U.S. patent application number 12/692078 was filed with the patent office on 2010-07-29 for macrocyclic compounds and their use as kinase inhibitors.
This patent application is currently assigned to INCYTE CORPORATION. Invention is credited to Michael Jason Bower, Andrew Paul Combs, Hao Feng, Richard B. Sparks, Eddy Wai Tsun Yue, Wenyu Zhu.
Application Number | 20100190804 12/692078 |
Document ID | / |
Family ID | 42270228 |
Filed Date | 2010-07-29 |
United States Patent
Application |
20100190804 |
Kind Code |
A1 |
Combs; Andrew Paul ; et
al. |
July 29, 2010 |
MACROCYCLIC COMPOUNDS AND THEIR USE AS KINASE INHIBITORS
Abstract
The present invention relates to macrocyclic compounds of
Formula I: ##STR00001## or pharmaceutically acceptable salts
thereof or quaternary ammonium salts thereof wherein constituent
members are provided hereinwith, as well as their compositions and
methods of use, which are JAK/ALK inhibitors useful in the
treatment of JAK/ALK-associated diseases including, for example,
inflammatory and autoimmune disorders, as well as cancer.
Inventors: |
Combs; Andrew Paul; (Kennett
Square, PA) ; Sparks; Richard B.; (Boothwyn, PA)
; Yue; Eddy Wai Tsun; (Landenberg, PA) ; Feng;
Hao; (Aston, PA) ; Bower; Michael Jason;
(Newark, DE) ; Zhu; Wenyu; (Media, PA) |
Correspondence
Address: |
Pepper Hamilton LLP
400 Berwyn Park, 899 Cassatt Road
Berwyn
PA
19312-1183
US
|
Assignee: |
INCYTE CORPORATION
Wilmington
DE
|
Family ID: |
42270228 |
Appl. No.: |
12/692078 |
Filed: |
January 22, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61146824 |
Jan 23, 2009 |
|
|
|
Current U.S.
Class: |
514/257 ;
540/469; 540/472 |
Current CPC
Class: |
C07D 487/22 20130101;
A61P 35/00 20180101; C07D 471/22 20130101; A61P 37/06 20180101 |
Class at
Publication: |
514/257 ;
540/469; 540/472 |
International
Class: |
A61K 31/4985 20060101
A61K031/4985; C07D 498/02 20060101 C07D498/02; C07D 487/22 20060101
C07D487/22; A61P 35/00 20060101 A61P035/00; A61P 37/06 20060101
A61P037/06 |
Claims
1. A compound of Formula I: ##STR00140## or pharmaceutically
acceptable salt thereof or quaternary ammonium salt thereof,
wherein: represents a single bond or a double bond; X.sup.1 is N or
CR.sup.1; X.sup.2 is N or CR.sup.2; X.sup.3 is N or CR.sup.3;
A.sup.1 and A.sup.2 are each, independently, selected from
CR.sup.2, N, NR.sup.6, O, and S; B.sup.1, B.sup.2, E.sup.1, and
E.sup.2 are each, independently, selected from CR.sup.5, N,
NR.sup.6, O, and S; D.sup.1 and D.sup.2 are each, independently,
selected from a bond, CR.sup.5, N, NR.sup.6, O, and S; wherein the
ring containing A.sup.1, B.sup.1, D.sup.1, and E.sup.1 is a 5- or
6-membered aromatic ring and wherein the ring containing A.sup.2,
B.sup.2, D.sup.2, and E.sup.2 is a 5- or 6-membered aromatic ring;
L.sup.1 and L.sup.2 are each, independently selected from a bond,
--(CR.sup.7R.sup.8).sub.n--,
--O--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.,
--S--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.,
--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--N.dbd., --(CR.sup.7R.sup.8).sub.m--O--,
--(CR.sup.7R.sup.8).sub.m--S--, --(CR.sup.7R.sup.8).sub.m--S(O)--,
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2--,
--(CR.sup.7R.sup.8).sub.m--C(O)--, --C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--C(O)O--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--OC(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9C(O)O--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--S(O).sub.2NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--S(O)NR.sup.9--, and
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2NR.sup.9--; wherein at least
one of L.sup.1 and L.sup.2 is other than a bond; R' and R'' are
each, independently, selected from H, halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, CN,
NO.sub.2, OR.sup.a2, SR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, OC(O)R.sup.b2,
OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2C(O)OR.sup.a2,
C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, S(O)R.sup.b2,
S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, and S(O).sub.2NR.sup.c2R.sup.d2; or R'
and R'' together with the C atom to which they are attached form a
3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered cycloalkyl group or
heterocycloalkyl group, each optionally substituted with 1, 2, or 3
substituents independently selected from halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, CN,
NO.sub.2, OR.sup.a2, SR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, OC(O)R.sup.b2,
OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2C(O)OR.sup.a2,
C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, S(O)R.sup.b2,
S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, and S(O).sub.2NR.sup.c2R.sup.d2;
R.sup.1 and R.sup.3 are each, independently, selected from H, halo,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, CN, NO.sub.2, SF.sub.5, OR.sup.a2, SR.sup.a2,
C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, OC(O)R.sup.b2,
OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2C(O)OR.sup.a2,
C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, S(O)R.sup.b2,
S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, and S(O).sub.2NR.sup.c2R.sup.d2; each
R.sup.2 is, independently, selected from H, halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, CN,
NO.sub.2, SF.sub.5, OR.sup.a2, SR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, OC(O)R.sup.b2,
OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2C(O)OR.sup.a2,
C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, S(O)R.sup.b2,
S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, and S(O).sub.2NR.sup.c2R.sup.d2; each
R.sup.5 is, independently, H, Cy.sup.1, halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,
halosulfanyl, CN, NO.sub.2, SF.sub.5, OR.sup.a1, SR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(S)R.sup.b1,
C(S)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
--W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1, OC(O)NR.sup.c1R.sup.d1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(S)R.sup.b1,
NR.sup.c1C(S)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.f1, or
P(O)OR.sup.e1OR.sup.f1, wherein each of said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl, or
heterocycloalkylalkyl, is optionally substituted by 1, 2, 3, 4, or
5 substituents independently selected from halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
Cy.sup.1, halosulfanyl, CN, NO.sub.2, SF.sub.5, OR.sup.a1,
SR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(S)R.sup.b1,
C(S)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
--W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1, OC(O)NR.sup.c1R.sup.d1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(S)R.sup.b1,
NR.sup.c1C(S)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O)NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.f1, and
P(O)OR.sup.e1OR.sup.f1; or two adjacent R.sup.5 on the same ring
can link to form a fused cycloalkyl or fused heterocycloalkyl
group, each optionally substituted by 1, 2, or 3 substituents
independently selected from halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,
halosulfanyl, Cy.sup.1, CN, NO.sub.2, OR.sup.a1, SR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, SF.sub.5, C(S)R.sup.b1,
C(S)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
--W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1, OC(O)NR.sup.c1R.sup.d1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(S)R.sup.b1,
NR.sup.c1C(S)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.g)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g)NR.sup.c1R.sup.d1,
NR.sup.c1S(O)NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.f1, and
P(O)OR.sup.e1OR.sup.f1, wherein each of said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl, or
heterocycloalkylalkyl, is optionally substituted by 1, 2, 3, 4, or
5 substituents independently selected from halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
Cy.sup.1, --W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1, halosulfanyl, CN,
NO.sub.2, SF.sub.5, OR.sup.a1, SR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OCH.sub.2C(O)R.sup.b1, OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1,
NR.sup.c1C(O)R.sup.b1, NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1C(O)OR.sup.a1, C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O)NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.c1).sub.2, P(O)R.sup.e1R.sup.f1, and
P(O)OR.sup.e1OR.sup.f1; R.sup.4 and R.sup.6 are each,
independently, selected from H, Cy.sup.2, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,
--W.sup.2--X.sup.2--Y.sup.2--Z.sup.2, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
S(O).sub.2NR.sup.c1R.sup.d1, P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2,
P(O)R.sup.e1R.sup.f1, and P(O)OR.sup.e1OR.sup.f1, wherein each of
said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,
or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4,
or 5 substituents independently selected from halo, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
Cy.sup.2, halosulfanyl, CN, NO.sub.2, OR.sup.a1, SR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
--W.sup.2-Q.sup.2-Y.sup.2--Z.sup.2, OC(O)NR.sup.c1R.sup.d1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.f1, and
P(O)OR.sup.e1OR.sup.f1; R.sup.7, R.sup.8, and R.sup.10 are each,
independently, selected from H, Cy.sup.3, halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,
--W.sup.3-Q.sup.3-Y.sup.3--Z.sup.3, CN, NO.sub.2, OR.sup.a1,
SR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
OC(O)R.sup.b1, OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1,
NR.sup.c1C(O)R.sup.b1, NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1C(O)OR.sup.a1, C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.f1, and
P(O)OR.sup.e1OR.sup.f1, wherein each of said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl, or
heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5
substituents independently selected from halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
halosulfanyl, CN, NO.sub.2, OR.sup.a1, SR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1, Cy.sup.3,
--W.sup.3-Q.sup.3-Y.sup.3--Z.sup.3, OC(O)NR.sup.c1R.sup.d1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.f1, and
P(O)OR.sup.e1OR.sup.f1; each R.sup.9 is, independently, H,
Cy.sup.4, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,
heterocycloalkylalkyl, --W.sup.4-Q.sup.4-Y.sup.4--Z.sup.4,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OC(O)NR.sup.c1R.sup.d1, C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
S(O)R.sup.b1, S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
S(O).sub.2NR.sup.c1R.sup.d1, P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2,
P(O)R.sup.e1R.sup.f1, or P(O)OR.sup.e1R.sup.f1 wherein each of said
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or
heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5
substituents independently selected from halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
halosulfanyl, CN, NO.sub.2, OR.sup.a1, SR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1, Cy.sup.4,
--W.sup.4-Q.sup.4-Y.sup.4--Z.sup.4, OC(O)NR.sup.c1R.sup.d1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.g)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.f1, and
P(O)OR.sup.e1OR.sup.f1; R.sup.11a, R.sup.11b, R.sup.12a, R.sup.12b,
and R.sup.13 are each, independently, selected from H, Cy.sup.3,
halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,
heterocycloalkylalkyl, CN, NO.sub.2, OR.sup.a1, SR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.f1, and
P(O)OR.sup.e1OR.sup.f1, wherein each of said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl, or
heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5
substituents independently selected from halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
halosulfanyl, CN, NO.sub.2, OR.sup.a1, SR.sup.a1, SF.sub.5,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
Cy.sup.3, --W.sup.3-Q.sup.3-Y.sup.3--Z.sup.3,
OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.f1, and
P(O)OR.sup.e1OR.sup.f1; W.sup.1, W.sup.2, W.sup.3, W.sup.4, and
W.sup.5 are each, independently, selected from absent, W.sup.6,
C.sub.1-6 alkylenyl, C.sub.2-6 alkenylenyl, C.sub.2-6 alkynylenyl,
(CR.sup.11aR.sup.11b).sub.p1O(CR.sup.11aR.sup.11b).sub.p2,
(CR.sup.11aR.sup.11b).sub.p1S(CR.sup.11aR.sup.11b).sub.p2,
(CR.sup.11aR.sup.11b).sub.p1NR.sup.e(CR
.sup.11aR.sup.11b).sub.p2,
(CR.sup.11aR.sup.11b).sub.p1C(O)(CR.sup.11aR.sup.11b).sub.p2,
(CR.sup.11aR.sup.11b).sub.p1C(S)(CR.sup.11aR.sup.11b).sub.p2,
(CR.sup.11aR.sup.11b).sub.p1C(O)O(CR.sup.11aR.sup.11b).sub.p2,
(CR.sup.11aR.sup.11b).sub.p1C(O)NR.sup.e(CR.sup.11aR.sup.11b).sub.p2,
(CR.sup.11aR.sup.11b).sub.p1C(S)NR.sup.e(CR.sup.11aR.sup.11b).sub.p2,
(CR.sup.11aR.sup.11b).sub.p1S(O)(CR.sup.11aR.sup.11b).sub.p2,
(CR.sup.11aR.sup.11b).sub.p1S(O).sub.2(CR.sup.11aR.sup.11b).sub.p2,
(CR.sup.11aR.sup.11b).sub.p1S(O)NR.sup.e(CR.sup.11aR.sup.11b).sub.p2,
(CR.sup.11aR.sup.11b).sub.p1S(O).sub.2NR.sup.e(CR.sup.11aR.sup.11b).sub.p-
2,
(CR.sup.11aR.sup.11b).sub.p1NR.sup.eC(O)NR.sup.f(CR.sup.11aR.sup.11b).s-
ub.p2,
(CR.sup.11aR.sup.11b).sub.p1NR.sup.eC(S)NR.sup.f(CR.sup.11aR.sup.11-
b).sub.p2,
(CR.sup.11aR.sup.11b).sub.p1NR.sup.eS(O).sub.2NR.sup.f(CR.sup.1-
1aR.sup.11b).sub.p2,
(CR.sup.11aR.sup.11b).sub.p1C(.dbd.NR.sup.g)NR.sup.e(CR.sup.11aR.sup.11b)-
.sub.p2,
(CR.sup.11aR.sup.11b).sub.p1NR.sup.eC(.dbd.NR.sup.g)NR.sup.f(CR.s-
up.11aR.sup.11b).sub.p2, O(CR.sup.11aR.sup.11b).sub.q1C(O),
S(CR.sup.11aR.sup.11b).sub.q1C(O),
NR.sup.e(CR.sup.11aR.sup.11b).sub.q1C(O),
C(O)(CR.sup.11aR.sup.11b).sub.q1C(O),
NR.sup.e(CR.sup.11aR.sup.11b).sub.q1NR.sup.f,
O(CR.sup.11aR.sup.11b).sub.q1NR.sup.f, and
O(CR.sup.11aR.sup.11b).sub.q1O, wherein each of the C.sub.1-6
alkylenyl, C.sub.2-6 alkenylenyl and C.sub.2-6 alkynylenyl is
optionally substituted by 1, 2, or 3 substituents independently
selected from halo, CN, NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b,
C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a,
C(.dbd.NR.sup.g)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.g)NR.sup.cR.sup.d,
NR.sup.cS(O).sub.2NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d; each W.sup.6 is independently
selected from NR.sup.e100C(O)NR.sup.f100 and
NR.sup.e200C(O)CR.sup.13R.sup.f200, wherein R.sup.e100 and
R.sup.f100 together with the intervening NC(O)N moiety to which
they are attached form a 4-7 membered heterocycloalkyl group which
is optionally substituted by 1, 2, or 3 substituents each
independently selected from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo, CN, NO.sub.2, OR.sup.a,
SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cC(O)OR.sup.a, C(.dbd.NR.sup.g)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.g)NR.sup.cR.sup.d,
NR.sup.cS(O).sub.2NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d, and wherein R.sup.e200 and
R.sup.f200 together with the intervening NC(O)CR.sup.13 moiety to
which they are attached form a 4-7 membered heterocycloalkyl group
which is optionally substituted by 1, 2, or 3 substituents each
independently selected from C.sub.1-6 alkyl, C.sub.1-6haloalkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo, CN, NO.sub.2, OR.sup.a,
SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cC(O)OR.sup.a, C(.dbd.NR.sup.g)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.g)NR.sup.cR.sup.d,
NR.sup.cS(O).sub.2NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d; Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4,
and Q.sup.5 are each, independently, selected from aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, each
optionally substituted by 1, 2, 3, 4, or 5 substituents
independently selected from C.sub.1-6 alkyl, C.sub.1-6haloalkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,
heterocycloalkylalkyl, halo, CN, NO.sub.2, OR.sup.a, SR.sup.a,
SF.sub.5, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cC(O)OR.sup.a, C(.dbd.NR.sup.g)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.g)NR.sup.cR.sup.d,
NR.sup.cS(O).sub.2NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d; Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4,
and Y.sup.5 are each, independently, selected from absent,
C.sub.1-6 alkylenyl, C.sub.2-6 alkenylenyl, C.sub.2-6 alkynylenyl,
(CR.sup.12aR.sup.12b).sub.p3O(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3S(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3NR.sup.e(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3C(O)(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3C(S)(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3C(O)O(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3C(O)NR.sup.e(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3C(S)NR.sup.e(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3S(O)(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3S(O).sub.2(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3S(O)NR.sup.e(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3S(O)NR.sup.e(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3NR.sup.eC(O)NR.sup.f(CR.sup.12aR.sup.12b).sub-
.p4,
(CR.sup.12aR.sup.12b).sub.p3NR.sup.eC(S)NR.sup.f(CR.sup.12aR.sup.12b)-
.sub.p4,
(CR.sup.12aR.sup.12b).sub.p3NR.sup.eS(O).sub.2NR.sup.f(CR.sup.12a-
R.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3C(.dbd.NR.sup.g)NR.sup.e(CR.sup.12aR.sup.12b)-
.sub.p4,
(CR.sup.12aR.sup.12b).sub.p3NR.sup.eC(.dbd.NR.sup.g)NR.sup.f(CR.s-
up.12R.sup.12b).sub.p4, O(CR.sup.12aR.sup.12b).sub.q2C(O),
S(CR.sup.12aR.sup.12b).sub.q2C(O),
NR.sup.e(CR.sup.12aR.sup.12b).sub.q2C(O),
NR.sup.e(CR.sup.12aR.sup.12b).sub.q2NR.sup.f,
O(CR.sup.12aR.sup.12b).sub.q2NR.sup.f, and
O(CR.sup.12aR.sup.12b).sub.q2O, wherein each of the C.sub.1-6
alkylenyl, C.sub.2-6 alkenylenyl and C.sub.2-6 alkynylenyl is
optionally substituted by 1, 2 or 3 substituents independently
selected from C.sub.1-6 alkyl, C.sub.1-6haloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, halo, CN, NO.sub.2, OR.sup.a, SR.sup.a,
SF.sub.5, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cC(O)OR.sup.a, C(.dbd.NR.sup.g)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.g)NR.sup.cR.sup.d,
NR.sup.cS(O).sub.2NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d; Z.sup.1, Z.sup.2, Z.sup.3, Z.sup.4,
and Z.sup.5 are each, independently, selected from H, halo, CN,
NO.sub.2, OH, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, amino,
C.sub.1-6 alkylamino, C.sub.2-8 dialkylamino, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl,
wherein each of the C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and
heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5
substituents independently selected from halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO.sub.2, OR.sup.a,
SR.sup.a, SF.sub.5, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.d, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cC(O)OR.sup.a, NR.sup.cS(O).sub.2R.sup.b,
NR.sup.cS(O).sub.2NR.sup.cR.sup.d; S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d; Cy.sup.1, Cy.sup.2, Cy.sup.3, and
Cy.sup.4 are each, independently, selected from aryl, cycloalkyl,
heteroaryl, and heterocycloalkyl, each optionally substituted by 1,
2, 3, 4, or 5 substituents independently selected from halo,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, SF.sub.5, Cy.sup.5,
-L.sup.b1-Cy.sup.5, --W.sup.5-Q.sup.5-Y.sup.5--Z.sup.5, C.sub.1-6
haloalkyl, halosulfanyl, CN, NO.sub.2, OR.sup.a1, SR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, and S(O).sub.2NR.sup.c1R.sup.d1;
Cy.sup.5 and Cy.sup.6 are each, independently, selected from aryl,
cycloalkyl, heteroaryl, and heterocycloalkyl, each optionally
substituted by 1, 2, 3, 4, or 5 substituents independently selected
from halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
aryl, cycloalkyl, heteroaryl, heterocycloalkyl, C.sub.1-6
haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,
heterocycloalkylalkyl, halosulfanyl, CN, NO.sub.2, OR.sup.a2,
SR.sup.a2, SF.sub.5, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2,
C(S)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, OC(O)R.sup.b2,
OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2C(O)OR.sup.a2,
C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, S(O)R.sup.b2,
S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, and S(O).sub.2NR.sup.c2R.sup.d2;
L.sup.b1 and L.sup.b2 are each, independently, selected from
C.sub.1-4 alkylenyl, O, S, C(O), C(S), C(O)NR.sup.c2,
C(S)NR.sup.c2, C(O)O, OC(O)NR.sup.c2, NR.sup.c2,
NR.sup.c2C(O)NR.sup.d2, NR.sup.c2C(S)NR.sup.d2,
C(.dbd.NR.sup.g)NR.sup.c2, NR.sup.c2C(.dbd.NR.sup.g)NR.sup.d2,
NR.sup.c2S(O).sub.2NR.sup.d2, S(O), S(O)NR.sup.c2, S(O).sub.2, and
S(O).sub.2NR.sup.c2, wherein said C.sub.1-4 alkylenyl is optionally
substituted by 1, 2, 3, 4, 5, 6, 7, or 8 substituents each
independently selected from halo, CN, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, OH, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, NH.sub.2,
NH(C.sub.1-4 alkyl), and N(C.sub.1-4 alkyl).sub.2; R.sup.a1,
R.sup.b1, R.sup.c1, and R.sup.d1 are each, independently, selected
from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl, and
heterocycloalkylalkyl, wherein each of said C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is
optionally substituted with 1, 2, 3, 4, or 5 substituents
independently selected from C.sub.1-6 alkyl, halo, CN, Cy.sup.6,
-L.sup.b2-Cy.sup.6, OR.sup.a2, SR.sup.a2, SF.sub.5, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(S)R.sup.b2, C(S)NR.sup.c2R.sup.d2,
C(O)OR.sup.a2, OC(O)R.sup.b2, OC(O)NR.sup.c2R.sup.d2,
NR.sup.c2R.sup.d2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2C(S)R.sup.b2,
NR.sup.c2C(S)NR.sup.c2R.sup.d2, NR.sup.c2C(O)OR.sup.a2,
C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, S(O)R.sup.b2,
S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, and S(O).sub.2NR.sup.c2R.sup.d2; or
R.sup.c1 and R.sup.d1 together with the N atom to which they are
attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or
heteroaryl group, each optionally substituted with 1, 2, or 3
substituents independently selected from C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, halo, CN, Cy.sup.6, -L.sup.b2-Cy.sup.6, OR.sup.a2,
SR.sup.a2, SF.sub.5, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2,
C(S)R.sup.b2, C(S)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, OC(O)R.sup.b2,
OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2C(S)R.sup.b2,
NR.sup.c2C(S)NR.sup.c2R.sup.d2, NR.sup.c2C(O)OR.sup.a2,
C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, S(O)R.sup.b2,
S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, and S(O).sub.2NR.sup.c2R.sup.d2; each
R.sup.e1 is, independently, H, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.2-6 alkenyl, (C.sub.1-6 alkoxy)-C.sub.1-6 alkyl,
C.sub.2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,
arylalkyl, cycloalkylalkyl, heteroarylalkyl, or
heterocycloalkylalkyl; each R.sup.f1 is, independently, H,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl;
R.sup.a2, R.sup.b2, R.sup.c2, and R.sup.d2 are each, independently,
selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and
heterocycloalkylalkyl, wherein each of said C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is
optionally substituted with 1, 2, or 3 substituents independently
selected from OH, CN, amino, halo, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, C.sub.1-6 haloalkyl, and C.sub.1-6 haloalkoxy; or R.sup.c2
and R.sup.d2 together with the N atom to which they are attached
form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or
heteroaryl group, each optionally substituted with 1, 2, or 3
substituents independently selected from OH, CN, amino, halo,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, and
C.sub.1-6 haloalkoxy; each R.sup.a is independently selected from
H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, aryl, cycloalkyl, heteroaryl and
heterocycloalkyl, wherein each of the C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,
heterocycloalkylalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
cycloalkyl, heteroaryl and heterocycloalkyl is optionally
substituted with 1, 2, 3, 4, or 5 substituents independently
selected from OH, CN, amino, halo, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 hydroxylalkyl, C.sub.1-6 cyanoalkyl, C.sub.1-6
alkoxy, C.sub.1-6 haloalkoxy, C.sub.2-8 alkoxyalkoxy, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and
heterocycloalkyl; each R.sup.b is independently selected from H,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, arylalkyl, heteroarylalkyl,
cycloalkylalkyl, heterocycloalkylalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein each of the C
.sub.1-6 alkyl, C.sub.1-6 haloalkyl, arylalkyl, heteroarylalkyl,
cycloalkylalkyl, heterocycloalkylalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or
5 substituents independently selected from OH, CN, amino, halo,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 hydroxylalkyl,
C.sub.1-6 cyanoalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy,
C.sub.2-8 alkoxyalkoxy, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl, and heterocycloalkyl; R.sup.c and
R.sup.d are independently selected from H, C.sub.1-10 alkyl,
C.sub.1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,
heterocycloalkylalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein
each of the C.sub.1-10 alkyl, C.sub.1-6 haloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, aryl, heteroaryl, cycloalkyl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or
5 substituents independently selected from OH, CN, amino, halo,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 hydroxylalkyl,
C.sub.1-6 cyanoalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy,
C.sub.2-8 alkoxyalkoxy, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl, and heterocycloalkyl; or R.sup.c and
R.sup.d together with the N atom to which they are attached form a
4-, 5-, 6- or 7-membered heterocycloalkyl group that is optionally
substituted with 1, 2, 3, 4, or 5 substituents independently
selected from OH, CN, amino, halo, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 hydroxylalkyl, C.sub.1-6 cyanoalkyl, C.sub.1-6
alkoxy, C.sub.1-6 haloalkoxy, C.sub.2-8 alkoxyalkoxy, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and
heterocycloalkyl; and R.sup.e and R.sup.f are each, independently,
selected from H, C.sub.1-10 alkyl, C.sub.1-6 haloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, aryl, heteroaryl, cycloalkyl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein each of the C.sub.1-10 alkyl,
C.sub.1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,
heterocycloalkylalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is
optionally substituted by OH, amino, halo, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or
heterocycloalkyl; R.sup.g, R.sup.g1, and R.sup.g2 are each,
independently, H, CN, or NO.sub.2; each p1 is, independently, 0, 1,
or 2; each p2 is, independently, 0, 1, or 2; each p3 is,
independently, 0, 1, or 2; each p4 is, independently, 0, 1, or 2;
each q1 is, independently, 1 or 2; each q2 is, independently, 1 or
2; each n is, independently, 1, 2, or 3; each m is, independently,
0, 1, or 2; and t is 1, 2, 3, or 4.
2. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein the ring
containing A.sup.1, B.sup.1, D.sup.1, and E.sup.1 is a 6-membered
aromatic ring; B.sup.1, D.sup.1, and E.sup.1 are each,
independently, CR.sup.5 or N; and A.sup.1 is CR.sup.2 or N.
3. The compound of claim 2, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein the ring
containing A.sup.1, B.sup.1, D.sup.1, and E.sup.1 is a 6-membered
aromatic ring; B.sup.1, D.sup.1, and E.sup.1 are each,
independently, CR.sup.5; and A.sup.1 is CR.sup.2.
4. The compound of claim 2, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein the ring
containing A.sup.1, B.sup.1, D.sup.1, and E.sup.1 is a benzene
ring.
5. The compound of claim 2, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein the ring
containing A.sup.1, B.sup.1, D.sup.1, and E.sup.1 is selected from
pyridine and pyrimidine rings.
6. The compound of claim 2, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein the ring
containing A.sup.1, B.sup.1, D.sup.1, and E.sup.1 is a pyridine
ring.
7. The compound of claim 6, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein D.sup.1 is
N.
8. The compound of claim 6, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein E.sup.1 is
N.
9. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein the ring
containing A.sup.1, B.sup.1, D.sup.1, and E.sup.1 is a 5-membered
aromatic ring.
10. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein the ring
containing A.sup.1, B.sup.1, D.sup.1, and E.sup.1 is a thiophene
ring.
11. The compound of claim 2, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein the ring
containing A.sup.2, D.sup.2, and E.sup.2 is a 6-membered aromatic
ring; B.sup.2, D.sup.2, and E.sup.2 are each, independently,
CR.sup.5 or N; and A.sup.2 is CR.sup.2 or N.
12. The compound of claim 2, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein the ring
containing A.sup.2, B.sup.2, D.sup.2, and E.sup.2 is a 6-membered
aromatic ring; B.sup.2, D.sup.2, and E.sup.2 are each,
independently, CR.sup.5; and A.sup.2 is CR.sup.2.
13. The compound of claim 2, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein the ring
containing A.sup.2, B.sup.2, D.sup.2, and E.sup.2 is a benzene
ring.
14. The compound of claim 2, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein the ring
containing A.sup.2, B.sup.2, D.sup.2, and E.sup.2 is selected from
pyridine and pyrimidine rings.
15. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein X.sup.1 is
CR.sup.1.
16. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein X.sup.2 is
N.
17. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein X.sup.3 is
CR.sup.3.
18. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein X.sup.3 is
C-halo.
19. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein X.sup.3 is
C--Cl.
20. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein X.sup.1 is
CR.sup.1; X.sup.2 is N; and X.sup.3 is CR.sup.3.
21. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein L.sup.1 and
L.sup.2 are each, independently, selected from a bond,
--(CR.sup.7R.sup.8).sub.n--,
--O--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.,
--S--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.,
--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--O--, --(CR.sup.7R.sup.8).sub.m--S--,
--(CR.sup.7R.sup.8).sub.m--S(O)--,
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2--,
--(CR.sup.7R.sup.8).sub.m--C(O)--, --C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--C(O)O--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--OC(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9C(O)O--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--S(O).sub.2NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--S(O)NR.sup.9--, and
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2NR.sup.9--.
22. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein L.sup.1 and
L.sup.2 together form
--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.CR.sup.10--(CR.sup.7R.sup.8-
).sub.m-- or
--(CR.sup.7R.sup.8).sub.m--(CR.sup.7R.sup.8).sub.n--.
23. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein L.sup.1 and
L.sup.2 together form --(CR.sup.7R.sup.8)--,
--(CR.sup.7R.sup.8).sub.2--, or --(CR.sup.7R.sup.8).sub.3.
24. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein L.sup.1 and
L.sup.2 together form --CH.sub.2--, --(CH.sub.2).sub.2--, or
--(CH.sub.2).sub.3--.
25. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein one of L.sup.1
and L.sup.2 is selected from --(CR.sup.7R.sup.8).sub.m--O--,
--(CR.sup.7R.sup.8).sub.m--S--, --(CR.sup.7R.sup.8).sub.m--S(O)--,
and --(CR.sup.7R.sup.8).sub.m--S(O).sub.2--; and the other is
selected from a bond, --(CR.sup.7R.sup.8).sub.n--,
--(CR.sup.7R.sup.8).sub.m--O--, --(CR.sup.7R.sup.8).sub.m--S--,
--(CR.sup.7R.sup.8).sub.m--S(O)--, and
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2--.
26. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein: L.sup.1 and
L.sup.2 together form --(CR.sup.7R.sup.8).sub.t1--S--,
--(CR.sup.7R.sup.8).sub.t1--O--,
--(CR.sup.7R.sup.8).sub.t1--S(O)--,
--(CR.sup.7R.sup.8).sub.t1--S(O).sub.2--,
--S--(CR.sup.7R.sup.8).sub.t2--S--,
--O--(CR.sup.7R.sup.8).sub.t2--S--,
--O--(CR.sup.7R.sup.8).sub.t2--S(O)--,
--O--(CR.sup.7R.sup.8).sub.t2--S(O).sub.2--, --S--S--,
--(CR.sup.7R.sup.8).sub.t3--O--(CR.sup.7R.sup.8).sub.t4--,
--(CR.sup.7R.sup.8).sub.t3--S--(CR.sup.7R.sup.8).sub.t4--,
--(CR.sup.7R.sup.8).sub.t3--S(O)--(CR.sup.7R.sup.8).sub.t4--, or
--(CR.sup.7R.sup.8).sub.t3--S(O).sub.2--(CR.sup.7R.sup.8).sub.t4--;
t1 is 1, 2, or 3; t2 is 1 2, 3, or 4; t3 is 1, 2, or 3; and t4 is 1
or 2.
27. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein L.sup.1 and
L.sup.2 together form --O--(CR.sup.7R.sup.8)--,
--O--(CR.sup.7R.sup.8).sub.2--, or
--O--(CR.sup.7R.sup.8).sub.3--.
28. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein L.sup.1 and
L.sup.2 together form --O--CH.sub.2--, --O--(CH.sub.2).sub.2--, or
--O--(CH.sub.2).sub.3--.
29. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein L.sup.1 is
--(CR.sup.7R.sup.8)--, --(CR.sup.7R.sup.8).sub.2--, or
--(CR.sup.7R.sup.8).sub.3--; and L.sup.2 is --O--.
30. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein L.sup.1 and
L.sup.2 together form --O--(CR.sup.7R.sup.8)--O--,
--O--(CR.sup.7R.sup.8).sub.2--O--, or
--O--(CR.sup.7R.sup.8).sub.3--O--.
31. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein L.sup.1 and
L.sup.2 together form --(CH.sub.2)--S--, --(CH.sub.2)--S(O)--,
--(CH.sub.2)--S(O).sub.2--, --(CH.sub.2)--O--,
--(CH.sub.2).sub.2--O--, --(CH.sub.2).sub.3--O--,
--O--(CH.sub.2).sub.2--O--, --O--(CH.sub.2).sub.2--S--,
--O--(CH.sub.2).sub.2--S(O)--, or
--O--(CH.sub.2).sub.2--S(O).sub.2--.
32. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein one of L.sup.1
and L.sup.2 is selected from --(CR.sup.7R.sup.8).sub.m--NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2--,
--(CR.sup.7R.sup.8).sub.m--C(O)--, --C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--OC(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9C(O)O--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--S(O).sub.2NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--S(O)NR.sup.9--, and
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2NR.sup.9--; and the other is
selected from a bond, --(CR.sup.7R.sup.8).sub.n--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2--,
--(CR.sup.7R.sup.8).sub.m--C(O)--, --C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--S(O)NR.sup.9--, and
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2NR.sup.9--.
33. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein L.sup.1 and
L.sup.2 together form --(CR.sup.7R.sup.8).sub.2--C(O)--,
--C(O)NR.sup.9--(CR.sup.7R.sup.8)--, --C(O)NR.sup.9--,
--(CR.sup.7R.sup.8)--S(O).sub.2NR.sup.9--,
--S(O).sub.2NR.sup.9--(CR.sup.7R.sup.8)--, or
--S(O).sub.2NR.sup.9--.
34. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein L.sup.1 and
L.sup.2 together form --C(O)NH-- or --S(O).sub.2NH--.
35. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein R.sup.1 and
R.sup.3 are each, independently, selected from H, halo, C.sub.1-3
alkyl, and C.sub.1-3 haloalkyl.
36. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein R.sup.1 is
selected from H and C.sub.1-3 alkyl; and R.sup.3 is selected from
halo, C.sub.1-3 alkyl, and C.sub.1-3 haloalkyl.
37. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein R.sup.1 is H;
and R.sup.3 is selected from halo and C.sub.1-3 alkyl.
38. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein R.sup.1 is H;
and R.sup.3 is halo.
39. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein each R.sup.2
is, independently, selected from H, F, Cl, CH.sub.3, and
CF.sub.3.
40. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein each R.sup.2
is H.
41. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein R.sup.4 is H
or C.sub.1-6 alkyl.
42. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein R.sup.4 is
H.
43. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein each R.sup.5
is, independently, selected from H, halo, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, Cy.sup.1, --W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1,
CN, NO.sub.2, SF.sub.5, OR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, NR.sup.c1R.sup.d1,
NR.sup.c1C(O)R.sup.b1, NR.sup.c1C(O)NR.sup.c1R.sup.d1,
S(O)R.sup.b1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, NR.sup.c1S(O).sub.2R.sup.b1,
and S(O).sub.2NR.sup.c1R.sup.d1, wherein each of said C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, or C.sub.1-6 haloalkyl
is optionally substituted by 1, 2, 3, 4, or 5 substituents each
independently selected from halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halosulfanyl,
Cy.sup.1, --W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1, CN, NO.sub.2,
SF.sub.5, OR.sup.a1, SR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.g)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.f1, and
P(O)OR.sup.e1OR.sup.f1.
44. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein each R.sup.5
is, independently, selected from H, halo, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, CN, NO.sub.2, SF.sub.5, OR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O).sub.2R.sup.b1, NR.sup.c1S(O).sub.2R.sup.b1, and
S(O).sub.2NR.sup.c1R.sup.d1.
45. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein: each R.sup.5
is, independently, selected from H, halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
Cy.sup.1, --W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1, CN, NO.sub.2,
OR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, and S(O).sub.2NR.sup.c1R.sup.d1,
wherein each of said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, or C.sub.1-6 haloalkyl, is optionally substituted by 1, 2,
3, 4 or 5 substituents each independently selected from halo,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, halosulfanyl, CN, NO.sub.2, SF.sub.5, OR.sup.a1,
SR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
OC(O)R.sup.b1, OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1,
NR.sup.c1C(O)R.sup.b1, NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1C(O)OR.sup.a1, NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1,
S(O)R.sup.b1, S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, and S(O).sub.2NR.sup.c1R.sup.d1;
R.sup.a1, R.sup.b1, R.sup.c1, and R.sup.d1 are each, independently,
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl,
wherein each of said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is
optionally substituted with 1, 2, 3, 4, or 5 substituents
independently selected from halo, C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.1-4 hydroxylalkyl, C.sub.1-4 cyanoalkyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO.sub.2, OH, SH,
O(C.sub.1-4 alkyl), O(C.sub.1-4 haloalkyl), O(aryl), O(arylalkyl),
S(C.sub.1-4 alkyl), S(C.sub.1-4 haloalkyl), S(aryl), S(arylalkyl),
amino, C.sub.1-4 alkylamino, C.sub.2-8 dialkylamino, C(.dbd.O)H,
C(.dbd.O)--(C.sub.1-4 alkyl), C(.dbd.O)-(arylalkyl),
C(.dbd.O)NH.sub.2, C(.dbd.O)NH(C.sub.1-4 alkyl),
C(.dbd.O)N(C.sub.1-4 alkyl).sub.2, C(.dbd.O)OH,
C(.dbd.O)O--(C.sub.1-4 alkyl), C(.dbd.O)O-(arylalkyl), OC(.dbd.O)H,
OC(.dbd.O)--(C.sub.1-4 alkyl), OC(.dbd.O)-(arylalkyl),
OC(.dbd.O)NH.sub.2, OC(.dbd.O)NH(C.sub.1-4 alkyl),
OC(.dbd.O)NH-(arylalkyl), OC(.dbd.O)N(C.sub.1-4 alkyl).sub.2,
NHC(.dbd.O)--(C.sub.1-4 alkyl), NHC(.dbd.O)O-(arylalkyl),
NHC(.dbd.O)O--(C.sub.1-4 alkyl), NHC(.dbd.O)O-(arylalkyl),
NHS(.dbd.O).sub.2--(C.sub.1-4 alkyl),
NHS(.dbd.O).sub.2-(arylalkyl), NHS(.dbd.O).sub.2--NH(C.sub.1-4
alkyl), NHS(.dbd.O).sub.2--N(C.sub.1-4 alkyl).sub.2,
NHS(.dbd.O).sub.2--NH(arylalkyl), S(.dbd.O).sub.2--(C.sub.1-4
alkyl), S(.dbd.O).sub.2-(arylalkyl), S(.dbd.O).sub.2NH.sub.2,
S(.dbd.O).sub.2NH(C.sub.1-4 alkyl), and
S(.dbd.O).sub.2NH(arylalkyl); or R.sup.c1 and R.sup.d1 together
with the N atom to which they are attached form a 4-, 5-, 6- or
7-membered heterocycloalkyl group or heteroaryl group, each
optionally substituted with 1, 2, or 3 substituents independently
selected from halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4
hydroxylalkyl, C.sub.1-4 cyanoalkyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, CN, NO.sub.2, OH, SH, O(C.sub.1-4 alkyl),
O(C.sub.1-4 haloalkyl), O(aryl), O(arylalkyl), S(C.sub.1-4 alkyl),
S(C.sub.1-4haloalkyl), S(aryl), S(arylalkyl), amino, C.sub.1-4
alkylamino, C.sub.2-8 dialkylamino, C(.dbd.O)H,
C(.dbd.O)--(C.sub.1-4 alkyl), C(.dbd.O)-(arylalkyl),
C(.dbd.O)NH.sub.2, C(.dbd.O)NH(C.sub.1-4 alkyl),
C(.dbd.O)N(C.sub.1-4 alkyl).sub.2, C(.dbd.O)OH,
C(.dbd.O)O--(C.sub.1-4 alkyl), C(.dbd.O)O-(arylalkyl), OC(.dbd.O)H,
OC(.dbd.O)--(C.sub.1-4 alkyl), OC(.dbd.O)-(arylalkyl),
OC(.dbd.O)NH.sub.2, OC(.dbd.O)NH(C.sub.1-4 alkyl),
OC(.dbd.O)NH-(arylalkyl), OC(.dbd.O)N(C.sub.1-4 alkyl).sub.2,
NHC(.dbd.O)--(C.sub.1-4 alkyl), NHC(.dbd.O)O-(arylalkyl),
NHC(.dbd.O)O--(C.sub.1-4 alkyl), NHC(.dbd.O)O-(arylalkyl),
NHS(.dbd.O).sub.2--(C.sub.1-4 alkyl),
NHS(.dbd.O).sub.2-(arylalkyl), NHS(.dbd.O).sub.2--NH(C.sub.1-4
alkyl), NHS(.dbd.O).sub.2--N(C.sub.1-4 alkyl).sub.2,
NHS(.dbd.O).sub.2--NH(arylalkyl), S(.dbd.O).sub.2--(C.sub.1-4
alkyl), S(.dbd.O).sub.2-(arylalkyl), S(.dbd.O).sub.2NH.sub.2,
S(.dbd.O).sub.2NH(C.sub.1-4 alkyl), and
S(.dbd.O).sub.2NH(arylalkyl).
46. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein at least one
R.sup.5 is Cy.sup.1.
47. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein at least one
R.sup.5 is --W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1.
48. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein at least one
R.sup.5 is
--(CR.sup.11aR.sup.11b).sub.p1O(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup-
.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup-
.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(O)(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.-
sup.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(O).sub.2(CR.sup.11aR.sup.11b).sub.p2-Q.su-
p.1-Y.sup.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.sup.-
1-Y.sup.1--Z.sup.1,
--NR.sup.eS(O)(CR.sup.11aR.sup.11b).sub.p1-Q.sup.1-Y.sup.1--Z.sup.1,
--S(O)NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup.1--Z.sup.1,
--NR.sup.eS(O).sub.2(CR.sup.11aR.sup.11b).sub.p1-Q.sup.1-Y.sup.1--Z.sup.1-
,
--S(O).sub.2NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup.1--Z.sup.-
1,
--NR.sup.eC(O)(CR.sup.11aR.sup.11b).sub.p1-Q.sup.1-Y.sup.1--Z.sup.1,
--C(O)NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup.1--Z.sup.1,
or
--NR.sup.eC(O)NR.sup.f(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup.1--Z.sup-
.1.
49. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein at least one
R.sup.5 is --W.sup.6-Q.sup.1-Y.sup.1--Z.sup.1.
50. The compound of claim 47, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein each Y.sup.1
is independently selected from absent,
(CR.sup.12aR.sup.12b).sub.p3O(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3S(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3NR.sup.e(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3C(O)(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3C(O)NR.sup.e(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3S(O).sub.2(CR.sub.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3S(O)NR.sup.e(CR.sup.12aR.sup.12b).sub.p4,
and
(CR.sup.12aR.sup.12b).sub.p3NR.sup.eC(O)NR.sup.f(CR.sup.12aR.sup.12b).sub-
.p4.
51. The compound of claim 47, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein each Z.sup.1
is independently selected from aryl, cycloalkyl, heteroaryl and
heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5
substituents independently selected from halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO.sub.2, OR.sup.a,
SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.d, NR.sup.cC(O)OR.sup.a,
NR.sup.cS(O).sub.2R.sup.b,
NR.sup.cS(O).sub.2S(O).sub.2NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d.
52. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein R.sup.7,
R.sup.8, and R.sup.10 are each, independently, selected from H,
halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, cycloalkyl, CN, NO.sub.2, OR.sup.a1,
SR.sup.a1, S(O)R.sup.b1, S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
NR.sup.c1C(O)R.sup.b1, NR.sup.c1C(O)NR.sup.c1R.sup.d1, and
NR.sup.c1R.sup.d1, wherein each of said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl and cycloalkyl is
optionally substituted by 1, 2, 3, 4, or 5 substituents
independently selected from halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, cycloalkyl, CN,
NO.sub.2, OR.sup.a1, SR.sup.a1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
NR.sup.c1C(O)R.sup.b1, NR.sup.c1C(O)NR.sup.c1R.sup.d1, and
NR.sup.c1R.sup.d1.
53. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein R.sup.7,
R.sup.8, and R.sup.10 are each, independently, selected from H,
halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, CN, NO.sub.2,
OR.sup.a1, and SR.sup.a1.
54. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein R' and R'' are
each, independently, selected from H, C.sub.1-4 alkyl, and
C.sub.1-4 haloalkyl.
55. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein R' and R'' are
each, independently, selected from H and C.sub.1-4 alkyl.
56. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein R' and R'' are
each, independently, selected from H and methyl.
57. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein at least one
of R' and R'' is methyl.
58. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein R' and R'' are
each H.
59. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein each n is,
independently, 1 or 2.
60. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein each m is,
independently, 0 or 1.
61. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein t is 1.
62. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein t is 2.
63. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein t is 3.
64. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein
--(CR'R'').sub.t-- is --CH.sub.2--, --CH(CH.sub.3)--,
--(CH.sub.2).sub.2--, or --(CH.sub.2).sub.3--.
65. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein the compound
is a compound of Formula II, IIa, or IIb: ##STR00141##
66. The compound of claim 65 or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein each R.sup.5
is, independently, selected from H, halo, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, CN, NO.sub.2, SF.sub.5, Cy.sup.1,
--W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1, OR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, NR.sup.c1R.sup.d1,
NR.sup.c1C(O)R.sup.b1, NR.sup.c1S(O).sub.2R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O).sub.2R.sup.b1, and S(O).sub.2NR.sup.c1R.sup.d1.
67. The compound of claim 65, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein: each R.sup.5
is, independently, H, Cy.sup.1, halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halosulfanyl, CN,
NO.sub.2, SF.sub.5, OR.sup.a1, SR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(S)R.sup.b1, C(S)NR.sup.c1R.sup.d1,
C(O)OR.sup.a1, OC(O)R.sup.b1, OC(O)NR.sup.c1R.sup.d1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(S)R.sup.b1,
NR.sup.c1C(S)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1, or
--W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1; or two adjacent R.sup.5 on the
same ring link to form a fused cycloalkyl or fused heterocycloalkyl
group, each optionally substituted by 1, 2, or 3 substituents
independently selected from halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,
halosulfanyl, Cy.sup.1, CN, NO.sub.2, OR.sup.a1, SR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(S)R.sup.b1,
C(S)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
--W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1, OC(O)NR.sup.c1R.sup.d1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1.
68. The compound of claim 65, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein at least one
R.sup.5 is --W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1.
69. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein the compound
is a compound of Formula IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg,
IIIh, IVa, IVb, IVc, IVd, or IVe: ##STR00142## ##STR00143##
##STR00144## wherein D.sup.1, E.sup.1, D.sup.2, and E.sup.2 are
each, independently, CR.sup.5 or N.
70. The compound of claim 69, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein: each R.sup.5
is, independently, H, Cy.sup.1, halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halosulfanyl, CN,
NO.sub.2, SF.sub.5, OR.sup.a1, SR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(S)R.sup.b1, C(S)NR.sup.c1R.sup.d1,
C(O)OR.sup.a1, OC(O)R.sup.b1, OC(O)NR.sup.c1R.sup.d1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(S)R.sup.b1,
NR.sup.c1C(S)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1, or
--W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1; or two adjacent R.sup.5 on the
same ring link to form a fused cycloalkyl or fused heterocycloalkyl
group, each optionally substituted by 1, 2, or 3 substituents
independently selected from halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,
halosulfanyl, Cy.sup.1, CN, NO.sub.2, OR.sup.a1, SR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(S)R.sup.b1,
C(S)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
--W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1, OC(O)NR.sup.c1R.sup.d1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1.
71. The compound of claim 9, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein at least one
R.sup.5 is --W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1.
72. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein R.sup.1 is
selected from H and C.sub.1-3 alkyl; each R.sup.2 is,
independently, selected from H, F, Cl, CH.sub.3, and CF.sub.3;
R.sup.3 is selected from halo, C.sub.1-3 alkyl, and C.sub.1-3
haloalkyl; R.sup.4 is H or methyl; R' and R'' are each,
independently, H or methyl; and t is 1, 2, or 3.
73. The compound of claim 1, or pharmaceutically acceptable salt
thereof or quaternary ammonium salt thereof, wherein R.sup.1 is
selected from H and methyl; each R.sup.2 is H; R.sup.3 is halo;
R.sup.4 is H or methyl; R' and R'' are each, independently, H or
methyl; and t is 1, 2, or 3.
74. A compound selected from:
6-Chloro-15-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).1(10,14)]tricos-
a-1(21),3(23),4,6,10(22),11,13,17,19-nonaene;
6-Chloro-15-oxa-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).1(10,14)]tetrac-
osa-1(22),3(24),4,6,10(23),11,13,18,20-nonaene;
6-Chloro-16-thia-2,4,8,15,23-pentaazatetracyclo[15.3.1.1(3,7).1(10,14)]tr-
icosa-1(21),3(23),4,6,10(22),11,13,17,19-nonaene 16,16-dioxide;
6-Chloro-2,4,8,15,23-pentaazatetracyclo[15.3.1.1(3,7).1(10,14)]tricosa-1(-
21),3(23),4,6,10(22),11,13,17,19-nonaen-16-one;
6-Chloro-15-oxa-2,4,8,25-tetraazatetracyclo[17.3.1.1(3,7).1(10,14)]pentac-
osa-1(23),3(25),4,6,10(24),11,13,19,21-nonaene;
(9R)-6-Chloro-9-methyl-15-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).1-
(10,14)]tricosa-1(21),3(23),4,6,10(22),11,13,17,19-nonaene;
6-Chloro-15,18-dioxa-2,4,8,25-tetraazatetracyclo[17.3.1.1(3,7).1(10,14)]p-
entacosa-1(23),3(25),4,6,10(24),11,13,19,21-nonaene;
19-Chloro-9-oxa-2,17,21,22-tetraazatetracyclo[16.3.1.1(3,7).1(10,14)]tetr-
acosa-1(22),3(24),4,6,10(23),11,13,18,20-nonaene;
6-Chloro-16-oxa-2,4,8,25-tetraazatetracyclo[17.3.1.1(3,7).1(11,15)]pentac-
osa-1(23),3(25),4,6,11(24),12,14,19,21-nonaene;
20-Chloro-9-oxa-2,18,22,23-tetraazatetracyclo[17.3.1.1(3,7).1(10,14)]pent-
acosa-1(23),3(25),4,6,10(24),11,13,19,21-nonaene;
6-Chloro-16-oxa-2,4,8,26-tetraazatetracyclo[18.3.1.1(3,7).1(11,15)]hexaco-
sa-1(24),3(26),4,6,11(25),12,14,20,22-nonaene;
21-Chloro-10-oxa-2,19,23,24-tetraazatetracyclo[18.3.1.1(3,7).1(11,15)]hex-
acosa-1(24),3(26),4,6,11(25),12,14,20,22-nonaene
11-Bromo-6-chloro-15-oxa-2,4,8,25-tetraazatetracyclo[17.3.1.1(3,7).1(10,1-
4)]pentacosa-1(23),3(25),4,6,10(24),11,13,19,21-nonaene;
6-Chloro-11-phenyl-15-oxa-2,4,8,25-tetraazatetracyclo[17.3.1.1(3,7).1(10,-
14)]pentacosa-1(23),3(25),4,6,10(24),11,13,19,21-nonaene;
12-Bromo-6-chloro-15-oxa-2,4,8,25-tetraazatetracyclo[17.3.1.1(3,7).1(10,1-
4)]pentacosa-1(23),3(25),4,6,10(24),11,13,19,21-nonaene; and
6-Chloro-2,4,8,19,23-pentaazatetracyclo[15.3.1.1(3,7).1(10,14)]tricosa-1(-
21),3(23),4,6,10(22),11,13,17,19-nonaen-13-amine, or
pharmaceutically acceptable salt thereof or quaternary ammonium
salt thereof.
75. A composition comprising a compound according to claim 1, or
pharmaceutically acceptable salt thereof or quaternary ammonium
salt thereof, and at least one pharmaceutically acceptable
carrier.
76. A method of treating an autoimmune disease in a patient
comprising administering to said patient a therapeutically
effective amount of a compound of claim 1, or pharmaceutically
acceptable salt thereof or quaternary ammonium salt thereof.
77. The method of claim 76 wherein said autoimmune disease is
selected from a skin disorder, multiple sclerosis, rheumatoid
arthritis, psoriatic arthritis, juvenile arthritis, type I
diabetes, lupus, psoriasis, inflammatory bowel disease, ankylosing
spondylitis, myasthenia gravis, immunoglobulin nephropathies, and
autoimmune thyroid disorder.
78. A method of treating a disease in a patient comprising
administering to said patient a therapeutically effective amount of
a compound of claim 1, or pharmaceutically acceptable salt thereof
or quaternary ammonium salt thereof, wherein said disease is
selected from a skin disorder, an autoimmune bullous skin disorder,
pemphigus vulgaris (PV), bullous pemphigoid (BP), psoriasis,
psoriasis vulgaris, atopic dermatitis, alopecia areata, psoriasis,
atopic dermatitis, alopecia areata, skin rash, skin irritation,
skin sensitization, contact dermatitis, allergic contact
dermatitis, multiple sclerosis, rheumatoid arthritis, psoriatic
arthritis, juvenile arthritis, type I diabetes, lupus, psoriasis,
inflammatory bowel disease, ulcerative colitis, Crohn's disease,
ankylosing spondylitis, myasthenia gravis, immunoglobulin
nephropathies, allergy or an allergic condition, asthma, food
allergy, atopic dermatitis, rhinitis, a viral disease, Epstein Barr
Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1,
Varicella-Zoster Virus (VZV), Human Papilloma Virus (HPV), cancer,
a solid tumor, prostate cancer, renal cancer, hepatic cancer,
colorectal cancer, pancreatic cancer, gastric cancer, breast
cancer, lung cancer, cancers of the head and neck, thyroid cancer,
glioblastoma, Kaposi's sarcoma, melanoma, hematological cancer or
malignancy, skin cancer, lymphoma, leukemia, multiple myeloma,
acute lymphoblastic leukemia, Chronic Lymphocytic Leukemia (CLL),
myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML),
chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia
(CMML), cutaneous T-cell lymphoma (CTCL) cutaneous B-cell lymphoma,
Sezary syndrome, mycosis fungoides, a lymphoma related disease,
Castleman's disease, waldenstrom's macroglobulinemia, Poems
syndrome, a paraneoplastic syndrome associated with cytokine
production in cancer, a myeloproliferative disorder (MPD),
polycythemia vera (PV), essential thrombocythemia (ET),
myelofibrosis with myeloid metaplasia (MMM), hypereosinophilic
syndrome (HES), systemic mast cell disease (SMCD), polycythemia
vera (PV), hypereosinophilic syndrome (HES), primary myelofibrosis
(PMF), post polycythemia vera myelofibrosis (Post-PV MF),
post-essential thrombocythemia myelofibrosis (Post-ET MF),
inflammation or an inflammatory disease, an inflammatory disease of
the eye, an inflammatory disease of the respiratory tract,
inflammatory myopathy, Systemic Inflammatory Response Syndrome
(SIRS), septic shock, dry eye disorder, iritis, uveitis, scleritis,
conjunctivitis, rhinitis, sinusitis, bronchitis, chronic
obstructive pulmonary disease, myocarditis, organ transplant
rejection, allograft rejection, graft versus host disease, an
ischemia reperfusion injury or a disease or condition related to an
inflammatory ischemic event, anorexia, cachexia, or fatigue
resulting from or associated with cancer, restenosis,
sclerodermitis, fibrosis, diabetic retinopathy or
neurodegeneration, an anaplastic large cell lymphoma, a non-Hodgkin
lymphoma, lung cancer, and autoimmune thyroid disorder.
79. A method of treating cancer in a patient comprising
administering to said patient a therapeutically effective amount of
a compound of claim 1, or pharmaceutically acceptable salt thereof
or quaternary ammonium salt thereof.
80. A method of treating myelofibrosis with myeloid metaplasia
(MMM) in a patient comprising administering to said patient a
therapeutically effective amount of a compound of claim 1, or
pharmaceutically acceptable salt thereof or quaternary ammonium
salt thereof.
Description
[0001] This application claims benefit of priority to U.S.
provisional patent application Ser. No. 61/146, 824 filed Jan. 23,
2009, which is hereby incorporated by reference in its
entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to macrocyclic compounds, and
compositions thereof as well as methods of use the same for
treatment of Janus Kinase and/or Anaplastic Lymphoma Kinase
(JAK/ALK)-associated diseases including, for example, inflammatory
disorders, autoimmune disorders, skin disorders, myeloid
proliferative disorders, as well as cancer.
BACKGROUND OF THE INVENTION
[0003] Protein kinases (PKs) are a group of enzymes that regulate
diverse, important biological processes including cell growth,
survival and differentiation, organ formation and morphogenesis,
neovascularization, tissue repair and regeneration, among others.
Protein kinases exert their physiological functions through
catalyzing the phosphorylation of proteins (or other substrates
such as lipids) and thereby modulating the cellular activities of
the substrates in various biological contexts. In addition to the
functions in normal tissues/organs, many protein kinases also play
a central role in a host of human diseases including cancer. A
subset of protein kinases (also referred to as oncogenic protein
kinases), when dysregulated, can cause tumor formation and
inappropriate tumor cell survival and proliferation, and further
contribute to tumor progression [See e.g. Blume-Jensen P. et al,
Nature 2001, 411(6835):355-365]. Thus far, oncogenic protein
kinases represent one of the largest and most attractive groups of
protein targets for cancer intervention and drug development.
[0004] Protein kinases can be categorized as receptor type and
non-receptor type. Receptor tyrosine kinases (RTKs) have an
extracellular portion, a transmembrane domain, and an intracellular
portion, while non-receptor tyrosine kinases are entirely
intracellular. RTK mediated signal transduction is typically
initiated by extracellular interaction with a specific growth
factor (ligand), typically followed by receptor dimerization,
stimulation of the intrinsic protein tyrosine kinase activity, and
receptor transphosphorylation. Binding sites are thereby created
for intracellular signal transduction molecules and lead to the
formation of complexes with a spectrum of cytoplasmic signaling
molecules that facilitate cellular responses such as cell survival,
proliferation, differentiation, metabolic effects, and changes in
the extracellular microenvironment.
