5b, R.sup.7b, R.sup.7c, R.sup.d, R.sup.7e, X, Y, and Z are
each as defined herein.
[0357] In yet another embodiment of a compound of Formula (XVI),
R.sup.7a is heterocyclyl, which is optionally substituted with one,
two, three, or four substituents Q.sup.a; and R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.6, R.sup.5a, R.sup.5b, R.sup.7b, R.sup.7c,
R.sup.7d, R.sup.7e, X, Y, and Z are each as defined herein.
[0358] In yet another embodiment of a compound of Formula (XVI),
R.sup.7a is 5-membered or 6-membered heterocyclyl, which is
optionally substituted with one, two, three, or four substituents
Q.sup.a, and R.sup.1, R.sup.2, R.sup.3. R.sup.4, R.sup.6, R.sup.5a,
R.sup.5b, R.sup.7b, R.sup.7c, R.sup.7d, R.sup.7e, X, Y, and Z are
each as defined herein.
[0359] In yet another embodiment of a compound of Formula (XVI),
R.sup.7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl,
or piperazinyl, each optionally substituted with one, two, three,
or four substituents Q.sup.a; and R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.6, R.sup.5a, R.sup.5b, R.sup.7b, R.sup.7c, R.sup.7d,
R.sup.7e, X, Y, and Z are each as defined herein.
[0360] In yet another embodiment of a compound of Formula (XVI),
R.sup.7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,
pyrrolidinyl, piperidinyl, or piperazinyl, each optionally
substituted with one, two, three, or four substituents Q.sup.a; and
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.5a, R.sup.5b,
R.sup.7b, R.sup.7c, R.sup.7d, R.sup.7e, X, Y, and Z are each as
defined herein.
[0361] In yet another embodiment of a compound of Formula (XVI),
R.sup.7a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl,
2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl,
3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl,
4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,
2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl
3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl
imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,
2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,
2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,
2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,
pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,
piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,
1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,
1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.
[0362] In yet another embodiment of a compound of Formula (XVI),
R.sup.7a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl,
2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl,
3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl,
4-methoxyphenyl, imidazol-1-yl, pyrozol-4-yl,
1-methyl-pyrozol-4-yl, 2-methylpyrazol-3-yl, pyridin-2-yl,
pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl,
2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or
4-methylpiperazin-1-yl; and R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.6, R.sup.5a, R.sup.5b, R.sup.7b, R.sup.7c, R.sup.7d,
R.sup.7e, X, Y, and Z are each as defined herein.
[0363] In one embodiment of a compound of Formula (XVI),
[0364] R.sup.1 is hydrogen or --OR.sup.1a, where R.sup.1a is
C.sub.1-6 alkyl, optionally substituted with one, two, three, four,
or five substituents Q.sup.a;
[0365] R.sup.2 is hydrogen.
[0366] R.sup.3 and R.sup.4 are hydrogen;
[0367] R.sup.6 is C.sub.1-6 alkyl, optionally substituted with one,
two, three, four, or five substituents Q.sup.a;
[0368] R.sup.5a and R.sup.5b are each independently C.sub.1-6
alkyl, optionally substituted with one, two, three, four, or five
substituents Q.sup.a;
[0369] R.sup.7a is C.sub.6-14 aryl, heteroaryl, or heterocyclyl,
each of which is optionally substituted with one, two, three, or
four substituents Q.sup.a; and
[0370] R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e are hydrogen.
[0371] In one embodiment of a compound of Formula (XVI),
[0372] R.sup.1 is hydrogen or methoxy;
[0373] R.sup.2 is hydrogen;
[0374] R.sup.3 and R.sup.4 are hydrogen;
[0375] R.sup.6 is C.sub.1-6 alkyl, optionally substituted with one
or more halo;
[0376] R.sup.5a and R.sup.5b are each independently C.sub.1-6
alkyl;
[0377] R.sup.7a is C.sub.6-14 aryl, heteroaryl, or heterocyclyl,
each of which is optionally substituted with one, two, three, or
four substituents Q.sup.a; and
[0378] R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e are hydrogen.
[0379] In one embodiment of a compound of Formula (XVI),
[0380] R.sup.1 is hydrogen or methoxy;
[0381] R.sup.2 is hydrogen;
[0382] R.sup.3 and R.sup.4 are hydrogen;
[0383] R.sup.6 is difluoromethyl;
[0384] R.sup.5a and R.sup.5b are methyl;
[0385] R.sup.7a is C.sub.6-14 aryl, monocyclic heteroaryl, or
monocyclic heterocyclyl, each of which is optionally substituted
with one, two, three, or four substituents Q.sup.a; and R.sup.7b,
R.sup.7c, R.sup.7d, and R.sup.7e are hydrogen.
[0386] In one embodiment of a compound of Formula (XVI),
[0387] R.sup.1 is hydrogen or methoxy;
[0388] R.sup.2 is hydrogen;
[0389] R.sup.3 and R.sup.4 are hydrogen;
[0390] R.sup.6 is difluoromethyl;
[0391] R.sup.5a and R.sup.5b are methyl;
[0392] R.sup.7a is phenyl, 5- or 6-membered heteroaryl, or 5- or
6-membered heterocyclyl, each of which is optionally substituted
with one, two, three, or four substituents Q.sup.a; and
[0393] R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e are hydrogen.
[0394] In one embodiment of a compound of Formula (XVI),
[0395] R.sup.1 is hydrogen or methoxy;
[0396] R.sup.2 is hydrogen.
[0397] R.sup.3 and R.sup.4 are hydrogen;
[0398] R.sup.6 is difluoromethyl;
[0399] R.sup.5a and R.sup.5b are methyl;
[0400] R.sup.7a is phenyl, imidazolyl, pyrozolyl, pyridinyl,
pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of
which is optionally substituted with one, two, three, four, or five
substituents Q.sup.a; and
[0401] R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e are hydrogen.
[0402] In one embodiment of a compound of Formula (XVI),
[0403] R.sup.1 is hydrogen or methoxy;
[0404] R.sup.2 is hydrogen;
[0405] R.sup.3 and R.sup.4 are hydrogen;
[0406] R.sup.6 is difluoromethyl;
[0407] R.sup.5a and R.sup.5b are methyl;
[0408] R.sup.7a is phenyl, imidazolyl, pyrozolyl, pyridinyl,
piperidinyl, or piperazinyl, each of which is optionally
substituted with one, two, three, or four substituents Q.sup.a;
and
[0409] R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e are hydrogen.
[0410] In one embodiment of a compound of Formula (XVI), R.sup.5a
and R.sup.5b are each independently (a) halo; (b) C.sub.1-3 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 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(NR.sup.1a)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(.dbd.NR.sup.1a)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.1c(O)OR.sup.1d,
--NR.sup.1aC(O)NR.sup.1bR.sup.1c,
--NR.sup.1aC(.dbd.NR.sup.1d)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.bR.sup.c; and R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.6, R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d, R.sup.7e,
R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d are defined herein
elsewhere.
[0411] In one embodiment of any of the formulae provided
herein,
R.sup.1 is hydrogen or --OR.sup.1a, where R.sup.1a is C.sub.1-6
alkyl, optionally substituted with one, two, three, four, or five
substituents Q.sup.a; R.sup.2 is hydrogen; R.sup.3 and R.sup.4 are
hydrogen; R.sup.6 is C.sub.1-6 alkyl, optionally substituted with
one, two, three, four, or five substituents Q.sup.a; R.sup.5a and
R.sup.5b are each independently hydrogen or C.sub.1-6 alkyl
optionally substituted with one, two, three, four, or five
substituents Q.sup.a; R.sup.7a is C.sub.6-14 aryl, heteroaryl, or
heterocyclyl, each of which is optionally substituted with one,
two, three, or four substituents Q.sup.a; R.sup.7b, R.sup.7c,
R.sup.7d, and R.sup.7e are hydrogen; and X, Y, and Z are each
independently N or CR.sup.X, with the proviso that at least two of
X, Y, and Z are N; where R.sup.X is a hydrogen or C.sub.1-6 alkyl,
optionally substituted with one, two, three, or four substituents
Q.sup.a.
[0412] In one embodiment of any of the formulae provided
herein,
R.sup.1 is hydrogen or methoxy; R.sup.2 is hydrogen; R.sup.3 and
R.sup.4 are hydrogen; R.sup.6 is C.sub.1-6 alkyl, optionally
substituted with one or more halo; R.sup.5a and R.sup.5b are each
independently hydrogen or C.sub.1-6 alkyl; R.sup.7a is C.sub.6-14
aryl, heteroaryl, or heterocyclyl, each of which is optionally
substituted with one, two, three or four substituents Q.sup.a;
R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e are hydrogen; and X, Y,
and Z are each independently N or CH.
[0413] In one embodiment of any of the formulae provided
herein,
R.sup.1 is hydrogen or methoxy; R.sup.2 is hydrogen; R.sup.3 and
R.sup.4 are hydrogen; R.sup.6 is difluoromethyl, R.sup.5a and
R.sup.5b are each independently hydrogen or C.sub.1-6 alkyl;
R.sup.7a is C.sub.6-14 aryl, monocyclic heteroaryl, or monocyclic
heterocyclyl, each of which is optionally substituted with one,
two, three, or four substituents Q.sup.a; R.sup.7b, R.sup.7c,
R.sup.7d, and R.sup.7e are hydrogen; and X, Y, and Z are each
independently N or CH.
[0414] In one embodiment of any of the formulae provided
herein,
R.sup.1 is hydrogen or methoxy; R.sup.2 is hydrogen; R.sup.3 and
R.sup.1a are hydrogen; R.sup.6 is difluoromethyl; R.sup.5a and
R.sup.5b are each independently hydrogen or C.sub.1-6 alkyl;
R.sup.7a is phenyl, 5- or 6-membered heteroaryl, or 5- or
6-membered heterocyclyl, each of which is optionally substituted
with one, two, three, or four substituents Q.sup.a; R.sup.7b,
R.sup.7c, R.sup.7d, and R.sup.7e are hydrogen; and X, Y, and Z are
each independently N or CH.
[0415] In one embodiment of any of the formulae provided
herein,
R.sup.1 is hydrogen or methoxy; R.sup.2 is hydrogen; R.sup.3 and
R.sup.4 are hydrogen; R.sup.6 is difluoromethyl; R.sup.5a and
R.sup.5b are each independently hydrogen or C.sub.1-6 alkyl;
R.sup.7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,
pyrrolidinyl, piperidinyl, or piperazinyl, each of which is
optionally substituted with one, two, three, or four substituents
Q.sup.a; R.sup.7b, R.sup.7c, R.sup.7d, and R.sup.7e are hydrogen;
and X, Y, and Z are each independently N or CH.
[0416] In one embodiment of any of the formulae provided
herein,
R.sup.1 is hydrogen or methoxy; R.sup.2 is hydrogen; R.sup.3 and
R.sup.4 are hydrogen; R.sup.6 is difluoromethyl; R.sup.5a and
R.sup.5b are each independently hydrogen or C.sub.1-6 alkyl;
R.sup.7a is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl,
or piperazinyl, each of which is optionally substituted with one,
two, three, or four substituents Q.sup.a; R.sup.7b, R.sup.7c,
R.sup.7d, and R.sup.7e are hydrogen; and X, Y, and Z are each
independently N or CH.
[0417] The groups or variables, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.6, R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, R.sup.5e,
R.sup.5f, R.sup.5g, R.sup.7a, R.sup.7b, R.sup.7c, R.sup.7d,
R.sup.7e, m, n, X, Y, and Z in Formulae provided herein, e.g.,
Formulae (I), (IX), (X), (XI), (XVI), are further defined in the
embodiments described herein. All combinations of the embodiments
provided herein for such groups and/or variables are within the
scope of this disclosure.
[0418] In certain embodiments, R.sup.1 is hydrogen. In certain
embodiments, R.sup.1 is cyano. In certain embodiments, R.sup.1 is
halo. In certain embodiments, R.sup.1 is fluoro, chloro, bromo, or
iodo. In certain embodiments, R.sup.1 is nitro. In certain
embodiments, R.sup.1 is C.sub.1-6 alkyl, optionally substituted
with one, two, three, four, or five substituents Q as described
herein. In certain embodiments, R.sup.1 is C.sub.2-6 alkenyl,
optionally substituted with one, two, three, four, or five
substituents Q as described herein. In certain embodiments, R.sup.1
is C.sub.2f alkynyl, optionally substituted with one, two, three,
four, or five substituents Q as described herein. In certain
embodiments, R.sup.1 is C.sub.3-10 cycloalkyl, optionally
substituted with one, two, three, four, or five substituents Q as
described herein. In certain embodiments, R.sup.1 is C.sub.6-14
aryl, optionally substituted with one, two, three, four, or five
substituents Q as described herein. In certain embodiments, R.sup.1
is C.sub.7-15 aralkyl, optionally substituted with one, two, three,
four, or five substituents Q as described herein. In certain
embodiments, R.sup.1 is heteroaryl, optionally substituted with
one, two, three, four, or five substituents Q as described herein.
In certain embodiments, R.sup.1 is heterocyclyl, optionally
substituted with one, two, three, four, or five substituents Q as
described herein.
[0419] 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(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 --OR.sup.1a, wherein R.sup.1a is as defined
herein. In certain embodiments, R.sup.1 is --O--C.sub.1-6 alkyl,
wherein the alkyl is optionally substituted with one, two, three,
four, or five substituents Q as described herein. In certain
embodiments, R.sup.1 is methoxy, ethoxy, propoxy, isopropoxy, or
3-dimethylaminopropoxy. In certain embodiments, R.sup.1 is
--OC(O)R.sup.1a, wherein 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(.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 --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.sup.1b and 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(.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.1aS(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.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.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 --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.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.
[0420] In certain embodiments, R.sup.2 is hydrogen. In certain
embodiments, R.sup.2 is cyano. In certain embodiments, R.sup.2 is
halo. In certain embodiments, R.sup.2 is fluoro, chloro, bromo, or
iodo. In certain embodiments, R.sup.2 is nitro. In certain
embodiments, R.sup.2 is C.sub.1-6 alkyl, optionally substituted
with one, two, three, four, or five substituents Q as described
herein. In certain embodiments, R.sup.2 is C.sub.2-6 alkenyl,
optionally substituted with one, two, three, four, or five
substituents Q as described herein. In certain embodiments, R.sup.2
is C.sub.2-6 alkynyl, optionally substituted with one, two, three,
four, or five substituents Q as described herein. In certain
embodiments, R.sup.2 is C.sub.3-10 cycloalkyl, optionally
substituted with one, two, three, four, or five substituents Q as
described herein. In certain embodiments, R.sup.2 is C.sub.3-7
cycloalkyl, optionally substituted with one, two, three, four, or
five substituents Q as described herein. In certain embodiments,
R.sup.2 is C.sub.6-14 aryl, optionally substituted with one, two,
three, four, or five substituents Q as described herein. In certain
embodiments, R.sup.2 is C.sub.7-15 aralkyl, optionally substituted
with one, two, three, four, or five substituents Q as described
herein. In certain embodiments, R.sup.2 is heteroaryl, optionally
substituted with one, two, three, four, or five substituents Q as
described herein. In certain embodiments, R.sup.2 is heterocyclyl,
optionally substituted with one, two, three, four, or five
substituents Q as described herein.
[0421] 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(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 --OR.sup.1a, wherein R.sup.1a is as defined
herein. In certain embodiments, R.sup.1 is --O--C.sub.1-6 alkyl,
wherein the alkyl is optionally substituted with one, two, three,
four, or five substituents Q as described herein. In certain
embodiments, R.sup.1 is methoxy, ethoxy, propoxy, isopropoxy, or
3-dimethylaminopropoxy. 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.a, 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(.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 --OS(O)R.sup.1a, wherein R.sup.1a is 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)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.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.2 is amino
(--NH.sub.2). 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.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(.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.1aS(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.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.2 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.2 is --SR.sup.1a, wherein R.sup.1a is 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.a, 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.2NR.sup.1bR.sup.1c; wherein
R.sup.1b and R.sup.1c are each as defined herein.
[0422] In certain embodiments, R.sup.3 is hydrogen. In certain
embodiments, R.sup.3 is C.sub.1-6 alkyl, optionally substituted
with one, two, three, four, or five substituents Q as described
herein. In certain embodiments, R.sup.3 is hydrogen, methyl, ethyl,
or propyl (e.g., n-propyl, isopropyl, or 2-isopropyl).
[0423] In certain embodiments, R.sup.1a is hydrogen. In certain
embodiments, R.sup.4 is C.sub.1-6 alkyl, optionally substituted
with one, two, three, four, or five substituents Q as described
herein. In certain embodiments, R.sup.4 is hydrogen, methyl, ethyl,
or propyl (e.g., n-propyl, isopropyl, or 2-isopropyl).
[0424] In certain embodiments, R.sup.3 and R.sup.4 are linked
together to form a bond. In certain embodiments, R.sup.3 and
R.sup.4 are linked together to form C.sub.1-6 alkylene, optionally
substituted with one, two, three, four, or five substituents Q as
described herein. In certain embodiments, R.sup.3 and R.sup.4 are
linked together to form methylene, ethylene, or propylene, each
optionally substituted with one, two, three, four, or five
substituents Q as described herein. In certain embodiments, R.sup.3
and R.sup.4 are linked together to form C.sub.1-6 heteroalkylene,
optionally substituted with one, two, three, four, or five
substituents Q as described herein. In certain embodiments, R.sup.3
and R.sup.4 are linked together to form C.sub.2-6 alkenylene,
optionally substituted with one, two, three, four, or five
substituents Q as described herein. In certain embodiments, R.sup.3
and R.sup.4 are linked together to form C.sub.2-6 heteroalkenylene,
optionally substituted with one, two, three, four, or five
substituents Q as described herein.
[0425] In certain embodiments, R.sup.6 is hydrogen. In certain
embodiments, R.sup.6 is C.sub.1-6 alkyl, optionally substituted
with one, two, three, four, or five substituents Q as described
herein. In certain embodiments, R.sup.6 is C, alkyl, optionally
substituted with one or more, in one embodiment, one, two, or
three, halo. In certain embodiments, R.sup.6 is C.sub.1-6 alkyl,
optionally substituted with one or more, in one embodiment, one,
two, or three, fluoro. In certain embodiments, R.sup.6 is methyl,
fluoromethyl, difluoromethyl, or trifluoromethyl. In certain
embodiments, R.sup.6 is difluoromethyl. In certain embodiments,
R.sup.6 is --S--C.sub.1-6 alkyl, wherein the alkyl is optionally
substituted with one, two, three, four, or five substituents Q as
described herein. In certain embodiments, R.sup.6 is
--S(O)--C.sub.1-6 alkyl, wherein the alkyl is optionally
substituted with one, two, three, four, or five substituents Q as
described herein. In certain embodiments, R.sup.6 is
--SO.sub.2--C.sub.1-6 alkyl, wherein the alkyl is optionally
substituted with one, two, three, four, or five substituents Q as
described herein.
[0426] In certain embodiments, R.sup.5a is hydrogen. In certain
embodiments, R.sup.5a is not hydrogen. In certain embodiments,
R.sup.5a is halo. In certain embodiments, R.sup.5a is fluoro,
chloro, bromo, or iodo. In certain embodiments, R.sup.5a is
C.sub.1-6 alkyl, optionally substituted with one, two, three, four,
or five substituents Q as described herein. In certain embodiments,
R.sup.5a is methyl, ethyl, propyl, or butyl, each optionally
substituted with one, two, three, four, or five substituents Q as
described herein. In certain embodiments, R.sup.5a is methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. In
certain embodiments, R.sup.5a is methyl. In certain embodiments,
R.sup.5a is C.sub.2-6 alkenyl, optionally substituted with one,
two, three, four, or five substituents Q as described herein. In
certain embodiments, R.sup.5a is C.sub.2-6 alkynyl, optionally
substituted with one, two, three, four, or five substituents Q as
described herein. In certain embodiments, R.sup.5a is C.sub.3-10
cycloalkyl, optionally substituted with one, two, three, four, or
five substituents Q as described herein. In certain embodiments,
R.sup.5a is C.sub.3-7 cycloalkyl, optionally substituted with one,
two, three, four, or five substituents Q as described herein. In
certain embodiments, R.sup.5a is C.sub.6-14 aryl, optionally
substituted with one, two, three, four, or five substituents Q as
described herein. In certain embodiments, R.sup.5a is C.sub.7-15
aralkyl, optionally substituted with one, two, three, four, or five
substituents Q as described herein. In certain embodiments, R.sup.5
is heteroaryl, optionally substituted with one, two, three, four,
or five substituents Q as described herein. In certain embodiments,
R.sup.5a is heterocyclyl, optionally substituted with one, two,
three, four, or five substituents Q as described herein.
[0427] In certain embodiments, R.sup.5a is --C(O)R.sup.1a, wherein
R.sup.1a, is as defined herein. In certain embodiments, R.sup.1a is
--C(O)OR.sup.1a, wherein R.sup.1a, is as defined herein. In certain
embodiments, R.sup.5a is --C(O)OR.sup.1a, wherein R.sup.1a is
C.sub.1-6 alkyl, optionally substituted with one, two, three, four,
or five substituents Q as described herein. In certain embodiments,
R.sup.5a is --C(O)OCH.sub.3. In certain embodiments, R.sup.5a 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.1a 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.5a is --OR.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.1a is --OC(O)R.sup.1a, wherein R.sup.1a
is as defined herein. In certain embodiments, R.sup.5a is
--OC(O)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.5a 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.5a 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.5a is --OS(O)R.sup.1a, wherein R.sup.1a
is as defined herein. In certain embodiments, R.sup.5a is
--OS(O).sub.2R.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.5a 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.5a 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.5a is --NR.sup.1bR.sup.1c, wherein R.sup.1b and
R.sup.1c are each as defined herein. In certain embodiments,
R.sup.5a is amino (--NH.sub.2). In certain embodiments, R.sup.5a 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.5a 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.5a 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.5a is --NR.sup.1c(.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.5a 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.5a 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.5a 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.5a 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.5a is --SR.sup.1a, wherein R.sup.1a is
as defined herein. In certain embodiments, R.sup.5a is
--S(O)R.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.5a is --S(O).sub.2R.sup.1a, wherein R.sup.1a is
as defined herein. In certain embodiments, R.sup.5a 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.5a is
--S(O).sub.2NR.sup.1bR.sup.1c; wherein R.sup.1b and R.sup.1c are
each as defined herein.
[0428] In certain embodiments, R.sup.5a is (a) hydrogen or halo;
(b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, or
heteroaryl, each of which is optionally substituted with one, two,
three, four, or five substituents Q.sup.a; or (c) --C(O)R.sup.1a,
--C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c,
--C(NR.sup.1a)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(.dbd.NR.sup.1a)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(.dbd.NR.sup.1d)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.a, --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. In certain embodiments, R.sup.5a is
(a) hydrogen or halo; or (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, or heteroaryl, each of which is optionally
substituted with one, two, three, four, or five substituents Q.