[0005] At present, at least nineteen (19) distinct RTK subfamilies
have been identified. One RTK subfamily, designated the HER
subfamily, includes EGFR, HER2, HER3 and HER4, and bind such
ligands as epithelial growth factor (EGF), TGF-.alpha.,
amphiregulin, HB-EGF, betacellulin and heregulin. A second family
of RTKs, designated the insulin subfamily, includes the INS-R, the
IGF-1R and the IR-R. A third family, the "PDGF" subfamily, includes
the PDGF alpha and beta receptors, CSFIR, c-kit and FLK-II. Another
subfamily of RTKs, referred to as the FLK subfamily, encompasses
the Kinase insert Domain-Receptor fetal liver kinase-1 (KDR/FLK-1),
the fetal liver kinase 4 (FLK-4) and the fms-like tyrosine kinase 1
(flt-1). Two other subfamilies of RTKs have been designated as the
FGF receptor family (FGFR1, FGFR2, FGFR3 and FGFR4) and the Met
subfamily (c-Met, Ron and Sea). For a detailed discussion of
protein kinases, see for example, Blume-Jensen, P. et al., Nature.
2001, 411(6835):355-365, and Manning, G. et al., Science. 2002,
298(5600):1912-1934.
[0006] The non-receptor type of tyrosine kinases are also composed
of numerous sub-families, including Src, Btk, Abl, Fak, and Jak.
Each of these subfamilies can be further subdivided into multiple
members that have been frequently linked to oncogenesis. The Src
family, for example, is the largest and includes Src, Fyn, Lck and
Fgr among others. For a detailed discussion of these kinases, see
Bolen J B, "Non-receptor tyrosine protein kinases, " Oncogene.,
1993, 8(8):2025-31.
[0007] A significant number of tyrosine kinases (both receptor and
nonreceptor) are associated with cancer (see Madhusudan S, Ganesan
T S. Tyrosine kinase inhibitors in cancer therapy. Clin Biochem.
2004, 37(7):618-35.). Clinical studies suggest that overexpression
or dysregulation of tyrosine kinases may also be of prognostic
value. For example, members of the HER family of RTKs have been
associated with poor prognosis in breast, colorectal, head and neck
and lung cancer. Mutation of c-Kit tyrosine kinase has been
associated with decreased survival in gastrointestinal stromal
tumors. In acute myelogenous leukemia (AML), Flt-3 mutation
predicts shorter disease free survival. VEGFR expression, which is
important for tumor angiogenesis, is associated with a lower
survival rate in lung cancer. Tie-1 kinase expression inversely
correlates with survival in gastric cancer. BCR-Abl expression is
an important predictor of response in chronic myelogenous leukemia
(CML) and Src tyrosine kinase is an indicator of poor prognosis in
all stages of colorectal cancer.
[0008] The immune system responds to injury and threats from
pathogens. Cytokines are low-molecular weight polypeptides or
glycoproteins that stimulate biological responses in virtually all
cell types. For example, cytokines regulate many of the pathways
involved in the host inflammatory response to sepsis. Cytokines
influence cell differentiation, proliferation and activation, and
they can modulate both proinflammatory and anti-inflammatory
responses to allow the host to react appropriately to
pathogens.
[0009] Binding of a cytokine to its cell surface receptor initiates
intracellular signaling cascades that transduce the extracellular
signal to the nucleus, ultimately leading to changes in gene
expression. The pathway involving the Janus kinase family of
protein tyrosine kinases (JAKs) and Signal Transducers and
Activators of Transcription (STATs) is engaged in the signaling of
a wide range of cytokines. Generally, cytokine receptors do not
have intrinsic tyrosine kinase activity, and thus require
receptor-associated kinases to propagate a phosphorylation cascade.
JAKs fulfill this function. Cytokines bind to their receptors,
causing receptor dimerization, and this enables JAKs to
phosphorylate each other as well as specific tyrosine motifs within
the cytokine receptors. STATs, and other proteins, recognize these
phosphotyrosine motifs and are recruited to the receptor where they
are activated by a JAK-dependent tyrosine phosphorylation events.
Upon activation, STATs dissociate from the receptors and
translocate to the nucleus to bind to specific DNA sites and alter
transcription [Scott, M. J., C. J. Godshall, et al. (2002). "Jaks,
STATs, Cytokines, and Sepsis." Clin Diagn Lab Immunol 9(6):
1153-9].
[0010] The Janus Kinase (JAK) family plays a role in the
cytokine-dependent regulation of proliferation and function of
cells involved in immune response. Currently, there are four known
mammalian JAK family members: JAK1 (also known as Janus kinase-1),
JAK2 (also known as Janus kinase-2), JAK3 (also known as Janus
kinase, leukocyte; JAKL; L-JAK and Janus kinase-3) and TYK2 (also
known as protein-tyrosine kinase 2). The JAK proteins range in size
from 120 to 140 kDa and comprise seven conserved JAK homology (JH)
domains; one of these is a functional catalytic kinase domain, and
another is a pseudokinase domain potentially serving a regulatory
function and/or serving as a docking site for STATs (Scott,
Godshall et al. 2002, supra).
[0011] While JAK1, JAK2 and TYK2 are widely expressed, JAK3 is
reported to be preferentially expressed in natural killer (NK)
cells and activated T cells, suggesting a role in lymphoid
activation (Kawamura, M., D. W. McVicar, et al. (1994). "Molecular
cloning of L-JAK, a Janus family protein-tyrosine kinase expressed
in natural killer cells and activated leukocytes." Proc Natl Acad
Sci USA 91(14): 6374-8).
[0012] Not only do the cytokine-stimulated immune and inflammatory
responses contribute to normal host defense, they also play roles
in the pathogenesis of diseases. Pathologies such as severe
combined immunodeficiency (SCID) can arise from hypoactivity, e.g.
the inability of various cytokines to signal through JAK3 (Macchi,
et al. Nature, 337:65-68, 1995). In contrast, hyperactive or
inappropriate immune/inflammatory responses can contribute to the
pathology of autoimmune diseases such as rheumatoid and psoriatic
arthritis, asthma and systemic lupus erythematosus, inflammatory
bowel disease, multiple sclerosis, type I diabetes mellitus,
myasthenia gravis, thyroiditis, immunoglobulin nephropathies,
myocarditis as well as illnesses such as scleroderma and
osteoarthritis (Ortmann, R. A., T. Cheng, et al. (2000). "Janus
kinases and signal transducers and activators of transcription:
their roles in cytokine signaling, development and
immunoregulation." Arthritis Res 2(1): 16-32). Furthermore,
syndromes with a mixed presentation of autoimmune and
immunodeficiency disease are quite common (Candotti, F., L.
Notarangelo, et al. (2002). "Molecular aspects of primary
immunodeficiencies: lessons from cytokine and other signaling
pathways." J Clin Invest 109(10): 1261-9). Thus, therapeutic agents
are typically aimed at augmentation or suppression of the immune
and inflammatory pathways, accordingly.
[0013] Deficiencies in expression of various JAK family members
have been associated with pathologies in rodents. Jak1-/- mice are
runted at birth, fail to nurse, and die perinatally (Rodig, S. J.,
M. A. Meraz, et al. (1998). "Disruption of the Jak1 gene
demonstrates obligatory and non-redundant roles of the Jaks in
cytokine-induced biologic responses." Cell 93(3): 373-83). Jak2-/-
mouse embryos are anemic and die around day 12.5 postcoitum due to
the absence of definitive erythropoiesis. In addition, JAK2
deficiency resulted in cell-type specific deficiencies in the
signaling of some cytokines such as those required for definitive
erythropoiesis (Neubauer, H., A. Cumano, et al. (1998). Cell 93(3):
397-409; Parganas, E., D. Wang, et al. (1998). Cell 93(3):
385-95.). JAK3 appears to play a role in normal development and
function of B and T lymphocytes. Mutations of JAK3 are reported to
be responsible for autosomal recessive severe combined
immunodeficiency (SCID) in humans (Candotti, F., S. A. Oakes, et
al. (1997). "Structural and functional basis for JAK3-deficient
severe combined immunodeficiency." Blood 90(10): 3996-4003).
[0014] The JAK/STAT pathway, and in particular all four members of
the JAK family, are believed to play a role in the pathogenesis of
the asthmatic response, chronic obstructive pulmonary disease,
bronchitis other related inflammatory diseases of the lower
respiratory tract, inflammatory diseases or conditions of the upper
respiratory tract such as those affecting the nose and sinuses
(e.g. rhinitis, sinusitis) whether classically allergic reactions
or not, Systemic Inflammatory Response Syndrome (SIRS), and septic
shock. See e.g., Pernis, A. B. and P. B. Rothman, "JAK--STAT
signaling in asthma, " J Clin Invest 109(10): 1279-83 (2002); and
Seto, Y., H. Nakajima, et al, "Enhanced Th2 cell-mediated allergic
inflammation in Tyk2-deficient mice." J Immunol 170(2): 1077-83
(2003).
[0015] The JAK/STAT pathway has also been implicated to play a role
in inflammatory diseases/conditions of the eye including, but not
limited to, dry eye disorder, iritis, uveitis, scleritis,
conjunctivitis, as well as chronic allergic responses. Therefore,
inhibition of JAK kinases may have a beneficial role in the
therapeutic treatment of these diseases.
[0016] As used herein, "dry eye disorder" is intended to encompass
the disease states summarized in a recent official report of the
Dry Eye Workshop (DEWS), which defined dry eye as "a multifactorial
disease of the tears and ocular surface that results in symptoms of
discomfort, visual disturbance, and tear film instability with
potential damage to the ocular surface. It is accompanied by
increased osmolarity of the tear film and inflammation of the
ocular surface." Lemp, "The Definition and Classification of Dry
Eye Disease: Report of the Definition and Classification
Subcommittee of the International Dry Eye WorkShop", The Ocular
Surface, 5(2), 75-92 April 2007, which is incorporated herein by
reference in its entirety. Dry eye is also sometimes referred to as
keratoconjunctivitis sicca. In some embodiments, the treatment of
the dry eye disorder involves ameliorating a particular symptom of
dry eye disorder, such as eye discomfort, visual disturbance, tear
film instability, tear hyperosmolarity, and inflammation of the
ocular surface.
[0017] The JAK/STAT pathway also plays a role in cancers of the
immune system. In adult T cell leukemia/lymphoma (ATLL), human CD4+
T cells acquire a transformed phenotype, an event that correlates
with acquisition of constitutive phosphorylation of JAKs and STATs.
Furthermore, an association between JAK3 and STAT-1, STAT-3, and
STAT-5 activation and cell-cycle progression was demonstrated by
both propidium iodide staining and bromodeoxyuridine incorporation
in cells of four ATLL patients tested. These results imply that
JAK/STAT activation is associated with expansion of leukemic cells
and that therapeutic approaches aimed at JAK/STAT inhibition may be
considered to halt neoplastic growth (Takemoto, S., J. C. Mulloy,
et al. (1997). "Proliferation of adult T cell leukemia/lymphoma
cells is associated with the constitutive activation of JAK/STAT
proteins." Proc Natl Acad Sci USA 94(25): 13897-902).
[0018] Blocking cytokine and growth factor signal transduction at
the level of the JAK kinases holds promise for the treatment of a
number of human cancers. For example, cytokines of the interleukin
6 (IL-6) family, which activate the signal transducer gp130, are
major survival and growth factors for human multiple myeloma (MM)
cells. The signal transduction of gp130 is believed to involve
JAK1, JAK2 and
[0019] Tyk2 and the downstream effectors STAT3 and the
mitogen-activated protein kinase (MAPK) and AKT pathways. In
IL-6-dependent MM cell lines treated with the JAK2 inhibitor
pyridone 6 STAT3 phosphorylation and tumor cell proliferation and
survival were inhibited (Pedranzini, L, et al, Cancer Research
66:9714-21, 2006.
[0020] Activation of JAK/STAT in cancers may occur by multiple
mechanisms including cytokine stimulation (e.g. IL-6 or GM-CSF) or
by a reduction in the endogenous suppressors of JAK signaling such
as SOCS (suppressor of cytokine signaling) or PIAS (protein
inhibitor of activated STAT) (Boudny, V., and Kovarik, J.,
Neoplasm. 49:349-355, 2002). Importantly, activation of STAT
signaling, as well as other pathways downstream of JAKs (e.g. Akt),
has been correlated with poor prognosis in many cancer types
(Bowman, T., et al. Oncogene 19:2474-2488, 2000). Moreover,
elevated levels of circulating cytokines that signal through
JAK/STAT may adversely impact patient health as they are thought to
play a causal role in cachexia and/or chronic fatigue. As such, JAK
inhibition may be therapeutic for the treatment of cancer patients
for reasons that extend beyond potential anti-tumor activity. The
cachexia indication may gain further mechanistic support with the
realization that the satiety factor leptin signals through
JAKs.
[0021] Pharmacological targeting of Janus kinase 3 (JAK3) has been
employed successfully to control allograft rejection and graft
versus host disease (GVHD). In addition to its involvement in
signaling of cytokine receptors, JAK3 is also engaged in the CD40
signaling pathway of peripheral blood monocytes. During
CD40-induced maturation of myeloid dendritic cells (DCs), JAK3
activity is induced, and increases in costimulatory molecule
expression, IL-12 production, and potent allogeneic stimulatory
capacity are observed. A rationally designed JAK3 inhibitor
WHI-P-154 prevented these effects arresting the DCs at an immature
level, suggesting that immunosuppressive therapies targeting the
tyrosine kinase JAK3 may also affect the function of myeloid cells
(Saemann, M. D., C. Diakos, et al. (2003). "Prevention of
CD40-triggered dendritic cell maturation and induction of T-cell
hyporeactivity by targeting of Janus kinase 3." Am J Transplant
3(11): 1341-9). In the mouse model system, JAK3 was also shown to
be an important molecular target for treatment of autoimmune
insulin-dependent (type 1) diabetes mellitus. The rationally
designed JAK3 inhibitor JANEX-1 exhibited potent immunomodulatory
activity and delayed the onset of diabetes in the NOD mouse model
of autoimmune type 1 diabetes (Cetkovic-Cvrlje, M., A. L. Dragt, et
al. (2003). "Targeting JAK3 with JANEX-1 for prevention of
autoimmune type 1 diabetes in NOD mice." Clin Immunol 106(3):
213-25).
[0022] It has been suggested that inhibition of JAK2 tyrosine
kinase can be beneficial for patients with myeloproliferative
disorders. (Levin, et al., Cancer Cell, vol. 7, 2005: 387-397)
Myeloproliferative disorders (MPD) include polycythemia vera (PV),
essential thrombocythemia (ET), myelofibrosis with myeloid
metaplasia (MMM), chronic myelogenous leukemia (CML), chronic
myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES),
systemic mast cell disease (SMCD) and the like. Although
myeloproliferative disorders (such as PV, ET and MMM) are thought
to be caused by acquired somatic mutation in hematopoietic
progenitors, the genetic basis for these diseases has not been
known. However, it has been reported that hematopoietic cells from
a majority of patients with PV and a significant number of patients
with ET and MMM possess a recurrent somatic activating mutation in
the JAK2 tyrosine kinase. It has also been reported that inhibition
of the JAK2V617F kinase with a small molecule inhibitor leads to
inhibition of proliferation of hematopoietic cells, suggesting that
the JAK2 tyrosine kinase is a potential target for pharmacologic
inhibition in patients with PV, ET and MMM. In addition, mutations
in the receptor for thrombopoietin have also been described in MPD
patients and due to the requirement of JAK2 for this receptor to
signal, inhibition of JAKs may be therapeutic (Tefferi, A. Leukemia
& Lymphoma, March 2008; 49(3): 388-397).
[0023] Inhibition of the JAK kinases is also envisioned to have
therapeutic benefits in patients suffering from skin immune
disorders such as psoriasis, and skin sensitization. In psoriasis
vulgaris, the most common form of psoriasis, it has been generally
accepted that activated T lymphocytes are important for the
maintenance of the disease and its associated psoriatic plaques
(Gottlieb, A. B., et al, Nat Rev Drug Disc., 4:19-34). Psoriatic
plaques contain a significant immune infiltrate, including
leukocytes and monocytes, as well as multiple epidermal layers with
increased keratinocyte proliferation. While the initial activation
of immune cells in psoriasis occurs by an ill defined mechanism,
the maintenance is believed to be dependent on a number of
inflammatory cytokines, in addition to various chemokines and
growth factors (JCI, 113:1664-1675). Many of these, including
interleukins -2, -4, -6, -7, -12, -15, -18, and -23 as well as
GM-CSF and IFNg, signal through the Janus (JAK) kinases (Adv
Pharmacol. 2000; 47:113-74). As such, blocking signal transduction
at the level of JAK kinases may result in therapeutic benefits in
patients suffering from psoriasis or other immune disorders of the
skin (Kimbal, A. B., et al. Arch Dermatol. 2008 February;
144(2):200-7).
[0024] It has been known that certain therapeutics can cause immune
reactions such as skin rash or diarrhea in some patients. For
instance, administration of some of the new targeted anti-cancer
agents such as Iressa, Erbitux, and Tarceva has induced acneiform
rash with some patients. Another example is that some therapeutics
used topically induce skin irritation, skin rash, contact
dermatitis or allergic contact sensitization. For some patients,
these immune reactions may be bothersome, but for others, the
immune reactions such as rash or diarrhea may result in the
inability to continue treatment. Although the driving force behind
these immune reactions has not been elucidated completely at the
present time, these immune reactions are likely linked to immune
infiltrate.
[0025] Inhibitors of Janus kinases or related kinases are widely
sought and several publications report effective classes of
compounds. For example, certain inhibitors are reported in WO
99/65909, US 2004/0198737; WO 2004/099204; WO 2004/099205; and WO
01/42246. Heteroaryl substituted pyrroles and other compounds are
reported in WO 2004/72063 and WO 99/62908. For another example,
certain JAK inhibitors, including pyrrolopyridine and
pyrrolopyrimidines, are reported in U.S. Ser. No. 11/637, 545,
filed Dec. 12, 2006.
[0026] Anaplastic lymphoma kinase (ALK), is a receptor tyrosine
kinase, believed to play an important role in the development and
function of the nervous system. ALK is normally expressed in the
central nervous system, with peak expression during the neonatal
period. However, due to chromosomal translocations, ALK is also
aberrantly expressed and activated in some cancers in the form of
oncogenic fusion proteins. ALK fusion proteins are responsible for
approximately 5-10% of all non-Hodgkin's lymphomas. Additional
mutations/translocations and increased expression have also been
identified in lung cancer and neurological tumors (Soda, M., et al.
Nature 448:561-566, 2007 and Mosse, Y P, AACR 2008). Accordingly,
ALK inhibitors are useful for the treatment of ALK-related tumors,
including anaplastic large cell lymphomas and non-Hodgkin lymphomas
in addition to skin diseases and lung cancers.
[0027] The annual incidence of ALK positive lymphomas is about 100,
000 worldwide. ALK is an excellent candidate for therapeutic
intervention, as it plays an essential role in oncogenicity and its
normal expression is mostly restricted to the central nervous
system.
[0028] Hence, a specific ALK inhibitor could be an efficient
treatment for ALK positive lymphomas with few associated clinical
side effects. Accordingly, potential ALK inhibitors are highly
desirable as potential treatments of ALK-related diseases/tumors.
For example, certain ALK inhibitors such staurosporine derivatives
are reported in WO2004079326.
[0029] Thus, new or improved agents which inhibit kinases such as
Janus kinases and/or ALK are continually needed for developing new
and more effective pharmaceuticals to treat cancer,
myeloproliferative disorders, autoimmune diseases, and inflammatory
diseases, to name a few. The compounds, compositions and methods
described herein are directed toward these needs and other
ends.
SUMMARY OF THE INVENTION
[0030] The present invention provides, inter alia, compounds of
Formula I:
##STR00002##
or pharmaceutically acceptable salts thereof or quaternary ammonium
salts thereof, wherein constituent members are provided below.
[0031] The present invention further provides pharmaceutical
compositions comprising a compound of Formula I, or
pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable carrier.
[0032] The present invention further provides methods of modulating
an activity of one or more JAK/ALK kinases, comprising contacting
the kinases with a compound of Formula I, or pharmaceutically
acceptable salt of the same.
[0033] The present invention further provides methods of inhibiting
an activity of one or more JAK/ALK kinases, comprising contacting
the kinases with a compound of Formula I, or pharmaceutically
acceptable salt of the same.
[0034] The present invention further provides methods of treating
one or more of the various JAK/ALK-associated conditions, diseases
and disorders named herein by administering to a patient a
therapeutically effective amount of a compound of Formula I, or
pharmaceutically acceptable salt of the same.
[0035] The present invention further provides compounds of Formula
I, or pharmaceutically acceptable salts thereof, for use in
therapy.
[0036] The present invention further provides use of the compounds
of Formula I, or pharmaceutically acceptable salts thereof, for the
manufacture/preparation of a medicament for use in therapy.
DETAILED DESCRIPTION
[0037] The present invention provides, inter alia, compounds of
Formula I:
##STR00003##
or pharmaceutically acceptable salts thereof or quaternary ammonium
salts thereof, wherein:
[0038] represents a single bond or a double bond;
[0039] X.sup.1 is N or CR.sup.1;
[0040] X.sup.2 is N or CR.sup.2;
[0041] X.sup.3 is N or CR.sup.3;
[0042] A.sup.1 and A.sup.2 are each, independently, selected from
CR.sup.2, N, NR.sup.6, O, and S;
[0043] B.sup.1, B.sup.2, E.sup.1, and E.sup.2 are each,
independently, selected from CR.sup.5, N, NR.sup.6, O, and S;
[0044] D.sup.1 and D.sup.2 are each, independently, selected from a
bond, CR.sup.5, N, NR.sup.6, O, and S;
[0045] wherein the ring containing A.sup.1, B.sup.1, D.sup.1, and
E.sup.1 is a 5- or 6-membered aromatic ring and wherein the ring
containing A.sup.2, B.sup.2, D.sup.2, and E.sup.2 is a 5- or
6-membered aromatic ring;
[0046] L.sup.1 and L.sup.2 are each, independently selected from a
bond, --(CR.sup.7R.sup.8).sub.n--,
--O--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.,
--S--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.,
--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--N.dbd., --(CR.sup.7R.sup.8).sub.m--O--,
--(CR.sup.7R.sup.8).sub.m--S--, --(CR.sup.7R.sup.8).sub.m--S(O)--,
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2--,
--(CR.sup.7R.sup.8).sub.m--C(O)--, --C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--C(O)O--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--OC(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9C(O)O--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--S(O).sub.2NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--S(O)NR.sup.9--, and
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2NR.sup.9--;
[0047] wherein at least one of L.sup.1 and L.sup.2 is other than a
bond;
[0048] R' and R'' are each, independently, selected from H, halo,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, CN, NO.sub.2, OR.sup.a2, SR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, OC(O)R.sup.b2,
OC(O)N.sup.c2R.sup.d2, N.sup.c2R.sup.d2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2C(O)OR.sup.a2,
C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, S(O)R.sup.b2,
S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, and S(O).sub.2NR.sup.c2R.sup.d2;
[0049] or R' and R'' together with the C atom to which they are
attached form a 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered
cycloalkyl group or heterocycloalkyl group, each optionally
substituted with 1, 2, or 3 substituents independently selected
from halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, CN, NO.sub.2, OR.sup.a2, SR.sup.a2,
C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, OC(O)R.sup.b2,
OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2C(O)OR.sup.a2,
C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, S(O)R.sup.b2,
S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, and S(O).sub.2NR.sup.c2R.sup.d2;
[0050] R.sup.1 and R.sup.3 are each, independently, selected from
H, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, CN, NO.sub.2, SF.sub.5, OR.sup.a2, SR.sup.a2,
C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, OC(O)R.sup.b2,
OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2C(O)OR.sup.a2,
C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, S(O)R.sup.b2,
S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, and S(O).sub.2NR.sup.c2R.sup.d2;
[0051] each R.sup.2 is, independently, selected from H, halo,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, CN, NO.sub.2, SF.sub.5, OR.sup.a2, SR.sup.a2,
C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, OC(O)R.sup.b2,
OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2C(O)OR.sup.a2,
C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, S(O)R.sup.b2,
S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, and S(O).sub.2NR.sup.c2R.sup.d2;
[0052] each R.sup.5 is, independently, H, Cy.sup.1, halo, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,
halosulfanyl, CN, NO.sub.2, SF.sub.5, OR.sup.a1, SR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(S)R.sup.b1,
C(S)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
--W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1, OC(O)NR.sup.c1R.sup.d1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(S)R.sup.b1,
NR.sup.c1C(S)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.f1, or
P(O)OR.sup.e1OR.sup.f1, wherein each of said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl, or
heterocycloalkylalkyl, is optionally substituted by 1, 2, 3, 4, or
5 substituents independently selected from halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
Cy.sup.1, halosulfanyl, CN, NO.sub.2, SF.sub.5, OR.sup.a1,
SR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(S)R.sup.b1,
C(S)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
--W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1, OC(O)NR.sup.c1R.sup.d1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(S)R.sup.b1,
NR.sup.c1C(S)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O)NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.f1, and
P(O)OR.sup.e1OR.sup.f1; or two adjacent R.sup.5 on the same ring
can link to form a fused cycloalkyl or fused heterocycloalkyl
group, each optionally substituted by 1, 2, or 3 substituents
independently selected from halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,
halosulfanyl, Cy.sup.1, CN, NO.sub.2, OR.sup.a1, SR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, SF.sub.5, C(S)R.sup.b1,
C(S)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
--W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1, OC(O)NR.sup.c1R.sup.d1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(S)R.sup.b1,
NR.sup.c1C(S)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.g)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g)NR.sup.c1R.sup.d1,
NR.sup.c1S(O)NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.f1, and
P(O)OR.sup.e1OR.sup.f1, wherein each of said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl, or
heterocycloalkylalkyl, is optionally substituted by 1, 2, 3, 4, or
5 substituents independently selected from halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
Cy.sup.3, , --W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1, halosulfanyl, CN,
NO.sub.2, SF.sub.5, OR.sup.a1, SR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OCH.sub.2C(O)R.sup.b1, OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1,
NR.sup.c1C(O)R.sup.b1, NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1C(O)OR.sup.a1, C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O)NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c2S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.f1, and
P(O)OR.sup.e1OR.sup.f1;
[0053] R.sup.4 and R.sup.6 are each, independently, selected from
H, Cy.sup.2, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,
heterocycloalkylalkyl, --W.sup.2-X.sup.2-Y.sup.2--Z.sup.2,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a2,
C(.dbd.NR.sup.g)NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
S(O).sub.2NR.sup.c1R.sup.d1, P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2,
P(O)R.sup.e1R.sup.f1, and P(O)OR.sup.e1OR.sup.f1, wherein each of
said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,
or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4,
or 5 substituents independently selected from halo, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
Cy.sup.2, halosulfanyl, CN, NO.sub.2, OR.sup.a1, SR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
--W.sup.2-Q.sup.2-Y.sup.2--Z.sup.2, OC(O)NR.sup.c1R.sup.d1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c2S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.f1, and
P(O)OR.sup.e1OR.sup.f1;
[0054] R.sup.7, R.sup.8, and R.sup.10 are each, independently,
selected from H, Cy.sup.3, halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,
--W.sup.3-Q.sup.3-Y.sup.3--Z.sup.3, CN, NO.sub.2, OR.sup.a1,
SR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
OC(O)R.sup.b1, OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1,
NR.sup.c1C(O)R.sup.b1, NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1C(O)OR.sup.a2, C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c2S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.f1, and
P(O)OR.sup.e1OR.sup.f1, wherein each of said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl, or
heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5
substituents independently selected from halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
halosulfanyl, CN, NO.sub.2, OR.sup.a1, SR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1, Cy.sup.3,
--W.sup.3-Q.sup.3-Y.sup.3--Z.sup.3, OC(O)NR.sup.c1R.sup.d1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.f1, and
P(O)OR.sup.e1OR.sup.f1;
[0055] each R.sup.9 is, independently, H, Cy.sup.4, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,
--W.sup.4-Q.sup.4-Y.sup.4--Z.sup.4, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OC(O)NR.sup.c1R.sup.d1, C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
S(O)R.sup.b1, S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
S(O).sub.2NR.sup.c1R.sup.d1, P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2,
P(O)R.sup.e1R.sup.f1, or P(O)OR.sup.e1OR.sup.f1 wherein each of
said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,
or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4,
or 5 substituents independently selected from halo, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
halosulfanyl, CN, NO.sub.2, OR.sup.a1, SR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1, Cy.sup.4,
--W.sup.4-Q.sup.4-Y.sup.4--Z.sup.4, OC(O)NR.sup.c1R.sup.d1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.g)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.f1, and
P(O)OR.sup.e1OR.sup.f1;
[0056] R.sup.11a, R.sup.11b, R.sup.12a, R.sup.12b, and R.sup.13 are
each, independently, selected from H, Cy.sup.3, halo, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,
CN, NO.sub.2, OR.sup.a1, SR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.f1, and
P(O)OR.sup.e1OR.sup.f1, wherein each of said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl, or
heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5
substituents independently selected from halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
halosulfanyl, CN, NO.sub.2, OR.sup.a1, SR.sup.a1, SF.sub.5,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
--W.sup.3-Q.sup.3-Y.sup.3--Z.sup.3, OC(O)NR.sup.c1R.sup.d1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.f1, and
P(O)OR.sup.e1OR.sup.f1;
[0057] W.sup.1, W.sup.2, W.sup.3, W.sup.4, and W.sup.5 are each,
independently, selected from absent, W.sup.6, C.sub.1-6 alkylenyl,
C.sub.2-6 alkenylenyl, C.sub.2-6 alkynylenyl,
(CR.sup.11aR.sup.11b).sub.p1O(CR.sup.11aR.sup.11b).sub.p2,
(CR.sup.11aR.sup.11b).sub.p1S(CR.sup.11aR.sup.11b).sub.p2,
(CR.sup.11aR.sup.11b).sub.p1NR.sup.e(CR.sup.11aR.sup.11b).sub.p2,
(CR.sup.11aR.sup.11b).sub.p1C(O)(CR.sup.11aR.sup.11b).sub.p2,
(CR.sup.11aR.sup.11b).sub.p1C(S)(CR.sup.11aR.sup.11b).sub.p2,
(CR.sup.11aR.sup.11b).sub.p1C(O)O(CR.sup.11aR.sup.11b).sub.p2,
(CR.sup.11aR.sup.11b).sub.p1C(O)NR.sup.e(CR.sup.11aR.sup.11b).sub.p2,
(CR.sup.11aR.sup.11b).sub.p1C(S)NR.sup.e(CR.sup.11aR.sup.11b).sub.p2,
(CR.sup.11aR.sup.11b).sub.p1S(O)(CR.sup.11aR.sup.11b).sub.p2,
(CR.sup.11aR.sup.11b).sub.p1S(O).sub.2(CR.sup.11aR.sup.11b).sub.p2,
(CR.sup.11aR.sup.11b).sub.p1S(O)NR.sup.e(CR.sup.11aR.sup.11b).sub.p2,
(CR.sup.11aR.sup.11b).sub.p1S(O).sub.2NR.sup.c(CR.sup.11aR.sup.11b).sub.p-
2,
(CR.sup.11aR.sup.11b).sub.p1NR.sup.cC(O)NR.sup.f(CR.sup.11aR.sup.11b).s-
ub.p2,
(CR.sup.11aR.sup.11b).sub.p1NR.sup.eC(S)NR.sup.f(CR.sup.11aR.sup.11-
b).sub.p2,
(CR.sup.11aR.sup.11b).sub.p1NR.sup.eS(O).sub.2NR.sup.f(CR.sup.1-
1aR.sup.11b).sub.p2,
(CR.sup.11aR.sup.11b).sub.p1C(.dbd.NR.sup.g)NR.sup.e(CR.sup.11aR.sup.11b)-
.sub.p2,
(CR.sup.11aR.sup.11b).sub.p1NR.sup.eC(.dbd.NR.sup.g)NR.sup.f(CR.s-
up.11aR.sup.11b).sub.p2, O(CR.sup.11aR.sup.11b).sub.q1C(O),
S(CR.sup.11aR.sup.11b).sub.q1C(O),
NR.sup.e(CR.sup.11aR.sup.11b).sub.q1C(O),
C(O)(CR.sup.11aR.sup.11b).sub.q1C(O),
NR.sup.e(CR.sup.11aR.sup.11b).sub.q1NR.sup.f,
O(CR.sup.11aR.sup.11b).sub.q1NR.sup.f, and
O(CR.sup.11aR.sup.11b).sub.q1O, wherein each of the C.sub.1-6
alkylenyl, C.sub.2-6 alkenylenyl and C.sub.2-6 alkynylenyl is
optionally substituted by 1, 2, or 3 substituents independently
selected from halo, CN, NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b,
C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NRCR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a,
C(.dbd.NR.sup.g)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.g)NR.sup.cR.sup.d,
NR.sup.cS(O).sub.2NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d;
[0058] each W.sup.6 is independently selected from
NR.sup.e100C(O)NR.sup.f100 and NR.sup.e200C(O)CR.sup.13R.sup.f200,
wherein R.sup.e100 and R.sup.f100 together with the intervening
NC(O)N moiety to which they are attached form a 4-7 membered
heterocycloalkyl group which is optionally substituted by 1, 2, or
3 substituents each independently selected from C.sub.1-6 alkyl,
C.sub.1-6haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo, CN,
NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d,
C(O)OR.sup.a, OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NRCR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cC(O)OR.sup.a, C(.dbd.NR.sup.g)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.g)NR.sup.cR.sup.d,
NR.sup.cS(O).sub.2NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d, and wherein R.sup.e200 and
R.sup.f200 together with the intervening NC(O)CR.sup.13 moiety to
which they are attached form a 4-7 membered heterocycloalkyl group
which is optionally substituted by 1, 2, or 3 substituents each
independently selected from C.sub.1-6 alkyl, C.sub.1-6haloalkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo, CN, NO.sub.2, OR.sup.a,
SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cC(O)OR.sup.a, C(.dbd.NR.sup.g)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.g)NR.sup.cR.sup.d,
NR.sup.cS(O).sub.2NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d;
[0059] Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, and Q.sup.5 are each,
independently, selected from aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and
heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4,
or 5 substituents independently selected from C.sub.1-6 alkyl,
C.sub.1-6haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, halo, CN,
NO.sub.2, OR.sup.a, SR.sup.a, SF.sub.5, C(O)R.sup.b,
C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NRCR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a,
C(.dbd.NR.sup.g)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.g)NR.sup.cR.sup.d,
NR.sup.cS(O).sub.2NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d;
[0060] Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4, and Y.sup.5 are each,
independently, selected from absent, C.sub.1-6 alkylenyl, C.sub.2-6
alkenylenyl, C.sub.2-6 alkynylenyl,
(CR.sup.12aR.sup.12b).sup.p3O(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3S(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3NR.sup.e(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3C(O)(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3C(S)(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3C(O)O(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3C(O)NR.sup.e(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3C(S)NR.sup.e(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3S(O)(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3S(O).sub.2(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3S(O)NR.sup.e(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3S(O).sub.2NR.sup.e(CR.sup.12aR.sup.12b).sub.p-
4,
(CR.sup.12aR.sup.12b).sub.p3NR.sup.eC(O)NR.sup.f(CR.sup.12aR.sup.12b).s-
ub.p4,
(CR.sup.12aR.sup.12b).sub.p3NR.sup.cC(S)NR.sup.f(CR.sup.12aR.sup.12-
b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3NR.sup.cS(O).sub.2NR.sup.f(CR.sup.1-
2aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3C(.dbd.NR.sup.g)NR.sup.e(CR.sup.12aR.sup.12b)-
.sub.p4,
(CR.sup.12aR.sup.12b).sub.p3NR.sup.eC(.dbd.NR.sup.g)NR.sup.f(CR.s-
up.12R.sup.12b).sub.p4, O(CR.sup.12aR.sup.12b).sub.q2C(O),
S(CR.sup.12aR.sup.12b).sub.q2C(O),
NR.sup.e(CR.sup.12aR.sup.12b).sub.q2C(O),
NR.sup.e(CR.sup.12aR.sup.12b).sub.q2NR.sup.f,
O(CR.sup.12aR.sup.12b).sub.q2NR.sup.f, and
O(CR.sup.12aR.sup.12b).sub.q2O, wherein each of the C.sub.1-6
alkylenyl, C.sub.2-6 alkenylenyl and C.sub.2-6 alkynylenyl is
optionally substituted by 1, 2 or 3 substituents independently
selected from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, halo, CN, NO.sub.2, OR.sup.a, SR.sup.a,
SF.sub.5, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cC(O)OR.sup.a, C(.dbd.NR.sup.g)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.g)NR.sup.cR.sup.d,
NR.sup.cS(O).sub.2NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b,
and S(O).sub.2NR.sup.cR.sup.d;
[0061] Z.sup.1, Z.sup.2, Z.sup.3, Z.sup.4, and Z.sup.5 are each,
independently, selected from H, halo, CN, NO.sub.2, OH, C.sub.1-6
alkoxy, C.sub.1-6 haloalkoxy, amino, C.sub.1-6 alkylamino,
C.sub.2-8dialkylamino, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and
heterocycloalkylalkyl, wherein each of the C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is
optionally substituted by 1, 2, 3, 4, or 5 substituents
independently selected from halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, aryl, cycloalkyl,
heteroaryl, heterocycloalkyl, CN, NO.sub.2, OR.sup.a, SR.sup.a,
SF.sub.5, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.d, NR.sup.cC(O)NR.sup.cR.sup.d,
NR.sup.cC(O)OR.sup.a, NR.sup.cS(O).sub.2R.sup.b,
NR.sup.cS(O).sub.2NR.sup.cR.sup.d; S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d;
[0062] Cy.sup.1, Cy.sup.2, Cy.sup.3, and Cy.sup.4 are each,
independently, selected from aryl, cycloalkyl, heteroaryl, and
heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5
substituents independently selected from halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, SF.sub.5, Cy.sup.5, -L.sup.b1-Cy.sup.5,
--W.sup.5-Q.sup.5-Y.sup.5--Z.sup.5, C.sub.1-6haloalkyl,
halosulfanyl, CN, NO.sub.2, OR.sup.a1, SR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.g)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, and S(O).sub.2NR.sup.c1R.sup.d1;
[0063] Cy.sup.5 and Cy.sup.6 are each, independently, selected from
aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, each optionally
substituted by 1, 2, 3, 4, or 5 substituents independently selected
from halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
aryl, cycloalkyl, heteroaryl, heterocycloalkyl, C.sub.1-6
haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,
heterocycloalkylalkyl, halosulfanyl, CN, NO.sub.2, OR.sup.a2,
SR.sup.a2, SF.sub.5, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2,
C(S)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, OC(O)R.sup.b2,
OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2C(O)OR.sup.a2,
C(.dbd.NR.sup.g)NR.sup.c2R.sup.d2,
NR.sup.c2C(.dbd.NR.sup.g)NR.sup.c2R.sup.d2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, S(O)R.sup.b2,
S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, and S(O).sub.2NR.sup.c2R.sup.d2;
[0064] L.sup.b1 and L.sup.b2 are each, independently, selected from
C.sub.1-4 alkylenyl, O, S, C(O), C(S), C(O)NR.sup.c2,
C(S)NR.sup.c2, C(O)O, OC(O)NR.sup.c2, NR.sup.c2,
NR.sup.c2C(O)NR.sup.d2, NR.sup.c2C(S)NR.sup.d2,
C(.dbd.NR.sup.g)NR.sup.c2, NR.sup.c2C(.dbd.NR.sup.g)NR.sup.d2,
NR.sup.c2S(O).sub.2NR.sup.d2, S(O), S(O)NR.sup.c2, S(O).sub.2, and
S(O).sub.2NR.sup.c2, wherein said C.sub.1-4 alkylenyl is optionally
substituted by 1, 2, 3, 4, 5, 6, 7, or 8 substituents each
independently selected from halo, CN, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, OH, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, NH.sub.2,
NH(C.sub.1-4 alkyl), and N(C.sub.1-4 alkyl).sub.2;
[0065] R.sup.a1, R.sup.b1, R.sup.c1, and R.sup.d1 are each,
independently, selected from H, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, cycloalkyl,
heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,
cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is
optionally substituted with 1, 2, 3, 4, or 5 substituents
independently selected from C.sub.1-6 alkyl, halo, CN, Cy.sup.6,
-L.sup.b2-Cy.sup.6, OR.sup.a2, SR.sup.a2, SF.sub.5, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(S)R.sup.b2, C(S)NR.sup.c2R.sup.d2,
C(O)OR.sup.a2, OC(O)R.sup.b2, OC(O)NR.sup.c2R.sup.d2,
NR.sup.c2R.sup.d2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2C(S)R.sup.b2,
NR.sup.c2C(S)NR.sup.c2R.sup.d2, NR.sup.c2C(O)OR.sup.a2,
C(.dbd.NR.sup.g)NR.sup.c2R.sup.d2,
NR.sup.c2C(.dbd.NR.sup.g)NR.sup.c2R.sup.d2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, S(O)R.sup.b2,
S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, and S(O).sub.2NR.sup.c2R.sup.d2;
[0066] or R.sup.c1 and R.sup.d1 together with the N atom to which
they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl
group or heteroaryl group, each optionally substituted with 1, 2,
or 3 substituents independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, halo, CN, Cy.sup.6, -L.sup.b2-Cy.sup.6,
OR.sup.a2, SR.sup.a2, SF.sub.5, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(S)R.sup.b2, C(S)NR.sup.c2R.sup.d2,
C(O)OR.sup.a2, OC(O)R.sup.b2, OC(O)NR.sup.c2R.sup.d2,
NR.sup.c2R.sup.d2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2C(S)R.sup.b2,
NR.sup.c2C(S)NR.sup.c2R.sup.d2, NR.sup.c2C(O)OR.sup.a2,
C(.dbd.NR.sup.g)NR.sup.c2R.sup.d2,
NR.sup.c2C(.dbd.NR.sup.g)NR.sup.c2R.sup.d2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, S(O)R.sup.b2,
S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, and S(O).sub.2NR.sup.c2R.sup.d2;
[0067] each R.sup.e1 is, independently, H, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, (C.sub.1-6
alkoxy)-C.sub.1-6 alkyl, C.sub.2-6 alkynyl, aryl, cycloalkyl,
heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl,
heteroarylalkyl, or heterocycloalkylalkyl;
[0068] each R.sup.f1 is, independently, H, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
cycloalkyl, heteroaryl, or heterocycloalkyl;
[0069] R.sup.a2, R.sup.b2, R.sup.c2, and R.sup.d2 are each,
independently, selected from H, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, cycloalkyl,
heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,
cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is
optionally substituted with 1, 2, or 3 substituents independently
selected from OH, CN, amino, halo, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, C.sub.1-6 haloalkyl, and C.sub.1-6 haloalkoxy;
[0070] or R.sup.c2 and R.sup.d2 together with the N atom to which
they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl
group or heteroaryl group, each optionally substituted with 1, 2,
or 3 substituents independently selected from OH, CN, amino, halo,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, and
[0071] C.sub.1-6 haloalkoxy;
[0072] each R.sup.a is independently selected from H, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, arylalkyl, heteroarylalkyl,
cycloalkylalkyl, heterocycloalkylalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, cycloalkyl, heteroaryl and
heterocycloalkyl, wherein each of the C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,
heterocycloalkylalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
cycloalkyl, heteroaryl and heterocycloalkyl is optionally
substituted with 1, 2, 3, 4, or 5 substituents independently
selected from OH, CN, amino, halo, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 hydroxylalkyl, C.sub.1-6 cyanoalkyl, C.sub.1-6
alkoxy, C.sub.1-6haloalkoxy, C.sub.2-8 alkoxyalkoxy, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and
heterocycloalkyl;
[0073] each R.sup.b is independently selected from H, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, arylalkyl, heteroarylalkyl,
cycloalkylalkyl, heterocycloalkylalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein each of the C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,
heterocycloalkylalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is
optionally substituted with 1, 2, 3, 4, or 5 substituents
independently selected from OH, CN, amino, halo, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.1-6 hydroxylalkyl, C.sub.1-6 cyanoalkyl,
C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy, C.sub.2-8 alkoxyalkoxy,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and
heterocycloalkyl;
[0074] R.sup.c and R.sup.d are independently selected from H,
C.sub.1-10 alkyl, C.sub.1-6 haloalkyl, arylalkyl, heteroarylalkyl,
cycloalkylalkyl, heterocycloalkylalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein each of the C.sub.1-10 alkyl,
C.sub.1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,
heterocycloalkylalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is
optionally substituted with 1, 2, 3, 4, or 5 substituents
independently selected from OH, CN, amino, halo, C.sub.1-6 alkyl,
C.sub.1-6haloalkyl, C.sub.1-6 hydroxylalkyl, C.sub.1-6 cyanoalkyl,
C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy, C.sub.2-8 alkoxyalkoxy,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and
heterocycloalkyl;
[0075] or R.sup.c and R.sup.d together with the N atom to which
they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl
group that is optionally substituted with 1, 2, 3, 4, or 5
substituents independently selected from OH, CN, amino, halo,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 hydroxylalkyl,
C.sub.1-6 cyanoalkyl, C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy,
C.sub.2-8 alkoxyalkoxy, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, cycloalkyl, and heterocycloalkyl; and
[0076] R.sup.e and R.sup.f are each, independently, selected from
H, C.sub.1-10 alkyl, C.sub.1-6 haloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, aryl, heteroaryl, cycloalkyl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and
heterocycloalkylalkyl, wherein each of the C.sub.1-10 alkyl,
C.sub.1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,
heterocycloalkylalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is
optionally substituted by OH, amino, halo, C.sub.1-6 alkyl,
C.sub.1-6haloalkyl, C.sub.1-6alkoxy, C.sub.1-6haloalkoxy, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or
heterocycloalkyl;
[0077] R.sup.g, R.sup.g1, and R.sup.g2 are each, independently, H,
CN, or NO.sub.2;
[0078] each p1 is, independently, 0, 1, or 2;
[0079] each p2 is, independently, 0, 1, or 2;
[0080] each p3 is, independently, 0, 1, or 2;
[0081] each p4 is, independently, 0, 1, or 2;
[0082] each q1 is, independently, 1 or 2;
[0083] each q2 is, independently, 1 or 2;
[0084] each n is, independently, 1, 2, or 3;
[0085] each m is, independently, 0, 1, or 2; and
[0086] t is 1, 2, 3, or 4.
[0087] In some embodiments, the compound of Formula I or
pharmaceutically acceptable salt thereof or quaternary ammonium
salt thereof is other than (9S)-6-Chloro-9-methyl-15-oxa-2, 4, 8,
23-tetraazatetracyclo[15.3.1.1(3, 7).1(10, 14)]tricosa-1(21),
3(23), 4, 6, 10(22), 11, 13, 17, 19-nonaene, or pharmaceutically
acceptable salt thereof or quaternary ammonium salt thereof.
[0088] In some embodiments, the compound of Formula I or
pharmaceutically acceptable salt thereof or quaternary ammonium
salt thereof is other than N-[6-Chloro-2, 4, 8, 19,
23-pentaazatetracyclo[15.3.1.1(3, 7).1(10, 14)]tricosa-1(21),
3(23), 4, 6, 10(22), 11, 13, 17, 19-nonaen-13-yl]benzamide, or
pharmaceutically acceptable salt thereof or quaternary ammonium
salt thereof.
[0089] In some embodiments, the compound of Formula I or
pharmaceutically acceptable salt thereof or quaternary ammonium
salt thereof is other than N-[6-Chloro-2, 4, 8, 19, 23-
pentaazatetracyclo[15.3.1.1(3, 7).1(10, 14)]tricosa-1(21), 3(23),
4, 6, 10(22), 11, 13, 17,
19-nonaen-13-yl]-2-cyanobenzenesulfonamide, or pharmaceutically
acceptable salt thereof or quaternary ammonium salt thereof.
[0090] In some embodiments, A.sup.1 and A.sup.2 are each,
independently, selected from CR.sup.2, N, NH, N(CH.sub.3), O, and
S. In some embodiments, one of A.sup.1 and A.sup.2 is selected from
NH, N(CH.sub.3), O, and S. In some embodiments, both A.sup.1 and
A.sup.2 are independently selected from NH, N(CH.sub.3), O, and
S.
[0091] In some embodiments, A.sup.1 and A.sup.2 are each,
independently, selected from CR.sup.2 and N. In some further
embodiments, A.sup.1 and A.sup.2 are each, independently, selected
from CR.sup.2.
[0092] In some embodiments, the ring containing A.sup.1, B.sup.1,
D.sup.1, and E.sup.1 is a 6-membered aromatic ring; B.sup.1,
D.sup.1, and E.sup.1 are each, independently, CR.sup.5 or N; and
A.sup.1 is CR.sup.2 or N.
[0093] In some embodiments, the ring containing A.sup.1, B.sup.1,
D.sup.1, and E.sup.1 is a 6-membered aromatic ring; B.sup.1,
D.sup.1, and E.sup.1 are each, independently, CR.sup.5; and A.sup.1
is CR.sup.2.
[0094] In some embodiments, the ring containing A.sup.1, B.sup.1,
D.sup.1, and E.sup.1 is a benzene ring (and the benzene is
optionally substituted with R.sup.2 and optionally substituted with
1, 2, or 3 R.sup.5.)
[0095] In some embodiments, the ring containing A.sup.1, B.sup.1,
D.sup.1, and E.sup.1 is a 6-membered aromatic ring wherein at least
one of A.sup.1, B.sup.1, D.sup.1, and E.sup.1 is N (and the
6-membered aromatic ring such can be optionally substituted, i.e.,
optionally substituted with R.sup.2 and optionally substituted with
one or more R.sup.5). In some further embodiments, the 6-membered
aromatic ring is selected from pyridine, pyrimidine, and pyrazine
rings (and the 6-membered aromatic rings such as pyridine,
pyrimidine, and pyrazine can be substituted or unsubstituted). In
yet further embodiments, the 6-membered aromatic ring is selected
from optionally substituted pyridine and pyrimidine rings. In some
embodiments, the 6-membered aromatic ring is an optionally
substituted pyridine ring. In some embodiments wherein the ring
containing A.sup.1, B.sup.1, D.sup.1, and E.sup.1 is an optionally
substituted pyridine ring, D.sup.1 is N. In some embodiments
wherein the ring containing A.sup.1, B.sup.1, D.sup.1, and E.sup.1
is an optionally substituted pyridine ring, E.sup.1 is N. In some
embodiments wherein the ring containing A.sup.1, B.sup.1, D.sup.1,
and E.sup.1 is an optionally substituted pyridine ring, B.sup.1 is
N. In some embodiments wherein the ring containing A.sup.1,
B.sup.1, D.sup.1, and E.sup.1 is an optionally substituted pyridine
ring, A.sup.1 is N. In some embodiments, the 6-membered aromatic
ring is an optionally substituted pyrimidine ring.
[0096] In some embodiments, the ring containing A.sup.1, B.sup.1,
D.sup.1, and E.sup.1 is a 5-membered aromatic ring (and the
aromatic ring is optionally substituted). In some further
embodiments, the 5-membered aromatic ring is selected from
1H-pyrrole, furan, thiophene, 1H-imidazole, 1H-pyrazole, oxazole,
thiazole, isoxazole, and isothiazole (and the 5-membered aromatic
rings can be substituted or unsubstituted). In yet further
embodiments, the 5-membered aromatic ring is selected from
1H-pyrrole, furan, and thiophene (and the 5-membered aromatic rings
can be optionally substituted). In still further embodiments, the
5-membered aromatic ring is an optionally substituted thiophene
ring
[0097] In some embodiments, the ring containing A.sup.2, B.sup.2,
D.sup.2, and E.sup.2 is a 6-membered aromatic ring; B.sup.2,
D.sup.2, and E.sup.2 are each, independently, CR.sup.5 or N; and
A.sup.2 is CR.sup.2 or N. In some further embodiments, E.sup.2 is
CR.sup.5 wherein the R.sup.5 of E.sup.2 is other than H. In some
other further embodiments, D.sup.2 is CR.sup.5 wherein the R.sup.5
of D.sup.2 is other than H. In some other further embodiments,
B.sup.2 is CR.sup.5 wherein the R.sup.5 of B.sup.2 is other than
H.
[0098] In some embodiments, the ring containing A.sup.2, B.sup.2,
D.sup.2, and E.sup.2 is a 6-membered aromatic ring; B.sup.2,
D.sup.2, and E.sup.2 are each, independently, CR.sup.5; and A.sup.2
is CR.sup.2. In some embodiments, the ring containing A.sup.2,
B.sup.2, D.sup.2, and E.sup.2 is a benzene ring (and the benzene
ring is optionally substituted).
[0099] In some embodiments, the ring containing A.sup.2, B.sup.2,
D.sup.2, and E.sup.2 is a 6-membered aromatic ring, wherein at
least one of A.sup.2, B.sup.2, D.sup.2, and E.sup.2 is N. In some
further embodiments, the 6-membered aromatic ring is selected from
pyridine, pyrimidine, and pyrazine rings (and the 6-membered
aromatic rings can be optionally substituted, i.e., optionally
substituted with R.sup.2 and optionally substituted with one or
more R.sup.5). In yet further embodiments, the 6-membered aromatic
ring is selected from optionally substituted pyridine and
pyrimidine rings. In some embodiments, the 6-membered aromatic ring
is an optionally substituted pyridine ring. In some embodiments,
the 6-membered aromatic ring is an optionally substituted
pyrimidine ring.
[0100] In some embodiments, the ring containing A.sup.2, B.sup.2,
D.sup.2, and E.sup.2 is a 5-membered aromatic ring (and the
aromatic ring is optionally substituted). In some further
embodiments, the 5-membered aromatic ring is selected from
1H-pyrrole, furan, thiophene, 1H-imidazole, 1H-pyrazole, oxazole,
thiazole, isoxazole, and isothiazole rings (and the 5-membered
aromatic rings can be substituted or unsubstituted). In yet further
embodiments, the 5-membered aromatic ring is selected from
1H-pyrrole, furan, and thiophene rings (and the 5-membered aromatic
rings can be optionally substituted). In still further embodiments,
the 5-membered aromatic ring is an optionally substituted thiophene
ring.
[0101] In some embodiments, X.sup.1 is CR.sup.1.
[0102] In some embodiments, X.sup.1 is N.
[0103] In some embodiments, X.sup.2 is CR.sup.2.
[0104] In some embodiments, X.sup.2 is N.
[0105] In some embodiments, X.sup.3 is CR.sup.3.
[0106] In some embodiments, X.sup.3 is C-halo. In some embodiments,
X.sup.3 is C--F, C--Cl, or C--Br.
[0107] In some embodiments, X.sup.3 is C--Cl.
[0108] In some embodiments, X.sup.3 is C--Br.
[0109] In some embodiments, X.sup.3 is C--Cl.
[0110] In some embodiments, X.sup.3 is N.
[0111] In some embodiments, R' and R'' are each, independently,
selected from H, halo, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.1-4 haloalkyl, CN, NO.sub.2, OR.sup.a2,
SR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2,
OC(O)R.sup.b2, OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2,
NR.sup.c2C(O)R.sup.b2, NR.sup.c2C(O)NR.sup.c2R.sup.d2,
NR.sup.c2C(O)OR.sup.a2, C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b2,
S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, and S(O).sub.2NR.sup.c2R.sup.d2.
[0112] In some embodiments, R' and R'' are each, independently,
selected from H, C.sub.1-6 alkyl, and C.sub.1-6 haloalkyl. In some
further embodiments, R' and R'' are each, independently, selected
from H, C.sub.1-3 alkyl, and C.sub.1-3 haloalkyl. In yet further
embodiments, R' and R'' are each, independently, selected from H
and C.sub.1-3 alkyl. In still further embodiments, R' and R'' are
each, independently, selected from H and methyl. In some
embodiments, R' and R'' are both H.
[0113] In some embodiments, R' and R'' are each, independently,
selected from H, halo, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, and C.sub.1-4 haloalkyl. In some further
embodiments, R' and R'' are each, independently, selected from H,
C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl.
[0114] In some embodiments, R' and R'' are each, independently,
selected from H and C.sub.1-4 alkyl. In some further embodiments,
R' and R'' are each, independently, selected from H and methyl.
[0115] In some embodiments, R' and R'' are each, independently,
selected from H and C.sub.1-3 alkyl. In some further embodiments,
at least one of R' and R'' is C.sub.1-3 alkyl. In yet further
embodiments, R' and R'' are both, independently, C.sub.1-3
alkyl.
[0116] In some embodiments, at least one of R' and R'' is
methyl.
[0117] In some embodiments, one of R' and R'' is methyl.
[0118] In some embodiments, R' and R'' are both H.
[0119] In some embodiments, R' and R'' together with the C atom to
which they are attached form a 3-, 4-, 5-, 6-, 7-, 8-, 9- or
10-membered cycloalkyl group optionally substituted with 1, 2, or 3
substituents independently selected from halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, CN,
NO.sub.2, OR.sup.a2, SR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, OC(O)R.sup.b2,
OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2C(O)OR.sup.a2,
C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, S(O)R.sup.b2,
S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, and S(O).sub.2NR.sup.c2R.sup.d2.
[0120] In some embodiments, R' and R'' together with the C atom to
which they are attached form a 3-, 4-, 5-, 6-, 7-, 8-, 9- or
10-membered cycloalkyl group optionally substituted with 1, 2, or 3
substituents independently selected from halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, CN,
NO.sub.2, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, --NH.sub.2,
--NH(C.sub.1-6 alkyl), and N(C.sub.1-6 alkyl).sub.2. In some
further embodiments, R' and R'' together with the C atom to which
they are attached form a 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered
cycloalkyl group optionally substituted with 1, 2, or 3
substituents independently selected from halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, CN,
NO.sub.2, C.sub.1-6 alkoxy, and C.sub.1-6 haloalkoxy.
[0121] In some embodiments, R' and R'' together with the C atom to
which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered
cycloalkyl group optionally substituted with 1, 2, or 3
substituents independently selected from halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, CN,
NO.sub.2, C.sub.1-6 alkoxy, and C.sub.1-6 haloalkoxy.
[0122] In some embodiments, R' and R'' together with the C atom to
which they are attached form a 3-, 4-, 5-, 6-, 7-, 8-, 9- or
10-membered heterocycloalkyl group optionally substituted with 1,
2, or 3 substituents independently selected from halo, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
CN, NO.sub.2, OR.sup.a2, SR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, OC(O)R.sup.b2,
OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2C(O)OR.sup.a2,
C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, S(O)R.sup.b2,
S(O)NRc2R.sup.d2, S(O).sub.2R.sup.b2, NR.sup.c2S(O).sub.2R.sup.b2,
and S(O).sub.2NR.sup.c2R.sup.d2.
[0123] In some embodiments, R' and R'' together with the C atom to
which they are attached form a 3-, 4-, 5-, 6-, 7-, 8-, 9- or
10-membered heterocycloalkyl group optionally substituted with 1,
2, or 3 substituents independently selected from halo, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
CN, NO.sub.2, C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy, --NH.sub.2,
--NH(C.sub.1-6 alkyl), and N(C.sub.1-6 alkyl).sub.2. In some
further embodiments, R' and R'' together with the C atom to which
they are attached form a 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered
heterocycloalkyl group optionally substituted with 1, 2, or 3
substituents independently selected from halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, CN,
NO.sub.2, C.sub.1-6 alkoxy, and C.sub.1-6 haloalkoxy.
[0124] In some further embodiments, R' and R'' together with the C
atom to which they are attached form a 3-, 4-, 5-, 6-, 7-, or
8-membered heterocycloalkyl group optionally substituted with 1, 2,
or 3 substituents independently selected from halo, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
CN, NO.sub.2, C.sub.1-6 alkoxy, and C.sub.1-6 haloalkoxy.
[0125] In some embodiments, R.sup.1 is selected from H, halo,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, CN, NO.sub.2, OR.sup.a2,
C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, and
NR.sup.c2R.sup.d2.
[0126] In some embodiments, R.sup.1 is selected from H, halo,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, CN, NO.sub.2, --O--(C.sub.1-6
alkyl), and --O--(C.sub.1-6 haloalkyl).
[0127] In some embodiments, R.sup.1 is selected from H, halo,
C.sub.1-6 alkyl, and C.sub.1-6 haloalkyl.
[0128] In some embodiments, R.sup.1 is selected from H, halo,
C.sub.1-3 alkyl, and C.sub.1-3 haloalkyl. In some embodiments,
R.sup.1 is selected from H, F, Cl, Br, methyl, ethyl, 1-propyl,
2-propyl, and C.sub.1-2 haloalkyl. In some embodiments, R.sup.1 is
selected from H, F, Cl, Br, methyl, ethyl, 1-propyl, 2-propyl, and
CF.sub.3. In some embodiments, R.sup.1 is selected from H, F, Cl,
Br, methyl, and CF.sub.3.
[0129] In some embodiments, R.sup.1 is SF.sub.5.
[0130] In some embodiments, R.sup.1 is selected from H, F, Cl, Br,
methyl, ethyl, and C.sub.1-2 haloalkyl.
[0131] In some embodiments, R.sup.1 is selected from H, F, Cl, and
Br.
[0132] In some embodiments, R.sup.1 is selected from H, CH.sub.3
and CF.sub.3. In some futher embodiments, R.sup.1 is H or CH.sub.3.
In yet futher embodiments, R.sup.1 is H.
[0133] In some embodiments, each R.sup.2 is, independently,
selected from H, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, CN,
NO.sub.2, SF.sub.5, OR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2,
C(O)OR.sup.a2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2C(O)OR.sup.a2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, NR.sup.c2S(O).sub.2R.sup.b2,
and NR.sup.c2R.sup.d2.
[0134] In some embodiments, each R.sup.2 is, independently,
selected from H, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, CN,
NO.sub.2, OR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2,
C(O)OR.sup.a2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2C(O)OR.sup.a2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, NR.sup.c2S(O).sub.2R.sup.b2,
and, NR.sup.c2R.sup.d2.
[0135] In some embodiments, each R.sup.2 is, independently,
selected from H, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, CN,
NO.sub.2, OR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2,
C(O)OR.sup.a2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2C(O)OR.sup.a2,
NR.sup.c2S(O).sub.2R.sup.b2, and NR.sup.c2R.sup.d2.
[0136] In some embodiments, each R.sup.2 is, independently,
selected from H, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, CN,
NO.sub.2, OR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2,
C(O)OR.sup.a2, and NR.sup.c2R.sup.d2.
[0137] In some embodiments, each R.sup.2 is, independently,
selected from H, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, CN,
NO.sub.2, amino, C.sub.1-4 alkylamino, C.sub.2-8 dialkylamino,
NHC(.dbd.O)--(C.sub.1-4 alkyl), NHC(.dbd.O)O-(arylalkyl),
NHC(.dbd.O)O--(C.sub.1-4 alkyl), NHC(.dbd.O)O-(arylalkyl),
NHC(.dbd.O)NH.sub.2, NHC(.dbd.O)NH--(C.sub.1-4 alkyl),
NHC(.dbd.O)N--(C.sub.1-4 alkyl).sub.2, NHC(.dbd.O)NH-(arylalkyl),
NHS(.dbd.O).sub.2--(C.sub.1-4 alkyl), and
NHS(.dbd.O).sub.2-(arylalkyl).
[0138] In some embodiments, each R.sup.2 is, independently,
selected from H, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, amino,
C.sub.1-4 alkylamino, C.sub.2-8 dialkylamino,
NHC(.dbd.O)--(C.sub.1-4 alkyl), NHC(.dbd.O)O-(arylalkyl),
NHC(.dbd.O)O--(C.sub.1-4 alkyl), NHC(.dbd.O)O-(arylalkyl),
NHC(.dbd.O)NH.sub.2, NHC(.dbd.O)NH--(C.sub.1-4 alkyl),
NHC(.dbd.O)N--(C.sub.1-4 alkyl).sub.2, NHC(.dbd.O)NH-(arylalkyl),
NHS(.dbd.O).sub.2--(C.sub.1-4 alkyl), and
NHS(.dbd.O).sub.2-(arylalkyl).
[0139] In some embodiments, each R.sup.2 is, independently,
selected from H, halo, C.sub.1-6 alkyl, and C.sub.1-6
haloalkyl.
[0140] In some embodiments, each R.sup.2 is, independently,
selected from H, halo, C.sub.1-3 alkyl, and C.sub.1-3 haloalkyl. In
some embodiments, each R.sup.2 is, independently, selected from H,
F, Cl, Br, methyl, ethyl, 1-propyl, 2-propyl, and C.sub.1-2
haloalkyl. In some embodiments, each R.sup.2 is, independently,
selected from H, F, Cl, Br, methyl, ethyl, 1-propyl, 2-propyl, and
CF.sub.3. In some embodiments, each R.sup.2 is, independently,
selected from H, F, Cl, Br, methyl, and CF.sub.3.
[0141] In some embodiments, each R.sup.2 is, independently,
selected from H, CH.sub.3, CF.sub.3, and halo. In some embodiments,
each R.sup.2 is, independently, selected from H, F, Cl, CH.sub.3,
and CF.sub.3. In some futher embodiments, each R.sup.2 is,
independently, selected from H, F, and Cl. In yet further
embodiments, each R.sup.2 is, independently, selected from H and
F.
[0142] In some embodiments, each R.sup.2 is, independently,
selected from H, CH.sub.3 and CF.sub.3. In some futher embodiments,
each R.sup.2 is H.
[0143] In some embodiments, R.sup.3 is selected from H, halo,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, CN, NO.sub.2, SF.sub.5,
OR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2,
NR.sup.c2C(O)R.sup.b2, NR.sup.c2C(O)NR.sup.c2R.sup.d2,
NR.sup.c2C(O)OR.sup.a2, NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2,
NR.sup.c2S(O).sub.2R.sup.b2, and NR.sup.c2R.sup.d2.
[0144] In some embodiments, R.sup.3 is selected from H, halo,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, CN, NO.sub.2, SF.sub.5,
OR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, and
NR.sup.c2R.sup.d2.
[0145] In some embodiments, R.sup.3 is selected from H, halo,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, amino, C.sub.1-4 alkylamino,
and C.sub.2-8 dialkylamino.
[0146] In some embodiments, R.sup.3 is selected from H, halo,
C.sub.1-3 alkyl, C.sub.1-3 haloalkyl, NH.sub.2, NH(C.sub.1-3
alkyl), and N(C.sub.1-3 alkyl).sub.2. In some embodiments, R.sup.3
is selected from H, F, Cl, Br, methyl, ethyl, 1-propyl, 2-propyl,
C.sub.1-2 haloalkyl, NH.sub.2, NH(C.sub.1-3 alkyl), and N(C.sub.1-3
alkyl).sub.2. In some embodiments, R.sup.3 is selected from H, F,
Cl, Br, methyl, ethyl, 1-propyl, 2-propyl, CF.sub.3, NH.sub.2,
NH(C.sub.1-3 alkyl), and N(C.sub.1-3 alkyl).sub.2. In some
embodiments, R.sup.3 is selected from H, Cl, Br, methyl, CF.sub.3,
NH.sub.2, NH(C.sub.1-3 alkyl), and N(C.sub.1-3 alkyl).sub.2.
[0147] In some embodiments, R.sup.3 is selected from H, halo,
C.sub.1-6 alkyl, and C.sub.1-6 haloalkyl.
[0148] In some embodiments, R.sup.3 is selected from H, halo,
C.sub.1-3 alkyl, and C.sub.1-3 haloalkyl. In some embodiments,
R.sup.3 is selected from H, F, Cl, Br, methyl, ethyl, 1-propyl,
2-propyl, and C.sub.1-2 haloalkyl. In some embodiments, R.sup.3 is
selected from H, F, Cl, Br, methyl, ethyl, 1-propyl, 2-propyl, and
CF.sub.3. In some embodiments, R.sup.3 is selected from H, F, Cl,
Br, methyl, and CF.sub.3.
[0149] In some embodiments, R.sup.3 is selected from F, Cl, Br, and
CF.sub.3. In some further embodiments, R.sup.3 is selected from F,
Cl, and Br. In yet further embodiments, R.sup.3 is selected from F,
Cl, and Br.
[0150] In some embodiments, R.sup.3 is F. In some embodiments,
R.sup.3 is Cl. In some embodiments, R.sup.3 is Br.
[0151] In some embodiments, R.sup.3 is SF.sub.5.
[0152] In some embodiments, R.sup.1 and R.sup.3 are each,
independently, selected from H, halo, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, CN, NO.sub.2, SF.sub.5, OR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2C(O)OR.sup.a2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, NR.sup.c2S(O).sub.2R.sup.b2,
and NR.sup.c2R.sup.d2.
[0153] In some embodiments, R.sup.1 and R.sup.3 are each,
independently, selected from H, halo, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, CN, NO.sub.2, SF.sub.5, OR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2C(O)OR.sup.a2,
NR.sup.c2S(O).sub.2R.sup.b2, and NR.sup.c2R.sup.d2.
[0154] In some embodiments, R.sup.1 and R.sup.3 are each,
independently, selected from H, halo, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, CN, NO.sub.2, SF.sub.5, OR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, and NR.sup.c2R.sup.d2.
[0155] In some embodiments, R.sup.1 and R.sup.3 are each,
independently, selected from H, halo, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, CN, NO.sub.2, SF.sub.5, amino, C.sub.1-4 alkylamino,
C.sub.2-8 dialkylamino, NHC(.dbd.O)--(C.sub.1-4 alkyl),
NHC(.dbd.O)O-(arylalkyl), NHC(.dbd.O)O--(C.sub.1-4 alkyl),
NHC(.dbd.O)O-(arylalkyl), NHC(.dbd.O)NH.sub.2,
NHC(.dbd.O)NH--(C.sub.1-4 alkyl), NHC(.dbd.O)N--(C.sub.1-4
alkyl).sub.2, NHC(.dbd.O)NH-(arylalkyl),
NHS(.dbd.O).sub.2--(C.sub.1-4 alkyl), and
NHS(.dbd.O).sub.2-(arylalkyl).
[0156] In some embodiments, R.sup.1 and R.sup.3 are each,
independently, selected from H, halo, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, amino, C.sub.1-4 alkylamino, C.sub.2-8 dialkylamino,
NHC(.dbd.O)--(C.sub.1-4 alkyl), NHC(.dbd.O)O-(arylalkyl),
NHC(.dbd.O)O--(C.sub.1-4 alkyl), NHC(.dbd.O)O-(arylalkyl),
NHC(.dbd.O)NH.sub.2, NHC(.dbd.O)NH--(C.sub.1-4 alkyl),
NHC(.dbd.O)N--(C.sub.1-4 alkyl).sub.2, NHC(.dbd.O)NH-(arylalkyl),
NHS(.dbd.O).sub.2--(C.sub.1-4 alkyl), and
NHS(.dbd.O).sub.2-(arylalkyl).
[0157] In some embodiments, R.sup.1 and R.sup.3 are each,
independently, selected from H, halo, C.sub.1-6 alkyl, and
C.sub.1-6 haloalkyl.
[0158] In some embodiments, R.sup.1 and R.sup.3 are each,
independently, selected from H, halo, C.sub.1-3 alkyl, and
C.sub.1-3 haloalkyl. In some embodiments, R.sup.1 and R.sup.3 are
each, independently, selected from H, F, Cl, Br, methyl, ethyl,
1-propyl, 2-propyl, and C.sub.1-2 haloalkyl. In some embodiments,
R.sup.1 and R.sup.3 are each, independently, selected from H, F,
Cl, Br, methyl, ethyl, 1-propyl, 2-propyl, and CF.sub.3. In some
embodiments, R.sup.1 and R.sup.3 are each, selected from H, F, Cl,
Br, methyl, and CF.sub.3.
[0159] In some embodiments, R.sup.1 is selected from H and
C.sub.1-3 alkyl; and R.sup.3 is selected from halo, C.sub.1-3
alkyl, and C.sub.1-3 haloalkyl.
[0160] In some embodiments, R.sup.1 is H; and R.sup.3 is selected
from halo and C.sub.1-3 alkyl.
[0161] In some embodiments, R.sup.1 is H; and R.sup.3 is halo.
[0162] In some embodiments, one of R.sup.1 and R.sup.3 is SF.sub.5.
In some further embodiments, R.sup.3 is SF.sub.5.
[0163] In some embodiments, R.sup.1 and R.sup.2 are each,
independently, selected from H, halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6haloalkyl, CN, NO.sub.2,
OR.sup.a2, SR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2,
C(O)OR.sup.a2, OC(O)R.sup.b2, OC(O)NR.sup.c2R.sup.d2,
NR.sup.c2R.sup.d2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2C(O)OR.sup.a2,
C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2C(.dbd.NR.sup.g2)NR.sup.c2R.sup.d2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, S(O)R.sup.b2,
S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, and S(O).sub.2NR.sup.c2R.sup.d2.
[0164] In some embodiments, R.sup.1 and R.sup.2 are each,
independently, selected from H, halo, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, CN, NO.sub.2, OR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2C(O)OR.sup.a2,
NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2, NR.sup.c2S(O).sub.2R.sup.b2,
and NRC.sup.2R.sup.d2.
[0165] In some embodiments, R.sup.1 and R.sup.2 are each,
independently, selected from H, halo, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, CN, NO.sub.2, OR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, and NR.sup.c2R.sup.d2. In
some further embodiments, R.sup.1 and R.sup.2 are each,
independently, selected from H, halo, C.sub.1-6 alkyl, and
C.sub.1-6 haloalkyl. In some embodiments, R.sup.1 and R.sup.2 are
each, independently, selected from H, methyl, and ethyl. In some
embodiments, R.sup.1 and R.sup.2 are each, independently, selected
from H and methyl. In some further embodiments, R.sup.1 and R.sup.2
are H.
[0166] In some embodiments, R.sup.1 and R.sup.2 are each,
independently, selected from H, F, Cl, Br, methyl, ethyl, and
C.sub.1-2 haloalkyl. In some further embodiments, R.sup.1 and
R.sup.2 are each, independently, selected from H, F, Cl, methyl,
and CF.sub.3. In yet further embodiments, R.sup.1 and R.sup.2 are
each, independently, selected from H and methyl. In still further
embodiments, R.sup.1 and R.sup.2 are each H.
[0167] In some embodiments, X.sup.1 is CR.sup.1; X.sup.2 is N; and
X.sup.3 is CR.sup.3. In some further embodiments, R.sup.1 is
selected from H and C.sub.1-3 alkyl; and R.sup.3 is selected from
halo, C.sub.1-3 alkyl, and C.sub.1-3 haloalkyl. In yet further
embodiments, R.sup.1 is H; and R.sup.3 is halo. In still further
embodiments, R.sup.1 is H; and R.sup.3 is F, Cl, or Br. In further
embodiments, R.sup.1 is H; and R.sup.3 is Cl.
[0168] In some embodiments, R.sup.4 is H or C.sub.1-6 alkyl. In
some embodiments, R.sup.4 is H.
[0169] In some embodiments, R.sup.4 is H or C.sub.1-3 alkyl. In
some further embodiments, R.sup.4 is C.sub.1-3 alkyl. In yet
further embodiments, R.sup.4 is methyl.
[0170] In some embodiments, L.sup.1 and L.sup.2 are each,
independently, selected from a bond, --(CR.sup.7R.sup.8).sub.n--,
--O--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.,
--S--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.,
--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--O--, --(CR.sup.7R.sup.8).sub.m--S--,
--(CR.sup.7R.sup.8).sub.m--S(O)--,
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2--,
--(CR.sup.7R.sup.8).sub.m--C(O)--, --C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--C(O)O--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--OC(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9C(O)O--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--S(O).sub.2NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--S(O)NR.sup.9--, and
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2NR.sup.9--.
[0171] In some embodiments, L.sup.1 and L.sup.2 are each,
independently, selected from a bond, --(CR.sup.7R.sup.8).sub.n--,
--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.,
--O--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.,
--S--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--O--, --(CR.sup.7R.sup.8).sub.m--S--,
--(CR.sup.7R.sup.8).sub.m--S(O)--,
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2--,
--(CR.sup.7R.sup.8).sub.m--C(O)--, --C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--C(O)O--,
--(CR.sup.7R.sup.8).sub.m--S(O)NR.sup.9--, and
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2NR.sup.9--.
[0172] In some embodiments, L.sup.1 and L.sup.2 are each,
independently, selected from a bond, --(CR.sup.7R.sup.8).sub.n--,
--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--O--, --(CR.sup.7R.sup.8).sub.m--S--,
--(CR.sup.7R.sup.8).sub.m--S(O)--,
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2--,
--(CR.sup.7R.sup.8).sub.m--C(O)--, --C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--C(O)O--,
--(CR.sup.7R.sup.8).sub.m--S(O)NR.sup.9--, and
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2NR.sup.9--.
[0173] As used herein, when one of L.sup.1 and L.sup.2 is selected
from --O--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.,
--S--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.,
--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd., and
--(CR.sup.7R.sup.8).sub.m--N.dbd., the other is also selected from
--O--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.,
--S--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.,
--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd., and
--(CR.sup.7R.sup.8).sub.m--N.dbd. (although L.sup.1 and L.sup.2 can
be the same or different in such embodiments). In such embodiments,
the moiety formed by L.sup.1 and L.sup.2 together can include a
moiety of "--CR.sup.10.dbd.CR.sup.10--" or "--CR.sup.10.dbd.N--".
In some further embodiments, the moiety formed by L.sup.1 and
L.sup.2 together includes a moiety of --CR.sup.10.dbd.CR.sup.10--.
In some embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.CR.sup.10--(CR.sup.7R.sup.8).sub-
.m--,
--O--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.CR.sup.10--(CR.sup.7R.su-
p.8).sub.m--,
--S--(CR.sup.7R.sup.8)--CR.sup.10.dbd.CR.sup.10--(CR.sup.7R.sup.8).sub.m--
-,
--O--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.CR.sup.10--(CR.sup.7R.sup.8-
).sub.m--O--,
--O--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.CR.sup.10--(CR.sup.7R.sup.8).-
sub.m--S--, or
--S--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.CR.sup.10--(CR.sup.7R.sup.8).-
sub.m--S--.
[0174] In some embodiments, L.sup.1 and L.sup.2 are each,
independently, selected from a bond, --(CR.sup.7R.sup.8).sub.n--,
and --(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd..
[0175] In some embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.CR.sup.10--(CR.sup.7R.sup.8).sub-
.m-- or --(CR.sup.7R.sup.8).sub.m--(CR.sup.7R.sup.8).sub.n--.
[0176] In some embodiments, L.sup.1 and L.sup.2 together form
--CR.sup.10.dbd.CR.sup.10--, --(CR.sup.7R.sup.8).sub.2--, or
--(CR.sup.7R.sup.8).sub.3--.
[0177] In some embodiments, L.sup.1 and L.sup.2 together form
--CR.sup.10.dbd.CR.sup.10-- or --(CR.sup.7R.sup.8).sub.2--. In some
embodiments, L.sup.1 and L.sup.2 together form --CH.dbd.CH-- or
--CH.sub.2--CH.sub.2--. In some embodiments, L.sup.1 and L.sup.2
together form --CH.dbd.CH--. In some embodiments, L.sup.1 and
L.sup.2 together form --CH.sub.2--CH.sub.2--.
[0178] In some embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.n--. In some further embodiments, L.sup.1
and L.sup.2 together form --(CR.sup.7R.sup.8)--,
--(CR.sup.7R.sup.8).sub.2--, or --(CR.sup.7R.sup.8).sub.3--. In yet
further embodiments, L.sup.1 and L.sup.2 together form
--CH.sub.2--, --(CH.sub.2).sub.2--, or --(CH.sub.2).sub.3--.
[0179] In some embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.2--. In further embodiments, L.sup.1 and
L.sup.2 together form --(CH.sub.2).sub.2--.
[0180] In some embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.3--. In some embodiments, L.sup.1 and
L.sup.2 together form --(CH.sub.2).sub.3--.
[0181] In some embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.4--, --(CR.sup.7R.sup.8).sub.5--, or
--(CR.sup.7R.sup.8).sub.6--. In some embodiments, L.sup.1 and
L.sup.2 together form --(CH.sub.2).sub.4--, --(CH.sub.2).sub.5--,
or --(CH.sub.2).sub.6--.
[0182] In some embodiments, one of L.sup.1 and L.sup.2 is selected
from --(CR.sup.7R.sup.8).sub.m--O--,
--(CR.sup.7R.sup.8).sub.m--S--, --(CR.sup.7R.sup.8).sub.m--S(O)--,
and --(CR.sup.7R.sup.8).sub.m--S(O).sub.2--; and the other is
selected from a bond, --(CR.sup.7R.sup.8).sub.n--,
--(CR.sup.7R.sup.8).sub.m--O--, --(CR.sup.7R.sup.8).sub.m--S--,
--(CR.sup.7R.sup.8).sub.m--S(O)--, and
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2--.
[0183] In some embodiments, L.sup.1 and L.sup.2 together form
--O--(CR.sup.7R.sup.8).sub.m--(CR.sup.7R.sup.8).sub.n--.
[0184] In some embodiments, L.sup.1 and L.sup.2 together form
--O--(CR.sup.7R.sup.8)--, --O--(CR.sup.7R.sup.8).sub.2--, or
--O--(CR.sup.7R.sup.8).sub.3--.
[0185] In some embodiments, L.sup.1 and L.sup.2 together form
--O--CH.sub.2--, --O--(CH.sub.2).sub.2--, or
--O--(CH.sub.2).sub.3--.
[0186] In some embodiments, L.sup.1 is --(CR.sup.7R.sup.8)--,
--(CR.sup.7R.sup.8).sub.2--, or --(CR.sup.7R.sup.8).sub.3--; and
L.sup.2 is --O--.
[0187] In some embodiments:
[0188] L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.t1--S--, --(CR.sup.7R.sup.8).sub.t1--O--,
--(CR.sup.7R.sup.8).sub.t1--S(O)--,
--(CR.sup.7R.sup.8).sub.t1--S(O).sub.2--,
--S--(CR.sup.7R.sup.8).sub.t2--S--,
--O--(CR.sup.7R.sup.8).sub.t2--S--,
--O--(CR.sup.7R.sup.8).sub.t2--S(O)--,
--O--(CR.sup.7R.sup.8).sub.t2--S(O).sub.2--, --S--S--,
--(CR.sup.7R.sup.8).sub.t3--O--(CR.sup.7R.sup.8).sub.t4--,
--(CR.sup.7R.sup.8).sub.t3--S--(CR.sup.7R.sup.8).sub.t4--,
--(CR.sup.7R.sup.8).sub.t3--S(O)--(CR.sup.7R.sup.8).sub.t4--, or
--(CR.sup.7R.sup.8).sub.t3--S(O).sub.2--(CR.sup.7R.sup.8).sub.t4--;
[0189] t1 is 1, 2, or 3;
[0190] t2 is 1, 2, 3 or 4;
[0191] t3 is 1, 2, or 3; and
[0192] t4 is 1 or 2.
[0193] In some embodiments:
[0194] L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.t1--S--, --(CR.sup.7R.sup.8).sub.t1--O--,
--(CR.sup.7R.sup.8).sub.t1--S(O)--,
--(CR.sup.7R.sup.8).sub.t1--S(O).sub.2--,
--S--(CR.sup.7R.sup.8).sub.t2--S--,
--O--(CR.sup.7R.sup.8).sub.t2--S--,
--O--(CR.sup.7R.sup.8).sub.t2--S(O)--,
--O--(CR.sup.7R.sup.8).sub.t2--S(O).sub.2--, or --S--S--;
[0195] t1 is 1, 2, or 3; and
[0196] t2 is 1, 2, 3 or 4;
[0197] In some embodiments:
[0198] L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.t3--O--(CR.sup.7R.sup.8).sub.t4--,
--(CR.sup.7R.sup.8).sub.t3--S--(CR.sup.7R.sup.8).sub.t4--,
--(CR.sup.7R.sup.8).sub.t3--S(O)--(CR.sup.7R.sup.8).sub.t4--, or
--(CR.sup.7R.sup.8).sub.t3--S(O).sub.2--(CR.sup.7R.sup.8).sub.t4--,
[0199] t3 is 1, 2, or 3; and
[0200] t4 is 1 or 2.
[0201] In some embodiments, L.sup.1 and L.sup.2 together form S--S,
--(CR.sup.7R.sup.8)--S--, --(CR.sup.7R.sup.8)--S(O)--,
--(CR.sup.7R.sup.8)--S(O).sub.2--, --(CR.sup.7R.sup.8)--O--,
--(CR.sup.7R.sup.8).sub.2--O--, --O--(CR.sup.7R.sup.8)--O--,
--O--(CR.sup.7R.sup.8).sub.2--S--,
--O--(CR.sup.7R.sup.8).sub.2--S(O)--, or
--O--(CR.sup.7R.sup.8).sub.2--S(O).sub.2.
[0202] In some embodiments, L.sup.1 and L.sup.2 together form S--S,
--(CH.sub.2)--S--, --(CH.sub.2)--S(O)--,
--(CH.sub.2)--S(O).sub.2--, --(CH.sub.2)--O--,
--(CH.sub.2).sub.2--O--, --O--(CH.sub.2).sub.2--O--,
--O--(CH.sub.2).sub.2--S--, --O--(CH.sub.2).sub.2--S(O)--, or
--O--(CH.sub.2).sub.2--S(O).sub.2--. In some embodiments, L.sup.1
and L.sup.2 together form S--S. In some embodiments, L.sup.1 and
L.sup.2 together form --(CH.sub.2)--S--, --(CH.sub.2)--S(O)--,
--(CH.sub.2)--S(O).sub.2--, --(CH.sub.2)--O--,
--(CH.sub.2).sub.2--O--, --O--(CH.sub.2).sub.2--O--,
--O--(CH.sub.2).sub.2--S--, --O--(CH.sub.2).sub.2--S(O)--, or
--O--(CH.sub.2).sub.2--S(O).sub.2--.
[0203] In some embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8)--O--, --(CR.sup.7R.sup.8)--S--,
--(CR.sup.7R.sup.8)--S(O)--, --(CR.sup.7R.sup.8)--S(O).sub.2--,
--(CR.sup.7R.sup.8).sub.2--O--, --(CR.sup.7R.sup.8).sub.2--S--,
--(CR.sup.7R.sup.8).sub.2--S(O)--,
--(CR.sup.7R.sup.8).sub.2--S(O).sub.2--,
--O--(CR.sup.7R.sup.8).sub.3--, --S--(CR.sup.7R.sup.8).sub.3--,
--S(O)--(CR.sup.7R.sup.8).sub.3--, or
--S(O).sub.2--(CR.sup.7R.sup.8).sub.3--.
[0204] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2)--O--, --(CH.sub.2)--S--, --(CH.sub.2)--S(O)--, or
--(CH.sub.2)--S(O).sub.2--. In some embodiments, L.sup.1 and
L.sup.2 together form --(CH.sub.2)--O-- or --(CH.sub.2)--S--.
[0205] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2)--O--.
[0206] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2)--S--.
[0207] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2)--S(O)--.
[0208] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2)--S(O).sub.2--.
[0209] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2).sub.2--O--, --(CH.sub.2).sub.2--S--,
--(CH.sub.2).sub.2--S(O)--, or --(CH.sub.2).sub.2--S(O).sub.2--. In
some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2).sub.2--O-- or --(CH.sub.2).sub.2--S--.
[0210] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2).sub.2--O.
[0211] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2).sub.2--S--.
[0212] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2).sub.2--S(O)--.
[0213] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2).sub.2--S(O).sub.2--.
[0214] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2).sub.3--O--, --(CH.sub.2).sub.3--S--,
--(CH.sub.2).sub.3--S(O)--, or --(CH.sub.2).sub.3--S(O).sub.2--. In
some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2).sub.3--O-- or --(CH.sub.2).sub.3--S--.
[0215] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2).sub.3--O--.
[0216] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2).sub.3--S--.
[0217] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2).sub.3--S(O)--.
[0218] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2).sub.3--S(O).sub.2--.
[0219] In some embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8)--O--(CR.sup.7R.sup.8)--,
--(CR.sup.7R.sup.8)--S--(CR.sup.7R.sup.8)--,
--(CR.sup.7R.sup.8)--S(O)--(CR.sup.7R.sup.8)--,
--(CR.sup.7R.sup.8)--S(O).sub.2--(CR.sup.7R.sup.8)--,
--(CR.sup.7R.sup.8)--O--(CR.sup.7R.sup.8).sub.2--,
--(CR.sup.7R.sup.8)--S--(CR.sup.7R.sup.8).sub.2--,
--(CR.sup.7R.sup.8)--S(O)--(CR.sup.7R.sup.8).sub.2--,
--(CR.sup.7R.sup.8)--S(O).sub.2--(CR.sup.7R.sup.8).sub.2--,
--(CR.sup.7R.sup.8).sub.2--O--(CR.sup.7R.sup.8).sub.2--,
--(CR.sup.7R.sup.8).sub.2--S--(CR.sup.7R.sup.8).sub.2--,
--(CR.sup.7R.sup.8).sub.2--S(O)--(CR.sup.7R.sup.8).sub.2--, or
--(CR.sup.7R.sup.8).sub.2--S(O).sub.2--(CR.sup.7R.sup.8).sub.2--.
[0220] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2)--O--(CH.sub.2)--, --(CH.sub.2)--S--(CH.sub.2)--,
--(CH.sub.2)--S(O)--(CH.sub.2)--,
--(CH.sub.2)--S(O).sub.2--(CH.sub.2)--,
--(CH.sub.2)--O--(CH.sub.2).sub.2--,
--(CH.sub.2)--S--(CH.sub.2).sub.2--,
--(CH.sub.2)--S(O)--(CH.sub.2).sub.2--,
--(CH.sub.2)--S(O).sub.2--(CH.sub.2).sub.2--,
--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--,
--(CH.sub.2).sub.2--S--(CH.sub.2).sub.2--,
--(CH.sub.2).sub.2--S(O)--(CH.sub.2).sub.2--, or
--(CH.sub.2).sub.2--S(O).sub.2--(CH.sub.2).sub.2--.
[0221] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2)--O--(CH.sub.2)-- or --(CH.sub.2)--S--(CH.sub.2)--.
[0222] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2)--O--(CH.sub.2)--.
[0223] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2)--S--(CH.sub.2)--.
[0224] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2)--O--(CH.sub.2).sub.2-- or
--(CH.sub.2).sub.2--S--(CH.sub.2).sub.2--.
[0225] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2)--O--(CH.sub.2).sub.2--.
[0226] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2)--S--(CH.sub.2).sub.2--.
[0227] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2-- or
--(CH.sub.2).sub.2--S--(CH.sub.2).sub.2--.
[0228] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--
[0229] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2).sub.2--S--(CH.sub.2).sub.2--.
[0230] In some embodiments, L.sup.1 and L.sup.2 together form
--O--(CR.sup.7R.sup.8)--O--, --O--(CR.sup.7R.sup.8).sub.2--O--, or
--O--(CR.sup.7R.sup.8).sub.3--O--.
[0231] In some embodiments, L.sup.1 and L.sup.2 together form
--O--(CH.sub.2)--O--, --O--(CH.sub.2).sub.2--O--, or
--O--(CH.sub.2).sub.3--O--. In some further embodiments, L.sup.1
and L.sup.2 together form --O--(CH.sub.2).sub.2--O--.
[0232] In some embodiments, L.sup.1 and L.sup.2 together form S--S,
--(CH.sub.2)--S--, --(CH.sub.2)--S(O)--,
--(CH.sub.2)--S(O).sub.2--, --(CH.sub.2)--O--,
--(CH.sub.2).sub.2--O--, --(CH.sub.2).sub.3--O--,
--O--(CH.sub.2).sub.2--O--, --O--(CH.sub.2).sub.2--S--,
--O--(CH.sub.2).sub.2--S(O)--, or
--O--(CH.sub.2).sub.2--S(O).sub.2--.
[0233] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2)--S--, --(CH.sub.2)--S(O)--,
--(CH.sub.2)--S(O).sub.2--, --(CH.sub.2)--O--,
--(CH.sub.2).sub.2--O--, --(CH.sub.2).sub.3--O--,
--O--(CH.sub.2).sub.2--O--, --O--(CH.sub.2).sub.2--S--,
--O--(CH.sub.2).sub.2--S(O)--, or
--O--(CH.sub.2).sub.2--S(O).sub.2--.
[0234] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2)--O--, --(CH.sub.2).sub.2--O--, or
--(CH.sub.2).sub.3--O--. In some embodiments, L.sup.1 is
--(CH.sub.2)--, --(CH.sub.2).sub.2--, or --(CH.sub.2).sub.3--; and
L.sup.2 is --O--.
[0235] In some embodiments, L.sup.1 and L.sup.2 together form
--O--(CH.sub.2).sub.2--O--, --O--(CH.sub.2).sub.2--S--,
--O--(CH.sub.2).sub.2--S(O)--, --O--(CH.sub.2).sub.2--S(O).sub.2--,
--S--(CH.sub.2).sub.2--S--, --S(O)--(CH.sub.2).sub.2--S(O)--, or
--S(O).sub.2--(CH.sub.2).sub.2--S(O).sub.2--.
[0236] In some embodiments, L.sup.1 and L.sup.2 together form
--O--(CH.sub.2).sub.2--O--, --O--(CH.sub.2).sub.2--S--,
--O--(CH.sub.2).sub.2--S(O)--, or
--O--(CH.sub.2).sub.2--S(O).sub.2--.
[0237] In some embodiments, L.sup.1 and L.sup.2 together form
--O--(CH.sub.2).sub.2--O--.
[0238] In some embodiments, L.sup.1 and L.sup.2 together form
--O--(CH.sub.2).sub.2--S--.
[0239] In some embodiments, L.sup.1 and L.sup.2 together form
--O--(CH.sub.2).sub.2--S(O)--.
[0240] In some embodiments, L.sup.1 and L.sup.2 together form
--O--(CH.sub.2).sub.2--S(O).sub.2--.
[0241] In some embodiments, one of L.sup.1 and L.sup.2 is selected
from --(CR.sup.7R.sup.8).sub.m--NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2--,
--(CR.sup.7R.sup.8).sub.m--C(O)--, --C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--S(O)NR.sup.9--, and
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2NR.sup.9--; and the other is
selected from a bond, --(CR.sup.7R.sup.8).sub.n--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2--,
--(CR.sup.7R.sup.8).sub.m--C(O)--, --C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--S(O)NR.sup.9--, and
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2NR.sup.9--.
[0242] In some embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.t5--C(O)--,
--(CR.sup.7R.sup.8).sub.t5--C(O)NR.sup.9--,
--C(O)NR.sup.9--(CR.sup.7R.sup.8).sub.t5--, --C(O)NR.sup.9--,
--S(O).sub.2NR.sup.9--(CR.sup.7R.sup.8).sub.t5--,
--(CR.sup.7R.sup.8).sub.t5--S(O).sub.2NR.sup.9--, or
--S(O).sub.2NR.sup.9--, wherein t5 is 1, 2, or 3.
[0243] In some embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.2--C(O)--,
--C(O)NR.sup.9--(CR.sup.7R.sup.8)--, --C(O)NR.sup.9--,
--(CR.sup.7R.sup.8)--S(O).sub.2NR.sup.9--,
--S(O).sub.2NR.sup.9--(CR.sup.7R.sup.8)--, or
--S(O).sub.2NR.sup.9--.
[0244] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2).sub.2--C(O)--, --C(O)NH--(CH.sub.2)--, --C(O)NH--,
--S(O).sub.2NH--(CH.sub.2)--, --(CH.sub.2)--S(O).sub.2NH--, or
--S(O).sub.2NH--.
[0245] In some embodiments, L.sup.1 and L.sup.2 together form
--C(O)NH-- or --S(O).sub.2NH--.
[0246] In some embodiments, L.sup.1 is --C(O)-- and L.sup.2 is
--NH--.
[0247] In some embodiments, wherein L.sup.1 is --S(O).sub.2-- and
L.sup.2 is --NH--.
[0248] In some embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.t5--C(O)--, --C(O)NR.sup.9--, or
--S(O).sub.2NR.sup.9--, and wherein t5 is 1, 2, or 3.
[0249] In some embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8)--C(O)--, --(CR.sup.7R.sup.8).sub.2--C(O)--, or
--(CR.sup.7R.sup.8).sub.3--C(O)--. In some embodiments, L.sup.1 and
L.sup.2 together form --(CR.sup.7R.sup.8)--C(O)--. In some
embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.2--C(O)--. In some embodiments, L.sup.1 and
L.sup.2 together form --(CR.sup.7R.sup.8).sub.3--C(O)--.
[0250] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2)--C(O)--, --(CH.sub.2).sub.2--C(O)--, or
--(CH.sub.2).sub.3--C(O)--. In some embodiments, L.sup.1 and
L.sup.2 together form --(CH.sub.2)--C(O)--. In some embodiments,
L.sup.1 and L.sup.2 together form --(CH.sub.2).sub.2--C(O)--. In
some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2).sub.3--C(O)--.
[0251] In some embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8)--C(O)NR.sup.9--,
--C(O)NR.sup.9--(CR.sup.7R.sup.8)--, or --C(O)NR.sup.9--. In some
embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2)--C(O)NR.sup.9--, --C(O)NR.sup.9--(CH.sub.2)--, or
--C(O)NR.sup.9--. In some embodiments, L.sup.1 and L.sup.2 together
form --(CH.sub.2)--C(O)NH--, --C(O)NH--(CH.sub.2)--, or --C(O)NH--.
In some embodiments, L.sup.1 and L.sup.2 together form
--C(O)NH--(CH.sub.2)--, or --C(O)NH--.
[0252] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2)--C(O)NH--.
[0253] In some embodiments, L.sup.1 and L.sup.2 together form
--C(O)NH--(CH.sub.2)--.
[0254] In some embodiments, L.sup.1 and L.sup.2 together form
--C(O)NH--.
[0255] In some embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.t7--C(O)NR.sup.9--(CR.sup.7R.sup.8).sub.t8,
wherein t7 is 1 or 2 and t8 is 1 or 2. In some embodiments, L.sup.1
and L.sup.2 together form
--(CR.sup.7R.sup.8)--C(O)NR.sup.9--(CR.sup.7R.sup.8)--. In some
embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2)--C(O)NH--(CH.sub.2)--.
[0256] In some embodiments, L.sup.1 and L.sup.2 together form
--S(O).sub.2NR.sup.9--(CR.sup.7R.sup.8).sub.t5--,
--(CR.sup.7R.sup.8).sub.t5--S(O).sub.2NR.sup.9--, or
--S(O).sub.2NR.sup.9--, wherein t5 is 1, 2, or 3.
[0257] In some embodiments, L.sup.1 and L.sup.2 together form
--S(O).sub.2NR.sup.9--(CR.sup.7R.sup.8)--,
--(CR.sup.7R.sup.8)--S(O).sub.2NR.sup.9--, or
--S(O).sub.2NR.sup.9--. In some further embodiments, R.sup.9 is H
or C.sub.1-3 alkyl.
[0258] In some embodiments, L.sup.1 and L.sup.2 together form
--S(O).sub.2NR.sup.9--(CH.sub.2)--,
--(CH.sub.2)--S(O).sub.2NR.sup.9--, or --S(O).sub.2NR.sup.9--. In
some further embodiments, L.sup.1 and L.sup.2 together form
--S(O).sub.2NH--(CH.sub.2)--, --(CH.sub.2)--S(O).sub.2NH--, or
--S(O).sub.2NH--.
[0259] In some embodiments, L.sup.1 and L.sup.2 together form
--S(O).sub.2NH--(CH.sub.2)--.
[0260] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2)--S(O).sub.2NH--.
[0261] In some embodiments, L.sup.1 and L.sup.2 together form
--S(O).sub.2NH--.
[0262] In some embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.t7--S(O).sub.2NR.sup.9--(CR.sup.7R.sup.8).sub.t8--
-, wherein t7 is 1 or 2 and t8 is 1 or 2. In some embodiments,
L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8)--S(O).sub.2NR.sup.9--(CR.sup.7R.sup.8).
[0263] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2)--S(O).sub.2NR.sup.9--(CH.sub.2)--.
[0264] In some embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--O--C(O)NR.sup.9--, or
--O--C(O)NR.sup.9--(CR.sup.7R.sup.8).sub.m--.
[0265] In some embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8)--NR.sup.9--C(O)NR.sup.9--,
--(CR.sup.7R.sup.8)--O--C(O)NR.sup.9--,
--O--C(O)NR.sup.9--(CR.sup.7R.sup.8)--, --NR.sup.9--C(O)NR.sup.9--,
or --O--C(O)NR.sup.9--.
[0266] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2)--NR.sup.9--C(O)NR.sup.9--. In some embodiments,
L.sup.1 and L.sup.2 together form --(CH.sub.2)--NH--C(O)NH--.
[0267] In some embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8)--O--C(O)NR.sup.9--. In some embodiments,
L.sup.1 and L.sup.2 together form --(CH.sub.2)--O--C(O)NH--.
[0268] In some embodiments, L.sup.1 and L.sup.2 together form
--O--C(O)NR.sup.9--(CR.sup.7R.sup.8)--. In some embodiments,
L.sup.1 and L.sup.2 together form --O--C(O)NH--(CH.sub.2)--.
[0269] In some embodiments, L.sup.1 and L.sup.2 together form
--NR.sup.9--C(O)NR.sup.9--, or --O--C(O)NR.sup.9--.
[0270] In some embodiments, L.sup.1 and L.sup.2 together form
--NH--C(O)NH--.
[0271] In some embodiments, L.sup.1 and L.sup.2 together form
--O--C(O)NH--.
[0272] In some embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.m--,
NR.sup.9--(CR.sup.7R.sup.8).sub.n--.
[0273] In some embodiments, L.sup.1 and L.sup.2 together form
--NR.sup.9--(CR.sup.7R.sup.8).sub.n--. In some embodiments, L.sup.1
and L.sup.2 together form --NR.sup.9--(CR.sup.7R.sup.8)--. In some
embodiments, L.sup.1 and L.sup.2 together form
--NR.sup.9--(CR.sup.7R.sup.8).sub.2--. In some embodiments, L.sup.1
and L.sup.2 together form
--NR.sup.9--(CR.sup.7R.sup.8).sub.3--.
[0274] In some embodiments, L.sup.1 and L.sup.2 together form
--NR.sup.9--(CH.sub.2).sub.n--. In some embodiments, L.sup.1 and
L.sup.2 together form --NR.sup.9--(CH.sub.2)--. In some
embodiments, L.sup.1 and L.sup.2 together form
--NR.sup.9--(CH.sub.2).sub.2--. In some embodiments, L.sup.1 and
L.sup.2 together form --NR.sup.9--(CH.sub.2).sub.3--.
[0275] In some embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.m2--NR.sup.9--(CR.sup.7R.sup.8).sub.n--,
wherein m2 is 1 or 2. In some embodiments, L.sup.1 and L.sup.2
together form --(CR.sup.7R.sup.8)--NR.sup.9--(CR.sup.7R.sup.8)--,
--(CR.sup.7R.sup.8)--NR.sup.9--(CR.sup.7R.sup.8).sub.2--, or
--(CR.sup.7R.sup.8).sub.2--NR.sup.9--(CR.sup.7R.sup.8).sub.2--. In
some further embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8)--NR.sup.9--(CR.sup.7R.sup.8)-- or
--(CR.sup.7R.sup.8)--NR.sup.9--(CR.sup.7R.sup.8).sub.2--. In some
further embodiments, R.sup.9 is H or C.sub.1-3 alkyl.
[0276] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2).sub.m2--NR.sup.9--(CH.sub.2).sub.n--, wherein m2 is 1
or 2. In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2)--NR.sup.9--(CH.sub.2)--,
--(CH.sub.2)--NR.sup.9--(CH.sub.2).sub.2--, or
--(CH.sub.2).sub.2--NR.sup.9--(CH.sub.2).sub.2--. In some further
embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2)--NR.sup.9--(CH.sub.2)-- or
--(CH.sub.2)--NR.sup.9--(CH.sub.2).sub.2--. In some further
embodiments, R.sup.9 is H or C.sub.1-3 alkyl.
[0277] In some embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8)--NR.sup.9--(CR.sup.7R.sup.8)--. In some
embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2)--NR.sup.9--(CH.sub.2)--.
[0278] In some embodiments, L.sup.1 and L.sup.2 together form
--NR.sup.9--(CR.sup.7R.sup.8).sub.t9--O-- wherein t9 is 1, 2, or 3.
In some embodiments, L.sup.1 and L.sup.2 together form
--NR.sup.9--(CR.sup.7R.sup.8)--O--. In some embodiments, L.sup.1
and L.sup.2 together form --NR.sup.9--(CR.sup.7R.sup.8).sub.2--O--.
In some embodiments, L.sup.1 and L.sup.2 together form
--NR.sup.9--(CR.sup.7R.sup.8).sub.3--O--.
[0279] In some embodiments, L.sup.1 and L.sup.2 together form
--NR.sup.9--(CH.sub.2)--O--.
[0280] In some embodiments, L.sup.1 and L.sup.2 together form
--NR.sup.9--(CH.sub.2).sub.2--O--.
[0281] In some embodiments, L.sup.1 and L.sup.2 together form
--NR.sup.9--(CH.sub.2).sub.3--O--.
[0282] In some embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.CR.sup.10--(CR.sup.7R.sup.8).sub-
.m--, --(CR.sup.7R.sup.8).sub.m--(CR.sup.7R.sup.8).sub.n--,
--NR.sup.9C(O)NR.sup.9,
--NR.sup.9C(O)NR.sup.9--(CR.sup.7R.sup.8)--,
--NR.sup.9C(O)NR.sup.9--(CR.sup.7R.sup.8).sub.2--,
--(CR.sup.7R.sup.8)--NR.sup.9C(O)NR.sup.9--(CR.sup.7R.sup.8)--,
--(CR.sup.7R.sup.8)--NR.sup.9C(O)NR.sup.9--(CR.sup.7R.sup.8).sub.2--,
--(CR.sup.7R.sup.8).sub.2--NR.sup.9C(O)NR.sup.9--(CR.sup.7R.sup.8).sub.2--
-, --OC(O)NR.sup.9--, --OC(O)NR.sup.9--(CR.sup.7R.sup.8)--,
--OC(O)NR.sup.9--(CR.sup.7R.sup.8).sub.2--,
--(CR.sup.7R.sup.8)--OC(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.2--OC(O)NR.sup.9--,
--(CR.sup.7R.sup.8)--OC(O)NR.sup.9--(CR.sup.7R.sup.8)--,
--(CR.sup.7R.sup.8)--OC(O)NR.sup.9--(CR.sup.7R.sup.8).sub.2--,
--(CR.sup.7R.sup.8).sub.2--OC(O)NR.sup.9--(CR.sup.7R.sup.8)--,
--(CR.sup.7R.sup.8).sub.2--OC(O)NR.sup.9--(CR.sup.7R.sup.8).sub.2--,
--NR.sup.9S(O).sub.2NR.sup.9,
--NR.sup.9S(O).sub.2NR.sup.9--(CR.sup.7R.sup.8)--,
--NR.sup.9S(O).sub.2NR.sup.9--(CR.sup.7R.sup.8).sub.2--,
--(CR.sup.7R.sup.8)--NR.sup.9S(O).sub.2NR.sup.9--(CR.sup.7R.sup.8)--,
--(CR.sup.7R.sup.8)--NR.sup.9S(O).sub.2NR.sup.9--(CR.sup.7R.sup.8).sub.2--
-, or
--(CR.sup.7R.sup.8).sub.2--NR.sup.9S(O).sub.2NR.sup.9--(CR.sup.7R.su-
p.8).sub.2--.
[0283] In some embodiments, L.sup.1 and L.sup.2 together form
--NR.sup.9C(O)NR.sup.9,
--NR.sup.9C(O)NR.sup.9--(CR.sup.7R.sup.8)--,
--NR.sup.9C(O)NR.sup.9--(CR.sup.7R.sup.8).sub.2--,
--(CR.sup.7R.sup.8)--NR.sup.9C(O)NR.sup.9--(CR.sup.7R.sup.8)--,
--(CR.sup.7R.sup.8)--NR.sup.9C(O)NR.sup.9--(CR.sup.7R.sup.8).sub.2--,
--(CR.sup.7R.sup.8).sub.2--NR.sup.9C(O)NR.sup.9--(CR.sup.7R.sup.8).sub.2--
-, --OC(O)NR.sup.9--, --OC(O)NR.sup.9--(CR.sup.7R.sup.8)--,
--OC(O)NR.sup.9--(CR.sup.7R.sup.8).sub.2--,
--(CR.sup.7R.sup.8)--OC(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.2--OC(O)NR.sup.9--,
--(CR.sup.7R.sup.8)--OC(O)NR.sup.9--(CR.sup.7R.sup.8)--,
--(CR.sup.7R.sup.8)--OC(O)NR.sup.9--(CR.sup.7R.sup.8).sub.2--,
--(CR.sup.7R.sup.8).sub.2--OC(O)NR.sup.9--(CR.sup.7R.sup.8)--,
--(CR.sup.7R.sup.8).sub.2--OC(O)NR.sup.9--(CR.sup.7R.sup.8).sub.2--,
--NR.sup.9S(O).sub.2NR.sup.9,
--NR.sup.9S(O).sub.2NR.sup.9--(CR.sup.7R.sup.8)--,
--NR.sup.9S(O).sub.2NR.sup.9--(CR.sup.7R.sup.8).sub.2--,
--(CR.sup.7R.sup.8)--NR.sup.9S(O).sub.2NR.sup.9--(CR.sup.7R.sup.8)--,
--(CR.sup.7R.sup.8)--NR.sup.9S(O).sub.2NR.sup.9--(CR.sup.7R.sup.8).sub.2--
-, or
--(CR.sup.7R.sup.8).sub.2--NR.sup.9S(O).sub.2NR.sup.9--(CR.sup.7R.su-
p.8).sub.2--.
[0284] In some embodiments, L.sup.1 and L.sup.2 together form
--NR.sup.9C(O)NR.sup.9, --NR.sup.9C(O)NR.sup.9--(CH.sub.2)--,
--NR.sup.9C(O)NR.sup.9--(CH.sub.2).sub.2--,
--(CH.sub.2)--NR.sup.9C(O)NR.sup.9--(CH.sub.2)--,
--(CH.sub.2)--NR.sup.9C(O)NR.sup.9--(CH.sub.2).sub.2--,
--(CH.sub.2).sub.2--NR.sup.9C(O)NR.sup.9--(CH.sub.2).sub.2--,
--OC(O)NR.sup.9--, --OC(O)NR.sup.9--(CH.sub.2)--,
--OC(O)NR.sup.9--(CH.sub.2).sub.2--, --(CH.sub.2)--OC(O)NR.sup.9--,
--(CH.sub.2).sub.2--OC(O)NR.sup.9--,
--(CH.sub.2)--OC(O)NR.sup.9--(CH.sub.2)--,
--(CH.sub.2)--OC(O)NR.sup.9--(CH.sub.2).sub.27,
--(CH.sub.2).sub.2--OC(O)NR.sup.9--(CH.sub.2)--,
--(CH.sub.2).sub.2--OC(O)NR.sup.9--(CH.sub.2).sub.2--,
--NR.sup.9S(O).sub.2NR.sup.9,
--NR.sup.9S(O).sub.2NR.sup.9--(CH.sub.2)--,
--NR.sup.9S(O).sub.2NR.sup.9--(CH.sub.2).sub.2--,
--(CH.sub.2)--NR.sup.9S(O).sub.2NR.sup.9--(CH.sub.2)--,
--(CH.sub.2)--NR.sup.9S(O).sub.2NR.sup.9--(CH.sub.2).sub.2--, or
--(CH.sub.2).sub.2--NR.sup.9S(O).sub.2NR.sup.9--(CH.sub.2).sub.2--.
[0285] In some embodiments, one of L.sup.1 and L.sup.2 is selected
from --(CR.sup.7R.sup.8).sub.m--NR.sup.9C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--OC(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9C(O)O--, and
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--S(O).sub.2NR.sup.9--; and the
other is selected from a bond, --(CR.sup.7R.sup.8).sub.n--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--O--, --(CR.sup.7R.sup.8).sub.m--S--,
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2--,
--(CR.sup.7R.sup.8).sub.m--C(O)--, --C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--S(O)NR.sup.9--, and
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2NR.sup.9--.
[0286] In some embodiments, one of L.sup.1 and L.sup.2 is selected
from --(CR.sup.7R.sup.8).sub.m--NR.sup.9C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--OC(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9C(O)O--, and
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--S(O).sub.2NR.sup.9--; and the
other is selected from a bond, and --(CR.sup.7R.sup.8).sub.n.
[0287] In some embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.m--NR.sup.9C(O)NR.sup.9--(CR.sup.7R.sup.8).sub.m--
-,
--(CR.sup.7R.sup.8).sub.m--OC(O)NR.sup.9--(CR.sup.7R.sup.8).sub.m--,
or
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--S(O).sub.2NR.sup.9--(CR.sup.7R.sup.8-
).sub.m--.
[0288] In some embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.m--NR.sup.9C(O)NR.sup.9--(CR.sup.7R.sup.8).sub.m--
-. In some embodiments, L.sup.1 and L.sup.2 together form
--NR.sup.9C(O)NR.sup.9,
--NR.sup.9C(O)NR.sup.9--(CR.sup.7R.sup.8).sub.m2--, or
--(CR.sup.7R.sup.8).sub.m1--NR.sup.9C(O)NR.sup.9--(CR.sup.7R.sup.8).sub.m-
2--, wherein m1 and m2 are each, independently 1 or 2.
[0289] In some embodiments, L.sup.1 and L.sup.2 together form
--NR.sup.9C(O)NR.sup.9.
[0290] In some embodiments, L.sup.1 and L.sup.2 together form
--NR.sup.9C(O)NR.sup.9--(CR.sup.7R.sup.8)--,
--NR.sup.9C(O)NR.sup.9--(CR.sup.7R.sup.8).sub.2--,
--(CR.sup.7R.sup.8)--NR.sup.9C(O)NR.sup.9--(CR.sup.7R.sup.8)--,
--(CR.sup.7R.sup.8)--NR.sup.9C(O)NR.sup.9--(CR.sup.7R.sup.8).sub.2--,
or
--(CR.sup.7R.sup.8).sub.2--NR.sup.9C(O)NR.sup.9--(CR.sup.7R.sup.8).sub.2--
-.
[0291] In some embodiments, L.sup.1 and L.sup.2 together form
--(CH.sub.2).sub.m--NR.sup.9C(O)NR.sup.9--(CH.sub.2).sub.m--. In
some embodiments, L.sup.1 and L.sup.2 together form
--NR.sup.9C(O)NR.sup.9,
--NR.sup.9C(O)NR.sup.9--(CH.sub.2).sub.m2--, or
--(CH.sub.2).sub.m1--NR.sup.9C(O)NR.sup.9--(CH.sub.2).sub.m2--
wherein m1 and m2 are each, independently 1 or 2.
[0292] In some embodiments, L.sup.1 and L.sup.2 together form
--NR.sup.9C(O)NR.sup.9--(CH.sub.2)--,
--NR.sup.9C(O)NR.sup.9--(CH.sub.2).sub.2--,
--(CH.sub.2)--NR.sup.9C(O)NR.sup.9--(CH.sub.2)--,
--(CH.sub.2)--NR.sup.9C(O)NR.sup.9--(CH.sub.2).sub.2--, or
--(CH.sub.2).sub.2--NR.sup.9C(O)NR.sup.9--(CH.sub.2).sub.2--.
[0293] In some embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.m--OC(O)NR.sup.9--(CR.sup.7R.sup.8).sub.m--.
[0294] In some embodiments, L.sup.1 and L.sup.2 together form
--OC(O)NR.sup.9--.
[0295] In some embodiments, L.sup.1 and L.sup.2 together form
--OC(O)NR.sup.9--(CR.sup.7R.sup.8)--,
--OC(O)NR.sup.9--(CR.sup.7R.sup.8).sub.2--,
--(CR.sup.7R.sup.8)--OC(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.2--OC(O)NR.sup.9--,
--(CR.sup.7R.sup.8)--OC(O)NR.sup.9--(CR.sup.7R.sup.8)--,
--(CR.sup.7R.sup.8)--OC(O)NR.sup.9--(CR.sup.7R.sup.8).sub.2--,
--(CR.sup.7R.sup.8).sub.2--OC(O)NR.sup.9--(CR.sup.7R.sup.8)--, or
--(CR.sup.7R.sup.8).sub.2--OC(O)NR.sup.9--(CR.sup.7R.sup.8).sub.2--.
[0296] In some embodiments, L.sup.1 and L.sup.2 together form
--OC(O)NR.sup.9--(CH.sub.2)--, --OC(O)NR.sup.9--(CH.sub.2).sub.2--,
--(CH.sub.2)--OC(O)NR.sup.9--, --(CH.sub.2).sub.2--OC(O)NR.sup.9--,
--(CH.sub.2)--OC(O)NR.sup.9--(CH.sub.2)--,
--(CH.sub.2)--OC(O)NR.sup.9--(CH.sub.2).sub.2--,
--(CH.sub.2).sub.2--OC(O)NR.sup.9--(CH.sub.2)--, or
--(CH.sub.2).sub.2--OC(O)NR.sup.9--(CH.sub.2).sub.2--.
[0297] In some embodiments, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.m--NR.sup.9S(O).sub.2NR.sup.9--(CR.sup.7R.sup.8).-
sub.m--. In some embodiments, L.sup.1 and L.sup.2 together form
--NR.sup.9S(O).sub.2NR.sup.9--,
--NR.sup.9S(O).sub.2NR.sup.9--(CR.sup.7R.sup.8).sub.m2--, or
--(CR.sup.7R.sup.8).sub.m1--NR.sup.9S(O).sub.2NR.sup.9--(CR.sup.7R.sup.8)-
.sub.m2--, wherein m1 and m2 are each, independently 1 or 2.
[0298] In some embodiments, L.sup.1 and L.sup.2 together form
--NR.sup.9S(O).sub.2NR.sup.9.
[0299] In some embodiments, L.sup.1 and L.sup.2 together form
--NR.sup.9S(O).sub.2NR.sup.9--(CR.sup.7R.sup.8)--,
--NR.sup.9S(O).sub.2NR.sup.9--(CR.sup.7R.sup.8).sub.2--,
--(CR.sup.7R.sup.8)--NR.sup.9S(O).sub.2NR.sup.9--(CR.sup.7R.sup.8)--,
--(CR.sup.7R.sup.8)--NR.sup.9S(O).sub.2NR.sup.9--(CR.sup.7R.sup.8).sub.2--
-, or
--(CR.sup.7R.sup.8).sub.2--NR.sup.9S(O).sub.2NR.sup.9--(CR.sup.7R.su-
p.8).sub.2--.