[0429] In certain embodiments, R.sup.5b is halo. In certain
embodiments, R.sup.5b is fluoro, chloro, bromo, or iodo. In certain
embodiments, R.sup.5b is C.sub.1-6 alkyl, optionally substituted
with one, two, three, four, or five substituents Q as described
herein. In certain embodiments, R.sup.5b is methyl, ethyl, propyl,
or butyl, each optionally substituted with one, two, three, four,
or five substituents Q as described herein. In certain embodiments,
R.sup.5b is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
or t-butyl. In certain embodiments, R.sup.5b is methyl. In certain
embodiments, R.sup.5b is C.sub.2-6 alkenyl, optionally substituted
with one, two, three, four, or five substituents Q as described
herein. In certain embodiments, R.sup.5b is C.sub.2-6 alkynyl,
optionally substituted with one, two, three, four, or five
substituents Q as described herein. In certain embodiments,
R.sup.5b is C.sub.3-10 cycloalkyl, optionally substituted with one,
two, three, four, or five substituents Q as described herein. In
certain embodiments, R.sup.5b is C.sub.3-7 cycloalkyl, optionally
substituted with one, two, three, four, or five substituents Q as
described herein. In certain embodiments, R.sup.5b is C.sub.6-14
aryl, optionally substituted with one, two, three, four, or five
substituents Q as described herein. In certain embodiments,
R.sup.5b is C.sub.7-15 aralkyl, optionally substituted with one,
two, three, four, or five substituents Q as described herein. In
certain embodiments, R.sup.5b is heteroaryl, optionally substituted
with one, two, three, four, or five substituents Q as described
herein. In certain embodiments, R.sup.5b is heterocyclyl,
optionally substituted with one, two, three, four, or five
substituents Q as described herein. In certain embodiments,
R.sup.5b is not heterocyclyl.
[0430] In certain embodiments, R.sup.5b is --C(O)R.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.5b is
--C(O)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.5b is --C(O)OR.sup.1a, wherein R.sup.1a is
C.sub.1-6 alkyl, optionally substituted with one, two, three, four,
or five substituents Q as described herein. In certain embodiments,
R.sup.5b is --C(O)OCH.sub.3. In certain embodiments, R.sup.5b 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.5b 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.5b is --OR.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.5b is --OC(O)R.sup.1a, wherein R.sup.1a
is as defined herein. In certain embodiments, R.sup.5b is
--OC(O)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.5b 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.5b 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.5b is --OS(O)R.sup.1a, wherein R.sup.1a
is as defined herein. In certain embodiments, R.sup.5b is
--OS(O).sub.2R.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.5b 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.5b 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.5b is --NR.sup.1bR.sup.1c, wherein R.sup.1b and
R.sup.1c are each as defined herein. In certain embodiments,
R.sup.5b is amino (--NH.sub.2). In certain embodiments, R.sup.5b 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.5b 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.5b 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.1b 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.5b 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.5b 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.5b 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.5b 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.1b is --SR.sup.1a, wherein R.sup.1a is
as defined herein. In certain embodiments, R.sup.1b is
--S(O)R.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.1b is --S(O).sub.2R.sup.1a, wherein R.sup.1a is
as defined herein. In certain embodiments, R.sup.5b 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.5b is
--S(O).sub.2NR.sup.1bR.sup.1c; wherein R.sup.1b and R.sup.1c are
each as defined herein.
[0431] In certain embodiments, R.sup.1a and R.sup.1b are each
independently methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, or t-butyl, each optionally substituted with one, two,
three, four, or five substituents Q as described herein. In certain
embodiments, R.sup.5a and R.sup.5b are each independently methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl, each
optionally substituted with one or more halo. In certain
embodiments, R.sup.5a and R.sup.5b are each independently methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. In
certain embodiments, R.sup.5a and R.sup.5b are each methyl.
[0432] In certain embodiments, R.sup.5c is C.sub.6-14 aryl,
optionally substituted with one, two, three, four, or five
substituents Q as described herein. In certain embodiments,
R.sup.5b is C.sub.6-14 aryl substituted at the 2-position with one
substituent Q as described herein. In certain embodiments, R.sup.5c
is phenyl or naphthyl, each optionally substituted with one, two,
three, four, or five substituents Q as described herein. In certain
embodiments, R.sup.5c is phenyl, naphtha-1-yl, or naphtha-2-yl,
each optionally substituted with one, two, three, four, or five
substituents Q as described herein. In certain embodiments,
R.sup.5c is phenyl, 4-chlorophenyl, 4-methoxyphenyl, or
naphtha-2-yl. In certain embodiments, R.sup.5c is heteroaryl,
optionally substituted with one or more substituents as described
herein. In certain embodiments, R.sup.5c is monocyclic heteroaryl,
optionally substituted with one or more substituents as described
herein. In certain embodiments. R.sup.5c is 5- or 6-membered
heteroaryl, optionally substituted with one or more substituents as
described herein. In certain embodiments, R.sup.5c is bicyclic
heteroaryl, optionally substituted with one or more substituents as
described herein.
[0433] In certain embodiments, R.sup.5c is
--(CR.sup.5fR.sup.5g)--(C.sub.6-14 aryl), wherein the C.sub.6-14
aryl is optionally substituted with one, two, three, four, or five
substituents Q as described herein. In certain embodiments,
R.sup.5c is benzyl, 2-phenethyl, 3-phenylpropyl, or 4-phenylbutyl,
wherein each of the phenyl moiety is optionally substituted with
one, two, three, four, or five substituents Q as described herein.
In certain embodiments, R.sup.5c is benzyl, 2-phenethyl,
3-phenylpropyl, or 4-phenylbutyl. In certain embodiments, R.sup.5c
is benzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, cyanobenzyl,
methylbenzyl, or methoxybenzyl. In certain embodiments, R.sup.5c is
(naphthalen-1-yl)methyl, (naphthalen-2-yl)methyl
2-(naphthalen-1-yl)ethyl, 2-(naphthalen-2-yl)ethyl,
3-(naphthalen-1-yl)propyl, 3-(naphthalen-2-yl)propyl,
4-(naphthalen-1-yl)butyl, or 4-(naphthalen-2-yl)butyl, wherein each
of the naphthyl moiety is optionally substituted with one, two,
three, four, or five substituents Q as described herein. In certain
embodiments, n is 0 or 1. In one embodiment, n is 1. In one
embodiment, n is 1, 2, 3, or 4. In certain embodiments, R.sup.5c
is-CH.sub.2, --(C.sub.6-14 aryl), wherein the C.sub.6-14 aryl is
optionally substituted with one, two, three, four, or five
substituents Q as described herein. In certain embodiments,
R.sup.5c is --C(CH.sub.3).sub.2--(C.sub.6-14 aryl), wherein the
C.sub.6-14 aryl is optionally substituted with one, two, three,
four, or five substituents Q as described herein. In certain
embodiments, R.sup.5c is --CH.sub.2-phenyl or --CH.sub.2-naphthyl,
wherein the phenyl or naphthyl is each optionally substituted with
one, two, three, four, or five substituents Q as described herein,
such as, e.g., optionally substituted with one or more F, Cl, Br,
I, --CN, --CH.sub.3, --CF.sub.3, --OCH.sub.3, or --OCF.sub.3. In
certain embodiments, R.sup.5c is --CH.sub.2-- phenyl,
--CH.sub.2-naphtha-1-yl, or --CH.sub.2-naphtha-2-yl, wherein the
phenyl or naphthyl is each optionally substituted with one, two,
three, four, or five substituents Q as described herein, such as,
e.g., optionally substituted with one or more F, Cl, Br, I, --CN,
--CH.sub.3, --CF.sub.3, --OCH.sub.3, or --OCF.sub.3. In certain
embodiments, R.sup.5c is --CH.sub.2-phenyl,
--CH.sub.2-naphtha-1-yl, or --CH.sub.2-naphtha-2-yl, wherein the
phenyl or naphthyl is each optionally substituted with one or more
F, Cl, Br, I, --CN, --CH.sub.3, --CF.sub.3, --OCH.sub.3,
--OCF.sub.3. In other embodiments. R.sup.5c is --CH.sub.2-phenyl,
--CH.sub.2-naphtha-1-yl, or --CH.sub.2-naphtha-2-yl, wherein the
phenyl or naphthyl is each optionally substituted with one or more
F, Cl, Br, I, --CN, --CH.sub.3, --CF.sub.3, --OCH.sub.3,
--OCF.sub.3, --O--(C.sub.1-4 alkylene)-N--(C.sub.1-4 alkyl).sub.2
(e.g., --O--CH.sub.2CH.sub.2--N(CH.sub.3).sub.2), --O-heterocyclyl
(e.g., --O--(N-methylpiperidinyl) or --O-piperidinyl),
--O-heteroaryl (e.g., --O-pyridyl), --NH-heterocyclyl (e.g.,
--NH--(N-methylpiperidinyl), --NH--(N-methylpyrrolidinyl),
--NH-piperidinyl, or --NH-pyrrolidinyl), --NH-- heteroaryl (e.g.,
--NH-pyridyl), --NCH.sub.3-heterocyclyl(e.g.,
--NCH.sub.3--(N-methylpiperidinyl),
--NCH.sub.3--(N-methylpyrrolidinyl), --NCH.sub.3-piperidinyl, or
--NCH.sub.3-pyrrolidinyl), --NCH.sub.3-heteroaryl (e.g.,
--NCH.sub.3-pyridyl), heterocyclyl (e.g., piperidinyl, piperazinyl,
N-methylpiperidinyl, or N-methylpiperazinyl), or heteroaryl (e.g.,
pyridyl or imidazolyl). In certain embodiments, R.sup.5c is
--CH.sub.2-phenyl, --C(CH.sub.3).sub.2-phenyl,
--CH.sub.2-(2-methylphenyl), --CH.sub.2-(2-methoxyphenyl),
--CH.sub.2-(2-fluorophenyl), --CH.sub.2-(2-chlorophenyl),
--CH.sub.2-(2-bromophenyl), --CH.sub.2--CH.sub.3-methylphenyl),
--CH.sub.2-(3-methoxyphenyl), --CH.sub.2-(3-fluorophenyl),
--CH.sub.2-(3-chlorophenyl), --CH.sub.2-(3-bromophenyl),
--CH.sub.2-(4-methylphenyl), --CH.sub.2--CH.sub.3-methoxyphenyl),
--CH.sub.2-(4-fluorophenyl), --CH.sub.2-(4-chlorophenyl),
--CH.sub.2-(4-bromophenyl), --CH.sub.2-naphtha-1-yl, or
--CH.sub.2-naphtha-2-yl.
[0434] In certain embodiments, R.sup.5c is
--(CR.sup.5fR.sup.5g)--(C.sub.6-14 aryl), wherein the C.sub.6-14
aryl is optionally substituted with one, two, three, four, or five
substituents Q as described herein, and wherein R.sup.5f and
R.sup.5g together with the carbon atom to which they are attached
form a 3- to 6-membered cycloalkyl or heterocyclyl. In one
embodiment, R.sup.5c is -cyclopropyl-phenyl. In one embodiment,
R.sup.5c is -cyclobutyl-phenyl. In one embodiment, R.sup.5c is
-cyclopentyl-phenyl. In one embodiment, R.sup.5c is
-cyclohexyl-phenyl.
[0435] In certain embodiments, R.sup.5c is
--(CR.sup.5fR.sup.5g).sub.n-heteroaryl, wherein the heteroaryl is
optionally substituted with one, two, three, four, or five
substituents Q as described herein, wherein n is defined herein
elsewhere. In certain embodiments, R.sup.5c is
--CH.sub.2-(monocyclic heteroaryl), wherein the heteroaryl is
optionally substituted with one or more substituents as described
herein. In certain embodiments, R.sup.5c is --CH.sub.2-(5- or
6-membered heteroaryl), wherein the heteroaryl is optionally
substituted with one or more substituents as described herein. In
certain embodiments, R.sup.5c is --CH.sub.2-(bicyclic heteroaryl),
wherein the heteroaryl is optionally substituted with one or more
substituents as described herein.
[0436] In certain embodiments, R.sup.5d is hydrogen. In certain
embodiments, R.sup.5d is halo. In certain embodiments, R.sup.5d is
fluoro, chloro, bromo, or iodo. In certain embodiments, R.sup.5d is
C.sub.1-6 alkyl, optionally substituted with one, two, three, four,
or five substituents Q as described herein. In certain embodiments,
R.sup.5d is methyl, optionally substituted with one, two, three,
four, or five substituents Q as described herein. In certain
embodiments, R.sup.5d is methyl. In certain embodiments, R.sup.5d
is methyl, ethyl, propyl, or butyl, each optionally substituted
with one, two, three, four, or five substituents Q as described
herein. In certain embodiments, R.sup.5d is methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. In certain
embodiments. R.sup.5d is C.sub.2-6 alkenyl, optionally substituted
with one, two, three, four, or five substituents Q as described
herein. In certain embodiments, R.sup.5d is C.sub.2-6 alkynyl,
optionally substituted with one, two, three, four, or five
substituents Q as described herein. In certain embodiments,
R.sup.5d is C.sub.3-10 cycloalkyl, optionally substituted with one,
two, three, four, or five substituents Q as described herein. In
certain embodiments, R.sup.5d is C.sub.2-6 aryl, optionally
substituted with one, two, three, four, or five substituents Q as
described herein. In certain embodiments, R.sup.5d is C.sub.7-15
aralkyl, optionally substituted with one, two, three, four, or five
substituents Q as described herein. In certain embodiments,
R.sup.5d is heteroaryl, optionally substituted with one, two,
three, four, or five substituents Q as described herein. In certain
embodiments, R.sup.5d is heterocyclyl, optionally substituted with
one, two, three, four, or five substituents Q as described
herein.
[0437] In certain embodiments, R.sup.5d is --C(O)R.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.5d is
--C(O)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.5d is --C(O)ORB, wherein R.sup.1a is C.sub.1-6
alkyl, optionally substituted with one, two, three, four, or five
substituents Q as described herein. In certain embodiments,
R.sup.5d is --C(O)OCH.sub.3. In certain embodiments, R.sup.5d 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.5d 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.5d is --OR.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.5d is --OC(O)R.sup.1a, wherein R.sup.1a
is as defined herein. In certain embodiments, R.sup.5d is
--OC(O)OR.sup.1a, wherein R.sup.a is as defined herein. In certain
embodiments, R.sup.5d 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.5d 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.5d is --OS(O)R.sup.1a, wherein R.sup.1a
is as defined herein. In certain embodiments, R.sup.5d is
--OS(O).sub.2R.sup.1, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.5d 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.5d 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.5d is --NR.sup.1bR.sup.1c, wherein R.sup.1b and
R.sup.1c are each as defined herein. In certain embodiments,
R.sup.5d is amino (--NH.sub.2). In certain embodiments, R.sup.5d 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.1d 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.5d 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.5d 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.5d 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.5d 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.5d 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.5d is --NR.sup.1aS(O).sub.2NR.sup.1bR.sup.1c, wherein
R.sup.1a, R.sup.1b, and R.sup.1 are each as defined herein. In
certain embodiments, R.sup.5d is-SR.sup.1a, wherein R.sup.1a is as
defined herein. In certain embodiments, R.sup.5d is --S(O)R.sup.1a,
wherein R.sup.1a is as defined herein. In certain embodiments,
R.sup.5d is --S(O).sub.2R.sup.a, wherein R.sup.1a is as defined
herein. In certain embodiments, R.sup.5d 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.5d is
--S(O).sub.2NR.sup.1bR.sup.1c; wherein R.sup.1b and R.sup.1c are
each as defined herein.
[0438] In certain embodiments, R.sup.5e is hydrogen. In certain
embodiments, R.sup.5e is halo. In certain embodiments, R.sup.5e is
fluoro, chloro, bromo, or iodo. In certain embodiments, R.sup.5e is
C.sub.1-6 alkyl, optionally substituted with one, two, three, four,
or five substituents Q as described herein. In certain embodiments,
R.sup.5e is methyl, optionally substituted with one, two, three,
four, or five substituents Q as described herein. In certain
embodiments, R.sup.5e is methyl. In certain embodiments, R.sup.e is
methyl, ethyl, propyl, or butyl, each optionally substituted with
one, two, three, four, or five substituents Q as described herein.
In certain embodiments. R.sup.5e is methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, or t-butyl. In certain embodiments.
R.sup.5e is C.sub.2-6 alkenyl, optionally substituted with one,
two, three, four, or five substituents Q as described herein. In
certain embodiments, R.sup.5e is C.sub.2-6 alkynyl, optionally
substituted with one, two, three, four, or five substituents Q as
described herein. In certain embodiments, R.sup.5e is C.sub.3-10
cycloalkyl, optionally substituted with one, two, three, four, or
five substituents Q as described herein. In certain embodiments,
R.sup.5e is C.sub.6-14 aryl, optionally substituted with one, two,
three, four, or five substituents Q as described herein. In certain
embodiments, R.sup.5e is C.sub.7-15 aralkyl, optionally substituted
with one, two, three, four, or five substituents Q as described
herein. In certain embodiments, R.sup.5e is heteroaryl, optionally
substituted with one, two, three, four, or five substituents Q as
described herein. In certain embodiments, R.sup.5e is heterocyclyl,
optionally substituted with one, two, three, four, or five
substituents Q as described herein.
[0439] In certain embodiments, R.sup.5e is --C(O)R.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.5e is
--C(O)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.1a is --C(O)OR.sup.1a, wherein R.sup.1a is
C.sub.1-6 alkyl, optionally substituted with one, two, three, four,
or five substituents Q as described herein. In certain embodiments,
R.sup.5e is --C(O)OCH.sub.3. In certain embodiments, R.sup.5e 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.5e 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.5e is --OR.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.5e is --OC(O)R.sup.1a, wherein R.sup.1a
is as defined herein. In certain embodiments, R.sup.5e is
--OC(O)OR.sup.1a, wherein R.sup.1a, is as defined herein. In
certain embodiments, R.sup.5e 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.5e 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.5e is --OS(O)R.sup.1a,
wherein R.sup.1a is as defined herein. In certain embodiments,
R.sup.5e is --OS(O).sub.2R.sup.1a, wherein R.sup.1a is as defined
herein. In certain embodiments, R.sup.5e 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.5e 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.5e is
--NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are each as
defined herein. In certain embodiments, R.sup.5e is amino
(--NH.sub.2). In certain embodiments, R.sup.5e 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.5e 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.5e 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.5c 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.1a 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.5e 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.5e 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.5e 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.5e is --SR.sup.1a, wherein R.sup.1a is
as defined herein. In certain embodiments, R.sup.5e is
--S(O)R.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.5e is --S(O).sub.2R.sup.1a, wherein R.sup.1a is
as defined herein. In certain embodiments, R.sup.5e 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.5c is
--S(O).sub.2NR.sup.1bR.sup.1c; wherein R.sup.1b and R.sup.1c are
each as defined herein.
[0440] In certain embodiments, R.sup.5f is hydrogen. In certain
embodiments, R.sup.5f is halo. In certain embodiments, R.sup.5f is
fluoro, chloro, bromo, or iodo. In certain embodiments, R.sup.5f is
C.sub.1-6 alkyl, optionally substituted with one, two, three, four,
or five substituents Q as described herein. In certain embodiments,
R.sup.5f is methyl, optionally substituted with one, two, three,
four, or five substituents Q as described herein. In certain
embodiments, R.sup.5f is methyl. In certain embodiments, R.sup.5f
is methyl, ethyl, propyl, or butyl, each optionally substituted
with one, two, three, four, or five substituents Q as described
herein. In certain embodiments, R.sup.5f is methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. In certain
embodiments, R.sup.5f is C.sub.2-6 alkenyl, optionally substituted
with one, two, three, four, or five substituents Q as described
herein. In certain embodiments, R.sup.5f is C.sub.2-6 alkynyl,
optionally substituted with one, two, three, four, or five
substituents Q as described herein. In certain embodiments,
R.sup.5f is C.sub.3-10 cycloalkyl, optionally substituted with one,
two, three, four, or five substituents Q as described herein. In
certain embodiments, R.sup.5f is C.sub.6-14 aryl, optionally
substituted with one, two, three, four, or five substituents Q as
described herein. In certain embodiments, R.sup.5f is C.sub.7-15
aralkyl, optionally substituted with one, two, three, four, or five
substituents Q as described herein. In certain embodiments,
R.sup.5f is heteroaryl, optionally substituted with one, two,
three, four, or five substituents Q as described herein. In certain
embodiments, R.sup.5f is heterocyclyl, optionally substituted with
one, two, three, four, or five substituents Q as described
herein.
[0441] In certain embodiments, R.sup.5f is --C(O)R.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.5f is
--C(O)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.5f is --C(O)OR.sup.1a, wherein R.sup.1a is
C.sub.1-6 alkyl, optionally substituted with one, two, three, four,
or five substituents Q as described herein. In certain embodiments,
R.sup.5f is --C(O)OCH.sub.3. In certain embodiments, R.sup.5f 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.5f 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.5f is --OR.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.5f is --OC(O)R.sup.1a, wherein R.sup.1a
is as defined herein. In certain embodiments, R.sup.5f is
--OC(O)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.5f 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.5f is --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, wherein
R.sup.1a, R.sup.1b, and R.sup.5f are each as defined herein. In
certain embodiments, R.sup.5f is --OS(O)R.sup.1a, wherein R.sup.1a
is as defined herein. In certain embodiments, R.sup.5f is
--OS(O).sub.2R.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.5f 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.5f 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.5f is --NR.sup.1bR.sup.1c, wherein R.sup.1b and
R.sup.1c are each as defined herein. In certain embodiments,
R.sup.5f is amino (--NH.sub.2). In certain embodiments, R.sup.5f 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.5f 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.5f 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.f 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.5f 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.5f 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.5f 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.5f 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.5f is --SR.sup.1a, wherein R.sup.1a is
as defined herein. In certain embodiments, R.sup.5f is
--S(O)R.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.5f is --S(O).sub.2R.sup.1a, wherein R.sup.1a is
as defined herein. In certain embodiments, R.sup.5f 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.5f is
--S(O).sub.2NR.sup.1bR.sup.1c, wherein R.sup.1b and R.sup.1c are
each as defined herein.
[0442] In certain embodiments, R.sup.5g is hydrogen. In certain
embodiments, R.sup.5g is halo. In certain embodiments, R.sup.5g is
fluoro, chloro, bromo, or iodo. In certain embodiments, R.sup.5g is
C alkyl, optionally substituted with one, two, three, four, or five
substituents Q as described herein. In certain embodiments,
R.sup.5g is methyl, optionally substituted with one, two, three,
four, or five substituents Q as described herein. In certain
embodiments, R.sup.5g is methyl. In certain embodiments, RU is
methyl, ethyl, propyl, or butyl, each optionally substituted with
one, two, three, four, or five substituents Q as described herein.
In certain embodiments, R.sup.5g is methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, or t-butyl. In certain embodiments,
R.sup.5g is C.sub.2-6 alkenyl, optionally substituted with one,
two, three, four, or five substituents Q as described herein. In
certain embodiments, R.sup.5g is C.sub.2-6 alkynyl, optionally
substituted with one, two, three, four, or five substituents Q as
described herein. In certain embodiments, R.sup.5g is C.sub.3-10
cycloalkyl, optionally substituted with one, two, three, four, or
five substituents Q as described herein. In certain embodiments,
R.sup.5g is C.sub.6-14 aryl, optionally substituted with one, two,
three, four, or five substituents Q as described herein. In certain
embodiments, R.sup.5g is C.sub.7-15 aralkyl, optionally substituted
with one, two, three, four, or five substituents Q as described
herein. In certain embodiments, R.sup.5g is heteroaryl, optionally
substituted with one, two, three, four, or five substituents Q as
described herein. In certain embodiments, R.sup.5g is heterocyclyl,
optionally substituted with one, two, three, four, or five
substituents Q as described herein.