[0300] As used herein, unless specifically indicated, a linkage--a
moiety that links two other moieties--can be attched to the other
two moieties in either direction, if the linkage is asymmetric. For
example, the moiety formed by L.sup.1 and L.sup.2 together in
compounds of Formula I can be linked to the ring containing
A.sup.1, B.sup.1, D.sup.1, and E.sup.1 and the containing A.sup.2,
B.sup.2, D.sup.2, and E.sup.2 in either direction. For example,
when L.sup.1 and L.sup.2 together form --O--(CH.sub.2).sub.2--S--,
the sulfur atom (S) can be linked to the ring containing A.sup.1,
B.sup.1, D.sup.1, and E.sup.1, and oxygen atom (O) to the ring
containing A.sup.2, B.sup.2, D.sup.2, and E.sup.2. Alternatively,
when L.sup.1 and L.sup.2 together form --O--(CH.sub.2).sub.2--S--,
the oxygen atom (O) can be linked to the ring containing A.sup.1,
B.sup.1, D.sup.1, and E.sup.1, and the sulfur atom (S) to the ring
containing A.sup.2, B.sup.2, D.sup.2, and E.sup.2. For another
example, when W.sup.1 in --W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1 is
O(CR.sup.11aR.sup.11b).sub.q1NR.sup.f, W.sup.1 can be linked to
Q.sup.1 either via the O or the N atom.
[0301] In some embodiments, R.sup.7, R.sup.8, and R.sup.10 are
each, independently, selected from H, halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
cycloalkyl, CN, NO.sub.2, OR.sup.a1, SR.sup.a1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
NR.sup.c1C(O)R.sup.b1, NR.sup.c1C(O)NR.sup.c1R.sup.d1, and
NR.sup.c1R.sup.d1, wherein each of said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl and cycloalkyl is
optionally substituted by 1, 2, 3, 4, or 5 substituents
independently selected from halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, cycloalkyl, CN,
NO.sub.2, OR.sup.a1, SR.sup.a1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
NR.sup.c1C(O)R.sup.b1, NR.sup.c1C(O)NR.sup.c1R.sup.d1, and
NR.sup.c1R.sup.d1.
[0302] In some embodiments, R.sup.7, R.sup.8, and R.sup.10 are
each, independently, selected from H, halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, CN,
NO.sub.2, OR.sup.a1, SR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, and NR.sup.c1R.sup.d1.
[0303] In some embodiments, R.sup.7, R.sup.8, and R.sup.10 are
each, independently, selected from H, halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, CN,
NO.sub.2, OR.sup.a1, and SR.sup.a1.
[0304] In some embodiments, R.sup.7, R.sup.8, and R.sup.10 are
each, independently, selected from H, halo, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, CN, NO.sub.2, OR.sup.a1, and SR.sup.a1.
[0305] In some embodiments, R.sup.7, R.sup.8, and R.sup.10 are
each, independently, selected from H, halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, CN,
NO.sub.2, OR.sup.a1, SR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, or NR.sup.c1R.sup.d1.
[0306] In some embodiments, R.sup.7, R.sup.8, and R.sup.10 are
each, independently, selected from H, halo, C.sub.1-6 alkyl, CN,
NO.sub.2, OH, C.sub.1-6alkoxy, C.sub.1-6haloalkoxy, and C.sub.2-8
alkoxyalkoxy. In some embodiments, R.sup.7, R.sup.8, and R.sup.10
are each, independently, selected from H, C.sub.1-4 alkyl, OH,
C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy, and C.sub.2-8
alkoxyalkoxy.
[0307] In some embodiments, R.sup.7 and R.sup.8 are each,
independently, selected from H, halo, C.sub.1-6 alkyl, CN,
NO.sub.2, OH, C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy, and C.sub.2-8
alkoxyalkoxy. In some further embodiments, R.sup.7 and R.sup.8 are
each, independently, selected from H, halo, C.sub.1-4 alkyl, CN,
NO.sub.2, C.sub.1-4 alkoxy, C.sub.1-4haloalkoxy, and C.sub.2-8
alkoxyalkoxy. In some further embodiments, R.sup.7 and R.sup.8 are
each, independently, selected from H, halo, C.sub.1-4 alkyl, OH,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, and C.sub.2-8 alkoxyalkoxy.
In some further embodiments, R.sup.7 and R.sup.8 are each,
independently, selected from H, OH, C.sub.1-4 alkoxy, C.sub.1-4
haloalkoxy, and C.sub.2-8 alkoxyalkoxy. In some further
embodiments, R.sup.7 and R.sup.8 are each, independently, selected
from H, OH, and C.sub.2-8 alkoxyalkoxy.
[0308] In some embodiments, R.sup.7 and R.sup.8 are each,
independently, selected from H and C.sub.1-6 alkyl. In some further
embodiments, R.sup.7 and R.sup.8 are each, independently, selected
from H and C.sub.1-4 alkyl.
[0309] In some embodiments, R.sup.7 and R.sup.8 are each,
independently, selected from H and C.sub.1-3 alkyl. In some further
embodiments, R.sup.7 and R.sup.8 are each, independently, selected
from H and CH.sub.3.
[0310] In some embodiments, R.sup.7 and R.sup.8 are both H. In some
embodiments, R.sup.7 and R.sup.8 are both CH.sub.3. In some
embodiments, one of R.sup.7 and R.sup.8 is H and the other is
CH.sub.3.
[0311] In some embodiments, each R.sup.9 is, independently, H,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, or C(O)OR.sup.a1. In some further
embodiments, each R.sup.9 is, independently, H, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C(O)R.sup.b1, or C(O)NR.sup.c1R.sup.d1.
[0312] In some embodiments, each R.sup.9 is, independently, H,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C(.dbd.O)--(C.sub.1-6 alkyl),
C(.dbd.O)-(arylalkyl), C(.dbd.O)NH.sub.2, C(.dbd.O)NH(C.sub.1-6
alkyl), C(.dbd.O)N(C.sub.1-6 alkyl).sub.2, C(.dbd.O)O--(C.sub.1-6
alkyl), or C(.dbd.O)O-(arylalkyl). In some embodiments, each
R.sup.9 is, independently, H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C(.dbd.O)--(C.sub.1-6 alkyl), C(.dbd.O)-(arylalkyl),
C(.dbd.O)NH.sub.2, C(.dbd.O)NH(C.sub.1-6 alkyl), or
C(.dbd.O)N(C.sub.1-4 alkyl).sub.2. In some embodiments, each
R.sup.9 is independently, H or C.sub.1-6 alkyl. In some
embodiments, each R.sup.9 is independently, H or C.sub.1-4 alkyl.
In some embodiments, each R.sup.9 is independently, H or C.sub.1-3
alkyl. In some embodiments, each R.sup.9 is H. In some embodiments,
each R.sup.9 is independently, C.sub.1-3 alkyl. In some
embodiments, each R.sup.9 is methyl.
[0313] In some embodiments, each R.sup.10 is, independently,
selected from H, halo, and C.sub.1-6 alkyl. In some embodiments,
each R.sup.10 is, independently, selected from H and C.sub.1-6
alkyl. In some embodiments, each R.sup.10 is, independently,
selected from H and C.sub.1-4 alkyl. In some further embodiments,
each R.sup.10 is H.
[0314] In some embodiments, each R.sup.5 is, independently,
selected from H, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
Cy.sup.1, --W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1, CN, NO.sub.2SF.sub.5,
OR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, NR.sup.c1S(O).sub.2R.sup.b1,
and S(O).sub.2NR.sup.c1R.sup.d1, wherein each of said C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, or C.sub.1-6 haloalkyl
is optionally substituted by 1, 2, 3, 4, or 5 substituents each
independently selected from halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halosulfanyl,
Cy.sup.1, --W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1, CN, NO.sub.2,
SF.sub.5, OR.sup.a1, SR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.f1, and
P(O)OR.sup.e1OR.sup.f1.
[0315] In some embodiments, each R.sup.5 is, independently,
selected from H, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, CN,
NO.sub.2, SF.sub.5, OR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1,
C(O)OR.sup.a1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, and S(O).sub.2NR.sup.c1R.sup.d1,
wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
or C.sub.1-6 haloalkyl, is optionally substituted by 1, 2, 3, 4 or
5 substituents each independently selected from halo, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
halosulfanyl, CN, NO.sub.2, SF.sub.5, OR.sup.a1, SR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.f1, and
P(O)OR.sup.e1OR.sup.f1.
[0316] In some embodiments:
[0317] each R.sup.5 is, independently, selected from H, halo,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, Cy.sup.3, --W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1, CN,
NO.sub.2, OR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1,
C(O)OR.sup.a1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, and S(O).sub.2NR.sup.c1R.sup.d1,
wherein each of said C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6alkynyl, or C.sub.1-6 haloalkyl, is optionally substituted
by 1, 2, 3, 4 or 5 substituents each independently selected from
halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, halosulfanyl, CN, NO.sub.2, SF.sub.5,
OR.sup.a1, SR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1,
C(O)OR.sup.a1, OC(O)R.sup.b1, OC(O)NR.sup.c1R.sup.d1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, and S(O).sub.2NR.sup.c1R.sup.d1; or
each R.sup.5 is, independently, selected from H, halo, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, CN, NO.sub.2, OR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, NR.sup.c1R.sup.d1,
NR.sup.c1C(O)R.sup.b1, NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1,
S(O).sub.2R.sup.b1, NR.sup.c1S(O).sub.2R.sup.b1, and
S(O).sub.2NR.sup.c1R.sup.d1, wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, or C.sub.1-6 haloalkyl, is
optionally substituted by 1, 2, 3, 4 or 5 substituents each
independently selected from halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halosulfanyl, CN,
NO.sub.2, SF.sub.5, OR.sup.a1, SR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.f1, and
P(O)OR.sup.e1OR.sup.f1;
[0318] R.sup.a1, R.sup.b1, R.sup.c1, and R.sup.d1 are each,
independently, selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl, and
heterocycloalkylalkyl, wherein each of said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and
heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or
5 substituents independently selected from halo, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 hydroxylalkyl, C.sub.1-4 cyanoalkyl,
aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO.sub.2, OH,
SH, O(C.sub.1-4 alkyl), O(C.sub.1-4haloalkyl), O(aryl),
O(arylalkyl), S(C.sub.1-4alkyl), S(C.sub.1-4haloalkyl), S(aryl),
S(arylalkyl), amino, C.sub.1-4 alkylamino, C.sub.2-8dialkylamino,
C(.dbd.O)H, C(.dbd.O)--(C.sub.1-4 alkyl), C(.dbd.O)-(arylalkyl),
C(.dbd.O)NH.sub.2, C(.dbd.O)NH(C.sub.1-4 alkyl),
C(.dbd.O)N(C.sub.1-4 alkyl).sub.2, C(.dbd.O)OH,
C(.dbd.O)O--(C.sub.1-4 alkyl), C(.dbd.O)O-(arylalkyl), OC(.dbd.O)H,
OC(.dbd.O)--(C.sub.1-4 alkyl), OC(.dbd.O)-(arylalkyl),
OC(.dbd.O)NH.sub.2, OC(.dbd.O)NH(C.sub.1-4 alkyl),
OC(.dbd.O)NH-(arylalkyl), OC(.dbd.O)N(C.sub.1-4 alkyl).sub.2,
NHC(.dbd.O)--(C.sub.1-4 alkyl), NHC(.dbd.O)O-(arylalkyl),
NHC(.dbd.O)O--(C.sub.1-4 alkyl), NHC(.dbd.O)O-(arylalkyl),
NHS(.dbd.O).sub.2--(C.sub.1-4 alkyl),
NHS(.dbd.O).sub.2-(arylalkyl), NHS(.dbd.O).sub.2--NH(C.sub.1-4
alkyl), NHS(.dbd.O).sub.2--N(C.sub.1-4 alkyl).sub.2,
NHS(.dbd.O).sub.2--NH(arylalkyl), S(.dbd.O).sub.2--(C.sub.1-4
alkyl), S(.dbd.O).sub.2-(arylalkyl), S(.dbd.O).sub.2NH(C.sub.1-4
alkyl) and S(.dbd.O).sub.2NH(arylalkyl);
[0319] or R.sup.c1 and R.sup.d1 together with the N atom to which
they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl
group or heteroaryl group, each optionally substituted with 1, 2,
or 3 substituents independently selected from halo, C.sub.1-4
alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 hydroxylalkyl, C.sub.1-4
cyanoalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN,
NO.sub.2, OH, SH, O(C.sub.1-4 alkyl), O(C.sub.1-4 haloalkyl),
O(aryl), O(arylalkyl), S(C.sub.1-4 alkyl), S(C.sub.1-4haloalkyl),
S(aryl), S(arylalkyl), amino, C.sub.1-4 alkylamino, C.sub.2-8
dialkylamino, C(.dbd.O)H, C(.dbd.O)--(C.sub.1-4 alkyl),
C(.dbd.O)-(arylalkyl), C(.dbd.O)NH.sub.2, C(.dbd.O)NH(C.sub.1-4
alkyl), C(.dbd.O)N(C.sub.1-4 alkyl).sub.2, C(.dbd.O)OH,
C(.dbd.O)O--(C.sub.1-4 alkyl), C(.dbd.O)O-(arylalkyl), OC(.dbd.O)H,
OC(.dbd.O)--(C.sub.1-4 alkyl), OC(.dbd.O)-(arylalkyl),
OC(.dbd.O)NH.sub.2, OC(.dbd.O)NH(C.sub.1-4 alkyl),
OC(.dbd.O)NH-(arylalkyl), OC(.dbd.O)N(C.sub.1-4 alkyl).sub.2,
NHC(.dbd.O)--(C.sub.1-4 alkyl), NHC(.dbd.O)O-(arylalkyl),
NHC(.dbd.O)O--(C.sub.1-4 alkyl), NHC(.dbd.O)O-(arylalkyl),
NHS(.dbd.O).sub.2--(C.sub.1-4 alkyl),
NHS(.dbd.O).sub.2-(arylalkyl), NHS(.dbd.O).sub.2--NH(C.sub.1-4
alkyl), NHS(.dbd.O).sub.2--N(C.sub.1-4 alkyl).sub.2,
NHS(.dbd.O).sub.2--NH(arylalkyl), S(.dbd.O).sub.2--(C.sub.1-4
alkyl), S(.dbd.O).sub.2-(arylalkyl), S(.dbd.O).sub.2NH(C.sub.1-4
alkyl) and S(.dbd.O).sub.2NH(arylalkyl).
[0320] In some embodiments:
[0321] each R.sup.5 is, independently, selected from H, halo,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, CN, NO.sub.2, OR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, and S(O).sub.2NR.sup.c1R.sup.d1,
wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
or C.sub.1-6 haloalkyl, is optionally substituted by 1, 2, 3, 4 or
5 substituents each independently selected from halo, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
halosulfanyl, CN, NO.sub.2, SF.sub.S, OR.sup.a1, SR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.bl,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, or S(O).sub.2NR.sup.c1R.sup.d1;
[0322] R.sup.a1, R.sup.b1, R.sup.c1, and R.sup.d1 are each,
independently, selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl, and
heterocycloalkylalkyl, wherein each of said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and
heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or
5 substituents independently selected from halo, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 hydroxylalkyl, C.sub.1-4 cyanoalkyl,
aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO.sub.2, OH,
SH, O(C.sub.1-4 alkyl), O(C.sub.1-4 haloalkyl), O(aryl),
O(arylalkyl), S(C.sub.1-4 alkyl), S(C.sub.1-4 haloalkyl), S(aryl),
S(arylalkyl), amino, C.sub.1-4 alkylamino, C.sub.2-8 dialkylamino,
C(.dbd.O)H, C(.dbd.O)--(C.sub.1-4 alkyl), C(.dbd.O)-(arylalkyl),
C(.dbd.O)NH.sub.2, C(.dbd.O)NH(C.sub.1-4 alkyl),
C(.dbd.O)N(C.sub.1-4 alkyl).sub.2, C(.dbd.O)OH,
C(.dbd.O)O--(C.sub.1-4 alkyl), C(.dbd.O)O-(arylalkyl), OC(.dbd.O)H,
OC(.dbd.O)--(C.sub.1-4 alkyl), OC(.dbd.O)-(arylalkyl),
OC(.dbd.O)NH.sub.2, OC(.dbd.O)NH(C.sub.1-4 alkyl),
OC(.dbd.O)NH-(arylalkyl), OC(.dbd.O)N(C.sub.1-4 alkyl).sub.2,
NHC(.dbd.O)--(C.sub.1-4 alkyl), NHC(.dbd.O)O-(arylalkyl),
NHC(.dbd.O)O--(C.sub.1-4 alkyl), NHC(.dbd.O)O-(arylalkyl),
NHS(.dbd.O).sub.2--(C.sub.1-4 alkyl),
NHS(.dbd.O).sub.2-(arylalkyl), NHS(.dbd.O).sub.2--NH(C.sub.1-4
alkyl), NHS(.dbd.O).sub.2--N(C.sub.1-4 alkyl).sub.2,
NHS(.dbd.O).sub.2--NH(arylalkyl), S(.dbd.O).sub.2--(C.sub.1-4
alkyl), S(.dbd.O).sub.2-(arylalkyl), S(.dbd.O).sub.2NH.sub.2,
S(.dbd.O).sub.2NH(C.sub.1-4 alkyl) and
S(.dbd.O).sub.2NH(arylalkyl);
[0323] or R.sup.c1 nd R.sup.d1 together with the N atom to which
they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl
group or heteroaryl group, each optionally substituted with 1, 2,
or 3 substituents independently selected from halo, C.sub.1-4
alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 hydroxylalkyl, C.sub.1-4
cyanoalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN,
NO.sub.2, OH, SH, O(C.sub.1-4 alkyl), O(C.sub.1-4 haloalkyl),
O(aryl), O(arylalkyl), S(C.sub.1-4 alkyl), S(C.sub.1-4haloalkyl),
S(aryl), S(arylalkyl), amino, C.sub.1-4 alkylamino, C.sub.2-8
dialkylamino, C(.dbd.O)H, C(.dbd.O)--(C.sub.1-4 alkyl),
C(.dbd.O)-(arylalkyl), C(.dbd.O)NH.sub.2, C(.dbd.O)NH(C.sub.1-4
alkyl), C(.dbd.O)N(C.sub.1-4 alkyl).sub.2, C(.dbd.O)OH,
C(.dbd.O)O--(C.sub.1-4 alkyl), C(.dbd.O)O-(arylalkyl), OC(.dbd.O)H,
OC(.dbd.O)--(C.sub.1-4 alkyl), OC(.dbd.O)-(arylalkyl),
OC(.dbd.O)NH.sub.2, OC(.dbd.O)NH(C.sub.1-4 alkyl),
OC(.dbd.O)NH-(arylalkyl), OC(.dbd.O)N(C.sub.1-4 alkyl).sub.2,
NHC(.dbd.O)--(C.sub.1-4 alkyl), NHC(.dbd.O)O-(arylalkyl),
NHC(.dbd.O)O--(C.sub.1-4 alkyl), NHC(.dbd.O)O-(arylalkyl),
NHS(.dbd.O).sub.2--(C.sub.1-4 alkyl),
NHS(.dbd.O).sub.2-(arylalkyl), NHS(.dbd.O).sub.2--NH(C.sub.1-4
alkyl), NHS(.dbd.O).sub.2--N(C.sub.1-4 alkyl).sub.2,
NHS(.dbd.O).sub.2--NH(arylalkyl), S(.dbd.O).sub.2--(C.sub.1-4
alkyl), S(.dbd.O).sub.2-(arylalkyl), S(.dbd.O).sub.2NH.sub.2,
S(.dbd.O).sub.2NH(C.sub.1-4 alkyl) and
S(.dbd.O).sub.2NH(arylalkyl).
[0324] In some embodiments, at least one of R.sup.5 is selected
C(O)NR.sup.c1R.sup.d1 or NR.sup.c1R.sup.d1, wherein:
[0325] R.sup.c1 and R.sup.d1 are each, independently, selected from
H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl,
wherein each of said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is
optionally substituted with 1, 2, 3, 4, or 5 substituents
independently selected from halo, C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.1-4 hydroxylalkyl, C.sub.1-4 cyanoalkyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO.sub.2, OH, SH,
O(C.sub.1-4 alkyl), O(C.sub.1-4 haloalkyl), O(aryl), O(arylalkyl),
S(C.sub.1-4 alkyl), S(C.sub.1-4 haloalkyl), S(aryl), S(arylalkyl),
amino, C.sub.1-4 alkylamino, C.sub.2-8 dialkylamino, C(.dbd.O)H,
C(.dbd.O)--(C.sub.1-4 alkyl), C(.dbd.O)-(arylalkyl),
C(.dbd.O)NH.sub.2, C(.dbd.O)NH(C.sub.1-4 alkyl),
C(.dbd.O)N(C.sub.1-4 alkyl).sub.2, C(.dbd.O)OH,
C(.dbd.O)O--(C.sub.1-4 alkyl), C(.dbd.O)O-(arylalkyl), OC(.dbd.O)H,
OC(.dbd.O)--(C.sub.1-4 alkyl), OC(.dbd.O)-(arylalkyl),
OC(.dbd.O)NH.sub.2, OC(.dbd.O)NH(C.sub.1-4 alkyl),
OC(.dbd.O)NH-(arylalkyl), OC(.dbd.O)N(C.sub.1-4 alkyl).sub.2,
NHC(.dbd.O)--(C.sub.1-4 alkyl), NHC(.dbd.O)O-(arylalkyl),
NHC(.dbd.O)O--(C.sub.1-4 alkyl), NHC(.dbd.O)O-(arylalkyl),
NHS(.dbd.O).sub.2--(C.sub.1-4 alkyl),
NHS(.dbd.O).sub.2-(arylalkyl), NHS(.dbd.O).sub.2--NH(C.sub.1-4
alkyl), NHS(.dbd.O).sub.2--N(C.sub.1-4 alkyl).sub.2,
NHS(.dbd.O).sub.2--NH(arylalkyl), S(.dbd.O).sub.2--(C.sub.1-4
alkyl), S(.dbd.O).sub.2-(arylalkyl), S(.dbd.O).sub.2NH.sub.2,
S(.dbd.O).sub.2NH(C.sub.1-4 alkyl) and
S(.dbd.O).sub.2NH(arylalkyl);
[0326] or R.sup.c1 and R.sup.d1 together with the N atom to which
they are attached form pyrrolidinyl, piperidinyl, piperazinyl, or
morpholinyl, each optionally substituted with 1, 2, or 3
substituents independently selected from halo, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 hydroxylalkyl, C.sub.1-4 cyanoalkyl,
aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO.sub.2, OH,
SH, O(C.sub.1-4 alkyl), O(C.sub.1-4haloalkyl), O(aryl),
O(arylalkyl), S(C.sub.1-4 alkyl), S(C.sub.1-4 haloalkyl), S(aryl),
S(arylalkyl), amino, C.sub.1-4 alkylamino, C.sub.2-8 dialkylamino,
C(.dbd.O)H, C(.dbd.O)--(C.sub.1-4 alkyl), C(.dbd.O)-(arylalkyl),
C(.dbd.O)NH.sub.2, C(.dbd.O)NH(C.sub.1-4 alkyl),
C(.dbd.O)N(C.sub.1-4 alkyl).sub.2, C(.dbd.O)OH,
C(.dbd.O)O--(C.sub.1-4 alkyl), C(.dbd.O)O-(arylalkyl), OC(.dbd.O)H,
OC(.dbd.O)--(C.sub.1-4 alkyl), OC(.dbd.O)-(arylalkyl),
OC(.dbd.O)NH.sub.2, OC(.dbd.O)NH(C.sub.1-4 alkyl),
OC(.dbd.O)NH-(arylalkyl), OC(.dbd.O)N(C.sub.1-4 alkyl).sub.2,
NHC(.dbd.O)--(C.sub.1-4 alkyl), NHC(.dbd.O)O-(arylalkyl),
NHC(.dbd.O)O--(C.sub.1-4 alkyl), NHC(.dbd.O)O-(arylalkyl),
NHS(.dbd.O).sub.2--(C.sub.1-4 alkyl),
NHS(.dbd.O).sub.2-(arylalkyl), NHS(.dbd.O).sub.2--NH(C.sub.1-4
alkyl), NHS(.dbd.O).sub.2--N(C.sub.1-4 alkyl).sub.2,
NHS(.dbd.O).sub.2--NH(arylalkyl), S(.dbd.O).sub.2--(C.sub.1-4
alkyl), S(.dbd.O).sub.2-(arylalkyl), S(.dbd.O).sub.2NH.sub.2,
S(.dbd.O).sub.2NH(C.sub.1-4 alkyl) and
S(.dbd.O).sub.2NH(arylalkyl).
[0327] In some embodiments, at least one of R.sup.5 is selected
C(O)NR.sup.c1R.sup.d1 or NR.sup.c1R.sup.d1, wherein:
[0328] R.sup.c1 and R.sup.d1 are each, independently, selected from
H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl,
wherein each of said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is
optionally substituted with 1, 2, 3, 4, or 5 substituents
independently selected from halo, C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.1-4 hydroxylalkyl, C.sub.1-4 cyanoalkyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO.sub.2, OH, SH,
O(C.sub.1-4 alkyl), O(C.sub.1-4 haloalkyl), O(aryl), O(arylalkyl),
S(C.sub.1-4 alkyl), S(C.sub.1-4 haloalkyl), S(aryl), S(arylalkyl),
amino, C.sub.1-4 alkylamino, C.sub.2-8 dialkylamino, C(.dbd.O)H,
C(.dbd.O)--(C.sub.1-4 alkyl), C(.dbd.O)-(arylalkyl),
C(.dbd.O)NH.sub.2, C(.dbd.O)NH(C.sub.1-4 alkyl),
C(.dbd.O)N(C.sub.1-4 alkyl).sub.2, C(.dbd.O)OH,
C(.dbd.O)O--(C.sub.1-4 alkyl), C(.dbd.O)O-(arylalkyl), OC(.dbd.O)H,
OC(.dbd.O)--(C.sub.1-4 alkyl), OC(.dbd.O)-(arylalkyl),
OC(.dbd.O)NH.sub.2, OC(.dbd.O)NH(C.sub.1-4 alkyl),
OC(.dbd.O)NH-(arylalkyl), OC(.dbd.O)N(C.sub.1-4 alkyl).sub.2,
NHC(.dbd.O)--(C.sub.1-4 alkyl), NHC(.dbd.O)O-(arylalkyl),
NHC(.dbd.O)O--(C.sub.1-4 alkyl), NHC(.dbd.O)O-(arylalkyl),
NHS(.dbd.O).sub.2--(C.sub.1-4 alkyl),
NHS(.dbd.O).sub.2-(arylalkyl), NHS(.dbd.O).sub.2--NH(C.sub.1-4
alkyl), NHS(.dbd.O).sub.2--N(C.sub.1-4 alkyl).sub.2,
NHS(.dbd.O).sub.2--NH(arylalkyl), S(.dbd.O).sub.2--(C.sub.1-4
alkyl), S(.dbd.O).sub.2-(arylalkyl), S(.dbd.O).sub.2NH.sub.2,
S(.dbd.O).sub.2NH(C.sub.1-4 alkyl) and
S(.dbd.O).sub.2NH(arylalkyl);
[0329] or R.sup.c1 and R.sup.d1 together with the N atom to which
they are attached form pyrrolidinyl, piperidinyl or morpholinyl,
each optionally substituted with 1, 2, or 3 substituents
independently selected from halo, C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.1-4 hydroxylalkyl, C.sub.1-4 cyanoalkyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO.sub.2, OH, SH,
O(C.sub.1-4 alkyl), O(C.sub.1-4 haloalkyl), O(aryl), O(arylalkyl),
S(C.sub.1-4 alkyl), S(C.sub.1-4 haloalkyl), S(aryl), S(arylalkyl),
amino, C.sub.1-4 alkylamino, C.sub.2-8 dialkylamino, C(.dbd.O)H,
C(.dbd.O)--(C.sub.1-4 alkyl), C(.dbd.O)-(arylalkyl),
C(.dbd.O)NH.sub.2, C(.dbd.O)NH(C.sub.1-4 alkyl),
C(.dbd.O)N(C.sub.1-4 alkyl).sub.2, C(.dbd.O)OH,
C(.dbd.O)O--(C.sub.1-4 alkyl), C(.dbd.O)O-(arylalkyl), OC(.dbd.O)H,
OC(.dbd.O)--(C.sub.1-4 alkyl), OC(.dbd.O)-(arylalkyl),
OC(.dbd.O)NH.sub.2, OC(.dbd.O)NH(C.sub.1-4 alkyl),
OC(.dbd.O)NH-(arylalkyl), OC(.dbd.O)N(C.sub.1-4 alkyl).sub.2,
NHC(.dbd.O)--(C.sub.1-4 alkyl), NHC(.dbd.O)O-(arylalkyl),
NHC(.dbd.O)O--(C.sub.1-4 alkyl), NHC(.dbd.O)O-(arylalkyl),
NHS(.dbd.O).sub.2--(C.sub.1-4 alkyl),
NHS(.dbd.O).sub.2-(arylalkyl), NHS(.dbd.O).sub.2--NH(C.sub.1-4
alkyl), NHS(.dbd.O).sub.2--N(C.sub.1-4 alkyl).sub.2,
NHS(.dbd.O).sub.2--NH(arylalkyl), S(.dbd.O).sub.2--(C.sub.1-4
alkyl), S(.dbd.O).sub.2-(arylalkyl), S(.dbd.O).sub.2NH.sub.2,
S(.dbd.O).sub.2NH(C.sub.1-4 alkyl) and
S(.dbd.O).sub.2NH(arylalkyl).
[0330] In some embodiments, each R.sup.5 is, independently,
selected from H, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, CN,
NO.sub.2, SF.sub.5, OR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1,
C(O)OR.sup.a1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, and S(O).sub.2NR.sup.c1R.sup.d1.
[0331] In some embodiments, each R.sup.5 is, independently,
selected from H, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, CN,
NO.sub.2, SF.sub.5, OR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1,
C(O)OR.sup.a1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, and S(O).sub.2NR.sup.c1R.sup.d1.
[0332] In some embodiments, each R.sup.5 is independently selected
from H, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, CN, NO.sub.2,
OR.sup.a1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2R.sup.b1, NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1,
S(O)R.sup.b1, S(O).sub.2R.sup.b1, and
S(O).sub.2NR.sup.c1R.sup.d1.
[0333] In some embodiments, each R.sup.5 is independently selected
from H, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, CN, NO.sub.2,
OR.sup.a1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O)R.sup.b1, S(O).sub.2R.sup.b1, and
S(O).sub.2NR.sup.c1R.sup.d1.
[0334] In some embodiments, each R.sup.5 is independently selected
from H, C.sub.1-6 alkyl, COOH, C(.dbd.O)--(C.sub.1-4 alkyl),
S(.dbd.O).sub.2--(C.sub.1-4 alkyl), S(.dbd.O).sub.2NH.sub.2,
S(.dbd.O).sub.2NH(C.sub.1-4 alkyl), NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, C(O)NR.sup.c1R.sup.d1, and
NR.sup.c1R.sup.d1.
[0335] In some embodiments, each R.sup.5 is independently selected
from H, C.sub.1-6 alkyl, COOH, C(.dbd.O)--(C.sub.1-4 alkyl),
S(.dbd.O).sub.2--(C.sub.1-4 alkyl), S(.dbd.O).sub.2NH.sub.2,
S(.dbd.O).sub.2NH(C.sub.1-4 alkyl), C(O)NR.sup.c1R.sup.d1 and
NR.sup.c1R.sup.d1, wherein:
[0336] R.sup.c1 and R.sup.d1 are each, independently, selected from
H, C.sub.1-6 alkyl, aryl, heteroaryl, arylalkyl, and
heteroarylalkyl, wherein each of said C.sub.1-6 alkyl, aryl,
heteroaryl, arylalkyl, heteroarylalkyl is optionally substituted
with 1, 2, or 3 substituents independently selected from halo,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 hydroxylalkyl,
C.sub.1-4 cyanoalkyl, aryl, heteroaryl, OH, O(C.sub.1-4alkyl),
O(C.sub.1-4haloalkyl), piperidinyl, pyrrolidinyl, morpholinyl, and
piperizinyl optionally substituted with C.sub.1-4 alkyl, aryl, or
arylalkyl;
[0337] or R.sup.c1 and R.sup.d1 together with the N atom to which
they are attached form pyrrolidinyl, piperidinyl, piperazinyl, or
morpholinyl, each optionally substituted with 1, 2, or 3
substituents independently selected from C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.1-4 hydroxylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, OH, O(C.sub.1-4 alkyl), and
O(C.sub.1-4haloalkyl).
[0338] In some embodiments, two adjacent R.sup.5 on the same ring
can link to form a fused cycloalkyl or fused heterocycloalkyl
group, each optionally substituted by 1, 2, or 3 substituents
independently selected from halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halosulfanyl, CN,
NO.sub.2, OR.sup.a1, SR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O)NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.f1, and
P(O)OR.sup.e1OR.sup.f1.
[0339] In some embodiments, two adjacent R.sup.5 on the ring
containing A.sup.1, B.sup.1, D.sup.1, and E.sup.1 can link to form
a fused cycloalkyl or fused heterocycloalkyl group, each optionally
substituted by 1, 2, or 3 substituents independently selected from
halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, halosulfanyl, CN, NO.sub.2, OR.sup.a1,
SR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
OC(O)R.sup.b1, OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1,
NR.sup.c1C(O)R.sup.b1, NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1C(O)OR.sup.a1, C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O)NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.f1, and
P(O)OR.sup.e1OR.sup.f1.
[0340] In some embodiments, two adjacent R.sup.5 on the ring
containing A.sup.2, B.sup.2, D.sup.2, and E.sup.2 canlink to form a
fused cycloalkyl or fused heterocycloalkyl group, each optionally
substituted by 1, 2, or 3 substituents independently selected from
halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, halosulfanyl, CN, NO.sub.2, OR.sup.a1,
SR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
OC(O)R.sup.b1, OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1,
NR.sup.c1C(O)R.sup.b1, NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1C(O)OR.sup.a1, C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O)NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.f1, and
P(O)OR.sup.e1OR.sup.f1.
[0341] In some embodiments, at least one R.sup.5 is other than H.
In some embodiments, at least one R.sup.5 on the ring containing
A.sup.1, B.sup.1, D.sup.1, and E.sup.1 is other than H. In some
embodiments, at least one R.sup.5 on the ring containing A.sup.2,
B.sup.2, D.sup.2, and E.sup.2 is other than H. In some embodiments,
one or two R.sup.5 on the ring containing A.sup.1, B.sup.1,
D.sup.1, and E.sup.1 are other than H. In some embodiments, one
R.sup.5 on the ring containing A.sup.1, B.sup.1, D.sup.1, and
E.sup.1 is other than H. In some embodiments, one or two R.sup.5 on
the ring containing A.sup.2, B.sup.2, D.sup.2, and E.sup.2 are
other than H. In some embodiments, one R.sup.5 on the ring
containing A.sup.2, B.sup.2, D.sup.2, and E.sup.2 is other than
H.
[0342] In some embodiments, at least one R.sup.5 is selected fom
halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, cycloalkyl, aryl,
hetroaryl, heterocycloalkylalkyl, Cy.sup.1,
--W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1, CN, NO.sub.2, OR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, and S(O).sub.2NR.sup.c1R.sup.d1,
wherein said C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, cycloalkyl,
aryl, hetroaryl, or heterocycloalkylalkyl, is optionally
substituted by 1, 2, 3, 4 or 5 substituents each independently
selected from halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, halosulfanyl, CN, NO.sub.2, SF.sub.5,
OR.sup.a1, SR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1,
C(O)OR.sup.a1, OC(O)R.sup.b1, OC(O)NR.sup.c1R.sup.d1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, or S(O).sub.2NR.sup.c1R.sup.d1.
[0343] In some embodiments, at least one R.sup.5 is selected fom
halo, C.sub.1-6 alkyl, aryl, hetroaryl, heterocycloalkylalkykl, CN,
OR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, and S(O).sub.2NR.sup.c1R.sup.d1,
wherein said C.sub.1-6 alkyl, aryl, hetroaryl, or
heterocycloalkylalkyl, is optionally substituted by 1, 2, 3, 4 or 5
substituents each independently selected from halo, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
halosulfanyl, CN, NO.sub.2, SF.sub.5, OR.sup.a1, SR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, or S(O).sub.2NR.sup.c1R.sup.d1.
[0344] In some embodiments, at least one R.sup.5 is selected fom
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, NR.sup.c1R.sup.d1,
NR.sup.c1C(O)R.sup.b1, NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, and S(O).sub.2NR.sup.c1R.sup.d1.
[0345] In some embodiments, at least one R.sup.5 is Cy.sup.1 or
--W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1.
[0346] In some embodiments, at least one R.sup.5 is Cy.sup.1. In
some embodiments, at least one R.sup.5 on the ring containing
A.sup.1, B.sup.1, D.sup.1, and E.sup.1 is Cy.sup.1. In some other
embodiments, at least one R.sup.5 on the ring containing A.sup.2,
B.sup.2, D.sup.2, and E.sup.2 is Cy.sup.1.
[0347] In some embodiments, at least one R.sup.5 is
--W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1. In some embodiments, at least
one R.sup.5 on the ring containing A.sup.1, B.sup.1, D.sup.1, and
E.sup.1 is --W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1. In some other
embodiments, at least one R.sup.5 on the ring containing A.sup.2,
B.sup.2, D.sup.2, and E.sup.2 is
--W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1.
[0348] In some embodiments, at least one R.sup.5 on the ring
containing A.sup.1, B.sup.1, D.sup.1, and E.sup.1 or on the ring
containing A.sup.2, B.sup.2, D.sup.2, and E.sup.2 is
--W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1 that is selected from
--(CR.sup.1laR.sup.11b).sub.p1-Q.sup.1-Y.sup.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1O(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup-
.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup-
.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup-
.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(O).sub.2(CR.sup.11aR.sup.11b).sub.p2-Q.su-
p.1-Y.sup.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.sup.-
1-Y.sup.1--Z.sup.1,
--NR.sup.eS(O)(CR.sup.11aR.sup.11b).sub.p1-Q.sup.1-Y.sup.1--Z.sup.1,
--S(O)NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup.1--Z.sup.1,
--NR.sup.eS(O).sub.2(CR.sup.11aR.sup.11b).sub.p1-Q.sup.1Y.sup.1--Z.sup.1,
--S(O).sub.2NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup.1--Z.sup.1-
,
NR.sup.eC(O)(CR.sup.11aR.sup.11b).sub.p1-Q.sup.1-Y.sup.1--Z.sup.1,
--C(O)NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup.1--Z.sup.1,
and
NR.sup.eC(O)NR.sup.f(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup.1--Z.sup.1-
.
[0349] In some embodiments, at least one R.sup.5 on the ring
containing A.sup.1, B.sup.1, D.sup.1, and E.sup.1 or on the ring
containing A.sub.2, B.sup.2, D.sup.2, and E.sup.2 is
--(CR.sup.11aR.sup.11b).sub.p1O(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup-
.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup-
.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(O)(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.-
sup.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(O).sub.2(CR.sup.11aR.sup.11b).sub.p2-Q.su-
p.1-Y.sup.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.sup.-
1-Y.sup.1--Z.sup.1,
--NR.sup.eS(O)(CR.sup.11aR.sup.11b).sub.p1-Q.sup.1-Y.sup.1--Z.sup.1,
--S(O)NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup.1--Z.sup.1,
NR.sup.eS(O).sub.2(CR.sup.11aR.sup.11b).sub.p1-Q.sup.1-Y.sup.1--Z.sup.1,
--S(O).sub.2NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup.1--Z.sup.1-
,
--C(O)NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup.1--Z.sup.1,
or
--NR.sup.eC(O)NR.sup.f(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup.1--Z.sup-
.1.
[0350] In some embodiments, at least one of Q.sup.1, Q.sup.2,
Q.sup.3, Q.sup.4, and Q.sup.5 is selected from cycloalkyl and
heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5
substituents independently selected from halo, CN, NO.sub.2, OH,
C.sub.1-6 alkyl, C.sub.1-6haloalkyl, C.sub.2-8alkoxyalkyl,
C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy, C.sub.2-8 alkoxyalkoxy,
cycloalkyl, heterocycloalkyl, C(O)OR.sup.a, C(O)NR.sup.cR.sup.d,
amino, C.sub.1-6 alkylamino and C.sub.2-8 dialkylamino.
[0351] In some embodiments, Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, and
Q.sup.5 are each, independently, selected from cycloalkyl and
heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5
substituents independently selected from halo, CN, NO.sub.2, OH,
C.sub.1-6 alkyl, C.sub.1-6haloalkyl, C.sub.2-8alkoxyalkyl,
C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy, C.sub.2-8 alkoxyalkoxy,
cycloalkyl, heterocycloalkyl, C(O)OR.sup.a, C(O)NR.sup.cR.sup.d,
amino, C.sub.1-6 alkylamino and C.sub.2-8 dialkylamino.
[0352] In some embodiments, at least one of Q.sup.1, Q.sup.2,
Q.sup.3, Q.sup.4, and Q.sup.5 is selected from aryl and heteroaryl,
each optionally substituted by 1, 2, 3, 4, or 5 substituents
independently selected from halo, CN, NO.sub.2, OH, C.sub.1-6
alkyl, C.sub.1-6haloalkyl, C.sub.2-8alkoxyalkyl, C.sub.1-6alkoxy,
C.sub.1-6haloalkoxy, C.sub.2-8 alkoxyalkoxy, cycloalkyl,
heterocycloalkyl, C(O)OR.sup.a, C(O)NR.sup.cR.sup.d, amino,
C.sub.1-6 alkylamino and C.sub.2-8 dialkylamino.
[0353] In some embodiments, at least one of Q.sup.1, Q.sup.2,
Q.sup.3, Q.sup.4, and Q.sup.5 is aryl optionally substituted by 1,
2, 3, 4, or 5 substituents independently selected from halo, CN,
NO.sub.2, OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-8
alkoxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy, C.sub.2-8
alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(O)OR.sup.a,
C(O)NR.sup.cR.sup.d, amino, C.sub.1-6 alkylamino and
C.sub.2-8dialkylamino.
[0354] In some embodiments, at least one of Q.sup.1, Q.sup.2,
Q.sup.3, Q.sup.4, and Q.sup.5 is heteroaryl optionally substituted
by 1, 2, 3, 4, or 5 substituents independently selected from halo,
CN, NO.sub.2, OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-8
alkoxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy, C.sub.2-8
alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(O)OR.sup.a,
C(O)NR.sup.cR.sup.d, amino, C.sub.1-6 alkylamino and
C.sub.2-8dialkylamino.
[0355] In some embodiments, at least one Q.sup.1 is selected from
aryl and heteroaryl, each optionally substituted by 1, 2, 3, 4, or
5 substituents independently selected from halo, CN, NO.sub.2, OH,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-8 alkoxyalkyl,
C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy, C.sub.2-8 alkoxyalkoxy,
cycloalkyl, heterocycloalkyl, C(O)OR.sup.a, C(O)NR.sup.cR.sup.d,
amino, C.sub.1-6 alkylamino and C.sub.2-8dialkylamino.
[0356] In some embodiments, each Q.sup.1 is independently selected
from aryl and heteroaryl, each optionally substituted by 1, 2, 3,
4, or 5 substituents independently selected from halo, CN,
NO.sub.2, OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-8
alkoxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy, C.sub.2-8
alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(O)OR.sup.a,
C(O)NR.sup.cR.sup.d, amino, C.sub.1-6 alkylamino and
C.sub.2-8dialkylamino. In some further embodiments, each Q.sup.1 is
independently selected from such optionally substituted cycloalkyl.
In other further embodiments, each Q.sup.1 is independently
selected from such optionally substituted heterocycloalkyl.
[0357] In some embodiments, at least one Q.sup.1 is heteroaryl
optionally substituted by 1, 2, 3, 4, or 5 substituents
independently selected from halo, CN, NO.sub.2, OH, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.2-8 alkoxyalkyl, C.sub.1-6
alkoxy, C.sub.1-6haloalkoxy, C.sub.2-8 alkoxyalkoxy, cycloalkyl,
heterocycloalkyl, C(O)OR.sup.a, C(O)NR.sup.cR.sup.d, amino,
C.sub.1-6 alkylamino and C.sub.2-8dialkylamino.
[0358] In some embodiments, each Q.sup.1 is independently
heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents
independently selected from halo, CN, NO.sub.2, OH, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.2-8 alkoxyalkyl, C.sub.1-6
alkoxy, C.sub.1-6haloalkoxy, C.sub.2-8 alkoxyalkoxy, cycloalkyl,
heterocycloalkyl, C(O)OR.sup.a, C(O)NR.sup.cR.sup.d, amino,
C.sub.1-6 alkylamino and C.sub.2-8dialkylamino. In some further
embodiments, each Q.sup.1 is independently selected from such
optionally substituted cycloalkyl. In other further embodiments,
each Q.sup.1 is independently selected from such optionally
substituted heterocycloalkyl.
[0359] In some embodiments, at least one Q.sup.1 is aryl optionally
substituted by 1, 2, 3, 4, or 5 substituents independently selected
from halo, CN, NO.sub.2, OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.2-8 alkoxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy,
C.sub.2-8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(O)OR.sup.a,
C(O)NR.sup.cR.sup.d, amino, C.sub.1-6 alkylamino and
C.sub.2-8dialkylamino.
[0360] In some embodiments, each Q.sup.1 is independently aryl
optionally substituted by 1, 2, 3, 4, or 5 substituents
independently selected from halo, CN, NO.sub.2, OH, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.2-8 alkoxyalkyl, C.sub.1-6
alkoxy, C.sub.1-6haloalkoxy, C.sub.2-8 alkoxyalkoxy, cycloalkyl,
heterocycloalkyl, C(O)OR.sup.a, C(O)NR.sup.cR.sup.d, amino,
C.sub.1-6 alkylamino and C.sub.2-8dialkylamino. In some further
embodiments, each Q.sup.1 is independently selected from such
optionally substituted cycloalkyl. In other further embodiments,
each Q.sup.1 is independently selected from such optionally
substituted heterocycloalkyl.
[0361] In some embodiments, at least one Q.sup.1 is selected from
cycloalkyl and heterocycloalkyl, each optionally substituted by 1,
2, 3, 4, or 5 substituents independently selected from halo, CN,
NO.sub.2, OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-8
alkoxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy, C.sub.2-8
alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(O)OR.sup.a,
C(O)NR.sup.cR.sup.d, amino, C.sub.1-6 alkylamino and
C.sub.2-8dialkylamino.
[0362] In some embodiments, each Q.sup.1 is independently selected
from cycloalkyl and heterocycloalkyl, each optionally substituted
by 1, 2, 3, 4, or 5 substituents independently selected from halo,
CN, NO.sub.2, OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-8
alkoxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy, C.sub.2-8
alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(O)OR.sup.a,
C(O)NR.sup.cR.sup.d, amino, C.sub.1-6 alkylamino and
C.sub.2-8dialkylamino. In some further embodiments, each Q.sup.1 is
independently selected from such optionally substituted cycloalkyl.
In other further embodiments, each Q.sup.1 is independently
selected from such optionally substituted heterocycloalkyl.
[0363] In some embodiments, at least one Q.sup.1 is selected from
heterocycloalkyl optionally substituted by 1, 2, 3, 4, or 5
substituents independently selected from halo, CN, NO.sub.2, OH,
C.sub.1-6 alkyl, C.sub.1-6haloalkyl, C.sub.2-8 alkoxyalkyl,
C.sub.1-6alkoxy, C.sub.1-6haloalkoxy, C.sub.2-8 alkoxyalkoxy,
cycloalkyl, heterocycloalkyl, C(O)OR.sup.a, C(O)NR.sup.cR.sup.d,
amino, C.sub.1-6 alkylamino and C.sub.2-8dialkylamino.
[0364] In some embodiments, each Q.sup.1 is independently selected
from heterocycloalkyl optionally substituted by 1, 2, 3, 4, or 5
substituents independently selected from halo, CN, NO.sub.2, OH,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-8 alkoxyalkyl,
C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy, C.sub.2-8 alkoxyalkoxy,
cycloalkyl, heterocycloalkyl, C(O)OR.sup.a, C(O)NR.sup.cR.sup.d,
amino, C.sub.1-6 alkylamino and C.sub.2-8dialkylamino.
[0365] In some embodiments, at least one Q.sup.1 is selected from
cycloalkyl optionally substituted by 1, 2, 3, 4, or 5 substituents
independently selected from halo, CN, NO.sub.2, OH, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.2-8 alkoxyalkyl, C.sub.1-6
alkoxy, C.sub.1-6haloalkoxy, C.sub.2-8 alkoxyalkoxy, cycloalkyl,
heterocycloalkyl, C(O)OR.sup.a, C(O)NR.sup.cR.sup.d, amino,
C.sub.1-6 alkylamino and C.sub.2-8dialkylamino.
[0366] In some embodiments, each Q.sup.1 is independently selected
from cycloalkyl optionally substituted by 1, 2, 3, 4, or 5
substituents independently selected from halo, CN, NO.sub.2, OH,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-8 alkoxyalkyl,
C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy, C.sub.2-8 alkoxyalkoxy,
cycloalkyl, heterocycloalkyl, C(O)OR.sup.a, C(O)NR.sup.cR.sup.d,
amino, C.sub.1-6 alkylamino and C.sub.2-8dialkylamino.
[0367] In some embodiments, each Q.sup.1 is independently selected
from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl,
pyrrolidinyl, piperidinyl, and piperazinyl, each optionally
substituted by 1, 2, 3, 4, or 5 substituents independently selected
from halo, CN, NO.sub.2, OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.2-8 alkoxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy,
C.sub.2-8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(O)OR.sup.a,
C(O)NR.sup.cR.sup.d, amino, C.sub.1-6 alkylamino and
C.sub.2-8dialkylamino. In some further embodiments, each Q.sup.1 is
independently selected from cyclopropyl, cyclobutyl, cyclopentyl,
and cyclohexyl, each optionally substituted by 1, 2, 3, 4, or 5
substituents independently selected from halo, CN, NO.sub.2, OH,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-8 alkoxyalkyl,
C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy, C.sub.2-8 alkoxyalkoxy,
cycloalkyl, heterocycloalkyl, C(O)OR.sup.a, C(O)NR.sup.cR.sup.d,
amino, C.sub.1-6 alkylamino and C.sub.2-8dialkylamino. In other
further embodiments, each Q.sup.1 is independently selected from
azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, each
optionally substituted by 1, 2, 3, 4, or 5 substituents
independently selected from halo, CN, NO.sub.2, OH, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.2-8 alkoxyalkyl, C.sub.1-6
alkoxy, C.sub.1-6haloalkoxy, C.sub.2-8 alkoxyalkoxy, cycloalkyl,
heterocycloalkyl, C(O)OR.sup.a, C(O)NR.sup.cR.sup.d, amino,
C.sub.1-6 alkylamino and C.sub.2-8dialkylamino. In some
embodiments, at least one Q.sup.1 is selected from such optionally
substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl.
[0368] In some embodiments, each Q.sup.1 is independently selected
from cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl,
piperidinyl, and piperazinyl, each optionally substituted by 1, 2,
3, 4, or 5 substituents independently selected from halo, CN,
NO.sub.2, OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-8
alkoxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy, C.sub.2-8
alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(O)OR.sup.a,
C(O)NR.sup.cR.sup.d, amino, C.sub.1-6 alkylamino and
C.sub.2-8dialkylamino. In some embodiments, at least one Q.sup.1 is
selected from such optionally substituted cyclobutyl, cyclopentyl,
cyclohexyl, pyrrolidinyl, piperidinyl, or piperazinyl.
[0369] In some embodiments, each Q.sup.1 is independently selected
from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl,
pyrrolidinyl, and piperidinyl, each optionally substituted by 1, 2,
3, 4, or 5 substituents independently selected from halo, CN,
NO.sub.2, OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-8
alkoxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy, C.sub.2-8
alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(O)OR.sup.a,
C(O)NR.sup.cR.sup.d, amino, C.sub.1-6 alkylamino and
C.sub.2-8dialkylamino. In some embodiments, at least one Q.sup.1 is
selected from such optionally substituted cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, or
piperidinyl.
[0370] In some embodiments, each Q.sup.1 is independently selected
from pyrrolidinyl, piperidinyl, and piperazinyl, each optionally
substituted by 1, 2, 3, 4, or 5 substituents independently selected
from halo, CN, NO.sub.2, OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.2-8 alkoxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy,
C.sub.2-8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(O)OR.sup.a,
C(O)NR.sup.cR.sup.d, amino, C.sub.1-6 alkylamino and
C.sub.2-8dialkylamino. In some embodiments, at least one Q.sup.1 is
selected from such optionally substituted pyrrolidinyl,
piperidinyl, or piperazinyl.
[0371] In some embodiments, each Q.sup.1 is independently selected
from pyrrolidinyl, and piperidinyl, each optionally substituted by
1, 2, 3, 4, or 5 substituents independently selected from halo, CN,
NO.sub.2, OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-8
alkoxyalkyl, C.sub.1-6alkoxy, C.sub.1-6haloalkoxy, C.sub.2-8
alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(O)OR.sup.a,
C(O)NR.sup.cR.sup.d, amino, C.sub.1-6 alkylamino and C.sub.2-8
dialkylamino. In some embodiments, at least one Q.sup.1 is selected
from such optionally substituted pyrrolidinyl or piperidinyl.
[0372] In some embodiments, at least one R.sup.5 is
--W.sup.6-Q.sup.1-Y.sup.1--Z.sup.1.
[0373] In some embodiments, at least one R.sup.5 is
--(CR.sup.11aR.sup.11b).sup.p1S(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup-
.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(O)(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.-
sup.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(O).sub.2(CR.sup.11aR.sup.11b).sub.p2-Q.su-
p.1-Y.sup.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(O)NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.-
sup.1-Y.sup.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p2NR.sup.eS(O)(CR.sup.11aR.sup.11b).sub.p1-Q.-
sup.1-Y.sup.1--Z.sup.1,
(CR.sup.11aR.sup.11b).sub.p1S(O).sub.2NR.sup.e(CR.sup.11aR.sup.11b).sub.p-
2-Q.sup.1-Y.sup.1--Z.sup.1, or
--(CR.sup.11aR.sup.11b).sub.p2NR.sup.eS(O).sub.2(CR.sup.11aR.sup.11b).sub-
.p1-Q.sup.1-Y.sup.1--Z.sup.1.
[0374] In some embodiments, at least one Y.sup.1 is selected from
absent,
(CR.sup.12a.sub.R.sup.12b).sub.p3O(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3S(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3NR.sup.e(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3C(O)(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3C(O)NR.sup.e(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3S(O).sub.2(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3S(O).sub.2NR.sup.e(CR.sup.12aR.sup.12b).sub.p-
4,
[0375] In some embodiments, each Y.sup.1 is independently selected
from absent,
(CR.sup.12aR.sup.12b).sub.p3O(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3S(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3NR.sup.e(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3C(O)(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3C(O)NR.sup.e(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3S(O).sub.2(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3S(O).sub.2NR.sup.e(CR.sup.12aR.sup.12b).sub.p-
4, and
(CR.sup.12aR.sup.12b).sub.p3NR.sup.eC(O)NR.sup.f(CR.sup.12aR.sup.12-
b).sub.p4.
[0376] In some embodiments, at least one Z.sup.1 is selected from
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, aryl, cycloalkyl, heteroaryl
and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or
5 substituents independently selected from halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO.sub.2, OR.sup.a,
SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NRCR.sup.d,
NR.sup.cC(O)R.sup.d, NR.sup.cC(O)OR.sup.a,
NR.sup.cS(O).sub.2R.sup.b,
NR.sup.cS(O).sub.2S(O).sub.2NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d.
[0377] In some embodiments, each Z.sup.1 is independently selected
from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, aryl, cycloalkyl,
heteroaryl and heterocycloalkyl, each optionally substituted by 1,
2, 3, 4, or 5 substituents independently selected from halo,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN,
NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d,
C(O)OR.sup.a, OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NRCR.sup.d,
NR.sup.cC(O)R.sup.d, NR.sup.cC(O)OR.sup.a,
NR.sup.cS(O).sub.2R.sup.b,
NR.sup.cS(O).sub.2S(O).sub.2NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d.
[0378] In some embodiments, at least one Z.sup.1 is selected from
aryl, cycloalkyl, heteroaryl and heterocycloalkyl, each optionally
substituted by 1, 2, 3, 4, or 5 substituents independently selected
from halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, CN, NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b,
C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NRCR.sup.d, NR.sup.cC(O)R.sup.d,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a,
NR.sup.cS(O).sub.2R.sup.b,
NR.sup.cS(O).sub.2S(O).sub.2NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d.
[0379] In some embodiments, each Z.sup.1 is independently selected
from aryl, cycloalkyl, heteroaryl and heterocycloalkyl, each
optionally substituted by 1, 2, 3, 4, or 5 substituents
independently selected from halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, aryl, cycloalkyl,
heteroaryl, heterocycloalkyl, CN, NO.sub.2, OR.sup.a, SR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.d,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a,
NR.sup.cS(O).sub.2R.sup.b,
NR.sup.cS(O).sub.2S(O).sub.2NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d.
[0380] In some embodiments, at least one Z.sup.1 is selected from
aryl, cycloalkyl, heteroaryl and heterocycloalkyl, each optionally
substituted by 1, 2, 3, 4, or 5 substituents independently selected
from halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, CN, NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b,
C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.d,
NR.sup.cC(O)OR.sup.a, NR.sup.cS(O).sub.2R.sup.b,
NR.sup.cS(O).sub.2S(O).sub.2NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d.
[0381] In some embodiments, each Z.sup.1 is independently selected
from aryl, cycloalkyl, heteroaryl and heterocycloalkyl, each
optionally substituted by 1, 2, 3, 4, or 5 substituents
independently selected from halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, aryl, cycloalkyl,
heteroaryl, heterocycloalkyl, CN, NO.sub.2, OR.sup.a, SR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.d,
NR.sup.cC(O)OR.sup.a, NR.sup.cS(O).sub.2R.sup.b,
NR.sup.cS(O).sub.2S(O).sub.2NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d.
[0382] In some embodiments, at least one Z.sup.1 is selected from
heteroaryl and heterocycloalkyl, each optionally substituted by 1,
2, 3, 4, or 5 substituents independently selected from halo,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN,
NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d,
C(O)OR.sup.a, OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.d, NR.sup.cC(O)OR.sup.a,
NR.sup.cS(O).sub.2R.sup.b,
NR.sup.cS(O).sub.2S(O).sub.2NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d.
[0383] In some embodiments, each Z.sup.1 is independently selected
from heteroaryl and heterocycloalkyl, each optionally substituted
by 1, 2, 3, 4, or 5 substituents independently selected from halo,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN,
NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d,
C(O)OR.sup.a, OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.d, NR.sup.cC(O)OR.sup.a,
NR.sup.cS(O).sub.2R.sup.b,
NR.sup.cS(O).sub.2S(O).sub.2NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d.
[0384] In some embodiments, at least one Z.sup.1 is selected from
aryl and heteroaryl, each optionally substituted by 1, 2, 3, 4, or
5 substituents independently selected from halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO.sub.2, OR.sup.a,
SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.d, NR.sup.cC(O)OR.sup.a,
NR.sup.cS(O).sub.2R.sup.b,
NR.sup.cS(O).sub.2S(O).sub.2NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d.
[0385] In some embodiments, each Z.sup.1 is independently selected
from aryl and heteroaryl, each optionally substituted by 1, 2, 3,
4, or 5 substituents independently selected from halo, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO.sub.2,
OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.d, NR.sup.cC(O)OR.sup.a,
NR.sup.cS(O).sub.2R.sup.b,
NR.sup.cS(O).sub.2S(O).sub.2NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d.
[0386] In some embodiments, each R.sup.6 is, independently, H,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
S(O)R.sup.b1, S(O).sub.2R.sup.b1, or S(O).sub.2NR.sup.c1R.sup.d1.
In some further embodiments, each R.sup.6 is, independently, H,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, or C.sub.1-6
haloalkyl. In yet furether embodiments, each R.sup.6 is,
independently, H or C.sub.1-6 alkyl. In still furether embodiments,
each R.sup.6 is H or C.sub.1-3 alkyl.
[0387] In some embodiments, each R.sup.6 is, independently, H,
C.sub.1-3 alkyl, C.sub.2-3 alkenyl, C.sub.2-3 alkynyl, or C.sub.1-3
haloalkyl. In some furether embodiments, each R.sup.6 is,
independently, H, C.sub.1-3 alkyl, or C.sub.1-3 haloalkyl. In some
furether embodiments, each R.sup.6 is, independently, C.sub.1-3
alkyl.
[0388] In some embodiments, each R.sup.6 is, independently, H or
methyl. In some embodiments, each R.sup.6 is H. In some other
embodiments, one R.sup.6 is methyl.
[0389] In some embodiments, R.sup.11a, R.sup.11b, R.sup.12a, and
R.sup.12b are each, independently, selected from H, halo, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
CN, NO.sub.2, OR.sup.a1, SR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c2C(O)OR.sup.a1,
C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, and S(O).sub.2NR.sup.c1R.sup.d1,
wherein each of said C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6alkynyl, or C.sub.1-6 haloalkyl, is optionally substituted
by 1, 2, 3, 4, or 5 substituents independently selected from halo,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, halosulfanyl, CN, NO.sub.2, OR.sup.a1, SR.sup.a1,
SF.sub.5, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
OC(O)R.sup.b1, OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1,
NR.sup.c1C(O)R.sup.b1, NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1C(O)OR.sup.a1, C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.bl,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, and S(O).sub.2NR.sup.c1R.sup.d1.
[0390] In some embodiments, R.sup.11a, R.sup.11b, R.sup.12a, and
R.sup.12b are each, independently, selected from H, halo, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
CN, NO.sub.2, OH, C.sub.1-6alkoxy, C.sub.1-6haloalkoxy, C.sub.2-8
alkoxyalkyl, cycloalkyl, heterocycloalkyl, C(O)OR.sup.a1,
C(O)NR.sup.c1R.sup.d1, amino, C.sub.1-6 alkylamino and C.sub.2-8
dialkylamino.
[0391] In some embodiments, R.sup.11a, R.sup.11b, R.sup.12a, and
R.sup.12b are each, independently, selected from H, and C.sub.1-6
alkyl. In some further embodiments, at least one of R.sup.11a,
R.sup.11b, R.sup.12a, and R.sup.12b is selected from C.sub.1-6
alkyl.
[0392] In some embodiments, R.sup.11a, R.sup.11b, R.sup.12a, and
R.sup.12 are each, independently, selected from H and C.sub.1-3
alkyl. In some embodiments, R.sup.11a, R.sup.11b, R.sup.12a, and
R.sup.12b are each, independently, selected from H and
CH.sub.3.
[0393] In some embodiments, each R.sup.13 is independently selected
from H, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6haloalkyl, CN, NO.sub.2, OR.sup.a1, SR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, and S(O).sub.2NR.sup.c1R.sup.d1,
wherein each of said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, or C.sub.1-6 haloalkyl, is optionally substituted by 1, 2,
3, 4, or 5 substituents independently selected from halo, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
halosulfanyl, CN, NO.sub.2, OR.sup.a1, SR.sup.a1, SF.sub.5,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g1)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, and S(O).sub.2NR.sup.c1R.sup.d1,
P(R.sup.f1).sub.2, P(OR.sup.e1).sub.2.
[0394] In some embodiments, each R.sup.13 is independently selected
from H, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, CN, NO.sub.2, OH, C.sub.1-6alkoxy,
C.sub.1-6haloalkoxy, C.sub.2-8alkoxyalkyl, cycloalkyl,
heterocycloalkyl, C(O)OR.sup.a1, C(O)NR.sup.c1R.sup.d1, amino,
C.sub.1-6 alkylamino and C.sub.2-8dialkylamino. In some further
embodiments, each R.sup.13 is H or C.sub.1-6 alkyl. In yet further
embodiments, each R.sup.13 is H.
[0395] In some embodiments, each p1 is, independently, 0 or 1. In
some other embodiments, each p1 is, independently, 1 or 2.
[0396] In some embodiments, each p2 is, independently, 0 or 1. In
some other embodiments, each p2 is, independently, 1 or 2.
[0397] In some embodiments, each p3 is, independently, 0 or 1. In
some other embodiments, each p3 is, independently, 1 or 2.
[0398] In some embodiments, each p4 is, independently, 0 or 1. In
some other embodiments, each p4 is, independently, 1 or 2.
[0399] In some embodiments, each q1 is 1. In some other
embodiments, each q1 is 2.
[0400] In some embodiments, each q2 is 1. In some other
embodiments, each q2 is 2.
[0401] In some embodiments, each n is, independently, 1 or 2. In
some embodiments, n is 1. In some embodiments, n is 2.
[0402] In some embodiments, n is 3.
[0403] In some embodiments, each m is 0 or 1. In some embodiments,
m is 0. In some embodiments, m is 1.
[0404] In some embodiments, m is 2.
[0405] In some embodiments, t is 1.
[0406] In some embodiments, t is 2.
[0407] In some embodiments, t is 3.
[0408] In some embodiments, --(CR'R'').sub.t-- is --CH.sub.2--,
--CH(CH.sub.3)--, --C(CH.sub.3).sub.2--, --(CH.sub.2).sub.2--,
--[CH(CH.sub.3)].sub.2--, --(CH.sub.2).sub.3-- or
--[CH(CH.sub.3)].sub.3--.
[0409] In some embodiments, --(CR'R'').sub.t-- is --CH.sub.2--,
--CH(CH.sub.3)--, --(CH.sub.2).sub.2--, or
--(CH.sub.2).sub.3--.
[0410] In some embodiments, X.sup.1 is CH; X.sup.2 is N; X.sup.3 is
CR.sup.3; R.sup.3 is halo; R.sup.4 is H or C.sub.1-3 alkyl; and at
least one R.sup.5 is selected fom C(O)NR.sup.c1R.sup.d1,
C(O)OR.sup.a1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1, Cy.sup.1,
and --W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1. In some further
embodiments, at least one R.sup.5 is
--W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1. In some further embodiments, at
least one R.sup.5 on the ring containing A.sup.1, B.sup.1, D.sup.1,
and E.sup.1 is --W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1. In some other
embodiments, at least one R.sup.5 on the ring containing A.sup.2,
B.sup.2, D.sup.2, and E.sup.2 is
--W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1. In further embodiments, each
Q.sup.1 is independently selected from cycloalkyl and
heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5
substituents independently selected from halo, CN, NO.sub.2, OH,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-8alkoxyalkyl,
C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.2-8 alkoxyalkoxy,
cycloalkyl, heterocycloalkyl, C(O)OR.sup.a, C(O)NR.sup.cR.sup.d,
amino, C.sub.1-6 alkylamino and C.sub.2-8 dialkylamino. In yet
further embodiments, each Q.sup.1 is independently selected from
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl,
pyrrolidinyl, piperidinyl, and piperazinyl, each optionally
substituted by 1, 2, 3, 4, or 5 substituents independently selected
from halo, CN, NO.sub.2, OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.2-8 alkoxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy,
C.sub.2-8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(O)OR.sup.a,
C(O)NR.sup.cR.sup.d, amino, C.sub.1-6 alkylamino and C.sub.2-8
dialkylamino.
[0411] In some embodiments, the ring containing A.sup.1, B.sup.1,
D.sup.1, and E.sup.1 is a 6-membered aromatic ring; B.sup.1,
D.sup.1, and E.sup.1 are each, independently, CR.sup.5 or N;
A.sup.1 is CR.sup.2 or N; and at least one of A.sup.1, B.sup.1,
D.sup.1, and E.sup.1 is N.
[0412] In some embodiments, the ring containing A.sup.2, B.sup.2,
D.sup.2, and E.sup.2 is a 6-membered aromatic ring; B.sup.2,
D.sup.2, and E.sup.2 are each, independently, CR.sup.5 or N;
A.sup.2 is CR.sup.2 or N; and at least one of A.sup.2, B.sup.2,
D.sup.2, and E.sup.2 is N.
[0413] In some embodiments, the ring containing A.sup.1, B.sup.1,
D.sup.1, and E.sup.1 is a 6-membered aromatic ring; B.sup.1,
D.sup.1, and E.sup.1 are each, independently, CR.sup.5 or N;
A.sup.1 is CR.sup.2 or N; the ring containing A.sup.2, B.sup.2,
D.sup.2, and E.sup.2 is a 6-membered aromatic ring; B.sup.2,
D.sup.2, and E.sup.2 are each, independently, CR.sup.5 or N; and
A.sup.2 is CR.sup.2 or N. In some further embodiments, at least one
of A.sup.1, B.sup.1, D.sup.1, and E.sup.1 is N. In other further
embodiments, at least one of A.sup.2, B.sup.2, D.sup.2, and E.sup.2
is N.
[0414] In some embodiments, the ring containing A.sup.1, B.sup.1,
D.sup.1, and E.sup.1 is a pyridine ring, wherein said pyridine ring
is optionally substituted by R.sup.2 and optionally by 1 or 2
R.sup.5; and the ring containing A.sup.2, B.sup.2, D.sup.2, and
E.sup.2 is a benzene ring, wherein said benzene ring optionally
substituted by R.sup.2 and optionally by 1, 2, or 3 R.sup.5.
[0415] In some embodiments, the ring containing A.sup.1, B.sup.1,
D.sup.1, and E.sup.1 is a pyridine ring, wherein said pyridine ring
is optionally substituted by 1 or 2 R.sup.5; and the ring
containing A.sup.2, B.sup.2, D.sup.2, and E.sup.2 is a benzene
ring, wherein said benzene ring substituted by
--W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1 and optionally substituted by 1
or 2 R.sup.5. In further embodiments, at least one Q.sup.1 is
selected from cycloalkyl and heterocycloalkyl, each optionally
substituted by 1, 2, 3, 4, or 5 substituents independently selected
from halo, CN, NO.sub.2, OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.2-8 alkoxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy,
C.sub.2-8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(O)OR.sup.a,
C(O)NR.sup.cR.sup.d, amino, C.sub.1-6 alkylamino and C.sub.2-8
dialkylamino. In yet further embodiments, at least one Q.sup.1 is
selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, each
optionally substituted by 1, 2, 3, 4, or 5 substituents
independently selected from halo, CN, NO.sub.2, OH, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.2-8 alkoxyalkyl, C.sub.1-6
alkoxy, C.sub.1-6haloalkoxy, C.sub.2-8 alkoxyalkoxy, cycloalkyl,
heterocycloalkyl, C(O)OR.sup.a, C(O)NR.sup.cR.sup.d, amino,
C.sub.1-6 alkylamino and C.sub.2-8 dialkylamino.
[0416] In some embodiments, the compound of Formula I of the
present invention is a compound of Formula II:
##STR00004##
[0417] In some embodiments of the compounds of Formula II, R.sup.1
is selected from H and C.sub.1-3 alkyl; each R.sup.2 is,
independently, selected from H, F, Cl, CH.sub.3, and CF.sub.3;
R.sup.3 is selected from halo, C.sub.1-3 alkyl, and C.sub.1-3
haloalkyl; R.sup.4 is H or C.sub.1-3 alkyl; and R' and R'' are
each, independently, H or C.sub.1-3 alkyl.
[0418] In some embodiments of the compounds of Formula II, R.sup.1
is selected from H and C.sub.1-3 alkyl; each R.sup.2 is,
independently, selected from H, F, Cl, CH.sub.3, and CF.sub.3;
R.sup.3 is selected from halo, C.sub.1-3 alkyl, and C.sub.1-3
haloalkyl; R.sup.4 is H or methyl; and R' and R'' are each,
independently, H or methyl.
[0419] In some embodiments of the compounds of Formula II, R.sup.1
is selected from H and methyl; each R.sup.2 is H; R.sup.3 is halo;
R.sup.4 is H or methyl; and R' and R'' are each, independently, H
or methyl.
[0420] In some embodiments, the compound of Formula I of the
present invention is a compound of formula IIa:
##STR00005## [0421] In some embodiments of the compounds of Formula
II or IIa:
[0422] R' and R'' are each, independently, selected from H and
C.sub.1-3 alkyl;
[0423] R' is selected from H and C.sub.1-3 alkyl;
[0424] R.sup.3 is selected from halo, C.sub.1-3 alkyl, and
C.sub.1-3 haloalkyl; and
[0425] R.sup.4 is H or C.sub.1-3 alkyl; [0426] In some embodiments
of the compounds of Formula II or IIa:
[0427] R' and R'' are each, independently, selected from H and
methyl;
[0428] R.sup.1 is H and;
[0429] R.sup.3 is halo; and
[0430] R.sup.4 is H. [0431] In some embodiments of the compounds of
Formula II or IIa:
[0432] R' and R'' are both H;
[0433] R.sup.1 is H and;
[0434] R.sup.3 is Cl; and
[0435] R.sup.4 is H.
[0436] In some embodiments, the compound of Formula I of the
present invention is a compound of Formula IIb:
##STR00006## [0437] In some embodiments of the compounds of Formula
IIb:
[0438] R' and R'' are each, independently, selected from H and
C.sub.1-3 alkyl;
[0439] R.sup.3 is selected from halo, C.sub.1-3 alkyl, and
C.sub.1-3 haloalkyl; and
[0440] R.sup.4 is H or C.sub.1-3 alkyl; [0441] In some embodiments
of the compounds of Formula II or IIa:
[0442] R' and R'' are each, independently, selected from H and
methyl;
[0443] R.sup.3 is halo; and
[0444] R.sup.4 is H. [0445] In some embodiments of the compounds of
Formula II or IIa:
[0446] R' and R'' are both H;
[0447] R.sup.3 is Cl; and
[0448] R.sup.4 is H.
[0449] In some embodiments of the compounds of Formula II, IIa, or
IIb, each R.sup.5 is, independently, selected from H, halo,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, CN, NO.sub.2, SF.sub.5,
Cy.sup.1, --W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1, OR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O).sub.2R.sup.b1, and S(O).sub.2NR.sup.c1R.sup.d1. In some
further embodiments, each R.sup.5 is, independently, selected from
H, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, CN, NO.sub.2,
SF.sub.5, OR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1,
C(O)OR.sup.a1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O).sub.2R.sup.b1, and S(O).sub.2NR.sup.c1R.sup.d1. In yet further
embodiments, each R.sup.5 is independently selected from H, halo,
C.sub.1-6 alkyl, C.sub.1-3 haloalkyl, CN, NO.sub.2, OR.sup.a1 ,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)NR.sup.c1R.sup.d1,
NR.sup.c1S(O).sub.2R.sup.b1, NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1,
S(O)R.sup.b1, S(O).sub.2R.sup.b1, and
S(O).sub.2NR.sup.c1R.sup.d1.
[0450] In some embodiments of the compounds of Formula II, IIa, or
IIb, L.sup.1 and L.sup.2 are each, independently, selected from a
bond, --(CR.sup.7R.sup.8).sub.n--,
--O--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.,
--S--(CR.sup.7R.sup.8)--CR.sup.10.dbd.,
--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--O--, --(CR.sup.7R.sup.8).sub.m--S--,
--(CR.sup.7R.sup.8).sub.m--S(O)--,
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2--,
--(CR.sup.7R.sup.8).sub.m--C(O)--, --C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--C(O)O--,
--(CR.sup.7R.sup.8).sub.mNR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--OC(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9C(O)O--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--S(O).sub.2NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--S(O)NR.sup.9--, and
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2NR.sup.9--.
[0451] In some embodiments of the compounds of Formula II, IIa, or
IIb, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.CR.sup.10--(CR.sup.7R.sup.8).sub-
.m-- or --(CR.sup.7R.sup.8).sub.m--(CR.sup.7R.sup.8).sub.n--.
[0452] In some embodiments of the compounds of Formula II, IIa, or
IIb, L.sup.1 and L.sup.2 together form --(CR.sup.7R.sup.8)--,
--(CR.sup.7R.sup.8).sub.2--, or --(CR.sup.7R.sup.8).sub.3--. In
some further embodiments, IIa, or IIb, L.sup.1 and L.sup.2 together
form --CH.sub.2--, --(CH.sub.2).sub.2--, or
--(CH.sub.2).sub.3--.
[0453] In some embodiments of the compounds of Formula II, IIa, or
IIb, one of L.sup.1 and L.sup.2 is selected from
--(CR.sup.7R.sup.8).sub.m--O--, --(CR.sup.7R.sup.8).sub.m--S--,
--(CR.sup.7R.sup.8).sub.m--S(O)--, and
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2--; and the other is selected
from a bond, --(CR.sup.7R.sup.8).sub.n--,
--(CR.sup.7R.sup.8).sub.m--O--, --(CR.sup.7R.sup.8).sub.m--S--,
--(CR.sup.7R.sup.8).sub.m--S(O)--, and
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2--.
[0454] In some embodiments of the compounds of Formula II, IIa, or
IIb:
[0455] L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.t1--S--, --(CR.sup.7R.sup.8).sub.t1--O--,
--(CR.sup.7R.sup.8).sub.t1--S(O)--,
--(CR.sup.7R.sup.8).sub.t1--S(O).sub.2--,
--S--(CR.sup.7R.sup.8).sub.t2--S--,
--O--(CR.sup.7R.sup.8).sub.t2--S--,
--O--(CR.sup.7R.sup.8).sub.t2--S(O)--,
--O--(CR.sup.7R.sup.8).sub.t2--S(O).sub.2--, --S--S--,
--(CR.sup.7R.sup.8).sub.t3--O--(CR.sup.7R.sup.8).sub.t4--,
--(CR.sup.7R.sup.8).sub.t3--S--(CR.sup.7R.sup.8).sub.t4--,
--(CR.sup.7R.sup.8).sub.t3S(O)--(CR.sup.7R.sup.8).sub.t4--, or
--(CR.sup.7R.sup.8).sub.t3--S(O).sub.2--(CR.sup.7R.sup.8).sub.t4--;
[0456] t1 is 1, 2, or 3;
[0457] t2 is 1 2, 3, or 4;
[0458] t3 is 1, 2, or 3; and
[0459] t4 is 1 or 2.
[0460] In some embodiments of the compounds of Formula II, IIa, or
IIb, L.sup.1 and L.sup.2 together form --O--(CR.sup.7R.sup.8)--,
--O--(CR.sup.7R.sup.8).sub.2--, or --O--(CR.sup.7R.sup.8).sub.3--.
In some further embodiments, L.sup.1 and L.sup.2 together form
--O--CH.sub.2--, --O--(CH.sub.2).sub.2--, or
--O--(CH.sub.2).sub.3--.
[0461] In some embodiments of the compounds of Formula II, IIa, or
IIb, L.sup.1 is --(CR.sup.7R.sup.8)--, --(CR.sup.7R.sup.8).sub.2--,
or --(CR.sup.7R.sup.8).sub.3--; and L.sup.2 is --O--.
[0462] In some embodiments of the compounds of Formula II, IIa, or
IIb, L.sup.1 and L.sup.2 together form --O--(CR.sup.7R.sup.8)--O--,
--O--(CR.sup.7R.sup.8).sub.2--O--, or
--O--(CR.sup.7R.sup.8).sub.3--O--.
[0463] In some embodiments of the compounds of Formula II, IIa, or
IIb, L.sup.1 and L.sup.2 together form --(CH.sub.2)--S--,
--(CH.sub.2)--S(O)--, --(CH.sub.2)--S(O).sub.2--,
--(CH.sub.2)--O--, --(CH.sub.2).sub.2--O--,
--(CH.sub.2).sub.3--O--, --O--(CH.sub.2).sub.2--O--,
--O--(CH.sub.2).sub.2--S--, --O--(CH.sub.2).sub.2--S(O)--, or
--O--(CH.sub.2).sub.2--S(O).sub.2--.
[0464] In some embodiments of the compounds of Formula II, IIa, or
IIb, one of L.sup.1 and L.sup.2 is selected from
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2--,
--(CR.sup.7R.sup.8).sub.m--C(O)--, --C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--OC(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9C(O)O--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--S(O).sub.2NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--S(O)NR.sup.9--, and
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2NR.sup.9--; and the other is
selected from a bond, --(CR.sup.7R.sup.8).sub.n--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2--,
--(CR.sup.7R.sup.8).sub.m--C(O)--, --C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--S(O)NR.sup.9--, and
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2NR.sup.9--.
[0465] In some embodiments of the compounds of Formula II, IIa, or
IIb, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.2--C(O)--,
--C(O)NR.sup.9--(CR.sup.7R.sup.8)--, --C(O)NR.sup.9--,
--(CR.sup.7R.sup.8)--S(O).sub.2NR.sup.9--,
--S(O).sub.2NR.sup.9--(CR.sup.7R.sup.8)--, or
--S(O).sub.2NR.sup.9--. In some further embodiments, L.sup.1 and
L.sup.2 together form --C(O)NH-- or --S(O).sub.2NH--.
[0466] In some embodiments, the compound of Formula I of the
present invention is a compound of Formula IIIa:
##STR00007##
wherein D.sup.1, E.sup.1, D.sup.2, and E.sup.2 are each,
independently, CR.sup.5 or N.
[0467] In some embodiments, the compound of Formula I of the
present invention is a compound of Formula IIIb:
##STR00008##
wherein D.sup.1, E.sup.1, and D.sup.2 are each, independently,
CR.sup.5 or N.
[0468] In some embodiments, the compound of Formula I of the
present invention is a compound of Formula IIIc:
##STR00009##
wherein D.sup.1 and E.sup.1 are each, independently, CR.sup.5 or
N.
[0469] In some embodiments, the compound of Formula I of the
present invention is a compound of Formula IIId:
##STR00010##
wherein E.sup.1 is CR.sup.5 or N.
[0470] In some embodiments, the compound of Formula I of the
present invention is a compound of Formula IIIe:
##STR00011##
wherein D.sup.1 is CR.sup.5 or N.
[0471] In some embodiments, the compound of Formula I of the
present invention is a compound of Formula IIIf:
##STR00012##
wherein D.sup.1 and E.sup.1 are each, independently, CR.sup.5 or
N.
[0472] In some embodiments, the compound of Formula I of the
present invention is a compound of Formula IIIg:
##STR00013##
wherein D.sup.1 is CR.sup.5 or N.
[0473] In some embodiments, the compound of Formula I of the
present invention is a compound of Formula IIIh:
##STR00014##
wherein E.sup.1 is CR.sup.5 or N.
[0474] In some embodiments, the compound of Formula I of the
present invention is a compound of Formula IVa:
##STR00015##
[0475] In some embodiments, the compound of Formula I of the
present invention is a compound of Formula IVb:
##STR00016##
[0476] In some embodiments, the compound of Formula I of the
present invention is a compound of Formula IVc:
##STR00017##
[0477] In some embodiments, the compound of Formula I of the
present invention is a compound of Formula IVd:
##STR00018##
[0478] In some embodiments, the compound of Formula I of the
present invention is a compound of Formula IVe:
##STR00019##
[0479] In some embodiments of the compound of Formula IIIa, IIIb,
IIIc, IIId, IIIe, or IVa, L.sup.1 and L.sup.2 are each,
independently, selected from a bond, --(CR.sup.7R.sup.8).sub.n--,
--O--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.,
--S--(CR.sup.7R.sup.8)--CR.sup.10.dbd.,
--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--O--, --(CR.sup.7R.sup.8).sub.m--S--,
--(CR.sup.7R.sup.8).sub.m--S(O)--,
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2--,
--(CR.sup.7R.sup.8).sub.m--C(O)--, --C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--C(O)O--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--OC(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9C(O)O--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--S(O).sub.2NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--S(O)NR.sup.9--, and
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2NR.sup.9--.
[0480] In some embodiments of the compound of Formula IIIa, IIIb,
IIIc, IIId, IIIe, or IVa, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.m--CR.sup.10.dbd.CR.sup.10--(CR.sup.7R.sup.8).sub-
.m-- or --(CR.sup.7R.sup.8).sub.m--, (CR.sup.7R.sup.8).sub.n.
[0481] In some embodiments of the compound of Formula IIIa, IIIb,
IIIc, IIId, IIIe, or IVa, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8)--, --(CR.sup.7R.sup.8).sub.2--, or
--(CR.sup.7R.sup.8).sub.3--. In some further embodiments, IIa, or
IIb, L.sup.1 and L.sup.2 together form --CH.sub.2--,
--(CH.sub.2).sub.2--, or --(CH.sub.2).sub.3--.
[0482] In some embodiments of the compound of Formula IIIa, IIIb,
IIIc, IIId, IIIe, or IVa, one of L.sup.1 and L.sup.2 is selected
from --(CR.sup.7R.sup.8).sub.m--O--,
--(CR.sup.7R.sup.8).sub.m--S--, --(CR.sup.7R.sup.8).sub.m--S(O)--,
and --(CR.sup.7R.sup.8).sub.m--S(O).sub.2--; and the other is
selected from a bond, --(CR.sup.7R.sup.8).sub.n--,
--(CR.sup.7R.sup.8).sub.m--O--, --(CR.sup.7R.sup.8).sub.m--S--,
--(CR.sup.7R.sup.8).sub.m--S(O)--, and
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2--.
[0483] In some embodiments of the compounds of Formula II, IIa, or
IIb:
[0484] L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.t1--S--, --(CR.sup.7R.sup.8).sub.t1--O--,
--(CR.sup.7R.sup.8).sub.t1--S(O)--,
--(CR.sup.7R.sup.8).sub.t1--S(O).sub.2--,
--S--(CR.sup.7R.sup.8).sub.2--S--,
--O--(CR.sup.7R.sup.8).sub.2--S--,
--O--(CR.sup.7R.sup.8).sub.2--S(O)--,
--O--(CR.sup.7R.sup.8).sub.2--S(O).sub.2--, --S--S--,
--(CR.sup.7R.sup.8).sub.t3--O--(CR.sup.7R.sup.8).sub.t4--,
--(CR.sup.7R.sup.8).sub.t3--S--(CR.sup.7R.sup.8).sub.t4--,
--(CR.sup.7R.sup.8).sub.t3--S(O)--(CR.sup.7R.sup.8).sub.t4--, or
--(CR.sup.7R.sup.8).sub.t3--S(O).sub.2--(CR.sup.7R.sup.8).sub.t4--;
[0485] t1 is 1, 2, or 3;
[0486] t2 is 1 2, 3, or 4;
[0487] t3 is 1, 2, or 3; and
[0488] t4 is 1 or 2.
[0489] In some embodiments of the compound of Formula IIIa, IIIb,
IIIc, IIId, IIIe, or IVa, L.sup.1 and L.sup.2 together form
--O--(CR.sup.7R.sup.8)--, --O--(CR.sup.7R.sup.8).sub.2--, or
--O--(CR.sup.7R.sup.8).sub.3--. In some further embodiments,
L.sup.1 and L.sup.2 together form --O--CH.sub.2--,
--O--(CH.sub.2).sub.2--, or --O--(CH.sub.2).sub.3--.
[0490] In some embodiments of the compound of Formula IIIa, IIIb,
IIIc, IIId, IIIe, or IVa, L.sup.1 is --(CR.sup.7R.sup.8)--,
--(CR.sup.7R.sup.8).sub.2--, or --(CR.sup.7R.sup.8).sub.3--; and
L.sup.2 is --O--.
[0491] In some embodiments of the compound of Formula IIIa, IIIb,
IIIc, IIId, IIIe, or IVa, L.sup.1 and L.sup.2 together form
--O--(CR.sup.7R.sup.8)--O--, --O--(CR.sup.7R.sup.8).sub.2--O--, or
--O--(CR.sup.7R.sup.8).sub.3--O--.
[0492] In some embodiments of the compound of Formula IIIa, IIIb,
IIIc, IIId, IIIe, or IVa, L.sup.1 and L.sup.2 together form
--(CH.sub.2)--S--, --(CH.sub.2)--S(O)--,
--(CH.sub.2)--S(O).sub.2--, --(CH.sub.2)--O--,
--(CH.sub.2).sub.2--O--, --(CH.sub.2).sub.3--O--,
--O--(CH.sub.2).sub.2--O--, --O--(CH.sub.2).sub.2--S--,
--O--(CH.sub.2).sub.2--S(O)--, or
--O--(CH.sub.2).sub.2--S(O).sub.2--.
[0493] In some embodiments of the compound of Formula IIIa, IIIb,
IIIc, IIId, IIIe, or IVa, one of L.sup.1 and L.sup.2 is selected
from --(CR.sup.7R.sup.8).sub.m--NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2--,
--(CR.sup.7R.sup.8).sub.m--C(O)--, --C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--OC(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9C(O)O--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--S(O).sub.2NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--S(O)NR.sup.9--, and
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2NR.sup.9--; and the other is
selected from a bond, --(CR.sup.7R.sup.8).sub.n--,
--(CR.sup.7R.sup.8).sub.m--NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2--,
--(CR.sup.7R.sup.8).sub.m--C(O)--, --C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m--S(O)NR.sup.9--, and
--(CR.sup.7R.sup.8).sub.m--S(O).sub.2NR.sup.9--.
[0494] In some embodiments of the compound of Formula IIIa, IIIb,
IIIc, IIId, IIIe, or IVa, L.sup.1 and L.sup.2 together form
--(CR.sup.7R.sup.8).sub.2--C(O)--,
--C(O)NR.sup.9--(CR.sup.7R.sup.8)--, --C(O)NR.sup.9--,
--(CR.sup.7R.sup.8)--S(O).sub.2NR.sup.9--,
--S(O).sub.2NR.sup.9--(CR.sup.7R.sup.8)--, or
--S(O).sub.2NR.sup.9--. In some further embodiments, L.sup.1 and
L.sup.2 together form --C(O)NH-- or --S(O).sub.2NH--.
[0495] In some embodiments of the compound of Formula II, IIa, IIb,
IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IVa, IVb, IVc, IVd,
or IVe, R' and R'' are each, independently, selected from H and
C.sub.1-3 alkyl; R.sup.1 is selected from H and C.sub.1-3 alkyl;
R.sup.3 is selected from halo, C.sub.1-3 alkyl, and C.sub.1-3
haloalkyl; and R.sup.4 is H or C.sub.1-3 alkyl;
[0496] In some embodiments of the compound of Formula II, IIa, IIb,
IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IVa, IVb, IVc, IVd,
or IVe, R' and R'' are each, independently, selected from H and
methyl; R.sup.1 is H; R.sup.3 is halo; and R.sup.4 is H.
[0497] In some embodiments of the compound of Formula II, IIa, Hb,
IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IVa, IVb, IVc, IVd,
or IVe, R' and R'' are both H; R.sup.1 is H and; R.sup.3 is Cl; and
R.sup.4 is H.
[0498] In some embodiments of the compound of Formula II, IIa,
I'll, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IVa, IVb,
IVc, IVd, or IVe, R.sup.1 is selected from H and C.sub.1-3 alkyl;
each R.sup.2 is, independently, selected from H, F, Cl, CH.sub.3,
and CF.sub.3; R.sup.3 is selected from halo, C.sub.1-3 alkyl, and
C.sub.1-3 haloalkyl; R.sup.4 is H or methyl; and R' and R'' are
each, independently, H or methyl.
[0499] In some embodiments of the compound of Formula II, IIa,
I'll, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IVa, IVb,
IVc, IVd, or IVe, R.sup.1 is selected from H and methyl; each
R.sup.2 is H; R.sup.3 is halo; R.sup.4 is H or methyl; and R' and
R'' are each, independently, H or methyl.
[0500] In some embodiments of the compound of Formula II, IIa, IIb,
IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IVa, IVb, IVc, IVd,
or IVe, or pharmaceutically acceptable salt thereof:
[0501] each R.sup.5 is, independently, H, Cy.sup.3, halo, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
halosulfanyl, CN, NO.sub.2, SF.sub.5, OR.sup.a1, SR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(S)R.sup.b1,
C(S)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(S)R.sup.b1,
NR.sup.c1C(S)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O).sub.2NR.sup.c1R.sup.d1, or
--W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1;
[0502] or two adjacent R.sup.5 on the same ring link to form a
fused cycloalkyl or fused heterocycloalkyl group, each optionally
substituted by 1, 2, or 3 substituents independently selected from
halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,
heterocycloalkylalkyl, halosulfanyl, Cy.sup.1, CN, NO.sub.2,
OR.sup.a1, SR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1,
C(S)R.sup.b1, C(S)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
--W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1, OC(O)NR.sup.c1R.sup.d1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1.
[0503] In some embodiments of the compound of Formula II, IIa, IIb,
IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IVa, IVb, IVc, IVd,
or IVe, or pharmaceutically acceptable salt thereof, at least one
R.sup.5 is --W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1. In some further
embodiments, at least one R.sup.5 on the ring containing A.sup.2,
B.sup.2, D.sup.2, and E.sup.2 is
--W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1.
[0504] In some embodiments of the compound of Formula II, IIa, IIb,
IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IVa, IVb, IVc, IVd,
or IVe, or pharmaceutically acceptable salt thereof, at least one
R.sup.5 is Cy.sup.1.
[0505] In some embodiments of the compound of Formula II, IIa,
III), IIIa, IIIb, IIIc, IIId, Hie, IIIf, IIIg, IIIh, IVa, IVb, IVc,
IVd, or IVe, or pharmaceutically acceptable salt thereof, at least
one R.sup.5 is
--(CR.sup.11aR.sup.11b).sub.p1-Q.sup.1-Y.sup.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1O(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup-
.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup-
.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(O)(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.-
sup.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(O).sub.2((CR.sup.11aR.sup.11b).sub.p2-Q.s-
up.1-Y.sup.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.sup.-
1-Y.sup.1--Z.sup.1,
--NR.sup.eS(O)(CR.sup.11aR.sup.11b).sub.p1-Q.sup.1-Y.sup.1--Z.sup.1,
--S(O)NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup.1--Z.sup.1,
--NR.sup.eS(O).sub.2(CR.sup.11aR.sup.11b).sub.p1-Q.sup.1-Y.sup.1--Z.sup.1-
,
--S(O).sub.2NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup.1--Z.sup.-
1,
--NR.sup.eC(O)(CR.sup.11aR.sup.11b).sub.p1-Q.sup.1Y.sup.1--Z.sup.1,
--C(O)NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup.1--Z.sup.1,
or
--NR.sup.eC(O)NR.sup.f(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup.1--Z.sup-
.1. In some further embodiments, each Q.sup.1 is independently
selected from cycloalkyl and heterocycloalkyl, each optionally
substituted by 1, 2, 3, 4, or 5 substituents independently selected
from halo, CN, NO.sub.2, OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.2-8 alkoxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy,
C.sub.2-8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(O)OR.sup.a,
C(O)NR.sup.cR.sup.d, amino, C.sub.1-6 alkylamino and C.sub.2-8
dialkylamino. In yet further embodiments, each Q.sup.1 is
independently selected from cyclopentyl, cyclohexyl, pyrrolidinyl,
and piperidinyl, each optionally substituted by 1, 2, 3, 4, or 5
substituents independently selected from halo, CN, NO.sub.2, OH,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-8 alkoxyalkyl,
C.sub.1-6 alkoxy, haloalkoxy, C.sub.2-8 alkoxyalkoxy, cycloalkyl,
heterocycloalkyl, C(O)OR.sup.a, C(O)NR.sup.cR.sup.d, amino,
C.sub.1-6 alkylamino and C.sub.2-8 dialkylamino.
[0506] In some embodiments of the compound of Formula II, IIa, IIb,
IIIa, IIIb, IIIc, IIId, IIe, IIIf, IIIg, IIIh, IVa, IVb, IVc, IVd,
or IVe, or pharmaceutically acceptable salt thereof, at least one
R.sup.5 is -Q.sup.1-Y.sup.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1O(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup-
.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup-
.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(O)(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.-
sup.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(O).sub.2(CR.sup.11aR.sup.11b).sub.p2-Q.su-
p.1-Y.sup.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.sup.-
1-Y.sup.1--Z.sup.1,
--NR.sup.eS(O)(CR.sup.11aR.sup.11b).sub.p1-Q.sup.1-Y.sup.1--Z.sup.1,
--S(O)NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup.1--Z.sup.1,
--NR.sup.eS(O).sub.2(CR.sup.11aR.sup.11b).sub.p1-Q.sup.1-Y.sup.1--Z.sup.1-
,
--S(O).sub.2NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup.1--Z.sup.-
1,
--NR.sup.eC(O)(CR.sup.11aR.sup.11b).sub.p1-Q.sup.1-Y.sup.1--Z.sup.1,
--C(O)NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup.1--Z.sup.1,
or
--NR.sup.eC(O)NR.sup.f(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup.1--Z.sup-
.1,
[0507] In some embodiments of the compound of Formula II, IIa, IIb,
IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IVa, IVb, IVc, IVd,
or IVe, or pharmaceutically acceptable salt thereof, at least one
R.sup.5 is
--(CR.sup.11aR.sup.11b).sub.p1O(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup-
.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup-
.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(O)(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.-
sup.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(O).sub.2((CR.sup.11aR.sup.11b).sub.p2-Q.s-
up.1-Y.sup.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.sup.-
1-Y.sup.1--Z.sup.1,
--NR.sup.eS(O)(CR.sup.11aR.sup.11b).sub.p1-Q.sup.1-Y.sup.1--Z.sup.1,
--S(O)NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup.1--Z.sup.1,
--NR.sup.eS(O).sub.2(CR.sup.11aR.sup.11b).sub.p1-Q.sup.1-Y.sup.1--Z.sup.1-
,
--S(O).sub.2NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup.1--Z.sup.-
1,
--NR.sup.eC(O)(CR.sup.11aR.sup.11b).sub.p1-Q.sup.1-Y.sup.1--Z.sup.1,
--C(O)NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup.1--Z.sup.1,
or
--NR.sup.eC(O)NR.sup.f(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup.1--Z.sup-
.1. In some further embodiments, each Q.sup.1 is independently
selected from cycloalkyl and heterocycloalkyl, each optionally
substituted by 1, 2, 3, 4, or 5 substituents independently selected
from halo, CN, NO.sub.2, OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.2-8 alkoxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy,
C.sub.2-8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(O)OR.sup.a,
C(O)NR.sup.cR.sup.d, amino, C.sub.1-6 alkylamino and C.sub.2-8
dialkylamino. In yet further embodiments, each Q.sup.1 is
independently selected from cyclopentyl, cyclohexyl, pyrrolidinyl,
and piperidinyl, each optionally substituted by 1, 2, 3, 4, or 5
substituents independently selected from halo, CN, NO.sub.2, OH,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-8 alkoxyalkyl,
C.sub.1-6 alkoxy, haloalkoxy, C.sub.2-8 alkoxyalkoxy, cycloalkyl,
heterocycloalkyl, C(O)OR.sup.a, C(O)NR.sup.cR.sup.d, amino,
C.sub.1-6 alkylamino and C.sub.2-8 dialkylamino.
[0508] In some embodiments of the compound of Formula II, IIa, IIb,
IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IVa, IVb, IVc, IVd,
or IVe, or pharmaceutically acceptable salt thereof, at least one
R.sup.5 is --W.sup.6-Q.sup.1-Y.sup.1--Z.sup.1. In some further
embodiments, at least one R.sup.5 on the ring containing A.sup.2,
B.sup.2, D.sup.2, and E.sup.2 is
--W.sup.6Q.sup.1-Y.sup.1--Z.sup.1.
[0509] In some embodiments of the compound of Formula II, IIa, IIb,
IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IVa, IVb, IVc, IVd,
or IVe, or pharmaceutically acceptable salt thereof, at least one
R.sup.5 is -Q.sup.1-Y.sup.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup-
.1--Z.sup.1,
--((CR.sup.11aR.sup.11b).sub.p1S(O)(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y-
.sup.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(O).sub.2((CR.sup.11aR.sup.11b).sub.p2-Q.s-
up.1-Y.sup.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(O)NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.-
sup.1-Y.sup.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p2NR.sup.eS(O)(CR.sup.11aR.sup.11b).sub.p1-Q.-
sup.1-Y.sup.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(O).sub.2NR.sup.e(CR.sup.11aR.sup.11b).sub-
.p2-Q.sup.1-Y.sup.1--Z.sup.1, or
--(CR.sup.11aR.sup.11b).sub.p2NR.sup.eS(O).sub.2(CR.sup.11aR.sup.11b).sub-
.p1-Q.sup.1-Y.sup.1--Z.sup.1.
[0510] In some embodiments of the compound of Formula II, IIa, IIb,
IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IVa, IVb, IVc, IVd,
or IVe, or pharmaceutically acceptable salt thereof, at least one
R.sup.5 is
--(CR.sup.11aR.sup.11b).sub.p1S(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.sup-
.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(O)(CR.sup.11aR.sup.11b).sub.p2-Q.sup.1-Y.-
sup.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(O).sub.2(CR.sup.11aR.sup.11b).sub.p2-Q.su-
p.1-Y.sup.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p1S(O)NR.sup.e(CR.sup.11aR.sup.11b).sub.p2-Q.-
sup.1-Y.sup.1--Z.sup.1,
--(CR.sup.11aR.sup.11b).sub.p2NR.sup.eS(O)(CR.sup.11aR.sup.11b).sub.p1-Q.-
sup.1-Y.sup.1--Z.sup.1,
(CR.sup.11aR.sup.11b).sub.p1S(O).sub.2NR.sup.e(CR.sup.11aR.sup.11b).sub.p-
2-Q.sup.1-Y.sup.1--Z.sup.1, or
--(CR.sup.11aR.sup.11b).sub.p2NR.sup.eS(O).sub.2(CR.sup.11aR.sup.11b).sub-
.p1-Q.sup.1-Y.sup.1--Z.sup.1.
[0511] In some embodiments of the compound of Formula II, IIa, IIb,
IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IVa, IVb, IVc, IVd,
or IVe, or pharmaceutically acceptable salt thereof, each Q.sup.1
is independently selected from aryl and heteroaryl, each optionally
substituted by 1, 2, 3, 4, or 5 substituents independently selected
from halo, CN, NO.sub.2, OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.2-8 alkoxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy,
C.sub.2-8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(O)OR.sup.a,
C(O)NR.sup.cR.sup.d, amino, C.sub.1-6 alkylamino and C.sub.2-8
dialkylamino.
[0512] In some embodiments of the compound of Formula II, IIa, IIb,
IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IVa, IVb, IVc, IVd,
or IVe, or pharmaceutically acceptable salt thereof, each Q.sup.1
is independently selected from cycloakyl or heterocycloalkyl, each
optionally substituted by 1, 2, 3, 4, or 5 substituents
independently selected from halo, CN, NO.sub.2, OH, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.2-8 alkoxyalkyl, C.sub.1-6
alkoxy, C.sub.1-6 haloalkoxy, C.sub.2-8 alkoxyalkoxy, cycloalkyl,
heterocycloalkyl, C(O)OR.sup.a, C(O)NR.sup.cR.sup.d, amino,
C.sub.1-6 alkylamino and C.sub.2-8 dialkylamino.
[0513] In some embodiments of the compound of Formula II, IIa, IIb,
IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IVa, IVb, IVc, IVd,
or IVe, or pharmaceutically acceptable salt thereof, each Q.sup.1
is independently selected from cycloakyl optionally substituted by
1, 2, 3, 4, or 5 substituents independently selected from halo, CN,
NO.sub.2, OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-8
alkoxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.2-8
alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(O)OR.sup.a,
C(O)NR.sup.cR.sup.d, amino, C.sub.1-6 alkylamino and C.sub.2-8
dialkylamino.
[0514] In some embodiments of the compound of Formula II, IIa, IIb,
IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IVa, IVb, IVc, IVd,
or IVe, or pharmaceutically acceptable salt thereof, each Q.sup.1
is independently selected from heterocycloalkyl optionally
substituted by 1, 2, 3, 4, or 5 substituents independently selected
from halo, CN, NO.sub.2, OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.2-8 alkoxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy,
C.sub.2-8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(O)OR.sup.a,
C(O)NR.sup.cR.sup.d, amino, C.sub.1-6 alkylamino and C.sub.2-8
dialkylamino.
[0515] In some embodiments of the compound of Formula II, IIa, IIb,
IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IVa, IVb, IVc, IVd,
or IVe, or pharmaceutically acceptable salt thereof, each Q.sup.1
is independently selected from cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, and
piperazinyl, each optionally substituted by 1, 2, 3, 4, or 5
substituents independently selected from halo, CN, NO.sub.2, OH,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-8 alkoxyalkyl,
C.sub.1-6 alkoxy, C.sub.1-6haloalkoxy, C.sub.2-8 alkoxyalkoxy,
cycloalkyl, heterocycloalkyl, C(O)OR.sup.a, C(O)NR.sup.cR.sup.d,
amino, C.sub.1-6 alkylamino and C.sub.2-8 dialkylamino. In some
further embodiments, each Q.sup.1 is independently selected from
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each
optionally substituted by 1, 2, 3, 4, or 5 substituents
independently selected from halo, CN, NO.sub.2, OH, C.sub.1-6
alkyl, C.sub.1-6haloalkyl, C.sub.2-8 alkoxyalkyl, C.sub.1-6 alkoxy,
C.sub.1-6haloalkoxy, C.sub.2-8 alkoxyalkoxy, cycloalkyl,
heterocycloalkyl, C(O)OR.sup.a, C(O)NR.sup.cR.sup.d, amino,
C.sub.1-6 alkylamino and C.sub.2-8 dialkylamino. In other further
embodiments, each Q.sup.1 is independently selected from
azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, each
optionally substituted by 1, 2, 3, 4, or 5 substituents
independently selected from halo, CN, NO.sub.2, OH, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.2-8 alkoxyalkyl, C.sub.1-6
alkoxy, C.sub.1-6 haloalkoxy, C.sub.2-8 alkoxyalkoxy, cycloalkyl,
heterocycloalkyl, C(O)OR.sup.a, C(O)NR.sup.cR.sup.d, amino,
C.sub.1-6 alkylamino and C.sub.2-8 dialkylamino.
[0516] In some embodiments of the compound of Formula II, IIa, IIb,
IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IVa, IVb, IVc, IVd,
or IVe, or pharmaceutically acceptable salt thereof, each Y.sup.1
is independently selected from absent,
(CR.sup.12aR.sup.12b).sub.p3O(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3S(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3NR.sup.e(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3C(O)(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3C(O)NR.sup.e(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3S(O).sub.2(CR.sup.12aR.sup.12b).sub.p4,
(CR.sup.12aR.sup.12b).sub.p3S(O).sub.2NR.sup.e(CR.sup.12aR.sup.12b).sub.p-
4, and
(CR.sup.12aR.sup.12b).sub.p3NR.sup.eC(O)NR.sup.f(CR.sup.12aR.sup.12-
b).sub.p4.
[0517] In some embodiments of the compound of Formula II, IIa, IIb,
IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IVa, IVb, IVc, IVd,
or IVe, or pharmaceutically acceptable salt thereof, each Z.sup.1
is independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, aryl, cycloalkyl,
heteroaryl and heterocycloalkyl, each optionally substituted by 1,
2, 3, 4, or 5 substituents independently selected from halo,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN,
NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d,
C(O)OR.sup.a, OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.eC(O)R.sup.d, NR.sup.cC(O)OR.sup.a,
NR.sup.cS(O).sub.2R.sup.b,
NR.sup.cS(O).sub.2S(O).sub.2NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d.
[0518] In some embodiments of the compound of Formula II, IIa, IIb,
IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IVa, IVb, IVc, IVd,
or IVe, or pharmaceutically acceptable salt thereof, each Z.sup.1
is independently selected from C.sub.1-6 alkyl, C.sub.1-6haloalkyl,
aryl, cycloalkyl, heteroaryl and heterocycloalkyl, each optionally
substituted by 1, 2, 3, 4, or 5 substituents independently selected
from halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, CN, NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b,
C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.d,
NR.sup.cC(O)OR.sup.a, NR.sup.cS(O).sub.2R.sup.b,
NR.sup.cS(O).sub.2S(O).sub.2NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d.
[0519] In some embodiments of the compound of Formula II, IIa, IIb,
IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IVa, IVb, IVc, IVd,
or IVe, or pharmaceutically acceptable salt thereof, each Z.sup.1
is independently selected from aryl, cycloalkyl, heteroaryl and
heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5
substituents independently selected from halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, aryl,
cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO.sub.2, OR.sup.a,
SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.d, NR.sup.cC(O)OR.sup.a,
NR.sup.cS(O).sub.2R.sup.b,
NR.sup.cS(O).sub.2S(O).sub.2NR.sup.cR.sup.d, S(O)R.sup.b,
S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d.
[0520] At various places in the present specification, substituents
of compounds of the invention are disclosed in groups or in ranges.
It is specifically intended that the invention include each and
every individual subcombination of the members of such groups and
ranges. For example, the term "C.sub.1-6 alkyl" is specifically
intended to individually disclose methyl, ethyl, C.sub.3 alkyl,
C.sub.4 alkyl, C.sub.5 alkyl, and C.sub.6 alkyl.
[0521] For compounds of the invention in which a variable appears
more than once, each variable can be a different moiety selected
from the Markush group defining the variable. For example, each of
R.sup.5, R.sup.6, --W.sup.1-Q.sup.1-Y.sup.1--Z.sup.1, Cy.sup.1, and
R.sup.a1 can be a different moiety selected from the Markush group
defining the variable. For another example, where a structure is
described having two R groups that are simultaneously present on
the same compound; the two R groups can represent different
moieties selected from the Markush group defined for R. In another
example, when an optionally multiple substituent is designated in
the form:
##STR00020##
then it is understood that substituent R can occur s number of
times on the ring, and R can be a different moiety at each
occurrence. Further, in the above example, should the variable
T.sup.1 be defined to include hydrogens, such as when T.sup.1 is
said to be CH.sub.2, NH, etc., any floating substituent such as R
in the above example, can replace a hydrogen of the T.sup.1
variable as well as a hydrogen in any other non-variable component
of the ring.
[0522] As used herein, the term "adjacent" in describing the
relative positions of two substitution groups on a same ring
structure refers to two substitution groups that are respectively
attached to two ring-forming atoms of the same ring, wherein the
two-ring forming atoms are directly connected through a chemical
bond. For example, in the following structure:
##STR00021##
R.sup.100a and R.sup.200 are two adjacent groups. For another
example, each of R.sup.200, R.sup.400a, and R.sup.400b is an
adjacent group of R.sup.300a. For yet another example, each of
R.sup.200, R.sup.400a, and R.sup.400b is an adjacent group of
R.sup.300b.
[0523] It is further appreciated that certain features of the
invention, which are, for clarity, described in the context of
separate embodiments, can also be provided in combination in a
single embodiment. Conversely, various features of the invention
which are, for brevity, described in the context of a single
embodiment, can also be provided separately or in any suitable
subcombination.
[0524] The term "n-membered" where n is an integer typically
describes the number of ring-forming atoms in a moiety where the
number of ring-forming atoms is n. For example, pyridine is an
example of a 6-membered heteroaryl ring and thiophene is an example
of a 5-membered heteroaryl group.
[0525] As used herein, the term "alkyl" is meant to refer to a
saturated hydrocarbon group which is straight-chained or branched.
Example alkyl groups include, but are not limited to, methyl (Me),
ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g.,
n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl,
neopentyl), and the like. An alkyl group can contain from 1 to
about 20, from 2 to about 20, from 1 to about 10, from 1 to about
8, from 1 to about 6, from 1 to about 4, or from 1 to about 3
carbon atoms. The term "alkylene" refers to a divalent alkyl
linking group. An example of alkylene is methylene (CH.sub.2).
[0526] As used herein, "alkenyl" refers to an alkyl group having
one or more double carbon-carbon bonds. Example alkenyl groups
include, but are not limited to, ethenyl, propenyl, cyclohexenyl,
and the like. The term "alkenylenyl" refers to a divalent linking
alkenyl group.
[0527] As used herein, "alkynyl" refers to an alkyl group having
one or more triple carbon-carbon bonds. Example alkynyl groups
include, but are not limited to, ethynyl, propynyl, and the like.
The term "alkynylenyl" refers to a divalent linking alkynyl
group.
[0528] As used herein, "haloalkyl" refers to an alkyl group having
one or more halogen substituents. Example haloalkyl groups include,
but are not limited to, CF.sub.3, C.sub.2F.sub.5, CHF.sub.2,
CCl.sub.3, CHCl.sub.2, C.sub.2Cl.sub.5, CH.sub.2CF.sub.3, and the
like.
[0529] As used herein, "aryl" refers to monocyclic or polycyclic
(e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as,
for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl,
indenyl, and the like. In some embodiments, aryl groups have from 6
to about 20 carbon atoms. In some embodiments, aryl groups have
from 6 to about 10 carbon atoms.
[0530] As used herein, "cycloalkyl" refers to non-aromatic cyclic
hydrocarbons including cyclized alkyl, alkenyl, and alkynyl groups
that contain up to 20 ring-forming carbon atoms. Cycloalkyl groups
can include mono- or polycyclic (e.g., having 2, 3 or 4 fused
rings) ring systems as well as spiro ring systems. A cycloalkyl
group can contain from 3 to about 15, from 3 to about 10, from 3 to
about 8, from 3 to about 6, from 4 to about 6, from 3 to about 5,
or from 5 to about 6 ring-forming carbon atoms. Ring-forming carbon
atoms of a cycloalkyl group can be optionally substituted by oxo or
sulfido. Example cycloalkyl groups include, but are not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl,
norbornyl, norpinyl, norcarnyl, adamantyl, and the like. Also
included in the definition of cycloalkyl are moieties that have one
or more aromatic rings fused (i.e., having a bond in common with)
to the cycloalkyl ring, for example, benzo or thienyl derivatives
of pentane, pentene, hexane, and the like (e.g.,
2,3-dihydro-1H-indene-1-yl, or 1H-inden-2(3H)-one-1-yl).
[0531] As used herein, "heteroaryl" groups refer to an aromatic
heterocycle having up to 20 ring-forming atoms and having at least
one heteroatom ring member (ring-forming atom) such as sulfur,
oxygen, or nitrogen. In some embodiments, the heteroaryl group has
at least one or more heteroatom ring-forming atoms each
independently selected from sulfur, oxygen, and nitrogen.
Heteroaryl groups include monocyclic and polycyclic (e.g., having
2, 3 or 4 fused rings) systems. Examples of heteroaryl groups
include without limitation, pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl,
imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl,
benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl,
tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl,
benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and
the like. In some embodiments, the heteroaryl group has from 1 to
about 20 carbon atoms, and in further embodiments from about 1 to
about 5, from about 1 to about 4, from about 1 to about 3, from
about 1 to about 2, carbon atoms as ring-forming atoms. In some
embodiments, the heteroaryl group contains 3 to about 14, 3 to
about 7, or 5 to 6 ring-forming atoms. In some embodiments, the
heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2
heteroatoms.
[0532] As used herein, "heterocycloalkyl" refers to non-aromatic
heterocycles having up to 20 ring-forming atoms including cyclized
alkyl, alkenyl, and alkynyl groups where one or more of the
ring-forming carbon atoms is replaced by a heteroatom such as an O,
N, or S atom. Hetercycloalkyl groups can be mono or polycyclic
(e.g., both fused and spiro systems). Example "heterocycloalkyl"
groups include morpholino, thiomorpholino, piperazinyl,
tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl,
1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl,
isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl,
thiazolidinyl, imidazolidinyl, pyrrolidin-2-one-3-yl, and the like.
Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl
group can be optionally substituted by oxo or sulfido. For example,
a ring-forming S atom can be substituted by 1 or 2 oxo [i.e., form
a S(O) or S(O).sub.2]. For another example, a ring-forming C atom
can be substituted by oxo (i.e., form carbonyl). Also included in
the definition of heterocycloalkyl are moieties that have one or
more aromatic rings fused (i.e., having a bond in common with) to
the nonaromatic heterocyclic ring, for example pyridinyl,
thiophenyl, phthalimidyl, naphthalimidyl, and benzo derivatives of
heterocycles such as indolene, isoindolene, isoindolin-1-one-3-yl,
4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-yl,
5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one-5-yl, and
3,4-dihydroisoquinolin-1(2H)-one-3yl groups. Ring-forming carbon
atoms and heteroatoms of the heterocycloalkyl group can be
optionally substituted by oxo or sulfido. In some embodiments, the
heterocycloalkyl group has from 1 to about 20 carbon atoms, and in
further embodiments from about 3 to about 20 carbon atoms. In some
embodiments, the heterocycloalkyl group contains 3 to about 14, 3
to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the
heterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2
heteroatoms. In some embodiments, the heterocycloalkyl group
contains 0 to 3 double bonds. In some embodiments, the
heterocycloalkyl group contains 0 to 2 triple bonds.
[0533] As used herein, "halo" or "halogen" includes fluoro, chloro,
bromo, and iodo.
[0534] As used herein, "halosulfanyl" refers to a sulfur group
having one or more halogen substituents. Example halosulfanyl
groups include pentahalosulfanyl groups such as SF.sub.5.
[0535] As used herein, "alkoxy" refers to an --O-alkyl group.
Example alkoxy groups include methoxy, ethoxy, propoxy (e.g.,
n-propoxy and isopropoxy), t-butoxy, and the like.
[0536] As used herein, "haloalkoxy" refers to an --O-haloalkyl
group. An example haloalkoxy group is OCF.sub.3.
[0537] As used herein, "cyanoalkyl" refers to an alkyl group
substituted by a cyano group (CN). One example of cyanoalkyl is
--CH.sub.2--CN.
[0538] As used herein, "alkoxyalkoxy" refers to an alkoxy group
substituted by an alkoxy group. One example of alkoxyalkoxy is
--OCH.sub.2CH.sub.2--OCH.sub.3.
[0539] As used herein, "arylalkyl" refers to a C.sub.1-6 alkyl
substituted by aryl and "cycloalkylalkyl" refers to C.sub.1-6 alkyl
substituted by cycloalkyl.
[0540] As used herein, "heteroarylalkyl" refers to a C.sub.1-6
alkyl group substituted by a heteroaryl group, and
"heterocycloalkylalkyl" refers to a C.sub.1-6 alkyl substituted by
heterocycloalkyl.
[0541] As used herein, "amino" refers to NH.sub.2.
[0542] As used herein, "alkylamino" refers to an amino group
substituted by an alkyl group.
[0543] As used herein, "dialkylamino" refers to an amino group
substituted by two alkyl groups.
[0544] As used herein, "hydroxylalkyl" or "hydroxylalkyl" refers to
an alkyl group substituted by a hydroxyl group. An example is
--CH.sub.2OH or --CH.sub.2CH.sub.2OH.