[0443] In certain embodiments, R.sup.5g is --C(O)R.sup.1a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.5g is
--C(O)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.5g is --C(O)OR.sup.1a, wherein R.sup.1a is
C.sub.1-6 alkyl, optionally substituted with one, two, three, four,
or five substituents Q as described herein. In certain embodiments,
R.sup.5g is --C(O)OCH.sub.3. In certain embodiments, R.sup.3g 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.5g 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.5g is --OR.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.5g is --OC(O)R.sup.1a, wherein R.sup.1a
is as defined herein. In certain embodiments, R.sup.5g is
--OC(O)OR.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.5g 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.5g 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.5g is --OS(O)R.sup.1a, wherein R.sup.1a is as
defined herein. In certain embodiments, R.sup.5g is
--OS(O).sub.2R.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.5g 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.5g 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.5g is --NR.sup.1bR.sup.1c, wherein R.sup.1b and
R.sup.1c are each as defined herein. In certain embodiments,
R.sup.5g is amino (--NH.sub.2). In certain embodiments, R.sup.5g 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.5a 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.5g 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.5g 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.5g 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.5g 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.5g 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.5g 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.5g is --SR.sup.1a, wherein R.sup.1a is
as defined herein. In certain embodiments, R.sup.5g is
--S(O)R.sup.1a, wherein R.sup.1a is as defined herein. In certain
embodiments, RR is --S(O).sub.2R.sup.1a, wherein R.sup.1a is as
defined herein. In certain embodiments, R.sup.5g 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.5g is
--S(O).sub.2NR.sup.1bR.sup.1c; wherein R.sup.1b and R.sup.1c are
each as defined herein.
[0444] In certain embodiments, when one occurrence of R.sup.5f and
one occurrence of R.sup.5g are attached to the same carbon atom,
the R.sup.5f and R.sup.5g together with the carbon atom to which
they are attached form a C.sub.3-10 cycloalkyl, optionally
substituted with one, two, three, four, or five substituents Q as
described herein. In certain embodiments, when one occurrence of
R.sup.5f and one occurrence of RU are attached to the same carbon
atom, the R.sup.5f and R.sup.5g together with the carbon atom to
which they are attached form a C.sub.3-7 cycloalkyl, optionally
substituted with one, two, three, four, or five substituents Q as
described herein. In certain embodiments, when one occurrence of
R.sup.5f and one occurrence of RR are attached to the same carbon
atom, the R.sup.5f and R.sup.5g together with the carbon atom to
which they are attached form a cyclopropyl, optionally substituted
with one, two, three, four, or five substituents Q as described
herein. In certain embodiments, when one occurrence of R.sup.5f and
one occurrence of R.sup.5g are attached to the same carbon atom,
the R.sup.5f and R.sup.5g together with the carbon atom to which
they are attached form a cyclobutyl, optionally substituted with
one, two, three, four, or five substituents Q as described herein.
In certain embodiments, when one occurrence of R.sup.5f and one
occurrence of R.sup.5g are attached to the same carbon atom, the
R.sup.5f and R.sup.5g together with the carbon atom to which they
are attached form a cyclopentyl, optionally substituted with one,
two, three, four, or five substituents Q as described herein. In
certain embodiments, when one occurrence of R.sup.5f and one
occurrence of R are attached to the same carbon atom, the R.sup.5f
and R.sup.5g together with the carbon atom to which they are
attached form a cyclohexyl, optionally substituted with one, two,
three, four, or five substituents Q as described herein. In certain
embodiments, when one occurrence of R.sup.5f and one occurrence of
R.sup.5g are attached to the same carbon atom, the R.sup.5f and
R.sup.5g together with the carbon atom to which they are attached
form a cycloheptyl, optionally substituted with one, two, three,
four, or five substituents Q as described herein. In certain
embodiments, when one occurrence of R.sup.5f and one occurrence of
R.sup.5g are attached to the same carbon atom, the R.sup.5f and
R.sup.5g together with the carbon atom to which they are attached
form a cyclopropyl.
[0445] In certain embodiments, when one occurrence of R.sup.5f and
one occurrence of R are attached to the same carbon atom, the
R.sup.5f and R.sup.5g together with the carbon atom to which they
are attached form a heterocyclyl, optionally substituted with one,
two, three, four, or five substituents Q as described herein. In
certain embodiments, when one occurrence of R.sup.5f and one
occurrence of R.sup.5g are attached to the same carbon atom, the
R.sup.5f and R.sup.5g together with the carbon atom to which they
are attached form a 3-membered heterocyclyl, optionally substituted
with one, two, three, four, or five substituents Q as described
herein. In certain embodiments, when one occurrence of R.sup.5f and
one occurrence of R.sup.5g are attached to the same carbon atom,
the R.sup.5f and R.sup.5g together with the carbon atom to which
they are attached form a 4-membered heterocyclyl, optionally
substituted with one, two, three, four, or five substituents Q as
described herein. In certain embodiments, when one occurrence of
R.sup.5f and one occurrence of R.sup.5g are attached to the same
carbon atom, the R.sup.5f and R.sup.5g together with the carbon
atom to which they are attached form a 5-membered heterocyclyl,
optionally substituted with one, two, three, four, or five
substituents Q as described herein. In certain embodiments, when
one occurrence of R.sup.5f and one occurrence of R.sup.5g are
attached to the same carbon atom, the R.sup.5f and R.sup.5g
together with the carbon atom to which they are attached form a
6-membered heterocyclyl, optionally substituted with one, two,
three, four, or five substituents Q as described herein.
[0446] In certain embodiments, R.sup.7a is hydrogen. In certain
embodiments, R.sup.7a is cyano. In certain embodiments, R.sup.7a is
halo. In certain embodiments, R.sup.7a is fluoro, chloro, bromo, or
iodo. In certain embodiments. R.sup.7a is nitro. In certain
embodiments, R.sup.7a is C.sub.1-6 alkyl, optionally substituted
with one, two, three, or four substituents Q.sup.a as described
herein. In certain embodiments, R.sup.7a is C.sub.2-6 alkenyl,
optionally substituted with one, two, three, or four substituents
Q.sup.a as described herein. In certain embodiments, R.sup.7a is
C.sub.2-6 alkynyl, optionally substituted with one, two, three, or
four substituents Q.sup.a as described herein. In certain
embodiments, R.sup.1a is C.sub.3-7 cycloalkyl, optionally
substituted with one, two, three, or four substituents Q.sup.a as
described herein. In certain embodiments, R.sup.1 is C.sub.3-10
cycloalkyl, optionally substituted with one, two, three, or four
substituents Q.sup.a as described herein. In certain embodiments,
R.sup.7a is C.sub.6-14 aryl, optionally substituted with one, two,
three, or four substituents Q.sup.a as described herein. In certain
embodiments, R.sup.7a is phenyl, optionally substituted with one,
two, three, or four substituents Q.sup.2 as described herein. In
certain embodiments, R.sup.7a is phenyl, optionally substituted
with one or more substituents, each of which is selected
independently from the group consisting of fluoro, chloro, bromo,
methyl, and methoxy. In certain embodiments, R.sup.7a is phenyl,
2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,
2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl,
4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl. In
certain embodiments, R.sup.7a is C.sub.7-15 aralkyl, optionally
substituted with one, two, three, or four substituents Q.sup.a as
described herein. In certain embodiments, R.sup.7a is heteroaryl,
optionally substituted with one, two, three, or four substituents
Q.sup.a as described herein. In certain embodiments, R.sup.7a is
monocyclic heteroaryl, optionally substituted with one, two, three,
or four substituents Q.sup.a as described herein. In certain
embodiments, R.sup.7a is 5-membered heteroaryl, optionally
substituted with one, two, three, or four substituents Q.sup.a as
described herein. In certain embodiments, R.sup.7a is imidazolyl or
pyrozolyl, optionally substituted with one, two, three, or four
substituents Q.sup.a as described herein. In certain embodiments,
R.sup.7a is imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl, or
2-methylpyrazol-3-yl. In certain embodiments, R.sup.7a is
6-membered heteroaryl, optionally substituted with one, two, three,
or four substituents Q.sup.a as described herein. In certain
embodiments, R.sup.7a is pyridinyl, optionally substituted with
one, two, three, or four substituents Q.sup.a as described herein.
In certain embodiments, R.sup.7a is pyridin-2-yl, pyridin-3-yl,
pyridin-4-yl, 2-methylpyridin-4-yl, or 2-methoxypyridin-4-yl. In
certain embodiments, R.sup.7a is heterocyclyl, optionally
substituted with one, two, three, or four substituents Q.sup.a as
described herein. In certain embodiments, R.sup.7a is monocyclic
heterocyclyl, optionally substituted with one, two, three, or four
substituents Q.sup.a as described herein. In certain embodiments,
R.sup.7a is 5-membered heterocyclyl, optionally substituted with
one, two, three, or four substituents Q.sup.a as described herein.
In certain embodiments, R.sup.7a is 6-membered heterocyclyl,
optionally substituted with one, two, three, or four substituents
Q.sup.a as described herein. In certain embodiments, R.sup.7a is
piperidinyl or piperazinyl, optionally substituted with one, two,
three, or four substituents Q.sup.a as described herein. In certain
embodiments, R.sup.7a is 1-methylpiperidin-4-yl, or
4-methylpiperazin-1-yl.
[0447] In certain embodiments, R.sup.7a is --C(O)R.sup.a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.7a is
--C(O)OR.sup.a, wherein R.sup.a is as defined herein. In certain
embodiments, R.sup.7a is --C(O)NR.sup.bR.sup.c, wherein R.sup.b and
R.sup.c are each as defined herein. In certain embodiments,
R.sup.7a is --C(NR.sup.a)NR.sup.bR.sup.c, wherein R.sup.a, R.sup.b,
and R.sup.c are each as defined herein. In certain embodiments,
R.sup.7a is --OR.sup.a, wherein R.sup.a is as defined herein. In
certain embodiments, R.sup.a is --O--C.sub.1-6 alkyl, wherein the
alkyl is optionally substituted with one, two, three, or four
substituents Q.sup.a as described herein. In certain embodiments,
R.sup.a is methoxy, ethoxy, propoxy, isopropoxy, or
3-dimethylaminopropoxy. In certain embodiments, R.sup.7a is
--OC(O)R.sup.a, wherein R.sup.a is as defined herein. In certain
embodiments, R.sup.7a is --OC(O)OR.sup.a, wherein R.sup.a is as
defined herein. In certain embodiments, R.sup.7a is
--OC(O)NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each as
defined herein. In certain embodiments, R.sup.7a is
--OC(.dbd.NR.sup.a)NR.sup.bR.sup.c, wherein R.sup.a, R.sup.b, and
R.sup.c are each as defined herein. In certain embodiments,
R.sup.7a is --OS(O)R.sup.a, wherein R.sup.a is as defined herein.
In certain embodiments, R.sup.7a is --OS(O).sub.2R.sup.a, wherein
R.sup.a is as defined herein. In certain embodiments, R.sup.7a is
--OS(O)NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each as
defined herein. In certain embodiments, R.sup.7a is
--OS(O).sub.2NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each
as defined herein. In certain embodiments, R.sup.7a is
--NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each as defined
herein. In certain embodiments, R.sup.7a is amino (--NH.sub.2). In
certain embodiments, R.sup.7a is --NR.sup.aC(O)R.sup.d, wherein
R.sup.a and R.sup.d are each as defined herein. In certain
embodiments, R.sup.7a is --NR.sup.aC(O)OR.sup.d, wherein R.sup.a
and R.sup.d are each as defined herein. In certain embodiments,
R.sup.7a is --NR.sup.aC(O)NR.sup.bR.sup.c, wherein R.sup.a,
R.sup.b, and R.sup.c are each as defined herein. In certain
embodiments, R.sup.7a is --NR.sup.aC(.dbd.NR.sup.d)NR.sup.bR.sup.c,
wherein R.sup.a, R.sup.b, R.sup.c, and R.sup.d are each as defined
herein. In certain embodiments, R.sup.1a is --NR.sup.aS(O)R.sup.d,
wherein R.sup.a and R.sup.d are each as defined herein. In certain
embodiments, R.sup.7a is --NR.sup.aS(O).sub.2R.sup.d, wherein
R.sup.a and R.sup.d are each as defined herein. In certain
embodiments, R.sup.7a is --NR.sup.aS(O)NR.sup.bR.sup.c, wherein
R.sup.a, R.sup.b, and R.sup.c are each as defined herein. In
certain embodiments, R.sup.7a is
--NR.sup.aS(O).sub.2NR.sup.bR.sup.c, wherein R.sup.a, R.sup.b, and
R.sup.c are each as defined herein. In certain embodiments,
R.sup.7a is --SR.sup.a, wherein R.sup.a is as defined herein. In
certain embodiments, R.sup.7a is --S(O)R.sup.a, wherein R.sup.a is
as defined herein. In certain embodiments, R.sup.7a is
--S(O).sub.2R.sup.a, wherein R.sup.a is as defined herein. In
certain embodiments, R.sup.7a is --S(O)NR.sup.bR.sup.c, wherein
R.sup.b and R.sup.c are each as defined herein. In certain
embodiments, R.sup.7a is --S(O).sub.2NR.sup.bR.sup.c; wherein
R.sup.b and R.sup.c are each as defined herein.
[0448] In certain embodiments, R.sup.7a is phenyl, imidazolyl,
pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or
piperazinyl, each optionally substituted with one, two, three, or
four substituents Q.sup.a. In certain embodiments, R.sup.7a is
phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl,
2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl,
3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl,
4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,
2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl,
3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl,
imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,
2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,
2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,
2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,
pyrimidin-5-yl, pyrrolidin-3-yl-1-methylpyrrolidin-3-yl,
piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,
1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,
1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.
[0449] In certain embodiments, R.sup.7b is hydrogen. In certain
embodiments, R.sup.7b is cyano. In certain embodiments, R.sup.7b is
halo. In certain embodiments, R.sup.7b is fluoro, chloro, bromo, or
iodo. In certain embodiments, R.sup.7b is nitro. In certain
embodiments, R.sup.7b is C.sub.3-7 alkyl, optionally substituted
with one, two, three, or four substituents Q.sup.a as described
herein. In certain embodiments, R.sup.7b is C.sub.2-6 alkenyl,
optionally substituted with one, two, three, or four substituents
Q.sup.a as described herein. In certain embodiments, R.sup.7b is
C.sub.2-6 alkynyl, optionally substituted with one, two, three, or
four substituents Q.sup.a as described herein. In certain
embodiments, R.sup.7b is C.sub.3-10 cycloalkyl, optionally
substituted with one, two, three, or four substituents Q.sup.a as
described herein. In certain embodiments, R.sup.1b is C.sub.3-10
cycloalkyl, optionally substituted with one, two, three, or four
substituents Q.sup.a as described herein. In certain embodiments,
R.sup.1b is C.sub.6-14 aryl, optionally substituted with one, two,
three, or four substituents Q.sup.a as described herein. In certain
embodiments, R.sup.7b is C.sub.7-15 aralkyl, optionally substituted
with one, two, three, or four substituents Q.sup.a as described
herein. In certain embodiments, R.sup.7b is heteroaryl, optionally
substituted with one, two, three, or four substituents Q.sup.a as
described herein. In certain embodiments, R.sup.7b is heterocyclyl,
optionally substituted with one, two, three, or four substituents
Q.sup.a as described herein.
[0450] In certain embodiments, R.sup.7b is --C(O)R.sup.a, wherein
R.sup.7a is as defined herein. In certain embodiments, R.sup.7b is
--C(O)OR.sup.a, wherein R.sup.a is as defined herein. In certain
embodiments, R.sup.7b is --C(O)NR.sup.bR.sup.c, wherein R.sup.b and
R.sup.c are each as defined herein. In certain embodiments,
R.sup.7b is --C(NR.sup.a)NR.sup.bR.sup.c, wherein R.sup.a, R.sup.b,
and R.sup.c are each as defined herein. In certain embodiments,
R.sup.7b is --OR.sup.a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.7a is --O--C.sub.1-6 alkyl, wherein the
alkyl is optionally substituted with one, two, three, or four
substituents Q.sup.a as described herein. In certain embodiments,
R.sup.7a is methoxy, ethoxy, propoxy, isopropoxy, or
3-dimethylaminopropoxy. In certain embodiments, R.sup.1b is
--OC(O)R.sup.a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.7b is --OC(O)OR.sup.a, wherein R.sup.1a is as
defined herein. In certain embodiments, R.sup.7b is
--OC(O)NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each as
defined herein. In certain embodiments, R.sup.7b is
--OC(.dbd.NR.sup.a)NR.sup.bR.sup.c, wherein R.sup.a, R.sup.b, and
R.sup.c are each as defined herein. In certain embodiments,
R.sup.7b is --OS(O)R.sup.a, wherein R.sup.7a is as defined herein.
In certain embodiments, R.sup.7b is --OS(O).sub.2R.sup.a, wherein
R.sup.7a is as defined herein. In certain embodiments, R.sup.b is
--OS(O)NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each as
defined herein. In certain embodiments, R.sup.7b is
--OS(O).sub.2NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each
as defined herein. In certain embodiments, R.sup.7b is
--NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each as defined
herein. In certain embodiments, R.sup.7b is amino (--NH.sub.2). In
certain embodiments, R.sup.7b is --NR.sup.aC(O)R.sup.d, wherein
R.sup.a and R.sup.d are each as defined herein. In certain
embodiments, R.sup.7b is --NR.sup.aC(O)OR.sup.d, wherein R.sup.a
and R.sup.d are each as defined herein. In certain embodiments,
R.sup.7b is --NR.sup.aC(O)NR.sup.bR.sup.c, wherein R.sup.a,
R.sup.b, and R.sup.c are each as defined herein. In certain
embodiments, R.sup.7b is --NR.sup.aC(.dbd.NR.sup.d)NR.sup.bR.sup.c,
wherein R.sup.a, R.sup.b, R.sup.c, and R.sup.d are each as defined
herein. In certain embodiments, R.sup.7b is --NR.sup.aS(O)R.sup.d,
wherein R.sup.a and R.sup.d are each as defined herein. In certain
embodiments, R.sup.7b is --NR.sup.aS(O).sub.2R.sup.d, wherein
R.sup.a and R.sup.d are each as defined herein. In certain
embodiments, R.sup.7b is --NR.sup.aS(O)NR.sup.bR.sup.c, wherein
R.sup.a, R.sup.b, and R.sup.c are each as defined herein. In
certain embodiments, R.sup.7b is
--NR.sup.aS(O).sub.2NR.sup.bR.sup.c, wherein R.sup.a, R.sup.b, and
R.sup.c are each as defined herein. In certain embodiments,
R.sup.7b is --SR.sup.a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.7b is --S(O)R.sup.a, wherein R.sup.1a is
as defined herein. In certain embodiments, R.sup.7b is
--S(O).sub.2R.sup.a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.7b is --S(O)NR.sup.bR.sup.c, wherein
R.sup.b and R.sup.c are each as defined herein. In certain
embodiments, R.sup.7b is --S(O).sub.2NR.sup.bR.sup.c; wherein
R.sup.b and R.sup.c are each as defined herein.
[0451] In certain embodiments, R.sup.7b is phenyl, imidazolyl,
pyrozolyl pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or
piperazinyl, each optionally substituted with one, two, three, or
four substituents Q.sup.a. In certain embodiments, R.sup.1b is
phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl,
2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl,
3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl,
4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,
2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl.
3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl,
imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,
2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,
2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,
2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,
pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,
piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,
1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,
1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.
[0452] In certain embodiments, R.sup.7c is hydrogen. In certain
embodiments, R.sup.7c is cyano. In certain embodiments, R.sup.7c is
halo. In certain embodiments, R.sup.7c is fluoro, chloro, bromo, or
iodo. In certain embodiments, R.sup.7c is nitro. In certain
embodiments, R.sup.7c is C.sub.1-6 alkyl, optionally substituted
with one, two, three, or four substituents Q.sup.a as described
herein. In certain embodiments, R.sup.7c is C.sub.2-6 alkenyl,
optionally substituted with one, two, three, or four substituents
Q.sup.a as described herein. In certain embodiments, R.sup.7c is
C.sub.2-6 alkynyl, optionally substituted with one, two, three, or
four substituents Q.sup.a as described herein. In certain
embodiments, R.sup.1c is C.sub.3-10 cycloalkyl, optionally
substituted with one, two, three, or four substituents Q.sup.a as
described herein. In certain embodiments, R.sup.7c is C.sub.3-7
cycloalkyl, optionally substituted with one, two, three, or four
substituents Q.sup.a as described herein. In certain embodiments,
R.sup.7c is C.sub.6-14 aryl, optionally substituted with one, two,
three, or four substituents Q.sup.a as described herein. In certain
embodiments, R.sup.7c is C.sub.7-15 aralkyl, optionally substituted
with one, two, three, or four substituents Q.sup.a as described
herein. In certain embodiments, R.sup.7c is heteroaryl, optionally
substituted with one, two, three, or four substituents Q.sup.a as
described herein. In certain embodiments, R.sup.7c is heterocyclyl,
optionally substituted with one, two, three, or four substituents
Q.sup.a as described herein.
[0453] In certain embodiments, R.sup.1c is --C(O)R.sup.a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.7c is
--C(O)OR.sup.a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.1c is --C(O)NR.sup.bR.sup.c, wherein R and
R.sup.c are each as defined herein. In certain embodiments,
R.sup.7c is --C(NR.sup.a)NR.sup.bR.sup.c, wherein R.sup.a, R.sup.b,
and R.sup.c are each as defined herein. In certain embodiments,
R.sup.7c is --OR.sup.a, wherein R.sup.1a is as defined herein. In
certain embodiments. R.sup.a is --O--C.sub.1-6 alkyl, wherein the
alkyl is optionally substituted with one, two, three, or four
substituents Q.sup.a as described herein. In certain embodiments,
R.sup.a is methoxy, ethoxy, propoxy, isopropoxy, or
3-dimethylaminopropoxy. In certain embodiments, R.sup.7c is
--OC(O)R.sup.a, wherein R.sup.a is as defined herein. In certain
embodiments, R.sup.7c is --OC(O)OR.sup.a, wherein R.sup.a is as
defined herein. In certain embodiments, R.sup.7c is
--OC(O)NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each as
defined herein. In certain embodiments, R.sup.7c is
--OC(.dbd.NR.sup.a)NR.sup.bR.sup.c, wherein R.sup.a, R.sup.b, and
R.sup.c are each as defined herein. In certain embodiments,
R.sup.7c is --OS(O)R.sup.a, wherein R.sup.a is as defined herein.
In certain embodiments, R.sup.7c is --OS(O).sub.2R.sup.a, wherein
R.sup.a is as defined herein. In certain embodiments, R.sup.7c is
--OS(O)NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each as
defined herein. In certain embodiments, R.sup.7c is
--OS(O)--NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each as
defined herein. In certain embodiments, R.sup.7c is
--NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each as defined
herein. In certain embodiments, R.sup.7c is amino (--NH.sub.2). In
certain embodiments, R.sup.7c is --NR.sup.aC(O)R.sup.d, wherein
R.sup.a and R.sup.d are each as defined herein. In certain
embodiments, R.sup.7c is --NR.sup.aC(O)OR.sup.d, wherein R.sup.a
and R.sup.d are each as defined herein. In certain embodiments,
R.sup.7c is --NR.sup.aC(O)NR.sup.bR.sup.c, wherein R.sup.a,
R.sup.b, and R.sup.c are each as defined herein. In certain
embodiments, R.sup.7c is --NR.sup.aC(.dbd.NR.sup.d)NR.sup.bR.sup.c,
wherein R.sup.a, R.sup.b, R.sup.c, and R.sup.d are each as defined
herein. In certain embodiments, R.sup.7c is --NR.sup.aS(O)R.sup.d,
wherein R.sup.a and R.sup.d are each as defined herein. In certain
embodiments, R.sup.7c is --NR.sup.aS(O).sub.2R.sup.d, wherein
R.sup.a and R.sup.d are each as defined herein. In certain
embodiments, R.sup.7c is --NR.sup.aS(O)NR.sup.bR.sup.c, wherein
R.sup.a, R.sup.b, and R.sup.c are each as defined herein. In
certain embodiments, R.sup.7c is
--NR.sup.aS(O).sub.2NR.sup.bR.sup.c, wherein R.sup.a, R.sup.b, and
R.sup.c are each as defined herein. In certain embodiments,
R.sup.7c is --SR.sup.a, wherein R.sup.a is as defined herein. In
certain embodiments, R.sup.7c is --S(O)R.sup.a, wherein R.sup.a is
as defined herein. In certain embodiments, R.sup.7c is
--S(O).sub.2R.sup.a, wherein R.sup.a is as defined herein. In
certain embodiments, R.sup.7c is --S(O)NR.sup.bR.sup.c, wherein
R.sup.b and R.sup.c are each as defined herein. In certain
embodiments, R.sup.7c is --S(O).sub.2NR.sup.bR.sup.c; wherein
R.sup.b and R.sup.c are each as defined herein.
[0454] In certain embodiments, R.sup.7c is phenyl, imidazolyl,
pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or
piperazinyl, each optionally substituted with one, two, three, or
four substituents Q.sup.a. In certain embodiments, R.sup.7c is
phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl,
2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl,
3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl,
4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,
2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl,
3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl,
imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,
2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,
2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,
2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,
pyrimidin-5'1, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,
piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,
1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl.
1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.
[0455] In certain embodiments, R.sup.7d is hydrogen. In certain
embodiments, R.sup.7d is cyano. In certain embodiments, R.sup.7d is
halo. In certain embodiments, R.sup.7d is fluoro, chloro, bromo, or
iodo. In certain embodiments, R.sup.7d is nitro. In certain
embodiments, R.sup.7d is C.sub.1-6 alkyl, optionally substituted
with one, two, three, or four substituents Q.sup.a as described
herein. In certain embodiments, R.sup.7d is C.sub.2-6, alkenyl,
optionally substituted with one, two, three, or four substituents
Q.sup.a as described herein. In certain embodiments, R.sup.7d is
C.sub.2-6 alkynyl, optionally substituted with one, two, three, or
four substituents Q.sup.a as described herein. In certain
embodiments, R.sup.7d is C.sub.3-10 cycloalkyl, optionally
substituted with one, two, three, or four substituents Q.sup.a as
described herein. In certain embodiments, R.sup.7d is C.sub.3-7
cycloalkyl, optionally substituted with one, two, three, or four
substituents Q.sup.a as described herein. In certain embodiments,
R.sup.7d is C.sub.6-14 aryl, optionally substituted with one, two,
three, or four substituents Q.sup.a as described herein. In certain
embodiments, R.sup.7d is C.sub.7-15 aralkyl, optionally substituted
with one, two, three, or four substituents Q.sup.a as described
herein. In certain embodiments, R.sup.7d is heteroaryl, optionally
substituted with one, two, three, or four substituents Q.sup.a as
described herein. In certain embodiments, R.sup.7d is heterocyclyl,
optionally substituted with one, two, three, or four substituents
Q.sup.a as described herein.
[0456] In certain embodiments, R.sup.7d is --C(O)R.sup.a, wherein
R.sup.a is as defined herein. In certain embodiments, R.sup.7d is
--C(O)OR.sup.a, wherein R.sup.7a is as defined herein. In certain
embodiments, R.sup.7d is --C(O)NR.sup.bR.sup.c, wherein R.sup.b and
R.sup.c are each as defined herein. In certain embodiments,
R.sup.7d is --C(NR.sup.a)NR.sup.bR.sup.c, wherein R.sup.a, R.sup.b,
and R.sup.c are each as defined herein. In certain embodiments,
R.sup.7d is --OR.sup.a, wherein R.sup.a is as defined herein. In
certain embodiments, R.sup.a is --O--C.sub.1-6 alkyl, wherein the
alkyl is optionally substituted with one, two, three, or four
substituents Q.sup.a as described herein. In certain embodiments,
R.sup.1a is methoxy, ethoxy, propoxy, isopropoxy, or
3-dimethylaminopropoxy. In certain embodiments, R.sup.7d is
--OC(O)R.sup.a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.7d is --OC(O)OR.sup.a, wherein R.sup.a is as
defined herein. In certain embodiments, R.sup.7d is
--OC(O)NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each as
defined herein. In certain embodiments, R.sup.7d is
--OC(.dbd.NR.sup.a)NR.sup.bR.sup.c, wherein R.sup.a, R.sup.b, and
R.sup.c are each as defined herein. In certain embodiments,
R.sup.7d is --OS(O)R.sup.a, wherein R.sup.a is as defined herein.
In certain embodiments, R.sup.7d is --OS(O).sub.2R.sup.a, wherein
R.sup.a is as defined herein. In certain embodiments, R.sup.7d is
--OS(O)NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each as
defined herein. In certain embodiments, R.sup.7d is
--OS(O).sub.2NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each
as defined herein. In certain embodiments, R.sup.7d is
--NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each as defined
herein. In certain embodiments, R.sup.1d is amino (--NH.sub.2). In
certain embodiments, R.sup.7d is --NR.sup.aC(O)R.sup.d, wherein
R.sup.a and R.sup.d are each as defined herein. In certain
embodiments, R.sup.1d is --NR.sup.aC(O)OR.sup.d, wherein R.sup.a
and R.sup.d are each as defined herein. In certain embodiments,
R.sup.1d is --NR.sup.aC(O)NR.sup.bR.sup.c, wherein R.sup.a,
R.sup.b, and R.sup.c are each as defined herein. In certain
embodiments, R.sup.1d is --NR.sup.aC(.dbd.NR.sup.d)NR.sup.bR.sup.c,
wherein R.sup.a, R.sup.b, R.sup.c, and R.sup.d are each as defined
herein. In certain embodiments, R.sup.1d is --NR.sup.aS(O)R.sup.d,
wherein R.sup.a and R.sup.d are each as defined herein. In certain
embodiments, R.sup.1d is --NR.sup.aS(O).sub.2R.sup.d, wherein
R.sup.a and R.sup.d are each as defined herein. In certain
embodiments, R.sup.1d is --NR.sup.aS(O)NR.sup.bR.sup.c, wherein
R.sup.a, R.sup.b, and R.sup.c are each as defined herein. In
certain embodiments, R.sup.7d is
--NR.sup.aS(O).sub.2NR.sup.bR.sup.c, wherein R.sup.a, R.sup.b, and
R.sup.c are each as defined herein. In certain embodiments,
R.sup.1d is --SR.sup.a, wherein R.sup.a is as defined herein. In
certain embodiments, R.sup.7d is --S(O)R.sup.a, wherein R.sup.a is
as defined herein. In certain embodiments, R.sup.7d is
--S(O).sub.2R.sup.a, wherein R.sup.a is as defined herein. In
certain embodiments, R.sup.7d is --S(O)NR.sup.bR.sup.c, wherein
R.sup.b and R.sup.c are each as defined herein. In certain
embodiments, R.sup.1d is --S(O).sub.2NR.sup.bR.sup.c; wherein
R.sup.b and R.sup.c are each as defined herein.
[0457] In certain embodiments, R.sup.7d is phenyl, imidazolyl,
pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or
piperazinyl, each optionally substituted with one, two, three, or
four substituents Q.sup.a. In certain embodiments, R.sup.1d is
phenyl, 2-fluorophenyl, 2-chlorphenyl, 2-bromophenyl,
2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl,
3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl,
4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,
2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl,
3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl,
imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,
2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,
2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,
2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,
pyrimidin-5-yl, pyrrolidin-3-yl-1-methylpyrrolidin-3-yl,
piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,
1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,
1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.
[0458] In certain embodiments, R.sup.7e is hydrogen. In certain
embodiments, R.sup.7e is cyano. In certain embodiments, R.sup.7e is
halo. In certain embodiments, R.sup.7e is fluoro, chloro, bromo, or
iodo. In certain embodiments, R.sup.7e is nitro. In certain
embodiments, R.sup.7e is C.sub.1-6 alkyl, optionally substituted
with one, two, three, or four substituents Q.sup.a as described
herein. In certain embodiments, R.sup.7e is C.sub.2-6 alkenyl,
optionally substituted with one, two, three, or four substituents
Q.sup.a as described herein. In certain embodiments, R.sup.7e is
C.sub.2-6 alkynyl, optionally substituted with one, two, three, or
four substituents Q.sup.a as described herein. In certain
embodiments, R.sup.7e is C.sub.3-1) cycloalkyl, optionally
substituted with one, two, three, or four substituents Q.sup.a as
described herein. In certain embodiments, R.sup.7e is C.sub.3-7
cycloalkyl, optionally substituted with one, two, three, or four
substituents Q.sup.a as described herein. In certain embodiments,
R.sup.7e is C.sub.6-14 aryl, optionally substituted with one, two,
three, or four substituents Q.sup.a as described herein. In certain
embodiments, R.sup.7e is C.sub.7-15 aralkyl, optionally substituted
with one, two, three, or four substituents Q.sup.a as described
herein. In certain embodiments, R.sup.7e is heteroaryl, optionally
substituted with one, two, three, or four substituents Q.sup.a as
described herein. In certain embodiments, R.sup.7e is heterocyclyl,
optionally substituted with one, two, three, or four substituents
Q.sup.a as described herein.
[0459] In certain embodiments, R.sup.7e is --C(O)R.sup.a, wherein
R.sup.a is as defined herein. In certain embodiments, R.sup.7e is
--C(O)OR.sup.a, wherein R.sup.a is as defined herein. In certain
embodiments, R.sup.7e is --C(O)NR.sup.bR.sup.c, wherein R.sup.b and
R.sup.c are each as defined herein. In certain embodiments,
R.sup.7c is --C(NR.sup.a)NR.sup.bR.sup.c, wherein R.sup.a, R.sup.b,
and R.sup.c are each as defined herein. In certain embodiments,
R.sup.7e is --OR.sup.1a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.a is --O--C.sub.1-6 alkyl, wherein the
alkyl is optionally substituted with one, two, three, or four
substituents Q.sup.a as described herein. In certain embodiments,
R.sup.1a is methoxy, ethoxy, propoxy, isopropoxy, or
3-dimethylaminopropoxy. In certain embodiments, R.sup.7e is
--OC(O)R.sup.a, wherein R.sup.1a is as defined herein. In certain
embodiments, R.sup.7e is --OC(O)OR.sup.a, wherein R.sup.1a is as
defined herein. In certain embodiments, R.sup.7e is
--OC(O)NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each as
defined herein. In certain embodiments, R.sup.7e is
--OC(.dbd.NR.sup.a)NR.sup.bR.sup.c, wherein R.sup.a, R.sup.b, and
R.sup.c are each as defined herein. In certain embodiments,
R.sup.7e is --OS(O)R.sup.a, wherein R.sup.1a is as defined herein.
In certain embodiments, R.sup.7e is --OS(O).sub.2R.sup.a, wherein
R.sup.1a is as defined herein. In certain embodiments, R.sup.7e is
--OS(O)NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each as
defined herein. In certain embodiments, R.sup.7e is
--OS(O).sub.2NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each
as defined herein. In certain embodiments, R.sup.7e is
--NR.sup.bR.sup.c, wherein R.sup.b and R.sup.c are each as defined
herein. In certain embodiments, R.sup.7e is amino (--NH.sub.2). In
certain embodiments, R.sup.7e is --NR.sup.aC(O)R.sup.d, wherein
R.sup.a and R.sup.d are each as defined herein. In certain
embodiments, R.sup.7e is --NR.sup.aC(O)OR.sup.d, wherein R.sup.a
and R.sup.d are each as defined herein. In certain embodiments,
R.sup.7c is --NR.sup.aC(O)NR.sup.bR.sup.c, wherein R.sup.a,
R.sup.b, and R.sup.c are each as defined herein. In certain
embodiments, R.sup.7c is --NR.sup.aC(.dbd.NR.sup.d)NR.sup.bR.sup.c,
wherein R.sup.a, R.sup.b, R.sup.c, and R.sup.d are each as defined
herein. In certain embodiments, R.sup.7e is --NR.sup.aS(O)R.sup.d,
wherein R.sup.a and R.sup.d are each as defined herein. In certain
embodiments, R.sup.7e is --NR.sup.aS(O).sub.2R.sup.d, wherein
R.sup.a and R.sup.d are each as defined herein. In certain
embodiments, R.sup.7e is --NR.sup.aS(O)NR.sup.bR.sup.c, wherein
R.sup.a, R.sup.b, and R.sup.c are each as defined herein. In
certain embodiments, R.sup.7e is
--NR.sup.aS(O).sub.2NR.sup.bR.sup.c, wherein R.sup.a, R.sup.b, and
R.sup.c are each as defined herein. In certain embodiments,
R.sup.7e is --SR.sup.a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.7e is --S(O)R.sup.a, wherein R.sup.1a is
as defined herein. In certain embodiments, R.sup.1c is
--S(O).sub.2R.sup.a, wherein R.sup.1a is as defined herein. In
certain embodiments, R.sup.7e is --S(O)NR.sup.bR.sup.c, wherein
R.sup.b and R.sup.c are each as defined herein. In certain
embodiments, R.sup.7e is --S(O).sub.2NR.sup.bR.sup.c; wherein
R.sup.b and R.sup.c are each as defined herein.
[0460] In certain embodiments, R.sup.7e is phenyl, imidazolyl,
pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or
piperazinyl, each optionally substituted with one, two, three, or
four substituents Q.sup.a. In certain embodiments, R.sup.7e is
phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl,
2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl,
3-fluorophenyl. 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl,
4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,
2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl.
3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl,
imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,
2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,
2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,
2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,
pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,
piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,
1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,
1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.
[0461] In certain embodiments, R.sup.7a and R.sup.7b together with
the carbon atoms to which they are attached form C.sub.3-10
cycloalkenyl, C.sub.6-14 aryl, heteroaryl, or heterocyclyl, each
optionally substituted with one, two, three, or four substituents
Q.sup.a. In certain embodiments, R.sup.7a and R.sup.7b together
with the carbon atoms to which they are attached form C.sub.3-10
cycloalkenyl, optionally substituted with one, two, three, or four
substituents Q.sup.a. In certain embodiments, R.sup.7a and R.sup.7b
together with the carbon atoms to which they are attached form
cyclohexenyl, optionally substituted with one, two, three, or four
substituents Q. In certain embodiments, R.sup.7a and R.sup.7b
together with the carbon atoms to which they are attached form
C.sub.6-14 aryl, optionally substituted with one, two, three, or
four substituents Q.sup.a. In certain embodiments, R.sup.1a and
R.sup.7b together with the carbon atoms to which they are attached
form phenyl, optionally substituted with one, two, three, or four
substituents Q.sup.a. In certain embodiments, R.sup.7a and R.sup.7b
together with the carbon atoms to which they are attached form
heteroaryl, optionally substituted with one, two, three, or four
substituents Q.sup.a. In certain embodiments, R.sup.7a and R.sup.7b
together with the carbon atoms to which they are attached form
monocyclic heteroaryl, optionally substituted with one, two, three,
or four substituents Q.sup.a. In certain embodiments, R.sup.7a and
R.sup.7b together with the carbon atoms to which they are attached
form 5- or 6-membered heteroaryl, optionally substituted with one,
two, three, or four substituents Q. In certain embodiments,
R.sup.7a and R.sup.7b together with the carbon atoms to which they
are attached form bicyclic heteroaryl, optionally substituted with
one, two, three, or four substituents Q.sup.a. In certain
embodiments, R.sup.7a and R.sup.7b together with the carbon atoms
to which they are attached form heterocyclyl, optionally
substituted with one, two, three, or four substituents Q.sup.a. In
certain embodiments, R.sup.7a and R.sup.7b together with the carbon
atoms to which they are attached form monocyclic heterocyclyl,
optionally substituted with one, two, three, or four substituents
Q.sup.a. In certain embodiments, R.sup.7a and R.sup.7b together
with the carbon atoms to which they are attached form 5- or
6-membered heterocyclyl, optionally substituted with one, two,
three, or four substituents Q.sup.a. In certain embodiments,
R.sup.1a and R.sup.7b together with the carbon atoms to which they
are attached form bicyclic heterocyclyl, optionally substituted
with one, two, three, or four substituents Q.sup.a.
[0462] In certain embodiments, R.sup.7b and R.sup.7c together with
the carbon atoms to which they are attached form C.sub.3-10
cycloalkenyl, C.sub.6-14 aryl, heteroaryl, or heterocyclyl, each
optionally substituted with one, two, three, or four substituents
Q.sup.a. In certain embodiments, R.sup.7b and R.sup.7c together
with the carbon atoms to which they are attached form C.sub.3-10
cycloalkenyl, optionally substituted with one, two, three, or four
substituents Q.sup.a. In certain embodiments, R.sup.7b and R.sup.7c
together with the carbon atoms to which they are attached form
cyclohexenyl, optionally substituted with one, two, three, or four
substituents Q.sup.a. In certain embodiments, R.sup.7b and R.sup.7c
together with the carbon atoms to which they are attached form
C.sub.6-14 aryl, optionally substituted with one, two, three, or
four substituents Q.sup.a. In certain embodiments, R.sup.7b and
R.sup.7c together with the carbon atoms to which they are attached
form phenyl, optionally substituted with one, two, three, or four
substituents Q.sup.a. In certain embodiments, R.sup.7b and R.sup.7c
together with the carbon atoms to which they are attached form
heteroaryl, optionally substituted with one, two, three, or four
substituents Q.sup.a. In certain embodiments, R.sup.7b and R.sup.7c
together with the carbon atoms to which they are attached form
monocyclic heteroaryl, optionally substituted with one, two, three,
or four substituents Q.sup.a. In certain embodiments, R.sup.7b and
R.sup.7c together with the carbon atoms to which they are attached
form 5- or 6-membered heteroaryl, optionally substituted with one,
two, three, or four substituents Q. In certain embodiments,
R.sup.7b and R.sup.7c together with the carbon atoms to which they
are attached form bicyclic heteroaryl, optionally substituted with
one, two, three, or four substituents Q.sup.a. In certain
embodiments, R.sup.7b and R.sup.7c together with the carbon atoms
to which they are attached form heterocyclyl, optionally
substituted with one, two, three, or four substituents Q.sup.a. In
certain embodiments, R.sup.7b and R.sup.7c together with the carbon
atoms to which they are attached form monocyclic heterocyclyl,
optionally substituted with one, two, three, or four substituents
Q.sup.a. In certain embodiments, R.sup.7b and R.sup.7c together
with the carbon atoms to which they are attached form 5- or
6-membered heterocyclyl, optionally substituted with one, two,
three, or four substituents Q.sup.a. In certain embodiments,
R.sup.7b and R.sup.7c together with the carbon atoms to which they
are attached form bicyclic heterocyclyl, optionally substituted
with one, two, three, or four substituents Q.sup.a.
[0463] In certain embodiments, R.sup.7c and R.sup.7d together with
the carbon atoms to which they are attached form C.sub.3-10
cycloalkenyl, C.sub.6-14 aryl, heteroaryl, or heterocyclyl, each
optionally substituted with one, two, three, or four substituents
Q.sup.a. In certain embodiments, R.sup.7c and R.sup.7d together
with the carbon atoms to which they are attached form C.sub.3-10
cycloalkenyl, optionally substituted with one, two, three, or four
substituents Q.sup.a. In certain embodiments, R.sup.7c and R.sup.7d
together with the carbon atoms to which they are attached form
cyclohexenyl, optionally substituted with one, two, three, or four
substituents Q.sup.a. In certain embodiments, R.sup.7c and R.sup.7d
together with the carbon atoms to which they are attached form
C.sub.6-14 aryl, optionally substituted with one, two, three, or
four substituents Q.sup.a. In certain embodiments, R.sup.7c and
R.sup.7d together with the carbon atoms to which they are attached
form phenyl, optionally substituted with one, two, three, or four
substituents Q.sup.a. In certain embodiments, R.sup.7c and R.sup.7d
together with the carbon atoms to which they are attached form
heteroaryl, optionally substituted with one, two, three, or four
substituents Q.sup.a. In certain embodiments, R.sup.7c and R.sup.7d
together with the carbon atoms to which they are attached form
monocyclic heteroaryl, optionally substituted with one, two, three,
or four substituents Q.sup.a. In certain embodiments, R.sup.7c and
R.sup.7d together with the carbon atoms to which they are attached
form 5- or 6-membered heteroaryl, optionally substituted with one,
two, three, or four substituents Q.sup.a. In certain embodiments,
R.sup.7c and R.sup.7d together with the carbon atoms to which they
are attached form bicyclic heteroaryl, optionally substituted with
one, two, three, or four substituents Q.sup.a. In certain
embodiments, R.sup.7c and R.sup.7d together with the carbon atoms
to which they are attached form heterocyclyl, optionally
substituted with one, two, three, or four substituents Q.sup.a. In
certain embodiments, R.sup.7c and R.sup.7d together with the carbon
atoms to which they are attached form monocyclic heterocyclyl,
optionally substituted with one, two, three, or four substituents
Q.sup.a. In certain embodiments, R.sup.7c and R.sup.7d together
with the carbon atoms to which they are attached form 5- or
6-membered heterocyclyl, optionally substituted with one, two,
three, or four substituents Q.sup.a. In certain embodiments,
R.sup.7c and R.sup.7d together with the carbon atoms to which they
are attached form bicyclic heterocyclyl, optionally substituted
with one, two, three, or four substituents Q.sup.a.
[0464] In certain embodiments, R.sup.7d and R.sup.7e together with
the carbon atoms to which they are attached form C.sub.3-10
cycloalkenyl, C.sub.6-14 aryl, heteroaryl, or heterocyclyl, each
optionally substituted with one, two, three, or four substituents
Q.sup.a. In certain embodiments, R.sup.7d and R.sup.7e together
with the carbon atoms to which they are attached form C.sub.3-10
cycloalkenyl, optionally substituted with one, two, three, or four
substituents Q.sup.a. In certain embodiments, R.sup.7d and R.sup.7e
together with the carbon atoms to which they are attached form
cyclohexenyl, optionally substituted with one, two, three, or four
substituents Q.sup.a. In certain embodiments, R.sup.7d and R.sup.7e
together with the carbon atoms to which they are attached form
C.sub.6-14 aryl, optionally substituted with one, two, three, or
four substituents Q.sup.a. In certain embodiments, R.sup.7d and
R.sup.7c together with the carbon atoms to which they are attached
form phenyl, optionally substituted with one, two, three, or four
substituents Q.sup.a. In certain embodiments, R.sup.7d and R.sup.7e
together with the carbon atoms to which they are attached form
heteroaryl, optionally substituted with one, two, three, or four
substituents Q.sup.a. In certain embodiments, R.sup.7d and R.sup.7e
together with the carbon atoms to which they are attached form
monocyclic heteroaryl, optionally substituted with one, two, three,
or four substituents Q.sup.a. In certain embodiments, R.sup.7d and
R.sup.7e together with the carbon atoms to which they are attached
form 5- or 6-membered heteroaryl, optionally substituted with one,
two, three, or four substituents Q.sup.a. In certain embodiments,
R.sup.7d and R.sup.7e together with the carbon atoms to which they
are attached form bicyclic heteroaryl, optionally substituted with
one, two, three, or four substituents Q.sup.a. In certain
embodiments, R.sup.7d and R.sup.7e together with the carbon atoms
to which they are attached form heterocyclyl, optionally
substituted with one, two, three, or four substituents Q.sup.a. In
certain embodiments, R.sup.7d and R.sup.7e together with the carbon
atoms to which they are attached form monocyclic heterocyclyl,
optionally substituted with one, two, three, or four substituents
Q.sup.a. In certain embodiments, R.sup.7d and R.sup.7e together
with the carbon atoms to which they are attached form 5- or
6-membered heterocyclyl, optionally substituted with one, two,
three, or four substituents Q.sup.a. In certain embodiments,
R.sup.7d and R.sup.7e together with the carbon atoms to which they
are attached form bicyclic heterocyclyl, optionally substituted
with one, two, three, or four substituents Q.sup.a.