[0545] As used here, C(O) refers to C(.dbd.O).
[0546] As used here, C(S) refers to C(.dbd.S).
[0547] As used here, S(O) refers to S(.dbd.O).
[0548] As used here, S(O).sub.2 refers to S(.dbd.O).sub.2.
[0549] As used used herein, the term "optionally substituted" means
that substitution is optional and therefore includes both
unsubstituted and substituted atoms and moieties. A "substituted"
atom or moiety indicates that any hydrogen on the designated atom
or moiety can be replaced with a selection from the indicated
substituent group, provided that the normal valency of the
designated atom or moiety is not exceeded, and that the
substitution results in a stable compound. For example, if a methyl
group (i.e., CH.sub.3) is optionally substituted, then 3 hydrogen
atoms on the carbon atom can be replaced with substituent
groups.
[0550] The compounds described herein can be asymmetric (e.g.,
having one or more stereocenters). All stereoisomers, such as
enantiomers and diastereomers, are intended unless otherwise
indicated. Compounds of the present invention that contain
asymmetrically substituted carbon atoms can be isolated in
optically active or racemic forms. Methods on how to prepare
optically active forms from optically active starting materials are
known in the art, such as by resolution of racemic mixtures or by
stereoselective synthesis. Many geometric isomers of olefins,
C.dbd.N double bonds, and the like can also be present in the
compounds described herein, and all such stable isomers are
contemplated in the present invention. Cis and trans geometric
isomers of the compounds of the present invention are described and
may be isolated as a mixture of isomers or as separated isomeric
forms. Where a compound capable of stereoisomerism or geometric
isomerism is designated in its structure or name without reference
to specific R/S or cis/trans configurations, it is intended that
all such isomers are contemplated.
[0551] Resolution of racemic mixtures of compounds can be carried
out by any of numerous methods known in the art. An example method
includes fractional recrystallization using a chiral resolving acid
which is an optically active, salt-forming organic acid. Suitable
resolving agents for fractional recrystallization methods are, for
example, optically active acids, such as the D and L forms of
tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,
mandelic acid, malic acid, lactic acid or the various optically
active camphorsulfonic acids such as .beta.-camphorsulfonic acid.
Other resolving agents suitable for fractional crystallization
methods include stereoisomerically pure forms of
.alpha.-methylbenzylamine (e.g., S and R forms, or
diastereomerically pure forms), 2-phenylglycinol, norephedrine,
ephedrine, N-methylephedrine, cyclohexylethylamine,
1,2-diaminocyclohexane, and the like.
[0552] Resolution of racemic mixtures can also be carried out by
elution on a column packed with an optically active resolving agent
(e.g., dinitrobenzoylphenylglycine). Suitable elution solvent
composition can be determined by one skilled in the art.
[0553] Compounds of the invention also include tautomeric forms.
Tautomeric forms result from the swapping of a single bond with an
adjacent double bond together with the concomitant migration of a
proton. Tautomeric forms include prototropic tautomers which are
isomeric protonation states having the same empirical formula and
total charge. Example prototropic tautomers include ketone-enol
pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic
acid pairs, enamine-imine pairs, and annular forms where a proton
can occupy two or more positions of a heterocyclic system, for
example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H-
and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be
in equilibrium or sterically locked into one form by appropriate
substitution.
[0554] Compounds of the invention further include hydrates and
solvates, as well as anhydrous and non-solvated forms.
[0555] The term, "compound," as used herein is meant to include all
stereoisomers, geometric iosomers, tautomers, and isotopes of the
structures depicted.
[0556] All compounds and pharmaceutically acceptable salts thereof,
can be prepared or present together with other substances such as
water and solvents (e.g. hydrates and solvates) or can be
isolated.
[0557] Compounds of the invention can also include all isotopes of
atoms occurring in the intermediates or final compounds. Isotopes
include those atoms having the same atomic number but different
mass numbers. For example, isotopes of hydrogen include tritium and
deuterium.
[0558] In some embodiments, the compounds of the invention, or
salts thereof, are substantially isolated. By "substantially
isolated" is meant that the compound is at least partially or
substantially separated from the environment in which is formed or
detected. Partial separation can include, for example, a
composition enriched in the compound of the invention. Substantial
separation can include compositions containing at least about 50%,
at least about 60%, at least about 70%, at least about 80%, at
least about 90%, at least about 95%, at least about 97%, or at
least about 99% by weight of the compound of the invention, or salt
thereof. Methods for isolating compounds and their salts are
routine in the art.
[0559] Compounds of the invention are intended to include compounds
with stable structures. As used herein, "stable compound" and
"stable structure" are meant to indicate a compound that is
sufficiently robust to survive isolation to a useful degree of
purity from a reaction mixture, and formulation into an efficacious
therapeutic agent.
[0560] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[0561] The expressions, "ambient temperature" and "room
temperature," as used herein, are understood in the art, and refer
generally to a temperature, e.g. a reaction temperature, that is
about the temperature of the room in which the reaction is carried
out, for example, a temperature from about 20.degree. C. to about
30.degree. C.
[0562] The present invention also includes pharmaceutically
acceptable salts of the compounds described herein. As used herein,
"pharmaceutically acceptable salts" refers to derivatives of the
disclosed compounds wherein the parent compound is modified by
converting an existing acid or base moiety to its salt form.
Examples of pharmaceutically acceptable salts include, but are not
limited to, mineral or organic acid salts of basic residues such as
amines; alkali or organic salts of acidic residues such as
carboxylic acids; and the like. The pharmaceutically acceptable
salts of the present invention include the conventional non-toxic
salts of the parent compound formed, for example, from non-toxic
inorganic or organic acids. The pharmaceutically acceptable salts
of the present invention can be synthesized from the parent
compound which contains a basic or acidic moiety by conventional
chemical methods. Generally, such salts can be prepared by reacting
the free acid or base forms of these compounds with a
stoichiometric amount of the appropriate base or acid in water or
in an organic solvent, or in a mixture of the two; generally,
nonaqueous media like ether, ethyl acetate, ethanol, isopropanol,
or acetonitrile (ACN) are preferred. Lists of suitable salts are
found in Remington's Pharmaceutical Sciences, 17th ed., Mack
Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of
Pharmaceutical Science, 66, 2 (1977), each of which is incorporated
herein by reference in its entirety.
[0563] The present invention also includes quaternary ammonium
salts of the compounds described herein, where the compounds are
primary amines, secondary amines, or tertiary amines. As used
herein, "quaternary ammonium salts" refers to derivatives of the
disclosed primary amine, secondary amine, or tertiary amine
compounds wherein the parent amine compounds are modified by
converting the amines to quaternary ammonium cations via alkylation
(and the cations are blanced by anions such as Cl.sup.-,
CH.sub.3COO.sup.-, or CF.sub.3COO.sup.-), for example methylation
or ethylation.
Synthesis
[0564] Compounds of the invention, including salts thereof, can be
prepared using known organic synthesis techniques and can be
synthesized according to any of numerous possible synthetic
routes.
[0565] The reactions for preparing compounds of the invention can
be carried out in suitable solvents which can be readily selected
by one of skill in the art of organic synthesis. Suitable solvents
can be substantially non-reactive with the starting materials
(reactants), the intermediates, or products at the temperatures at
which the reactions are carried out, e.g., temperatures which can
range from the solvent's freezing temperature to the solvent's
boiling temperature. A given reaction can be carried out in one
solvent or a mixture of more than one solvent. Depending on the
particular reaction step, suitable solvents for a particular
reaction step can be selected by the skilled artisan.
[0566] Preparation of compounds of the invention can involve the
protection and deprotection of various chemical groups. The need
for protection and deprotection, and the selection of appropriate
protecting groups, can be readily determined by one skilled in the
art. The chemistry of protecting groups can be found, for example,
in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic
Synthesis, 3.sup.rd Ed., Wiley & Sons, Inc., New York (1999),
which is incorporated herein by reference in its entirety.
[0567] Reactions can be monitored according to any suitable method
known in the art. For example, product formation can be monitored
by spectroscopic means, such as nuclear magnetic resonance
spectroscopy (e.g., .sup.1H or .sup.13C), infrared spectroscopy,
spectrophotometry (e.g., UV-visible), mass spectrometry, or by
chromatographic methods such as high performance liquid
chromatography (HPLC) or thin layer chromatography (TLC).
[0568] The compounds of invention can be prepared according to the
synthetic procedures described below in the Example section.
[0569] As shown in Scheme 1a, macrocycle 1-2 of the present
invention (wherein R.sup.4 can be H, methyl, ethyl, or the like)
can be synthesized by cyclizing precursor 1-1 [wherein Lg.sup.1 is
a leaving group such as halo (e.g., chloro)] under acidic
condition, or basic condition, or in the presence of a transition
metal catalysis [such as a Palladium catalyst (e.g.,
Pd(PPh.sub.3).sub.4) or a Pd(II) catalyst] to afford the desired
macrocycle 1-2. Precursors 1-1 [wherein Lg.sup.1 is a leaving group
such as halo (e.g. chloro)], 1-1a [wherein Lg.sup.1 is a leaving
group such as halo (e.g., chloro)], 1-3 [wherein Lg.sup.1 is a
leaving group such as halo (e.g., chloro)], and 1-3a [wherein
Lg.sup.1 is a leaving group such as halo (e.g., chloro)] can
undergo similar transformations to afford products 1-2, 1-4, and
1-4 (wherein R.sup.4 can be H, methyl, ethyl, or the like)
respectively.
##STR00022##
[0570] As shown in Scheme 1b, bis-olefin precursor 1-5 [wherein
L.sup.1f and L.sup.2f can be independently selected from
--(CR.sup.7R.sup.8).sub.m--, --(CR.sup.7R.sup.8).sub.m--O--, or
--(CR.sup.7R.sup.8).sub.m--S--] can be cyclized in the presence of
a metathesis catalyst (ruthenium, such as the Grubbs catalysts or
molybdenum catalysts, such as the Hoveyda catalysts) to afford the
desired macrocycle 1-6 that contains an olefin moiety of
CR.sup.10.dbd.CR.sup.10. The olefin moiety of compound 1-6 can be
further reduced under suitable hydrogenation conditions [such as in
the presence of a palladium catalyst (e.g., 5% Pd/C)] to afford
macrocycle 1-7.
##STR00023##
[0571] As shown in Scheme 1b-1, macrocycle 1-7a can be obtained
similarly according to the transformations described in Scheme
1b.
##STR00024##
[0572] Acyclic precursors 1-1, 1-1a, 1-3, and 1-3a can be
synthesized by a variety of appropriate ways that would be
recognized by those skilled in organic synthesis. For example,
compound 2-1 [wherein R.sup.101 is H or an amine protecting group
(such as tert-butyloxycarbonyl or BOC); R.sup.4 can be H, methyl,
ethyl, or the like] can be reacted with substituted heteroaromatic
compound 2-2 [wherein Lg.sup.1 and Lg.sup.2 are each,
independently, a leaving group such as halo (e.g., chloro)] in the
presence of a suitable base (such as a inorganic base, for example
a metal carbonate (e.g., potassium carbonate), a metal hydride
(e.g., sodium hydride), a metal hydroxide (e.g., sodium hydroxide),
a metal alkoxide (e.g., sodium ethoxide)] and/or in the presence of
a transition metal catalyst for example a palladium catalyst [e.g.,
Pd(PPh.sub.3).sub.4].
##STR00025##
[0573] Precursors for the macrocycles of the present invention (for
example, precursors 1-1, 1-1a, 1-3, 1-3a, and 1-5) can be prepared
by a variety of methods. For example, Mitsunobu coupling, thioether
formation, amine alkylation, amide formation, sulfonamide
formation, urea formation and carbamate formation can be utilized
in synthesizing these compounds. Some non-limiting examples are
depicted in the following schemes.
[0574] As shown in Scheme 3a, compound 3-1 [wherein R.sup.201 can
be NO.sub.2 or NHR.sup.101; R.sup.101 can be H or Pg.sup.4;
Pg.sup.4 is an amine protecting group (such as
tert-butyloxycarbonyl or BOC); L.sup.1a can be
--(CR.sup.7R.sup.8).sub.m-- (such as a bond or methylene) or
L.sup.1a is selected from --(CR.sup.7R.sup.8).sub.n--,
--(CR.sup.7R.sup.8).sub.m1--NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m1--O--, --(CR.sup.7R.sup.8).sub.m1--S--,
--(CR.sup.7R.sup.8).sub.m1--S(O)--,
--(CR.sup.7R.sup.8).sub.m1--S(O).sub.2--,
--(CR.sup.7R.sup.8).sub.m1--C(O)--,
--(CR.sup.7R.sup.8).sub.m1--C(O)O--,
--(CR.sup.7R.sup.8).sub.m1--NR.sup.9C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m1--OC(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m1--NR.sup.9C(O)O--,
--(CR.sup.7R.sup.8).sub.m1--NR.sup.9--S(O).sub.2NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m1--S(O)NR.sup.9--, and
--(CR.sup.7R.sup.8).sub.m1--S(O).sub.2NR.sup.9--, wherein m1 is 1
or 2] can be reacted with compound 3-2 [wherein R.sup.252 can be
NHR.sup.4 or NO.sub.2 wherein the NHR.sup.4 can also be protected
by an appropriate protecting group; R.sup.4 can be H, methyl,
ethyl, or the like; L.sup.2a is selected from
--(CR.sup.7R.sup.8).sub.n--,
--(CR.sup.7R.sup.8).sub.m1--NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m1--O--, --(CR.sup.7R.sup.8).sub.m1--S--,
--(CR.sup.7R.sup.8).sub.m1--S(O)--,
--(CR.sup.7R.sup.8).sub.m1--S(O).sub.2--,
--(CR.sup.7R.sup.8).sub.m1--C(O)--,
--(CR.sup.7R.sup.8).sub.m1--C(O)O--,
--(CR.sup.7R.sup.8).sub.m1--NR.sup.9C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m1--OC(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m1--NR.sup.9C(O)O--,
--(CR.sup.7R.sup.8).sub.m1--NR.sup.9--S(O).sub.2NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m1--S(O)NR.sup.9--, and
--(CR.sup.7R.sup.8).sub.m1--S(O).sub.2NR.sup.9--, wherein m1 is 1
or 2; or L.sup.2a can be --(CR.sup.7R.sup.8).sub.m-- (such as a
bond or methylene)] under Mitsunobu coupling reaction conditions to
afford compound 3-3 [wherein L.sup.1a can be
--(CR.sup.7R.sup.8).sub.m-- and L.sup.2a is selected from
--(CR.sup.7R.sup.8).sub.n--,
--(CR.sup.7R.sup.8).sub.m1--NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m1--O--, --(CR.sup.7R.sup.8).sub.m1--S--,
--(CR.sup.7R.sup.8).sub.m1--S(O)--,
--(CR.sup.7R.sup.8).sub.m1--S(O).sub.2--,
--(CR.sup.7R.sup.8).sub.m1--C(O)--,
--(CR.sup.7R.sup.8).sub.m1--C(O)O--,
--(CR.sup.7R.sup.8).sub.m1--NR.sup.9C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m1--OC(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m1--NR.sup.9C(O)O--,
--(CR.sup.7R.sup.8).sub.m1--NR.sup.9--S(O).sub.2NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m1--S(O)NR.sup.9--, and
--(CR.sup.7R.sup.8).sub.m1--S(O).sub.2NR.sup.9--, wherein m1 is 1
or 2; or L.sup.2acan be --(CR.sup.7R.sup.8).sub.m-- and L.sup.1a is
selected from --(CR.sup.7R.sup.8).sub.n--,
--(CR.sup.7R.sup.8).sub.m1--NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m1--O--, --(CR.sup.7R.sup.8).sub.m1--S--,
--(CR.sup.7R.sup.8).sub.m1--S(O)--,
--(CR.sup.7R.sup.8).sub.m1--S(O).sub.2--,
--(CR.sup.7R.sup.8).sub.m1--C(O)--,
--(CR.sup.7R.sup.8).sub.m1--C(O)O--,
--(CR.sup.7R.sup.8).sub.m1--NR.sup.9C(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m1--OC(O)NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m1--NR.sup.9C(O)O--,
--(CR.sup.7R.sup.8).sub.m1--NR.sup.9--S(O).sub.2NR.sup.9--,
--(CR.sup.7R.sup.8).sub.m1--S(O)NR.sup.9--, and
--(CR.sup.7R.sup.8).sub.m1--S(O).sub.2NR.sup.9--, wherein m1 is 1
or 2.]. Compound 3-3 can undergo further chemical transformations
if and when appropriate. For example, when R.sup.252 of compound
3-3 is protected (i.e., NR.sup.4Pg.sup.4), it can be deprotected
according to the amine protecting group Pg.sup.4. For another
example, when R.sup.252 of compound 3-3 is NO.sub.2, it can be
reduced to NH.sub.2 under suitable conditions.
[0575] Compounds 3-4 and 3-5 [wherein Lg.sup.3 is a leaving group
such as halo (e.g., Br or Cl); R.sup.201, L.sup.1a, and L.sup.2a
can be the same as those in compounds 3-1 and 3-2] can be reacted
under basic conditions to afford compound 3-6. Alternatively
compound 3-6 can be obtained by reacting compound 3-7 with compound
3-8 (wherein Lg.sup.3, R.sup.201, L.sup.1a, and L.sup.2a can be the
same as those in compounds 3-4 and 3-5). The NO.sub.2 of compound
3-6 can be reduced to NH.sub.2 under suitable conditions.
##STR00026## ##STR00027##
[0576] Useful intermediates 3-3a and 3-6a can be made according to
the methods as shown in Scheme 3a-1 (similar to the reactions
depicted in Scheme 3a, and wherein R.sup.301 can be NO.sub.2 or
NHR.sup.101; R.sup.101, R.sup.201, L.sup.1a, and L.sup.2a can be
the same as those in Scheme 3a). The protecting group Pg.sup.4 of
compound 3-3a and 3-6a, when present, can be removed under suitable
conditions. Compounds 3-3a and 3-6a can undergo further chemical
transformations when suitable reactive groups are present. For
example, the NO.sub.2 of compound 3-3a and 3-6a can be reduced to
NH.sub.2 under suitable conditions.
##STR00028## ##STR00029##
[0577] As shown in Scheme 3b, compounds 3-9a and 3-9b [wherein
R.sup.201, L.sup.1a, and L.sup.2a can be the same as those in
compounds 3-4 and 3-5] can be reacted under appropriate conditions
to afford compound 3-10. For example, when R.sup.102 is Lg.sup.3 (a
leaving group), amine alkylation can be carried out under basic
conditions. When R.sup.102 is --C(.dbd.O)H (i.e., compound 3-9a is
an aldehyde), reductive aminations can be carried out. Similarly,
compound 3-11c can be obtained by reacting compound 3-11a with
compound 3-11b [wherein L.sup.1a and L.sup.2a can be the same as
those in compounds 3-4 and 3-5] under suitable conditions. The
protecting group Pg.sup.4 of compound 3-10 or 3-11c can be removed
under suitable conditions. Compounds 3-10 and 3-11c can undergo
further chemical transformations when suitable reactive groups are
present. For example, when R.sup.252 is NO.sub.2, it can be reduced
to NH.sub.2 under suitable conditions.
##STR00030##
[0578] Useful intermediates 3-10-1 and 3-11c-1 can be made
according to the methods outlined in Scheme 3b-1 (similar to the
reactions depicted in Scheme 3b, and wherein L.sup.1a and L.sup.2a
can be the same as those in Scheme 3a). The protecting group
Pg.sup.4 of compound 3-10-1 and 3-11c-1 can be removed under
suitable conditions. Compounds 3-10-1 and 3-11c-1 can undergo
further chemical transformations when suitable reactive groups are
present. For example, the NO.sub.2 of compound 3-10-1 and 3-11c-1
can be reduced to NH.sub.2 under suitable conditions.
##STR00031##
[0579] As shown in Scheme 3c, amide compounds 3-12c, 3-13c, 3-14c,
and 3-15c [wherein Pg.sup.4, R.sup.252, L.sup.1a, and L.sup.2a can
be the same as those in Scheme 3a] can be obtained from an
appropriate acid such as acid 3-12a, 3-13b, 3-14b, or 3-15a and an
appropriate amine such as amine 3-12b, 3-13a, 3-14a, or 3-15b by
standard coupling reactions [such as in the presence of an amide
coupling reagent such as
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (BOP),
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HBTU),
O-(7-azabenzotriazol1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), or
dicyclohexylcarbodimide (DCC), and in the presence of a suitable
base such as triethylamine, diisopropylethylamine,
N-methylmorpholine, or N-N-dimethylaminopyridine]. Alternatively,
the acid 3-12a, 3-13b, 3-14b, or 3-15a can be converted to a more
reactivate species such as an acid halide (e.g., acid chloride) or
a mixed anhydride, and the more reactive species can be reacted
with the appropriate amine 3-12b, 3-13a, 3-14a, or 3-15b
respectively.
[0580] The protecting group Pg.sup.4 of compound 3-12c, 3-13c,
3-14c, or 3-15c can be removed under suitable conditions. Compounds
3-12c, 3-13c, 3-14c, and 3-15c can undergo further transformation
when suitable reactive groups are present. For example, when
R.sup.252 is NO.sub.2, it can be reduced to NH.sub.2 under suitable
conditions.
##STR00032## ##STR00033##
[0581] Useful intermediates 3-12c-1, 3-13c-1, 3-14c-1, and 3-15c-1
[wherein Pg.sup.4, L.sup.1a, and L.sup.2a can be the same as those
in Scheme 3a] can be made according to the methods outlined in
Scheme 3c-1 (similar to the reactions depicted in Scheme 3c). The
protecting group Pg.sup.4 of compounds 3-12c-1, 3-13c-1, 3-14c-1,
and 3-15c-1 can be removed under suitable conditions. Compounds
3-12c-1, 3-13c-1, 3-14c-1, and 3-15c-1 can undergo further chemical
transformations when suitable reactive groups are present. For
example, the NO.sub.2 of compounds 3-12c-1, 3-13c-1, 3-14c-1, and
3-15c-1 can be reduced to NH.sub.2 under suitable conditions.
##STR00034## ##STR00035##
[0582] As shown in Scheme 3d, sulfonamide compounds 3-17 and 3-19
[wherein Pg.sup.4, R.sup.252, L.sup.1a, and L.sup.2a can be the
same as those in Scheme 3a] can be obtained by reacting an
appropriate sulfonyl halide (such as chloride) with an appropriate
amine. The protecting group Pg.sup.4 of compounds 3-17 or 3-19 can
be removed under suitable conditions. Compounds 3-17 and 3-19 can
undergo further chemical transformations when suitable reactive
groups are present. For example, when R.sup.252 is NO.sub.2, it can
be reduced to NH.sub.2 under suitable conditions.
##STR00036##
[0583] Useful intermediates 3-17-1 and 3-19-1 [wherein Pg.sup.4,
R.sup.252, L.sup.1a and L.sup.2a can be the same as those in Scheme
3a] can be made according to the methods outlined in Scheme 3d-1
(similar to the reactions depicted in Scheme 3d). The protecting
group Pg.sup.4 of compounds 3-17-1 and 3-19-1 can be removed under
suitable conditions. Compounds 3-17-1 and 3-19-1 can undergo
further chemical transformations when suitable reactive groups are
present. For example, the NO.sub.2 of compounds 3-17-1 and 3-19-1
can be reduced to NH.sub.2 under suitable conditions.
##STR00037##
[0584] As shown in Scheme 3e, urea compound 3-21 [wherein
R.sup.201a, Pg.sup.4, and R.sup.252 can be the same as those in
Scheme 3d; and L.sup.1d and L.sup.2d can be each, independently,
--(CR.sup.7R.sup.8).sub.m-- (such as a bond or methylene)] can be
obtained by reacting two appropriate amines with phosgene
[C(.dbd.O)Cl.sub.2] or a phosgene equivalent [e.g., triphosgene,
ethyl chloroformate, trichloromethyl chloroformate, or phenyl
chlorocarbonate]. Similarly, carbamates 3-23 and 3-25 can be made
by reacting an appropriate amine and an appropriate alcohol with
phosgene or its equivalent. Sulfamide 3-25c can be made by reacting
amines 3-25a and 3-25b with SO.sub.2Cl.sub.2 or its equivalent
(such as other thionyl halides, e.g., SO.sub.2Br.sub.2). The
protecting group Pg.sup.4 of compounds 3-21, 3-23, or 3-25 can be
removed under suitable conditions. Compounds 3-21, 3-23, and 3-25
can undergo further chemical transformations when suitable reactive
groups are present. For example, when R.sup.252 (and/or R.sup.201a)
is NO.sub.2, it can be reduced to NH.sub.2 under suitable
conditions.
##STR00038## ##STR00039##
[0585] Useful intermediates 3-21-1, 3-23-1, 3-25-1, or 3-25-1c
[wherein Pg.sup.4, L.sup.1d, and L.sup.2d can be the same as those
in Scheme 3e] can be made according to the methods outlined in
Scheme 3e-1 (similar to the reactions depicted in Scheme 3e). The
protecting group Pg.sup.4 of compounds 3-21, 3-23, or 3-25 can be
removed under suitable conditions. Compounds 3-21, 3-23, or 3-25
can undergo further chemical transformations when suitable reactive
groups are present. For example, the NO.sub.2 of compound 3-21,
3-23, or 3-25 can be reduced to NH.sub.2 under suitable
conditions.
##STR00040## ##STR00041##
[0586] A more detailed scheme (similar to Scheme 3d-1) is provided
in Scheme 3f. Sulfonamide 3-27 [wherein L.sup.1a, and L.sup.2a can
be the same as those in Scheme 3a] can be obtained by reacting
sulfonyl halide 3-26a (such as chloride) with amine 3-26b. The
NO.sub.2 of compound 3-27 can be reduced to NH.sub.2, for example
in the presence of Fe/CH.sub.3COOH, to afford compound 3-27a. The
Boc group of compound 3-27 can be removed, for example, in the
presence of HCl, to afford compound 3-27b.
##STR00042##
[0587] In Schemes 3a, 3b, 3b-1, 3c, 3c-1, 3d, 3e, 3e-1, and 3f
wherein the compounds have a moiety of --(CR'R'').sub.t--NO.sub.2
[for example, --(CR'R'').sub.t--R.sup.252 wherein R.sup.252 is
NO.sub.2; --(CR'R'').sub.t--R.sup.301 wherein R.sup.301 is
NO.sub.2, or --(CR'R'').sub.t--R.sup.301a wherein R.sup.301a is
NO.sub.2], the moiety --(CR'R'').sub.t--NO.sub.2 can be replaced
with a moiety of --(CR'R'').sub.ttt--CN (wherein ttt is 0, 1, or
2). Subsequently, the moiety of --(CR'R'').sub.ttt--CN can be
reduced to --(CR'R'').sub.ttt--CH.sub.2NH.sub.2 under suitable
conditions such as hydrogenation in the presence of Raney nickel,
to provide additional useful intermediates.
[0588] As shown in Scheme 4, macrocycle 4-2 [wherein L.sup.1a and
L.sup.2a can be the same as those in Scheme 3a] can be cyclized
from acyclic precursor 4-1 by intramolecular Mitsunobu
reaction/coupling. Preferably, one of L.sup.1a and L.sup.2a of
acyclic precursor 4-1 is a bond in the intramolecular Mitsunobu
reactions/couplings. Alternatively, one of the OH groups can be
converted to a better leaving group such as halo or mesylate, and
the intramolecular cyclization can be performed under suitable
conditions.
##STR00043##
[0589] As shown in Scheme 4-1, the free OH group of compound 4-1a
(wherein Pg.sup.100 is a hydroxyl protecting group such as methyl)
can be converted to a better leaving group for example Br under
suitable conditions (for example, using boron tribromide to convert
OH to Br) to provide compound 4-2a. Removal of the protecting group
Pg.sup.100 of 4-2a provides acyclic precursor 4-3a. Macrocycle 4-4a
[wherein L.sup.1a and L.sup.2a can be the same as those in Scheme
3a] can be cyclized from acyclic precursor 4-3a [wherein Lg.sup.1
is a good leaving group such as halo (e.g Br)] under suitable
conditions (such as in the presence of a base such as NaOH).
Alternatively, the above described chemical transformation can be
started with a compound similar to compound 4-1a, except that the
hydroxyl protecting group Pg.sup.100 is on the OH attached to
L.sup.2a; and that a free OH group (instead of OPg.sup.100) is
attached to L.sup.1a.
##STR00044##
[0590] In addition, many other intramolecular macrocyclizations can
be useful for synthesizing the compounds of the present invention.
For example, amine alkylations and reductive aminations can be
useful for cyclizations as shown in Scheme 5a [wherein L.sup.1a and
L.sup.2a can be the same as those in Scheme 3b].
##STR00045##
[0591] Amide couplings can be useful for cyclizations as shown in
Scheme 5b (similar to the reactions depicted in Scheme 3c, and
wherein L.sup.1a and L.sup.2a can be the same as those in Scheme
3c).
##STR00046## ##STR00047##
[0592] Sulfonamide formation can be useful for cyclization as shown
in Scheme 6a (similar to the reactions depicted in Scheme 3d, and
wherein L.sup.1a and L.sup.2a can be the same as those in Scheme
3d).
##STR00048##
[0593] Urea formation and carbamate formation can be useful for
cyclizations as shown in Scheme 6b (similar to the reactions
depicted in Scheme 3e, and wherein L.sup.1d and L.sup.2d are the
same as those in Scheme 3e).
##STR00049## ##STR00050##
[0594] Useful intermediates 7-4, 7-10, and 7-13 can be made
according to the methods outlined in Scheme 7. Aryl halide or
heteroaryl halide 7-1 can be reacted with alkyne 7-2 under
Sonogashira coupling reaction conditions to afford alkyne 7-3.
[See, K. Sonogashira, Y. Tohda, N. Hagihara (1975). "A convenient
synthesis of acetylenes: catalytic substitutions of acetylenic
hydrogen with bromoalkenes, iodoarenes and bromopyridines".
Tetrahedron Letters 16 (50): 4467-4470.]. The amino group of alkyne
7-3 can be protected with a protecting group Pg.sup.4, followed by
the C.ident.C bond being reduced to a saturated bond by
hydrogenation to afford intermediate 7-4.
[0595] Aryl halide or heteroaryl halide 7-5 can be reacted with
silyl substituted acetylene 7-6 [e.g. (trimethylsilyl)-acetylene]
under Sonogashira coupling reaction conditions, followed by removal
of the silyl group under suitable conditions [e.g., in the presence
of a base (e.g., K.sub.2CO.sub.3)] to afford alkyne 7-7. Alkyne 7-7
can be reacted with aryl halide or heteroaryl halide 7-8 under
Sonogashira coupling reaction condition to afford alkyne 7-9.
Alkyne 7-9 can be reduced via hydrogenation to produce intermediate
7-10. Aryl halide or heteroaryl halide 7-11 can be reacted with
alkyne 7-12 under Sonogashira coupling reaction conditions,
followed by hydrogenation to reduce the C.ident.C bond, to afford
alkyne 7-13.
##STR00051## ##STR00052##
[0596] Useful intermediates 7-4a, 7-10a, and 7-13a can be made
according to the methods outlined in Scheme 7-1 (similar to the
reactions depicted in Scheme 7). Alternatively, in Scheme 7-1
wherein the compounds have a moiety of --(CR'R'').sub.t--NO.sub.2
(i.e. compounds 7-1a, 7-3a, 7-5a, 7-7a,), the moiety of
--(CR'R'').sub.t--NO.sub.2 can be replaced with a moiety of
--(CR'R'').sub.ttt--CN (wherein ttt is 0, 1, or 2). Subsequently,
the moiety of --(CR'R'').sub.ttt--CN (such as those in compounds
7-3a and 7-7a) can be reduced to
--(CR'R'').sub.ttt--CH.sub.2NH.sub.2 under suitable conditions such
as hydrogenation in the presence of Raney nickel, to provide
additional useful intermediates.
##STR00053## ##STR00054##
[0597] Useful intermediates 7-4b, 7-10b, and 7-13b can be made
according to the methods outlined in Scheme 7-2. Aryl
halide/triflate or heteroaryl halide/triflate 7-5b can be reacted
with vinylboronate 7-6b (R groups can be each, independently, H
(e.g., compound 7-6b is a vinylboronic acid when both R are H) or
alklyl; or together with the --O--B--O-- to which they are attached
form an optionally substituted heterocycloalkyl) under
Suzuki-Miyaura reaction condition/Suzuki coupling to form alkene
7-2b [for reviews of the Suzuki-Miyaura reaction, see e.g. Miyaura,
N; Suzuki, A. Chem. Rev., 1995, 95:2457-2483]. Alternatively, a
vinyl stannane (such as tributyl(vinyl)stannane, equivalent to
vinylboronate 7-6b in the Suzuki-Miyaura reaction described herein)
can be used to react with aryl halide or heteroaryl halide 7-5b to
form alkene 7-2b under Stille reaction conditions [See e.g. P.
Espinet, A. M. Echavarren "The Mechanisms of the Stille Reaction";
Angewandte Chemie International Edition; 43 (36): 4704-4734
(2004)]. Aryl halide/triflate or heteroaryl halide/triflate 7-1b
can be reacted with alkene 7-2b under Heck coupling reaction
conditions to afford alkene 7-3b. [See e.g. Heck, R. F.; Nolley,
Jr., J. P., "Palladium-catalyzed vinylic hydrogen substitution
reactions with aryl, benzyl, and styryl halides"; J. Org. Chem.,
37(14): 2320-2322 (1972)]. The amino group of alkene 7-3b can
optionally be protected by an amine protecting group such as Boc
group, followed by reduction of the C.dbd.C bond to a saturated
bond via hydrogenation to afford intermediate 7-4b under an
appropriate condition such as palladium catalyzed hydrogenation or
using a hydrazine compound. [See e.g. Y. Imada, H. Iida, T. Naota,
J. Am. Chem. Soc., 2005, 127, 14544-14545].
[0598] Intermediate 7-10b can be synthesized starting from aryl
halide/triflate or heteroaryl halide/triflate 7-1b (also
substituted with a nitro group) through similar chemical
transformations to those described in the formation of intermediate
7-4b.
[0599] Alternatively, aryl halide/triflate or heteroaryl
halide/triflate 7-11b can be reacted with alkene 7-12b under Heck
coupling reaction conditions, followed by reduction of the C.dbd.C
bond, for example, via hydrogenation, to afford intermediate
7-13b.
##STR00055## ##STR00056##
[0600] Useful intermediates 7-4c, 7-10c, and 7-13c can be made
according to the methods outlined in Scheme 7-3 (similar to those
depicted in Scheme 7-2). Alternatively, in Scheme 7-1 wherein the
compounds have a moiety of --(CR'R'').sub.t--NO.sub.2 (i.e.
compounds 7-1c, 7-3c, 7-5c, 7-7c,), the moiety of
--(CR'R'').sub.t--NO.sub.2 can be replaced with a moiety of
--(CR'R'').sub.ttt--CN (wherein ttt is 0, 1, or 2). Subsequently,
the moiety of --(CR'R'').sub.ttt--CN (such as those in compounds
7-3c and 7-7c) can be reduced to
--(CR'R'').sub.ttt--CH.sub.2NH.sub.2 under suitable conditions such
as hydrogenation in the presence of Raney nickel, to provide
additional useful intermediates.
##STR00057## ##STR00058##
[0601] Useful intermediates 7-2d, 7-4d, 7-10d, and 7-13d can be
made according to the methods outlined in Scheme 7-4 (similar to
the reactions depicted in Scheme 7). The trimethylsilyl (TMS) group
of 7-2-2d can be removed in the presence of a base such as
K.sub.2CO.sub.3 to give compound 7-2d.
##STR00059## ##STR00060##
[0602] As shown in Scheme 8, aryl (or heteroaryl) methyl ketone 8-1
can be reacted with aryl (or heteroaryl) aldehyde 8-2 under basic
conditions [(such as in the presence of an alkali metal hydroxide
(e.g. NaOH)] to afford derivative 8-3. Intermediate 8-3 can be
reduced via hydrogenation (such as in the presence of Pd/C,
hydrogen and acetic acid) to afford compound 8-4, which further can
be reduced to compound 8-5. R.sup.201a and R.sup.301a groups of
compounds 8-4 or 8-5 can undergo further chemical transformations.
For example, the NO.sub.2 group can be reduced to NH.sub.2; and a
protected amino group can be de-protected to NH.sub.2.
Alternatively, in Scheme 8 wherein the compounds have a moiety of
--(CR'R'').sub.t--NO.sub.2 (i.e. R.sup.301a is NO.sub.2), the
moiety --(CR'R'').sub.t--NO.sub.2 can be replaced with a moiety of
--(CR'R'').sub.ttt--CN (wherein ttt is 0, 1, or 2). Subsequently,
the moiety of --(CR'R'').sub.ttt--CN (such as those in compounds
8-3 and 8-5) can be reduced to --(CR'R'').sub.ttt--CH.sub.2NH.sub.2
under suitable conditions such as hydrogenation in the presence of
Raney nickel, to provide additional useful intermediates.
##STR00061##
[0603] Useful intermediates 8-3a, 8-4a, and 8-5a can be made
according to the methods outlined in Scheme 8-1 (similar to the
reactions depicted in Scheme 8). Alternatively, in Scheme 8-1
wherein the compounds have a moiety of --(CR'R'').sub.t--NO.sub.2
(i.e. R.sup.201a is NO.sub.2), the moiety
--(CR'R'').sub.t--NO.sub.2 can be replaced with a moiety of
--(CR'R'').sub.ttt--CN (wherein ttt is 0, 1, or 2). Subsequently,
the moiety of --(CR'R'').sub.ttt--CN (such as those in compounds
8-3a and 8-5a) can be reduced to
--(CR'R'').sub.ttt--CH.sub.2NH.sub.2 under suitable conditions such
as hydrogenation in the presence of Raney nickel, to provide
additional useful intermediates.
##STR00062##
[0604] Some additional useful intermediates can be made by the
methods outlined in Scheme 9. Aryl (or heteroaryl) compound 9-1 can
be reacted with a halogenating reagent [such as bromine (Br.sub.2),
N-bromoacetamide (NBA), N-bromosuccinimide (NBS),
1,3-dibromo-5,5-dimethylhydantoin (DBDMH),
1,3-dichloro-5,5-dimethylhydantoin (DCDMH), N-chlorosuccinimide
(NCS)] to afford halogenated compounds 9-2.
[0605] A fluorinated compound 9-3 can be reacted with an amine, an
alcohol, or thioalcohol in the presence of a base (such as a
tertiary amine, e.g., TEA) to form compound 9-4. Where R.sup.50 is
SR.sup.a1, compound 9-4 can be oxidized to sulfinyl or sulfonyl
compounds 9-5 (wherein y is 1 or 2), using an oxidizing reagent
such as m-chloroperoxybenzoic acid (mCPBA).
[0606] A fluorinated compound 9-6 can be reacted with an amine, an
alcohol, or thioalcohol in the presence of a base (such as a
tertiary amine, e.g., triethylamine or TEA) to form compound 9-7.
Where R.sup.50 is SR.sup.a1, compound 9-7 can be oxidized to
sulfinyl or sulfonyl compound 9-8 (wherein y is 1 or 2), using an
oxidizing reagent such as m-chloroperoxybenzoic acid (mCPBA). The
nitro (NO.sub.2) group of compound 9-8 can be reduced, for example,
in the presence of Fe (or Zn) and acetic acid, followed by
introduction of an amine protecting group (such as Boc), to afford
compound 9-9.
##STR00063##
[0607] As shown in Scheme 10, compound 10-1 [wherein R.sup.4 can be
H, methyl, ethyl, or the like; and Lg.sup.3 is a leaving group such
as halo (e.g., chloro)] can be reacted with substituted
heteroaromatic compound 10-2 [wherein Lg.sup.1 and Lg.sup.2 are
each, independently, a leaving group such as halo (e.g., chloro)]
in the presence of a suitable base (such as an inorganic base, for
example a metal carbonate (e.g., potassium carbonate), a metal
hydride (e.g., sodium hydride), a metal hydroxide (e.g., sodium
hydroxide), a metal alkoxide (e.g., sodium ethoxide)] and/or in the
presence of a transition metal catalyst for example a palladium
catalyst [e.g., Pd(PPh.sub.3).sub.4] to afford compound 10-3.
Reaction of compound 10-3 and alkene 10-4 under Heck coupling
reaction conditions gives alkene compound 10-5. Reduction of the
C.dbd.C bond (between the two aromatic rings) of compound 10-5 to a
saturated bond under an appropriate condition such as palladium
catalyzed hydrogenation or using a hydrazine compound, followed by
optional deprotection (when R.sup.101 is an amine protecting group)
and ring closure step [in the presence of an acid (e.g.
p-toluenesulfonic acid (PTSA) or HCl,) or a Pd catalyst], gives
compound 10-6.
##STR00064##
[0608] Similar to the chemical reactions/transformations depicted
in Scheme 10, compound 11-6 can be synthesized according to the
methods shown in Scheme 11 wherein alkene 11-4 is substituted with
a nitro group.
##STR00065##
[0609] As shown in Scheme 12, arylamine 12-1 can be converted to
its corresponding diazonium salt intermediate using NaNO.sub.2
under acidic condition, followed by conversion of the diazonium
salt to halide 12-2 [Se e.g., "The Chemistry of Functional Groups.
The Chemistry of Diazonium and Diazo Groups" Wiley: New York, 1978,
the articles by Hegarty, pt. 2, pp. 511-591, and Schank, pt. 2, pp.
645-657; See also, P. S. Kalsi, "Organic Reactions Stereochemistry
and Mechanism: Through Solved Problems"; Chapter 6, page 362
(Sandmeyer Reaction), New Age Publishers, 4th edition, 2006]. The
compound 12-2 can be converted to a carbamate compound such as the
BOC-protected amine 12-3 via Curtis rearrangement [See Ende, D. J.
a.; DeVries, K. M.; Clifford, P. J.; Brenek, S. J. Org. Proc. Res.
Dev. 1998, 2, 382-392]. The CN group of compound 12-3 can be
reduced to CH.sub.2NH.sub.2, followed by coupling to compound 12-5
(for example, in the presence of a base or a Pd catalyst), to
afford compound 12-6. Compound 12-6 can be reacted with alkene 12-7
under Heck Reaction conditions to afford compound 12-8. Reduction
of the C.dbd.C bond (between the two aromatic rings) of compound
12-8 to a saturated bond via hydrogenation, followed by ring
closure step (for example in the presence of a Pd catalyst or an
acid such as HCl or PTSA), gives compound 12-9. Optional
deprotection (when R.sup.101 is an amine protecting group) of
compound 12-9, followed by further chemical modifications such as
acylation (or sulfonylation, urea formation, carbamate formation,
or arylation/heteraylation) can afford different compounds of
invention such as compound 12-10.
##STR00066## ##STR00067##
[0610] As shown in Scheme 13, compound 13-6 can be synthesized
starting from amine 13-1, by chemical reactions similar to those
for making compound 12-9 in Scheme 12. After the demethylation step
(see. e.g. J. F. W. McOmie, M. L. Watts, and D. E. West,
"Demethylation of aryl methyl ethers by boron tribromide";
Tetrahedron, Volume 24, Issue 5, 1968, Pages 2289-2292), the OH
group of compound 13-6 can undergo further chemical modifications
such as ether formation (R.sup.300 can be, e.g., C.sub.1,.sub.6
alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or
heterocycloalkylalkyl), ester formation (R.sup.300 can be, e.g.,
C(O)R.sup.b1), or carbamate formation (R.sup.300 can be, e.g.,
C(O)NR.sup.c1R.sup.d1).
##STR00068##
[0611] Additional starting materials and intermediates useful for
making the compounds of the present invention can be obtained from
chemical vendors such as Sigma-Aldrich or can be made according to
methods described in the chemical art. For example, introducing
pentafluorosulfanyl (SF.sub.5) group to aromatic rings can be
achieved according to the methods disclosed in U.S. Pat. No.
6,919,484 and/or the references cited therein.
[0612] Those skilled in the art can recognize that in all of the
schemes described herein, if there are functional (reactive) groups
present on a substituent group such as R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
L.sup.1, L.sup.2, etc., further modification can be made if
appropriate and/or desired. For example, a CN group can be
hydrolyzed to afford an amide group; a carboxylic acid can be
converted to an amide; a carboxylic acid can be converted to an
ester, which in turn can be reduced to an alcohol, which in turn
can be further modified. For another example, an OH group can be
converted into a better leaving group such as mesylate, which in
turn is suitable for nucleophilic substitution, such as by CN. For
another example, an --S-- can be oxidized to --S(O)-- and/or
--S(O).sub.2--. For yet another example, unsaturated bond such as
C.dbd.C or C.ident.C can be reduced to saturated bond by
hydrogenation. In some embodiments, a primary amine or a secondary
amine moiety (present on a substituent group such as R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, R.sup.10, L.sup.1, L.sup.2, etc.) can be converted to
amide, sulfonamide, urea, or thiourea moiety by reacting it with an
appropriate reagent such as an acid chloride, a sulfonyl chloride,
an isocyanate, or a thioisocyanate compound. In some embodiments, a
primary amine, a secondary amine, or a tertiary amine moiety
(present on a substituent group such as R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
L.sup.1, L.sup.2, etc.) can be alkylated to form a quaternary
ammonium salt. One skilled in the art will recognize further such
modifications. Thus, a compound of Formula I (such as compound 1-2
of Scheme 1) having a substituent which contains a functional group
can be converted to another compound of Formula I having a
different substituent group.
[0613] As used herein, the term "reacting" refers to the bringing
together of designated chemical reactants such that a chemical
transformation takes place generating a compound different from any
initially introduced into the system. Reacting can take place in
the presence or absence of solvent.
Methods
[0614] Compounds of the invention can modulate activity of one or
more Janus kinases (JAKs). The term "modulate" is meant to refer to
an ability to increase or decrease the activity of one or more
members of the JAK family of kinases. Accordingly, compounds of the
invention can be used in methods of modulating a JAK by contacting
the JAK with any one or more of the compounds or compositions
described herein. In some embodiments, compounds of the present
invention can act as inhibitors of one or more JAKs. In further
embodiments, the compounds of the invention can be used to modulate
activity of a JAK in an individual in need of modulation of the
enzyme by administering a modulating amount of a compound of the
invention.
[0615] JAKs to which the present compounds bind and/or modulate
include any member of the JAK family. In some embodiments, the JAK
is JAK1, JAK2, JAK3 or TYK2. In some embodiments, the JAK is JAK1
or JAK2. In some embodiments, the JAK is JAK2. In some embodiments,
the JAK is JAK3. In some embodiments, the JAK is TYK2.
[0616] Another aspect of the present invention pertains to methods
of treating a JAK-associated disease or disorder in an individual
(e.g., patient) by administering to the individual a
therapeutically effective amount or dose of a compound of the
present invention or a pharmaceutical composition thereof. In some
embodiments, the individual has been diagnosed to have a
JAK-associated disease or disorder and is in need of treatment for
the disease or disorder. A JAK-associated disease can include any
disease, disorder or condition that is directly or indirectly
linked to expression or activity of the JAK, including over
expression and/or abnormal activity levels. A JAK-associated
disease can also include any disease, disorder or condition that
can be prevented, ameliorated, or cured by modulating JAK
activity.
[0617] Examples of JAK-associated diseases include diseases
involving the immune system including, for example, organ
transplant rejection (e.g., allograft rejection and graft versus
host disease).
[0618] Further examples of JAK-associated diseases include
autoimmune diseases such as multiple sclerosis, rheumatoid
arthritis, juvenile arthritis, psoriatic arthritis, type I
diabetes, lupus, psoriasis, inflammatory bowel disease (e.g,
ulcerative colitis and Crohn's disease), ankylosing spondylitis,
myasthenia gravis, immunoglobulin nephropathies, autoimmune thyroid
disorders, and the like. In some embodiments, the autoimmune
disease is an autoimmune bullous skin disorder such as pemphigus
vulgaris (PV) or bullous pemphigoid (BP). In some embodiments,
JAK-associated diseases include rheumatoid arthritis.
[0619] Further examples of JAK-associated diseases include allergic
conditions such as asthma, food allergies, atopic dermatitis and
rhinitis. Further examples of JAK-associated diseases include viral
diseases such as Epstein Barr Virus (EBV), Hepatitis B, Hepatitis
C, HIV, HTLV 1, Varicella-Zoster Virus (VZV) and Human Papilloma
Virus (HPV).
[0620] Further examples of JAK-associated diseases or conditions
include skin disorders such as psoriasis (for example, psoriasis
vulgaris), atopic dermatitis, alopecia areata, skin rash, skin
irritation, skin sensitization (e.g., contact dermatitis or
allergic contact dermatitis). For example, certain substances
including some pharmaceuticals when topically applied can cause
skin sensitization. In some embodiments, co-administration or
sequential administration of at least one JAK inhibitor of the
invention together with the agent causing unwanted sensitization
can be helpful in treating such unwanted sensitization or
dermatitis. In some embodiments, the skin disorder is treated by
topical administration of at least one JAK inhibitor of the
invention.
[0621] In further embodiments, the JAK-associated disease is cancer
including those characterized by solid tumors (e.g., prostate
cancer, renal cancer, hepatic cancer, colorectal cancer, pancreatic
cancer, gastric cancer, breast cancer, lung cancer, cancers of the
head and neck, thyroid cancer, glioblastoma, Kaposi's sarcoma,
melanoma etc.), hematological cancers or malignancies [e.g.,
lymphoma, leukemia such as acute lymphoblastic leukemia, Chronic
Lymphocytic Leukemia (CLL), myelodysplastic syndrome (MDS), acute
myelogenous leukemia (AML), chronic myelogenous leukemia (CML),
chronic myelomonocytic leukemia (CMML), or multiple myeloma, and
other lymphoma related diseases including Castleman's disease,
Waldenstrom's macroglobulinemia, and Poems syndrome], and skin
cancer such as cutaneous T-cell lymphoma (CTCL) and cutaneous
B-cell lymphoma. Examples of cutaneous T-cell lymphomas include
Sezary syndrome and mycosis fungoides. Other kinase associated
diseases may also include paraneoplastic syndromes associated with
cytokine production in cancer.
[0622] JAK-associated diseases can further include those
characterized by expression of a mutant JAK such as those having at
least one mutation in the pseudo-kinase and/or kinase domain (e.g.,
JAK2V617F or JAK1R724H) or genetic or epigenetic alterations known
or thought to result in dysregulated JAK activity (e.g. SOCS gene
methylation or MPL mutation).
[0623] JAK-associated diseases can further include
myeloproliferative disorders (MPDs) such as polycythemia vera (PV),
essential thrombocythemia (ET), myelofibrosis with myeloid
metaplasia (MMM), hypereosinophilic syndrome (HES), systemic mast
cell disease (SMCD), and the like. In some embodiments, the
myeloproliferative disorder is myelofibrosis with myeloid
metaplasia (MMM). In some embodiments, the myeloproliferative
disorder is selected from primary myelofibrosis (PMF). PMF has been
known by a variety of terms including myelofibrosis with myeloid
metaplasia (MMM), agnogenic myeloid metaplasia, and chronic
idiopathic myelofibrosis. Myelofibrosis (MF) can present as a de
novo disorder (PMF) or evolve from previous PV or ET
[post-polycythemia vera myelofibrosis (Post-PV MF) or
post-essential thrombocythemia myelofibrosis (Post-ET MF)].
Myelofibrosis develops in 10% to 20% of patients with PV (see e.g.
J. L. Spivak, G. Barosi, G. Tognoni, T. Barbui, G. Finazzi, R.
Marchioli, and M. Marchetti; "Chronic Myeloproliferative
Disorders"; Hematology, January 2003; 2003: 200-224) and in 2% to
3% of patients with ET (See e.g. D.R. Berk and A. Ahmed; "Portal,
splenic, and superior mesenteric vein thrombosis in a patient with
latent essential thrombocythemia and hyperhomocysteinemia"; J.
Clin. Gastroenterol., 2006; 40: 3: 227-8).
[0624] Further JAK-associated diseases include inflammation and
inflammatory diseases. Examples of inflammatory diseases include
inflammatory diseases of the eye (e.g., iritis, uveitis, scleritis,
conjunctivitis, or related disease), inflammatory diseases of the
respiratory tract (e.g., the upper respiratory tract including the
nose and sinuses such as rhinitis or sinusitis or the lower
respiratory tract including bronchitis, chronic obstructive
pulmonary disease, and the like), inflammatory myopathy (such as
myocarditis), Systemic Inflammatory Response Syndrome (SIRS),
septic shock, and other inflammatory diseases.
[0625] The JAK antagonists/inhibitors described herein can further
be used to treat ischemia reperfusion injuries or a disease or
condition related to an inflammatory ischemic event such as stroke
or cardiac arrest. The JAK antagonists/inhibitors described herein
can further be used to treat anorexia, cachexia, or fatigue such as
that resulting from or associated with cancer. The JAK
antagonists/inhibitors described herein can further be used to
treat restenosis, sclerodermitis, or fibrosis. The JAK
antagonists/inhibitors described herein can further be used to
treat conditions associated with hypoxia or astrogliosis such as,
for example, diabetic retinopathy, cancer, or neurodegeneration.
See, e.g., Dudley, A. C. et al. Biochem. J. 2005, 390(Pt 2):427-36
and Sriram, K. et al. J. Biol. Chem. 2004, 279(19):19936-47. Epub
2004 Mar. 2.
[0626] The JAK/ALK antagonists/inhibitors described herein can be
used to treat any of the JAK-associated diseases, disorders or
conditions and/or ALK-associated diseases, disorders or conditions,
or any combination thereof. In some embodiments, the JAK
antagonists/inhibitors described herein can be used to treat any of
the JAK-associated diseases diseases, disorders or conditions, or
any combination thereof.
[0627] The JAK antagonists/inhibitors described herein can further
be used to treat any of the JAK-associated diseases or any
combination thereof.
[0628] Certain compounds of the invention (the IC.sub.50 of which
with respect to ALK is less than about 10 .mu.M) can also modulate
activity of ALK kinases. The term "modulate" is meant to, in this
context, refer to an ability to increase or decrease the activity
of the ALK kinases. Certain compounds of the invention can be used
in methods of modulating an ALK by contacting the ALK with any one
or more of the compounds or compositions described herein. In some
embodiments, certain compounds of the present invention (the
IC.sub.50 of which with respect to ALK is less than about 10 .mu.M)
can act as antagonists/inhibitors of ALK. Certain compounds of the
invention (the IC.sub.50 of which with respect to ALK is less than
about 10 .mu.M) can be used to modulate activity of an ALK in an
individual in need of modulation of the enzyme by administering a
modulating amount of a compound of the invention.
[0629] Another aspect of the present invention pertains to methods
of treating an ALK-associated disease or disorder in an individual
(e.g., patient) by administering to the individual a
therapeutically effective amount or dose of a compound of the
present invention (the IC.sub.50 of which with respect to ALK is
less than about 10 .mu.M) or a pharmaceutical composition thereof.
In some embodiments, the individual is diagnosed to have an
ALK-associated disease or disorder and is in need of treatment for
the disease or disorder. An ALK-associated disease can include any
disease, disorder or condition that is directly or indirectly
linked to expression or activity of the ALK, including over
expression and/or abnormal activity levels. An ALK-associated
disease can also include any disease, disorder or condition that
can be prevented, ameliorated, or cured by modulating ALK activity.
Examples of ALK-associated diseases include diseases involving
ALK-related tumors including anaplastic large cell lymphomas and
non-Hodgkin lymphomas in addition to lung cancers.
[0630] Treatment of the diseases/disorders herein includes treating
one or more symptoms associated with the diseases/disorders. For
example, symptoms of a JAK-associated skin disorder (such as
psoriasis, atopic dermatitis, skin rash, skin irritation, or skin
sensitization) include itching (prutitus).
[0631] As used herein, the term "contacting" refers to the bringing
together of indicated moieties in an in vitro system or an in vivo
system. For example, "contacting" a JAK/ALK with a compound of the
invention includes the administration of a compound of the present
invention to an individual or patient, such as a human, having a
JAK/ALK, as well as, for example, introducing a compound of the
invention into a sample containing a cellular or purified
preparation containing the JAK/ALK.
[0632] As used herein, the term "individual" or "patient," used
interchangeably, refers to any animal, including mammals,
preferably mice, rats, other rodents, rabbits, dogs, cats, swine,
cattle, sheep, horses, or primates, and most preferably humans.
[0633] As used herein, the phrase "therapeutically effective
amount" refers to the amount of active compound or pharmaceutical
agent that elicits the biological or medicinal response that is
being sought in a tissue, system, animal, individual or human by a
researcher, veterinarian, medical doctor or other clinician.
[0634] As used herein, the term "treating" or "treatment" refers to
one or more of (1) preventing the disease; for example, preventing
a disease, condition or disorder in an individual who may be
predisposed to the disease, condition or disorder but does not yet
experience or display the pathology or symptomatology of the
disease; (2) inhibiting/retarding the disease; for example,
inhibiting/retarding a disease, condition or disorder in an
individual who is experiencing or displaying the pathology or
symptomatology of the disease, condition or disorder; and (3)
ameliorating the disease; for example, ameliorating a disease,
condition or disorder in an individual who is experiencing or
displaying the pathology or symptomatology of the disease,
condition or disorder (i.e., reversing the pathology and/or
symptomatology) such as decreasing the severity of disease or
completely eliminating/curing the disease. As used herein, treating
a disease further includes treating one or more symptoms associated
with the disease.
Combination Therapies
[0635] One or more additional pharmaceutical agents such as, for
example, chemotherapeutics, anti-inflammatory agents, steroids,
immunosuppressants, as well as Bcr-Abl, Flt-3, RAF, IKK, EGFR, MET,
IGF1R, and FAK, ALK kinase inhibitors such as, for example, those
described in WO 2006/056399, or other agents can be used in
combination with the compounds of the present invention for
treatment of JAK/ALK-associated diseases, disorders or conditions.
The one or more additional pharmaceutical agents can be
administered to a patient simultaneously or sequentially.
[0636] Examples of chemotherapeutics include proteosome inhibitors
(e.g., bortezomib), thalidomide, revlimid, pomalidomide,
DNA-damaging agents such as melphalan, doxorubicin,
cyclophosphamide, vincristine, etoposide, carmustine, tubulin
targeted agents (e.g. taxanes and vincristine), topoisomerase
inhibitors (e.g. irinotecan), enzymes (e.g. L-asparaginase),
antimetabolites (e.g. gemcitabine and hyroxyurea), and the
like.
[0637] Examples of steroids include coriticosteroids such as
dexamethasone or prednisone.
[0638] Examples of Bcr-Abl inhibitors include the compounds, and
pharmaceutically acceptable salts thereof, of the genera and
species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281,
EP2005/009967, EP2005/010408, and U.S. Ser. No. 60/578,491.
[0639] Examples of suitable Flt-3 inhibitors include compounds, and
their pharmaceutically acceptable salts, as disclosed in WO
03/037347, WO 03/099771, and WO 04/046120.
[0640] Examples of suitable RAF inhibitors include compounds, and
their pharmaceutically acceptable salts, as disclosed in WO
00/09495 and WO 05/028444.
[0641] Examples of suitable FAK inhibitors include compounds, and
their pharmaceutically acceptable salts, as disclosed in WO
04/080980, WO 04/056786, WO 03/024967, WO 01/064655, WO 00/053595,
and WO 01/014402.