[0465] In certain embodiments, m is 0. In certain embodiments, m is
1.
[0466] In certain embodiments, n is 0. In certain embodiments, n is
1. In certain embodiments, n is 2. In certain embodiments, n is 3.
In certain embodiments, n is 4. In certain embodiments, n is 0, 1,
or 2. In certain embodiments, n is 0, 1, 2, or 3. In certain
embodiments, n is 1, 2, or 3. In certain embodiments, n is 1 or
2.
[0467] In certain embodiments, m is 0, and n is 0, 1, 2, or 3. In
certain embodiments, m is 0, n is 0, 1, or 2. In certain
embodiments, m is 0, and n is 0 or 1. In certain embodiments, m is
0, and n is 0. In certain embodiments, m is 0, and n is 1. In
certain embodiments, m is 1, and n is 0, 1, 2, or 3. In certain
embodiments, m is 1, and n is 0, 1, or 2. In certain embodiments, m
is 1, and n is 0 or 1. In certain embodiments, m is 1, and n is 0.
In certain embodiments, m is 1, and n is 1.
[0468] In specific embodiments, m is 0, n is 1, and R.sup.5a and
R.sup.5b are each methyl.
[0469] In certain embodiments, X is N In certain embodiments, X is
CR.sup.X, wherein R.sup.X is as defined herein. In certain
embodiments, X is CH.
[0470] In certain embodiments, Y is N In certain embodiments, Y is
CR.sup.X, wherein R.sup.X is as defined herein. In certain
embodiments, Y is CH.
[0471] In certain embodiments, Z is N In certain embodiments, Z is
CR.sup.X, wherein R.sup.X is as defined herein. In certain
embodiments, Z is CH.
[0472] In certain embodiments, X, Y, and Z are N. In certain
embodiments, X and Y are N, and Z is CH. In certain embodiments, X
and Z are N, and Y is CH. In certain embodiments, Y and Z are N,
and X is CH.
[0473] In certain embodiments, the compound provided herein is not
4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-N-(2-phenyl--
2-(pyrrolidin-1-yl)ethyl)-1,3,5-triazin-2-amine. In certain
embodiments, the compound provided herein is not
6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(4-((R)-3-(methoxyme-
thyl)morpholino)phenyl)ethyl)-2-morpholinopyrimidin-4-amine.
[0474] In certain embodiments, when X, Y, and Z are N, and R.sup.5a
is hydrogen, R.sup.5b is not heterocyclyl. In certain embodiments,
when X, Y, and Z are N, and R.sup.5a is hydrogen, R.sup.5b is not
5-membered heterocyclyl. In certain embodiments, when X, Y, and Z
are N, and R.sup.5a is hydrogen. R.sup.5b is not pyrrolidinyl. In
certain embodiments, when X, Y, and Z are N, and R.sup.5a is
hydrogen, R.sup.5b is not pyrrolidin-1-yl.
[0475] In certain embodiments, when X and Z are N, Y is CH, and
R.sup.5a is hydrogen, R.sup.5b is morpholino-substituted phenyl. In
certain embodiments, when X and Z are N, Y is CH, and R.sup.5a is
hydrogen, R.sup.5b is not
4-((R)-3-(methoxymethyl)morpholino)phenyl.
[0476] In one embodiment, provided herein is a compound selected
from:
##STR00018## ##STR00019## ##STR00020## ##STR00021## ##STR00022##
##STR00023## ##STR00024## ##STR00025##
[0477] In one embodiment, the PI3K inhibitor is Compound A35,
isotopic variants, pharmaceutically acceptable salts, solvates,
hydrates, and prodrugs thereof. In one embodiment, the PI3K
inhibitor is Compound A36, isotopic variants, pharmaceutically
acceptable salts, solvates, hydrates, and prodrugs thereof. In one
embodiment, the PI3K inhibitor is Compound A68, isotopic variants,
pharmaceutically acceptable salts, solvates, hydrates, and prodrugs
thereof. In one embodiment, the PI3K inhibitor is Compound A70,
isotopic variants, pharmaceutically acceptable salts, solvates,
hydrates, and prodrugs thereof. In one embodiment, the PI3K
inhibitor is Compound A37, isotopic variants, pharmaceutically
acceptable salts, solvates, hydrates, and prodrugs thereof. In one
embodiment, the PI3K inhibitor is Compound A38, isotopic variants,
pharmaceutically acceptable salts, solvates, hydrates, and prodrugs
thereof. In one embodiment, the PI3K inhibitor is Compound A41,
isotopic variants, pharmaceutically acceptable salts, solvates,
hydrates, and prodrugs thereof. In one embodiment, the PI3K
inhibitor is Compound A42, isotopic variants, pharmaceutically
acceptable salts, solvates, hydrates, and prodrugs thereof. In one
embodiment, the PI3K inhibitor is Compound A43, isotopic variants,
pharmaceutically acceptable salts, solvates, hydrates, and prodrugs
thereof. In one embodiment, the PI3K inhibitor is Compound A44,
isotopic variants, pharmaceutically acceptable salts, solvates,
hydrates, and prodrugs thereof. In one embodiment, the PI3K
inhibitor is Compound A62, isotopic variants, pharmaceutically
acceptable salts, solvates, hydrates, and prodrugs thereof. In one
embodiment, the PI3K inhibitor is Compound A63, isotopic variants,
pharmaceutically acceptable salts, solvates, hydrates, and prodrugs
thereof. In one embodiment, the PI3K inhibitor is Compound A64,
isotopic variants, pharmaceutically acceptable salts, solvates,
hydrates, and prodrugs thereof. In one embodiment, the PI3K
inhibitor is Compound A65, isotopic variants, pharmaceutically
acceptable salts, solvates, hydrates, and prodrugs thereof. In one
embodiment, the PI3K inhibitor is Compound A66, isotopic variants,
pharmaceutically acceptable salts, solvates, hydrates, and prodrugs
thereof. In one embodiment, the PI3K inhibitor is Compound A67,
isotopic variants, pharmaceutically acceptable salts, solvates,
hydrates, and prodrugs thereof.
[0478] Synthesis of compounds of any of the Formulae provided
herein, e.g., Formulae (I), (IX), (X), (XI), and/or (XVI), is
described in U.S. Pat. No. 9,056,852 B2, which is incorporated by
reference for such disclosure.
CD20 Inhibitors
[0479] Described herein are PI3K inhibitors in combination with
CD20 inhibitors.
[0480] B lymphocytes are the origin of humoral immunity, represent
a substantial portion of hematopoietic malignancies, and contribute
to autoimmunity. Consequently, cell surface molecules expressed by
B cells and their malignant counterparts are important targets for
immunotherapy. CD20, a B cell-specific member of the MS4A gene
family, is expressed on the surface of immature and mature B cells
and their malignant counterparts.
[0481] A limited analysis of CD20 transcripts in mouse cell lines
and tissues suggests that mouse CD20 is also B cell-specific. Both
human and mouse CD20 cDNAs encode a membrane-embedded protein with
hydrophobic regions of sufficient length to pass through the
membrane four times. Mouse and human CD20 are well conserved (73%)
in amino acid sequence, particularly the transmembrane and long
amino- and carboxyl-terminal cytoplasmic domains. The cytoplasmic
domains are serine- and threonine-rich with multiple consensus
sequences for phosphorylation. Human CD20 is not glycosylated, but
three isoforms (33-, 35- and 37.000 Mr) result from the
differential phosphorylation of a single protein on different
serine and threonine residues.
[0482] CD20 plays a role in the regulation of human B cell
activation, proliferation, and Ca.sup.2+ transport. Antibody
ligation of CD20 can generate transmembrane signals that result in
enhanced CD20 phosphorylation, induction of c-my and B-myb oncogene
expression, induced serine/threonine and tyrosine phosphorylation
of cellular proteins, increased CD18, CD58 and MHC class 11
molecule expression, and protein tyrosine kinase activation that
induces B cell adhesion. CD20 ligation promotes transmembrane
Ca.sup.2+ transport, but does not usually lead to increased
intracellular calcium ([Ca.sup.2+].sub.i).sub.3 levels, except
after extensive crosslinking. Antibody binding to CD20 inhibits B
cell progression from the G1 phase into the S/G2+M stages of cell
cycle following mitogen stimulation, and inhibits mitogen-induced B
cell differentiation and antibody secretion. Extensive CD20
cross-linking can also influence apoptosis. These divergent
observations may be explained in part by the finding that CD20 is a
component of an oligomeric complex that forms a membrane
transporter or Ca.sup.2+ ion channel that is activated during cell
cycle progression. Despite this, B cell development and function in
a line of CD20-deficient (CD20-/-) mice is reported to be
normal.
[0483] The majority of human B cell-lineage malignancies express
CD20. Chimeric or radiolabeled monoclonal antibody-based therapies
directed against CD20 have been used for B cell malignancies such
as non-Hodgkin's lymphoma.
[0484] Any suitable CD20 inhibitor may be used in combination with
a PI3K inhibitor described herein. In some embodiments, the CD20
inhibitor is an antagonist of CD20. In some embodiments, the CD20
inhibitor is an antibody, variant, or biosimilar thereof. In some
embodiments, the CD20 inhibitor is a monoclonal antibody.
[0485] Some embodiments provided herein describe a pharmaceutical
compositions or methods for using the pharmaceutical compositions
comprising a PI3K inhibitor described herein in combination with a
CD20 inhibitor. CD20 inhibitors for use in pharmaceutical
compositions and methods provided herein include but are not
limited to ofatumumab, obinutuzumab, rituximab, ocaratuzumab,
ocrelizumab, tositumomab, ibritumomab tiuxetan, tisotumab vedotin,
ublituximab. TRU-015, veltuzumab, BTCT4465A (RG7828), EDC9,
MT-3724, BLX-301, 1 F5, ATCC deposit HB-96450, BM-ca, C2H7,
PRO131921, BVX-20, MEDI-522, or a variant or biosimilar thereof, or
combinations thereof. In some embodiments, the CD20 inhibitor for
use in pharmaceutical compositions and methods provided herein is
ofatumumab, obinutuzumab, rituximab, ocaratuzumab, ocrelizumab,
tositumomab, ibritumomab tiuxetan, tisotumab vedotin, ublituximab,
TRU-015, veltuzumab, BTCT4465A (RG7828), EDC9, MT-3724, or a
variant or biosimilar thereof, or combinations thereof. In some
embodiments, the CD20 inhibitor for use in pharmaceutical
compositions and methods provided herein is ofatumumab,
obinutuzumab, rituximab, ocaratuzumab, ocrelizumab, tositumomab,
ibritumomab tiuxetan, tisotumab vedotin, ublituximab, veltuzumab,
or a variant or biosimilar thereof, or combinations thereof. In
some embodiments, the CD20 inhibitor for use in pharmaceutical
compositions and methods provided herein is obinutuzumab or
rituximab, or a variant or biosimilar thereof or combinations
thereof.
[0486] In some embodiments, the CD20 inhibitor is ofatumumab, an
ofatumumab variant, or an ofatumumab biosimilar. In some
embodiments, the CD20 inhibitor is obinutuzumab, an obinutuzumab
variant, or an obinutuzumab biosimilar. In some embodiments, the
CD20 inhibitor is rituximab, a rituximab variant, or a rituximab
biosimilar. In some embodiments, the rituximab biosimilar is
CT-P10, Reditux.RTM., ABP 798, AcellBia, BI 695500, Mabal1,
JHL1101, Novex, MabionCD20, PF-05280586, Kikuzubam, SAIT101, GP
2013, HLX01, CMAB304, BT-D004, AP-052 or TL-011. In some
embodiments, the CD20 inhibitor is ocaratuzumab, an ocaratuzumab
variant, or an ocaratuzumab biosimilar. In some embodiments, the
CD20 inhibitor is ocrelizumab, an ocrelizumab variant, or an
ocrelizumab biosimilar. In some embodiments, the CD20 inhibitor is
tositumomab, a tositumomab variant, or a tositumomab biosimilar. In
some embodiments, the CD20 inhibitor is ibritumomab tiuxetan, an
ibritumomab tiuxetan variant, or an ibritumomab tiuxetan
biosimilar. In some embodiments, the CD20 inhibitor is tisotumab
vedotin, a tisotumab vedotin variant, or a tisotumab vedotin
biosimilar. In some embodiments, the CD20 inhibitor is ublituximab,
an ublituximab variant, or an ublituximab biosimilar. In some
embodiments, the CD20 inhibitor is TRU-015, a TRU-015 variant, or a
TRU-015 biosimilar. In some embodiments, the CD20 inhibitor is
veltuzumab, a veltuzumab variant, or a veltuzumab biosimilar. In
some embodiments, the CD20 inhibitor is BTCT4465A (RG7828), a
BTCT4465A (RG7828) variant, or a BTCT4465A (RG7828) biosimilar. In
some embodiments, the CD20 inhibitor is EDC9, an EDC9 variant, or
an EDC9 biosimilar. In some embodiments, the CD20 inhibitor is
MT-3724, a MT-3724 variant, or a MT-3724 biosimilar.
Methods of Use
[0487] Idelalisib is a PI3K inhibitor studied for relapsed chronic
lymphocytic leukemia (CLL) in combination with rituximab. However,
the combination of idelalisib and a CD20 inhibitor (e.g., rituximab
or ofatumumab) has demonstrated an alarming increase in the risk of
death due to infection and/or severe adverse effects, limiting the
utility of the combination. Undesirable effects observed include
but are not limited to infections, neutropenia, diarrhea/colitis,
elevated liver transaminases (alanine aminotransferase/aspartate
aminotransferase>5.times. upper limit of normal), pneumonitis,
rash, hepatic impairment, renal impairment, pyrexia, increased
triglycerides, or combinations thereof. Combinations of a PI3K
inhibitor and a CD20 inhibitor with reduced side effects are needed
to effectively treat cancers described herein (e.g., CLL).
[0488] Some embodiments provided herein describe a method for
treating or preventing a proliferative disease or disorder
comprising administering a PI3K inhibitor in combination with a
CD20 inhibitor. In some embodiments provided herein is a method for
preventing relapse of a proliferative disease or disorder, the
method comprising administering a PI3K inhibitor in combination
with a CD20 inhibitor. In some embodiments provided herein is a
method for achieving and retaining partial cancer remission, the
method comprising administering a PI3K inhibitor in combination,
with a CD20 inhibitor. In some embodiments provided herein is a
method for achieving and retaining complete cancer remission, the
method comprising administering a PI3K inhibitor in combination
with a CD20 inhibitor. In some embodiments, the combination therapy
of a PI3K inhibitor described herein (e.g., a compound of Formula
(I)) and a CD20 inhibitor provides a synergistic effect. In some
embodiments, the combination therapy of a PI3K inhibitor described
herein (e.g., a compound of Formula (I)) and a CD20 inhibitor
provides a synergistic antitumor or anti-cancer activity. In
certain embodiments, the combination therapy described herein
permits the use of lower dosages of the PI3K inhibitor and/or the
CD20 inhibitor. In some embodiments, the combination therapy
described herein permits less frequent administration of the PI3K
inhibitor and/or the CD20 inhibitor to a subject. In some
embodiments, the combination therapy described herein reduces the
toxicity associated with the administration of the PI3K inhibitor
and/or the CD20 inhibitor to a subject without reducing the
efficacy in the prevention, management, treatment, or amelioration
of cancer, such as a B cell malignancy. In some embodiments, the
synergistic effect observed with the combination therapy described
herein results in improved efficacy of therapies in the prevention,
management, treatment, or amelioration of cancer, such as a B cell
malignancy.
[0489] In some embodiments, the combination therapy described
herein avoids or reduces adverse or unwanted side effects
associated with the use of the PI3K inhibitor and/or the CD20
inhibitor. In some embodiments, the combination therapy described
herein avoids, reduces, or minimizes the risk of death due to
infections. In some embodiments, the combination therapy described
herein avoids, reduces, or minimizes infections, neutropenia,
diarrhea/colitis, elevated liver transaminases (alanine
aminotransferase/aspartate aminotransferase>5.times. upper limit
of normal), pneumonitis, rash, hepatic impairment, renal
impairment, pyrexia, or increased triglycerides, or a combination
thereof in patients receiving the combination therapy. In certain
embodiments, the combination therapy described herein avoids,
reduces, or minimizes the incidence of infection associated with
the use of the PI3K inhibitor and/or the CD20 inhibitor. In certain
embodiments, the combination therapy described herein avoids,
reduces, or minimizes the incidence of neutropenia. In certain
embodiments, the combination therapy described herein avoids,
reduces, or minimizes the incidence of diarrhea/colitis. In certain
embodiments, the combination therapy described herein avoids,
reduces, or minimizes the incidence of elevated liver
transaminases. In certain embodiments, the combination therapy
described herein avoids, reduces, or minimizes the incidence of
pneumonitis. In certain embodiments, the combination therapy
described herein avoids, reduces, or minimizes the incidence of a
rash. In certain embodiments, the combination therapy described
herein avoids, reduces, or minimizes the incidence of hepatic
impairment or renal impairment. In certain embodiments, the
combination therapy described herein avoids, reduces, or minimizes
the incidence of pyrexia. In certain embodiments, the combination
therapy described herein avoids, reduces, or minimizes the
incidence of increased triglycerides. In certain embodiments, the
combination therapy described herein avoids, reduces, or minimizes
enterocolitis (manifested as diarrhea), cutaneous toxicities, liver
toxicity (manifested as elevation of transaminases), pulmonary
toxicity (manifested as non-infectious pneumonitis), infections, or
combinations thereof.
[0490] In some embodiments, the combination therapy described
herein provides a high objective response rate (ORR) as determined
by tumor assessment from radiological tests and/or physical
examination. In some embodiments, the combination therapy described
herein provides a durable response (DR) and/or increased durable
response rate (DRR; a continuous response [complete or partial
objective response] beginning within 12 months of treatment and
lasting.gtoreq.6 months) in the subject or patient. In some
embodiments, the combination therapy described herein provides
complete remission. In some embodiments, the combination therapy
described herein provides a better response compared to the
monotherapy treatment of a compound of formula (I) and/or a CD20
inhibitor. In some embodiments, the combination therapy described
herein provides complete remission beginning within 12 months of
treatment and lasting.gtoreq.6 months. In some embodiments, the
combination therapy described herein provides a complete response
(CR) and/or no evidence of disease (NED) beginning within 12 months
of treatment and lasting.gtoreq.6 months.
[0491] In certain embodiments, provided herein are methods for
treating or preventing a disease comprising administering an
effective amount of a compound of Formula (I), or an isotopic
variant thereof or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof and an effective amount of a CD20
inhibitor. In some embodiments, the compound of Formula (I) is
Compound A35 or an isotopic variant, pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof. In some embodiments,
the compound of Formula (I) is Compound A36 or an isotopic variant,
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof. In some embodiments, the compound of Formula (I) is
Compound A68 or an isotopic variant, pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof. In some embodiments,
the compound of Formula (I) is Compound A70 or an isotopic variant,
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof. In some embodiments, the compound of Formula (I) is
Compound A37 or an isotopic variant, pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof. In some embodiments,
the compound of Formula (I) is Compound A38 or an isotopic variant,
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof. In some embodiments, the compound of Formula (I) is
Compound A41 or an isotopic variant, pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof. In some embodiments,
the compound of Formula (I) is Compound A42 or an isotopic variant,
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof. In some embodiments, the compound of Formula (I) is
Compound A43 or an isotopic variant, pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof. In some embodiments,
the compound of Formula (I) is Compound A44 or an isotopic variant,
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof. In some embodiments, the compound of Formula (I) is
Compound A62 or an isotopic variant, pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof. In some embodiments,
the compound of Formula (I) is Compound A63 or an isotopic variant,
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof. In some embodiments, the compound of Formula (I) is
Compound A64 or an isotopic variant, pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof. In some embodiments,
the compound of Formula (I) is Compound A65 or an isotopic variant,
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof. In some embodiments, the compound of Formula (I) is
Compound A66 or an isotopic variant, pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof. In some embodiments,
the compound of Formula (I) is Compound A67 or an isotopic variant,
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof. In some embodiments, the CD20 inhibitor is ofatumumab,
obinutuzumab, rituximab, ocaratuzumab, ocrelizumab, tositumomab,
ibritumomab tiuxetan, tisotumab vedotin, ublituximab. TRU-015,
veltuzumab, BTCT4465A (RG7828), EDC9, MT-3724, or a variant or
biosimilar thereof. In some embodiments, the CD20 inhibitor is
rituximab.
[0492] In some embodiments, the compound of Formula (I) is Compound
A35 or an isotopic variant, pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof and the CD20 inhibitor is
rituximab, or a variant, or biosimilar thereof. In some
embodiments, the compound of Formula (I) is Compound A35 or an
isotopic variant, pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof and the CD20 inhibitor is obinutuzumab,
or a variant, or biosimilar thereof. In some embodiments, the
compound of Formula (I) is Compound A35 or an isotopic variant,
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof and the CD20 inhibitor is ofatumumab, or a variant, or
biosimilar thereof. In some embodiments, the compound of Formula
(I) is Compound A35 or an isotopic variant, pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof and the CD20
inhibitor is ocaratuzumab, or a variant, or biosimilar thereof. In
some embodiments, the compound of Formula (I) is Compound A35 or an
isotopic variant, pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof and the CD20 inhibitor is tositumomab,
or a variant, or biosimilar thereof. In some embodiments, the
compound of Formula (I) is Compound A35 or an isotopic variant,
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof and the CD20 inhibitor is ibritumomab tiuxetan, or a
variant, or biosimilar thereof. In some embodiments, the compound
of Formula (I) is Compound A35 or an isotopic variant,
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof and the CD20 inhibitor is ublituximab, or a variant, or
biosimilar thereof. In some embodiments, the compound of Formula
(I) is Compound A35 or an isotopic variant, pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof and the CD20
inhibitor is EDC9, or a variant, or biosimilar thereof. In some
embodiments, the compound of Formula (I) is Compound A35 or an
isotopic variant, pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof and the CD20 inhibitor is MT-3724, or a
variant, or biosimilar thereof.
[0493] In some embodiments, the compound of Formula (I) is Compound
A36 or an isotopic variant, pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof and the CD20 inhibitor is
rituximab, or a variant, or biosimilar thereof. In some
embodiments, the compound of Formula (I) is Compound A36 or an
isotopic variant, pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof and the CD20 inhibitor is obinutuzumab,
or a variant, or biosimilar thereof. In some embodiments, the
compound of Formula (I) is Compound A36 or an isotopic variant,
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof and the CD20 inhibitor is ofatumumab, or a variant, or
biosimilar thereof. In some embodiments, the compound of Formula
(I) is Compound A36 or an isotopic variant, pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof and the CD20
inhibitor is ocaratuzumab, or a variant, or biosimilar thereof. In
some embodiments, the compound of Formula (I) is Compound A36 or an
isotopic variant, pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof and the CD20 inhibitor is tositumomab,
or a variant, or biosimilar thereof. In some embodiments, the
compound of Formula (I) is Compound A36 or an isotopic variant,
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof and the CD20 inhibitor is ibritumomab tiuxetan, or a
variant, or biosimilar thereof. In some embodiments, the compound
of Formula (I) is Compound A36 or an isotopic variant,
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof and the CD20 inhibitor is ublituximab, or a variant, or
biosimilar thereof. In some embodiments, the compound of Formula
(I) is Compound A36 or an isotopic variant, pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof and the CD20
inhibitor is EDC9, or a variant, or biosimilar thereof. In some
embodiments, the compound of Formula (I) is Compound A36 or an
isotopic variant, pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof and the CD20 inhibitor is MT-3724, or a
variant, or biosimilar thereof.