[0642] Examples of suitable ALK inhibitors include compounds, and
their pharmaceutically acceptable salts, as disclosed in WO
04/079326.
[0643] In some embodiments, one or more of the compounds of the
invention can be used in combination with one or more other kinase
inhibitors including imatinib, particularly for treating patients
resistant to imatinib or other kinase inhibitors.
[0644] In some embodiments, one or more JAK/ALK inhibitors of the
invention can be used in combination with a chemotherapeutic in the
treatment of cancer, such as multiple myeloma, and may improve the
treatment response as compared to the response to the
chemotherapeutic agent alone, without exacerbation of its toxic
effects. Examples of additional pharmaceutical agents used in the
treatment of multiple myeloma, for example, can include, without
limitation, melphalan, melphalan plus prednisone [MP], doxorubicin,
dexamethasone, and Velcade (bortezomib). Further additional agents
used in the treatment of multiple myeloma include Bcr-Abl, Flt-3,
IGF1R, RAF and FAK kinase inhibitors. Additive or synergistic
effects are desirable outcomes of combining a JAK/ALK inhibitor of
the present invention with an additional agent. Furthermore,
resistance of multiple myeloma cells to agents such as
dexamethasone may be reversible upon treatment with a JAK/ALK
inhibitor of the present invention. The agents can be combined with
the present compounds in a single or continuous dosage form, or the
agents can be administered simultaneously or sequentially as
separate dosage forms.
[0645] In some embodiments, a corticosteroid such as dexamethasone
is administered to a patient in combination with at least one
JAK/ALK inhibitor where the dexamethasone is administered
intermittently as opposed to continuously.
[0646] In some further embodiments, combinations of one or more
JAK/ALK inhibitors of the invention with other therapeutic agents
can be administered to a patient prior to, during, and/or after a
bone marrow transplant or stem cell transplant.
Pharmaceutical Formulations and Dosage Forms
[0647] When employed as pharmaceuticals, the compounds of the
invention can be administered in the form of pharmaceutical
compositions. These compositions can be prepared in a manner well
known in the pharmaceutical art, and can be administered by a
variety of routes, depending upon whether local or systemic
treatment is desired and upon the area to be treated.
Administration may be topical (including transdermal, epidermal,
ophthalmic and to mucous membranes including intranasal, vaginal
and rectal delivery), pulmonary (e.g., by inhalation or
insufflation of powders or aerosols, including by nebulizer;
intratracheal or intranasal), oral or parenteral. Parenteral
administration includes intravenous, intraarterial, subcutaneous,
intraperitoneal intramuscular or injection or infusion; or
intracranial, e.g., intrathecal or intraventricular,
administration. Parenteral administration can be in the form of a
single bolus dose, or may be, for example, by a continuous
perfusion pump. Pharmaceutical compositions and formulations for
topical administration may include transdermal patches, ointments,
lotions, creams, gels, drops, suppositories, sprays, liquids and
powders. Conventional pharmaceutical carriers, aqueous, powder or
oily bases, thickeners and the like may be necessary or desirable.
Coated condoms, gloves and the like may also be useful.
[0648] This invention also includes pharmaceutical compositions
which contain, as the active ingredient, one or more of the
compounds of the invention above in combination with one or more
pharmaceutically acceptable carriers (excipients). In making the
compositions of the invention, the active ingredient is typically
mixed with an excipient, diluted by an excipient or enclosed within
such a carrier in the form of, for example, a capsule, sachet,
paper, or other container. When the excipient serves as a diluent,
it can be a solid, semi-solid, or liquid material, which acts as a
vehicle, carrier or medium for the active ingredient. Thus, the
compositions can be in the form of tablets, pills, powders,
lozenges, sachets, cachets, elixirs, suspensions, emulsions,
solutions, syrups, aerosols (as a solid or in a liquid medium),
ointments containing, for example, up to 10% by weight of the
active compound, soft and hard gelatin capsules, suppositories,
sterile injectable solutions, and sterile packaged powders.
[0649] In preparing a formulation, the active compound can be
milled to provide the appropriate particle size prior to combining
with the other ingredients. If the active compound is substantially
insoluble, it can be milled to a particle size of less than 200
mesh. If the active compound is substantially water soluble, the
particle size can be adjusted by milling to provide a substantially
uniform distribution in the formulation, e.g. about 40 mesh.
[0650] The compounds of the invention may be milled using known
milling procedures such as wet milling to obtain a particle size
appropriate for tablet formation and for other formulation types.
Finely divided (nano particulate) preparations of the compounds of
the invention can be prepared by processes known in the art, for
example see International Patent Application No. WO
2002/000196.
[0651] Some examples of suitable excipients include lactose,
dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,
calcium phosphate, alginates, tragacanth, gelatin, calcium
silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, water, syrup, and methyl cellulose. The formulations can
additionally include: lubricating agents such as talc, magnesium
stearate, and mineral oil; wetting agents; emulsifying and
suspending agents; preserving agents such as methyl- and
propylhydroxy-benzoates; sweetening agents; and flavoring agents.
The compositions of the invention can be formulated so as to
provide quick, sustained or delayed release of the active
ingredient after administration to the patient by employing
procedures known in the art.
[0652] The compositions can be formulated in a unit dosage form,
each dosage containing from about 5 to about 1000 mg (1 g), more
usually about 100 to about 500 mg, of the active ingredient. The
term "unit dosage forms" refers to physically discrete units
suitable as unitary dosages for human subjects and other mammals,
each unit containing a predetermined quantity of active material
calculated to produce the desired therapeutic effect, in
association with a suitable pharmaceutical excipient.
[0653] The active compound can be effective over a wide dosage
range and can be generally administered in a pharmaceutically
effective amount. For example, the dosage of the active compounds
of the invention as employed for the treatment of a patient in need
thereof (such as an adult human) may range from 0.1 to 3000 mg per
day, depending on the route and frequency of administration. Such a
dosage corresponds to 0.001 to 50 mg/kg per day. In some
embodiments, the dosage of the active compounds of the invention as
employed for the treatment of a patient in need thereof (such as an
adult human) may range from 1 to 2000 mg per day, from 1 to 1000 mg
per day, from 10 to 1000 mg per day, or from 10 to 500 mg per day.
It will be understood, however, that the amount of the compound
actually administered will usually be determined by a physician,
according to the relevant circumstances, including the condition to
be treated, the chosen route of administration, the actual compound
administered, the age, weight, and response of the individual
patient, the severity of the patient's symptoms, and the like.
[0654] For preparing solid compositions such as tablets, the
principal active ingredient can be mixed with a pharmaceutical
excipient to form a solid pre-formulation composition containing a
homogeneous mixture of a compound of the present invention. When
referring to these pre-formulation compositions as homogeneous, the
active ingredient is typically dispersed evenly throughout the
composition so that the composition can be readily subdivided into
equally effective unit dosage forms such as tablets, pills and
capsules. This solid pre-formulation is then subdivided into unit
dosage forms of the type described above containing from, for
example, about 0.1 to about 1000 mg of the active ingredient of the
present invention.
[0655] The tablets or pills of the present invention can be coated
or otherwise compounded to provide a dosage form affording the
advantage of prolonged action. For example, the tablet or pill can
comprise an inner dosage and an outer dosage component, the latter
being in the form of an envelope over the former. The two
components can be separated by an enteric layer which serves to
resist disintegration in the stomach and permit the inner component
to pass intact into the duodenum or to be delayed in release. A
variety of materials can be used for such enteric layers or
coatings, such materials including a number of polymeric acids and
mixtures of polymeric acids with such materials as shellac, cetyl
alcohol, and cellulose acetate.
[0656] The liquid forms in which the compounds and compositions of
the present invention can be incorporated for administration orally
or by injection include aqueous solutions, suitably flavored
syrups, aqueous or oil suspensions, and flavored emulsions with
edible oils such as cottonseed oil, sesame oil, coconut oil, or
peanut oil, as well as elixirs and similar pharmaceutical
vehicles.
[0657] Compositions for inhalation or insufflation include
solutions and suspensions in pharmaceutically acceptable, aqueous
or organic solvents, or mixtures thereof, and powders. The liquid
or solid compositions may contain suitable pharmaceutically
acceptable excipients as described supra. In some embodiments, the
compositions are administered by the oral or nasal respiratory
route for local or systemic effect. Compositions in can be
nebulized by use of inert gases. Nebulized solutions may be
breathed directly from the nebulizing device or the nebulizing
device can be attached to a face masks tent, or intermittent
positive pressure breathing machine. Solution, suspension, or
powder compositions can be administered orally or nasally from
devices which deliver the formulation in an appropriate manner.
[0658] The amount of compound or composition administered to a
patient will vary depending upon what is being administered, the
purpose of the administration, such as prophylaxis or therapy, the
state of the patient, the manner of administration, and the like.
In therapeutic applications, compositions can be administered to a
patient already suffering from a disease in an amount sufficient to
cure or at least partially arrest the symptoms of the disease and
its complications. Effective doses will depend on the disease
condition being treated as well as by the judgment of the attending
clinician depending upon factors such as the severity of the
disease, the age, weight and general condition of the patient, and
the like.
[0659] The compositions administered to a patient can be in the
form of pharmaceutical compositions described above. These
compositions can be sterilized by conventional sterilization
techniques, or may be sterile filtered. Aqueous solutions can be
packaged for use as is, or lyophilized, the lyophilized preparation
being combined with a sterile aqueous carrier prior to
administration. The pH of the compound preparations typically will
be between 3 and 11, more preferably from 5 to 9 and most
preferably from 7 to 8. It will be understood that use of certain
of the foregoing excipients, carriers, or stabilizers will result
in the formation of pharmaceutical salts.
[0660] The therapeutic dosage of the compounds of the present
invention can vary according to, for example, the particular use
for which the treatment is made, the manner of administration of
the compound, the health and condition of the patient, and the
judgment of the prescribing physician. The proportion or
concentration of a compound of the invention in a pharmaceutical
composition can vary depending upon a number of factors including
dosage, chemical characteristics (e.g., hydrophobicity), and the
route of administration. For example, the compounds of the
invention can be provided in an aqueous physiological buffer
solution containing about 0.1 to about 10% w/v of the compound for
parenteral administration. Some typical dose ranges are from about
1 .mu.g/kg to about 1 g/kg of body weight per day. In some
embodiments, the dose range is from about 0.01 mg/kg to about 100
mg/kg of body weight per day. The dosage is likely to depend on
such variables as the type and extent of progression of the disease
or disorder, the overall health status of the particular patient,
the relative biological efficacy of the compound selected,
formulation of the excipient, and its route of administration.
Effective doses can be extrapolated from dose-response curves
derived from in vitro or animal model test systems.
[0661] The compositions of the invention can further include one or
more additional pharmaceutical agents such as a chemotherapeutic,
steroid, anti-inflammatory compound, or immunosuppressant, examples
of which are listed hereinabove.
Labeled Compounds and Assay Methods
[0662] Another aspect of the present invention relates to labeled
compounds of the invention (radio-labeled, fluorescent-labeled,
etc.) that would be useful not only in radio-imaging but also in
assays, both in vitro and in vivo, for localizing and quantitating
the enzyme in tissue samples, including human, and for identifying
ligands by inhibition binding of a labeled compound. Accordingly,
the present invention includes enzyme assays that contain such
labeled compounds.
[0663] The present invention further includes isotopically-labeled
compounds of the invention. An "isotopically" or "radio-labeled"
compound is a compound of the invention where one or more atoms are
replaced or substituted by an atom having an atomic mass or mass
number different from the atomic mass or mass number typically
found in nature (i.e., naturally occurring). Suitable radionuclides
that may be incorporated in compounds of the present invention
include but are not limited to .sup.2H (also written as D for
deuterium), .sup.3H (also written as T for tritium), .sup.11C,
.sup.13C, .sup.14C, .sup.13N, .sup.15N, .sup.15O, .sup.17O,
.sup.18O, .sup.18F, .sup.35S, .sup.36Cl, .sup.82Br, .sup.75Br,
.sup.76Br, .sup.77Br, .sup.123I, .sup.124I, .sup.125I and
.sup.131I. The radionuclide that is incorporated in the
radio-labeled compounds will depend on the specific application of
that radio-labeled compound. For example, for in vitro receptor
labeling and competition assays, compounds that incorporate
.sup.3H, .sup.14C, .sup.82Br, .sup.125I, .sup.131I, .sup.35S or
will generally be most useful. For radio imaging applications
.sup.11C, .sup.18F, .sup.125I, .sup.123I, .sup.124I, .sup.131I,
.sup.75Br, .sup.76Br or .sup.77Br will generally be most
useful.
[0664] It is understood that a "radio-labeled compound" is a
compound that has incorporated at least one radionuclide. In some
embodiments the radionuclide is selected from .sup.3H, .sup.14C,
.sup.125I, .sup.35S and .sup.82Br.
[0665] In some embodiments, the labeled compounds of the present
invention contain a fluorescent label.
[0666] Synthetic methods for incorporating radio-isotopes and
fluorescent labels into organic compounds are well known in the
art.
[0667] A labeled compound of the invention (radio-labeled,
fluorescent-labeled, etc.) can be used in a screening assay to
identify/evaluate compounds. For example, a newly synthesized or
identified compound (i.e., test compound) which is labeled can be
evaluated for its ability to bind a JAK/ALK by monitoring its
concentration variation when contacting with the JAK/ALK, through
tracking the labeling. For another example, a test compound
(labeled) can be evaluated for its ability to reduce binding of
another compound which is known to bind to JAK/ALK (i.e., standard
compound). Accordingly, the ability of a test compound to compete
with the standard compound for binding to the JAK/ALK directly
correlates to its binding affinity. Conversely, in some other
screening assays, the standard compound is labeled and test
compounds are unlabeled. Accordingly, the concentration of the
labeled standard compound is monitored in order to evaluate the
competition between the standard compound and the test compound,
and the relative binding affinity of the test compound is thus
ascertained.
Kits
[0668] The present invention also includes pharmaceutical kits
useful, for example, in the treatment or prevention of
JAK/ALK-associated diseases or disorders such as prostate cancer,
renal cancer, hepatic cancer, breast cancer, lung cancer, and other
diseases referred to herein which include one or more containers
containing a pharmaceutical composition comprising a
therapeutically effective amount of a compound of the invention.
Such kits can further include, if desired, one or more of various
conventional pharmaceutical kit components, such as, for example,
containers with one or more pharmaceutically acceptable carriers,
additional containers, etc., as will be readily apparent to those
skilled in the art. Instructions, either as inserts or as labels,
indicating quantities of the components to be administered,
guidelines for administration, and/or guidelines for mixing the
components, can also be included in the kit.
[0669] The invention will be described in greater detail by way of
specific examples. The following examples are offered for
illustrative purposes, and are not intended to limit the invention
in any manner. Those of skill in the art will readily recognize a
variety of non-critical parameters which can be changed or modified
to yield essentially the same results. In some instances where the
compounds of the examples were isolated by preparative HPLC in the
presence of trifluoroacetic acid (TFA) or other acid, the compound
may have been obtained as the corresponding salt. Certain compounds
of the Examples were found to be inhibitors of JAK/ALK according to
one or more of the assays provided herein. In some embodiments, the
IC.sub.50 value for the compound of invention with respect one or
more of JAK/ALK is less than about 100, 80, 50, 20, 10, 8, 5, 2, or
1 .mu.M. In some embodiments, the IC.sub.50 value for the compound
of invention with respect to one or more of ALK is less than about
100, 80, 50, 20, 10, 8, 5, 2, or 1 .mu.M. In some embodiments, the
IC.sub.50 value for the compound of invention with respect to one
or more of JAK is less than about 100, 80, 50, 20, 10, 8, 5, 2, or
1 .mu.M. In some embodiments, the IC.sub.50 value for the compound
of invention with respect one or more of JAK/ALK is less than about
1000, 800, 500, 200, 100, 80, 50, 20, or 10 nM. Certain compounds
described in Tables 1 and in the Example section were tested for
inhibitory activity of JAK/ALK targets according to assays such as
those described herein or those known in the art [e.g., ALK assays
described in WO 04/079326; and TYK2 assays described by James E.
Thompson et. al, "Photochemical preparation of a pyridone
containing tetracycle: A JAK protein kinase inhibitor," Bioorganic
& Medicinal Chemistry Letters, Volume 12, Issue 8, 22 Apr.
2002, Pages 1219-1223]. For instance, Examples 1-10 and 12-16 were
found to have IC.sub.50 values less than 1000 nM, 800 nM, 500 nM,
200 nM, or 100 nM for at least one of JAK1, JAK2, JAK3, TYK2, and
ALK. Some exemplary data of the compounds of the invention are
shown in Table 1 in the experimental section.
Examples
[0670] Experimental procedures for compounds of the invention are
provided below. Some of the compounds prepared were separated on a
preparative scale by reverse-phase high performance liquid
chromatography (RP-HPLC) with MS detector or flash chromatography
(silica gel) as indicated in the Examples. Typical preparative
reverse-phase high performance liquid chromatography (RP-HPLC)
column conditions are as follows:
[0671] pH=2 purifications: Waters Sunfire.TM. C.sub.18 5 Tm,
19.times.100 mm column, eluting with mobile phase A: 0.1% TFA
(trifluoroacetic acid) in water and mobile phase B: 0.1% TFA in
acetonitrile; the flow rate was 30 mL/minute, the separating
gradient was optimized for each compound using the Compound
Specific Method Optimization protocol as described in the
literature [see "Preparative LCMS Purification: Improved Compound
Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A.
Combs, J. Comb. Chem., 6, 874-883 (2004)].
[0672] pH=10 purifications: Waters XBridge C.sub.18 5 Tm,
19.times.100 mm column, eluting with mobile phase A: 0.15%
NH.sub.4OH in water and mobile phase B: 0.15% NH.sub.4OH in
acetonitrile; the flow rate was 30 mL/minute, the separating
gradient was optimized for each compound using the Compound
Specific Method Optimization protocol as described in the
literature [See "Preparative LCMS Purification: Improved Compound
Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A.
Combs, J. Comb. Chem., 6, 874-883 (2004)].
[0673] The compounds separated were typically subjected to
analytical liquid chromatography mass spectrometry (LCMS) for
purity under the following conditions: Instrument; Agilent 1100
series, LC/MSD, Column: Waters Sunfire.TM. C.sub.18 5 Tm,
2.1.times.5.0 mm, Buffers: mobile phase A: 0.025% TFA in water and
mobile phase B: 0.025% TFA in acetonitrile; gradient 2% to 80% of B
in 3 minutes with flow rate 1.5 mL/minute.
Example 1
6-Chloro-15-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).1(10,14)]tricosa-
-1(21),3(23),4,6,10(22),11,13,17,19-nonaene trifluoroacetate
##STR00069##
[0674] Step A:
2,5-Dichloro-N-(3-methoxybenzyl)pyrimidin-4-amine
##STR00070##
[0676] To a solution of 3-methoxybenzylamine (0.75 g, 5.4 mmol) and
2,4,5-trichloropyrimidine (1.1 g, 6.0 mmol) in
N,N-dimethylformamide (20 mL) was added potassium carbonate (2.3 g,
16 mmol). The resulting mixture was stirred overnight at room
temperature. The reaction was quenched with water. Ethyl acetate
("EtOAc") was added and the layers were separated. The aqueous
layer was extracted with EtOAc once. The combined organic layers
were washed with water and brine successively, then dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The crude product
was purified by silica gel column chromatography to give the
desired product as a white powder (1.43 g, 92%). LCMS for
C.sub.12H.sub.12ClN.sub.3O (M+H).sup.+: m/z=284.0, 286.0.
Step B:
[3-({5-Chloro-4-[(3-methoxybenzyl)amino]pyrimidin-2-yl}amino)pheny-
l]methanol
##STR00071##
[0678] Into the reaction flask was added
2,5-dichloro-N-(3-methoxybenzyl)pyrimidin-4-amine (0.82 g, 2.9
mmol), 1,4-dioxane (20 mL), 3-aminobenzyl alcohol (0.53 g, 4.3
mmol), and p-toluenesulfonic acid monohydrate (0.22 g, 1.2 mmol).
The mixture was heated at 105.degree. C. for 3 hours and then was
heated at 70.degree. C. overnight. The reaction was quenched with
NaHCO.sub.3 (saturated). The organic solvent was removed under
vacuum, followed by the addition of water and EtOAc. The aqueous
layer was extracted with EtOAc twice. The organic layers were
combined, dried over Na.sub.2SO.sub.4 and concentrated under vacuum
to give the desired product as a brown powder (1.05 g, 98%). LCMS
for C.sub.19H.sub.20N.sub.4O.sub.2 (M+H).sup.+: m/z=371.1, 373.0.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.54 (s, 1H), 8.28 (s,
1H), 8.03 (s, 1H), 7.54 (s, 1H), 7.40 (d, J=8.3 Hz, 1H), 7.20 (t,
J=8.3 Hz, 1H), 7.14 (t, J=7.9 Hz, 1H), 6.89 (m, 1H), 6.77 (ddd,
J=8.3, 2.2, 1.4 Hz, 1H), 4.59 (d, J=6.2 Hz, 2H), 4.38 (s, 2H), 3.64
(s, 3H).
Step C:
3-{[(2-{[3-(Bromomethyl)phenyl]amino}-5-chloropyrimidin-4-yl)amino-
]methyl}phenol
##STR00072##
[0680] Into a 1-neck round-bottom flask were added
[3-({5-chloro-4-[(3-methoxybenzyl)amino]pyrimidin-2-yl}amino)phenyl]metha-
nol (0.66 g, 1.8 mmol) and 5 mL of methylene chloride. To the above
mixture was slowly added a solution of boron tribromide in
methylene chloride (2.7 mL, 2.7 mmol, 1.0 M) at 0.degree. C. The
mixture was allowed to warm up to room temperature ("rt") and
stirred overnight. The resultant mixture was cooled in a dry ice
bath when water (10 mL) was added. The mixture was allowed to warm
up to rt, followed by an addition of EtOAc. The aqueous layer was
extracted with EtOAc twice. The organic layers were combined and
solvent removed under vacuum. The crude was purified by prep-HPLC
to give the desired product (730 mg, 99%). LCMS for
C.sub.18H.sub.17BrClN.sub.4O (M+H).sup.+: m/z=418.9, 420.9. .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 9.55 (s, 1H), 9.34 (br s, 1H),
8.18 (s, 1H), 8.04 (s, 1H), 7.68 (t, J=1.7 Hz, 1H), 7.41 (m, 1H),
7.16 (t, J=7.9 Hz, 1H), 7.09 (t, J=7.9 Hz, 1H), 6.98 (d, J=7.7 Hz,
1H), 6.70 (m, 1H), 6.59 (m, 1H), 4.58 (d, J=6.6 Hz, 2H), 4.49 (s,
2H).
Step D:
6-Chloro-15-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).1(10,14)-
]tricosa-1(21),3(23),4,6,10(22),11,13,17,19-nonaene
trifluoroacetate
[0681] Into the reaction flask was added
3-{[(2-{[3-(bromomethyl)phenyl]amino}-5-chloropyrimidin-4-yl)amino]methyl-
}phenol (0.15 g, 0.36 mmol), DMF (5 mL), and potassium carbonate
(0.20 g, 1.4 mmol). The reaction mixture was stirred at rt
overnight and water (5 mL) was added. The aqueous layer was
extracted with EtOAc twice. The combined organic layers were dried
over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum. The
crude was purified by silica gel column chromatography to give the
desired product as an off-white powder (10 mg, 8%). LCMS for
C.sub.18H.sub.16ClN.sub.4O (M+H).sup.+: m/z=339.0, 341.0. .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 9.00 (s, 1H), 7.87 (t, J=5.7
Hz, 1H), 7.85 (s, 1H), 7.45 (t, J=1.9 Hz, 1H), 7.21 (t, J=7.8 Hz,
1H), 7.17 (t, J=7.8 Hz, 1H), 6.97 (m, 2H), 6.73 (d, J=7.9 Hz, 1H),
5.13 (s, 2H), 4.23 (d, J=5.9 Hz, 2H).
Example 2
6-Chloro-15-oxa-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).1(10,14)]tetraco-
sa-1(22),3(24),4,6,10(23),11,13,18,20-nonaene trifluoroacetate
##STR00073##
[0682] Step A: 2-(3-Aminophenyl)ethanol
##STR00074##
[0684] Into a pressure bottle were added 2-(3-nitrophenyl)ethanol
(3.0 g, 18 mmol) and methanol (100 mL) and 10% palladium on carbon
(0.1 g, 0.08 mmol). The reaction mixture was hydrogenated at 45 psi
overnight. The resultant mixture was filtered and concentrated to
provide the desired product (2.44 g, 99%) as a white solid. LCMS
for C.sub.8H.sub.12NO (M+H).sup.+: m/z=138.1.
Step B:
2-[3-({5-Chloro-4-[(3-methoxybenzyl)amino]pyrimidin-2-yl}amino)phe-
nyl]ethanol
##STR00075##
[0686] Into a reaction flask were added
2,5-dichloro-N-(3-methoxybenzyl)pyrimidin-4-amine (0.33 g, 1.2
mmol) (prepared according to Example 1, step A), 1,4-dioxane (20
mL), 2-(3-aminophenyl)ethanol (0.22 g, 1.6 mmol), and
p-toluenesulfonic acid monohydrate (0.080 g, 0.42 mmol). The
mixture was heated at 105.degree. C. for 3 hours and then an
aqueous solution of NaHCO.sub.3 (saturated) was added. The organic
solvent was removed under vacuum followed by the addition of water
and EtOAc. The aqueous layer was extracted with EtOAc twice. The
organic layers were combined, dried over Na.sub.2SO.sub.4, and
concentrated under vacuum. The crude was purified by silica gel
column chromatography to provide the desired product as a white
solid (0.33 g, 74% yield). LCMS for
C.sub.20H.sub.22ClN.sub.4O.sub.2 (M+H).sup.+: m/z=385.1.
Step C:
3-{[(2-{[3-(2-Bromoethyl)phenyl]amino}-5-chloropyrimidin-4-yl)amin-
o]methyl}phenol
##STR00076##
[0688] Into a 1-neck round-bottom flask were added
2-[3-(15-chloro-4-[(3-methoxybenzyl)amino]pyrimidin-2-yl}amino)phenyl]eth-
anol (0.20 g, 0.52 mmol) and dichloromethane ("DCM", 5 mL). To the
reaction mixture was added a solution of boron tribromide in
methylene chloride (1.6 mL, 1.6 mmol, 1.0 M) at 0.degree. C. The
resulting mixture was allowed to warm up to rt and stirred
overnight. The resulted mixture was cooled in a dry ice bath when
water (10 mL) was added. The mixture was allowed to warm up to rt
and EtOAc was added. The aqueous layer was extracted with EtOAc
twice. The organic layers were combined and concentrated under
vacuum. The crude product was purified by silica gel column
chromatography to give the desired product as a light brown powder
(34 mg, 20%). LCMS for C.sub.19H.sub.19BrClN.sub.4O (M+H).sup.+:
m/z=371.1, 373.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.30
(s, 1H), 9.11 (s, 1H), 7.95 (s, 1H), 7.74 (t, J=6.1 Hz, 1H), 7.42
(m, 1H), 7.08 (t, J=7.9 Hz, 1H), 7.03 (dd, J=8.7, 7.6 Hz, 1H), 6.71
(dd, J=11.5, 7.6 Hz, 1H), 6.69 (s, 1H), 6.58 (dd, J=8.0, 2.3 Hz,
1H), 4.56 (m, 2H), 3.50 (m, 2H), 2.56 (t, J=7.1 Hz, 2H).
Step D:
6-Chloro-15-oxa-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).1(10,14)-
]tetracosa-1(22),3(24),4,6,10(23),11,13,18,20-nonaene
trifluoroacetate
[0689] Into a reaction flask were added
3-{[(2-{[3-(2-bromoethyl)phenyl]amino}-5-chloropyrimidin-4-yl)amino]methy-
l}phenol (36 mg, 0.083 mmol) and 1,4-dioxane (2.0 mL) and a
solution of sodium hydroxide in water (1.0 mL, 3 M). The mixture
was stirred at 70.degree. C. for 3 hours. To the reaction mixture
were added methanol (1 mL) and HCl aqueous solution (2 mL, 2 N).
The resulted solution was filtered and purified by prep-HPLC to
give the desired product as an off-white powder (5 mg, 18%). LCMS
for C.sub.19H.sub.18ClN.sub.4O (M+H).sup.+: m/z=353.0, 355.0.
Example 3
6-Chloro-16-thia-2,4,8,15,23-pentaazatetracyclo[15.3.1.1(3,7).1(10,14)]tri-
cosa-1(21),3(23),4,6,10(22),11,13,17,19-nonaene 16,16-dioxide
trifluoroacetate
##STR00077##
[0690] Step A:
tert-Butyl(3-{[(2,5-dichloropyrimidin-4-yl)amino]methyl}phenyl)carbamate
##STR00078##
[0692] To a solution of tert-butyl [3-(aminomethyl)phenyl]carbamate
(0.50 g, 2.2 mmol) and 2,4,5-trichloropyrimidine (0.45 g, 2.5 mmol)
in N,N-dimethylformamide (6 mL) was added potassium carbonate (0.62
g, 4.5 mmol). The resultant mixture was stirred overnight at room
temperature. The reaction was quenched with water. EtOAc was added
and the layers were separated. The aqueous layer was extracted with
EtOAc twice. The combined organic layers were washed with water and
brine successively, then dried (Na.sub.2SO.sub.4), filtered, and
concentrated. The resulted residue was triturated with methylene
chloride and hexanes to give the desired product as an off-white
powder (0.75 g, 90%). LCMS for
C.sub.12H.sub.11Cl.sub.2N.sub.4O.sub.2 (M-tBu+H).sup.+: m/z=313.0,
315.0.
Step B: N-(3-Aminobenzyl)-2,5-dichloropyrimidin-4-amine.hydrogen
chloride
##STR00079##
[0694] Into a reaction flask were added tert-butyl
(3-{[(2,5-dichloropyrimidin-4-yl)amino]methyl}phenyl)carbamate
(0.50 g, 1.4 mmol), 1,4-dioxane (7 mL), and a solution of hydrogen
chloride in 1,4-dioxane (7 mL, 4.0 M). The reaction mixture was
stirred at rt for 2 hours. After concentration, the crude off-white
powder product (0.46 g, 99%) was used in the next step without
further purification. LCMS for C.sub.11H.sub.11Cl.sub.2N.sub.4
(M+H).sup.+: m/z=269.0, 271.0.
Step C:
N-(3-{[(2,5-Dichloropyrimidin-4-yl)amino]methyl}phenyl)-3-nitroben-
zenesulfonamide
##STR00080##
[0696] To a mixture of
N-(3-aminobenzyl)-2,5-dichloropyrimidin-4-amine.hydrogen chloride
(0.20 g, 0.58 mmol) and triethylamine (0.32 mL, 2.3 mmol) in THF (3
mL) was added slowly m-nitrobenzenesulfonyl chloride (0.13 g, 0.58
mmol). The resulting mixture was stirred at rt for 2 hours and the
solvent was removed under vacuum. The residue was treated with
EtOAc and water. The organic layer was dried over Na.sub.2SO.sub.4,
filtered, and concentrated under vacuum to provide the desired
product (0.30 g, 95%). LCMS for
C.sub.17H.sub.14Cl.sub.2N.sub.5O.sub.4S (M+H).sup.+: m/z=453.9,
455.9.
Step D:
3-Amino-N-(3-{[(2,5-dichloropyrimidin-4-yl)amino]methyl}phenyl)ben-
zenesulfonamide
##STR00081##
[0698] Into a reaction flask was added
N-(3-{[(2,5-dichloropyrimidin-4-yl)amino]methyl}phenyl)-3-nitrobenzenesul-
fonamide (0.20 g, 0.44 mmol), methanol (20 mL), acetic acid (2.0
mL), and water (1 mL). Then iron (0.25 g, 4.5 mmol) powder was
added. The reaction mixture was heated at 70.degree. C. for 2
hours. After cooling, the mixture was filtered and washed with
EtOAc. The filtrate was concentrated under vacuum to give a
residue, which was treated with NaHCO.sub.3 (saturated aqueous
solution) and EtOAc. The organic layer was dried and concentrated
under vacuum. The resulting crude product was then purified by
silica gel column chromatography to provide the desired product (46
mg, 25%). LCMS for C.sub.17H.sub.16Cl.sub.2N.sub.5O.sub.2S
(M+H).sup.+: m/z=424.0, 426.0.
Step E:
6-Chloro-16-thia-2,4,8,15,23-pentaazatetracyclo[15.3.1.1(3,7).1(10-
,14)]tricosa-1(21),3(23),4,6,10(22),11,13,17,19-nonaene
16,16-dioxide trifluoroacetate
[0699] To a solution of
3-amino-N-(3-{[(2,5-dichloropyrimidin-4-yl)amino]methyl}phenyl)benzenesul-
fonamide (46 mg, 0.11 mmol) in 2-methoxyethanol (1.5 mL) was added
a solution of hydrogen chloride in 1,4-dioxane (0.072 mL, 4.00 M).
The resultant mixture was heated at 150.degree. C. in a microwave
for 15 minutes. The mixture was concentrated and purified by
prep-HPLC to give the desired product as a white powder (20 mg,
14%). LCMS for C.sub.17H.sub.15ClN.sub.5O.sub.2S (M+H).sup.+:
m/z=388.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.78 (s,
1H), 9.49 (s, 1H), 8.49 (br, 1H), 8.01 (s, 1H), 7.59 (m, 1H), 7.55
(t, J=7.9 Hz, 1H), 7.33 (ddd, J=7.9, 1.9, 1.4 Hz, 1H), 7.27 (t,
J=7.8 Hz, 2H), 7.16 (m, 2H), 6.98 (m, 1H), 4.22 (d, J=5.8 Hz,
2H).
Example 4
6-Chloro-2,4,8,15,23-pentaazatetracyclo[15.3.1.1(3,7).1(10,14)]tricosa-1(2-
1),3(23),4,6,10(22),11,13,17,19-nonaen-16-one trifluoroacetate
##STR00082##
[0700] Step A:
N-(3-{[(2,5-Dichloropyrimidin-4-yl)amino]methyl}phenyl)-3-nitrobenzamide
##STR00083##
[0702] To a mixture of
N-(3-aminobenzyl)-2,5-dichloropyrimidin-4-amine.hydrogen chloride
(0.10 g, 0.29 mmol) (prepared according to Example 3, step B) and
triethylamine (0.16 mL, 1.2 mmol) in THF (3 mL) was added slowly
3-nitrobenzoyl chloride (54 mg, 0.29 mmol). The resulting mixture
was stirred at rt for 2 hours and concentrated under vacuum. The
residue was partitioned in EtOAc and water. The organic layer was
dried over Na.sub.2SO.sub.4, filtered, and concentrated under
vacuum to give the desired product as a yellow solid (90 mg, 70%).
LCMS for C.sub.18H.sub.14Cl.sub.2N.sub.5O.sub.3 (M+H).sup.+:
m/z=418.0, 420.0.
Step B:
3-Amino-N-(3-{[(2,5-dichloropyrimidin-4-yl)amino]methyl}phenyl)ben-
zamide
##STR00084##
[0704] Into a reaction flask were added
N-(3-{[(2,5-dichloropyrimidin-4-yl)amino]methyl}phenyl)-3-nitrobenzamide
(0.30 g, 0.72 mmol), methanol (20 mL), acetic acid (2.0 mL), and
water (1 mL). Then iron (0.50 g, 9.0 mmol) powder was added. The
reaction mixture was heated at 70.degree. C. overnight. After
cooling, the mixture was filtered and washed with EtOAc. The
filtrate was concentrated under vacuum to give a residue, which was
treated with NaHCO.sub.3 (saturated aqueous solution) and EtOAc.
The organic layer was dried and concentrated under vacuum to
provide the desired product (0.27 g, 97%). LCMS for
C.sub.18H.sub.16Cl.sub.2N.sub.5O (M+H).sup.+: m/z=388.0, 390.0.
Step C:
6-Chloro-2,4,8,15,23-pentaazatetracyclo[15.3.1.1(3,7).1(10,14)]tri-
cosa-1(21),3(23),4,6,10(22),11,13,17,19-nonaen-16-one
trifluoroacetate
[0705] To a solution of
3-amino-N-(3-{[(2,5-dichloropyrimidin-4-yl)amino]methyl}phenyl)benzamide
(72 mg, 0.18 mmol) in 2-methoxyethanol (1.5 mL) was added a
solution of hydrogen chloride in 1,4-dioxane (0.072 mL, 4.00 M).
The resulting mixture was heated at 150.degree. C. in a microwave
for 15 minutes. The mixture was concentrated and purified by
prep-HPLC to give the desired product as a white powder (6 mg,
10%). LCMS for C.sub.18H.sub.15ClN.sub.5O (M+H).sup.+:
m/z=352.0.
Example 5
6-Chloro-15-oxa-2,4,8,25-tetraazatetracyclo[17.3.1.1(3,7).1(10,14)]pentaco-
sa-1(23),3(25),4,6,10(24),11,13,19,21-nonaene trifluoroacetate
##STR00085##
[0706] Step A:
3-[3-({5-Chloro-4-[(3-methoxybenzyl)amino]pyrimidin-2-yl}amino)phenyl]pro-
pan-1-ol
##STR00086##
[0708] Into a reaction flask were added
2,5-dichloro-N-(3-methoxybenzyl)pyrimidin-4-amine (0.20 g, 0.70
mmol, prepared according to Example 1, step A), 1,4-dioxane (20
mL), 3-(3-aminophenyl)propan-1-ol (0.16 g, 1.0 mmol, prepared
according to Example 12, step A & B), and p-toluenesulfonic
acid monohydrate (0.049 g, 0.26 mmol). The mixture was heated at
105.degree. C. for 2 days and NaHCO.sub.3 (saturated aqueous
solution) was added. The organic solvent was removed under vacuum
followed by an addition of water and EtOAc. The aqueous layer was
extracted with EtOAc twice. The organic layers were combined, dried
over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum. The
crude product was purified by silica gel column chromatography to
give the desired product (0.18 g, 64%) as a white solid. LCMS for
C.sub.21H.sub.24lN.sub.4O.sub.2 (M+H).sup.+: m/z=399.1.
Step B:
3-{[(2-{[3-(3-Bromopropyl)phenyl]amino}-5-chloropyrimidin-4-yl)ami-
no]methyl}phenol
##STR00087##
[0710] Into a 1-neck round-bottom flask were added
3-[3-({5-chloro-4-[(3-methoxybenzyl)amino]pyrimidin-2-yl}amino)phenyl]pro-
pan-1-ol (0.18 g, 0.45 mmol) and DCM (5 mL). To the reaction
mixture was added a solution of boron tribromide in methylene
chloride (3.0 mL, 3.0 mmol, 1.0 M) at 0.degree. C. The mixture was
allowed to warm up to rt and stirred overnight. The resultant
mixture was cooled in a dry ice bath when NaHCO.sub.3 (saturated
aqueous solution, 10 mL) was added. The mixture was allowed to warm
up to rt and DCM was added. The aqueous layer was extracted with
DCM twice. The organic layers were combined, dried, filtered, and
concentrated under vacuum to give the desired product as an
off-white powder (150 mg, 74%). LCMS for
C.sub.20H.sub.21BrClN.sub.4O (M+H).sup.+: m/z=447.0, 449.0.
Step C:
6-Chloro-15-oxa-2,4,8,25-tetraazatetracyclo[17.3.1.1(3,7).1(10,14)-
]pentacosa-1(23),3(25),4,6,10(24),11,13,19,21-nonaene
trifluoroacetate
[0711] Into a reaction flask were added
3-{[(2-{[3-(3-bromopropyl)phenyl]amino}-5-chloropyrimidin-4-yl)amino]meth-
yl}phenol (0.053 g, 0.12 mmol), tetrahydrofuran (1.5 mL), and a
solution of sodium hydroxide in water (1.0 mL, 0.5 M). The reaction
mixture was stirred at rt overnight. To the reaction mixture was
added an aqueous solution of HCl (0.5 mL, 2 N). The resultant
mixture was filtered and the crude product was purified by
prep-HPLC to give the desired product as an off-white powder (10
mg, 25%). LCMS for C.sub.20H.sub.20ClN.sub.4O (M+H).sup.+:
m/z=367.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.46 (s,
1H), 8.69 (br s, 1H), 8.05 (s, 1H), 7.23 (m, 1H), 7.20 (t, J=7.9
Hz, 1H), 6.98 (m, 1H), 6.80 (ddd, J=8.1, 2.4, 0.8 Hz, 1H), 6.52
(br, 1H), 4.34 (d, J=6.1 Hz, 2H), 4.12 (t, J=6.1 Hz, 2H), 2.67 (m,
2H), 1.76 (m, 2H).
Example 6
(9R)-6-Chloro-9-methyl-15-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).1(-
10,14)]tricosa-1(21),3(23),4,6,10(22),11,13,17,19-nonaene
trifluoroacetate
##STR00088##
[0712] Step A:
2,5-Dichloro-N-[(1R)-1-(3-methoxyphenyl)ethyl]pyrimidin-4-amine
##STR00089##
[0714] To a solution of (1R)-1-(3-methoxyphenyl)ethanamine (1.50 g,
9.92 mol) (R-isomer, >98% ee purity) and
2,4,5-trichloropyrimidine (1.19 mL, 10.4 mmol) in
N,N-dimethylformamide (30 mL) was added potassium carbonate (4.1 g,
30 mmol). The resultant mixture was stirred over two days at room
temperature. The reaction was quenched with water. EtOAc was added
and the layers were separated. The aqueous layer was extracted with
EtOAc twice. The combined organic layers were washed with water and
brine successively, then dried (Na.sub.2SO.sub.4), filtered,
concentrated, and triturated with cold EtOAc to give the desired
product as a light yellow gel (2.81 g, 95%). LCMS for
C.sub.13H.sub.14Cl.sub.2N.sub.3O (M+H).sup.+: m/z=298.0.
Step B:
{3-[(5-Chloro-4-{[(1R)-1-(3-methoxyphenyl)ethyl]amino}pyrimidin-2--
yl)amino]phenyl}methanol
##STR00090##
[0716] Into a reaction flask were added
2,5-dichloro-N-[(1R)-1-(3-methoxyphenyl)ethyl]pyrimidin-4-amine
(0.21 g, 0.70 mmol), 1,4-dioxane (20 mL), 3-aminobenzyl alcohol
(0.13 g, 1.0 mmol), and p-toluenesulfonic acid monohydrate (0.049
g, 0.26 mmol). The mixture was heated at 105.degree. C. for 2 days.
To the reaction mixture was added NaHCO.sub.3 (saturated aqueous
solution) and the organic solvent was removed under vacuum. Water
and EtOAc were added to the residue. The aqueous layer was
extracted with EtOAc twice. The organic layers were combined, dried
over Na.sub.2SO.sub.4, filtered, and concentrated. The crude
product was purified by silica gel column chromatography to give
the desired product (0.27 g, 96%). LCMS for
C.sub.20H.sub.22ClN.sub.4O.sub.2 (M+H).sup.+: m/z=385.1.
Step C:
3-{(1R)-1-[(2-{[3-(Bromomethyl)phenyl]amino}-5-chloropyrimidin-4-y-
l)amino]ethyl}phenol
##STR00091##
[0718] Into a 1-neck round-bottom flask were added
{3-[(5-chloro-4-{[(1R)-1-(3-methoxyphenyl)ethyl]amino}pyrimidin-2-yl)amin-
o]phenyl}methanol (0.26 g, 0.68 mmol) and methylene chloride (5
mL). To the mixture was added a solution of boron tribromide in
methylene chloride (3.0 mL, 3.0 mmol, 1.0 M) at 0.degree. C. The
mixture was allowed to warm up to rt and stirred overnight. The
resultant mixture was cooled in dry ice when NaHCO.sub.3 (saturated
aqueous solution, 10 mL) was added. The mixture was allowed to warm
up to rt and DCM was added. The aqueous layer was extracted with
DCM twice. The organic layers were combined, dried, filtered, and
concentrated under vacuum. The crude product was purified by silica
gel column chromatography to give the desired product (40 mg, 30%).
LCMS for C.sub.19H.sub.19BrClN.sub.4O (M+H).sup.+: m/z=432.9,
434.9.
Step D:
(9R)-6-Chloro-9-methyl-15-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1-
(3,7).1(10,14)]tricosa-1(21),3(23),4,6,10(22),11,13,17,19-nonaene
trifluoroacetate
[0719] Into a reaction flask were added
3-{(1R)-1-[(2-{[3-(bromomethyl)phenyl]amino}-5-chloropyrimidin-4-yl)amino-
]ethyl}phenol (40 mg, 0.09 mmol), tetrahydrofuran (1.5 mL), and a
solution of sodium hydroxide in water (1.0 mL, 0.5 M). The reaction
mixture was stirred at rt overnight. To the mixture was added an
aqueous solution of HCl (0.5 mL, 2N). The resultant solution was
filtered and purified by prep-HPLC to give the desired product (10
mg, 30%). LCMS for C.sub.19H.sub.18ClN.sub.4O (M+H).sup.+:
m/z=353.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.54 (s,
1H), 8.02 (s, 2H), 7.33 (t, J=7.9 Hz, 1H), 7.24 (t, J=7.6 Hz, 1H),
7.17 (d, J=7.6 Hz, 1H), 7.05 (m, 1H), 6.81 (ddd, J=7.9, 2.4, 0.9
Hz, 1H), 6.71 (s, 1H), 5.32 (d, J=13.2 Hz, 1H), 4.81 (d, J=13.3 Hz,
1H), 4.52 (q, J=6.9 Hz, 1H), 1.49 (d, J=7.2 Hz, 3H).
Example 7
6-Chloro-15,18-dioxa-2,4,8,25-tetraazatetracyclo[17.3.1.1(3,7).1(10,14)]pe-
ntacosa-1(23),3(25),4,6,10(24),11,13,19,21-nonaene
trifluoroacetate
##STR00092##
[0720] Step A:
5-Chloro-N(4)-(3-methoxybenzyl)-N(2)-(3-methoxyphenyl)pyrimidine-2,4-diam-
ine
##STR00093##
[0722] Into a reaction flask were added
2,5-dichloro-N-(3-methoxybenzyl)pyrimidin-4-amine (0.20 g, 0.70
mmol) (prepared according to Example 1, step A), 1,4-dioxane (20
mL), 3-methoxy-benzenamine (0.13 g, 1.0 mmol), and
p-toluenesulfonic acid monohydrate (49 mg, 0.26 mmol). The mixture
was heated at 105.degree. C. for 2 days. To the mixture was added
an aqueous solution of NaHCO.sub.3 (saturated, 0.5 mL) and the
organic solvent was removed under vacuum. The aqueous layer was
extracted with DCM twice. The combined organic layers were dried,
filtered and concentrated. The crude product was purified by silica
gel column chromatography to provide the desired product (90 mg,
30%). LCMS for C.sub.19H.sub.20ClN.sub.4O.sub.2 (M+H).sup.+:
m/z=371.1.
Step B:
3-({5-Chloro-4-[(3-hydroxybenzyl)amino]pyrimidin-2-yl}amino)phenol
##STR00094##
[0724] Into a 1-neck round-bottom flask were added
5-chloro-N(4)-(3-methoxybenzyl)-N(2)-(3-methoxyphenyl)pyrimidine-2,4-diam-
ine (90 mg, 0.2 mmol) and methylene chloride (5 mL). To the mixture
was added a solution of boron tribromide in methylene chloride (3.0
mL, 3.0 mmol, 1.0 M) at 0.degree. C. The mixture was allowed to
warm up to rt and stirred overnight. The resultant mixture was
cooled in a dry ice bath when NaHCO.sub.3 (saturated aqueous
solution, 10 mL) was added. The mixture was allowed to warm up to
rt and DCM was added. The aqueous layer was extracted with DCM
twice. The organic layers were combined, dried, filtered, and
concentrated under vacuum to give the desired product (40 mg, 50%).
LCMS for C.sub.17H.sub.16ClN.sub.4O.sub.2 (M+H).sup.+:
m/z=343.0.
Step C:
6-Chloro-15,18-dioxa-2,4,8,25-tetraazatetracyclo[17.3.1.1(3,7).1(1-
0,14)]pentacosa-1(23),3(25),4,6,10(24),11,13,19,21-nonaene
trifluoroacetate
[0725] Into a reaction flask were added
3-[(5-chloro-4-[(3-hydroxyphenyl)amino]pyrimidin-2-yl)amino]phenol
(40 mg, 0.12 mmol), 1,2-diiodoethane (0.34 g, 1.2 mmol),
tetrahydrofuran (1.0 mL), and a solution of sodium hydroxide in
water (1.0 mL, 0.5 M). The mixture was stirred at rt for 3 hours.
To the mixture were added methanol (1 mL) and HCl (0.25 mL, 2 N
aqueous solution). The resultant mixture was filtered and purified
by prep-HPLC to give the desired product (4 mg, 5%). LCMS for
C.sub.19H.sub.18ClN.sub.4O.sub.2 (M+H).sup.+: m/z=369.0.
Example 8
19-Chloro-9-oxa-2,17,21,22-tetraazatetracyclo[16.3.1.1(3,7).1(10,14)]tetra-
cosa-1(22),3(24),4,6,10(23),11,13,18,20-nonaene
##STR00095##
[0726] Step A:
2,5-Dichloro-N-[2-(3-methoxyphenyl)ethyl]pyrimidin-4-amine
##STR00096##
[0728] To a solution of 3-methoxyphenethylamine (1.93 mL, 13.2
mmol) and 2,4,5-trichloropyrimidine (1.59 mL, 13.9 mmol) in
N,N-dimethylformamide (40 mL) was added potassium carbonate (5.5 g,
40 mmol). The resultant mixture was stirred overnight at room
temperature. The reaction was quenched with water. EtOAc was added
and the layers were separated. The aqueous layer was extracted with
EtOAc twice. The combined organic layers were washed with water and
brine successively, then dried (Na.sub.2SO.sub.4), filtered, and
concentrated to give the desired product as a yellow gel (3.74 g,
95%). LCMS for C.sub.13H.sub.14Cl.sub.2N.sub.3O (M+H).sup.+:
m/z=298.0, 300.0.
Step B:
{3-[(5-Chloro-4-{[2-(3-methoxyphenyl)ethyl]amino}pyrimidin-2-yl)am-
ino]phenyl}methanol
##STR00097##
[0730] To a solution of
2,5-dichloro-N-[2-(3-methoxyphenyl)ethyl]pyrimidin-4-amine (0.70 g,
2.3 mmol) and 3-aminobenzyl alcohol (0.39 g, 3.2 mmol) in
1,4-dioxane (20.0 mL) was added p-toluenesulfonic acid monohydrate
(0.16 g, 0.85 mmol). The mixture was heated at 100.degree. C. for
16 h and the reaction was complete. To the mixture was added
NaHCO.sub.3 (saturated aqueous solution) and the organic solvent
was removed under vacuum, followed by the addition of water and
EtOAc. The aqueous layer was extracted with EtOAc twice. The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered,
and concentrated (then triturated with cold EtOAc) to give the
desired product as an off-white powder (0.90 g, 100%). LCMS for
C.sub.20H.sub.22ClN.sub.4O.sub.2 (M+H).sup.+: m/z=385.1.
Step C:
3-{2-[(2-{[3-(Bromomethyl)phenyl]amino}-5-chloropyrimidin-4-yl)ami-
no]ethyl}phenol
##STR00098##
[0732] To a solution of
{3-[(5-chloro-4-{[2-(3-methoxyphenyl)ethyl]amino}pyrimidin-2-yl)amino]phe-
nyl}methanol (0.30 g, 0.78 mmol) in methylene chloride (5.0 mL) was
added slowly a solution of boron tribromide in methylene chloride
(2.3 mL, 2.3 mmol, 1.0 M) at 0.degree. C. The mixture was allowed
to warm up to rt and stirred overnight. The resultant mixture was
cooled in a dry ice bath when water was added. The mixture was
allowed to warm up to rt. Both aqueous layer (no product in it) and
organic layer (containing small amounts of product, plus
byproducts) were checked and discarded. The remaining solid residue
was triturated with cold EtOAc and then filtered. The cake was
washed with cold EtOAc and then H.sub.2O to give the desired
product as a white powder (0.30 g, 89%). LCMS for
C.sub.19H.sub.19BrClN.sub.4O (M+H).sup.+: m/z=433.0, 435.0, 437.0.
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.94 (s, 1H), 7.60 (s,
1H), 7.40 (m, 2H), 7.32 (m, 1H), 7.05 (m, 1H), 6.60 (m, 3H), 4.54
(s, 2H), 3.76 (t, J=6.4 Hz, 2H), 2.85 (t, J=7.6 Hz, 2H).
Step D:
19-Chloro-9-oxa-2,17,21,22-tetraazatetracyclo[16.3.1.1(3,7).1(10,1-
4)]tetracosa-1(22),3(24),4,6,10(23),11,13,18,20-nonaene
[0733] To a solution of
3-{2-[(2-{[3-(bromomethyl)phenyl]amino}-5-chloropyrimidin-4-yl)amino]ethy-
l}phenol (25.0 mg, 0.0576 mmol) in tetrahydrofuran (0.561 mL) was
added a solution of sodium hydroxide in water (0.46 mL, 0.50 M).
The resultant solution was stirred at rt for 16 hours until the
reaction was complete. The reaction mixture was neutralized with
aqueous HCl solution (3 M) to pH 7. The aqueous layer was extracted
with EtOAc twice. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, and concentrated (then triturated with
cold EtOAc) to give the desired product as an off-white powder (13
mg, 65%). LCMS for C.sub.19H.sub.18ClN.sub.4O (M+H).sup.+:
m/z=353.0. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.72 (s, 1H),
7.52 (s, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.19 (s, 1H), 7.10 (dd,
J=7.6, 0.8 Hz, 1H), 7.06 (t, J=7.2 Hz, 1H), 6.93 (dd, J=7.2, 0.8
Hz, 1H), 6.73 (dd, J=2.4, 0.8 Hz, 1H), 6.66 (d, J=7.2 Hz, 1H), 5.25
(s, 2H), 3.70 (m, 2H), 2.72 (t, J=6.8 Hz, 1H).
Example 9
6-Chloro-16-oxa-2,4,8,25-tetraazatetracyclo[17.3.1.1(3,7).1(11,15)]pentaco-
sa-1(23),3(25),4,6,11(24),12,14,19,21-nonaene
##STR00099##
[0734] Step A:
2-{3-[(5-Chloro-4-{[2-(3-methoxyphenyl)ethyl]amino}pyrimidin-2-yl)amino]p-
henyl}ethanol
##STR00100##
[0736] To a solution of
2,5-dichloro-N-[2-(3-methoxyphenyl)ethyl]pyrimidin-4-amine (0.50 g,
1.7 mmol) (prepared according to Example 8, step A) and
2-(3-aminophenyl)ethanol (0.31 g, 2.3 mmol) (prepared according to
Example 22, Step B) in 1,4-dioxane (14.3 mL) was added
p-toluenesulfonic acid monohydrate (0.12 g, 0.61 mmol). The mixture
was heated at 100.degree. C. for 16 h and the reaction was
complete. To the mixture was added NaHCO.sub.3 (saturated aqueous
solution). The organic solvent was removed under vacuum and
water/EtOAc was added. After layer separation, the aqueous layer
was extracted with EtOAc twice. The combined organic layers were
dried over Na.sub.2SO.sub.4, filtered, and concentrated (then
triturated with cold EtOAc) to give the desired product as a light
brown powder (0.64 g, 96%). LCMS for
C.sub.21H.sub.24ClN.sub.4O.sub.2 (M+H).sup.+: m/z=399.1.
Step B:
3-{2-[(2-{[3-(2-Bromoethyl)phenyl]amino}-5-chloropyrimidin-4-yl)am-
ino]ethyl}phenol
##STR00101##
[0738] To a solution of
2-{3-[(5-chloro-4-{[2-(3-methoxyphenyl)ethyl]amino}pyrimidin-2-yl)amino]p-
henyl}ethanol (0.30 g, 0.75 mmol) in methylene chloride (4.8 mL)
was added slowly a solution of boron tribromide in methylene
chloride (2.2 mL, 2.2 mmol, 1.0 M) at 0.degree. C. The mixture was
allowed to warm up to rt and stirred overnight and the reaction was
not complete. Thus additional 2 molar equivalents of BBr.sub.3 (1.5
mL, 1.5 mmol, 1.0M) were added, and the reaction mixture was
stirred at rt for one more day and then the reaction was complete.
To the mixture was added NaHCO.sub.3 (saturated aqueous solution).
The organic solvent was removed under vacuum and water/EtOAc was
added. The aqueous layer was extracted with EtOAc twice. The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered,
and concentrated (then triturated with cold EtOAc) to give the
desired product as an off-white powder (222 mg, 65%). LCMS for
C.sub.20H.sub.21BrClN.sub.4O (M+H).sup.+: m/z=447.0, 449.0. .sup.1H
NMR (400 MHz, CD.sub.3OD): .delta. 7.92 (s, 1H), 7.37 (m, 3H), 7.20
(d, J=7.6 Hz, 1H), 7.04 (t, J=8.0 Hz, 1H), 6.58 (m, 3H), 3.74 (t,
J=7.6 Hz, 2H), 3.61 (t, J=7.2 Hz, 2H), 3.14 (t, J=7.2 Hz, 2H), 2.83
(t, J=7.2 Hz, 2H).
Step C:
6-Chloro-16-oxa-2,4,8,25-tetraazatetracyclo[17.3.1.1(3,7).1(11,15)-
]pentacosa-1(23),3(25),4,6,11(24),12,14,19,21-nonaene
[0739] To a solution of
3-{2-[(2-{[3-(2-bromoethyl)phenyl]amino}-5-chloropyrimidin-4-yl)amino]eth-
yl}phenol (50.0 mg, 0.112 mmol) in tetrahydrofuran (1.09 mL) was
added a solution of sodium hydroxide in water (0.893 mL, 0.50 M).
The resultant solution was stirred at rt for 2 days until the
reaction was complete. The reaction was neutralized with HCl (3 M,
aqueous solution) to pH 7. The aqueous layer was extracted with
EtOAc twice. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, and concentrated to give the crude,
which was purified by silica gel column chromatography to give the
desired product as a white powder (8.5 mg, 21%). LCMS for
C.sub.20H.sub.20ClN.sub.4O (M+H).sup.+: m/z=367.0. .sup.1H NMR (400
MHz, CD.sub.3OD): .delta. 7.81 (s, 1H), 7.70 (s, 1H), 7.57 (m, 1H),
7.22 (t, J=8.0 Hz, 1H), 7.08 (m, 2H), 6.69 (s, 1H), 6.67 (m, 2H),
5.73 (dd, J=6.8, 0.8 Hz, 2H), 5.14 (dd, J=7.2, 1.2 Hz, 2H), 3.72
(t, J=7.6 Hz, 2H), 2.86 (t, J=7.6 Hz, 2H).