[0494] In some embodiments, the compound of Formula (I) is Compound
A68 or an isotopic variant, pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof and the CD20 inhibitor is
rituximab, or a variant, or biosimilar thereof. In some
embodiments, the compound of Formula (I) is Compound A68 or an
isotopic variant, pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof and the CD20 inhibitor is obinutuzumab,
or a variant, or biosimilar thereof. In some embodiments, the
compound of Formula (I) is Compound A68 or an isotopic variant,
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof and the CD20 inhibitor is ofatumumab, or a variant, or
biosimilar thereof. In some embodiments, the compound of Formula
(I) is Compound A68 or an isotopic variant, pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof and the CD20
inhibitor is ocaratuzumab, or a variant, or biosimilar thereof. In
some embodiments, the compound of Formula (I) is Compound A68 or an
isotopic variant, pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof and the CD20 inhibitor is tositumomab,
or a variant, or biosimilar thereof. In some embodiments, the
compound of Formula (I) is Compound A68 or an isotopic variant,
pharmaceutically acceptable salt, solvate, hydrate or prodrug
thereof and the CD20 inhibitor is ibritumomab tiuxetan, or a
variant, or biosimilar thereof. In some embodiments, the compound
of Formula (I) is Compound A68 or an isotopic variant,
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof and the CD20 inhibitor is ublituximab, or a variant, or
biosimilar thereof. In some embodiments, the compound of Formula
(I) is Compound A68 or an isotopic variant, pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof and the CD20
inhibitor is EDC9, or a variant, or biosimilar thereof. In some
embodiments, the compound of Formula (I) is Compound A68 or an
isotopic variant, pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof and the CD20 inhibitor is MT-3724, or a
variant, or biosimilar thereof.
[0495] In some embodiments, the compound of Formula (I) is Compound
A70 or an isotopic variant, pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof and the CD20 inhibitor is
rituximab, or a variant, or biosimilar thereof. In some
embodiments, the compound of Formula (I) is Compound A70 or an
isotopic variant, pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof and the CD20 inhibitor is obinutuzumab,
or a variant, or biosimilar thereof. In some embodiments, the
compound of Formula (I) is Compound A70 or an isotopic variant,
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof and the CD20 inhibitor is ofatumumab, or a variant, or
biosimilar thereof. In some embodiments, the compound of Formula
(I) is Compound A70 or an isotopic variant, pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof and the CD20
inhibitor is ocaratuzumab, or a variant, or biosimilar thereof. In
some embodiments, the compound of Formula (I) is Compound A70 or an
isotopic variant, pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof and the CD20 inhibitor is tositumomab,
or a variant, or biosimilar thereof. In some embodiments, the
compound of Formula (I) is Compound A70 or an isotopic variant,
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof and the CD20 inhibitor is ibritumomab tiuxetan, or a
variant, or biosimilar thereof. In some embodiments, the compound
of Formula (I) is Compound A70 or an isotopic variant,
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof and the CD20 inhibitor is ublituximab, or a variant, or
biosimilar thereof. In some embodiments, the compound of Formula
(I) is Compound A70 or an isotopic variant, pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof and the CD20
inhibitor is EDC9, or a variant, or biosimilar thereof. In some
embodiments, the compound of Formula (I) is Compound A70 or an
isotopic variant, pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof and the CD20 inhibitor is MT-3724, or a
variant, or biosimilar thereof.
[0496] In some embodiments, the compound of Formula (I) is Compound
A37 or an isotopic variant, pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof and the CD20 inhibitor is
rituximab, or a variant, or biosimilar thereof. In some
embodiments, the compound of Formula (I) is Compound A37 or an
isotopic variant, pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof and the CD20 inhibitor is obinutuzumab,
or a variant, or biosimilar thereof. In some embodiments, the
compound of Formula (I) is Compound A37 or an isotopic variant,
pharmaceutically acceptable salt, solvate, hydrate or prodrug
thereof and the CD20 inhibitor is ofatumumab, or a variant, or
biosimilar thereof. In some embodiments, the compound of Formula
(I) is Compound A37 or an isotopic variant, pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof and the CD20
inhibitor is ocaratuzumab, or a variant, or biosimilar thereof. In
some embodiments, the compound of Formula (I) is Compound A37 or an
isotopic variant, pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof and the CD20 inhibitor is tositumomab,
or a variant, or biosimilar thereof. In some embodiments, the
compound of Formula (I) is Compound A37 or an isotopic variant,
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof and the CD20 inhibitor is ibritumomab tiuxetan, or a
variant, or biosimilar thereof. In some embodiments, the compound
of Formula (I) is Compound A37 or an isotopic variant,
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof and the CD20 inhibitor is ublituximab, or a variant, or
biosimilar thereof. In some embodiments, the compound of Formula
(I) is Compound A37 or an isotopic variant, pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof and the CD20
inhibitor is EDC9, or a variant, or biosimilar thereof. In some
embodiments, the compound of Formula (I) is Compound A37 or an
isotopic variant, pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof and the CD20 inhibitor is MT-3724, or a
variant, or biosimilar thereof.
[0497] In some embodiments, the proliferative disease is cancer. In
certain embodiments, the proliferative disease is a hematological
malignancy.
[0498] In certain embodiments, the cancer treatable with the
methods provided herein includes, but is not limited to, (1)
leukemias, including, but not limited to, acute leukemia, acute
lymphocytic leukemia, acute myelocytic leukemias such as
myeloblastic, promyelocytic, myelomonocytic, monocytic,
erythroleukemia leukemias and myelodysplastic syndrome or a symptom
thereof (such as anemia, thrombocytopenia, neutropenia, bicytopenia
or pancytopenia), refractory anemia (RA), RA with ringed
sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in
transformation (RAEB-T), preleukemia, and chronic myelomonocytic
leukemia (CMML), (2) chronic leukemias, including but not limited
to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic
leukemia, and hairy cell leukemia; (3) polycythemia vera; (4)
lymphomas, including, but not limited to, Hodgkin's disease and
non-Hodgkin's disease; (5) multiple myelomas, including, but not
limited to, smoldering multiple myeloma, non-secretory myeloma,
osteosclerotic myeloma, plasma cell leukemia, solitary
plasmacytoma, and extramedullary plasmacytoma; (6) Waldenstrom's
macroglobulinemia; (7) monoclonal gammopathy of undetermined
significance; (8) benign monoclonal gammopathy; (9) heavy chain
disease; (10) bone and connective tissue sarcomas, including, but
not limited to, bone sarcoma, osteosarcoma, chondrosarcoma, Ewing's
sarcoma, malignant giant cell tumor, fibrosarcoma of bone,
chordoma, periosteal sarcoma, soft-tissue sarcomas, angiosarcoma
(hemangiosarcoma), fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma,
liposarcoma, lymphangiosarcoma, metastatic cancers, neurilemmoma,
rhabdomyosarcoma, and synovial sarcoma; (11) brain tumors,
including, but not limited to, glioma, astrocytoma, brain stem
glioma, ependymoma, oligodendroglioma, nonglial tumor, acoustic
neurinoma, craniopharyngioma, medulloblastoma, meningioma,
pineocytoma, pineoblastoma, and primary brain lymphoma; (12) breast
cancer, including, but not limited to, adenocarcinoma, lobular
(small cell) carcinoma, intraductal carcinoma, medullary breast
cancer, mutinous breast cancer, tubular breast cancer, papillary
breast cancer, primary cancers, Paget's disease, and inflammatory
breast cancer; (13) adrenal cancer, including but not limited to,
pheochromocytoma and adrenocortical carcinoma; (14) thyroid cancer,
including, but not limited to, papillary or follicular thyroid
cancer, medullary thyroid cancer, and anaplastic thyroid cancer;
(15) pancreatic cancer, including, but not limited to, insulinoma,
gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and
carcinoid or islet cell tumor; (16) pituitary cancer, including,
but limited to, Cushing's disease, prol actin-secreting tumor,
acromegaly, and diabetes insipidus; (17) eye cancer, including, but
not limited, to ocular melanoma such as iris melanoma, choroidal
melanoma, and ciliary body melanoma, and retinoblastoma; (18)
vaginal cancer, including, but not limited to, squamous cell
carcinoma, adenocarcinoma, and melanoma; (19) vulvar cancer,
including, but not limited to, squamous cell carcinoma, melanoma,
adenocarcinoma, basal cell carcinoma, sarcoma, and Paget's disease;
(20) cervical cancers, including, but not limited to, squamous cell
carcinoma, and adenocarcinoma; (21) uterine cancer, including, but
not limited to, endometrial carcinoma and uterine sarcoma; (22)
ovarian cancer, including, but not limited to, ovarian epithelial
carcinoma, borderline tumor, germ cell tumor, and stromal tumor.
(23) esophageal cancer, including, but not limited to, squamous
cancer, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid
carcinoma, adenosquamous carcinoma, sarcoma, melanoma,
plasmacytoma, verrucous carcinoma, and oat cell (small cell)
carcinoma; (24) stomach cancer, including, but not limited to,
adenocarcinoma, fungating (polyploid), ulcerating, superficial
spreading, diffusely spreading, malignant lymphoma, liposarcoma,
fibrosarcoma, and carcinosarcoma; (25) colon cancer; (26) rectal
cancer; (27) liver cancer, including, but not limited to,
hepatocellular carcinoma and hepatoblastoma; (28) gallbladder
cancer, including, but not limited to, adenocarcinoma; (29)
cholangiocarcinoma, including, but not limited to, papillary,
nodular, and diffuse; (30) lung cancer, including, but not limited
to, non-small cell lung cancer, squamous cell carcinoma (epidermoid
carcinoma), adenocarcinoma, large-cell carcinoma, and small-cell
lung cancer; (31) testicular cancer, including, but not limited to,
germinal tumor, seminoma, anaplastic, classic (typical),
spermatocyte, nonserninoma, embryonal carcinoma, teratoma
carcinoma, and choriocarcinoma (yolk-sac tumor); (32) prostate
cancer, including, but not limited to, adenocarcinoma,
leiomyosarcoma, and rhabdomyosarcoma; (33) penal cancer; (34) oral
cancer, including, but not limited to, squamous cell carcinoma;
(35) basal cancer; (36) salivary gland cancer, including, but not
limited to, adenocarcinoma, mucoepidermoid carcinoma, and
adenoidcystic carcinoma; (37) pharynx cancer, including, but not
limited to, squamous cell cancer and verrucous; (38) skin cancer,
including, but not limited to, basal cell carcinoma, squamous cell
carcinoma and melanoma, superficial spreading melanoma, nodular
melanoma, lentigo malignant melanoma, and acral lentiginous
melanoma; (39) kidney cancer, including, but not limited to, renal
cell cancer, adenocarcinoma, hypernephroma, fibrosarcoma, and
transitional cell cancer (renal pelvis and/or uterer); (40) Wilms'
tumor, (41) bladder cancer, including, but not limited to,
transitional cell carcinoma, squamous cell cancer, adenocarcinoma,
and carcinosarcoma; (42) reproductive cancers, such as cervical
cancer, uterus cancer, ovarian cancer, or testicular cancer; (43)
esophagus cancer; (44) laryngeal cancer; (45) head and neck cancer
(such as mouth, nose, throat, larynx, sinuses, or salivary glands
cancer); and other cancer, including, not limited to, myxosarcoma,
osteogenic sarcoma, endotheliosarcoma,
lymphangio-endotheliosarcoma, mesothelioma, synovioma,
hemangioblastoma, epithelial carcinoma, cystadenocarcinoma,
bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland
carcinoma, papillary carcinoma, and papillary adenocarcinomas (See
Fishman et al., 1985, Medicine, 2d Ed., J.B. Lippincott Co.,
Philadelphia and Murphy et al., 1997, Informed Decisions: The
Complete Book of Cancer Diagnosis, Treatment, and Recovery, Viking
Penguin, Penguin Books U.S.A., Inc., United States of America). In
some embodiments, the cancer is non-small cell lung cancer,
melanoma, renal cell cancer, head and neck cancer, colon cancer, or
mesothelioma. In some embodiments, the cancer is non-small cell
lung cancer. In some embodiments, the cancer is melanoma.
[0499] In certain embodiments, provided herein are methods of
treating hematological malignancy with a combination of an
effective amount of a compound of Formula (I), or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof and an effective amount of CD20
inhibitor in a patient. In certain embodiments, the hematological
malignancy is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's
lymphoma, a Hodgkin's lymphoma, T-cell malignancy, or a B-cell
malignancy. In some embodiments, the hematological malignancy is
Hodgkin's lymphoma.
[0500] In certain embodiments, the hematological malignancy is a
T-cell malignancy. In certain embodiments, T-cell malignancies
include peripheral T-cell lymphoma not otherwise specified
(PTCL-NOS), anaplastic large cell lymphoma, angioimmunoblastic
lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma
(ATLL), blastic NK-cell lymphoma, enteropathy-type T-cell lymphoma,
hepatosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma,
nasal NK/T-cell lymphomas, or treatment-related T-cell
lymphomas.
[0501] In certain embodiments, the hematological malignancy is a
B-cell malignancy. In some embodiments, the synergistic combination
a PI3K inhibitor described herein and a CD20 inhibitor is used in
the treatment of B cell malignancies. In certain embodiments, B
cell malignancies include acute lymphoblastic leukemia (ALL), acute
myelogenous leukemia (AML), chronic myelogenous leukemia (CML),
acute monocytic leukemia (AMoL), chronic lymphocytic leukemia
(CLL), high-risk chronic lymphocytic leukemia (CLL), small
lymphocytic lymphoma (SLL), high-risk small lymphocytic lymphoma
(SLL), follicular lymphoma (FL), diffuse large B-cell lymphoma
(DLBCL), mantle cell lymphoma (MCL), Waldenstrom's
macroglobulinemia, multiple myeloma, extranodal marginal zone B
cell lymphoma, nodal marginal zone B cell lymphoma, Burkitts
lymphoma, non-Burkitt high grade B cell lymphoma, primary
mediastinal B-cell lymphoma (PMBL), immunoblastic large cell
lymphoma, precursor B-lymphoblastic lymphoma. B cell prolymphocytic
leukemia, lymphoplasmacytic lymphoma, splenic marginal zone
lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic)
large B cell lymphoma, intravascular large B cell lymphoma, primary
effusion lymphoma, or lymphomatoid granulomatosis. In certain
embodiments, the B cell malignancy is selected from non-Hodgkin's
lymphoma, Burkitt's lymphoma, small lymphocytic lymphoma, primary
effusion lymphoma, diffuse large B-cell lymphoma, splenic marginal
zone lymphoma, MALT (mucosa-associated lymphoid tissue) lymphoma,
hairy cell leukemia, chronic lymphocytic leukemia, B-cell
prolymphocytic leukemia, B cell lymphomas (e.g. various forms of
Hodgkin's disease, B cell non-Hodgkin's lymphoma (NHL), leukemias
(e.g. acute lymphoblastic leukemia (ALL), chronic lymphocytic
leukemia (CLL; also termed B cell chronic lymphocytic leukemia
BCLL), hairy cell leukemia and chronic myoblastic leukemia) and
myelomas (e.g. multiple myeloma). In certain embodiments, the
B-cell malignancy is diffuse large B-cell lymphoma (DLBCL). In
certain embodiments, the hematological malignancy is diffuse large
B-cell lymphoma (DLBCL). In certain embodiments, the DLBCL is an
activated B-cell DLBCL (ABC-DLBCL), a germinal center B-cell like
DLBCL (GBC-DLBCL), a double hit DLBCL (DH-DLBCL), or a triple hit
DLBCL (TH-DLBCL). In some embodiments, the hematological malignancy
is B-cell non-Hodgkin's lymphoma (NHL). In some embodiments, the
hematological malignancy is B-cell indolent non-Hodgkin's lymphoma
(NHL). In certain embodiments, the B-cell malignancy is selected
from chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma
(SLL), follicular lymphoma (FL), marginal zone B cell lymphoma
(MZL), diffuse large B-cell lymphoma (DLBCL), and high grade
non-Hodgkin's lymphoma. In certain embodiments, the B-cell
malignancy is selected from chronic lymphocytic leukemia (CLL),
follicular lymphoma (FL), marginal zone B cell lymphoma (MZL), or
diffuse large B-cell lymphoma (DLBCL).
[0502] In certain embodiments, the hematological malignancy is a
relapsed or refractory hematological malignancy. In certain
embodiments, the relapsed or refractory hematological malignancy is
a relapsed or refractory T-cell malignancy. In certain embodiments,
the relapsed or refractory hematological malignancy is a relapsed
or refractory B-cell malignancy. In some embodiments, the cancer is
relapsed B-cell non-Hodgkin's lymphoma (NHL) or chronic lymphocytic
leukemia (CLL). In some embodiments, the hematological malignancy
is relapsed B-cell non-Hodgkin's lymphoma (NHL) or chronic
lymphocytic leukemia (CLL).
Dosages and Dosing Regimens
[0503] Depending on the disorder, disease, or condition to be
treated, and the subject's condition, the compounds or
pharmaceutical compositions provided herein can be administered by
oral, parenteral (e.g., intramuscular, intraperitoneal,
intravenous, ICV, intracisternal injection or infusion,
subcutaneous injection, or implant), inhalation, nasal, vaginal,
rectal, sublingual, or topical (e.g., transdermal or local) routes
of administration and can be formulated, alone or together, in
suitable dosage unit with pharmaceutically acceptable excipients,
carriers, adjuvants, and vehicles appropriate for each route of
administration as described elsewhere herein.
[0504] In certain embodiments, the methods provided herein comprise
administering a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof and a CD20 inhibitor to a patient simultaneously
or sequentially by the same or different routes of
administration.
[0505] The suitability of a particular route of administration
employed for a particular active agent will depend on the active
agent itself (e.g., whether it can be administered orally without
decomposing prior to entering the blood stream) and the disease
being treated.
[0506] In certain embodiments, the compound of Formula (I), or an
isotopic variant thereof, or a pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof and a CD20 inhibitor is
administered simultaneously, at essentially the same time, or
sequentially. If administration takes place sequentially the CD20
inhibitor may be administered before or after administration of a
compound of Formula (I), or an isotopic variant thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof. In some embodiments, the CD20 inhibitor is administered
before administration of a compound of Formula (I), or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof. In some embodiments, the CD20
inhibitor is administered simultaneously with administration of a
compound of Formula (I), an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof. In some embodiments, the CD20 inhibitor is administered
after the administration of a compound of Formula (I), an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof.
[0507] A compound of Formula (I), or an isotopic variant thereof or
a pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof and the CD20 inhibitor need not be administered by means of
the same vehicle. In some embodiments, the CD20 inhibitor and a
compound of Formula (I), or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof are administered in different vehicles. The CD20 inhibitor
may be administered one or more times, and the number of
administrations of each component of the combination may be the
same or different. In addition, a compound of Formula (I), or an
isotopic variant thereof or a pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof and the CD20 inhibitor need
not be administered at the same site.
[0508] In some instances, the methods described herein further
comprise administering the PI3K inhibitor in combination with CD20
inhibitor to the subject or patient in need thereof in multiple
cycles repeated on a regular schedule with periods of rest in
between each cycle. For example, in some instances, treatment is
given for one week followed by three weeks of rest is one treatment
cycle.
[0509] In some instances, a cycle comprises administration of the
PI3K inhibitor at the same time as administration of the CD20
inhibitor. In some instances, the PI3K inhibitor and the CD20
inhibitor are administered for about 1 day, about 2 days, about 3
days, about 4 days, about 5 days, about 6 days, about 7 days, about
8 days, about 9 days, about 10 days, about 11 days, about 12 days,
about 13 days, about 14 days, about 15 days, about 16 days, about
17 days, about 18 days, about 19 days, about 20 days, about 21
days, about 22 days, about 23 days, about 24 days, about 25 days,
about 26 days, about 27 days, or about 28 days.
[0510] In some instances, a cycle comprises administration of the
PI3K inhibitor first followed by administration of the CD20
inhibitor second. In some instances, the PI3K inhibitor is
administered for about 1 day, about 2 days, about 3 days, about 4
days, about 5 days, about 6 days, about 7 days, about 8 days, about
9 days, about 10 days, about 11 days, about 12 days, about 13 days,
or about 14 days followed by administration of the CD20 inhibitor
for about 1 day, about 2 days, about 3 days, about 4 days, about 5
days, about 6 days, about 7 days, about 8 days, about 9 days, about
10 days, about 11 days, about 12 days, about 13 days, or about 14
days.
[0511] In some instances, a cycle comprises administration of the
PI3K inhibitor first followed by concurrent administration of the
CD20 inhibitor. In some instances, the PI3K inhibitor is first
administered for about 1 day, about 2 days, about 3 days, about 4
days, about 5 days, about 6 days, about 7 days, about 8 days, about
9 days, about 10 days, about 11 days, about 12 days, about 13 days,
or about 14 days followed by the concurrent administration of the
CD20 inhibitor for about 1 day, about 2 days, about 3 days, about 4
days, about 5 days, about 6 days, about 7 days, about 8 days, about
9 days, about 10 days, about 11 days, about 12 days, about 13 days,
or about 14 days. In some instances, the PI3K inhibitor is first
administered for about 1 day, about 2 days, about 3 days, about 4
days, about 5 days, about 6 days, or about 7 days followed by the
concurrent administration of the CD20 inhibitor for about 1 day,
about 2 days, about 3 days, about 4 days, about 5 days, about 6
days, about 7 days, about 8 days, about 9 days, about 10 days,
about 11 days, about 12 days, about 13 days, or about 14 days. In
some instances, the PI3K inhibitor is first administered for about
7 days followed by the concurrent administration of the CD20
inhibitor for about 1 day, about 2 days, about 3 days, about 4
days, about 5 days, about 6 days, about 7 days, about 8 days, about
9 days, about 10 days, about 11 days, about 12 days, about 13 days,
or about 14 days. In some instances, the PI3K inhibitor is first
administered for about 7 days followed by the concurrent
administration of the CD20 inhibitor for about 10 days, about 11
days, about 12 days, about 13 days, or about 14 days.
[0512] In some instances, a cycle comprises administration of the
PI3K inhibitor only. In some instances, the PI3K inhibitor is
administered for about 1 day, about 2 days, about 3 days, about 4
days, about 5 days, about 6 days, about 7 days, about 8 days, about
9 days, about 10 days, about 11 days, about 12 days, about 13 days,
about 14 days, about 15 days, about 16 days, about 17 days, about
18 days, about 19 days, about 20 days, about 21 days, about 22
days, about 23 days, about 24 days, about 25 days, about 26 days,
about 27 days, or about 28 days.
[0513] In some instances, a cycle comprises administration of the
CD20 inhibitor only. In some instances, the CD20 inhibitor is
administered for about 1 day, about 2 days, about 3 days, about 4
days, about 5 days, about 6 days, about 7 days, about 8 days, about
9 days, about 10 days, about 11 days, about 12 days, about 13 days,
about 14 days, about 15 days, about 16 days, about 17 days, about
18 days, about 19 days, about 20 days, about 21 days, about 22
days, about 23 days, about 24 days, about 25 days, about 26 days,
about 27 days, or about 28 days.