Example 10
20-Chloro-9-oxa-2,18,22,23-tetraazatetracyclo[17.3.1.1(3,7).1(10,14)]penta-
cosa-1(23),3(25),4,6,10(24),11,13,19,21-nonaene
##STR00102##
[0740] Step A:
2,5-Dichloro-N-[3-(3-methoxyphenyl)propyl]pyrimidin-4-amine
##STR00103##
[0742] To a solution of 3-(3-methoxyphenyl)propan-1-amine
hydrochloride (2.00 g, 9.92 mmol) and 2,4,5-trichloropyrimidine
(1.19 mL, 10.4 mmol) in N,N-dimethylformamide (30 mL) was added
potassium carbonate (4.80 g, 34.7 mmol). The resultant mixture was
stirred overnight at room temperature. The reaction was quenched
with water. EtOAc was added and the layers were separated. The
aqueous layer was extracted with EtOAc twice. The combined organic
layers were washed with water and brine successively, then dried
(Na.sub.2SO.sub.4), filtered, and concentrated (then triturated
with cold EtOAc) to give the desired product as a light brown gel
(2.82 g, 91%). LCMS for C.sub.14H.sub.16Cl.sub.2N.sub.3O
(M+H).sup.+: m/z=312.0, 314.0.
Step B:
{3-[(5-Chloro-4-{[3-(3-methoxyphenyl)propyl]amino}pyrimidin-2-yl)a-
mino]phenyl}methanol
##STR00104##
[0744] To a solution of
2,5-dichloro-N-[3-(3-methoxyphenyl)propyl]pyrimidin-4-amine (0.70
g, 2.2 mmol) and 3-aminobenzyl alcohol (0.38 g, 3.0 mmol) in
1,4-dioxane (19.1 mL) was added p-toluenesulfonic acid monohydrate
(0.16 g, 0.82 mmol). The mixture was heated at 100.degree. C. for
16 hours and the reaction was complete. After cooling, the mixture
was filtered under vacuum. The cake was washed with cold EtOAc and
then H.sub.2O to give the desired product as an off-white powder
(0.71 g, 79%). LCMS for C.sub.21H.sub.24ClN.sub.4O.sub.2
(M+H).sup.+: m/z=399.1.
Step C:
3-{3-[(2-{[3-(Bromomethyl)phenyl]amino}-5-chloropyrimidin-4-yl)ami-
no]propyl}phenol
##STR00105##
[0746] To a solution of
{3-[(5-chloro-4-{[3-(3-methoxyphenyl)propyl]amino}pyrimidin-2-yl)amino]ph-
enyl}methanol (0.30 g, 0.75 mmol) in methylene chloride (4.8 mL)
was added slowly a solution of boron tribromide in methylene
chloride (3.8 mL, 1.0 M) at 0.degree. C. The mixture was allowed to
warm up to rt and stirred overnight. The resultant mixture was
cooled in a dry ice bath when water was added. The mixture was
allowed to warm up to rt. After methylene chloride layer was
separated, water and EtOAc were added. The aqueous layer was
extracted with EtOAc twice. The combined organic layers were dried
over Na.sub.2SO.sub.4, filtered, and concentrated (then triturated
with cold EtOAc) to give the desired product as an off-white powder
(252 mg, 75%). LCMS for C.sub.20H.sub.21BrClN.sub.4O (M+H).sup.+:
m/z=447.0, 449.0. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.92
(s, 1H), 7.63 (s, 1H), 7.39 (s, 1H), 7.38 (m, 2H), 7.03 (t, J=7.2
Hz, 1H), 6.61 (m, 2H), 6.58 (s, 1H), 4.56 (s, 2H), 3.60 (t, J=7.6
Hz, 2H), 2.58 (t, J=7.6 Hz, 2H), 1.96 (m, 2H).
Step D:
20-Chloro-9-oxa-2,18,22,23-tetraazatetracyclo[17.3.1.1(3,7).1(10,1-
4)]pentacosa-1(23),3(25),4,6,10(24),11,13,19,21-nonaene
[0747] To a solution of
3-{3-[(2-{[3-(bromomethyl)phenyl]amino}-5-chloropyrimidin-4-yl)amino]prop-
yl}phenol (50.0 mg, 0.112 mmol) in tetrahydrofuran (1.09 mL) was
added a solution of sodium hydroxide in water (0.893 mL, 0.50 M).
The resultant solution was stirred at rt for 16 hours until the
reaction was complete. The reaction mixture was neutralized with
HCl (3 M aqueous solution) to pH=7. The aqueous layer was extracted
with EtOAc twice. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, and concentrated to give the crude
product, which was purified by silica gel column chromatography to
give the desired product as a white powder (8 mg, 20%). LCMS for
C.sub.20H.sub.20ClN.sub.4O (M+H).sup.+: m/z=367.0. .sup.1H NMR (400
MHz, CD.sub.3OD): .delta. 7.94 (s, 1H), 7.75 (s, 1H), 7.26 (m, 1H),
7.17 (m, 2H), 7.03 (t, J=7.6 Hz, 1H), 6.88 (m, 1H), 6.70 (m, 1H),
6.60 (m, 1H), 5.17 (s, 2H), 3.48 (t, J=7.6 Hz, 2H), 2.74 (t, J=6.8
Hz, 2H), 1.91 (m, 2H).
Example 11
(9S)-6-Chloro-9-methyl-15-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).1(-
10,14)]tricosa-1(21),3(23),4,6,10(22),11,13,17,19-nonaene
trifluoroacetate
##STR00106##
[0748] Step A:
2,5-Dichloro-N-[(1S)-1-(3-methoxyphenyl)ethyl]pyrimidin-4-amine
##STR00107##
[0750] To a solution of (1S)-1-(3-methoxyphenyl)ethanamine (1.50 g,
9.92 mol) (S-isomer, >99% ee purity) and
2,4,5-trichloropyrimidine (1.19 mL, 10.4 mmol) in
N,N-dimethylformamide (30 mL) was added potassium carbonate (4.1 g,
30 mmol). The resultant mixture was stirred overnight at room
temperature. The reaction was quenched with water. Then EtOAc was
added and the layers were separated. The aqueous layer was
extracted with EtOAc twice. The combined organic layers were washed
with water and then dried (Na.sub.2SO.sub.4), filtered, and
concentrated to give the desired product as a light yellow thick
oil (2.84 g, 96%). LCMS for C.sub.13H.sub.14Cl.sub.2N.sub.3O
(M+H).sup.+: m/z=298.0, 300.0, 302.0 (9:6:1).
Step B:
{3-[(5-Chloro-4-{[(1S)-1-(3-methoxyphenyl)ethyl]amino}pyrimidin-2--
yl)amino]phenyl}methanol
##STR00108##
[0752] To a solution of
2,5-dichloro-N-[(1S)-1-(3-methoxyphenyl)ethyl]pyrimidin-4-amine
(0.70 g, 2.3 mmol) and 3-aminobenzyl alcohol (0.39 g, 3.2 mmol) in
1,4-dioxane (20.0 mL) was added p-toluenesulfonic acid monohydrate
(0.16 g, 0.85 mmol). The mixture was heated at 100.degree. C. for
16 hours and NaHCO.sub.3 (saturated aqueous solution) was added.
The organic solvent was removed under vacuum and water/EtOAc was
added. The aqueous layer was extracted with EtOAc twice. The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered,
and concentrated (then triturated with cold EtOAc) to give the
desired product as a light brown powder (0.81 g, 90%). LCMS for
C.sub.20H.sub.22ClN.sub.4O.sub.2 (M+H).sup.+: m/z=385.1.
Step C:
3-{(1S)-1-[(2-{[3-(Bromomethyl)phenyl]amino}-5-chloropyrimidin-4-y-
l)amino]ethyl}phenol
##STR00109##
[0754] To a solution of
{3-[(5-chloro-4-{[(1S)-1-(3-methoxyphenyl)ethyl]amino}pyrimidin-2-yl)amin-
o]phenyl}methanol (0.30 g, 0.78 mmol) in methylene chloride (5.0
mL) was added slowly a solution of boron tribromide in methylene
chloride (3.9 mL, 3.9 mmol, 1.0 M) at 0.degree. C. The mixture was
allowed to warm up to rt and stirred overnight. The resultant
mixture was cooled in a dry ice bath when water was added. The
mixture was allowed to warm up to rt. Water and EtOAc were added.
The aqueous layer was extracted with EtOAc twice. The combined
organic layers were dried over Na.sub.2SO.sub.4, filtered, and
concentrated (then triturated with cold EtOAc) to give the desired
product as a white powder (0.255 g, 75%). LCMS for
C.sub.19H.sub.19BrClN.sub.4O (M+H).sup.+: m/z=433.0, 435.0.
Step D:
(9S)-6-Chloro-9-methyl-15-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1-
(3,7).1(10,14)]tricosa-1(21),3(23),4,6,10(22),11,13,17,19-nonaene
trifluoroacetate
[0755] To a solution of
3-{(1S)-1-[(2-{[3-(bromomethyl)phenyl]amino}-5-chloropyrimidin-4-yl)amino-
]ethyl}phenol (100 mg, 0.1 mmol) in tetrahydrofuran (2.24 mL) was
added a solution of sodium hydroxide in water (1.84 mL, 0.50 M).
The resultant solution was stirred at rt for 16 hours until the
reaction was complete. The reaction mixture was neutralized with
HCl (3 M aqueous solution) to pH=7. The aqueous layer was extracted
with EtOAc twice. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, concentrated, and purified by prep-HPLC
(pH2 method) to give the desired product as a white powder (5 mg,
8%). LCMS for C.sub.19H.sub.18BrClN.sub.4O (M+H).sup.+:
m/z=352.9.
Example 12
6-Chloro-16-oxa-2,4,8,26-tetraazatetracyclo[18.3.1.1(3,7).1(11,15)]hexacos-
a-1(24),3(26),4,6,11(25),12,14,20,22-nonaene
##STR00110##
[0756] Step A: 3-(3-Nitrophenyl)propan-1-ol
##STR00111##
[0758] 3-(3-Nitrophenyl)propanoic acid (3.0 g, 15 mmol) was
dissolved in dry tetrahydrofuran (7.6 mL) in a flame-dried flask
and cooled in an ice bath. A solution of borane in tetrahydrofuran
(20 mL, 20 mmol, 1.0 M) was added dropwise over a period of 30
minutes. The reaction mixture was stirred for an additional 2 hours
at rt, then quenched slowly with ice water, and followed by an
addition of ether (40 mL). The ether layer was washed with water
and saturated aqueous solution of NaHCO.sub.3 successively, dried,
and concentrated to give the desired product as a yellow gel (2.7
g, 97%).
Step B: 3-(3-Aminophenyl)propan-1-ol
##STR00112##
[0760] To a solution of 3-(3-nitrophenyl)propan-1-ol (2.70 g, 14.9
mmol) in methanol (50.0 mL) was added 10% palladium on carbon (0.54
g, 0.46 mmol). The resultant mixture was hydrogenated at 50 psi
overnight. The reaction mixture was then filtered and concentrated
to give the desired product as a light brown thick oil (2.16 g,
96%). LCMS for C.sub.9H.sub.14NO (M+H).sup.+: m/z=152.1.
Step C:
3-{3-[(5-Chloro-4-{[2-(3-methoxyphenyl)ethyl]amino}pyrimidin-2-yl)-
amino]phenyl}propan-1-ol
##STR00113##
[0762] To a solution of
2,5-dichloro-N-[2-(3-methoxyphenyl)ethyl]pyrimidin-4-amine (0.50 g,
1.7 mmol) (prepared according to Example 8, Step A) and
3-(3-aminophenyl)propan-1-ol (0.34 g, 2.3 mmol) in 1,4-dioxane
(14.3 mL) was added p-toluenesulfonic acid monohydrate (0.12 g,
0.61 mmol). The mixture was heated at 100.degree. C. for 16 hours
and the reaction was complete. To the mixture was added NaHCO.sub.3
aqueous solution (saturated). The organic solvent was removed under
vacuum. Water and EtOAc were added to the residue. The aqueous
layer was extracted with EtOAc twice. The combined organic layers
were dried over Na.sub.2SO.sub.4, filtered, and concentrated (then
triturated with cold EtOAc) to give the desired product as a light
brown gel (0.634 g, 92%). LCMS for C.sub.22H.sub.26ClN.sub.4O.sub.2
(M+H).sup.+: m/z=413.0.
Step D:
3-{2-[(2-{[3-(3-Bromopropyl)phenyl]amino}-5-chloropyrimidin-4-yl)a-
mino]ethyl}phenol
##STR00114##
[0764] To a solution of
3-{3-[(5-chloro-4-{[2-(3-methoxyphenyl)ethyl]amino}pyrimidin-2-yl)amino]p-
henyl}propan-1-ol (0.41 g, 0.73 mmol) in methylene chloride (4.7
mL) was added slowly a solution of boron tribromide in methylene
chloride (3.6 mL, 3.6 mmol, 1.0 M) at 0.degree. C. The mixture was
allowed to warm up to rt and stirred overnight. The resultant
mixture was cooled in dry ice when Na.sub.2CO.sub.3 (saturated
aqueous solution) was added. The mixture was filtered and the solid
collected was triturated with EtOAc, followed by washing with EtOAc
and water successively to give the desired product as an off-white
powder (322 mg, 96%). LCMS for C.sub.21H.sub.23BrClN.sub.4O
(M+H).sup.+: m/z=461.0, 463.0. .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 7.96 (s, 1H), 7.92 (s, 1H), 7.37 (m, 3H), 7.16 (t, J=7.2
Hz, 1H), 6.94 (m, 1H), 6.62 (m, 2H), 3.75 (t, J=7.6 Hz, 2H), 3.43
(t, J=6.8 Hz, 2H), 2.84 (t, J=8.0 Hz, 2H), 2.76 (t, J=8.0 Hz, 2H),
2.15 (m, 2H).
Step E:
6-Chloro-16-oxa-2,4,8,26-tetraazatetracyclo[18.3.1.1(3,7).1(11,15)-
]hexacosa-1(24),3(26),4,6,11(25),12,14,20,22-nonaene
[0765] To a solution of
3-{2-[(2-{[3-(3-bromopropyl)phenyl]amino}-5-chloropyrimidin-4-yl)amino]et-
hyl}phenol (50.0 mg, 0.108 mmol) in tetrahydrofuran (1.0 mL) was
added a solution of sodium hydroxide in water (1.0 mL, 1.0 M). The
resultant solution was stirred at rt for 60 hours until the
reaction was complete. The reaction mixture was neutralized with
HCl (3 M aqueous solution) to pH=7. The aqueous layer was extracted
with EtOAc twice. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, and concentrated to give a residue,
which was purified by silica gel column chromatography to give the
desired product as a white powder (4.0 mg, 10%). LCMS for
C.sub.21H.sub.22ClN.sub.4O (M+H).sup.+: m/z=381.0. .sup.1H NMR (400
MHz, CD.sub.3OD): .delta. 7.95 (s, 1H), 7.90 (s, 1H), 7.30 (m, 3H),
7.12 (t, J=7.4 Hz, 1H), 6.94 (m, 1H), 6.65 (m, 2H), 3.70 (t, J=7.6
Hz, 2H), 3.48 (t, J=6.8 Hz, 2H), 2.80 (m, 2H), 2.72 (m, 2H), 2.10
(m, 2H).
Example 13
21-Chloro-10-oxa-2,19,23,24-tetraazatetracyclo[18.3.1.1(3,7).1(11,15)]hexa-
cosa-1(24),3(26),4,6,11(25),12,14,20,22-nonaene
##STR00115##
[0766] Step A:
2-{3-[(5-Chloro-4-{[3-(3-methoxyphenyl)propyl]amino}pyrimidin-2-yl)amino]-
phenyl}ethanol
##STR00116##
[0768] To a solution of
2,5-dichloro-N-[3-(3-methoxyphenyl)propyl]pyrimidin-4-amine (0.50
g, 1.6 mmol) (prepared according to Example 10, Step A) and
2-(3-aminophenyl)ethanol (0.30 g, 2.2 mmol) (prepared according to
Example 2, Step A) in 1,4-dioxane (13.6 mL) was added
p-toluenesulfonic acid monohydrate (0.11 g, 0.58 mmol). The mixture
was heated at 100.degree. C. for 16 hours and the reaction was
complete. After cooling, the mixture was filtered under vacuum. The
cake was washed with cold EtOAc and H.sub.2O successively to give
the desired product as a light brown gum (0.61 g, 92%). LCMS for
C.sub.22H.sub.26ClN.sub.4O.sub.2 (M+H).sup.+: m/z=413.1.
Step B:
3-{3-[(2-{[3-(2-Bromoethyl)phenyl]amino}-5-chloropyrimidin-4-yl)am-
ino]propyl}phenol
##STR00117##
[0770] To a solution of
2-{3-[(5-chloro-4-{[3-(3-methoxyphenyl)propyl]amino}pyrimidin-2-yl)amino]-
phenyl}ethanol (0.35 g, 0.73 mmol) in methylene chloride (4.7 mL)
was added slowly a solution of boron tribromide in methylene
chloride (3.6 mL, 3.6 mmol, 1.0 M) at 0.degree. C. The mixture was
allowed to warm up to rt and stirred overnight. The resultant
mixture was cooled in dry ice when Na.sub.2CO.sub.3 (saturated
aqueous solution) was added. The mixture was filtered and the solid
collected was triturated with EtOAc, followed by washing with EtOAc
and water successively to give the desired product as an off-white
powder (303 mg, 90%). LCMS for C.sub.21H.sub.23BrClN.sub.4O
(M+H).sup.+: m/z=461.0, 463.0. .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 7.95 (s, 1H), 7.91 (s, 1H), 7.44 (d, J=7.2 Hz, 1H), 7.38
(m, 1H), 7.08 (m, 1H), 6.97 (s, 1H), 6.68 (d, J=2.8 Hz, 1H), 6.59
(m, 2H), 3.60 (m, 4H), 3.18 (m, 2H), 2.66 (t, J=7.6 Hz, 2H), 1.99
(t, J=7.6 Hz, 2H).
Step C:
21-Chloro-10-oxa-2,19,23,24-tetraazatetracyclo[18.3.1.1(3,7).1(11,-
15)]hexacosa-1(24),3(26),4,6,11(25),12,14,20,22-nonaene
[0771] To a solution of
3-{3-[(2-{[3-(2-bromoethyl)phenyl]amino}-5-chloropyrimidin-4-yl)amino]pro-
pyl}phenol (50.0 mg, 0.108 mmol) in tetrahydrofuran (1.0 mL) was
added a solution of sodium hydroxide in water (1.0 mL, 1.0 M). The
resultant solution was stirred at rt for 60 hours until the
reaction was complete. The reaction mixture was neutralized with
HCl (3 M aqueous solution) to pH=7. The aqueous layer was extracted
with EtOAc three times. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, and concentrated to give the crude,
which was purified by silica gel column chromatography to give the
desired product as a white powder (4.5 mg, 11%). LCMS for
C.sub.21H.sub.22ClN.sub.4O (M+H).sup.+: m/z=381.0. .sup.1H NMR (400
MHz, CD.sub.3OD): .delta. 7.98 (s, 1H), 7.92 (s, 1H), 7.48 (d,
J=7.6 Hz, 1H), 7.40 (m, 1H), 7.06 (m, 1H), 6.97 (s, 1H), 6.70 (d,
J=2.4 Hz, 1H), 6.62 (m, 2H), 3.60 (m, 4H), 3.20 (m, 2H), 2.68 (t,
J=7.6 Hz, 2H), 2.02 (t, J=7.6 Hz, 2H).
Example 14
11-Bromo-6-chloro-15-oxa-2,4,8,25-tetraazatetracyclo[17.3.1.1(3,7).1(10,14-
)]pentacosa-1(23),3(25),4,6,10(24),11,13,19,21-nonaene
##STR00118##
[0772] Step A: 1-(2-Bromo-5-methoxyphenyl)methanamine
##STR00119##
[0774] 2-Bromo-5-methoxybenzonitrile (10.0 g, 47.2 mmol) was
dissolved in dry tetrahydrofuran (100 mL) in a flame-dried flask
and cooled in an ice bath. A solution of borane in tetrahydrofuran
(75 mL, 75 mmol, 1.0 M) was added dropwise over a period of 30
minutes. The reaction mixture was stirred overnight at rt, then
quenched slowly with ice water and Na.sub.2CO.sub.3 (saturated
aqueous solution). After removal of THF, the residue was extracted
with large amounts of EtOAc three times. The combined organic
layers were washed with water, dried, and concentrated to give the
crude, which was purified by silica gel column chromatography to
give the desired product as a white powder (3.65 g, 36%). LCMS for
C.sub.8H.sub.10BrNO (M+H)+: m/z=216.9, 219.0.
Step B:
N-(2-Bromo-5-methoxybenzyl)-2,5-dichloropyrimidin-4-amine
##STR00120##
[0776] To a solution of 1-(2-bromo-5-methoxyphenyl)methanamine (3.6
g, 13 mmol) and 2,4,5-trichloropyrimidine (1.60 mL, 14 mmol) in
N,N-dimethylformamide (41.3 mL) was added potassium carbonate (5.53
g, 40 mmol). The resulting mixture was stirred overnight at room
temperature. The reaction was quenched with water. EtOAc was added
and the layers were separated. The aqueous layer was extracted with
EtOAc twice. The combined organic layers were washed with water and
brine successively, then dried (Na.sub.2SO.sub.4), filtered, and
concentrated to give the desired product as a light yellow gel
(4.65 g, 96%). LCMS for C.sub.12H.sub.10BrCl.sub.2N.sub.3O (M+H)+:
m/z=361.9, 363.9.
Step C:
3-[3-({4-[(2-Bromo-5-methoxybenzyl)amino]-5-chloropyrimidin-2-yl)a-
mino]phenyl}propan-1-ol
##STR00121##
[0778] To a solution of
N-(2-bromo-5-methoxybenzyl)-2,5-dichloropyrimidin-4-amine (4.0 g,
11 mmol) and 3-(3-aminophenyl)propan-1-ol (2.3 g, 15 mmol, prepared
according to Example 12, Step B) in 1,4-dioxane (90 mL) was added
p-toluenesulfonic acid monohydrate (0.31 g, 1.6 mmol). The mixture
was heated at 80.degree. C. over two days and the reaction was
complete. After cooling, the mixture was filtered under vacuum. The
cake was washed with cold EtOAc to give the desired product as an
off-white powder (4.35 g, 83%). LCMS for
C.sub.21H.sub.22BrClN.sub.4O.sub.2 (M+H)+: m/z=477.0, 479.0.
Step D:
4-Bromo-3-{[(2-{[3-(3-bromopropyl)phenyl]amino}-5-chloropyrimidin--
4-yl)amino]methyl}phenol
##STR00122##
[0780] To a solution of
3-[3-({4-[(2-bromo-5-methoxybenzyl)amino]-5-chloropyrimidin-2-yl}amino)ph-
enyl]propan-1-ol (3.0 g, 6.3 mmol) in methylene chloride (40 mL)
was added slowly a solution of boron tribromide in methylene
chloride (31 mL, 31 mmol, 1.0 M) at 0.degree. C. The mixture was
allowed to warm up to rt and stirred over the weekend. The
resultant mixture was cooled in dry ice when Na.sub.2CO.sub.3
(saturated aqueous solution) was added. The mixture was filtered
and the solid collected was triturated with EtOAc, followed by
washing with cold water to give the desired product (3.0 grams,
91%) as an off-white powder. LCMS for
C.sub.20H.sub.19Br.sub.2ClN.sub.4O (M+H)+: m/z=524.8, 526.8,
528.7.
Step E:
11-Bromo-6-chloro-15-oxa-2,4,8,25-tetraazatetracyclo[17.3.1.1(3,7)-
.1(10,14)]pentacosa-1(23),3(25),4,6,10(24),11,13,19,21-nonaene
[0781] To a solution of
4-bromo-3-{[(2-{[3-(3-bromopropyl)phenyl]amino}-5-chloropyrimidin-4-yl)am-
ino]methyl}phenol (1.00 g, 1.90 mmol) in tetrahydrofuran (9.0 mL)
was added a solution of sodium hydroxide in water (18 mL, 4.0 M).
The resultant solution was then treated with benzyltriethylammonium
chloride (30.0 mg, 0.13 mmol) and heated at 35.degree. C. for 40
hours. The reaction mixture could not be purified by silica gel
column chromatography or prep-HPLC. However, after cooling, THF and
alkaline NaOH layers could be separated. THF layer was washed with
brine and concentrated to give a light yellow solid residue, which
was triturated with MeOH/EtOAc (90:10). After vacuum filtration,
the cake was washed with MeOH to provide the desired pure product
(300 mg, 35%) as an off-white powder. LCMS for
C.sub.20H.sub.18BrClN.sub.4O (M+H)+: m/z=444.9, 446.9. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 8.76 (s, 1H), 7.86 (s, 1H), 7.50
(s, 1H), 7.31 (d, J=8.8 Hz, 1H), 7.27 (m, 1H), 7.16 (m, 1H), 7.04
(m, 2H), 6.68 (m, 1H), 6.20 (m, 1H), 4.23 (m, 2H), 4.02 (t, 2H),
3.15 (m, 1H), 2.65 (m, 2H), 1.96 (m, 2H).
Example 15
6-Chloro-11-phenyl-15-oxa-2,4,8,25-tetraazatetracyclo[17.3.1.1(3,7).1(10,1-
4)]pentacosa-1(23),3(25),4,6,10(24),11,13,19,21-nonaene
##STR00123##
[0783] A mixture of
11-bromo-6-chloro-15-oxa-2,4,8,25-tetraazatetracyclo[17.3.1.1(3,7).1(10,1-
4)]pentacosa-1(23),3(25),4,6,10(24),11,13,19,21-nonaene (30.0 mg,
0.067 mmol) (prepared according to Example 14, Step E),
phenylboronic acid (9.8 mg, 0.081 mmol),
tetrakis(triphenylphosphine)palladium(0) (7.8 mg, 0.0067 mmol),
1,2-dimethoxyethane (0.50 mL), and a solution of sodium carbonate
in water (0.17 mL, 2.0 M) was sealed into a microwave vial and the
resultant suspension was de-gassed by bubbling with N.sub.2. After
degassing, the vial was microwaved at 150.degree. C. for 20 min.
The reaction mixture was diluted with EtOAc, filtered, and
concentrated to give a residue, which was purified by silica gel
column chromatography to provide the desired product (8 mg, 27%) as
a white powder. LCMS for C.sub.26H.sub.23ClN.sub.4O (M+H)+:
m/z=443.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.96 (s,
1H), 7.78 (s, 1H), 7.56 (s, 1H), 7.41 (dd, J=6.0, 1.2 Hz, 2H), 7.32
(m, 2H), 7.14 (m, 1H), 7.05 (m, 1H), 6.96 (m, 1H), 6.87 (m, 2H),
6.75 (m, 1H), 5.70 (t, 2H), 4.62 (m, 2H), 4.16 (m, 1H), 4.04 (m,
1H), 2.68 (m, 2H), 1.84 (m, 2H).
Example 16
12-Bromo-6-chloro-15-oxa-2,4,8,25-tetraazatetracyclo[17.3.1.1(3,7).1(10,14-
)]pentacosa-1(23),3(25),4,6,10(24),11,13,19,21-nonaene
##STR00124##
[0784] Step A: 1-(3-Bromo-5-methoxyphenyl)methanamine
##STR00125##
[0786] 3-Bromo-5-methoxybenzonitrile (13.1 g, 61.8 mmol) was
dissolved in dry tetrahydrofuran (100 mL) in a flame-dried flask
and cooled in an ice bath. A solution of borane in tetrahydrofuran
(100 mL, 0.10 mol, 1.0 M) was slowly added over a period of 30
minutes. After the addition was complete, the mixture was heated at
70.degree. C. overnight and quenched slowly with ice water and
Na.sub.2CO.sub.3 (saturated aqueous solution). After removal of
THF, the residue was extracted with large amounts of EtOAc three
times. The combined organic layers were washed with water, dried,
and concentrated to give the crude product, which was purified by
silica gel column chromatography to give the desired product as a
white powder (2.57 g, 19%). LCMS for C.sub.8H.sub.10BrNO
(M+H).sup.+: m/z=216.9, 218.9.
Step B:
N-(3-Bromo-5-methoxybenzyl)-2,5-dichloropyrimidin-4-amine
##STR00126##
[0788] To a solution of 1-(3-bromo-5-methoxyphenyl)methanamine
(2.57 g, 11.9 mmol) and 2,4,5-trichloropyrimidine (2.4 g, 13 mmol)
in N,N-dimethylformamide (30 mL) was added potassium carbonate (3.3
g, 24 mmol). The resultant mixture was stirred overnight at room
temperature. The reaction mixture was quenched with water. EtOAc
was added and the layers were separated. The aqueous layer was
extracted with EtOAc twice. The combined organic layers were washed
with water and brine successively, then dried (Na.sub.2SO.sub.4),
filtered, and concentrated. The residue was purified by silica gel
column chromatography to give the desired product (3.7 g, 87%).
LCMS for C.sub.12H.sub.10BrCl.sub.2N.sub.3O (M+H).sup.+: m/z=361.9,
363.9.
Step C:
3-[3-({4-[(3-Bromo-5-methoxybenzyl)amino]-5-chloropyrimidin-2-yl}a-
mino)phenyl]propan-1-ol
##STR00127##
[0790] Into a reaction flask were added
N-(3-bromo-5-methoxybenzyl)-2,5-dichloropyrimidin-4-amine (2.0 g,
5.5 mmol), 1,4-dioxane (30 mL), 3-(3-aminophenyl)propan-1-ol (1.2
g, 8.3 mmol, prepared according to Example 12, Step B), and
p-toluenesulfonic acid monohydrate (0.12 g, 0.63 mmol). The mixture
was heated at 70.degree. C. over two days and NaHCO.sub.3
(saturated aqueous solution) was added. After removal of the
organic solvent, the aqueous layer was extracted with methylene
chloride twice. The combined organic layers were washed with water
and brine successively, then dried (Na.sub.2SO.sub.4), filtered,
and concentrated to give the desired product as a white powder (2.6
g, 99%). LCMS for C.sub.21H.sub.22BrClN.sub.4O.sub.2 (M+H).sup.+:
m/z=477.0, 479.0.
Step D:
3-Bromo-5-{[(2-{[3-(3-bromopropyl)phenyl]amino}-5-chloropyrimidin--
4-yl)amino]methyl}phenol
##STR00128##
[0792] Into a reaction flask was added
3-[3-({4-[(3-bromo-5-methoxybenzyl)amino]-5-chloropyrimidin-2-yl}amino)ph-
enyl]propan-1-ol (2.70 g, 5.65 mmol), methylene chloride (30 mL),
and a solution of boron tribromide in methylene chloride (17.0 mL,
17.0 mmol, 1.0 M). The mixture was stirred at rt overnight. The
resultant mixture was cooled in dry ice when NaHCO.sub.3 (saturated
aqueous solution) was added. After removal of the organic solvent,
the aqueous layer was extracted with methylene chloride twice. The
combined organic layers were washed with water and brine
successively, then dried (Na.sub.2SO.sub.4), filtered, and
concentrated to give the desired product (2.97 g, 100%). LCMS for
C.sub.20H.sub.19Br.sub.2ClN.sub.4O (M+H).sup.+: m/z=526.9,
528.8.
Step E:
12-Bromo-6-chloro-15-oxa-2,4,8,25-tetraazatetracyclo[17.3.1.1(3,7)-
.1(10,14)]pentacosa-1(23),3(25),4,6,10(24),11,13,19,21-nonaene
[0793] Into a reaction flask were added
3-bromo-5-{[(2-{[3-(3-bromopropyl)phenyl]amino}-5-chloropyrimidin-4-yl)am-
ino]methyl}phenol (2.97 g, 5.64 mmol), tetrahydrofuran (30 mL), and
a solution of sodium hydroxide in water (33.8 mL, 1.0 M). The
reaction mixture was stirred at rt over two days. The mixture was
filtered, and then the cake was washed with water, MeOH, and EtOAc
successively to provide the desired product (1.33 g, 53%) as an
off-white powder. LCMS for C.sub.20H.sub.18BrClN.sub.4O
(M+H).sup.+: m/z=444.9, 446.9. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 9.04 (s, 1H), 7.95 (s, 1H), 7.93 (s, 1H), 7.36 (s, 1H),
7.10 (m, 1H), 7.07 (m, 1H), 6.92 (d, J=7.9 Hz, 1H), 6.86 (s, 1H),
6.78 (d, J=7.5 Hz, 1H), 4.42 (d, J=5.5 Hz, 2H), 4.18 (t, 2H), 3.60
(m, 1H), 2.65 (m, 2H), 1.65 (m, 2H).
Example 17
6-Chloro-2,4,8,19,23-pentaazatetracyclo[15.3.1.1(3,7).1(10,14)]tricosa-1(2-
1),3(23),4,6,10(22),11,13,17,19-nonaen-13-amine
##STR00129##
[0794] Step A: tert-Butyl
{5-[(trimethylsilyl)ethynyl]pyridin-3-yl}carbamate
##STR00130##
[0796] Into a reaction flask were added tert-butyl
(5-bromopyridin-3-yl)carbamate (3.0 g, 11.0 mmol), tetrahydrofuran
(30 mL), and triethylamine (1.7 mL, 12 mmol). The reaction mixture
was stirred under N.sub.2 bubbling for 5 min.
(Trimethylsilyl)acetylene (1.60 g, 16.3 mmol), copper(I) iodide (84
mg, 0.44 mmol), and bis(triphenylphosphine)palladium(II) chloride
(0.31 g, 0.44 mmol) were then added. The resultant mixture was
heated at 50.degree. C. overnight. The solvent was removed under
vacuum and the residue was diluted with EtOAc and water. After
separation, the organic layer was dried over Na.sub.2SO.sub.4 and
concentrated under vacuum. The crude product was purified by silica
gel column chromatography to give the desired product as a white
powder (2.0 g, 63%). LCMS for C.sub.15H.sub.23N.sub.2O.sub.2Si
(M+H).sup.+: m/z=291.1.
Step B: tert-Butyl (5-ethynylpyridin-3-yl)carbamate
##STR00131##
[0798] Into a reaction flask were added tert-butyl
{5-[(trimethylsilyl)ethynyl]pyridin-3-yl}carbamate (2.0 g, 6.9
mmol), methanol (25 mL), and a solution of potassium carbonate (7.1
g, 52 mmol) in water (25 mL). The reaction mixture was stirred at
rt overnight. The solvent was removed under vacuum and the residue
was diluted with EtOAc and water. After separation, the organic
layer was dried over Na.sub.2SO.sub.4 and concentrated under
vacuum. The crude product was purified by silica gel column
chromatography to give the desired product as a white powder (1.0
g, 67%). LCMS for C.sub.12H.sub.15N.sub.2O.sub.2 (M+H).sup.+:
m/z=219.0.
Step C: tert-Butyl (4-cyano-2-iodophenyl)carbamate
##STR00132##
[0800] Sodium hydride (0.59 g, 24 mmol) was added slowly to a
stirring solution of 4-amino-3-iodobenzonitrile (5.0 g, 20 mmol) in
N,N-dimethylformamide (90 mL) at 0.degree. C., followed by an
addition of di-tert-butyldicarbonate (4.9 g, 22 mmol). The mixture
was slowly warmed up to rt and stirred overnight. The reaction
mixture was diluted with EtOAc and water. The aqueous layer was
extracted with EtOAc twice. The combined organic layers were dried
over Na.sub.2SO.sub.4 and concentrated under vacuum. The crude
product was purified by silica gel column chromatography to give
the desired product as a white powder (4.0 g, 57%). LCMS for
C.sub.12H.sub.14IN.sub.2O.sub.2 (M+H).sup.+: m/z=344.6.
Step D: tert-Butyl
[5-({2-[(tert-butoxycarbonyl)amino]-5-cyanophenyl}ethynyl)pyridin-3-yl]ca-
rbamate
##STR00133##
[0802] Into a reaction flask were added tert-butyl
(4-cyano-2-iodophenyl)carbamate (1.4 g, 4.1 mmol), copper(I) iodide
(31 mg, 0.16 mmol), bis(triphenylphosphine)palladium(II) chloride
(0.12 g, 0.16 mmol), tetrahydrofuran (10 mL), and triethylamine
(0.63 mL, 4.5 mmol). The mixture was stirred under N.sub.2 bubbling
for 5 minutes and tert-butyl (5-ethynylpyridin-3-yl)carbamate (0.90
g, 4.1 mmol) (prepared according to Example 17, Step B) was then
added. The reaction mixture was stirred at 65.degree. C. for 2
hours. The solvent was removed under vacuum and the residue was
diluted with EtOAc and water. After separation, the organic layer
was dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The
crude was purified by silica gel column chromatography to give the
desired product (0.94 g, 52%). LCMS for
C.sub.24H.sub.27N.sub.4O.sub.4 (M+H).sup.+: m/z=435.2.
Step E: tert-Butyl
[5-(2-{2-[(tert-butoxycarbonyl)amino]-5-cyanophenyl}ethyl)pyridin-3-yl]ca-
rbamate
##STR00134##
[0804] Into a reaction flask were added tert-butyl
[5-({2-[(tert-butoxycarbonyl)amino]-5-cyanophenyl}ethynyl)pyridin-3-yl]ca-
rbamate (0.94 g, 2.2 mmol), methanol (50 mL), and 10% palladium on
carbon (0.40 g, 0.38 mmol). The mixture was hydrogenated at 60 psi
for 6 hours. After filtration to remove the catalyst, the mixture
was concentrated under vacuum to give the desired product as an
off-white powder (0.94 g, 99%). LCMS for
C.sub.24H.sub.31N.sub.4O.sub.4 (M+H).sup.+: m/z=439.2.
Step F: tert-Butyl
[5-(2-{5-(aminomethyl)-2-[(tert-butoxycarbonyl)amino]phenyl}ethyl)pyridin-
-3-yl]carbamate
##STR00135##
[0806] Into a pressure bottle were added tert-butyl
[5-(2-{2-[(tert-butoxycarbonyl)amino]-5-cyanophenyl}ethyl)pyridin-3-yl]ca-
rbamate (0.80 g, 1.8 mmol), tetrahydrofuran (3 mL), methanol (10
mL), and Raney nickel (0.30 g, 5 mmol). The reaction mixture was
hydrogenated at 45 psi for 2 hours. After filtration to remove the
catalyst, the mixture was concentrated under vacuum to give the
desired product as an off-white powder (0.30 g, 99%). LCMS for
C.sub.24H.sub.35N.sub.4O.sub.4 (M+H).sup.+: m/z=443.2.
Step G: tert-Butyl
{5-[2-(2-[(tert-butoxycarbonyl)amino]-5-{[(2,5-dichloropyrimidin-4-yl)ami-
no]methyl}phenyl)ethyl]pyridin-3-yl}carbamate
##STR00136##
[0808] To a solution of tert-butyl
[5-(2-{5-(aminomethyl)-2-[(tert-butoxycarbonyl)amino]phenyl}ethyl)pyridin-
-3-yl]carbamate (0.81 g, 1.8 mmol) and 2,4,5-trichloropyrimidine
(0.45 g, 2.4 mmol) in N,N-dimethylformamide (10 mL) was added
potassium carbonate (1.30 g, 9.37 mmol). The resultant mixture was
stirred overnight at 45.degree. C. The reaction was quenched with
water. EtOAc was added and the layers were separated. The aqueous
layer was extracted with EtOAc once. The combined organic layers
were washed with water, and then dried (Na.sub.2SO.sub.4),
filtered, and concentrated under vacuum. The crude product was
purified by silica gel column chromatography to give the desired
product as a white powder (0.44 g, 40%). LCMS for
C.sub.28H.sub.35Cl.sub.2N.sub.6O.sub.4 (M+H).sup.+: m/z=589.1,
591.1.
Step H:
N-{4-Amino-3-[2-(5-aminopyridin-3-yl)ethyl]benzyl}-2,5-dichloropyr-
imidin-4-amine trihydrochloride
##STR00137##
[0810] Into a reaction flask were added tert-butyl
{5-[2-(2-[(tert-butoxycarbonyl)amino]-5-{[(2,5-dichloropyrimidin-4-yl)ami-
no]methyl}phenyl)ethyl]pyridin-3-yl}carbamate (0.44 g, 0.75 mmol),
methanol (3 mL), and a solution of hydrogen chloride in 1,4-dioxane
(5 mL, 4.0 M). The reaction mixture was stirred at rt overnight and
concentrated under vacuum to give the desired product as a white
powder (0.40 g, 98%). LCMS for C.sub.18H.sub.19Cl.sub.2N.sub.6
(M+H).sup.+: m/z=389.0, 391.0.
Step I:
6-Chloro-2,4,8,19,23-pentaazatetracyclo[15.3.1.1(3,7).1(10,14)]tri-
cosa-1(21),3(23),4,6,10(22),11,13,17,19-nonaen-13-amine
[0811] Into a reaction flask were added
N-{4-amino-3-[2-(5-aminopyridin-3-yl)ethyl]benzyl}-2,5-dichloropyrimidin--
4-amine trihydrochloride (0.29 g, 0.74 mmol), 1,4-dioxane (5 mL),
and triethylamine (0.31 mL, 2.2 mmol). The mixture was stirred at
rt under N.sub.2 for 5 minutes, followed by an addition of
palladium acetate (5 mg, 0.02 mmol),
(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (12.9 mg,
0.02 mmol), and cesium carbonate (500 mg, 2.0 mmol). The reaction
mixture was degassed with N.sub.2 bubbling. The tube was then
sealed and heated at 160.degree. C. for 2 hours. After
concentration, the crude product was purified by silica gel column
chromatography to give the desired product as a white powder (100
mg, 42%). LCMS for C.sub.18H.sub.18ClN.sub.6 (M+H).sup.+:
m/z=353.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.65 (s,
1H), 8.44 (d, J=1.6 Hz, 2H), 8.16 (d, J=2.3 Hz, 1H), 8.01 (s, 1H),
7.11 (m, 2H), 7.03 (m, 2H), 6.69 (s, 1H), 4.14 (d, J=5.8 Hz, 2H),
2.88 (m, 4H).
Example 18
N-[6-Chloro-2,4,8,19,23-pentaazatetracyclo[15.3.1.1(3,7).1(10,14)]tricosa--
1(21),3(23),4,6,10(22),11,13,17,19-nonaen-13-yl]benzamide
bis(trifluoroacetate)
##STR00138##
[0813] Into a reaction flask were added
6-chloro-2,4,8,19,23-pentaazatetracyclo[15.3.1.1(3,7).1(10,14)]tricosa-1(-
21),3(23),4,6,10(22),11,13,17,19-nonaen-13-amine (20 mg, 0.06
mmol), N,N-dimethylformamide ("DMF", 1.0 mL), triethylamine (11 mg,
0.11 mmol), and benzoyl chloride (10 mg, 0.074 mmol). The reaction
mixture was stirred at rt for 5 minutes. The mixture was diluted
with DMF and was purified directly on prep-HPLC to provide the
desired product (2.4 mg, 19%) as a white solid. LCMS for
C.sub.25H.sub.22ClN.sub.6O (M+H).sup.+: m/z=457.2. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 9.95 (s, 1H), 9.53 (s, 1H), 8.35 (d,
J=1.5 Hz, 1H), 8.24 (d, J=2.3 Hz, 1H), 8.01 (s, 1H), 7.94 (m, 2H),
7.48-7.62 (m, 4H), 7.16-7.25 (m, 3H), 4.25 (d, J=5.7 Hz, 2H), 2.88
(m, 4H).
Example 19
N-[6-Chloro-2,4,8,19,23-pentaazatetracyclo[15.3.1.1(3,7).1(10,14)]tricosa--
1(21),3(23),4,6,10(22),11,13,17,19-nonaen-13-yl]-2-cyanobenzenesulfonamide
bis(trifluoroacetate)
##STR00139##
[0815] Into a reaction flask were added
6-chloro-2,4,8,19,23-pentaazatetracyclo[15.3.1.1(3,7).1(10,14)]tricosa-1(-
21),3(23),4,6,10(22),11,13,17,19-nonaen-13-amine (20 mg, 0.06
mmol), N,N-dimethylformamide (1.0 mL), triethylamine (11 mg, 0.11
mmol), and 2-cyanobenzenesulfonyl chloride (15 mg, 0.074 mmol). The
reaction mixture was stirred at rt for 5 minutes. The mixture was
diluted with DMF and was purified directly on prep-HPLC to provide
the desired product (4.5 mg, 30%) as a white solid. LCMS for
C.sub.25H.sub.19ClN.sub.7O.sub.2S (M+H).sup.+: m/z=519.0.
Example AA
In Vitro JAK Kinase Assay
[0816] One or more compounds herein were tested for inhibitory
activity of JAK targets according to the following in vitro assay
described in Park et al., Analytical Biochemistry 1999, 269,
94-104. The catalytic domains of human JAK1 (a.a. 837-1142), JAK2
(a.a. 828-1132) and JAK3 (a.a. 781-1124) with an N-terminal His tag
were expressed using baculovirus in insect cells and purified. The
catalytic activity of JAK1, JAK2 or JAK3 was assayed by measuring
the phosphorylation of a biotinylated peptide. The phosphorylated
peptide was detected by homogenous time resolved fluorescence
(HTRF). IC.sub.50s of compounds were measured for each kinase in
the reactions that contain the enzyme, ATP and 500 nM peptide in 50
mM Tris (pH 7.8) buffer with 100 mM NaCl, 5 mM DTT, and 0.1 mg/mL
(0.01%) BSA. The ATP concentration in the reactions was 90 .mu.M
for JAK1, 30 .mu.M for JAK2 and 3 .mu.M for JAK3. Reactions were
carried out at room temperature for 1 hr and then stopped with 20
.mu.L 45 mM EDTA, 300 nM SA-APC, 6 nM Eu-Py20 in assay buffer
(Perkin Elmer, Boston, Mass.). Binding to the Europium labeled
antibody took place for 40 minutes and HTRF signal was measured on
a Fusion plate reader (Perkin Elmer, Boston, Mass.).
Example BB
Cellular Assays
[0817] One or more compounds herein were tested for inhibitory
activity of JAK targets according to at least one of the following
cellular assays.
[0818] Cancer cell lines dependent on cytokines and hence JAK/STAT
signal transduction, for growth, were plated at 6000 cells per well
(96 well plate format) in RPMI 1640, 10% FBS, and 1 nG/mL of
appropriate cytokine. Compounds were added to the cells in
DMSO/media (final concentration 0.2% DMSO) and incubated for 72
hours at 37.degree. C., 5% CO.sub.2. The effect of compound on cell
viability was assessed using the CellTiter-Glo Luminescent Cell
Viability Assay (Promega) followed by TopCount (Perkin Elmer,
Boston, Mass.) quantitation. Potential off-target effects of
compounds were measured in parallel using a non-JAK driven cell
line with the same assay readout. All experiments were performed in
duplicate.
[0819] The above cell lines can also be used to examine the effects
of compounds on phosphorylation of JAK kinases or potential
downstream substrates such as STAT proteins, Akt, Shp2, or Erk.
These experiments can be performed following an overnight cytokine
starvation, followed by a brief preincubation with compound (2
hours or less) and cytokine stimulation of approximately 1 hour or
less. Proteins are then extracted from cells and analyzed by
techniques familiar to those schooled in the art including Western
blotting or ELISAs using antibodies that can differentiate between
phosphorylated and total protein. These experiments can utilize
normal or cancer cells to investigate the activity of compounds on
tumor cell survival biology or on mediators of inflammatory
disease. For example, with regards to the latter, cytokines such as
IL-6, IL-12, IL-23, or IFN can be used to stimulate JAK activation
resulting in phosphorylation of STAT protein(s) and potentially in
transcriptional profiles (assessed by array or qPCR technology) or
production and/or secretion of proteins, such as IL-17. The ability
of compounds to inhibit these cytokine mediated effects can be
measured using techniques common to those schooled in the art.
[0820] Compounds herein can also be tested in cellular models
designed to evaluate their potency and activity against mutant
JAKs, for example, the JAK2V617F mutation found in myeloid
proliferative disorders. These experiments often utilize cytokine
dependent cells of hematological lineage (e.g. BaF/3) into which
the wild-type or mutant JAK kinases are ectopically expressed
(James, C., et al. Nature 434:1144-1148; Staerk, J., et al. JBC
280:41893-41899). Endpoints include the effects of compounds on
cell survival, proliferation, and phosphorylated JAK, STAT, Akt, or
Erk proteins.
[0821] Certain compounds herein have been or can be evaluated for
their activity inhibiting T-cell proliferation. Such as assay can
be considered a second cytokine (i.e. JAK) driven proliferation
assay and also a simplistic assay of immune suppression or
inhibition of immune activation. The following is a brief outline
of how such experiments can be performed. Peripheral blood
mononuclear cells (PBMCs) are prepared from human whole blood
samples using Ficoll Hypaque separation method and T-cells
(fraction 2000) can be obtained from PBMCs by elutriation. Freshly
isolated human T-cells can be maintained in culture medium (RPMI
1640 supplemented with10% fetal bovine serum, 100 U/mL penicillin,
100 .mu.g/mL streptomycin) at a density of 2.times.10.sup.6
cells/mL at 37.degree. C. for up to 2 days. For IL-2 stimulated
cell proliferation analysis, T-cells are first treated with
Phytohemagglutinin (PHA) at a final concentration of 10 .mu.g/mL
for 72 hours. After washing once with PBS, 6000 cells/well are
plated in 96-well plates and treated with compounds at different
concentrations in the culture medium in the presence of 100 U/mL
human IL-2 (ProSpec-Tany TechnoGene; Rehovot, Israel). The plates
are incubated at 37.degree. C. for 72 hours and the proliferation
index is assessed using CellTiter-Glo Luminescent reagents
following the manufactory suggested protocol (Promega; Madison,
Wis.).
Example CC
In Vivo Anti-Tumor Efficacy
[0822] Compounds herein can be evaluated in human tumor xenograft
models in immune compromised mice. For example, a tumorigenic
variant of the INA-6 plasmacytoma cell line can be used to
inoculate SCID mice subcutaneously (Burger, R., et al. Hematol J.
2:42-53, 2001). Tumor bearing animals can then be randomized into
drug or vehicle treatment groups and different doses of compounds
can be administered by any number of the usual routes including
oral, i.p., or continuous infusion using implantable pumps. Tumor
growth is followed over time using calipers. Further, tumor samples
can be harvested at any time after the initiation of treatment for
analysis as described above (Example B) to evaluate compound
effects on JAK activity and downstream signaling pathways. In
addition, selectivity of the compound(s) can be assessed using
xenograft tumor models that are driven by other know kinases (e.g.
Bcr-Abl) such as the K562 tumor model.
Example DD
Murine Skin Contact Delayed Hypersensitivity Response Test
[0823] Compounds herein can also be tested for their efficacies (of
inhibiting JAK targets) in the T-cell driven murine delayed
hypersensitivity test model. The murine skin contact delayed-type
hypersensitivity (DTH) response is considered to be a valid model
of clinical contact dermatitis, and other T-lymphocyte mediated
immune disorders of the skin, such as psoriasis (Immunol Today.
1998 January; 19(1):37-44). Murine DTH shares multiple
characteristics with psoriasis, including the immune infiltrate,
the accompanying increase in inflammatory cytokines, and
keratinocyte hyperproliferation. Furthermore, many classes of
agents that are efficacious in treating psoriasis in the clinic are
also effective inhibitors of the DTH response in mice (Agents
Actions. 1993 January; 38(1-2):116-21).
[0824] On Day 0 and 1, Balb/c mice are sensitized with a topical
application, to their shaved abdomen with the antigen
2,4,dinitro-fluorobenzene (DNFB). On day 5, ears are measured for
thickness using an engineer's micrometer. This measurement is
recorded and used as a baseline. Both of the animals' ears are then
challenged by a topical application of DNFB in a total of 20 .mu.L
(10 .mu.L on the internal pinna and 10 .mu.L on the external pinna)
at a concentration of 0.2%. Twenty-four to seventy-two hours after
the challenge, ears are measured again. Treatment with the test
compounds was given throughout the sensitization and challenge
phases (day-1 to day 7) or prior to and throughout the challenge
phase (usually afternoon of day 4 to day 7). Treatment of the test
compounds (in different concentration) was administered either
systemically or topically (topical application of the treatment to
the ears). Efficacies of the test compounds are indicated by a
reduction in ear swelling comparing to the situation without the
treatment. Compounds causing a reduction of 20% or more were
considered efficacious. In some experiments, the mice are
challenged but not sensitized (negative control).
[0825] The inhibitive effect (inhibiting activation of the JAK-STAT
pathways) of the test compounds can be confirmed by
immunohistochemical analysis. Activation of the JAK-STAT pathway(s)
results in the formation and translocation of functional
transcription factors. Further, the influx of immune cells and the
increased proliferation of keratinocytes should also provide unique
expression profile changes in the ear that can be investigated and
quantified. Formalin fixed and paraffin embedded ear sections
(harvested after the challenge phase in the DTH model) are
subjected to immunohistochemical analysis using an antibody that
specifically interacts with phosphorylated STAT3 (clone 58E12, Cell
Signaling Technologies). The mouse ears are treated with test
compounds, vehicle, or dexamethasone (a clinically efficacious
treatment for psoriasis), or without any treatment, in the DTH
model for comparisons. Test compounds and the dexamethasone can
produce similar transcriptional changes both qualitatively and
quantitatively, and both the test compounds and dexamethasone can
reduce the number of infiltrating cells. Both systemically and
topical administration of the test compounds can produce inhibitive
effects, i.e., reduction in the number of infiltrating cells and
inhibition of the transcriptional changes.
Example EE
In Vivo Anti-Inflammatory Activity
[0826] Compounds herein can be evaluated in rodent or non-rodent
models designed to replicate a single or complex inflammation
response. For instance, rodent models of arthritis can be used to
evaluate the therapeutic potential of compounds dosed
preventatively or therapeutically. These models include but are not
limited to mouse or rat collagen-induced arthritis, rat
adjuvant-induced arthritis, and collagen antibody-induced
arthritis. Autoimmune diseases including, but not limited to,
multiple sclerosis, type I-diabetes mellitus, uveoretinitis,
thyroditis, myasthenia gravis, immunoglobulin nephropathies,
myocarditis, airway sensitization (asthma), lupus, or colitis may
also be used to evaluate the therapeutic potential of compounds
herein. These models are well established in the research community
and are familiar to those schooled in the art (Current Protocols in
Immunology, Vol 3., Coligan, J. E. et al, Wiley Press.; Methods in
Molecular Biology: Vol. 225, Inflammation Protocols., Winyard, P.
G. and Willoughby, D. A., Humana Press, 2003.).
Example FF
pALK Assay
[0827] To determine the activity of numerous compounds on the
phosphorylation of ALK in cells, an ELISA method testing lymphoma
cell lysates was developed. Human lymphoma cells were treated with
examples for 4 hours. Cells were lysed in lysis buffer (Cell
Signaling #9803, Danvers, Mass.) supplemented with complete mini
protease inhibitor cocktail tablets (Roche Applied Science,
Indianapolis, Ind.) on ice and after 15 minutes, lysates were
cleared by centrifugation. According to the manufacturer's
instructions, lysates were placed in wells precoated with
anti-phospho-ALK antibody (Cell Signaling #7324, Danvers, Mass.)
and allowed to incubate overnight at 4.degree. C. After washing, an
anti-ALK antibody is added to wells. Colorimetric (TMB) detection
of HRP-linked anti-mouse IgG is used to quantify relative levels of
phospho-ALK.
Example GG
Cell Proliferation Assay
[0828] The activity of numerous compounds on ALK driven
proliferation was assessed using Karpas-299 human anaplastic
lymphoma cells. Cells were seeded at 2500 cells per well in clear
bottom 96 well plates. On the first day, replicate plates were
treated with various concentrations of compounds or processed using
the manufacturer's instructions for Cell Titer Glo (Promega,
Madison, Wis.) to determine baseline levels. After 72 hours, the
dosed plate was processed using Cell Titer Glo. After calculating
the specific proliferation of cells in the presence of compounds,
IC.sub.50s were determined using Prism software (GraphPad Software,
San Diego, Calif.).
Example HH
ALK HTRF Kinase Assay
[0829] Materials: Recombinant Human Anaplastic Lymphoma Kinase was
purchased from Invitrogen, Carlsbad, Calif. Peptide substrate
(Biotin-KKKGPWLEEEEEAYGWLDF-amide) was custom synthesized at
EZBiolab, Westfield, Ind. Streptavidin conjugated
SureLight-Allophycocyania and LANCE Eu-W1024 labeled
anti-phosphotyrosine antibody were from Perkin-Elmer, Boston, Mass.
Microplates were from Corning Inc., Acton, Mass. All other reagents
were from Sigma, St. Louis, Mo.
[0830] HTRF kinase assay: 40 .mu.L reactions were run in black 384
well polystyrene plates in assay buffer (50 mM Tris, pH 7.8, 100 mM
NaCI, 0.1 mg/mL BSA, 5 mM DTT), containing 0.5 .mu.M Biotinylated
peptide substrate, 10 mM MgCl.sub.2, 90 .mu.M ATP, and 0.25 nM
enzyme for 2 hours at 25.degree. C. Reactions were stopped by
addition of 20 .mu.L assay buffer supplemented with an additional
50 mM NaCl, 0.4 mg/mL BSA, 45 mM EDTA, 4.5 nM LANCE Eu-W1024
labeled anti-phosphotyrosine antibody and 200 nM streptavidin
conjugated SureLight-allophycocyanin. Plates were read in Fusion
.alpha.-FP instrument (Perkin-Elmer). The concentrations needed to
reach 50% inhibition, the IC.sub.50 value, were determined by
fitting the assay signal to the following equation using Graphpad
Prizm.
Signal=Bottom+(Top-Bottom)/(1+10 ((Log(IC50)-Log [I])*Hill
Slope)
Bottom and Top refer to the post and pre-transition baselines,
respectively.
[0831] The IC.sub.50 value for the example compounds of invention
with respect one or more of JAK/ALK are provided in Table 1 as
follows.
TABLE-US-00001 TABLE 1 Example JAK1 JAK2 JAK3 TYK2 ALK Number
IC.sub.50 (nM) IC.sub.50 (nM) IC.sub.50 (nM) IC.sub.50 (nM)
IC.sub.50 (nM) Example 1 51 49 17 400 >1,000 Example 2 13 10 9.2
35 1530 Example 3 300 589 325 830 >10,000 Example 4 96 104 21
>1,000 >10,000 Example 5 4.2 1.9 2.4 25 706 Example 6 346 350
140 >1,000 >10,000 Example 7 16 8.3 6.4 43 2,050 Example 8
600 333 300 438 >10,000 Example 9 28 23 55 53 1,230 Example 10
122 117 180 237 >1,000 Example 11 >1,000 >1,000 >1,000
>1,000 >10,000 Example 12 300 120 315 400 >10,000 Example
13 32 25 62 106 >10,000 Example 14 100 91 57 300 8200 Example 15
81 41 31 400 >1,000 Example 16 15 5 15 149 280 Example 17 102
447 114 386 >1000 Example 18 >1,000 >1,000 >1,000
>1,000 >1,000 Example 19 >1,000 >1,000 >1,000
>1,000 >1,000 a. when the experiment limit is set as "a" and
the IC.sub.50 measurement of the example compound exceeds the
limit, then the IC.sub.50 data is shown as "> a"
[0832] Various modifications of the invention, in addition to those
described herein, will be apparent to those skilled in the art from
the foregoing description. Such modifications are also intended to
fall within the scope of the appended claims. Each reference cited
in the present application is herein incorporated by reference in
its entirety.
* * * * *