[0514] In some instances, the method for multiple cycle
chemotherapy comprises the administration of a second cycle within
about 60 days or about 3 months. In some instances, the method for
multiple cycle chemotherapy comprises the administration of a
second cycle within 50 days. In another instance, the second cycle
is administered within 45, 40, 35, 30, 25, 21, 20, 15, 14, 10, 9,
8, 7, 6, 5, 4, 3, 2 or 1 day(s) of the first cycle. In some
embodiments, the administration of any additional cycles is within
50 days of the previous cycle. In some embodiments, the
administration of any additional cycles is within 10 days of the
previous cycle. In some embodiments, the administration of any
additional cycles is within 9 days of the previous cycle. In some
embodiments, the administration of any additional cycles is within
8 days of the previous cycle. In some embodiments, the
administration of any additional cycles is within 7 days of the
previous cycle. In some embodiments, the administration of any
additional cycles is within 6 days of the previous cycle. In some
embodiments, the administration of any additional cycles is within
5 days of the previous cycle. In some embodiments, the
administration of any additional cycles is within 4 days of the
previous cycle. In some embodiments, the administration of any
additional cycles is within 3 days of the previous cycle. In some
embodiments, the administration of any additional cycles is within
2 days of the previous cycle. In some embodiments, the
administration of any additional cycles is within 1 day of the
previous cycle. In another embodiment, the additional cycle is
administered within 45, 40, 35, 30, 25, 21, 20, 15, 14, 10, 9, 8,
7, 6, 5, 4, 3, 2, or 1 days of the previous cycle.
[0515] The length of a treatment cycle depends on the treatment
being given. In some embodiments, the length of a treatment cycle
ranges from two to six weeks. In some embodiments, the length of a
treatment cycle ranges from four to six weeks. In some embodiments,
the length of a treatment cycle is 28 days. In some embodiments,
the length of a treatment cycle is 56 days. In some embodiments, a
treatment cycle lasts one, two, three, or four weeks. In some
embodiments, a treatment cycle lasts four weeks. The number of
treatment doses scheduled within each cycle also varies depending
on the drugs being given.
[0516] In certain instances, the compound of Formula (I), or an
isotopic variant thereof; or a pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof, is administered to the
subject on a 28-day cycle. In some embodiments, the compound of
Formula (I), or an isotopic variant thereof; or a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof, is
administered to the subject for at least one 28-day cycle. In some
embodiments, the compound of Formula (I), or an enantiomer, a
mixture of enantiomers, a mixture of two or more diastereomers, or
an isotopic variant thereof; or a pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof, is administered to the
subject for at least two 28-day cycles.
[0517] In certain embodiments, the compound of Formula (I), or an
enantiomer, a mixture of enantiomers, a mixture of two or more
diastereomers, or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, is administered to the subject for a period of up to about
7 days. In some embodiments, the days over which the compound of
Formula (I), or an enantiomer, a mixture of enantiomers, a mixture
of two or more diastereomers, or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof are intermittent. In some embodiments, administering to
subject the compound of Formula (I), or an enantiomer, a mixture of
enantiomers, a mixture of two or more diastereomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof for about 7 consecutive days in a
28-day cycle.
[0518] In some embodiments, the method comprises an intermittent
dosing schedule (IS), comprising administering to subject the
compound of Formula (I), or an enantiomer, a mixture of
enantiomers, a mixture of two or more diastereomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof once daily for 7 consecutive days
followed by 21 days without treatment in a 28-day cycle. In some
embodiments, the compound of Formula (I), or an enantiomer, a
mixture of enantiomers, a mixture of two or more diastereomers, or
an isotopic variant thereof; or a pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof, is administered to the
subject for at least one 28-day cycle. In some embodiments, the IS
avoids or reduces adverse or unwanted side effects associated with
the use of the PI3K inhibitor, such as enterocolitis (manifested as
diarrhea), cutaneous toxicities, liver toxicity (manifested as
elevation of transaminases), pulmonary toxicity (manifested as
non-infectious pneumonitis), and infections. In some embodiments,
the IS avoids or reduces enterocolitis, rash, transaminitis, or
combinations thereof.
[0519] In some embodiments, the method comprises a continuous daily
dosing schedule (CS), comprising administering to subject the
compound of Formula (I), or an enantiomer, a mixture of
enantiomers, a mixture of two or more diastereomers, or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof once daily for 28 consecutive days in a
28-day cycle. In some embodiments, the compound of Formula (I), or
an enantiomer, a mixture of enantiomers, a mixture of two or more
diastereomers, or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof, is administered to the subject for at least two CS 28-day
cycles. In certain instances, the method comprises a continuous
daily dosing schedule (CS) for at least two CS 28-day cycles,
followed by an intermittent dosing schedule (IS), comprising
administering to subject the compound of Formula (I), or an
enantiomer, a mixture of enantiomers, a mixture of two or more
diastereomers, or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof once daily for 7 consecutive days followed by 21 days
without treatment in a 28-day cycle after the at least two CS
28-day cycles. In some embodiments, the dosing schedule avoids or
reduces adverse or unwanted side effects associated with the use of
the PI3K inhibitor, such as enterocolitis (manifested as diarrhea),
cutaneous toxicities, liver toxicity (manifested as elevation of
transaminases), pulmonary toxicity (manifested as non-infectious
pneumonitis), and infections. In some embodiments, the dosing
schedule avoids or reduces enterocolitis, rash, transaminitis, or
combinations thereof.
[0520] In some instances, the method for the administration of
multiple compounds comprises administering compounds within 48
hours or less of each other. In some embodiments administration
occurs within 24 hours, 12 hours, 6 hours, 3 hours, 1 hour, or 15
minutes. In some instances, the compounds are administered
simultaneously. One example of simultaneous administration is the
injection of one compound immediately before, after, or during the
oral administration of the second compound, immediately referring
to a time less than about 5 minutes.
[0521] In some instances, the method for the administration of
multiple compounds occurs in a sequential order, wherein the PI3K
inhibitor is administered before the CD20 inhibitor. In another
instance, the CD20 inhibitor is administered before the PI3K
inhibitor.
[0522] In some instances, the method for administering the PI3K
inhibitor is oral and the method for administering the CD20
inhibitor is by injection. In some instances, the method for
administering the PI3K inhibitor is by inhalation and the method
for administering the CD20 inhibitor is by injection. In some
instances, the method for administering the PI3K inhibitor is by
injection and the method for administering the CD20 inhibitor is by
injection.
[0523] In certain embodiments, a compound of Formula (I), or an
isotopic variant thereof; or a pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof and a CD20 inhibitor is
cyclically administered to a patient. As discussed above, cycling
therapy involves the administration of an active agent or a
combination of active agents for a period of time, followed by a
rest for a period of time, and repeating this sequential
administration. In some embodiments, cycling therapy reduces the
development of resistance to one or more of the therapies, avoid or
reduce the side effects of one of the therapies, and/or improves
the efficacy of the treatment.
[0524] In some embodiments, the compound of Formula (I) is
administered daily, every other day, every other day 3 times a
week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks,
every 3 days, every 4 days, every 5 days, every 6 days, weekly,
bi-weekly, 3 times a week, 4 times a week, 5 times a week, 6 times
a week, once a month, twice a month, 3 times a month, once every 2
months, once every 3 months, once every 4 months, once every 5
months, or once every 6 months. In some embodiments, the compound
of Formula (I) is administered daily. In some embodiments, the
compound of Formula (I) is administered daily for a period of up to
about 28 days. In some embodiments, the compound of Formula (I) is
administered daily for a period of up to about 7 days.
[0525] In some embodiments, the CD20 inhibitor is administered
daily, every other day, every other day 3 times a week, every 3
days, every 4 days, every 5 days, every 6 days, weekly, every 2
weeks, every 3 weeks, every 4 weeks, every 5 weeks, bi-weekly, 3
times a week, 4 times a week, 5 times a week, 6 times a week, once
a month, twice a month, 3 times a month, once every 2 months, once
every 3 months, once every 4 months, once every 5 months, or once
every 6 months. In some embodiments, the CD20 inhibitor is
administered 8 times in 6 months.
[0526] In some instances, the compound of Formula (I) or the CD20
inhibitor is optionally given continuously; alternatively, the dose
of drug being administered is temporarily reduced or temporarily
suspended for a certain length of time (i.e., a "drug holiday"). In
some embodiments, the length of the drug holiday varies between 2
days and 1 year, including by way of example only, 2 days. 3 days,
4 days. 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 12 days,
14 days, 15 days, 20 days, 21 days, 28 days, 35 days, 50 days, 70
days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days,
280 days, 300 days, 320 days, 350 days, or 365 days. The dose
reduction during a drug holiday includes from 10%-10.sup.0%,
including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%,
40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or
100%.
[0527] In certain embodiments, in the treatment, prevention, or
amelioration of one or more symptoms of the disorders, diseases, or
conditions described herein, an appropriate dosage level of a
compound of Formula (I), or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof generally is ranging from about 1 to 1000 mg, from about 1
to about 500 mg, from about 5 to about 500 mg, from about 5 to
about 200 mg, from about 5 to about 250 mg or from about 10 to
about 150 mg which can be administered in single or multiple doses.
In certain embodiments, the compound of Formula (I), or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof is administered in an amount of about
1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80,
85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150,
155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 225, 250, 275,
300, 325, 350, 375, 400, 450 or 500 mg. In certain embodiments, the
compound of Formula (I), or an isotopic variant thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof is administered in an amount of about 60 mg, about 120 mg,
about 150 mg, or about 180 mg. In certain embodiments, the compound
of Formula (I), or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof is administered in an amount of about 60 mg. In certain
embodiments, the compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof is administered in an amount of about 1, about
5, about 10, about 15, about 20, about 25, about 30, about 35,
about 40, about 45, about 50, about 55, about 60, about 65, about
70, about 75, about 80, about 85, about 90, about 95, about 100,
about 105, about 110, about 115, about 120, about 125, about 130,
about 135, about 140, about 145, about 150, about 155, about 160,
about 165, about 170, about 175, about 180, about 185, about 190,
about 195, about 200, about 225, about 250, about 275, about 300,
about 325, about 350, about 375, about 400, about 450, or about 500
mg/day. In certain embodiments, the compound of Formula (I), or an
isotopic variant thereof; or a pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof is administered in an amount
of about 45 mg/day. In certain embodiments, the compound of Formula
(I), or an isotopic variant thereof; or a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof is
administered in an amount of about 60 mg/day. In certain
embodiments, the compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof is administered in an amount of about 90 mg/day.
In certain embodiments, the compound of Formula (I), or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof is administered in an amount of about
120 mg/day. In certain embodiments, the compound of Formula (I), or
an isotopic variant thereof; or a pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof is administered in an amount
of about 150 mg/day. In certain embodiments, the compound of
Formula (I), or an isotopic variant thereof; or a pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof is
administered in an amount of about 180 mg/day.
[0528] For oral administration, the pharmaceutical compositions
provided herein can be formulated in the form of tablets containing
from about 1.0 to about 1,000 mg of a compound of Formula (I), or
an isotopic variant thereof; or a pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof, in one embodiment, about 1,
about 5, about 10, about 15, about 20, about 25, about 50, about
75, about 100, about 150, about 200, about 250, about 300, about
400, about 500, about 600, about 750, about 800, about 900, and
about 1,000 mg of the a compound of Formula (I), or an isotopic
variant thereof; or a pharmaceutically acceptable salt, solvate,
hydrate, or prodrug thereof for the symptomatic adjustment of the
dosage to the patient to be treated.
[0529] In some embodiments, the pharmaceutical compositions
provided herein can be formulated in the form of tablets containing
about 45 mg of a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof. The pharmaceutical compositions can be
administered on a regimen of 1 to 4 times per day, including once,
twice, three times, and four times per day. In certain embodiments,
a compound of Formula (I), or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof is administered to a patient in need thereof in an amount
of about 45 mg daily for 28 days or 56 days. In certain specific
embodiments, a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof is administered to a patient in need thereof in
an amount of about 45 mg daily for 28 days. In other specific
embodiments, a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof is administered to a patient in need thereof in
an amount of about 45 mg daily for 56 days.
[0530] In some embodiments, the pharmaceutical compositions
provided herein can be formulated in the form of tablets containing
about 60 mg of a compound of Formula (I), or an isotopic variant
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof. The pharmaceutical compositions can be
administered on a regimen of 1 to 4 times per day, including once,
twice, three times, and four times per day. In certain embodiments,
a compound of Formula (I), or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof is administered to a patient in need thereof in an amount
of about 60 mg daily for 28 days or 56 days. In certain specific
embodiments, a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof is administered to a patient in need thereof in
an amount of about 60 mg daily for 28 days. In other specific
embodiments, a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof is administered to a patient in need thereof in
an amount of about 60 mg daily for 56 days.
[0531] In some embodiments, the pharmaceutical compositions
provided herein can be formulated in the form of tablets containing
about 90 mg of a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof. The pharmaceutical compositions can be
administered on a regimen of 1 to 4 times per day, including once,
twice, three times, and four times per day. In certain embodiments,
a compound of Formula (I), or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof is administered to a patient in need thereof in an amount
of about 90 mg daily for 28 days or 56 days. In certain specific
embodiments, a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof is administered to a patient in need thereof in
an amount of about 90 mg daily for 28 days. In other specific
embodiments, a compound of Formula (I), or an isotopic variant
thereof or a pharmaceutically acceptable salt, solvate, hydrate, or
prodrug thereof is administered to a patient in need thereof in an
amount of about 90 mg daily for 56 days.
[0532] In some embodiments, the pharmaceutical compositions
provided herein can be formulated in the form of tablets containing
about 120 mg of a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof. The pharmaceutical compositions can be
administered on a regimen of 1 to 4 times per day, including once,
twice, three times, and four times per day. In certain embodiments,
a compound of Formula (I), or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof is administered to a patient in need thereof in an amount
of about 120 mg daily for 28 days or 56 days. In certain specific
embodiments, a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof is administered to a patient in need thereof in
an amount of about 120 mg daily for 28 days. In other specific
embodiments, a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof is administered to a patient in need thereof in
an amount of about 120 mg daily for 56 days.
[0533] In some embodiments, the pharmaceutical compositions
provided herein can be formulated in the form of tablets containing
about 150 mg of a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof. The pharmaceutical compositions can be
administered on a regimen of 1 to 4 times per day, including once,
twice, three times, and four times per day. In certain embodiments,
a compound of Formula (I), or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof is administered to a patient in need thereof in an amount
of about 150 mg daily for 28 days or 56 days. In certain specific
embodiments, a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof is administered to a patient in need thereof in
an amount of about 150 mg daily for 28 days. In other specific
embodiments, a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof is administered to a patient in need thereof in
an amount of about 150 mg daily for 56 days.
[0534] In some embodiments, the pharmaceutical compositions
provided herein can be formulated in the form of tablets containing
about 180 mg of a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof. The pharmaceutical compositions can be
administered on a regimen of 1 to 4 times per day, including once,
twice, three times, and four times per day. In certain embodiments,
a compound of Formula (I), or an isotopic variant thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof is administered to a patient in need thereof in an amount
of about 180 mg daily for 28 days or 56 days. In certain specific
embodiments, a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof is administered to a patient in need thereof in
an amount of about 180 mg daily for 28 days. In other specific
embodiments, a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof is administered to a patient in need thereof in
an amount of about 180 mg daily for 56 days.
[0535] In certain embodiments, the CD20 inhibitor used in
combination with a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug, is rituximab. In certain embodiments, the methods
described herein further comprise administering rituximab as an
intravenous infusion in 28 days cycles. In certain embodiments,
rituximab is administered as an intravenous infusion for multiple
28 days cycles. In certain embodiments, rituximab is administered
as an intravenous infusion at a dose of 375 mg/m.sup.2 in the first
cycle and 500 mg/m.sup.2 in cycles 2-6. In certain embodiments,
rituximab is administered intravenously as an infusion at a dose of
375 mg/m.sup.2 per cycle. In certain embodiments, rituximab is
administered as an intravenous infusion at a dose of 375 mg/m.sup.2
for a total of 8 doses in 6 months.
[0536] In certain embodiments, the CD20 inhibitor used in
combination with a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug, is ofatumumab. In certain embodiments, the methods
described herein further comprise administering ofatumumab as an
intravenous infusion every week. In certain embodiments, ofatumumab
is administered as an intravenous infusion for multiple cycles. In
certain embodiments, ofatumumab is administered as an intravenous
infusion at a dose of 300 mg initial dose, followed 1 week later by
2,000 mg weekly for 7 doses, followed 4 weeks later by 2,000 mg
every 4 weeks for 4 doses.
[0537] In certain embodiments, the CD20 inhibitor used in
combination with a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug is obinutuzumab. In certain embodiments, the methods
described herein further comprise administering obinutuzumab as an
intravenous infusion in 28 days cycles. In certain embodiments,
obinutuzumab is administered as an intravenous infusion for
multiple cycles 28 days cycles. In certain embodiments,
obinutuzumab is administered as an intravenous infusion at a dose
of 100 mg on day 1 and 900 mg on day 2 Cycle 1, 1000 mg on day 8
and 15 of Cycle 1, and 1000 mg on day 1 of Cycles 2-6. In certain
embodiments, obinutuzumab is administered as an intravenous
infusion at a dose of 1000 mg on day 1, 8 and 15 of Cycle 1, and
1000 mg on day 1 of Cycles 2-6, and then every 2 months for 2
years.
[0538] In certain embodiments, the CD20 inhibitor used in
combination with a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug, is ocaratuzumab. In certain embodiments, the methods
described herein further comprise administering ocaratuzumab as a
subcutaneous injection every week. In certain embodiments,
ocaratuzumab is administered as a subcutaneous injection for
multiple cycles. In certain embodiments, ocaratuzumab is
administered at a dose between about 20 mg to about 100 mg per
week. In certain embodiments, ocaratuzumab is administered at a
dose of about 40 mg per week. In certain embodiments, ocaratuzumab
is administered at a dose of about 80 mg per week.
[0539] In certain embodiments, the CD20 inhibitor used in
combination with a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug is ocrelizumab. In certain embodiments, the methods
described herein further comprise administering ocrelizumab as an
intravenous infusion in 24 weeks cycles. In certain embodiments,
ocrelizumab is administered as an intravenous infusion for multiple
cycles. In certain embodiments, ocrelizumab is administered as an
intravenous infusion at a dose of 600 mg as a 300 mg infusions on
days 1 and 15 for the first dose and as a single infusion of 600 mg
for all subsequent infusions every 24 weeks.
[0540] In certain embodiments, the CD20 inhibitor used in
combination with a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug, is ublituximab. In certain embodiments, the methods
described herein further comprise administering ublituximab as an
intravenous infusion in cycles. In certain embodiments, ublituximab
is administered as an intravenous infusion for multiple cycles. In
certain embodiments, ublituximab is administered as an intravenous
infusion at day 1, day 8 and day 15 of every cycle.
[0541] In certain embodiments, the CD20 inhibitor used in
combination with a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug is BTCT4465A. In certain embodiments, the methods
described herein further comprise administering BTCT4465A as an
intravenous infusion in 21 days cycles. In certain embodiments,
BTCT4465A is administered as an intravenous infusion for multiple
cycles. In certain embodiments, BTCT4465A is administered as an
intravenous infusion on Day 1 of each 21-day cycle. In certain
embodiments, BTCT4465A is administered as an intravenous infusion
on Days 1, 8, and 15 of Cycle 1 and thereafter on Day 1 of each
21-day cycle.
[0542] In certain embodiments, the CD20 inhibitor used in
combination with a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug, is veltuzumab. In certain embodiments, the methods
described herein further comprise administering veltuzumab as an
intravenous infusion or a subcutaneous injection in weekly cycles.
In certain embodiments, veltuzumab is administered as an
intravenous infusion or a subcutaneous injection for multiple
weekly cycles. In certain embodiments, veltuzumab is administered
as an intravenous infusion or a subcutaneous injection at a dose of
80 mg/m.sup.2 once weekly for 4 weeks. In certain embodiments,
veltuzumab is administered as an intravenous infusion or a
subcutaneous injection at a dose of 120 mg/m.sup.2 once weekly for
4 weeks. In certain embodiments, veltuzumab is administered as an
intravenous infusion or a subcutaneous injection at a dose of 200
mg/m.sup.2 once weekly for 4 weeks. In certain embodiments,
veltuzumab is administered as an intravenous infusion or a
subcutaneous injection at a dose of 375 mg/m.sup.2 once weekly for
4 weeks.
[0543] In certain embodiments, the CD20 inhibitor used in
combination with a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug, is TRU-015. In certain embodiments, the methods
described herein further comprise administering TRU-015 as a
intravenous infusion in weekly cycles. In certain embodiments,
TRU-015 is administered as an intravenous infusion for multiple
weekly cycles. In certain embodiments, TRU-015 is administered at a
dose between about 100 mg to about 1200 mg per week. In certain
embodiments, TRU-015 is administered at a dose of about 400 mg per
week. In certain embodiments, TRU-015 is administered at a dose of
about 700 mg per week. In certain embodiments, TRU-015 is
administered at a dose of about 1000 mg per week.
[0544] In certain embodiments, a CD20 inhibitor is administered
once per day, twice per day, or three times per day. In certain
embodiments, the CD20 inhibitor is administered once per day. In
certain embodiments, the CD20 inhibitor is administered once per
day, twice per day, or three times per day. In certain embodiments,
the CD20 inhibitor is administered once per day. In certain
embodiments, the CD20 inhibitor is co-administered (e.g., in a
single dosage form), once per day.
[0545] In certain embodiments, the CD20 inhibitor is administered
weekly. In certain embodiments, the CD20 inhibitor is administered
once every two, three, four, or five weeks. In certain embodiments,
the CD20 inhibitor is administered once every four weeks. In
certain embodiments, the CD20 inhibitor is administered is 21 days
cycles. In certain embodiments, the CD20 inhibitor is administered
is 28 days cycles. In certain embodiments, the CD20 inhibitor is
administered intravenously. In certain embodiments, the CD20
inhibitor is administered as an intravenous infusion. In certain
embodiments, the CD20 inhibitor is administered subcutaneously.
[0546] It will be understood, however, that the specific dose level
and frequency of dosage for any particular patient 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.
Additional Combination Therapy
[0547] In certain embodiments, the methods of combination therapy
comprising a compound of Formula (I), an isotopic variant thereof;
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof and a CD20 inhibitor can also be combined or used in
combination with a third agent or therapies useful in the
treatment, prevention, or amelioration of one or more symptoms of a
proliferative disorders, diseases, or conditions.
[0548] Suitable third agent of therapies include, but are not
limited to, (1) alpha-adrenergic agents; (2) antiarrhythmic agents.
(3) anti-atherosclerotic agents, such as ACAT inhibitors; (4)
antibiotics, such as anthracyclines, bleomycins, mitomycin,
dactinomycin, and plicamycin; (5) anticancer agents and cytotoxic
agents. e.g., alkylating agents, such as nitrogen mustards, alkyl
sulfonates, nitrosoureas, ethylenimines, and triazenes; (6)
anticoagulants, such as acenocoumarol, argatroban, bivalirudin,
lepirudin, fondaparinux, heparin, phenindione, warfarin, and
xirnelagatran, (7) anti-diabetic agents, such as biguanides (e.g.,
metformin), glucosidase inhibitors (e.g., acarbose), insulins,
meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride,
glyburide, and glipizide), thiazolidinediones (e.g., troglitazone,
rosiglitazone, and pioglitazone), and PPAR-gamma monists; (8)
antifungal agents, such as amorolfine, amphotericin B,
anidulafungin, bifonazole, butenafine, butoconazole, caspofungin,
ciclopirox, clotrimazole, econazole, fenticonazole, filipin,
fluconazole, isoconazole, itraconazole, ketoconazole, micafungin,
miconazole, naftifine, natamycin, nystatin, oxyconazole,
ravuconazole, posaconazole, rimocidin, sertaconazole, sulconazole,
terbinafine, terconazole, tioconazole, and voriconazole; (9)
anti-inflammatories, e.g., non-steroidal anti-inflammatory agents,
such as aceclofenac, acemetacin, amoxiprin, aspirin, azapropazone,
benzoylate, bromfenac, carprofen, celecoxib, choline magnesium
salicylate, diclofenac, diflunisal, etodolac, etoricoxib,
fisalamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen,
indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen,
lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam,
methamizole, methyl salicylate, magnesium salicylate, nabumetone,
naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone,
piroxicam, salicyl salicylate, sulindac, sulfinpyrazone, suprofen,
tenoxicam, tiaprofenic acid, and tolmetin; (10) antimetabolites,
such as folate antagonists, purine analogues, and pyrimidine
analogues; (11) anti-platelet agents, such as GPIIb/IIIa blockers
(e.g., abciximab, eptifibatide, and tirofiban), P2Y (AC)
antagonists (e.g., clopidogrel, ticlopidine and CS-747),
cilostazol, dipyridamole, and aspirin; (12) antiproliferatives,
such as methotrexate, FK506 (tacrolimus), and mycophenolate
mofetil; (13) anti-TNF antibodies or soluble TNF receptor, such as
etanercept, rapamycin, and leflunomide; (14) aP2 inhibitors; (15)
beta-adrenergic agents, such as carvedilol and metoprolol; (16)
bile acid secjuestrants, such as questran; (17) calcium channel
blockers, such as amlodipine besylate; (18) chemotherapeutic
agents; (19) cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib
and rofecoxib; (20) cyclosporins; (21) cytotoxic drugs, such as
azathioprine and cyclophosphamide; (22) diuretics, such as
chlorothiazide, hydrochlorothiazide, flumethiazide,
hydroflumethiazide, bendroflumethiazide, methylchlorothiazide,
trichloromethiazide, polythiazide, benzothiazide, ethacrynic acid,
ticrynafen, chlorthalidone, furosenide, muzolimine, bumetanide,
triamterene, amiloride, and spironolactone; (23) endothelin
converting enzyme (ECE) inhibitors, such as phosphoramidon; (24)
enzymes, such as L-asparaginase; (25) Factor VIIa Inhibitors and
Factor Xa Inhibitors; (26) farnesyl-protein transferase inhibitors;
(27) fibrates; (28) growth factor inhibitors, such as modulators of
PDGF activity; (29) growth hormone secretagogues; (30) HMG CoA
reductase inhibitors, such as pravastatin, lovastatin,
atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin, nisvastatin,
or nisbastatin), and ZD-4522 (also known as rosuvastatin,
atavastatin, or visastatin); neutral endopeptidase (NEP)
inhibitors; (31) hormonal agents, such as glucocorticoids (e.g.,
cortisone), estrogens/antiestrogens, androgens/antiandrogens,
progestins, and luteinizing hormone-releasing hormone antagonists,
and octreotide acetate. (32) immunosuppressants; (33)
mineralocorticoid receptor antagonists, such as spironolactone and
eplerenone; (34) microtubule-disruptor agents, such as
ecteinascidins; (35) microtubule-stabilizing agents, such as
paclitaxel, docetaxel, and epothilones A-F; (36) MTP Inhibitors;
(37) niacin; (38) phosphodiesterase inhibitors, such as PDE III
inhibitors (e.g., cilostazol) and PDE V inhibitors (e.g.,
sildenafil, tadalafil, and vardenafil); (39) plant-derived
products, such as Vinca alkaloids, epipodophyllotoxins, and
taxanes; (40) platelet activating factor (PAF) antagonists; (41)
platinum coordination complexes, such as cisplatin, satraplatin,
and carboplatin; (42) potassium channel openers; (43)
prenyl-protein transferase inhibitors; (44) protein tryosine kinase
inhibitors; (45) renin inhibitors; (46) squalene synthetase
inhibitors; (47) steroids, such as aldosterone, beclometasone,
betamethasone, deoxycorticosterone acetate, fludrocortisone,
hydrocortisone (cortisol), prednisolone, prednisone,
methylprednisolone, dexamethasone, and triamcinolone; (48)
TNF-alpha inhibitors, such as tenidap; (49) thrombin inhibitors,
such as hirudin; (50) thrombolytic agents, such as antistreplase,
reteplase, tenecteplase, tissue plasminogen activator (tPA),
recombinant tPA, streptokinase, urokinase, prourokinase, and
anisoylated plasminogen streptokinase activator complex (APSAC);
(51) thromboxane receptor antagonists, such as ifetroban; (52)
topoisomerase inhibitors; (53) vasopeptidase inhibitors (dual
NEP-ACE inhibitors), such as omapatrilat and gemopatrilat, and (54)
other miscellaneous agents, such as, hydroxyurea, procarbazine,
mitotane, hexamethylmelamine, and gold compounds.
[0549] In certain embodiments, the third therapies that may be used
in combination with the methods provided herein include, but are
not limited to, surgery, endocrine therapy, biologic response
modifiers (e.g., interferons, interleukins, and tumor necrosis
factor (TNF)), hyperthermia and cryotherapy, and agents to
attenuate any adverse effects (e.g., antiemetics).
[0550] In certain embodiments, the third therapeutic agents that
may be used in combination with the compounds provided herein
include, but are not limited to, alkylating drugs (mechlorethamine,
chlorambucil, cyclophosphamide, melphalan, and ifosfamide),
antimetabolites (cytarabine (also known as cytosine arabinoside or
Ara-C), and methotrexate), purine antagonists and pyrimidine
antagonists (6-mercaptopurine, 5-fluorouracil, cytarabine, and
gemcitabine), spindle poisons (vinblastine, vincristine, and
vinorelbine), podophyllotoxins (etoposide, irinotecan, and
topotecan), antibiotics (daunorubicin, doxorubicin, bleomycin, and
mitomycin), nitrosoureas (carmustine and lomustine), enzymes
(asparaginase), and hormones (tamoxifen, leuprolide, flutamide, and
megestrol), imatinib, adriamycin, dexamethasone, and
cyclophosphamide.
[0551] In another embodiment, the method provided herein comprises
administration of a compound of Formula (I), or an isotopic variant
thereof, or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof and a CD20 inhibitor, together with
administering one or more chemotherapeutic agents and/or therapies
selected from: alkylation agents (e.g., cisplatin, carboplatin);
antimetabolites (e.g., methotrexate and 5-FU); antitumor
antibiotics (e.g., adrianmycin and bleomycin); antitumour vegetable
alkaloids (e.g., taxol and etoposide); antitumor hormones (e.g.,
dexamethasone and tamoxifen); antitumour immunological agents
(e.g., interferon .alpha., .beta., and .gamma.); radiation therapy;
and surgery. In certain embodiments, the one or more
chemotherapeutic agents and/or therapies are administered to the
subject before, during, or after the administration of a compound
of Formula (I), or an isotopic variant thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof and a CD20 inhibitor.
[0552] Such other agents, or drugs, can be administered, by a route
and in an amount commonly used therefor, simultaneously or
sequentially with a compound of Formula (I), or an isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
or prodrug thereof and a CD20 inhibitor. When a compound of Formula
(I) and a CD20 inhibitor are used contemporaneously with one or
more other drugs, a pharmaceutical composition containing such
other drugs in addition to the compound of Formula (I), or an
isotopic variant thereof; or a pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof and a CD20 inhibitor can be
utilized, but is not required. Accordingly, the pharmaceutical
compositions provided herein include those that also contain one or
more other active ingredients or therapeutic agents, in addition to
a compound of Formula (I).
Pharmaceutical Compositions and Routes of Administration
[0553] Provided herein is a pharmaceutical composition comprising a
compound of Formula (I), a CD20 inhibitor and a pharmaceutically
acceptable excipient, adjuvant, carrier, buffer, or stabilizer. In
some embodiments, the compound of Formula (I) and a CD20 inhibitor
are present in the same pharmaceutical composition. In some
embodiments, the compound of Formula (I) and the CD20 inhibitor are
in different pharmaceutical compositions.
[0554] In one embodiment, the pharmaceutical compositions are
provided in a dosage form for oral administration, which comprise a
compound provided herein, and one or more pharmaceutically
acceptable excipients or carriers. The pharmaceutical compositions
provided herein that are formulated for oral administration may be
in tablet, capsule, powder, or liquid form. In some embodiments, a
tablet comprises a solid carrier or an adjuvant. Liquid
pharmaceutical compositions generally comprise a liquid carrier
such as water, petroleum, animal or vegetable oils, mineral oil, or
synthetic oil. Physiological saline solution, dextrose or other
saccharide solution, or glycols such as ethylene glycol, propylene
glycol, or polyethylene glycol may be included. In some
embodiments, a capsule comprises a solid carrier such as
gelatin.
[0555] In another embodiment, the pharmaceutical compositions are
provided in a dosage form for parenteral administration, which
comprise a compound provided herein, and one or more
pharmaceutically acceptable excipients or carriers. Where
pharmaceutical compositions may be formulated for intravenous,
cutaneous or subcutaneous injection, the active ingredient will be
in the form of a parenterally acceptable aqueous solution, which is
pyrogen-free and has a suitable pH, isotonicity, and stability.
Those of relevant skill in the art are well able to prepare
suitable solutions using, for example, isotonic vehicles, such as
Sodium Chloride injection, Ringer's injection, or Lactated Ringer's
injection. In some embodiments, preservatives, stabilizers,
buffers, antioxidants, and/or other additives are included.
[0556] In yet another embodiment, the pharmaceutical compositions
are provided in a dosage form for topical administration, which
comprise a compound provided herein, and one or more
pharmaceutically acceptable excipients or carriers.
[0557] The pharmaceutical compositions can also be formulated as
modified release dosage forms, including delayed-, extended-,
prolonged-, sustained-, pulsatile-, controlled-, accelerated-,
fast-, targeted-, and 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).
[0558] 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.
[0559] 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.
[0560] In certain embodiments, the pharmaceutical compositions
provided herein further comprise one or more chemotherapeutic
agents as defined herein.
A. Oral Administration
[0561] 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.
[0562] 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 1500); 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 RC-581, AVICEL-PH-105
(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 50 to
about 99% by weight in the pharmaceutical compositions provided
herein.
[0563] 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.
[0564] 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 0.5 to about 15% or from
about 1 to about 5% by weight of a disintegrant.
[0565] 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 5% by weight of a
lubricant.
[0566] 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.
[0567] It should be understood that many carriers and excipients
may serve several functions, even within the same formulation.
[0568] 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.
[0569] 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.
[0570] 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. 4,328,245; 4,409,239; and 4,410,545. 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.
[0571] 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.
[0572] 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-350-dimethyl ether, polyethylene
glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether,
wherein 350, 550, and 750 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.
[0573] 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. 6,350,458.
[0574] 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.
[0575] Coloring and flavoring agents can be used in all of the
above dosage forms.
[0576] 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
[0577] 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.
[0578] 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).
[0579] 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.
[0580] 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.
[0581] 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 carboxymethylcellulose,
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.).
[0582] 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 fungi static concentrations. All parenteral
formulations must be sterile, as known and practiced in the
art.
[0583] 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.
[0584] 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.
[0585] 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.
[0586] 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 metliacrylic acid, collagen,
cross-linked polyvinyl alcohol, and cross-linked partially
hydrolyzed polyvinyl acetate.
[0587] 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, buty]
rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,
ethylene/vinyl acetate/vinyl alcohol terpolymer, and
ethylene/vinyloxyethanol copolymer.
Article of Manufacture
[0588] 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. 5,323,907;
5,052,558; and 5,033,252. 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.
[0589] 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 one or more
containers and a dosage form of a compound of Formula (I), or an
isotopic variant thereof; or a pharmaceutically acceptable salt,
solvate, hydrate, or prodrug thereof and a CD20 inhibitor.
[0590] In certain embodiments, the kit provided herein includes one
or more containers and a dosage form of a compound of Formula (I),
or an isotopic variant thereof, or a pharmaceutically acceptable
salt, solvate, hydrate, or prodrug thereof and CD20 inhibitor. 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.
[0591] 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.
[0592] The disclosure will be further understood by the following
non-limiting examples.
EXAMPLES
[0593] 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 or the Journal of
Biological Chemistry. Specifically, but without limitation, the
following abbreviations may be used in the examples and throughout
the specification: g (grams); mg (milligrams); mL (milliliters);
.mu.L, (microliters); M (molar); mM (millimolar), .mu.M (micro
molar); eq. (equivalent); mmol (millimoles), Hz (Hertz), MHz
(megahertz); hr or hrs (hour or hours); min (minutes); and MS (mass
spectrometry).
[0594] For all of the following examples, standard work-up and
purification methods known to those skilled in the art can be
utilized. Unless otherwise indicated, all temperatures are
expressed in .degree. C. (degrees Centigrade). All reactions
conducted at room temperature unless otherwise noted. Synthetic
methodologies illustrated herein are intended to exemplify the
applicable chemistry through the use of specific examples and are
not indicative of the scope of the disclosure.
[0595] Syntheses of Compounds I-XVI are described in U.S. Pat. No.
9,056,852 B2, which is incorporated by reference for such
disclosure.
Example 1: Study of a Combination of a PI3K Inhibitor and a CD20
Inhibitor in Patients with Relapsed-Refractory CLL or Richter's
Transformation
[0596] The purpose of this study is to evaluate the safety and
effectiveness of Compound A35, A36, A68, or A70 (three does: 60 mg,
120 mg, and 150 mg/day) and rituximab, in patients with advanced
CLL or Richter's Transformation.
TABLE-US-00001 Condition Intervention Phase Chronic Drug: Compound
Phase 1/Phase 2 Lymphocytic A35, A36, A68, Leukemia or A70
Biological: rituximab Study Type: Interventional Study Design:
Intervention Model: Single Group Assignment Masking: No masking
Primary Purpose: Treatment
[0597] Primary Outcome Measures: [0598] Determine Acceptable
Adverse Events That Are Related to Treatment [Time Frame: 6 months
of therapy]. To determine the incidence of adverse events, any
potential abnormal laboratory results and any dose-limiting
toxicities
[0599] Secondary Outcome Measures: [0600] Overall Response Rate
[lime Frame: Up to 1 year]. The overall response rate (ORR) in
patients with CLL and Richter's Transformation treated with a
combination of Compound A35, A36, A68, or A70 and rituximab.
TABLE-US-00002 [0600] Arms Assigned Interventions Experimental:
Drug: rituximab + Compound A35, A36, A68, Compound A35, A36, or A70
rituximab - 375 mg/m.sup.2 in the A68, or A70 first cycle and 500
mg/m.sup.2 in cycles A once daily oral agent 2-6, administered
every 28 days Biological: rituximab Compound A35, A36, A68, or A70
IV anti-CD20 oral daily dose - 60 mg monoclonal antibody
Experimental: Drug: rituximab + Compound A35, A36, A68, Compound
A35, A36, or A70 rituximab - 375 mg/m.sup.2 in the A68, or A70
first cycle and 500 mg/m.sup.2 in cycles A once daily oral agent
2-6, administered every 28 days Biological: rituximab Compound A35,
A36, A68, or A70 IV anti-CD20 oral daily dose - 120 mg monoclonal
antibody Experimental: Drug: rituximab + Compound A35, A36, A68,
Compound A35, A36, or A70 rituximab - 375 mg/m.sup.2 in the A68, or
A70 first cycle and 500 mg/m.sup.2 in cycles A once daily oral
agent 2-6, administered every 28 days Biological: rituximab
Compound A35, A36, A68, or A70 IV anti-CD20 oral daily dose - 150
mg monoclonal antibody
Eligibility
[0601] Ages Eligible for Study: 18 Years and older (Adult,
Senior)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria:
[0602] Confirmed diagnosis of B-cell Chronic Lymphocytic Leukemia
or Richter's Transformation [0603] Refractory to or relapsed after
at least 1 prior treatment regimen [0604] Eastern Cooperative
Oncology Group (ECOG) score of 0 to 2
Exclusion Criteria:
[0604] [0605] Any major surgery, chemotherapy or immunotherapy
within the last 14 days [0606] Known hepatitis B virus, hepatitis C
virus or HIV infection [0607] Active autoimmune disorder (with the
exception of autoimmune hemolytic anemia or ITP)
Example 2: Study of a Combination of a PI3K Inhibitor and a CD20
Inhibitor in Patients with Relapsed B-Cell Non-Hodgkin's Lymphoma
(NHL), Including Chronic Lymphocytic Leukemia (CLL)
[0608] The purpose of this study is to evaluate the safety and
effectiveness of Compound A35 (single dose: 60 mg/day) and
rituximab, in patients with relapsed B-cell malignancies.
TABLE-US-00003 Condition Intervention Phase Chronic Lymphocytic
Leukemia (CLL) Drug: Compound Phase 1b Small Lymphocytic Lymphoma
(SLL) A35 Follicular Lymphoma (FL) Biological: Marginal Zone B Cell
Lymphoma rituximab (MZL) Diffuse Large B-cell Lymphoma (DLBCL) High
Grade Non-Hodgkin's Lymphoma Study Type: Interventional Study
Design: Intervention Model: Single Group Assignment Masking: No
masking Primary Purpose: Treatment
[0609] Primary Outcome Measures: [0610] Determine Acceptable
Adverse Events That Are Related to Treatment [Time Frame: 6 months
of therapy]. To determine the incidence of adverse events, any
potential abnormal laboratory results and any dose-limiting
toxicities
[0611] Secondary Outcome Measures: [0612] Efficacy of Compound A35
with Rituximab as assessed by Overall Response (OR) [Time Frame: 2
years]. The efficacy of Compound A35 with Rituximab will be
determined by the overall response of subjects calculated as the
percent of subjects achieving a complete remission (CR) or a
complete remission with incomplete marrow recovery (CRi) or a
partial response (PR) according to the International Workshop on
Chronic Lymphocytic Leukemia (IWCLL). [0613] Evaluate the PK of
Compound A35 with Rituximab (AUC) [Time Frame: 2 years] Determined
by the Area Under the Concentration time curve (AUC) [0614]
Evaluate the PK of Compound A35 with Rituximab (Cmax) [Time Frame:
2 years] Determined by Peak Plasma Concentration (Cmax)
TABLE-US-00004 [0614] Arms Assigned Interventions Experimental:
rituximab + Compound Drug: Compound A35 A35 rituximab - 375
mg/m.sup.2, A once daily oral agent administered for a total of 8
doses Biological: rituximab in 6 months IV anti-CD20 monoclonal
Compound A35 oral daily dose - 60 mg antibody
Eligibility
[0615] Ages Eligible for Study: 18 Years and older (Adult,
Senior)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria:
[0616] Diagnosis of relapsed/refractory CLL SLL or FL, MZL, DLBCL
and high-grade B-cell lymphoma Subjects must meet the following
criteria for relapsed or refractory disease: [0617] Relapsed
disease; a subject who previously achieved a CR or PR, but
demonstrated disease progression after a response duration of >6
months [0618] Refractory disease: a subject who demonstrated
disease progression within 6 months of most recent therapy [0619]
No prior therapy with PI3K.delta. inhibitors [0620] No prior
therapy with Bruton tyrosine kinase (BTK) inhibitors unless the
subject was intolerant of BTK therapy [0621] Subjects with CLL,
SLL, FL, and MZL must have a failure of at least 1 prior systemic
therapy and be considered by the investigator a candidate for
therapy with a rituximab-based regimen; subjects with DLBCL and
high-grade B-cell lymphoma must have a failure of at least 2 prior
therapies. [0622] QT-interval corrected according to Fridericia's
formula (QTcF).ltoreq.450 milliseconds (ms) [0623] Left ventricular
ejection fraction>50% [0624] For subjects, except those with
CLL, must have at least one bi-dimensionally measurable nodal
lesion>1.5 cm, as defined by 2014 Lugano Classification (Cheson
et al., J Clin Oncol 2014; 32(27):3059-68) [0625] Willingness to
participate in collection of pharmacokinetic samples [0626] A
negative serum pregnancy test within 14 days of study Day 0 for
females of childbearing potential
Exclusion Criteria:
[0626] [0627] Known histological transformation from CLL to an
aggressive lymphoma [0628] Uncontrolled autoimmune hemolytic anemia
or immune thrombocytopenia [0629] Subjects who have tested positive
for hepatitis B surface antigen and/or hepatitis B core antibody
[0630] Positive for hepatitis C virus antibody (HCV Ab) or human
immunodeficiency virus (HIV) antibody [0631] Ongoing drug-induced
pneumonitis [0632] History of clinically significant cardiovascular
abnormalities
Baseline Characterization
[0633] Fifteen patients were enrolled. The demographics and disease
characteristics are consistent with those of patients with relapsed
B-cell NHL and CLL/SLL enrolled in other trials.
TABLE-US-00005 DLBCL/ FL MZL/CLL Total N = 9 N = 6 N = 15 Age in
years, median 61 (38-81) 71 (57-78) 62 (38-78) (range) Men, N (%) 7
(78%) 2 (33%) 9 (60%) Number of prior 3 (1-10) 2 (1-3) 2 (1-10)
therapies, median (range) Subjects with prior 9 (100%) 5/5 (100%) *
14/14 (100%) anti-CD20 therapy, N (%) Subjects with prior 9 (100%)
4/5 (80%) * 13/14 (93%) alkylating therapy, N (%) Subjects with
lymph 3 (33%) 4/5 (80%) * 7/14 (50%) nodes .gtoreq.5 cm, N (%) *
Data not available in 1 patient with CLL recently enrolled in the
study
Dosing Schedule for Compound A35
[0634] Dosing of Compound A35 is done on a continuous dosing
schedule (CS) or an intermittent dosing schedule (IS). On an IS,
patients take 60 mg administered once a day on 7 consecutive days
followed by 21 days without therapy, with cycles repeated every 28
days. On a CS, patients take 60 mg/day for the entirety of a 28 day
cycle. All patients are started on a CS dosing regimen. Patients
who complete two cycles of CS are switched to the IS.
[0635] In all cases, the dosing of rituximab is 375 mg/m2,
administered for a total of 8 doses in 6 months.
Results
[0636] On the CS of Compound A35, a response was reported in 7 of
10 patients (70%) with indolent non-Hodgkin's lymphoma (NHL), 9
patients with FL and 1 patient with MZL. Only 1 patient had disease
progression and discontinued from the study. For the other 9
patients, the median follow-up is 5.4 months (range, 3.3-7.7
months). Compound A35 in combination with rituximab achieves a very
high rate of response in patients.
[0637] A response was reported in 1 of 4 patients (25%) with DLBCL.
The patient who achieved a disease response has been on study for
5.4 months and the other 3 patients were discontinued due to
disease progression.
[0638] Switch to the IS after 2 Cycles on the CS
[0639] 15 patients were treated with a regimen consisting of
rituximab 375 mg/m.sup.2.times.8 doses over 6 months and Compound
A35 at 60 mg on the CS for 2 cycles then switching to the IS.
[0640] To date 10/15 patients have completed 2 cycles on the CS and
were switched to the IS, and only 1/10 patients (10%) developed
delayed immune-related toxicity with a median follow-up of 3.4
months (range, 1.5-5.7) on the IS.
[0641] Of the 8 patients who achieved a disease response after 2
cycles of therapy, none had disease progression on the IS, with a
median follow-up of 5.2 months (range, 3.1-7.5) from
enrollment.
[0642] Compound A35 in combination with rituximab achieves a very
high rate of response in patients with relapsed indolent NHL and
CLL/SLL. These responses appear durable. These results compare
favorably to other treatment approaches in these disease.
Preliminary data suggest that the IS appears to reduce the
incidence of delayed onset immune toxicities without erosion in
treatment efficacy.
* * * * *